Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space

Abstract

Crossed [2 + 2] cycloaddition yields bicyclo[2.1.1]hexanes with 11 different substitution patterns. ortho-, meta- and polysubstituted benzene bioisosteres, and structures with substituent patterns that go beyond aromatic chemical space can be prepared.

Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

“…Consequently, considerable effort has been devoted to the development of efficient methods for the synthesis of these rigid bridge rings [7–11] . Among those methods for synthesizing BCHs, the most common and well‐known process is intramolecular crossed [2+2] cycloaddition of 1,5‐dienes [8b–f] . Alternatively, the intermolecular [2π+2σ] cycloaddition of 2π‐components and bicyclo[1.1.0]butanes (BCBs) [9] is also an efficient method for making BCHs [7b,10] and hetero‐BCHs [11] .…”

Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

“…[33] Similar methods to construct 1,4-disubsituded and polysubstituted BCHs were independently developed by Bach [34] and Walker. [35] Both methods use visible light with an iridium photocatalyst and the authors demonstrated broad substrate scopes bearing a wide varieties of functional groups, including boronic esters 85, alcohols (not shown), carboxylic acids (not shown), and polyfluorinated substrates 87. Even an aza-Paternò-Büchi reaction [36] with a methoxyimine to give a 5-aza-BCH derivative 86 was effective in this system.…”

“…In 2022, scientists at AstraZeneca further developed a method to access disubstituted 2‐aza‐BCH derivatives 84 using an iridium photocatalyst under blue light irradiation [33] . Similar methods to construct 1,4‐disubsituded and polysubstituted BCHs were independently developed by Bach [34] and Walker [35] . Both methods use visible light with an iridium photocatalyst and the authors demonstrated broad substrate scopes bearing a wide varieties of functional groups, including boronic esters 85 , alcohols (not shown), carboxylic acids (not shown), and polyfluorinated substrates 87 .…”

Light‐Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres

“…Under these conditions, the [2 + 2]-photocycloaddition process afforded a variety of 1,4-disubstituted [2.1.1]-BCHs 129 in moderate to excellent yields (19 examples, 61-97 % yield). Recently, a similar work by Walker and co-workers [66] further extended the scope of this transformation to the use of polysubstituted dienes, thus giving a rapid access to densely functionalized [2.1.1]-BCHs.…”