ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes

Abstract

Dearomative photocycloadditions are valuable chemical transformations, serving as an efficient platform to create three-dimensional molecular complexity. However, the photolability of the original addition product especially within the context of ortho cycloadditions often causes undesired consecutive rearrangements, rendering these ortho cycloadducts elusive. Herein, we report an ortho-selective intermolecular photocycloaddition of bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach. With bicyclo[1.1.0]butanes as coupling partners, this dearomative [2π + 2σ] cycloaddition enables the straightforward construction of C(sp3)-rich bicyclo[2.1.1]hexanes directly connected to N-heteroarenes. Photophysical experiments and DFT calculations revealed the origin of the [2π + 2σ] selectivity and indicate that, in addition to the originally proposed energy transfer or direct excitation pathways, a chain reaction mechanism is operative depending on the reaction conditions.

1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene

“…Despite numerous studies on the topic, 7–15 we needed a practical approach to bicyclo[2.1.1]hexanes with only two substituents (two exit vectors) at the 1- and 2-positions of the core (Scheme 1) without additional (poly)substitution at other positions. Moreover, one substituent should be (hetero)aromatic, and another one should be the carboxylic group, which is needed for the subsequent modifications of the core via amide coupling.…”

“…Pleasingly, these studies were well received by the scientific community, and the groups of Glorius, 7 Brown, 8 Procter, 9 Li, 10 Wang, 11 and Studer 12 subsequently developed alternative approaches to di- and poly-substituted bicyclo[2.1.1]hexanes based on the functionalization of bicyclo[1.1.0]butanes. 13–15…”

Strain-Release Photocatalysis

“…More recently, Glorius et al combined their seminal work on the site-selective dearomative cycloaddition of aza-arenes , and the strain-release chemistry of BCBs to access heteroarene-functionalized BCHs (Figure A, left) . As BCHs possess negligible ring strain, no further rearrangements (as in ref ) can occur.…”

“…(A) Salient features of aza-containing BCH and polysubstituted oxa-BCH . (B) Glorius and co-workers’ synthesis of polysubstituted BCH …”

2-Isopropylthioxanthone-Catalyzed Divergent Functionalization of Bicyclo[1.1.0]butanes under Visible-Light Irradiation

“…Functionalization of bicyclo[1.1.0]­butanes (BCBs) has been recognized as a powerful approach for assembling cyclobutane motifs in “strain-release” chemistry . In recent years, photoinduced functionalization of BCBs in a mild and efficient manner has attracted a tremendous amount of attention. , In addition to photoinduced [2π+2δ] cycloaddition of BCBs with diverse unsaturated bonds, considerable effort has been devoted to developing new protocols of photoinduced alkylation of BCBs. In 2020, Cintrat and Jui developed protocols of photoredox-catalyzed alkylation of BCBs using carboxylic acids and tertiary amines as alkyl sources, respectively (Scheme B).…”