Pyridine → [(R)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate

HRID 558012Notes

Reaction equation

HRID 558012 reaction equation
[CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:14][C:15]1([CH3:24])[C:18](=[C:19]([CH3:21])[CH3:20])[CH2:17][C@H:16]1[CH2:22]O.N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C.CN(C=O)C.CO>[CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:22][C@@H:16]1[CH2:17][C:18](=[C:19]([CH3:21])[CH3:20])[C:15]1([CH3:24])[CH3:14])=[O:4]

Participants

9

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 448893(S)-2-methylbutanoic acidHCID 11298085((1R)-2,2-dimethyl-3-(propan-2-ylidene)cyclobutyl)methanol

Product 1

HCID 11299404[(R)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoateYield 79%

Reagents, catalysts & solvents 4

HCID 241BenzeneSolvent2×HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 2.2 mL (20.1 mmol) of (S)-(+)-2-methylbutanoic acid {Aldrich, 99% ee, [α]24D+24.0 (c 0.1, MeOH)} in 15 mL of benzene was treated with 2.2 mL (25.2 mmol) of oxalyl chloride and 10 μl of DMF. After 1.5 h at room temperature, the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene. The acid chloride residue was dissolved in 15 mL of benzene, and then a solution of 1.65 g (10.7 mmol) of 6a and 18 ml (22.2 mmol) of pyridine in 15 mL of benzene were added dropwise. After stirring at room temperature for 1 h, the solvent was removed. The residue was treated with 20 mL of water, and extracted with ether. The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated to afford yellow oil. Pure 2a (2.0 g, 79% yield) was obtained by chromatography (silica gel, 2% of ethyl acetate in hexanes). Optical purity: 99% ee; [α]24D−0.79 (c 2.03, MeOH); 1H NMR (C6D6): δ 0.84 (3H, t, J=7.19 Hz), 1.08 (3H, d, J=6.82 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.36 (1H, m), 1.40 (3H, bs), 1.51 (3H, t, J=1.89 Hz), 1.67 (2H, m), 2.05 (1H, m), 2.17 (1H, m), 2.27 (1H, m), 2.48 (1H, ddt, J=14.75, 8.79, 1.52 Hz), 4.15 (2H, d, J=7.57 Hz); 13C NMR (C6D6): δ 175.76, 137.48, 122.55, 65.30, 44.43, 41.39, 39.71, 28.62, 27.79, 27.13, 21.17, 19.60, 18.64, 16.85, 11.80; EI-MS m/z (%): 238 [M]+ (2), 136 (29), 121 (100), 107 (12), 93 (20), 81 (26), 67 (5), 57 (16), 41 (10); HREIMS: obsd. 238.1929, calcd. for C15H26O2 (M+): 238.1933.

Workup

  1. customthe benzene and excess oxalyl chloride were removed
  2. additionfollowed by the addition of another 15 mL portion of benzene
  3. dissolutionThe acid chloride residue was dissolved in 15 mL of benzene
  4. customthe solvent was removed
  5. additionThe residue was treated with 20 mL of water
  6. extractionextracted with ether
  7. washThe organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customto afford yellow oil

Sources & evidence

ORD record
ord-d8815367058144348740917f6f69ac67
Source dataset
uspto-grants-2011_11
Patent number
US08062651B1

Reaction notes

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