# Understanding Coupling Reactions of Heteroaryls

> **NIH NIH R35** · WEST VIRGINIA UNIVERSITY · 2021 · $320,062

## Abstract

Project Summary
Heterobiaryls are an important class of substructures found in a large number of biologically
active molecules and FDA approved drugs. These scaffolds are typically constructed through
traditional cross-coupling strategies. Unfortunately, these protocols are inefficient for the
incorporation of heteroaryl fragments. The objective of the work proposed here is to develop a
fundamental understanding of the cross-coupling reactions of heteroarenes. We also aim to
apply our findings to the development of new efficient and predictable cross-coupling reactions
of heteroaromatic coupling partners. This work will ultimately allow synthetic and medicinal
chemists to design predictable and reliable synthetic strategies to access these biologically
relevant intermediates and target compounds. We recently identified the field effect of ortho-
substituents as being a dominant predictor in the rate of decarboxylation and oxidative
decarboxylative coupling (ODC) reactions of benzoic acids. The first phase of research will
extend this predictive power to the ODC reactions of heteroaromatic carboxylates and
benzoates without the typically required ortho-substituents. We hypothesize that new ligand
scaffolds can be designed to mitigate the need for ortho-substituents in these reactions because
the field effect parameter describes a through-space influence. In the final phase of our study,
we will apply these new ligand structures to other classes of cross-coupling reactions that have
historically suffered from related ortho-substituent limitations. The development of a large
collection of predictable and reliable cross-coupling reactions that operate efficiently for a broad
scope of (hetero)aromatic coupling partners is significant because it provides access to a large
library of biologically relevant core structures. Thus, the development of a fundamental
understanding of the trends and limitations in these and other coupling reactions of
heteroarenes would allow existing and developing synthetic methods to be adapted for the
construction of complex and pharmaceutically relevant structures.

## Key facts

- **NIH application ID:** 10241334
- **Project number:** 5R35GM133566-03
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Jessica M Hoover
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,062
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241334

## Citation

> US National Institutes of Health, RePORTER application 10241334, Understanding Coupling Reactions of Heteroaryls (5R35GM133566-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241334. Licensed CC0.

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