Skeletal Transformation of Unactivated Arenes Enabled by a Low-Temperature Dearomative (3 + 2) Cycloaddition

Abstract

Simple aromatic compounds like benzene are abundant feedstocks, for which the preparation of derivatives chiefly begins with electrophilic substitution reactions or, less frequently, reductions. Their high stability makes them particularly reluctant to participate in cycloadditions under ordinary reaction conditions. Here, we demonstrate the exceptional ability of 1,3-diaza-2-azoniaallene cations to undergo formal (3 + 2) cycloadditions with unactivated benzene derivatives below room temperature, providing thermally stable dearomatized adducts on a multi-gram scale. The cycloaddition, which tolerates polar functional groups, activates the ring toward further elaboration. On treatment with dienophiles, the cycloadducts undergo a (4 + 2) cycloaddition–cycloreversion cascade to yield substituted or fused arenes, including naphthalene derivatives. The overall sequence results in the transmutation of arenes through an exchange of the ring carbons: a two-carbon fragment from the original aromatic ring is replaced with another from the incoming dienophile, introducing an unconventional disconnection for the synthesis of ubiquitous aromatic building blocks. Applications of this two-step sequence to the preparation of substituted acenes, isotopically labeled molecules, and medicinally relevant compounds are demonstrated.

Skeletal editing of pyridines through atom-pair swap from CN to CC

“…We also show that our method can be readily applied in late-stage to transform pyridine cores into the corresponding substituted benzenes and naphthalenes. During revision of our manuscript, a paper describing C=C pair exchange of arenes with dienophiles via a dearomatization–cycloaddition–retrocycloaddition process was published 39 .…”