# Harnessing Electrophilic N-Aryl Catalytic Intermediates for Versatile C-N Bond Formation

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $305,825

## Abstract

Abstract
The pervasive presence of N-heterocycles in chemical probes, pharmaceuticals and materials that improve the
quality of life and health of humans continues to spur the development of new reactions to simplify access to
these scaffolds. Our research program addresses important unsolved problems in organic synthesis through the
development of new reactions for the selective construction of C–NHAr, C–C and C–O bonds by harnessing the
unique reactivity of N-aryl nitrogen catalytic and reactive intermediates generated in situ from nitroarenes and
unactivated anilines. Despite the ubiquity of the C–NHAr bond in bioactive N-heterocycles, it cannot be formed
using existing metal-catalyzed N-atom transfer reactions because these processes require a strong electron-
withdrawing N-substituent. In contrast to the well-established chemistry of N-sulfonyl- or N-carbamoyl metal
nitrenes, whose strong electron-withdrawing group is critical for their reactivity with C–H bonds and π-systems,
the reactivity of N-aryl nitrenes and nitroarenes is poorly understood because of the difficulties in generating
them and taming their reactivity. This lack of understanding has produced a gap in synthesis that obstructs
access to complex, functionalized N-heterocyclic compounds and emphasizes the need for the development of
methods to provide solutions to these problems. Our prior research efforts have established that N-aryl nitrenes
can be formed from azides and that their reactivity is distinct to nitrenes bearing strong electron withdrawing
groups. These efforts have provided the basis to support our future efforts in discovering new reactions of N-aryl
nitrenes and nitrosoarenes that we will harness to simplify the synthesis of privileged N-heterocyclic scaffolds
embedded in synthetic targets. Within this proposal, we have leveraged our understanding these N-aryl nitogen
reactive intermediates to develop new transformations that create C–NHAr bonds. Towards this end, in Aim 1
we will develop new Fe(II)-catalyzed reductive cascade reactions that construct sp3-C–NHAr bonds intra- or
intermolecularly from nitroarenes using silane reductants; in Aim 2 we will develop new single-electron transfer
processes that generate N-aryl reactive intermediates with tunable oxygen transfer abilities for the synthesis of
N-hydroxyindoles and oxindoles; and in Aim 3, we will develop oxidative methods for accessing electrophilic N-
aryl nitrenoids from anilines and apply to the intra- and intermolecular synthesis of N-heterocycles. By
establishing new strategies and tactics for the stereoselective formation of C–NAr, C–C and C–O bonds through
harnessing the reactivity of N-aryl nitrogen intermediates, successful realization of these Aims will produce new
tools to simplify the construction of novel and bioactive N-heterocycles.

## Key facts

- **NIH application ID:** 10225603
- **Project number:** 5R01GM138388-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Tom G Driver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $305,825
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225603

## Citation

> US National Institutes of Health, RePORTER application 10225603, Harnessing Electrophilic N-Aryl Catalytic Intermediates for Versatile C-N Bond Formation (5R01GM138388-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10225603. Licensed CC0.

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