(R)-(+)-1-(4-PYRIDYL)ETHANOL

White needles

General procedure: BHEXAMPLE 1bR-(+)-α-methyl-4-pyridinemethanolThe same reduction was performed using 1percent of catalyst 10 (1, 3, 2-dioxaborolan-2-yloxy)diphenylmethyl)pyrrolidine. Borane-DMS complex (10M, 1.6 mL, 16.00 mmol) was added to a solution of catalyst 10 (32 mg, 0.10 mmol) in dry THF (5 mL) at room temperature and the mixture was stirred for 1 hour. A solution of 4-acetylpyridine (1.21 g, 10.00 mmol) in THF (5 mL) was added for 5 h using an infusion pump. The reaction mixture was stirred at room temperature for over 1 hour, then cooled to 0° C. and quenched with methanol (10 mL). After refluxing for 12 h, the solvents were removed under vacuum, the residue was distilled (directly without chromatography purification) in a Kugelrohr apparatus under vacuum to give the final product as a white crystalline material (1.135 g, 92percent yield). Chiral GC of O-acetyl derivative indicated 98.8percent ee.; EXAMPLE 1cR-(+)-α-methyl-4-pyrydylmethanolThe same reaction was again performed using 10percent of catalyst 10 (1, 3, 2-dioxaborolan-2-yloxy)diphenylmethyl)pyrrolidine). Borane-DMS complex (10M, 1.7 mL, 17.00 mmol) was added to a solution of catalyst 10 (323 mg, 1.00 mmol) in dry THF (10 mL) at room temperature (during the addition hydrogen evolved) and mixture was stirred for 1 hour. A solution of 4-acetylpyridine (1.21 g, 10.00 mmol) in THF (5 mL) was added for 5 hours using an infusion pump. The reaction mixture was stirred at room temperature for over 1 hour, then cooled to 0° C. and quenched with methanol (10 mL). After refluxing for 12 hours, the solvents were removed under vacuum, the residue was distilled (directly without chromatography purification) in a Kugelrohr apparatus under vacuum to give the final product as white crystalline material (1.077 g, 88percent yield). Chiral GC of O-acetyl derivative indicated 99.0percent ee.EXAMPLE 1aR-(+)-α-methyl-4-pyridylmethanolTo a 100 mL round flask equipped with a septa and nitrogen flow, 10percent of catalyst 6 (0.325 g, 1.0 mmol) was added. Then dry THF (30 mL) was added to make a solution. Borane complex with dimethyl sulfoxide 10.0 M (2.0 mL, 20.00 mmol) was added to the catalyst solution. The mixture was stirred for about 15 minutes. A solution of 4-acetylpyridine (1.211 g, 10.0 mmol) with dry THF (10 mL) was added to the reaction mixture during 1 hour. The reaction was allowed to react overnight. The reaction mixture was cooled to 0° C. MeOH (20 mL) was added and the mixture was heated to reflux for 4 hours. A sample of the mixture was analyzed by Triethylamine (315 mL, 2.26 mol) was added dropwise to formic acid (150 mL, 3.91 mol) with overhead stirring while maintaining the internal temperature below 60° C. with ice-bath cooling. Neat 4-acetylpyridine (100 mL, 0.904 mol) was then added rapidly while maintaining the temperature below 50° C. Following this addition, the reaction was allowed to cool to 28° C. and the chiral ruthenium catalyst [N-[(1R, 2R)-2-(amino-N)-1, 2-diphenylethyl]-2, 4, 6-trimethylbenzenesulfonamidato-N]chloro[(1, 2, 3, 4, 5, 6-n)-1-methyl-4-(1-methylethyl)benzene]ruthenium (CAS No.177552-91-9; for catalyst preparation, see: Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.; J. Am. Chem. Soc. 1996, 118, 4916-4917) (3 g, 4.46 mmol) was added. The mixture was stirred under house vacuum for 4 h and then overnight under an atmosphere of nitrogen. The reaction mixture was added dropwise to a stirred solution of 10percent NaGeneral procedure: Definite quantities of catalyst, chiral diamine, base, solvent, and heteroaromatic methyl ketones were placed into a 60mL stainless steel autoclave equipped with a magnetic stirrer bar. The autoclave was purged with hydrogen three times and the hydrogen pressure was increased to the desired level. The mixture was then stirred at room temperature for a suitable time. At the end of the reaction, the reactor was decompressed. Finally, the products were separated by centrifugation and analyzed by a GC instrument with an FID detector and β-DEX120 capillary column. The ee value was calculated from the equation: ee (percent)=100×(S−R)/(S+R).A mixture of (±)-1g (50.3mg, 0.41mmol), vinyl acetate (53.8mg, 0.61mmol), and PYGeneral procedure: BH3·SMe2 (2.0 M in toluene, 250 muL, 500 mumol) was added to a solution of the B-alkoxy oxazaborolidine 8 (7.43 mg, 25.0 mumol in toluene (1 mL), prepared prior to use according to procedure 1.2.6). After 15 min at 50 C, the reaction mixture was adjusted to 20 C and a solution of acetophenone (1a, 60.1 mg, 58.3 muL, 500 mumol) in toluene (1 mL) was continuously introduced over a period of 60 min via syringe pump. After addition, the reaction was stirred for additional 10 min and quenched with methanolic H2SO4 (1.1 M, 500 muL). The mixture was stirred for further 15 min and directly subjected to column chromatography (SiO2, pentane/Et2O 2:1) to give (R)-phenylethanol ((R)-2a, 58.3 mg, 477 mumol, 95%, 97% ee) as a colorless oil.EXAMPLE 1bR-(+)-alpha-methyl-4-pyridinemethanolThe same reduction was performed using 1% of catalyst 10 (1, 3, 2-dioxaborolan-2-yloxy)diphenylmethyl)pyrrolidine. Borane-DMS complex (10M, 1.6 mL, 16.00 mmol) was added to a solution of catalyst 10 (32 mg, 0.10 mmol) in dry THF (5 mL) at room temperature and the mixture was stirred for 1 hour. A solution of 4-acetylpyridine (1.21 g, 10.00 mmol) in THF (5 mL) was added for 5 h using an infusion pump. The reaction mixture was stirred at room temperature for over 1 hour, then cooled to 0 C. and quenched with methanol (10 mL). After refluxing for 12 h, the solvents were removed under vacuum, the residue was distilled (directly without chromatography purification) in a Kugelrohr apparatus under vacuum to give the final product as a white crystalline material (1.135 g, 92% yield). Chiral GC of O-acetyl derivative indicated 98.8% ee.; EXAMPLE 1cR-(+)-alpha-methyl-4-pyrydylmethanolThe same reaction was again performed using 10% of catalyst 10 (1, 3, 2-dioxaborolan-2-yloxy)diphenylmethyl)pyrrolidine). Borane-DMS complex (10M, 1.7 mL, 17.00 mmol) was added to a solution of catalyst 10 (323 mg, 1.00 mmol) in dry THF (10 mL) at room temperature (during the addition hydrogen evolved) and mixture was stirred for 1 hour. A solution of 4-acetylpyridine (1.21 g, 10.00 mmol) in THF (5 mL) was added for 5 hours using an infusion pump. The reaction mixture was stirred at room temperature for over 1 hour, then cooled to 0 C. and quenched with methanol (10 mL). After refluxing for 12 hours, the solvents were removed under vacuum, the residue was distilled (directly without chromatography purification) in a Kugelrohr apparatus under vacuum to give the final product as white crystalline material (1.077 g, 88% yield). Chiral GC of O-acetyl derivative indicated 99.0% ee.EXAMPLE 1aR-(+)-alpha-methyl-4-pyridylmethanolTo a 100 mL round flask equipped with a septa and nitrogen flow, 10% of catalyst 6 (0.325 g, 1.0 mmol) was added. Then dry THF (30 mL) was added to make a solution. Borane complex with dimethyl sulfoxide 10.0 M (2.0 mL, 20.00 mmol) was added to the catalyst solution. The mixture was stirred for about 15 minutes. A solution of 4-acetylpyridine (1.211 g, 10.0 mmol) with dry THF (10 mL) was added to the reaction mixture during 1 hour. The reaction was allowed to react overnight. The reaction mixture was cooled to 0 C. MeOH (20 mL) was added and the mixture was heated to reflux for 4 hours. A sample of the mixture was analyzed by 11B-NMR and the N-BH3 complex signal was observed at -13.28 ppm. More MeOH (10 mL) was added and heated for 4 hours again. After decomposition of N-BH3 complex confirmed by 11B-NMR the mixture was concentrated to colorless oil. The residue was purified by column chromatography through Alumina (acid) (50 g) with an EtOAc/Hexane 1:1 mixture. The white crystalline alpha-methyl-4-pyridinemethanol was obtained in an 85% yield (1.048 g.) (Mp: 55-58 C.) According with the G.C. analysis (Column: CP-Chirasil-Dex CB, Method: Iso135) the alcohol was observed at retention time 12.39 minutes and some aminoalcohol at retention time 11.64 minutes. The enantiomeric excess of 97.2% ee was determined by 11P-NMR of the phosphorus derivative.An analysis of the product gave the following results:1H-NMR (400 MHz, CDCl3): delta1.39 (d, J=6.4 Hz, 3H); 4.80 (q, J=6.4 Hz, 1H); 5.096 (s, 1H); 7.22 (d, J=6.0 Hz, 2H); 8.309 (d, J=5.6 Hz, 2H) (?98% purity).13C-NMR (100 MHz, CDCl3): delta 24.99 (CH3); 68.21 (C-H(OH); 120.60 (CHAr); 148.97 (CHAr); 155.97.[alpha]23D=+49.0 (c=0.025, CHCl3).To a solution of diphenyl-(5)-pyrrolidin-2-ylmethanol (10.5g, 41.3mmol) in THF (800mL) was added trimethoxyborane (5.52mL, 49.5mmol) and the reaction was stirred at r.t. for 1 h. The mixture was cooled to 0C and borane dimethylsulfide (78mL, 825.5mmol) was added, followed by a solution of 4-acetylpyridine (50g, 410.7mmol) in THF (200mL), over 1 h. The reaction was stirred for a further 1 h before being quenched with 2M HC1. After stirring for 10 min the reaction mixture was basified with sat. NaHCC'3 solution. The precipitate that formed was filtered, and the remaining filtrate was extracted with EtOAc (x 10). The organic fractions were combined, dried (MgS04) and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 9: 1) afforded the title compound: 1H NMR deltaEta (300MHz , CDC13): 8.49 (s, 2H), 7.30 (s, 1H), 4.93 - 4.84 (m, 1H), 3.08 - 2.86 (m, 1H), 1.51 - 1.48 (m, 3H).(+)-(R)-1-(4-Pyridyl)ethyl 1-adamantanecarboxylate The method followed that described in Example 1, but using (+)-(R)-1-(4-pyridyl)ethanol (369 mg, 3.0 mmol) in THF (12 ml), n-butyllithium (2.5 M, 1.2 ml, 3.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (656 mg, 3.3 mmol) in THF (3 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, afforded the title compound (754 mg, 88%). [alpha]D +25.8 (c 1, CHCl3); IR numax 1730 cm-1; 1 H-NMR (CDCl3) delta1.50 (3H, d, J 6.6 Hz, CHCH3), 1.73 and 1.93 (12H, 2s, adamantyl CH2), 2.04 (3H, s, adamantyl CH), 5.80 (1H, q, J 6.6 Hz, OCH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5H), 8.58 (2H, d, J 6.1 Hz, Py 2 and 6H); MS m/z 285 (M+). By passing hydrogen chloride gas through a solution of the product in ether, the hydrochloride was obtained, m.p. 164-166 C. Anal. Calcd: C, 67.17; H, 7.52; N, 4.35. Found: C, 67.58; H, 7.51; N, 4.36%.