# Strategies for the Catalytic Synthesis of Nitrogen-Containing Molecules

> **NIH NIH R35** · DUKE UNIVERSITY · 2024 · $383,666

## Abstract

Project Abstract for NIH R35 (MIRA):
The discovery and development of new methods for the efficient synthesis of N-containing and F-containing
chemical building blocks is an important goal in organic synthesis as a large number of pharmaceuticals and
other bioactive molecules contain these atoms within a diverse set of chemical functional groups. More rapid
and/or selective assembly of known motifs, and moreover the preparation of new chemical landscapes, requires
innovative approaches to drug-like scaffolds, including the discovery of new reagents and new catalysts/catalytic
strategies.
The current goals of this project fall under three main focus areas. 1) We will develop 2-azatrienes, a novel class
of enamine umpolung reagents, for myriad catalytic enantioselective approaches towards chiral amines.
Representative reactions that will be developed include 6,3-, 6,5- and 5,6-hydrofunctionalizations including
reductive couplings with carbonyls and imines, hydroalkynylations, and hydroarylations. Azadienes generated
from 6,5- and 5,6-hydrofunctionalizations of the azatriene reagents may be utilized in myriad downstream
reactions, including other catalytic processes, thereby providing a diastereodivergent avenue towards highly
complex chiral amines through sequential catalysis. 2) We will expand upon our prior work in enantioselective
transformations of 2-azadienes, the first class of enamine umpolung reagents developed in our laboratory.
Examples include reductive couplings with aromatic heterocycles, such as quinoline N-oxides, catalytic
enantioselective fluorofunctionalizations with 4,4-difluoro-2-azadienes, cascade desymmetrization reactions,
and reductive [3+2]-cycloadditions. 3) We will develop catalytic remote C–C and C–B coupling reactions that
result in the loss of a halide from a trifluoromethyl group or H-atom abstraction from a difluoromethyl group to
deliver difluorocarbons in a number of settings. In one case, we will carry out borylation or enantioselective
alkylation of a 3-trifluoromethylpyridine scaffold to yield medicinally important and highly functionalized 3-
(difluoromethyl)pyridines. In another area, we will execute a radical hydrogen atom abstraction of 4-
difluoromethyl-2-azadienes to furnish a difluoro-2-azapentadienyl radical, which then may be engaged in
catalytic cross-couplings to furnish chiral allylic amines bearing a difluoroalkene unit.
Together, these undertakings will enable new chemical space for drug discovery to be obtained readily and with
great diversity from simple reagents. We will access more established N-containing motifs more quickly and with
greater levels of regio/stereocontrol compared to known approaches because of the invention of new reagents
and the novel reactivity that they embody.

## Key facts

- **NIH application ID:** 10857263
- **Project number:** 5R35GM145285-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Steven Joseph Malcolmson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,666
- **Award type:** 5
- **Project period:** 2022-09-10 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857263

## Citation

> US National Institutes of Health, RePORTER application 10857263, Strategies for the Catalytic Synthesis of Nitrogen-Containing Molecules (5R35GM145285-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10857263. Licensed CC0.

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