* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium formate In water; toluene at 50℃; for 24 h;
3.36 g (40.0 mmol) of HCOOK as the hydrogen source, 2.609 mg (4.0 μmol) of Cp*IrCl[(S,S)-MsDPEN] as the catalyst, and 1.349 g (8.0 mmol) of β-chloropropiophenone were introduced in a 20 mL Schlenk tube, and the mixture was subjected to argon substitution. 2 mL of water and 2 ml of toluene were added and the resulting mixture was maintained at 50° C. for 24 hr while stirring. The organic phase was washed three times with 3 mL of water, and the toluene was distilled off under reduced pressure to give an optically-active alcohol. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 85percent ee was produced in 94percent yield.
94%
With dimethylsulfide borane complex; (R)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine In tetrahydrofuran at 20℃; for 2 h;
Cat-6 (1.78 mmol, 575 mg) prepared in Preparation 2.6 was dissolved in 25 mL of THF, BH3-DMS (12.5 mmol, 1.18 mL) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) dissolved in 6 ml of THF dropwise over 10 minutes. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. Example 1.1.(S) -3-chloro-1-phenyl-propanol (yield: 94percent, 91percent ee).The above compound was recrystallized from the nucleic acid to obtain (S) -3-chloro-1-phenyl-propanol (84percent recovery) with 99percent ee.
94%
With dimethylsulfide borane complex; (R)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine In tetrahydrofuran at 20℃; for 2.16667 h;
Cat-1 (1.78 mmol, 575 mg) prepared in Preparation 1.1 was dissolved in 25 mL of THF, BH3-DMS (12.5 mmol, 1.18 mL) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The organic layers were combined, dried over Na2SO4, and filtered. The obtained filtrate was concentrated and purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain (S) -3-chloro-1-phenylpropan-1-ol (yield: 94percent & Lt; / RTI & gt; The above compound was recrystallized in a nucleic acid to obtain (S) -3-chloro-1-phenylpropan-1-ol (84percent recovery) at 99percent ee.
79%
Stage #1: With borane N,N-diethylaniline complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In toluene at 20℃; for 6 h; Inert atmosphere Stage #2: With hydrogenchloride In methanol; water; toluene for 0.166667 h; Inert atmosphere
To a stirred solution of (R)-(+)-2-methyl-CBS-oxazaborolidine (29 mg, 0.107 mmol) in anhydrous toluene (3 mL) was added N,N-diethylaniline borane (0.63 mL, 3.558 mmol) at room temperature. 3-Chloropropiophenone (2) (0.3 g, 1.779 mmol) in anhydrous toluene (3 mL) was slowly added with the aid of a syringe pump over 5 h under N2. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with MeOH (1 mL) followed by addition of 1 N HCl (1 mL) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL .x. 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (n-hexane/EtOAc = 6:1) to afford 239 mg (79percent) of 3 as a white solid.Rf = 0.48 (n-hexane/EtOAc = 4/1); [α]22D -23.5 (c 0.1, CHCl3); IR (neat) ν 3060, 2878, 1620, 1612, 1596, 1452, 1215, 1190, 1042, 1020, 988 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.92 (d, J = 3.3 Hz, 1H), 2.08-2.13 (m, 1H), 2.18-2.28 (m, 1H), 3.52-3.60 (m, 1H), 3.70-3.78 (m, 1H), 4.92-4.97 (m, 1H), 7.27-7.40 (m, 5H); 13C NMR (500 MHz, CDCl3) δ 41.7, 41.9, 71.6, 126.0, 128.1, 128.9, 143.9; HRMS (EI) Calcd for C9H11ClO [M+H]+ 170.0498, found 170.0500; HPLC (Chiralcel OD-H column, n-hexane:i-PrOH = 92:8, 1 mL/min, 210 nm): tmajor = 8.38 min, tminor = 9.87 min; ee > 99.9percent.
73%
With (S)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine; phenylsilane; copper(II) acetate monohydrate In toluene at -20℃; for 24 h; Inert atmosphere; Schlenk technique
Following a procedure recently reported by Wu and Li,25Cu(OAc)2·H2O (119.8 mg, 0.6 mmol) and (S)-P-Phos (151.4 mg, 0.2mmol) were weighed under air and dissolved in toluene (66 mL). The reaction mixture was stirred at r.t. for 20 min, then a solution of phenylsilane(3 mL, 24 mmol) in toluene (32 mL) was added. The mixturewas cooled to –20 °C and a solution of 3-chloro-1-propiophenone(13) (3.4 g, 20 mmol) in toluene (32 mL) was added under vigorous stirring. The flask was stoppered and the reaction mixture was stirred for 24 h at the above temperature. Upon completion, the mixture was treated with 10percent HCl (130 mL) and the organic product was extracted with Et2O (3 × 150 mL). The combined organic layers were washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (hexane/EtOAc, 10:1)afforded alcohol (S)-23 (2.5 g, 73percent) as a white solid.The ee value was determined by chiral HPLC analysis with a Chiralcel IB column (eluent: hexane/2-propanol = 98:2; flow rate: 1 mL/min;detection: 254 nm), tR (R) = 16.2 min (areapercent 97), tR (S) = 18.1 min (areapercent3). Spectral data matched those previously reported for 23. Theoptical rotation matched literature data.32 [α]D27.4 –23 (c 1.0, CHCl3).
84 mg
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the medium consisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
Reference：
[1] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 7; 14
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 6, p. 1009 - 1017
[3] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0176-0179
[4] Patent: KR2016/44117, 2016, A, . Location in patent: Paragraph 0063-0066
[5] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[6] Chirality, 2012, vol. 24, # 10, p. 847 - 853,7
[7] Tetrahedron Letters, 2012, vol. 53, # 28, p. 3680 - 3682
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 4929 - 4931
[9] Synthesis (Germany), 2016, vol. 48, # 19, p. 3241 - 3253
[10] Tetrahedron Asymmetry, 2006, vol. 17, # 12, p. 1769 - 1774
[11] Journal of Organic Chemistry, 1988, vol. 53, # 13, p. 2916 - 2920
[12] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 11, p. 1767 - 1769
[13] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 11, p. 1767 - 1769
[14] Tetrahedron Asymmetry, 1992, vol. 3, # 4, p. 525 - 528
[15] Chemistry - A European Journal, 2011, vol. 17, # 50, p. 14234 - 14240
[16] Journal of Molecular Catalysis B: Enzymatic, 2011, vol. 70, # 3-4, p. 114 - 118
[17] Chirality, 2012, vol. 24, # 10, p. 847 - 853,7
[18] Tetrahedron Asymmetry, 2014, vol. 25, # 18-19, p. 1264 - 1269
2
[ 936-59-4 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
With dimethylsulfide borane complex; C23H22BNO3 In tetrahydrofuran at 20℃; for 2 h;
Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH3-DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF was added dropwise to the reaction mixture. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropanol (yield: 75percent, 73percent ee) was obtained in the same manner as in Example 1.1.
77 % ee
With hydrogen In methanol at 60℃; for 24 h;
6.127 mg (8.0 μmol) of Cp*Ir(OTf)[(S,S)-MsDPEN] and 1.249 g (8.0 mmol) of β-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60° C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 77percent ee was produced in 12percent yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
80 % ee
With dimethylsulfide borane complex; (1R,2S,3R,5R)-2-(1',3',2'-dioxaborolan-2'-yloxy)apopinan-3-amine In tetrahydrofuran at 20℃; for 1 h;
General procedure: To a solution of 1 (0.005–0.01 mmol, 0.5–1 mol percent) in dry THF(3 mL) at room temperature, a solution of BH3SMe2 (10 M,100 lL, 1 mmol) in THF (2 mL) was added dropwise at a rate of3.2 mL per hour using a syringe pump. At the same time a solutionof ketone (1 mmol) in THF (2 mL) was also added to the reactionflask at a rate of 3 mL per hour. After the addition of both reagents,the reaction mixture was stirred for 20 min, quenched by the additionof MeOH (1 mL) at room temperature, and stirred for 30 min. Subsequently, the solvents were evaporated under vacuum and theproduct was isolated by column chromatography using hexane/EtOAc (4:1) as the eluent.
66 % ee
at 20℃; for 20 h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91percent isolated yield). The ee was measured by chiral GLC.
Reference：
[1] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0143; 0154; 0155
[2] Tetrahedron Letters, 2005, vol. 46, # 3, p. 495 - 498
[3] Tetrahedron Letters, 1993, vol. 34, # 26, p. 4145 - 4148
[4] Journal of the Chemical Society, Chemical Communications, 1986, # 13, p. 1018 - 1019
[5] Tetrahedron, 2002, vol. 58, # 6, p. 1069 - 1074
[6] Tetrahedron Asymmetry, 2001, vol. 12, # 16, p. 2323 - 2329
[7] Organic Letters, 2006, vol. 8, # 14, p. 2969 - 2972
[8] Tetrahedron Letters, 2007, vol. 48, # 33, p. 5799 - 5802
[9] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 8; 14
[10] Organic Letters, 2009, vol. 11, # 2, p. 305 - 308
[11] Organic Process Research and Development, 2012, vol. 16, # 4, p. 710 - 713
[12] Green Chemistry, 2014, vol. 16, # 5, p. 2680 - 2688
[13] Catalysis Letters, 2014, vol. 144, # 7, p. 1289 - 1295
[14] Chemistry - A European Journal, 2014, vol. 20, # 38, p. 12190 - 12200
[15] Tetrahedron Asymmetry, 2015, vol. 26, # 24, p. 1453 - 1458
[16] Organic and Biomolecular Chemistry, 2016, vol. 14, # 18, p. 4304 - 4311
[17] Journal of Molecular Catalysis A: Chemical, 2016, vol. 421, p. 138 - 145
[18] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 426 - 431
3
[ 108-22-5 ]
[ 18776-12-0 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
88 % ee
With Burkholderia species lipoprotein lipase; C51H77NO17; dextrin In toluene at 25℃; for 6 h; Enzymatic reaction
General procedure: In a typical procedure, isopropenyl acetate (1.5 equiv.) was added to a 4 mL-vial containing BSLPL-1c-D (3 mg), substrate (0.3 mmol), and anhydrous toluene (0.5 M). The resulting solution was then shaken at 25 °C until the reaction reached 46–50percent conversion. After being diluted with methylene chloride, the reaction mixture was filtered through a celite pad, concentrated, and then analyzed by HPLC to determine the enantiomeric excesses of remaining substrate and acetylated product. The enantioselectivity (E) was then calculated using the equation: E = ln[1−c(1+eep)]/ln[1−c(1−eep)] where c = ees/(ees+eep). The kinetic resolution of 4a: (S)-4a (82percent ee) and (R)-5a (97percent ee); 46percent conversion; E = >100. The kinetic resolution of 4b: (S)-4b (>99percent ee) and (R)-5b (97percent ee); 50percent conversion; E=>100.
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 6, p. 1972 - 1977
[2] Journal of Molecular Catalysis B: Enzymatic, 2016, vol. 134, p. 148 - 153
4
[ 936-59-4 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
60.526 % ee
at 28℃; for 48 h; Microbiological reaction; Enzymatic reaction
General procedure: Fresh plates of each yeast strain were streaked from the frozen stock in PDA. A single colony was used to inoculate 100mL of YM Broth. The culture was incubated at 28°C and 150rpm for 48h and the cells were collected by centrifugation at 4000rpm and 4°C for 15min. The pellet was washed three times with 50mL physiological serum. Afterward, 2g of yeast cells (wet weight) were suspended in 20mL of 10percent dextrose solution and 30mg of the appropriate substrate were added. The culture was incubated at 28°C and 150rpm in an orbital shaker ZHICHENG ZHWY-211B for 48h.
23 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 6 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 102, p. 94 - 98
[2] Tetrahedron Asymmetry, 2014, vol. 25, # 18-19, p. 1264 - 1269
5
[ 936-59-4 ]
[ 1565-74-8 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
21 %Chromat.
With yeast culture of Aphanocladium album KCh 417 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces cerevisiae KCh 464 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces pastorianus KCh 906 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Candida parapsilosis KCh 909 In acetone at 25℃; for 72 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
57 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Saccharomyces brasiliensis KCh 905 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Rhodotorula rubra KCh 4 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With dimethylsulfide borane complex; C23H22BNO3 In tetrahydrofuran at 20℃; for 2 h;
Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH3-DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF was added dropwise to the reaction mixture. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropanol (yield: 75percent, 73percent ee) was obtained in the same manner as in Example 1.1.
77 % ee
With hydrogen In methanol at 60℃; for 24 h;
6.127 mg (8.0 μmol) of Cp*Ir(OTf)[(S,S)-MsDPEN] and 1.249 g (8.0 mmol) of β-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60° C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 77percent ee was produced in 12percent yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
80 % ee
With dimethylsulfide borane complex; (1R,2S,3R,5R)-2-(1',3',2'-dioxaborolan-2'-yloxy)apopinan-3-amine In tetrahydrofuran at 20℃; for 1 h;
General procedure: To a solution of 1 (0.005–0.01 mmol, 0.5–1 mol percent) in dry THF(3 mL) at room temperature, a solution of BH3SMe2 (10 M,100 lL, 1 mmol) in THF (2 mL) was added dropwise at a rate of3.2 mL per hour using a syringe pump. At the same time a solutionof ketone (1 mmol) in THF (2 mL) was also added to the reactionflask at a rate of 3 mL per hour. After the addition of both reagents,the reaction mixture was stirred for 20 min, quenched by the additionof MeOH (1 mL) at room temperature, and stirred for 30 min. Subsequently, the solvents were evaporated under vacuum and theproduct was isolated by column chromatography using hexane/EtOAc (4:1) as the eluent.
66 % ee
at 20℃; for 20 h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91percent isolated yield). The ee was measured by chiral GLC.
Reference：
[1] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0143; 0154; 0155
[2] Tetrahedron Letters, 2005, vol. 46, # 3, p. 495 - 498
[3] Tetrahedron Letters, 1993, vol. 34, # 26, p. 4145 - 4148
[4] Journal of the Chemical Society, Chemical Communications, 1986, # 13, p. 1018 - 1019
[5] Tetrahedron, 2002, vol. 58, # 6, p. 1069 - 1074
[6] Tetrahedron Asymmetry, 2001, vol. 12, # 16, p. 2323 - 2329
[7] Organic Letters, 2006, vol. 8, # 14, p. 2969 - 2972
[8] Tetrahedron Letters, 2007, vol. 48, # 33, p. 5799 - 5802
[9] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 8; 14
[10] Organic Letters, 2009, vol. 11, # 2, p. 305 - 308
[11] Organic Process Research and Development, 2012, vol. 16, # 4, p. 710 - 713
[12] Green Chemistry, 2014, vol. 16, # 5, p. 2680 - 2688
[13] Catalysis Letters, 2014, vol. 144, # 7, p. 1289 - 1295
[14] Chemistry - A European Journal, 2014, vol. 20, # 38, p. 12190 - 12200
[15] Tetrahedron Asymmetry, 2015, vol. 26, # 24, p. 1453 - 1458
[16] Organic and Biomolecular Chemistry, 2016, vol. 14, # 18, p. 4304 - 4311
[17] Journal of Molecular Catalysis A: Chemical, 2016, vol. 421, p. 138 - 145
[18] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 426 - 431
25
[ 108-22-5 ]
[ 18776-12-0 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
88 % ee
With Burkholderia species lipoprotein lipase; C51H77NO17; dextrin In toluene at 25℃; for 6 h; Enzymatic reaction
General procedure: In a typical procedure, isopropenyl acetate (1.5 equiv.) was added to a 4 mL-vial containing BSLPL-1c-D (3 mg), substrate (0.3 mmol), and anhydrous toluene (0.5 M). The resulting solution was then shaken at 25 °C until the reaction reached 46–50percent conversion. After being diluted with methylene chloride, the reaction mixture was filtered through a celite pad, concentrated, and then analyzed by HPLC to determine the enantiomeric excesses of remaining substrate and acetylated product. The enantioselectivity (E) was then calculated using the equation: E = ln[1−c(1+eep)]/ln[1−c(1−eep)] where c = ees/(ees+eep). The kinetic resolution of 4a: (S)-4a (82percent ee) and (R)-5a (97percent ee); 46percent conversion; E = >100. The kinetic resolution of 4b: (S)-4b (>99percent ee) and (R)-5b (97percent ee); 50percent conversion; E=>100.
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 6, p. 1972 - 1977
[2] Journal of Molecular Catalysis B: Enzymatic, 2016, vol. 134, p. 148 - 153
26
[ 936-59-4 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
60.526 % ee
at 28℃; for 48 h; Microbiological reaction; Enzymatic reaction
General procedure: Fresh plates of each yeast strain were streaked from the frozen stock in PDA. A single colony was used to inoculate 100mL of YM Broth. The culture was incubated at 28°C and 150rpm for 48h and the cells were collected by centrifugation at 4000rpm and 4°C for 15min. The pellet was washed three times with 50mL physiological serum. Afterward, 2g of yeast cells (wet weight) were suspended in 20mL of 10percent dextrose solution and 30mg of the appropriate substrate were added. The culture was incubated at 28°C and 150rpm in an orbital shaker ZHICHENG ZHWY-211B for 48h.
23 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 6 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 102, p. 94 - 98
[2] Tetrahedron Asymmetry, 2014, vol. 25, # 18-19, p. 1264 - 1269
27
[ 936-59-4 ]
[ 1565-74-8 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
21 %Chromat.
With yeast culture of Aphanocladium album KCh 417 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces cerevisiae KCh 464 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces pastorianus KCh 906 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Candida parapsilosis KCh 909 In acetone at 25℃; for 72 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
57 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Saccharomyces brasiliensis KCh 905 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
(R)-(-)-1-chloro-3-(2-iodophenoxy)-3-phenylpropane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.4%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 96h;
Embodiment 1 Synthesis of (R)-(-)-1-Chloro-3-(2-iodophenoxy)-3-phenylpropane (1-A) 2-iodophenol (1.29 g, 5.86 mmole), (S)-(-)-<strong>[100306-34-1]3-chloro-1-phenylpropanol</strong> (1.10 g, 5.86 mmole), triphenylphosphine (1.54 g, 5.86 mmole), and diethyl azodicarboxylate (2.7 ml, 5.86 mmole) were dissolved in dry tetrahydrofuran (20 ml), and stirred at room temperature for 4 days. After concentration under vacuum, n-hexane was added (50 ml) for extracting the residue. The extract was concentrated under vacuum, and purified through liquid chromatography, in which a stationary phase was silica (SiO2), and a mobile phase was chloroform:n-hexane=1:20, to obtain the product as an oil (1.44 g, 67.4%). The chemical structure of the oil product was analyzed through 1H and 13C nuclear magnetic resonance (NMR) spectra-mass spectrometry (MS), and the data was as follows. 1H and 13C NMR spectra: 1H NMR (CDCl3) delta 7.81 (dd, J=6.6 and 1.5 Hz, 1H, Ph), 7.33 (m, 5H, Ph), 7.13 (td, J=7.9 and 1.4 Hz, 1H, Ph), 6.70 (m, 2H, Ph), 5.49 (dd, J=8.6 and 4.4 Hz, 1H, H1, 4.0 (m, 1H, H2), 3.74 (m, 1H, H2), 2.58 (m, 1H, H3), 2.29 (m, 1 H, H3). 13C NMR (CDCl3) delta 156.04, 140.04, 139.33, 129.19, 128.81, 128.0, 125.82, 122.61, 113.69, 86.98 (Ph), 77.73 (CH), 41.45 and 41.38 (CH2CH2Cl). MS: m/z is 374 and 372 (M+).
With dimethylsulfide borane complex; C23H22BNO3; In tetrahydrofuran; at 20℃; for 2h;
Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH3-DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF was added dropwise to the reaction mixture. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropanol (yield: 75%, 73% ee) was obtained in the same manner as in Example 1.1.
With hydrogen;Cp*Ir(OTf)[(S,S)-Msdpen]; In methanol; at 60℃; under 7600.51 Torr; for 24h;Product distribution / selectivity;
6.127 mg (8.0 mumol) of Cp*Ir(OTf)[(S,S)-MsDPEN] and 1.249 g (8.0 mmol) of beta-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60 C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 77% ee was produced in 12% yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
With dimethylsulfide borane complex; (1R,2S,3R,5R)-2-(1',3',2'-dioxaborolan-2'-yloxy)apopinan-3-amine; In tetrahydrofuran; at 20℃; for 1h;
General procedure: To a solution of 1 (0.005-0.01 mmol, 0.5-1 mol %) in dry THF(3 mL) at room temperature, a solution of BH3SMe2 (10 M,100 lL, 1 mmol) in THF (2 mL) was added dropwise at a rate of3.2 mL per hour using a syringe pump. At the same time a solutionof ketone (1 mmol) in THF (2 mL) was also added to the reactionflask at a rate of 3 mL per hour. After the addition of both reagents,the reaction mixture was stirred for 20 min, quenched by the additionof MeOH (1 mL) at room temperature, and stirred for 30 min. Subsequently, the solvents were evaporated under vacuum and theproduct was isolated by column chromatography using hexane/EtOAc (4:1) as the eluent.
With silver tetrafluoroborate; diethoxymethylane; C26H29N3O2*Cl(1-)*Ir(1+)*C8H12; at 20℃; for 20h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91% isolated yield). The ee was measured by chiral GLC.
With potassium formate;Cp*IrCl[(S,S)-MsDPEN]; In water; toluene; at 50℃; for 24h;Product distribution / selectivity;
3.36 g (40.0 mmol) of HCOOK as the hydrogen source, 2.609 mg (4.0 mumol) of Cp*IrCl[(S,S)-MsDPEN] as the catalyst, and 1.349 g (8.0 mmol) of beta-chloropropiophenone were introduced in a 20 mL Schlenk tube, and the mixture was subjected to argon substitution. 2 mL of water and 2 ml of toluene were added and the resulting mixture was maintained at 50 C. for 24 hr while stirring. The organic phase was washed three times with 3 mL of water, and the toluene was distilled off under reduced pressure to give an optically-active alcohol. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 85% ee was produced in 94% yield.
94%
With dimethylsulfide borane complex; (R)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; In tetrahydrofuran; at 20℃; for 2h;
Cat-6 (1.78 mmol, 575 mg) prepared in Preparation 2.6 was dissolved in 25 mL of THF, BH3-DMS (12.5 mmol, 1.18 mL) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) dissolved in 6 ml of THF dropwise over 10 minutes. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. Example 1.1.(S) -3-chloro-1-phenyl-propanol (yield: 94%, 91% ee).The above compound was recrystallized from the nucleic acid to obtain (S) -3-chloro-1-phenyl-propanol (84% recovery) with 99% ee.
94%
With dimethylsulfide borane complex; (R)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; In tetrahydrofuran; at 20℃; for 2.16667h;
Cat-1 (1.78 mmol, 575 mg) prepared in Preparation 1.1 was dissolved in 25 mL of THF, BH3-DMS (12.5 mmol, 1.18 mL) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The organic layers were combined, dried over Na2SO4, and filtered. The obtained filtrate was concentrated and purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain (S) -3-chloro-1-phenylpropan-1-ol (yield: 94% & Lt; / RTI & gt; The above compound was recrystallized in a nucleic acid to obtain (S) -3-chloro-1-phenylpropan-1-ol (84% recovery) at 99% ee.
79%
To a stirred solution of (R)-(+)-2-methyl-CBS-oxazaborolidine (29 mg, 0.107 mmol) in anhydrous toluene (3 mL) was added N,N-diethylaniline borane (0.63 mL, 3.558 mmol) at room temperature. 3-Chloropropiophenone (2) (0.3 g, 1.779 mmol) in anhydrous toluene (3 mL) was slowly added with the aid of a syringe pump over 5 h under N2. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with MeOH (1 mL) followed by addition of 1 N HCl (1 mL) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (n-hexane/EtOAc = 6:1) to afford 239 mg (79%) of 3 as a white solid.Rf = 0.48 (n-hexane/EtOAc = 4/1); [alpha]22D -23.5 (c 0.1, CHCl3); IR (neat) nu 3060, 2878, 1620, 1612, 1596, 1452, 1215, 1190, 1042, 1020, 988 cm-1; 1H NMR (300 MHz, CDCl3) delta 1.92 (d, J = 3.3 Hz, 1H), 2.08-2.13 (m, 1H), 2.18-2.28 (m, 1H), 3.52-3.60 (m, 1H), 3.70-3.78 (m, 1H), 4.92-4.97 (m, 1H), 7.27-7.40 (m, 5H); 13C NMR (500 MHz, CDCl3) delta 41.7, 41.9, 71.6, 126.0, 128.1, 128.9, 143.9; HRMS (EI) Calcd for C9H11ClO [M+H]+ 170.0498, found 170.0500; HPLC (Chiralcel OD-H column, n-hexane:i-PrOH = 92:8, 1 mL/min, 210 nm): tmajor = 8.38 min, tminor = 9.87 min; ee > 99.9%.
73%
With (S)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine; phenylsilane; copper(II) acetate monohydrate; In toluene; at -20℃; for 24h;Inert atmosphere; Schlenk technique;
Following a procedure recently reported by Wu and Li,25Cu(OAc)2·H2O (119.8 mg, 0.6 mmol) and (S)-P-Phos (151.4 mg, 0.2mmol) were weighed under air and dissolved in toluene (66 mL). The reaction mixture was stirred at r.t. for 20 min, then a solution of phenylsilane(3 mL, 24 mmol) in toluene (32 mL) was added. The mixturewas cooled to -20 C and a solution of 3-chloro-1-propiophenone(13) (3.4 g, 20 mmol) in toluene (32 mL) was added under vigorous stirring. The flask was stoppered and the reaction mixture was stirred for 24 h at the above temperature. Upon completion, the mixture was treated with 10% HCl (130 mL) and the organic product was extracted with Et2O (3 × 150 mL). The combined organic layers were washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (hexane/EtOAc, 10:1)afforded alcohol (S)-23 (2.5 g, 73%) as a white solid.The ee value was determined by chiral HPLC analysis with a Chiralcel IB column (eluent: hexane/2-propanol = 98:2; flow rate: 1 mL/min;detection: 254 nm), tR (R) = 16.2 min (area% 97), tR (S) = 18.1 min (area%3). Spectral data matched those previously reported for 23. Theoptical rotation matched literature data.32 [alpha]D27.4 -23 (c 1.0, CHCl3).
84 mg
With yeast culture of Candida viswanathii KCh 120; In acetone; at 25℃; for 24h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the medium consisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast strain Pichia sp. CR; at 28℃; for 48h;Microbiological reaction; Enzymatic reaction;
General procedure: Fresh plates of each yeast strain were streaked from the frozen stock in PDA. A single colony was used to inoculate 100mL of YM Broth. The culture was incubated at 28C and 150rpm for 48h and the cells were collected by centrifugation at 4000rpm and 4C for 15min. The pellet was washed three times with 50mL physiological serum. Afterward, 2g of yeast cells (wet weight) were suspended in 20mL of 10% dextrose solution and 30mg of the appropriate substrate were added. The culture was incubated at 28C and 150rpm in an orbital shaker ZHICHENG ZHWY-211B for 48h.
With sodium iodide; In acetone; for 16h;Heating / reflux;
To a solution of (S)- (-)-3-CHLORO-L-PHENYL-L-PROPANOL (5 g, 29.3 mmol) in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). The resulting solution was heated at reflux for 16 h. The solution was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane : ethyl acetate [100: 0 to 3: 1] to yield the iodo compound (7.44g, 97%); 8H (300 MHz, CDC13) 7.36 (5H, m, Ar), 4.83 (1H, m, O-CH), 3.34-3. 15 (2H, m, CH2), 2.28-2. 15 (2H, m, CH2).
With triethylamine; In dichloromethane; butanone;
PREPARATION O. (S)-3-Iodo-1-phenyl-1-propanol. Commerically available <strong>[100306-34-1](S)-3-chloro-1-phenyl-1-propanol</strong> (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100 C. for 20 hours. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product.
With triethylamine; In dichloromethane; butanone;
EXAMPLE 15 (S)-3-Iodo-1-phenyl-1-propanol Commercially available <strong>[100306-34-1](S)-3-chloro-1-phenyl-1-propanol</strong> (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100 C. for 20 h. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product.
With sodium iodide; In acetone; for 17h;Reflux;
(S)-3-Iodo-1-phenylpropan-1-ol [Robertson, D. W. et al. J. Med. Chem. 1988, 31 (7), 1412-1417] (0306) (S)-3-Chloro-1-phenylpropan-1-ol (2.2 g, 12.9 mmol) was dissolved in a saturated solution of NaI in acetone (150 mL) and refluxed for 17 h. Once cooled to room temperature, it was filtered and concentrated under vacuum. The residue was dissolved in EtOAc and washed with brine (×3), dried over anhydrous MgSO4 and evaporated to dryness under vacuum to afford 3.2 g of an orange solid that was used in the following step without further purification.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 40℃; for 72h;Heating / reflux;
(S)-(-)-3-chloro-1-phenyl-1-propanol (1 g, 5.8 mmol) ANDTHIENO [3, 2-B] pyridin-7-ol (1.15 g, 7.6 mmol, commercially available from the Aldrich Chemical Company) in dry THF (6 ml) were stirred under an inert atmosphere of nitrogen. PPh3 (1.99 g, 7.6 mmol) followed by DEAD (1 ML, 7.6 mmol) were added and the resulting solution was allowed to stir for a further 72 h while heating at 40 C before the solvent was removed ILL vacuo. The residue was purified by flash chromatography, eluting silica gel with hexane: ethyl acetate [100: 0 to 1: 3] to yield the title compound (1.38 g, 78%); mass spectrum (ion spray): M/Z = 304.05 (M+1)
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 24h;
4-[(1R)-3-chloro-1-phenylpropyl]oxy}-1,2-dimethoxybenzene: A mixture of 3,4-dimethoxyphenol (4.07 g, 26.4 mmol), (S)-(-)-3-chloro-phenyl-1-propanol (4.50 g, 26.4 mmol, 99%ee, Aldrich Chemical Co.), triphenylphosphine (6.92 g, 26.4 mmol) and diethyl azodicarboxylate (4.59 g, 26.4 mmol) in THF (110 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. At this point, the residue can either be washed with pentane (×3) and the combined pentane extracts were concentrated and chromatographed (silica with hexanes-EtOAc 8:1 as the eluent) to give the desired product (as described as a general procedure by: Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem. 1988, 53, 2916-2920). This procedure was performed on a smaller scale reaction and only a 40% yield of the product was realized. [00549] Alternatively, on a larger scale (26.4 mmol), the crude product was triturated with a small amount of dichloromethane and the precipitated triphenylphosphine oxide was filtered. The filtrate was concentrated and the crude product was chromatographed to give the desired product as a thick yellow oil (7.30 g, 88.9% yield): 1H NMR (400 MHz, CDCl3) delta 7.39-7.32 (m, 4H), 7.20 (m, 1H), 6.64 (d, 1H, J=8.7 Hz), 6.51 (d, 1H, J=2.7 Hz), 6.30 (dd, 1H, J=2.7, 8.7 Hz), 5.27 (apparent dd, 1H, J=4.5, 8.7 Hz), 3.79 (s, 3H), 3.77 (s, 3H), 3.61 (m, 1H), 2.45 (m, 1H), 2.20 (m, 1H), 1.80 (s, 1H); ESMS m/e: 307.11 (M+H)+. [00550] N-(3-{1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of potassium carbonate (321 mg, 2.32 mmol), sodium iodide (522 mg, 3.48 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (570 mg, 2.32 mmol) and 4-[(1R)-3-chloro-1-phenylpropyl]oxy}-1,2-dimethoxybenzene (712 mg, 2.32 mmol) in DMF (5.0 mL) was stirred at 100 C. for 3 hrs, at which time TLC indicated that the reaction was complete. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Prep-TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the product (970 mg, 90.1%) as a thick oil.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 23℃; for 96h;
1-(3-[{(1R)-3-CHLORO-PHENYLPROPYL]OXY}PHENYL)ETHANONE: Azodicarboxylate (5.37 g, 0.0310 mol) was added to a solution of triphenylphosphine (8.09 g, 0.0308 mol), 1S-3-chloro-1-phenyl-1-propanol (4.20 g, 0.031 mol) and, 1-(3-hydroxyphenyl)ethanone in THF (150 mL). The reaction mixture was stirred for 4 days at 23 C. The solvent was removed under reduced pressure and the residue was triturated with ether/hexane (1:2, (3×100 mL). The combined organic fractions were concentrated in vacuo and the crude product was purified by chromatography using EtOAc/hexane (1:14) to give the desired product (6.55 g, 74%). 1H NMR (400 MHz, CDCl3) delta 7.48-7.31 (m, 6H), 7.26 (t, 2H, J=8.2 Hz), 7.04 (d, 1H, J=8.1 Hz), 5.44 (dd, 1H, J=4.4, 8.1 Hz), 3.83-3.74 (m, 1H), 3.63-3.56 (m, 1H), 2.51 (s, 3H), 2.51-2.45 (m, 1H), 2.29-2.17 (m, 1H); ESMS m/e: 289.0 (M+H)+.
With triphenylphosphine; In tetrahydrofuran; toluene;
a 4-Chloro-2-[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile (S)-alpha-(2-Chloroethyl)benzenemethanol (170 mg, 1.0 mmol), 4-chloro-2-hydroxybenzonitrile (154 mg, 1.0 mmol.) and triphenylphosphine (260 mg, 1.0 mmol.) in dry tetrahydrofuran (5 ml) were stirred in an ice bath under nitrogen whilst diethyl azodicarboxylate (0.16 ml, 1.0 mmol.) was added. The reaction mixture was allowed to warn to room temperature and stirred for 3 days. The solvent was evaporated and the residue dissolved in toluene, added to the top of a flash chromatography column and eluted with 10percent ether/isohexane to give the product (220 mg, 72percent) as a viscous oil. 1H NMR 300 MHz (CDCl3) 7.21 (1H, d), 7.24-7.33 (5H, m), 6.92 (1H, d of d), 6.75 (1H, d), 5.43 (1H, m), 3.80 (1H, m), 3.56 (1H, m), 2.50 (1H, m), 2.18 (1H, m).
b 2-[[(1R)-3-Chloro-1-phenylpropyl]oxy]-5-fluoro-4-methylbenzonitrile The subtitle compound was prepared by the method of Example 5(a) using 5-fluoro-2-hydroxy-4-methylbenzonitrile and S-alpha-(2-chloroethyl)benzenemethanol. 1H NMR 300 MHz (CDCl3) 7.41-7.29 (5H, m), 7.16 (1H, d), 6.63 (1H, d), 5.45 (1H, m), 3.89 (1H, m), 3.63 (1H, m), 2.55 (1H,), 2.24 (1H, m), 2.17 (3H, s).
With sodium hydroxide; sodium chloride; In N-methyl-acetamide;
A. Preparation of (S)-3-phthalimido-1-phenylpropanol. To a solution of 470 mg of (S)-(-)-3-chloro-1phenylpropanol in 4 ml of dimethylformamide were added 612 mg of potassium phthalimide in 4 ml of dimethylformamide. The mixture was heated at 100 C. for 6 hours, allowed to cool to room temperature, and stirred overnight. The mixture was filtered, the filtrate diluted with water, and the solution extracted with ethyl acetate. The organic layer was washed once with water, once with 0.2 N sodium hydroxide, once again with water, and once with a saturated solution of sodium chloride, dried over sodium sulfate, and concentrated in vacuo to provide 730 mg of an opaque oil that solidified. Crystallization from ethyl acetate/hexanes provided 350 mg of the title intermediate as a white powder, m.p. 80-82.5 C. Analysis for C17 H15 NO3: Calc.: C, 72.58; H, 5.38; N, 4.98; Found: C, 72.57; H, 5.40; N, 4.96.
(1S)-3-(1-naphthyloxy)-1-phenyl-1-propanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.5 g (54%)
In water; N,N-dimethyl-formamide; mineral oil;
1. Using sodium hydride in DMF To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5 C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5 C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3*50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76-78 C.
(R)-N-methyl-3-(3-iodophenoxy)-3-phenylpropanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine;
EXAMPLE 1 Preparation of [R]-(-)-N-Methyl-3-phenyl-3-(3-iodophenoxy)propylamine (Compound 4, FIG. 1) Triphenylphosphine (1.54 g, 5.88 mmole) and ethyl azodicarboxylate (8.93 mL, 1.03 g, 5.88 mmol) were added to a solution of [S]-<strong>[100306-34-1]3-chloro-1-phenylpropanol</strong> (1.0 g, 5.88 mmol) and 3-iodophenol at room temperature for 15 hours. THF was removed under aspirator vacuum. The residue was triturated with petroleum ether (3*15 mL). The combined fractions were concentrated, and the crude product was purified by flash column chromatography on silica gel. Elution with petroleum ether and removal of solvent afforded 1.64 g (75%) of [R]-(+)-11-chloro-3-phenyl-3-(3-iodophenoxy)propane, Compound 2, as a thick colorless liquid: [alpha]25D +1.85 (c 5.4, CHCL3); 1 H NMR (CDCL3 250 MHz)delta 7.40-7.20 (m, 7H), 6.90-6.76 (m, 2H), 5.34 (dd, J=4.6, 9.2 Hz, 1H), 3.82-3.72 (m, 1H), 3.62-3.53 (m, 1H), 2.51--2.38 (m, 1H), 2.26-2.14 (m, 1H). Anal. C15 H14 Cl I O; C,H. In a sealed tube, a mixture of Compound 2 (0.56 g, 1.50 mmol), aqueous methylamine (40%, 4 mL) and ethanol (1.5 mL) was heated at 130 C. for 3 hours. The cooled mixture was poured into water (5 mL) and was extracted with CH2 CL2 (3*5 mL). The organic solution was dried, filtered and concentrated to give a yellowish oil. Flash-column chromatography of the crude produce on silica gel (5% MeOH/CH2 Cl2) afforded 0.28 g (51%) of [R]-(-)-N-Methyl-3-phenyl-3-(3-iodophenoxy)propylamine (Compound 3) as a pale yellow oil; Rf 0.29 (10% MeOH/CH2 Cl2); [alpha]25D -0.71 (c 1.83, CHCl3); 1 H NMR (CDCl3, 250 MHz) delta 7.35-7.15 (m, 7H), 6.90-6.72 (m, 2H), 5.23 (dd, J=4.6, 8.5 Hz, 1H) 3.50 (br s, 1H), 2.81 (br t, 1H), 2.48 (br s, 3H), 2.30-2.16 (m, 1H), 2.16-2.03 (m, 1H); FTIR (neat) 3400 (br, NH), 3100-300 (ArH), 29500-2750 (CH), 1575, 1475, 1225 cm-1. MS m/1 367 (M+1)
EXAMPLE 59 [R]-(+)-1-Chloro-3-phenyl-3-(4-trifluoromethylphenoxy)propane The title compound was prepared by the method of example 55 using [S]-<strong>[100306-34-1]3-chloro-1-phenylpropanol</strong> (2.57g, 15 mmol), alpha,alpha,alpha-trifluoro-cresol (2.4 g, 15 mmol) in THF (40 ml) at room temperature. Workup provided the optically pure title compound as a thick liquid, bp 180-200 C./0/5 mm. [alpha]D +2.3 (c 10, CHCl3; 13 C NMR (CDCl3): 140.50, 129.39, 128.66, 127,56, 127.38, 127.19, 127.01, 126.34, 116.45, 77.82, 41.69, 41.38. Mass spectrum (EI): 153/155 (45), 91 (100). (CI): 314/316, (1, M+), 153/155 (100). Anal. Calcd. for C16 H14 ClNO: C, 61.05; H, 4.45; Cl, 11.29; F, 18.12. Found: C, 61.06; H, 4.51; Cl, 11.16; F, 18.22.
With triphenylphosphine; In tetrahydrofuran; pentane;
EXAMPLE 55 [R]-(-)-1-Chloro-3-phenyl-3-(2-methylphenoxy)propane Triphenylphosphine (5.25 g, 20 mmol) and ethylazodicarboxylate (3.15 ml, 3.48 g, 20 mmol) were added to a solution of [S]-1-chloro-3-phenyl-3-propanol (3.4g, 20 mmol) and o-cresol (2.06 ml, 2.16 mmol) in THF (50 ml). The mixture was stirred at room temperature overnight until the reaction was complete as determined by TLC. THF was removed under aspirator vacuum and the residue treated with pentane (3*50 ml). The combined pentane fractions were concentrated and the residue chromatographed on neutral alumina. Elution with pentane and removal of solvent afforded 3.6 g (70% yield) of the chloro ether as a thick liquid which was found to be 99% pure by gas chromatograph. Bp 180-200 C./0.5mm; [alpha]D23 -21.7 (c 3.9, CHCl3); 13 C-NMR:150.67, 147.81, 128,76, 127,98, 125.32, 122.23, 120.96, 117.35, 112.71, 59.02, 56.02, 41.61. Mass spectrum (EI): 260/262 (1,M+), 224 (1, M+ -HCl), 153 (21, M+ -C7 H8 O), 91 (100, C7 H7). (CI): 261 (7.4, M+ +H),153/155 (100, M+ +H-C7 H8).
1-[4-(4-{(2S,3R)-2-(3'-hydroxybiphenyl-4-yl)-3-[(3S)3-hydroxy-3-phenylpropyl]-4-oxoazetidin-1-yl}phenyl)butyl]-1-azoniabicyclo[2.2.2]octane chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen fluoride; potassium carbonate;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0);
A quaternary salt is made in the following manner. (3-[tert- butyl(dimethyl)silyl]oxy}phenyl)boronic acid and 4-bromostyrene are coupled under Suzuki conditions with tetrakis(triphenylphosphine)palladium(0) and 2.0 M aqueous potassium carbonate in toluene-ethanol solvent. The product is reacted with chlorosulfonyl isocyanate in ethereal solvent followed by alkali aqueous work-up to generate a beta-lactam. The amide proton is exchanged for an aryl group by reaction with 4-iodophenylcarbonylallyl (generated from the commercially available acid by borane reduction and protected with allyl chloroformate) using trans- 1,2- cyclohexanediamine and copper (T) iodide in decane-dioxane as solvent. Deprotonation of the 3-position of the beta-lactam with a suitable base, such as lithium diisopropylamide, and subsequent quenching with tert-butyl[(lS)-4-iodo-l- phenylbutyl]oxy}dimethylsilane (generated from the commercially available (S)-(-)-3- chloro-1 -phenyl- 1-propanol by protection with tert-butyldimethylchlorosilane and Finkelstein reaction with sodium iodide) provide the 3-substituted intermediate. The allyloxycarbonate protecting group is removed with ammonium formate and tetrakis(triphenylphosphine)palladium(0) in tetrahydrofuran and the resulting alcohol converted into the bromide using carbon tetrabromide and triphenylphosphine in dichloromethane. The silyl protecting groups are removed from the benzyl alcohol EPO <DP n="234"/>and the phenol using 48% hydrofluoric acid in acetonitrile. The resulting compound is reacted with a tertiary amine, such as quinuclidine, purified by HPLC and passed through a chloride ion-exchange column to afford l-[4-(4-{(2S,3R)-2-(3'- hydroxybiphenyl-4-yl)-3 - [(3 S)-3 -hydroxy-3 -phenylpropyl] -4-oxoazetidin- 1 - yl}phenyl)butyl]- 1 -azoniabicyclo[2.2.2]octane chloride.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 16h;
To a mixture of 1-(3-bromopropyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.28 g, 1.0 mmol), (S)-(-)-3-chloro-1-phenyl-1-propanol (0.17 g, 1.0 mmol), and triphenylphosphine (314 mg, 1.2 mmol) in anhydrous THF (15 mL) was added DIAD (0.23 mL, 1.2 mmol) under nitrogen at 25 C. The mixture was stirred for 16 hours followed by concentration of the mixture in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-40% ethyl acetate in hexane) to afford 0.17 g of 1-(4-Chloro-phenyl)-3-(3-chloro-1-phenyl-propyl)-1,3-dihydro-benzo[1,2,5]-thiadiazole 2,2-dioxide that was immediately carried on to the next step. MS (ESI) m/z [M-H]- 431;
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h;
To a mixture of 1-ethyl-1,3-dihydro-benzimidazol-2-one (1 g, 6.2 mmol), (S)-(-)-3-chloro-1-phenyl-1-propanol (1.16 g, 6.8 mmol), and triphenylphosphine (1.78 g, 6.8 mmol) in anhydrous THF (25 mL) was added DIAD (1.38 g, 6.8 mmol) under nitrogen at room temperature. The mixture was stirred under nitrogen at room temperature for 18 hrs and solvent removed in vacuo. The residue was purified by a silica gel column (33percent ethyl acetate in hexane) to afford 1-[(1R)-3-chloro-1-phenylpropyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one as an oil (0.5g, 26percent). MS (ESI) m/z 315.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
To a mixture of 3,3-dimethyloxindole (409 mg, 2.53 mmol), <strong>[100306-34-1](S)-3-chloro-1-phenyl-1-propanol</strong> (376 mg, 2.20 mmol) and triphenylphosphine (664 mg, 2.53 mmol) in tetrahydrofuran (5 mL) under nitrogen was added slowly diisopropyl azodicarboxylate (490 muL, 2.53 mmol) via a syringe. The resulting solution was stirred at room temperature overnight. Solvent was removed under reduced pressure and the viscous brown liquid residue was purified using Isco CombiFlash Companion chromatography (RediSep 12-g silica column, 0-12% ethyl acetate/hexane) to give 236 mg (34%) of 1-[(1R)-3-chloro-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a viscous colorless liquid. MS (ES) m/z 314.1 ([M+H]+); HRMS: calculated for C19H20ClNO+H+, 314.1306; found (ESI, [M+H]+), 314.1299.
With NaOH; triphenylphosphine; In tetrahydrofuran; diethyl ether; water;
(R)-3-(3-fluorophenoxy)-3-phenylpropylchloride A solution of (S)-(-)-3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) was dissolved in THF (200 mL). The mixture was cooled to 0 C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3*50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl/satd. aq. NaCl (25 mL), 0.1 M NaOH/satd. aq. NaCl (2*25 mL), and finally H2O (2*25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an oil. The crude product was chromatographed on silica gel, elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7) of product as a colorless oil.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃;
EXAMPLES were made following the reaction route outlined in Scheme 1 below to make the free base and the HCl salt:[0097] The conditions and reagents for the steps are as follows: (a) DIAD, TPP5THF, 00C; (b) 40% aqueous CH3NH2, NaI, 800C, 2h; (c) 2N HCl in EtOAc.[0098] For a particular stereoconformation, the following specific embodiment of Scheme 1 can be used as an example: <n="24"/>[0099] In this embodiment, starting with commercially available optically pure (S)- (-)-3-chloro-l-phenylpropan-l-ol, utilizing mild Mitsunobu reaction conditions, condensed with substituted pyridinols in the presence of diisopropanyl azodicarboxylate (DIAD) and triphenyl phosphine (TPP) (O. Mitsunobu, Synthesis, 1-30(1981)). The reactions resulted in complete inversion of the chiral benzylic carbon to give the corresponding chiral (R)-chloro compounds (K. Yasushi et al., Nucl. Med. Biol, 3 L: 147-153(2004)). Treatment of chloro compounds with excess 40% aqueous methylamine in ethyl alcohol in the presence of catalytic amount of NaI at 1300C under sealed flask afforded methyl amine compounds. The hydrochloride salts were obtained directly by adding 2N hydrogen chloride in ethyl acetate to methyl amine compounds. Similarly, the (S) enantiomer of the compounds above may be prepared using the (R)-(-)-3-chloro-l-phenylpropan-l-ol starting material in the Mitsunobu reaction as discussed herein.[0100] The final compounds were not stable when exposed to air, especially when the sample is dissolved in solution, so the pure products were kept in freezer under nitrogen. All the compounds were confirmed by 1HNMR, LC-MS and 13CNMR. The data of EXAMPLE 6 (R)-(-)-NM-methyl-3-(2-bromo-3-pyridinoxy)-3-phenylpropanamine were, for example, LC-MS, EI (m/z): 321 (100%, M+), 323 (98%, (M+2)+). 1HNMR(CD3OD), 400Mhz), delta(ppm): 7.95 (dd, J=4.2, 1.8Hz, I H), 7.49 (m, 5H), 7.25 (m, 2H), 5.66 (dd, J=4.0, 8.5Hz, IH), 3.32 (m, 2H), 2.82 (s, 3H), 2.49 (m, I H), 2.38 (m, IH). 13C NMR (CDCl3, 100MHz), delta(ppm): 151.18, 145.85, 139.88, 133.08, 131.34, 131.06, 128.86, 126.41, 126.14, 83.01 , <n="25"/>1.01,39.13,33.82.
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