Anion-Gated Dual Catalysis: Alkene Difunctionalization Accelerated by High Throughput Experimentation

Catalytic multicomponent reactions that transform the C=C bonds of alkene feedstocks into complex molecules for the interrogation of biological systems are a cornerstone of modern synthesis. The intrinsic multifaceted reactivity of C=C bonds can be unlocked by many catalytic activation modes. When combined with the structural & functional diversity inherent to the ubiquitous classes of alkene feedstock, these activation modes offer remarkable flexibility for programmable synthesis of complex architectures.1 Among many classes of these reactions, transformations that form new C-C & C-N bonds are an attractive starting point for new methodologies involving transition metal-catalyzed aminoarylation. Recently, we reported a distinct catalysis platform that enables a multicomponent coupling of alkenes, aryl-electrophiles & NaN3, providing single-step access to synthetically versatile & functionally diverse beta-arylethylamine derivatives. Driven by visible-light, two discrete Cu-catalysts orchestrate Ar-radical formation & azido-group transfer steps, which underpin an alkene azido-arylation (AAA) process. The reaction exhibits broad scope in alkene & Ar-components & the azide-anion performs a multifaceted role as both nitrogen source & in mediating the redox-neutral dual-catalysis platform via inner-sphere electron transfer. The synthetic capabilities of this anion-mediated AAA & development of its related reactions is likely to be of utility in a variety of pharmaceutically relevant & wider synthetic applications.

Despite several notable advances, the vast majority of synthetic chemistry is conducted in 'one-at-a-time' batch fashion using equipment that has not, essentially, changed since urea was first synthesized by Wöhler in 1828. Most synthetic chemistry is still based on a work flow that often involves routine operations and is labour-intensive & time consuming. Over the last four years, the PI & team have established a ns-HTE platform, such that we can execute & analyse 1000s of parallel & discretely programmable reactions across a wide range of chemical reaction space. The platform is facilitated by liquid handling robots (LHRs), which enables reactions to be set up on a micro or nanomolar scale. To analyse reaction mixtures from 384 or 1536-well plates, we can choose from quantitative & semi-quantitative LC-MS, high-throughput (HT) qNMR & parallel HT-TLC. Together these techniques allow unparalleled quantification & structure determination of products on a short timescale.

Together we aim to use HTE to epxlore a new type a catalysis for the synthesis of complex molecules from alkenes. The 'anion-gated dual catalysis' platform brings together three readily available building blocks in a process controlled, ultimately, by a simple anion. The products can be advnaced to functional molecules that have unexplored properties in biologial systems, providing a means to explore new chemical and biology space.