# Construction of Heteroarenes Through Single Atom Insertion Strategies

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2022 · $410,000

## Abstract

Project Abstract
 This proposal concerns the development of new reagents and strategies for the
preparation of basic, aromatic, nitrogenous heterocycles through single-atom insertion
reactions. The medicinal importance of such structures (pyridines, pyrimidines,
pyridazines) is difficult to overstate – of the thirty new small molecule drugs approved in
2019, ten of them contain one or more of these motifs and their prevalence among
medicinally-relevant compounds is a long-standing trend. This privileged status has
prompted the development of a variety of synthetic strategies for their preparation, which
can largely be subdivided into de novo assembly of the heteroaromatic nucleus (typically
condensations), and attachment of preformed heteroarenes via cross-coupling and
nucleophilic aromatic substitution approaches. These strategies have enabled the
proliferation of such compounds for wide-ranging medicinal applications, but their
implementation is nonetheless far from trivial, necessitating the continuing development
of novel strategies.
 A conceptual mid-point exists between de novo synthesis and attachment wherein
one heterocyclic structure is converted into another. Such an approach has limited
historical precedent but holds substantial promise due to the orthogonal reactivity
preferences (e.g. nucleophilic vs. electrophilic) and reaction compatibility of 5- vs. 6-
membered heterocycles. We propose herein a set of reagents which will enable such
transformations to be realized in a synthetically straightforward manner.
 Our focus on single-atom changes is calculated: rearrangement reactions, though
lauded, are rarely employed in synthesis due to their retrosynthetic complexity. By
developing transformations that are easy to recognize in a retrosynthetic sense (e.g.
“remove this nitrogen atom”) we hope to provide user-friendly tools for medicinal chemists
to employ. Moreover, the ability to transform pyrroles, pyrazoles, and imidazoles into a
variety of 6-membered ring heterocycles feeds naturally into late-stage skeletal editing of
pharmaceuticals, allowing diversification of bioactive scaffolds for more efficient structure-
activity relationship determination and for site-specific isotopic labeling. As such,
successful realization of the goals enumerated herein will advance the ability for chemists
to interrogate biological function of heteroaromatic compounds by affording a powerful
new set of tools for their synthesis.

## Key facts

- **NIH application ID:** 10428643
- **Project number:** 5R35GM142768-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Mark Daniel Levin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428643

## Citation

> US National Institutes of Health, RePORTER application 10428643, Construction of Heteroarenes Through Single Atom Insertion Strategies (5R35GM142768-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428643. Licensed CC0.

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