# Organocatalytic Site-Selective C-H Bond Functionalization

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $293,163

## Abstract

Project Summary/Abstract
Site-selective functionalization of aliphatic C–H bonds can provide shortcuts to the synthesis of bioactive
molecules, including those that cannot be feasibly or practically made using other synthetic approaches. Given
the prevalence of nitrogen- and oxygen-containing functional groups in approved drugs, the importance of
developing general methods for aliphatic C–H amination and hydroxylation in particular is widely recognized.
Although catalytic methods for both selective intermolecular and directed C–H hydroxylations of aliphatic C–H
bonds have been successfully developed, their generality is greatly limited by a lack of functional group
compatibility and limited ability to override substrate control of selectivity. Similar challenges exist for aliphatic
C–H amination, and they are comparatively greater given that only a handful of site-selective methods have yet
been reported. As such, new catalytic methods for selective aliphatic C–H hydroxylation and amination that are
more tolerant of a wide range of functional groups and that are amenable to new strategies to control site
selectivity will greatly improve the generality and scope of this synthetic approach. In turn, these new methods
will improve the ability of synthetic chemists to efficiently synthesize therapeutic leads. We propose a new,
unified catalytic strategy to achieve site-selective aliphatic hydroxylation and amination. The strategy features
the use of iminium salt organocatalysts developed in our lab, that we have discovered overcome functional
group compatibility issues inherent to other catalytic methods. The objective of Aim 1 is to develop iminium
salt-catalyzed intermolecular site-selective hydroxylation reactions that are compatible with alcohol functional
groups, including hydroxylations of methylene C–H bonds that are selective for alcohol products. The objective
of Aim 2 is to develop intermolecular iminium salt-catalyzed amidation reactions that are selective for one of
many sp3 C–H bonds. Finally, the objective of Aim 3 is to apply these organocatalytic methods to directed
aliphatic C–H hydroxylations and aminations to achieve remote functionalizations of aldehyde and ketone
substrates that are not addressed by existing catalytic methods. The proposed research will result in new
methods for accessing synthons common to bioactive molecules and new methods for the late-stage
diversification of therapeutic leads.

## Key facts

- **NIH application ID:** 9962899
- **Project number:** 5R01GM124092-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Michael Kenneth Hilinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,163
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962899

## Citation

> US National Institutes of Health, RePORTER application 9962899, Organocatalytic Site-Selective C-H Bond Functionalization (5R01GM124092-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9962899. Licensed CC0.

---

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