# New Methods for Direct Carbon-Hydrogen Bond Functionalization

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $299,880

## Abstract

PROJECT SUMMARY
The main goal of the proposed research is to develop new and useful transformations using carbon-hydrogen
bond functionalization reactions. Use of C-H bonds as a transformable functional group is advantageous since
these bonds are typically the most abundant functionality in organic molecules, and most starting materials that
are available on large scale contain only carbon-carbon and carbon-hydrogen bonds. Direct conversion of
these bonds to the desired functionality shortens synthetic pathways saving reagents, solvents, and labor.
However, obvious problems, such as low reactivity of alkane sp3 C-H bonds and difficulty to attain
regioselective functionalization of these bonds, have prevented widespread use of C-H functionalization
methodology. Our efforts are directed towards addressing these issues in the context of pharmaceutically
relevant transformations. Specifically, the project will focus on the auxiliary-directed alkane C-H bond
functionalization and group 11 metal-catalyzed sp3 C-H bond functionalization via carbene intermediates. We
have a substantial amount of preliminary data showing that proposed chemistry is viable and may lead to
useful methodology.
We will develop second-generation auxiliaries for sp3 C-H bond functionalization that will replace
aminoquinoline directing group and address its remaining challenges. Specifically, monodentate 1-
aminopyridine and pyrazole derivatives will be used to direct sp3 C-H bond functionalization. The key
difference from first-generation auxiliaries is easier removal, lack or product inhibition, possibility of ligand-
accelerated catalysis while matching the outstanding directing abilities of aminoquinoline, and ability to
functionalize β-positions in amine derivatives. These studies will have important implications, and have already
resulted in superior auxiliaries for arylation of sp3 C-H bonds. The reactions arising from C-H bond activation
will complement the current methods for C-C and C-heteroatom bond formation and will have a substantial
impact on synthetic methodology.
We have obtained preliminary results showing that non-directed group 11 metal-catalyzed sp3 C-H bond
functionalization with alkyl diazo and fluorinated diazo compounds is feasible. These unique transformations
cannot be easily achieved by using other methodology. The new catalysts should allow for unprecedented late-
stage functionalization of medicinally relevant molecules.
The specific aims of the research are as follows: 1. New auxiliary and reaction development for directed C-H
functionalization, 2. Enantioselective C-H bond functionalization, 3. Group 11 metal-catalyzed C-H
functionalization via carbenoid intermediates.

## Key facts

- **NIH application ID:** 9928061
- **Project number:** 5R01GM077635-13
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Olafs Daugulis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $299,880
- **Award type:** 5
- **Project period:** 2007-06-05 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928061

## Citation

> US National Institutes of Health, RePORTER application 9928061, New Methods for Direct Carbon-Hydrogen Bond Functionalization (5R01GM077635-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928061. Licensed CC0.

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