Alkenyl Isocyanide Conjugate Additions: A Rapid Route to γ-Carbolines

Abstract

Isocyanides are exceptional building blocks, the wide deployment of which in multicomponent and metal-insertion reactions belies their limited availability. The first conjugate addition/alkylation to alkenyl isocyanides is described, which addresses this deficiency. An array of organolithiums, magnesiates, enolates, and metalated nitriles add conjugately to β- and β,β-disubstituted arylsulfonyl alkenyl isocyanides to rapidly assemble diverse isocyanide scaffolds. The intermediate metalated isocyanides are efficiently trapped with electrophiles to generate substituted isocyanides incorporating contiguous tri- and tetra-substituted centers. The substituted isocyanides are ideally functionalized for elaboration into synthetic targets as illustrated by the three-step synthesis of γ-carboline N-methyl ingenine B.

Keywords: conjugate addition; isocyanides; organometallics; synthetic methods; γ-carbolines.

Figure 1

Isocyanide representations.

Scheme 1

Synthesis and addition to sulfonylisocyanide 3a.

Scheme 2

Conjugate addition-alkylation mechanism.

Scheme 3

Isocyanide cyclization to γ-carbolines.

Scheme 4

Synthesis of N-Methyl ingenine B (20).