US20010037031A1 - Preparation of substituted indoles - Google Patents

Preparation of substituted indoles Download PDF

Info

Publication number
US20010037031A1
US20010037031A1 US09/782,310 US78231001A US2001037031A1 US 20010037031 A1 US20010037031 A1 US 20010037031A1 US 78231001 A US78231001 A US 78231001A US 2001037031 A1 US2001037031 A1 US 2001037031A1
Authority
US
United States
Prior art keywords
groups
group
hydrocarbon radical
substituted
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US09/782,310
Other versions
US6384235B2 (en
Inventor
Jochem Henkelmann
Jan-Dirk Arndt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Assigned to BASF AKTIENGESELLSCHAFT reassignment BASF AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARNDT, JAN-DIRK, HENKELMANN, JOCHEM
Publication of US20010037031A1 publication Critical patent/US20010037031A1/en
Application granted granted Critical
Publication of US6384235B2 publication Critical patent/US6384235B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for preparing substituted indoles of the formula (I), in which substituted 2-alkynylanilines are cyclized in a polar aprotic solvent with the aid of a suitable alkali metal compound.
  • the process should furthermore permit the synthesis of substituted indoles having a large number of different substituents.
  • A is a hydrocarbon radical which, together with the carbons to which it is attached, forms a substituted or unsubstituted mono- or polycyclic aromatic system which may contain one or more heteroatoms from the group consisting of N, O and S, and
  • R 1 , R 2 independently of one another are H, a saturated, linear or branched aliphatic C 1 -C 20 -hydrocarbon radical, an unsaturated, linear or branched aliphatic C 2 -C 20 -hydrocarbon radical, a saturated or unsaturated, unsubstituted or alkyl-substituted cycloaliphatic C 3 -C 20 -hydrocarbon radical or an aromatic C 5 -C 20 -hydrocarbon radical, where these radicals may contain in their molecular skeleton one or more heteroatoms from the group consisting of the halogens, N, P, O, S, Si, Sn and B and may be substituted or unsubstituted,
  • R 1 and R 2 are as defined in formula (I) and R 1 , R 2 or A may be attached to an organic or inorganic carrier,
  • the substituents R 1 and R 2 independently of one another are selected from the group consisting of H, linear and branched C 1 -C 12 -alkyl groups, linear and branched C 2 -C 12 -alkenyl groups, C 3 -C 8 -cycloalkyl groups, C 3 -C 8 -cycloalkenyl groups, C 5 - and C 6 -heterocycles having one or more ring atoms selected from the group consisting of N, O and S and mono- or bicyclic aromatics having one or more ring atoms selected from the group consisting of N, O and S.
  • the substituents R 1 and R 2 may have one or more substituents in their molecular skeleton.
  • Examples of preferred substituents are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, thioether groups, amide and ester groups, sulfaryl groups and sulfoxide groups.
  • the aromatic system in the compounds of the formula (I) can be a mono- or polycyclic aromatic which comprises exclusively carbon and hydrogen or which may have one or more heteroatoms selected from the group consisting of N, O and S.
  • the aromatic system is preferably a mono- or bicyclic aromatic. More preferably, the aromatic system is a C 5 -heterocycle or a benzene or naphthalene derivative which may contain one or more of the heteroatoms N, O and S mentioned, examples being benzene and naphthalene, aza-, diaza- and triazabenzene, aza-, diaza- and triazanaphthalene, thiophene and furan.
  • the aromatic system in the formula (I) is selected from the group consisting of benzene, naphthalene, pyridine, pyrazine, pyrimidine, quinoline, thiophene and furan.
  • the aromatic system may have one or more substituents which, similarly to the substituents R 1 and R 2 , may vary extremely.
  • substituents are alkanes and alkenes which are either unsubstituted or may carry customary substituents, for example halogens, amines, nitro groups, ether and hydroxyl groups or thiol- and thioether groups.
  • substituents on the aromatic system are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, sulfaryl groups, sulfoxide groups, thioether groups, amide and ester groups.
  • the synthesis of the indole derivatives (I) can be carried out by attaching the alkynylaminoaromatic (II) used as starting material to an organic or inorganic carrier and immobilizing it.
  • organic or inorganic carrier are known to the person skilled in the art and correspond to the customary carrier materials used, for example, for solid-phase peptide synthesis or for fixing transition metal catalyst systems.
  • Merrifield resin 4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucyl- methylbenzhydrylamino-(divinylbenzene-crosslinked polystyrene) resin, also known under the name Rink-MBHA resin, which is generally used after deprotection by removal of the 9-fluorenylmethoxycarbonyl-(Fmoc) group, and the carrier resin which is commercially available under the name trityl chloride resin, if appropriate after appropriate modification.
  • These carriers are either bonded to the aromatic system of the starting materials (II), or the substituent R 1 is attached to the carrier. If appropriate, the carrier may have suitable spacer groups which are attached to the starting material. Following the synthesis of the corresponding indole compound, the bond between the carrier and the target molecule is broken in a customary manner known to the person skilled in the art, for example by cleaving the bond between carrier and spacer group using trifluoroacetamide.
  • a further embodiment of the present invention allows the synthesis of compounds (I) in which the aromatic system, which is fused with the pyrroline unit, forming a bicyclic indole unit, is fused with a further pyrroline unit, forming a tricyclic bifunctional indole.
  • the starting material (II) used is a compound which does not only have one acetylene function and one amino function in a vicinal position, but in each case two of these functions.
  • the synthesis element according to the invention can also be widened such that the resulting indole does not only contain 2 pyrroline units, but 3 or even more of these units.
  • a starting material (II) is used which contains 3 or even more vicinal acetylene and amino functions.
  • the synthesis according to the invention is carried out using a suitable compound of Na, K, Rb or Cs, which is employed in combination with a polar aprotic solvent having ion-solvating properties.
  • a suitable compound of Na, K, Rb or Cs which is employed in combination with a polar aprotic solvent having ion-solvating properties.
  • NMP N-methylpyrrolidone
  • NBP N-butylpyrrolidone
  • DMSO dimethyl sulfoxide
  • sulfolane tetrahydrothiophene 1,1-dioxide
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • ethers hexamethylphosphoric triamide (HMPT) and N,N′-dimethylpropyleneurea.
  • ethers which can be obtained from ethylene oxide and/or propylene oxide.
  • This can be ethylene glycol and propylene glycol ethers, oligo- or polyethylene glycol, oligo- and polypropylene glycol and ethylene glycol/propylene glycol copolymers or block copolymers, such as, for example, the compounds known under the names glyme, diglyme, triglyme or the names Pluronic® and Pluriol® (from BASF AG).
  • ethers which are prepared by condensing ethylene oxide and/or propylene oxide with polyvalent amines for example the products available under the names Tetronic® and Lutensol® (in each case from BASF AG).
  • Suitable ethers are also crown ethers and cryptands.
  • solvents can be used on their own, as a mixture or as additive to other solvents. They have to be added in an amount which is sufficient to achieve the desired ion solvation and thus the required reactivity.
  • the compounds of Na, K, Rb and Cs which are employed are those which dissociate well in the solvents mentioned and whose ions are sufficiently solvated by these solvents.
  • suitable compounds of the alkali metals quoted are hydroxides, hydrides, alkoxides, amides and aminopropylamides.
  • Particularly suitable compounds are hydroxides and alkoxides.
  • the alkali metal compounds used according to the invention can be employed in stoichiometric or superstoichiometric amounts, but also in catalytic amounts.
  • the minimum amount of alkali metal compounds is about 5 mol %; however, it is also possible to use amounts of up to 250 mol %, based on the substrate.
  • the reaction temperatures required for the process according to the invention are about ⁇ 100° C.
  • the process according to the invention is preferably carried out at temperatures of about 20-60° C., most preferably of about 20-40° C.
  • the reaction times are from about 2 to 20 hours, preferably from 2 to 8 hours.
  • the starting materials (II) are obtained by the Sonogashira reaction (see K. Sonogashira et al., Synthesis 1980, 627 ff., K. Sakomoto, Synthesis 1983, 312 ff., G. C. Fu et al., Angew. Chem. Int. Ed. Engl. 38 (1999), 2411 ff.) from the corresponding 2-iodo- or 2-bromoanilines by reaction with 1 -alkynes.
  • Rink-MBHA resin (2 g; 0.64 mmol/g, obtainable by reaction of Rink-MBHA resin with piperidine, was, in a shaker glass fitted with septum and filled with argon, swollen for about 10 min in dichloromethane (15 ml) and then admixed with 4-iodobenzoic acid (478 mg; 1.92 mmol) and N,N′-diisopropylcarbodiimide (DIC) (240 mg; 1.92 mmol). The suspension was shaken at room temperature for 20 h. The polymer was filtered and washed alternately with dichloromethane, methanol, THF and DMF (in each case about 15 ml). The washing procedure was repeated three times. The polymer was then washed four times with dichloromethane (in each case about 15 ml) and dried at 55° C. for about 16 h.
  • 4-iodobenzoic acid (478 mg; 1.92 mmol)
  • DIC N
  • polymer-bound 4-iodobenzamide 500 mg; 0.25 mmol
  • Pd(PPh 3 ) 2 Cl 2 17.4 mg; 0.025 mmol
  • CuI 11.8 mg; 0.062 mmol
  • Diethylamine 5 ml was then added, the mixture was cooled to 0° C. and trimethylsilylacetylene (245 mg; 2.5 mmol) was added.
  • the mixture was stirred at room temperature for 12 h and the polymer was then filtered and washed with DMF, methanol and THF (in each case about 10 ml). The washing procedure was repeated four times.
  • the polymer was then washed four times with dichloromethane (in each case about 10 ml) and then admixed with TBAF (5 ml; 0.25 M in THF) and shaken for about 15 min.
  • the resin was washed as described above and dried at 55° C. for about 16 h.
  • the second coupling was carried out like the first coupling, including washing procedure and drying.
  • the resulting resin-bound amino-substituted diphenylacetylene can also be obtained in one step from the resin-bound 4-iodobenzamide and 2-trimethylsilylethynylaniline.
  • This process is carried out exactly like the first coupling, including washing procedure and drying, the only modification being that here the terminal alkyne is generated beforehand by deprotection with tetrabutylammonium fluoride (TBAF) in THF and added after substantial removal of the solvent under high vacuum.
  • TBAF tetrabutylammonium fluoride
  • the polymer-bound starting material (200 mg; 0.09 mmol) was initially charged in a Schlenk tube, fitted with septum and filled with argon, and swollen in NMP (4 ml) for about 5 min. The mixture was then cooled to 0° C., and a solution of KOtBu (150 mg; 1.35 mmol) in NMP (12 ml) was added dropwise. The mixture was then stirred at room temperature for 24 h, and the resin was filtered and washed with dichloromethane, THF, methanol, DMF (in each case about 5 ml). The washing procedure was repeated about ten to twelve times. The polymer was then washed four times with dichloromethane (in each case about 5 ml) and dried at 55° C. for about 16 h.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present application describes a process for preparing compounds of the indole type of the formula
Figure US20010037031A1-20011101-C00001
in which A is a hydrocarbon radical which, together with the carbons to which it is attached, forms a substituted or unsubstituted mono- or polycyclic aromatic system which may contain one or more heteroatoms from the group consisting of N, O and S, and
R1, R2 independently of one another are H, a saturated, linear or branched aliphatic C1-C20-hydrocarbon radical, an unsaturated, linear or branched aliphatic C2-C20-hydrocarbon radical, a saturated or unsaturated, unsubstituted or alkyl-substituted cycloaliphatic C3-C20-hydrocarbon radical or an aromatic C5-C20-hydrocarbon radical, where these radicals may contain in their molecular skeleton one or more heteroatoms from the group consisting of the halogens, N, P, O, S, Si, Sn and B and may be substituted or unsubstituted,
by cyclization of alkynylaminoaromatics of the formula
Figure US20010037031A1-20011101-C00002
in which R1 and R2 are as defined in formula (I) and R1, R2 or A may be attached to an organic or inorganic carrier,
which comprises carrying out the reaction in a polar aprotic ion-solvating solvent in the presence of a suitable compound of Na, K, Rb or Cs.
Using this process, it is possible to prepare substituted indoles in a simple manner and in high yields.

Description

  • The present invention relates to a process for preparing substituted indoles of the formula (I), in which substituted 2-alkynylanilines are cyclized in a polar aprotic solvent with the aid of a suitable alkali metal compound. [0001]
  • Simple, low-cost indole syntheses are of great general interest, since the indole structure is found in numerous natural products and in particular in pharmacologically active substances. To date, there are a number of principal routes leading to the desired indole derivatives. [0002]
  • Intramolecular addition of amino groups to a carbon-carbon triple bond with formation of indole derivatives is a reaction known from the literature. The reaction can be catalyzed, for example, by palladium complexes. This is described, inter alia, in the publication by K. Utimoto et al. in Tetrahedron Letters 29 (1992), 3915 ff. [0003]
  • Other publications disclose the use of molybdenum(0) compounds in these cyclization reactions. This can be found in the publications by F. E. McDonald et al. in Tetrahedron Letters 38 (1997), 7687 ff. and in Chem. Eur. J. 5 (1999), 3103 ff. [0004]
  • In a variant described in a plurality of publications by S. Cacchi et al., for example in Tetrahedron Letters 33 (1992), 3915 ff., Synlett 1997, 1393 ff., Tetrahedron Letters 50 (1994), 437 ff., it is possible to use, instead of the alkynylanilines, the corresponding trifluoroacetamides, the catalysts used here again being palladium complexes. [0005]
  • The synthesis of substituted indoles is furthermore described by Yamanaka et al. in Heterocycles 24 (1986), 31/32. Here, alkynylcarbanilates are cyclized in the presence of Na ethoxylate, and the N-bonded C(O)O-alkyl unit is removed by hydrolysis. This cyclization reaction does not work if the starting material used is a 2-alkynylaniline. [0006]
  • However, in all of these reactions it is frequently necessary to heat the reaction mixture to relatively high temperatures, and frequently, long reaction times are additionally required to achieve acceptable yields. These harsh reaction conditions, which are generally required, strongly restrict, inter alia, the range of the various functionalities which can be present in the 2-alkynylanilines. [0007]
  • It is an object of the present invention to provide a process which allows a simple preparation of the substituted indoles, with good yields and using short reaction times and low reaction temperatures. The process should furthermore permit the synthesis of substituted indoles having a large number of different substituents. [0008]
  • We have found that this object is achieved by a process for preparing compounds of the indole type of the formula [0009]
    Figure US20010037031A1-20011101-C00003
  • in which A is a hydrocarbon radical which, together with the carbons to which it is attached, forms a substituted or unsubstituted mono- or polycyclic aromatic system which may contain one or more heteroatoms from the group consisting of N, O and S, and [0010]
  • R[0011] 1, R2 independently of one another are H, a saturated, linear or branched aliphatic C1-C20-hydrocarbon radical, an unsaturated, linear or branched aliphatic C2-C20-hydrocarbon radical, a saturated or unsaturated, unsubstituted or alkyl-substituted cycloaliphatic C3-C20-hydrocarbon radical or an aromatic C5-C20-hydrocarbon radical, where these radicals may contain in their molecular skeleton one or more heteroatoms from the group consisting of the halogens, N, P, O, S, Si, Sn and B and may be substituted or unsubstituted,
  • by cyclization of alkynylaminoaromatics of the formula [0012]
    Figure US20010037031A1-20011101-C00004
  • in which R[0013] 1 and R2 are as defined in formula (I) and R1, R2 or A may be attached to an organic or inorganic carrier,
  • which comprises carrying out the reaction in a polar aprotic ion-solvating solvent in the presence of a suitable compound of Na, K, Rb or Cs. [0014]
  • We have found that the process according to the invention permits access to a large number of compounds of the indole type of a range which has not been possible with the processes of the prior art. By using the alkali metal compounds which are employed in the process according to the invention, it is possible to prepare indole derivatives which may have virtually any customary substituents R[0015] 1, R2. In the individual case, the accessibility of certain substituted indole derivatives depends on the influence of certain parameters. These are, for example, steric interactions between the individual substituents present, and possibly also the aromatic system of the indole derivative. The range of the different substituents R1 and R2 and of the substituents which may be present on the aromatic system of the formula (I) is enormously wide and comprises virtually all compound classes and functional groups which are included in the definition given above.
  • In a preferred embodiment of the present invention, the substituents R[0016] 1 and R2 independently of one another are selected from the group consisting of H, linear and branched C1-C12-alkyl groups, linear and branched C2-C12-alkenyl groups, C3-C8-cycloalkyl groups, C3-C8-cycloalkenyl groups, C5- and C6-heterocycles having one or more ring atoms selected from the group consisting of N, O and S and mono- or bicyclic aromatics having one or more ring atoms selected from the group consisting of N, O and S.
  • Both in the preferred and the not preferred embodiments, the substituents R[0017] 1 and R2 may have one or more substituents in their molecular skeleton.
  • Examples of preferred substituents are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, thioether groups, amide and ester groups, sulfaryl groups and sulfoxide groups. [0018]
  • The aromatic system in the compounds of the formula (I) can be a mono- or polycyclic aromatic which comprises exclusively carbon and hydrogen or which may have one or more heteroatoms selected from the group consisting of N, O and S. [0019]
  • The aromatic system is preferably a mono- or bicyclic aromatic. More preferably, the aromatic system is a C[0020] 5-heterocycle or a benzene or naphthalene derivative which may contain one or more of the heteroatoms N, O and S mentioned, examples being benzene and naphthalene, aza-, diaza- and triazabenzene, aza-, diaza- and triazanaphthalene, thiophene and furan.
  • In the most preferred embodiment of the present invention, the aromatic system in the formula (I) is selected from the group consisting of benzene, naphthalene, pyridine, pyrazine, pyrimidine, quinoline, thiophene and furan. [0021]
  • Both in the preferred and the not preferred embodiments, the aromatic system may have one or more substituents which, similarly to the substituents R[0022] 1 and R2, may vary extremely. Non-limiting examples of such substituents are alkanes and alkenes which are either unsubstituted or may carry customary substituents, for example halogens, amines, nitro groups, ether and hydroxyl groups or thiol- and thioether groups. Further examples of substituents on the aromatic system are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, sulfaryl groups, sulfoxide groups, thioether groups, amide and ester groups.
  • In one embodiment of the present invention, the synthesis of the indole derivatives (I) can be carried out by attaching the alkynylaminoaromatic (II) used as starting material to an organic or inorganic carrier and immobilizing it. These carriers are known to the person skilled in the art and correspond to the customary carrier materials used, for example, for solid-phase peptide synthesis or for fixing transition metal catalyst systems. Examples are Merrifield resin, 4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucyl- methylbenzhydrylamino-(divinylbenzene-crosslinked polystyrene) resin, also known under the name Rink-MBHA resin, which is generally used after deprotection by removal of the 9-fluorenylmethoxycarbonyl-(Fmoc) group, and the carrier resin which is commercially available under the name trityl chloride resin, if appropriate after appropriate modification. [0023]
  • These carriers are either bonded to the aromatic system of the starting materials (II), or the substituent R[0024] 1 is attached to the carrier. If appropriate, the carrier may have suitable spacer groups which are attached to the starting material. Following the synthesis of the corresponding indole compound, the bond between the carrier and the target molecule is broken in a customary manner known to the person skilled in the art, for example by cleaving the bond between carrier and spacer group using trifluoroacetamide.
  • A further embodiment of the present invention allows the synthesis of compounds (I) in which the aromatic system, which is fused with the pyrroline unit, forming a bicyclic indole unit, is fused with a further pyrroline unit, forming a tricyclic bifunctional indole. To this end, the starting material (II) used is a compound which does not only have one acetylene function and one amino function in a vicinal position, but in each case two of these functions. [0025]
  • The synthesis element according to the invention can also be widened such that the resulting indole does not only contain 2 pyrroline units, but 3 or even more of these units. To this end, a starting material (II) is used which contains 3 or even more vicinal acetylene and amino functions. [0026]
  • The synthesis according to the invention is carried out using a suitable compound of Na, K, Rb or Cs, which is employed in combination with a polar aprotic solvent having ion-solvating properties. By using these solvents, it is possible to increase the electrophilicity of the ions of the metals mentioned such that the cyclization according to the invention can be carried out under mild conditions. [0027]
  • These polar aprotic ion-solvating solvents are known to the person skilled in the art, examples being N-methylpyrrolidone (NMP), N-butylpyrrolidone (NBP), dimethyl sulfoxide (DMSO), sulfolane (tetrahydrothiophene 1,1-dioxide), dimethylformamide (DMF), tetrahydrofuran (THF), ethers, hexamethylphosphoric triamide (HMPT) and N,N′-dimethylpropyleneurea. [0028]
  • Examples of suitable ethers are ethers which can be obtained from ethylene oxide and/or propylene oxide. This can be ethylene glycol and propylene glycol ethers, oligo- or polyethylene glycol, oligo- and polypropylene glycol and ethylene glycol/propylene glycol copolymers or block copolymers, such as, for example, the compounds known under the names glyme, diglyme, triglyme or the names Pluronic® and Pluriol® (from BASF AG). It is also possible to use ethers which are prepared by condensing ethylene oxide and/or propylene oxide with polyvalent amines, for example the products available under the names Tetronic® and Lutensol® (in each case from BASF AG). [0029]
  • It is also possible to use the respective ethers, for example the methyl ethers, of all of the abovementioned ethylene glycol and propylene glycol ethers, which, for example in the case of Pluronic®, Pluriol® and Tetronic®, may still have free terminal hydroxyl groups. Suitable ethers are also crown ethers and cryptands. [0030]
  • These solvents can be used on their own, as a mixture or as additive to other solvents. They have to be added in an amount which is sufficient to achieve the desired ion solvation and thus the required reactivity. [0031]
  • The compounds of Na, K, Rb and Cs which are employed are those which dissociate well in the solvents mentioned and whose ions are sufficiently solvated by these solvents. Examples of suitable compounds of the alkali metals quoted are hydroxides, hydrides, alkoxides, amides and aminopropylamides. [0032]
  • Particularly suitable compounds are hydroxides and alkoxides. [0033]
  • Among the abovementioned metals Na, K, Rb and Cs, the best reactivities are obtained when K and Cs are used, and their use is preferred. The alkali metal compounds used according to the invention can be employed in stoichiometric or superstoichiometric amounts, but also in catalytic amounts. The minimum amount of alkali metal compounds is about 5 mol %; however, it is also possible to use amounts of up to 250 mol %, based on the substrate. The reaction temperatures required for the process according to the invention are about <100° C. The process according to the invention is preferably carried out at temperatures of about 20-60° C., most preferably of about 20-40° C. The reaction times are from about 2 to 20 hours, preferably from 2 to 8 hours. The starting materials (II) are obtained by the Sonogashira reaction (see K. Sonogashira et al., Synthesis 1980, 627 ff., K. Sakomoto, Synthesis 1983, 312 ff., G. C. Fu et al., Angew. Chem. Int. Ed. Engl. 38 (1999), 2411 ff.) from the corresponding 2-iodo- or 2-bromoanilines by reaction with 1 -alkynes. If the process according to the invention is carried out on a carrier, in solid phase, the corresponding iodo- or bromoaniline is, prior to the Sonogashira coupling, fixed to the carrier using methods known to the person skilled in the art. The invention is now illustrated by the examples below.[0034]
    • EXAMPLE 1
  • Synthesis of 2-phenylindole using different alkali metal compounds [0035]
  • A solution of 1.05 mmol of the alkali metal compound in question was dissolved or suspended under argon in 4 ml of NMP. 97 mg (0.5 mmol) of 2-phenylethynylaniline in 1 ml of NMP were then added. The solution was then stirred vigorously at the temperatures given in Table 1, for the stated reaction times. 1 ml of water and 50 ml of dichloromethane were then added, and the resulting solution was washed with a saturated NaCl solution. The solution was dried over MgSO[0036] 4, the residue was filtered off, the solution was concentrated under reduced pressure and the resulting residue was then purified chromatographically on a silica gel column using a CH2Cl2/pentane mixture. Removal of the solvent gave the pure product.
  • The results are shown in Table 1. The stated yields are based on analytically pure end product. [0037]
    TABLE 1
    Temp. Time Yield
    Experiment Base [° C.] [h] [%]
    A NaH 60 8 >5
    B NaOEt 80 15  66
    C KOt-Bu 25 4 79
    D KH 25 5 72
    E CsOH 90 5 68
    F CsOt-Bu 25 5 71
    • EXAMPLE 2
  • Synthesis of different indole and azaindole derivatives [0038]
  • Method A [0039]
  • Under argon, 0.5 mmol of the starting material in question is added to a stirred solution of 42 mg (1.05 mmol) of KH in 4 ml of NMP. After 3 to −12 hours at room temperature, the reaction solution was worked up as in Example 1. The results are shown in Table 2. [0040]
  • Method B [0041]
  • The reaction was carried out as described under A, using the alkali metal compound KOt-Bu. The reaction time was 4 hours at room temperature. Work-up, too, was carried out as described in Example 1. The results are also shown in Table 2. [0042]
    TABLE 2
    Ex- Indole derivative Yield
    periment Aniline used obtained Method [%]
    1
    Figure US20010037031A1-20011101-C00005
    Figure US20010037031A1-20011101-C00006
    1a:R = Ph 2a:R = Ph A(B) 72(79)
    2 1b:R = Bu 2b:R = Bu A(B) 76(78)
    3 1c:R = 1-cyclo- 2c:R = A 67
    hexenyl 1-cyclohexenyl
    4 1d:R = H 2d:R = H B 62
    5 1e:R = (CH2)2OH 2e:R = (CH2)2OH A 61
    6 1f:R = CH(OEt)2 2f:R = CH(Oet)2 B 81
    7 1g:R2-thienyl 2g:R = 2-thienyl A 70
    8 1h:R = 2-thiazole 2h:R = 2-thiazole A 61
    9 1i:R3-chloropropyl 2i:R = 3-cyclo- A 75
    propyl
    10 1j:R = 2j:R = 2-amino- A 82
    2-aminophenyl phenyl
    11
    Figure US20010037031A1-20011101-C00007
    Figure US20010037031A1-20011101-C00008
         		A 80
    12
    Figure US20010037031A1-20011101-C00009
    Figure US20010037031A1-20011101-C00010
         		B 77
    13
    Figure US20010037031A1-20011101-C00011
    Figure US20010037031A1-20011101-C00012
         		A 72
    14
    Figure US20010037031A1-20011101-C00013
    Figure US20010037031A1-20011101-C00014
         		A 74
    15
    Figure US20010037031A1-20011101-C00015
    Figure US20010037031A1-20011101-C00016
         		B 78
    16
    Figure US20010037031A1-20011101-C00017
    Figure US20010037031A1-20011101-C00018
         		B 61a)
    17
    Figure US20010037031A1-20011101-C00019
    Figure US20010037031A1-20011101-C00020
         		B 80b)
    18
    Figure US20010037031A1-20011101-C00021
    Figure US20010037031A1-20011101-C00022
         		B 90b)
    • EXAMPLE 3
  • Solid-phase synthesis of substituted indoles [0043]
    Figure US20010037031A1-20011101-C00023
  • a) preparation of starting material 3 [0044]
  • Deprotected Rink-MBHA resin (2 g; 0.64 mmol/g, obtainable by reaction of Rink-MBHA resin with piperidine, was, in a shaker glass fitted with septum and filled with argon, swollen for about 10 min in dichloromethane (15 ml) and then admixed with 4-iodobenzoic acid (478 mg; 1.92 mmol) and N,N′-diisopropylcarbodiimide (DIC) (240 mg; 1.92 mmol). The suspension was shaken at room temperature for 20 h. The polymer was filtered and washed alternately with dichloromethane, methanol, THF and DMF (in each case about 15 ml). The washing procedure was repeated three times. The polymer was then washed four times with dichloromethane (in each case about 15 ml) and dried at 55° C. for about 16 h. [0045]
  • b) The resulting product was then subjected to two successive Sonogashira couplings, the cyclization according to the invention and cleavage from the polymer resin. [0046]
  • To this end, in the first coupling, polymer-bound 4-iodobenzamide (500 mg; 0.25 mmol), Pd(PPh[0047] 3)2Cl2 (17.4 mg; 0.025 mmol) and CuI (11.8 mg; 0.062 mmol) were initially charged in a Schlenk tube, fitted with septum and filled with argon, and swollen in toluene (5 ml) for about 10 min. Diethylamine (5 ml) was then added, the mixture was cooled to 0° C. and trimethylsilylacetylene (245 mg; 2.5 mmol) was added. The mixture was stirred at room temperature for 12 h and the polymer was then filtered and washed with DMF, methanol and THF (in each case about 10 ml). The washing procedure was repeated four times. The polymer was then washed four times with dichloromethane (in each case about 10 ml) and then admixed with TBAF (5 ml; 0.25 M in THF) and shaken for about 15 min. The resin was washed as described above and dried at 55° C. for about 16 h.
  • The second coupling was carried out like the first coupling, including washing procedure and drying. [0048]
  • The following amounts were used: [0049]
  • Resin-bonded 4-ethynylbenzamide (400 mg; 0.22 mmol); Pd(PPh[0050] 3)2Cl2 (15.4 mg; 0.022 mmol); CuI (10.5 mg; 0.055 mmol); toluene (4 ml); diethylamine (4 ml); 2-iodoaniline (450 mg; 2.2 mmol).
  • The resulting resin-bound amino-substituted diphenylacetylene can also be obtained in one step from the resin-bound 4-iodobenzamide and 2-trimethylsilylethynylaniline. This process is carried out exactly like the first coupling, including washing procedure and drying, the only modification being that here the terminal alkyne is generated beforehand by deprotection with tetrabutylammonium fluoride (TBAF) in THF and added after substantial removal of the solvent under high vacuum. [0051]
  • The following amounts were used: [0052]
  • Resin-bound 4-iodobenzamide (500 mg; 0.25 mmol); Pd(PPh[0053] 3)2Cl2 (17.5 mg; 0.025 mmol); CuI (11.9 mg; 0.063 mmol); toluene (5 ml); diethylamine (5 ml); 2-trimethylsilylethynylaniline (475 mg; 2.5 mmol); TBAF (11.0 ml, 2.75 mmol).
  • The resulting intermediate was then cyclized to give the indole, as follows: [0054]
  • The polymer-bound starting material (200 mg; 0.09 mmol) was initially charged in a Schlenk tube, fitted with septum and filled with argon, and swollen in NMP (4 ml) for about 5 min. The mixture was then cooled to 0° C., and a solution of KOtBu (150 mg; 1.35 mmol) in NMP (12 ml) was added dropwise. The mixture was then stirred at room temperature for 24 h, and the resin was filtered and washed with dichloromethane, THF, methanol, DMF (in each case about 5 ml). The washing procedure was repeated about ten to twelve times. The polymer was then washed four times with dichloromethane (in each case about 5 ml) and dried at 55° C. for about 16 h. [0055]
  • The resulting resin was then cleaved using TFA/dichloromethane 1:1. [0056]
    Figure US20010037031A1-20011101-C00024
  • The Sonogashira coupling was carried out as described above under A, but at 80° C. over the course of 18 h, and the starting material used was resin-bound 2-bromo-4-methylaniline. 50 mol % of CuI were used. The reaction with KOt-Bu was then carried out by method A, as was the cleavage of the resin. [0057]

Claims (10)

We claim:
1. A process for preparing compounds of the indole type of the formula
Figure US20010037031A1-20011101-C00025
in which A is a hydrocarbon radical which, together with the carbons to which it is attached, forms a substituted or unsubstituted mono- or polycyclic aromatic system which may contain one or more heteroatoms from the group consisting of N, O and S, and
R1, R2 independently of one another are H, a saturated, linear or branched aliphatic C1-C20-hydrocarbon radical, an unsaturated, linear or branched aliphatic C2-C20-hydrocarbon radical, a saturated or unsaturated, unsubstituted or alkyl-substituted cycloaliphatic C3-C20-hydrocarbon radical or an aromatic C5-C20-hydrocarbon radical, where these radicals may contain in their molecular skeleton one or more heteroatoms from the group consisting of the halogens, N, P, O, S, Si, Sn and B and may be substituted or unsubstituted,
by cyclization of alkynylaminoaromatics of the formula
Figure US20010037031A1-20011101-C00026
in which R1 and R2 are as defined in formula (I) and R1, R2 or A may be attached to an organic or inorganic carrier,
which comprises carrying out the reaction in a polar aprotic ion-solvating solvent in the presence of a suitable compound of Na, K, Rb or Cs, preferably K or Cs.
2. A process as claimed in
claim 1
, wherein the substituents R1 and R2 independently of one another are selected from the group consisting of H, linear and branched C1-C12-alkyl groups, linear and branched C2-C12-alkenyl groups, C3-C8-cycloalkyl groups, C3-C8-cycloalkenyl groups, C5- and C6-heterocycles having one or more ring atoms selected from the group consisting of N, O and S and mono- or bicyclic aromatics having one or more ring atoms selected from the group consisting of N, O and S.
3. A process as claimed in
claim 1
, wherein the hydrocarbon groups defined for R1 and R2 carry one or more substituents selected from the group consisting of amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, thioether groups, amide and ester groups, sulfaryl groups and sulfoxide groups.
4. A process as claimed in
claim 1
, wherein a hydride, hydroxide, alkoxide, amide or aminopropylamide of Na, K, Rb or Cs is used.
5. A process as claimed in
claim 1
, wherein the solvent used is N-methylpyrrolidone, N-butylpyrrolidone, dimethyl sulfoxide, sulfolane, dimethylformamide, tetrahydrofuran, hexamethylphosphoric triamide, N,N′-dimethylpropyleneurea or an ether, in particular an ether prepared from ethylene oxide and/or propylene oxide or from ethylene oxide and propylene oxide and a polyvalent amine, or a mixture of these solvents.
6. A process as claimed in
claim 1
, wherein the aromatic system in the compound of the formula (I) is a substituted or unsubstituted mono- or bicyclic aromatic, preferably a substituted or unsubstituted aromatic selected from the group consisting of C5-heterocycles, benzene and naphthalene derivatives, most preferably from the group consisting of benzene, naphthalene, pyridine, pyrazine, pyrimidine, quinoline, thiophene and furan.
7. A process as claimed in
claim 1
, wherein the alkali metal compound is employed in an amount of from 5 mol % to 150 mol %, based on the substrate.
8. A process as claimed in
claim 1
, wherein the process is carried out at temperatures <100° C., preferably at 20-60° C., most preferably at 20-40° C.
9. A process as claimed in
claim 1
, wherein the reaction time is from 2 to 20 hours, preferably from 2 to 8 hours.
10. A process as claimed in
claim 1
, wherein the alkynylaminoaromatic (II) used as starting material is attached to an organic or inorganic carrier, preferably selected from the group consisting of Merrifield resin, rink-MHBA resin and trityl chloride resin, if appropriate after appropriate modification, and immobilized, and the bond between carrier material and target molecule is broken in a manner known per se when the synthesis has ended.
US09/782,310 2000-02-25 2001-02-14 Preparation of substituted indoles Expired - Fee Related US6384235B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10009000A DE10009000A1 (en) 2000-02-25 2000-02-25 Process for the preparation of substituted indoles
DE10009000 2000-02-25
DE10009000.1 2000-02-25

Publications (2)

Publication Number Publication Date
US20010037031A1 true US20010037031A1 (en) 2001-11-01
US6384235B2 US6384235B2 (en) 2002-05-07

Family

ID=7632464

Family Applications (1)

Application Number Title Priority Date Filing Date
US09/782,310 Expired - Fee Related US6384235B2 (en) 2000-02-25 2001-02-14 Preparation of substituted indoles

Country Status (4)

Country Link
US (1) US6384235B2 (en)
EP (1) EP1127874A3 (en)
JP (1) JP2001233855A (en)
DE (1) DE10009000A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100035884A1 (en) * 2006-09-11 2010-02-11 Sanofi-Aventis Kinase inhibitor
CN115894335A (en) * 2022-10-26 2023-04-04 华南理工大学 Method for synthesizing 2-phenylindole compound by using alkyne halide and aniline compound

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
OA12514A (en) 1999-12-24 2006-05-29 Aventis Pharma Ltd Azaindoles.
DE10022925A1 (en) * 2000-05-11 2001-11-15 Basf Ag New indole-carboxamide or azepino-indole derivatives and analogs, are poly-ADP ribose polymerase inhibitors useful e.g. for treating neurodegenerative disease, ischemia, epilepsy, tumors, sepsis or diabetes mellitus
GB0115109D0 (en) 2001-06-21 2001-08-15 Aventis Pharma Ltd Chemical compounds
WO2003024931A1 (en) * 2001-09-14 2003-03-27 Merck & Co., Inc. Tyrosine kinase inhibitors
SI1603877T1 (en) 2003-03-04 2009-04-30 Addex Pharma Sa NOVEL AMINOPYRIDINE DERIVATIVES AS mGIuR5 ANTAGONISTS
SE0300908D0 (en) * 2003-03-31 2003-03-31 Astrazeneca Ab Azaindole derivatives, preparations thereof, uses thereof and compositions containing them
AU2004259703A1 (en) * 2003-07-15 2005-02-03 Smithkline Beecham Corporation Novel compounds
CA2536887C (en) * 2003-08-26 2012-03-06 Teijin Pharma Limited Pyrrolopyrimidinone derivatives
US20060183758A1 (en) * 2005-02-17 2006-08-17 Cb Research And Development, Inc. Method for synthesis of AZA-annelated pyrroles, thiophenes, and furans
US20090306115A1 (en) * 2005-04-22 2009-12-10 Cosford Nicholas D Phenyl ethyne compounds
DE102005025225A1 (en) * 2005-06-01 2006-12-07 Sanofi-Aventis Deutschland Gmbh Process for the preparation of 2- (2-amino-pyrimidin-4-yl) -1H-indole-5-carboxylic acid derivatives
US20100291533A1 (en) 2008-01-04 2010-11-18 Soon Ha Kim Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100035884A1 (en) * 2006-09-11 2010-02-11 Sanofi-Aventis Kinase inhibitor
US8658649B2 (en) 2006-09-11 2014-02-25 Sanofi Kinase inhibitor
CN115894335A (en) * 2022-10-26 2023-04-04 华南理工大学 Method for synthesizing 2-phenylindole compound by using alkyne halide and aniline compound

Also Published As

Publication number Publication date
DE10009000A1 (en) 2001-08-30
JP2001233855A (en) 2001-08-28
US6384235B2 (en) 2002-05-07
EP1127874A2 (en) 2001-08-29
EP1127874A3 (en) 2004-01-07

Similar Documents

Publication Publication Date Title
US6384235B2 (en) Preparation of substituted indoles
Antonio et al. A versatile approach to 2, 3-disubstituted indoles through the palladium-catalysed cyclization of o-alkynyltrifluoroacetanilides with vinyl triflates and aryl halides.
US6166226A (en) Synthesis of aryl ethers
Verniest et al. Synthesis of substituted β-carbolines via gold (III)-catalyzed cycloisomerization of N-propargylamides
Wender et al. Transition metal-catalyzed intramolecular [4+ 2] cycloadditions: a novel method for the assembly of nitrogen heterocycles and its application to yohimban alkaloid synthesis
IE832956L (en) SUBSTITUTED 5H-PYRIMIDO £5,4-b| INDOLES
KR20200058468A (en) 7- (4,7-diazaspiro [2.5] octane-7-yl) -2- (2,8-dimethylimidazo [1,2-b] pyridazine-6-yl) pyrido [1 , 2-a] Preparation method of pyrimidin-4-one derivative
CN107531672A (en) Chemical process for preparing pyrimidine derivatives and intermediates thereof
WO2008059771A1 (en) Process for producing fullerene derivative
Alvarez et al. Synthesis of 3-Aryl-and 3-Heteroaryl-7-azaindoles
Borah et al. Ir (iii)-Catalyzed [4+ 2] cyclization of azobenzene and diazotized Meldrum's acid for the synthesis of cinnolin-3 (2 H)-one
WO2023284262A1 (en) 3,4-fused seven-membered heterocyclic oxindole, synthesis method therefor and application thereof
FI84066C (en) Process for the preparation of novel therapeutically useful carbolic derivatives
CN109438317B (en) Preparation method of nitrogen-alkyl (deuterated alkyl) aromatic heterocycle and alkyl (deuterated alkyl) aryl ether compound
US6531607B2 (en) Immobilized palladium complexes
Hu et al. A facile synthesis of 4-aryl-1, 2, 3, 4-tetrahydroisoquinolines
US20020016512A1 (en) Heterogeneously catalyzed process for cross coupling aryl chlorides with aryl boronic acids
Tietze et al. Efficient Synthesis of the Pharmacophore of the Highly Potent Antitumor Antibiotic CC‐1065
CN110156657B (en) Synthesis method of 4-aminoindole
WO2022104599A1 (en) N-heterocyclic carbene catalyst and preparation method therefor
Umeda et al. Synthesis of Indoles: Sulfur-assisted Reaction of 2-Nitrostilbenes with Carbon Monoxide
Sakai et al. Friedel–Crafts reaction of indoles with N-silyl-N, O-acetal catalyzed by Cu (OTf) 2 in the presence of TMSCl leading to indolyl primary amines
CA2190202C (en) Cyclopentenecarboxamide derivative, method for preparing the same and bicycloamide derivative used therein
Hiroya et al. The optimization for cyclization reaction of 2-(2-carbomethoxyethynyl) aniline derivatives and formal synthesis of pyrroloquinoline quinone and its analogue utilizing a sequential coupling-cyclization reaction
CN112979529B (en) Aromatic amine indole naphthoquinone derivative and preparation method thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: BASF AKTIENGESELLSCHAFT, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HENKELMANN, JOCHEM;ARNDT, JAN-DIRK;REEL/FRAME:011559/0272

Effective date: 20001122

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20100507