P-Anisidine → 3-[[3-[(4-Methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

HRID 48029Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:23][CH:24]([O:29][Si](C(C)(C)C)(C)C)[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:43][O:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:43][O:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:2]2[CH:3]=[C:4]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:11]=3)[CH2:23][CH:24]([OH:29])[C:25]([F:26])([F:28])[F:27])[CH:5]=[CH:6][CH:7]=2)=[CH:47][CH:46]=1

Participants

Conditions

Temperature: 95 °C

Procedure

A mixture containing N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy) benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (57.5 mg, 0.176 mmol), 4-methoxyaniline (18.6 mg, 0.151 mmol) tris(dibenzylideneacetone) dipalladium(0) (4.6 mg, 0.005 mmol), R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.7 mg, 0.0075 mmol) and toluene (2.5 mL) was heated to 95° C. in a sealed vial for 48 h. Tetrabutylammonium fluoride (1 M, THF, 0.372 mL, 0.372 mmol) was added, and the reaction was stirred at 23° C. for 1.5 h. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 49 mg (73%) of the desired 3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C25H23F7N2O3: 532.1597, found: 532.1592 [M]+. 1H NMR (CDCl3) δ3.48-3.57 (m, 1H), 3.77 (s, 3H), 3.83 (dd, 1H), 4.33 (m, 1H), 4.59 (s, 2H), 5.87 (tt, 1H), 6.27 (m, 1H), 6.33 (bd, 1H), 6.86 (dd, 4H), 7.02-7.12 (m, 4H), 7.31 (t, 1H), 7.41 (m, 1H), 7.60 (m, 1H). 19F NMR (CDCl3) δ-137.201 (d, 2F), -88.515 (s, 2F), -79.120 (s, 3F).

Workup

filtrationThe reaction mixture was filtered through celite
customthe solvent was evaporated
customThe residue was purified by silica gel chromatography
washeluting with 20% ethyl acetate in hexane

Sources & evidence

ORD record: ord-9efc16201bc74f16953c8d7cd64b6c66
Source dataset: uspto-grants-2004_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06699898B2

Reaction notes

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