# Mechanistic Studies to Rationally Design Ni and Pd Catalysts for Cross-Coupling

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $64,900

## Abstract

Project Summary/Abstract
Transition metal catalyzed cross-coupling is one of the most powerful synthetic methods and is
used extensively in the preparation of active pharmaceutical ingredients. The goal of this work is
to use fundamental mechanistic studies to develop improved Ni and Pd catalysts for new and
existing cross-coupling reactions. Recently, our group developed the commercially available
precatalyst scaffold (3-1-tBu-indenyl)Pd(L)(Cl) (IndPdL, L = N-Heterocyclic carbene (NHC) or
PR3), which generates highly active catalysts for a range of important cross-coupling reactions.
To design even better catalysts, which can facilitate new reactions and operate at milder
conditions, we will perform detailed mechanistic studies using IndPdL derived systems, involving
both experiment and theory. Our studies will encompass all aspects of the catalytic process
including elucidating the pathway for precatalyst activation, understanding the elementary steps
in catalytic cycles and determining the catalyst decomposition pathway. Initially, we will study
the mechanism of activation of IndPdL to the monoligated Pd0 active species under a variety of
conditions used for cross-coupling. This will be the first comprehensive study of the activation of
any cross-coupling precatalyst under a range of commonly used reaction conditions. This
information will be used in combination with knowledge of the fundamental steps in catalysis,
which will be gained through stoichiometric studies and kinetics experiments, to rationally
develop systems for fluoride free Hiyama reactions with aryl chlorides, carbamates and
sulfamates and Suzuki-Miyaura couplings with 2-aryl and 2-alkylaziridines.
The discovery of Ni catalysts with comparable activity to Pd systems is preferred because Ni is
cheaper, more abundant and has lower levels of toxicity. Accordingly, we will also use an
approach based on rational design to develop Ni based catalysts for cross-coupling. In
preliminary results we showed that several highly active Ni precatalysts for the Suzuki-Miyaura
reaction rapidly form a NiI complex under catalytic conditions. Here, we will establish the role of
NiI species in catalysis with systems supported by monodentate and bidentate phosphine
ligands, as well as NHC ligands. This information will be used to develop improved systems for
the Suzuki-Miyaura and Buchwald-Hartwig reactions with aryl carbamates and sulfamates. A
major additional benefit of our mechanistic approach is that the general trends we elucidate in
regard to catalyst design and reaction conditions for Ni and Pd catalyzed cross-coupling will be
generalizable to a plethora of other reactions, which are relevant to the synthesis of
pharmaceuticals, but will not specifically be studied in this proposal.

## Key facts

- **NIH application ID:** 10133974
- **Project number:** 3R01GM120162-05S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nilay Hazari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,900
- **Award type:** 3
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133974

## Citation

> US National Institutes of Health, RePORTER application 10133974, Mechanistic Studies to Rationally Design Ni and Pd Catalysts for Cross-Coupling (3R01GM120162-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133974. Licensed CC0.

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