# A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2022 · $299,141

## Abstract

Project Abstract.
The goal of this project is to introduce a new synthetic strategy to functionalize pyridine heterocycles. Pyridines
are the second most common nitrogen heterocycle found in FDA approved drugs, an unsurprising fact because
of their propensity for hydrogen bonding and suite of valuable physiochemical properties such as aqueous
solubility, net polarity, and resistance to oxidative metabolism. Synthetic methods to directly and selectively
functionalize pyridines are critical in drug discovery efforts because drug-developers require variation in
positional selectivity, various carbon- and heteroatom bearing groups on the scaffold a wide variance in their
steric and electronic properties. However, general approaches to transform pyridine C–H bonds into valuable
derivatives are lacking. In this proposal, we outline a dearomatization strategy by converting pyridines into Zincke
imine and iminium adducts. In effect, these adducts make pyridines react like a series of alkenes rather than an
aromatic system and thus open up the plethora of reactions associated with olefins that were previously
ineffective on pyridines themselves. We will show that pyridines can now participate in numerous processes,
such as halogenation, reaction with sp2-carbon electrophiles radical reactions that were either not viable or
operated under extreme reaction conditions. The processes will occur with exclusive control of regioselectivity
for the 3-position of Zincke intermediates and are also switchable to the 5-position based on the Zincke adduct's
structure. The ring-opening-functionalization-ring-closing is sequencable into one-pot processes in many cases.
We will also use the Zincke platform to access pyridine isotopologs for ADME studies and new methods to form
N–oxides. We plan to employ this strategy for simple building block pyridines, drug-like intermediates and for
late-stage functionalization of complex pyridine-containing drugs.

## Key facts

- **NIH application ID:** 10344085
- **Project number:** 1R01GM144591-01
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Andrew McNally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,141
- **Award type:** 1
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10344085

## Citation

> US National Institutes of Health, RePORTER application 10344085, A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates (1R01GM144591-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10344085. Licensed CC0.

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