Divergent C-H Insertion-Cyclization Cascades of N-Allyl Ynamides

Abstract

Gold carbene reactivity patterns were accessed by ynamide insertion into a C(sp(3) )H bond. A substantial increase in molecular complexity occurred through the cascade polycyclization of N-allyl ynamides to form fused nitrogen-heterocycle scaffolds. Exquisite selectivity was observed despite several competing pathways in an efficient gold-catalyzed synthesis of densely functionalized C(sp(3) )-rich polycycles and a copper-catalyzed synthesis of fused pyridine derivatives. The respective gold-keteniminium and ketenimine activation pathways have been explored through a structure-reactivity study, and isotopic labeling identified turnover-limiting CH bond-cleavage in both processes.

Keywords: carbenes; cyclopropanation; gold; nitrogen heterocycles; ynamides.

Scheme 1

Generation of gold carbenes from ynamides by carbocyclization. PG=protecting group.

Scheme 2

Structural effects on the ynamide C—H insertion–cyclopropanation cascade. Yields are for the isolated product after flash column chromatography. In each case, the major diastereomer is shown. [a] o‐Xylene (0.1 m) was used as the solvent. [b] Product 3 h was isolated as a complex mixture of four diastereomers. [c] The product was purified on NEt₃‐deactivated silica. [d] The diastereomeric ratio before purification was 3.1:1. NR=no reaction, Ns=4‐nitrobenzenesulfonyl, Ts=p‐toluenesulfonyl.

Scheme 3

Reactions to probe individual steps within the polycyclization cascade.

Scheme 4

Initial exploration of the ynamide cascade cyclization initiated by an aza‐Claisen reaction.

Scheme 5

Proposed mechanistic outline of competing pathways. For clarity, conformational changes are not shown. ERC=electrocyclic ring closure.