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

HRID 238847Notes

Reaction equation

HRID 238847 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-9206d51592ad41ce801dc9c536a08d7e
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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