2-Chloromethyl 2-(trimethylsilyl)ethyl ether → (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one

HRID 1641655Notes

Reaction equation

HRID 1641655 reaction equation
[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1

Participants

6

Reactant 3

HCID 27242712-Chloromethyl 2-(trimethylsilyl)ethyl etherHCID 58160438(S)-5-[(Biphenyl-4-yl)methyl]pyrrolidin-2-oneHCID 178418339Butyllithium

Product 1

HCID 59318461(S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

804 mg (3.2 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 16 ml dry THF and cooled to −78° C. After the addition of 2.21 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 680 μl (640 mg=3.84 mmol) (2-chloromethoxyethyl)-trimethylsilane (SEM-Cl) is added and stirring is continued at −20° C. for 5 h. The mixture is then allowed to warm up to room temperature overnight. The reaction is then quenched by addition of 10 ml saturated NH4Cl solution followed by 10 ml water and extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer dried over MgSO4, filtered and evaporated. The resulting residue (1.33 g) is purified using column chromatography (dichloromethane:triethylamine=99.5:0.5→dichloromethane:methanol:triethylamine=98.5:1:0.5) to give (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one (1-a, R1=SEM) as a yellow oil. NMR (400 MHz, CDCl3, δ/ppm): 7.58 (m, 4 H); 7.47 (m, 2 H); 7.37 (m, 1 H); 7.30 (m, 2 H); 5.04 (d, J=10.6, 1 H); 4.70 (d, J=10.6, 1 H); 4.03 (m, 1 H); 3.59 (m, 2 H); 3.24 (dd, J=4.2, 13.4, 1 H); 2.67 (dd, J=9.1, 13.4, 1 H); 2.33 (t, J=8.2, 2 H); 2.10 (m, 1H); 1.81 (m, 1 H); 1.00 (m, 2 H); 0.06 (s, 9 H). MS (ESI, m/e) 382 [M+H]+; 763 [2M+H]+. IR (solution in CH2Cl2, ν/cm−1): 3057; 2951; 1702; 1487; 1414; 1249; 1073; 859; 836; 759; 697.

Workup

  1. stirringstirring
  2. waitis continued at −20° C. for 5 h
  3. temperatureto warm up to room temperature overnight
  4. customThe reaction is then quenched by addition of 10 ml saturated NH4Cl solution
  5. extractionextracted with 2×40 ml isopropyl acetate
  6. customThe layers are separated
  7. dry with materialthe organic layer dried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customThe resulting residue (1.33 g) is purified

Sources & evidence

ORD record
ord-f5ad409b6dd04805a15e4bcf6db21273
Source dataset
uspto-grants-2012_02
Patent number
US08115016B2

Reaction notes

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