bis(6-methylheptyl) benzene-1,2-dicarboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g (+) Diop (2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg [α]D25 +1.1° C5.5% in CD3CN. An e.e. of about 10% is estimated based on the reported [α]D25 value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products. was added during eight hours was continued overnight The mixture was filtered the filtrate was concentrated to an oil which was diluted with an equal volume of toluene had been formed in approximately equal amounts

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of Complexes using C2 symmetric bis-P ligands (DIOP, BINAP, Cl-MeO-BIPHEP, SEGPHOS, PhanePHOS, DIPAMP, DuPHOS, BDPP, CHIRAPHOS, PPM, PYRPHOS) uses the compound [RuCl2(benzene)], RuCl2(PPh3)3 and trans-RuCl2(NBD)(py)2 as the starting material, while the complexes were prepared in accordance with the procedure published in the literature (Noyori, R.; Takeshi, O.; Hirohito, O. Shohei, H.; Takao, I. J. Am. Chem. Soc. 1995, 117, 2675; Akotsi, O. M.; Meters, K.; Reid, R. D.; McDonald, R.; Bergens, S. H. Chirality 2000, 12, 514-522; BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, DIOP=4,5-Bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane, Cl-MeO-BIPHEP=5,5′-Dichloro-6,6′-dimethoxy-2,2′-bis(diphenylphosphino)-1,1′-biphenyl, SEGPHOS=5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole, PhanePHOS=4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane, DIPAMP=1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane, Me-DuPHOS=1,2-Bis((2S,5S)-2,5-dimethylphospholano)benzene, BDPP=2,4-Bis(diphenylphosphino)pentane, CHIRAPHOS=Bis(diphenylphosphino)butane, PYRPHOS=3,4-bis(diphenylphosphino)-Pyrrolidine, PPM=4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]-Pyrrolidine. Synthesis of Complexes using C1 symmetric bis-P ligand (JosiPHOS, WalPHOS, MandyPHOS) uses the compound RuCl2(PPh3)3 as the starting material which can be obtained easily from hydrated RuCl3 and PPh3 (Steohenson, T. A.; Wilkinson, G. J. Inorg. Nucl. Chem. 1966, 28, 945-956; Josiphos=1-[Diarylphosphano]-2-[1-(dicyclohexylphosphano)ethyl]ferrocene.), while the complexes and RuCl2[(R,S)-Josiphos](PPh3) were prepared in accordance with the procedure published in the literature (Baratta, W.; Ballico, M.; Chelucci, G.; Siega, K.; Rigo, P. Angew. Chem. Int. Ed. 2008, 47, 4362-4365). The monochloride complex (11) was prepared from (10) by reacting with Et3N. The pre-catalysts used for in situ hydrogenation were [RuCl2BINAP(pyridine)2, RuCl2DIOP(pyridine)2, RuCl2(Josiphos)(pyridine)2]. As non-limiting examples of the present invention the synthesis and the characteristics of the complexes (8-25) are described in detail. All the syntheses were carried out under argon atmosphere, using freshly distilled solvents. Synthesis of Complexes while the complexes were prepared in accordance with the procedure Synthesis of Complexes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of Complexes using C2 symmetric bis-P ligands (DIOP, BINAP, Cl-MeO-BIPHEP, SEGPHOS, PhanePHOS, DIPAMP, DuPHOS, BDPP, CHIRAPHOS, PPM, PYRPHOS) uses the compound [RuCl2(benzene)], RuCl2(PPh3)3 and trans-RuCl2(NBD)(py)2 as the starting material, while the complexes were prepared in accordance with the procedure published in the literature (Noyori, R.; Takeshi, O.; Hirohito, O. Shohei, H.; Takao, I. J. Am. Chem. Soc. 1995, 117, 2675; Akotsi, O. M.; Meters, K.; Reid, R. D.; McDonald, R.; Bergens, S. H. Chirality 2000, 12, 514-522; BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, DIOP=4,5-Bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane, Cl-MeO-BIPHEP=5,5′-Dichloro-6,6′-dimethoxy-2,2′-bis(diphenylphosphino)-1,1′-biphenyl, SEGPHOS=5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole, PhanePHOS=4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane, DIPAMP=1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane, Me-DuPHOS=1,2-Bis((2S,5S)-2,5-dimethylphospholano)benzene, BDPP=2,4-Bis(diphenylphosphino)pentane, CHIRAPHOS=Bis(diphenylphosphino)butane, PYRPHOS=3,4-bis(diphenylphosphino)-Pyrrolidine, PPM=4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]-Pyrrolidine. Synthesis of Complexes using C1 symmetric bis-P ligand (JosiPHOS, WalPHOS, MandyPHOS) uses the compound RuCl2(PPh3)3 as the starting material which can be obtained easily from hydrated RuCl3 and PPh3 (Steohenson, T. A.; Wilkinson, G. J. Inorg. Nucl. Chem. 1966, 28, 945-956; Josiphos=1-[Diarylphosphano]-2-[1-(dicyclohexylphosphano)ethyl]ferrocene.), while the complexes and RuCl2[(R,S)-Josiphos](PPh3) were prepared in accordance with the procedure published in the literature (Baratta, W.; Ballico, M.; Chelucci, G.; Siega, K.; Rigo, P. Angew. Chem. Int. Ed. 2008, 47, 4362-4365). The monochloride complex (11) was prepared from (10) by reacting with Et3N. The pre-catalysts used for in situ hydrogenation were [RuCl2BINAP(pyridine)2, RuCl2DIOP(pyridine)2, RuCl2(Josiphos)(pyridine)2]. As non-limiting examples of the present invention the synthesis and the characteristics of the complexes (8-25) are described in detail. All the syntheses were carried out under argon atmosphere, using freshly distilled solvents. Synthesis of Complexes while the complexes were prepared in accordance with the procedure Synthesis of Complexes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g (+) Diop (2,3-0-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg [α]25D +1.1° C5.5% in CD3CN. An e.e. of about 10% is estimated based on the reported [α]25D value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products. was added during eight hours was continued overnight The mixture was filtered the filtrate was concentrated to an oil which was diluted with an equal volume of toluene had been formed in approximately equal amounts

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g (+) Diop (2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg [α]D25 +1.1° C5.5% in CD3CN. An e.e. of about 10% is estimated based on the reported [α]D25 value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products. was added during eight hours was continued overnight The mixture was filtered the filtrate was concentrated to an oil which was diluted with an equal volume of toluene had been formed in approximately equal amounts

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g (+) Diop (2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg α! D25 +1.1° C5.5 % in CD3CN. An e.e. of about 10% is estimated based on the reported α! D25 value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products. was added during eight hours was continued overnight The mixture was filtered the filtrate was concentrated to an oil which was diluted with an equal volume of toluene had been formed in approximately equal amounts

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g (+) Diop (2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg {α})D25 +1.1°C5.5% in CD3CN. An e.e. of about 10% is estimated based on the reported {α}D25 value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products. was added during eight hours was continued overnight The mixture was filtered the filtrate was concentrated to an oil which was diluted with an equal volume of toluene had been formed in approximately equal amounts

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 4 was repeated in which the DTDR was replaced by an equivalent amount of DODDR and the DIOP was replaced by an equivalent amount of (-)-2,3-bis(diphenylphosphinomethyl)-1,4-dioxaspiro[4,4]nonane, prepared by: (a) reacting L-(+)-diethyl tartrate with cyclopentanone in benzene in the presence of p-toluenesulphonic acid to give diethyl 1,4-dioxaspiro[4,4]nonan-2,3-dicarboxylate, b.p. 154°-158° C./6.0 mm., (b) reducing this with lithium aluminium hydride to give (-)-2,3-O-cyclopentylidene-L-threitol, b.p. 124°-130° C./0.2 mm., (c) converting this to (-)-1,4-ditosyl-2,3-O-cyclopentylidene-L-threitol m.p. 109°-115.5° C. by reaction with p-toluenesulphonyl chloride in pyridine and (d) treating with potassium and diphenylphosphine in tetrahydrofuran to give the desired compound m.p. 93°-95° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DIOP (64.8 mg.) was added to a solution of DTDR (46 mg.) in benzene (9 ml.) under nitrogen and the mixture allowed to stand for 15 minutes. This complex was then added to a mixture, prepared by adding ethanol (16 ml.) followed by (-)-α-methylbenzylamine (24 mg.) in ethanol (2 ml.) to the product of Example 2 (0.5 g.), under hydrogen. The reaction mixture was stirred under hydrogen for 51/2 hours at room temperature and then kept under hydrogen overnight. The solution was concentrated under reduced pressure and the residue treated with ether and aqueous 10% potassium carbonate. The ether extract was treated with the potassium carbonate extract, which was then acidified. The oil which separated, solidified and was extracted with ether and the extract dried, filtered, evaporated and the product recrystallised from light petroleum (b.p. 60°-80° C.) to give 2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 101°-103° C., having an optical rotation [α]D20 +35.5° C. representing 89% of the (+) isomer in the product. This complex was then added to a mixture prepared kept under hydrogen overnight The solution was concentrated under reduced pressure the residue treated with ether and aqueous 10% potassium carbonate The ether extract was treated with the potassium carbonate extract The oil which separated was extracted with ether the extract dried filtered evaporated the product recrystallised from light petroleum (b.p. 60°-80° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 4 was repeated in which the DTDR was replaced by an equivalent amount of DODDR and the DIOP was replaced by an equivalent amount of (-)-2,3-bis(diphenylphosphinomethyl)-1,4-dioxaspiro[4,4]nonane, prepared by: (a) reacting L-(+)-diethyl tartrate with cyclopentanone in benzene in the presence of p-toluenesulphonic acid to give diethyl 1,4-dioxaspiro[4,4]nonan-2,3-dicarboxylate, b.p. 154°-158° C./6.0 mm., (b) reducing this with lithium aluminium hydride to give (-)-2,3-O-cyclopentylidene-L-threitol, b.p. 124°-130° C./0.2 mm., (c) converting this to (-)-1,4-ditosyl-2,3-O-cyclopentylidene-L-threitol m.p. 109°-115.5° C. by reaction with p-toluenesulphonyl chloride in pyridine and (d) treating with potassium and diphenylphosphine in tetrahydrofuran to give the desired compound m.p. 93°-95° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DIOP (64.8 mg.) was added to a solution of DTDR (46 mg.) in benzene (9 ml.) under nitrogen and the mixture allowed to stand for 15 minutes. This complex was then added to a mixture, prepared by adding ethanol (16 ml.) followed by (-)-α-methylbenzylamine (24 mg.) in ethanol (2 ml.) to the product of Example 2 (0.5 g.), under hydrogen. The reaction mixture was stirred under hydrogen for 51/2 hours at room temperature and then kept under hydrogen overnight. The solution was concentrated under reduced pressure and the residue treated with ether and aqueous 10% potassium carbonate. The ether extract was treated with the potassium carbonate extract, which was then acidified. The oil which separated, solidified and was extracted with ether and the extract dried, filtered, evaporated and the product recrystallised from light petroleum (b.p. 60°-80° C.) to give 2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 101°-103° C., having an optical rotation [α]D20 +35.5° representing 89% of the (+) isomer in the product. This complex was then added to a mixture prepared kept under hydrogen overnight The solution was concentrated under reduced pressure the residue treated with ether and aqueous 10% potassium carbonate The ether extract was treated with the potassium carbonate extract The oil which separated was extracted with ether the extract dried filtered evaporated the product recrystallised from light petroleum (b.p. 60°-80° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of Complexes using C2 symmetric bis-P ligands (DIOP, BINAP, Cl-MeO-BIPHEP, SEGPHOS, PhanePHOS, DIPAMP, DuPHOS, BDPP, CHIRAPHOS, PPM, PYRPHOS) uses the compound [RuCl2(benzene)], RuCl2(PPh3)3 and trans-RuCl2(NBD)(py)2 as the starting material, while the complexes were prepared in accordance with the procedure published in the literature (Noyori, R.; Takeshi, O.; Hirohito, O. Shohei, H.; Takao, I. J. Am. Chem. Soc. 1995, 117, 2675; Akotsi, O. M.; Meters, K.; Reid, R. D.; McDonald, R.; Bergens, S. H. Chirality 2000, 12, 514-522; BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, DIOP=4,5-Bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane, Cl-MeO-BIPHEP=5,5′-Dichloro-6,6′-dimethoxy-2,2′-bis(diphenylphosphino)-1,1′-biphenyl, SEGPHOS=5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole, PhanePHOS=4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane, DIPAMP=1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane, Me-DuPHOS=1,2-Bis((2S,5S)-2,5-dimethylphospholano)benzene, BDPP=2,4-Bis(diphenylphosphino)pentane, CHIRAPHOS=Bis(diphenylphosphino)butane, PYRPHOS=3,4-bis(diphenylphosphino)-Pyrrolidine, PPM=4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]-Pyrrolidine. Synthesis of Complexes using C1 symmetric bis-P ligand (JosiPHOS, WalPHOS, MandyPHOS) uses the compound RuCl2(PPh3)3 as the starting material which can be obtained easily from hydrated RuCl3 and PPh3 (Steohenson, T. A.; Wilkinson, G. J. Inorg. Nucl. Chem. 1966, 28, 945-956; Josiphos=1-[Diarylphosphano]-2-[1-(dicyclohexylphosphano)ethyl]ferrocene.), while the complexes and RuCl2[(R,S)-Josiphos](PPh3) were prepared in accordance with the procedure published in the literature (Baratta, W.; Ballico, M.; Chelucci, G.; Siega, K.; Rigo, P. Angew. Chem. Int. Ed. 2008, 47, 4362-4365). The monochloride complex (11) was prepared from (10) by reacting with Et3N. The pre-catalysts used for in situ hydrogenation were [RuCl2BINAP(pyridine)2, RuCl2DIOP(pyridine)2, RuCl2(Josiphos)(pyridine)2]. As non-limiting examples of the present invention the synthesis and the characteristics of the complexes (8-25) are described in detail. All the syntheses were carried out under argon atmosphere, using freshly distilled solvents. Synthesis of Complexes while the complexes were prepared in accordance with the procedure Synthesis of Complexes