Soft Enolization of 3-Substituted Cycloalkanones Exhibits Significantly Improved Regiocontrol vs Hard Enolization Conditions
Natalie C. Dwulet, Vincenzo Ramella and Christopher D. Vanderwal*
*Department of Chemistry, University of California, Irvine, California 92697-2025, United States,
Email: cdv
uci.edu
N. C. Dwulet, V. Ramella, C. D. Vanderwal, Org. Lett., 2021, 23, 9616-9619.
DOI: 10.1021/acs.orglett.1c03844
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Abstract
Soft enolization conditions are markedly better than the typically applied hard enolization protocols for regioselective enoxysilane formation from unsymmetrical 3-substituted cycloalkanones. In all but one case, regioselectivities were ≥11:1 for enolization away from the substituent.
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General Procedure:
A solution of cycloalkanone (0.5 mmol) and iPr2NEt (freshly distilled over CaH2, 0.30 mL, 1.75 mmol, 3.5 equiv.) in CH2Cl2 (2 mL) was cooled to -78°C. A solution of TMSOTf (freshly distilled, 0.27 mL, 1.5 mmol, 3 equiv.) in CH2Cl2 (0.5 mL) was added dropwise over 10 min. After completion as observed by TLC (typically ~1 h), the reaction was quenched at -78°C by addition of sat. aq. NaHCO3 (2 mL). The mixture was diluted with pentane or hexanes (10 mL) and H2O (5 mL), the layers were separated, and the aqueous layer was extracted with pentane or hexanes (3 x 5 mL). The combined organic extracts were washed with 0.5 M CuSO4 (3 x 15 mL) and brine (1 x 15 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting colorless oil was purified by column chromatography with basic alumina (100% pentane or 5% Et3N in pentane).
Key Words
ID: J54-Y2021
