* 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.
General procedure: To a stirred solution of Grignard reagent (1.0 M in THF, 10 mmol) was slowly added Weinrebamide 2 (500 mg, 3.3 mmol) in dry THF (5 mL) under argon atmosphere overa period of 10-15 min at 0-5°C. The reaction mixture was stirred at 0-5°C till completion of the reaction (indicated by TLC) (see Table S-2). The reaction mixture was then quenched with saturated aqueous solution of NH4Cl(20 mL), diluted with ice water (20 mL) and extracted into ethyl acetate (2×20 mL). The organic layers were collected, combined, washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered,and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (100-200 mesh) using 8-10percent EtOAc / n-hexane asan eluent to afford the desired compound.
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 7, p. 1969 - 1973
3
[ 6638-79-5 ]
[ 403-43-0 ]
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Yield
Reaction Conditions
Operation in experiment
97%
With pyridine In dichloromethane
Step 1. N-methoxy-N-methyl-4-fluorobenzamide. To a 0° C. solution of 4-fluorobenzoyl chloride (11.9 g, 75.0 mmol) in CH2 Cl2 (150 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.00 g, 82.0 mmol) and a solution of pyridine (13.0 g, 164 mmol) in CH2 Cl2 (25 mL). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature and then was washed with 0.5N aqueous HCl (3*100 mL), saturated aqueous NaHCO3, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-4-fluorobenzamide (13.3 g, 97percent) as an oil.
96%
With pyridine In chloroform at 0 - 22℃; for 1 h;
4-Fluorobenzoyl chloride (15g, 94.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.1g, 104mmol) were dissolved in CHCl3 (200mL) and stirred at room temperature. The solution was cooled to 0°C and pyridine (17.3mL, 230mmol) was added. The mixture was warmed and stirred at room temperature for 1h and then poured into aq. sat. NaCl solution (300mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×100mL). The combined organic layers were washed with water (3×50mL), dried (anhyd. Na2SO4) and then evaporated. The crude 4-fluoro-N-methoxy-N-methylbenzamide 7a was purified via distillation under vacuum to afford a colourless liquid (96percent), bp=120°C at 0.3 mmHg (lit. b.p. 70°C at 0.1mmHg [13]); νmax 583, 905, 918, 1262, 1375, 1508, 1582, 1630, 2972, 3274cm−1; δH 3.34 (3H, s, CH3), 3.52 (3H, s, OCH3), 7.08 (2H, m, Ar–H), 7.73 (2H, m, Ar–H).
88%
With triethylamine In dichloromethane at 5℃; for 0.5 h;
In A VOLUMETRIC flask N,O-dimethylhydroxylamine hydrochloride (25.54 g, 261.8 mmol) and CH2Cl2 (443 mL) were introduced under argon atmosphere at 0°C. 4- Fluorobenzoyl chloride (34. 59 G, 218. 2 MMOL) WAS ADDED FOLLOWED BY THE SLOW addition OF TRIETHYLAMINE (48. 13 G, 475. 6 MMOL). THE REACTION WAS STIRRED FOR 30 min at 5 C and allowed to reach room temperature. It was washed with 5percent aqueous citric acid (180 ML) and with 5percent aqueous NaHCO3 (180 ML). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 20. 23 G OF THE DESIRED COMPOUND (YIELD : 88percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 1, p. 49 - 64
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 5, p. 1352 - 1357
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3337 - 3340
[4] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5828 - 5831
[5] Patent: US5616596, 1997, A,
[6] Dyes and Pigments, 2015, vol. 113, p. 239 - 250
[7] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 3, p. 333 - 336
[8] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 8; 9
[9] Patent: WO2004/76450, 2004, A1, . Location in patent: Page 37
[10] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[11] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[12] Patent: WO2004/18458, 2004, A1, . Location in patent: Page/Page column 57-58
[13] Patent: US2014/107097, 2014, A1, . Location in patent: Paragraph 0420; 0421
[14] Molecular Pharmacology, 2016, vol. 89, # 6, p. 667 - 677
[15] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
[16] Patent: US2018/237419, 2018, A1, . Location in patent: Paragraph 0314
4
[ 456-22-4 ]
[ 6638-79-5 ]
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Yield
Reaction Conditions
Operation in experiment
96%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
92%
Stage #1: With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In tetrahydrofuran; ethyl acetate at 0 - 5℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 25℃; for 1.33333 h; Inert atmosphere
General procedure: To a solution of acid 1 (1.0g, 8.9 mmol) in THF (15 mL) was added Et3N (3.1 mL, 22.2 mmol), and T3P (50percent solution in EtOAc, 10.6mL, 17.7 mmol) at 0-5 °C and the solution was stirred for about 10 min under a nitrogen atmosphere. Then N,O-dimethylhydroxylaminehydrochloride salt (1.1g, 13.3 mmol) was added to the reaction mixture at 0-5 °C and the heterogeneous mixture was allowed to stir at room temperature till the completion of the reactionas indicated by TLC (see Table S-1). The mixture was then diluted with water(20 mL) followed by ethyl acetate (20 mL) and stirred for about 10 min. The separated organic layer was collected, washed with 5percent citric acid (2 x10 mL),5percent Na2CO3 (2 x 10 mL), and then brine solution. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude product obtainedwas purified by flash column chromatography over silicagel (100-200 mesh) using 12-15percent EtOAc / n-hexane as eluent to affordthe desired compound.
79%
at 20℃; for 2 h;
Step 4a: 4-Fluoro-N-methoxy-N-methyl-benzamide (4a)To a solution of 4-fluorobenzoic acid (6.8 g, 48.57 mmole) in 100 mL of DMF at room temperature, is added diisopropylethylamine (25.3 mL, 145.7 mmole). After stirring at room temperature for 20 minutes, HOBT (7.22 g, 53.43 mmole), HBTU (20.26 g, 53.43 mmole) and N,O-dimethyl hydroxylamine hydrochloride (5.69 g, 58.29 mmole) are added to the reaction solution. After stirring at room temperature for 2 hours, the reaction solution is diluted with 200 mL of EtOAc and washed with 4.x.50 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70percent, EtOAc 30percent) to yield 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (7.0 g, yield 79percent).
77%
Stage #1: With chloroformic acid ethyl ester; triethylamine In dichloromethane at 10℃; for 0.833333 h; Stage #2: With triethylamine In dichloromethane at 10℃; for 1 h;
Method C: a solution of ethyl chloroformate (3.40mL, 35.68mmol) in anhydrous dichloromethane (6mL) was added dropwise at 10°C to a solution of 4-fluorobenzoic acid (5.00g, 35.68mmol) and triethylamine (5mL, 35.68mmol) in anhydrous dichloromethane (50mL). This reaction mixture was stirred at 10°C for 50min, and then N,O-dimethylhydroxylamine hydrochloride (3.48g, 35.68mmol) and triethylamine (5mL, 35.68mmol) were added. The resulting mixture was stirred for 1h at 10°C and the suspension was taken up in water (150mL) and extracted with CH2Cl2 (150mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was finally chromatographed on silica gel eluting with ethyl acetate:petroleum ether (gradient from 0/100 to 20/80 v/v) to give 77percent of 3a as clear oil. 1H NMR (300MHz, CDCl3) δ 7.69 (m, 2H, F-Ph-2,6), 7.02 (m, 2H, F-Ph-3,5), 3.47 (d, 3H, J=1.2Hz, OCH3), 3.29 (d, 3H, J=1.2Hz, NCH3). 13C NMR (75MHz, CDCl3) δ 168.7, 164.0 (J=249Hz), 130.8 (2×C, J=9Hz), 129.8 (J=3Hz), 115.0 (2×C, J=22Hz), 61.0, 33.6.
57%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57percent). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90percent (UV254).
53.9%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4279 - 4289
[2] Tetrahedron Letters, 2016, vol. 57, # 35, p. 3924 - 3928
[3] Patent: US2011/65726, 2011, A1, . Location in patent: Page/Page column 14
[4] European Journal of Medicinal Chemistry, 2015, vol. 89, p. 386 - 400
[5] Patent: US2015/111887, 2015, A1, . Location in patent: Paragraph 0293; 0294; 0295
[6] Patent: WO2018/153279, 2018, A1, . Location in patent: Paragraph 87-88
5
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Yield
Reaction Conditions
Operation in experiment
80%
With palladium diacetate; triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In 1,4-dioxane at 90℃; for 1 h; Sealed tube
General procedure: A mixture of arylhalide (I, Br) (1 mmol), Weinreb amine hydrochloride(1.5 mmol), Pd(OAc)2 (5 mol percent), xantphos (6 mol percent), triethylamine (3 mmol), and cobalt carbonyl (0.3 mmol) in 1,4-dioxane was heated at 90 °C for 1h in a septum-closed sealed tube. After cooling, the reaction mixture was concentrated in vacuum and the residue was extracted with ethylacetate and water. The ethylacetate layer was concentrated and the residue obtained was purified by flash column chromatography to get the desired product. Note: Carbon monoxide gas is highly toxic and should be handled by trained professionals in a well-ventilated fumehood with appropriate ventilation. In all the reactions, Co2(CO)8 was handled carefully in fumehoods using appropriate personal protective clothing and equipment.
(a) 4-Fluoro-N-methoxy-N-methylbenzamide --To a mixture containing methoxymethylamine hydrochloride (44 g, 0.45 mol) and triethylamine (138 mL, 0.99 mol) in CH2 Cl2 (500 mL) at 0° C. was added over 30 min, 4-fluorobenzoyl chloride (50 mL, 0.41 mol). The resulting mixture was allowed to warm to rt and stirring was continued for 30 min, at which time the mixture was poured into H2 O and extracted with Et2 O. The Organic extract was washed with saturated aqueous NaCl and dried (MgSO4). Removal of the solvent in vacuo afforded the title compound (80 g, 100percent), which was used without further purification: 1 H NMR (CDCl3): δ7.72 (dd, 2H); 7.06 (apparent t, 2H); 3.52 (s, 3H); 3.43 (s, 3H).
Reference：
[1] Patent: US5686455, 1997, A,
[2] Patent: WO2016/77724, 2016, A1, . Location in patent: Page/Page column 53
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