Bifunctional Molecular Linchpins: A Three-Component Coupling Protocol Employing 2-Bromoallyltrimethylsilane

Abstract

A new three-component coupling protocol, exploiting 2-bromoallyltrimethylsilane as a bifunctional linchpin, has been developed. The reaction sequence entails the following steps: lithiation of the vinyl bromide, addition of an aromatic or aliphatic aldehyde, execution of a solvent controlled 1,4-Brook rearrangement induced by HMPA to generate an allyl anion, and addition of a reactive second electrophile. Yields are moderate to good.

Brook rearrangement - multicomponent coupling - bifunctional linchpins - organolithium reagents

References

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<A NAME="RY02404ST-6">6</A>

Enolization of propionaldehyde led to homoaldol coupled products. α-Branched aldehydes such as isobutyraldehyde and cyclohexane carboxaldehyde afforded similar results, although minor amounts of the tricomponent coupled products were observed.

<A NAME="RY02404ST-7">7</A>

A representative procedure for the three-component coupling is as follows. To a solution of 2-bromo-allyltrimethylsilane (1.12 g, 5.8 mmol) in 18 mL dry THF under argon was added 6.8 mL t-BuLi (1.7 M solution in hexanes) at -78 °C. The resulting yellow solution was stirred at -78 °C for 1 h. Benzaldehyde (590 µL, 5.8 mmol) was added and the reaction mixture was stirred an additional 3 h at -78 °C. A solution of HMPA (4 mL, 23 mmol) and allyl bromide (1.5 mL, 17 mmol) in 4 mL THF was added. The reaction mixture was then warmed to 0 °C in an ice bath and allowed to warm slowly to r.t. and stir overnight. The reaction was then quenched with 5 mL HCl (1 M). An additional 15 mL H₂O were added and the aqueous layer was extracted with Et₂O (3 × 60 mL). The combined organic layers were then dried over MgSO₄, filtered and concentrated under reduced pressure. Purification by silica gel flash column chromatography (eluent 7:1 hexanes-ethyl acetate) afforded 700 mg of 16 (69%) as a colorless oil.