Abstract
Abstract1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para‐substituted aromatic rings. The most direct route to these structures is via multicomponent ring‐opening reactions of [1.1.1]propellane. However, challenges associated with these transformations mean that difunctionalized BCPs are more commonly prepared by multistep reaction sequences with BCP‐halide intermediates. Herein, we report three‐ and four‐component 1,3‐difunctionalizations of [1.1.1]propellane with organometallic reagents, organoboronic esters, and a variety of electrophiles. This process is achieved by trapping intermediate BCP‐metal species with boronic esters to form boronate complexes, which are versatile intermediates whose electrophile‐induced 1,2‐metallate rearrangement chemistry enables a broad range of C−C bond‐forming reactions.
Highlights
1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para-substituted aromatic rings
Direct transformation of 1 into unsymmetrical 1,3-disubstituted BCP derivatives via three-component coupling reactions is challenging because of competing oligomerization of the intermediate BCP radicals or carbanions.[4d,8] This is especially apparent for radical processes, of which there is only a single report by Uchiyama and co-workers describing a threecomponent aminoalkylation of 1.[9]. In contrast, BCP-Grignard intermediates 2 are relatively stable to oligomerization with 1 and can be intercepted in palladium- or nickel-catalyzed crosscouplings,[10] copper-catalyzed alkylations,[11] or acylation reactions (Scheme 1c).[10b,10d,11] We were intrigued by the possibility of intercepting BCP-Grignards 2 with boronic esters to form BCP-boronate complexes 3 (Scheme 1d)
These versatile intermediates can be utilized in a wide range C–C bond forming reactions via 1,2-metallate rearrangements,[12] providing a significant expansion to the range of unsymmetrical 1,3-disubstituted BCP derivatives accessible in one step from 1
Summary
1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para-substituted aromatic rings. This strategy could be extended to a fourcomponent coupling by trapping alkenyl BCP-boronate complexes with a range of electrophiles, enabling rapid access to highly functionalized BCP-derivatives. Our initial studies focused on the reaction of BCP-Grignard reagent 2 in Zweifel olefinations with alkenylboronic esters to provide synthetically useful alkenyl-BCPs 4 (Scheme 2).[13] Using conditions developed by Knochel and co-workers,[10d] BCPGrignard 2a was conveniently accessed from 2-tolylmagnesium bromide (5a) and 1.
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