2-(Bromomethyl)benzonitrile → t-Butyl (2S,3R,5R)-5-(2-cyanobenzyl)-6-oxo-2,3-diphenyl-4-morpholine carboxylate

HRID 1078150Notes

Reaction equation

HRID 1078150 reaction equation
[O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.Br[CH2:28][C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][C@H:7]1[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3][C:2]1=[O:1])#[N:36]

Participants

5

Reactant 3

HCID 895992-(Bromomethyl)benzonitrileHCID 9812251,1-Dimethylethyl (2S,3R)-6-oxo-2,3-diphenyl-4-morpholinecarboxylateHCID 2724254Sodium bis(trimethylsilyl)amide

Product 1

HCID 53819028t-Butyl (2S,3R,5R)-5-(2-cyanobenzyl)-6-oxo-2,3-diphenyl-4-morpholine carboxylateYield 63%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of 9.68 g (27.4 mmol) of t-butyl (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholine carboxylate (Aldrich Chemical Company) and 5.91 g (30.1 mmol, 1.1 eq) of α-bromo-o-tolunitrile in 140 mL of tetrahydrofuran at -78° C. was added dropwise 28.8 mL of a 1.0M THF solution of sodium hexamethyldisilazide (28.8 mmol) over 15 min. The mixture was stirred at -78° C. for 3 h, then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (5×150 mL) and the combined organic extracts washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. Chromatography on silica gel (elution with 20% ethyl acetate-hexanes) gave the product as a white solid (8.01 g, 63%). 1H NMR indicates this compound exists as an approximately 5:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3): major rotamer--δ0.92 (s, 9H), 3.52 (dd; 10, 14 Hz; 1H), 3.62 (dd; 5, 14 Hz; 1H), 5.08 (d, 3 Hz, 1H), 5.40 (dd; 5, 10 Hz; 1H); 5.79 (d, 3 Hz, 1H), 6.52 (d, 8 Hz, 2H), 6.92 (d, 8 Hz, 2H), 7.00-7.70 (m, 1 OH). FAB-MS: calculated for C29H28N2O4 468; found 469 (M+H,30%), 369 (M-BOC, 100%).

Workup

  1. customquenched with saturated aqueous ammonium chloride
  2. extractionextracted with ethyl acetate (5×150 mL)
  3. washthe combined organic extracts washed with water, saturated aqueous sodium chloride
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationthe filtrate concentrated under reduced pressure

Sources & evidence

ORD record
ord-f0e0a2dcbd5645d29f2b22897baac7d0
Source dataset
uspto-grants-1996_08
Patent number
US05545735

Reaction notes

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