Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl- and Aryl-Substituted Cyclobutenes

Abstract

Bicyclo[1.1.0]butanes (BCBs), strained carbocycles comprising two fused cyclopropane rings, have become well-established building blocks in organic synthesis, medicinal chemistry, and chemical biology due to their diverse reactivity profile with radicals, nucleophiles, cations, and carbenes. The constraints of the bicyclic ring system confer high p-character on the interbridgehead C−C bond, leading to this broad reaction profile; however, the use of BCBs in pericyclic processes has to date been largely overlooked in favor of such stepwise, non-concerted additions. Here, we describe the use of BCBs as substrates for ene-like reactions with strained alkenes and alkynes, which give rise to cyclobutenes decorated with highly substituted cyclopropanes and arenes. The former products are obtained from highly stereoselective reactions with cyclopropenes, generated in situ from vinyl diazoacetates under blue light irradiation (440 nm). Cyclobutenes featuring a quaternary aryl-bearing carbon atom are prepared from equivalent reactions with arynes, which proceed in high yields under mild conditions. Mechanistic studies highlight the importance of electronic effects in this chemistry, while computational investigations support a concerted pathway and rationalize the excellent stereoselectivity of reactions with cyclopropenes.

Umpolung reactivity of strained C–C σ-bonds without transition-metal catalysis

“…The regioselectivity is the same as our product 6 in Fig. 5 and their mechanism studies also support an Alder-ene process, not a radical pathway 62 . The concerted transition state of the C–C σ bond cleavage in BCBs together with hydrogen transfer contributes to the chemoselectivity.…”

Oxidative sulfonylarylation of strained C–C σ-bonds for the synthesis of 3-spirocyclic oxindoles initiated by insertion of sulfur dioxide

“…3 Among them, the cycloaddition reaction of BCBs with a diverse array of reaction partners has been widely reported, 4 which provides an efficient protocol for the construction of three-dimensional C(sp 3 )-rich cyclic frameworks with important physiochemical properties. In addition, polar addition reactions, 5 carbene insertion reactions, 6 and other reactions 7 have been well investigated.…”

Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

“…In recent years, bicyclo[1.1.0]-butanes (BCBs) have garnered attention as intriguing synthons capable of engaging in diverse ring-opening reactions, thanks to the significant strain present in BCBs (Fig. 1c) 6,[37][38][39][40][41][42][43][44][45][46][47] . Of particular interest is their involvement in cycloaddition reactions, where the selective cleavage of the bridgehead C-C bond facilitates the assembly of ring-enlarged, yet conformationally restricted bridged bicycles.…”