Alkylation of Active Methylenes via Benzhydryl Cations

Abstract

The acid mediated reaction between active methylenes and benzhydryl alcohols, or their derivatives, is reported. Ethyl acetoacetate, acetylacetone, and N,N-dibenzyl-malonamic acid methyl ester are benzhydrylated in quantitative yields in the presence of molar amounts of BF₃·OEt₂ in CH₂Cl₂ at r.t. TMSOTf and H₂SO₄ appear to be equally efficient. Use of benzhydryl acetate in place of the starting free alcohol allows lowering of the Lewis acid to catalytic amounts. A general mechanism for this scarcely studied C-C bond formation is presented. Due to the easier availability of alcohols with respect to halides the method may favorably compare with the more classical halide-based basic conditions.

Key words

boron - carbocations - enols - Lewis acids - benzhydryl­ation

References

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2

Poli, G.; Giambastiani, G. J. Org. Chem., 2002 in press.

5

Representative experimental procedure: To a stirred solution of benzhydryl alcohol (202 mg, 1.1 mmol) and ethyl acetoacetate (127 µL, 1 mmol) in CH₂Cl₂ (20 mL) under nitrogen was added BF₃·OEt₂ (217 µL, 1.2 mmol) at r.t. The mixture was stirred for 1 hour before saturated NaHCO₃ solution (10 mL) was added. The aqueous layer was extracted with CH₂Cl₂ (10 mL). The organic layers were washed with brine (10 mL) dried (MgSO₄) and concentrated under reduced pressure. Short column chromatography (hexane/EtOAc = 8:2) afforded quantitatively ethyl 2-benzhydryl-3-oxo-butanoate. ¹H NMR (CDCl₃, 400 MHz): δ(ppm) 7.5-7.1 (m, 10 H, H), 4.81 (d, 1 H, ³ J = 12.3 Hz), 4.58 (d, 1 H, ³ J = 12.3 Hz), 4.01 (q, 2 H, ³ J = 7.1 Hz), 2.12 (s, 3 H), 1.02 (t, 3 H, 7.1). ¹³C NMR: δ(ppm) 201.7, 167.6, 141.5, 141.2, 128.8-126.8, 65.2, 61.4, 50.8, 30.0, 13.7.

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Experiments with dimethyl malonate, methyl phenylsulfonyl acetate and bis-phenylsulfonylmethane gave back the unreacted methylene plus benzhydryl alcohol dismutation. Meldrum’s acid gave an alkylated/transesterified product. Ethyl malononitrile gave a complex mixture.

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¹H NMR (CDCl₃, 400 MHz): coordinated keto form δ = 4.17 (q, ³ J = 7 Hz, 2 H), 3.38 (br s, 2 H); 2.24 (br s, 3 H), 1.26 (t, ³ J = 7 Hz, 3 H); coordinated enol form δ = 11,98 (s, 1 H), 5.32 (s, 1 H), 4.47 (q, ³ J = 7 Hz, 2 H), 2.14 (s, 3 H), 1.38 (t, ³ J = 7 Hz, 3 H).