Isopropanol → (R)-N-((R)-1-(1-benzylpiperidin-4-yl)-1-cyanopent-4-enyl)-2-methylpropane-2-sulfinamide

HRID 579584Notes

Reaction equation

HRID 579584 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[C:14](=[N:19]\[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al]([C:31]#[N:32])(CC)CC.CC(O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([C:31]#[N:32])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 3776IsopropanolHCID 16683962(cyano-C)diethylaluminiumHCID 87173115(NZ,R)-N-[1-(1-benzylpiperidin-4-yl)pent-4-enylidene]-2-methylpropane-2-sulfinamide

Product 1

HCID 66833653(R)-N-((R)-1-(1-benzylpiperidin-4-yl)-1-cyanopent-4-enyl)-2-methylpropane-2-sulfinamideYield 67.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of (R,Z)—N-(1-(1-benzylpiperidin-4-yl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (2.74 g, 7.6 mmol) in THF (130 mL, 0.06 M) was cooled to −78° C. Separately, a 1 M solution of Et2AlCN (11.4 mmol, 11.4 mL) was dissolved in THF (20 mL) and cooled to −78° C. iPrOH (0.64 mL, 8.26 mmol) was added dropwise and the solution was warmed to RT over 20 min, then added dropwise to the sulfinamide solution. The reaction was allowed to warm gradually to RT and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and filtered through Celite. The Celite pad was washed with ethyl acetate (3×) and the combined organics were washed saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (1-9% methanol in dichloromethane and again with 2-5% methanol in ethyl acetate) to afford the desired product (1.99 g, 67%) along with its undesired diastereoisomer (0.46 g, 15%). Rf 0.26 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.25 (m, 5H), 5.83-5.78 (m, 1H), 5.13-5.03 (m, 2H), 3.51 (d, J=1.5 Hz, 2H), 3.41 (s, 1H), 3.00 (d, J=11.0 Hz, 2H), 2.34-2.29 (m, 2H), 2.05-1.83 (m, 6H), 1.60-1.44 (m, 3H), 1.25 (s, 9H). ESI MS found for C22H33N3OS m/z [388.4 (M+1)].

Workup

  1. additionwas added dropwise
  2. temperatureto warm gradually to RT
  3. customThe reaction was quenched with saturated aqueous ammonium chloride (50 mL)
  4. filtrationfiltered through Celite
  5. washThe Celite pad was washed with ethyl acetate (3×)
  6. washthe combined organics were washed saturated aqueous sodium chloride
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was chromatographed on silica gel (1-9% methanol in dichloromethane

Sources & evidence

ORD record
ord-2289ecd1f4ca4bfdb55de078a02abeb0
Source dataset
uspto-grants-2015_05
Patent number
US09040703B2

Reaction notes

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