Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings

Abstract

Bicyclo­[1.1.1]­pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C­(sp2)–C­(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]­pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.

Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates

“…Efficient coupling of triuoromethyl-substituted BCP 17e is an unsolved challenge in the current synthetic literature. In a recent report, it could only be converted to the corresponding BF 3 K in 4.5% yield, 17 highlighting the potential utility of a coupling method which obviates the need for BF 3 K formation. Gratifyingly, under our standard conditions, we observed a 54% yield of the desired arylation product 18e (Scheme 6, bottom le).…”

“…Decarboxylative borylation of a BCP N-hydroxypthalimide ester furnished the BCP boronate, but this method was not general due to the limited availability of diverse BCP carboxylic acids. 17,18 Thus, general methods to prepare high value BCP boronate intermediates with diverse substitution patterns are still limited. 19 Despite these recent developments, synthetic routes to BCP analogues of many motifs prevalent in drug-like molecules remain elusive.…”

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[413] BCP-derived trifluoroborates 89 were prepared via decarboxylative borylation of the corresponding carboxylic acids (Scheme 50). [414] These compounds appeared to be useful for the CÀ C coupling under the Ir/Nicatalyzed photoredox reaction conditions. Silaboration of [1.1.1] propellane was also reported; a possibility to address both the functionalities in the molecule of bicyclo[1.1.1]pentane 90 chemoselectively was demonstrated.…”

Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (BCP)

“…The compound was first synthesized by Aggarwal, 28 and recently, VanHeyst, Qi, and co-workers from Merck used it for practical photoredox cross-couplings of heterocycles. 29 …”