# Diversity Supplement for Mechanistically Guided Cross-Electrophile Coupling Approaches to Useful Csp2-Csp2 and Csp2- Csp3 Bonds

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $53,849

## Abstract

Project Summary/Abstract
Rapid advancements in biological and computational tools to find new therapeutic targets have outstripped
available synthetic tools to synthesize drug candidates. Many proposed molecules are not tested because of the
synthetic and time constraints of medicinal chemistry, where lead cores must be rapidly diversified in a
modular fashion using robust, well-established methods, such as palladium-catalyzed cross-coupling and
Grignard reactions. The major hurdles are the limited accessibility of carbon nucleophiles and the limited
tolerance of most methods for the broad range of functional groups and reactivity present in drug candidates.
We propose to develop collections of cross-electrophile coupling reactions that address these challenges and
are adapted to modern parallel synthesis. Cross-electrophile coupling leverages the increased diversity of
carbon electrophiles compared to nucleophiles (100 to 1000 times more commercially available derivatives);
but achieving selectivity for cross-coupled product over dimeric products can be challenging and the factors
that govern successful coupling remain unclear. 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 postdocs will build upon the advances of the previous grant period to develop fourteen new
cross-electrophile coupling reactions, explore new ways to utilize the largest substrate pools (organic
chlorides, alcohols, amines, and carboxylic acids), and shed light on the reactive nickel intermediates that
govern these processes. Our guiding hypothesis is that these challenges can be addressed by a combination of
mechanistic studies, mechanism-guided design of new electrophiles, 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) improve Csp2–Csp3 cross-electrophile coupling by the development of methods to engage new
electrophiles, new combinations of old electrophiles, and by tailoring our optimization to the needs of
medicinal chemistry; (2) address challenging Csp2–Csp2 cross-couplings by developing new, universal routes
to challenging di(hetero)aryl ketones and bi(hetero)aryls; (3) shed light on the principles that govern nickel-
catalyzed reactions by using electrochemical methods to study otherwise inaccessible reaction intermediates.
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:** 10621607
- **Project number:** 3R01GM097243-13S1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Daniel John Weix
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $53,849
- **Award type:** 3
- **Project period:** 2011-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10621607

## Citation

> US National Institutes of Health, RePORTER application 10621607, Diversity Supplement for Mechanistically Guided Cross-Electrophile Coupling Approaches to Useful Csp2-Csp2 and Csp2- Csp3 Bonds (3R01GM097243-13S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10621607. Licensed CC0.

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