Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes

Abstract

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using an electrocatalytic strategy. Electrochemistry allows for the seamless combination of two classic radical reactions-cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation-to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidant. We harness electrochemistry's unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis sheds light on the origin of enantioinduction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions that direct the enantio-determining C-CN bond formation. This discovery demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry. File list (2) download file view on ChemRxiv 01_Lin_MS.pdf (1.70 MiB) download file view on ChemRxiv 00_Lin_TOC.png (333.52 KiB)

Recent Advances in Asymmetric Catalytic Electrosynthesis

“…The suggested mechanism for the transformation resembles that proposed for the Lin group's preceding work on Cu-catalyzed alkene functionalization in Scheme 11 [77]. The first anodic event leads to the formation of a C-centered radical and the second anodic event produces the active Along the same lines, the Lin group published a second anodically driven enantioselective functionalization of alkenes [78]. In conjunction with a cobalt(salen) complex, the use of the same type of asymmetric Cu catalyst as in their prior work enabled hydrocyanation of differently substituted olefins using PhSiH 3 and TMSCN in an undivided cell at 0 • C and constant potential, equipped with a carbon anode and Pt cathode (Scheme 12).…”

“…With the new ligand, an increase in ee from 84% to 95% was observed for the benchmark substrate. Along the same lines, the Lin group published a second anodically driven enantioselective functionalization of alkenes [78]. In conjunction with a cobalt(salen) complex, the use of the same type of asymmetric Cu catalyst as in their prior work enabled hydrocyanation of differently substituted olefins using PhSiH3 and TMSCN in an undivided cell at 0 °C and constant potential, equipped with a carbon anode and Pt cathode (Scheme 12).…”

A Multifunctional Microfluidic Platform for High‐Throughput Experimentation of Electroorganic Chemistry

“…Moreover, the discovery of new reactivities enabled by electrochemistry promotes further adoption of this technique [6] . A number of exciting electrochemical methodologies have recently been discovered, achieving transformations that would be, otherwise, either challenging or even impossible with conventional techniques [7–12] …”

“…[6] A number of exciting electrochemical methodologies have recently been discovered, achieving transformations that would be, otherwise, either challenging or even impossible with conventional techniques. [7][8][9][10][11][12] Nevertheless, electrochemical synthesis is still considered as a niche technique with high entry barriers, [4,6,13] such as the relative low experimentation throughput, attributed to the complex electrochemistry setup, limiting the ability to quickly identify and optimize new chemistries. Both academic groups and commercial companies have devoted to developing electrochemistry-friendly screening methodologies and standardized equipment to streamline the adoption of electroorganic synthesis.…”

Electrochemical activation of C–H by electron-deficient W2C nanocrystals for simultaneous alkoxylation and hydrogen evolution

“…Electrochemical transformation is recognized as an environmentally friendly method for the production of various functional molecules driven by electricity under mild conditions [9][10][11] . Pioneering works of electrochemical synthesis using homogeneous catalysts have demonstrated the advantages of this technique for C−H activation 11 , which includes selective oxidation 12 , amination 13 , epoxidation 14 and dehydrogenative coupling reactions 15 . Most of these reactions have high atom economy and excellent compatibility with ow reactors for continuous synthesis 16,17 .…”