* 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.
Reference：
[1] Chemistry - A European Journal, 1999, vol. 5, # 4, p. 1320 - 1330
[2] Chemistry - A European Journal, 1999, vol. 5, # 4, p. 1320 - 1330
[3] Angewandte Chemie - International Edition, 2001, vol. 40, # 7, p. 1235 - 1238
[4] Angewandte Chemie - International Edition, 2008, vol. 47, # 5, p. 894 - 897
2
[ 445-27-2 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With RuBr2[(S,S)-2,4-bis(diphenylphosphino)pentane](2-picolylamine); potassium <i>tert</i>-butylate; hydrogen In ethanol at 40℃; for 19 h; Inert atmosphere; Autoclave
General procedure: In an autoclave, 1.32 mg of RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) (1.29×10−3 mmol, S/C=10000) and 5.79 mg of potassium tert-butoxide (5.16×10−2 mmol) are placed, and replaced with argon gas. Under argon gas flow, 1.5 mL of acetophenone (12.9 mmol) and 2.9 mL of ethanol was added while measuring by a syringe, pressurized with hydrogen to 10 atm, stirred at 40° C. for 19 hours, then the reduction of the hydrogen pressure was confirmed and phenylethanol was obtained at 100percent yield. The optical purity was 88.0percent ee as measured by GC (CP-Chirasil-DEX CB (0.25 mml. D×25 m, DF=0.25 μm, from VARIAN), constant at 110° C., pressure: 102.0 kPa, column flow: 1.18 mL/min, vaporizing chamber temperature: 250° C., detector temperature: 275° C., the retention time of each enantiomer was: (R): 11.7 min, (S): 12.4 min), and (S) isomer has predominantly been generated.The reaction was carried out in similar way as Working Example 1 except that the complex was changed to RuBr2 [(S,S)-xylskewphos](pica), and the reaction solvent and substrate were changed as indicated in the Table below. The results are summarized in the Table below, which also describes the results from Comparative Example 1. Analysis conditions indicated in the Table is the same as the Table provided from Working Examples ito 6. From the results, it is clear that RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) has a better enantioselectivity as compared to RuBr2[(S,S)-xyl- skewphos] (pica) complex.
83.7 % ee
With dodecacarbonyl-triangulo-triruthenium; (S,S)-N-{1,2-diphenyl-2-[(pyridin-2-ylmethyl)amino]ethyl}-4-methylbenzenesulfonamide In isopropyl alcohol at 80℃; for 48 h; Inert atmosphere; Schlenk technique
General procedure: A mixture of catalyst (2 molpercent) and Ru3 (CO)12 (0.67 molpercent) in IPA (10 cm3) was stirred at 80 °C under an inert atmosphere in a schlenk tube for 30 min. To this solution, ketone (1 mmol) was added and the resulting mixture was stirred at 80 °Cfor 48 h. The reaction mixture was filtered through a short column of silica using (EtOAc:hexane 1:1), a small amount of the filtrate was dilluted in EtOAc and then injected on the GC to determine the conversion and enantiomeric excess.
89.8 % ee
at 60℃; for 5 h; Schlenk technique
General procedure: As Examples 20 to 35, hydrogen transfer reactions to ketones shown in Tables 1, 2, and 3 below were conducted by the same operation as in Examples 16 and 18. In these reactions, the catalyst ratios (S/C) were as shown in the tables, the reaction temperature was 60° C., and a formic acid-triethylamine (5:2) azeotrope was used as a hydrogen source in such an amount that the concentration of the substrate was 2 mol/L. The conversions and the optical purities were determined by analyzing the reaction liquids by GC after predetermined periods.; In addition, as Comparative Examples, results of reactions in which RuCl ((S,S)-Tsdpen) (mesitylene) was used in the same manner are also shown in each table. Note that, in these tables, conv. represents the conversion of the ketone substrate, selec. represents the selectivity for the target product, percent ee represents the optical purity, and S/C represents a value represented by the number of moles of the ketone substrate/the number of moles of the catalyst.
73 % ee
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate In water at 20℃; for 5 h;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2 . The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
73 % ee
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate In water at 20℃; for 5 h; Green chemistry
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2. The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
81 % ee
Stage #1: With dimethylsulfide borane complex; 3-(5-((3R,5S)-5-(hydroxydiphenylmethyl)pyrrolidin-3-yloxy)-5-oxopentyl)-1-methyl-1H-imidazol-3-ium hexafluorophosphate In tetrahydrofuran at 70℃; for 0.5 h; Inert atmosphere; Schlenk technique Stage #2: With hydrogenchloride In waterInert atmosphere; Schlenk technique
General procedure: In a schlenk tube, BH3·SMe2(0.55 mmol, 275 L) was added inthe solution of IL 5 (28 mg, 10 molpercent) dissolved in THF (1 mL), undernitrogen atmosphere. The homogenous mixture was stirred andheated at 70C for 30 min. Later, a solution of ketone (0.5 mmolin THF (0.5 mL)) was added within 30 min. After the addition wascompleted, the solvent was evaporated under vacuum. An aqueoussolution of 1M HCl (5 mL) was added and the product was extractedwith DCM. The solvent was dried on anhydrous sodium sulfateand evaporated under reduced pressure. Crude residue was furtherpurified by column chromatography on silica gel using hexane-ethyl acetate as eluent. Enantiomeric excesses of all alcohols weredetermined by HPLC analysis using Chiralcel OD–H/AD–H chiralcolumn, isopropanol-n-hexane as mobile phase and HPLC condi-tions are given in SI.
74 % ee
at 82℃; for 0.5 h; Inert atmosphere; Schlenk technique
General procedure: Typical procedure for the catalytic hydrogen-transfer reaction: a solution of the Ru(II)-complexes 17–24 (0.005 mmol), KOH (0.025mmol) and the corresponding ketone (0.5 mmol) in degassed 2-propanol (5 mL) was refluxed until the reaction was completed. Periodically samples taken from the reaction medium were passed through acetone silica gel column and conversion rates were observed in gas chromatography, which were calculated based on unreacted ketone.
Reference：
[1] Patent: US2015/31920, 2015, A1, . Location in patent: Page/Page column 0167
[2] Tetrahedron, 1996, vol. 52, # 2, p. 589 - 598
[3] Journal of Organic Chemistry, 1999, vol. 64, # 7, p. 2186 - 2187
[4] European Journal of Inorganic Chemistry, 2000, # 8, p. 1687 - 1692
[5] Tetrahedron: Asymmetry, 2003, vol. 14, # 6, p. 710 - 716
[6] Organic Letters, 2004, vol. 6, # 2, p. 169 - 172
[7] European Journal of Organic Chemistry, 2005, # 15, p. 3221 - 3227
[8] Advanced Synthesis and Catalysis, 2005, vol. 347, # 9, p. 1193 - 1197
[9] Organic Letters, 2006, vol. 8, # 14, p. 3025 - 3027
[10] Tetrahedron Asymmetry, 2006, vol. 17, # 8, p. 1179 - 1185
[11] Angewandte Chemie - International Edition, 2006, vol. 45, # 9, p. 1432 - 1435
[12] Chemical Communications, 2005, # 32, p. 4039 - 4041
[13] Chemical Communications, 2004, # 18, p. 2070 - 2071
[14] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5301 - 5306
[15] Tetrahedron Letters, 2004, vol. 45, # 12, p. 2603 - 2605
[16] Advanced Synthesis and Catalysis, 2007, vol. 349, # 17-18, p. 2556 - 2562
[17] Chemistry - A European Journal, 2006, vol. 12, # 12, p. 3218 - 3225
[18] European Journal of Organic Chemistry, 2008, # 5, p. 934 - 940
[19] Angewandte Chemie - International Edition, 2008, vol. 47, # 48, p. 9240 - 9244
[20] Angewandte Chemie - International Edition, 2008, vol. 47, # 48, p. 9240 - 9244
[21] Tetrahedron Asymmetry, 2009, vol. 20, # 13, p. 1521 - 1525
[22] Tetrahedron Letters, 2009, vol. 50, # 46, p. 6321 - 6324
[23] Chirality, 2010, vol. 22, # 1, p. 173 - 181
[24] Catalysis Letters, 2010, vol. 137, # 1-2, p. 104 - 109
[25] Catalysis Communications, 2010, vol. 11, # 7, p. 584 - 587
[26] Catalysis Communications, 2010, vol. 11, # 5, p. 373 - 377
[27] Chinese Chemical Letters, 2010, vol. 21, # 5, p. 576 - 579
[28] Journal of Molecular Catalysis A: Chemical, 2010, vol. 333, # 1-2, p. 20 - 27
[29] Dalton Transactions, 2011, vol. 40, # 10, p. 2338 - 2347
[30] Monatshefte fur Chemie, 2009, vol. 140, # 10, p. 1189 - 1194
[31] Organic and Biomolecular Chemistry, 2012, vol. 10, # 25, p. 4864 - 4877
[32] Tetrahedron Letters, 2012, vol. 53, # 30, p. 3839 - 3842
[33] Organometallics, 2012, vol. 31, # 11, p. 4241 - 4250
[34] Tetrahedron Asymmetry, 2012, vol. 23, # 11-12, p. 834 - 837
[35] Organic Letters, 2012, vol. 14, # 20, p. 5230 - 5233,4
[36] Organic Letters, 2012, vol. 14, # 20, p. 5230 - 5233
[37] Tetrahedron Letters, 2013, vol. 54, # 32, p. 4250 - 4253
[38] Patent: US2014/51871, 2014, A1, . Location in patent: Paragraph 0129; 0130; 0138; 0139; 0140
[39] ChemistryOpen, 2013, vol. 2, # 2, p. 50 - 54
[40] ChemCatChem, 2014, vol. 6, # 5, p. 1368 - 1374
[41] Applied Organometallic Chemistry, 2014, vol. 28, # 7, p. 517 - 522
[42] Catalysis Communications, 2014, vol. 57, p. 111 - 114
[43] Catalysis Communications, 2012, vol. 28, p. 5 - 8
[44] Catalysis Communications, 2014, vol. 57, p. 111 - 114
[45] European Journal of Organic Chemistry, 2006, # 16, p. 3606 - 3616
[46] Journal of Molecular Catalysis A: Chemical, 2015, vol. 398, p. 184 - 189
[47] Applied Organometallic Chemistry, 2015, vol. 29, # 11, p. 764 - 770
[48] Applied Organometallic Chemistry, 2015, vol. 29, # 11, p. 764 - 770
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[53] Applied Organometallic Chemistry, 2018, vol. 32, # 1,
[54] European Journal of Inorganic Chemistry, 2018, vol. 2018, # 12, p. 1383 - 1393
3
[ 394-46-7 ]
[ 50919-06-7 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Reference：
[1] Chemistry - A European Journal, 1999, vol. 5, # 4, p. 1320 - 1330
[2] Chemistry - A European Journal, 1999, vol. 5, # 4, p. 1320 - 1330
[3] Angewandte Chemie - International Edition, 2001, vol. 40, # 7, p. 1235 - 1238
[4] Angewandte Chemie - International Edition, 2008, vol. 47, # 5, p. 894 - 897
4
[ 75-24-1 ]
[ 446-52-6 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2005, vol. 44, # 15, p. 2232 - 2234
With RuBr2[(S,S)-2,4-bis(diphenylphosphino)pentane](2-picolylamine); potassium tert-butylate; hydrogen; In ethanol; at 40℃; under 7600.51 Torr; for 19h;Inert atmosphere; Autoclave;
General procedure: In an autoclave, 1.32 mg of RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) (1.29×10-3 mmol, S/C=10000) and 5.79 mg of potassium tert-butoxide (5.16×10-2 mmol) are placed, and replaced with argon gas. Under argon gas flow, 1.5 mL of acetophenone (12.9 mmol) and 2.9 mL of ethanol was added while measuring by a syringe, pressurized with hydrogen to 10 atm, stirred at 40 C. for 19 hours, then the reduction of the hydrogen pressure was confirmed and phenylethanol was obtained at 100% yield. The optical purity was 88.0% ee as measured by GC (CP-Chirasil-DEX CB (0.25 mml. D×25 m, DF=0.25 mum, from VARIAN), constant at 110 C., pressure: 102.0 kPa, column flow: 1.18 mL/min, vaporizing chamber temperature: 250 C., detector temperature: 275 C., the retention time of each enantiomer was: (R): 11.7 min, (S): 12.4 min), and (S) isomer has predominantly been generated.The reaction was carried out in similar way as Working Example 1 except that the complex was changed to RuBr2 [(S,S)-xylskewphos](pica), and the reaction solvent and substrate were changed as indicated in the Table below. The results are summarized in the Table below, which also describes the results from Comparative Example 1. Analysis conditions indicated in the Table is the same as the Table provided from Working Examples ito 6. From the results, it is clear that RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) has a better enantioselectivity as compared to RuBr2[(S,S)-xyl- skewphos] (pica) complex.
With (S,S)-DPENDS; C36H24Cl2O18P2RuS6(6-)*6Na(1+); hydrogen; potassium hydroxide; In water; at 30℃; under 37503.8 Torr; for 3h;Autoclave;
General procedure: To a 60 mL stainless autoclave with a glass liner and magnetic stirrer were added PEG-400, H2O, RuCl2(TPPTS)2, (S,S)-DPENDS, KOH, and reactant. Hydrogen was introduced to the desired pressure after the reaction mixture had been purged with H2 five times. The products were extracted by n-hexane and analyzed by GC-960 with a FID detector and beta-DEX120 capillary column (30 m × 0.25 mm, 0.25 mum film) at 115 C. The enantiomeric excess (ee value) was calculated from the equation: ee (%) = 100 × (R - S)/(R + S).
With dodecacarbonyl-triangulo-triruthenium; (S,S)-N-{1,2-diphenyl-2-[(pyridin-2-ylmethyl)amino]ethyl}-4-methylbenzenesulfonamide; In isopropyl alcohol; at 80℃; for 48h;Inert atmosphere; Schlenk technique;
General procedure: A mixture of catalyst (2 mol%) and Ru3 (CO)12 (0.67 mol%) in IPA (10 cm3) was stirred at 80 C under an inert atmosphere in a schlenk tube for 30 min. To this solution, ketone (1 mmol) was added and the resulting mixture was stirred at 80 Cfor 48 h. The reaction mixture was filtered through a short column of silica using (EtOAc:hexane 1:1), a small amount of the filtrate was dilluted in EtOAc and then injected on the GC to determine the conversion and enantiomeric excess.
With formic acid; (S,S)-RuCl(eta6-CH3C6H4CH2CH2CH2CH2NHCH(C6H5)CH(C6H5)NSO2Ts); C32H35ClN2O2RuS; triethylamine; at 60℃; for 5h;Schlenk technique;Catalytic behavior;
General procedure: As Examples 20 to 35, hydrogen transfer reactions to ketones shown in Tables 1, 2, and 3 below were conducted by the same operation as in Examples 16 and 18. In these reactions, the catalyst ratios (S/C) were as shown in the tables, the reaction temperature was 60 C., and a formic acid-triethylamine (5:2) azeotrope was used as a hydrogen source in such an amount that the concentration of the substrate was 2 mol/L. The conversions and the optical purities were determined by analyzing the reaction liquids by GC after predetermined periods.; In addition, as Comparative Examples, results of reactions in which RuCl ((S,S)-Tsdpen) (mesitylene) was used in the same manner are also shown in each table. Note that, in these tables, conv. represents the conversion of the ketone substrate, selec. represents the selectivity for the target product, % ee represents the optical purity, and S/C represents a value represented by the number of moles of the ketone substrate/the number of moles of the catalyst.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate; In water; at 20℃; for 5h;Catalytic behavior;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2 . The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate; In water; at 20℃; for 5h;Green chemistry;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2. The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
General procedure: In a schlenk tube, BH3·SMe2(0.55 mmol, 275 L) was added inthe solution of IL 5 (28 mg, 10 mol%) dissolved in THF (1 mL), undernitrogen atmosphere. The homogenous mixture was stirred andheated at 70C for 30 min. Later, a solution of ketone (0.5 mmolin THF (0.5 mL)) was added within 30 min. After the addition wascompleted, the solvent was evaporated under vacuum. An aqueoussolution of 1M HCl (5 mL) was added and the product was extractedwith DCM. The solvent was dried on anhydrous sodium sulfateand evaporated under reduced pressure. Crude residue was furtherpurified by column chromatography on silica gel using hexane-ethyl acetate as eluent. Enantiomeric excesses of all alcohols weredetermined by HPLC analysis using Chiralcel OD-H/AD-H chiralcolumn, isopropanol-n-hexane as mobile phase and HPLC condi-tions are given in SI.
With (2R)-2-[benzyl([6-({benzyl[(1R)-2-[(diphenylphosphanyl)oxy]-1-phenylethyl]amino}methyl)pyridin-2-yl]methyl})amino]-2-phenylethyl diphenylphosphinite bis(dichloro-eta6-p-cymeneruthenium(II)); isopropyl alcohol; potassium hydroxide; at 82℃; for 0.5h;Inert atmosphere; Schlenk technique;Catalytic behavior;
General procedure: Typical procedure for the catalytic hydrogen-transfer reaction: a solution of the Ru(II)-complexes 17-24 (0.005 mmol), KOH (0.025mmol) and the corresponding ketone (0.5 mmol) in degassed 2-propanol (5 mL) was refluxed until the reaction was completed. Periodically samples taken from the reaction medium were passed through acetone silica gel column and conversion rates were observed in gas chromatography, which were calculated based on unreacted ketone.
With [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); sodium formate; In methanol; water; at 50℃; for 12h;Green chemistry;
0.5 mmol of 1-(2-fluorophenyl)ethanol was added to the test tube, 1.5 mmol of dipropylene glycol dimethyl ether was added to the oxygen balloon, and the reaction was completed at 120 C for 12 hours until the reaction was completed, and sodium formate was added to the reaction system, 2.5 mmol. Then add 0.0025 mmol of catalyst B, add 4 mL of methanol:water (3:1), replace with nitrogen three times, react at 50 C for 12 h, wash with water after the reaction, extract the aqueous phase with ethyl acetate three times, and concentrate the organic phase to dry Column chromatography (petroleum ether: ethyl acetate = 10:1) gave (S)-1-(2-fluorophenyl)ethanol (61.6 mg), yield 88%, ee value 86%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane / isopropanol = 98: 2 (volume ratio), flow rate: 1.0 ml / min, wavelength: 254 nm, temperature, 25 C, t1 = 11.82min, t2=12.72min;
With glucose dehydrogenase; D-glucose; NAD; acetophenone reductase from Geotrichum candidum NBRC 4597 (Trp288Ala mutant); In aq. buffer; at 30℃; for 14h;pH 7.2;Enzymatic reaction;Kinetics;
General procedure: Reductions were performed in 50 mL of 100 mM HEPES-NaOH buffer (pH 7.2) consisting of1.4 mM NAD+, 0.23-0.39 mmol of 2a-13a, cofactor regeneration reagent written in Table S1, and purified GcAPRD with the amount written in Table S1. Reactions were done for 14 h at 30C with a rotational speed of 130 rpm. The product was extracted with diethyl ether, dried over MgSO4, and evaporated under reduced pressure. Silica gel column chromatography (hexane:ethyl acetate 4:1) were performed to give the corresponding chiral alcohols 2b-13b.
With (S,S)-RuCl2(2,2'-bis(di-3,5-xylylphosphino)-1,1'-binaphthyl)(1,1-dianisyl-2-isopropyl-1,2-ethylenediamine); potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 26 - 30℃; for 13h;
95%
With water; sodium formate; sodium dodecyl-sulfate at 39.84℃; for 96h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
93%
With bromopentacarbonylmanganese(I); hydrogen; C45H43FeNP2; potassium hydroxide In methanol; toluene at 20℃; for 36h; enantioselective reaction;
91%
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; N-(tert-butoxycarbonyl)-L-valine-(6-O-benzoyl-1-O-benzyl-5-deoxy-2,3-O-isopropylidene-5-thioamido-α-D-mannofuranose); potassium <i>tert</i>-butylate; lithium chloride In tetrahydrofuran; isopropyl alcohol at 20℃; for 3h; enantioselective reaction;
90%
With dimethylsulfide borane complex In tetrahydrofuran for 1h; Heating;
82%
Stage #1: 2'-Fluoroacetophenone With Triethoxysilane; (S,E)-(+)-2,6-diisopropyl-N-(2-((2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)amino)benzylidene)aniline; sodium triethylborohydride; cobalt(II) chloride In tetrahydrofuran; dichloromethane at 20℃; for 15h; Schlenk technique; Inert atmosphere;
Stage #2: With potassium carbonate In tetrahydrofuran; methanol; dichloromethane at 20℃; for 2h; Schlenk technique; Inert atmosphere; enantioselective reaction;
81%
With C22H27Cl2CoN3O; sodium triethylborohydride; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In tetrahydrofuran; diethyl ether at 20℃; for 2h; Inert atmosphere; enantioselective reaction;
With borane N,N-diethylaniline complex; (S)-C17H18BNO In toluene at 45℃; for 0.75h;
Multi-step reaction with 2 steps
1: sodium borohydride / methanol
2: aq. phosphate buffer / 192 h / Microbiological reaction
90.6 % ee
Stage #1: 2'-Fluoroacetophenone With dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at 20℃;
Stage #2: With methanol In tetrahydrofuran
35.1
Step 1: 2'-Fluoroacetophenone (25 g, 180 mmol) and (S)-(-)-2-methyl-CBS-oxazaborolidine (6.02 g, 22 mmol) were combined in THF (200 mL). Borane methyl sulfide complex (2M in THF; 59.4 mL, 119 mmol) was added over 20 minutes, and the reaction was stirred at room temperature for 30 minutes. Methanol was added, and the mixture was worked-up with dichloromethane and water. The organic layer was concentrated to give (R)-1-(2-fluoro-phenyl)-ethanol in 90.6% e.e.
90.6 % ee
Stage #1: 2'-Fluoroacetophenone With dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at 20℃; for 0.833333h;
Stage #2: With methanol In tetrahydrofuran
1.1
2'-Fluoroacetophenone (25g, 180mmol) and (S)-(-)-2-methyl-CBS-oxazaborolidine (6.02g, 22mmol) were combined in THF (20OmL). Borane methyl sulfide complex (2M in THF; 59.4mL, 119mmol) was added over 20 minutes, and the reaction was stirred at room temperature for 30 minutes. MeOH was added, and the mixture was worked-up with CH2CI2 and H2O. The organic layer was concentrated to give the title compound in 90.6% e.e., determined by HPLC analysis of the acetate derivative (made by reacting the benzyl alcohol with acetyl chloride and triethylamne in methylene chloride) using Chiralcel OD eluted with 99.8:0.2 Hexanes:EtOH; R isomer retention time 5.9 minutes.
With formic acid; [RhCl2(p-cymene)]2; C18H24N2O2S; triethylamine at 40℃; for 28h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
With formic acid; C31H33ClN2O3RuS; triethylamine at 40℃; for 9h; Inert atmosphere; enantioselective reaction;
97 % ee
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 25℃; for 4h;
38
A solution of the ketone in 2-propanol was added to a 50 mL Schlenk flask. After evacuating and refilling with argon, a mixture of the catalyst and base (eg. KO'Bu) was added. The resulting mixture was then injected into a 50 mL autoclave which had been previously placed under an atmosphere of hydrogen. The autoclave was pressurized with hydrogen gas and the reaction mixture was stirred at the desired temperature. The reaction progress was monitored by TLC. Upon completion of the reaction, the solvent was removed under vacuum and the mixture was filtered through a short pad of silica gel (ca. 6 cm) using hexane/ethyl acetate. The solvent was then removed from the filtrate affording the product.
With C46H43Cl2FeNOP2Ru; potassium isopropoxide; isopropyl alcohol at 20℃; for 0.0833333h; optical yield given as %ee; enantioselective reaction;
Multi-step reaction with 3 steps
1.1: sodium iodide / acetonitrile / 0.08 h / 20 °C / Inert atmosphere
1.2: 20 °C / Inert atmosphere
2.1: bis(pentafluorophenyl)borohydride; C52H58; tri-tert-butyl phosphine; hydrogen / toluene; pentane / 24 h / 50 °C / 30003 Torr / Autoclave
3.1: tetrabutyl ammonium fluoride / toluene; pentane; tetrahydrofuran / 0.5 h / 20 °C
Multi-step reaction with 2 steps
1: C52H58; bis(pentafluorophenyl)borohydride; tri-tert-butyl phosphine / toluene; pentane / 4 h / 50 °C / Sealed tube; Inert atmosphere; Glovebox
2: tetrabutyl ammonium fluoride / toluene; pentane; tetrahydrofuran / 0.5 h / 20 °C / Sealed tube; Inert atmosphere; Glovebox
98.9 % ee
With SmADH31 Enzymatic reaction; stereoselective reaction;
Stage #1: (R)-1-(2-fluorophenyl)ethanol With diphenyl phosphoryl azide In toluene at 20℃; for 18h;
Stage #2: With triphenylphosphine In tetrahydrofuran; water for 16h;
Stage #3: trifluoroacetic acid Further stages.;
Stage #1: 5-(4-Bromo-3-methyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene for 0.166667h;
Stage #2: (R)-1-(2-fluorophenyl)ethanol In toluene at 85℃; for 3h;
36.5
Step 5: [5-(4-Bromo-3-methyl-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester5-(4-Bromo-3-methyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid (1.78 g, 6.0 mmol) was dissolved in toluene (50 mL). Triethylamine (0.92 mL, 6.6 mmol) was added, followed by diphenylphosphoryl azide (1.43 mL, 6.6 mmol), and the mixture was stirred for 10 minutes. (R)-1-(2-Fluoro-phenyl)-ethanol (0.924 g, 6.6 mmol) was added, and the reaction was stirred at 85° C. for 3 hours, and then overnight at room temperature. The mixture was concentrated, and the residue was diluted with dichloromethane and purified by silica gel chromatography to give the title compound.
1.1
2'-Fluoroacetophenone (25g, 180mmol) and (S)-(-)-2-methyl-CBS-oxazaborolidine (6.02g, 22mmol) were combined in THF (20OmL). Borane methyl sulfide complex (2M in THF; 59.4mL, 119mmol) was added over 20 minutes, and the reaction was stirred at room temperature for 30 minutes. MeOH was added, and the mixture was worked-up with CH2CI2 and H2O. The organic layer was concentrated to give the title compound in 90.6% e.e., determined by HPLC analysis of the acetate derivative (made by reacting the benzyl alcohol with acetyl chloride and triethylamne in methylene chloride) using Chiralcel OD eluted with 99.8:0.2 Hexanes:EtOH; R isomer retention time 5.9 minutes.
With diphenyl phosphoryl azide; triethylamine In toluene at 80℃; for 1h;
1.2
To a solution of 3-(4-bromophenyl)-5-methylisoxazole-4-carboxylic acid (0.10Og, 0.35mmol) in toluene (3mL) was added triethylamine (0.054mL, 0.39mmol) anddiphenylphosphoryl azide (0.084mL, 0.39mmol), followed by (R)-l-(2-fluoro-phenyl)-ethanol (0.055g, 0.39mmol), and the reaction was stirred at 800C for 1 hour. Once no starting material was seen by analytical LCMS, standard aqueous work-up was performed. The organic layer was treated with silica gel, and the mixture was concentrated and purified by silica gel chromatography to give the title compound.
Stage #1: bis(trichloromethyl) carbonate; 1-[4'-(5-amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester With triethylamine In dichloromethane; toluene at 90℃; for 0.166667h; Inert atmosphere;
Stage #2: (R)-1-(2-fluorophenyl)ethanol In dichloromethane; toluene at 85℃; for 2h; Inert atmosphere;
[3-(4-bromo-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.4%
With diphenyl phosphoryl azide; triethylamine In toluene at 80℃; for 6h; Inert atmosphere;
5.1 Step 1: [3-(4-Bromo-phenyl)-5-methyl-3H-[l,2,3]triazol-4-yl]-carbamic acid (R)-l-(2- fluoro-phenyl)-ethyl ester
In a 20 mL reaction vial, 3-(4-bromo-phenyl)-5-methyl-3H-[l,2,3]triazole-4-carboxylic acid 100 mg, 0.354 mmol), (R)-l-(2-fluorophenyl)ethanol (49.6 mg, 49 μ, 0.354 mmol) and triethylamine (35.8 mg, 49.3 μ, 0.354 mmol) were combined with toluene (2.5 mL) to give a yellow suspension and to this was added diphenylphosphorylazide (97.4 mg, 76.3 μ, 0.354 mmol). The vial's atmosphere was purged with nitrogen, sealed, heated in an oil bath at 80 °C for 4 h, and cooled to room temperature overnight. Additional reagents were added, (R)-l-(2-fluorophenyl)ethanol (24.8 mg, 24.5 μ, 0.177 mmol), triethylamine (72.6 mg, 100 μ, 0717 mmol), and diphenylphosphorylazide (97.4 mg, 76.3 μ, 0.354 mmol). The vial's atmosphere was purged with nitrogen, sealed, heated in an oil bath at 80°C for 2 h, and cooled to room temperature. The reaction was supported on celite and purified by flash chromatography (silica gel, 12 g Redisep, 20 mL/min, 0% to 40% EtOAc in hexanes). Appropriate fractions combined, concentrated, dried from DCM / hexanes, to obtain [3-(4- Bromo-phenyl)-5-methyl-3H-[ 1 ,2,3]triazol-4-yl]-carbamic acid (R)- 1 -(2-fluoro-phenyl)- ethyl ester (95.7 mg, 64.4% yield) as solid. LC/MS calcd. for Ci8Hi6BrFN402 (m/e) 418/420, obsd. 419/421 (M+H, ES+).
With diphenyl phosphoryl azide; triethylamine In toluene at 65℃; for 2h; Inert atmosphere;
Stage #1: ((1-(2-fluorophenyl)vinyl)oxy)trimethylsilane With tri-tert-butyl phosphine; C52H54; hydrogen; bis(pentafluorophenyl)borohydride In 1,3,5-trimethyl-benzene; pentane at 50℃; for 24h; Inert atmosphere; Sealed tube;
Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran; 1,3,5-trimethyl-benzene; pentane at 20℃; for 1h; enantioselective reaction;
Multi-step reaction with 2 steps
1: bis(pentafluorophenyl)borohydride; C52H58; tri-tert-butyl phosphine; hydrogen / toluene; pentane / 24 h / 50 °C / 30003 Torr / Autoclave
2: tetrabutyl ammonium fluoride / toluene; pentane; tetrahydrofuran / 0.5 h / 20 °C
2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-[1,1'-biphenyl]-4-yl}-5-fluorothiophene-3-carboxylic acid[ No CAS ]
[ 162427-79-4 ]
(R)-1-{4'-[5-fluoro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-[1,1'-biphenyl]-4-yl}-5-fluorothiophene-3-carboxylic acid With diphenylphosphoranyl azide; triethylamine In toluene at 20℃; for 1h; Inert atmosphere;
Stage #2: (R)-1-(2-fluorophenyl)ethanol In toluene at 70℃; for 2h; Inert atmosphere;
31 (Example 31) (R)-1-{4'-[5-Fluoro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester (Compound No. I-102)
201.9 mg (0.492 mmol) of 2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-[1,1'-biphenyl]-4-yl}-5-fluorothiophene-3-carboxylic acid synthesized in analogy to Reference Example 33 was added, and dehydrated toluene (2 ml) was added. The mixture was subjected to azeotropic dehydration treatment, and subsequently the atmosphere was replaced with argon. Then, 4 ml of dehydrated toluene, 0.083 mL of triethylamine (0.60 mmol) and 0.127 ml (0.590 mmol) of diphenylphosphoryl azide were added, and the mixture was stirred at room temperature for one hour. Then, 103.5 mg (0.738 mmol) of (R)-1-(2-fluorophenyl)ethanol (Apollo) was added, and the mixture was heated and stirred at 70°C for 2 hours. After completion of the reaction, the reaction mixture was cooled, and water and ethyl acetate were added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 100:0 to 76:24 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 271.7 mg (0.413 mmol (purity 83% by weight), yield 84%) of the title compound as a colorless foam. Mass spectrum (EI, m/z): 547 [M]+. 1H-NMR spectrum (400 MHz, DMSO-d6, 75°C) δ : 9.06 (1H, brs), 7.69-7.64 (2H, m), 7.63-7.59 (2H, m), 7.55-7.51 (2H, m), 7.45-7.39 (3H, m), 7.37-7.30 (1H, m), 7.23-7.11 (2H, m), 6.75 (1H, d, J = 2.8 Hz), 5.94 (1H, q, J = 6.6 Hz), 4.06 (2H, q, J = 7.1 Hz), 1.52 (2H, dd, J = 7.0, 4.0 Hz), 1.49 (3H, d, J = 6.7 Hz), 1.22 (2H, dd, J = 7.0, 4.1 Hz), 1.13 (3H, t, J = 7.0 Hz).
1-[4'-(3-carbamoyl-5-chlorothiophen-2-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl]cyclopropane-1-carboxylic acid ethyl ester[ No CAS ]
[ 162427-79-4 ]
(R)-1-{4'-[5-chloro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With pyridine; bis-[(trifluoroacetoxy)iodo]benzene In toluene at 80℃; for 1.5h; Inert atmosphere;
53 (Example 53) (R)-1-{4'-[5-Chloro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester (Compound No. I-352)
To a solution of 103 mg (0.23 mmol) of 1-[4'-(3-carbamoyl-5-chlorothiophen-2-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl]cyclopro-panecarboxylic acid ethyl ester synthesized in analogy to Reference Example 30, 41 mg (0.29 mmol) of (R)-1-(2-fluorophenyl)ethanol (Apollo) and 0.080 ml (0.99 mmol) of pyridine in toluene (4 ml) was added 120 mg (0.28 mmol) of [bis(trifluoroacetoxy)iodo]benzene under a nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 80°C for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 99:1 to 80:20 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 98 mg (0.16 mmol, yield 73%) of the title compound as an orange foam. Mass spectrum (EI, m/z): 593 [M]+. 1H-NMR spectrum (400 MHz, DMSO-d6) δ : 9.47 (1H, brs), 7.48-7.31 (7H, m), 7.24-7.16 (4H, m), 7.13-7.07 (1H, m), 5.95 (1H, q, J = 6.4 Hz), 4.06 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 1.54-1.43 (5H, m), 1.23 (2H, dd, J = 7.0, 4.1 Hz), 1.13 (3H, t, J = 7.1 Hz).
2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-2-methoxy-[1,1'-biphenyl]-4-yl}-5-fluorothiophene-3-carboxylic acid[ No CAS ]
[ 162427-79-4 ]
(R)-1-{4'-[5-fluoro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-2-methoxy-[1,1'-biphenyl]-4-yl}-5-fluorothiophene-3-carboxylic acid With diphenylphosphoranyl azide; triethylamine In toluene at 20℃; for 0.5h; Inert atmosphere;
Stage #2: (R)-1-(2-fluorophenyl)ethanol In toluene at 70℃; for 2h; Inert atmosphere;
86 (Example 86) (R)-1-{4'-[5-Fluoro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester (Compound No. I-422)
To a solution of 72 mg (0.16 mmol) of 2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-2-methoxy-[1,1-biphenyl]-4-yl}-5-fluorothio-phene-3-carboxylic acid synthesized in analogy to Reference Example 34 in toluene (4 ml) was added 0.045 ml (0.32 mmol) of triethylamine and 0.045 ml (0.21 mmol) of diphenylphosphoryl azide under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Then, 35 mg (0.25 mmol) of (R)-1-(2-fluorophenyl)ethanol (Apollo) was added, and the mixture was heated and stirred at 70°C for 2 hours. After completion of the reaction, to the reaction mixture were added ethyl acetate and water to separate the organic layer. The resulting organic layer was washed with saturated brine, subsequently dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 93:7 to 72:28 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 67 mg (0.081 mmol (purity 73% by weight, yield 52%) of the title compound as a colorless oil. Mass spectrum (EI, m/z): 577 [M]+. 1H-NMR spectrum (400 MHz, CDCl3) δ : 7.53-7.46 (2H, m), 7.43-7.33 (4H, m), 7.31-7.26 (1H, m), 7.18-7.10 (2H, m), 7.08-6.98 (2H, m), 6.97 (1H, d, J = 1.6 Hz), 6.84 (1H, brs), 6.13 (1H, q, J = 6.7 Hz), 4.13 (2H, q, J = 7.1 Hz), 3.81 (3H, s), 1.62 (2H, dd, J = 7.0, 4.0 Hz), 1.60 (3H, d, J = 6.7 Hz), 1.24 (2H, dd, J = 6.9, 3.9 Hz), 1.20 (3H, t, J = 7.2 Hz).
1-[4'-(3-carbamoyl-5-chlorothiophen-2-yl)-[1,1'-biphenyl]-4-yl]cyclopropane-1-carboxylic acid ethyl ester[ No CAS ]
[ 162427-79-4 ]
(R)-1-{4'-[5-chloro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; bis-[(trifluoroacetoxy)iodo]benzene In toluene at 80℃; for 1h; Inert atmosphere;
9 (Example 9) (R)-1-{4'-[5-Chloro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester (Compound No. I-26)
To a solution of 160 mg (0.38 mmol) of 1-[4'-(3-carbamoyl-5-chlorothiophen-2-yl)-[1,1'-biphenyl]-4-yl]cyclopropanecarboxylic acid ethyl ester synthesized in analogy to Reference Example 24, 72 mg (0.51 mmol) of (R)-1-(2-fluorophenyl)ethanol (Apollo) and 0.10 ml (1.2 mmol) of pyridine in toluene (3 ml) was added 199 mg (0.46 mmol) of [bis(trifluoroacetoxy)iodo]benzene under a nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 80°C for one hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 87:13 to 66:34 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 195 mg (0.30 mmol (purity 87% by weight), yield 80%) of the title compound as a brown oil. Mass spectrum (CI, m/z): 563 [M]+. 1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.47 (1H, brs), 7.74-7.69 (2H, m), 7.66-7.62 (2H, m), 7.59-7.32 (6H, m), 7.31-7.15 (3H, m), 5.93 (1H, q, J = 6.1 Hz), 4.05 (2H, q, J = 7.1 Hz), 1.56-1.43 (5H, m), 1.24 (2H, dd, J = 7.1, 4.1 Hz), 1.12 (3H, t, J = 7.1 Hz).
(S)-2-((3-(4-hydroxyphenyl)propyl)amino)propionamide[ No CAS ]
[ 162427-79-4 ]
C20H25FN2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 90℃;
34 13.2 Preparation of Compound I-13
Take 142mg (0.54mmol) of triphenylphosphine and 124mg (0.54mmol) of di-tert-butyl azodicarboxylate in a 10mL sealed tube,Add 2mL of tetrahydrofuran and stir until it is clear, add 77mg (0.54mmol) of 2-chlorobenzyl alcohol and stir until it is clear, add 222mg (0.45mmol) (S)-2-((3-(4-hydroxyphenyl)propyl) Amino) propionamide was slowly heated to 90°C, after overnight reaction, it was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 51 mg of white solid with a yield of 33%.
Stage #1: With C36H28FeMnN2O3P(1+)*Br(1-); potassium carbonate In ethanol at 20℃; for 0.0833333h; Glovebox;
Stage #2: With hydrogen In ethanol at 50℃; for 16h; Glovebox; Autoclave;
16 Example 11 Asymmetric hydrogenation of acetophenone with Mn-PNN catalyst
General procedure: In the glove box, add Mn-Cat.1 catalyst (3.8mg, 0.005mmol) and substrate acetophenone (120mg, 1mmol) into a 5mL clear glass vial, then potassium carbonate (1.4 mg, 0.01 mmol) and absolute ethanol (3 mL) were added, and the mixture was stirred at room temperature for 5 min. Finally, the hydrogenation bottle was put into the autoclave, the hydrogen was replaced three times and then filled with 30 bar H2, and reacted at 50°C for 16h. After the reaction is completed, the hydrogen is released carefully, the solvent is spin-dried under reduced pressure, and the hydrogenated product (R)-1-phenylethanol is purified by silica gel column, a colorless and transparent liquid, >99% conversion, 95% yield, 77% ee,
37
(S)-2-((3-(4-hydroxyphenyl)propyl)amino)propionamide[ No CAS ]
[ 162427-79-4 ]
(S)-2-((3-(4-((R)-1-(2-fluorophenyl)ethoxy)phenyl)propyl)amino)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 90℃;
2.15 General procedure for synthesis of the compounds 19a-i
General procedure: Triphenylphosphine (142 mg, 0.54 mmol), di-tert-butyl azodicarboxylate (124 mg, 0.54 mmol) and anhydrous tetrahydrofuran (2 mL) were added to a 10 mL reaction tube, equipped with a stirrer bar. Then, the substituted benzyl alcohol (0.54 mmol) and the compound 18 (0.45 mmol) were added sequentially. The reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography on silica gel to give the compounds 19a-i. 2.15.1. (S)-2-((3-(4-((R)-1-(2-fluorophenyl)ethoxy)phenyl)propyl)amino)propan amide (19a) 19a (54 mg, 35%) was obtained as a white solid after purification by column chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide (20:1:0.2). Mp: 64.0-65.6 °C. 1H NMR (400 MHz, CD3OD) δ 7.51 - 7.32 (m, 1H), 7.22 (d, J = 5.4 Hz, 1H), 7.12 - 6.94 (m, 4H), 6.74 (t, J = 11.9 Hz, 2H), 5.71 - 5.47 (m, 1H), 3.29 - 3.16 (m, 1H), 2.54 (dd, J = 13.6, 6.6 Hz, 4H), 1.80 - 1.67 (m, 2H), 1.60 - 1.51 (m, 3H), 1.28 - 1.20 (m, 3H). 13C NMR (151 MHz, CD3OD) δ 179.5, 161.0 (d, J = 244.0 Hz), 157.1, 135.4, 131.4 (d, J = 13.6 Hz), 130.2 (d, J = 7.8 Hz), 128.2 (d, J = 3.6 Hz), 125.6 (d, J = 2.6 Hz), 116.6, 116.2 (d, J = 21.9 Hz), 70.5, 58.3, 48.3, 33.4, 32.3, 23.3, 19.3. HRMS (ESI, m/z): calculated for C20H26FN2O2 [M + H]+ 345.1973, found 345.1980.
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