Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls

Abstract

Construction of C-C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C-C bonds in a tricomponent process.

Scheme 1. Boron enolates and the deoxygenative α-alkylation/arylation of 1,2-dicarbonyls.

Scheme 2. Deoxygenative α-alkylation/arylation of ester 6. Reaction conditions: ester 6 (0.2 mmol), BEt₃ (0.3 mmol), P(OMe)₃ (0.24 mmol), THF (2 mL), 50 °C.

Scheme 3. Scope of 1,2-dicarbonyl compounds. Reaction conditions: 1,2-dicarbonyl (0.1–0.2 mmol), BEt₃ (1.5–2 equiv.), P(OMe)₃ (1.2–2 equiv.) THF (1–4 mL), 50 °C. ^a80 °C. ^bP(NMe₂)₃ was used.

Scheme 4. Scope of organoboron reagents. Reaction conditions: see footnote for Scheme 2.

Scheme 5. Synthesis of NSAIDs 72–74 with trimethylborane.

Scheme 6. Scope of the tricomponent reaction. Reaction conditions: see footnote for Scheme 2, in the presence of electrophile.

Scheme 7. Construction of quaternary all-carbon α-positions in carboxylic acids and the structure of intermediate 98.

Fig. 1. Kinetic studies of the deoxygenative α-alkylation and boron enolate formation. (A) Order in α-keto ester. (B) Order in trimethyl phosphite. (C) Order in triethylborane. (D) Time course of triethylborane consumption and boron enolate formation during the reaction of ester 6 with triethylborane and trimethyl phosphite.

Fig. 2. Computed Gibbs free energy profile of the deoxygenative α-alkylation reaction, ΔG, kcal mol⁻¹.