# New directions in Ni-catalyzed cross coupling

> **NIH NIH R35** · PRINCETON UNIVERSITY · 2021 · $48,546

## Abstract

7. Project Summary/Abstract
The overarching goal of this program is to facilitate the discovery and preparation of complex, biologically
active small molecules by devising novel chemical reactions and elucidating new principles of catalysis in the
field of transition metal-catalyzed cross coupling. Our laboratory's early work demonstrated that oxidative
addition of Ni to iminium or oxocarbenium ion intermediates offers a novel entry to C(sp3)–C cross coupling.
This strategy leverages the modularity of cross-coupling catalysis to deliver new bond-forming reactions with
classic reactive intermediates in organic synthesis. Recently, we and others recognized that Ni catalysis
presents a powerful opportunity to functionalize another class of reactive intermediate in organic synthesis:
carbon-centered radicals. In the current proposal, we advance this concept, building on strong preliminary
data, to develop fundamentally new bond-forming reactions under exceptionally mild conditions. An example
is the development of a unified platform for the enantioselective synthesis of α- and β-substituted amines and
ethers, some of the most ubiquitous scaffolds in medicinal chemistry, via Ni-catalyzed coupling with radicals
derived from acetals, aziridines, and iminium ions accessed via condensation of an amine and carbonyl
derivative. Such transformations are uniquely suited to late-stage diversification under mild conditions and
address many challenges and limitations of ether and amine synthesis by C–O/N bond formation. Our group
has also established a new paradigm for catalytic C(sp3)–H functionalization that uses photocatalysis to deliver
free radical species from C(sp3)–H bonds, and Ni catalysis to functionalize these radicals. This strategy offers
numerous opportunities for late-stage C(sp3)–C bond formation that complement current approaches to C–H
functionalization in selectivity and scope. We describe plans to advance these reaction platforms in terms of
scope of coupling partners, catalyst control of regio- and stereoselectivity, and amenability to late-stage
derivatization of natural products and medicinal compounds. Critical to our success will be the development
and study of three ligand classes for Ni: phosphines featuring remote steric hindrance, bioxazolines, and
electron-deficient olefins. Since most effort in the field of Ni catalysis has focused on reaction discovery, we
expect that the development of ligands designed specifically for Ni will play a crucial role in advancing the
capabilities of this field. Similarly, we will build on our lab's prior mechanistic work with the goal of developing
predictive models for the reactivity of Ni with radicals and understanding the photochemistry and
photophysics of Ni that could lay the foundation for advances in numerous fields.

## Key facts

- **NIH application ID:** 10113643
- **Project number:** 5R35GM126986-04
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Abigail Gutmann Doyle
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,546
- **Award type:** 5
- **Project period:** 2018-04-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113643

## Citation

> US National Institutes of Health, RePORTER application 10113643, New directions in Ni-catalyzed cross coupling (5R35GM126986-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10113643. Licensed CC0.

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