WO2001030734A1 - Novel hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand - Google Patents
Novel hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand Download PDFInfo
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- WO2001030734A1 WO2001030734A1 PCT/SE2000/002090 SE0002090W WO0130734A1 WO 2001030734 A1 WO2001030734 A1 WO 2001030734A1 SE 0002090 W SE0002090 W SE 0002090W WO 0130734 A1 WO0130734 A1 WO 0130734A1
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- dihydro
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- naphthalen
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- 0 Cc1c(*)c(*)c(C2C=CC3*2)c3c1 Chemical compound Cc1c(*)c(*)c(C2C=CC3*2)c3c1 0.000 description 6
- BLAFSMXCRFQMMZ-HUUCEWRRSA-N CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1 Chemical compound CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1 BLAFSMXCRFQMMZ-HUUCEWRRSA-N 0.000 description 1
- XONGBDXIFQIQBN-UHFFFAOYSA-N CS(c(cc1)ccc1[N+]([O-])=O)(=O)=O Chemical compound CS(c(cc1)ccc1[N+]([O-])=O)(=O)=O XONGBDXIFQIQBN-UHFFFAOYSA-N 0.000 description 1
- AJRZXPGXYQJEEW-FGZHOGPDSA-N Cc(cc1)ccc1S(N(C)[C@@H]([C@@H](CC1)N2CCCC2)c2c1cccc2)(=O)=O Chemical compound Cc(cc1)ccc1S(N(C)[C@@H]([C@@H](CC1)N2CCCC2)c2c1cccc2)(=O)=O AJRZXPGXYQJEEW-FGZHOGPDSA-N 0.000 description 1
- VDUJYQAAPRPZFR-NFJWQWPMSA-N OC1c2ccccc2C=C[C@H]1OC=O Chemical compound OC1c2ccccc2C=C[C@H]1OC=O VDUJYQAAPRPZFR-NFJWQWPMSA-N 0.000 description 1
- SASFZAFXKVHJPR-HZPDHXFCSA-N O[C@@H]1c2ccccc2C=C[C@H]1Oc(cc1)ccc1Br Chemical compound O[C@@H]1c2ccccc2C=C[C@H]1Oc(cc1)ccc1Br SASFZAFXKVHJPR-HZPDHXFCSA-N 0.000 description 1
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Definitions
- Novel hydronaphtalene compounds prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand
- the present invention is directed to methods for chemically synthesizing compounds containing a hydronaphthalene ring stmcture. It encompasses the compounds made by the methods, pharmaceutical preparations containing the compounds, and methods for treating patients using these pharmaceutical preparations.
- hydronaphthalene structure can be found in many natural products and pharmaceutical agents. These include homochelidonine (structure 1 below; Slavik, J.; et al, Collect. Czech. Chem. Commun. 30:3691 (1965); Spath, E., et al., Ber., 64: 1123 (1931); 3ersch. H. W., Arch. Pharm. (Weinheim, Ger.), 2914:91 (1958)) an alkaloid isolated from Ch ⁇ lido ⁇ ium plants, dihydrexidine (structure 2 below; Snyder, S. E., J. Med.
- Duan and Chen developed a method of introducing aryl groups by using catalytic amounts of palladium (Duan, J.-P., et al, Tetrahedron Lett., 54:4019 (1993); Duan, J.-P., et al, Organometallics 14:1608 (1995)).
- Moinet et al later developed an enantioselective version of this reaction but the yields were low (Tetrahedron Lett., 36:2051 (1995)).
- the present invention is based upon the discovery of a rhodium catalyzed ring opening reaction of oxabenzonorbornadienes or azabicyclic compounds to produce a new carbon-oxygen bond via an intermolecular reaction with various alcohols. This reaction occurs in good yields with complete regio and diastereoselectivity and excellent enantioselectivity (e.g., eq. 1).
- Z is O or NR a .
- This reaction will work when oxabenzonor- bornadienes or azabicyclic compounds are reacted with nitrogen nucleophiles, carboxylate nucleophiles, carbon nucleophiles or phenol nucleophiles.
- the invention encompasses not only the chemical reactions but also the compounds made by the reactions and the use of such compounds in the treatment of a variety of diseases and conditions.
- the invention is directed to a compound according to formula I:
- R is selected from the group consisting of: (a) H;
- the compounds of formula I described above may be prepared by reacting a compound of formula ROH with a compound of formula V:
- reaction is catalyzed by [Rh(COD)Cl] 2 in the presence of a phosphine ligand, preferably selected from the group consisting of: DPPF; (R)-(S)- BPPFA; and (R)-(S)-PPF-P ! Bu 2 .
- a phosphine ligand preferably selected from the group consisting of: DPPF; (R)-(S)- BPPFA; and (R)-(S)-PPF-P ! Bu 2 .
- R is selected from the group consisting of:
- the compounds of formula II described above may be prepared by reacting a compound of formula ROH with a compound of formula V:
- R, X, Y, and Z are as defined above in connection with formula II and in which the reaction is catalyzed by [Rh(COD)Cl] 2 in the presence of a phosphine ligand, preferably (S)-(R)- PPF-P l Bu 2 .
- the invention is also directed to a compound according to formula III:
- TBDMSO is a tert-butyldimethylsiloxy group
- R, X, and Y are as defined in above in connection with formula I.
- These compounds may be made by preparing a compound of formula I according to the process described above and then reacting the compound formed with a salt of tert-butyldimethylsilylic acid.
- the compound formed is (lR*,2R*)-malonic acid (1 -tert-butyldimethylsiloxy- l,2-dihydro-naphthalen-2-yl) ester ethyl ester and ROH is tert- butyldimethylsilylic acid.
- the invention is directed to a compound according to formula IV:
- R 9 is a C -C 6 aryl optionally substituted at one or more positions with a group selected from: a C>-C 3 alkyl; a C1-C3 alkoxy; CI; F; NO 2 ; and CF 3 ; or R 9 together with N form a ring structure selected from: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; said ring structure being optionally substituted at one or more positions with a group selected from: a C 1 -C 3 alkyl; a C t -C 3 alkoxy; CI; F; NO 2 ; and CF 3 ; d) X and Y are independently selected from the group consisting of H; NH 2 ; F; CI; Br; a C 1 -C 3 alky
- Rs in formula IV is H and R 9 together with N form a ring selected from the group consisting of a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; the ring being optionally substituted at one or more positions with a group selected from: a C ⁇ -C 3 alkyl; a C 1 -C 3 alkoxy; CI; F; NO ; and CF 3 .
- Z is NR a
- R a is preferably methyl
- the compounds of formula IV described above may be prepared by reacting a compound of formula R 9 -(CH 2 )tNHR 8 with a compound of formula V
- R 8 , R , t, X, Y, and Z are as defined above in connection with compounds of formula IV and the reaction is catalyzed by [Rh(COD)Cl] 2 in the presence of a phosphine ligand; preferably selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-P l Bu 2 .
- a phosphine ligand preferably selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-P l Bu 2 .
- Z is NR a
- the reaction will produce a product in which R- 0 is H.
- a subsequent reaction may be used to convert Rio to a methyl as set forth in the Examples section below.
- R 9 together with N form a ring selected from the group consisting of: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; said ring structures being optionally substituted at one or more positions with a group selected from: a C 1 -C 3 alkyl; a C ⁇ -C alkoxy; CI; F; NO 2 ; and CF 3 .
- the invention also encompasses seven other processes.
- (lS,2S)-N-(l-hydroxy- l,2-dihydro-naphthalen-2-yl)-benzene sulfonamide is formed by reacting oxabenzonorbornadiene with benzenesulfonamide.
- (lS*,2R*)-2-(hydroxy-l,2-dihydro-naphthalen-2- yl)malonic acid dimethyl ester is formed by reacting oxabenzonorbornadiene with dimethyl malonate. Both reactions are catalyzed by [Rh(COD)Cl] 2 in the presence of a phosphine ligand.
- the compound of formula VI is formed by reacting a compound of formula IV, which is produced as described above in connection with formation of compounds of formula IV, with iodomethane.
- the compound made is N,4-dimethyl-N-[(lR,2S)-2-(l- pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide.
- the compound of formula VII is formed by reacting compound of formula VI with hydrogen in the presence of palladium catalyst.
- the compound made is N,4-dimethyl-N-[(lR,2S)-2-(l-pyrrolidinyl)-l,2,3,4- tetrahydro-l-naphthalenyl]benzenesulfonamide.
- the compound of formula VIII is formed by reacting the compound of formula VII with sodium borohydride.
- the compound made using this reaction is (lE,2S)-N-methyl-2-(l-pyrrolidinyl)-l,2,3,4-tetrahydro-l-naphthalenamine.
- the compound of formula IX is formed by reacting a compound of formula IV which is produced as described above in connection with formation of compounds of formula IV, with iodomethane.
- the compound made using this reaction is ⁇ -methyl-4-nitro- ⁇ -[(lR,2S)-2-(l- pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide.
- the compound of formula X is formed by reacting a compound of formula I which is produced as described above in connection with formation of compounds of formula I, with iodomethane.
- the compound made using this reaction is (lE,2S)-l- ⁇ methyl[(4-methylphenyl)sulfonyl]amino ⁇ -l,2-dihydro-2- naphthalenyl acetate.
- the most preferred compounds of the invention are: a) ( 1 S,2S)-2-methoxy- 1 ,2-dihydro-naphthalen- 1 -ol; b) ( 1 S,2S)-2-(ethoxy)- 1 ,2-dihydro-naphthalen- 1 -ol; c) (lS,2S)-2-(isopropoxy)-l,2-dihydro-naphthalen-l-ol; d) (lS,2S)-2-(l-propenyloxy)-l,2-dihydro-naphthalen-l-ol; e) ( 1 S,2S)-2-(2-trimethylsilyl-ethoxy) 1 ,2-dihydro-naphthalen- 1 -ol; f) ( 1 S,2S)-2-benzyloxy- 1 ,2-dihydro-naphthalen- 1 -ol; g) (lS,2S)-2-benz
- Any of the compounds described above may be incorporated into a pharmaceutical preparation and administered to a patient in an amount effect for relieving one or more symptoms associated with a variety of diseases and conditions.
- diseases that may be treated are Parkinson's disease, cancer and AIDS.
- the present invention is based upon the discovery of a new process for the formation of enantiomerically enriched compounds containing the hydronaphthalene ring structure.
- the process involves reacting an aza- or oxabenzonorbomadiene compound with a nucleophile in the presence of a rhodium catalyst and a phosphine ligand.
- a nucleophile in the presence of a rhodium catalyst and a phosphine ligand.
- Preferred nucleophiles are alcohols, phenols, amines, and stabilized carbanions such as malonates and malonate equivalents.
- reactions should be performed in the presence of a tertiary amine hydrochloride. This is not necessary for other types of amines.
- carboxylic acids When carboxylic acids are used, reactions should be carried out in the presence of a tertiary amine, e.g., triethylamine.
- the sodium or potassium salt of the carboxylic acid may be reacted in the presence of the hyrochloride of a tertiary amine, e.g. in the presence of triethylamine hydrochloride.
- carboxylate ring-opened products can be made to undergo a subsequent transformation to produce 1 ,4-disubstituted dihyronaphthalenes. This is accomplished by an S ⁇ 2' addition of nucleophiles under catalytic or non-catalytic conditions to the allyl acetate functionality.
- the preferred catalyst is [Rh(COD)Cl] 2 and, depending upon the particular product desired, preferred ligands are DPPF or a chiral analogue of DPPF, (R)-(S)-BPPFA; (R)-(S)-PPF- P l Bu and (S)-(R)-PPF-P'Bu 2 .
- the ligands may be prepared by any process described in the literature (see, e.g., Togni et al, J. Am. Chem. Soc. 116:4062 (1994)). Reactions may be carried out using trifluoroethanol (TFE) or tetrahydrofuran (THF) as solvents under an inert atmosphere, preferably of nitrogen.
- TFE trifluoroethanol
- THF tetrahydrofuran
- the compounds fo ⁇ ned may be incorporated into a pharmaceutical composition and used in the treatment of a variety of diseases and conditions. Specifically, the compounds may be used in the treatment of Parkinson ' s disease, cancers, and AIDS.
- the total daily dosage of compound administered to a patient should be at least the amount required to reduce or eliminate one or more symptoms associated with the condition being treated. For example, in the treatment of Parkinson's disease, sufficient agent should be administered to reduce the severity or frequency of tremors or other movement disorders associated with the disease.
- agents should typically be given at a dosage sufficient to reduce tumor size or at a dosage sufficient to reduce the total number of cancerous cells in a patient.
- the actual dose selected for an individual patient will be determined by the attending physician based upon clinical conditions and using methods well known in the art. Agents may be provided in either a single or multiple dosage regimen, e.g., a patient may be administered compounds twice a day.
- any route of administration and dosage form is compatible with the present invention, and therapeutic agents may be administered as either the sole active ingredient or in combination with other therapeutically active drugs.
- Routes of delivery compatible with the invention include parenteral, peroral, internal, pulmonary, rectal, nasal, vaginal, lingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous routes.
- Specific dosage forms that may be used include tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil aqueous suspensions, solutions, and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see, e.g., Remington's Pharmaceutical Sciences. 16 th ed., A. Oslo, editor, Easton PA (1980)).
- Therapeutic agents may be used in conjunction with any of the vehicles and excipients nly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations designed for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esthers of glycerine, and the like.
- compositions containing compounds may be prepared using conventional techniques and include sterile isotonic saline, water, 1,3-butane diol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
- a patient may be initially given a relatively low dose of therapeutic agent in order to determine whether any adverse side effects are experienced. This may be particularly important in cases where a patient is taking other medications or has clinical characteristics that suggest that they may not be able to tolerate high drug dosages. If adverse side effects are not experienced by a patient, dosage may be gradually increased until a satisfactory alleviation of symptoms is achieved. For example, the dosage given to a patient with AIDS may be increased until blood counts return to a normal or more normal level.
- the cis isomer of 15 was prepared by reaction of 1,2-dihydronaphthalene with OSO 4 followed by methylation with dimethylsulfate (DMS).
- the trans isomer was prepared by epoxidation of 1,2-dihydronaphthalene followed by ring opening with hyroxide and dimethylation with DMS).
- DPPF was very efficient, however, giving 14 in 88%> yield.
- One advantage of DPPF is that a number of chiral analogues have been prepared and could be studied to determine enantioselectivity.
- JOSIPHOS ligands (Togni, A.., et al, J. Am. Chem. Soc. 116:4062 (1994)) were among the chiral ligands examined which gave the most promising results.
- PPF-P l Bu 2 16 gave 14 in 84%) yield and 86%> ee at 60°C. The ee could be significantly improved to 97% when the reaction temperature was increased by 20°C.
- the resulting solid was purified by flash chromatography (20%> ethyl acetate in hexanes) to give 14 a white crystalline solid (31.7 mg, 96%>).
- the ee was determined to be 97% using HPLC analysis on a
- the resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 16 as a white crystalline solid (553 mg, 84%).
- the resulting oil was purified by flash chromatography (10% ethyl acetate in hexanes) to give 18 as a colourless oil (133.7 mg, 94%).
- the resulting oil was purified by flash chromatography (10%> ethyl acetate in hexanes) to give 20 as a colourless oil (84.7 mg, 53%>).
- the resulting solid was purified by flash chromatography (10%> ethyl acetate in hexanes) to give 17 as a white crystalline solid (594 mg, 70%>).
- the ee was determined to be 98% using HPLC analysis on a CHIRALCEL OD column, ⁇ - 254 nm. Retention times in 4% > isopropanol in hexanes were 11.3 min (major) and 13.3 min.
- the resulting solid was purified by flash chromatography (30%> ethyl acetate in hexanes) to give 28 as a white crystalline solid (127.5 mg, 90%).
- the resulting mixture was purified by flash chromatography (20%o ethyl acetate in hexanes) to give 4 a white crystalline solid (129 mg, 70%).
- CDCI 3 ⁇ 136.5, 135.9, 132.5, 130.1, 128.0, 127.7, 126.9, 126.5, 126.4, 126.2, 122.6, 122.0,
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) giving a white crystalline solid 4 (160 mg, 88%>).
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30%> ethyl acetate in hexanes) giving a white crystalline solid 5 (177 mg, 91%>).
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10%> ethyl acetate in hexanes) to give a white crystalline solid 6 (184 mg, 87%).
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10%) ethyl acetate in hexanes) giving a white crystalline solid 7 (163 mg, 92%>).
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (5%> ethyl acetate in hexanes) giving a white crystalline solid 8 (169 mg, 89%).
- the ee was determined to be 92% by formation of Mosher's ester.
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash cliromatography on silica gel (10%) ethyl acetate in hexanes) as a white crystalline solid 9 (193 mg, 73%).
- the ee was determined by deiodinating 9 (40 mg, 0.11 mmol) by reaction with t-BuLi (0.32 mL, 1.7M) in diethyl ether (2 mL) at -78°C followed by quenching with isopropanol.
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (5%> ethyl acetate in hexanes) giving a white crystalline solid 11 (57 mg, 65%).
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10%) ethyl acetate in hexanes) as a white crystalline solid 12 (159 mg, 85%).
- aqueous extracts were combined and back-extracted three times with diethyl ether.
- the combined ether extracts were washed with brine and dried with anhydrous sodium sulfate.
- the solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (5% ethyl acetate in hexanes) as a white crystalline solid 13 (75 mg, 37%).
- Example 11 Compounds Formed in Reactions Involving Nitrogen or Carbon Nucleophiles
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Abstract
The present invention is directed to a procedure for making an enantiomerically enriched compound containing a hydronaphthalene ring structure. The process involves reacting oxabenzonorbornadienes with nucleophiles using rhodium as a catalyst and in the presence of a phosphine ligand. The compounds synthesized may be used in pharmaceutical preparations for the treatment of a variety of diseases and conditions.
Description
Novel hydronaphtalene compounds , prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand
Field of the Invention The present invention is directed to methods for chemically synthesizing compounds containing a hydronaphthalene ring stmcture. It encompasses the compounds made by the methods, pharmaceutical preparations containing the compounds, and methods for treating patients using these pharmaceutical preparations.
Background of the Invention
The hydronaphthalene structure can be found in many natural products and pharmaceutical agents. These include homochelidonine (structure 1 below; Slavik, J.; et al, Collect. Czech. Chem. Commun. 30:3691 (1965); Spath, E., et al., Ber., 64: 1123 (1931); 3ersch. H. W., Arch. Pharm. (Weinheim, Ger.), 2914:91 (1958)) an alkaloid isolated from Chεlidoπium plants, dihydrexidine (structure 2 below; Snyder, S. E., J. Med. Chem., 55:2395 (1995)) which shows antiparkinsonian character, etoposide (structure 3 below; Kamal, A., et al., Tetrahedron Lett. 57:3359 (1996)) which is used in the treatment of various cancers, and SF-2315B (structure 4 below; Kim, K., et al, J. Org. Chem. -50:6866 (1995)) which is a viral reverse transcriptase inhibitor. In addition, CNS agents, immunoregulatory agents and antibiotics contain variations on this framework (Perrone, R., et al., J. Med. Chem. 38:942 (1995)).
Structure 1
Previous work on oxabicyclic ring opening reactions led to a catalytic enantioselective route to dihydronaphthol (Lautens, M., et al, Tetrahedron 54:\ \01 (1998)) which was a key step in the total synthesis of sertraline (Lautens, M., et al, J. Org. Chem. 63:5216 (1997)). However, little is known about the ring opening of oxabenzonorbornadiene or similar compounds with the incorporation of nucleophiles during the ring opening step. Duan and Chen developed a method of introducing aryl groups by using catalytic amounts of palladium (Duan, J.-P., et al, Tetrahedron Lett., 54:4019 (1993); Duan, J.-P., et al, Organometallics 14:1608 (1995)). Moinet et al, later developed an enantioselective version of this reaction but the yields were low (Tetrahedron Lett., 36:2051 (1995)).
Catalytic organometallic processes that form carbon-heteroatom bonds are far fewer in number than those which form carbon-carbon bonds. The Wacker Process (Henry, P.M., Paladium Catalvsed Oxidation of Hvdrocarbons. vol. 2, Reidel, Boston, (1980)), oxidative carbonylations of amines and alcohols ("Applied Homogeneous Catalysis with Organometallic Compounds: A Comprehensive Handbook in Two Volumes (eds.: B. Cornils, W.A. Herrmann), NCH, New York, (1984)) and the formation of arylamines and aryl ethers (Hartwig, J.F., Agnew. Chem. Int. Ed. 37:2046 (1998); Widenhoefer, R.A., et al, J. Am. Chem. Soc. 119:61^1 (1997)) are a few that have been described to date.
Summary of the Invention
The present invention is based upon the discovery of a rhodium catalyzed ring opening reaction of oxabenzonorbornadienes or azabicyclic compounds to produce a new carbon-oxygen bond via an intermolecular reaction with various alcohols. This reaction occurs in good yields with complete regio and diastereoselectivity and excellent enantioselectivity (e.g., eq. 1).
93 to >99% ee
In the reaction above, Z is O or NRa. This reaction will work when oxabenzonor- bornadienes or azabicyclic compounds are reacted with nitrogen nucleophiles, carboxylate nucleophiles, carbon nucleophiles or phenol nucleophiles. The invention encompasses not only the chemical reactions but also the compounds made by the reactions and the use of such compounds in the treatment of a variety of diseases and conditions.
In its first aspect, the invention is directed to a compound according to formula I:
in which R is selected from the group consisting of: (a) H;
(b) a Cι-C6 straight or branched alkyl; ( (cc)) a straight or branched C2-C6 alkenyl; (d) -(CH2)nRι, wherein R\ is a C -C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO2; I; Br; a Cι-C3 alkyl; and a Cι-C alkoxy wherein n=0-3;
(e) -C(O)R2, wherein R2 is selected from the group consisting of: H; -(CH2)nRι, wherein Ri is as described above and n=0-3; and -(CH2)nC(O)R3, wherein R3 is a Cι-C6 straight or branched alkyl and n=0-3;
09 -C(O)(CH2)p-C(O)-O-R4, wherein R4 is a straight or branched C C6 alkyl and wherein p=0-3;
(g) -Rd(CF3)j, wherein Rd is a Cι-C straight or branched alkyl and j=l-3; ( (hh)) -(CH2)rTMS, wherein TMS is trimethylsilyl, and j=l-3;
X and Y are independently selected from the group consisting of H; NH2; F; CI; Br; a Ci- C alkyl; and a Cι-C alkoxy; or wherein the combination XY or YY together form a C -C6 carbocyclic ring or a C -C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and in which Z is selected from O or NRa, wherein Ra is selected from: (i) phenyl;
(j) (O)C-O-Rb , wherein Rb is a straight or branched Cι-C6 alkyl; (k) -SO -Rc, wherein Rς is selected from the group consisting of: i) Ci-Cδ straight or branched alkyl; ii) -(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO ; CN;I; Br; a straight or branched Cι-C3 alkyl; a Cι-C alkoxy; and -C(O)Rt-, wherein Rf is a -C alkyl; -(CH2)rCF3, wherein r=0-3; iii) -Rg(CF3)s, wherein Rg is a Cι-C straight or branched alkyl and s=l-3; iv) -(CH2)S-TMS, wherein TMS = trimethylsilyl and s= 1-3; (1) -SO2-(CH2)q- Si(CH3)3 wherein q is 1-3.
Preferably, R in formula I is -(CH2)nRι and Ri is a C -C6 aryl optionally substituted at one or more positions with a group selected from: CI; F; NO2; I; Br; a C>-C3 alkyl; and a Cι-C alkoxy and wherein n=0-3. When Z is NRa, Ra is preferably phenyl; (O)C-O-C-(CH3)3; -SO2-(CH2)2- Si(CH ) ; or -SO2-Rc, wherein Re is -(CH2)qRe, wherein q=0-3 and Re is a C -C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO ; CN; I; Br; a straight or branched Cι-C alkyl; a Cι-C3 alkoxy; and -C(O)Rf, wherein Rf is a Cι-C3 alkyl; -(CH )rCF3, wherein r=0-3.
The compounds of formula I described above may be prepared by reacting a compound of formula ROH with a compound of formula V:
In a second aspect the invention is directed to a compound according to formula II:
in which R is selected from the group consisting of:
(a) a Cι-C-6 straight or branched alkyl;
(b) -(CH2)qR5, wherein q=0-3 and R5 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a straight or branched Cι-C alkyl; a
C1-C3 alkoxy; Br; I; CI; CN; F; NO2; -(CH2)rCF3, wherein r=0-3; and -C(O)R6, wherein R6 is a C1-C3 alkyl;
(c) -R7(CF3)S, wherein R7 is a C1-C3 straight or branched alkyl and s=l-3;
(d) -(CH2)S-TMS, wherein TMS=trimethylsilyl and s=l-3; X and Y are independently selected from the group consisting of H; NH2; F; CI; Br; a d- C3 alkyl; and a C1-C3 alkoxy; or wherein the combination XY or YY together form a C -C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and in which Z is selected from O or NRa, wherein Ra is selected from:
(e) phenyl;
(f) (O)C-O-Rb , wherein Rb is a straight or branched Cι-C6 alkyl;
(g) -SO -Rc, wherein Rς is selected from the group consisting of: i) Cι-C6 straight or branched alkyl; ii) -(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO2; CN;I; Br; a straight or branched Cι-C3 alkyl; a Cι-C alkoxy; and -C(O)Rf, wherein Rf is a C1-C3 alkyl; -(CH2)rCF3, wherein r=0-3; iii) -Rg(CF3)s, wherein Rg is a Cι-C3 straight or branched alkyl and s=l-3; iv) -(CH2)S-TMS, wherein TMS = trimethylsilyl and s= 1-3;
(h) -SO2-(CH2)q- Si(CH3)3 wherein q isl-3.
Preferably, R in formula II is -(CH2)qR5 wherein q=0-3 and R5 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a straight or branched Cι-C3 alkyl; a C,-C3 alkoxy; I; CI; CN; F; NO2; -(CH2)rCF3, wherein r=0-3; and -C(O)R6, wherein Re is a Cι-C alkyl.
The compounds of formula II described above may be prepared by reacting a compound of formula ROH with a compound of formula V:
The invention is also directed to a compound according to formula III:
wherein TBDMSO is a tert-butyldimethylsiloxy group, and R, X, and Y are as defined in above in connection with formula I. These compounds may be made by preparing a compound of formula I according to the process described above and then reacting the compound formed with a salt of tert-butyldimethylsilylic acid. Preferably, the compound formed is (lR*,2R*)-malonic acid (1 -tert-butyldimethylsiloxy- l,2-dihydro-naphthalen-2-yl) ester ethyl ester and ROH is tert- butyldimethylsilylic acid.
In another aspect, the invention is directed to a compound according to formula IV:
a) in which Rg is H or CH3; b) t=0-3 c) R9 is a C -C6 aryl optionally substituted at one or more positions with a group selected from: a C>-C3 alkyl; a C1-C3 alkoxy; CI; F; NO2; and CF3; or R9 together with N form a ring structure selected from: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring;
said ring structure being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a Ct-C3 alkoxy; CI; F; NO2; and CF3; d) X and Y are independently selected from the group consisting of H; NH2; F; CI; Br; a C1-C3 alkyl; and a CpC alkoxy; or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; e) Z is selected from O or NRa, wherein Ra is selected from: (i) a straight or branched Cι-C6 alkyl;
(ii) phenyl; (iii) (O)C-O-Rb , wherein Rb is a straight or branched Cι-C6 alkyl;
(iv) -SO2-Rc, wherein Re is an unsubstituted phenyl or a phenyl substituted with a Cι-C3 alkyl or NO2; and (v) -SO2-(CH2)q- Si(CH3)3 wherein q is 1-3; and f) when Z is O, RIQ is H; when Z is NRa, Rι0 is either H or CH3.
Preferably, Rs in formula IV is H and R9 together with N form a ring selected from the group consisting of a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; the ring being optionally substituted at one or more positions with a group selected from: a Cι-C3 alkyl; a C1-C3 alkoxy; CI; F; NO ; and CF3. When Z is NRa, Ra is preferably methyl;
The compounds of formula IV described above may be prepared by reacting a compound of formula R9-(CH2)tNHR8 with a compound of formula V
The invention also encompasses seven other processes. In the first (lS,2S)-N-(l-hydroxy- l,2-dihydro-naphthalen-2-yl)-benzene sulfonamide is formed by reacting oxabenzonorbornadiene with benzenesulfonamide. In the second, (lS*,2R*)-2-(hydroxy-l,2-dihydro-naphthalen-2-
yl)malonic acid dimethyl ester is formed by reacting oxabenzonorbornadiene with dimethyl malonate. Both reactions are catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand. In the third, the compound of formula VI is formed by reacting a compound of formula IV, which is produced as described above in connection with formation of compounds of formula IV, with iodomethane. In preferred reactions, the compound made is N,4-dimethyl-N-[(lR,2S)-2-(l- pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide. In the fourth, the compound of formula VII is formed by reacting compound of formula VI with hydrogen in the presence of palladium catalyst. The compound made is N,4-dimethyl-N-[(lR,2S)-2-(l-pyrrolidinyl)-l,2,3,4- tetrahydro-l-naphthalenyl]benzenesulfonamide. In the fifth, the compound of formula VIII is formed by reacting the compound of formula VII with sodium borohydride. The compound made using this reaction is (lE,2S)-N-methyl-2-(l-pyrrolidinyl)-l,2,3,4-tetrahydro-l-naphthalenamine. In the sixth, the compound of formula IX is formed by reacting a compound of formula IV which is produced as described above in connection with formation of compounds of formula IV, with iodomethane. The compound made using this reaction is Ν-methyl-4-nitro-Ν-[(lR,2S)-2-(l- pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide. In the seventh, the compound of formula X is formed by reacting a compound of formula I which is produced as described above in connection with formation of compounds of formula I, with iodomethane. The compound made using this reaction is (lE,2S)-l-{methyl[(4-methylphenyl)sulfonyl]amino}-l,2-dihydro-2- naphthalenyl acetate.
Overall, the most preferred compounds of the invention are: a) ( 1 S,2S)-2-methoxy- 1 ,2-dihydro-naphthalen- 1 -ol; b) ( 1 S,2S)-2-(ethoxy)- 1 ,2-dihydro-naphthalen- 1 -ol; c) (lS,2S)-2-(isopropoxy)-l,2-dihydro-naphthalen-l-ol; d) (lS,2S)-2-(l-propenyloxy)-l,2-dihydro-naphthalen-l-ol; e) ( 1 S,2S)-2-(2-trimethylsilyl-ethoxy) 1 ,2-dihydro-naphthalen- 1 -ol; f) ( 1 S,2S)-2-benzyloxy- 1 ,2-dihydro-naphthalen- 1 -ol; g) (lS,2S)-2-(4-methoxybenzyloxy)-l,2-dihydro-naphthalen-l-ol; h) (lS,2S)-2-(2,2,2-trifluoro-ethoxy)-l,2-dihydro-naphthalen-l-ol; i) (lS,2S)-2-(2,2,2-trifluoro-l-trifluoromethyl-ethoxy)-l,2-dihydro-naphthalen-l-ol; j) (lS,2S)-6,7-difluoro-2-methoxy-l,2-dihydro-naphthalen-l-ol; k) (lS,2S)-6-methoxy-5,6-dihydro-naphthol[2,3-d][l,3]dioxol-5-ol;
1) (lS,2S)-6,7-dibromo-2-methoxy-5,8-dimethyl-l,2-dihydro-naphthalen-l-ol; m) ( 1 R* ,2R*)-acetic acid 1 -hydroxy- 1 ,2-dihydro-naphthalen-2-yl-ester; n) (lR*,2R*)-propionic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester; o) (lR,2R)-benzoic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester; P) (lR*,2R*)-formic acid 1 -hydroxy- 1 ,2-dihydro-naphthalen-2-yl-ester; q) (lR*,2R*)-2-methyl acrylic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester; r) (lR*,2R*)-malonic acid ethyl ester (1 -hydroxy- l,2-dihydro-naphthalen-2-yl) ester; s) ( 1 R* ,2R*)-malonic acid ( 1 -tert-butylbimethylsiloxy- 1 ,2-dihydro-naphthalen-2-yl) ethyl ester; t) (lS*,2S*)4-tert-butyldimethylsiloxy-l,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester; u) (lR,2R)-2-(l-hydroxy-l,2-dihydro-naphthalen-2-yl)-isoindole-l,3-dione; v) (lS,2S)-N-(l-hydroxy-l,2-dihydro-naphthalen-2-yl)-benzene sulfonamide; w) ( 1 R*,2R*)-2-pyrrolidin- 1 -yl- 1 ,2-dihydro-naphthalen- 1 -ol;
x) (1 R*,2R*)-2-piperidin- 1 -yl- 1 ,2-dihydro-naphthalen- 1 -ol; y) ( 1 R,2R)-2-(3,4-dihydro-2H-quinolin- 1 -yl)- 1 ,2-dihydro-naphthalen- 1 -ol; z) (1 R,2R)-2-(methyl-phenyl-amino)- 1 ,2-dihydro-naphthalen- 1 -ol; aa) (lR*,2R*)-2-benzylamino- 1,2-dihydro-naphthalen-l-ol; bb) (lR*,2R*)-2-(4-methoxy-benzylamino)-l,2-dihydro-naphthalen-l-ol; cc) ( 1 R,2R)-2-indol- 1 -yl- 1 ,2-dihydro-naphthalen- 1 -ol; dd) (1 S*,2R*)-2-(hydroxy-l ,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester; ee) ( 1 S,2S)-2-phenoxy- 1 ,2-dihydro-naphthalen- 1 -ol; ft) ( 1 S,2S)-2-(4-nitrophenoxy)- 1 ,2-dihydro-naphthalen- 1 -ol; gg) (lS,2S)-2-(4-cyanophenoxy)-l,2-dihydro-naphthalen-l-ol; hh) (lS,2S)-2-(4-acylphenoxy)-l,2-dihydro-naphthalen-l-ol; ii) (lS,2S)-2-(4-trifluoromethylphenoxy)-l,2-dihydro-naphthalen-l-ol; jj) (lS,2S)-2-(4-fluorophenoxy)-l,2-dihydro-naphthalen-l-ol; kk) (lS,2S)-2-(4-chlorophenoxy)-l,2-dihydro-naρhthalen-l-ol; 11) (lS,2S)-2-(4-iodophenoxy)- 1,2-dihydro-naphthalen-l-ol; mm) (lR,2R)-2-(4-bromo-phenoxy)-l,2-dihydro-naphthalen-l-ol; nn) (lS,2S)-2-(4-methylphenoxy)-l,2-dihydro-naphthalen-l-ol; oo) (lS,2S)-2-(4-methoxyphenoxy)-l,2-dihydro-naphthalen-l-ol; pp) (lS,2S)-2-(2-bromophenoxy)- 1,2-dihydro-naphthalen-l-ol; qq) 4-methyl-N-[(lE,2S)-2-(l-piperidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide; rr) N- [( 1 R,2S)-2-(3 ,4-dihydro- 1 (2H)-quinolinyl)- 1 ,2-dihydro- 1 -naphthalenyl] -4- methylbenzenesulfonamide; ss) N-[(lE,2S)-2-(3,4-dihydro-2(lH)-isoquinolinyl)-l,2-dihydro-l-naphthalenyl]-4- methylbenzenesulfonamide; tt) N-[( li?,2S)-2-(lH-indol- 1 -yl)- 1 ,2-dihydro- 1 -naphthalenyl]-4-methylbenzenesulfonamide; uu) ( lE,2S)-2-methoxy-N-phenyl- 1 ,2-dihydro- 1 -naphthalenamine; vv) tert-butyl (lE,2S)-2-methoxy-l ,2-dihydro-l -naphthalenylcarbamate; ww) N-[(lE,2S)-2-methoxy-l,2-dihydro-l-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide; xx) N,4-dimethyl-N-[(lE,2S)-2-(l-ρyrrolidinyl)-l,2,3,4-tetrahydro-l-naphthalenyl]- benzenesulfonamide; yy) N,4-dimethyl-N-[( 1 R,2S)-2-( 1 -pyrrolidinyl)- 1 ,2-dihydro- 1 -naphthalenyl] - benzenesulfonamide; zz) N-hydroxy-4-( {methyl[(l ?,2S)-2-(l -pyrrolidinyl)- 1,2-dihydro-l - naphthalenyl] amino } sulfonyl) -N-oxobenzenaminium;
aaa) N-methyl-4-nitro-N-[(lE,2S)-2-(l-pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]- benzenesulfonamide; bbb) (lE,2S)-N-methyl-2-(l -pyrrolidinyl)- 1, 2, 3,4-tetrahydro-l-naphthalenamine; ccc) N-[(lE,2S)-2-methoxy-l,2,3,4-tetrahydro-l-naphthalenyl]-4-methylbenzenesulfonamide ddd) N-[(lE,2S)-2-methoxy-l,2,3,4-tetrahydro-l-naphthalenyl]-4-methylbenzenesulfonamide eee) 4-methyl-N-[(lE,2S)-2-phenoxy-l,2,3,4-tetrahydro-l-naphthalenyl]benzenesulfonamide: fff) (IR,2S)- 1 - {[(4-methylphenyl)sulfonyl] amino} - 1 ,2,3 ,4-tetrahydro-2-naphthalenyl acetate: ggg) (lE,2S)-l-{[(4-methylphenyl)sulfonyl]amino}-l,2-dihydro-2-naphthalenyl benzoate; hhh) (\R,2S)-l-{ [(4-methylphenyl)sulfonyl] amino } - 1 ,2-dihydro-2-naphthalenyl pivalate; iii) N-[(lE,2S)-2-methoxy-l,2-dihydro-l-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide; jjj) tert-butyl (lE,2S)-2-methoxy-l,2-dihydro-l-naphthalenylcarbamate; and kkk) 4-nitro-N-[( \R,2S)-2-( 1 -pyrrolidinyl)- 1 ,2-dihydro- 1 -naphthalenyl]benzenesulfonamide.
Any of the compounds described above may be incorporated into a pharmaceutical preparation and administered to a patient in an amount effect for relieving one or more symptoms associated with a variety of diseases and conditions. Among the diseases that may be treated are Parkinson's disease, cancer and AIDS.
Detailed Description of the Invention The present invention is based upon the discovery of a new process for the formation of enantiomerically enriched compounds containing the hydronaphthalene ring structure. The process involves reacting an aza- or oxabenzonorbomadiene compound with a nucleophile in the presence of a rhodium catalyst and a phosphine ligand. Detailed procedures for the formation of precursor compounds and their use in reactions are set forth in the Examples section below. Preferred nucleophiles are alcohols, phenols, amines, and stabilized carbanions such as malonates and malonate equivalents. In cases where simple aliphatic amines are used, reactions should be performed in the presence of a tertiary amine hydrochloride. This is not necessary for other types of amines. When carboxylic acids are used, reactions should be carried out in the presence of a tertiary amine, e.g., triethylamine. Alternatively, the sodium or potassium salt of the carboxylic acid may be reacted in the presence of the hyrochloride of a tertiary amine, e.g. in the presence of triethylamine hydrochloride. It has been found that carboxylate ring-opened products can be made to undergo a subsequent transformation to produce 1 ,4-disubstituted dihyronaphthalenes. This is accomplished by an SΝ2' addition of nucleophiles under catalytic or non-catalytic conditions to the allyl acetate functionality. For an example of the conversion of (1R*,2R*)-
Malonic acid (1 -tert-butyldimethylsiloxy- l,2-dihydro-naphthalen-2-yl) ester ethyl ester to (lS*,2S*)-(4-Tert-butyldimethylsiloxy-l,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester see the Examples section below.
The preferred catalyst is [Rh(COD)Cl]2 and, depending upon the particular product desired, preferred ligands are DPPF or a chiral analogue of DPPF, (R)-(S)-BPPFA; (R)-(S)-PPF- PlBu and (S)-(R)-PPF-P'Bu2. The ligands may be prepared by any process described in the literature (see, e.g., Togni et al, J. Am. Chem. Soc. 116:4062 (1994)). Reactions may be carried out using trifluoroethanol (TFE) or tetrahydrofuran (THF) as solvents under an inert atmosphere, preferably of nitrogen. The reaction temperature should typically be at least 60°C and preferably about 80°C.
The compounds foπned may be incorporated into a pharmaceutical composition and used in the treatment of a variety of diseases and conditions. Specifically, the compounds may be used in the treatment of Parkinson's disease, cancers, and AIDS. The total daily dosage of compound administered to a patient should be at least the amount required to reduce or eliminate one or more symptoms associated with the condition being treated. For example, in the treatment of Parkinson's disease, sufficient agent should be administered to reduce the severity or frequency of tremors or other movement disorders associated with the disease. In treating cancers, agents should typically be given at a dosage sufficient to reduce tumor size or at a dosage sufficient to reduce the total number of cancerous cells in a patient. The actual dose selected for an individual patient will be determined by the attending physician based upon clinical conditions and using methods well known in the art. Agents may be provided in either a single or multiple dosage regimen, e.g., a patient may be administered compounds twice a day.
Any route of administration and dosage form is compatible with the present invention, and therapeutic agents may be administered as either the sole active ingredient or in combination with other therapeutically active drugs. Routes of delivery compatible with the invention include parenteral, peroral, internal, pulmonary, rectal, nasal, vaginal, lingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous routes. Specific dosage forms that may be used include tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil aqueous suspensions, solutions, and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared
using methods that are standard in the art (see, e.g., Remington's Pharmaceutical Sciences. 16th ed., A. Oslo, editor, Easton PA (1980)).
Therapeutic agents may be used in conjunction with any of the vehicles and excipients nly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations designed for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esthers of glycerine, and the like. Parenteral compositions containing compounds may be prepared using conventional techniques and include sterile isotonic saline, water, 1,3-butane diol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
If desired, a patient may be initially given a relatively low dose of therapeutic agent in order to determine whether any adverse side effects are experienced. This may be particularly important in cases where a patient is taking other medications or has clinical characteristics that suggest that they may not be able to tolerate high drug dosages. If adverse side effects are not experienced by a patient, dosage may be gradually increased until a satisfactory alleviation of symptoms is achieved. For example, the dosage given to a patient with AIDS may be increased until blood counts return to a normal or more normal level.
Examples I. Compounds Made Using Oxabenzonorbornadienes Example 1: Rhodium Catalysed Synthesis of Enatiomerically Enriched trans-2-
Alkoxy-l,2-dihydro-naphthalen-l-ols
In 1973, Hogeveen and Middelkoop reported a [Rh(CO)2Cl]2 catalyzed ring opening reaction of 5 by reaction with methanol giving 6. (Hogeveen, H., et al, Tetrahedron Lett. 190:1 (1973)) Subsequently, Ashworth and Berchtold reported the stereochemistry of this reaction to be cis as shown after the formation of a Diels- Alder adduct with 9 (scheme 1) (Ashworth, R. W., et al, Tetrehedron Lett. 339 (1977)). This stereochemistry is in keeping with the observation of exo attack by nucleophiles with other oxabicyclic starting materials (Lautens, M., Synlett 179 (1993)). Hogeveen and Middelkoop also reported that the reaction was regioselective when only one of the bridgehead positions was substituted, that is 11 gave only regioisomer 12.
5: R = H 7: R = H 10
6: R = Me 8: R = Me
11 12 Scheme 1
When 13 (Stiles, M., e al, J. Am. Chem. Soc. 52:3802 (I960)) was subjected to the Hogeveen and Middelkoop conditions, no reaction was observed. However, by changing the solvent system to a 1 :1 mixture of trifluoroethanol (TFE):methanol and by increasing the temperature to 60°C, the desired product 14 was isolated in 70% yield. Remarkably, the stereochemistry of 14 was trans as proven by comparison with authentic samples of both stereoisomers of dimethoxytetrahydronaphthalene 15 (eq. 2) (The cis isomer of 15 was prepared by reaction of 1,2-dihydronaphthalene with OSO4 followed by methylation with dimethylsulfate (DMS). The trans isomer was prepared by epoxidation of 1,2-dihydronaphthalene followed by ring opening with hyroxide and dimethylation with DMS).
70%
Given the ability of this reaction to set up two stereocentres with complete regio and stereocontrol, the possibility of rendering it asymmetric was investigated. A serious drawback of the existing catalyst [Rh(CO)2Cl]2, however, was that the addition of phosphine ligands completely inhibited the reaction. By changing to a rhodium source possessing the more labile COD ligand, [Rh(COD)Cl] , it was possible to examine the catalytic ability of several chiral phosphine ligands. Not all rhodium-ligand combinations performed equally well. DPPE and BLNAP did not produce the desired product, and phosphites resulted in poor yields. DPPF was
very efficient, however, giving 14 in 88%> yield. One advantage of DPPF is that a number of chiral analogues have been prepared and could be studied to determine enantioselectivity. JOSIPHOS ligands (Togni, A.., et al, J. Am. Chem. Soc. 116:4062 (1994)) were among the chiral ligands examined which gave the most promising results. For example, PPF-PlBu2 16 gave 14 in 84%) yield and 86%> ee at 60°C. The ee could be significantly improved to 97% when the reaction temperature was increased by 20°C.
Table 1: Effects of Sovlent and Atmosphere
Atmosphere Solvent / Equiv. TFE Yield 19 ee 2 TFE / neat 0%*
CO TFE / neat 70% 98%
N2 THF / 5 eq. TFE 70% 98%
* only product observed is naphthol
Reactions run in alcohols other that TFE proceeded at a much slower rate. When the solvent was changed to THF, the reaction worked equally well with a broad range of alcohols under racemic and enantioselective conditions, and only five equivalents of the alcohol were required. THF also allowed the use of very low catalyst loadings, typically in the range of 0.125 mol% of [Rh(COD)Cl]2 and 0.25 mol% of 16. While TFE would only add to give 17 when the reaction was run under a CO atmosphere in neat TFE, this was not the case in THF. When THF was used as the solvent, TFE added efficiently under an inert nitrogen atmosphere to give 17 in 70% yield and 98%> ee. Even the very weakly nucleophilic hexafluoroisopropanol (HFI) added under these reaction conditions to give 23 in 90%o yield and 93% ee (table 2).
Table 2: Rhodium Catalysed Ring Opening of 12 with Various Alcohols
THF
80°C
ROH Product Yield(%) ee(%)
MeOH a 14 96 97
EtOH a 16 84 97
'PrOH a 18 94 93
Ally! Alcohol 19 92 >99
TMS Ethanol 3 20 53 95
Benzyl Alcohol 21 66 >98 p-Methoxybenzyl Alcohol 22 87 97
TFE 17 70 98
HFI 23 90 93
3 These reactions were performed under unoptimised conditions using 10 eq ROH
" ee determined by formation of oshers ester or by HPLC analysis with a Chiralcel OO column
In order to investigate the effects of substituents on the aromatic ring of 13, difluoro (24), methylenedioxy (25), and dimethyldibromo (26) substrates were prepared (Hart, H., Tetrahedron 43:5203 (1987)) and reacted them under the standard conditions. All gave the corresponding ring opened products in good yields and excellent ee's (chart 1) indicating that this reaction is not sensitive to remote substitution or electronic effects on the aromatic ring.
Chart 1
Example 2: Formation of l,4-epoxy-l,4-dihydronaphthanlene (13)
To furan (100 ml, 1.37 ml) in DME (100 ml) at 50°C in a flame dried three neck flask with a reflux condenser and two addition funnels attached was added simultaneously over two hours a solution of anthranilic acid (27.5 g, 200 mmol) in DME (100 ml) and a separate solution of isoamylnitrite (40 mL, 298 mmol) in DME (50 mL). Upon completion of addition, the reaction was allowed to stir at 50°C for 30 min until no further gas was evolved. The reaction mixture was then cooled to room temperature and portioned between Et O and saturated K2CO and the aqueous layer was extracted three times with Et O. The combined organic layer were washed with brine, dried over MgSO4 and concentrated. Bulb to bulb distillation gave 13 (18.5 g, 64%>) as a white solid. The spectral data correspond well with the literature data.17
Example 3: Compounds Formed by Reactions Involving Alcohols
(lS,2S)-2-Methoxy-l,2-dihydro-naphthalen-l-ol (14) To a flame dried round bottom flask, [Rh(COD)Cl]2 (0.5 mg, 0.0009 mmol), (R)-(S)-PPF-PlBu2 (1.0 mg, 0.0018 mmol) and 13 (27 mg, 0.187 mmol) were added followed by addition of THF (0.5 mL) and methanol (0.5 mL). The mixture was heated for 15 hours and the solvents were removed in vacuo. The resulting solid
was purified by flash chromatography (20%> ethyl acetate in hexanes) to give 14 a white crystalline solid (31.7 mg, 96%>). The ee was determined to be 97% using HPLC analysis on a
CHIRALCEL OD column, λ= 486 nm. Retention times in 4% isopropanol in hexanes were 10.1 min (major) and 11.1 min. Rr= 0.29 on silica gel (10% ethyl acetate:hexanes); mp 86-87° (Et2O); [α]25 D= -208° (c= 10.1, CHC13); R 0.39 on silica (20% ethyl acetate: hex anes). IR (KBr, cm"1) 3277 (br), 2971 (m), 1466(m), 1285(m), 1114(s), 1048(m), 979(m), 775(s); Η NMR (400MHz, acetone-d) δ 7.60-7.62 (IH, m), 7.30-7.21 (2H, m), 7.13-7.11 (IH, m), 6.50 (IH, dd, J= 9.9,1.8
Hz), 6.04 (IH, dd, J= 9.9, 2.2 Hz), 4.85 (IH, dd, J= 9.9, 6.2 Hz), 3.50 (3H, s), 2.89 (IH, d, J= 12.8
Hz); 13C NMR (400MHz, acetone-d) δ 138.5, 133.2, 129.1, 128.4, 128.3, 128.2, 126.8, 126.3, 83.1, 73.0, 57.1. HRMS calcd for CπH,2O2 (M+): 176.0837. Found: 176.0835.
(lS,2S)-2-(Ethoxy)-l,2-dihydro-naphthalen-l-ol (16): : To a flame dried round bottom flask, [Rh(COD)Cl]2 (2.1 mg, 0.043 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.087 mmol) and 13 (500 mg, 3.47 mmol) were added followed by addition of ethanol (4 mL) and THF (4 mL). The mixture was heated to reflux for five hours and the solvent was removed in vacuo. The resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 16 as a white crystalline solid (553 mg, 84%). The ee was determined to be 91% using HPLC analysis on a CHIRALCEL OD column, λ = 254 nm. Retention times in 1.5% isopropanol in hexanes were 13.6 min and 14.2 min (major). Rt= 0.26 on silica gel (20%> ethyl acetate:hexanes); mp 33° (Et2O); [α]25 D= 185.9° (c= 9.6, CHC13); ER (KBr, cm"1) 3601 (br), 3040 (m), 2977 (s), 1454 (s), 1396 (m), 1185 (s), 1104 (s); lH NMR (400MHz, CDC13) δ 7.59-7.57 (IH, m), 7.27-7.20 (2H, m), 7.07-7.05 (IH, m), 6.43 (IH, dd, J= 9.9, 2.2 Hz), 6.01 (IH, dd, A 9.9, 2.2 Hz), 4.90 (IH, d, J= 10.6 Hz), 4.18 (IH, ddd, J= 10.6, 2.2, 2.2 Hz), 3.79 (IH, AB, dq, J= 9.4, 6.9 Hz), ), 3.58 (IH, AB, dq, J= 9.4, 6.9 Hz), 2.65 (IH, s), 1.27 (3H, t, J= 6.9 Hz),; 13C NMR (400MHz, CDC13) δ 135.9, 131.9, 128.0, 127.8, 127.8, 126.1, 124.9, 80.7, 72.5, 64.6, 15.5. HRMS calcd for Cι2H,4O2 (M+): 190.0994. Found: 190.0993.
(lS,2S)-3-(l-propenyloxy)-l,2-dihydro-naphthaIen-l-ol (19): : To a flame dried round bottom flask, [Rh(COD)Cl]2 (9.1 mg, 0.018 mmol), (S)-(R)-PPF-PlBu2 (15 mg, 0.028 mmol) and
13 (1.06 g, 7.35 mmol) were added followed by addition of THF (1.5 mL) and allyl alcohol (2 mL, 29.4 mmol). The mixture was heated to 80°C for two hours and the THF was removed in vacuo. The resulting oil was purified by flash chromatography (10% ethyl acetate in hexanes) to give 19 as a colourless oil (898mg, 60%) which solidified on sitting. The ee was determined to be >99% using HPLC analysis on a CHIRALCEL OD column, λ = 486 nm. Retention times in 1.5% isopropanol in hexanes were 15.2 min and 16.3 min (major). Rt= 0.17 on silica gel (10%> ethyl acetate:hexanes); mp 25-26° (Et2O); [α]25 D= +195.1° (c= 1 1.5, CHC13); IR (KBr, cm"1)
3435(br), 3037(m), 2857(s), 1454(s), 1165(s), 1083(s); Η NMR (400MHz, CDCI3) δ 7.61-7.58
(IH, m), 7.27-7.20 (2H, m), 7.08-7.05 (IH, m), 6.44 (IH, dd, J= 9.9, 2.0 Hz), 6.00 (IH, dd, J= 9.9, 2.4 Hz), 6.00-5.92 (lH,m), 5.32 (1 H, ddd, J= 17.2, 3.3, 1.6 Hz), 5.21 (IH, ddd, J= 10.4, 2.9,
1.3 Hz), 4.94 (IH, d, J= 10.2 Hz), 4.27 (IH, ddd, J= 10.3, 2.2, 2.2 Hz), ), 4.23 (IH, dddd, J =
12.8, 5.5, 1.5, 1.5 Hz), 4.12 (IH, dddd, J = 12.8, 5.9, 1.5, 1.5 Hz), 3.09 (IH, s); 13C NMR
(400MHz, CDC13) 6135.8, 134.5, 131.8, 128.1, 127.7, 127.6, 127.4, 126.1, 125.0, 117.5, 80.1, 76.7, 72.4, 70.2. HRMS calcd for C14H14O2 (M+):202.0994. Found: 202.0994.
(lS,2S)-2-(2-Trimethylsilyl-ethoxy)-l,2-dihydro-naphthalen-l-ol (20): : To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), (S)-(R)-PPF-PtBu2 (9.4 mg, 0.0174 mmol) and 13 (100 mg, 0.694 mmol) were added followed by addition of THF (1.25 mL) and trimethylsilylethanol (1.25 mL). The mixture was heated to reflux for two hours and the THF was removed in vacuo. The resulting oil was purified by flash chromatography (10%> ethyl acetate in hexanes) to give 20 as a colourless oil (84.7 mg, 53%>). The ee was determined to be 95% using HPLC analysis on a CHIRALCEL OD column, λ = 486nm. Retention times in 0.5% isopropanol in hexanes were 17.9 min and 18.5 min (major). R 0.25 on silica gel (10% ethyl acetate:hexanes); [α]25 D= +119.2° (c= 13.0, CHC13); LR (KBr, cm"0 3447(br), 3037(m), 2972(s), 1454(m), 1381(m), 1118(s), 1078(s); Η NMR (400MHz, CDC13) 8 7.59-7.57 (IH, m), 7.28-7.21 (2H, m), 7.08-7.06 (IH, m), 6.43 (IH, dd, J= 9.9, 2.0 Hz), 6.03 (IH, dd, J= 9.9, 2.2 Hz), 4.89 (1 H, d, J= 10.6 Hz), 4.18 (IH, ddd, J= 10.6, 2.2, 2.2 Hz), 3.85-3.78 (2H, m), 3.63-3.56 (2H, m), 2.79 (IH, s), 1.05-0.97 (2H, m), 0.36 (9H, m); 1 C NMR (400MHz, CDCI3) δ. 135.9, 132.0, 127.9, 127.9, 127.8, 127.6, 126.1, 124.9, 80.4, 72.6, 66.5, 18.6, -1.4. HRMS calcd for Cl5H22O2Si (M+): 262.1389. Found: 262.1388.
(lS,2S)-2-BenzyIoxy-l,2-dihydro-naphthalen-l-ol (21): To a flame dried round bottom flask, [Rh(COD)Cl]2 (9.0 mg, 0.018 mmol), (S),(R)-PPF-PlBu2 (19.0 mg, 0.035 mmol), and 13 (1.00 g, 6.94 mmol) were added followed by addition of THF (1.8 mL) and benzylalcohol (3.6 mL, 34.7 mmol) and heating to 80°C for 24 hours. The THF was then removed in vacuo and the resulting oil was purified by flash chromatography (10%> ethyl acetate in hexanes) to give 21 as a crystalline solid (1.22 g, 70%). The ee was determined to be >98% using HPLC analysis on a CHIRALCEL OD column, λ = 486 nm. Retention times in 1.5% isopropanol in hexanes were
29.0 min and 32.5 min (major). Rt= 0.34 on silica gel (20% ethyl acetate:hexanes); mp 52-54° (Et2O); [α]25 D= +167.3° (c= 10.0, CHC13); IR (KBr, cm"1) 3305 (br), 3020 (w), 2876 (w), 1496 (m), 1352 (m), 1281 (m). 1169 (m), 1050 (s), 777 (s); 1H NMR (400MHz, CDC13) δ 7.58-7.56 (IH, m), 7.41-7.22 (7H, m), 7.22-7.07 (IH, m), 6.46 (IH, dd, J= 9.9, 2.1 Hz), 6.05 (IH, dd, J= 9.9, 2.1 Hz), 4.98 (IH, d, A 10.4 Hz), 4.78 (IH, d, J= 11.7 Hz), 4.63 (IH, d, J= 1 1.7 Hz), 4.33 (IH, ddd, J= 10.4, 2.2, 2.2 Hz), 2.61 (IH, s); 13C NMR (400MHz, CDC13) δ 138.0, 135.9, 131.9, 128.5, 128.3, 128.1, 127.9, 127.9, 127.8, 127.4, 126.2, 125.1, 80.4, 72.6, 71.3. HRMS calcd for Cι7H16O2 (M+): 252.1150. Found: 252.1148.
(lS,2S)-2-(4-Methoxybenzyloxy-l,2-dihydro-naphthalen-l-ol (22): To a flame dried round bottom flask, [Rh(COD)Cl]2 (6.0 mg, 0.012 mmol), (S),(R)-PPF-PlBu2 (13.0 mg, 0.024 mmol), and 13 (693 mg, 4.81 mmol) were added followed by addition of THF (1.5 mL) and anisyl alcohol (3.0 mL, 24.1 mmol) and heating to 80°C for 24 hours. . The THF was then removed in vacuo and the resulting oil was purified by flash chromatography (20%> ethyl acetate in hexanes) to give 22 as a crystalline solid (1.18 g, 87%>). The ee was determined to be 97%> using HPLC analysis on a CHIRALCEL OD column, λ = 486 nm. Retention times in 1.5% isopropanol in hexanes were 37.1 min and 42.1 min (major). Rt= 0.53 on silica gel (30%> ethyl acetate:hexanes); mp 63-64° (Et2O); [α]25 D= +138.5° (c= 10.5, CHC13); IR (KBr, cm"1) 3435(br), 3035(m), 2836(s), 1612(s), 1513(s), 1454(m), 1249(s), 1082(s); Η NMR (400MHz, CDC13) δ 7.59-7.57 (IH, m), 7.32 (2H, ddd, J= 8.7, 2.8, 1.9 Hz), 7.28-7.22 (IH, m), ), 6.90 (2H, ddd, J= 8.7, 2.8, 1.9 Hz), 6.46 (IH, dd, J= 9.9, 2.1 Hz), 6.04 (IH, dd, J= 9.9, 2.4 Hz), 4.96 (IH, d, J= 10.1 Hz), 4.64 (IH, dd, J= 57.1 , 11.4 Hz), 4.32 (IH, ddd, J= 10.2, 2.2, 2.2 Hz), 3.80 (IH, s), 2.96 (IH, s); 13C NMR (400MHz, CDC13) δ 159.2, 135.9, 131.9, 129.9, 129.5, 128.1, 127.8, 127.6, 127.5, 126.1, 125.0, 1 13.8, 80.0, 72.5, 70.9, 55.1. HRMS calcd for C H16O2 (M+): 252.1150. Found: 252.1148.
(lS,2S)-2-(2,2,2-Trifluoro-l-trifluoromethyl-ethoxy)-l,2-dihydro-naphthalen-l-ol
(23): To a flame dried round bottom flask, [Rh(COD)Cl]2 (1.7 mg, 0.003 mmol),(S)-(R)-PPF- P'Bu2 (3.8 mg, 0.007 mmol) and 13 (55 mg, 0.382 mmol) were added followed by addition of
THF (2.0 mL) and hexafluoroisopropanol (240 mg, 1.74 mmol). The mixture was heated to reflux for two hours and the solvent was removed in vacuo. The resulting solid was purified by flash chromatography (10% ethyl acetate in hexanes) to give 23 as a white solid (107. lmg, 90%>).
The ee was determined to be 93% using HPLC analysis on a CHIRALCEL OD column, λ = 486 nm. Retention times in 1.5% isopropanol in hexanes were 11.3 min and 17.6 min (major); Rf=
0.28 on silica gel (10%> ethyl acetate:hexanes); mp 88.5-90° (Et2O); [α]25 D= +101.8° (c= 10.9,
CHCI3); IR (KBr, cm"1) 3191 (br), 2937 (m), 1379 (s), 1280 (s), 1247 (s), 1194 (s), 1100 (s), 954
(s), 753 (m); Η NMR (400MHz, CDCI3) δ 7.55-7.53 (IH, m), 7.31-7.26 (2H, m), 7.11-7.09 (IH, m), 6.49 (IH, dd, J= 9.9, 2.1 Hz), 5.92 (IH, dd, J= 9.9, 2.4 Hz), 5.07 (IH, dd, J= 9.7, 5.0 Hz), 4.63 (IH, ddd, J= 9.9, 1.5. 1.5 Hz), 4.58 (IH, h, f'F= 6.1 Hz), 2.50 (IH, d, J= 4.2 Hz); 13C NMR
(400MHz, CDC13) δ 135.2, 131.5, 129.7, 128.5, 128.3, 126.7, 125.2, 122.9, 120.1, 85.4, 75.4 (h, f-F= 32.2 Hz), 73.5. HRMS calcd for Ci3H,oO2F6 (M+): 312.0585 Found: 312.0574.
6,7-Difluoro-l,4-epoxy-l,4-dihydronaphthalene (24). To 3,4-difluoro-l,2-dibromo- benzene (0.75 g, 2.78 mmol) and furan (1 mL, 14.7 mmol) in Et2O (15 mL) at -78°C was added BuLi (1.1 mL, 2.5M in hexanes, 2.75 mmol) dropwise. The reaction was stirred for two hours at -78°C and then was allowed to warm to room temperature. After 2 hours, the reaction mixture was quenched with water dropwise and then was poured into water. The organic layer was separated and the aqueous layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, concentrated and chromatographed (25%> ethyl acetate:hexanes) on silica gel to give 24 (350 mg, 70%>) as a colourless oil. R = 0.21 on silica gel (20%) ethyl acetate:hexanes); bp 40°C @ 0.5mmHg]; ER (neat, cm"1), 3017 (M), 1624 (s), 1465 (s), 1365 (s), 1253 (s), 1190 (m), 1040 (s), 857 (s). Η NMR (400MHz, CDC13) δ 7.06 (2H, dd, f'F= 1.1, 1.1 Hz), 7.01 (2H, s), 5.67 (2H, s); 13C NMR (400MHz, CDCI3) δ 147.2 (dd, f~F= 247.9, 14.5 Hz), 145.1 (dd, J ' = 4.3, 4.3 Hz), 143.1, 110.8 (m), 82.1. HRMS calcd for Cι0H6O (M+): 180.0387. Found: 180.0394.
5,6-Dibromo-4,7-dimethyl-l,4-epoxy-l,4-dihydronaphthalene (26): To tetrabromo para-xylene (2.1 g, 5.0 mmol) and furan (4 g, 58.8 mmol) in PhMe (55 mL) at -78°C was added BuLi (2.2 mL, 2.5M in hexanes, 5.5 mmol) dropwise. The reaction was stirred for two hours at -78°C and the allowed to warm to rt. After 3 hours, MeOH (2 mL) was added and the reaction mixture was poured into water. . The organic layer was separated and the aqueous layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silca gel gave 26 (185 mg, 50%) as a white solid. The spectral data correlates well with the literature values.
(lS,2S)-6,7-Difluoro-2-methoxy-l,2-dihydro-naphthalen-l-ol (27): To a flame dried round bottom flask, [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), (S)-(R)-PPF-P'Bu2 (5.4 mg, O.OlOmmol) and 24 (72 mg, 0.40 mmol) were added followed by addition of THF (1.0 mL) and methanol (1.0 mL). The mixture was heated to reflux for 1 hour. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (20%> ethyl acetate in hexanes) to give 27 as a white crystalline solid (74.9 mg, 88%). The ee was determined to be 96.4% using HPLC analysis on a CHIRALCEL OD column, λ = 486 nm. Retention times in 4% isopropanol in hexanes were 8.9 min and 10.1 min (major). Rf= 0.27 on silica gel (30%> ethyl acetate:hexanes); mp 129-131° (Et2O); [α]25 D= +134.4° (c= 9.3, CHC13); ER (KBr, cm"1) 3269 (br), 2937 (w), 1597 (m), 1503 (s), 1306 (s), 1103 (s), 893 (s); 1H NMR (400MHz, CDC13) δ 7.40 (IH, ddd, f-F= 10.8, 7.8 Hz, J^O.6 Hz), 6.85 (IH, dd, J""F= 10.9, 7.8 Hz), 6.31 (IH, dd, J= 10.0, 2.0 Hz), 6.05 (IH, dd, A 10.0, 2.0 Hz), 4.79 (IH, d, J= 11.0 Hz), 4.05 (IH, ddd, J= 11.0, 2.0, 2.0 Hz), 3.49 (3H, s), 2.94 (IH, d, J= 2.2 Hz); ,3C NMR (400MHz, CDCI3) δ 151.0 (d, j"-F=
12.5 Hz), 148.5 (dd, f'F= 12.5,2.9 Hz), 133.2 (dd, f'F= 5.2, 3.6 Hz), 128.9 (dd, f'F= 6.6, 4.4 Hz), 128.0 (d, / "^ 2.2 Hz), 126.5 (άά, f-F= 2.2, 1.5 Hz), 115.1 (d, j"-F= 18.3 Hz), 114.8 (d, J"" F= 19.8 Hz), 82.3, 72.0, 57.0. HRMS calcd for C, ιHι0O2F2 (M+): 212.0649. Found: 212.0658.
(lS,2S)-6-Methoxy-5,6-dihydro-naphtho[2,3-d][l,3]dioxoI-5-ol (28): To a flame dried round bottom flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-P'Bu2 (3.8 mg, 0.0069 mmol) and 25 (100 mg, 0.694 mmol) were added followed by addition of THF (1.0 mL) and methanol (1.0 mL) and heating to reflux for 30 minutes. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (30%> ethyl acetate in hexanes) to give 28 as a white crystalline solid (127.5 mg, 90%). The ee was determined to be 95%> using HPLC analysis on a CHIRALCEL OD column, λ = 486 nm. Retention times in 4% isopropanol in hexanes were 19.2 min (major) and 22.6 min. Rf= 0.24 on silica (30% ethyl acetate:hexanes); mp 117-119° (Et2O); [α]25 D= +298.7° (c= 11.1, CHC13); IR (KBr, cm"1) 3248 (br), 2926 (s), 1600 (m), 1483 (s), 1260 (s), 1113 (s), 941 (s), 876 (s); Η NMR (400MHz, acetone-d) δ 7.06 (IH, s), 6.65 (IH, s), 6.35 (IH, dd, j= 10.0, 2.0 Hz), 5.94 (2H, dd, j= 9.8, 1.0 Hz), 5.91 (IH, dd, j= 10.0, 2.5 Hz), 4.72 (IH, dt, j= 9.9 Hz), 4.02 (IH, dt, j= 10.3, 2.2 Hz), 3.48 (3H, s), 2.87 (IH, d, j= 13.2 Hz); 13C NMR (400MHz, acetone-d) δ 147.8, 147.6, 133.0, 128.1, 127.2, 127.2, 107.5, 107.5, 101.9, 82.1, 73.0, 57.0. HRMS calcd for Cl2Hι2O4 (M+): 220.0736. Found: 220.0684.
(lS,2S)-6,7-Dibromo-2-methoxy-5,8-dimethyl-l,2-dihydro-naphthalen-l-ol (29): To a flame dried round bottom flask, [Rh(COD)Cl]2 (1.5 mg, 0.0029 mmol), (R)-(S)-PPF-PlBu2 (3.2 mg, 0.0059 mmol) and 26 (195 mg, 0.59 mmol) were added followed by addition of trifluoroethanol (1.0 mL) and methanol (1.0 mL). The mixture was heated to reflux for 20 hours. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (50% ethyl acetate in hexanes) to give 29 as a white crystalline solid (171.6 mg, 79%). The ee was determined to be 97% using HPLC analysis on a CHIRALCEL OD column,
λ = 486 nm. Retention times in 4% isopropanol in hexanes were 16.8 min (major) and 19.3 min. Rr= 0.39 on silica gel (50% ethyl acetate:hexanes); mp 114-116° (Et2O); [α]25 D= -197.1° (c= 10.0, CHC13); IR (KBr, cm"1) 3349 (s), 2901 (m), 1700 (w), 1532 (w), 1404 (m), 1258 (m), 1081 (s), 936 (s); 1H NMR (400MHz, CDC13) δ 6.96-6.93 (IH, m), 6.23-6.19 (IH, m), 4.89 (IH, s), 3.96- 3.90 (IH, m), 3.38-3.35 (3H, m), 2.61-2.57 (3H, m), 2.54 (3H, s), 1.82-1.54 (IH, m); 13C NMR (400MHz, CDC13) δ 137.3, 134.4, 133.2, 129.7, 129.5, 129.0, 128.1, 125.3, 75.3, 66.6, 56.6, 21.0, 20.6. HRMS calcd for Cι3Hι6O2Br2 (M+): 361.9518. Found: 361.9335.
Example 4: Compounds Formed From Reactions Involving Carboxylate Nucleophiles
(1R*,2R*)-Acetic acid l-hydroxy-l,2-dihydro-naphthalen-2-yl-ester (2): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.008 mmol DPPF (9.6 mg, 0.017 mmol), 1 (50 mg, 1.39 mmol), and sodium acetate (142 mg, 1.74 mmol) were added followed by addition of THF (2 mL) and triethylamine hydrochloride (239 mg, 1.74 mmol). The mixture was heated at reflux for 3 hours and the solvents were removed in vacuo. The resulting mixture was purified by flash chromatography (30% ethyl acetate in hexanes) to give 2 as a crystalline solid (41 mg), 63%). Rf= 0.26 on silica gel (20% ethyl acetate:hexanes); mp 67-68° (Et2O); ER (KBr, cm"1) 1H NMR (400MHz, CDC13) δ 7.54-7.53 (IH, m), 7.29-7.24 (2H, m), 7.10-7.08 (IH, m), 6.50 (IH, dd, J= 3.9, 1.3 Hz), 5.85 (IH, dd, J= 9.9, 3.1 Hz), 5.59 (IH, ddd, J= 9.0, 2.8, 1.9 Hz), 4.92 (IH, d, J= 9.0 Hz), 2.64 (IH, s), 2.12 (3H, s); 13C NMR (400MHz, CDC13) δ 171.3, 135.2, 131.5, 129.5, 128.3, 126.7, 126.0, 125.4, 75.3, 71.7, 21.2. HRMS calcd for C12H,2O3 (M+): 204.0786. Found: 204.0791.
(lR*,2R*)-Propionic acid l-hydroxy-l,2-dihydro-naphthaIen-2-yl-ester (3): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), DPPF (9.6 mg, 0.017 mmol) and 1 (50 mg, 0.347 mmol) were added followed by addition of THF (2.5 mL), triethylamine (242 μL, 1.735 mmol) and propionic acid (130 μL, 1.735 mmol). The mixture was heated at reflux for 3 hours and the solvents were removed in vacuo. The resulting mixture was purified by flash chromatography (20% ethyl acetate in hexanes) to give 3 a white crystalline solid (50 mg, 66%). R,= 0.24 on silica gel (% 20 ethyl acetate:hexanes); mp 55-56° (Et2O); ER (KBr, cm"1) 3491 (br), 3048 (w), 2984 (w), 1739 (s), 1454 (m), 1363 (w), 1182 (s), 1083 (m). Η NMR (400MHz, CDC13) δ 7.55-7.52 (IH, m), 7.29-7.24 (2H, m), 7.11-7.08 (IH, m), 6.50 (IH, dd, J= 10.0, 2.0 Hz), 5.85 (IH, dd, J= 12.8, 2.8 Hz), 5.61 (IH, ddd, = 9.2, 2.8, 2.0 Hz), 4.93 (IH, d, J= 9.2 Hz), 2.40 (2H, qd, J= 7.6, 1.2 Hz), 1.16 (3H, t, J= 7.6 Hz); 13C NMR (400MHz, CDC13) δ 174.8, 135.3, 131.5, 129.4, 128.3, 128.3, 126.7, 125.9, 125.5, 75.2, 71.9, 27.7, 9.0. HRMS calcd Cι3Hι4O3 (M+): 218.0943. Found: 218.0938
(lR,2R)-Benzoic acid l-hydroxy-l,2-dihydro-naphthalen-2-yl-ester (4): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), (R)-(S)-BPPFA (9.6 mg, 0.017 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (4 mL), triethylamine (483 μL, 3.47 mmol) and benzoic acid (424 mg, 3.47 mmol). The mixture was heated at reflux for 6 hours and the solvents were removed in vacuo. The resulting mixture was purified by flash chromatography (20%o ethyl acetate in hexanes) to give 4 a white crystalline solid (129 mg, 70%). The ee was determined to be 76% using HPLC analysis on a CHIRALCEL OD column, 10%) isopropanol in hexanes, λ=254 nm. Retention times were 10.0 min (major) and
12.9 min. Rt= 0.3 on silica gel (10% ethyl acetate:hexanes); mp 107-109° (Et2O); [α]25 D= -298.4° (c= 11.3, CHC13); ER (KBr, cm"1) 3619 (br), 3071 (w), 2977 (w), 1724 (s), 1451 (m), 1324 (m), 1265 (s), 1110 (s). Η NMR (400MHz, CDCI3) δ 8.10 (2H, d, J= 7.6 Hz), 7.64-7.59 (2H, m), 7.48-7.45 (2H, m), 7.34-7.32 (2H, m), 7.13-7.11 (IH, m), 6.55 (IH, d, J= 10.0 Hz), 5.97 (IH, dd, = 9.8, 2.9 Hz), 5.86 (IH, ddd, J= 9.8, 2.0, 2.0 Hz), 5.11 (IH, d, J= 9.0 Hz), 2.84 (IH, s); 13C NMR (400MHz, CDC13) δ 166.9, 135.3, 133.3, 131.6, 129.9, 129.8, 129.7, 128.4, 128.4, 128.4, 126.8, 126.1, 125.5, 76.1. 71.9. HRMS calcd for C,7Hl4O3 (M+): 266.0943. Found: 266.0938.
(lR*,2R*)-Formic acid l-hydroxy-l,2-dihydro-naphthalen-2-yl-ester (5): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), DPPF (9.6 mg, 0.017 mmol), 1 (100 mg, 0.694 mmol), and ammonium formate (219 mg, 3.47 mmol), were added followed by addition of THF (5 mL). The mixture was heated at reflux for 3 hours and the solvents were removed in vacuo. The resulting mixture was purified by flash chromatography (30%> ethyl acetate in hexanes) to give 5 a white crystalline solid (84 mg, 64%>). R= 0.25 on silica gel (30% ethyl acetate:hexanes); mp 133-135° (Et2O); IR (KBr, cm"1) 3146 (br), 2935 (w), 1720 (s), 1482 (w), 1186 (s), 1049 (m), 968 (m); Η NMR (400MHz, CDCI3) δ 8.17 (IH, d, J= 0.8 Hz), 7.52- 7.50 (IH, m), 7.29-7.27 (2H, m), 7.13-7.11 (IH, m), 6.54 (IH, dd, J= 9.6, 1.6 Hz), 5.88 (IH, dd, J= 9.6, 2.8 Hz), 5.71-5.68 (IH, m), 4.96 (IH, d, J= 8.8 Hz), 2.8 (IH, s); 13C NMR (400MHz, CDCI3) δ 160.9, 134.8, 131.4, 130.0, 128.5, 126.9, 126.1, 124.6, 74.8, 71.4. HRMS calcd for CπH10O3 (M+): 190.0630. Found: 190.0625.
(lR*,2R*)-2-Methyl acrylic acid l-hydroxy-l,2-dihydro-naphthalen-2-yl-ester (6):
To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), DPPF (9.6 mg, 0.017 mmol) and 1 (50 mg, 0.347 mmol) were added followed by addition of THF (2.5 mL),
triethylamine (242 μL, 1.735 mmol) and methacrylic acid (147 μL, 1.735 mmol). The mixture was heated at reflux for 3 hours and the solvents were removed in vacuo. The resulting mixture was purified by flash chromatography (30% ethyl acetate in hexanes) to give 6 a white crystalline solid (50 mg, 63%). R 0.32 on silica gel (20% ethyl acetate:hexanes); mp 80-82° (Et2O); ER (KBr, cm"1) 3450 (br), 3030 (w), 2928 (w), 1722 (s), 1637 (m), 1454 (m), 1289 (m), 1163 (s); 1H NMR (400MHz, CDC13) δ 7.56-7.55 (IH, m), 7.29-7.24 (2H, m), 7.10-7.09 (IH, m), 6.51 (IH, dd, J= 9.9, 1.9 Hz), 6.15 (IH, s), 5.87 (IH, dd, J- 9.9, 3.0 Hz), 5.67 (IH, ddd, J= 9.3, 2.1, 2.1 Hz), 5.61 (IH, s), 5.01 (IH, dd, J= 9.0, 5.7 Hz), 2.74 (IH, d, J= 6.1 Hz), 1.96 (3H, s); 13C NMR (400MHz, CDCI3) δ 167.6, 135.9, 135.3, 131.5, 129.4, 128.3, 128.2, 126.6, 126.4, 125.8, 125.5, 75.9, 71.9, 18.3. . HRMS calcd C,4H,2O2 (M+-H2O): 212.0837. Found: 212.0831
(lR*,2R*)-Malonic acid ethyl ester (l-hydroxy-l,2-dihydro-naphthalen-2-yl) ester
(7): To a flame dried round bottom flask, [Rh(COD)Cl]2 (8.6 mg, 0.017 mmol DPPF (19.2 mg,
0.035 mmol), 1 (200 mg, 1.39 mmol), ethyl malonate potassium salt (590 mg, 3.47 mmol), and triethylamine hydrochloride (478 mg, 3.47 mmol) were added followed by addition of THF (8 mL). The mixture was heated at reflux for 3 hours and the solvents were removed in vacuo. The resulting mixture was purified by flash chromatography (30% ethyl acetate in hexanes) to give 7 a colourless oil (300 mg), 79%). Rt= 0.29 on silica gel (30% ethyl acetate:hexanes); ER (KBr, cm"1) 3470 (br), 2983 (w), 1731 (s), 1453 (w), 1370 (m), 1150 (s), 1031 (m); Η NMR (400MHz, CDCI3) δ 7.56-7.54 (IH, m), 7.27-7.21 (2H, m), 7.08-7.06 (IH, m), 6.48 (IH, dd, J= 9.9, 2.1 Hz), 5.83 (IH, dd, J= 9.7, 2.8 Hz), 5.70 (IH, ddd, J= 9.7, 2.5, 2.2 Hz), 4.97 (IH, d, J= 9.5 Hz), 4.18 (2H, q, J= 7.2 Hz), 3.43 (2H, dd, J= 23.6, 15.9 Hz), 3.21 (IH, s), 1.25 (3H, t, J= 7.1 Hz); 13C NMR (400MHz, CDCI3) δ 167.1, 166.5, 135.0, 131.5, 129.6, 128.3, 128.1, 126.6, 125.6, 125.1, 77.0, 71.6, 61.9, 41.6, 14.0. HRMS calcd for Cι5Hι4O4 (M+-H2O): 258.0892. Found: 258.0899.
8
(lR*,2R*)-Malonic acid (l-tert-butyldimethylsiloxy-l,2-dihydro-naphthalen-2-yl) ester ethyl ester (8): To a dried round bottom flask, 7 (270 mg, 0.98 mmol), imidazole (134 mg,
1.96 mmol), dimethylaminopyridine (6 mg, 0.05 mmol) were dissolved in dichloromethane (4 mL). Tert-butyldimethylsilyl chloride (222 mg, 1.47 mmol) was then added portionwise and allowed to react for 24 hours. The reaction was then quenched with water, extracted with dichloromethane, dried over Na2SO and concentrated in vacuo. Flash chromatography (10% ethyl acetate in hexanes) gave a colourless oil 8 (343 mg, 90%>). Rt= 0.48 on silica gel (10%> ethyl acetate:hexanes. ER (KBr, cm-1) 2983 (w), 1731 (s), 1453 (w), 1370 (m), 1150 (s), 1031 (m); lH NMR (400MHz, CDCl3) δ 7.41-7.39 (IH, m), 7.24-7.22 (2H, m), 7.07-7.05 (IH, m), 6.47 (IH, dd, J= 9.9, 1.8 Hz), 5.83 (IH, dd, J= 9.7, 2.7 Hz), 5.60 (IH, ddd, J= 9.3, 2.9, 2.0 Hz), 5.00 (IH, dd, J= 9.3, 0.5 Hz), 4.22-4.15 (2H, m), 3.40 (2H, dd, J= 19.6, 16.0 Hz), 1.57 (IH, s), 1.25 (3H, t, J= 7.1 Hz), 0.92 (9H, s), 0.13 (3H, s), 0.09 (3H, s); 13C NMR (400MHz, CDCI3) δ 166.3, 166.2, 136.2, 132.1, 129.4, 128.0, 127.9, 126.5, 125.9, 125.7, 76.4, 71.6, 61.6, 41.7, 25.8, 18.1, 14.0, - 4.3, -4.5. HRMS calcd for C17H2ιO5Si (M+-C4H9): 333.1158. Found: 333.1149.
(lS*,2S*)-(4-Tert-butyldimethylsiloxy-l,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester (9): To a dried round bottom flask, 8 (100 mg, 0.256 mmol) was dissolved in THF (4 mL). Potassium hydride (11.3 mg, 0.28 mmol) was then added portionwise and allowed to react for five minutes at room temperature. Triphenylphosphine (34.1 mg, 0.13 mmol) was then added followed by Pd(PPh3)4 (14.8 mg, 0.013 mmol). The reaction was then heated to reflux for two hours. The solvent was then removed in vacuo and the resulting oil purified by flash
chromatography (5% ethyl acetate in hexanes) giving 9 a colourless oil (54 mg, 61%). R = 0.27 on silica gel (5% ethyl acetate:hexanes); IR (KBr, cm"1) 3036(w), 2956(s), 1735(s), 1472(m), 1257(s), 1077(s); Η NMR (400MHz, CDC13) δ 7.54-7.52 (IH, m), 7.30-7.23 (3H, m), 6.09 (IH, ddd, J= 2.4, 4.6, 10.2 Hz), 6.02 (IH, ddd, J= 10.2, 2.0, 0.5 Hz), 5.22-5.21 (IH, m), 4.15 (2H, q, J= 7.2 Hz), 3.92-3.87 (IH, m), 2.62 (IH, dd, J= 15.7, 5.7 Hz), 2.39 (IH, dd, J= 15.2, 9.0 Hz), 1.25 (3H, t, J= 7.2 Hz), 0.98 (9H, s), 0.21 (3H, s), 0.15 (3H, s); 13C NMR (400MHz, CDC13) δ 171.7, 138.3, 136.1, 131.8, 128.2, 127.2, 127.0, 126.9, 126.6, 65.3, 60.5, 42.7, 36.5, 25.9, 18.2, 14.2, - 4.2, -4.5. HRMS calcd C,7H2ιO5Si (M+-C4H9): 289.1260. Found: 289.1257
Example 5: Compounds Formed In Reactions Involving Nitrogen Nucleophiles
(lR,2R)-2-(l-hydroxy-l,2-dihydro-naphthalen-2-yl)-isoindole-l,3-dione (2): To a flame dried round bottom flask, [Rh(COD)Cl]2 (5.4mg, 0.011 mmol), (R)-(S)-BPPFA (12.2 mg, 0.022 mmol), phthalimide (510 mg, 3.47 mmol) and 1 (100 mg, 0.69 mmol) were added. THF (4 mL) was then added, followed by heating to 80°C for 3 days. The reaction mixture was then poured in to water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine dried over Na2SO4, and concentrated in vacuo. The resulting solid was purified by flash chromatography (30%> ethyl acetate in hexanes) to give 2 as a white crystalline solid (103.5 mg, 52%). The ee was determined to be 74% using HPLC analysis on a CHIRALCEL OD column, λ= 486nm. Retention times in 10%> isopropanol in hexanes were 21.1 min (major)and 29.1 min. Rt= 0.36 on silica gel (30% ethyl acetate exanes); mp 175-176° (dec); [α V -6.1° (c= 12.9, CHC13); ER (KBr, cm"1) 3536 (br), 3067 (w), 2921 (w), 1772 (m), 1693 (s), 1388 (s), 1084 (m), 955 (m), 719 (s); Η NMR (400MHz, CDCI3) δ 7.78-7.75 (2H, m), 7.68- 7.64 (2H, m), 7.57-7.55 (IH, m), 7.26-7.22 (2H, m), 7.09-7.07 (IH, m), 6.51 (IH, dd, J= 9.7, 2.7 Hz), 5.84 (IH, ddd, J= 9.7, 2.7, 2.2 Hz), 5.48 (IH, d, J= 12.8 Hz), 5.12 (IH, ddd, = 12.8, 2.5, 2.4 Hz), 2.82 (IH, s); 13C NMR (400MHz, CDC13) δ 168.6, 137.3, 134.2, 132.6, 132.1, 128.7, 128.2, 128.1, 126.9, 126.5, 124.4, 123.5, 70.9, 55.3. HRMS calcd for Cι8HuNO2 (M+-H2O): 273.2939. Found: 273.0793.
(lS,2S)-N-(l-Hydroxy-l,2-dihydro-naphthalen-2-yl)-benzene sulfonamide (3): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), (S)-(R)-PPF-PlBu2 (9.4 mg, 0.0173 mmol), benzenesulfonamide (545 mg, 3.47 mmol) and 1 (100 mg, 0.69 mmol) were added. THF (2 mL) was then added, followed by heating to 80°C for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine dried over Na2SO , and concentrated in vacuo. The resulting solid was purified by flash chromatography (30%> ethyl acetate in hexanes) to give 3 a white crystalline solid (223 mg, 96%>). The ee was determined to be 95%o by Mosher's ester formation and HPLC analysis on a CHERALCEL OD column, λ= 486nm. Retention times in 10%) isopropanol in hexanes were 26.6 min (major) and 39.4 min. Rf= 0.22 on silica gel (30%> ethyl acetate:hexanes); mp 128-130° (dec); [α] 5 D= 70 ° (c= 8.3, CHC13); ER (KBr, cm"1) 3462 (br), 3200 (m), 2957 (w), 1447 (m), 1329 (m), 1329 (m), 1164 (s), 1093 (m). Η NMR (400MHz, CDC13) δ 7.91-7.90 (2H, m), 7.62-7.58 (IH, m), 7.54-7.50 (2H, m), 7.47-7.45 (IH, m), 7.27-7.23 (2H, m), 6.40 (IH, dd, J= 9.7, 1.7 Hz), 5.55 (IH, dd, J= 9.7, 3.1 Hz), 5.26 (IH, s), 4.77 (IH, d, J= 8.8 Hz), 4.13-4.07 (IH, m), 2.91 (IH, s); 13C NMR (400MHz, CDC13) δ 140.2, 134.9, 132.9, 131.3, 129.5, 129.2, 128.4, 128.4, 127.1, 126.4, 126.0, 72.0, 56.3. HRMS calcd for Cι6H[5NO3S (M+): 301.0773. Found: 301.0769.
(lR*,2R*)-2-Pyrrolidin-l-yl-l,2-dihydro-naphthaIen-l-ol (4): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3mg, 0.009 mmol), DPPF (9.6 mg, 0.017 mmol), pyrrolidine (146 mg, 3.47 mmol), triethylamine hydrochloride (478 mg, 3.47 mmol) and 1 (125 mg, 0.865 mmol) followed by addition of THF (3 mL) and heating to reflux for 8 hours. The solvent was then removed in vacuo and the resulting mixture purified by flash chromatography (10% methanol in
acetone) to give 4 a white crystalline solid (119 mg, 80%>).
0.14 on silica gel (10%> methanol in acetone); mp 97-98° (Et2O); IR (KBr, cm"1) 3496 (br), 3035 (m), 2967 (s), 1454 (m), 1193 (s), 1117 (m), 1048 (s). Η NMR (400MHz, CDC13) δ 7.56 (lH, .d, J= 7.1 Hz), 7.29-7.21 (2H, m), 7.08-7.06 (IH, m), 6.57 (IH, dd, J= 9.9, 2.4 Hz), 6.05 (IH, dd, J= 9.9, 2.4 Hz), 4.83 (IH, d, J= 11.3 Hz), 3.66 (IH, ddd, J= 11.3, 2.4, 2.4 Hz), 3.57 (IH, s), 2.81-2.79 (2H, m), 2.73-2.71 (2H, m), 1.84-1.80 (4H, m); 13C NMR (400MHz, CDC13) δ 136.9, 131.8, 129.6, 127.7, 127.3, 126.1, 125.4, 124.7, 69.8, 63.3, 48.7, 23.8. HRMS calcd for C,4H17NO (M+): 215.1310. Found: 215.1314.
(lR*,2R*)-2-Piperidin-l-yl-l,2-dihydro-naphthalen-l-ol: To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.0087 mmol), DPPF (9.6 mg, 0.0173 mmol), piperidine hydrochloride (422 mg, 3.47 mmol), triethylamine (350 μiL, 2.51 mmol) and 1 (100 mg, 0.69 mmol) were added followed by THF (3 mL) and heating to 80°C for 12 hours. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (50% ethyl acetate, 48% hexanes, 2% methanol) to give 5 a white crystalline solid (130 mg, 82%o). Rf= 0.24 on silica gel (50% ethyl acetate, 48% hexanes, 2% methanol); mp 62-64° (Et2O); ER (KBr, cm"1) 3482 (br), 3036 (w), 2937 (s), 2853 (m), 1453 (s), 1193 (s), 1109 (s), 1046 (s). 1H NMR (400MHz, CDC13) δ 7.57 (IH, d, J= 7.1 Hz), 7.27-7.18 (2H, m), 7.05 (IH, dd, J= 6.9, 0.9 Hz), 6.49 (IH, dd, J= 9.9, 2.6 Hz), 6.12 (IH, dd, J= 9.9, 2.4 Hz), 4.87 (IH, d, J= 12.2 Hz), 3.58 (IH, s), 3.37 (IH, ddd, J= 12.2, 2.4, 2.4 Hz), 2.79-2.73 (2H, m), 2.48 (2H, m), 1.67-1.57 (4H, m), 1.56-1.46 (2H, m); 13C NMR (400MHz, CDC13) δ 137.4, 131.8, 128.8, 127.1, 125.9, 125.2, 124.4, 68.2, 67.6, 50.4, 26.5, 24.6. HRMS calcd for d5Hι8NO (M+-H): 228.1388. Found: 228.1318.
(lR*,2R*)-2-Benzylamino-l,2-dihydro-naphthalen-l-ol (8): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.009 mmol), DPPF (9.6 mg, 0.017 mmol), benzylamine hydrochloride (279 mg, 1.74 mmol), triethylamine (242 μL, 1.74 mmol) and 1 (50 mg, 0.347 mmol) followed by addition of THF (3 mL) and heating to reflux for 3 days. The solvent was then removed in vacuo and the resulting mixture purified by flash chromatography (50%> ethyl acetate in hexanes) to give 8 a white crystalline solid (26.9 mg, 31%>). R = 0.44 on silica gel (50% ethyl acetate, 48% hexanes, 2% methanol); mp 115-117° (dec) (Et2O); IR (KBr, cm"1) 3528 (br), 3030 (w), 2849 (w), 1455 (s), 1190 (m), 1112 (m), 1048 (m). !H NMR (400MHz, CDC13) δ 7.47- 7.45 (IH, m), 7.29-7.24 (4H, m), 7.24-7.17 (3H, m), 7.02-7.01 (IH, m), 6.41 (IH, dd, J= 9.7, 2.0 Hz), 6.00 (IH, dd, J= 9.7, 2.5 Hz), 4.64 (IH, d, J= 9.0 Hz), 3.94 (IH, AB, J= 13.0 Hz), 3.75 (IH, AB, J= 13.0 Hz), 3.42 (IH, ddd, J= 11.0, 2.4, 2.4 Hz), 2.44 (IH, s); 13C NMR (400MHz, CDC13) δ 139.8, 136.6, 132.1, 128.8, 128.5, 128.2, 127.9, 127.8, 127.6, 127.2, 126.1, 124.9, 72.1, 59.7, 50.7. HRMS calcd for Cι7H17NO (M+): 251.1310. Found: 251.1316.
(lR*,2R*)-2-(4-Methoxy-benzylamino)-l,2-dihydro-naphthalen-l-ol (9): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3mg, 0.009 mmol), DPPF (9.6 mg, 0.017 mmol), p- methoxybenzylamine (238 mg, 1.74 mmol), triethylamine hydrochloride (239 mg, 1.74 mmol) and 1 (50 mg, 0.728 mmol) followed by addition of THF (3 mL) and heating to reflux for 3 days. The solvent was then removed in vacuo and the resulting mixture purified by flash chromatography (50% ethyl acetate in hexanes) to give 9 a white crystalline solid (43 mg, 44%).
Rr= 0.27 on silica gel (50% ethyl acetate, 48% hexanes, 2% methanol); mp 96-98° (dec) (Et2O); IR (KBr, cm'1) 3528 (br), 3033 (w), 2835 (m), 1612 (m), 1512 (s), 1455 (m), 1248 (s), 1040 (m). Η NMR (400MHz, CDC13) δ 7.52-7.50 (IH, m), 7.26-7.22 (4H, m), 7.08-7.06 (IH, m), 6.85 (2H, d, J= 9.0 Hz), 6.47 (IH, dd, J- 9.7, 2.0 Hz), 6.05 (IH, dd, J- 9.9, 2.6 Hz), 4.68 (IH, d, J= 11.0 Hz), 3.95 (IH, d, J= 12.9 Hz), 3.79 (3H, s), 3.75 (IH, d, J= 2.9 Hz), 3.46 (IH, ddd, J= 11.0, 2.4, 2.4 Hz), 3.0-2.0 (2H, s (br)); 13C NMR (400MHz, CDC13) δ 158.7, 136.7, 132.1, 131.9, 129.4, 128.9, 127.9, 127.7, 127.5, 126.0, 124.9, 113.9, 72.1, 59.6, 55.2, 50.1. HRMS calcd for C,8H19NO2 (M+): 281.1416. Found: 281.1403.
10
(lR,2R)-2-Indol-l-yl-l,2-dihydro-naphthalen-l-ol (10): To a flame dried round bottom flask, [Rh(COD)Cl]2 (4.3 mg, 0.009 mmol), (R)-(S)-BPPFA (9.6 mg, 0.017 mmol), indole (407 mg, 3.47 mmol) and 1 (100 mg, 0.69 mmol) were added. THF (4 mL) was then added, followed by heating to 80°C for 3 days. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (30% ethyl acetate in hexanes) to give 10 a colourless oil (147 mg, 81%). The ee was determined to be 79% using HPLC analysis on a CHIRALCEL OD column, λ= 254nm. Retention times in 10%> isopropanol in hexanes were 28.5 min (major) and 30.1 min. Rt= 0.26 on silica gel (30% ethyl acetate: hexanes); [α]25o= -46.7° (c=
11.3, CHC13); IR(KBr, cm"1) 3485 (br), 3059 (m), 1592 (m), 1455 (s), 1414 (s), 1245 (m), 1091
(m), 908 (m); Η NMR (400MHz, CDCI3) δ 8.13 (IH, s), 7.79 (IH, d, J= 7.8 Hz), 7.42 (IH, d,
J= 7.3 Hz), 7.34-7.19 (6H, m), 6.85 (IH, d, J= 2.2 Hz), 6.69 (IH, dd, J= 9.5, 2.0 Hz), 6.20 (IH, dd, J= 9.5, 3.8 Hz), 5.06 (IH, d, J= 7.9 Hz), 4.12-4.08 (IH, m), 2.35 (IH, s); 13C NMR (400MHz,
CDCI3) δ 136.5, 135.9, 132.5, 130.1, 128.0, 127.7, 126.9, 126.5, 126.4, 126.2, 122.6, 122.0,
119.3, 119.2, 113.9, 111.4, 72.7, 41.0. HRMS calcd for Cι8H15NO (M+): 261.1154. Found:
261.1141.
Example 6: Compounds Formed In Reactions Involving Carbon Nucleophiles
(lS*,2R*)-2-(Hydroxy-l,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester (2): To a flame dried round bottom flask, [Rh(COD)Cl]2 (8.6 mg, 0.0174 mmol), DPPF (19.2 mg, 0.0347 mmol), dimethyl malonate (137 mg, 1.041 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (1.5 mL) and heating to 80°C for 24 hours. The reaction mixture was then poured in to water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by flash chromatography (20%o ethyl acetate in hexanes then increasing to 50%) ethyl acetate in hexanes) to give 2 a colourless oil which crystallized on sitting (124.3 mg, 65%). Rf= 0.27 on silica gel (50% ethyl acetate:hexanes); mp 65-67° (Et2O); ER (neat, cm"1) 3490 (br), 3024 (m), 2954 (s), 1744 (s), 1436 (s), 1159 (s), 1026 (s), 913 (m), 783 (s); Η NMR (400MHz, CDC13) δ 7.40-7.38 (IH, m), 7.30-7.24 (2H, m), 7.13-7.11 (IH, m), 6.57 (IH, dd, J= 9.7, 1.5 Hz), 5.97 (IH, dd, J= 9.7, 4.2 Hz), 4.70 (IH, dd, J= 6.2, 6.2 Hz), 3.73 (3H, s), 3.70 (3H, s), 3.52 (IH, d, J= 7.6 Hz), 3.37-3.35 (IH, m), 2.09 (IH, d, J= 6.2 Hz); 13C NMR (400MHz, CDC13) δ 168.6, 168.3, 135.4, 131.9, 128.3, 128.1, 126.8, 126.7, 70.3, 52.6, 52.6, 52.5, 42.3. HRMS calcd for Cl 5H16O5 (M+): 276.0998. Found: 276.0104.
Example 7: Compounds Formed In Reactions Involving Phenol Nucleophiles
(lS,2S)-2-Phenoxy-l,2-dihydro-naphthalen-l-ol (2): To a flame dried round bottom flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-P(Bu2 (3.8 mg, 0.0069 mmol, and 1 (100 mg, 0.694 mmol) were added. THF (2 mL) and phenol (327 mg, 3.47 mmol) were then added followed by heating to 80°C for 1.5 hours. The reaction mixture was then poured in to
ether and washed three times with 5% aqueous Noah. The aqueous layers were combined and back extracted three times with ether. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 2 as a white crystalline solid (130.7 mg, 83%). The ee was determined to be 99.2% using HPLC analysis on a CHIRALCEL OD column, λ= 486 nm. Retention times in 4% isopropanol in hexanes were 15.2 min (major) and 17.8 min. Fr= 0.26 on silica gel (10% ethyl acetate:hexanes); mp 109-110°C (Et2O); [ ]25 D= +204.7° (c= 10.1, CHC13); IR (KBr, cm"1) 3337 (br), 3029 (w), 2866 (w), 1600 (m), 1496 (s), 1249 (s), 1062 (s); Η NMR (400 MHz, CDC13) δ 7.65-7.63 (IH, m), 7.33-7.25 (4H, m), 7.13-7.11 (IH, m), 7.01-6.95 (3H, m), 6.51 (IH, dd, J= 9.9, 1.6 Hz), 6.02 (IH, dd, J= 9.9, 2.2 Hz), 5.19 (IH, d, J= 10.4 Hz), 5.11 (IH, ddd, J= 10.4, 2.0, 2.0 Hz), 2.66 (IH, s); 13C NMR (400 MHz, CDC13) δ 157.4, 135.5, 131.9, 129.7, 129.0, 128.2, 128.0, 126.4, 126.1, 125.2, 121.5, 115.9, 79.1, 72.4. HRMS calcd for C,6Hι4O2 (M+): 238.0994. Found: 238.0984.
(lS,2S)-2-(4-nitrophenoxy)-l,2,-dihydro-naphthalen-l-ol (3): To a flame dried round- bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-nitrophenol
(483 mg, 3.47 mmol). The mixture was heated at 80°C for 45 minutes, then poured into diethyl ether and extracted 3 times with 10%> aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) giving a white crystalline solid 3 (184 mg, 94%>). The ee was determined to be 97%o by formation of Mosher's ester. Fr = 0.43 on silica (30% ethyl acetate:hexanes); mp 123-
125°C (dec); [α]25 D = +169.9° (c = 10.3, CHCI3); ER (KBr, cm"1) 3351 (br), 3113 (w), 3071 (w), 2884 (w), 2843 (w), 1591 (s), 1503 (s), 1342 (s), 1295 (m), 1110 (m), 896 (w); Η NMR (400
MHz, CDCI3): δ 8.18 (2H, d, J=9.2 Hz), 7.62-7.60 (IH, m), 7.31-7.29 (2H, m), 7.15-7.13 (IH, m), 6.99 (2H, d, J= 9.2 Hz), 6.57 (IH, d, J= 9.9 Hz), 5.94 (IH, d, J= 9.9 Hz), 5.20 (2H, s), 2.61
(IH, s); 13C NMR (400 MHz, CDCI3): δ 162.6, 141.8, 135.0, 131.5, 130.2, 128.5, 128.4, 126.8, 126.0, 125.5, 124.1, 115.4, 79.6, 72.0.
(lS,2S)-2-(4-Cyanophenoxy)-l,2,-dihydro-naphthalen-l-ol (4): To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-P'Bib (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4- cyanophenol (413 mg, 3.47 mmol). The mixture was heated at 80°C for 5 hours, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) giving a white crystalline solid 4 (160 mg, 88%>). The ee was determined to be 97%> by HPLC analysis on a CHERALCEL OD column, λ= 256 nm. Retention times in 3% isopropanol in hexanes were 35.3 min and 37.7 min (major). Fr = 0.40 on silica (30%> ethyl acetate in hexanes); mp 140-141°C (Et2O); [α]25 D - +182.3° (c = 11.2, CHC13) ER (KBr, cm"1) 3303 (b) 3050 (w) 2210 (m) 1598 (s) 1503 (s) 1238 (s) 1025 (m) 859 (m) 778 (m); 1H NMR (400 MHz, CDCI3): δ 7.62-7.57 (3H, m), 7.33-7.27 (3H, m), 7.14-7.12 (IH, m), 6.56 (IH, dd, J= 1.4, 9.7 Hz), 5.93 (IH, dd, J= 1.4, 9.7 Hz), 5.20-5.13 (2H, m), 2.25 (IH, s). 13C NMR (400 MHz, CDCI3): δ 160.8, 135.0, 134.2, 131.5, 130.0, 128.5, 128.3, 126.7, 125.4, 124.4, 119.0, 116.2, 104.6, 79.2, 72.0. HRMS calcd for (M-H2O)+ (C17H..ON): 245.0841. Found: 245.0845.
(lS,2S)-2-(4-acylphenoxy)-l,2,-dihydro-naphtha!en-l-ol (5): To a flame dried round- bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-PlBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-
hydroxyacetophenone (472 mg, 3.47 mmol). The mixture was heated at 80° C for 2.5 hours, then poured into diethyl ether and extracted 3 times with 10%> aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30%> ethyl acetate in hexanes) giving a white crystalline solid 5 (177 mg, 91%>). The ee was determined to be > 99% by formation of Mosher's ester; Rf = 0.28 on silica (30%> ethyl acetate in hexanes); mp 124-126°C (Et2O); [α]25 D = +153° (c = 9.8, CHC13). ER (KBr, cm"1) 3367 (b), 3069 (w), 2916 (w), 1668 (s), 1601 (s), 1265 (s), 1053 (m), 835 (m), 779 (m); 1H NMR (400 MHz, CDC13): δ 7.94 (2H, d, J=8.8 Hz), 7.66-7.64 (IH, m), 7.34-7.27 (2H, m), 7.16-7.14 (IH, m), 6.98 (2H, d, J= 8.8 Hz), 6.57 (IH, d, J= 9.9 Hz), 5.99 (IH, d, J= 9.9 Hz), 5.21 (2H, s), 2.85 (IH, s), 2.56 (3H, s); 13C NMR (400 MHz, CDC13): δ 196.8, 161.4, 135.3, 131.7, 130.7, 130.6, 129.6, 128.3, 128.1, 126.6, 125.4, 125.0, 115.2, 79.0, 72.0, 26.3. HRMS calcd for (M-H2O)+ (CI 8H14O2): 262.0994. Found: 262.0989.
(1S,2S)- 2-(4-Trifluoromethylphenoxy)-l,2,-dihydro-naphthalen-l-ol (6): To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-PlBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and4-trifluoromethylphenyl (563 mg, 3.47 mmol). The mixture was heated at 80° C for 8 hours, then poured into diethyl ether and extracted 3 times with 10%> aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10%> ethyl acetate in hexanes) to give a white crystalline solid 6 (184 mg, 87%). The ee was determined to be 95% by HPLC analysis on a CHIRALCEL OD column, λ= 486 nm. Retention times in 4% isopropanol in hexanes were 14.8 min and 17.3 min (major). Rf = 0.46 on silica (20% ethyl acetate in hexanes); mp 118-119°C (Et2O); [ ]25 D = +178° (c = 9.6, CHCI3). ER (KBr, cm"1) 3360 (br), 3061 (w), 2874 (w), 1617 (m), 1518 (m), 1326 (s), 1103 (s), 1051 (m), 839 (m), 782 (m), 745 (w); Η NMR (400 MHz, CDCI3): δ 7.63-7.54 (IH,
m), 7.55 (2H, d, J= 8.6 Hz), 7.33-7.24 (2H, m), 7.14-7.12 (IH, m), 7.01 (2H, d, J= 8.6 Hz), 6.55 (IH, dd, J= 1.6, 9.9 Hz), 5.97 (IH, dd, J= 2.0, 9.9 Hz), 5.21-5.13 (2H, m), 2.47 (IH, d, J= 3.6 Hz); 13C NMR (400 MHz, CDCl3): δ 159.9, 135.2, 131.7, 129.6, 128.4, 128.2, 127.1 (q, "F= 3.6 Hz), 126.6, 125.4, 124.9, 123.4 (d, "^ 33.0 Hz), 122.9 (d, "F= 271.6 Hz), 115.6, 79.1, 72.1; HRMS calcd for (M+) (C] 7H13O2F3): 306.0868. Found: 306.0852.
(lS,2S)-2-(4-Fluorophenoxy)-l,2,-dihydro-naphthalen-l-ol (7): To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-P'Bu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4- fluorophenol (389 mg, 3.47 mmol). The mixture was heated at 80°C for 5 hours, then poured into diethyl ether and extracted 3 times with 10%o aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (10%) ethyl acetate in hexanes) giving a white crystalline solid 7 (163 mg, 92%>). The ee was determined to be 97% by HPLC analysis on a CHIRALCEL OD column, λ= 486 nm). Retention times in 1.5% isopropanol in hexanes were 28.1 min (major) and 29.5 min. Rf = 0.39 on silica (20% ethyl acetate in hexanes); mp 127-129°C (Et2O); [α]25 D = +216° (c = 9.5, CHC13). ER (KBr, cm"1) 3309 (b), 3071 (w), 2864 (w), 1504 (s), 1284 (m), 1052 (s), 781 (s), 692 (m); 1H NMR (400 MHz, CDCI3): δ 7.63-7.61 (IH, m), 7.31-7.26 (2H, m), 7.12-7.10 (IH, m), 7.00-6.95 (2H, m), 6.92-6.88 (2H, m), 6.51 (IH, dd, J= 2.1, 9.9 Hz), 5.98 (IH, dd, J= 2.2, 9.9 Hz), 5.15 (IH, dd, J= 3.6, 10.0 Hz), 5.01 (IH, ddd, J= 2.1, 2.1, 10.1 Hz), 2.54 (IH, d, J= 3.8 Hz); 13C NMR (400 MHz, CDCI3): δ 157.6 (d, "F- 239 Hz), 156.4, 153.4, 135.4, 131.8, 129.1, 128.2, 126.5, 125.7, 125.2, 117.5 (d, "F= 8 Hz), 116.1 (d, "F= 23.5 Hz);. HRMS calcd for (M*) (C16H13O2F): 256.0810. Found: 256.0911.
(lS,2S)-2-(4-Iodophenoxy)-l,2,-dihydro-naphthalen-l-oI (9): To a flame dried round- bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-P'Bu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4- iodophenol (763 mg, 3.47 mmol). The mixture was heated at 80°C for 12 hours, then poured into diethyl ether and extracted 3 times with 10%> aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash cliromatography on silica gel (10%) ethyl acetate in hexanes) as a white crystalline solid 9 (193 mg, 73%). The ee was determined by deiodinating 9 (40 mg, 0.11 mmol) by reaction with t-BuLi (0.32 mL, 1.7M) in diethyl ether (2 mL) at -78°C followed by quenching with isopropanol. Extraction with ether from
water, washing with brine, drying over anhydrous sodium sulfate and removal of the solvents in vacuo gave a white crystalline solid (24 mg, 92%>). The ee was determined to be 98% by HPLC analysis on a CHIRALCEL OD column, λ= 256 nm. Retention times in 4% isopropanol in hexanes were 15.2 min (major) and 17.9 min; Rf = 0.44 on silica (20% ethyl acetate in hexanes); mp 160-162°C (Et2O); [ ]25 D = +107° (c = 9.7, CHC13). ER (KBr, cm"1) 3264 (br), 3050 (w), 2926 (w), 2843 (w), 1581 (m), 1485 (s), 1388 (w), 1279 (m), 1246 (s), 1046 (m), 824 (m), 780 (m), 571 (w); Η NMR (400 MHz, CDCI3): δ 7.63-7.61 (IH, m), 7.58-7.55 (2H, m), 7.30-7.27 (2H, m), 7.13-7.11 (IH, m), 6.73 (2H, ddd, J= 2.2, 2.2, 9.0 Hz), 6.52 (IH, dd, J= 1.8, 9.8 Hz), 5.96 (lH,dd, J= 2.2, 9.8 Hz), 5.16 (IH, d, J= 10.0 Hz), 5.05 (IH, ddd, J= 2.0, 2.0, 10.0 Hz), 2.54 (IH, s); 13C NMR (400 MHz, CDCl3): δ 157.3, 138.5, 135.3, 131.7, 129.4, 128.3, 128.1, 126.6, 125.3, 125.3, 118.1, 83.6, 79.2, 72.2. HRMS calcd for (M-H2O)+ (C16HπOι): 345.9855. Found: 345.9849.
(lR,2R)-2-(4-Bromo-phenoxy)-l,2-dihydro-naphthalen-l-ol: To a flame dried round bottom flask, [Rh(COD)Cl]2 (2.1 mg, 0.0043 mmol), (R)-(S)- PPF-PlBu2 (4.6 mg, 0.0085 mmol, and 1 (122 mg, 0.85 mmol) were added. ). THF (2 mL) and p-bromophenol (734 mg, 4.245 mmol) were then added followed by heating to 80°C for 1.5 hours. The reaction mixture was then poured in to ether and washed three times with 5%> aqueous NaOH. The aqueous layers were combined and back extracted three times with ether. The organic layers were combined, washed with brine, dried over Na2SO , and concentrated in vacuo. The resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 10 a white crystalline solid (239.7 mg, 90%i). The ee was determined by debrominating 10 (44 mg, 0.139 mmol) by reaction with t-BuLi (0.2 mL, 1.7M) in ether (2mL) at -78°C followed by quenching with isopropanol. Extraction with ether from water, washing with brine, drying over Na2SO4 and concentration gave a white crystalline solid 2 (31.5 mg, 95%). The ee was determined to be 96.8%> by HPLC analysis on a CHIRALCEL OD column, λ= 486nm. Retention times in 4%> isopropanol in hexanes were 15.2 min and 17.5 min (major). Rt= 0.26 on silica gel (10%> ethyl acetate:hexanes); mp 145-146° (Et2O); [α]25 D= -135.7° (c= 10.2, CHCI3); IR (KBr, cm"1) 3290 (br), 3060 (m), 2870 (w), 1583 (m), 1484 (s), 1227 (s), 1052 (m), 980 (s), 776 (s); Η NMR (400MHz, CDCI3) δ 7.70-7.65 (IH,
m), 7.44-7.42 (2H, m), 7.35-7.32 (2H, m), 7.18-7.16 (IH, m), 6.88-6.86 (2H, m), 6.56 (IH, dd, J= 10.0, 2.0 Hz), 6.00 (IH, dd, J= 9.7, 2.2 Hz), 5.20 (IH, dd, J= 9.7, 3.6 Hz), 5.09 (IH, ddd, J= 10.0, 2.0, 2.0 Hz), 2.70 (IH, d, J= 3.9 Hz); 13C NMR (400MHz, CDC13) δ 156.5, 135.3, 132.5, 131.7, 129.3, 128.3, 128.1, 126.5, 125.3, 117.6, 113.7, 79.4, 72.2. HRMS calcd for C,6H, ,OBr (M-H2O)+ 297.9994. Found: 297.9995.
11
(lS,2S)-2-(4-Methylphenoxy)-l,2,-dihydro-naphthalen-l-ol (11): To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-PlBu2 (3.8 mg, 0.0069 mmol) and 1 (50 mg, 0.347 mmol) were added followed by addition of THF (2.5 mL) and p- cresol (188 mg, 1.74 mmol). The mixture was heated at 80°C for 24 hours, then poured into diethyl ether and extracted 3 times with 10%o aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (5%> ethyl acetate in hexanes) giving a white crystalline solid 11 (57 mg, 65%). The ee was determined to be 91%> by HPLC analysis on a CHERALCEL OD column, λ=256 nm. Retention times in 1%> isopropanol in hexanes were 33.8 min (major) and 37.1 min. Rf = 0.49 on silica (20% ethyl acetate in hexanes); mp 80-81°C (Et2O); [α]25 D = +145° (c = 12.1, CHCU). R (KBr, cm"1) 3303 (br), 3050 (w), 2210 (m), 1598 (s), 1503 (s), 1238 (s), 1025 (m), 859 (m), 778 (m); 'H NMR (400 MHz, CDC13): δ 7.67-7.65 (IH, m), 7.33-7.28 (2H, m), 7.14-7.11 (3H, m), 6.88 (2H, d, J= 8.4 Hz), 6.51 (IH, dd, J= 1.8, 9.9 Hz), 6.04 (IH, dd, J= 2.0, 9.9 Hz), 5.20 (IH, dd, J= 1.6, 10.2 Hz), 5.09 (IH, ddd, J= 1.8, 1.8, 10.2 Hz), 2.87 (IH, d, J= 2.7 Hz), 2.33 (3H, s). 13C NMR (400 MHz, CDCI3): δ 155.0, 135.4, 131.8, 130.7, 130.1, 128.8, 128.1, 127.9, 126.4, 126.2, 125.1, 115.6, 79.0, 72.3, 20.5. HRMS calcd for (M+) (C17H16O2): 252.1150. Found: 252.1140.
13
(lS,2S)-2-(2-Bromophenoxy)-l,2,-dihydro-naphthalen-l-ol (13): To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)- PPF-PlBu (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 2- bromophenol (0.40 mL, 3.47 mmol). The mixture was heated at 80°C for 24 hours, then poured into diethyl ether and extracted 3 times with 10%> aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica
gel (5% ethyl acetate in hexanes) as a white crystalline solid 13 (75 mg, 37%). The ee was determined to be 81% by HPLC analysis on a CHIRALCEL OD column, λ= 486 nm. Retention times in 1.5% isopropanol in hexanes were 22.8 min and 32.1 min (major). Rt- = 0.44 on silica (20% ethyl acetate in hexanes); mp 120-122°C (Et2O); [α]25 D = +254° (c = 9.2, CHC13). ER (KBr, cm"1) 3341 (br), 3071 (w), 2884 (w), 1581 (m), 1472 (s), 1358 (m), 1237 (s), 1028 (s), 987 (s), 780 (s), 689 (m), 569 (m); 'H NMR (400 MHz, CDC13): δ 7.67 (IH, d J= 6.8 Hz), 7.58 (IH, dd, J= 1.5, 7.9 Hz), 7.33-7.23 (3H, m), 7.14-7.12 (IH, m), 6.95(1H, dd, J= 1.1, 8.2 Hz), 6.92-6.87 (IH, m), 6.52 (IH, dd, J= 2.0, 9.9 Hz), 6.06 (IH, dd, J= 1.8, 9.9 Hz), 5.32 (IH, d, J= 11.0 Hz), 5.10 (IH, ddd, J= 2.0, 2.0, 11.0 Hz), 2.85 (IH, d, J= 3.2 Hz). 13C NMR (400 MHz, CDC13): δ 154.3, 135.4, 133.6, 131.8, 129.1, 128.6, 128.3, 128.0, 126.4, 126.0, 124.9, 122.9, 115.6, 113.5, 82.2, 72.5. HRMS calculated for (M-H2O)+ (C16H..OBr): 297.9993. Found: 297.9976.
II. Compounds Made Using Azabicyclics
Example 8: Azabicyclic Starting Materials:
Example 9: Compounds Formed in Reactions Involving Alcohols
To a round bottomed flask was added 1 (44 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) and MeOH (1 ml) were then added and the solution heated to reflux for 6 hours. The reaction mixture was then concentrated and chromatographed to give 6 (28 mg, 56%) a colourless oil. Η NMR (400MHz, CDC13) δ 7.35
(IH, d, J= 7.2Hz), 7.28-7.13 (4H, m), 6.76-6.68 (4H, m), 6.64 (IH, d, J= 9.9Hz), 6.11 (IH, dd, J- 4.0, 9.7Hz), 5.73 (IH, d, J= 6.0Hz), 4.21 (IH, dd, J= 4.3, 4.3Hz), 3.82 (IH, s), 3.42 (3H, s); 13C NMR (400MHz, CDC13) δ 147.1, 135.2, 132.0, 129.9, 129.4, 129.3, 128.4, 128.3, 128.1, 127.0, 126.5, 126.5, 75.8, 56.1, 55.8. HRMS calcd for C,7Hι7NO (M+): 251.1310. Found: 251.1315.
7
To a round bottomed flask was added 2 (49 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) and MeOH (1 ml) were then added and the solution heated to reflux for 48 hours. The reaction mixture was then concentrated and chromatographed (10% ethyl acetate :hexanes) to give 7 (41 mg, 74%>) a white solid. The regiochemistry and relative stereochemistry was proven by X-ray crystal diffraction. Rf= 0.25 on silica gel (10% ethyl acetate:hexanes); 1H NMR (400MHz, CDC13) δ 7.35-7.34 (IH, m), 7.25-
7.20 (2H, m), 7.10-7.08 (IH, m), 6.58 (2H, d, J= 9.7Hz), 6.07 (IH, dd, J= 4.3, 9.7Hz), 4.98 (IH, dd, J= 5.5, 8.0Hz), 4.61 (IH, d, J= 7.7Hz), 4.00 (IH, dd, J= 4.6, 4.6Hz), 3.45 (3H, s), 1.44 (9H, s); 13C NMR (400MHz, CDCI3) δ 155.3, 134.1, 131.9, 130.0, 130.0, 128.3, 128.3, 127.0, 125.9,
79.6, 56.3, 51.3, 28.4. HRMS calcd for Cl 6H2INO3 (M+): 275.1521. Found: 275.1518.
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) and MeOH (1 ml) were then added and the solution heated to reflux for 9 hours (Note: 3 and 8 nearly co-spot by TLC but 8 stains red with permanganate whereas 3 stains white). The reaction mixture was then concentrated and chromatographed to give 8 (60 mg, 91 %) a crystalline solid, mp 128-129°C; Η NMR (400MHz, CDCI3) δ 7.78 (2H, d, J= 8.0Hz), 7.33 (2H, d, J= 7.9Hz), 7.25-7.18 (IH, m), 7.11-7.04 (2H, m), 6.80 (2H, d, J= 7.5Hz), 6.60 (IH, d, J= 9.7Hz), 6.06 (IH, dd, J= 5.1, 9.2Hz), 4.50 (2H, s (br)), 3.98 (IH, s), 2.29 (3H, s), 2.47 (3H, s); 13C NMR (400MHz, CDC13) δ 144.9, 137.2, 132.4, 131.7,
130.3, 129.6, 128.8, 128.4, 127.3, 124.9, 77.2, 56.5, 54.1, 21.6. Anal. Calcd for C,8H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.74; H, 5.89; N, 4.19.
To a round bottomed flask was added 5 (61 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) and MeOH (1 ml) were then added and the solution heated to reflux for 6 hours. The reaction mixture was then concentrated and chromatographed to give 9 (53 mg, 78%) a colourless oil. Η NMR (400MHz, CDC13) δ 7.51- 7.47 (IH, m), 7.30-7.24 (2H, m), 7.14-7.10 (IH, m), 6.59 (IH, d, J= 9.9Hz), 6.10 (IH, dd, J= 3.7, 9.9Hz), 5.41 (IH, dd, J= 8.8, 8.8Hz), 4.55 (IH, d, J= 8.8Hz), 4.06 (IH, dd, J= 3.6, 6.9Hz), 3.45 (3H, s), 3.04-2.95 (2H, m), 1.07-0.85 (2H, m), 0.03 (6H, s); 13C NMR (400MHz, CDC13) δ 133.7, 131.9, 129.9, 128.7, 128.4, 127.7,127.2, 125.5, 77.3, 56.5, 55.5, 50.2, 10.5, -2.0. HRMS calcd for Cι6H25NO3SSi (M+): 339.1324. Found: 339.1327.
Example 10: Compounds Formed in Reactions Involving Phenol Nucleophiles
10 To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) and PhOH (94 mg, 1.0 mmol) were added and the solution heated to reflux for 12 hours. The reaction mixture was then concentrated and chromatographed to give 10 (63 mg, 81%>) a crystalline solid. 1H NMR (400MHz, CDC13) δ 7.72 (2H, d, J= 8.2Hz), 7.30-7.20 (5H, m), 7.14-7.09 (2H, m), 6.98-6.92 (IH, m), 6.87 (IH, d, J= 7.4Hz), 6.77 (2H, d, J= 8.4Hz), 6.64 (IH, d, J= 10.2Hz), 6.06 (IH, dd, J= 4.6, 9.2Hz), 5.00 (IH, dd, J= 4.7, 4.7Hz), 4.71-4.64 (2H, m), 2.44 (3H, s); 13C NMR (400MHz, CDCI3) δ 156.8, 143.6, 137.5, 132.5, 131.7, 130.9, 129.7, 129.5, 128.9, 128.6, 128.2, 127.4, 127.4, 124.2, 121.4, 115.9,
73.2, 54.4, 21.5. Anal. Calcd for C23H2ιNO3S: C, 70.56; H, 5.41; N, 3.58. Found: C, 70.58; H, 5.43; N, 4.18.
Example 11 : Compounds Formed in Reactions Involving Nitrogen or Carbon Nucleophiles
11
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) and N-methylaniline (107 mg, 1.0 mmol) were added and the solution heated to reflux for 8 hours. The reaction mixture was then concentrated and chromatographed to give 11 (72 mg, 89%>) a crystalline solid, mp 136-142°C; 1H NMR (400MHz, CDC13) δ 7.62 (2H, d, J= 8.1Hz), 7.26-7.18 (4H, m), 7.14-7.08 (2H, m), 6.90 (IH, d, J= 7.3Hz), 6.80-6.68 (4H, m), 5.86 (IH, dd, J= 4.6, 9.9Hz), 4.73-4.53 (2H, m), 2.42 (3H, s), 2.34 (3H, s); 13C NMR (400MHz, CDC13) δ 148.9, 143.4, 137.5, 133.7, 132.2, 130.4, 129.6, 129.2, 128.7, 128.4, 127.7, 127.3, 127.0, 126.0, 117.6, 113.8, 58.9, 54.6, 32.3, 21.5. Anal. Calcd for C24H24N2O2S: C, 71.26; H, 5.98; N, 6.93. Found: C, 71.32; H, 6.01; N, 4.16.
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) and tetrahydroquinoline (133 mg, 1.0 mmol) were added and the solution heated to reflux for 9 hours. The reaction mixture was then concentrated and chromatographed to give 12 (63 mg, 73%>) a crystalline solid, mp 135-137°C; Η NMR (400MHz, CDC13) δ 7.63 (2H, d, J= 8.2Hz), 7.25-7.20 (IH, m), 7.18 (2H, d, J- 8.2Hz), 7.11-7.00 (3H, m), 6.90 (IH, d, J= 6.4Hz), 6.83 (2H, d, J= 7.9Hz), 6.71 (IH, d, J= 9.7Hz), 6.64- 6.58 (IH, m), 5.84 (IH, dd, J= 5.0, 9.7Hz), 4.83 (IH, d, J= 8.1Hz), 4.66 (IH, dd, J= 4.6, 4.6Hz), 4.58 (IH, dd, J= 4.7, 7.8Hz), 3.00-2.94 (IH, m), 2.62-2.40 (3H, m), 2.41 (3H, s), 1.60-1.52 (2H, m); 13C NMR (400MHz, CDC13) δ 144.3, 143.2, 137.7, 133.8, 132.2, 130.7, 129.5, 129.5, 128.6,
128.2, 127.8, 127.1, 127.1, 127.0, 125.8, 123.3, 116.4, 111.7, 57.1, 53.9, 43.0, 28.0, 22.2, 21.5. Anal. Calcd for C26H26N2O2S: C, 72.53; H, 6.09; N, 6.51. Found: C, 72.55; H, 6.11 ; N, 6.50.
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) and indole (117 mg, 1.0 mmol) were added and the solution heated to reflux for 11 hours. The reaction mixture was then concentrated and chromatographed to give 13 (75 mg, 91%) a white solid, mp 132-135°C; 1H NMR (400MHz, CDC13) δ 7.84 (IH, s), 7.70-7.64 (3H, m), 7.24-7.07 (7H, m), 6.95-6.89 (IH, m), 6.65 (IH, d, J= 9.7Hz), 6.57 (IH, d, J= 2.4Hz), 6.50 (IH, d, J= 7.5Hz), 6.09 (IH, dd, J= 5.1, 9.5Hz), 4.99 (IH, d, J= 7.7Hz), 4.54 (IH, dd, J= 2.9, 7.7Hz), 4.26-4.22 (IH, m), 2.38 (3H, s); 13C NMR (400MHz, CDCI3) δ 143.2, 136.5, 132.4, 132.2, 132.2, 129.5, 128.9, 128.7, 128.6, 127.7, 127.1, 127.0, 126.4, 126.3, 122.5, 122.0, 119.5, 119.0, 112.2, 111.2, 56.0, 38.8, 21.5. HRMS calcd for C25H22N2O S (M+): 414.1402. Found: 414.1407.
14
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) was then added followed by triethylamine hydrochloride (138 mg, 1.0 mmol) and pyrrolidine (83 μl, 1.0 mmol). The resulting heterogeneous mixture was heated to reflux for 14 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 14 (70 mg, 96%o) a white solid. The regiochemistry and relative stereochemistry was proven by X-ray diffraction. 1H NMR (400MHz, CDCI3) δ 7.74 (2H, d, J= 8.3Hz), 7.30 (2H, d, J= 8.2Hz), 7.22-7.17 (IH, m), 7.08-7.02 (2H, m), 6.84 (IH, d, J= 7.5Hz), 6.61 (IH, d, J= 9.7Hz), 5.93 (IH, dd, J= 4.9, 9.7Hz), 4.70 (IH, br s), 4.45 (IH, d, J= 3.7Hz), 3.89 (IH, dd, J= 4.2, 4.2Hz), 2.58-2.49 (2H, m), 2.45 (3H, s), 2.36-2.29 (2H,
m), 1.63-1.58 (4H, m); Anal. Calcd for C2ιH24N2O2S: C, 68.45; H, 6.56; N, 7.60. Found: C, 68.51; H, 6.62; N, 7.55.
15 To a round bottomed flask was added 4 (66 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) was then added followed by triethylamine hydrochloride (138 mg, 1.0 mmol) and pyrrolidine (83 μl, 1.0 mmol). The resulting heterogeneous mixture was heated to reflux for 16 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 15 (67 mg, 84%) a white solid, mp 142-145°C; 1H NMR (400MHz, CDC13) δ 8.30 (2H, d, J= 8.8Hz), 7.99 (2H, d, J= 8.8Hz), 7.24-7.18 (IH, m), 7.10-7.04 (2H, m), 6.95-6.90 (IH, m), 6.63 (IH, d, J= 9.9Hz), 5.93 (IH, dd, J= 4.7, 9.7Hz), 5.20- 4.80 (IH, br s), 4.60 (IH, d, J= 3.8Hz), 3.40-3.35 (IH, m), 2.58-2.50 (2H, m), 2.43-2.34 (2H, m), 1.64-1.57 (4H, m); 13C NMR (400MHz, CDC13) δ 149.8,147.1, 132.8, 131.9, 129.7, 128.8, 128.2, 128.1, 128.0, 127.1, 125.0, 124.1, 61.4, 54.4, 50.0, 23.4. Anal. Calcd for C20H21N3O4S: C, 60.13; H, 5.30; N, 10.52. Found: C, 60.16; H, 5.33; N, 10.50.
16
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) was then added followed by triethylamine (140 μl, 1.0 mmol) and piperidine hydrochloride (121 mg, 1.0 mmol). The resulting heterogeneous mixture was heated to reflux for 14 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 16 (72 mg, 94%>) a white solid, mp 116-117°C; 1H NMR (400MHz, CDC13) δ 7.75 (2H, d, J= 8.2Hz), 7.30 (2H, d, J= 7.8Hz), 7.21-7.18 (IH, m), 7.10-7.05 (IH, m), 7.04 (IH, d, J= 7.5Hz), 6.94 (IH, d, J= 7.5Hz), 6.61 (IH, dd, J= 1.0, 9.7Hz), 5.91 (IH, dd, J= 4.8, 9.7Hz), 4.82 (IH, s (br)), 4.53 (IH, d, J= 4.4Hz), 3.38-3.35 (IH, m), 2.44 (3H, s), 2.41-2.34 (2H, m), 2.16-2.09 (2H, m), 1.40-1.26 (6H, m); 13C NMR (400MHz, CDCI3)
δ 143.3, 137.7, 134.2, 132.2, 129.6, 129.4, 128.2, 128.0, 127.7, 127.2, 126.6, 125.0, 64.2, 50.9, 49.6, 26.2, 24.3, 21.5. HRMS calcd for C22H26N2O2S (M+): 382.1715. Found: 382.1713.
17 To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (2 ml) was then added followed by triethylamine hydrochloride (138 mg, 1.0 mmol) and tetrahydroisoqinoline (125 μl, 1.0 mmol). The resulting heterogeneous mixture was heated to reflux for 15 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 17 (70 mg, 81%>) a white solid, mp 142-146°C; Η NMR (400MHz, CDC13) δ 7.73 (2H, d, J= 8.2Hz), 7.26-7.18 (3H, m), 7.12-6.98 (5H, m), 6.90 (IH, d, J= 8.1Hz), 6.80 (IH, d, J= 6.8Hz), 6.67 (IH, d, J= 9.7Hz), 5.95 (IH, dd, J= 4.7, 9.7Hz), 4.80 (IH, s), 4.62 (IH, s), 3.68 (IH, AB, d, J= 15.0Hz), 3.63 (IH, dd, J= 4.5, 4.5Hz), 3.40 (IH, AB, d, J= 15.0Hz), 2.68-2.56 (4H, m), 2.40 (3H, s); 13C NMR (400MHz, CDC13) δ 143.4, 137.7, 137.7, 134.1, 133.8, 132.2, 129.9, 129.6, 128.6, 128.5, 128.3, 127.9, 127.2, 126.8, 126.5, 125.9, 125.4, 124.6. Anal. Calcd for C26H26N2O2S: C, 72.53; H, 6.09; N, 6.51. Found: C, 72.56; H, 6.12; N, 6.50.
18
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) was then added followed by triethylamine hydrochloride (138 mg, 1.0 mmol) and potassium acetate (98 mg, 1.0 mmol). The resulting heterogeneous mixture was heated to reflux for 15 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 18 (63 mg, 88%) a white solid. Η NMR (400MHz, CDCI3) δ 7.77 (2H, d, J= 8.3Hz), 7.31(2H, d, J= 8.2Hz), 7.27-7.22 (IH, m), 7.19-7.07 (3H, m), 6.54 (IH, d, J= 10.2Hz), 5.88 (IH, dd, J= 3.7, 10.2Hz), 5.48 -5.44 (IH, m), 4.90 (IH, d, J= 8.4Hz), 4.74-4.69 (IH, m), 2.44 (3H, s), 1.78 (3H, s); 13C NMR (400MHz, CDC13) δ 170.6, 143.4, 138.2, 132.8, 131.9, 130.3, 129.7, 128.7, 128.5, 127.4, 127.1, 127.1, 125.0, 71.0, 55.7,
21.5, 20.7. Anal. Calcd for C,9H19NO4S: C, 63.85; H, 5.36; N, 3.92. Found: C, 63.88; H, 5.40; N, 3.81.
19 To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) was then added followed by triethylamine (140 μl, 1.0 mmol) and benzoic acid (122 mg, 1.0 mmol). The resulting homogeneous solution was heated to reflux for 15 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 19 (73 mg, 87%) a white solid, mp 158-162°C; Η NMR (400MHz, CDC13) δ 7.77 (2H, d, J= 7.1Hz), 7.65 (2H, d, J= 8.3Hz), 7.56-7.50 (IH, m), 7.40-7.32 (3H, m), 7.30-7.22 (2H, m), 7.11 (IH, dd, J= 1.3, 7.2Hz), 6.98 (2H, d, J= 8.1Hz), 6.56 (IH, dd, J= 1.3, 9.9Hz), 5.93 (IH, dd, J= 3.3, 9.7Hz), 5.79 (IH, ddd, J= 1.7, 3.3, 9.2Hz), 5.12 (IH, d, J= 8.4Hz), 4.90 (IH, dd, J= 8.8, 8.8Hz), 2.19 (3H, s); 13C NMR (400MHz, CDC13) δ 166.4, 143.3, 138.0, 133.4, 133.3, 132.3, 130.4, 130.0, 129.7, 128.8, 128.8, 128.3, 127.5, 127.2, 126.9, 125.7, 72.3, 56.8, 21.6. HRMS calcd for C24H21NO4S (M+): 419.1191. Found: 419.1997.
20
To a round bottomed flask was added 3 (60 mg, 0.2 mmol), [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), and DPPF (5.5 mg, 0.01 mmol). THF (1 ml) was then added followed by triethylamine (140 μl, 1.0 mmol) and pivalic acid (102 mg, 1.0 mmol). The resulting homogeneous solution was heated to reflux for 15 hours. Upon completion, the reaction mixture was concentrated and chromatographed to give 20 (61 mg, 77%) a white solid. Η NMR (400MHz, CDC13) δ 7.75 (2H, d, J= 8.0Hz), 7.28 (2H, d, J= 8.0Hz), 7.16-7.00 (3H, m), 6.85 (IH, d, J= 7.6Hz), 6.55 (IH, d, J= 9.7Hz), 5.91 (IH, dd, J= 4.1, 9.7Hz), 5.34 (IH, dd, J= 5.9, 5.9Hz), 4.98 (IH, d, J= 8.4Hz), 4.70 (IH, dd, J= 7.3, 7.3Hz), 2.42 (3H, s), 1.07 (9H, s). HRMS calcd for C22H25NO4S (M+): 399.1504. Found: 399.1507.
21
To a round bottomed flask was added 21 (100 mg, 0.27 mmol) and potassium carbonate (1 12 mg, 0.81 mmol). Acetone (3 ml) was then added followed by iodomethane (18 μl, 0.28 mmol). The mixture was stirred at room temperature for 4 hours then quenched with water. Extraction with ethylacetate, combining of the organic fractions and concentration gave a light yellow solid. Chromatography gave pure 21 (101 mg, 98%) a white crystalline solid, mp 109- 111°C; Η NMR (400MHz, CDC13) δ 7.86 (2H, d, J= 8.0Hz), 7.31 (2H, d, J= 8.0Hz), 7.26-7.12 (3H, m), 7.06 (IH, d, J- 6.9Hz), 6.58 (IH, d, J= 9.7Hz), 5.95 (IH, dd, J= 4.6, 9.9Hz), 5.35 (IH, d, J= 4.5Hz), 3.42 (IH, dd, J= 4.5, 4.5Hz), 2.62-2.48 (4H, m), 2.50 (3H, s), 2.45 (3H, s), 1.70- 1.63 (4H, m); 13C NMR (400MHz, CDC13) δ 143.0, 137.7, 133.6, 132.1, 129.5, 129.1, 128.9, 128.2, 128.1, 127.4, 126.5, 125.9, 58.2, 56.5, 48.6, 29.6, 23.5, 21.5. Anal. Calcd for C22H26N2O2S: C, 69.08; H, 6.85; N, 7.32. Found: C, 69.14; H, 6.91; N, 7.30.
22 To a round bottomed flask was added 21 (100 mg, 0.26 mmol), ethylacetate (2 ml) and palladium on carbon (5mg). Hydrogen was added over this heterogeneous mixture via balloon for 15 hours. Upon completion, the mixture was filtred through celite and concentrated to give 22 a white solid. Crude Η NMR showed that this crude product was >95% pure. Further purification could be obtained by chromatography giving pure 22 (98 mg, 98%>). mp 109-110°C; Η NMR (400MHz, CDC13) δ 7.99 (2H, d, J= 8.1Hz), 7.30 (2H, d, J= 8.3Hz), 7.15-7.02 (4H, m), 5.29 (IH, d, J= 8.1Hz), 3.03-2.67 (5H, m), 2.65-2.52 (2H, m), 2.44 (3H, s), 2.43 (3H, s), 2.05- 1.96 (lH, m), 1.90-1.80 (lH, m), 1.72-1.64 (4H, m); 13C NMR (400MHz, CDCl3) δ 142.8, 138.5, 137.5, 133.9, 129.2, 128.5, 127.7, 127.1, 126.4, 60.0, 59.3, 48.7, 30.3, 27.9, 23.6, 21.5, 21.4. Anal. Calcd for C22H28N2O2S: C, 68.72; H, 7.34; N, 7.29. Found: C, 68.79; H, 7.37; N, 7.22.
23 To a quartz tube was added 22 (80 mg, 0.2 mmol), 1,4-dimethoxybenzene (110 mg, 0.8 mmol) and sodium borohydride (76 mg, 2.0 mmol) followed by 90% aqueous ethanol solution (3 ml). The mixture was irradiated at 254 nm in a rayonet reactor for 2.5 hours. The crude mixture was concentrated azeotropically with ethanol and then chromatographed (90%) acetone, 9% MeOH, 1% triethylamine) to give 23 (42 mg, 91%). Spectral data was identical to the literature data.
To a round bottomed flask was added 16 (100 mg, 0.25 mmol) and potassium carbonate (112 mg, 0.81 mmol). Acetone (3 ml) was then added followed by iodomethane (18 μl, 0.28 mmol). The mixture was stirred at room temperature for 4 hours then quenched with water. Extraction with ethylacetate, combining of the organic fractions and concentration gave a light yellow solid. Chromatography gave pure 24 (101 mg, 98%>) a white crystalline solid, mp 139- 141°C; Η NMR (400MHz, CDC13) δ 8.35 (2H, d, J= 8.8Hz), 8.22 (2H, d, J= 8.8Hz), 7.28-7.22 (3H, m), 7.09 (IH, d, J= 6.2Hz), 6.60 (IH, d, J= 9.9Hz), 5.95 (IH, dd, J= 4.0, 9.9Hz), 5.43 (IH, d, J= 6.6Hz), 3.54-3.49 (IH, m), 2.62 (3H, s), 2.60-2.54 (4H, m), 1.72-1.66 (4H, m); 13C NMR (400MHz, CDC13) δ 149.8, 146.6, 133.6, 131.6, 129.5, 128.6, 128.3, 128.0, 126.8, 125.3, 124.0, 58.4, 58.0, 48.5, 29.8, 23.7. Anal. Calcd for C2ιH23N3O4S: C, 61.00; H, 5.61; N, 10.16. Found: C, 61.1 1 ; H, 5.65; N, 10.12.
25 To a round bottomed flask was added 18 (70 mg, 0.20 mmol) and potassium carbonate
(1 10 mg, 0.80 mmol). Acetone (2.5 ml) was then added followed by iodomethane (15 μl, 0.24
mmol). The mixture was stirred at room temperature for 4 hours then quenched with water. Extraction with ethylacetate, combining of the organic fractions and concentration gave a light yellow solid. Chromatography gave pure 25 (67 mg, 91%) a white crystalline solid, mp 113- 116°C; 1H NMR (400MHz, CDC13) δ 7.78 (2H, d, J= 8.2Hz), 7.32 (2H, d, J= 8.2Hz), 7.25-7.17 (2H, m), 7.13-6.98 (2H, m), 6.46 (IH, dd, J= 1.8, 9.9Hz), 5.85 (IH, dd, J= 2.9, 9.9Hz), 5.71 (IH, ddd, J= 2.0, 2.6, 10.1Hz), 5.60 (IH, d, J= 10.1Hz), 2.69 (3H, s), 2.44 (3H, s), 1.90 (3H, s); 13C NMR (400MHz, CDC13) δ 170.2, 143.4, 137.3, 133.2, 131.4, 129.6, 129.2, 128.4, 128.3, 127.1, 126.7, 126.4, 69.7, 60.0, 29.5, 21.4, 20.8. Anal. Calcd for C20H2,NO4S: C, 64.67; H, 5.70; N, 3.77. Found: C, 64.75; H, 5.77; N, 3.72.
Abbreviations
ee "enantiomerically enriched," or '"enantiomeric enrichment"
THF tetrahydrofuran
DPPE 1 ,2-bis(diphenylphosphino)ethane
BINAP 2,2 '-bis(diphenylphosphino)- 1 , 1 '-binaphthyl
Claims
What is Claimed is:
A compound according to formula I:
wherein R is selected from the group consisting of:
(a) H;
(b) a Cι-C6 straight or branched alkyl;
(c) a straight or branched C2-C6 alkenyl;
(d) -(CH2)nRι, wherein Ri is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO2; I; Br; a C1-C3 alkyl; and a C1-C3 alkoxy wherein n=0-3;
(e) -C(O)R2, wherein R is selected from the group consisting of: H; -(CH2)nRι, wherein Ri is as described above and n=0-3; and -(CH2)nC(O)R3, wherein R3 is a Cι-C6 straight or branched alkyl and n=0-3;
(f) -C(O)(CH2)p-C(O)-O-R4, wherein R4 is a straight or branched d-C6 alkyl and wherein p=0-3;
(g) -RCj(CF3)J, wherein Rd is a C1-C3 straight or branched alkyl and j=l-3; (h) -(CH2)rTMS, wherein TMS is trimethylsilyl, and j=l-3
wherein X and Y are independently selected from the group consisting of H; NH2; F; CI; Br; a C,-C3 alkyl; and a C C3 alkoxy; or wherein the combination XY or YY together form a C3-C-3 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and
wherein Z is selected from O or NRa, wherein Ra is selected from: (i) phenyl;
0") (O)C-O-Rb , wherein R is a straight or branched Ci- , alkyl;
CO -SO2-Rc, wherein Rc is selected from the group consisting of: i) Cι-C6 straight or branched alkyl; ii) -(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO2; CN;I; Br; a straight or branched Cι-C3 alkyl; a C1-C3 alkoxy; and -C(O)Rf, wherein Rt is a C1-C3 alkyl; -(CH2)rCF3, wherein r=0-3; iii) -Rg(CF3)s, wherein Rg is a C1-C3 straight or branched alkyl and s=l-3; iv) -(CH2)S-TMS, wherein TMS = trimethylsilyl and s= 1-3;
(1) -SO2-(CH2)q- Si(CH3)3 wherein q is 1-3.
2. A compound according to claim 1, wherein R is -(CH2)nRι and R> is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: CI; F; NO2; I; Br; a C1-C3 alkyl; and a C>-C3 alkoxy and wherein n=0-3.
3. A compound according to formula II:
(a) a Cι-C6 straight or branched alkyl;
(b) -(CH2)qR5, wherein q=0-3 and R5 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a straight or branched C1-C3 alkyl; a C,-C3 alkoxy; Br; I; CI; CN; F; NO2; -(CH2)rCF3, wherein r=0-3; and -C(O)R6, wherein R6 is a C1-C3 alkyl;
(c) -R (CF3)S, wherein R is a C1-C3 straight or branched alkyl and s=l-3;
(d) -(CH2)S-TMS , wherein TMS=trimethylsilyl and s= 1 -3 ;
wherein X and Y are independently selected from the group consisting of H; NH2; F; CI; Br; a C1-C3 alkyl; and a C1-C3 alkoxy;
or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C0 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and wherein Z is selected from O or NRa, wherein Ra is selected from:
(e) phenyl;
(f) (O)C-O-Rb , wherein Rb is a straight or branched Cι-C6 alkyl;
(g) -SO2-Rc, wherein Re is selected from the group consisting of: i) Ci -C6 straight or branched alkyl; ii) -(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: CI; F; NO2; CN;I; Br; a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; and -C(O)Rf, wherein Rf is a Cι-C3 alkyl; -(CH2)rCF3, wherein r=0-3; iii) -Rg(CF3)s, wherein Rg is a C1-C3 straight or branched alkyl and s=l-3; iv) -(CH2)s-TMS , wherein TMS = trimethylsilyl and s= 1 -3 ; (h) -SO2-(CH2)q- Si(CH3)3 wherein q is 1-3.
4. A compound according to claim 3, wherein R is -(CH2)qR5 wherein q=0-3 and R5 is a
C3-C6 aryl optionally substituted at one or more positions with a group selected from: a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; I; CI; CN; F; NO2; -(CH2)rCF3, wherein r=0-3; and -C(O)R6, wherein R is a C1-C3 alkyl.
A compound according to formula III:
wherein: a) in which R8 is H or CH3; b) t=0-3 c) R is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; CI; F; ΝO2; and CF3; or R9 together with N form a ring structure selected from: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; said ring structure being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; CI; F; NO2; and CF3; d) X and Y are independently selected from the group consisting of H; NH ; F; CI; Br; a C1-C3 alkyl; and a C1-C3 alkoxy; or wherein the combination XY or YY together form a C3-C3 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; e) Z is selected from O or NRa, wherein Ra is selected from: (i) a straight or branched Cι-C6 alkyl;
(ii) phenyl;
(iii) (O)C-O-R , wherein Rb is a straight or branched Cι-C6 alkyl;
(iv) -SO2-Rc, wherein Re is an unsubstituted phenyl or a phenyl substituted with a C1-C3 alkyl or NO2; and (v) -SO2-(CH2)q- Si(CH3)3 wherein q isl-3; and f) when Z is O, Rι0 is H; when Z is NRa, Rι0 is either H or CH3.
7. The compound of claim 6, wherein R8 is H and R9 together with N form a ring selected from the group consisting of a phthalamide ring; a pyrrolidine ring; a piperidine ring; a
tetrahydroquinoline ring; and an indole ring; said ring structure being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; CI; F; NO2; and CF3
8. The compound of any one of claims 1-7, wherein X=H and Y=H.
9. A pharmaceutical composition comprising a compound according to any one of claims 1,
3, 5, or 6.
10. A method of treating a patient for pain, comprising administering to said patient an effective amount of the pharmaceutical compound of claim 9.
11. A method of treating a patient for Parkinson's disease, comprising administering an effective amount of the pharmaceutical composition of claim 9.
12. A method of treating a patient for cancer, comprising administering an effective amount of the pharmaceutical compound of claim 9.
13. A method of treating a patient for AIDS, comprising administering an effective amount of the pharmaceutical compound of claim 9.
14. A compound selected from the group consisting of: (lS,2S)-2-methoxy- 1,2-dihydro-naphthalen-l-ol; ( 1 S,2S)-2-(ethoxy)- 1 ,2-dihydro-naphthalen- 1 -ol; (lS,2S)-2-(isopropoxy)-l,2-dihydro-naphthalen-l-ol; ( 1 S ,2S)-2-( 1 -propenyloxy)- 1 ,2-dihydro-naphthalen- 1 -ol; (lS,2S)-2-(2-trimethylsilyl-ethoxy)l,2-dihydro-naphthalen-l-ol; (1 S,2S)-2-benzyloxy- 1 ,2-dihydro-naphthalen- 1 -ol; (lS,2S)-2-(4-methoxybenzyloxy)-l,2-dihydro-naphthalen-l-ol; (lS,2S)-2-(2,2,2-trifluoro-ethoxy)-l,2-dihydro-naphthalen-l-ol; ( 1 S,2S)-2-(2,2,2-trifluoro- 1 -trifluoromethyl-ethoxy)- 1 ,2-dihydro-naphthalen- 1 -ol; ( 1 S,2S)-6,7-difluoro-2-methoxy- 1 ,2-dihydro-naphthalen- 1 -ol; (lS,2S)-6-methoxy-5,6-dihydro-naphthol[2,3-d][l,3]dioxol-5-ol; (lS,2S)-6,7-dibromo-2-methoxy-5,8-dimethyl- 1,2-dihydro-naphthalen-l-ol;
(lR*,2R*)-acetic acid 1 -hydroxy- 1 ,2-dihydro-naphthalen-2-yl-ester;
( 1 R* ,2R*)-propionic acid 1 -hydroxy- 1 ,2-dihydro-naphthalen-2-yl-ester ;
(lR,2R)-benzoic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester;
(lR*,2R*)-formic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester;
(lR*,2R*)-2-methyl acrylic acid l-hydroxy-l,2-dihydro-naphthalen-2-yl-ester;
(lR*,2R*)-malonic acid ethyl ester (1 -hydroxy- 1 ,2-dihydro-naphthalen-2-yl) ester;
( 1 R* ,2R*)-malonic acid ( 1 -tert-butylbimethylsiloxy- 1 ,2-dihydro-naphthalen-2-yl) ethyl ester;
(1 S*,2S*)4-tert-butyldimethylsiloxy-l ,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester;
(lR,2R)-2-(l-hydroxy-l,2-dihydro-naphthalen-2-yl)-isoindole-l,3-dione;
(lS,2S)-N-(l-hydroxy-l,2-dihydro-naphthalen-2-yl)-benzene sulfonamide;
( lR*,2R*)-2-pyrrolidin- 1 -yl- 1 ,2-dihydro-naphthalen- 1 -ol;
( 1 R* ,2R*)-2-piperidin- 1 -yl- 1 ,2-dihydro-naphthalen- 1 -ol;
(lR,2R)-2-(3,4-dihydro-2H-quinolin-l-yl)-l,2-dihydro-naphthalen-l-ol;
(lR,2R)-2-(methyl-phenyl-amino)-l,2-dihydro-naphthalen-l-ol;
(lR*,2R*)-2-benzylamino- 1,2-dihydro-naphthalen-l-ol;
(lR*,2R*)-2-(4-methoxy-benzylamino)- 1,2-dihydro-naphthalen-l-ol;
(lR,2R)-2-indol-l-yl-l,2-dihydro-naphthalen-l-ol;
(lS*,2R*)-2-(hydroxy-l,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester;
( 1 S,2S)-2-phenoxy- 1 ,2-dihydro-naphthalen- 1 -ol;
(lS,2S)-2-(4-nitrophenoxy)-l,2-dihydro-naphthalen-l-ol;
(lS,2S)-2-(4-cyanophenoxy)-l,2-dihydro-naphthalen-l-ol;
( 1 S,2S)-2-(4-acylphenoxy)- 1 ,2-dihydro-naphthalen- l-ol;
( 1 S,2S)-2-(4-trifluoromethylphenoxy)- 1 ,2-dihydro-naphthalen- 1 -ol;
(lS,2S)-2-(4-fluorophenoxy)-l,2-dihydro-naphthalen-l-ol;
(lS,2S)-2-(4-chlorophenoxy)- 1,2-dihydro-naphthalen-l-ol;
(lS,2S)-2-(4-iodophenoxy)-l,2-dihydro-naphthalen-l-ol;
(lR,2R)-2-(4-bromo-phenoxy)- 1,2-dihydro-naphthalen-l-ol;
(lS,2S)-2-(4-methylphenoxy)-l,2-dihydro-naphthalen-l-ol;
( 1 S,2S)-2-(4-methoxyphenoxy)- 1 ,2-dihydro-naphthalen- 1 -ol; and
( 1 S,2S)-2-(2-bromophenoxy)- 1 ,2-dihydro-naphthalen- l-ol.
4-methyl-N-[(lΛ,2S)-2-(l-piperidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide;
N-[( 1 R,2S)-2-(3 ,4-dihydro- 1 (2H)-quinolinyl)- 1 ,2-dihydro- 1 -naphthalenyl] -4- methylbenzenesulfonamide;
N-[(li?,2S)-2-(3,4-dihydro-2(lH)-isoquinolinyl)-l,2-dihydro-l-naphthalenyl]-4- methylbenzenesulfonamide; N-[(lE,2S)-2-(lH-indol-l-yl)-l,2-dihydro-l-naphthalenyl]-4-methylbenzenesulfonamide;
( lE,2S)-2-methoxy-N-phenyl- 1 ,2-dihydro- 1 -naphthalenamine; tert-butyl ( lE,2S)-2-methoxy- 1 ,2-dihydro- 1 -naphthalenylcarbamate;
N-[(li?,2S)-2-methoxy-l,2-dihydro-l-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide;
N,4-dimethyl-N-[( \R,2S)-2-( 1 -pyrrolidinyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl] - benzenesulfonamide;
N,4-dimethyl-N-[(lE,2S)-2-( 1 -pyrrolidinyl)- 1 ,2-dihydro- 1 -naphthalenyl] - benzenesulfonamide;
N-hydroxy-4-( {methyl[( lE,2S)-2-(l -pyrrolidinyl)- 1 ,2-dihydro- 1 - naphthalenyl] amino} sulfonyl) -N-oxobenzenaminium; N-methyl-4-nitro-N-[(lE,2S)-2-(l-pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]- benzenesulfonamide;
(lE:,2S)-N-methyl-2-(l-pyrrolidinyl)-l,2,3,4-tetrahydro-l-naphthalenamine;
N-[( lE,2S)-2-methoxy- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl]-4-methylbenzenesulfonamide;
N-[(lE,2S)-2-methoxy-l,2,3,4-tetrahydro-l-naphthalenyl]-4-methylbenzenesulfonamide; 4-methyl-N-[(lE,2S)-2-phenoxy-l,2,3,4-tetrahydro-l-naphthalenyl]benzenesulfonamide;
(\R,2S)-\-{ [(4-methylphenyl)sulfonyl] amino} - 1 ,2,3 ,4-tetrahydro-2-naphthalenyl acetate;
(lE,25)-l-{[(4-methylphenyl)sulfonyl]amino}-l,2-dihydro-2-naphthalenyl benzoate;
( 1E,2S)- 1 - { [(4-methylphenyl)sulfonyl] amino} - 1 ,2-dihydro-2-naphthalenyl pivalate;
N-[(lE,2S)-2-methoxy-l,2-dihydro-l-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide; tert-butyl (li?,2S)-2-methoxy-l,2-dihydro-l -naphthalenylcarbamate; and
4-nitro-N-[(lE,2S)-2-(l-pyrrolidinyl)-l,2-dihydro-l-naphthalenyl]benzenesulfonamide.
15. A pharmaceutical composition comprising a compound according to claim 14.
16. A method of treating a patient for pain, comprising administering to said patient an effective amount of the pharmaceutical of claim 15.
17. A method of treating a patient for Parkinson's Disease, comprising administering to said patient an effective amount of the pharmaceutical composition of claim 15.
18. A method of treating a patient for cancer, comprising administering to said patient an effective amount of the pharmaceutical composition of claim 15.
19. A method of treating a patient for AIDS, comprising administering to said patient an effective amount of the pharmaceutical composition of claim 15.
20. A process for preparing a compound according to formula I of claim 1, comprising reacting a compound of formula ROH with a compound of formula V:
21. The process of claim 20, wherein said phosphine ligand is selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-PtBu2.
22. A process for preparing a compound according to formula II of claim 3, comprising reacting a compound of formula ROH with a compound of formula V:
23. The process of claim 22, wherein said phosphine ligand is (S)-(R)-PPF-P(Bu2.
24. A process for preparing a compound according to formula III of claim 5, comprising:
(a) preparing a compound of formula I according to the process of claim 20; and
(b) reacting the compound foπned in step (a) with a salt of tert- butyldimethylsilylic acid.
25. A process for preparing a compound of formula IN according to claim 6, comprising reacting a compound of formula R9-(CH2)tΝHR8 with a compound of formula V
wherein R8, R9, t, X, Y, and Z are as defined in claim 6 and wherein said reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand.
26. The process of claim 25, wherein said phosphine ligand is selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-PlBu2.
27. The process of claim 26, wherein R9 together with N form a ring selected from the group consisting of: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; said ring structure being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a Cι-C3 alkoxy; CI; F; NO2; and CF3.
28. The process of claim 22, wherein said compound of formula II is (lS,2S)-2 -methoxy- 1,2- dihydro-naphthalen-l-ol, and said compound of formula ROH is methanol.
29. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(ethoxy)- 1,2- dihydro-naphthalen-l-ol, and said compound of formula ROH is ethanol.
30. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-isopropoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is isopropanol.
31. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-l- propenyloxy)- 1,2-dihydro-naphthalen-l-ol, and said compound of formula ROH is allyl alcohol.
32. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(2- trimethylsilyl-ethoxy)- 1,2-dihydro-naphthalen-l-ol, and said compound of formula ROH is trimethylsilylethanol.
33. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-benzyloxy- 1,2-dihydro-naphthalen-l-ol, and said compound of formula ROH is benzylalcohol.
34. The process of claim 22, wherein said compound of formula π is (lS,2S)-2-4- methoxybenzyloxy- 1,2-dihydro-naphthalen-l-ol, and said compound of formula of ROH is anisylalcohol.
35. The method of claim 22, wherein said compound of formula II is (lS,2S)-2-(2,2,2- trifluoro-ethoxy)- 1,2-dihydro-naphthalen-l-ol, and said compound of formula ROH is trifluoroethanol.
36. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(2,2,2- trifluoro-l-trifluoromethyl-ethoxy)-l,2-dihydro-naphthalen-l-ol and said compound of formula ROH is hexafluoroisopropanol.
37. The process of claim 22, wherein said compound of formula II is (lS,2S)-6,7-difluoro-2- methoxy- 1,2-dihydro-naphthalen-l-ol and wherein said compound of formula ROH is methanol.
38. The method of claim 22, wherein said compound of formula II is (lS,2S)-6-methoxy-5,6- dihydro-naphtho[2,3-d][l,3]dioxol-5-ol and wherein said compound of formula ROH is methanol.
39. The method of claim 22, wherein said compound of formula II is (lS,2S)-6,7-dibromo-2- methoxy-5,8-dimethyl-l,2-dihydro-naphthalen-l-ol and said compound of formula ROH is methanol.
40. The process of claim 20, wherein said compound of formula I is (lR*,2R*)-acetic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl ester and said compound of formula ROH is acetic acid.
41. The process of claim 20, wherein said compound of formula I is (lR*,2R*)-propionic acid 1 -hydroxy- 1, 2— dihydro-naphthalen-2-yl ester and said compound of formula ROH is propionic acid.
42. The process of claim 20, wherein said compound of formula I is (lR,2R)-benzoic acid 1- hydroxy-l,2-dihydro-naphthalen-2-yl-ester and said compound of formula ROH is benzoic acid.
43. The process of claim 20, wherein said compound of formula I is (lR*,2R*)-formic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester and said compound of formula ROH is formic acid.
44. The process of claim 20, wherein said compound of formula I is (lR*,2R*)-2-methyl acrylic acid 1 -hydroxy- l,2-dihydro-naphthalen-2-yl-ester and said compound of formula ROH is methacrylic acid.
45. The process of claim 20, wherein said compound of formula I is (lR*,2R*)-malonic acid ethyl-ester (l-hydroxy-l,2-dihydro-naphthalen-2-yl) ester and said compound of formula ROH is ethyl malonic acid.
46. The method of claim 24, wherein said compound of formula III is (lR*,2R*)-malonic acid (1 -tert-butyldimethylsiloxy- 1 ,2-dihydro-naphthalen-2-yl) ester ethyl ester and said compound of formula ROH is tert-butyldimethylsilylic acid.
47. The method of claim 22, wherein said compound of formula II is (1 S,2S)-2-phenoxy- 1 ,2- dihydro-naphthalen-l-ol and said compound of formula ROH is phenol.
48. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- nitrophenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 4- nitrophenol.
49. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- cycanophenoxy)-l,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 4- trifluoromethylphenyl.
50. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- acylphenoxy)-l,2,-dihydro-naphthalen-l-ol and said compound of formula ROH is 4- hydroxyacetophenone.
51. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- trifluoromethylphenoxy)-l,2,-dihydro-naphthalen-l-ol and said compound of formula ROH is 4-trifluoromethylphenyl.
52. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- fluorophenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 4- fluorophenol.
53. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- chlorophenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 4- chlorophenol.
54. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- iodophenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 4- iodophenol.
55. The process of claim 20, wherein said compound of formula I is (lR,2R)-2-(4-bromo- phenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is p- bromophenol.
56. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- methylphenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is p- cresol.
57. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(4- methoxyphenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 4-methoxypheno 1.
58. The process of claim 22, wherein said compound of formula II is (lS,2S)-2-(2- bromophenoxy)- 1,2-dihydro-naphthalen-l-ol and said compound of formula ROH is 2- bromophenol.
59. The process of claim 25, wherein said compound of formula IV is (lR,2R)-2-(l-hydroxy- 1 ,2-dihydro-naphthalen-2-yl) isoindole-l,3-dione and said compound of formula R9- (CH2)SNHR8 is phthalimide.
60. The process of claim 25, wherein said compound of formula IV is (lR*,2R*)-2-pyrrolidin- 1-yl- 1,2-dihydro-naphthalen-l-ol and said compound of formula R9-(CH2)SNHR8 pyrrolidine.
61. The process of claim 25, wherein said compound of formula IN is (lR*,2R*)-2-piperidin- 1-yl- 1,2-dihydro-naphthalen-l-ol and said compound of formula R9-(CH2)SΝHR8 is piperidine.
62. The process of claim 25, wherein said compound of formula IV is (lR,2R)-2-(3,4- dihydro-2H-quinolin- 1-yl)- 1,2-dihydro-naphthalen-l-ol and said compound of formula R -(CH2)SNHR8 is tetrahydroisoquinoline.
63. The process of claim 25, wherein said compound of formula IV is (lR,2R)-2(methyl- phenyl-amino)- 1,2-dihydro-naphthalen-l-ol and said compound of formula R9-
(CH2)SNHR8 is N-methylaniline.
64. The process of claim 25, wherein said compound of formula IV is (lR*,2R*)-2- benzylamino- 1,2-dihydro-naphthalen-l-ol and said compound of formula R9-(CH )SNHR8 is benzylamine.
65. The process of claim 25, wherein said compound of formula IV is (lR*,2R*)-2-(4- methoxy-benzylamino)- 1,2-dihydro-naphthalen-l-ol and said compound of formula R - (CH2)SNHR8 is p-methoxybenzylamine.
66. The process of claim 25, wherein said compound of formula IV is (lR,2R)-2-indol-l-yl- 1 ,2-dihydro-naphthalen- 1 -ol and said compound of formula R9-(CH2)SNHR8 is indole.
67. A process for preparing (lS,2S)-N-(l-hydroxy-l,2-dihydro-naphthalen-2-yl)-benzene sulfonamide, comprising reacting oxabenzonorbornadiene with benzenesulfonamide, wherein said reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand.
68. A process for preparing (lS*,2R*)-2-(hydroxy-l,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester, comprising reacting oxabenzonorbornadiene with dimethyl malonate, wherein said reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand.
Priority Applications (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE60013471T DE60013471T2 (en) | 1999-10-29 | 2000-10-26 | NEW HYDRONAPHTHALENE MADE BY A RHODIUM-CATALYZED RING OPENING REACTION IN THE PRESENCE OF A PHOSPHIN LIGAND |
| SI200030491T SI1228024T1 (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphthalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| AU13206/01A AU776118B2 (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| AT00975109T ATE275120T1 (en) | 1999-10-29 | 2000-10-26 | NEW HYDRONAPHTHALENS PRODUCED BY A RHODIUM-CATALYzed RING-OPENING REACTION IN THE PRESENCE OF A PHOSPHINE LIGAND |
| US09/763,759 US6525068B1 (en) | 1999-10-29 | 2000-10-26 | Hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| BR0015117-3A BR0015117A (en) | 1999-10-29 | 2000-10-26 | Compound, pharmaceutical composition, methods to treat a patient for pain, for parkinson's disease, for cancer, for AIDS, processes for preparing a compound, for preparing (1s, 2s) -n- (1-hydroxy-1 , 2-dihydro-naphthalen-2-yl) - benzene sulfonamide, and to prepare the dimethyl ester of the acid (1s *, 2r *) -2- (hydroxy -1,2-dihydro - naphthalen -2- yl) maleic |
| DK00975109T DK1228024T3 (en) | 2000-10-26 | 2000-10-26 | Novel hydronaphthalene compounds prepared by a rhodium-catalyzed ring-opening reaction in the presence of a phosphine ligand |
| IL14936800A IL149368A0 (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphthalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| JP2001533091A JP2003512446A (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphthalene compounds prepared by rhodium-catalyzed ring opening in the presence of phosphine ligands |
| CA002387675A CA2387675C (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| NZ518451A NZ518451A (en) | 1999-10-29 | 2000-10-26 | A hydronaphtalene ring compound, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| MXPA02004224A MXPA02004224A (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand. |
| EP00975109A EP1228024B1 (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphthalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| NO20021968A NO328015B1 (en) | 1999-10-29 | 2002-04-25 | The novel hydronaphthalene compound prepared by rhodium-catalyzed ring-opening reaction in the presence of phosphine ligand, as well as preparations comprising such compounds |
| IL149368A IL149368A (en) | 1999-10-29 | 2002-04-25 | Hydronaphthalene compounds, pharmaceutical compositions comprising them, use thereof, and their preparation by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| HK02108588.9A HK1047083B (en) | 1999-10-29 | 2002-11-28 | Novel hydronaphthalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| US10/855,783 US7420003B2 (en) | 1999-10-29 | 2004-05-28 | Compounds and a novel process for their preparation |
| US12/219,752 US20080300271A1 (en) | 1999-10-29 | 2008-07-28 | Novel compounds and a novel process for their preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9903930-7 | 1999-10-29 | ||
| SE9903930A SE9903930D0 (en) | 1999-10-29 | 1999-10-29 | Novel compounds and a novel process for their preparation |
Related Child Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/763,759 A-371-Of-International US6525068B1 (en) | 1999-10-29 | 2000-10-26 | Hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
| US09763759 A-371-Of-International | 2000-10-26 | ||
| US10/317,183 Division US6784210B2 (en) | 1999-10-29 | 2002-12-12 | Compound and a novel process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001030734A1 true WO2001030734A1 (en) | 2001-05-03 |
Family
ID=20417551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2000/002090 WO2001030734A1 (en) | 1999-10-29 | 2000-10-26 | Novel hydronaphtalene compounds, prepared by a rhodium catalyzed ring opening reaction in the presence of phosphine ligand |
Country Status (20)
| Country | Link |
|---|---|
| US (4) | US6525068B1 (en) |
| EP (2) | EP1498406A1 (en) |
| JP (1) | JP2003512446A (en) |
| KR (1) | KR100741177B1 (en) |
| CN (1) | CN1231439C (en) |
| AT (1) | ATE275120T1 (en) |
| AU (1) | AU776118B2 (en) |
| BR (1) | BR0015117A (en) |
| CA (1) | CA2387675C (en) |
| DE (1) | DE60013471T2 (en) |
| ES (1) | ES2225253T3 (en) |
| HK (1) | HK1047083B (en) |
| IL (2) | IL149368A0 (en) |
| MX (1) | MXPA02004224A (en) |
| NO (1) | NO328015B1 (en) |
| NZ (1) | NZ518451A (en) |
| PT (1) | PT1228024E (en) |
| SE (1) | SE9903930D0 (en) |
| WO (1) | WO2001030734A1 (en) |
| ZA (1) | ZA200203050B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2852958A1 (en) * | 2003-03-25 | 2004-10-01 | Fournier Lab Sa | New N-heterocycloalkylbenzene sulfonamide derivatives used for treating pain and inflammatory disorders |
| WO2004087700A1 (en) * | 2003-03-25 | 2004-10-14 | Laboratoires Fournier S.A. | Benzenesulphonamide derivatives, method for production and use thereof for treatment of pain |
| WO2006108713A2 (en) * | 2005-04-14 | 2006-10-19 | Schering Aktiengesellschaft | 1-amino-1, 2,3,4-tetrahydro-naphthaline-2-ol derivates as anti-inflammatory agents |
| EP2070903A1 (en) | 2007-12-12 | 2009-06-17 | Laboratorios del Dr. Esteve S.A. | Microwave-assisted ring opening reaction |
| EP2070904A1 (en) | 2007-12-12 | 2009-06-17 | Laboratorios Del. Dr. Esteve, S.A. | Rhodium-phosphorus complexes and their use in ring opening reactions |
| EP2098511A1 (en) | 2008-03-07 | 2009-09-09 | Solvias AG | Process for preparing compounds containing a hydronaphtalene structure with an unsymmetrically substituted benzene ring |
| US7638515B2 (en) | 2003-10-08 | 2009-12-29 | Bayer Schering Pharma Aktiengesellschaft | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
| US7659297B2 (en) | 2003-10-08 | 2010-02-09 | Bayer Schering Pharma, AG | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
| US7662821B2 (en) | 2003-10-08 | 2010-02-16 | Bayer Schering Pharma Ag | Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
| US7880042B2 (en) | 2006-03-15 | 2011-02-01 | Bayer Schering Pharma Ag | Tetrahydronaphthalene derivatives, methods for the production thereof, and the use thereof as antiphlogistics |
| US8097627B2 (en) | 2004-04-05 | 2012-01-17 | Bayer Pharma AG | Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents |
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| KR101229822B1 (en) | 2008-03-04 | 2013-02-05 | 연세대학교 산학협력단 | Pharmaceutical Compositions for Inhibiting Angiogenesis |
| JP5656364B2 (en) * | 2009-04-20 | 2015-01-21 | 株式会社トクヤマ | Method for producing naphthopyran derivatives |
| MY163936A (en) * | 2010-01-27 | 2017-11-15 | Takeda Pharmaceuticals Co | Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent |
| JP6236785B2 (en) * | 2012-02-28 | 2017-11-29 | 株式会社リコー | Arylamine compound, organic EL material and method for producing the same |
| CN105399752B (en) * | 2015-11-04 | 2019-03-15 | 云南民族大学 | A kind of new compound and its preparation method and application |
| US11560384B2 (en) | 2017-05-04 | 2023-01-24 | University Of Utah Research Foundation | Benzonorbornadiene derivatives and reactions thereof |
| CN108863855B (en) * | 2018-05-29 | 2020-12-15 | 云南民族大学 | Method for synthesizing (1R,2S) -1,2-dihydronaphthalene-1, 2-diamine derivative |
| CN111471005B (en) * | 2020-05-21 | 2023-04-07 | 南方科技大学 | Indole-dihydronaphthalene compound and preparation method and application thereof |
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| AU4031097A (en) * | 1997-08-27 | 1999-03-16 | Kyowa Hakko Kogyo Co. Ltd. | Process for preparing optically active 1,2-diols |
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| WO2006108713A3 (en) * | 2005-04-14 | 2006-12-14 | Schering Ag | 1-amino-1, 2,3,4-tetrahydro-naphthaline-2-ol derivates as anti-inflammatory agents |
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| EP2070904A1 (en) | 2007-12-12 | 2009-06-17 | Laboratorios Del. Dr. Esteve, S.A. | Rhodium-phosphorus complexes and their use in ring opening reactions |
| EP2070903A1 (en) | 2007-12-12 | 2009-06-17 | Laboratorios del Dr. Esteve S.A. | Microwave-assisted ring opening reaction |
| WO2009109648A1 (en) * | 2008-03-07 | 2009-09-11 | Solvias Ag | Process for preparing compounds containing a hydronaphtalene structure with an unsymmetrically substituted benzene ring |
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