WO2007134421A1 - 2-VINYL INDOLES, PYRIDO AND AZEPINO INDOLE DERIVATIVES, 2-ALKYNYL INDOLES, 2-ALKYNYL BENZO[b]FURANS, THEIR PRECURSORS AND NOVEL PROCESSES FOR THE PREPARATION THEREOF - Google Patents

2-VINYL INDOLES, PYRIDO AND AZEPINO INDOLE DERIVATIVES, 2-ALKYNYL INDOLES, 2-ALKYNYL BENZO[b]FURANS, THEIR PRECURSORS AND NOVEL PROCESSES FOR THE PREPARATION THEREOF Download PDF

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WO2007134421A1
WO2007134421A1 PCT/CA2007/000289 CA2007000289W WO2007134421A1 WO 2007134421 A1 WO2007134421 A1 WO 2007134421A1 CA 2007000289 W CA2007000289 W CA 2007000289W WO 2007134421 A1 WO2007134421 A1 WO 2007134421A1
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lower alkyl
group
compound
aryl
formula
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PCT/CA2007/000289
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French (fr)
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Mark Lautens
Aude Fayol
Masatoshi Nagamochi
Yuanqing Fang
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Mark Lautens
Aude Fayol
Masatoshi Nagamochi
Yuanqing Fang
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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Definitions

  • the present invention relates to novel processes for the preparation of indole compounds, in particular to 2-vinyl indoles, pyrido and azepino derivatives, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-vinyl indoles from ortho-gem- dibromovinylaniline compounds and alkene reagents using a palladium pre- catalyst, a base, and, in some instances, a ligand or additive.
  • the present invention also relates to the preparation of pyrido and azepino derivatives via a palladium-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction of appropriately functionalized ortho-gem- dibromovinylanilines.
  • the invention also relates to processes for the production of or/A ⁇ -gem-dibromovinylanilines which are useful as starting materials in the production of 2-vinyl indoles, pyrido and azepino derivatives, and novel compounds prepared by these processes.
  • the present invention also relates to novel processes for the preparation of indole compounds, in particular to 2-alkynyl indoles, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-alkynyl indoles from ortho-gem- dibromovinylaniline compounds, which can be synthesized using above mentioned processes, and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand.
  • the present invention also relates to novel processes for the preparation of benzo[6]furan compounds, in particular to 2-alkynyl benzo[ ⁇ ]furans, which may be optionally substituted at other positions on benzo[ ⁇ ]furan ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-alkynyl benzo[ ⁇ ]furans from ⁇ rt ⁇ -gem-dibromovinylphenol compounds and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand. The invention also relates to processes for the production of ortho-gem -dibromovinylphenols which are useful as starting materials in the production of 2-alkynyl benzo[5]furans, and novel compounds prepared by these processes.
  • 2-vinyl indoles have been prepared using Wittig related olefination reactions (Scheme 1) on 2-formyl- or 2-ketoindoles (Eitel, M.; Pindur, U. Synthesis 1989, 364; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Conzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810) and by treatment of indol-2- ylmethyltriphenylphosphorane or diethylphosphonates with carbonyl compounds (Nagarathnam, D. Synthesis 1992, 743 and references cited therein).
  • Scheme 1 Wittig related olefination reactions
  • Hetero-Cope rearrangement has been shown to provide short and stereoselective syntheses of 2-vinyl indoles by a tandem process involving a N- phenylhydroxylamine, aldehyde and electron deficient allene (Wilkens, J.; Kuhling, A.; Blechert, S. Tetrahedron 1987, 43, 3237; Blechert, S. Synthesis 1989, 71; Scheme 3).
  • a radical cyclization of 2-alkenylphenyl isocyanide provides access to 2-stannyl indoles as intermediates which can be readily converted to 2-vinyl indoles by a palladium-mediated cross-coupling reaction in a one-pot procedure (Tokuyama, H.; Kaburagi, Y.; Chen, X., Fukuyama, T. Synthesis 2000, 429; Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127).
  • Fluvastatin is currently sold as a racemate of two erthryo enantiomers of which one exerts the pharmacological activity. Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form (Compendium of Pharmaceuticals and Specialities (CPS), 2005, 40 th Edition, Canadian Pharmacists Association). Synthetic methods exist for the synthesis of the racemic version of the drug (Repic, O.; Prasad, K.; and Lee, G. T. Organic Process Research & Development 2001, 5, 519-527), however, processes for making the enantiopure drug are highly desired.
  • SB-242782 Another important indole containing a 2-vinyl substitution is the following potent and selective inhibitor of the osteoclatic Vacuolar H+-ATPase named SB-242782 (Farina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan, M.; Delimoge, L; Pietro, B.; Zocchetti, A.; James, L; Zembryki, D. Bioorganic & Medicinal Chemistry Letters 1998, 8, 3621; Visentin, L.; Dodds, R. A.; valente, M.; Misiano, P.; Bradbeer, J.
  • 2-vinylindoles have proven to be versatile dienes in Diels- Alder reactions aiming at regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest, both in inter- and intramolecular reactions (for reviews, see: Pindur, U. Heterocycles 1998, 27, 1253; Pindur, U. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; Cycloaddition Reaction of Indoles Derivatives; JAI Press: Greenwich, 1995; Vol.
  • the carbazole ring is the core of a wide range of alkaloids, and therefore is a very important building block in the synthesis of pharmacologically active compounds.
  • 2-Alkynyl indoles have been prepared using Stille coupling reaction (Scheme 17) with 2-bromoindoles (Eitel, M.; Pindur, U. J. Heterocyclic Chemistry 2006, 43, 701; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Conzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810) and by treatment of 1-bromo-l -alkynes with 2-stannylindoles (Nagarathnam, D. Synlett 1993, 771 and references cited therein).
  • a 2-alkynylindole is used as a pivotal intermediate during the synthesis of SB- 242782 (referenced above). It was achieved by a cross-coupling process via an organotin intermediate as well as by a reduction-isomerization sequence (Conde, J. J.; McGuire, M.; Wallace, M. Tetrahedron Lett. 2003, 44, 3081; Scheme 20).
  • lipid metabolism regulator SQ-33600 the structure of which is shown below in its sodium salt form (Karanewsky, D. S.; Badia, M. C; Adams, B. C; Michael, G. E.; Joseph, S. M.; DE 3817298 Al 19881201, Bristol-Myers Squibb, 1988; Karanewsky, D. S.; Badia, M. C; Ciosek, C. P. Jr; Robl, J. A.; Sofia, M. J.; Simpkins, L. M.; DeLange, B.; Harrity, T. W.; Biller, S. A.; Gordon, E. M. J. Med. Chem.
  • the present invention provides novel and versatile processes for synthesizing 2- vinyl indole compounds, pyrido-indoles, azepino-indoles and derivatives. As aforementioned, it is envisioned that these processes may be used in the preparation of commercially important indole compounds.
  • each Ri is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , -C(0)NR * 2 , - NR * C0-R * , -NR * COO-R * , -NR * C0NR * wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R a , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri
  • R 3 is selected from the group comprising alkyl; lower alkyl-hydroxy; lower alkyl-O-R b wherein R b is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R ** , - C(O)OR ** , -C(O)NR ** 2 , -SO 2 R ** , -SO 2 MT 2 , lower alkyl-CO-R ** , lower alkyl-CO- OR ** , lower alkyl-C(O)NR ** 2 , lower alkyl-NR ** CO-R * ⁇ lower alkyl-NR ** COO-R ** wherein R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R 3 is -C(0)NR ** 2 both R ** groups may form a heterocycl
  • the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
  • 2-vinyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest.
  • the invention provides an improved process for the preparation of a compound of the following Formula (II)
  • each Ri is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(O)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * C0NR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R a , wherein R 3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n 1 is a whole integer from 1
  • R 2 is H
  • the invention provides novel ⁇ rt/jo-gem-dibromovinylaniline compounds or salts thereof selected from the group consisting of:
  • the invention provides a process for the preparation of a c -o i:mpound of Formula (IV) and/or Formula (IV)'
  • each R 4 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , -C(0)NR * 2 , -
  • R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR 2 , wherein
  • R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of R» and R * are unsubstituted or substituted; the process comprising reacting an ⁇ rt/zo-ge/M-dibromovinylaniline compound of Formula (V):
  • R 4 is as defined above, n is 0 to 3,
  • R 5 is selected from the group comprising H, lower alkyl; lower alkyl- hydroxy; lower alkyl-O-R b wherein R b is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; - C(O)R ** , -C(O)OR ** , -C(0)NR ** 2 , -SO 2 R ** , -SO 2 NR ** 2 , lower alkyl-CO-R ** , lower alkyl-CO-OR ** , lower alkyl-C(O)NR ** 2 , lower alkyl-NR ** CO-R", lower alkyl- NR ** COO-R ** wherein R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R 5 and R" are unsubstituted or substituted;
  • the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:
  • the present invention also provides novel and versatile processes for synthesizing 2-alkynyl indole compounds. As aforementioned, it is envisioned that these processes may be used in the preparation of pharmaceutically important indole compounds.
  • each R] is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(0)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * C0NR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R a , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to
  • R 2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
  • Rg is selected from the group comprising -SiR 1 R 11 R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O- R b wherein R b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R ** , lower alkyl-CO-OR' * , lower alkyl-C(O)NR" 2 , lower alkyl-NR"CO-R' ⁇ lower alkyl-NR ** COO-R ** wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R" are unsubstitute
  • the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
  • 2-alkynyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [ ⁇ ]annulated indole derivatives of pharmacological interest.
  • the present invention also provides novel and versatile processes for synthesizing 2-alkynyl benzo[ ⁇ ]furan compounds. As aforementioned, it is envisioned that these processes may be used in the preparation of pharmaceutically important benzo[&]furan compounds.
  • each R 6 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(0)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * CONR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR 3 , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4
  • R 9 is H or lower alkyl
  • R 1 , R", and R 1 " are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl -hydroxy; lower alkyl-O-R b wherein R b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R", lower alkyl- CO-OR ** , lower alkyl-C(O)NR ** 2 , lower alkyl-NR ** CO-R * ⁇ lower alkyl- NR ** COO-R ** wherein R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R **
  • the invention provides novel 2-substituted benzo[&]furans or salts thereof selected from the group consisting of:
  • the 2-alkynyl benzo[6]furan compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of benzo[ ⁇ ]furan derivatives of pharmacological interest.
  • the invention provides an improved process for the preparation of a compound of the following Formula (XI)
  • each R 6 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(0)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * C0NR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR 3 , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to
  • R 7 is selected from the group consisting of H, or a suitable protective group
  • the invention provides novel ort/20-ge/w-dibromovinylphenol compounds or salts thereof selected from the group consisting of:
  • suitable substituent as used in the context of the present invention is meant to include independently H; hydroxyl; protected hydroxyl groups such as - O-THP (tetrahydropyranyl) and -O-TBDPS (t-butyldiphenylsilyl); cyano; alkyl, such as lower alkyl, such as methyl, ethyl, propyl, n-butyl, t-butyl, hexyl and the like; alkoxy, such as lower alkoxy such as methoxy, ethoxy, and the like; aryloxy, such as phenoxy and the like; vinyl; alkenyl, such as hexenyl and the like; alkynyl; formyl; haloalkyl, such as lower haloalkyl which includes CF 3 , CCl 3 and the like; halide; aryl, such as phenyl and naphthyl; heteroaryl, such as thien
  • lower alkyl as used herein either alone or in combination with another substituent means acyclic, straight or branched chain alkyl substituent containing from one to six carbons and includes for example, methyl, ethyl, 1 -methylethyl, 1-methylpropyl, 2- methylpropyl, and the like.
  • lower alkoxy as used herein includes methoxy, ethoxy, t-butoxy.
  • alkyl encompasses lower alkyl, and also includes alkyl groups having more than six carbon atoms, such as, for example, acyclic, straight or branched chain alkyl substituents having seven to ten carbon atoms.
  • aryl as used herein, either alone or in combination with another substituent, means an aromatic monocyclic system containing 6 carbon atoms or a polycyclic aromatic system, such as an aromatic bicyclic system containing 10 carbon atoms.
  • aryl includes a phenyl or a naphthyl ring.
  • heteroaryl as used herein, either alone or in combination with another substituent means a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatoms selected from nitrogen, oxygen, and sulphur and which form an aromatic system.
  • cycloalkyl as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent that includes for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkyl-alkyl- as used herein means an alkyl radical to which a cycloalkyl radical is directly linked; and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl,
  • alkyl A similar use of the "alkyl” term is to be understood for aryl-alkyl-, heteroaryl- alkyl-, and the like as used herein.
  • aryl-alkyl- means an alkyl radical, to which an aryl is bonded.
  • aryl-alkyl- include, but are not limited to, benzyl (phenylmethyl), 1 -phenyl ethyl, 2-phenylethyl and phenylpropyl.
  • heterocycle either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a three- to seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, hydantoin, diazepine, imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine, homopiperazine, 1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, and the like.
  • alkenyl as used herein, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a double bond.
  • examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.
  • alkynyl as used herein is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.
  • alkoxy as used herein, either alone or in combination with another radical, means the radical -O-(Ci -n )alkyl wherein alkyl is as defined above containing 1 or more carbon atoms and includes for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy.
  • n 1 to 6
  • aryloxy as used herein alone or in combination with another radical means -O-aryl, wherein aryl is defined as noted above.
  • heteroatom means O, S or N.
  • suitable protective group is to be understood to denote a protective group for a functionality, such as a hydroxyl group, that does not interfere with the formation of the desired product by the claimed processes of the present invention.
  • Suitable protective groups are known to those of skill in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981, the details of which are incorporated herein by reference.
  • the present invention provides novel processes for the preparation of indole compounds, in particular to 2-vinyl indoles, pyrido and azepino derivatives, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors.
  • the invention provides a process for the preparation of a compound of Formula (I):
  • each R 1 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , -C(0)NR * 2 , - NR * C0-R * , -NR * C00-R * , -NR * C0NR * wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R a , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of
  • R 2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
  • R 3 is selected from the group comprising alkyl; lower alkyl-hydroxy; lower alkyl-O-R b wherein R b is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R", -
  • R 3 is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR 1 R 11 R'", where R 1 , R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R 1 , R", and R" 1 is H; and R b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl 3 CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
  • the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
  • 2-vinylindoles have proven to be versatile dienes in Diels- Alder reactions aiming at regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [b]annelated indole derivatives of pharmological interest, both in inter- and intramolecular reactions (Pindur, U. Heterocycles 1998, 27, 1253; Pindur, U. hi Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; Cycloaddition Reaction of Indoles Derivatives; JAI Press: Greenwich, 1995; Vol. 1, p 121; Sundberg, R.
  • the carbazole ring is a very important building block in the synthesis of pharmacologically active compounds, as it is the core of a wide range of alkaloids. It is expected that the 2-vinyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest.
  • the invention provides an improved process for the preparation of a compound of the following Formula (II)
  • each R] is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(O)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * CONR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R a , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n' is a whole integer from 1
  • R a is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR 1 R 11 R'", where R 1 , R", and R" 1 are independently selected from H, lower alkyl and aryl, with the proviso that only one of R 1 , R", and R 1 " is H.
  • R is isopropyl.
  • the compound of Formula (VII) is isolated via recrystallization.
  • the compound of Formula (VII) is isolated via addition of HOAc/HCl followed by a basic workup procedure.
  • the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:
  • the invention provides a process for the preparation of a compound of Formula (IV) and/or Formula (IV)'
  • each R 4 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , -C(0)NR * 2 , - NR * C0-R * , -NR * C00-R * , -NR * CONR * wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR 3 , wherein R 3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of R 4 and R are
  • R 4 is as defined above, n is 0 to 3,
  • R 5 is selected from the group comprising H, lower alkyl; lower alkyl- hydroxy; lower alkyl-O-R b wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -
  • R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R 5 and R ** are unsubstituted or substituted;
  • R a is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR 1 R 11 R'", where R 1 , R", and R 1 " are independently selected from H, lower alkyl and aryl with the proviso that only one of R', R", and R'" is H; and R b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl 3 CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
  • the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:
  • the palladium pre-catalyst used in the processes of the present invention for preparing 2-substituted indoles, and pyrido and azepino derivatives thereof is Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(CH 3 CN) 2 Cl 2 , PdCl 2 , K 2 PdCl 4 , Pd/C or Pd 2 (dba) 3 -HCCl 3 .
  • Palladium pre-catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art.
  • the quantity of pre-catalyst which can be used can be any quantity which allows for the formation of the desired product.
  • the pre-catalyst is present in an amount of about 1.5 mole percent to about 6 mole percent relative to the ortAo-gem-dihalovinylaniline compound used in the reaction.
  • Ligands for use in the present processes for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof comprise a phosphorous- containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X- Phos, P(o-tol) 3 , PPh 3 , P(O-CF 3 -Ph) 3 , P(JBu) 3 , BINAP, tol- BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh 3 , DavePhos, HP(tBu) 3 BF 4 , and
  • the ligand is S-Phos. In another embodiment, the ligand is P(o-tol) 3 .
  • Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. In other embodiments, no additional ligand is necessary in order for the desired reaction to occur.
  • the quantity of ligand which can be used can be any quantity which allows for the formation of the 2-substituted indoles, and pyrido and azepino derivatives thereof.
  • the ligand is present in amount of about 3 mole % to about 12 mole % relative to the ortAo-gem-dihalovinylaniline compound used in the reaction.
  • the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof.
  • the base comprises K 3 PO 4 -H 2 O, K 3 PO 4 , NEt 3 , iPr 2 NH or Cy 2 NMe.
  • the base comprises NEt 3 /K 3 PO 4 .H 2 O. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S.
  • the additive has multiple roles according the literature; details are provided in: Jeffery, T. Tetrahedron 1996, 52, 10113.
  • Any solvent may be used in the processes of the present invention for the formation of 2-substituted indoles, and pyrido and azepino derivatives thereof, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable.
  • a suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, and the like.
  • the reagents may be mixed together or added together in any order for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.
  • the process conditions for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof can be any operable conditions which yield the desired indole product.
  • a preferred temperature for the processes for the production of the indoles of the present invention is about 120 0 C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 80 and 14O 0 C). Typical reaction times are between 3 and 48 hours, although longer or shorter times may be used if necessary.
  • the 2-substituted indoles, and pyrido and azepino derivatives thereof can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography.
  • the yield of the indole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used.
  • the desired indoles are provided in a yield greater than 40 %, preferably in a yield of greater than 65 %, more preferably in a yield greater than 75 %.
  • the process may also include an additional step of cleavage of the optionally substituted N- benzyl group to afford a 2-vinyl indole wherein R 2 is H.
  • Methods and reaction conditions for the cleavage of benzyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981, the details of which are incorporated herein by reference.
  • the present invention also provides novel processes for the preparation of indole compounds, in particular to 2-alkynyl indoles, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors.
  • the invention provides a process for the preparation of a compound of Formula (VIII):
  • each R 1 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(0)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * CONR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR 2 , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n 1 is a whole integer from 1 to 4; and each
  • R is selected from the group comprising -SiR 1 R 11 R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O- R b wherein R b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R ** , lower alkyl-CO-OR ** , lower alkyl-C(O)NR ** 2 , lower alkyl-NR"CO-R", lower alkyl-NR ** COO-R" wherein R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ** are unsubstituted or substitute
  • R a is selected from MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR 1 R 11 R'", where R 1 , R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R 1 , R", and R 1 " is H; and R b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl 3 CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr .
  • the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
  • the palladium pre-catalyst used in the processes of the present invention for preparing 2-alkynyl indoles is Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(CH 3 CN) 2 Cl 2 , Pd(PhCN) 2 Cl 2 , PdCl 2 , Pd(acac), K 2 PdCl 4 , Na 2 PdCl 4 , Pd/C, Pd(OH) 2 /C (Pearlman's catalyst), Pd-Al 2 O 3 , Pd-BaSO 4 , Pd-CaCO 3 , [Pd(allyl)Cl] 2 , or Pd 2 (dba) 3 HCCl 3 but is not limited to these pre-catalysts.
  • Palladium pre- catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art.
  • a description of general synthetic techniques used for preparing such pre-catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference.
  • Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II):
  • the quantity of palladium pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynylindole product, hi one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort ⁇ o-gew-dihalovinylaniline compound used in the reaction.
  • the palladium pre-catalyst is Pearlman's catalyst, such as 10% Pd/C Pearlman (50% wetted powder) from Strem (product # 46-1706). Palladium on carbon is an ideal palladium source for industrial processes due to its lower cost, easy recovery, and low level of palladium contamination in the product.
  • the copper pre-catalyst used in the processes of the present invention for preparing 2-alkynyl indoles is CuI, Cu(OAc), CuCl, CuBr, or Cu(OTf), but is not limited to these pre-catalysts. Copper pre-catalysts are commercially available, hi one embodiment, the copper pre-catalyst is CuI.
  • the quantity of copper pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynylindole product.
  • the pre-catalyst is present in an amount of about 1 mole percent to about 10 mole percent relative to the ort/jo-gem-dihalovinylaniline compound used in the reaction.
  • Ligands for use in the present processes for the preparation of 2-alkynyl indoles comprise a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, an alcohol-containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X-Phos, P(o-tol) 3 , P( ⁇ -tol-p-OMe) 3 , P(o- MeOPh) 3 , P(p-MeOPh) 3 , PPh 3 , P(O-CF 3 -Ph) 3 , P(tBu) 3 , BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh 3 , DavePhos, HP(tBu) 3 BF 4, 1,10-phenanthroline, neocuproine,
  • the ligand is P(/?-MeOPh) 3 .
  • the ligand is PPh 3 .
  • the quantity of ligand which can be used can be any quantity which allows for the formation of the 2-alkynyl indoles.
  • the ligand is present in amount of about 4 mole % to about 10 mole % relative to the ortho-gem- dihalovinylaniline compound used in the reaction.
  • the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof.
  • the base comprises K 2 CO 3 , K 3 PO 4 , NEt 3 , iPr 2 NH, iPr 2 NEt, DABCO or Cy 2 NMe.
  • the base is iPr 2 NH. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A.
  • Any solvent may be used in the processes of the present invention for the formation of 2-alkynyl indoles, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable.
  • a suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, H 2 O and the like.
  • the reagents may be mixed together or added together in any order for the preparation of 2-alkynyl indoles. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.
  • the process conditions for the preparation of 2-alkynyl indoles can be any operable conditions which yield the desired indole product.
  • a preferred temperature for the processes for the production of the 2-alkynyl indoles of the present invention is about 100 0 C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 20 and 140°C). Typical reaction times are between 1 and 48 hours, although longer or shorter times may be used if necessary.
  • the 2-alkynyl indoles can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography.
  • the yield of the indole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used.
  • the desired indoles are provided in a yield greater than 40 %, preferably in a yield of greater than 65 %, more preferably in a yield greater than 75 %.
  • the process may also include an additional step of cleavage of the optionally substituted N-benzyl group to afford a 2-alkynyl indole wherein R 2 is H.
  • Methods and reaction conditions for the cleavage of benzyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981), the details of which are incorporated herein by reference.
  • the present invention also provides novel processes for the preparation of benzo[ ⁇ ]furan compounds, in particular to 2-alkynyl benzo[Z>]furan, which may be optionally substituted at other positions on the benzo[ ⁇ ]furan ring, compounds prepared by such processes, and their synthetic precursors.
  • the invention provides a process for the preparation of a compound Formula (X) :
  • each R ⁇ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(0)NR * 2 , -NR * C0-R * , -NR * C00-R * , and -NR * C0NR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR 3 , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to
  • R 9 is H or lower alkyl
  • R$ and R 9 are as defined above,
  • Rg is selected from the group comprising -SiR 1 R 11 R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R"' is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-R b wherein R b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R ** , lower alkyl- CO-OR ** , lower alkyl-C(O)NR ** 2 , lower alkyl-NR ** CO-R ** , lower alkyl- NR ** COO-R ** wherein R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ** are unsubstitute
  • R a is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR 1 R 11 R'", where R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; and R b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl 3 CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
  • the invention provides novel 2-substituted benzo[ ⁇ ]furan or salts thereof selected from the group consisting of:
  • the palladium pre-catalyst used in the processes of the present invention for preparing 2-alkynyl benzo[fr]furans is Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(CH 3 CN) 2 Cl 2 , Pd(PhCN) 2 Cl 2 , PdCl 2 , Pd(acac), K 2 PdCl 4 , Na 2 PdCl 4 , Pd/C, Pd(OH) 2 /C (Pearlman's catalyst), Pd-Al 2 O 3 , Pd-BaSO 4 , Pd-CaCO 3 , [Pd(allyl)Cl] 2 , or Pd 2 (dba) 3 HCCl 3 but is not limited to these pre-catalysts.
  • Palladium pre-catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art.
  • a description of general synthetic techniques used for preparing such pre-catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference.
  • Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di( ⁇ -acetato)bis[o-(di- ⁇ -tolylphosphino)benzyl]dipalladium (II):
  • the quantity of palladium pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynyl benzo[ ⁇ ]furan product.
  • the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort/zo-gem-dihalovinylphenol compound used in the reaction.
  • the palladium pre-catalyst is Pearlman's catalyst.
  • the copper pre-catalyst used in the processes of the present invention for preparing 2-alkynyl benzo[&]furans is Cu(OAc), CuCl, CuBr, CuI, or Cu(OTf), but is not limited to these pre-catalysts. Copper pre-catalysts are commercially available. In one embodiment, the copper pre-catalyst is CuI.
  • the quantity of copper pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynyl benzo[Z?]furan product.
  • the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort/?o-ge/r ⁇ -dihalovinylphenol compound used in the reaction.
  • Ligands for use in the present processes for the preparation of 2-alkynyl benzo[6]furans comprise a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, alcohol containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X-Phos, P(O-U)I) 3 , P(o-tol- P-OMQ) 3 , P(O-MeOPh) 3 , P( ⁇ -MeOPh) 3 , PPh 3 , P(O-CF 3 -Ph) 3 , P(JBu) 3 , BINAP, tol- BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh 3 , DavePhos, HP(tBu) 3 BF 4, 1,10-phenanthroline, neo
  • the ligand is P(P-MeOPh) 3 .
  • the quantity of ligand which can be used can be any quantity which allows for the formation of the 2-alkynyl benzo[ ⁇ ]furans.
  • the ligand is present in amount of about 2 mole % to about 10 mole % relative to the ortho- gem-dihalovinylphenol compound used in the reaction.
  • the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof.
  • the base comprises K 2 CO 3 , iPr 2 NEt, DABCO, K 3 PO 4 H 2 O, K 3 PO 4 , NEt 3 , iPr 2 NH or Cy 2 NMe.
  • the base is iPr 2 NEt. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A.
  • Any solvent may be used in the processes of the present invention for the formation of 2-alkynyl benzo[ ⁇ ]furans, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable.
  • a suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, H 2 O and the like. In one embodiment, toluene is the solvent, hi another embodiment, a mixture of toluene and water is used.
  • the reagents may be mixed together or added together in any order for the preparation of 2-alkynyl benzo[Z?]furans. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.
  • the process conditions for the preparation of 2-alkynyl benzo[6]furan can be any operable conditions which yield the desired benzo[6]furan product.
  • a preferred temperature for the processes for the production of the indoles of the present invention is about 100 0 C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 20 and 140 0 C). Typical reaction times are between 1 and 48 hours, although longer or shorter times may be used if necessary.
  • the 2-alkynyl benzo[ ⁇ ]furan can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography.
  • the yield of the benzo[&]furan product will vary depending upon the specific pre- catalyst, ligand, base, starting materials and process conditions used.
  • the desired benzo[b]furan are provided in a yield greater than 50 %, preferably in a yield of greater than 75 %, more preferably in a yield greater than 90 %.
  • the invention provides an improved process for the preparation of a compound of the following Formula (XI)
  • each R 6 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R * , -C(O)O-R * , - C(O)NR * 2 , -NR * C0-R * , -NR * COO-R * , and -NR * C0NR * , wherein R * is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR a , wherein R a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer
  • R 7 is selected from the group consisting of H, or a suitable protective group
  • the protective group is selected from the group comprising a silyl protective group, an ester protective group, and an ether protective group.
  • the silyl protective group is selected from the group comprising TMS, TBS, TBDPS and TES.
  • the ester protective group is selected from the group comprising Ac, Piv, and Bz.
  • the ether protective group is selected from the group comprising MOM, Tr and MEM.
  • the invention provides novel ort ⁇ -gem-dibromovinylphenol compounds or salts thereof selected from the group consisting of:
  • reaction conditions have been optimized using two substrates as shown below by screening different Pd sources, ligands, organic and inorganic bases, additives, reaction time and reaction temperature. Three conditions giving good yields have been found depending on the type of the R 2 group (for Heck conditions with quaternary ammonium salt, see: T. Jeffery, Tetrahedron 1996, 52, 10113; T. Jeffery, Tetrahedron 1994, 35, 3051).
  • Procedure A needs longer reaction times but yields, depending on the substrate, are generally better than those obtained with Procedure B.
  • Procedure C is recommended when there is an aryl group on the aniline nitrogen; otherwise, with Procedures A and B, undesired by-products are observed, although the desired reaction products are still obtained.
  • R 2 Bn or Ph
  • Procedure A Pd(OAc) 2 (4 mol%), Me 4 NCI, NEt 3 /K 3 PO 4 .H 2 O, toluene, 12O 0 C
  • Procedure B Pd(OAc) 2 (4 mol%), P(o-tolyl) 3 (8 mol%), NEt 3 /K 3 PO 4 .H 2 O, toluene, 12O 0 C
  • R 3 may be selected from the group including but not limited to alkyl; lower alkyl-hydroxy; lower alkyl-O-R- b wherein R b is a suitable protective group; lower alkenyl; lower
  • Procedure A Pd(OAc) 2 (4 mol%), Me 4 NCI, NEt 3 /K 3 PO 4 .H 2 O, toluene, 120 0 C
  • Procedure B Pd(OAc) 2 (4 mol%), P(o-tolyl) 3 (8 mol%), NEt 3 /K 3 PO 4 .H 2 O, toluene, 120 0 C
  • Procedure C Pd 2 dba 2 (3 mol%), S-Phos (12 mol%), NEt 3 /K 3 PO 4 .H 2 O, toluene, 120 0 C
  • Procedure A Pd(OAc) 2 (4 mol%), Me 4 NCI, NEt 3 /K 3 PO 4 .H 2 O, toluene, 12O 0 C
  • Procedure B Pd(OAc) 2 (4 mol%), P(o-tolyl) 3 (8 mol%), NEt 3 /K 3 PO 4 .H 2 O, toluene, 12O 0 C
  • novel and versatile processes of the present invention may be used to synthesize commercially important indole compounds, such as, for example, Fluvastatin, and the potent and selective inhibitor of the osteoclatic Vacuolar H+-ATPase named SB-242782 (Farina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan, M.; Delimoge, I.; Pietro, B.; Zocchetti, A.; James, I.; Zembryki, D. Bioorganic & Medicinal Chemistry Letters 1998, 8, 3621; Visentin, L.; Dodds, R.
  • SB-242782 Fluvastatina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan,
  • the ⁇ rt/z ⁇ -ge/n-dibromovinylaniline is obtained from the olefination of 2-nitrobenzaldehyde by treatment with CBr 4 /PPh 3 (92%) followed by SnCl 2 -2H 2 O, or Fe, HOAc, or Fe, FeCl 3 , HOAc or H 2 , V-doped Pt/C.
  • CBr 4 /PPh 3 97%
  • SnCl 2 -2H 2 O or Fe, HOAc, or Fe, FeCl 3 , HOAc or H 2 , V-doped Pt/C.
  • at least two equivalents of solid triphenylphosphine are generated as a byproduct. Isolation of the desired product can sometimes be problematic.
  • the new improved process of the present invention comprises reaction of 2- nitrobenzaldehydes using trialkyl- or triphenylphosphite, which is more readily available and less expensive. Additionally, the product ort ⁇ o-gem-dibromovinylnitrobenzenes can be easily isolated from liquid trialkyl- or triphenylphosphate byproduct.
  • VII Reduction of or ⁇ o-gem-dibromovinylnitrobenzene using SnCl 2 -2H 2 O; or Fe, HOAc; or Fe, FeCl 3 , HOAc; or H 2 , V-doped Pt/C will result in the desired ortho-gem- dibromovinylaniline.
  • An intramolecular version introduction.
  • An intramolecular version of the processes of the invention has also been developed to provide pyrido and azepino indole structures of Formula (IV)/(IV)'. These processes involve a Pd-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction from readily accessible and appropriately functionalized ortAo-gew-dibromovinylanilines of Formula (V).
  • n can be between 0 and 3 to make five to eight membered rings.
  • Intramolecular Heck reactions are described in S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 6.
  • the substrate 3a shown below has been used to optimize the reaction conditions by screening different Pd sources, ligands, organic and inorganic bases, additives, reaction times and reaction temperatures. It appears that the optimal conditions are Pd 2 dba 3 (4 mol%), «Bu 4 NCl (1 equiv.), NEt 3 /K 3 PO 4 .H 2 O (2 equiv. of each), toluene, 120 0 C, 15h
  • the pyrido indole 4 is obtained as an easily separable mixture of 4a and 4a' with 76% (4a/4a': 3/1; Scheme 38).
  • reaction conditions have been optimized using [2-(2,2-dibromovinyl)phenyl]-amine and oct-1-yne as shown below by screening different Pd sources, different copper sources, ligands, organic and inorganic bases, solvents, reaction time and reaction temperature.
  • monodentate triarylphosphines were more effective than electron-rich and sterically hindered phosphines such as S-Phos, P( ⁇ Bu) 3 , or bidentate ligands such as dppf.
  • Procedure A Pearlman's catalyst (2 mol%), CuI (4 mol%), P(MeOPh) 3 (8 mol%), iPr 2 NH (2.5 equiv.), toluene (0.17 M), 100 0 C, 1.5h, 83%
  • Procedure B Pd-C (5 mol%), CuI (5 mol%), PPh 3 (11 mol%), iPr 2 NH (2.5 equiv.), toluene (0.17 M), 100 0 C, Ih, 92%
  • Procedure B Pd-C (5 mol%), CuI (5 mol%), PPh 3 (1 1 mol%), iPr 2 NH (2.5 equiv.), 20 toluene (0.17 M), 100 0 C
  • R 8 maybe selected from the group including but not limited to, -SiR 1 R 11 R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-R b wherein R b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl- nitrile; lower alkyl-CO-R ** , lower alkyl-CO-OR", lower alkyl-C(O)NR ** 2 , lower alkyl- NR ** CO-R ** , lower alkyl-NR ** COO-R" wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ** are un
  • the reaction conditions have been optimized using 2-(2,2-dibromovinyl)-phenol and oct-1-yne or ethynylbenzene as shown below by screening different Pd sources, different copper sources, ligands, organic and inorganic bases, solvents, reaction time and reaction temperature. Two conditions giving good yields have been found depending on the type of the R 8 group. Procedure A generally gives better yields of the products than those obtained with Procedure B. However when using the aryl substituted acetylenes or trimethylsilylacetylene as the terminal alkynes, Procedure B gives the products in much better yield. It is thought that the positive effect of water may be due to its ability to remove bromide from the organic phase. A control experiment, in which an external source of bromide (Bu 4 NBr) was found to inhibit the reaction progress, lends support to this proposal.
  • R 8 is selected from the group including, but not limited to, -SiR 1 R 11 R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-R b wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl- nitrile; lower alkyl-CO-R ** , lower alkyl-CO-OR", lower alkyl-C(O)NR ** 2 , lower alkyl- NR ** CO-R", lower alkyl-NR"COO-R ** wherein R ** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R 8 and R" are unsub
  • reaction time 64 h.
  • a typical method of preparing ort/z ⁇ -gem-dibromovinylphenols used in the processes of 10 invention is shown in Scheme 45.
  • the ort/zo-gem-dibromophenol is obtained from silylation of 2-hydroxybenzaldehyde by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate and 2,6-lutidine followed by olefination of the aldehyde functionality using CBr 4 ZPPh 3 and subsequent removal of TBS group with TBAF.
  • Toluene was distilled under N 2 from Na/benzophenone, dichloromethane was distilled from automatic distillation (SPS system) and 1,2-dichloroethane was distilled from CaH 2 immediately prior to use.
  • EtOH and DMF were purchased from Aldrich and were used without further distillation.
  • S-Phos was purchased from Strem Chemical Company, and other pre-catalysts or reagents were obtained from commercial sources without further purification.
  • 10% Pd-C Pearlman's catalyst was purchased from Strem (Palladium, 10% on activated carbon, Pearlman (50% wetted powder), Strem # 46-1706), which was originally produced by Degussa (Degussa E4, lot No. 20058613).
  • a tube (24x150 mm) of Carousel reaction station was charged with ortho-gem- dibromovinylaniline (1.0 equiv.), powdered K 3 PO 4 -H 2 O (2.0 equiv.) and Procedure A: Pd(OAc) 2 (4.0 mol %), Me 4 NCl (1.0 equiv.) or Procedure B: Pd(OAc) 2 (4.0 mol %), P( ⁇ -tolyl) 3 (8.0 mol %) or Procedure C: Pd 2 dba 3 (3.0 mol %), S-Phos (12.0 mol %) and the mixture was purged with argon and vacuum three times.
  • Triethylamine 2.0 equiv.
  • alkene 2.0 equiv.
  • toluene 0.1M
  • the reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated.
  • the crude product was purified by flash chromatography (typically 2% EtOAc in hexanes) to afford the indole 2.
  • Triethylamine (151.0 ⁇ L, 1.089 mmol), tertbuty ⁇ acrylate (160.0 ⁇ L, 1.089 mmol) and toluene (5.5 mL, 0.1M) were added and the reaction stirred at 120 0 C until all the starting material had been consumed (15 h).
  • the reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated.
  • the crude product was purified by flash chromatography (2 % EtOAc in hexanes) to afford 2a.
  • Example 2i and 2i' Preparation of l-(l-Benzyl-lH-indol-2-yl)-decan-3-one and 1- (l-Benzyl-lH-indol-2-yl)-dec-l-en-3-ol
  • Example 2aa Preparation of 3-[3-(4-Fluoro-phenyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester
  • Example 4a and 4a' Preparation of (6,7-Dihydro-pyrido[l,2-a]indol-9-yl)-acetic acid tert-butyl ester and (7,8-Dihydro-6H-pyrido[l,2-a]indol-9-ylidene)-acetic acid tert-butyl ester
  • Example 4b and 4b' Preparation of (2-Benzyloxy-6,7-dihydro-pyrido[l,2-a]indol-9- yl)-acetic acid tert-butyl ester and (2-Benzyloxy-7,8-dihydro-6H-pyrido[l,2-a]indol- 9-yIidene)-acetic acid tert-butyl ester
  • Example 4c and 4c' Preparation of 9-tert-Butoxycarbonylmethyl-6,7-dihydro- pyrido[l,2-a]indole-3-carboxylic acid methyl ester and 9-tert- Butoxycarbonylmethylene- ⁇ S ⁇ -tetrahydro-pyridofljl-aJindoleO-carboxylic acid methyl ester
  • Example 4e and 4e' Preparation of 8-Dihydro-6H-azepino[l,2-a]indoI-10-yl)-acetic acid tert-butyl ester and (6,7,8,9-Tetrahydro-azepino[l,2-a]indol-10-ylidene)-acetic acid tert-butyl ester
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-Dibromovinyl)aniline (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (9.2 mg, 0.0087 mmol, 2 mol%), P(P-MeOPh) 3 (12.0 mg, 0.034 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-Dibromovinyl)aniline 120 mg, 0.43 mmol
  • Pearlman's catalyst (Degussa E4) (9.2 mg, 0.0087 mmol, 2 mol%)
  • P(P-MeOPh) 3 (12.0 mg, 0.034 mmol, 8 mol%)
  • CuI 3.9 mg, 0.020 mmol, 4 mol%)
  • a carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 2 mol%), P(P-OMePh) 3 (14.2 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)aniline 139 mg, 0.50 mmol
  • Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 2 mol%)
  • P(P-OMePh) 3 (14.2 mg, 0.040 mmol, 8 mol%)
  • CuI 3.8 mg, 0.020 mmol, 4 mol%)
  • a carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%), PO-OMePh) 3 (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • a carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%), P(p-MeOPh) 3 (12.0 mg, 0.034 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)aniline 139 mg, 0.50 mmol
  • Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%)
  • P(p-MeOPh) 3 (12.0 mg, 0.034 mmol, 8 mol%)
  • CuI 3.9 mg, 0.020 mmol, 4 mol%)
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(P-MeOPh) 3 (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)aniline 139 mg, 0.50 mmol
  • Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%)
  • P(P-MeOPh) 3 (14.1 mg, 0.040 mmol, 8 mol%)
  • CuI 3.8 mg, 0.020 mmol, 4 mol%)
  • a carousel reaction tube (24x150 mm) was charged with [2-(2,2- dibromovinyl)phenyl]methylamine (130 mg, 0.45 mmol), Pearlman's catalyst (Degussa E4) (14.2 mg, 0.013 mmol, 3 mol%), P( ⁇ -MeOPh) 3 (6.3 mg, , 0.018 mmol, 4 mol%), and CuI (1.7 mg, 0.0089 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • a carousel reaction tube (24x150 mm) was charged with [2-(2,2-dibromovinyl)- phenyljisopropylamine (160 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (26.5 mg, 0.025 mmol, 5 mol%), P(p-MeOPh) 3 (14.1 mg, , 0.040 mmol, 8 mol%), and CuI (6.0 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • [2-(2,2-dibromovinyl)- phenyljisopropylamine 160 mg, 0.50 mmol
  • Pearlman's catalyst (Degussa E4) (26.5 mg, 0.025 mmol, 5 mol%)
  • P(p-MeOPh) 3 (14.1 mg, , 0.040 mmol, 8 mol%)
  • CuI 6.0 mg, 0.020 mmol, 4
  • a carousel reaction tube (24x150 mm) was charged with Benzyl[2-(2,2- dibromovinyl)phenyl]amine (120 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (23.7 mg, 0.022 mmol, 7 mol%), P( ⁇ -MeOPh) 3 (11.2 mg, , 0.033 mmol, 10 mol%), and CuI (6.0 mg, 0.033 mmol, 10 mol%), and was evacuated and purged with argon three times.
  • Benzyl[2-(2,2- dibromovinyl)phenyl]amine 120 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound
  • Pearlman's catalyst (Degussa E4) (23.7 mg, 0.022 mmol, 7 mol%)
  • a carousel reaction tube (24x150 mm) was charged with [2-(2,2- dibromovinyl)phenyl]phenylamine (130 mg, 0.37 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (3.9 mg, 0.0037 mmol, 1 mol%), P(/?-MeOPh) 3 (5.2 mg, , 0.015 mmol, 4 mol%), and CuI (1.4 mg, 0.0074 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2- dibromovinyl)naphthalen-l-ylamine (110 mg, 0.34 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (7.1 mg, 0.0066 mmol, 2 mol%), P(p-MeOPh) 3 (4.6 mg, 0.013 mmol, 4 mol%), and CuI (2.8 mg, 0.0066 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2- dibromovinyl)naphthalen-l-ylamine 110 mg, 0.34 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound
  • Pearlman's catalyst (Degussa E4) (7.1 mg, 0.0066 mmol, 2 mol%)
  • a carousel reaction tube (24 ⁇ 150 mm) was charged with 3-benzyloxy-2-(2,2- dibromovinyl)-4-methoxyphenylamine (136 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (7.0 mg, 0.0066 mmol, 2 mol%), P( ⁇ -MeOPh) 3 (4.6 mg, 0.013 mmol, 4 mol%), and CuI (1.3 mg, 0.0063 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-3- fluorophenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound; 150 mg, 0.51 mmol), Pearlman's catalyst (Degussa E4)) (10.6 mg, 0.010 mmol, 2 mol%), P( ⁇ -MeOPh) 3 (7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • a carousel reaction tube (24x 150 mm) was charged with 4-amino-3-(2,2- dibromovinyl)benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound; 110 mg, 0.33 mmol), Pearlman's catalyst (Degussa E4) (17.5 mg, 0.017 mmol, 5 mol%), P(/?-MeOPh) 3 (9.2 mg, 0.026 mmol, 8 mol%), and CuI (2.7 mg, 0.014 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • Pearlman's catalyst (Degussa E4) (17.5 mg, 0.017 mmol, 5 mol%)
  • P(/?-MeOPh) 3 (9.2 mg, 0.026 mmol, 8 mol%)
  • CuI 2.7 mg, 0.014 mmol, 4 mol%)
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (115 mg, 0.41 mmol), Pearlman's catalyst (Degussa E4) (4.4 mg, 0.0041 mmol, 1 mol%), P( ⁇ -MeOPh) 3 (5.8 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0083 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(p-MeOPh) 3 (6.0 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J.
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(p-MeOPh) 3 (6.0 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J.
  • a carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (140 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 1 mol%), P( ⁇ -OMePh) 3 (7.1 mg, 0.02 mmol, 4 mol%), and CuI (1.9 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetra
  • a carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P( ⁇ -MeOPh) 3 (6.1 mg, 0.017 mmol, 4 mol%), and CuI (1.7 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J.
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0043 mmol, 1 mol%), P(p-OMePh) 3 (7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J.
  • Example 6i Preparation of (8 ⁇ ,95,135,145,17S)-17-Benzofuran-2-ylethynyl-13- methyl-7,8,9,ll,12,13,14,15,16,17-decahydro-6H-cyclopenta[fl]phenanthrene-3,17- diol
  • a carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (100 mg, 0.36 mmol), Pearlman's catalyst (Degussa E4) (3.8 mg, 0.0036 mmol, 1 mol%), P(p-OMePh) 3 (5.1 mg, 0.014 mmol, 4 mol%), and CuI (1.4 mg, 0.0072 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • 2-(2,2-dibromovinyl)phenol prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J.
  • a carousel reaction tube (24x150 mm) was charged with l-(2,2- dibromovinyl)naphthalen-2-ol 7a (135 mg, 0.41 mmol), Pearlman's catalyst (Degussa E4) (4.4 mg, 0.0041 mmol, 1 mol%), P( ⁇ -MeOPh) 3 (5.8 mg, 0.016 mmol, 4 mol%), and CuI (1.7 mg, 0.0082 mmol, 2 mol%), and was evacuated and purged with argon three times.
  • a carousel reaction tube (24x150 mm) was charged with 3-(2,2-dibromovinyl)-4- hydroxybenzoic acid methyl ester 7b (105 mg, 0.31 mmol), Pearlman's catalyst (Degussa E4) (6.6 mg, 0.0062 mmol, 2 mol%), P( ⁇ -OMePh) 3 (8.8 mg, 0.025 mmol, 8 mol%), and CuI (2.4 mg, 0.013 mmol, 4 mol%), and was evacuated and purged with argon three times.
  • 3-(2,2-dibromovinyl)-4- hydroxybenzoic acid methyl ester 7b 105 mg, 0.31 mmol
  • Pearlman's catalyst (Degussa E4) (6.6 mg, 0.0062 mmol, 2 mol%)
  • P( ⁇ -OMePh) 3 (8.8 mg, 0.025 mmol, 8 mol%)
  • CuI 2.4 mg, 0.013 mmol, 4

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Abstract

The present invention relates to the preparation of 2-vinyl indoles from ortho-gem-dibromovinylaniline compounds and alkene reagents using a palladium pre-catalyst, a base, and, in some instances, a ligand or additive. The present invention also relates to the preparation of pyrido and azepino derivatives via a palladium-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction of appropriately functionalized ortho-gem-dibromovinylanilines. The present invention also relates to the preparation of 2-alkynyl indoles from ortho-gem-dibromovinylaniline compounds and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand. Novel processes for the preparation of benzo[b]furan compounds are also disclosed, wherein the 2-alkynyl benzo[b]furans are prepared from ortho-gem-dibromovinylphenol compounds and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand.

Description

2- Vinyl Indoles, Pyrido and Azepino Indole Derivatives, 2-Alkynyl Indoles, 2- Alkynyl Benzo[Z»|furans, Their Precursors and Novel Processes for the Preparation Thereof
Cross-reference to Related Application
This application claims priority from U.S. Provisional Application Serial No. 60/802,801, filed May 24, 2006.
1. Field of the Invention
The present invention relates to novel processes for the preparation of indole compounds, in particular to 2-vinyl indoles, pyrido and azepino derivatives, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-vinyl indoles from ortho-gem- dibromovinylaniline compounds and alkene reagents using a palladium pre- catalyst, a base, and, in some instances, a ligand or additive. The present invention also relates to the preparation of pyrido and azepino derivatives via a palladium-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction of appropriately functionalized ortho-gem- dibromovinylanilines. The invention also relates to processes for the production of or/Aø-gem-dibromovinylanilines which are useful as starting materials in the production of 2-vinyl indoles, pyrido and azepino derivatives, and novel compounds prepared by these processes.
The present invention also relates to novel processes for the preparation of indole compounds, in particular to 2-alkynyl indoles, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-alkynyl indoles from ortho-gem- dibromovinylaniline compounds, which can be synthesized using above mentioned processes, and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand.
The present invention also relates to novel processes for the preparation of benzo[6]furan compounds, in particular to 2-alkynyl benzo[ό]furans, which may be optionally substituted at other positions on benzo[ό]furan ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-alkynyl benzo[ό]furans from ørtλø-gem-dibromovinylphenol compounds and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand. The invention also relates to processes for the production of ortho-gem -dibromovinylphenols which are useful as starting materials in the production of 2-alkynyl benzo[5]furans, and novel compounds prepared by these processes.
2. Brief Description of the Related Art.
Numerous processes have been developed for the synthesis of 2-vinyl indoles and derivatives thereof, several of which are shown below with the reported yields for the preparation of various 2-vinyl indoles.
To date, many of the prior art processes are reported to have numerous drawbacks such as being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. Moreover, direct methodologies to synthesize 2-vinyl indoles are rare; usually pre-functionalized indoles are required. A general description of several prior art processes is set out below in Schemes 1-14, additional details of which are set out in the references as indicated.
2-vinyl indoles have been prepared using Wittig related olefination reactions (Scheme 1) on 2-formyl- or 2-ketoindoles (Eitel, M.; Pindur, U. Synthesis 1989, 364; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Conzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810) and by treatment of indol-2- ylmethyltriphenylphosphorane or diethylphosphonates with carbonyl compounds (Nagarathnam, D. Synthesis 1992, 743 and references cited therein).
Scheme 1
Figure imgf000004_0001
R = PPh3 Br" R = PO(OR)2
Direct formation of 2-vinyl indoles also occurring via a Wittig reaction (shown in Scheme 2) has been reported to have occurred intramolecularly (Eitel, M.; Pindur, U. Synthesis 1989, 364 and references cited therein).
Scheme 2
Figure imgf000004_0002
Hetero-Cope rearrangement has been shown to provide short and stereoselective syntheses of 2-vinyl indoles by a tandem process involving a N- phenylhydroxylamine, aldehyde and electron deficient allene (Wilkens, J.; Kuhling, A.; Blechert, S. Tetrahedron 1987, 43, 3237; Blechert, S. Synthesis 1989, 71; Scheme 3). Scheme 3
Figure imgf000005_0001
36-77%
A synthesis of N-hydroxy 2-vinylindoles (Scheme 4) has been realized via the cyclization of allyl nitroaryl acetonitriles (Wrobel, Z., Makosza, M. Synlett 1993, 597).
Scheme 4
Figure imgf000005_0002
A two step synthesis of 2-vinyl indoles has also been described. Reaction of the anions of methyl indole carboxylates with ketone or aldehyde derivatives leads directly to 2-vinyl indoles as shown in Scheme 5 (Macor, J. E., Newman, M. E.; Ryan, K. Tetrahedron Lett. 1989, 30, 2509).
Scheme 5
Figure imgf000005_0003
33-99%
A palladium-catalyzed intermolecular alkenylation of indoles is shown in Scheme 6. The regioselectivity of the reaction is dependant on the choice of solvent (Grimster, N. P.; Gauntlett, C; Godfrey, C. R. A.; Gaunt, MJ. Angew. Chem. Int. Ed. 2005, 44, 3125; see also: Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854; Lu, W.; Jia, C; Kitamura, T.; Fujiwara, Y. Org. Lett. 2000, 2, 2927; Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc. Perkin Trans. / 1983, 1361). Scheme 6
Figure imgf000006_0001
62-91 % 51 -57%
Another way to produce 2-vinyl indoles is via a Stille cross-coupling reaction between 2-halo indole and vinyl stannane (Scheme 7) (Somei, M.; Sayama, S.; Naka, K.; Yamada, F. Heterocycles 1988, 27, 1988; Beccalli, E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353) or between 2-stannyl indole and vinyl halide (Hudkins, R. L.; Dielbold, J. L.; Marsh, F. D. J. Org. Chem. 1995, 60, 6218).
Scheme 7
Figure imgf000006_0002
X, Y = halogen or SnR3
A radical cyclization of 2-alkenylphenyl isocyanide (Scheme 8) provides access to 2-stannyl indoles as intermediates which can be readily converted to 2-vinyl indoles by a palladium-mediated cross-coupling reaction in a one-pot procedure (Tokuyama, H.; Kaburagi, Y.; Chen, X., Fukuyama, T. Synthesis 2000, 429; Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127).
Scheme 8
Figure imgf000006_0003
Also reported by Fukuyama, T. and coworkers is a similar type of cyclization using a Heck cross-coupling reaction or Stille cross-coupling reaction in one pot or by isolating the 2-iodo indole intermediate. (Scheme 9, Tokuyama, H.; Kaburagi, Y.; Chen, X., Fukuyama, T. Synthesis 2000, 429). Scheme 9
Figure imgf000007_0001
Annulation of 2-alkynylanilines catalyzed by gold (III) (Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610) or palladium (II) (Cacchi, S.; Carcicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475, 289) affords 2-vinyl indoles (Scheme 10).
Scheme 10
Figure imgf000007_0002
Having regard to the synthesis of pyrido indoles, one group has reported a synthesis from 2-iodoindole by an intramolecular Heck reaction, as shown in Scheme 11, (Germain, A. L.; Gilchrist, T. L.; Kemmitt, P. D. Heterocycles 1994, 37, 697; Gilchrist, T. L.; Kemmitt, P.D. Tetrahedron 1997, 53, 4447).
Scheme 11
Figure imgf000007_0003
Pyrido and azepino indoles have also been prepared by Ring Closing Metathesis of conveniently functionalized substrates catalyzed by Grubb's ruthenium catalyst (Scheme 12) (Conzalez-Perez, P.; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Perez-Castells, J. Tetrahedron Lett. 2002, 43, Al 61). Scheme 12
Figure imgf000008_0001
A Dieckmann approach (Scheme 13) was used to prepare pyrido and azepino indoles in two steps from 2-carboxylate indoles (Bit, R. A.; Davis, P. D.; Hill, C.H.; Keech, E.; Vesey, D. R. Tetrahedron 1991, 47, 4645).
Scheme 13
Figure imgf000008_0002
A intramolecular combination of a [Cp2TiMe2]-catalyzed hydroamination of alkynes with Pd-catalyzed N-arylation of an imine results in synthesis of pyrido indoles (Scheme 14, Siebeneicher, H.; Bytschkov, L; Doye, S. Angew. Chem. Int. Ed. 2003, 42, 3042).
Scheme 14
Figure imgf000008_0003
In view of the above, there remains a need for novel and versatile processes for synthesizing 2-vinyl indole compounds, pyrido-indoles, azepino-indoles and derivatives. The development and implementation of such processes could simplify the preparation of commercially important indole compounds. One such commercially important indole containing a 2-vinyl substitution is the lipid metabolism regulator fluvastatin (sold as Lescol®), the structure of which is shown below in its sodium salt form:
Figure imgf000009_0001
Fluvastatin is currently sold as a racemate of two erthryo enantiomers of which one exerts the pharmacological activity. Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form (Compendium of Pharmaceuticals and Specialities (CPS), 2005, 40th Edition, Canadian Pharmacists Association). Synthetic methods exist for the synthesis of the racemic version of the drug (Repic, O.; Prasad, K.; and Lee, G. T. Organic Process Research & Development 2001, 5, 519-527), however, processes for making the enantiopure drug are highly desired.
Another important indole containing a 2-vinyl substitution is the following potent and selective inhibitor of the osteoclatic Vacuolar H+-ATPase named SB-242782 (Farina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan, M.; Delimoge, L; Pietro, B.; Zocchetti, A.; James, L; Zembryki, D. Bioorganic & Medicinal Chemistry Letters 1998, 8, 3621; Visentin, L.; Dodds, R. A.; valente, M.; Misiano, P.; Bradbeer, J. N.; Oneta, S.; Liang, X.; Gowen, M.; Farina, C. Journal of Clinical Investigation 2000, 106, 309; Price, P.A.; June, H. H.; Buckley, J. R.; Williamson, M. K. Circulation Reasearch 2002, 91, 547; Whyteside, G.; Meek, P.J.; Ball, S. K.; Dixon, N.; Finbow, M. E.; Kee, T. P.; Findlay, J.B.C.; Harrison, M. A. Biochemistry 2005, 44, 15024):
Figure imgf000010_0001
Methods for synthesizing SB-242782 are known in the art and provide the desired compound (Conde, J. J.; .McGuire, M.; Wallace, M. Tetrahedron Lett. 2003, 44, 3081; Yu, M.S.; Lopez de Leon, L.; McGuire, M.A.; Botha, G. Tetrahedron Lett. 1998, 39, 9347). The presently published synthesis suffers from linearity and the synthesis is relatively long; with the new methodology of the present invention, it is envisioned that SB-242782 can be obtained in fewer steps with a convergent synthesis.
2-vinylindoles have proven to be versatile dienes in Diels- Alder reactions aiming at regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest, both in inter- and intramolecular reactions (for reviews, see: Pindur, U. Heterocycles 1998, 27, 1253; Pindur, U. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; Cycloaddition Reaction of Indoles Derivatives; JAI Press: Greenwich, 1995; Vol. 1 , p 121 ; Sundberg, R.In Best Synthetic Methods, Sub-series Key Systems and Functional Group; Meth-Cohen, O., Ed. Indoles; Academic Press: London, 1996; p 159). The carbazole ring is the core of a wide range of alkaloids, and therefore is a very important building block in the synthesis of pharmacologically active compounds.
Numerous processes have been developed for the synthesis of 2-alkynyl indoles and derivatives thereof, several of which are shown below with the reported yields for the preparation of various 2-alkynyl indoles.
To date, many of the prior art processes are reported to have numerous drawbacks such as being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring toxic reagents, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. Moreover, direct methodologies to synthesize 2-alkynyl indoles are rare; usually pre-functionalized indoles are required. A general description of several prior art processes is set out below in Schemes 15-21, additional details of which are set out in the references as indicated.
Sonogashira coupling reaction of 2-haloindoles with terminal alkynes have been reported to synthesize 2-alkynyl indoles. (Zhang, H.; Larock, R. C J Org. Chem., 2002, 67, 7048; Scheme 15)
Scheme 15
Figure imgf000011_0001
Sonogashira coupling reaction with (2-trifluoromethanesulfonyloxy)indoles and terminal alkynes has also been reported. (Elisabetta, R.; Giorgio, A.; Valentina, C; Giuseppe, C; Elsa, M. Synthesis., 2006, 2, 299; Scheme 16)
Scheme 16
Figure imgf000011_0002
2-Alkynyl indoles have been prepared using Stille coupling reaction (Scheme 17) with 2-bromoindoles (Eitel, M.; Pindur, U. J. Heterocyclic Chemistry 2006, 43, 701; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Conzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810) and by treatment of 1-bromo-l -alkynes with 2-stannylindoles (Nagarathnam, D. Synlett 1993, 771 and references cited therein). Scheme 17
Figure imgf000012_0001
A five-step transformation from a 2-methoxycarbonyl indole to a 2-alkynyl indole has also been reported. In this case, a 2-dibromovinylindole was prepared from the corresponding ester derivative in three steps. Then the 2-dibromovinylindole was converted to the 2-ethynylindole using first potassium tert-amylate and then dimethyl phosphate as shown in Scheme 18 (Thottathil, J. K., Li, W. S. US patent 5298625, 1994).
Scheme 18
Figure imgf000012_0002
A direct formation of 2-vinyl indoles using low-valent titanium has been reported (Furstner, A.; Ernst, A.; Krause, H.; Ptock, A. Tetrahedron 1996, 52 7329; Scheme 19). Scheme 19
Figure imgf000013_0001
A 2-alkynylindole is used as a pivotal intermediate during the synthesis of SB- 242782 (referenced above). It was achieved by a cross-coupling process via an organotin intermediate as well as by a reduction-isomerization sequence (Conde, J. J.; McGuire, M.; Wallace, M. Tetrahedron Lett. 2003, 44, 3081; Scheme 20).
Scheme 20
Figure imgf000013_0002
2-alkynyl indoles have also played important roles as key intermediates for the synthesis of natural products. Fukuyama, T. and coworkers achieved the total synthesis of (-)-Aspidophytine using an 2-alkynylindole as a key intermediate. This intermediate is obtained by a Sonogashira coupling between a terminal alkyne and an 2-iodoindole which was prepared from vanillin in 11 steps (Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571; Scheme 21). Scheme 21
Figure imgf000014_0001
In view of the above, there remains a need for novel and versatile processes for synthesizing 2-alkynyl indole compounds and derivatives. The development and implementation of such processes could simplify the preparation of pharmaceutically important indole containing compounds and provide rapid access to a new class of indoles exhibiting broad pharmacological properties.
One such important indole containing a 2-alkynyl substitution is the lipid metabolism regulator SQ-33600, the structure of which is shown below in its sodium salt form (Karanewsky, D. S.; Badia, M. C; Adams, B. C; Michael, G. E.; Joseph, S. M.; DE 3817298 Al 19881201, Bristol-Myers Squibb, 1988; Karanewsky, D. S.; Badia, M. C; Ciosek, C. P. Jr; Robl, J. A.; Sofia, M. J.; Simpkins, L. M.; DeLange, B.; Harrity, T. W.; Biller, S. A.; Gordon, E. M. J. Med. Chem. 1990, 33, 2952; Jagoda, E.; Stouffer, B.; Ogan, M.; Tsay, H. M.; Turabi, N.; Mantha, S.; Yost, F.; Tu, J. I. Therapeutic Drug Monitoring 1993, 15, 213);
Figure imgf000014_0002
Methods for synthesizing SQ-33600 are known in the art and provide the desired compound (Karanewsky, D. S.; Badia, M. C; Ciosek, C. P. Jr; Robl, J. A.; Sofia,
M. J.; Simpkins, L. M.; DeLange, B.; Harrity, T. W.; Biller, S. A.; Gordon, E. M.
J. Med. Chem. 1990, 33, 2952). The presently published synthesis suffers from linearity and the synthesis is relatively long; with the new methodology of the present invention, it is envisioned that SQ-33600 can be obtained in fewer steps with a convergent synthesis.
Regarding 2-alkynyl benzo[&]furans and derivatives, there have not been many reports on the processes for the synthesis of such compounds. Some representative examples of these are shown below in Schemes 22-26 with the reported yields for the preparation of various 2-vinyl benzo[6]furans. Additional details are set out in the references as indicated.
In addition, some of the prior art processes have been reported to have numerous drawbacks, such as a narrow scope, being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. Moreover, direct methodologies to synthesize 2-alkynyl benzo[Z>]furans are rare; usually pre-functionalized benzo[6]furans are required.
Sonogashira coupling reaction of 2-halobenzo[6]furans with terminal alkynes has been reported to synthesize 2-alkynyl benzo[6]furans. (Bach, T.; Bartels, M. Synlett, 2001, 8, 1284; Scheme 22)
Scheme 22
Figure imgf000015_0001
2-Ethynylbenzo[ό]furan has been prepared by a coupling of 2-iodobenzo[ό]furan with ethynylzinc bromide. (Negishi, E.; Xu, C; Kotora, M.. Heterocycles, 1997, 46, 209; Scheme 23)
Scheme 23
Figure imgf000015_0002
72% Generation of an 2-iodobenzo[&]furan has been reported using intermolecular anionic cyclization of ø-cinnamyloxybenzylideneamines even though in low yield. (Tsuge, O.; Ueno, K.; Oe, K. Chem. Lett., 1981, 135; Scheme 24)
Scheme 24
Figure imgf000016_0001
The two-step synthesis of a benzo[ό]furandiyne has been conducted from 1,2- diformylbenzo[ό]furan. (Sahu, B.; Namboothiri, I. N. N.; Persky, R. Tetrahedron. Lett., 2005, 46, 2593; Scheme 25)
Scheme 25
Figure imgf000016_0002
The reaction of 2-lithiobenzo[&]furan with phenylethynyl- IH-1, 2,3 -benzotriazole derived from benzoyl chloride in three steps has been reported to give 2- phenylethynylbenzo[6]furan. (Sahu, B.; Namboothiri, I. N. N.; Persky, R. Tetrahedron. Lett., 2005, 46, 2593; Scheme 26)
Scheme 26
Figure imgf000016_0003
In view of the above, there remains a need for novel and versatile processes for synthesizing 2-alkynyl benzo[ό]furan compounds and derivatives. The development and implementation of such processes could simplify the preparation of pharmaceutically important benzo[Z>]furan containing compounds and provide rapid access to a new class of indoles exhibiting broad pharmacological properties.
Summary of the Invention
The present invention provides novel and versatile processes for synthesizing 2- vinyl indole compounds, pyrido-indoles, azepino-indoles and derivatives. As aforementioned, it is envisioned that these processes may be used in the preparation of commercially important indole compounds.
Included in the scope of the invention is a process for the preparation of 2-vinyl indole compounds, hi particular, in one aspect, the invention provides a process for the preparation of a compound of Formula (I):
Figure imgf000017_0001
(I)
wherein
each Ri is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, - NR*C0-R*, -NR*COO-R*, -NR*C0NR* wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R* are unsubstituted or substituted; R2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
the process comprising reacting an ort/zo-gem-dibromovinylaniline compound of Formula (II)
Figure imgf000018_0001
wherein Rj and R2 are as defined above,
with an alkene Heck acceptor of the Formula (III)
(III)
wherein R3 is selected from the group comprising alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R**, - C(O)OR**, -C(O)NR** 2, -SO2R**, -SO2MT2, lower alkyl-CO-R**, lower alkyl-CO- OR**, lower alkyl-C(O)NR** 2, lower alkyl-NR**CO-R*\ lower alkyl-NR**COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R3 is -C(0)NR** 2 both R** groups may form a heterocyclic ring with the nitrogen atom; and each of R3 and R" are unsubstituted or substituted;
in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (I).
In another aspect, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
Figure imgf000019_0001
It is expected that the 2-vinyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest.
In another aspect, the invention provides an improved process for the preparation of a compound of the following Formula (II)
Figure imgf000019_0002
(II)
wherein each Ri is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(O)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*C0NR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein R3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n1 is a whole integer from 1 to 4; and each of Ri and R* are unsubstituted or substituted;
and R2 is H;
comprising reaction of a compound of Formula (VI)
Figure imgf000020_0001
(Vl)
with CBr4 and P(OR)3, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, to form a compound of Formula (VII)
Figure imgf000020_0002
isolating the compound of Formula (VII), and reducing the compound of Formula (VII) to obtain the compound of Formula (II).
In another aspect, the invention provides novel σrt/jo-gem-dibromovinylaniline compounds or salts thereof selected from the group consisting of:
Figure imgf000021_0001
These derivatives are useful in the preparation of the desired 2-vinyl indole compounds.
In yet another aspect, the invention provides a process for the preparation of a c -o i:mpound of Formula (IV) and/or Formula (IV)'
Figure imgf000021_0002
wherein
each R4 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, -
NR*C0-R*, -NR*C00-R*, -NR*CONR* wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR2, wherein
Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of R» and R* are unsubstituted or substituted; the process comprising reacting an ørt/zo-ge/M-dibromovinylaniline compound of Formula (V):
Figure imgf000022_0001
wherein R4 is as defined above, n is 0 to 3,
and R5 is selected from the group comprising H, lower alkyl; lower alkyl- hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; - C(O)R**, -C(O)OR**, -C(0)NR** 2, -SO2R**, -SO2NR** 2, lower alkyl-CO-R**, lower alkyl-CO-OR**, lower alkyl-C(O)NR** 2, lower alkyl-NR**CO-R", lower alkyl- NR**COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R5 and R" are unsubstituted or substituted;
in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (IV) and/or Formula (IV)'.
In yet another aspect, the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:
Figure imgf000022_0002
These compounds are useful in the preparation of the compounds of Formulas (IV) and (IV)'. The present invention also provides novel and versatile processes for synthesizing 2-alkynyl indole compounds. As aforementioned, it is envisioned that these processes may be used in the preparation of pharmaceutically important indole compounds.
Included in the scope of the invention is also a process for the preparation of a compound of Formula (VIII):
Figure imgf000023_0001
wherein
each R] is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(0)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*C0NR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R* are unsubstituted or substituted;
R2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
the process comprising reacting an ortho-gem-dibromovinylaniline compound of Formula (II)
Figure imgf000024_0001
wherein Rj and R2 are as defined above,
with an alkyne of the Formula (IX)
Figure imgf000024_0002
(IX)
wherein Rg is selected from the group comprising -SiR1R11R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O- Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R**, lower alkyl-CO-OR'*, lower alkyl-C(O)NR"2, lower alkyl-NR"CO-R'\ lower alkyl-NR**COO-R** wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R" are unsubstituted or substituted;
in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a ligand to form the compound of Formula (VIII).
In another aspect, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
Figure imgf000025_0001
It is expected that the 2-alkynyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [ό]annulated indole derivatives of pharmacological interest.
The present invention also provides novel and versatile processes for synthesizing 2-alkynyl benzo[ό]furan compounds. As aforementioned, it is envisioned that these processes may be used in the preparation of pharmaceutically important benzo[&]furan compounds.
Included in the scope of the invention is also a process for the preparation of 2- alkynyl benzo[ό]furan compounds, hi particular, in one aspect, the invention provides a process for the preparation of a compound Formula (X):
Figure imgf000026_0001
(X)
wherein
each R6 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(0)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*CONR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of Re and R* are unsubstituted or substituted;
and R9 is H or lower alkyl;
the process comprising reacting an ortho-gem-dibromovinylphenol compound of Formula (XI)
Figure imgf000026_0002
wherein R6 and R9 are as defined above,
with an alkyne of the Formula (IX)
= — 1 (IX) Rs is selected from the group comprising -SiR1R11R'" wherein R1, R", and R1" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl -hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R", lower alkyl- CO-OR**, lower alkyl-C(O)NR** 2, lower alkyl-NR**CO-R*\ lower alkyl- NR**COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R** are unsubstituted or substituted;
in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a ligand to form the compound of Formula (X).
In another aspect, the invention provides novel 2-substituted benzo[&]furans or salts thereof selected from the group consisting of:
Figure imgf000027_0001
It is expected that the 2-alkynyl benzo[6]furan compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of benzo[ό]furan derivatives of pharmacological interest. In another aspect, the invention provides an improved process for the preparation of a compound of the following Formula (XI)
Figure imgf000028_0001
wherein
each R6 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(0)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*C0NR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of R6 and R are unsubstituted or substituted;
comprising reaction of a compound of Formula (XII)
Figure imgf000028_0002
wherein R7 is selected from the group consisting of H, or a suitable protective group,
with CBr4 and P(OR)3, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, under reaction conditions effective to form a compound of Formula (XIII)
Figure imgf000029_0001
(XIII)
isolating the compound of Formula (XIII), and deprotection, if needed, of the protective group under conditions effective to yield the compound of Formula (XI).
In another aspect, the invention provides novel ort/20-ge/w-dibromovinylphenol compounds or salts thereof selected from the group consisting of:
Figure imgf000029_0002
These derivatives are useful in the preparation of the desired 2-alkynyl benzo[&]furan compounds.
Detailed Description
Chemical terms used herein are to be given meanings in keeping with what is understood by those of skill in the art.
The term "suitable substituent" as used in the context of the present invention is meant to include independently H; hydroxyl; protected hydroxyl groups such as - O-THP (tetrahydropyranyl) and -O-TBDPS (t-butyldiphenylsilyl); cyano; alkyl, such as lower alkyl, such as methyl, ethyl, propyl, n-butyl, t-butyl, hexyl and the like; alkoxy, such as lower alkoxy such as methoxy, ethoxy, and the like; aryloxy, such as phenoxy and the like; vinyl; alkenyl, such as hexenyl and the like; alkynyl; formyl; haloalkyl, such as lower haloalkyl which includes CF3, CCl3 and the like; halide; aryl, such as phenyl and naphthyl; heteroaryl, such as thienyl and furanyl and the like; amide such as C(O)N(CH3)2 and the like; acyl, such as C(O)- C6H5, and the like; ester such as -C(O)OCH3 the like; ethers and thioethers, such as O-Bn and the like; amino; thioalkoxy; phosphino and the like. It is to be understood that a suitable substituent as used in the context of the present invention is meant to denote a substituent that does not interfere with the formation of the desired product by the claimed processes of the present invention.
As used in the context of the present invention, the term "lower alkyl" as used herein either alone or in combination with another substituent means acyclic, straight or branched chain alkyl substituent containing from one to six carbons and includes for example, methyl, ethyl, 1 -methylethyl, 1-methylpropyl, 2- methylpropyl, and the like. A similar use of the term is to be understood for "lower alkoxy", "lower thioalkyl", "lower alkenyl" and the like in respect of the number of carbon atoms. For example, "lower alkoxy" as used herein includes methoxy, ethoxy, t-butoxy.
The term "alkyl" encompasses lower alkyl, and also includes alkyl groups having more than six carbon atoms, such as, for example, acyclic, straight or branched chain alkyl substituents having seven to ten carbon atoms.
The term "aryl" as used herein, either alone or in combination with another substituent, means an aromatic monocyclic system containing 6 carbon atoms or a polycyclic aromatic system, such as an aromatic bicyclic system containing 10 carbon atoms. For example, the term "aryl" includes a phenyl or a naphthyl ring.
The term "heteroaryl" as used herein, either alone or in combination with another substituent means a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatoms selected from nitrogen, oxygen, and sulphur and which form an aromatic system. The term "cycloalkyl" as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent that includes for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "cycloalkyl-alkyl-" as used herein means an alkyl radical to which a cycloalkyl radical is directly linked; and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl,
2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl and 2-cyclohexyl ethyl.
A similar use of the "alkyl" term is to be understood for aryl-alkyl-, heteroaryl- alkyl-, and the like as used herein. For example, the term "aryl-alkyl-" means an alkyl radical, to which an aryl is bonded. Examples of aryl-alkyl- include, but are not limited to, benzyl (phenylmethyl), 1 -phenyl ethyl, 2-phenylethyl and phenylpropyl.
As used herein, the term "heterocycle", either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a three- to seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, hydantoin, diazepine, imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine, homopiperazine, 1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, and the like.
The term "alkenyl", as used herein, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.
The term "alkynyl", as used herein is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. The term "alkoxy" as used herein, either alone or in combination with another radical, means the radical -O-(Ci-n)alkyl wherein alkyl is as defined above containing 1 or more carbon atoms and includes for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. Where n is 1 to 6, the term "lower alkoxy" applies, as noted above, whereas the term "alkoxy" encompasses "lower alkoxy" as well as alkoxy groups where n is greater than 6 (for example, n = 7 to 10). The term "aryloxy" as used herein alone or in combination with another radical means -O-aryl, wherein aryl is defined as noted above.
As used herein the term "heteroatom" means O, S or N.
The term "suitable protective group" is to be understood to denote a protective group for a functionality, such as a hydroxyl group, that does not interfere with the formation of the desired product by the claimed processes of the present invention. Suitable protective groups are known to those of skill in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981, the details of which are incorporated herein by reference.
The present invention provides novel processes for the preparation of indole compounds, in particular to 2-vinyl indoles, pyrido and azepino derivatives, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors.
In one embodiment, the invention provides a process for the preparation of a compound of Formula (I):
Figure imgf000032_0001
(I)
wherein
each R1 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, - NR*C0-R*, -NR*C00-R*, -NR*C0NR* wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R are unsubstituted or substituted;
R2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
the process comprising reacting an ortAo-ge/«-dibromovinylaniline compound of Formula (II)
Figure imgf000033_0001
wherein Ri and R2 are as defined above,
with an alkene Heck acceptor of the Formula (III)
(III)
wherein R3 is selected from the group comprising alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R", -
C(O)OR**, -C(0)NR** 2, -SO2R**, -SO2NR** 2, lower alkyl-CO-R**, lower alkyl-CO- OR", lower alkyl-C(O)NR"2, lower alkyl-NR"CO-R", lower alkyl-NR"COO-R" wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R3 is -C(O)NR 2 both R groups may form a heterocyclic ring with the nitrogen atom; and each OfR3 and R** are unsubstituted or substituted;
in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (I). In one embodiment, R3 is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R1, R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R1, R", and R"1 is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
In another embodiment, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
Figure imgf000034_0001
As aforementioned, 2-vinylindoles have proven to be versatile dienes in Diels- Alder reactions aiming at regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [b]annelated indole derivatives of pharmological interest, both in inter- and intramolecular reactions (Pindur, U. Heterocycles 1998, 27, 1253; Pindur, U. hi Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; Cycloaddition Reaction of Indoles Derivatives; JAI Press: Greenwich, 1995; Vol. 1, p 121; Sundberg, R. in Best Synthetic Methods, Sub- series Key Systems and Functional Group; Meth-Cohen, O., Ed. Indoles; Academic Press: London, 1996; p 159). The carbazole ring is a very important building block in the synthesis of pharmacologically active compounds, as it is the core of a wide range of alkaloids. It is expected that the 2-vinyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest.
In another embodiment, the invention provides an improved process for the preparation of a compound of the following Formula (II)
Figure imgf000035_0001
(II)
wherein
each R] is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(O)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*CONR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R* are unsubstituted or substituted; and R2 is H;
comprising reaction of a compound of Formula (VI)
Figure imgf000036_0001
(Vl)
with CBr4 and P(OR)3, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, to form a compound of Formula (VII)
Figure imgf000036_0002
isolating the compound of Formula (VII), and reducing the compound of Formula (VII) to obtain the compound of Formula (II). In one embodiment, Ra is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R1, R", and R"1 are independently selected from H, lower alkyl and aryl, with the proviso that only one of R1, R", and R1" is H.
In another embodiment, R is isopropyl. In yet another embodiment, the compound of Formula (VII) is isolated via recrystallization. In still another embodiment, the compound of Formula (VII) is isolated via addition of HOAc/HCl followed by a basic workup procedure.
In another embodiment, the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:
Figure imgf000037_0001
These derivatives are useful in the preparation of the desired 2-vinyl indole compounds.
In yet another embodiment, the invention provides a process for the preparation of a compound of Formula (IV) and/or Formula (IV)'
Figure imgf000037_0002
wherein
each R4 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, - NR*C0-R*, -NR*C00-R*, -NR*CONR* wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein R3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of R4 and R are unsubstituted or substituted;
the process comprising reacting an ort/zo-gerø-dibromovinylanihne compound of Formula (V):
Figure imgf000038_0001
wherein R4 is as defined above, n is 0 to 3,
and R5 is selected from the group comprising H, lower alkyl; lower alkyl- hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -
C(O)R**, -C(O)OR", -C(O)NR** 2, -SO2R**, -SO2NR** 2, lower alkyl-CO-R**, lower alkyl-CO-OR*', lower alkyl-C(O)NR** 2, lower alkyl-NR**CO-R**, lower alkyl-
NR**COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R5 and R** are unsubstituted or substituted;
in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (IV) and/or Formula (IV)'. In one embodiment, Ra is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R1, R", and R1" are independently selected from H, lower alkyl and aryl with the proviso that only one of R', R", and R'" is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
In another embodiment, the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:
Figure imgf000039_0001
These compounds are useful in the preparation of the compounds of Formulas (IV) and (IV)'.
In one embodiment, the palladium pre-catalyst used in the processes of the present invention for preparing 2-substituted indoles, and pyrido and azepino derivatives thereof, is Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3, Pd(CH3CN)2Cl2, PdCl2, K2PdCl4, Pd/C or Pd2(dba)3-HCCl3. Palladium pre-catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre- catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di(μ-acetato)bis[o-(di-o- tolylphosphino)benzyl] dipalladium (II) :
Figure imgf000039_0002
The quantity of pre-catalyst which can be used can be any quantity which allows for the formation of the desired product. In one embodiment, the pre-catalyst is present in an amount of about 1.5 mole percent to about 6 mole percent relative to the ortAo-gem-dihalovinylaniline compound used in the reaction.
Ligands for use in the present processes for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof, comprise a phosphorous- containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X- Phos, P(o-tol)3,
Figure imgf000040_0001
PPh3, P(O-CF3-Ph)3, P(JBu)3, BINAP, tol- BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh3, DavePhos, HP(tBu)3 BF4, and
Mes^ \^ Mes
+ cr , and the like, hi one embodiment, the ligand is S-Phos. In another embodiment, the ligand is P(o-tol)3. Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. In other embodiments, no additional ligand is necessary in order for the desired reaction to occur.
The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-substituted indoles, and pyrido and azepino derivatives thereof. In one embodiment, the ligand is present in amount of about 3 mole % to about 12 mole % relative to the ortAo-gem-dihalovinylaniline compound used in the reaction.
In another embodiment of the processes of the present invention for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof. In one embodiment, the base comprises K3PO4-H2O, K3PO4, NEt3, iPr2NH or Cy2NMe. hi one embodiment, the base comprises NEt3/K3PO4.H2O. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3 the details of which as relating to the bases is hereby incorporated herein by reference. Additives for use in the processes of the present invention for the formation of 2- substituted indoles, and pyrido and azepino derivatives thereof are of the type R4NX (R = lower alkyl and X = halogen, OAc) and include nBu4NCl, 11Bu4NOAc, and Me4NCl. The additive has multiple roles according the literature; details are provided in: Jeffery, T. Tetrahedron 1996, 52, 10113.
Any solvent may be used in the processes of the present invention for the formation of 2-substituted indoles, and pyrido and azepino derivatives thereof, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, and the like.
In general, the reagents may be mixed together or added together in any order for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.
The process conditions for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof can be any operable conditions which yield the desired indole product. A preferred temperature for the processes for the production of the indoles of the present invention is about 120 0C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 80 and 14O0C). Typical reaction times are between 3 and 48 hours, although longer or shorter times may be used if necessary.
The 2-substituted indoles, and pyrido and azepino derivatives thereof can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the indole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the desired indoles are provided in a yield greater than 40 %, preferably in a yield of greater than 65 %, more preferably in a yield greater than 75 %. In another embodiment of the present invention, when R2 is benzyl, or a substituted benzyl in the final 2-substituted indole, and pyrido and azepino derivatives thereof, prepared by the processes of the present invention, the process may also include an additional step of cleavage of the optionally substituted N- benzyl group to afford a 2-vinyl indole wherein R2 is H. Methods and reaction conditions for the cleavage of benzyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981, the details of which are incorporated herein by reference.
The present invention also provides novel processes for the preparation of indole compounds, in particular to 2-alkynyl indoles, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors.
In one embodiment, the invention provides a process for the preparation of a compound of Formula (VIII):
Figure imgf000042_0001
wherein
each R1 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(0)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*CONR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR2, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n1 is a whole integer from 1 to 4; and each of Ri and R are unsubstituted or substituted; R2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
the process comprising reacting an ortho-gem-dibromovinylaniline compound of Formula (II)
Figure imgf000043_0001
wherein Ri and R2 are as defined above,
with an alkyne of the Formula (IX)
(IX)
wherein Rs is selected from the group comprising -SiR1R11R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O- Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R**, lower alkyl-CO-OR**, lower alkyl-C(O)NR** 2, lower alkyl-NR"CO-R", lower alkyl-NR**COO-R" wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R** are unsubstituted or substituted;
in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a Ii gand to form the compound of Formula (VIII). In one embodiment, Ra is selected from MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R1, R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R1, R", and R1" is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr .
In another embodiment, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:
Figure imgf000044_0001
In one embodiment, the palladium pre-catalyst used in the processes of the present invention for preparing 2-alkynyl indoles is Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3, Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, PdCl2, Pd(acac), K2PdCl4, Na2PdCl4, Pd/C, Pd(OH)2/C (Pearlman's catalyst), Pd-Al2O3, Pd-BaSO4, Pd-CaCO3, [Pd(allyl)Cl]2, or Pd2(dba)3 HCCl3 but is not limited to these pre-catalysts. Palladium pre- catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre-catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II):
Figure imgf000045_0001
The quantity of palladium pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynylindole product, hi one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ortλo-gew-dihalovinylaniline compound used in the reaction. In another embodiment, the palladium pre-catalyst is Pearlman's catalyst, such as 10% Pd/C Pearlman (50% wetted powder) from Strem (product # 46-1706). Palladium on carbon is an ideal palladium source for industrial processes due to its lower cost, easy recovery, and low level of palladium contamination in the product.
In one embodiment, the copper pre-catalyst used in the processes of the present invention for preparing 2-alkynyl indoles is CuI, Cu(OAc), CuCl, CuBr, or Cu(OTf), but is not limited to these pre-catalysts. Copper pre-catalysts are commercially available, hi one embodiment, the copper pre-catalyst is CuI.
The quantity of copper pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynylindole product. In one embodiment, the pre-catalyst is present in an amount of about 1 mole percent to about 10 mole percent relative to the ort/jo-gem-dihalovinylaniline compound used in the reaction.
Ligands for use in the present processes for the preparation of 2-alkynyl indoles, comprise a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, an alcohol-containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X-Phos, P(o-tol)3, P(σ-tol-p-OMe)3, P(o- MeOPh)3, P(p-MeOPh)3, PPh3, P(O-CF3-Ph)3, P(tBu)3, BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh3, DavePhos, HP(tBu)3 BF4, 1,10-phenanthroline, neocuproine, trans- 1,2-cyclohexyldiamine, cis-\,2- cyclohexyldiamine, ethylenediamine, N-methylethylenediamine, N,N- dimethylethylenediamine, dipivaloylmethane, 2-acetylcyclohexanone, 2- propionylcyclohexanone, 2-isobutyrylcyclohexanone, iV,./V-dimethylsalicylamides, ethylene glycol, ethanolamine,
and
Mes SV^ Mes
+ cr , and the like. Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Pn one embodiment, the ligand is P(/?-MeOPh)3. In another embodiment, the ligand is PPh3.
The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-alkynyl indoles. In one embodiment, the ligand is present in amount of about 4 mole % to about 10 mole % relative to the ortho-gem- dihalovinylaniline compound used in the reaction.
In another embodiment of the processes of the present invention for the preparation of 2-alkynyl indoles, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof. Pn one embodiment, the base comprises K2CO3, K3PO4, NEt3, iPr2NH, iPr2NEt, DABCO or Cy2NMe. In another embodiment, the base is iPr2NH. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3 the details of which as relating to the bases is hereby incorporated herein by reference.
Any solvent may be used in the processes of the present invention for the formation of 2-alkynyl indoles, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, H2O and the like.
In general, the reagents may be mixed together or added together in any order for the preparation of 2-alkynyl indoles. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.
The process conditions for the preparation of 2-alkynyl indoles can be any operable conditions which yield the desired indole product. A preferred temperature for the processes for the production of the 2-alkynyl indoles of the present invention is about 100 0C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 20 and 140°C). Typical reaction times are between 1 and 48 hours, although longer or shorter times may be used if necessary.
The 2-alkynyl indoles can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the indole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the desired indoles are provided in a yield greater than 40 %, preferably in a yield of greater than 65 %, more preferably in a yield greater than 75 %.
In another embodiment of the present invention, when R2 is benzyl, or a substituted benzyl in the final 2-alkynyl indole prepared by the processes of the present invention, the process may also include an additional step of cleavage of the optionally substituted N-benzyl group to afford a 2-alkynyl indole wherein R2 is H. Methods and reaction conditions for the cleavage of benzyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981), the details of which are incorporated herein by reference.
The present invention also provides novel processes for the preparation of benzo[ό]furan compounds, in particular to 2-alkynyl benzo[Z>]furan, which may be optionally substituted at other positions on the benzo[ό]furan ring, compounds prepared by such processes, and their synthetic precursors.
In one embodiment, the invention provides a process for the preparation of a compound Formula (X) :
Figure imgf000048_0001
(X)
wherein
each R^ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(0)NR* 2, -NR*C0-R*, -NR*C00-R*, and -NR*C0NR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of RO and R are unsubstituted or substituted;
and R9 is H or lower alkyl;
the process comprising reacting an ortho-gem-dibromovinylphenol compound of
Formula (XI)
Figure imgf000049_0001
wherein R$ and R9 are as defined above,
with an alkyne of the Formula (IX)
≡^R8 (IX)
Rg is selected from the group comprising -SiR1R11R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R"' is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R**, lower alkyl- CO-OR**, lower alkyl-C(O)NR** 2, lower alkyl-NR**CO-R**, lower alkyl- NR**COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R** are unsubstituted or substituted;
in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a ligand to form the compound of Formula (X). In one embodiment, Ra is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
In another embodiment, the invention provides novel 2-substituted benzo[ό]furan or salts thereof selected from the group consisting of:
Figure imgf000050_0001
In one embodiment, the palladium pre-catalyst used in the processes of the present invention for preparing 2-alkynyl benzo[fr]furans is Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3, Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, PdCl2, Pd(acac), K2PdCl4, Na2PdCl4, Pd/C, Pd(OH)2/C (Pearlman's catalyst), Pd-Al2O3, Pd-BaSO4, Pd-CaCO3, [Pd(allyl)Cl]2, or Pd2(dba)3 HCCl3 but is not limited to these pre-catalysts. Palladium pre-catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre-catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di(μ-acetato)bis[o-(di-σ-tolylphosphino)benzyl]dipalladium (II):
Figure imgf000050_0002
The quantity of palladium pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynyl benzo[ό]furan product. In one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort/zo-gem-dihalovinylphenol compound used in the reaction. In one embodiment, the palladium pre-catalyst is Pearlman's catalyst.
In one embodiment, the copper pre-catalyst used in the processes of the present invention for preparing 2-alkynyl benzo[&]furans is Cu(OAc), CuCl, CuBr, CuI, or Cu(OTf), but is not limited to these pre-catalysts. Copper pre-catalysts are commercially available. In one embodiment, the copper pre-catalyst is CuI.
The quantity of copper pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynyl benzo[Z?]furan product. In one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort/?o-ge/rø-dihalovinylphenol compound used in the reaction.
Ligands for use in the present processes for the preparation of 2-alkynyl benzo[6]furans, comprise a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, alcohol containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X-Phos, P(O-U)I)3, P(o-tol- P-OMQ)3, P(O-MeOPh)3, P(^-MeOPh)3, PPh3, P(O-CF3-Ph)3, P(JBu)3, BINAP, tol- BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh3, DavePhos, HP(tBu)3 BF4, 1,10-phenanthroline, neocuproine, trans- 1,2-cyclohexyldiamine, cώ-l,2-cyclohexyldiamine, ethyl enediamine, N-methylethylenediamine, N,N- dimethylethylenediamine, dipivaloylmethane, 2-acetylcyclohexanone, 2- propionylcyclohexanone, 2-isobutyrylcyclohexanone, N,iV-dimethylsalicylamides, ethylene glycol, ethanolamine,
and Mes -N\^ Mes cr , and the like. In one embodiment, the ligand is P(P-MeOPh)3.
Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. .
The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-alkynyl benzo[ό]furans. hi one embodiment, the ligand is present in amount of about 2 mole % to about 10 mole % relative to the ortho- gem-dihalovinylphenol compound used in the reaction.
In another embodiment of the processes of the present invention for the preparation of 2-alkynyl benzo[Z?]furans, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof. In one embodiment, the base comprises K2CO3, iPr2NEt, DABCO, K3PO4 H2O, K3PO4, NEt3, iPr2NH or Cy2NMe. In one embodiment, the base is iPr2NEt. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3 the details of which as relating to the bases is hereby incorporated herein by reference.
Any solvent may be used in the processes of the present invention for the formation of 2-alkynyl benzo[ό]furans, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, H2O and the like. In one embodiment, toluene is the solvent, hi another embodiment, a mixture of toluene and water is used.
In general, the reagents may be mixed together or added together in any order for the preparation of 2-alkynyl benzo[Z?]furans. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.
The process conditions for the preparation of 2-alkynyl benzo[6]furan can be any operable conditions which yield the desired benzo[6]furan product. A preferred temperature for the processes for the production of the indoles of the present invention is about 100 0C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 20 and 1400C). Typical reaction times are between 1 and 48 hours, although longer or shorter times may be used if necessary.
The 2-alkynyl benzo[ό]furan can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the benzo[&]furan product will vary depending upon the specific pre- catalyst, ligand, base, starting materials and process conditions used. Typically, the desired benzo[b]furan are provided in a yield greater than 50 %, preferably in a yield of greater than 75 %, more preferably in a yield greater than 90 %.
In another embodiment, the invention provides an improved process for the preparation of a compound of the following Formula (XI)
Figure imgf000053_0001
wherein
each R6 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, - C(O)NR* 2, -NR*C0-R*, -NR*COO-R*, and -NR*C0NR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; ORa, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of Rό and R* are unsubstituted or substituted;
comprising reaction of a compound of Formula (XII)
Figure imgf000054_0001
(XII)
wherein R7 is selected from the group consisting of H, or a suitable protective group,
with CBr4 and P(OR)3, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, under reaction conditions effective to form a compound of Formula (XIII)
Figure imgf000054_0002
isolating the compound of Formula (XIII), and deprotection, if needed, of the protective group under conditions effective to yield the compound of Formula (XI). In one embodiment, the protective group is selected from the group comprising a silyl protective group, an ester protective group, and an ether protective group. In another embodiment, the silyl protective group is selected from the group comprising TMS, TBS, TBDPS and TES. In another embodiment, the ester protective group is selected from the group comprising Ac, Piv, and Bz. In yet another embodiment, the ether protective group is selected from the group comprising MOM, Tr and MEM. In another embodiment, the invention provides novel ortλø-gem-dibromovinylphenol compounds or salts thereof selected from the group consisting of:
Figure imgf000055_0001
These derivatives are useful in the preparation of the desired 2-alkynyl benzo[ό]furan compounds.
Presentation of the reaction. We report a highly efficient and modular synthesis of 2- vinyl indoles of Formula (I) from readily available starting material ortho-gem- dibromovinylanilines of Formula (II) via a Pd-catalyzed tandem C-N/C-C coupling with alkenes of Formula (III):
Scheme 27
Figure imgf000055_0002
(H) (D
Optimization of the reaction conditions. The reaction conditions have been optimized using two substrates as shown below by screening different Pd sources, ligands, organic and inorganic bases, additives, reaction time and reaction temperature. Three conditions giving good yields have been found depending on the type of the R2 group (for Heck conditions with quaternary ammonium salt, see: T. Jeffery, Tetrahedron 1996, 52, 10113; T. Jeffery, Tetrahedron 1994, 35, 3051). Procedure A needs longer reaction times but yields, depending on the substrate, are generally better than those obtained with Procedure B. Procedure C is recommended when there is an aryl group on the aniline nitrogen; otherwise, with Procedures A and B, undesired by-products are observed, although the desired reaction products are still obtained. Procedures A and B work if R2 = phenyl (Procedure A, 48% yield with R2 = Ph; Procedure B, 50% yield with R2 = Ph), and Procedure C yields the desired product in 55 % yield when R2 = Bn.
Scheme 28
Figure imgf000056_0001
R2 = Bn or Ph
Procedure A: Pd(OAc)2 (4%), Me4NCl (1 equiv.), NEt3/K3PO4.H2O (2 equiv. each), toluene (0.1 M), 1200C, 4Oh, 79% (R2 = Bn)
Procedure B: Pd(OAc)2 (4%), P-(o-tolyl)3 (8%), NEt3/K3PO4.H2O (2 equiv. each) toluene (0.1 M), 1200C, 15h, 71% (R2 = Bn)
Procedure C: Pd2dba3 (3%), S-Phos (12%), NEt3/K3PO4.H2O (2 equiv. each), toluene (0.1 M), 12O0C, 15h, 78% (R2= Ph)
Proposed mechanism. Without being bound by theory, we propose the following stepwise cyclization catalytic cycle to explain the formation of the product (Scheme 29). It is believed to involve an alkyne formation (for alkyne formation from gem- dibromoalkenes and higher reactivity of trans C-Br bond, see: Zapata, A. J., Ruiz, J. J. Organomet. Chem. 1994, 479 ; Shen, W. ; Wang, L. J. Org. Chem. 1999, 64, 8873 ; Shen, W. Synlett 2000, 737 ; W. Shen, S. Thomas Org. Lett. 2000, 2, 2857) and occurs via an Buchwald-Hartwig animation following by a Heck cross-coupling reaction: Scheme 29
Figure imgf000057_0001
Scope of the reaction. The following Tables 1, 2 and 3 present representative examples illustrating the scope of the new processes of the present invention.
The results of various tandem C-N and C-C bond formation reactions to afford 2-vinyl indoles in good yield using various alkenes of different electronic and steric character and benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine are shown in Table 1 (entries 1-11). The reaction conditions can tolerate a wide variety of alkene reagents, such as vinyl esters, sulfones, nitriles, primary and secondary amides, vinyl ketones, aryl alkenes with neutral, electron-rich or electron-poor substituents, allylic and vinylic alcohols. Table 1
Figure imgf000058_0001
Procedure A: Pd(OAc)2 (4 mol%), Me4NCI, NEt3/K3PO4.H2O, toluene, 12O0C Procedure B: Pd(OAc)2 (4 mol%), P(o-tolyl)3 (8 mol%), NEt3/K3PO4.H2O, toluene, 12O0C
Figure imgf000058_0002
Figure imgf000059_0001
Alkene Heck acceptors commonly known in the literature may be used in the processes of the present invention. Examples of these are given in the following reviews, the contents of which are herein incorporated by reference in this regard: N J. Whitcombe, 5 K.K. Hii, S. E. Gibson, Tetrahedron 2001, 57, 7449; I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009; S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3. Thus, R3 may be selected from the group including but not limited to alkyl; lower alkyl-hydroxy; lower alkyl-O-R-b wherein Rb is a suitable protective group; lower alkenyl; lower
10 haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R**, -C(O)OR**, - C(O)NR** 2, -SO2R", -SO2NR** 2, lower alkyl-CO-R**, lower alkyl-CO-OR**, lower alkyl- C(O)NR** 2, lower alkyl-NR*'CO-R", lower alkyl-NR**COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R3 is -C(O)NR** 2 both R** groups may form a heterocyclic ring with the nitrogen
15 atom; and each Of R3 and R** are unsubstituted or substituted. The effect of substitution on the aniline nitrogen of the ort/zo-gem-dihalovinylaniline starting materials is shown in Table 2 (entry 1-8). The tandem coupling reaction proceeded smoothly to afford the desired product in good to excellent yield with different substitution. Use of the N-benzyl secondary amine (R2 = benzyl) as starting material yielded similar results as the phenyl-substituted amine (R2 = phenyl), and a variety of different substituents on the phenyl group were tolerated (electron-withdrawing and electron-rich groups). Alkyl substitution on the nitrogen atom, whether sterically hindered or not, was also tolerated. The use of the non-protected aniline as starting materials yielded the desired product, but yields were lower under the optimized 0 conditions. The use of electron- withdrawing and activating acetyl protecting groups on the nitrogen group gave no result under optimized conditions.
Table 2
Figure imgf000060_0001
Procedure A: Pd(OAc)2 (4 mol%), Me4NCI, NEt3/K3PO4.H2O, toluene, 1200C Procedure B: Pd(OAc)2 (4 mol%), P(o-tolyl)3 (8 mol%), NEt3/K3PO4.H2O, toluene, 1200C Procedure C: Pd2dba2 (3 mol%), S-Phos (12 mol%), NEt3/K3PO4.H2O, toluene, 1200C
Figure imgf000060_0002
Figure imgf000061_0001
(5.0 mol%) and P(o-tolyl)3 (10.0 mol%).
In Table 3 (entry 1-8), various substituted ort/zø-gem-dibromovinylanilines were reacted with tert-buty\ acrylate under the reaction conditions noted below. This methodology
5 proved to be a very general and efficient method to prepare several functionalized indoles. In general, electronic factors had little effect on yield. This method is compatible with a broad spectrum of electron-donating and electron-withdrawing functionalities. In terms of limitations, yields tend to be poor for 3-substituted indoles.
Table 3
Figure imgf000062_0001
Procedure A: Pd(OAc)2 (4 mol%), Me4NCI, NEt3/K3PO4.H2O, toluene, 12O0C Procedure B: Pd(OAc)2 (4 mol%), P(o-tolyl)3 (8 mol%), NEt3/K3PO4.H2O, toluene, 12O0C
Figure imgf000062_0002
Figure imgf000063_0001
For the above-mentioned processes, it should also be noted that yields are poor when any of Ri, R2, and R3 are iodo-substituted aryl or alkene groups.
5 To summarize, the following novel 2-vinyl indole compounds have been prepared by this new methodology:
Figure imgf000064_0001
The novel and versatile processes of the present invention may be used to synthesize commercially important indole compounds, such as, for example, Fluvastatin, and the potent and selective inhibitor of the osteoclatic Vacuolar H+-ATPase named SB-242782 (Farina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan, M.; Delimoge, I.; Pietro, B.; Zocchetti, A.; James, I.; Zembryki, D. Bioorganic & Medicinal Chemistry Letters 1998, 8, 3621; Visentin, L.; Dodds, R. A.; valente, M.; Misiano, P.; Bradbeer, J. N.; Oneta, S.; Liang, X.; Gowen, M.; Farina, C. Journal of Clinical Investigation 2000, 106, 309; Price, P.A.; June, H. H.; Buckley, J. R.; Williamson, M. K. Circulation Reasearch 2002, 91, 547; Whyteside, G.; Meek, P.J.; Ball, S. K.; Dixon, N.; Finbow, M. E.; Kee, T. P.; Findlay, J.B.C.; Harrison, M. A. Biochemistry 2005, 44, 15024):
Figure imgf000065_0001
It is envisioned that the active compound SB-242782 should be obtained easily in few steps using this new methodology. The major step of this synthesis is as proposed in Scheme 30:
Scheme 30
Figure imgf000065_0002
Description of the Synthesis of ørt/tø-ge/M-dibromovinylanilines
Methods of preparing ortAo-gem-dihalovinylanilines are known to those skilled in the art. For example, see Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907-910 and Topolski, M. J. Org. Chem. 1995, 60, 5588-5594. Additional methods for the preparation of ortho-gem-dibmmovinyl compounds are disclosed in Eymery, F.; Iorga, B, Synthesis, 2000, 185-213.
Another method of preparing orrto-gem-dibromovinylanilines is described in PCT Application Publication Number WO/2006/047888 (International Application No. PCT/CA2005/001703, filed November 4, 2005, published May 11, 2006) to Mark Lautens and Yuanqing Fang entitled "2-Substituted Indoles, their Precursors and Novel Processes for the Preparation Thereof", the contents of which are hereby incorporated by reference in this regard. This method is shown in Scheme 31. Using this method, the ørt/zø-ge/n-dibromovinylaniline is obtained from the olefination of 2-nitrobenzaldehyde by treatment with CBr4/PPh3 (92%) followed by SnCl2-2H2O, or Fe, HOAc, or Fe, FeCl3, HOAc or H2, V-doped Pt/C. However, in the process, at least two equivalents of solid triphenylphosphine are generated as a byproduct. Isolation of the desired product can sometimes be problematic.
Scheme 31
Figure imgf000066_0001
85% 2 steps one pot
The new improved process of the present invention comprises reaction of 2- nitrobenzaldehydes using trialkyl- or triphenylphosphite, which is more readily available and less expensive. Additionally, the product ortλo-gem-dibromovinylnitrobenzenes can be easily isolated from liquid trialkyl- or triphenylphosphate byproduct.
Among various phosphites tested (Table 4), triisopropyl phosphite was found to be optimal, giving 92% isolated yield. The product or/Ao-gem-dibromovinylnitrobenzene (Compound "A" in the reaction scheme shown in Table 4) can be isolated from the reaction mixture either by recrystallization from hexanes or treatment of HOAc/HCl to hydrolyze trialkyl- or triphenylphosphate byproducts into phosphoric acid and isopropanol, which can be easily removed under basic workup procedure (Scheme 32). No chromatographic purification is needed.
Table 4
(3 eq.)
Figure imgf000067_0002
Figure imgf000067_0001
Figure imgf000067_0004
Scheme 32
Figure imgf000067_0003
(VII) (VII) Reduction of or^o-gem-dibromovinylnitrobenzene using SnCl2-2H2O; or Fe, HOAc; or Fe, FeCl3, HOAc; or H2, V-doped Pt/C will result in the desired ortho-gem- dibromovinylaniline.
Several new ort/jø-gem-dibromovinylanilines presenting a substituent on the nitrogen of the aniline have been prepared according following schemes. The alkylation step of different or^o-gem-dibromovinylanilines has been accomplished by reductive amination with different aldehydes or by alkylation with benzyl bromide.
Scheme 33
Figure imgf000068_0001
1c 42%
Scheme 34
Figure imgf000068_0002
1f 40% Scheme 35
Figure imgf000069_0001
1b
Scheme 36
Figure imgf000069_0002
To summarize, the following novel orώo-gem-dibromovinylanilines have been prepared as described above and in the Examples:
Figure imgf000070_0001
An intramolecular version: introduction. An intramolecular version of the processes of the invention has also been developed to provide pyrido and azepino indole structures of Formula (IV)/(IV)'. These processes involve a Pd-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction from readily accessible and appropriately functionalized ortAo-gew-dibromovinylanilines of Formula (V).
Figure imgf000070_0002
In the above-referenced formulas (IV)/(IV)' and (V), n can be between 0 and 3 to make five to eight membered rings. Intramolecular Heck reactions are described in S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 6.
Optimization. The substrate 3a shown below has been used to optimize the reaction conditions by screening different Pd sources, ligands, organic and inorganic bases, additives, reaction times and reaction temperatures. It appears that the optimal conditions are Pd2dba3 (4 mol%), «Bu4NCl (1 equiv.), NEt3/K3PO4.H2O (2 equiv. of each), toluene, 1200C, 15h The pyrido indole 4 is obtained as an easily separable mixture of 4a and 4a' with 76% (4a/4a': 3/1; Scheme 38).
Scheme 38
Figure imgf000071_0001
Scope of the reaction. The versatility of the reaction is illustrated by the results shown in Table 5 (entry 1-5). Substituents on the aromatic ring having different electronic properties have been used with success (entries 1-3) and the reaction also proceeds with a non-activated alkene (entry 4). Moreover, seven membered rings fused with the indole 10 moiety have been produced easily using this new methodology (entry 5).
Table 5
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000072_0001
To summarize, the following novel pyrido and azepino indoles have been prepared as described above and in the Examples:
Figure imgf000073_0001
Preparation of starting materials for pyrido and azepino indoles synthesis. The starting materials needed for the above-mentioned reactions were prepared in one step from ort/zo-gem-dibromovinylaniline and aldehydes containing the alkene unit (easily prepared in two or three steps (S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284) or commercially available) by a reductive amination procedure (Richard C. Larock, in Comprehensive Organic Transformation, Wiley VCH, New York, copyright 1999; Reddy, TJ. et al. Synlett 2005, 583; Abdel-Magid, A. F. et al J. Org. Chem. 1996, 61, 3849; Bomann, M.D. et al. J. Org. Chem. 1995, 60, 5995). Table 6 presents the details of the synthesis of these precursors.
Table 6
Figure imgf000074_0001
Figure imgf000074_0002
To summarize, the following compounds have been prepared using the procedures described above and in the Examples:
Figure imgf000075_0001
Presentation of the reaction. We also report a highly efficient and modular synthesis of 2-alkynyl indoles of Formula (VIII) from readily available starting material ortho-gem- dibromovinylanilines of Formula (II) via a Pd-catalyzed tandem C-N/C-C coupling with alkynes of Formula (IX):
Scheme 39
Figure imgf000075_0002
Optimization of the reaction conditions. The reaction conditions have been optimized using [2-(2,2-dibromovinyl)phenyl]-amine and oct-1-yne as shown below by screening different Pd sources, different copper sources, ligands, organic and inorganic bases, solvents, reaction time and reaction temperature. In general, it was found that monodentate triarylphosphines were more effective than electron-rich and sterically hindered phosphines such as S-Phos, P(^Bu)3, or bidentate ligands such as dppf. It was revealed that subjecting the two substrates to the reaction conditions using Pearlman's catalyst, CuI, P(MeOPh)3 and iPr2NH in toluene at 100 0C. (Procedure A) or using Pd-C, CuI, PPh3 and iPr2NH in toluene at 100 0C . gave good yields of the product (Procedure B). It was also found that adding water as the co-solvent under Procedure A could reduce the Pd-catalyst loading down to 0.1 mol %, even though a longer reaction time was needed (Procedure C). Scheme 40
base
Figure imgf000076_0001
.
Figure imgf000076_0002
Procedure A: Pearlman's catalyst (2 mol%), CuI (4 mol%), P(MeOPh)3 (8 mol%), iPr2NH (2.5 equiv.), toluene (0.17 M), 1000C, 1.5h, 83% Procedure B: Pd-C (5 mol%), CuI (5 mol%), PPh3 (11 mol%), iPr2NH (2.5 equiv.), toluene (0.17 M), 1000C, Ih, 92%
Procedure C: Pd-C (0.1 mol%), CuI (2 mol%), P(MeOPh)3 (4 mol%), iPr2NH (2.5 equiv.), toluene-H2O (2:1, 0.17 M), 1000C, 36h, 82%
Proposed mechanism. We propose the following catalytic cycle to explain the formation of the product (Scheme 41). It is believed to involve an initial indole formation followed by typical Sonogashira coupling between the resulting 2-bromoindole and an alkyne:
Scheme 41
Figure imgf000076_0003
This reaction mechanism is supported by the following experiments. When the tandem C- N/Sonogashira reaction was performed in the presence of a catalytic amount of CuI(PPh3 )2 in the absence of Pd-C using HNzPr2 as the base, no desired product was observed. However, a significant amount of 2-bromoindole was observed, presumably formed via an intramolecular Ullman reaction (Ullmann, F. Chem. Ber. 1903, 36, 2382). When the reaction was performed in the presence of Pd/C and PPh3 without CuI, only the starting material was recovered.
Scope of the reaction. The following Tables 7, 8 and 9 present representative examples illustrating the scope of the new processes of the present invention.
10 The results of various tandem C-N and C-C bond formation reactions to afford 2-alkynyl indoles in good yield using various alkenes of different electronic and steric character and [2-(2,2-dibromovinyl)phenyl] -amine are shown in Table 7 (entries 1-9). A wide variety of alkyne reagents, such as alcohol containing alkynes, chloro containing alkynes, nitrile containg alkynes, pyridine containing alkynes can tolerate the reaction conditions.
15 Table 7
Figure imgf000077_0001
Procedure A: Pearlman's catalyst (2 mol%), CuI (4 mol%), P(MeOPh)3 (8 mol%), iPr2NH (2.5 equiv.), toluene (0.17 M), 1000C
Procedure B: Pd-C (5 mol%), CuI (5 mol%), PPh3 (1 1 mol%), iPr2NH (2.5 equiv.), 20 toluene (0.17 M), 1000C
Figure imgf000077_0002
Figure imgf000078_0001
Alkyne units in the Sonogashira coupling reaction commonly known in the literature may be used in the processes of the present invention. Examples of these are given in the following reviews, the contents of which are herein incorporated by reference in this regard: K. Sonogashira, S. Takahashi, Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053; K. Sonogashira. Handbook of Organopalladium Chemistry for Organic Synthesis (Ed: E. Negishi), Wiley, Hoboken, 2002, Chap. 1, 493-529. Thus, R8 maybe selected from the group including but not limited to, -SiR1R11R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl- nitrile; lower alkyl-CO-R**, lower alkyl-CO-OR", lower alkyl-C(O)NR** 2, lower alkyl- NR**CO-R**, lower alkyl-NR**COO-R" wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R** are unsubstituted or substituted.
The effect of substitution on the aniline nitrogen of the or/Λo-gem-dihalovinylaniline starting materials is shown in Table 8 (entry 1-4). The tandem coupling reaction proceeded smoothly to afford the desired product in good yield with different substitution. Use of the N-substituted secondary amine as starting material yielded poorer
10 results as compared with non-substituted aniline under the optimized conditions and higher catalyst loadings both of palladium and copper sources were required to complete the conversion of starting materials.
Table 8
Figure imgf000079_0001
Procedure A
Figure imgf000079_0003
Figure imgf000079_0002
15 Procedure A: Pearlman's catalyst, CuI, P(MeOPh)3 , iPr2NH (2.5 equiv.), toluene (0.17 M), 100°C for 24h
Figure imgf000079_0004
Figure imgf000080_0001
In Table 9 (entry 1-4), various substituted ortho-gem -dibromovinylanilines were reacted with oct-1-yne under the reaction conditions noted below. This methodology proved to be a very general and efficient method to prepare several functionalized indoles. In general, substrates with electron-withdrawing substituents tend to show low reactivities to the tandem coupling reactions and higher catalyst loadings are required to obtain higher yields of the products. However, this method is still compatible with a broad spectrum of electron-donating and electron-withdrawing functionalities. In terms of limitations, the optimized conditions fail to give 3 -substituted indoles.
Table 9
F
Figure imgf000081_0001
Procedure A: Pearlman's catalyst, CuI, P(MeOPh)3, iPr2NH (2.5 equiv.), toluene (0.17 M), 1000C for 12h
Figure imgf000081_0002
To summarize, the following novel 2-alkynyl indole compounds have been prepared by this new methodology:
Figure imgf000082_0001
Presentation of the reaction. We also report a highly efficient and modular synthesis of 2-alkynyl benzo[6]furan of Formula (X) from readily available starting material ortho- gem-dibromovinylphenols of Formula (XI) via a Pd-catalyzed tandem C-N/C-C coupling with alkynes of Formula (IX):
Scheme 42
Figure imgf000082_0002
Optimization of the reaction conditions. The reaction conditions have been optimized using 2-(2,2-dibromovinyl)-phenol and oct-1-yne or ethynylbenzene as shown below by screening different Pd sources, different copper sources, ligands, organic and inorganic bases, solvents, reaction time and reaction temperature. Two conditions giving good yields have been found depending on the type of the R8 group. Procedure A generally gives better yields of the products than those obtained with Procedure B. However when using the aryl substituted acetylenes or trimethylsilylacetylene as the terminal alkynes, Procedure B gives the products in much better yield. It is thought that the positive effect of water may be due to its ability to remove bromide from the organic phase. A control experiment, in which an external source of bromide (Bu4NBr) was found to inhibit the reaction progress, lends support to this proposal.
Scheme 43
Figure imgf000083_0001
Procedure A: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh)3 (4 mol%), iPr2NH (2.5 equiv.), toluene-H2O (2:1, 0.17 M), 1000C, 12h, 80%
Figure imgf000083_0002
Procedure B: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh)3 (4 mol%), iPr2NH (2.5 equiv.), toluene (0.17 M), 1000C, 12h, 71%
Proposed mechanism. We propose the following catalytic cycle to explain the formation of the product the same as the 2-alkynyl indole cases (Scheme 44). It is believed to involve an initial benzo[6]furan formation followed by typical Sonogashira coupling between the resulting 2-bromobenzo[6]furan and an alkyne: Scheme 44
Figure imgf000084_0001
(X)
Figure imgf000084_0002
Scope of the reaction. The following Tables 10 and 11 present representative examples illustrating the scope of the new processes of the present invention. The results of various tandem C-O and C-C bond formation reactions to afford 2-alkynyl benzo[ό]furans in good yields using various alkenes of different electronic and steric character and 2-(2,2- dibromovinyl)-phenol are shown in Table 10 (entries 1-9). A wide variety of alkyne reagents, such as alcohol containing alkynes, phenol containing alkynes, chloro containing alkynes, nitrile containing alkynes, pyridine containing alkynes can tolerate the reaction conditions.
Table 10
Figure imgf000085_0001
Procedure A: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh)3 (4 mol%), iPr2NH (2.5 equiv.), toluene-H2O (2:1, 0.17 M), 1000C, 12h
10 Procedure B: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh)3 (4 mol%), iPr2NH (2.5 equiv.), toluene (0.17 M), 1000C, 12h
Figure imgf000085_0002
Figure imgf000086_0001
Alkyne units in the Sonogashira coupling reaction commonly known in the literature may be used in the processes of the present invention. Examples of these are given in the following reviews, the contents of which are herein incorporated by reference in this regard: K. Sonogashira, S. Takahashi, Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053; K. Sonogashira. Handbook of Organopalladium Chemistry for Organic Synthesis (Ed: E. Negishi), Wiley, Hoboken, 2002, Chap. 1, 493-529. Thus, R8 is selected from the group including, but not limited to, -SiR1R11R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl- nitrile; lower alkyl-CO-R**, lower alkyl-CO-OR", lower alkyl-C(O)NR** 2, lower alkyl- NR**CO-R", lower alkyl-NR"COO-R** wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R8 and R" are unsubstituted or substituted.
The effect of substitution on the phenyl ring of the ort/zo-gem-dihalovinylphenol starting materials is shown in Table 11 (entry 1-4). The tandem coupling reaction using oct-1-yne proceeded smoothly to afford the desired product in good to excellent yields. This methodology proved to be a very general and efficient method to prepare several functionalized benzo[ό]furans. In general, electronic factors had little effect on yields. This method is compatible with a broad spectrum of electron-donating and electron- withdrawing functionalities. However, in the case of the substrate with the ortho methoxy group, a higher catalyst loading and a longer reaction time are required for the complete conversion, probably due to the coordination of 6-methoxy group to the copper which deactivate the catalytic system.
Table 11
Figure imgf000087_0001
Procedure A: Pearlman's catalyst, CuI, P(MeOPh)3, 1Pr2NH (2.5 equiv.), toluene-H2O (2:1, 0.17 M), 1000C, 12h
Figure imgf000087_0002
Figure imgf000088_0001
reaction time was 64 h.
To summarize, the following novel 2-alkynyl benzo[6]furan compounds have been prepared by this new methodology:
Figure imgf000088_0002
Description of the starting material synthesis used for the 2-alkynyl benzo[b]furans synthesis.
A typical method of preparing ort/zø-gem-dibromovinylphenols used in the processes of 10 invention is shown in Scheme 45. The ort/zo-gem-dibromophenol is obtained from silylation of 2-hydroxybenzaldehyde by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate and 2,6-lutidine followed by olefination of the aldehyde functionality using CBr4ZPPh3 and subsequent removal of TBS group with TBAF.
Scheme 45
Figure imgf000089_0001
Several new ort/zo-gem-dibromovinylphenol possessing a substituent on the phenyl ring have been prepared according following schemes.
Scheme 46
Figure imgf000089_0002
Scheme 47
Figure imgf000089_0003
7b Scheme 48
Figure imgf000090_0001
Scheme 49
Figure imgf000090_0002
7d
To summarize, the following novel ortho-gem-dibromovinylphenols have been prepared as describe above and in the Examples:
Figure imgf000090_0003
Examples
General Procedures: All reactions were carried out under N2. Solvents and solutions were added with a syringe, unless otherwise noted. Analytical TLC was performed using EM separations precoated silica gel 0.2 mm layer UV fluorescent sheets. Column chromatography was carried out as "flash chromatography" as reported by Still using Merck 60 (230-400 mesh) silica gel (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-5). Unless otherwise specified, extracts were dried over MgSO4 and solvents were removed with a rotary evaporator at aspirator pressure.
Toluene was distilled under N2 from Na/benzophenone, dichloromethane was distilled from automatic distillation (SPS system) and 1,2-dichloroethane was distilled from CaH2 immediately prior to use. EtOH and DMF were purchased from Aldrich and were used without further distillation. S-Phos was purchased from Strem Chemical Company, and other pre-catalysts or reagents were obtained from commercial sources without further purification. 10% Pd-C Pearlman's catalyst was purchased from Strem (Palladium, 10% on activated carbon, Pearlman (50% wetted powder), Strem # 46-1706), which was originally produced by Degussa (Degussa E4, lot No. 20058613).
Melting points were taken on a Fisher- Johns melting point apparatus without correction. IR spectra were obtained using Nicolet DX FT IR spectrometer as a chloroform solution with NaCl cellule. High-resolution mass spectra were obtained from a VG 70-250S (double focusing) mass spectrometer at 70 eV. 1H, 13C, and 19F NMR spectra were obtained using Varian Mercury 400 or Mercury 300 spectrometers. Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; quint., quintuplet; sext, sextuplet; sept., septuplet; m, multiplet and br, broad peak. 1H spectra were referenced to tetramethylsilane (TMS, 0 ppm) using CDCl3 as solvent; 13C spectra were referenced to solvent carbons (77.0 ppm for CDCl3).
In the examples which follow, PCT Application Publication Number WO/2006/047888 is referenced for the preparation of certain compounds (International Application No. PCT/CA2005/001703, filed November 4, 2005, published May 11, 2006, to Mark Lautens and Yuanqing Fang entitled "2-Substituted Indoles, their Precursors and Novel Processes for the Preparation Thereof), the contents of which are hereby incorporated by reference in this regard.
Preparation of ort/to-gg/«-dibromovinylaniline compounds of Formula (II)
General optimization process for the preparation of ortho-gem- dibromovinylnitrobenzenes :
To a solution of o-nitrobenzaldehyde (0.151 g, 1 mmol) and CBr4 (0.49 g, 1.5 mmol) in DCM (4 mL) was added dropwise a solution of corresponding phosphine or phosphite (3.0 mmol) in DCM (1 mL) at 0 0C. After 30 min, the reaction was warmed to rt, quenched with NaHCO3, extracted with Et2O, dried over MgSO4. The product was isolated using column chromatography and yields are shown in Table 4 above. The 1H NMR spectrum of the product was identical to the authentic sample.
Example A: Synthesis of l-(2,2-dibromo-vinyl)-2-nitro-benzene with non- chromatographic purification:
Figure imgf000092_0001
To a solution of o-nitrobenzaldehyde (2.0 g, 13.2 mmol) and CBr4 (6.6 g, 19.9 mmol) in dichloromethane (DCM) (50 mL) was added dropwise a solution of corresponding triisopropylphosphite (7.2 mL, 29 mmol) in DCM (10 mL) at 0 0C. After 30 min, the reaction was warmed to rt, quenched with NaHCO3, extracted with Et2O. After removal of solvent, the mixture was taken into concentrated HCl (12 N, 15 mL) and HOAc (15 mL) and refluxed overnight. The mixture was cooled to rt, diluted with H2O (50 mL), neutralized by Na2CO3, extracted with Et2O. After dried over MgSO4, the solvent was removed in vacuum to give an off-white solid (3.51 g, 87%). The 1H NMR showed the product was analytically pure and identical to the authentic sample.
Example Ia: Preparation of Butyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine
Figure imgf000092_0002
2-(2,2-dibromo-vinyl)phenylamine (600.0 mg, 2.166 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and butyraldehyde (195.0 μL, 2.166 mmol) were mixed in 1 ,2-dichloroethane (8.0 mL, 0.28 M) and then treated with sodium triacetoxyborohydride (640.0 mg, 3.031 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 h. The reaction mixture was then quenched by addition of aqueous saturated NaHCO3, and the product was extract with EtOAc. The organic phase was dried (Na2SO4) and the solvent was evaporated to give the crude product. The mixture was purified by flash chromatography (30/l:hexanes/EtOAc) to afford a yellow solid (0.66 g, 92 %). mp 34-36 0C; IR (CHCl3) v 3423, 2960, 2932, 1602, 1578, 1506, 1456, 1319 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.26-7.20 (m, 3H), 6.69 (t, J= 7.5 Hz, IH), 6.63 (d, J= 8.3 Hz, IH), 3.52 (br, IH), 3.12 (t, J= 7.1 Hz, 2H), 1.63 (quint., J= 7.4 Hz, 2H), 1.43 (sext, J= 7.4 Hz, 2H), 0.96 (t, J= 7.3Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.2, 134.1, 129.8, 129.1, 121.3, 116.4, 110.6, 92.9, 43.5, 31.5, 20.3, 13.9; MS (EI) m/z 330.8 [79Br79BrM]+, 332.8 [79Br81BrM]+, 334.8 [81Br81BrM]+, 251.9 [79Br81BrM-81Br]+; HRMS (EI) m/z calcd. for: [79Br79BrM]+ 330.9571, m/z found: 330.9577.
Example Ib: Preparation of [2-(2,2-Dibromo-vinyl)-phenyl]-isopropyl-amine
Figure imgf000093_0001
1b
To a solution of 2-(2,2-dibromo-vinyl)phenylamine (0.554 g, 2.0 mmol) in DCE (6.0 mL) was sequentially added vinyl methyl ether (287.0 μL, 2.0 mmol), acetic acid (114.0 μL) and NaBH(O AC)3 (0.636 g) in one portion. The mixture was stirred at room temperature for 20 h. The mixture was quenched by pouring into NaHCO3 solution, extract with DCM and dried over Na2SO4. The mixture was purified by flash chromatography (5 % EtOAc in hexanes). Yield: 100 %, white solid, 1H NMR (400 MHz, CDCl3) δ 7.26-7.19 (m, 3H), 6.71-6.42 (m, 2H), 3.65 (m, IH), 3.38 (br, IH), 1.23 (d, 6H).
Example Ic: Preparation of (2-Bromo-benzyl)-[2-(2,2-dibromo-vinyl)-phenyl]-amine
Figure imgf000094_0001
Following the same procedure as for Ia with 2-(2,2-dibromo-vinyl)phenylamine (see
PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-bromobenzaldehyde. Yield: 42 %, yellow solid, mp 144-146 0C; IR (CHCl3) v 3443, 1603, 1458, 1321 cm'1; 1H NMR (400 MHz, CDCl3) δ 7.59-7.48 (m,
IH), 7.35 (m, 2H), 7.28-7.23 (m, 2H), 7.18-7.15 (m, 2H), 6.75 (t, J= 7.4 Hz, IH), 6.53 (d,
J= 8.2 Hz, IH), 4.45 (s, 2H), 4.18 (br, IH); 13C NMR (100 MHz, CDCl3) δ 144.4, 137.6,
134.0, 132.8, 129.8, 129.2, 128.9, 128.7, 127.6, 123.2, 121.9, 117.4, 111.3, 93.7, 48.3;
MS (EI) m/z 442.9 [M]+, 444.9 [M]+, 446.9 [M]+, 448.9 [M]+, 365.9 [M-81Br]+; HRMS (EI) m/z calcd. for: [M]+ 442.8510, m/z found: 442.8519.
Example Id: Preparation of 3-BenzyIamino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester
Figure imgf000094_0002
1d
Following the same procedure as for Ia with 3-amino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzaldehyde. Yield: 66 %, yellow oil; IR (CHCl3) v 3441, 2952, 2846, 1717, 1571, 1438, 1299, 1265, 1201 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 9H), 4.77 (s, 2H), 4.00 (br, IH), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.0, 144.8, 138.3, 133.2, 131.2, 129.2, 128.7 (2C), 127.6 (2C), 127.5, 125.8, 118.3, 111.8, 94.7, 52.1, 48.0; MS (EI) m/z 425.0 [79Br81BrM]+; HRMS (EI) m/z calcd. for: [79Br79BrM]+ 422.9469, m/z found: 422.9469.
Example Ie: Preparation of Benzyl-[2-(2,2-dibromo-vinyl)-5-fluoro-phenyl]-amine
Figure imgf000095_0001
1e
Following the same procedure as for Ia with 2-(2,2-dibromo-vinyl)-5-fluoro- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzaldehyde. Yield: 43 %, white solid, mp 94-95 0C; IR (CHCl3) v 3440, 3035, 3011, 1613, 1590, 1514, 1202 cm'1; 1H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 4H), 7.22-6.27 (m, 3H), 6.40 (td, J= 8.3, 2.4 Hz, IH), 6.29 (dd, J = 11.5, 2.4 Hz, IH), 4.32 (d, J= 5.5 Hz, 2H), 4.12 (br, IH); 13C NMR (400 MHz, CDCl3) δ 164.1 (JCF= 245.7 Hz), 146.6 {JCF= 11.1 Hz), 138.1, 133.1, 130.6 (JCF= 10.4 HZ), 128.8 (2C), 127.5, 127.3 (2C), 117.4 (JCF= 2.7 Hz), 103.7 (JCF= 22.2 Hz), 98.3 (JCf= 26.5 Hz), 93.9, 48.0; MS (EI) m/z 385.0 [M]+; HRMS (EI) m/z calcd. for: [M]+ 382.9320, m/z found: 382.9322.
Example If: Preparation of BenzyI-[4-benzyloxy-2-(2,2-dibromo-vinyl)-phenyl]- amine
Figure imgf000095_0002
1f
Following the same procedure as for Ia with 2-(2,2-dibromo-vinyl)-4-phenoxy- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzaldehyde. Yield: 40 %, orange oil; 1H NMR (300
MHz, CDCl3) δ 7.42-7.35 (m, 6H), 7.31-7.24 (m, 5H), 7.00 (d, J= 2.9 Hz, IH), 6.87 (ddJ = 2.9, 8.9 Hz, IH), 6.58 (d, J= 8.9 Hz, IH), 4.99 (s, 2H), 4.32 (s, 2H), 3.72 (br, IH); 13C NMR (75 MHz, CDCl3) δ 150.6, 139.5, 139.1, 137.3, 133.7, 128.6 (2C), 128.5 (2C), 127.8, 127.4 (2C), 127.3 (2C), 127.2, 122.6, 117.0,, 116.0, 112.6, 93.1, 70.9, 48.8; MS (EI) m/z 473.1 [79Br81BrM]+; HRMS (EI) m/z calcd. for: [79Br79BrM]+ 470.9822, m/z found: 470.9833.
Example Ig: Benzyl-[3-benzyloxy-2-(2,2-dibromo-vinyl)-4-methoxy-phenyl]-amine
Figure imgf000096_0001
ig
Following the same procedure as for Ii with 2-(2,2-dibromo-vinyl)-4-methoxy-3- phenoxy-phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzyl bromide. Yield: 77 %, brown oil; IR (CHCl3) v 3443, 3044, 1580, 1439 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.46-7.24 (m, 11 H), 7.13 (s, IH), 6.83 (d, J= 8.8 z, IH), 6.31 (d, J= 8.8 Hz, IH), 4.99 (s, 2H), 4.33 (s, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.8, 144.7, 139.6, 139.4, 137.6, 132.5, 128.6 (2C), 128.4 (2C), 128.3 (2C), 127.9, 127.2 (2C), 127.1, 117.6, 114.8, 106.3, 95.2, 75.0, 56.7, 48.7; MS (EI) m/z 500.7 [79Br79BrM]+, 502.7 [79Br81BrM]+, 504.7 [81Br81BrM]+; HRMS (EI) m/z calcd. for: [79Br79BrM]+ 500.9939, m/z found: 500.9924.
Example Ih: Preparation of Benzyl-[2-(2,2-dibromo-vinyl)-3-methyl-phenyl]-amine
Figure imgf000096_0002
Following the same procedure as for Ii with 2-(2,2-dibromo-vinyl)-3-methyl- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzyl bromide. Yield: 71 %, white solid, mp 44-46
0C; IR (CHCl3) v 3444, 3065, 3004, 2921, 1582, 1496, 1471, 1452, 1322 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 6H), 7.07 (t, J= 7.8 Hz, IH), 6.57 (d, J= 7.5 Hz, IH), 6.43 (d, J= 8.2 Hz, IH), 4.37 (s, 2H), 4.14 (br, IH), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 139.2, 136.4, 134.8, 129.2, 128.6 (2C), 127.1, 127.0 (2C), 121.4, 118.8, 108.3, 95.3, 48.0, 20.0; MS (EI) m/z 379.1 [79Br79BrM]+, 381.1 [79Br81BrM]+, 383.1 [81Br81BrM]+, 300.0 [M-81Br]+; HRMS (ESI) m/z calcd. for: [79Br79BrM+H]+ 379.9643, m/z found: 379.9640.
Example Ii: Preparation of Benzyl-[2-(2,2-dibromo-vinyl)-naphthalen-l-yl]-amine
Figure imgf000097_0001
To a suspension of the 2-(2,2-dibromo-vinyl)-naphthalen-l-ylamine (200.0 mg, 0.615 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and K2CO3 (102.0 mg, 0.738 mmol) in DMF (2.0 ml) was added benzyl bromide (90.0 μL, 0.738 mmol). The mixture was stirred at room temperature for 48 h under nitrogen. Then mixture was diluted with Et2O, washed with
H2O, brine. The mixture was purified by flash chromatography (2 % EtOAc in hexanes) to afford an orange oil (151.0 mg, 59 %). IR (CHCl3) v 3445, 3064, 3002, 1567, 1511,
1453, 1391 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J= 8.3 Hz, IH), 7.78 (d, J= 9.3
Hz, IH), 7.55-7.41 (m, 5H), 7.34-7.28 (m, 5H), 4.34 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 142.9, 139.9, 136.1, 134.4, 128.7 (2C), 128.6, 127.9 (2C), 127.7, 127.6, 126.6,
126.5, 125.9, 123.8, 122.2, 122.0, 91.4, 54.9; MS (EI) m/z 414.8 [79Br79BrM]+, 416.8 [79Br81BrM]+, 418.8 [81Br81BrM]+; HRMS (EI) m/z calcd. for: [79Br79BrM]+ 414.9571, m/z found: 141.9587.
Example Ij: Preparation of 2-(2,2-Dibromo-vinyl)-6-methoxy-phenylamine
Figure imgf000098_0001
To a solution of the 3-methoxy-2-nitrobenzaldehyde (1.087 g, 6.0 mmol) and carbon tetrabromide (2.985 g, 9.0 mmol) in CH2Cl2 (30.0 niL) at 0 0C was added dropwise a solution of triphenylphosphine (4.721 g, 18.0 mmol) in CH2Cl2 (20.0 mL). After the addition was complete, the reaction was stirred at 0 0C for 0.5 h then warmed to rt and stirred for another hour. The solvent was removed in vacuo and the crude material purified using chromatography eluting with 20% EtOAc/hexane to give a yellow solid (1.866 g, 5.5 mmol). Yield: 92 %, yellow solid, mp 98-99 0C; IR (neat) v 1602, 1514, 1289, 1069 cm"1; 1H NMR (400 MHz, CDCl3) δ .46 (IH, t, J 8.1), 7.39 (IH, s), 7.22 (IH, d, J 7.9), 7.06 (IH, d, J 8.6), 3.93 (3H, s); 13C NMR (100 MHz, CDCl3) δ 151.3, 131.3, 130.7, 129.9, 121.4, 113.0, 96.2, 56.8; HRMS (EI) m/z calcd. for: [M]+ 334.8793, m/z found: 334.8792. The substrate (1.80 g, 5.3 mmol) and acetic acid (1.6 mL) in EtOH (16.0 mL) were warmed to 40 0C, then Fe (2.07 g, 37.1 mmol) and FeCl3-OH2O (143.0 mg, 0.53 mmol) added to it. After 3.5 h, tic showed incomplete reaction, therefore another 0.10 mL of acetic acid was added to the reaction. After an additional 0.5 h the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The solvent was removed in vacuo to yield the pure product as an off-white solid (1.524 g, 4.9 mmol). Yield: 93 %, white solid, mp 0C; IR (CHCl3) v 3333, 2942, 1619, 1463, 1241 cm" '; 1H NMR (400 MHz, CDCl3) δ 7.37 (IH, s), 6.99-6.94 (IH, m), 6.82-6.71 (2H, m), 3.91 (2H, br s), 3.87 (3H, s); 13C NMR (100 MHz, CDCl3) δ 147.5, 134.1 (2C), 121.8, 121.1, 117.7, 110.2, 92.8, 55.8; HRMS (EI) m/z calcd. for: [M]+ 304.9051, m/z found: 304.9051.
Preparation of 2-vinyl indoles of Formula (D
The results of the preparation of various 2-substituted indoles of Tables 1, 2 and 3 above are shown in Examples 2a-2aa below. General Procedures A, B and C for intermolecular palladium-catalyzed tandem reactions using an alkene reagent
A tube (24x150 mm) of Carousel reaction station was charged with ortho-gem- dibromovinylaniline (1.0 equiv.), powdered K3PO4-H2O (2.0 equiv.) and Procedure A: Pd(OAc)2 (4.0 mol %), Me4NCl (1.0 equiv.) or Procedure B: Pd(OAc)2 (4.0 mol %), P(σ-tolyl)3 (8.0 mol %) or Procedure C: Pd2dba3 (3.0 mol %), S-Phos (12.0 mol %) and the mixture was purged with argon and vacuum three times. Triethylamine (2.0 equiv.), alkene (2.0 equiv.) and toluene (0.1M) were added and the reaction stirred at 1200C until all the starting material had been consumed (typically 15-96 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na2SO4) and the solvent was evaporated. The crude product was purified by flash chromatography (typically 2% EtOAc in hexanes) to afford the indole 2.
Example 2a: Preparation of 3-(l-Benzyl-lH-indol-2-yl)-acrylic acid tert-butyl ester
Figure imgf000099_0001
2a
Following General Procedure A. A tube (24><150 mm) of carousel reaction station was charged with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) (200.0 g, 0.545 mmol), powdered K3PO4-H2O (250.0 mg, 1.089 mmol), Pd(OAc)2 (4.9 mg, 0.022 mmol, 4.0 mol %), Me4NCl (60.0 mg, 0.545 mmol) and the mixture was purged with argon and vacuum three times. Triethylamine (151.0 μL, 1.089 mmol), tertbutyϊ acrylate (160.0 μL, 1.089 mmol) and toluene (5.5 mL, 0.1M) were added and the reaction stirred at 1200C until all the starting material had been consumed (15 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na2SO4) and the solvent was evaporated. The crude product was purified by flash chromatography (2 % EtOAc in hexanes) to afford 2a. Yield: 79 %, yellow solid, mp 84-86 0C; IR (CHCl3) v 3015, 2981, 1698, 1629, 1453, 1347, 1369, 1314, 1288, 1147 cm'1; 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J= 15.7 Hz, IH), 7.64 (d, J= 7.8 Hz, IH), 7.29-7.25 (m, 5H), 7.23 (t, J= 6.8 Hz, IH), 7.13 (t, J= 6.8 Hz, IH), 7.05-7.02 (m, 2H), 6.41 (d, J= 15.7 Hz, IH), 5.46 (s, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.1, 138.7, 137.2, 135.1, 131.5, 128.8 (2C), 127.7, 127.5, 126.0 (2C), 123.6, 121.3, 120.7, 120.6, 110.0, 103.6, 80.5, 46.7, 28.2 (3C); MS (EI) m/z 333.2 [M]+, 232.1 [M-CO2^Bu]+; HRMS (EI) m/z calcd.for: [M]+ 333.1728, m/z found: 333.1731.
Example 2b: Preparation of l-Benzyl-2-styryl-lH-indole
Figure imgf000100_0001
2b
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and styrene. Yield: 65 %, yellow solid, mp 98-101 0C; IR (CHCl3) v 3061,
3006, 2976, 1597, 1496, 1453, 1348, 1319 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d,
J= 6.8 Hz, IH), 7.36 (m, 2H), 7.29-7.15 (m, 8H), 7.11-7.00 (m, 5H), 6.85 (s, IH), 5.39 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 138.3, 137.9, 137.7, 137.0, 131.1, 128.8 (2C), 128.7 (2C), 128.0, 127.8, 127.4, 126.4 (2C), 126.0 (2C), 122.0, 120.5, 120.2, 116.9, 109.5, 99.6,
46.7; MS (EI) m/z 309.2 [M]+, 91.0 [Bn]+; HRMS (EI) m/z calcd.for: [M]+ 309.1517, m/z found: 309.1521.
Example 2c: Preparation of l-Benzyl-2-[2-(4-chloro-phenyl)-vinyl]-lH-indole
Figure imgf000100_0002
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and l-chloro-4-vinyl -benzene. Yield: 71 %, yellow solid, mp 132-135 0C; IR (CHCl3) v 3030, 3023, 3006, 1490, 1453, 1348, 1319 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J= 6.6 Hz, IH), 7.33-7.23 (m, 8H), 7.18-7.11 (m, 2H), 7.08-6.99 (m, 4H), 6.88 (s, IH), 5.44 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 138.0, 137.9, 137.7, 135.5, 133.3, 129.7 (4C), 128.8, 128.1, 127.5 (2C), 127.4, 126.0 (2C), 122.2, 120.6, 120.3, 117.5, 109.5, 99.9, 46.8; MS (EI) m/z 343.1 [M]+; HRMS (EI) m/z calcd. for: [M]+ 343.1127, m/z found: 343.1126.
Example 2d: Preparation of l-Benzyl-2-[2-(4-methoxy-phenyl)-vinyl]-lH-indole
Figure imgf000101_0001
Following General Procedure B with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and l-methoxy-4-vinyl-benzene. Yield: 73 %, yellow solid, mp 151-155 0C; IR (CHCl3) v 3061, 3006, 2936, 1605, 1509, 1453, 1250, 1175 cm"1; 1U NMR (400 MHz, CDCl3) δ 7.61 (m, IH), 7.33 (d, J= 8.6 Hz, 2H), 7.27-7.20 (m, 4H), 7.14-7.05 (m, 5H), 6.92 (s, IH), 6.88-6.83 (m, 3H), 5.41 (s, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 138.7, 137.8 (2C), 130.9, 129.8, 128.8 (2C), 128.2, 127.7 (2C), 127.3, 126.0 (2C), 121.7, 120.3, 120.1, 114.8, 114.1 (2C), 109.4, 98.9, 55.3, 46.7; MS (EI) m/z 339.3 [M]+; HRMS (EI) m/z calcd. for: [M]+ 339.1623, m/z found: 339.1622.
Example 2e: Preparation of 3-(l-Benzyl-lH-indol-2-yl)-acrylonitrile
Figure imgf000101_0002
Following General Procedure B with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and acrylonitrile. Yield: 70 % (conversion 80 %), yellow white solid, mp 121-124 0C; IR (CHCl3) v 3023, 2216, 1616, 1521, 1454, 1348, 1324, 1234, 1215, 1201 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.65 (dt, J= 8.0, 0.9 Hz, IH), 7.33 (d, J= 16.3 Hz, IH), 7.31-7.24 (m, 5H), 7.15 (t, J= 8.0 Hz, IH), 7.02 (s, IH), 6.98-6.96 (m, 2H), 5.80 (d, J= 16.3 Hz, IH), 5.40 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 139.1, 138.2, 136.6, 133.7, 129.0 (2C), 127.8, 127.3, 125.7 (2C), 124.7, 121.7, 121.1, 118.3, 110.0, 104.6, 95.7, 46.8; MS (EI) m/z 258.2 [M]+, 91.0 [Bn]+; HRMS (EI) m/z calcd. for: [M]+ 258.1156, m/z found: 258.1159.
Example 2f: Preparation of 2-(2-Benzenesulfonyl-vinyl)-l-benzyl-lH-indole
Figure imgf000102_0001
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and ethenesulfonyl-benzene. Yield: 40 %, brown solid, mp 133-137 0C; IR (CHCl3) v 3024, 3009, 1606, 1521, 1447, 1347, 1324, 1147, 1085 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.77 (m, 3H), 7.69 (d, J= 15.2 Hz, IH), 7.62 (d, J= 8.0 Hz, IH), 7.58 (m, IH), 7.48 (m, IH), 7.32-7.23 (m, 6H), 7.14 (t, J= 7.9 Hz, IH), 7.00-6.97 (m, 2H), 6.77 (d, J= 15.2 Hz, IH), 5.47 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 140.7, 139.2, 136.9, 133.2, 132.3, 130.8, 129.2 (2C), 128.9 (2C), 127.7, 127.5 (2C), 127.4, 126.6, 126.0 (2C), 124.6, 121.7, 121.0, 110.0, 105.9, 46.9; MS (ESI) m/z 374.1 [M+H]+, 396.1 [M+Na]+; HRMS (ESI) m/z calcd. for: [M+H]+ 374.1209, m/z found: 374.1215.
Example 2g: Preparation of l-(l-BenzyI-lH-indol-2-yl)-pent-l-en-3-one
Figure imgf000102_0002
Following General Procedure B with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and pent- l-en-3 -one. Yield: 38 %, orange solid, mp 122-125 0C; IR (CHCl3) v 3025, 3007, 1657, 1598, 1454, 1349, 1322 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J= 8.0 Hz, IH), 7.57 (d, J= 15.8 Hz, IH), 7.25-7.16 (m, 5H), 7.09 (m, IH), 7.03 (s, IH), 6.97 (m, 2H), 6.74 (d, J= 15.8 Hz, IH), 5.42 (s, 2H), 2.54 (q, J= 7.3 Hz, 2H), 1.07 (t, J= 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 139.1, 137.2, 135.0, 129.8, 128.9 (2C), 127.9, 127.6, 125.9 (2C), 125.8, 123.9, 121.5, 120.8, 110.0, 104.3, 46.8, 34.7, 8.2; MS (EI) m/z 289.2 [M]+, 232.2 [M-C3H5O]+, 91.0 [Bn]+; HRMS (EI) m/z calcd.for: [M]+ 289.1466, m/z found: 289.1465.
Example 2h: Preparation of Acetic acid 3-(l-benzyl-lH-indol-2-yl)-allyl ester
Figure imgf000103_0001
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and acetic acid allyl ester. Yield: 36 %, yellow solid, mp 83-85 0C; IR (CHCl3) v 3031, 3009, 1735, 1454, 1235, 1219 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J= 7.5 Hz, IH), 7.27-7.22 (m, 4H), 7.16-7.10 (m, 2H), 7.01 (m, 2H), 6.76 (s, IH), 6.62 (d, J= 15.8 Hz, IH), 6.35 (t, J= 6.4 Hz, IH), 6.31 (t, J= 6.4 Hz, IH), 5.38 (s, 2H), 4.67 (dd, J= 6.4, 1.2 Hz, IH), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 137.7, 137.6, 136.7, 128.8 (2C), 127.9, 127.4, 125.9 (2C), 125.8, 122.7, 122.2, 120.6, 120.2, 109.6, 100.3, 64.8, 46.7, 20.9; MS (EI) m/z 305.1 [M]+, 262.1 [M-Ac]+, 246.1 [M-OAc]+, 91.0 [Bn]+; HRMS (EI) m/z calcd.for: [M]+ 305.14154, m/z found: 305.1414.
Example 2i and 2i': Preparation of l-(l-Benzyl-lH-indol-2-yl)-decan-3-one and 1- (l-Benzyl-lH-indol-2-yl)-dec-l-en-3-ol
Figure imgf000103_0002
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and cec-l-en-3-ol. Yield: 82 % (2i/2i': 3/1). 2i: yellow solid, 49-51 0C; IR
(CHCl3) v 3006, 2929, 2857, 1711, 1496, 1463, 1453, 1409, 1355 cm"1; 1H NMR (400
MHz, CDCl3) δ 7.55 (m, IH), 7.23-7.20 (m, 4H), 7.13-7.05 (m, 2H), 6.97-9.94 (m, 2H),
6.29 (d, J=Hz, IH), 5.34 (s, 2H), 2.96 (m, 2H), 2.77 (m, 2H), 2.36 (t, J= 7.5 Hz, 2H), 1.53 (m, 2H), 1.25 (m, 8H), 0.87 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
209.6, 139.8, 137.7, 137.2, 128.7 (2C), 127.9, 127.2, 125.9 (2C), 121.1, 119.8, 119.6,
109.3, 99.2, 46.3, 42.9, 41.1, 31.6, 29.1, 29.0, 23.8, 22.6, 20.5, 14.0; MS (EI) m/z 361.1
[M]+, 234.0 [M-C8Hi5O]+, 91.0 [Bn]+; HRMS (EI) m/z calcd. for: [M]+ 361.2405, m/z found: 361.2390. 2i': white solid, mp 45-48 0C; IR (CHCl3) v 3602, 3008, 2929, 2857, 1496, 1453, 1354, 1318, 1199 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J= 6.9, 1.3 Hz, IH), 7.27-7.20 (m, 4H), 7.14-7.06 (m, 2H), 7.00 (m, 2H), 6.71 (s, IH), 6.55 (d, J= 15.7 Hz, IH), 6.27 (dd, J= 15.7, 6.4 Hz, IH), 5.37 (s, 2H), 4.21 (m, IH), 1.54 (m, 4H), 1.25 (m, 8H), 0.87 (t, J= 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 137.7, 137.6, 137.5, 135.7, 128.7 (2C), 128.0, 127.3, 126.0 (2C), 121.9, 120.4, 120.0, 118.8, 109.5, 99.5, 72.8, 46.7, 37.3, 31.8, 29.5, 29.2, 25.3, 22.6, 14.1; MS (EI) m/z 361.1 [M]+, 234.0 [M-C8H15O]+, 91.0 [Bn]+; HRMS (EI) m/z calcd. for: [M]+ 361.2405, m/z found: 361.2411.
Example 2j : Preparation of 3-(l-Benzyl-lH-indol-2-yl)-N-tert-butyl-acrylamide
Figure imgf000104_0001
Following General Procedure A with benzyl- [2-(2,2-dibromo-vinyl)-phenyl] -amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and N-tert-butyl-acrylamide. Yield: 45 %, white solid, mp 215-217 0C; IR (CHCl3) v 3434, 3005, 1664, 1621, 1507, 1453, 1348, 1320 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J= 15.2 Hz, IH), 7.61(d, J= 7.8 Hz, IH), 7.25-7.17 (m, 6H), 7.11 (t, J= 6.9 Hz, IH), 6.99 (m, 2H), 6.92 (s, IH), 6.37 (d, J= 15.2 Hz, IH), 5.44 (s, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 164.7, 138.4, 137.3, 135.6, 128.8 (2C), 128.4, 127.7, 127.4, 125.9 (2C), 123.2, 122.9, 121.0, 120.5, 110.0, 102.3, 51.5, 46.6, 28.8 (3C); MS (EI) m/z 332.3 [M]+, 91.0 [Bn]+; HRMS (EI) m/z calcd. for: [M]+ 332.1888, m/z found: 332.1885.
Example 2k: Preparation of 3-(l-Benzyl-lH-indol-2-yl)-l-morpholin-4-yl- propenone
Figure imgf000105_0001
Following General Procedure C with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and l-morpholin-4-yl-propenone. Yield: 63 %, yellow solid, mp 155-157 0C; IR (CHCl3) v 3019, 2925, 2861, 1641, 1597, 1454, 1434, 1347, 1221, 1209 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J= 15.2 Hz, IH), 7.63 (d, J= 7.9 Hz, IH), 7.29-7.20 (m, 6H), 7.13 (t, J= 7.7 Hz, IH), 7.02 (m, 2H), 6.98 (s, IH), 6.82 (d, J= 15.2 Hz, IH), 5.47 (s, 2H), 3.68 (m, 5H), 3.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.1, 138.8, 137.4, 135.7, 131.4, 128.8 (2C), 127.6, 127.5, 125.9 (2C), 123.6, 121.2, 120.6, 117.0, 109.9, 103.5, 66.7, 46.9; MS (EI) m/z 346.1 [M]+, 232.1 [M-C5H8NO2]+, 91.0 [Bn]+; HRMS (EI) m/z calcd. for: [M]+ 346.1681, m/z found: 346.1676.
Example 21: Preparation of 3-(lH-Indol-2-yl)-acrylic acid tert-butyl ester
Figure imgf000105_0002
Following General Procedure B with with 2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tertbutylacrylate. Pd(OAc)2 (6.0 % mol) and P(o-tolyl)3 (12.0 % mol) were used and were added a second time after 24 h of reflux. Yield: 50 %, yellow-orange solid, mp 131-134 0C; IR (CHCl3) v 3471, 3012, 2982, 1696, 1615, 1631, 1615, 1369, 1297, 1153 cm"1; 1H NMR (400 MHz, CDCl3) δ 8.77 (br, IH), 7.58 (d, J= 16.0 Hz, IH), 7.57 (m, IH), 7.34 (m, IH), 7.24 (t, J= 7.5 Hz, IH), 7.10 (t, J= 7.4 Hz, IH), 6.77 (s, IH), 6.25 (d, J= 16.0 Hz, IH), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.5, 137.8, 133.6, 133.5, 128.4, 124.3, 121.4, 120.4, 117.6, 111.1, 108.4, 80.8, 28.2 (3C); MS (ESI) m/z 266.1 [M+Na]+; HRMS (ESI) m/z calcd. for: [M+Na]+ 266.1151, m/z found: 266.1169 (Grimster, N. P.; Gauntlett, C; Godfrey, CR. A.; Gaunt, M.J. Angew. Chem. Int. Ed. 2005, 44, 3125).
Example 2m: Preparation of 3-(l-Butyl-lH-indol-2-yl)-acrylic acid tert-butyl ester
Figure imgf000106_0001
Following General Procedure A with butyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine Ia and tertbutylacrylate. Yield: 69 %, yellow solid, mp 50-52 0C; IR (CHCl3) v 3060, 2963, 2875, 1699, 1630, 1521, 1456, 1406, 1368, 1314, 1145 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J= 15.7 Hz, IH), 7.59 (d, J= 7.6 Hz, IH), 7.31 (m, IH), 7.22 (t, J= 7.6 Hz, IH), 7.09 (t, J= 7.4 Hz, IH), 6.92 (s, IH), 6.43 (d, J= 15.7 Hz, IH), 4.21 (t, J= 7.3 Hz, 2H), 1.75 (quint., J= 7.5 Hz, 2H), 1.55 (s, 9H), 1.35 (sext, J= 7.4 Hz, 2H), 0.94 (t, J= 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 138.2, 134.6, 131.6, 127.5, 123.1, 121.3, 120.2 (2C), 109.7, 102.8, 80.6, 43.1, 32.7, 28.2 (3C), 20.2, 13.7; MS (EI) m/z 299.3 [M]+, 243.2 [M-C4Hg]+; HRMS (EI) m/z calcd. for: [M]+ 299.1885, m/z found: 299.1884.
Example 2n: Preparation of 3-(l-Isopropyl-lH-indol-2-yl)-acrylic acid tert-butyl ester
Figure imgf000106_0002
Following General Procedure A with [2-(2,2-Dibromo-vinyl)-phenyl]-isopropyl-amine Ib and rerfbutylacrylate. Yield: 67 %, yellow solid, mp 75-76 0C; IR (CHCl3) v 2981, 2935, 1697, 1626, 1369, 1314, 1279, 1149 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J= 15.4 Hz, IH), 7.59 (d, J= 7.7 Hz, IH), 7.47 (d, J= 7.6 Hz, IH), 7.19 (t, J= 7.8 Hz, IH), 7.06 (t, J= 7.8 Hz, IH), 6.88 (s, IH), 6.39 (d, J= 15.5 Hz, IH), 4.86 (sept, J= 7.0 Hz, IH), 1.64 (d, J= 7.0 Hz, 6H), 1.55 (s, 9H) ; 13C NMR (100 MHz, CDCl3) δ 166.4, 137.0, 134.7, 132.6, 128.2, 122.7, 121.4, 120.6, 119.9, 111.5, 103.3, 80.6, 47.2, 28.2 (3C), 22.0 (2C); MS (ESI) m/z 286.2 [M+H]+, 308.2 [M+Na]+; HRMS (ESI) m/z calcd. for: 286.1801 [M+H]+, m/z found: 286.1790.
Example 2o: Preparation of 3-[l-(2-Bromo-benzyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester
Figure imgf000107_0001
Following General Procedure A with (2-Bromo-benzyl)-[2-(2,2-dibromo-vinyl)-phenyl]- amine Ic and tertbutylacrylate. Yield: 62 %, yellow solid, mp 110-115 0C; IR (CHCl3) v 3005, 2981, 1699, 1629, 1456, 1444, 1407, 1369, 1314, 1291, 1148 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J= 7.7 Hz, IH), 7.60 (d, J= 7.7 Hz, IH), 7.52 (d, J= 15.7 Hz, IH), 7.18-7.04 (m, 6H), 6.40 (d, J= 15.7 Hz, IH), 6.27 (d, J= 7.4 Hz, IH), 5.47 (s, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.1, 138.6, 136.1, 135.1, 132.7, 131.1, 129.0, 127.9, 127.7, 127.0, 123.8, 121.5, 121.4, 121.0, 120.9, 109.9, 103.9, 80.7, 47.1, 28.2 (3C); MS (EI) m/z 411.2 [79BrM]+, 413.2 [82BrM]+; HRMS (EI) m/z calcd. for: [79Br M]+ 411.0833, m/z found: 411.0825.
Example 2p: Preparation of 3-(l-Phenyl-lH-indol-2-yl)-acrylic acid tert-butyl ester
Figure imgf000108_0001
Following General Procedure C with [2-(2,2-dibromo-vinyl)-phenyl]-phenyl-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tertbutylacrylate. Yield: 78 %, yellow oil; IR (CHCl3) v 3019, 1699, 1629, 1501, 1392, 1343, 1230, 1154, 1142 cm'1; 1H NMR (300 MHz, CDCl3) δ 7.65 (m, IH), 7.57-7.44 (m, 4H), 7.38-7.32 (m, 2H), 7.17-7.12 (m, 3H), 7.07 (s, IH), 6.26 (d, J= 15.9 Hz, IH), 1.47 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.2, 139.6, 136.9, 135.5, 132.4, 129.7 (2C), 128.3 (2C), 128.3, 127.6, 123.8, 121.2, 121.0, 120.1, 110.7, 104.4, 80.4, 28.1 (3C); MS (EI) m/z 319.0 [M]+, 218.0 [M-CO2^Bu]+; HRMS (EI) m/z calcd. for: [M]+ 319.1572, m/z found: 319.1575.
Example 2q: Preparation of 3-[l-(4-Trifluoromethyl-phenyl)-lH-indol-2-yl]-acrylic acid tert-butyl ester
Figure imgf000108_0002
Following General Procedure C with [2-(2,2-dibromo-vinyl)-phenyl]-(4-trifluoromethyl- phenyl)-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tør/butylacrylate. Yield: 68 %, yellow oil; IR (CHCI3) v 3005, 2981, 2933, 1701, 1629, 1522, 1450, 1393, 1369, 1325, 1107 cm'1; 1H NMR (W MHz, CDCl3) δ 7.82 (d, J= 8.3 Hz, 2H), 7.65 (m, IH), 7.47 (d, J= 8.2 Hz, 2H), 7.37 (d, J- 15.8 Hz, IH), 7.21-7.13 (m, 3H), 7.10 (s, IH), 6.32 (d, J= 15.8 Hz, IH), 1.49 (s, 9H); MS (EI) m/z 387.1 [M]+.
Example 2r: Preparation of 3-[l-(4-Fluoro-phenyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester
Figure imgf000109_0001
Following General Procedure C with [2-(2,2-dibromo-vinyl)-phenyl]-(4-fluoro-phenyl)- amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tørtbutylacrylate and use Pd(OAc)2 (5.0 % mol), P(o- tolyl)3 (10.0 % mol). Yield: 60 %, yellow solid, mp 95-1000C; IR (CHCl3) v 3004, 2981, 2933, 1699, 1629, 1512, 1451, 1393, 1369, 1343, 1312, 1142 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.63 (m, IH), 7.37 (d, J= 15.9 Hz, IH), 7.30-7.13 (m, 6H), 7.07-7.04 (m, 2H), 6.24 (d, J= 15.9 Hz, IH), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.1, 162.1 (JCF= 248.7 Hz), 139.7 (JCF=3.2 Hz), 135.5, 132.8, 132.0, 130.0, 129.9, 127.5, 123.9, 121.1 (JcF= 6.2 Hz, 2C), 120.3, 116.7 (JCF= 22.8 Hz, 2C), 110.5, 104.5, 80.5, 28.1 (3C); MS (EI) m/z 337.0 [M]+; HRMS (EI) m/z calcd. for: [M]+ 337.1478, m/z found: 337.1472.
Example 2s: Preparation of 3-[l-(3,4-Dimethoxy-phenyl)-lH-indol-2-yl]-acrylic acid tert-butyl ester
Figure imgf000110_0001
Following General Procedure B with [2-(2,2-Dibromo-vinyl)-phenyl]-(3,4-dimethoxy- phenyl)-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tertbutylacrylate. Yield: 60 %, white solid, mp 136- 140 0C; IR (CHCl3) v 3006, 2981, 2937, 1698, 1628, 1516, 1456, 1346, 1310, 1255, 1141 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=7.7 Hz, IH), 7.42 (d, J= 15.9 Hz, IH), 7.19-7.10 (m, 3H), 7.04 (s, IH), 7.00 (m, IH), 6.91 (m, IH), 6.83 (d, J=2.2 Hz, IH), 6.25 (d, J= 15.9 Hz, IH), 3.97 (s, 3H), 3.86 (s, 3H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.3, 149.6, 149.1, 140.0, 135.7, 132.5, 129.6, 127.4, 123.8, 121.2, 120.9, 120.7, 119.9, 111.6, 111.4, 110.8, 104.1, 80.4, 56.1 (2C), 28.1 (3C); MS (EI) m/z 379.1 [M]+; HRMS (EI) m/z calcd. for: [M]+ 379.1783, m/z found: 379.1785.
Example 2t: Preparation of l-Benzyl-2-(2-tert-butoxycarbonyl-vinyl)-lH-indole-6- carboxylic acid methyl ester
Figure imgf000110_0002
Following General Procedure A with 3-benzylamino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester Id and tertbutylacrylate. Yield: 71 %, yellow solid, 120-123 0C; IR (CHCl3) v 3017, 2981, 1701, 1633, 1610, 1454, 1436, 1368, 1354, 1313, 1277, 1242, 1150 cm"1; 1H NMR (400 MHz, CDCl3) δ 8.06 (s, IH), 7.80 (dd, J= 8.4, 1.3 Hz, IH), 7.64 (d, J= 8.4 Hz, IH), 7.60 (d, J= 15.7 Hz, IH), 7.29-7.22 (m, 3H), 7.01-7-6.99 (m, 3H), 6.45 (d, J= 15.7 Hz, IH), 5.50 (s, 2H), 3.90 (s, 3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.7, 165.7, 138.1, 137.9, 136.8, 131.0, 130.8, 128.9 (2C), 127.7, 125.9 (2C), 124.9, 122.7, 121.5, 120.9, 112.2, 103.2, 80.8, 52.0, 46.8, 28.1 (3C); MS (EI) m/z 391.2 [M]+; HRMS (EI) m/z calcd. for: [M]+ 391.1783, m/z found: 391.1777.
Example 2u: Preparation of 3-(l-Benzyl-6-fluoro-lH-iudol-2-yl)-acrylic acid tert- butyl ester
Figure imgf000111_0001
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-5-fluoro-phenyl]- amine Ie and tertbutylacrylate. Yield: 70 %, yellow solid, mp 105-107 0C; DR. (CHCl3) v 3005, 2979, 1698, 1628, 1491, 1361, 1315, 1248, 1146, 1146, 1098 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J= 15.7 Hz, IH), 7.54 (m, IH), 7.28-7.25 (m, 3H), 7.00 (m, 2H), 6.93 (s, IH), 6.91-6.86 (m, 2H), 6.36 (d, J= 15.7 Hz, IH), 5.37 (s, 2H), 1.50 (s, 9H); 19F NMR (282 MHz, CDCl3) δ -111.2; 13C NMR (100 MHz, CDCl3) δ 166.1, 160.7 (JCF= 240.7 Hz), 138.8 (JCF= 11.6 Hz), 136.7, 135.7 (JCF= 4.0 Hz), 131.1, 128.9, 127.7 (2C), 125.9 (2C), 124.2, 122.3 (JCF= 10.0 Hz), 120.5, 109.7 (JCF= 25.2 Hz), 103.7, 96.3 (JCF= 26.2 Hz), 80.6, 47.0, 28.2 (3C); MS (EI) m/z 351.3 [M]+; HRMS (EI) m/z calcd. for: [M]+ 351.1634, m/z found: 351.1628.
Example 2v: Preparation of 3-(l-Benzyl-6-benzyloxy-lH-indol-2-yl)-acryIic acid tert-butyl ester
Figure imgf000111_0002
Following General Procedure A with benzyl-[4-benzyloxy-2-(2,2-dibromo-vinyl)- phenyl]-amine If and /ertbutylacrylate. Yield: 64 %, yellow solid, mp 126-128 0C; IR (CHCl3) v 3007, 2978, 1697, 1617, 1453, 1369, 1314, 1298, 1185, 1151 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J= 15.7 Hz, IH), 7.47-7.13 (m, 10H), 7.00-6.90 (m, 4H), 6.36 (d, J= 15.7 Hz, IH), 5.39 (s, 2H), 5.08 (s, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.2, 153.9, 137.4, 137.3, 135.4, 134.3, 131.4, 128.8 (2C), 128.5 (2C), 127.9, 127.8, 127.5 (2C), 125.9 (2C), 120.4, 115.2, 110.9, 103.5, 103.1, 80.5, 70.6, 46.8, 28.3 (3C); MS (EI) m/z 439.4 [M]+; HRMS (EI) m/z calcd. for: [M]+ 439.2147, m/z found: 439.2153.
Example 2w: Preparation of 3-(l-Benzyl-4-benzyloxy-5-methoxy-lH-indol-2-yl)- acrylic acid tert-butyl ester
Figure imgf000112_0001
Following General Procedure A with benzyl-[3-benzyloxy-2'-(2,2-dibromo-vinyl)-4- methoxy-phenyl] -amine Ig and te/tbutylacrylate. Yield: 39 %, orange solid, mp 104-107 0C; IR (CHCl3) v 3005, 2978, 1697, 1629, 1496, 1369, 1341, 1296, 1252, 1149 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J= 15.7 Hz, IH), 7.55-7.52 (m, 2H), 7.41-7.23 (m, 7H), 7.01-6.99 (m, 2H), 6.95 (d, J= 8.8 Hz, IH), 6.90 (d, J= 8.8 Hz, IH), 6.37 (d, J= 15.7 Hz, IH), 5.37 (s, 2H), 5.25 (s, 2H), 3.88 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.1, 145.4, 141.0, 138.1, 137.2, 136.0, 135.3, 131.3, 128.8 (2C), 128.3 (2C), 128.0 (2C), 127.8 127.5, 126.0 (2C), 123.2, 120.8, 113.9, 105.2, 100.7, 80.5, 75.0, 58.3, 46.9, 28.2 (3C); MS (EI) m/z 469.0 [M]+, 378.0 [M-Bn]+; HRMS (EI) m/z calcd. for: [M]+ 469.2279, m/z found: 469.2269.
Example 2x: Preparation of 3-(l-Benzyl-4-methyl-lH-indol-2-yl)-acrylic acid tert- butyl ester
Figure imgf000112_0002
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-3-methyl-phenyl]- amine Ih and tør/butylacrylate. Yield: 38 %, yellow solid, mp 55-58 0C; IR (CHCl3) v 3005, 2980, 2932, 1699, 1628, 1496, 1455, 1369, 1350, 1314, 1145 cm"1; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J= 15.7 Hz, IH), 7.28-7.23 (m, 3H), 7.11-7.09 (m, 2H), 7.04- 7.00 (m, 3H), 6.92 (m, IH), 6.41 (d, J= 15.7 Hz, IH), 5.43 (s, 2H), 2.56 (s, 3H), 1.50 (s, 9H); 13C NMR (IOO MHZ, CDCl3) δ 166.2, 138.5, 137.3, 134.5, 131.5, 130.9, 128.8 (2C), 127.7, 127.5, 126.0 (2C), 123.8, 120.7, 120.4, 107.6, 102.2, 80.5, 46.9, 28.2 (3C), 18.6; MS (EI) m/z 347.2 [M]+; HRMS (EI) m/z calcd. for: [M]+ 347.1885, m/z found: 347.1882.
Example 2y: Preparation of 3-(l-Benzyl-lH-benzo[g]indol-2-yl)-acrylic acid tert- butyl ester
Figure imgf000113_0001
Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-naphthalen-l-yl]- amine Ii and førtbutylacrylate. 4.0 mol % of Pd(OAc)2 and 8.0 mol % P(o-tolyl)3 was added after 48 h of reflux. Yield: 43 %, yellow solid, mp 123-125 0C; IR (CHCl3) v 3008, 2977, 1696, 1622, 1388, 1368, 1290, 1147 cm"1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J= 8.1 Hz, IH), 7.89 (m, IH), 7.69 (d, J= 8.6 Hz, IH), 7.66 (d, J= 15.6 Hz, IH), 7.51 (d, J= 8.6 Hz, IH), 7.38-7.25 (m, 6H), 7.18-7.12 (m, 2H), 6.42 (d, J= 15.6 Hz, IH), 5.89 (s, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.4, 137.1, 135.0, 132.8, 132.4, 131.3, 129.4, 129.1 (2C), 127.6, 125.7 (2C), 125.2, 124.2, 122.6, 122.3, 121.2, 120.7, 119.9, 105.2, 80.5, 49.5, 28.2 (3C); MS (EI) m/z 383.3 [M]+; HRMS (EI) m/z calcd. for: [M]+ 383.1885, m/z found: 383.1885.
Example 2z: Preparation of 3-(7-Methoxy-lH-indol-2-yl)-acrylic acid tert-butyl ester
Figure imgf000114_0001
Following General Procedure B with 2-(2,2-Dibromo-vinyl)-6-methoxy-phenylamine Ij and tertbutylacrylate. Yield: 53 %, yellow solid, mp 163-166 0C; IR (CHCl3) v 3470, 3005, 2979, 1698, 1634, 1369, 1330, 1307, 1256, 1152 cm"1; 1H NMR (400 MHz, CDCl3) δ 8.47 (br, IH), 7.57 (d, J= 16.0 Hz, IH), 7.20 (d, J= 7.9 Hz, IH), 7.01 (t, J= 7.9 Hz, IH), 6.74 (d, J= 2.3 Hz, IH), 6.67 (d, J= 7.9 Hz, IH), 6.18 (d, J= 16.0 Hz, IH), 3.95 (s, 3H), 1.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.1, 145.9, 133.3, 133.2, 129.6, 128.4, 120.9, 117.6, 113.9, 108.5, 103.7, 80.5, 55.4, 28.2 (3C); MS (EI) m/z 273.1 [M]+; HRMS (EI) m/z calcd. for: [M]+ 273.1364, m/z found: 273.1360.
Example 2aa: Preparation of 3-[3-(4-Fluoro-phenyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester
Figure imgf000114_0002
Following General Procedure B with 2-[2,2-Dibromo-l-(4-fluoro-phenyl)-vinyl]- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and fertbutylacrylate. Yield: 16 % (conversion 76 %), yellow-white, mp 230-232 0C; IR (CHCl3) v 3470, 3023, 1696, 1626, 1613, 1502, 1229 1153 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.30 (br, IH), 7.62 (d, J= 16.0 Hz, IH), 7.60 (d, J= 7.9 Hz, IH), 7.45-7.41 (m, 2H), 7.32 (m, IH), 7.28 (t, J= 8.0 Hz, IH), 7.16-7.10 (m, 3H), 6.15 (d, J= 16.0 Hz, IH), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.3, 162.2 (JcF= 245.6 Hz), 137.0, 132.1, 131.6 (JCF= 8.0 Hz, 2C), 130.0, 129.4 (JCF= 3.4 Hz), 127.7, 125.2, 122.6, 120.8, 120.3, 117.6, 115.7 (JCF= 21.4 Hz, 2C), 111.1, 80.8, 28.2 (3C); MS (EI) m/z 337. 1 [M]+; HRMS (EI) m/z calcd. for: [M]+ 337.1478, m/z found: 337.1480.
Preparation of ortΛo-ggm-dibromovinylaniline containing an alkene of Formula (V)
The results of the preparation of various cyclization precursors of the compounds shown in Table 5, above are shown in Examples 3a-3e below and in Table 6 above.
General Procedure D for reductive amination. Example 3a : Preparation of 6- [2- (2,2-Dibromo-vinyl)-phenylamino]-hex-2-enoic acid tert-butyl ester
Figure imgf000115_0001
2-(2,2-dibromo-vinyl)phenylamine (900.0 mg, 3.26 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2- hexenenoic acid-6-oxo-tbutyl ester (600.0 mg, 3.26 mmol; for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284) were mixed in 1,2-dichloroethane (15.0 mL, 0.22 M) and then treated with sodium triacetoxyborohydride (900.0 mg, 4.24 mmol) and glacial acetic acid (186.0 μL, 3.26 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture was then quenched by addition of aqueous saturated NaHCO3, and the product was extract with EtOAc. The organic phase was dried (Na2SO4) and the solvent was evaporated to give the crude product. The mixture was purified by flash chromatography (3/l:hexanes/CH2Cl2) to afford a pink solid (0.88 g, 60 %). mp 33-35 0C; IR (CHCl3) v 3438, 3006, 2980, 2936, 1705, 1653, 1602, 1507, 1457, 1368, 1318, 1259, 1154 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.24 (m, 3H), 6.87 (dt, , J= 15.6, 6.8 Hz IH), 6.71 (t, J= 7.4 Hz, IH), 6.62 (d, J= 8.1 Hz, IH), 5.79 (d, J= 15.6, 7.4 Hz, IH), 3.56 (br, IH), 3.17 (t, J= 6.9 Hz, 2H), 2.29 (q, J= 7.1 Hz, 2H), 1.80 (quint., J= 7.1 Hz, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.7, 146.5, 144.8, 134.0, 129.8, 129.2, 123.6, 121.5, 116.8, 110.6, 93.1, 80.1, 43.1, 29.4, 28.1 (3C), 27.8; MS (EI) m/z 444.9 [M]+; HRMS (EI) m/z calcd. for: [M]+ 443.0095, m/z found: 443.0092.
Example 3b: Preparation of 6-[4-Benzyloxy-2-(2,2-dibromo-vinyl)-phenylamino]- hex-2-enoic acid tert-butyl ester
Figure imgf000116_0001
Following General Procedure D as for 3a with 4-Benzyloxy-2-(2,2-dibromo-vinyl)- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-hexenenoic acid-6-oxo-Autyl ester (for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284). Yield: 54 %, brown liquid; IR (CHCl3) v 3435, 3005, 2980, 2936, 1705, 1505, 1653, 1454, 1369, 1292, 1155 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.43-7.25 (m, 6H), 6.99-6.85 (m, 3H), 6.59 (d, J= 8.8 Hz, IH), 5.78 (dt, J= 15.6, 1.5 Hz, IH), 5.00 (s, 2H), 3.25 (br, IH), 3.13 (t, J= 7.1 Hz, 2H), 2.29 (m, 2H), 1.79 (quint, J= 7.3 Hz, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.8, 150.5, 146.6, 139.5, 137.3, 133.7, 128.4 (2C), 127.7, 127.4 (2C), 123.6, 122.6, 117.1, 115.9, 112.3, 92.9, 80.1, 70.9, 43.9, 29.5, 28.1 (3C), 27.9; MS (EI) m/z 551.0 [M]+, 460 [M-CH2Ph]+; HRMS (EI) m/z calcd. for: [M]+ 549.0515, m/z found: 549.0514.
Example 3c: Preparation of 3-(5-tert-Butoxycarbonyl-pent-4-enylamino)-4-(2,2- dibromo-vinyl)-benzoic acid methyl ester
Figure imgf000117_0001
Following General Procedure D as for 3a with 3-amino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-hexenenoic acid-6-oxo-/butyl ester (for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P.
D. Price, A.D. Smith Org.ά. Bio. Chem. 2005, 3, 1284). Yield: 65 %, orange oil; IR
(CHCl3) v 3009, 2981, 1710, 1572, 1439, 1299, 1254, 1155 cm"1; 1K NMR (300 MHz,
CDCl3) δ 7.38-7.25 (m, 4H), 6.87 (dt, J= 15.6, 6.8 Hz, IH), 5.80 (dt, J= 15.6, 1.5 Hz,
IH), 3.90 (s, 3H), 3.67 (br, IH), 3.24 (t, J= 7.0 Hz, 2H), 2.31 (m, 2H), 1.85 (quint., J= 7.2 Hz, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 167.1, 165.8, 146.4, 144.8, 133.2,
131.2, 129.2, 125.7, 123.7, 118.0, 111.4, 94.6, 80.2, 52.1, 43.1, 29.4, 28.1 (3C), 27.8; MS
(EI) m/z 502.9 [M]+, 445.8 [M-^Bu]+; HRMS (EI) m/z calcd. for: [M]+ 501.0150, m/z found: 501.0156.
Example 3d: Preparation of [2-(2,2-Dibromo-vinyl)-phenyl]-pent-4-enyl-amine
Figure imgf000117_0002
Following General Procedure D as for 3a with 2-(2,2-dibromo-vinyl)phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 4-pentenal (commercially available at Alfa-Aesar). Yield: 91 %, incolor oil; IR (CHCl3) v 3421, 3078, 3005, 2935, 2860, 1640, 1602, 1578, 1506, 1457, 1319, 1261 cm"1; 1U NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 3H), 6.71 (td, J= 7.4, 1.0 Hz, IH), 6.64 (d, J= 8.3 Hz, IH), 5.85 (m, IH), 5.08 (m, IH), 5.02 (m, IH), 3.58 (br, IH), 3.17 (t, J= 7.1 Hz, 2H), 2.18 (m, 2H), 1.76 (quint, J= 7.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 145.1, 137.9, 134.1, 129.8; 129.2, 121.4, 116.6, 115.3, 110.6, 93.0, 43.3, 31.3, 28.4; MS (EI) m/z 342.9 [79Br79BrM]+, 344.9 [79Br81BrM]+, 346.9 [81Br81BrM]+; HRMS (EI) m/z calcd.for: [79Br79BrM]+ 342.9571, m/z found: 342.9585.
Example 3e: Preparation of 7-[2-(2,2-Dibromo-vinyl)-phenylamino]-hept-2-enoic acid tert-butyl ester
Figure imgf000118_0001
Following General Procedure D as for 3a with 2-(2,2-dibromo-vinyl)phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-heptenoic acid-7-oxo-tbutyl ester (for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284). Yield: 61 %, brown-white solid, mp 45-47 0C; IR (CHCl3) v 3420, 3006, 2980, 2936, 2862, 1704, 1652, 1602, 1578, 1507, 1457, 1368, 1317, 1154 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 3H), 6.85 (dt, J = 15.6, 6.9 Hz, IH), 6.71 (t, J= 7.5 Hz, IH), 6.63 (d, J= 8.4 Hz, IH), 5.76 (dt, J= 15.6, 1.5 Hz, IH), 3.5 (br, IH), 3.1 (t, J= 6.8 Hz, 2H), 2.24 (m, 2H), 1.69 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.9, 147.1, 145.0, 134.0, 129.8, 129.2, 123.4, 121.4, 116.6, 110.6, 93.0, 80.0, 43.5, 31.6, 28.9, 28.1, 25.6 (3C); MS (EI) m/z 458.8 [M]+, 401.7 [M- ^Bu]+; HRMS (EI) m/z calcd.for: [M]+ 457.0252, m/z found: 457.0239.
Preparation of pyrido- and azepino-indoles of Formula (IVV(IV)'
The results of the preparation of various tricyclic indole derivatives of Table 5, above are shown in Examples 4a, 4a'-4e, 4e' below.
General Procedure E for intramolecular palladium-catalyzed tandem reactions. A tube (24x150 mm) of carousel reaction station was charged with 3 (1.0 equiv.), powdered K3PO4-H2O (2.0 equiv.) and Pd2dba3 (4.0 mol %), Bu4NCl (1.0 equiv.) and the mixture was purged with argon and vacuum three times. Triethylamine (2.0 equiv.) and toluene (0.1 M) were added and the reaction stirred at 1200C until all the starting material had been consumed (typically 15-22 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na2SO4) and the solvent was evaporated to give the crude product. The residue was purified by flash chromatography (typically 2 % EtOAc in hexanes) to afford the tricyclic indole adducts 4 and 4'.
Example 4a and 4a': Preparation of (6,7-Dihydro-pyrido[l,2-a]indol-9-yl)-acetic acid tert-butyl ester and (7,8-Dihydro-6H-pyrido[l,2-a]indol-9-ylidene)-acetic acid tert-butyl ester
Figure imgf000119_0001
Following General Procedure E. A tube (24x150 mm) of carousel reaction station was charged with 3a (138.0 mg, 0.331 mmol), powdered K3PO4-H2O (135.0 mg, 0.623 mmol), Pd2dba3 (10.7 mg, 0.012 mmol, 4 mol %), Bu4NCl (81.0 mg, 0.331 mmol) and the mixture was purged with argon and vacuum three times. Triethylamine (82.0 μL,
0.623 mmol) and toluene (3.0 mL, 0.1 M) were added and the reaction stirred at 120 0C until all the starting material had been consumed (15 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with
EtOAc, the organic phase was dried (Na2SO4) and the solvent was evaporated to give the crude product. The residue was purified by flash chromatography (2 % EtOAc in hexanes) to afford the tricyclic adducts 4a and 4a'. Yield: 76 % (4a/4a': 3/1). 4a: yellow solid, mp 78-82 0C; IR (CHCl3) v 3026, 3010, 2979, 1727, 1456, 1369, 1339, 1220, 1200, 1148 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J= 7.8 Hz, IH), 7.25 (m, IH), 7.18 (t,
J= 7.7 Hz, IH), 7.05 (t, J= 7.7 Hz, IH), 6.44 (s, IH), 5.89 (t, J= 4.5 Hz, IH), 4.09 (t, J= 7.0 Hz, 2H), 3.34 (s, 2H), 2.66 (m, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.6, 137.0, 135.7, 128.3, 125.8, 123.1, 121.9, 120.7, 119.5, 108.7, 98.0, 80.9, 39.8, 39.4, 28.0 (3C), 24.3; MS (EI) m/z 283.1 [M]+; HRMS (EI) m/z calcd. for: [M]+ 283.1572, m/z found: 283.1566. 4a': yellow solid, mp 100-105 0C; IR (CHCl3) v 3007, 2979, 1692, 1618, 1476, 1368, 1249, 1141 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J= 8.0 Hz, IH), 7.31-7.20 (m, 2H), 7.10 (t, J= 7.9Hz, IH), 6.93 (s, IH), 6.41 (s, IH), 4.12 (t, J= 5.9 Hz, 2H), 3.27 (t, J= 7.2 Hz, 2H), 2.13 (quint., J= 6.1 Hz, 2H), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.5, 145.4, 137.2, 134.9, 127.4, 122.7, 121.2, 120.4, 113.7, 109.2, 98.9, 79.9, 41.7, 28.3, 25.0, 22.8 (3C); MS (EI) m/z 283.1 [M]+; HRMS (EI) m/z calcd. for: [M]+ 283.1572, m/z found: 283.1573.
Example 4b and 4b': Preparation of (2-Benzyloxy-6,7-dihydro-pyrido[l,2-a]indol-9- yl)-acetic acid tert-butyl ester and (2-Benzyloxy-7,8-dihydro-6H-pyrido[l,2-a]indol- 9-yIidene)-acetic acid tert-butyl ester
Figure imgf000120_0001
Following General Procedure E with 3b as starting material. Yield: 58 % (4b/4b': 3/1).
4b: brown oil; IR (CHCl3) v 3006, 2979, 1726, 1480, 1369, 1336, 1281, 1182, 1148 cm -"11; 1H NMR (300 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.40-7.30 (m, 3H), 7.13 (d, J= 8.8 Hz, IH), 7.11 (d, J= 2.3 Hz, IH), 6.92 (dd, J= 8.8, 2.3 Hz, IH), 6.35 (s, IH), 5.86 (t, J= 4.5 Hz, IH), 5.09 (s, 2H), 4.03 (t, J= 7.0 Hz, 2H), 3.31 (d, J= 1.1 Hz, 2H), 2.64 (m, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.6, 153.2, 137.7, 136.4, 132.6, 128.6, 128.4 (2C), 127.7, 127.5 (2C), 125.7, 122.8, 112.9, 109.3, 104.4, 97.7, 80.8, 70.9, 39.7, 39.6, 28.0 (3C), 24.3; MS (EI) m/z 389.0 [M]+, 298.0 [M-Bn]+; HRMS (EI) m/z calcd. for: [M]+ 389.1990, m/z found: 389.1989. 4b': yellow solid, mp 115-120 0C; IR (CHCl3) v 3027, 3018, 1691, 1610, 1521, 1368, 1201, 1145 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.48-7.31 (m, 5H), 7.19 (d, J= 8.9 Hz, IH), 7.09 (d, J= 2.3 Hz, IH), 6.97 (dd, J= 8.9, 2.4 Hz, IH), 6.83 (s, IH), 6.36 (t, J= 1.9 Hz, IH), 5.13 (s, 2H), 4.08 (t, J= 5.8 Hz, 2H), 3.24 (m, 2H), 2.10 (quint., J= 6.1 Hz, 2H), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.5, 153.8, 145.3, 137.5, 135.3, 133.0, 128.5 (2C), 127.8, 127.7, 127.5 (2C), 114.5, 113.4, 110.0, 103.5, 98.5, 79.9, 70.7, 41.8, 28.3 (3C), 24.8, 22.8; MS (EI) m/z 389.0 [M]+, 298.0 [M-Bn]+; HRMS (EI) m/z calcd.for: [M]+ 389.1990, m/z found: 389.1994.
Example 4c and 4c': Preparation of 9-tert-Butoxycarbonylmethyl-6,7-dihydro- pyrido[l,2-a]indole-3-carboxylic acid methyl ester and 9-tert- Butoxycarbonylmethylene-θ^S^-tetrahydro-pyridofljl-aJindoleO-carboxylic acid methyl ester
Figure imgf000121_0001
Following General Procedure E with 3c as starting material. Yield: 67 % (4c/4c': 7/1). 4c: brown oil; IR (CHCl3) v 3006, 2981, 2952, 1708, 1456, 1436, 1369, 1338, 1267, 1245, 1148 cm"1; 1H NMR (300 MHz, CDCl3) δ 8.01 (s, IH), 7.58 (dd, J= 8.3, 1.4 Hz, IH), 7.56 (d, J= 8.3 Hz, IH), 6.46 (s, IH), 5.99 (t, J= 4.5 Hz, IH), 4.16 (t, J= 7.1 Hz, 2H), 3.93 (s, 3H), 3.35 (d, J= Hz, 2H), 2.69 (m, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.3, 168.1, 138.7, 136.3, 132.0, 125.5, 125.0, 123.3, 120.7, 120.1, 111.0, 98.2, 81.1, 51.8, 39.6, 39.4, 28.0 (3C), 24.2; MS (EI) m/z 341.0 [M]+; HRMS (EI) m/z calcd. for: [M]+ 341.1627, m/z found: 341.1632. 4c': orange solid, mp 137-140 0C; IR (CHCl3) v 3026, 3014, 2953, 1697, 1607, 1436, 1367, 1241, 1201, 1146 cm"1; 1H NMR (300 MHz, CDCl3) δ 8.07 (s, IH), 7.78 (dd, J= 8.4, 1.4 Hz, IH), 7.60 (d, J= 8.4 Hz, IH), 6.93 (s, IH), 6.45 (t, J= 1.9 Hz, IH), 4.20 (t, J= 6.0 Hz, 2H), 3.94 (s, 3H), 3.28 (m, 2H), 2.16 (quint., J= 6.0 Hz, 2H), 1.53 (s, 9H); MS (EI) m/z 341.0 [M]+; HRMS (EI) m/z calcd. for: [M]+ 341.1627, m/z found: 341.1628.
Example 4d: Preparation of 9-Methyl-6,7-dihydro-pyrido[l,2-a]indoIe
Figure imgf000122_0001
Following General Procedure E with 3d as starting material but 4 mol % Pd(OAc)2 and
8 mol % P(o-tolyl)3 was used instead of Pd2dba3 (4 mol %) and Bu4NCl. Yield: 72 %, white solid, mp 74-750C; IR (CHCl3) v 3026, 3007, 1473, 1456, 1416, 1361, 1314 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J= 7.8 Hz, IH), 7.25-7.14 (m, 2H), 7.04 (t, J= 6.7
Hz, IH), 6.42 (s, IH), 5.72 (m, IH), 4.04 (t, J= 7.08 Hz, 2H), 2.57 (m, 2H), 2.09 (q, J=
1.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 137.3, 136.9, 128.4, 127.5, 121.7, 120.6,
120.2, 119.4, 108.7, 97.4, 39.6, 24.2, 18.3; MS (EI) m/z 183.2 [M]+, 168.2 [M-Me]+;
HRMS (EI) m/z calcd. for: [M]+ 183.1048, m/z found: 183.1043 (Gilchrist, T. L., Kemmitt, P.D. Tetrahedron 1997, 53, 4447).
Example 4e and 4e': Preparation of 8-Dihydro-6H-azepino[l,2-a]indoI-10-yl)-acetic acid tert-butyl ester and (6,7,8,9-Tetrahydro-azepino[l,2-a]indol-10-ylidene)-acetic acid tert-butyl ester
Figure imgf000122_0002
Following General Procedure E with 3e as starting material. Yield: 70 % (4e/4e': 2/3). 4e: white solid, 117-119 0C; IR (CHCl3) v 3020, 3009, 2979, 1724, 1464, 1393, 1368, 1324, 1220, 1148 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J= 7.8 Hz, IH), 7.28 (m, IH), 7.17 (t, J= 6.9 Hz, IH), 7.04 (t, J= 6.9 Hz, IH), 6.50 (s, IH), 5.87 (t, J= 5.4 Hz, IH), 4.25 (m, 2H), 3.39 (d, J= 0.9 Hz, 2H), 2.48 (m, 2H), 2.13 (m, 2H), 1.38 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.4, 139.0, 137.3, 130.1, 127.6, 126.1, 121.7, 120.6, 119.2, 108.8, 101.5, 80.7, 44.7, 44.2, 29.4, 28.0 (3C), 27.9; MS (EI) m/z 297.3 [M]+; HRMS (EI) m/z calcd. for: [M]+ 297.1728, m/z found: 297.1726. 4e': white solid, 95-97 0C; IR (CHCl3) v 3027, 3018, 2979, 2935, 1696, 1624, 1455, 1393, 1368, 1226, 1144 cm"1; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J= 7.9 Hz, IH), 7.29 (m, IH), 7.21 (t, J= 6.9 Hz, IH), 7.08 (t, J= 7.9 Hz, IH), 6.60 (d, J= 0.7 Hz, IH), 6.17 (s, IH), 4.17 (m, 2H), 3.12 (m, 2H), 2.00 (m, 2H), 1.89 (m, 2H), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.9, 150.7, 143.2, 138.3, 127.4, 122.2, 121.0, 119.7; 119.7, 109.2, 101.4, 80.2, 44.1, 29.4, 28.3 (3C), 27.8, 25.8; MS (EI) m/z 297.2 [M]+; HRMS (EI) m/z calcd. for: [M]+ 297.1728, m/z found: 297.1729.
Preparation of 2-alkynyl indoles of Formula (VIII)
The results of the preparation of various 2-substituted indoles of Tables 7, 8 and 9 above are shown in Examples 5a-5q below.
Example 5a: Preparation of 2-Oct-l-ynyl-lH-indole
Figure imgf000123_0001
To a tube (24x150 mm) of Carousel reaction station was charged with ortho-gem- dibromovinylaniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(p-MeOPh)3 (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and the tube was evacuated and purged with argon three times followed by addition of toluene (3 mL, degassed), /Pr2NH (175 μL, 1.25 mmol), and 1- octyne (110 μL, 0.75 mmol). The reaction mixture was heated to 100 0C for 1.5 h. H2O (10 mL) was added, and the mixture was extracted with EtOAc (2 x 15 mL), and dried over MgSO4. The crude material after removal of solvent was purified by flash chromatography using 3% EtOAc in hexane to afford the titled compound as a pale yellow oil (93.5 mg, 83%). IR (neat, cm"1) 3410, 2931, 2858, 2231, 1453, 1349, 1296, 1145. 1H NMR (300 MHz, CDCl3) δ 8.07 (IH, br), 7.55 (IH, d, J= 7.9 Hz), 7.26 (IH, d, J= 8.0 Hz), 7.19 (IH, J= 7.6, 7.6, 0.9 Hz), 7.09 (IH, ddd, J= 7.4, 7.4, 1.2 Hz), 6.65 (IH, m), 2.44 (2H, t, J = 7.1 Hz), 1.66-1.56 (2H, m), 1.49-1.41 (2H, m), 1.34-1.28 (4H, m), 0.91 (3H, t, J = 6.8 Hz) ); 13C NMR (100 MHz, CDCl3) δ 135.9, 128.0, 123.1, 120.7, 120.4, 119.8, 110.7, 107.6, 94.1, 73.2, 31.6, 28.8, 28.7, 22.7, 19.8, 14.3. HRMS (ESI) calc'd for Ci6H19N ([M]+): 225.1518. Found: 225.1517. Example 5b: Preparation of 2-Phenylethynyl-lH-indole
Figure imgf000124_0001
To a 10 niL round-bottomed flask was charged with 10% Pd-C (26.6 mg, 0.025 mmol) and PPh3 (14.4 mg, 0.055 mmol), and the flask was purged with argon for at least 10 min. To the second separate flask was charged with ørt/20-gewz-dibromovinylaniline (0.139 g, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and the flask was purged with argon for 10 min, followed by addition of toluene (5 mL), phenylacetylene (82 μL, 0.75 mmol), and /Pr2NH (174 μL, 1.25 mmol). After the mixture in the second flask became homogenous, it was cannulated into the first flask, and the resulting mixture was heated at 100 0C for 1 h. The mixture was diluted with Et2O (30 mL), washed with H2O (20 mL), brine (15 mL), and dried over MgSO4. The crude material after removal of solvent was purified by flash chromatography using 5 -»10% EtOAc in hexane to give the title compound as a pale yellow solid (0.088 g, 85%). mp 161-162 0C. IR (neat, cm"1): 3384, 3052, 2213, 1596, 1482, 1442, 1398, 1353, 1308, 1235, 1104. 1H NMR (300 MHz, CDCl3) δ 8.22 (IH, br), 7.60 (IH, d, J - 7.9 Hz), 7.56-7.52 (2H, m), 7.37-7.32 (4H, m), 7.24 (IH, ddd, J = 7.6, 7.6, 1.0 Hz), 7.13 (IH, ddd, J= 7.5, 7.5, 0.9 Hz), 6.84 (IH, d, J= 1.6 Hz); 13C NMR (75 MHz, CDCl3) δ 136.4, 131.7, 128.8, 128.0, 123.8, 122.8, 121.1, 120.7, 119.0, 110.9, 109.1, 92.8, 82.0.
Example 5c: Preparation of 5-(lH-Indol-2-yl)-pent-4-yn-l-ol
Figure imgf000124_0002
To a 10 mL round-bottomed flask was charged with 10% Pd-C (26.6 mg, 0.025 mmol) and PPh3 (14.4 mg, 0.055 mmol), and the flask was purged with argon for at least 10 min. To the second separate flask was charged with ørt/20-gem-dibromovinylaniline (0.139 g, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and the flask was purged with argon for 10 min, followed by addition of toluene (5 mL), pent-4-yn-l-ol (69 μL, 0.75 mmol), and /Pr2NH (174 μL, 1.25 mmol). After the mixture in the second flask became homogenous, it was cannulated into the first flask, and the resulting mixture was heated at 100 °C for 1 h. The mixture was diluted with Et2O (30 mL), washed with H2O (20 mL), brine (15 mL), and dried over MgSO4. The crude material was purified by flash chromatography using 3.5->5% EtOAc in hexane to afford the product as a pale yellow oil (0.065 g, 65%). IR (neat, cm"1): 3541, 3396, 2948, 2233, 1451, 1350, 1296, 1046. 1H NMR (300 MHz, CDCl3) δ 8.35 (IH, br), 7.55 (IH, d, J= 7.9 Hz), 7.25 (IH, d, J= 8.1 Hz), 7.18 (IH, J = 7.6, 7.6, 1.1 Hz), 7.09 (IH, ddd, J= 7.5, 7.5, 0.9 Hz), 6.65 (IH, d, J= 1.5 Hz), 3.80 (2H, t, J= 5.3 Hz), 2.56 (2H, t, J= 7.0 Hz), 1.97 (IH, br), 1.85 (2H, quintet, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 136.0, 127.9, 123.2, 120.8, 120.4, 119.4, 110.9, 107.7, 92.9, 73.8, 61.8, 31.3, 16.3. HRMS (EI) calc'd for Ci3Hi3NO ([M]+): 199.0997. Found: 199.0995.
Example 5d: Preparation of 2-[5-(Tetrahydropyran-2-yloxy)-pent-l-ynyl]-lH- indole
Figure imgf000125_0001
To a 10 mL round-bottomed flask was charged with 10% Pd-C (26.6 mg, 0.025 mmol) and PPh3 (14.4 mg, 0.055 mmol), and the flask was purged with argon for at least 10 min. To the second separate flask was charged with ort/zo-gem-dibromovinylaniline (0.139 g, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and the flask was purged with argon for 10 min, followed by addition of toluene (5 mL), 2-pent-4-ynyloxytetrahydropyran (0.115 g, 0.676 mmol), and /Pr2NH (174 μL, 1.25 mmol). After the mixture in the second flask became homogenous, it was cannulated into the first flask, and the resulting mixture was heated at 100 0C for 1 h. The crude material was purified by flash chromatography using 15→20% EtOAc in hexanes to afford the product as a slightly yellow oil (0.105 g, 71%). IR (neat, cm"1): 3406, 3283, 2944, 2870, 2244, 1452, 1350, 1296, 1137, 1119, 1033. 1H NMR (300 MHz, CDCl3) δ 8.27 (IH, br), 7.55 (IH, d, J = 7.8 Hz), 7.28 (IH, d, J = 8.1 Hz), 7.19 (IH, J = 7.5, 7.5, 0.9 Hz), 7.09 (IH, t, J = 7.6 Hz), 6.64 (IH, d, J = 1.8 Hz), 4.65 (IH, t, J = 3.4 Hz), 3.95-3.88 (2H, m), 3.59-3.50 (2H, m), 2.58 (2H, t, J= 7.1 Hz), 1.96-1.70 (4H, m), 1.63-1.54 (4H, m); 13C NMR (75 MHz, CDCl3) δ 135.9, 127.9, 123.1, 120.8, 120.4, 119.6, 110.8, 107.6, 99.1, 93.2, 73.6, 66.1, 62.5, 30.9, 28.9, 25.7, 19.7, 16.7. HRMS (EI) calc'd for Ci8H2iNO2 ([M]+): 283.1572. Found: 283.1572.
Example 5e: Preparation of 3-(l//-Indol-2-yl)prop-2-yn-l-ol
Figure imgf000126_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-Dibromovinyl)aniline (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (9.2 mg, 0.0087 mmol, 2 mol%), P(P-MeOPh)3 (12.0 mg, 0.034 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (157 μL, 1.12 mmol) and propargyl alcohol (0.30 ml, 5.2 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 50→ 60% EtOAc in hexane to afford the titled compound as a pale brown solid (29.6 mg, 40%). m.p.:49-51°C; IR (CHCl3) v 3398, 2923, 2228, 1450, 1403, 1350, 1299, 1229, 1038, 1012 cm"1; 1H-NMR (CDCl3) δ: 8.19 (IH, s), 7.58 (IH, d, J= 7.6 Hz), 7.19-7.19 (2H, m), 7.12 (IH, t, J= 7.3 Hz), 6.76 (IH, br s), 4.54 (2H, s), 1.82 (IH, br s); 13C NMR (75 MHz, CDCl3) δ 127.7, 123.9, 121.1, 120.7, 111.0, 109.3, 90.8, 51.8; HRMS (EI) m/z calcd.for: [M]+ 171.0684, m/z found: 171.0682.
Example 5f: Preparation of 2-TrimethylsilanylethynyI-l//-indole
Figure imgf000126_0002
A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 2 mol%), P(P-OMePh)3 (14.2 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (175 μL, 1.25 mmol) and trimethylsilylacetylene (0.71 ml, 5.0 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 10% EtOAc in hexane to afford the titled compound as a pale brown solid (61.0 mg, 57%). m.p.: 91-92°C; IR (CHCl3) v 3402, 2961, 2157, 1398, 1343, 1249 cm"1; 1H-NMR (CDCl3) δ: 8.16 (IH, br s), 7.57 (IH, d, J = 7.9 Hz), 7.29 (IH, dd, J = 7.9, 1.2 Hz), 7.22 (IH, td, J = 7.9, 1.2 Hz), 7.11 (2H, td, J = 7.9, 1.2 Hz), 6.77 (IH, d, J = 1.2 Hz), 0.27 (9H, s); 13C NMR (75 MHz, CDCl3) δ 135.8, 127.4, 123.6, 120.9, 120.4, 118.5, 110.6, 109.2, 98.3, 96.8, -0.20; HRMS (EI) m/z calcd. for: [M]+ 213.0974, m/z found: 213.0974.
Example 5g: Preparation of 6-(l//-Indol-2-yl)hex-5-ynenitrile
Figure imgf000127_0001
A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%), PO-OMePh)3 (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (180 μL, 1.28 mmol) and 5-hexynenitrile (80 μL, 0.75 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 25% EtOAc in hexane to afford the titled compound as a pale brown oil (52.3 mg, 50%). IR (CHCl3) v 3390, 2358, 1995, 1350, 1295 cm"1; 1H- NMR (CDCl3) δ: 8.23 (IH, s), 7.56 (IH, d, J= 7.9 Hz), 7.33-7.07 (3H, m), 6.68 (IH, br s), 2.65 (2H, t, J = 6.7 Hz), 2.56 (2H, t, J = 7.0 Hz), 2.03-1.92 (2H, m); 13C NMR (75 MHz, CDCl3) δ 136.0, 127.8, 123.5, 120.9, 120.6, 119.4, 118.8, 110.9, 108.2, 90.6, 75.2, 24.5, 19.0, 16.5; HRMS (EI) m/z calcd.for: [M]+ 208.1000, m/z found: 208.0996.
Example 5h: Preparation of 2-(6-Chlorohex-l-ynyl)-l//-indole
Figure imgf000128_0001
A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%), P(p-MeOPh)3 (12.0 mg, 0.034 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 rnL, degassed), Z-Pr2NH (175 μL, 1.25 mmol) and 6-chloro-l-hexyne (80 μL, 0.75 mmol), and then heated to 100 0C with stirring for 48 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a pale yellow oil (81.3 mg, 70%). IR (CHCl3) v 3405, 2950, 1615, 1538, 1451, 1349, 1295 cm"1; 1H-NMR (CDCl3) δ: 8.08 (IH, s), 7.55 (IH, d, J= 7.9 Hz), 7.33-7.05 (3H, m), 6.66
(IH, d, J= 1.5 Hz), 3.60 (2H, t, J= 6.4 Hz), 2.50 (2H, t, J= 6.9 Hz), 2.02-1.71 (4H, m);
13C NMR (75 MHz, CDCl3) δ 135.9, 127.9, 123.3, 120.8, 120.5, 119.4, 110.8, 107.9,
93.0, 73.8, 44.7, 31.9, 25.9, 19.1; HRMS (ESI) m/z calcd. for: [M+H]+ 232.0890, m/z found: 232.0887.
Example 5i: Preparation of 2-Pyridin-3-ylethynyl-lH-indole
Figure imgf000129_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(P-MeOPh)3 (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), zPr2NH (175 μL, 1.25 mmol) and 3-ethynylpyridine (80.0 mg, 0.77 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 40% EtOAc in hexane to afford the titled compound as a colorless solid (88.0 mg, 81%). m.p.: 209-2110C; IR (CHCl3) v 3403, 2157, 1652, 1558, 1539, 1506, 1457, 1249 cm"1; 1H-NMR (CDCl3) δ: 8.83 (IH, s), 8.60 (IH, s), 7.83 (IH, dt, J= 8.1, 1.8 Hz), 7.63 (IH, d, J= 8.1 Hz), 7.41-7.22 (4H, m), 7.19-7.10 (IH, m), 6.89 (IH, dd, J = 2.1, 0.9 Hz); 13C NMR (75 MHz, OMSO-d6) δ 152.0, 149.7, 139.0, 137.2, 127.7, 124.4, 123.9, 121.2, 120.6, 119.8, 118.1, 112.0, 109.0, 89.2, 86.5; HRMS (EI) m/z calcd.for: [M]+ 218.0844, m/z found: 218.0846.
Example 5j: Preparation of l-Methyl-2-oct-l-ynyl-l.H-indole
Figure imgf000129_0002
To a solution of [2-(2,2-dibromovinyl)phenyl]amine (1.15 g, 4.15 mmol), formaldehyde (37 wt. % solution in H2O, 400 mg), acetic acid (0.5 mL) in dichloroethane (3 mL) and MeOH (3 mL) was added sodium triacetoxyborohydride (1.10 g, 5.19 mmol) at 00C, and the mixture was stirred for 24 h at rt. The solvent was removed in vacuo and the resultant crude material was dissolved with EtOAc (50 mL) and sat. NaHCO3 (20 rnL). The mixture was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered and then concentrated in vacuo. The resulting material was purified by flash chromatography eluting with 3%→ 5% EtOAc in hexane to yield [2-(2,2-dibromovinyl)phenyl]methylamine as a pale yellow oil (495 mg, 41%). IR (CHCl3) v 3418, 2913, 2815, 1602, 1520, 1316, 1259, 1166cm"1; 1H-NMR (CDCl3) δ: 7.31-7.23 (3 H, m), 6.73 (IH, dt, J = 7.6, 0.9 Hz), 6.64 (IH, d, J = 8.5 Hz), 3.65 (IH, br s), 2.87 (3H, s); 13C NMR (75 MHz, CDCl3) δ 146.2, 134.3, 130.1, 129.3, 121.7, 116.9, 110.3, 93.2, 30.8; HRMS (EI) m/z calcd. for: [M]+ 288.9102, m/z found: 288.9103
A carousel reaction tube (24x150 mm) was charged with [2-(2,2- dibromovinyl)phenyl]methylamine (130 mg, 0.45 mmol), Pearlman's catalyst (Degussa E4) (14.2 mg, 0.013 mmol, 3 mol%), P(^-MeOPh)3 (6.3 mg, , 0.018 mmol, 4 mol%), and CuI (1.7 mg, 0.0089 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (190 μL, 1.34 mmol) and 1-octynye (100 μL, 0.67 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 1%→ 3% EtOAc in hexane to afford the titled compound as a pale yellow oil (65.1 mg, 61%). IR (CHCl3) v 2928, 2856, 1462, 1385, 1340, 1313, 1237 cm"1; 1H-NMR (CDCl3) δ: 7.54 (IH, dt, J = 7.9, 1.0 Hz), 7.27- 7.18 (2H, m), 7.12-7.05 (IH, m), 6.65 (IH, s), 3.77 (3H, s), 2.50 (2H, t, J= 7.0 Hz), 1.71- 1.59 (2H, m), 1.55-1.26 (6H, m), 0.91 (3H, t, J= 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 136.8, 127.2, 122.9, 122.4, 120.6, 119.8, 109.2, 106.0, 96.6, 72.2, 31.3, 30.4, 28.6(2C), 22.5, 19.6, 14.0; HRMS (EI) m/z calcd. for: [M]+ 239.1674, m/z found: 239.1678.
Example 5k: Preparation of l-Isopropyl-2-oct-l-ynyl-lH-indole
Figure imgf000131_0001
A carousel reaction tube (24x150 mm) was charged with [2-(2,2-dibromovinyl)- phenyljisopropylamine (160 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (26.5 mg, 0.025 mmol, 5 mol%), P(p-MeOPh)3 (14.1 mg, , 0.040 mmol, 8 mol%), and CuI (6.0 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (210 μL, 1.49 mmol) and 1- octynye (110 μL, 0.75 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting 2.5% EtOAc in hexane to afford the titled compound as a pale yellow oil (80.0 mg, 60%). IR (CHCl3) v 2929, 2856, 2361, 2340, 1454, 1408, 1352, 1313, 1192 cm'1; 1H-NMR (CDCl3) δ: 7.54 (IH, d, J = 7.9 Hz), 7.42 (IH, d, J = 8.5 Hz), 7.21-7.13 (IH, m), 7.10-7.02 (IH, m), 6.65 (IH, s), 5.04-4.88 (IH, m), 2.49 (2H, t, J= 7.0 Hz), 1.70-1.28 (8H, m), 1.64 (6H, d, J= 7.0 Hz), 0.91 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 135.2, 128.1, 122.1, 121.7, 121.0, 119.6, 110.8, 107.5, 96.9, 73.3, 48.3, 31.5, 28.8, 28.7, 22.8, 21.8, 19.9, 14.2; HRMS (EI) m/z calcd. for: [M]+ 267.1987, m/z found: 267.1987.
Example 51: Preparation of l-Benzyl-2-oct-l-ynyl-l//-indole
Figure imgf000131_0002
A carousel reaction tube (24x150 mm) was charged with Benzyl[2-(2,2- dibromovinyl)phenyl]amine (120 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (23.7 mg, 0.022 mmol, 7 mol%), P(^-MeOPh)3 (11.2 mg, , 0.033 mmol, 10 mol%), and CuI (6.0 mg, 0.033 mmol, 10 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (115 μL, 0.82 mmol) and 1-octynye (72 μL, 0.49 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2.5% EtOAc in hexane to afford the titled compound as a pale yellow solid (52.6 mg, 51%). m.p.: 43-44°C; IR (CHCl3) v 3029, 2927, 2855, 1454, 1391, 1345, 1312, 1161 cm"1; 1H-NMR (CDCl3) δ: 7.58-7.54 (IH, m), 7.34-7.04 (8H, m), 6.73 (IH, s), 5.41 (2H, s), 2.44 (2H, t, J= 7.0 Hz), 1.62-1.23 (8H, m), 0.87 (3H, t, J= 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 138.1, 136.5, 128.8, 127.8, 127.5, 126.9, 122.8, 120.9, 120.3, 122.8, 120.9, 120.3, 110.1, 106.8, 97.1, 72.5, 48.0, 31.5, 28.8, 28.7, 22.7, 19.9, 14.2; HRMS (EI) m/z calcd. for: [M]+ 315.1987,
Figure imgf000132_0001
Example 5m: Preparation of 2-Oct-l-ynyl-l-phenyl-lH-indole
Figure imgf000132_0002
A carousel reaction tube (24x150 mm) was charged with [2-(2,2- dibromovinyl)phenyl]phenylamine (130 mg, 0.37 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (3.9 mg, 0.0037 mmol, 1 mol%), P(/?-MeOPh)3 (5.2 mg, , 0.015 mmol, 4 mol%), and CuI (1.4 mg, 0.0074 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (134 μL, 0.97 mmol) and 1-octynye (81 μL, 0.55 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2% EtOAc in hexane to afford the titled compound as a colorless oil (72.1 mg, 65%). IR (CHCl3) v 3057, 2928, 2854, 1596, 1499, 1449, 1377, 1360, 1330, 1314, 1241, 1201, 1144 cm"1; 1H- NMR (CDCl3) δ: 7.63-7.37 (6H, m), 7.24-7.09 (3 H, m), 6.82 (IH, s), 2.32 (2H, t, J= 7.0 Hz), 1.39-1.39 (2H, m), 1.15-1.14 (6H, m), 0.87 (3H, t, J= 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 138.0, 137.3, 129.3, 129.1, 127.8, 127.6, 127.5, 123.2, 122.9, 120.8, 110.6, 108.4, 96.9, 72.8, 31.5, 28.6, 28.4, 22.7, 19.7, 14.3; HRMS (EI) m/z calcd. for: [M]+ 301.1831, m/z found: 301.1834.
Example 5n: Preparation of 2-Oct-l-ynyl-l//-benzo[i*]indole
Figure imgf000133_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2- dibromovinyl)naphthalen-l-ylamine (110 mg, 0.34 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (7.1 mg, 0.0066 mmol, 2 mol%), P(p-MeOPh)3 (4.6 mg, 0.013 mmol, 4 mol%), and CuI (2.8 mg, 0.0066 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (120 μL, 0.84 mmol) and 1-octynye (80 μL, 0.54 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a pale brown solid (51.0 mg, 55%). m.p.: 90- 910C; IR (CHCl3) v 3414, 2930, 1519, 1393 cm"1; 1H-NMR (CDCl3) δ: 8.83 (IH, s), 7.85-7.85 (2H, m), 7.61 (IH, d, J= 8.8 Hz), 7.54-7.37 (3H, m), 6.78 (IH, d, J= 2.1 Hz), 2.48 (2H, t, J= 7.0 Hz), 1.72-1.23 (8H, m), 0.92 (3H, t, J= 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 131.0, 130.6, 129.1, 125.8, 124.4, 124.0, 121.5, 121.4, 120.6, 119.7, 118.0, 109.2, 93.9, 73.2, 31.6, 28.9, 28.8, 22.8, 19.8, 14.3; HRMS (EI) m/z calcd. for: [M]+ 275.1674, m/z found: 275.1679.
Example 5o: Preparation of 4-Benzyloxy-5-methoxy-2-oct-l-ynyl-lH-indole
Figure imgf000134_0001
A carousel reaction tube (24χ150 mm) was charged with 3-benzyloxy-2-(2,2- dibromovinyl)-4-methoxyphenylamine (136 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (7.0 mg, 0.0066 mmol, 2 mol%), P(^-MeOPh)3 (4.6 mg, 0.013 mmol, 4 mol%), and CuI (1.3 mg, 0.0063 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (140 μL, 1.0 mmol) and 1-octynye (118 μL, 0.85 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 5% EtOAc in hexane to afford the titled compound as a colorless oil (96.0 mg, 81%). IR (CHCl3) v 3334, 3031, 2930, 2857, 1583, 1504, 1463, 1454, 1428, 1331, 1282, 1245, 1174, 1093 cm"1; 1H-NMR (CDCl3) δ: 7.98 (IH, s), 7.55-7.48 (2H, m), 7.41-7.27 (3H, m), 6.94 (2H, t, J= 9.4 Hz), 6.69 (IH, d, J= 2.1 Hz), 5.21 (2H, s), 3.87 (3H, s), 2.43 (2H, t, J= 7.0 Hz), 1.67-1.24 (8H, m), 0.91 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 145.5, 140.8, 138.4, 133.0, 128.5, 128.2, 127.9, 123.4, 120.1, 113.3, 105.9, 105.1, 94.1, 75.2, 73.0, 58.6, 31.5, 28.8, 28.7, 22.7, 19.7, 14.2; HRMS (EI) m/z calcd. for: [M]+ 361.2042, m/z found: 361.2046.
Example 5p: Preparation of 4-Fluoro-2-oct-l-ynyl-lH-indole
Figure imgf000135_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-3- fluorophenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound; 150 mg, 0.51 mmol), Pearlman's catalyst (Degussa E4)) (10.6 mg, 0.010 mmol, 2 mol%), P(^-MeOPh)3 (7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), *Pr2NH (180 μL, 1.25 mmol) and 1-octynye (110 μL, 0.75 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 5% EtOAc in hexane to afford the titled compound as a pale yellow oil (88.0 mg, 72%). IR (CHCl3) v 3412, 2925, 2856, 1582, 1534, 1507, 1351, 1237, 1168, 1036 cm"1; 1H-NMR (CDCl3) δ: 8.15 (IH, s), 7.15-7.02 (2H, m), 6.80-6.69 (2H, m), 2.44 (2H, t, J= 7.0 Hz), 1.68-1.24 (8H, m), 0.91 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 156.1 (JCF = 246.0 Hz), 138.1 (JCF = 10.5 Hz), 123.6 (JCF = 7.5 Hz), 119.9, 117.2, 106.8 (JCF = 3.8 Hz), 105.1 (JCF = 18.8 Hz), 103.5, 94.5, 72.6, 31.5, 28.8, 28.6, 22.7, 19.7, 14.2; HRMS (ESI) m/z calcd. for: [M+H]+ 244.1495, m/z found: 244.1496.
Example 5q: Preparation of l-Oct-l-ynyl-lH-indole-S-carboxylic acid methyl ester
Figure imgf000135_0002
A carousel reaction tube (24x 150 mm) was charged with 4-amino-3-(2,2- dibromovinyl)benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound; 110 mg, 0.33 mmol), Pearlman's catalyst (Degussa E4) (17.5 mg, 0.017 mmol, 5 mol%), P(/?-MeOPh)3 (9.2 mg, 0.026 mmol, 8 mol%), and CuI (2.7 mg, 0.014 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (140 μL, 1.00 mmol) and 1-octynye (80 μL, 0.54 mmol), and then heated to 100 0C with stirring for 24 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 10% EtOAc in hexane to afford the titled compound as a pale brown solid (78.1 mg, 84%). m.p.:87- 880C; IR (CHCl3) v 3317, 2931, 2857, 1694, 1615, 1538, 1435, 1347, 1315, 1259, 1156 cm"1; 1H-NMR (CDCl3) δ: 8.42-8.30 (2H, m), 7.90 (IH, dd, J= 8.6, 1.8 Hz), 7.29 (IH, d, J = 8.6 Hz), 6.72 (IH, s), 3.92 (3H, s), 2.44 (2H, t, J= 7.0 Hz), 1.22-1.22 (8H, m), 0.91 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 168.2, 138.4, 127.6, 124.5, 123.7, 122.6, 121.3, 110.4, 108.6, 95.1, 72.5, 52.0, 31.5, 28.8, 28.6, 22.7, 19.7, 14.2; HRMS (EI) m/z ceded, for: [M]+ 283.1572, m/z found: 283.1577.
Preparation of 2-alkvnyl benzofblfurans of Formula (X)
The results of the preparation of various 2-substituted indoles of Tables 9 and 10 above are shown in Examples 6a-6n below.
Example 6a: Preparation of 2-Oct-l-ynylbenzofuran
Figure imgf000136_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (115 mg, 0.41 mmol), Pearlman's catalyst (Degussa E4) (4.4 mg, 0.0041 mmol, 1 mol%), P(^-MeOPh)3 (5.8 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0083 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (145 μL, 1.03 mmol) and 3-ethynylpyridine (83 μL, 0.75 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with
EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4CI and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2% EtOAc in hexane to afford the titled compound as a colorless solid (74.5 mg, 80%). IR (CHCl3) v 2927, 2855, 2230, 1567, 1448, 1349,
1304, 1253, 1196, 1156, 1141, 1107, 1009 cm"1; 1H-NMR (CDCl3) δ: 7.55-7.49 (IH, m),
7.45-7.40 (IH, m), 7.33-7.18 (2H, m), 6.81 (IH, s), 2.48 (2H, t, J = 7.0 Hz), 1.71-1.24
(8H, m), 0.91 (3H, t, J= 6.9 Hz); 13C NMR (75 MHz, DMSO-J6) δ 139.5, 125.2, 123.2, 121.1, 111.2, 110.2, 97.3, 71.4, 31.5, 28.8, 28.4, 22.7, 19.8, 14.2; HRMS (EI) m/z calcd. for: [M]+ 226.1358, m/z found: 226.1356.
Example 6b: Preparation of (2-Phenylethynyl)benzofuran
Figure imgf000137_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.;
Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0043 mmol, 1 mol%), P(^-MeOPh)3
(7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (176 μL, 1.25 mmol) and phenylacetylene (83 μL, 0.75 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 1% EtOAc in hexane to afford the titled compound as a colorless solid (77.7 mg, 71%). m.p.: 71-72°C; IR (CHCl3) v 2926, 2857, 1595, 1499, 1450, 1377, 1313 cm4; 1H-NMR (CDCl3) δ: 7.62-7.55 (3H, m), 7.48 (IH, d, J= 7.9 Hz), 7.42-7.23 (5H, m), 7.02 (IH, s); 13C NMR (75 MHz, DMSO-J6) δ 154.9, 138.7, 131.6, 129.1, 128.5, 127.7, 125.6, 123.3, 121.8, 121.2, 111.6, 111.2, 95.0, 79.6; HRMS (EI) m/z calcd. for: [M]+ 218.0732, m/z found: 218.0732.
Example 6c: Preparation of (4-Benzofuran-2-yl)but-3-yn-l-ol
Figure imgf000138_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(p-MeOPh)3 (6.0 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (157 μL, 1.12 mmol) and 3-butyn-l-ol (50 μL, 0.65 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 20%→ 30% EtOAc in hexane to afford the titled compound as a pale yellow oil (50.6 mg, 63%). IR (CHCl3) v 3376, 2886, 2234, 1566, 1471, 1448, 1350, 1304, 1253, 1190, 1158, 1141, 1108, 1043, 1010 cm"1; 1H-NMR (CDCl3) δ: 7.54 (IH, d, J= 8.4 Hz), 7.43 (IH, d, J= 8.4 Hz), 7.35-7.19 (2H, m), 6.87 (IH, s), 3.87 (2H, q, J = 6.3 Hz), 2.78 (2H, t, J = 6.3 Hz), 1.80 (IH, t, J = 6.3 Hz); 13C NMR (75 MHz, DMSO-rf6) δ 154.7, 138.8, 127.8, 125.6, 123.4, 121.3, 111.3, 111.0, 93.4, 73.2, 60.9, 24.2; HRMS (EI) m/z calcd. for: [M]+ 186.0685, m/z found: 186.0681.
Example 6d: Preparation of (3-Benzofuran-2-yl)prop-2-yn-l-ol
Figure imgf000139_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(p-MeOPh)3 (6.0 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (157 μL, 1.12 mmol) and propargyl alcohol (0.10 ml, 1.30 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 33% EtOAc in hexane to afford the titled compound as a colorless oil (36.0 mg, 49%). IR (CHCl3) v 3350, 2224, 1566, 1448, 1349, 1306, 1265, 1189, 1157, 1141, 1108, 1027 cm"1; 1H-NMR (CDCl3) O: 7.55 (IH, d, J= 7.6 Hz),
7.45 (IH, d, J = 7.3 Hz), 7.38-7.20 (2H, m), 6.95 (IH, s), 4.56 (2H, d, J = 6.0 Hz), 1.80
(IH, t, J = 6.0 Hz); 13C NMR (75 MHz, DMSO-J6) δ 155.0, 137.9, 127.6, 125.9, 123.5,
121.5, 112.2, 111.5, 93.5, 76.5, 51.7; HRMS (EI) m/z calcd. for: [M]+ 172.0532, m/z found: 172.0524.
Example 6e: Preparation of [(3-Benzofuran-2-yl)prop-2-ynyloxy]-tert- butyldiphenylsilane
Figure imgf000139_0002
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol
[prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (140 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0050 mmol, 1 mol%), P(^-MeOPh)3 (7.1 mg, 0.020 mmol, 4 mol%), and CuI (1.9 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (175 μL, 1.25 mmol) and tert- butyldiphenylprop-2-ynyloxysilane (221 mg, 0.75 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 4% EtOAc in hexane to afford the titled compound as a colorless oil (165 mg, 80%). IR (CHCl3) v 3071, 2931, 2857, 1589, 1568, 1471, 1463, 1450, 1428, 1372, 1255, 1191, 1113 cm"1; 1H-NMR (CDCl3) δ: 7.78-7.72 (4H, m), 7.57-7.20 (1OH, m), 6.86 (IH, d, J= 0.6 Hz), 4.58 (2H, s), 1.09 (9H, s); 13C NMR (75 MHz, DMSO-J6) δ 154.7, 138.3, 135.6, 132.8, 129.9, 127.8, 127.5, 125.5, 123.2, 121.1, 111.7, 111.2, 93.7, 75.5, 53.0, 26.7, 19.2; HRMS (EI) m/z calcd.for: [M]+ 410.1702, m/z found: 410.1704.
Example 6f : Preparation of Benzofuran-2-ylethynyltrimethylsilane
Figure imgf000140_0001
A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (140 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 1 mol%), P(^-OMePh)3 (7.1 mg, 0.02 mmol, 4 mol%), and CuI (1.9 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (180 μL, 1.28 mmol) and trimethylsilylacetylene (0.71 ml, 5.0 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 0.2% EtOAc in hexane to afford the titled compound as a colorless oil (50.0 mg, 47%). IR (CHCl3) v 2960, 2900, 2160, 1557, 1448, 1413, 1352, 1307, 1252, 1181, 1108, 1010 cm"1; 1H-NMR (CDCl3) δ: 7.25 (IH, d, J= 7.6 Hz), 7.14 (IH, d, J= 8.5 Hz), 7.07-6.90 (2H, m), 6.65 (IH, s), 0.03 (9H, t, J = 11.7 Hz); 13C NMR (75 MHz, DMSO- d6) δ 155.0, 138.8, 127.7, 126.1, 123.6, 121.6, 123.6, 121.6, 112.3, 111.6, 102.2, 94.6, 0.0; HRMS (EI) m/z calcd.for: [M]+ 214.0814, m/z found: 214.0820.
Example 6g: Preparation of (6-Benzofuran-2-yl)hex-5-ynenitrile
Figure imgf000141_0001
A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(^-MeOPh)3 (6.1 mg, 0.017 mmol, 4 mol%), and CuI (1.7 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (160 μL, 1.18 mmol) and 5-hexynenitrile (70 μL, 0.65 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a colorless oil (68.5 mg, 76%). IR (CHCl3) v 3061, 2945, 2246, 1732, 1568, 1450, 1428, 1351, 1306, 1253, 1199, 1158, 1142, 1109, 1010 cm'1; 1H-NMR (CDCl3) δ: 7.54 (IH, d, J = 7.6 Hz), 7.44 (IH, d, J= 8.2 Hz), 7.37-7.20 (2H, m), 6.87 (IH, s), 2.70 (2H, t, J= 6.9 Hz), 2.58 (2H, t, J= 6.9 Hz), 2.03 (2H, q, J= 6.9 Hz); 13C NMR (75 MHz, DMSO-J6) δ 154.8, 138.6, 127.7, 125.7, 123.4, 121.3, 119.1, 111.3, 111.2, 93.6, 73.3, 24.4, 18.9, 16.5; HRMS (EI) m/z calcd.for: [M]+ 209.0841, m/z found: 209.0839.
Example 6h: Preparation of 3-Benzofuran-2-ylethynyl-pyridine
Figure imgf000142_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0043 mmol, 1 mol%), P(p-OMePh)3 (7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr2NH (180 μL, 1.28 mmol) and 3-ethynylpyridine (77.8 mg, 0.75 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 25%→ 30% EtOAc in hexane to afford the titled compound as a colorless solid (67.3 mg, 61%). m.p.: 75-76°C; IR (CHCl3) v 2357, 1558, 1506, 1472, 1447, 1407, 1257, 1169, 947 cm"1; 1H-NMR (CDCl3) δ: 8.83 (IH, s), 8.60 (IH, s), 7.86 (IH, dt, J = 7.9, 1.8 Hz), 7.60 (IH, d, J = 7.6 Hz), 7.49 (IH, d, J = 8.2 Hz), 7.40-7.23 (3H, m), 7.07 (IH, s); 13C NMR (75 MHz, DMSO-J6) δ 155.2, 152.4, 149.5, 138.6, 127.7, 126.2, 123.6, 123.3, 121.6, 112.7, 111.5, 91.8, 83.1; HRMS (EI) m/z calcd. for: [M]+ 219.0684, m/z found: 219.0683.
Example 6i: Preparation of (8^,95,135,145,17S)-17-Benzofuran-2-ylethynyl-13- methyl-7,8,9,ll,12,13,14,15,16,17-decahydro-6H-cyclopenta[fl]phenanthrene-3,17- diol
Figure imgf000143_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (100 mg, 0.36 mmol), Pearlman's catalyst (Degussa E4) (3.8 mg, 0.0036 mmol, 1 mol%), P(p-OMePh)3 (5.1 mg, 0.014 mmol, 4 mol%), and CuI (1.4 mg, 0.0072 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (180 μL, 1.28 mmol) and 17-α- ethynylestradiol (148 mg, 0.54 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 35%→ 40% EtOAc in hexane to afford the titled compound as a colorless solid (102.0 mg, 69%). m.p.: 208-2100C; IR (CHCl3) v 3378, 3017, 2913, 2398, 1578, 1493, 1436, 1358, 1216, 1134, 1108, 1059, 1006 cm-1; 1H- NMR (DMSO-J6) δ: 8.98 (IH, s), 7.61 (IH, d, J = 7.0 Hz), 7.55 (IH, d, J = 8.5 Hz), 7.39- 7.19 (3H, m), 7.05 (IH, d, J= 8.5 Hz), 6.50 (IH, dd, J= 8.4, 2.4 Hz), 6.42 (IH, d, J= 2.4 Hz), 5.74 (IH, s), 2.70 (2H, s), 2.38-2.18 (2H, m), 2.15-1.90 (2H, m), 1.86-1.56 (5H, m), 1.48-1.16 (4H, m), 0.92 (3H, s); 13C NMR (75 MHz, DMSO-J6) δ 155.6, 154.7, 138.6, 137.8, 130.8, 127.9, 126.8, 126.4, 124.1, 122.0, 115.6, 113.4, 111.9, 111.7, 101.9, 79.5, 75.5, 50.2, 48.0, 43.9, 33.6, 29.8, 27.6, 26.8, 23.3, 13.5.
Example 6j: Preparation of 2-Oct-l-ynylnaphtho[2,l-Z>]furan
Figure imgf000144_0001
A carousel reaction tube (24x150 mm) was charged with l-(2,2- dibromovinyl)naphthalen-2-ol 7a (135 mg, 0.41 mmol), Pearlman's catalyst (Degussa E4) (4.4 mg, 0.0041 mmol, 1 mol%), P(^-MeOPh)3 (5.8 mg, 0.016 mmol, 4 mol%), and CuI (1.7 mg, 0.0082 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (145 μL, 1.03 mmol) and 1-octyne (100 μL, 0.66 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 0.8% EtOAc in hexane to afford the titled compound as a colorless oil (112.0 mg, 98%). IR (CHCl3) v 3056, 2930, 2857, 2233, 1629, 1556, 1524, 1455, 1386, 1344, 1326, 1292, 1236, 1218, 1158, 1135, 1079 cm 1; 1H-NMR (CDCl3) δ: 8.06 (IH, d, J = 8.2 Hz), 7.90 (IH, d, J= 8.2 Hz), 7.71 (IH, d, J = 9.1 Hz), 7.61-7.43 (3H, m), 7.30 (IH, s), 2.51 (2H, t, J = 7.0 Hz), 1.72-1.23 (8H, m), 0.91 (3H, t, J= 6.3 Hz); 13C NMR (75 MHz, DMSO-J6) δ 152.3, 138.9, 130.6, 128.9, 127.5, 126.7, 126.3, 124.9, 123.6, 123.3, 112.3, 109.3, 97.3, 71.6, 31.5, 28.8, 28.5, 22.7, 19.9, 14.3; HRMS (EI) m/z calcd.for: [M]+ 276.1505, m/z found: 276.1514.
Example 6k: Preparation of 7-Methoxy-2-oct-l-ynylbenzofuran
Figure imgf000144_0002
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-6- methoxyphenol 7c (120 mg, 0.39 mmol), Pearlman's catalyst (Degussa E4) (29.0 mg, 0.027 mmol, 7 mol%), P(^-MeOPh)3 (13.7 mg, 0.039 mmol, 10 mol%), and CuI (3.7 mg, 0.020 mmol, 5 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (164 μL,
1.17 mmol) and 1-octyne (86 μL, 0.58 mmol), and then heated to 100 0C with stirring for
64 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2% EtOAc in hexane to afford the titled compound as a pale yellow oil (80.0 mg, 80%). IR (CHCl3) v 2934,
2857, 2234, 1621, 1615, 1593, 1494, 1489, 1455, 1435, 1359, 1318, 1270, 1210, 1183,
1159, 1098, 1061 cm"1; 1H-NMR (CDCl3) δ: 7.17-7.08 (2H, m), 6.84-6.74 (2H, m), 4.00 (3H, s), 2.46 (2H, t, J = 7.0 Hz), 1.68-1.23 (8H, m), 0.90 (3H, t, J = 6.9 Hz). 13C NMR
(75 MHz, OMSO-d6) δ 145.3, 144.0, 139.7, 129.6, 123.9, 113.4, 110.3, 107.3, 97.1, 71.2,
56.3, 31.5, 28.8, 28.4, 22.7, 19.7, 14.2; HRMS (EI) m/z calcd. for: [M]+ 256.1468, m/z found: 256.1463.
Example 61: Preparation of l-Oct-l-ynyl-benzofuran-S-carboxylic acid methyl ester
Figure imgf000145_0001
A carousel reaction tube (24x150 mm) was charged with 3-(2,2-dibromovinyl)-4- hydroxybenzoic acid methyl ester 7b (105 mg, 0.31 mmol), Pearlman's catalyst (Degussa E4) (6.6 mg, 0.0062 mmol, 2 mol%), P(^-OMePh)3 (8.8 mg, 0.025 mmol, 8 mol%), and CuI (2.4 mg, 0.013 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (123 μL, 0.875 mmol) and 1-octyne (70 μL, 0.47 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 3% EtOAc in hexane to afford the titled compound as a colorless oil (82.4 mg, 93%). IR (CHCl3) v 2920, 2234, 1732, 1615, 1574, 1435, 1348, 1311, 1197, 1148, 1116, 1087 cm"1; 1H-NMR (CDCl3) δ: 8.26 (IH, d, J= 1.5 Hz), 8.02 (IH, dd, J = 8.8, 1.8 Hz), 7.44 (IH, d, J = 8.5 Hz), 6.86 (IH, s), 3.93 (3H, s), 2.49 (2H, t, J= 7.2 Hz), 1.71-1.24 (8H, m), 0.91 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, DMSO-J6) δ 167.3, 157.1, 140.9, 128.1, 126.9, 125.7, 123.6, 111.1, 110.4, 98.2, 70.9, 52.3, 31.5, 28.8, 28.3, 22.7, 19.8, 14.2; HRMS (EI) m/z calcd.for: [M]+ 284.1416, m/z found: 284.1412.
Example 6m: Preparation of 3-Methyl-2-oct-l-ynyl-benzofuran
Figure imgf000146_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-Dibromo-l- methylvinyl)phenol [prepared from 2-hydroxyacetophenone according to the procedure by Topolski (Topolski, M. J. Org. Chem. 1995, 60, 5588)] (145 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(p-MeOPh)3 (13.9 mg, 0.040 mmol, 8 mol%), and CuI (4.0 mg, 0.022 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (210 μL, 1.49 mmol) and 1-octyne (100 μL, 0.66 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 0.5%→ 1.0% EtOAc in hexane to afford the titled compound as a colorless oil (98.4 mg, 82%). IR (CHCl3) v 2927, 2857, 2228, 1995, 1586, 1451, 1360, 1348, 1256, 1197, 1115, 1094 cm"1; 1H-NMR (CDCl3) δ: 7.48-7.43 (IH, m), 7.40-7.35 (IH, m), 7.29 (IH, dt, J= 7.3, 1.5 Hz), 7.21 (IH, dt, J= 7.3, 1.2 Hz), 2.52 (2H, t, J= 7.2 Hz), 2.28 (3H, s), 1.72-1.59 (2H, m), 1.55-1.21 (6H, m), 0.91 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, DMSO-J6) δ 154.2, 136.6, 129.2, 125.2, 122.7, 119.6 (2C), 111.2, 99.4, 70.8, 31.5, 28.8, 28.6, 22.7, 19.9, 14.2, 8.9; HRMS (EI) m/z calcd. for: [M]+ 240.1514, m/z found: 240.1508. Example 6n: Preparation of (4,6-Dimethoxybenzofuran-2-ylethynyl)trimethylsilane
Figure imgf000147_0001
A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-3,5- dimethoxyphenol 7d (120 mg, 0.355 mmol), Pearlman's catalyst (Degussa E4) (18.8 mg, 0.017 mmol, 5 mol%), P(p-OMePh)3 (5.1 mg, 0.014 mmol, 4 mol%), and CuI (2.8 mg, 0.014 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H2O (1 mL, degassed), /Pr2NH (180 μL,
1.28 mmol) and trimethylsilylacetylene (0.5 mL, 3.6 mmol), and then heated to 100 0C with stirring for 12 h. The reaction mixture was then cooled to rt and H2O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH4Cl and brine, then dried and solvent removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 7% EtOAc in hexane to afford the titled compound as a pale yellow solid (36.0 mg, 37%). m.p.: 58-600C; IR (CHCl3) v 2958, 2837, 2153,1615, 1501, 1455, 1372, 1320, 1293, 1251, 1217, 1157, 1134, 1105, 1042 cm"1; 1H-NMR (CDCl3) δ: 6.95 (IH, d, J= 0.9 Hz), 6.59-6.54 (IH, m),
6.29 (IH, d, J = 2.1 Hz), 3.88 (3H, s), 3.83 (3H, s), 0.28 (9H, s); 13C NMR (75 MHz, DMSO-J6) δ 160.5, 156.5, 153.5, 136.2, 111.5, 109.7, 101.1, 94.6, 87.8, 55.7, 55.6, -0.3 (3C); HRMS (EI) m/z calcd.for: [M ]+ 274.1025, m/z found: 274.1018.
Preparation of ortho-gem-dibromovinylphenol compounds of Formula (XI) Example 7a: Preparation of l-(2,2-Dibromovinyl)naphthaIen-2-ol
Figure imgf000147_0002
To a solution of 2-hydroxy-l-naphthaldehyde (3.0 g, 17.4 mmol) and Et3N (4.9 ml, 35 mmol) in CH2Cl2 (50 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (5.2 mL, 22.6 mmol) at O 0C, and the mixture was stirred for 3 h at rt. Sat. NaHCO3 (30 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 100 mL). The combined extracts were washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 10% EtOAc in hexane to afford 2-(tert-butyldimethylsilyloxy)naphthalene-l-carbaldehyde as a colorless oil (4.6 g, 93%). IR (CHCl3) v 2928, 1673, 1632, 1592, 1507, 1463, 1435, 1314, 1245, 1155, 1012 m 1; 1H-NMR (CDCl3) δ: 10.87 (IH, s), 9.28 (IH, d, J = 8.8 Hz), 7.95 (IH, d, J = 9.1 Hz), 7.76 (IH, d, J= 7.3 Hz), 7.65-7.57 (IH, m), 7.46-7.39 (IH, m), 7.06 (IH, d, J = 8.8 Hz), 1.05 (9H, s), 0.32 (6H, t, J = 3.2 Hz); 13C NMR (75 MHz, DMSO-J6) δ 196.4, 165.6, 141.1, 135.8, 133.6, 133.0, 132.2, 129.0 (2C), 124.7, 123.2, 29.7, 22.5, 0.0; HRMS (EI) m/z calcd.for: [M]+ 287.1467, m/z found: 287.1465.
To a solution of 2-(te/t-butyldimethylsilyloxy)naphthalene-l-carbaldehyde (3.2 g, 11.2 mmol) in CH2Cl2 (50 mL) was added carbon tetrabromide (5.56 g, 16.8 mmol) and triphenylphosphine (8.78 g, 33.5 mmol) at 0 0C, and the mixture was stirred for 12 h at rt. IM Na2S2O3 (30 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 120 mL). The combined extracts were washed with sat. NaHCO3, H2O and brine, then dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 2% EtOAc in hexane to afford ter/-butyl-[l-(2,2- dibromovinyl)naphthalen-2-yloxy]dimethylsilane as a colorless oil (4.05 g, 82%). IR (CHCl3) v 3062, 2955, 2928, 2857, 1592, 1505, 1471, 1463, 1429, 1377, 1338, 1282, 1250, 1143, 1075 cm"1; 1H-NMR (CDCl3) δ: 7.56-7.48 (3H, m), 7.37 (IH, s), 7.25 (IH, t, J= 6.7 Hz), 7.11 (IH, t, J= 8.2 Hz), 6.83 (IH, d, J= 8.8 Hz), 0.82 (9H, s), 0.00 (6H, s); 13C NMR (75 MHz, DMSO-J6) δ 154.4, 138.1, 135.5, 134.0, 133.2 (2C), 130.7, 128.5, 128.0, 125.8, 124.9, 98.4, 81.5, 81.0, 80.6, 29.8, 22.2, 0.0; HRMS (EI) m/z calcd. for: [M]+ 439.9823, m/z found: 439.9807.
To a solution of tert-butyl-[l-(2,2-dibromovinyl)naphthalen-2-yloxy]dimethylsilane (3.7 g, 8.3 mmol) in THF (45 mL) was added TBAF (11.7 mL, 11.7 mmol) at 0 0C, and the mixture was stirred for 2 h at rt. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with sat. NH4Cl and brine, then dried (MgSO4) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 20%→ 25% EtOAc in hexane to afford the titled compound as a colorless solid (2.60 g, 95%). m.p.: 74-75 0C; IR (CHCl3) v 3534, 1620, 1596, 1514, 1466, 1432, 1387, 1346, 1264, 1201, 1141 cm"1; 1H- NMR (CDCl3) δ: 7.80 (2H, d, J = 8.5 Hz), 7.68 (IH, d, J = 9.1 Hz), 7.66 (IH, s), 7.51 (IH, dt, J= 7.9, 1.2 Hz), 7.42-7.34 (IH, m), 7.17 (IH, d, J = 9.1 Hz), 5.23 (IH, s); 13C NMR (75 MHz, DMSO-4) δ 150.0, 132.3, 131.6, 131.0, 129.0, 128.6, 127.3, 124.2, 123.7, 118.0, 115.7, 97.2; HRMS (EI) m/z calcd. for: [M]+ 325.8940, m/z found: 325.8942.
Example 7b: Preparation of 3-(2,2-Dibromovinyl)-4-hydroxybenzoic acid methyl ester
Figure imgf000149_0001
To a solution of 3-formyl-4-hydroxybenzoic acid (1.00 g, 5.9 mmol) in toluene-MeOH (2:1, 30 mL) was added (trirnethylsilyl)diazomethane (2.0 M solution in hexane, 16 mL, 32 mmol) at 0 0C, and the mixture was stirred for 1 h at rt. After evaporating the solvent, the resulting residue was filtrated through a plug of silica gel eluting with 15% EtOAc in hexane to afford 3-formyl-4-hydroxybenzoate as a colorless solid (1.06 g, 99%). To a solution of methyl 3-formyl-4-hydroxybenzoate (900 mg, 5.0 mmol) and 2,6-lutidine (0.93 ml, 8.0 mmol) in CH2Cl2 (11 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.5 mL, 6.5 mmol) at 0 °C, and the mixture was stirred for 3 h at rt. Sat. NaHCO3 (10 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 30 mL). The combined extracts were washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 10%→ 15% EtOAc in hexane to afford methyl A-tert- butyldimethylsilyloxy-3-formylbenzoate as a colorless solid (1.18 g, 81%). m.p.: 52- 530C; IR (CHCl3) v 2952, 1725, 1692, 1607, 1491, 1272, 1118 cm'1; 1H-NMR (CDCl3) 5: 10.46 (IH, s), 8.50 (IH, d, J= 2.3 Hz), 8.14 (IH, dd, J= 8.8, 2.3 Hz), 6.93 (IH, d, J = 8.8 Hz), 3.91 (3H, s), 1.03 (9H, s), 0.32 (6H, s); 13C NMR (75 MHz, DMSO-^) δ 193.5, 170.2, 166.5, 140.9, 134.9, 131.0, 127.8, 124.3, 56.4, 29.9 (3C), 22.6, 0.0 (2C); HRMS (EI) m/z calcd.for: [M-ZBu]+ 237.0583, m/z found: 237.0581.
To a solution of methyl 4-fert-butyldimethylsilyloxy-3-formylbenzoate (500 mg, 1.70 mmol) in CH2Cl2 (50 mL) was added carbon tetrabromide (5.56 g, 16.8 mmol) and triphenylphosphine (8.78 g, 33.5 mmol) at 0 0C, and the mixture was stirred for 15 h at rt. IM Na2S2O3 (30 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 120 mL). The combined extracts were washed with sat. NaHCO3, H2O and brine, then dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5% EtOAc in hexane to afford A-(tert- Butyldimethylsilyloxy)-3-(2,2-dibromovinyl)benzoic acid methyl ester as a colorless oil (660 mg, 86%). IR (CHCl3) v 2953, 2858, 1732, 1605, 1488, 1286, 1116, 998 cm"1; 1H- NMR (CDCl3) δ: 8.36-8.33 (IH, m), 7.91 (IH, dd, J = 8.5, 2.1 Hz), 7.56 (IH, s), 6.81 (IH, d, J= 8.5 Hz), 3.89 (3H, s), 1.02 (9H, s), 0.24 (6H, s); 13C NMR (75 MHz, DMSO- d6) δ 170.8, 161.4, 137.4, 135.7, 135.6, 131.7, 127.4, 123.4, 95.6, 56.4, 30.0, 29.9, 22.5, 0.0; HRMS (EI) m/z calcd.for: [M]+ 448.9792, m/z found: 448.9777.
To a solution of 4-(tert-Butyldimethylsilyloxy)-3-(2,2-dibromovinyl)benzoic acid methyl ester (600 mg, 1.32 mmol) in THF (45 mL) was added TBAF (2.0 mL, 2.0 mmol) at 0 0C, and the mixture was stirred for 3 h at rt. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with sat. NH4Cl and brine, then dried (MgSO4) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 10%→ 30% EtOAc in hexane to afford the titled compound as a colorless solid (365 mg, 82%). m.p.:199-200°C; IR (CHCl3) v 3411, 1770, 1683, 1652, 1270 cm"1; 1H-NMR (CDCl3) δ: 8.40 (IH, d, J= 2.1 Hz), 8.10 (IH, dd, J= 8.4, 2.1 Hz), 7.68 (IH, s), 7.03 (IH, d, J= 8.4 Hz), 5.61 (IH, s), 4.06 (3H, s); 13C NMR (75 MHz, DMSO-J6) δ 166.3, 159.8, 133.0, 132.0, 130.9, 122.9, 120.7, 116.2, 91.1, 52.5; HRMS (EI) m/z calcd. for: [M]+ 334.8929, m/z found: 334.8912. Example 7c: Preparation of 2-(2,2-Dibromovinyl)-6-methoxyphenol
Figure imgf000151_0001
To a solution of o-vanillin (6.0 g, 39.4 mmol) and 2,6-lutidine (7.34 ml, 63.0 mmol) in CH2Cl2 (SO niL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (12.7 mL, 55.0 mmol) at 0 0C, and the mixture was stirred for 3 h at rt. Sat. NaHCO3 (20 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 50 mL). The combined extracts were washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5%→ 8% EtOAc in hexane to afford 2-hydroxy-3-methoxy-benzaldehyde as a colorless oil (8.50 g, 81%). To a solution of 2-hydroxy-3-methoxy-benzaldehyde (5.0 g, 18.7 mmol) in CH2Cl2 (250 mL) was added carbon tetrabromide (9.35 g, 28.2 mmol) and triphenylphosphine (14.7 g, 56.1 mmol) at 0 0C, and the mixture was stirred for 24 h at rt. IM Na2S2O3 (40 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 60 mL). The combined extracts were washed with H2O and brine, then dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5% EtOAc in hexane to afford tert-butyl[2-(2,2-dibromovinyl)-6- methoxyphenoxyjdimethylsilane as a colorless oil (7.50 g, 95%). IR (CHCl3) v 2927, 2854, 1576, 1476, 1256, 1229, 1076 cm"1; 1H-NMR (CDCl3) δ: 7.59 (IH, s), 7.24-7.19 (IH, m), 6.89 (IH, d, J = 8.0 Hz), 6.84 (IH, dd, J= 8.0, 1.8 Hz), 3.79 (3H, s), 1.02 (9H, s), 0.17 (6H, s); 13C NMR (75 MHz, DMSO-^6) δ 150.4, 142.6, 134.3, 127.9, 120.8 (2C), 111.8, 90.0, 55.1, 25.9, 18.7, -4.2; HRMS (EI) m/z calcd. for: [M-ZBu]+ 362.9052, m/z found: 362.9047.
To a solution of fert-butyl[2-(2,2-dibromovinyl)-6-methoxyphenoxy]dimethylsilane (7.5 g, 17.7 mmol) in THF (80 mL) was added TBAF (26 mL, 26.0 mmol) at 0 0C, and the mixture was stirred for 3 h at rt. This mixture was then concentrated on a rotary evaporator to approximately 40 ml. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 60 mL). The combined extracts were washed with sat. NH4Cl and brine, then dried (MgSO4) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 20% EtOAc in hexane to afford the titled compound as a colorless solid (4.42 g, 81%). m.p.: 43-44°C; IR (CHCl3) v 3504, 2935, 2837, 1613, 1473, 1359, 1258, 1068 cm"1; 1H-NMR (CDCl3) δ: 7.65 (IH, s), 7.38-7.30 (IH, m), 6.89-6.82 (2H, m), 5.85 (IH, s), 3.90 (3H, s); 13C NMR (75 MHz, DMSO-J6) δ 146.6, 143.5, 132.1, 122.0, 120.9, 119.4, 110.8, 90.3, 56.3; HRMS (EI) m/z calcd.for: [M]+ 305.8891, m/z found: 305.8898.
Example 7d: Preparation of 2-(2,2-Dibromovinyl)-3,5-dimethoxyphenol
Figure imgf000152_0001
To a solution of methyl 4,6-dimethoxysalicylaldehyde (commercially available from Aldrich) (1.0 g, 5.5 mmol) and 2,6-lutidine (1.64 ml, 7.1 mmol) in CH2Cl2 (I l mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.6 mL, 7.1 mmol) at 0 0C, and the mixture was stirred for 3 h at rt. Sat. NaHCO3 (10 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 30 mL). The combined extracts were washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 10%→ 15% EtOAc in hexane to afford 2- (fert-butyldimethylsilanyloxy)-4,6-dimethoxybenzaldehyde as a colorless oil (1.50 g, 92%). IR (CHCl3) v 2930, 2857, 1682, 1605, 1470, 1455, 1410, 1347, 1303, 1255, 1209, 1158, 1120, 1052, 1004 cm"1; 1H-NMR (CDCl3) δ: 10.34 (IH, s), 6.10 (IH, d, J = 2.2 Hz), 5.98 (IH, d, J = 2.2 Hz), 3.87 (3H, s), 3.83 (3H, s), 1.01 (9H, s), 0.26 (6H, s); 13C NMR (75 MHz, DMSO-J6) δ 188.0, 165.6, 163.1, 161.7, 111.5, 97.7, 91.8, 56.0, 55.4, 25.7 (3C), 18.4, -4.3 (2C); HRMS (EI) m/z calcd. for: [M-fBuSiMe2+H]+ 182.0579, m/z found: 182.0580.
To a solution of 2-(tert-butyldimethylsilanyloxy)-4,6-dimethoxybenzaldehyde (940 mg, 3.17 mmol) in CH2Cl2 (OO mL) was added carbon tetrabromide (1.65 g, 4.98 mmol) and triphenylphosphine (2.49 g, 9.5 mmol) at 0 0C, and the mixture was stirred for 24 h at rt. IM Na2S2O3 (10 mL) was added, and the resulting mixture was extracted with CH2Cl2 (2 x 60 mL). The combined extracts were washed with H2O and brine, then dried (MgSO4) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5% EtOAc in hexane to afford tert-butyl-[2-(2,2- dibromovinyl)-3,5-dimethoxyphenoxy]-dimethylsilane as a colorless oil (600 mg, 42%). IR (CHCl3) v 2930, 2856, 1601, 1574, 1463, 1417, 1361, 1254, 1221, 1202, 1153, 1117, 1055, 1003 cm'1; 1H-NMR (CDCl3) δ: 7.15 (IH, s), 6.12 (IH, d, J= 2.3 Hz), 6.02 (IH, d, J = 2.3 Hz), 3.79 (3H, s), 3.77 (3H, s), 1.01 (9H, s), 0.20 (6H, s); 13C NMR (75 MHz, DMSO-έfc) δ 161.1, 158.1, 154.2, 131.9, 110.3, 97.7, 93.1, 91.8, 55.6, 55.3, 25.6 (3C), 18.1, -4.4 (2C); HRMS (EI) m/z calcd.for: [M]+ 449.9857, m/z found: 449.9861.
To a solution of ierf-butyl-[2-(2,2-dibromovinyl)-3,5-dimethoxyphenoxy]-dimethylsilane (600 mg, 1.32 mmol) in THF (10 mL) was added TBAF (2.0 mL, 2.0 mmol) at 0 0C, and the mixture was stirred for 3 h at rt. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined extracts were washed with sat. NH4Cl and brine, then dried (MgSO4) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a colorless oil (320 mg, 72%). IR (CHCl3) v 3417, 2935, 1621, 1615, 1505, 1456, 1343, 1203, 1150, 1099, 1049 cm"1; 1H-NMR (CDCl3) δ: 6.12 (IH, d, J = 2.3 Hz), 6.06 (IH, d, J = 2.3 Hz), 5.14 (IH, s), 3.78 (6H, s); 13C NMR (75 MHz, DMSO-(Z6) δ 162.1, 158.4, 153.8, 131.2, 105.3, 94.2, 93.5, 91.6, 55.9, 55.6; HRMS (ESI) m/z calcd.for: [M+H]+ 336.9069, m/z found: 336.9064.
Every reference cited herein is hereby incorporated by reference in its entirety.

Claims

Claims:
1. A process for the preparation of a compound of Formula (I):
Figure imgf000154_0001
(I)
wherein
each R1 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, -NR*C0-R*, - NR*C00-R*, -NR*C0NR* wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein R3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Rj and R* are unsubstituted or substituted;
R2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
the process comprising reacting an orrto-gem-dibromovinylaniline compound of Formula (H)
wherein Ri and R2 are as defined above,
with an alkene Heck acceptor of the Formula (III) ^R3
(III)
wherein R3 is selected from the group comprising alkyl; lower alkyl -hydroxy; lower alkyl-O-R-b wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R", -C(O)OR", -C(O)NR"2, -SO2R", -SO2NR"2, lower alkyl-CO-R", lower alkyl-CO-OR", lower alkyl-C(O)NR"2, lower alkyl-NR"CO-R", lower alkyl-NR"COO-R" wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R3 is - C(O)NR 2 both R groups may form a heterocyclic ring with the nitrogen atom; and each of R3 and R** are unsubstituted or substituted;
in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (I).
2. The process as claimed in claim 1, further comprising the presence of at least one of a ligand and an additive.
3. The process as claimed in claim 1 or 2, wherein Ra is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
4. The process as claimed in any one of claims 1 to 3, wherein the palladium metal pre-catalyst is selected from the group comprising Pd(OAc)2, Pd(PPh3),*, Pd2(dba)3, Pd(CH3CN)2Cl2, PdCl2, K2PdCl4, Pd/C, Pd2(dba)3 -HCCl3, and
Figure imgf000155_0001
5. The process as claimed in any one of claims 1 to 3, wherein the base is selected from the group comprising an organic base, an inorganic base, or combinations thereof.
6. The process as claimed in claim 5, wherein the base is selected from the group comprising K3PO4-H2O, K3PO4, NEt3, iPr2NH, Cy2NMe, and combinations thereof.
7. The process as claimed in any one of claims 2 to 4, wherein the ligand is selected from the group comprising a phosphorous-containing ligand and a nitrogen-containing carbenoid ligand.
8. The process as claimed in claim 7, wherein the ligand is selected from the group comprising S-Phos, X-Phos, P(o-tol)3, P(o-tol-/>OMe)3, PPh3, P(O-CF3-Ph)3, P(JBu)3, BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh3, DavePhos, HP(tBu)3 BF4, and
N.
Mes' 1^ Mes
+ Cl"
9. The process as claimed in any one of claims 2 to 4, wherein the additive comprises a compound of the formula R4NX, wherein R = lower alkyl and X = halogen or OAc.
10. The process as claimed in claim 9, wherein the additive is selected from the group comprising nBu+NCl, nBu4N0Ac, and Me4NCl.
11. The process as claimed in any one of claims 1 to 10, wherein the palladium metal pre-catalyst is present in an amount of about 1.5 mole percent to about 6 mole percent relative to the compound of Formula (II).
12. The process as claimed in any one of claims 2 to 11, wherein the ligand is present in an amount of about 3 mole percent to about 12 mole percent relative to the compound of Formula (II).
13. The process as claimed in any one of claims 2 to 11, wherein the palladium metal pre-catalyst comprises Pd(OAc)2, the additive comprises Me4NCl, and the base comprises NEt3/K3PO4.H2O.
14. The process as claimed in claim 13, wherein Ri is selected from the group comprising H, -C(O)O-lower alkyl, fluoro, lower alkoxy, benzyloxy, and lower alkyl, each of which are unsubstituted or substituted.
15. The process as claimed in claim 13 or 14, wherein R2 is selected from the group comprising benzyl or lower alkyl which are unsubstituted or substituted.
16. The process as claimed in any one of claims 13 to 15, wherein R3 is selected from the group comprising aryl,, -C(O)O-lower alkyl, -SO2-lower alkyl, lower alkyl-OAc, alkyl, -C(O)NH(lower alkyl), and
Figure imgf000157_0001
wherein the alkyl and aryl groups are unsubstituted or substituted.
17. The process as claimed in any one of claims 2 to 12, wherein the palladium metal pre-catalyst comprises Pd(OAc)2, the ligand comprises P-(o-tolyl)3, and the base comprises NEt3/K3PO4.H2O.
18. The process as claimed in claim 17, wherein Ri is selected from the group comprising H, lower alkoxy, benzyloxy, and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; each of which are unsubstituted or substituted.
19. The process as claimed in claim 17 or 18, wherein R2 is selected from the group comprising H, benzyl, and aryl, which are unsubstituted or substituted.
20. The process as claimed in any one of claims 17 to 19, wherein R3 is selected from the group comprising aryl, nitrile, -C(O)-lower alkyl, and -C(O)O-lower alkyl, each of which are unsubstituted or substituted.
21. The process as claimed in any one of claims 2 to 12, wherein the palladium metal pre-catalyst comprises Pd2dba3, the ligand comprises S-Phos, and the base comprises NEt3/K3PO4.H2O.
22. The process as claimed in claim 21, wherein Ri is H.
23. The process as claimed in claim 21 or 22, wherein R2 is substituted or unsubstituted aryl.
24. The process as claimed in any one of claims 21 to 23, wherein R3 is -C(O)O- lower alkyl.
25. A novel 2-substituted indole or a salt thereof selected from the group consisting of:
Figure imgf000159_0001
26. An improved process for the preparation of a compound of the following Formula (H)
Figure imgf000160_0001
wherein
each R1 is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(O)NR* 2, -NR*CO-R*, - NR COO-R*, and -NR CONR , wherein R is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R* are unsubstituted or substituted;
and R2 is H;
comprising reaction of a compound of Formula (VI)
Figure imgf000160_0002
(Vl)
with CBr4 and P(OR)3, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, to form a compound of Formula (VII)
Figure imgf000160_0003
isolating the compound of Formula (VII), and reducing the compound of Formula (VII) to obtain the compound of Formula (II).
27. The process as claimed in claim 26, wherein R3 is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R', R", and R"' are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H.
28. The process as claimed in claim 26 or 27, wherein the compound of Formula (VII) is isolated via recrystallization.
29. The process as claimed in claim 26 or 27, wherein the compound of Formula (VII) is isolated via addition of HOAc/HCl followed by a basic workup procedure.
30. A novel ort/jo-gem-dibromovinylaniline compound or a salt thereof selected from the group consisting of:
Figure imgf000161_0001
Figure imgf000161_0002
Figure imgf000161_0003
Figure imgf000161_0004
31. A process for the preparation of a compound of Formula (IV) and/or Formula (IV)'
Figure imgf000161_0005
wherein
each R4 is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(O)NR* 2, -NR*C0-R*, - NR*COO-R*, -NR*C0NR* wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each OfR4 and R* are unsubstituted or substituted;
the process comprising reacting an or£/zogem-dibromovinylaniline compound of Formula (V):
Figure imgf000162_0001
wherein R4 is as defined above, n is O to 3,
and Rs is selected from the group comprising H, lower alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R**, -C(O)OR**, -C(0)NR** 2, -SO2R", -SO2NR** 2, lower alkyl-CO-R**, lower alkyl-CO-OR", lower alkyl-C(O)NR** 2, lower alkyl-NR**CO-R**, lower alkyl-NR**COO-R" wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R5 and R" are unsubstituted or substituted;
in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (IV) and/or Formula (IV)'.
32. The process as claimed in claim 31, further comprising the presence of at least one of a ligand and an additive.
33. The process as claimed in claim 31 or 32, wherein Ra is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R', R", and R"' are independently selected from H, lower alkyl and aryl with the proviso that only one of R', R", and R'" is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
34. The process as claimed in any one of claims 31 to 33, wherein the palladium metal pre-catalyst is selected from the group comprising Pd(OAc)2, Pd(PPh3 )4, Pd2(dba)3, Pd(CH3CN)2Cl2, PdCl2, K2PdCl4, Pd2(dba)3 HCCl3, Pd/C, and
Figure imgf000163_0001
35. The process as claimed in any one of claims 31 to 33, wherein the base is selected from the group comprising an organic base, an inorganic base, and combinations thereof.
36. The process as claimed in claim 35, wherein the base is selected from the group comprising K3PO4-H2O, K3PO4, NEt3, iPr2NH, Cy2NMe, and combinations thereof.
37. The process as claimed in claim 32 or 33, wherein the additive comprises a compound of the formula R4NX, wherein R = lower alkyl and X = halogen or OAc.
38. The process as claimed in claim 37, wherein the additive is selected from the group comprising nBu4NCl, nBu4N0Ac, and Me4NCl.
39. The process as claimed in any one of claims 31 to 38, wherein the palladium metal pre-catalyst is present in an amount of about 1.5 mole percent to about 6 mole percent relative to the compound of Formula (V).
40. The process as claimed in any one of claims 32 to 39, wherein the palladium metal pre-catalyst comprises Pd2dba3, the additive comprises nBu4NCl, and the base comprises NEt3/K3PO4.H2O.
41. The process as claimed in claim 40, wherein R4 is selected from the group comprising H, benzyloxy, and -C(O)O-lower alkyl; R5 is selected from the group comprising H and -C(O)O-lower alkyl; and n is 1 or 2.
42. A novel or/Ao-gem-dibromovinylaniline compound or a salt thereof selected from the group consisting of:
Figure imgf000164_0001
43. A process for the preparation of a compound of Formula (VIII):
Figure imgf000164_0002
(VIII)
wherein
each Ri is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, -NR*C0-R*, - NR*COO-R*, and -NR*C0NR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein Ra is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n1 is a whole integer from I to 4; and each of Ri and R* are unsubstituted or substituted;
R2 is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;
the process comprising reacting an ortho-gem-dibromovinylaniline compound of Formula (H)
Figure imgf000165_0001
wherein Ri and R2 are as defined above,
with an alkyne of the Formula (IX)
(IX)
wherein Rg is selected from the group comprising -SiR1R11R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R**, lower alkyl-CO-OR", lower alkyl- C(O)NR** 2, lower alkyl-NR"CO-R", lower alkyl-NR"COO-R" wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R" are unsubstituted or substituted;
in the presence of a base, a palladium metal pre-catalyst, a copper metal pre-catalyst and a ligand to form the compound of Formula (VIII).
44. A process as claimed in claim 43, wherein R3 is selected from MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R"', where R', R", and R"' are independently selected from H, lower alkyl and aryl, with the proviso that only one of R1, R", and R111 is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr .
45. The process as claimed in claim 43 or 44, wherein the palladium metal precatalyst is selected from the group comprising Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3, Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, PdCl2, Pd(acac), K2PdCl4, Na2PdCl4, Pd/C, Pearlman's catalyst, Pd-Al2O3, Pd-BaSO4, Pd-CaCO3, [Pd(aHyl)Cl]2, Pd2(dba)3ΗCCl3 and
Figure imgf000166_0001
46. The process as claimed in claim 43 or 44, wherein the copper metal precatalyst is selected from the group comprising CuI, Cu(OAc), CuCl, CuBr, and Cu(OTf).
47. The process as claimed in claim 43 or 44, wherein the base is selected from the group comprising an organic base, an inorganic base, and combinations thereof.
48. The process as claimed in claim 47, wherein the base is selected from the group comprising K2CO3, K3PO4, NEt3, iPr2NH, iPr2NEt, DABCO, Cy2NMe, and combinations thereof.
49. The process as claimed in claim 43 or 44, wherein the ligand is selected from the group comprising a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, an alcohol-containing ligand and a nitrogen-containing carbenoid ligand.
50. The process claimed in claim 49, wherein the ligand is selected from the group comprising S-Phos, X-Phos, P(o-tol)3, P(o-tol-p-OMe)3, P(O-MeOPh)3, P(p-MeOPh)3, PPh3, P(O-CF3-Ph)3, P(IBu)3, BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh3, DavePhos, HP(tBu)3 BF4; 1,10-phenanthroline, neocuproine, trans- 1,2-cyclohexyldiamine, cis-l,2-cyclohexyldiamine, ethylenediamine, N- methylethylenediamine, N,N-dimethylethylenediamine, dipivaloylmethane, 2- acetylcyclohexanone, 2-propionylcyclohexanone, 2-isobutyrylcyclohexanone, N5N- dimethylsalicylamides, ethylene glycol, ethanolamine, and
Mes 'N\^ Mes
+ Cl"
51. The process claimed in any one of claims 43 to 50, wherein the palladium metal precatalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the compound of Formula (II).
52. The process claimed in any one of claims 43 to 51, wherein the copper metal precatalyst is present in an amount of about 1.0 mole percent to about 10 mole percent relative to the compound of Formula (II).
53. The process as claimed in any one of claims 43 to 52, wherein the ligand is present in an amount of about 4 mole percent of to about 10 mole percent relative to the compound of Formula (II).
54. The process as claimed in any one of claims 43 to 53, wherein the palladium metal pre-catalyst comprises Pearlman's catalyst, the copper metal pre-catalyst comprises CuI, the ligand comprises P(p-MeOPh)3, and the base comprises iPr2NH.
55. The process as claimed in claim 54, wherein Ri is selected from the group comprising H, lower alkoxy, benzyloxy, fluoro, -C(O)O-lower alkyl, and and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring.
56. The process as claimed in claim 54 or 55, wherein R2 is selected from the group comprising H, lower alkyl, benzyl, and aryl.
57. The process as claimed in any one of claims 54 to 56, wherein R8 is selected from the group comprising lower alkyl, lower alkyl-hydroxyl, TMS, lower alkyl-nitrile, lower haloalkyl, and heterocyclic.
58. The process as claimed in any one of claims 43 to 53, wherein the palladium metal pre-catalyst comprises Pd/C, the copper metal pre-catalyst comprises CuI, the ligand comprises PPh3, and the base comprises iPr2NH.
59. The process as claimed in claim 58, wherein Ri is H.
60. The process as claimed in claim 58 or 59, wherein R2 is H.
61. The process as claimed any one of claims 58 to 60, wherein R8 is selected from the group comprising aryl, lower alkyl-hydroxyl, and lower alkyl-OTHP.
62. A novel 2-substituted indole or a salt thereof selected from the group consisting of:
Figure imgf000169_0001
63. A process for the preparation of a compound Formula (X):
Figure imgf000169_0002
(X)
wherein each Re is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, -NR*C0-R*, - NR*C00-R*, and -NR*CONR*, wherein R* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0Ra, wherein R3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of Rn and R* are unsubstituted or substituted;
and R9 is H or lower alkyl;
the process comprising reacting an ortho-gem-dibromovinylphenol compound of Formula (XI)
Figure imgf000170_0001
wherein R$ and R9 are as defined above,
with an alkyne of the Formula (IX)
^= Re (IX)
Rs is selected from the group comprising -SiR1R11R'" wherein R1, R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-Rb wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R", lower alkyl-CO-OR", lower alkyl- C(0)NR** 2, lower alkyl-NR**CO-R", lower alkyl-NR**COO-R" wherein R** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rg and R** are unsubstituted or substituted; in the presence of a base, a palladium metal pre-catalyst, a copper metal pre-catalyst and a ligand to form the compound of Formula (X).
64. The process as claimed in claim 63, wherein Ra is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR1R11R'", where R1, R", and R"1 are independently selected from H, lower alkyl and aryl, with the proviso that only one of R1, R", and R"1 is H; and Rb is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl3CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.
65. The process as claimed in claim 63 or 64, wherein the palladium metal precatalyst is selected from the group comprising Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3, Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, PdCl2, Pd(acac), K2PdCl4, Na2PdCl4, Pd/C, Pd(OH)2/C, Pd-Al2O3, Pd- BaSO4, Pd-CaCO3, [Pd(allyl)Cl]2, Pd2(dba)3 -HCCl3 and
Figure imgf000171_0001
66. The process as claimed in claim 63 or 64, where the copper metal precatalyst is selected from the group comprising CuI, Cu(OAc), CuCl, CuBr, or Cu(OTf).
67. The process as claimed in claim 63 or 64, wherein the base is selected from the group comprising an organic base, an inorganic base, and combinations thereof.
68. The process as claimed in claim 67, wherein the base is selected from the group comprising K2CO3, K3PO4, K3PO4 H2O, NEt3, iPr2NH, iPr2NEt, DABCO, Cy2NMe, and combinations thereof.
69. The process as claimed in claim 63 or 64, wherein the ligand is selected from the group comprising a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, an alcohol-containing ligand, and a nitrogen-containing carbenoid ligand.
70. The process claimed in claim 69, wherein the ligand is selected from the group comprising S-Phos, X-Phos, P(o-tol)3, P(o-tol-p-OMe)3, P(O-MeOPh)3, P(p-MeOPh)3, PPh3, P(O-CF3-Ph)3, P(tBu)3, BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh3, DavePhos, HP(tBu)3 BF4; 1,10-phenanthroline, neocuproine, trans- 1 ,2-cyclohexyldiamine, cis-l,2-cyclohexyldiamine, ethylenediamine, N- methylethylenediamine, N,N-dimethylethylenediamine, dipivaloylmethane, 2- acetylcyclohexanone, 2-propionylcyclohexanone, 2-isobutyrylcyclohexanone, N,N- dimethylsalicylamides, ethylene glycol, ethanolamine, and
Figure imgf000172_0001
Cl"
71. The process claimed in any one of claims 63 to 70, wherein the palladium metal precatalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the compound of Formula (XI).
72. The process claimed in any one of claims 63 to 70, wherein the copper metal precatalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the compound of Formula (XI).
73. The process as claimed in any one of claims 63 to 70, wherein the ligand is present in an amount of about 2 mole percent of to about 10 mole percent relative to the compound of Formula (XI).
74. The process as claimed in any one of claims 63 to 73, wherein the palladium metal pre-catalyst comprises Pearlman's catalyst, the copper metal pre-catalyst comprises CuI, the ligand comprises P(p-MeOPh)3, and the base comprises iPr2NH.
75. The process as claimed in claim 74, wherein R6 is selected from the group comprising H, lower alkoxy, -C(O)O-lower alkyl, and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring.
76. The process as claimed in claim 74 or 75, wherein R8 is selected from the group comprising lower alkyl, aryl, lower alkyl-hydroxy, lower alkyl-OTBDPS, TMS, lower alkyl-nitrile, heteroaryl, and
Figure imgf000173_0001
77. The process as claimed in any one of claims 74 to 76, wherein R9 is selected from the group comprising H and methyl.
78. A novel 2-substituted benzo[b]furan or a salt thereof selected from the group consisting of:
Figure imgf000173_0002
79. An improved process for the preparation of a compound of the following Formula
(XI)
Figure imgf000174_0001
wherein
each Re is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R*, -C(O)O-R*, -C(0)NR* 2, -NR*C0-R*, - NR*C00-R , and -NR*CONR , wherein R is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR3, wherein R3 is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused nionocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of R^ and R are unsubstituted or substituted;
comprising reaction of a compound of Formula (XII)
Figure imgf000174_0002
(XII)
wherein R7 is selected from the group consisting of H, or a suitable protective group,
with CBr4 and P(OR)3, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, under reaction conditions effective to form a compound of Formula (XIII)
Figure imgf000175_0001
(XIII)
isolating the compound of Formula (XIII), and deprotection, if needed, of the protective group under conditions effective to yield the compound of Formula (XI).
80. The process of claim 79 wherein the protective group is selected from the group comprising a silyl protective group, an ester protective group, and an ether protective group.
81. The process of claim 80, wherein the silyl protective group is selected from the group comprising TMS, TBS, TBDPS and TES.
82. The process of claim 80, wherein the ester protective group is selected from the group comprising Ac, Piv, and Bz.
83. The process of claim 80, wherein the ether protective group is selected from the group comprising MOM, Tr and MEM.
84. A novel ortho-gem-dibτomo vinyl phenol or a salt thereof selected from the group consisting of:
Figure imgf000175_0002
PCT/CA2007/000289 2006-05-24 2007-02-23 2-VINYL INDOLES, PYRIDO AND AZEPINO INDOLE DERIVATIVES, 2-ALKYNYL INDOLES, 2-ALKYNYL BENZO[b]FURANS, THEIR PRECURSORS AND NOVEL PROCESSES FOR THE PREPARATION THEREOF WO2007134421A1 (en)

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CN115340485A (en) * 2022-08-25 2022-11-15 河南师范大学 Method for synthesizing indole terpene analogue through palladium-catalyzed serial Heck/carbonyl ortho-alkylation reaction

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CN108675950A (en) * 2018-06-07 2018-10-19 河南师范大学 A kind of synthetic method of 2- alkenyls Benzazole compounds
CN111187198A (en) * 2020-01-14 2020-05-22 湖南理工学院 Preparation method of 3, 3' -disubstituted indole-2-ketone compound
CN111187198B (en) * 2020-01-14 2023-10-31 湖南理工学院 Preparation method of 3,3' -disubstituted indol-2-one compound
CN113321675A (en) * 2021-04-26 2021-08-31 西华师范大学 Chiral 3-methylene indoline compound and preparation method thereof
CN113321675B (en) * 2021-04-26 2022-07-01 西华师范大学 Chiral 3-methylene indoline compound and preparation method thereof
CN114835665A (en) * 2022-03-25 2022-08-02 湖南大学 Novel cis-styryl benzofuranone compound and efficient synthesis method thereof
CN114835664A (en) * 2022-03-25 2022-08-02 湖南大学 Novel trans-styryl benzofuranone compound and efficient synthesis method thereof
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CN115340485B (en) * 2022-08-25 2023-10-03 河南师范大学 Method for synthesizing indole terpene analogues by palladium-catalyzed cascade Heck/carbonyl ortho-alkylation reaction

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