Dearomative ring expansion of thiophenes by bicyclobutane insertion

Abstract

Skeletal ring enlargement is gaining renewed interest in synthetic chemistry and has recently focused on insertion of one or two atoms. Strategies for heterocyclic expansion through small-ring insertion remain elusive, although they would lead to the efficient formation of bicyclic products. Here, we report a photoinduced dearomative ring enlargement of thiophenes by insertion of bicyclo[1.1.0]butanes to produce eight-membered bicyclic rings under mild conditions. The synthetic value, broad functional-group compatibility, and excellent chemo- and regioselectivity were demonstrated by scope evaluation and product derivatization. Experimental and computational studies point toward a photoredox-induced radical pathway.

Strain-Release Photocatalysis

“…The strategy enabled the syntheses of aryl-BCHep-amines, which can be seen as partially aliphatic replacements for highly carcinogenic aminobiphenyls. This methodology, in the same vein of the ring-in-aheterocycle approach by Glorius, 89 proves that distonic radical species can offer valuable synthetic equivalents to access larger bridged systems. Future Directions.…”

“…This specificity both limits the breadth of attainable products and requires tailor-made solutions to a specific synthetic problem, in an exceedingly intense effort compared to standard methodologies (e.g., cross-coupling, amide coupling). We are witnessing growing interest in adding further vectors to disubstituted systems, ,,,, and we can anticipate that the trend will only grow in the near future. Additionallydespite their relevance in marketed and in-development drugsthe territory of N-containing heterocycle saturated isosteres is still largely uncharted.…”

“…In addition to strategies where BCBs can insert over two coupling partners (vide current section) or an unsaturated system (vide next section), Glorius et al developed a photocatalytic approach to ring-in-heterocycle addition of BCBs (12.3) in thiophenes (12.1) and benzothiophenes (12.2, Figure 12A). 89 Skeletal ring editing�in particular enlarge-ment�has garnered significant attention, since it can straightforwardly upgrade a promising lead candidate skeleton in a single step (versus de novo synthesis). 90 The authors leveraged the highly oxidizing power of [Acr-Mes 2 ] + to trigger single-electron oxidation of (benzo)thiophenes (Figure 12B).…”

syn-Selective Difunctionalization of Bicyclobutanes Enabled by Photoredox-Mediated C–S σ-Bond Scission

“…With the advent of strain-release-driven syntheses, bicyclo[1.1.0]­butanes (BCBs) emerged as privileged building blocks for a divergent strategy to construct cyclobutanes. − Simple attachment of cyclobutane to amines was achieved by Baran and coworkers through the nucleophilic opening of sulfone-substituted BCBs, followed by desulfonylation . Targeting more densely substituted cyclobutanes, Fox and coworkers reported the enantioselective Rh-catalyzed construction of 1,2-disubstituted BCBs, which could be opened by organocuprates and intercepted with electrophiles with limited diastereocontrol .…”

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).…”