# Development of Nontrigonal Phosphorus Catalysts for Redox-Mediated Cross-Coupling Transformations

> **NIH NIH F32** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $67,174

## Abstract

PROJECT SUMMARY/ABSTRACT
 Transition metal-catalyzed cross-couplings afford innumerous pathways for the construct of new C–X bonds
with high regio-, stereo-, and chemoselectivity. This has led to widespread adoption of cross-coupling in the
synthesis of active pharmaceutical ingredients (APIs), most commonly using Pd-based catalysts. However, even
traces of Pd must be purged from the API to meet FDA standards, often requiring additional purification steps
that negatively impact overall yields and increases cost. Therefore, the development of transition metal-free
catalysts for cross-coupling would be beneficial by requiring less stringent purification and also affording access
to new areas of complementary reactivity. This proposal describes a new approach that utilizes rigidly planar
nontrigonal phosphines to catalyze nucleophile-electrophile and electrophile-electrophile cross-coupling
reactions for C–C bond construction. In nucleophile-electrophile couplings, phosphorus catalysts will be
developed for Kumada and Negishi cross-couplings via a PIII/PV redox cycle. The use of a phosphorus center in
catalysis will subvert traditional reactivity trends in aryl halide oxidative addition by favoring the activation of C–
F and C–Cl bonds over C–Br and C–I bonds. Initial efforts will focus on understanding limitations in stepwise
reactivity and the underlying thermodynamics that dictate each transformation before investigating catalysis. In
a complementary thrust, the one electron reactivity of nontrigonal phosphinyl radical anions will be merged with
two-electron oxidative addition and reductive elimination to drive reductive cross-coupling of aryl halides. The
two electrophile activation steps in this process are expected to exhibit inverse orders of reactivity for aryl halide
bonds, allowing for chemoselectivity to dictate C–C bond formation. This ultimately will severely diminish the
formation of undesired homocoupling byproducts, something that can be difficult for transition metal-catalyzed
systems. The development of these phosphorus-catalyzed transformations will not only demonstrate alternative
approaches to traditionally transition metal-based processes in the synthesis of APIs, but will also highlight
undiscovered areas of complementary reactivity that will enhance the chemical diversity accessible to drug
discovery efforts.
 This proposal aligns with the fellowship training plan by ensuring the development of new skills in main group
catalysis and organic reaction design will take place. The Radosevich lab at MIT is an ideal environment for the
development of these skills and the proposed work due to their pioneering work in phosphorus redox catalysis.
Additionally, Prof. Radosevich’s commitment to developing postdoctoral researchers into successful
independent investigators guarantees that professional development goals will be met. Furthermore, the
resources available at MIT will ensure access to the necessary equipment, training, and sup...

## Key facts

- **NIH application ID:** 10468667
- **Project number:** 5F32GM143865-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Quinton James Bruch
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 5
- **Project period:** 2021-08-02 → 2024-08-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468667

## Citation

> US National Institutes of Health, RePORTER application 10468667, Development of Nontrigonal Phosphorus Catalysts for Redox-Mediated Cross-Coupling Transformations (5F32GM143865-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10468667. Licensed CC0.

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