# Selective Functionalization of Pyridines and Diazines via Heterocyclic Phosphonium Salts

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2021 · $281,642

## Abstract

Project Abstract.
The aim of this proposal is to develop a general process to functionalize pyridines and diazines so that
biologically active molecules can be accessed in an accelerated fashion. Pyridines are the second most common
nitrogen heterocycle observed in FDA approved drugs and related diazines (pyrimidines, pyrazines and
pyridazines) are also widely found. Traditional methods to functionalize these heterocycles are limited by
functional group tolerance, poor regiocontrol and lack of applicability to complex substrates. Our strategy to
functionalize these heterocycles will install a versatile functional group that enables a number of subsequent
bond-forming reactions. Specifically, we will transform pyridines and diazines into phosphonium salts and use
the unique reactivity of the phosphonium ion to make medicinally relevant derivatives. The 4-selective reaction
to make phosphonium salts will use common reagents, be trivial to perform and have a broad substrate scope.
We also propose to use this approach for late-stage functionalization of pharmaceuticals. Transforming
phosphonium salts into important pyridine and diazine derivatives will occur through distinct mechanistic
pathways. Direct reactions with nucleophiles will form C–C, C–O, C–S, C–N, and C–Hal bonds that occur via
SNAr processes or ligand coupling at the phosphorus center. Metal-catalyzed cross-coupling, using nickel and
cobalt catalysts, will be exploited for arylation and alkylation reactions. Base-mediated fragmentation reactions
form heteroaryl anions that will be used to install deuterium and tritium isotopes and form organometallics. A
conceptually new approach to make important bis-heterobiaryls will be developed base on phosphorus ligand
coupling processes. Collectively, this program will provide rapid access to pyridine and diazine derivatives that
have multiple applications in the pharmaceutical sciences. The long-term objective is for these methods to be
used as routine tools by medicinal chemists.

## Key facts

- **NIH application ID:** 10071164
- **Project number:** 5R01GM124094-04
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Andrew McNally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $281,642
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071164

## Citation

> US National Institutes of Health, RePORTER application 10071164, Selective Functionalization of Pyridines and Diazines via Heterocyclic Phosphonium Salts (5R01GM124094-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071164. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*