# Rational Design of Nickel Catalysts for Directing Group-Assisted Alkyne Hydrofunctionalization

> **NIH NIH R15** · NORTH DAKOTA STATE UNIVERSITY · 2024 · $431,400

## Abstract

PROJECT SUMMARY
 Nickel-catalyzed cross-coupling reactions have become a widely used method in chemical
synthesis. A recent milestone in Ni catalysis was the advancement of C-N and C-O couplings via
strategic activation of Ni amide and Ni alkoxide intermediates to promote reductive elimination as
the bond-formation step in catalysis. With remarkable success of this strategy in cross couplings of
aryl halides with amines and alcohols, it is desirable to leverage the reactivity of Ni amides and
alkoxides for broad catalytic applications including alkyne additions with amines (hydroamination)
and alcohols (hydroetherification). Such reactions of alkyne hydro(hetero)functionalization create
valuable carbon-heteroatom bonds via atom-efficient combination of abundant building blocks (i.e.
alkynes and amine/alcohols), although their demonstrations in Ni catalysis have been scarce.
 The overall objective of this proposal is to develop nickel-based catalysts for alkyne
hydrofunctionalization reactions assisted by directing groups. The long-term goal of our proposed
research is to advance the general strategy of alkyne hydrofunctionalization for selective and
atom-efficient construction of carbon-heteroatom bonds using abundant building blocks. Our study
is based on the central hypothesis that alkyne-tethered directing groups such as 2-pyridyl moiety
can enhance reaction efficiency, regio- and stereo-selectivity for Ni-catalyzed alkyne
hydroamination and hydroetherification reactions via reactivity modulation of relevant Ni amide and
alkoxide intermediates. We aim to test this hypothesis by conducting experimental and
computational studies on structure-reactivity correlations of proposed organonickel intermediates
guided by Machine Learning. The obtained mechanistic insights will guide the rational design of Ni
catalysts and ancillary ligands for broad-scope alkyne hydrofunctionalization reactions. The
feasibility of this research is demonstrated by our published and unpublished results on several Ni-
catalyzed alkyne hydroamination and hydroetherification reactions.
 This proposal includes Three Specific Aims: (1) To improve the reaction scope and efficiency
of Ni-catalyzed hydroetherification of 2-pyridylalkynes. (2) To advance relevant mechanism
understanding and rational catalyst design guided by Machine Learning. (3) To develop Ni-
catalyzed broad-scope alkyne hydrofunctionalization reactions with directing-group assistance.
 Our proposed research is innovative because it advances alkyne hydrofunctionalization as a
general strategy for Ni-catalyzed carbon-heteroatom bond construction. Results from these studies
are significant because they provide efficient catalytic methods that utilize simple and abundant
building blocks to synthesize nitrogen- and oxygen-containing compounds of biomedical relevance.

## Key facts

- **NIH application ID:** 10974957
- **Project number:** 1R15GM155845-01
- **Recipient organization:** NORTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Changhui Yan
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $431,400
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10974957

## Citation

> US National Institutes of Health, RePORTER application 10974957, Rational Design of Nickel Catalysts for Directing Group-Assisted Alkyne Hydrofunctionalization (1R15GM155845-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10974957. Licensed CC0.

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