# Cross-Electrophile Coupling for C(sp2)–C(sp3) Bond Formation: Broadened Access to Abundant Electrophiles, Solutions to Challenging Couplings, and Improved Mechanistic Understanding

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $371,172

## Abstract

Project Summary/Abstract
The discovery of new potential drugs and biological tools is necessarily limited to the conveniently-available
chemical space. Historically, this space has been dominated by biaryls because their synthesis is reliable and
amenable to the needs of medicinal chemistry, where a core structure is diversified and built outwards by
iterative rounds of synthesis. Recently, cross-electrophile approaches show promise for providing convenient
access to more C(sp3)-rich molecules, a feature predicted to improve the odds of success in drug development.
Despite recent advances, cross-electrophile coupling of aryl electrophiles with alkyl electrophiles has yet to
realize its considerable potential. This is because many of the most abundant pools of substrates have very
different reactivity. We propose to develop new strategies in cross-electrophile coupling that address these
challenges and are adapted to modern medicinal chemistry approaches. This program's long-term goals are the
development of methods for the selective cross-coupling of every major class of electrophile and the discovery
of the fundamental properties that control selectivity and reactivity. In the proposed grant, a team of graduate
students and a postdoc will build upon the advances of the previous grant period to develop protocols to cross-
couple starting materials sourced from the largest substrate pools (organic chlorides, alcohols, amines, and
carboxylic acids), access more hindered C(sp2)–C(sp3) bonds, and shed light on how the nature of the coupling
partners and ancillary ligands govern success. Our guiding hypothesis is that these challenges can be addressed
by a combination of mechanistic studies, mechanism-guided tuning of catalysts and activating agents, and an
optimization approach that focuses on a collection of substrates rather than a single substrate pair. The specific
aims of this proposal are to: (1) develop protocols for C(sp2)–C(sp3) cross-electrophile coupling between the
largest pools of aryl, vinyl, and alkyl substrate pools; (2) address the challenge of forming C(sp2)–C(sp3) bonds
by developing new catalysts based upon nickel and cobalt; (3) study how ancillary ligands influence the stability
and reactivity of arylnickel(II) complexes to both improve catalytic reactions and to enable new types of
stoichiometric reactions for medicinal chemistry applications, such as DNA-encoded libraries. The approach is
innovative because cross-electrophile coupling is less studied than other cross-coupling methods and the
proposed mechanistic studies will shed light on these little-understood processes. The proposed research is
significant because the chemistry is increasingly important to industrial and academic chemical synthesis and
the development of nickel chemistry has outpaced our understanding.

## Key facts

- **NIH application ID:** 10878453
- **Project number:** 2R01GM097243-15
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Daniel John Weix
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $371,172
- **Award type:** 2
- **Project period:** 2011-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878453

## Citation

> US National Institutes of Health, RePORTER application 10878453, Cross-Electrophile Coupling for C(sp2)–C(sp3) Bond Formation: Broadened Access to Abundant Electrophiles, Solutions to Challenging Couplings, and Improved Mechanistic Understanding (2R01GM097243-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878453. Licensed CC0.

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