Difunctionalization of C–C σ-Bonds Enabled by the Reaction of Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles: Reaction Development, Scope, and Stereochemical Origins

Abstract

Difunctionalization reactions of C−C -bonds have the potential to streamline access to molecules that would otherwise be difficult to prepare. However, the development of such reactions is challenging because C−C -bonds are typically unreactive.Exploiting the high ring-strain energy of polycyclic carbocycles is a common strategy to weaken and facilitate the reaction of C−C -bonds, but there are limited examples of highly strained C−C -bonds being used in difunctionalization reactions. We demonstrate that highly strained bicyclo[1.1.0]butyl boronate complexes (strain energy: ca. 65 kcal/mol), which were prepared by reacting boronic esters with bicyclo[1.1.0]butyl lithium, react with electrophiles to achieve the diastereoselective difunctionalization of the strained central C−C -bond of the bicyclo[1.1.0]butyl unit. The reaction shows broad substrate scope, with a range of different electrophiles and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclobutanes (>50 examples) with high diastereoselectivity. The high diastereoselectivity observed has been rationalized based on a combination of experimental data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating depending upon the migrating substituent and electrophile used. This material is available free of charge via the Internet at http://pubs.acs.org.

Bicyclobutanes: from curiosities to versatile reagents and covalent warheads

“…Aggarwal and co-workers, building on their related work with in situ generated BCB boronate complexes, 76,77 demonstrated that these boronates can be efficiently attacked by electrophilic radicals. Indeed, BCB-containing boronate complexes undergo triuoromethylation via bridgehead bond homolysis upon irradiation with blue LED light (Scheme 7D).…”

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

“…resulted in similar transformations and allowed the modular construction of bifunctional diastereomerically enriched cyclobutanes (Scheme 81 B). [338] Moreover, radical addition to the central σ-bond of bicyclo [1.1.0]butane derivative 291 was developed. [339] Thus, electrondeficient radicals derived from the corresponding alkyl iodides under visible light irradiation can add to 291 1,3-dialkylsubstituted cyclobutyl boronates with high efficiency and stereocontrol (Scheme 81 C).…”

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

“…In 2020, Aggarwal and coworkers reported a more general protocol for the 1,2-metallate rearrangement of bicyclo[1.1.0]butylboronic ester ate-complex (Scheme 10). 31 The authors revealed that the ate-complex was reactive toward a broad range of electrophiles to trigger 1,2-metallate rearrangement. In addition to a halogenating agent (bromonium, chloronium), which are well known to trigger the metallate rearrangement of vinylboronic ester ate-complex, carbonyl compounds (aldehyde, ketone, imine, acid chloride, chloroformate, and CO 2 ) could also be successfully used as an electrophile to afford the corresponding 1,3-dialkyl substituted cyclobutylboronic esters in good yield with high cis-selectivity (6367).…”