Formic Acid → N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide

HRID 1712812Notes

Reaction equation

HRID 1712812 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH2:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:21](OC(=O)C)=[O:22].C(OC(=O)C)(=O)C.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:13][CH:21]=[O:22])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1

Participants

6

Reactant 4

HCID 284Formic AcidHCID 7918Acetic AnhydrideHCID 75269Acetic-formic anhydrideHCID 59459148(3-Fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine

Product 1

HCID 86613062N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamideYield 94%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (315 mg, 1.1 mmol) in CH2Cl2 (2 mL) at 0° C. was added acetic formic anhydride (314 uL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified on a 40 g column of silica gel, eluting with 0 to 100% EtOAc/hexane, to give N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 94% yield) as a clear, viscous oil. LCMS: RT=1.37 min [M+H] 316.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 6.13 (bs, 1H), 6.34 (d, J=7.47 Hz, 1H), 7.05-7.20 (m, 5H), 7.27-7.34 (m, 2H), 8.35 (s, 1H). To a solution of N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 1.04 mmol) in THF (5 mL) at 0° C. was added Et3N (0.79 mL, 5.7 mmol) followed by phosphorous oxychloride (0.125, 1.35 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ice-water (25 mL) and extracted with Et2O (3×20 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous Na2SO4, the filtered through basic alumina. The filtrate was concentrated to give 1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene (268 mg, 93% yield) as a pale brown oil. LCMS: RT=1.71 min [M−NC] 271.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); IR νmax cm−1 neat: 2139 (N═C); NMR: 500 MHz 1H (CDCl3) δ ppm 5.94 (s, 1H), 7.12 (t, J=8.52 Hz, 2H), 7.25-7.29 (m, 1H), 7.30-7.35 (m, 3H), 7.41 (s, 1H).

Workup

  1. customformed
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. customthe residue was purified on a 40 g column of silica gel
  4. washeluting with 0 to 100% EtOAc/hexane

Sources & evidence

ORD record
ord-aee4cf58db0b4a10a9c48c162f84e57b
Source dataset
uspto-grants-2010_09
Patent number
US07790770B2

Reaction notes

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