* 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] Journal of Organic Chemistry, 1955, vol. 20, p. 1330,1335
[2] Journal of Organic Chemistry, 1951, vol. 16, p. 1541,1544
2
[ 936-59-4 ]
[ 1662-01-7 ]
Reference：
[1] Journal of Organic Chemistry, 1951, vol. 16, p. 1541,1544
3
[ 936-59-4 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[2] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[3] Chinese Journal of Chemistry, 2011, vol. 29, # 3, p. 504 - 510
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 3, p. 268 - 275
4
[ 18776-12-0 ]
[ 936-59-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
With dihydrogen peroxide; acetic acid; sodium bromide In water at 60℃; for 2 h; Inert atmosphere
General procedure: Under nitrogen atmosphere, to a solution of substrate alcohol (0.5 mmol) in aceticacid (1.0 mL) was added a stock-solution of aqueous NaBr solution (1.94 M, 25 μL)and 30percent aqueous H2O2 (50 μL, 0.5 mmol). After stirring the mixture for one hour at60 °C, additional 30percent aqueous H2O2 (50 μL, 0.5 mmol) was added, and stirring wascontinued for another one hour. After cooling, the mixture was poured into a saturatedaqueous NaHCO3 solution (ca. 30 mL) with the aid of CH2Cl2, and resulting mixturewas extracted with CH2Cl2. The combined organic layers were dried over anhydrousMgSO4, filtered and concentrated in vacuo. The residue was chromatographed onsilica gel (flash column or preparative TLC) to afford the corresponding ketone.
Reference：
[1] Synlett, 2016, vol. 27, # 5, p. 789 - 793
[2] Journal of Organic Chemistry USSR (English Translation), 1969, vol. 5, p. 323 - 326[3] Zhurnal Organicheskoi Khimii, 1969, vol. 5, # 2, p. 337 - 340
5
[ 625-36-5 ]
[ 71-43-2 ]
[ 936-59-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere
3-Chloropropionyl chloride (0.151 g; 1.19 mmol) followed by anhydrous benzene (0.084 g; 1.08 mmol) were added in a dropwise fashion to a solution of aluminum trichloride(0.173 g; 1.30 mmol) dissolved in anhydrous CH2CI2 (1 ml_), under N2 atmosphere at 0°C. The reaction mixture was allowed to warm to room temperature and left overnight.The reaction mixture was then cooled to 0°C and quenched by lumps of ice. The aqueous phase was extracted with CH2CI2 and the combined organic phases were dried over MgS04, filtered and concentrated. The product was purified by column chromatography (pentane) and isolated as yellow crystals in quantitative yield (0.200 g;1.19 mmol).Rf (pentane) 0.31. Mp (uncorr.): 45.9-48.7°C. 1H-NMR (400 MHz, CDCI3) δΗ 8.00-7.93 (m, 2H), 7.64-7.55 (m, 1 H), 7.53-7.44 (m, 2H), 3.93 (t, 2H, J 6.8 Hz), 3.46 (t, 2H, J 6.8 Hz). 13C-NMR (100 MHz, CDCI3) 5C 196.8, 136.5, 133.7, 128.9, 128.2, 41.4, 38.8. The NMR data are in accordance with those previously reported (Moriyama, K.;Takemura, M.; Togo, H. Org. Lett. 2012, 14, 2414-2417).
21 g
With aluminum (III) chloride In benzene at 0 - 5℃; for 8 h;
To a solution of 3-chloropropanoic acid (17.5 g, 189.8 mmol) in benzene (100 mL) was added thionyl chloride (45.2 g, 379.6 mmol, 28 mL) at room temperature. The resulting mixture was heated at 80-90°C for 4h. Excess thionyl chloride was removed by azeotropic distillation with dry benzene. 3-Chloropropionyl chloride thus obtained was diluted with benzene (150 mL). Anhydrous aluminum chloride (45 g, 340.0 mmol) was added slowly into flask over a period of 6h at 0-5°C under stirring. The reaction mixture was further stirred at 0-5°C for 2h. Excess aluminum chloride was decomposed carefully in ice-water and the reaction mixture was extracted with ethyl acetate (30 mL x 3). Combined organic layer was washed with water (10 mL x 5) to neutral pH and dried over sodium sulfate. Sodium sulfate was filtered off, washed with ethyl acetate (10 mL x 2) and the filtrate was concentrated under reduced pressure to give crude product, which was purified by column chromatography (5percent ethyl acetate/hexane) to provide 21.0 g of compound 2. Brown solid; Yield 69percent; Mp 46-49°C; IR (KBr): 3110, 2922, 1670 cm-1; ESI-MS: m/z 169 (M++1),171 (M++3); 1H NMR (300 MHz, CDCl3): d 7.93-7.91 (m, 2H), 7.64-7.38 (m, 3H), 3.88 (t, 2H, J = 6.9 Hz), 3.41 (t, 2H, J = 6.9 Hz); Anal. calcd. for C9H9ClO: C, 64.11; H, 5.38; Found: C, 64.12; H, 5.34.
Reference：
[1] Patent: WO2013/26455, 2013, A1, . Location in patent: Page/Page column 74
[2] Bulletin de la Societe Chimique de France, 1984, vol. 2, # 7-8, p. 285 - 291
[3] Bulletin de la Societe Chimique de France, 1984, vol. 2, # 7-8, p. 285 - 291
[4] Organic Preparations and Procedures International, 1997, vol. 29, # 2, p. 214 - 218
[5] Pharmaceutical Research, 2017, vol. 34, # 12, p. 2873 - 2890
[6] Chirality, 2012, vol. 24, # 10, p. 847 - 853,7
[7] Journal of the Chemical Society, 1935, p. 299,301[8] Chemische Berichte, 1936, vol. 69, p. 16,17
[9] Recueil des Travaux Chimiques des Pays-Bas, 1962, vol. 81, p. 645 - 649
[10] Journal of Organic Chemistry, 1949, vol. 14, p. 346,349
[11] Journal of the American Chemical Society, 1932, vol. 54, p. 736,747
[12] Journal of Organic Chemistry, 1972, vol. 37, p. 1494 - 1499
[13] Archiv der Pharmazie, 1962, vol. 295 /67, p. 241 - 243
[14] Journal of the American Chemical Society, 1965, vol. 87, p. 1515 - 1521
[15] Journal of Medicinal Chemistry, 2004, vol. 47, # 16, p. 3924 - 3926
[16] Tetrahedron Asymmetry, 2008, vol. 19, # 9, p. 1078 - 1083
[17] Journal of Medicinal Chemistry, 2008, vol. 51, # 13, p. 3841 - 3855
[18] Patent: WO2008/35358, 2008, A2, . Location in patent: Page/Page column 8; 9-10
[19] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 176 - 181
[20] Advanced Synthesis and Catalysis, 2015, vol. 357, # 14-15, p. 3262 - 3272
[21] Russian Journal of Bioorganic Chemistry, 2015, vol. 41, # 1, p. 37 - 45[22] Bioorg. Khim., 2015, vol. 41, # 1, p. 44 - 53,10
[23] Organic and Biomolecular Chemistry, 2016, vol. 14, # 16, p. 3883 - 3888
6
[ 2687-12-9 ]
[ 936-59-4 ]
Yield
Reaction Conditions
Operation in experiment
90 %Chromat.
With iron(III) chloride; tetraphenylsilane In <i>tert</i>-butyl alcohol at 80℃; for 24 h;
In a 25 mL reaction flask, ferric chloride (0.05 mmol), ene 1ag (0.5 mmol), tetraphenyl disilane (2.0 mmol) and tert-butanol (2.0 mL) were added successively to the 25 mL reaction flask.After mixing at room temperature, the reaction mixture was reacted at 80 ° C for 24 h.The reaction was completed, aqueous ammonia (0.5 mL) was added and stirred for 1 h.Then, 5 mL of water was added and extracted with ether (5 mL x 3). The organic phases were combined and the solvent was evaporated under reduced pressure. Column chromatography gave 90percent yield.
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 41, p. 12712 - 12717[2] Angew. Chem., 2017, vol. 129, p. 12886 - 12891,6
[3] Patent: CN106748690, 2017, A, . Location in patent: Paragraph 0124; 0125; 0126
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 48, p. 6430 - 6433
[2] American Chemical Journal, 1909, vol. 42, p. 393
9
[ 93-55-0 ]
[ 936-59-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2014, vol. 356, # 6, p. 1266 - 1274
10
[ 18776-12-0 ]
[ 936-59-4 ]
[ 100306-33-0 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 19, p. 6495 - 6497
11
[ 625-36-5 ]
[ 936-59-4 ]
Reference：
[1] Journal of Organic Chemistry, 1959, vol. 24, p. 957,962
12
[ 98-88-4 ]
[ 936-59-4 ]
Reference：
[1] Canadian Journal of Research, 1933, vol. 8, p. 440,444
13
[ 2674-04-6 ]
[ 625-36-5 ]
[ 936-59-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1984, vol. 2, # 7-8, p. 285 - 291
14
[ 623-71-2 ]
[ 936-59-4 ]
[ 24626-27-5 ]
Reference：
[1] Journal of the Chemical Society, 1936, p. 401
15
[ 50-00-0 ]
[ 98-86-2 ]
[ 936-59-4 ]
[ 39192-57-9 ]
[ 54589-56-9 ]
[ 768-03-6 ]
Reference：
[1] Russian Journal of General Chemistry, 2007, vol. 77, # 4, p. 611 - 619
16
[ 60-29-7 ]
[ 623-71-2 ]
[ 936-59-4 ]
[ 24626-27-5 ]
Reference：
[1] Journal of the Chemical Society, 1936, p. 401
17
[ 936-59-4 ]
[ 18776-12-0 ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium tetrahydroborate; ethanol In tetrahydrofuran at -10 - -5℃; for 0.333333 h; Inert atmosphere
To a stirred solution of 3-chloro-1 -phenylpropan-1 -one (7.80 g, 46.26 mmol) in THF (35 mL) and EtOH (35 mL), at -10 °C and under a nitrogen atmosphere, sodium borohydride (2.20 g, 48.83 mmol) was added portion-wise over 10 min. The reaction mixture was stirred for additional 10 min at -5 °C then cautiously poured into a stirred mixture of saturated ammonium chloride (85 mL) and ice (40 g). The mixture was extracted with ether twice, the organic phase was dried and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 95/5) to give the title compound 3-chloro-1 -phenylpropan-1 -ol (p281 , 7.50 g, y= 95percent) as pale yellow oil. NMR: 1 H NMR (CDC ) δ: 7.39 (d, 5H), 4.91 -5.01 (m, 1 H), 3.70-3.83 (m, 1 H), 3.59 (s, 1 H), 2.20-2.32 (m, 1 H), 2.1 1 (d, 1 H)
83.1%
Stage #1: With (S)-1-Pyrrolidin-2-yl-methanol In ethanol at 35 - 40℃; for 0.25 h; Stage #2: With potassium borohydrite In ethanol for 2 h; Reflux
Take 5600 ml of 95percent ethanol, add to a 10 L reaction bottle, and start stirring. Then, 800 g of 3-chloropropiophenone and 360 g of L-prolinol were sequentially added to the reaction flask, and stirred at 35-40 ° C for 15 minutes, until the reaction solution was almost completely dissolved.Cool to 27 ° C. Boron potassium hydride 320g was added to the reaction mixture in portions, and the addition speed was taken to prevent the gas from being generated in a large amount to cause the reaction liquid to expand and overflow. After the addition and the incubation reaction was carried out for 0.8 hours, the reaction solution was refluxed for 1.2 hours.The reaction solution was concentrated to 1.2 L under reduced pressure, and then added to 7870 ml of n-hexane, and heated to 55-60 ° C. After dissolved, 80 g of activated carbon was added, and the mixture was decolorized for 0.6 hours. The mixture was filtered while hot, and the filtrate was washed with 700 ml of n-hexane to collect filtrate. The mixture was decanted at 0-5 ° C for 1.3 hours, filtered, and the filter cake was rinsed once with 500 ml of n-hexane and dried under vacuum.White flocculent solid 3-chlorophenylpropanol 677g,The yield was 83.1percent.The HPLC content was 98percent and the ee value was 99percent.
82%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 2 h;
To a solution of 3-chloropropiophenone (8.46 g, 50.0 mmol) in methanol (100 mL) wasadded NaBH4 (0.981 g, 25.9 mmol) at 0 °C and the mixture was warmed to roomtemperature with stirring for 2 h. HClaq (1 M, 100 mL) was added at 0 °C. Themixture was extracted with ethyl acetate (2 x 100 mL) and washed with water (2 x 150mL). The combined organic layer was dried over MgSO4 and evaporated. The residuewas purified by distillation under reduced pressure to give the product (6.99 g, 82percent).The spectral data were exactly matched to the reported data.30
16.5 g
at 0 - 15℃; for 2 h;
In 250mlAdd 15.97g in a three-necked flask3-chloropropiophenone and methanol 120ml, At 0 ~ 5 3.87g KBH4 was added in portions,The temperature of the reaction mixture is controlled within the range of 0 to 5 ° C.,Then control the temperature at 5 ~ 15 for 2 hours,Methanol was evaporated under reduced pressure, 80 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate * 3. The combined organic layers were dried and the organic layer was dried. Ethyl acetate was distilled off under reduced pressure at 50 ° C,3-chlorophenyl propanol 16.5g
Reference：
[1] Pharmaceutical Research, 2017, vol. 34, # 12, p. 2873 - 2890
[2] Biological and Pharmaceutical Bulletin, 2011, vol. 34, # 4, p. 538 - 544
[3] Patent: WO2016/67043, 2016, A1, . Location in patent: Page/Page column 325
[4] Organic Process Research and Development, 2000, vol. 4, # 6, p. 513 - 519
[5] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 11, p. 1767 - 1769
[6] Angewandte Chemie - International Edition, 2013, vol. 52, # 12, p. 3490 - 3493[7] Angew. Chem., 2013, vol. 125, # 12, p. 3574 - 3577,4
[8] Chinese Journal of Chemistry, 2011, vol. 29, # 3, p. 504 - 510
[9] Letters in Drug Design and Discovery, 2011, vol. 8, # 3, p. 268 - 275
[10] Patent: CN108383703, 2018, A, . Location in patent: Paragraph 0019; 0020; 0021
[11] Chemistry Letters, 2017, vol. 46, # 8, p. 1116 - 1118
[12] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[13] Journal of the Chemical Society, Chemical Communications, 1986, # 13, p. 1018 - 1019
[14] Journal of Chemical Research, Miniprint, 1987, # 12, p. 3242 - 3264
[15] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 12, p. 3197 - 3206
[16] Synthesis, 2011, # 18, p. 2921 - 2928
[17] Angewandte Chemie - International Edition, 2015, vol. 54, # 29, p. 8511 - 8514[18] Angew. Chem., 2015, vol. 54, # 29, p. 8511 - 8514,4
[19] Journal of the American Chemical Society, 1957, vol. 79, p. 948,950
[20] Journal of the American Chemical Society, 1933, vol. 55, p. 2927,2930
[21] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1969, p. 2113 - 2116[22] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1969, # 10, p. 2266 - 2269
[23] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3101 - 3108
[24] Journal of the American Chemical Society, 1974, vol. 96, p. 7968 - 7974
[25] Tetrahedron Asymmetry, 1992, vol. 3, # 4, p. 525 - 528
[26] Tetrahedron, 1994, vol. 50, # 19, p. 5775 - 5782
[27] Bulletin de la Societe Chimique de France, 1994, vol. 131, # 6, p. 632 - 635
[28] Tetrahedron, 1997, vol. 53, # 15, p. 5563 - 5572
[29] Bioorganic and medicinal chemistry letters, 2003, vol. 13, # 7, p. 1291 - 1292
[30] Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532
[31] Journal of Medicinal Chemistry, 2004, vol. 47, # 16, p. 3924 - 3926
[32] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 589 - 593
[33] Journal of Organic Chemistry, 2001, vol. 66, # 19, p. 6495 - 6497
[34] Journal of Medicinal Chemistry, 2008, vol. 51, # 13, p. 3841 - 3855
[35] Organic Letters, 2009, vol. 11, # 2, p. 305 - 308
[36] Patent: WO2008/35358, 2008, A2, . Location in patent: Page/Page column 8; 10
[37] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 176 - 181
[38] Organic Letters, 2011, vol. 13, # 10, p. 2762 - 2765
[39] Tetrahedron Asymmetry, 2014, vol. 25, # 18-19, p. 1264 - 1269
[40] Molecules, 2015, vol. 20, # 1, p. 1712 - 1730
[41] Russian Journal of General Chemistry, 2015, vol. 85, # 4, p. 922 - 925
[42] Synlett, 2016, vol. 27, # 5, p. 789 - 793
[43] Organic and Biomolecular Chemistry, 2016, vol. 14, # 16, p. 3883 - 3888
[44] Synthesis (Germany), 2016, vol. 48, # 19, p. 3241 - 3253
[45] Patent: CN106748817, 2017, A, . Location in patent: Paragraph 0041; 0042; 0043
18
[ 936-59-4 ]
[ 613-87-6 ]
[ 18776-12-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
60 %Chromat.
With yeast culture of Rhodotorula rubra KCh 82 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
20
[ 936-59-4 ]
[ 100306-34-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
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
21
[ 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
22
[ 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
23
[ 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 borane-THF; (S)-diphenylprolinol In tetrahydrofuran; toluene at 20℃; for 1.5 h;
Step 1: a flask was charged with (S)-(−)-α,α-diphenylprolinol (0.30 g, 1.19 mmol) and anhydrous toluene (7 ml). The mixture was placed under nitrogen by evacuation and filling three times. The borane tetrahydrofuran complex solution [BH3•THF; 1M solution in THF, stabilized with 5mM NaBH4] (0.35 ml, 3.56 mmol) was added in a dropwise fashion at 30°C and the clear solution was stirred for 30min. Step 2: to this stirred solution, 3-chloro-1-phenylpropan-1-one 12 (1 g, 5.93 mmol) in anhydrous toluene (1 ml) was added. The reaction mixture was then stirred at room temperature for 15min followed by the addition of BH3·THF (6 ml, 61.44 mmol) over a period of 3 min. After stirring for additional 9 0min, the reaction flask was cooled in ice bath and quenched successively with MeOH (10 ml), isopropanole (10 ml), and HCl (3 ml), and was passed through a pad of Celite. The filtrate was concentrated to dryness and crystallized from hexane. The title compound was obtained as white fluffy solid (4.91g). Yield: 97percent; m.p. 57–59°C; [α]D25=+ 25.7° (c 1, CHCl3); 1H NMR (400MHz, CDCl3): δ 2.07–2.16 (m, 2H), 2.20–2.32 (m, 1H), 3.51–3.62 (m, 1H), 3.71–3.80 (m, 1H), 4.91–4.98 (m, 1H), 7.37–7.43 (m, 5H), 13C NMR (400MHz, CDCl3): δ 41.45, 41.73, 71.34, 125.80, 127.94, 128.69, 143.71; MS (EI+) m/z: 170 [M+], 172 [M+2] showing relative intensity ratio∼3:1.
95%
With 2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2 h;
Preparative Example 2.2. Dissolving the 2-cat (1.78 mmol, 575 mg) prepared inaccordance with the 25 of THF and, after the addition of BH3 DMS (12.5 mmol,1.18 ), which was stirred for 7 minutes. Over a solution of 3-chloro-propiophenone(17.8 mmol, 3.0 g) was dissolved in THF 6 to the reaction mixture was addeddropwise a 10 minute dropwise. After reacting at room temperature for an 2 hour, thereaction was terminated by adding methanol. Example 1.1. And purified in the samemanner as (R) -3- chloro-1-phenyl-propanol to give the (yield: 95percent, 93percent ee).The compound was recrystallized from a nucleic acid of 99percent ee (R) -3- chloro-1-phenyl-propanol to give the (86percent recovery).
95%
With 2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2.16667 h;
Cat-2 (1.78 mmol, 575 mg) prepared in Preparation Example 1.2 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. (R) -3-chloro-1-phenylpropan-1-ol (yield 95percent, 93percent ee) was obtained in the same manner as in Preparation Example 2.2. The above compound was recrystallized from a nucleic acid to obtain (R) -3-chloro-1-phenylpropan-1-ol (86percent recovery) with 99percent ee.
91%
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C55H92N6O4S(2+)*2I(1-); sodium formate In water
A solution of 1.3 mg (0.002 mmol) metal [RhCl2Cp*]2 and 5.2 mg (0.004 mmol) ligand XIV is in the thick wall of the test tube, add 5 ml water placed in the 40 °C activation stirring 2 hours. 0.4 mmol 3-chlorophenylacetone and 2 mmol sodium formate, stirring the reaction. The solution was extracted with ethyl acetate 5 ml × 3 extraction, combined the organic phase, dried with anhydrous sodium sulfate, the solvent was evaporated. Column chromatography purification (petroleum ether / ethyl acetate = 20/1). HPLC detection ee value. For the product passes through the derivatization ee value detected: the obtained product is dissolved in 5 ml dichloromethane in, adding 49 mg 4-dimethylaminopyridine (0.4 mmol) and 82 mg of acetic anhydride (0.8 mmol), stir at room temperature 3h. Processing, dichloromethane is used for solution 5 ml × 3 extraction, the combined organic phase, dried with anhydrous sodium sulfate, the solvent, then the GC detection ee value. Isolation yield 91percent, 95percent ee
86%
With dimethylsulfide borane complex In tetrahydrofuran for 2 h;
EXAMPLE 8R-(+)-3-chloro-1-phenylpropan-1-olFollowing similar procedure as before, BH3.SMe2 (10 M, 0.7 mL, 7 mmol) was added to a solution of complex derived from ethylene glycol and diphenyl prolinol (EG-DDP), catalyst 10, (323 mg, 0.1 mmol) in dry THF (35 mL) at room temperature. The reaction mixture was stirred for approximately one hour. A solution of dry 3-chloropropiophenone (1.69 g, 10 mmol) in dry THF (5 mL) was added by a syringe using infusion pump for 1 hour. (Rate: 6 mL/h). The 3-chloropropiophenone solution was light yellow but after adding to the complex, the total solution was clear. Following similar procedure as above for the work-up, the crude product was obtained: 1.66 g (97percent yield). The product was analyzed by 31P-NMR: 145.0 ppm (5.7percent), 134.5 ppm (94.3percent)-->88.6percent ee. The product was purified by column chromatography with 30 g of silica and a mobile phase of hexane/ethyl acetate (2:1).(Yield: 1.47 g, 86percent). The product was analyzed by 1H, 13C, and 31P-NMR (derivative with a phosphonate (CDA). 31P-NMR: 145.1 ppm (3percent), 134.6 ppm (97percent): 94percent ee; [α]20=+21.0 c=0.030 (CHCl3).
86.7%
With (+)-diiso-2-ethylapophosphate pinacylboraneheptane In tetrahydrofuran at -20℃; for 6 h;
3-Chlorophenylacetone (40 g) was dissolved in tetrahydrofuran (160 ml)(152 ml) of 65percent (+) diiso-2-ethylapopamate-pinacylborane n-heptane was added at -10 ° C,The reaction was carried out for 8 hours and concentrated under reduced pressure. The residue was added with diethyl ether (400 ml), followed by addition of diethanolamine (37.4 g), stirred for 2 h and filtered. (R) - (+) - 3-chlorophenyl propanol 7.4g, the yield was 86.7percent, mp56 ~ 57 (m), and the mixture was stirred at room temperature for 4 hours. ° C; [a] 23d = + 25.1, c = 1, CHC13; 99percent ee.
9%
With hydrogen In methanol at 60℃; for 24 h;
5.010 mg (8.0 μmol) of RuCl[(R,R)-TsDPEN](p-cymene) 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 90percent ee was produced in 9percent yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
Reference：
[1] Tetrahedron Letters, 1989, vol. 30, # 39, p. 5207 - 5210
[2] Synthetic Communications, 2009, vol. 39, # 15, p. 2737 - 2746
[3] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 3, p. 431 - 435
[4] Chemical Communications, 2015, vol. 51, # 26, p. 5725 - 5727
[5] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 157 - 172
[6] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0143; 0156-0158
[7] Patent: KR2016/44117, 2016, A, . Location in patent: Paragraph 0069-0072
[8] Organic and Biomolecular Chemistry, 2014, vol. 12, # 6, p. 1009 - 1017
[9] Patent: CN105061126, 2017, B, . Location in patent: Paragraph 0095; 0096; 0097; 0098; 0099
[10] Patent: US2008/200672, 2008, A1, . Location in patent: Page/Page column 7
[11] Patent: CN105732309, 2016, A, . Location in patent: Paragraph 0037; 0049; 0050
[12] Chinese Journal of Chemistry, 2013, vol. 31, # 3, p. 349 - 354
[13] Organic Letters, 2016, vol. 18, # 18, p. 4658 - 4661
[14] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 8; 14
[15] Journal of Organic Chemistry, 2001, vol. 66, # 19, p. 6495 - 6497
[16] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 11, p. 1767 - 1769
[17] Tetrahedron Asymmetry, 1992, vol. 3, # 4, p. 525 - 528
[18] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 4929 - 4931
[19] Organic Process Research and Development, 2012, vol. 16, # 4, p. 710 - 713
[20] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1697 - 1702
[21] Chemical Communications, 2015, vol. 51, # 86, p. 15728 - 15731
[22] Advanced Synthesis and Catalysis, 2018, vol. 360, # 11, p. 2119 - 2124
[23] Angewandte Chemie - International Edition, 2018, vol. 57, # 32, p. 10231 - 10235[24] Angew. Chem., 2018, vol. 130, p. 10388 - 10392,5
31
[ 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
32
[ 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
33
[ 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 sodium tetrahydroborate; ethanol; In tetrahydrofuran; at -10 - -5℃; for 0.333333h;Inert atmosphere;
To a stirred solution of 3-chloro-1 -phenylpropan-1 -one (7.80 g, 46.26 mmol) in THF (35 mL) and EtOH (35 mL), at -10 C and under a nitrogen atmosphere, sodium borohydride (2.20 g, 48.83 mmol) was added portion-wise over 10 min. The reaction mixture was stirred for additional 10 min at -5 C then cautiously poured into a stirred mixture of saturated ammonium chloride (85 mL) and ice (40 g). The mixture was extracted with ether twice, the organic phase was dried and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 95/5) to give the title compound 3-chloro-1 -phenylpropan-1 -ol (p281 , 7.50 g, y= 95%) as pale yellow oil. NMR: 1 H NMR (CDC ) delta: 7.39 (d, 5H), 4.91 -5.01 (m, 1 H), 3.70-3.83 (m, 1 H), 3.59 (s, 1 H), 2.20-2.32 (m, 1 H), 2.1 1 (d, 1 H)
83.1%
Take 5600 ml of 95% ethanol, add to a 10 L reaction bottle, and start stirring. Then, 800 g of <strong>[936-59-4]3-chloropropiophenone</strong> and 360 g of L-prolinol were sequentially added to the reaction flask, and stirred at 35-40 C for 15 minutes, until the reaction solution was almost completely dissolved.Cool to 27 C. Boron potassium hydride 320g was added to the reaction mixture in portions, and the addition speed was taken to prevent the gas from being generated in a large amount to cause the reaction liquid to expand and overflow. After the addition and the incubation reaction was carried out for 0.8 hours, the reaction solution was refluxed for 1.2 hours.The reaction solution was concentrated to 1.2 L under reduced pressure, and then added to 7870 ml of n-hexane, and heated to 55-60 C. After dissolved, 80 g of activated carbon was added, and the mixture was decolorized for 0.6 hours. The mixture was filtered while hot, and the filtrate was washed with 700 ml of n-hexane to collect filtrate. The mixture was decanted at 0-5 C for 1.3 hours, filtered, and the filter cake was rinsed once with 500 ml of n-hexane and dried under vacuum.White flocculent solid 3-chlorophenylpropanol 677g,The yield was 83.1%.The HPLC content was 98% and the ee value was 99%.
82%
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 2h;
To a solution of <strong>[936-59-4]3-chloropropiophenone</strong> (8.46 g, 50.0 mmol) in methanol (100 mL) wasadded NaBH4 (0.981 g, 25.9 mmol) at 0 C and the mixture was warmed to roomtemperature with stirring for 2 h. HClaq (1 M, 100 mL) was added at 0 C. Themixture was extracted with ethyl acetate (2 x 100 mL) and washed with water (2 x 150mL). The combined organic layer was dried over MgSO4 and evaporated. The residuewas purified by distillation under reduced pressure to give the product (6.99 g, 82%).The spectral data were exactly matched to the reported data.30
ExampIe-2:Preparation of 3-Chloro-l-phenyl-propan-l-ol:1 kg of pure compound (a) and 5 L of methylene dichloride is taken into the round bottom flask. The reaction mixture is stirred for 15 minutes at 250C to 350C and cooled to O0C to 50C. An ethanolic solution of NaBH4 (14Og of NaBH4 in 2.5 L of ethanol) is added into the reaction mixture at 00C to 50C over a period of 1-1.5 hours. The temperature of the reaction is raised to 1O0C to 2O0C and stirred for 3 hours at the same temperature. Dilute acetic acid (250 mL in 1750 niL of water) is added slowly into the reaction mixture with stirring at the same temperature to ensure the pH of 4.5 in 1 hour and the reaction mixture is stirred for further 30 minutes at 25C to 350C. The methylene dichloride layer is separated. The aqueous layer is extracted with methylene dichloride. The separated organic layer is combined and washed with 5% NaHCO3 solution (pH - 8) at 250C to 350C. The layers are again separated and methylene dichloride layer is washed with water followed by further separation. The excess of solvent is removed by distillation and by applying vacuum to get compound (b).
With sodium tetrahydroborate; In tetrahydrofuran; ethanol; at -10 - -5℃; for 0.166667h;
General procedure: Starting materials 7 or 8, respectively (1 mmol) was dissolved in THF (1 mL) and EtOH (1 mL) was added. The mixture was cooled to -10 C and NaBH4 (1.05 mmol) was slowly added at this temperature.The solution was stirred at -5 C for 10 min and thereafter, poured into a mixture of saturated aqueous ammonium chloride (3 mL) in ice (1.5 g). The product was extracted with diethyl ether, dried over Na2SO4 and evaporated to dryness. The crude product was employed directly in the subsequent reaction step without further purification.
With sodium tetrahydroborate; In methanol; at 0℃; for 4h;
General procedure: To a solution of the corresponding ketone in methanol (0.60 M) was added sodiumborohydride (0.33 equiv.) and the resulting mixture was stirred for 2 h at 0 C. Afterstirring, additional sodium borohydride (0.33 equiv.) was added to the mixture tocomplete the transformation. After 2 h, water was added to quench the reaction, andthe mixture was extracted with diethyl ether (3 times). The extracts were dried overanhydrous MgSO4, filtered, and concentrated under reduced pressure. The residuewas chromatographed on silica gel to afford desired alcohol.
With sodium tetrahydroborate; In methanol; at 0 - 20℃;Inert atmosphere; Schlenk technique;
Following a literature reported procedure,16 NaBH4 (5.7 g, 150 mmol)was added in small portions at 0 C to a stirred solution of 3-chloro-1-propiophenone (13) (8.4 g, 50 mmol) in MeOH (104 mL). The mixture was stirred at r.t. for 18 h and was then quenched with H2O (90mL). The solvent was removed in vacuo and the residue was extracted with Et2O (3 × 50 mL). The combined organic layers were dried overMgSO4 and concentrated in vacuo to give the title compound as a colourless oil (8.4 g, 98% yield). The product was used in the next step without further purification. All analytical data matched that previouslyreported.16 1H NMR (400 MHz, CDCl3): delta = 7.37-7.26 (m, 5 H, Ar-H), 4.93 (dd, J1 =11.3 Hz, J2 = 6.4 Hz, 1 H, CH-OH), 3.73 (ddd, J1 = 14.5 Hz, J2 = 10.8 Hz,J3 = 7.6 Hz, 1 H, CH2-Cl), 3.55 (m, 1 H, CH2-Cl), 2.23 (m, 1 H, CH2-CH),2.10 (m, 1 H, CH2-CH), 2.03 (br s, 1 H, OH).13C NMR (101 MHz, CDCl3): delta = 143.83 (Ar-C), 128.81 (2 C, Ar-C),128.06 (Ar-C), 125.91 (2 C, Ar-C), 71.49 (CH), 41.84 (CH2), 41.59 (CH2).
16.5 g
With methanol; potassium borohydride; at 0 - 15℃; for 2h;
In 250mlAdd 15.97g in a three-necked flask<strong>[936-59-4]3-chloropropiophenone</strong> and methanol 120ml, At 0 ~ 5 3.87g KBH4 was added in portions,The temperature of the reaction mixture is controlled within the range of 0 to 5 C.,Then control the temperature at 5 ~ 15 for 2 hours,Methanol was evaporated under reduced pressure, 80 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate * 3. The combined organic layers were dried and the organic layer was dried. Ethyl acetate was distilled off under reduced pressure at 50 C,3-chlorophenyl propanol 16.5g
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 dihydrogen peroxide; acetic acid; sodium bromide; In water; at 60℃; for 2h;Inert atmosphere;
General procedure: Under nitrogen atmosphere, to a solution of substrate alcohol (0.5 mmol) in aceticacid (1.0 mL) was added a stock-solution of aqueous NaBr solution (1.94 M, 25 muL)and 30% aqueous H2O2 (50 muL, 0.5 mmol). After stirring the mixture for one hour at60 C, additional 30% aqueous H2O2 (50 muL, 0.5 mmol) was added, and stirring wascontinued for another one hour. After cooling, the mixture was poured into a saturatedaqueous NaHCO3 solution (ca. 30 mL) with the aid of CH2Cl2, and resulting mixturewas extracted with CH2Cl2. The combined organic layers were dried over anhydrousMgSO4, filtered and concentrated in vacuo. The residue was chromatographed onsilica gel (flash column or preparative TLC) to afford the corresponding ketone.
With sulfuric acid; trimethyl orthoformate; In dichloromethane; at 45℃; for 6h;
Compound 4 (100 g, 0.6 mol, leq)Was dissolved in 500 mL of dichloromethane (DCM)Followed by the addition of ethylene glycol (133 ml, 4eq), the trimethyl orthoformate (126.3g about 130 ml, 1 . 19mol, 2eq), the mass percentage of 98% concentrated sulfuric acid (the mass percentage refers to the mass of sulfuric acid as a percentage of the total mass of concentrated sulfuric acid reagent) (5.8 g, 0 leq).The reaction solution was heated to reflux (45 C). After stirring for 6 h, the compound 4 was removed by TLC and cooled and cooled. Add 20g NaHC03 solid pH 7, stirring lOmin. The organic layer was washed with water (100 mL), dried and concentrated to give about 152 g of an oil. The residue was added to 100 mL of isopropanol, crystallized overnight and filtered to give about 112. 5 g of a white solid(2- (2-chloroethyl) -2-phenyl-1,3-dioxolane) in 89% yield.
With toluene-4-sulfonic acid; In benzene; for 10h;Reflux; Dean-Stark;
General procedure: A solution of the phenone prepared at the previous step (10 mmol), the corresponding diol (100 mmol),and TSA (0.5 g, 2.6 mmol) were mixed in dry benzene (70 mL). The resulting solution was refluxed for 10 h using a Dean-Stark trap. The reaction mixture was cooled and a solution semisaturated sodium hydrocarbonate (50 mL) was added. The organic layer was separated, and the aqueous phase was extracted with benzene (3 × 30 mL). The united organic extracts were dried with anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography (l = 5 cm, d = 5 cm) on silica gel eluting with methylene chloride.
With potassium carbonate; In N,N-dimethyl-formamide; at 35℃; for 16h;
EXAMPLE 50B 1-phenyl-3-[4-(1,3-thiazol-2-yl)piperazin-1-yl]propan-1-one 3-Chloropropiophenone (8 g, 47.44 mmol), the product from Example 50A (8.83 g, 52.18 mmol), and K2CO3 (6.56 g, 47.44 mmol) were combined in DMF and heated at 35 C. for 16 hours. The mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous Na2CO3, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) delta 2.65 (br.s, 4H), 2.95 (br.s, 2H), 3.22 (br.s. 2H), 3.22 (br.s, 2H), 3.45 (br.s, 4H), 6.45 (d, J=3 Hz, 1H), 7.2 (d, J=3 Hz, 1H), 7.45 (m, 2H), 7.6 (m,1H), 7.9 (m, 2H); MS (DCI/NH3) m/z 302 (M+H)+. Anal. calcd for C16H19N3OS: C, 63.76; H, 6.35; N, 13.94. Found: C, 61.50; H, 6.43; N, 13.21.
With potassium carbonate;potassium iodide; In acetonitrile; at 70℃; for 17h;
[00402] 2. 3-Chloropropiophenone (7.14 g, 24.4 mmol). K2CO3 (8.79 g, 1.50 equiv) and KI (1.41 mg, 0.2 equiv) were added to a solution of the purified 1-(tert-butyloxycarbonyl)homopiperazine (8.486 g, 42.4 mmol) in CH3CN (60 mL). The reaction mixture was stirred at 70 C. for 17 h and then AcOEt (200 mL) was added to the cooled mixture. The precipitated solid was removed by filtration and washed with AcOEt (50 mL). The combined filtrate was evaporated to afford an oil which was purified by column chromatography (SiO2, 0%-20% CH3CN/AcOEt) to give 1-(tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropyl)homopiperazine: 11.27 g, 80% yield, pale yellow oil: 1H NMR (CDCl3, 300 MHz) delta 1.40-1.65 (m, 9H), 1.80-1.95 (m, 2H), 2.65-2.85 (m, 4H), 3.01 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=6.9 Hz), 3.35-3.55 (m, 4H), 7.47 (t, 2H, J=7.7 Hz), 7.55-7.65 (m, 1H), 7.90-8.02 (m, 2H). The purity was determined by RPLC/MS (Method B). RPLC tR=5.53 min (95%), 220 nm; ESI/MS m/e 333.4 (M++H, C19H29N2O3).
Example 61 1-phenyl-3-(3-thiazolidinyl)propan-1-one A solution containing 8.43 g (0.05 mol) of beta-chloropropiophenone, 4.10 g (0.05 mol) of anhydrous sodium acetate and 4.01 g (0.045 mol) of thiazolidone in 30 ml of ethanol is stirred at 25C for 8 hours. After filtering off the precipitate and evaporating the solvent from the solution, the oily yellowish residue weighing 9.3 g is converted to the hydrochloride salt in a mixture of acetone and ether in the usual way to give 9.9 g of product. After recrystallization from methanol, the hydrochloride of the title product thus obtained melts at 170-171C; it is identical to the hydrochloride salt of Examples 1 and 43 above.
Present intermediate 3 was prepared in the same way as intermediate 14 of WO 2004/011436, i.e. according to Example A9 of WO 2004/011436, but starting from 3-chloropropiophenone. Yield: 98% of present intermediate 3
Step B: Preparation of tert-baixl methoxy(3-oxo-3-phcny]propyl)carbamate: To a cooled (O0C) solution of tert-butvl mcthoxycarbamatc (2.35 g, 16.0 mmol) in THF (50 mL) was slowly added NaH (0.640 g, 16.0 mmol). After stirring at 00C for 5 minutes and then at room temperature for 30 minutes, the mixture was added dropwisc to a solution of 3-chloro-l- phenylpropan-1-onc (2.84 g, 16.8 mmol) in THF (25 mL). After stirring at room temperature for 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographcd (10% ethyl acetate in hexancs) to provide the product (1.80 g, 40% yield) as a clear oil.
General Procedure:To a solution of 3-chloro-1-phenylpropan-1-one (2, 2.0 mmol) in toluene (25-30 mL) was added azoles (3.0 mmol) and triethylamine (4.0 mmol) at room temperature. The reaction mixture was heated at reflux under stirring for 3-4h in an oil bath. Solvent was distilled off under reduced pressure and the residue was taken into ethyl acetate (20 mL). Organic layer was washed with water (10 mL x 3) and dried over sodium sulfate. Sodium sulfate was filtered off and washed with ethyl acetate (5 mL x 2). The combined filtrate was concentrated under reduced pressure to yield crude product which was purified by recrystallization with ethyl acetate/hexane to give 3-(substituted 1H- azol-1-yl)-1-phenylpropan-1-one (3-9).
In tetrahydrofuran; at -78℃; for 0.5h;Inert atmosphere;
Step 2: l-chloro-3-phenylhex-5-en-3-ol; To a solution of 3-chloro-l-phenylpropan-l-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, lmol/L) at - 78 C under nitrogen. The formed mixture was stirred for 30 min at -78 C. The reaction was quenched with aqueous NaHCOs solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtO Ac=I 00:1) to afford 1- chloro-3-phenylhex-5-en-3-ol (180 g, 86%). 1H NMR (CDCl3): 2.27 (m, 2H), 2.51 (m, IH), 2.74 (m, IH), 3.22 (m, IH), 3.58 (m, IH), 5.16 (m, 2H), 5.53 (m, IH), 7.23 (m, IH), 7.39 (m, 4H).
86%
In tetrahydrofuran; at -78℃; for 0.5h;Inert atmosphere;
Step 2: l-chloro-3-phenylhex-5-en-3-olTo a solution of 3-chloro-l-phenylpropan-l-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, lmol/L) at -78 C under nitrogen. The formed mixture was stirred for 30 min at -78 C. The reaction was quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc= 100:1) to afford l-chloro-3-phenylhex-5-en- 3-ol (180 g, 86%). 1H NMR (CDCl3): 2.27 (m, 2H), 2.51 (m, IH), 2.74 (m, IH), 3.22 (m, IH), 3.58 (m, IH), 5.16 (m, 2H), 5.53 (m, IH), 7.23 (m, IH), 7.39 (m, 4H).
86%
To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1 mol/L) at -78 C. under nitrogen. The formed mixture was stirred for 30 min at -78 C. The reaction was quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%). 1H NMR (CDCl3): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1H), 3.22 (m, 1H), 3.58 (m, 1H), 5.16 (m, 2H), 5.53 (m, 1H), 7.23 (m, 1H), 7.39 (m, 4H).
86%
To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1 mol/L) at -78 0C under nitrogen. The formed mixture was stirred for 30 min at -78 0C. The reaction was15 quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc= 100:1 ) to afford1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%). 1H NMR (CDCI3): 2.27 (m, 2H), 2.51 (m,BOST 1499943 1 - 80 - 1 H), 2.74 (m, 1 H), 3.22 (m, 1 H), 3.58 (m, 1 H), 5.16 (m, 2H), 5.53 (m, 1 H), 7.23 (m, 1 H), 7.39 (m, 4H).
82%
A 1000-mL flask was charged with anhydrous CeCI3 (50 g, 0.2 mol) and THF(360 ml_). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to -78 C, and a solution of allylmagnesium bromide (1.0 M in THF, 200 ml.) was added. After stirring for 2 h at -78 0C, a solution of 3-chloro-1-phenyl- propan-1-one (25 g, 149 mmol) in THF (269 mL) was added dropwise. The reaction mixture was allowed to slowly warm to rt while stirring overnight. The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-phenyl-hex-5-en-3-ol (25 g, 82%) as an oil. 1H NMR (CDCI3): 2.30 (m, 2H), 2.51 (m, 1 H), 2.72 (m, 1 H), 3.20 (m, 1 H), 3.54 (m, 1 H), 5.16 (m, 2H), 5.51 (m, 1 H), 7.24 (m, 1 H)1 7.35 (m, 4H).
To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 mL of THF (H2O<100 ppm based on Karl Fischer titration) was charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then 3-chloro-2-methylprop-1-ene (160 g, 1.77 mol) was introduced while maintaining the internal temperature below 30 C. The resulting solution was agitated for 2 h at rt. The solution was titrated in the presence of 1.1'-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask containing 307.0 g of anhydrous CeCl3 (1.25 mol) at rt under nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to -10 C. and agitated for 0.5 h. To the slurry was added 200 g of 3-chloro-1-phenylpropan-1-one (1.19 mol) in 200 mL of THF while maintaining the internal temperature below 0 C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M aq HCl was added to obtain a clear solution while maintaining the internal temperature below 30 C. After the phase cut, the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced crude 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol, which was chased with THF to achieve H2O<500 ppm based on Karl Fischer titration. The crude product (306 g, 83 wt %, 95% yield) was used directly in Step 3. 1H-NMR spectroscopy (500 MHz, CDCl3) delta 7.38-7.37 (d. J=7.8 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 3.57 (ddd, J=5.6, 10.7, and 10.7, 1H), 3.13 (ddd, J=4.7, 10.7 and 10.7 Hz, 1H), 2.66 (d, J=13.3 Hz, 1H), 2.54 (d, J=11.3 Hz, 1H), 2.53 (s, 1H), 2.36 (ddd, J=5.4, 10.6 and 13.9 Hz. 1H), 2.29 (ddd, J=5.6, 11.3 and 13.3 Hz, 1H), 1.29 (s, 3H). 13C-NMR spectroscopy (125 MHz, CDCl3) delta 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2, 46.0, 39.9, 23.9.
95%
To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 ml. of 5 THF (H2O 100 ppm based on Karl Fischer titration) was charged 53.0 ml. of 1M DIBAL-H in hexane under nitrogen at rt. Then 3-chloro-2-methylprop-1-ene (160 g, 1.77 mol) was introduced while maintaining the internal temperature below 30 0C. The resulting solution was agitated for 2 h at rt. The solution was titrated in the presence of 1.1 '-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask10 containing 307.0 g of anhydrous CeCI3 (1.25 mol) at rt under nitrogen was added1556.8 ml. of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to -10 0C and agitated for 0.5 h. To the slurry was added 200 g of3-chloro-1-phenylpropan-1-one (1.19 mol) in 200 ml. of THF while maintaining the internal temperature below 0 0C. After the mixture was stirred for 0.5 h, 1200 ml. of 115 M aq HCI was added to obtain a clear solution while maintaining the internaltemperature below 30 0C. After the phase cut, the aqueous layer was extracted with EtOAc (500 ml_). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced crude1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol, which was chased with THF to achieve H2OBOST_1499943 1 - 84 - 500 ppm based on Karl Fischer titration. The crude product (306 g, 83wt%, 95% yield) was used directly in Step 3. 1H-NMR spectroscopy (500 MHz, CDCI3) delta 7.38-7.37 (d. J= 7.8 Hz, 2H), 7.33 (t, J= 7.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 1 H), 4.91 (s, 1 H), 4.76 (s, 1 H), 3.57 (ddd, J= 5.6, 10.7, and 10.7, 1 H), 3.13 (ddd, J= 4.7, 10.7 and 10.7 Hz, 1 H), 5 2.66 (d, J= 13.3 Hz, 1 H), 2.54 (d, J= 1 1.3 Hz, 1 H), 2.53 (s, 1 H), 2.36 (ddd, J= 5.4, 10.6 and 13.9 Hz. 1 H), 2.29 (ddd, J=5.6, 1 1.3 and 13.3 Hz, 1 H), 1.29 (s, 3H). 13C-NMR spectroscopy (125 MHz, CDCI3) 5 144.3, 141.4, 128.0, 126.6, 124.8, 1 16.1 , 74.2, 51.2, 46.0, 39.9, 23.9.
EXAMPLE 1 :; l-Chloro-S-methyl-S-phenyl-hex-S-en-S-ol (3). To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 mL of THF (KF <100 ppm) was charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at room temperature. Then beta-methylallylic chloride (16O g, 1.77 mol) was introduced while maintaining the internal temperature below 30 0C. The resulting solution was agitated for 2 h at room temperature. The solution was titrated in the presence of l.l '-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask containing 307.0 g of anhydrous CeCl3 (1.25 mol) at room temperature under nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to -10 0C and agitated for 0.5 h. To the slurry was added 200 g of the ketone (1.19 mol) in 200 mL of THF while maintaining the internal temperature below 0 0C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M HCl was added to obtain a clear solution while maintaining the internal temperature below 30 0C. After the phase cut, the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced the crude product, which was chased with THF to achieve KF <500 ppm. The crude product (306 g, 83wt%, 95% yield) was used directly for subsequent coupling. Analytical data for 3: 1H- NMR spectroscopy (500 MHz, CDCl3) delta 7.38-7.37 (d. J= 7.8 Hz, 2H), 7.33 (t, J= 7.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 1 H), 4.91 (s, IH), 4.76 (s, IH), 3.57 (ddd, J= 5.6, 10.7, and 10.7, IH), 3.13 (ddd, J= 4.7, 10.7 and 10.7 Hz, IH), 2.66 (d, J= 13.3 Hz, IH), 2.54 (d, J= 11.3 Hz, IH), 2.53 (s, IH), 2.36 (ddd, J= 5.4, 10.6 and 13.9 Hz. IH), 2.29 (ddd, J=5.6, 11.3 and 13.3 Hz, IH), 1.29 (s, 3H). 13C-NMR spectroscopy (125 MHz, CDCl3) delta 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2, 46.0, 39.9, 23.9.
Step 1. l-Chloro-S-methyl-S-phenyl-hex-S-en-S-ol To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 mL ofTHF (H2O <;100 ppm based on Karl Fischer titration) was charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then 3-chloro-2-methylprop-l-ene (16O g, 1.77 mol) was introduced while maintaining the internal temperature below 30 0C. The resulting solution was agitated for 2 h at rt. The solution was titrated in the presence of 1.1 '-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask containing 307.0 g of anhydrous CeCl3 (1.25 mol) at rt under nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to -10 0C and agitated for 0.5 h. To the slurry was added 200 g of 3-chloro-l- phenylpropan-1-one (1.19 mol) in 200 mL of THF while maintaining the internal temperature below 0 0C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M aq HCl was added to obtain a clear solution while maintaining the internal temperature below 30 0C. After the phase cut, the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced crude l-chloro-5-methyl-3- phenyl-hex-5-en-3-ol, which was chased with THF to achieve H2O <;500 ppm based on Karl Fischer titration. The crude product (306 g, 83wt%, 95% yield) was used directly in Step 3. 1H-NMR spectroscopy (500 MHz, CDCl3) delta 7.38-7.37 (d. J= 7.8 Hz, 2H), 7.33 (t, J= 7.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 1 H), 4.91 (s, IH), 4.76 (s, IH), 3.57 (ddd, J= 5.6, 10.7, and 10.7, IH), 3.13 (ddd, J= 4.7, 10.7 and 10.7 Hz, IH), 2.66 (d, J= 13.3 Hz, IH), 2.54 (d, J= 11.3 Hz, IH), 2.53 (s, IH), 2.36 (ddd, J= 5.4, 10.6 and 13.9 Hz. IH),2.29 (ddd, 7=5.6, 11.3 and 13.3 Hz, IH), 1.29 (s, 3H). 13C-NMR spectroscopy (125 MHz, CDCl3) delta 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2, 46.0, 39.9, 23.9.
To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 mL of THF (H2O <100 ppm based on Karl Fischer titration) was charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then 3-chloro-2-methylprop-1-ene (160 g, 1.77 mol) was introduced while maintaining the internal temperature below 30 0C. The resulting solution was agitated for 2 h at rt. The solution was titrated in the presence of 1.1 '-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask containing 307.0 g of anhydrous CeCI3 (1.25 mol) at rt under nitrogen was added 1556.8 ml. of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to -10 0C and agitated for 0.5 h. To the slurry was added 200 g of 3-chloro-1-phenylpropan-1-one (1.19 mol) in 200 m L of THF while maintaining the internal temperature below 0 0C. After the mixture was stirred for 0.5 h, 1200 ml. of 1 M aq HCI was added to obtain a clear solution whilemaintaining the internal temperature below 30 0C. After the phase cut, the aqueous layer was extracted with EtOAc (500 ml_). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced crude 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol, which was chased with THF to achieve H2O <500 ppm based on Karl Fischer titration. The crude product (306 g, 83wt%, 95% yield) was used directly in Step 3. 1H-NMR spectroscopy (500 MHz, CDCI3) delta 7.38-7.37 (d. J= 7.8 Hz, 2H), 7.33 (t, J= 7.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 1 H), 4.91 (s, 1 H), 4.76 (s, 1 H), 3.57 (ddd, J= 5.6, 10.7, and 10.7, 1 H), 3.13 (ddd, J= 4.7, 10.7 and 10.7 Hz, 1 H), 2.66 (d, J= 13.3 Hz, 1 H), 2.54 (d, J= 11.3 Hz, 1 H), 2.53 (s, 1 H), 2.36 (ddd, J= 5.4, 10.6 and 13.9 Hz. 1 H), 2.29 (ddd, J=5.6, 11.3 and 13.3 Hz, 1 H), 1.29 (s, 3H). 13C-NMR spectroscopy (125 MHz, CDCI3) delta 144.3, 141.4, 128.0, 126.6, 124.8, 1 16.1 , 74.2, 51.2, 46.0, 39.9, 23.9.
Intermediate I 3-[(S)-I -(4-Chloro-phenyl)-ethylaminol-l-phenyl-propan-l -oneNEt3 (60 mL) followed by (S)-l-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-l-phenyl-propan-l-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent. Yield: 38.0 g (quantitative); Mass spectrum (ESI+): m/z = 288/290 (Cl) [M+H]+
With triethylamine; In tetrahydrofuran; at 20℃;
Intermediate I3-[(S)-1-(4-Chloro-phenyl)-ethylamino]-1-phenyl-propan-1-one NEt3 (60 mL) followed by (S)-1-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-1-phenyl-propan-1-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent.Yield: 38.0 g (quantitative); Mass spectrum (EST+): m/z=288/290 (Cl) [M+H]+
3-(substituted 1H- azol-1-yl)-1-phenylpropan-1-one (3-9, Scheme 1)
General Procedure:To a solution of 3-chloro-1-phenylpropan-1-one (2, 2.0 mmol) in toluene (25-30 mL) was added azoles (3.0 mmol) and triethylamine (4.0 mmol) at room temperature. The reaction mixture was heated at reflux under stirring for 3-4h in an oil bath. Solvent was distilled off under reduced pressure and the residue was taken into ethyl acetate (20 mL). Organic layer was washed with water (10 mL x 3) and dried over sodium sulfate. Sodium sulfate was filtered off and washed with ethyl acetate (5 mL x 2). The combined filtrate was concentrated under reduced pressure to yield crude product which was purified by recrystallization with ethyl acetate/hexane to give 3-(substituted 1H- azol-1-yl)-1-phenylpropan-1-one (3-9).
General Procedure:To a solution of 3-chloro-1-phenylpropan-1-one (2, 2.0 mmol) in toluene (25-30 mL) was added azoles (3.0 mmol) and triethylamine (4.0 mmol) at room temperature. The reaction mixture was heated at reflux under stirring for 3-4h in an oil bath. Solvent was distilled off under reduced pressure and the residue was taken into ethyl acetate (20 mL). Organic layer was washed with water (10 mL x 3) and dried over sodium sulfate. Sodium sulfate was filtered off and washed with ethyl acetate (5 mL x 2). The combined filtrate was concentrated under reduced pressure to yield crude product which was purified by recrystallization with ethyl acetate/hexane to give 3-(substituted 1H- azol-1-yl)-1-phenylpropan-1-one (3-9).
General Procedure:To a solution of 3-chloro-1-phenylpropan-1-one (2, 2.0 mmol) in toluene (25-30 mL) was added azoles (3.0 mmol) and triethylamine (4.0 mmol) at room temperature. The reaction mixture was heated at reflux under stirring for 3-4h in an oil bath. Solvent was distilled off under reduced pressure and the residue was taken into ethyl acetate (20 mL). Organic layer was washed with water (10 mL x 3) and dried over sodium sulfate. Sodium sulfate was filtered off and washed with ethyl acetate (5 mL x 2). The combined filtrate was concentrated under reduced pressure to yield crude product which was purified by recrystallization with ethyl acetate/hexane to give 3-(substituted 1H- azol-1-yl)-1-phenylpropan-1-one (3-9).
With titanium tetrachloride; zinc; In 2-methyltetrahydrofuran; at 15 - 50℃;Product distribution / selectivity;
Hydroxyethoxybenzophenone (67.66g, 279.3 mmol, 1 eq), 3- chloropropiophenone (47.24 g, 279.3 mmol, 1 eq), zinc powder (69.45 g, 1062 mmol, 3.8 eq) and 2-methyltetrahydrofuran (895 g, 1041 ml) were charged to the reactor. The slurry was degassed and the vessel was filled with nitrogen gas. The slurry was cooled to <15C and then titanium tetrachloride (101.5 g, 535.1 mmol, 1.92 eq.) was slowly dosed maintaining a temperature below 20C. The slurry was heated to 50C and the temperature was maintained for 15 minutes. The slurry was heated to 70C and the pressure was reduced and 2- methyltetrahydrofuran (403 g) was distilled off at 70C and 650 mbar over 1 hour. Zinc(s) was filtered off and the filter was rinsed with 2-methyltetrahydrofuran (64 g). The pressure was reduced to 200 mbar and 2-methyltetrahydrofuran (344 g) was distilled off at 43-53C and 200-160 mbar pressure (total amount of pure 2- methyltetrahydrofuran recycled is 76%). Toluene (151g) was charged. A mixture of hydrochloric acid (aq) (116 g, 37 %) and water (281 g) was added maintaining a temperature below 20C. The lower aqueous phase was cut (at 30C) and discarded. Water (128 g) was added. The lower aqueous phase was cut (at 55C) and discarded. Water (131 g) was added again and the lower aqueous phase was cut again (at 55C) and discarded. The pressure was reduced and 2- methyltetrahydrofuran + toluene + water was distilled off at 150-50 bar and 37- 60C until there was a residual volume of about 130 ml. Before the crystallisation/precipitation process, the ratio of Z:E isomers of Ospemifene was about 5.5:1. Then, methanol (125 g) was charged and the solution was filtered. To the filtrate was added methanol to a total weight of 572 g (content estimated to 121 g raw product + toluene and 451 g methanol). Water (148 g) was added to the filtrate and the solution was heated to 50C. The solution was then cooled to 48C and seeded. The mixture was slowly cooled to 15C over 5 hours and maintained at this temperature overnight. The product was isolated by filtration and the filter cake was rinsed with methanol(aq) (74%, 141 g). Yield 50.4 g after drying (47.6%). Purity >99% by HPLC (standard). The raw product contained 98.81 % Z-isomer, 0.61% E-isomer (hence a Z:£ ratio of 162:1 ) and 0.58% of other products. The product obtained (in a yield of 96%; hence, advantageously yield is not significantly decreased) after recrystallisation was 99.9% Z-isomer, 0.05% E-isomer (hence a Z:E ratio of 1991 : 1 ) and 0.05% of other products. Hence, an extremely pure and selective Z-isomer of the compound of formula I is obtained by this method of the invention.
With titanium tetrachloride; zinc; In 2-methyltetrahydrofuran; at -10 - 80℃; for 5.5h;Inert atmosphere;
Zn powder (172 g, 2.6 mol) was added to the 3 L reaction flask, respectively2-methyltetrahydrofuran (1800 mL),Stir well and cool to -10 C,Nitrile was slowly added, TiCl4 (250 g, 1.32 mol) was slowly added dropwise,Add to warm up to room temperature for 30min,And then heated to 80 C for 2 h.Cooling to 40 ,A solution of 2- (4-benzophenoxy) -1-ethanol (108 g, 0.45 mol) was added dropwise3-chlorophenylacetone (76 g, 0.45 mol)2-methyltetrahydrofuran solution (800 ml).Plus heating temperature to 80 under the reaction 3h,After TLC detection reaction is completed,React and cool the system temperature to room temperature
With yeast strain Aureobasidium pullulans CQA; 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.
30%Chromat.; 23%Chromat.
With yeast culture of Candida viswanathii KCh 120; In acetone; at 25℃; for 6h;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 strain Rhodotorula glutinis H93; 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.
91%Chromat.; 9%Chromat.
With yeast culture of Rhodotorula rubra KCh 82; In acetone; at 25℃; for 24h;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 formic acid; C30H31ClN2O2RuS; triethylamine; at 60℃; for 1.5h;Inert atmosphere;
This compound is known [17]. From 3-chloropropiophenone 13: A degassed solution of 3-chloropropiophenone (170 mg, 1.01 mmol, 1.0 eq) and (S,S)-2 (3.1 mg, 0.005 mmol, 0.5%) in FA/TEA (5:2, 0.5 mL) was stirred at 60 C for 1.5 h. The mixture was diluted with ethyl acetate (5 mL) and quenched with NaHCO3 (sat., 5 mL), the aqueous layer was extracted further with ethyl acetate (2 5 mL) and the organic extracts dried over Na2SO4 and concentrated to give a brown oil. The crude was dissolved in diethyl ether and passed through a silica plug to yield the product 14 as a red oil (123 mg, 0.97 mmol, 96%) in 100% conv and 95% ee as measured by GC. [α]D22 -43.5 (c 0.35 in CHCl3); lit [17] [α]D22 -43.6 (S) (c 1.0 in CHCl3); δH (300 MHz, CDCl3) 7.29-7.15 (5H, m, Ph), 4.49 (1H, dt, J = 3.2, 6.6 Hz, CHOH), 1.85 (1H, brs, OH), 1.78-1.57 (2H, m, CH2), 0.82 (3H, t, J = 7.4 Hz, CH3); δC (75 MHz, CDCl3) 143.9, 127.8, 126.9, 125.4, 75.4, 31.3, 9.5; Chiral GC; (CP-Chirasil-Dex-Cβ, 25 m 0.25 mm x 0.25 μm column, oven: hold 12 min at 125 C, then ramp 1 C/min, final temp 145 C, inj.: split 220 C, det.: FID 250 C, 18 Psi He), retention times: 11.2 (R) and 11.4 (S) minutes. From phenyl vinyl ketone 15: Compound 14 could also be prepared with 100% conversion and 95% ee with the same method, starting from 15 (prepared by elimination of HCl from 3-chloropropriophenone [18], 126 mg, 0.95 mmol, 1 eq), (S,S)-2 catalyst (3.5 mg, 0.006 mmol, 0.5%) and FA/TEA (5:2, 0.5 mL). The product was isolated as a clear oil (103 mg, 0.76 mmol, 79%). Attempted reduction of 1-phenylprop-2-en-1-ol 17. Application of the same method to commercially available α-vinylbenzyl alcohol 17 (134 mg) and (S,S)-2 catalyst (3.3 mg, 5 μmol, 0.5%) in FA/TEA (5:2. 0.5 mL) gave no reaction in 1.5 h at 60 C.
100%Chromat.
With yeast culture of Rhodotorula marina KCh 77; In acetone; at 25℃; for 144h;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 Aphanocladium album KCh 417; In acetone; at 25℃; for 144h;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 144h;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 24h;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 24h;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 72h;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.
28%Chromat.; 57%Chromat.
With yeast culture of Candida viswanathii KCh 120; In acetone; at 25℃; for 144h;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 24h;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 216h;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.
8%Chromat.
With yeast culture of Yarrowia lipolytica 1-101-1,31-K1; In acetone; at 25℃; for 216h;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.
58%Chromat.
With yeast culture of Yarrowia lipolytica ATCC 32-338 A; In acetone; at 25℃; for 72h;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 82; In acetone; at 25℃; for 6h;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.
1,1-bis(4-hydroxyphenyl)-2-phenyl-4-chlorobut-1-ene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran at 0 - 20℃; for 5h; Inert atmosphere; Reflux;
86%
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Reflux;
81.1 Step 1: Preparation of 4,4’-(4-chloro-2-phenylbut-1-ene-1,1-diyl)biphenol (SIAIS208102) according to Scheme 18:
A dry three-necked flask equiped with a reflux device was charged with Zinc powder (6.5 g, 100 mmol), evacuatedand refilled with the air three times, and then THF (80 mL) was added under Ar gas, and followed by dropping TiCl4 (9.5g, 50 mmol) at 0°C. After removing the ice bath, the reaction mixture was warmed to room temperature and heated toreflux for 2 h. After cooling to room temperature, solutions of compounds 1 (2.14 g, 10 mmol) and 2 (5.1 g, 30 mmol) inTHF (80 mL) were added, and refluxed for 3 h in the dark. After the reaction is complete, the reaction mixture was cooledand rotary-evaporated to remove most of the solvent, quenched with saturated ammonium chloride solution, and extractedwith ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried with anhydroussodium sulfate, rotary-evaporated to dryness, and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=2:1) to obtain 3 g of yellow solid product with a yield of 86%. 1H NMR (500 MHz, CDCl3) δ 7.21 -7.10 (m, 7H), 6.84 - 6.81 (m, 2H), 6.75 - 6.72 (m, 2H), 6.49 - 6.46 (m, 2H), 4.99 (s, 1H), 4.73 (s, 1H), 3.45 - 3.36 (m,2H), 2.99 - 2.91 (m, 2H). HRMS (ESI) m/z: calcd for, C22H20ClO2+ [M+H]+, 351.1146; found, 351.1138.
86%
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 3h; Inert atmosphere; Reflux; Darkness;
1 Synthesis of 4,4'-(4-chloro-2-phenylbut-1-ene-1,1-diyl)biphenol (SIAIS 208102)
A dried three-necked flask equipped with a reflux condenser was charged with Zinc powder (6.5 g, 100 mmol), followed by evacuation and refilling with argon gas for three times, and then addition of THF (80 mL) under argon. TiCl4 was added dropwise at 0° C. The mixture was warmed to r.t., and refluxed for 2 h. After the mixture was cooled to room temperature, a solution of compound 1 (2.14 g, 10 mmol) and compound 2 (5.1 g, 30 mmol) in THF (80 mL) was added, and refluxed in the dark for 3 h. After the reaction was complete, the resulting mixture was cooled down to r.t., and rotary evaporated to remove most of the solvent. The reaction was quenched with saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was then separated and purified by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate=2:1) to obtain a yellow solid product (3 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.21-7.10 (m, 7H), 6.84-6.81 (m, 2H), 6.75-6.72 (m, 2H), 6.49-6.46 (m, 2H), 4.99 (s, 1H), 4.73 (s, 1H), 3.45-3.36 (m, 2H), 2.99-2.91 (m, 2H). HRMS (ESI) m/z: calcd for C22H20ClO2+ [M+H]+, 351.1146; found, 351.1138.
86%
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 3h; Inert atmosphere; Reflux; Darkness;
1 Synthesis of 4,4'-(4-chloro-2-phenylbut-1-ene-1,1-diyl)biphenol (SIAIS 208102)
A dried three-necked flask equipped with a reflux condenser was charged with Zinc powder (6.5 g, 100 mmol), followed by evacuation and refilling with argon gas for three times, and then addition of THF (80 mL) under argon. TiCl4 was added dropwise at 0° C. The mixture was warmed to r.t., and refluxed for 2 h. After the mixture was cooled to room temperature, a solution of compound 1 (2.14 g, 10 mmol) and compound 2 (5.1 g, 30 mmol) in THF (80 mL) was added, and refluxed in the dark for 3 h. After the reaction was complete, the resulting mixture was cooled down to r.t., and rotary evaporated to remove most of the solvent. The reaction was quenched with saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was then separated and purified by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate=2:1) to obtain a yellow solid product (3 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.21-7.10 (m, 7H), 6.84-6.81 (m, 2H), 6.75-6.72 (m, 2H), 6.49-6.46 (m, 2H), 4.99 (s, 1H), 4.73 (s, 1H), 3.45-3.36 (m, 2H), 2.99-2.91 (m, 2H). HRMS (ESI) m/z: calcd for C22H20ClO2+ [M+H]+, 351.1146; found, 351.1138.
70%
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux;
4.1.1. Method A. McMurry reductive coupling reaction
General procedure: General procedure: To a stirred suspension of zinc powder (31 mmol) in dry THF (30 mL) was added TiCl4 (14 mmol), under Ar, at 10 C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. After titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 C and then a solution of 4,4'-hydroxybenzophenone (2.3 mmol)and substituted-phenone (6.7 mmol) in dry THF (40 mL) at 0 C was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature (25 C); and quenched with 10% aqueous potassium carbonate(50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo.
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran
3-(2,4-dihydroxynaphthalen-1-yl)-1-phenylpropan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: 1,3-dihydroxynaphthalene With sodium hydroxide In tetrahydrofuran; water at 20℃; for 0.25h; Green chemistry;
Stage #2: 3-chloropropiophenone In tetrahydrofuran; water for 2h; Green chemistry;
General Experimental Procedure
General procedure: A solution of 2-Naphthol (865mg, 6 mmol) in THF (3 ml) was added dropwise to the solution of sodium hydroxide (0.3g, 7.5mmol) in H2O(1.5 ml) at room tempera-ture. The mixture was stirred for 15 min. Thensolution of 3-chloro-1-phenylacetone (843.1 mg, 5 mmol) in THF (3 ml) was added slowly. Afteraddition, the mixture was stirred for another 2 h. TLC indicated the3-chloro-1-phenyl acetone was consumed up. Thenethyl acetate and water were added, after separation, the organic phasewas washed with brine, dried over Na2SO4 ,thenconcentrated. The residue was purified via flash column chromatography on silica gel
6-hydroxy-5-(3-oxo-3-phenylpropyl)-2-naphthonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
General procedure: A solution of 2-Naphthol (865mg, 6 mmol) in THF (3 ml) was added dropwise to the solution of sodium hydroxide (0.3g, 7.5mmol) in H2O(1.5 ml) at room tempera-ture. The mixture was stirred for 15 min. Thensolution of 3-chloro-1-phenylacetone (843.1 mg, 5 mmol) in THF (3 ml) was added slowly. Afteraddition, the mixture was stirred for another 2 h. TLC indicated the3-chloro-1-phenyl acetone was consumed up. Thenethyl acetate and water were added, after separation, the organic phasewas washed with brine, dried over Na2SO4 ,thenconcentrated. The residue was purified via flash column chromatography on silica gel
Stage #1: 2-Naphthalenethiol With sodium hydroxide In tetrahydrofuran; water at 20℃; for 0.25h; Green chemistry;
Stage #2: 3-chloropropiophenone In tetrahydrofuran; water for 2h; Green chemistry;
General Experimental Procedure
General procedure: A solution of 2-Naphthol (865mg, 6 mmol) in THF (3 ml) was added dropwise to the solution of sodium hydroxide (0.3g, 7.5mmol) in H2O(1.5 ml) at room tempera-ture. The mixture was stirred for 15 min. Thensolution of 3-chloro-1-phenylacetone (843.1 mg, 5 mmol) in THF (3 ml) was added slowly. Afteraddition, the mixture was stirred for another 2 h. TLC indicated the3-chloro-1-phenyl acetone was consumed up. Thenethyl acetate and water were added, after separation, the organic phasewas washed with brine, dried over Na2SO4 ,thenconcentrated. The residue was purified via flash column chromatography on silica gel
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1). (E)-Chalcone (3a) [21]. Yield 90%, pale yellow solid. 1HNMR (400 MHz, CDCl3): delta = 8.11 (d, J = 7.3 Hz, 2H, aromatic CH),7.90 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.72 (dd, J = 6.3, 2.8 Hz,2H, aromatic CH), 7.69-7.55 (m, 4H, aromatic CH andCH=CHCOPh), 7.52-7.46 (m, 3H, aromatic CH).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 90℃; under 750.075 Torr; for 16h;Inert atmosphere;
General procedure: A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 C)/EtOAc (v/v = 30:1).
(Z)-(4-chloro-1-(4-methoxyphenyl)but-1-ene-1,2-diyl)dibenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Reflux;
1.1. (Z)-(4-Chloro-1-(4-methoxyphenyl)but-1-ene-1,2-diyl)dibenzene(3)
To a stirred suspension of zinc dust (6.5 mmol)in dry THF at -10°C, under dry nitrogen atmosphere, was addeddropwise TiCl4 (3.5 mmol) in about 20 minutes maintainingthe temperature below 0 °C. After the addition is complete, thereaction mixture was allowed to reflux for 2h. The reaction temperature waslowered to 0 °C and a solution of reactants 1 (1 mmol) and 2 (1mmol) in dry THF was added dropwise over a period of 20 min. On completion, thereaction mixture was again refluxed for 2h. The progress of the reaction wasmonitored by TLC. The reaction mixture was then cooled to room temperature,transferred to stirred solution of 10% K2CO3 andfiltered. The filtrate was concentrated under reduced pressure to recover THF.The crude material so obtained was dissolved in ethyl acetate and washed withbrine followed by water, and dried over anhydrous sodium sulphate. The solventwas removed under reduced pressure and the obtained oily mass was recrystallizedfrom a mixture (1:9) of water and methanol to obtain solid product 3. White solid, Yield 65%; m.pt 87-89°C;IR (KBr) νmax: 1604, 1508, 1490 cm-1; 1H NMR (600 MHz, CDCl3): δH2.96 (t, 2H, J = 7.8 Hz, -H2C-CH2-), 3.46(t, 2H, J = 7.8 Hz, -H2C-Cl), 3.71 (s, 3H, H3C-O),6.59 (d, 2H, J = 7.2 Hz, c”), 6.83(d, 2H, J = 7.2 Hz, b”), 7.24 (m, 8H,aromatic), 7.40 (dd, 2H, J = 7.2 Hz,c); 13C NMR (150 MHz, CDCl3): δC 38.6, 42.9,55.0, 112.9, 126.6, 126.9, 127.4, 128.2, 128.3, 128.4, 129.6, 130.5, 130.6,131.7, 134.8, 135.2, 141.0, 141.8, 142.9, 157.8. MS m/z: 349 (M+).Analysis calculated for C23H21ClO: C, 79.18; H, 6.07.Found: C, 79.21; H, 6.05.
65%
With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 2.33333h; Inert atmosphere; Reflux;
2 (Z)-(4-Chloro-l-(4-methoxyphenyl)but-l-ene-l,2-diyl)dibenzene (11)
To a stirred suspension of zinc dust (6.5 mmol) in dry THF at -10 °C, under dry nitrogen atmosphere, was added dropwise TiCU (3.5 mmol) in about 20 minutes maintaining the temperature below 0 °C. After the addition was complete, the reaction mixture was allowed to reflux for 2h. The reaction temperature was lowered to 0 °C and a solution of reactants 9 (1 mmol) and 10 (1 mmol) in dry THF were added dropwise over a period of 20 min. On completion, the reaction mixture was again refluxed for 2h. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature, transferred to stirred solution of 10% K2CO3 and filtered. The filtrate/solvent were concentrated under reduced pressure to recover THF. The crude material so obtained was dissolved in ethyl acetate and washed with brine followed by water, and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the obtained oily mass was recrystallized from a mixture (1 :9) of water and methanol to obtain solid product 11. White solid, Yield 65%; m.pt 87-89 °C; IR (KBr) Vmax: 1604, 1508, 1490 cm 1; NMR (600 MHz, CDCh): δΗ 2.96 (t, 2H, J= 7.8 Hz, -H2C-CH2-), 3.46 (t, 2H, J= 7.8 Hz, -H2C-CI), 3.71 (s, 3H, H3C-O-), 6.59 (d, 2H, J= 7.2 Hz, c"), 6.83 (d, 2H, J= 7.2 Hz, b"), 7.24 (m, 8H, aromatic), 7.40 (dd, 2H, J= 7.2 Hz, c); 13C NMR (150 MHz, CDCb): 5c 38.6, 42.9, 55.0, 66.7, 1 12.9, 126.6, 126.9, 127.4, 128.2, 128.3, 128.4, 129.6, 130.5, 130.6, 131.7, 134.8, 135.2, 141.0, 141.8, 142.9, 157.8. MS m/z: 349 (M+). Analysis calculated for C23H21CIO: C, 79.18; H, 6.07. Found: C, 79.21 ; H, 6.05.
With titanium tetrachloride; zinc In tetrahydrofuran for 6h; Reflux; Inert atmosphere;
With potassium carbonate; In acetone; at 45 - 47℃; for 20h;
General procedure: To 3-chloro-1-phenyl-1-propanone (253 mg, 1.5 mmol) in acetone (20 mL), anhydrous potassium carbonate (414 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, a solution of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (1.5 mmol) in acetone (10 mL) was then added, and the mixture was reacted for 20 hours by heating to 45 to 47° C. The completion of the reaction was confirmed by thin-layer chromatography, and the solvent was then distilled off under reduced pressure. To the residue, water (20 ml) was added. The aqueous layer was subjected to extraction with ethyl acetate (50 mL) three times. The organic layer was washed with water and saline and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid at a yield of 77percent. (0296) 1H NMR (300 MHz, CDCl3) delta 2.24-2.33 (m, 5H), 2.50-2.61 (m, 10H), 2.82-2.92 (m, 2H), 3.16-3.26 (m, 2H), 7.44-7.62 (m, 3H), 7.94-8.03 (m, 2H) (0297) MS (TOF Mass): m/z calcd for C19H28N2O (M+1) 301.22. found: 301.23
Stage #1: diethyl propargylmalonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.75h;
Stage #2: 3-chloropropiophenone In tetrahydrofuran at 0 - 20℃;
Diethyl (3-Oxo-3-phenylpropyl)(prop-2-ynyl)malonate (1a)
After NaH (60% dispersion in paraffin, 1.28 g, 32.0 mmol) was washed by dry hexane, THF (45 mL) was added. Diethyl (prop-2-ynyl)malonate (5.01 g, 25.3 mmol) was added to the suspension of NaH in THF at 0°C. After 15 min the mixture was warmed to room temperature and stirred for 30 min. The resultant solution was recooled to 0°C, and then a solution of 3-chloro-1-phenyl-propan-1-one (4.58 g, 27.2 mmol) in THF (20 mL) was added. After being stirred for 15 min, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was treated with saturated aqueous NH4Cl and water, and extracted two times with Et2O. The combined organic layer was dried over Na2SO4 and evaporated. Purification of the residual oil by silica-gel column chromatography (hexane-AcOEt 10:1) gave the title compound (1a, 6.04 g, 18.3 mmol) in 72% yield. 1a: 1HNMR (300 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 6H), 2.04 (t, J = 2.6 Hz, 1H), 2.47-2.54 (m, 2H), 2.90 (d, J = 2.6 Hz, 2H), 3.01-3.09 (m, 2H), 4.13-4.30 (m, 4H), 7.43-7.49 (m, 2H), 7.53-7.59 (m, 1H), 7.95-7.98 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 14.0, 23.8, 27.0, 33.7, 56.1, 61.8, 71.8, 78.6, 128.1, 128.6, 133.1, 136.6, 170.0, 198.6. These data agree with the previously reported data. 7,8
Titanium tetrachloride (6.54 mL, 20 mmol) was added to the degassed mixture of toluene (26 mL) and 2-methyl tetrahydrofuran (21 mL) below 13 C. under N2, and the mixture was stirred at 0 C. for 10 minutes. The obtained solution was Liquid A. (0081) A solution of orthochlorophenol (7.71 g, 60 mmol) in 2-methyltetrahydrofuran (26 mL) was added to the suspension of Compound 1 (10.4 g, 30 mmol), zinc (7.85 g, 120 mmol), potassium chloride (8.95 g, 120 mmol) and 3-chloro-propiophenone (5.06 g, 30 mmol) in toluene (26 mL). The suspension was degassed three times. (0082) Then Liquid A was added dropwise to the suspension below 11 C., washed with 2-methyl tetrahydrofuran (5 mL). The suspension was degassed three times again. The suspension was heated from 0 to 70 C. for 45 minutes, and the suspension was stirred at 70 C. for 60 minutes. The suspension was cooled to room temperature, and toluene (25 mL) was added to the suspension. Water (100 mL) and concentrated hydrochloric acid (100 mL) was added with ice-cooling, and the mixture was stirred for 10 minutes at room temperature. The mixture was extracted with toluene (25 mL) twice, and the organic layer was washed with water (50 mL), 2 mol/L aqueous sodium hydroxide solution (100 mL), water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain yellow oily crude product (approximately 16 g). (0083) The obtained oily crude product was dissolved in tetrahydrofuran-methanol (1:1, 80mL), and then, 2 mol/L aqueous sodium hydroxide solution (30 mL) was added. The mixture was stirred at room temperature for 2 hours. Water-saturated aqueous sodium chloride (5:1, 90ml) was added and the mixture was extracted with toluene (100 mL and 50 mL) twice. The organic layer was washed with water-saturated aqueous sodium chloride (5:1, 90ml) and washed with saturated aqueous sodium chloride solution (25 mL). The combined organic layers were dried over anhydrous magnesium sulfate and filtrated to obtain a solution (244 g) containing the crude product. (0084) 1/30 of the solution containing the obtained crude product was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexanes-ethyl acetate) to obtain Compound 2 (249 mg, purity 99.5%, 66% in terms of yield, Z E=4.2:1). (0085) 29/30 of the solution containing the crude product was evaporated under reduced pressure, and methanol (50 mL) was added to the residue. The mixture was evaporated under reduced pressure to obtain an oil (13.5 g). The oil was dissolved in methanol (57 mL). The mixture was headed to 50 C., and water (14.2 mL) was added. The mixture was heated at 40 C. for 30 minutes. (When the temperature of solution was at 40 C., and seed crystals A was added.) And then, the mixture was cooled at 15 C. for 60 minutes, stirred at the temperature for 60 minutes. The precipitate was filtered, washed with the filtrate, then methanol-water (3:1, 3 mL) twice and methanol-water (3:1, 2mL). The obtained solid was dried with heating under reduced pressure to obtain Ospemifene as a white solid (8.4 g, Z:E=11.6:1). The obtained Ospemifene was dissolved in methanol (44 mL) at 50 C., and water (11 mL) was added dropwise to the mixture. The mixture was cooled to room temperature for 60 minutes and was standing for 14 hours. The mixture was stirred at 15 C. for 30 minutes, and filtered. The resulting solid was washed with the filtrate, then methanol-water (2:1, 4mL) three times. The obtained solid was dried under heating under reduced pressure to obtain Ospemifene as a white solid (9.1 g, Z:E=53.5:1). The obtained Ospemifene was dissolved in methanol (44 mL) at 58 C., and then, water (11 mL) was added dropwise to the mixture. The mixture was cooled to room temperature for 15 C. for 30 minutes. The precipitate was filtered, washed with the filtrate, then washed with methanol-water (2:1, 5 mL) twice. The obtained solid was dried with heating under reduced pressure to obtain Ospemifene as a white solid (4.90 g, yield: 45%, Z:E=341:1).
2-(pyrrolidin-3-yl)-1H-benzo[d]imidazole-4-carboxamide[ No CAS ]
[ 936-59-4 ]
2-(1-(3-oxo-3-phenylpropyl)pyrrolidin-3-yl)-1H-benzo[d]imidazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 3h;
General procedure: A solution of N3 (200 mg, 0.87 mmol), 2-chloro-N-phenylacetamide (221 mg, 1.30 mmol) in DMF (5 mL) was treatedwith K2CO3 (240 mg, 1.74 mmol) and KI (14.4 mg, 0.09 mmol) at 50 C for 3 h. The solution wasconcentrated, and the residue was purified by column chromatography (silica gel, DCM/MeOH = 30:1,Rf value 0.22) to give the title compound (111 mg, 35%).
69%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3h;
P1C (300 mg, 1.30 mmol), <strong>[936-59-4]3-chloropropiophenone</strong> (263.62 mg, 1.56 mmol)And potassium carbonate (360.11 mg, 2.61 mmol) was added to DMF (12 mL).After stirring at 50 C for 3 hours, the solution was concentrated.The residue was purified by column chromatography (silica gel, dichloromethane / methanol)Compound 3 (326 mg, yield 69.0%) was obtained.
Stage #1: procaine hydrochloride With sodium hydroxide
Stage #2: 3-chloropropiophenone With triethylamine In tetrahydrofuran Reflux;
General Procedure A (GP-A) for the synthesis of derivatives 2c-f and 3c
General procedure: Procainehydrochloride (0.02 mol, 5.45 g) (for the synthesis of compounds 2c-f) or procainamidehydrochloride (0.02 mol, 5.43 g) (for the synthesis of compound 3c) was solubilized inNaOH 1 N (200 mL) and extracted with ethyl acetate (3 100 mL). The organic layerwas dried over Na2SO4 and concentrated under reduced pressure to give a pale yellowoil that was subsequently dissolved in anhydrous THF (90 mL). Triethyl amine (15.7 mL,0.024 mol) and the proper arylpropan-1-one (0.017 mol) were then added, and the reactionwas stirred at reflux for 15 h [21]. The mixture was cooled to ambient temperature and thesolvent was reduced under vacuum. Water (300 mL) was added, and the crude product was extracted with ethyl acetate (3 200 mL). The organic layers were combined, washedwith brine, dried over Na2SO4, filtered, and concentrated to dryness. The raw materialwas purified by column chromatography on silica gel (chloroform/methanol 5:1 as eluent)or directly recrystallized (isopropanol) to give pure compound 3c as a pale yellow solid.For each derivative, the amount of the proper arylpropan-1-one, yield (%), melting point,recrystallization solvent, IR, 1H NMR, and elemental analysis are reported.
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