Trimethylaluminum → (R)-N-((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide

HRID 238768Notes

Reaction equation

HRID 238768 reaction equation
Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](=[N:36]/[S@@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])/[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:23]=1[O:43][CH3:44].[Al](C)(C)C.FC1C=C([Li])C=C(OC(F)(F)C(F)F)C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@:28]([NH:36][S@@:37]([C:39]([CH3:40])([CH3:42])[CH3:41])=[O:38])([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:23]=1[O:43][CH3:44]

Participants

8

Reactant 5

HCID 16682925TrimethylaluminumHCID 236551051-Bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzeneHCID 59459069(NE,R)-N-[1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene]-2-methylpropane-2-sulfinamideHCID 178418339ButyllithiumHCID 178506746HCID 178506746, compound

Product 1

HCID 59458676(R)-N-((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideYield 42.4%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (357 mg, 1.23 mmol) in toluene (1.5 mL) at −60° C. was added n-BuLi (2.5 M in hexane, 352 mL, 0.88 mmol). The reaction mixture was stirred for 1.5 h at −20° C. to −55° C. In a separate vial, to a −78° C. solution of (R,E)-N-(1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene)-2-methylpropane-2-sulfinamide (122 mg, 0.35 mmol) in toluene (1 mL) was added Al(CH3)3 (210 mL, 0.42 mmol). The resulting solution was stirred for 10-15 min, then added to the mixture of (3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)lithium. The combined reaction mixture was stirred at −55° C. overnight and then diluted with EtOAc. The organic portion was washed with H2O and the aqueous portion was extracted with EtOAc (3×). The combined organic portions were concentrated under reduced pressure and the residue was purified by preparative HPLC (Phenomenex Luna AXIA 100A, C18, 5μ; 10%-90% ACN/H2O containing 0.1% TFA, monitoring at 220 nm) to yield (R)—N—((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (83 mg, 42% yield). LCMS: RT=3.49 min [M+H] 560.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ 7.21-7.12 (m, 3H), 7.08 (dd, J=11, 8 Hz, 1H), 7.00-6.94 (m, 1H), 6.91-6.81 (m, 4H), 6.72-6.62 (m, 2H), 5.99-5.70 (m, 1H), 4.36 (s, 1H), 3.96 (d, J=13 Hz, 1H), 3.77 (s, 3H), 3.55 (d, J=13 Hz, 1H), 1.21 (s, 9H).

Workup

  1. stirringThe resulting solution was stirred for 10-15 min
  2. customThe combined reaction mixture
  3. stirringwas stirred at −55° C. overnight
  4. washThe organic portion was washed with H2O
  5. extractionthe aqueous portion was extracted with EtOAc (3×)
  6. concentrationThe combined organic portions were concentrated under reduced pressure
  7. customthe residue was purified by preparative HPLC (Phenomenex Luna AXIA 100A

Sources & evidence

ORD record
ord-0681d337ffec4fc9a80bd60fb32e5828
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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