Recent advances in the chemistry of bicyclo- and 1-azabicyclo[1.1.0]butanes

Abstract

Bicyclo[1.1.0]- and 1-azabicyclo[1.1.0]butanes are structurally unique compounds that exhibit diverse chemistry. Bicyclo[1.1.0]butane is a four-membered carbocycle with a bridging C(1)-C(3) bond and 1-azabicyclo[1.1.0]butane is an analog of bicyclo[1.1.0]butane featuring a nitrogen atom at one bridgehead. These structures are highly strained, allowing them to participate in a range of strain-releasing reactions which typically cleave the central, strained bond to deliver cyclobutanes or azetidines. However, despite these molecules being discovered in the 1950s and 1960s, and possessing a myriad of alluring chemical features, the chemistry and applications of bicyclo[1.1.0]- and 1-azabicyclo[1.1.0]butanes remain underexplored. In the past 5 years, there has been a resurgent interest in their chemistry driven by the pharmaceutical industry’s increasing desire for new methods to access cyclobutanes and azetidines. This short review intends to provide a timely summary of the most recent developments in the chemistry of bicyclo[1.1.0]- and 1-azabicyclo[1.1.0]butane to highlight the diverse chemistry they can access, their value as synthetic precursors to cyclobutanes and azetidines, and to identify areas for future research.

Semipinacol-Type Rearrangements of [3-(Arylsulfonyl)bicyclo[1.1.0]butan-1-yl]alkanols

“…Previously, our group studied the preparation of (bicyclo[1.1.0]­butan-1-yl)­alkylamines 1 and their thermal and transition metal-catalyzed conversions to five-, six-, and seven-membered heterocycles such as 2 and 3 . ,, Other noteworthy discoveries in the field include enantioselective routes to bicyclo[1.1.0]­butanes 5 , diastereoselective additions to substituted cyclobutanes 7 and 10 , and insertions to access 2,2-dihalobicyclo[1.1.1]­pentanes 12 (Scheme ). Very recently, and independent of our concomitant studies, Gregson et al disclosed strain-release semipinacol rearrangements of isoelectronic azabicyclo[1.1.0]­butyl carbinols 14 toward azetidines 15 …”

Small rings in the bigger picture: ring expansion of three- and four-membered rings to access larger all-carbon cyclic systems

“…The bicyclo[1.1.0]butane ring system is a fascinating moiety since it is probably the most strained bicyclic compound (66.3 kcal mol À1 ). 14 As a result of its highly puckered conformation, both nucleophiles and electrophiles can engage in reaction with bicyclo[1.1.0]butanes. The nucleophilic addition of the Grignard reagent occurs along the axis of the 2p-orbitals forming the central bent s-bond, thus explaining the relative diastereoselectivity observed (see nucleophilic approach Scheme 2).…”

Strain-release Difunctionalization of C–C σ- and π-bonds of an Organoboron Ate-complex through 1,2-Metallate Rearrangement

“…As shown in selected examples, vinyl and alkyl groups efficiently rearranged to produce cyclobutylboronic ester (23,24). Grignard reagent was also used as a nucleophile to generate the atecomplex, while the addition of LiCl was essential (25). 8b They also reported that other cationic carbon electrophiles such as iminium salt and tropylium could be used in the reaction to give 26 and 27.…”

“…Because of this highly strained structure, the central carboncarbon σ-bond of bicyclo[1.1.0]butane is relatively weak and several unique reactions that proceed through scission of the σ-bond have been reported. 25 Recently, Aggarwal and coworkers reported a series of reactions exploiting a bicyclo[1.1.0]butylboronic ester scaffold. The general scheme for the 1,2-difunctionalization of bicyclo[1.1.0]butyl boronic ester ate-complex is depicted in Scheme 7.…”