Al(OTf)₃: An Efficient Lewis Acid Additive for Domino Addition–Elimination of Grignard Reagents to Activated Ketones

Abstract

It has been demonstrated that aluminium triflate in either stoichiometric or catalytic quantities facilitates the addition–elimination of Grignard reagents to electron-rich ketones, such as methoxy substituted acetophenones, propiophenone and chromanone in a one-pot process, and that it has an enhancing effect on the addition of these reagents to the ketones. It has also been found that the reactions are highly stereoselective towards one regioisomer of the alkene in the case of oxygenated aryl-alkyl substituted substrates, but not when the elimination originates from a double benzylic alcohol intermediate.

Key words

aluminium triflate - Grignard reagent - ketone - olefin - addition–dehydration - one-pot reaction

• References and Notes

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• 17 General Procedure: A solution of carbonyl compound in anhydrous CH₂Cl₂ (2–5 mL) was cooled to –30 °C. Al(OTf)₃ (1.0 equiv) was added and the reaction mixture was stirred at –30 °C for 30 min under Ar. Grignard reagent (3.0 M in Et₂O, 2.0 equiv) was subsequently added and the reaction mixture was allowed to warm to r.t. while being stirred. Once the reaction was deemed complete (TLC analysis), the reaction mixture was neutralised with aq NH₄Cl and the product was extracted into EtOAc (3 × 50 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. Purification by prep. TLC gave the corresponding alkenes or alcohols (Table 1). (Z)-2,4-Dimethoxy-α,β-dimethylstyrene (16): The general procedure with 2′,4′-dimethoxyacetophenone (3; 0.217 g, 1.22 mmol) and Al(OTf)₃ (0.531 g, 1.12 mmol, 0.9 equiv) in CH₂Cl₂ (5 mL) and ethylmagnesium bromide (3 M, 0.7 mL, 1.7 equiv) yielded 16 (0.107 g, 46%) as a colourless oil. R_f = 0.61 (hexane–acetone, 8:2). ¹H NMR (600 MHz, CDCl₃): δ = 7.06 (d, J = 8.2 Hz, 1 H, H-6), 6.48 (d, J = 2.4 Hz, 1 H, H-3), 6.46 (dd, J = 8.2, 2.4 Hz, 1 H, H-5), 5.55 (qq, J = 6.7, 1.3 Hz, 1 H, H-β), 3.83 (s, 6 H, OMe), 2.00–1.98 (m, 3 H, α-CH ₃ ), 1.80–1.78 (m, 3 H, β-CH₃). ¹³C NMR (151 MHz, CDCl₃): δ = 159.8 (C-2/4), 157.6 (C-2/4), 135.3 (C-1/α), 130.0 (C-6), 128.1 (C-1/α), 123.5 (C-β), 103.9 (C-5), 98.7 (C-3), 55.4 (-OMe), 17.0 (α-CH₃), 14.0 (β-CH₃). MS (EI, 70 eV): m/z (%) = 192.1 (100) [M]⁺. HRMS (AP⁺): m/z = 193.1233 [MH]⁺.
• 18 Chemical shift of the residual β-proton in the E-isomer of aryl substituted 2-butenes of δ = 5.78 and 5.90 ppm vs. δ = 5.52–5.58 ppm for the Z-isomer.²⁰ Chemical shift of the residual β-proton in the E-isomer of methyl substituted stilbenes was δ = 6.78 and 6.81 vs. δ ≈ 6.32 ppm for the Z-isomer.²¹
• 19 NMR analysis of the crude product mixture before work-up indicated that the olefin was the major product.
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