Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes**

Abstract

The development of two divergent and complementary Lewis acid catalyzed additions of bicyclobutanes to imines is described. Microscale high‐throughput experimentation was integral to the discovery and optimization of both reactions. N‐arylimines undergo formal (3+2) cycloaddition with bicyclobutanes to yield azabicyclo[2.1.1]hexanes in a single step; in contrast, N‐alkylimines undergo an addition/elimination sequence to generate cyclobutenyl methanamine products with high diastereoselectivity. These new products contain a variety of synthetic handles for further elaboration, including many functional groups relevant to pharmaceutical synthesis. The divergent reactivity observed is attributed to differences in basicity and nucleophilicity of the nitrogen atom in a common carbocation intermediate, leading to either nucleophilic attack (N‐aryl) or E1 elimination (N‐alkyl).

Bicyclobutanes: from curiosities to versatile reagents and covalent warheads

“…To move beyond strictly carbocyclic isosteres (whose benets of higher C sp 3 may be countered by their high clog P), Leitch and co-workers explored if BCBs could be progenitors to 2-azabicyclo[2.1.1]hexanes (aza-BCHs) through a reaction with imines (Scheme 13). 116 This hypothesis expands on the reports in the early 1980s by Amey and Dougherty, 102,103 as well as the more recent work of Lu, 27 who found that BCBs undergo strainrelieving cycloadditions upon irradiation with 1,2,4-triazoline-3,5-diones. The latter have been recently been popularized by Sarlah for dearomative cycloaddition reactions and utilized for the aforementioned bioconjugation reported by Malins.…”

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

“…Leitch and co-workers went beyond the use of alkenes and reported the insertion of imines into BCBs in a Lewis acidcatalysed stepwise cyclisation to aza-BCHs (Fig. 5B) 88 . BCBs bearing both a carbonyl and aryl group were necessary for the reaction, but a range of typical aromatic and heteroaromatic systems were tolerated (as in 99 and 100) as were amide substituents (as in 101).…”

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

“…However, in stark contrast to the numerous sp 3 -rich bioisosteres for ortho-and para-substituted arenes 2,9,10,12 , a geometrically-accurate bioisostere for meta-arenes is yet to be discovered. Recent reports on the use of (hetero)bicyclo[2.1.1]hexanes [13][14][15][16][17] and bridge-substituted BCPs [18][19][20] have contributed to this arena (Fig. 1b).…”