Ethyl bromodifluoroacetate → (4-Amino-3-methyl-5-nitro-phenyl)-difluoro-acetic acid ethyl ester
Reaction equation
I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15][C:16](=[O:21])[C:17](Br)([F:19])[F:18])[CH3:14]>CS(C)=O.[Cu]>[CH2:13]([O:15][C:16](=[O:21])[C:17]([C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1)([F:19])[F:18])[CH3:14]Participants
Conditions
- Temperature
- 60 °C
Procedure
To a solution of 4-iodo-2-methyl-6-nitroaniline (2.78 g, 10 mmol) and 2-bromo-2,2-difluoroacetic acid ethyl ester (2.03 g, 10 mmol) in anhydrous DMSO (20 mL) was added copper powder (1.28 g, 20 mmol). The mixture was purged with N2 and heated at 60° C. in a sealed vial for 14 h. After being cooled to the room temperature, the reaction mixture was poured into 20% aqueous NH4Cl solution (300 mL). The resulting mixture was basified to pH=8.5 with saturated aqueous Na2CO3 solution and was extracted with EtOAc (3×100 mL). The organic extract was washed with brine (2×30 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (40:1 hexanes/EtOAc) to afford the title compound (1.79 g, 65%). 1H NMR (CDCl3) δ 1.36 (t, 3H), 2.30 (s, 3H), 4.36 (q, 2H), 6.41 (br s, 2H NH), 7.51 (s, 1H), 8.33 (s, 1H). ESI-MS m/z 275 (MH+), 255 (M-F)+, 297 (M+Na)+, 549 (2M+1)+ and 571 (2M+Na)+.
Workup
- customThe mixture was purged with N2
- temperatureAfter being cooled to the room temperature
- additionthe reaction mixture was poured into 20% aqueous NH4Cl solution (300 mL)
- extractionwas extracted with EtOAc (3×100 mL)
- extractionThe organic extract
- washwas washed with brine (2×30 mL)
- dry with materialdried over Na2SO4
- concentrationconcentrated
- customThe residue was purified by chromatography (40:1 hexanes/EtOAc)
Sources & evidence
- ORD record
- ord-655116c904c34a70b1446d555263f423
- Source dataset
- uspto-grants-2014_01
- Patent number
- US08629147B2
Reaction notes
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