# Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $385,617

## Abstract

Project Summary
 Site-selective functionalization of C–H bonds in arenes and heteroarenes can potentially
transform the synthesis of bioactive molecules, as it can enable the flexible molecular editing of
a scaffold to rapidly generate a diverse set of structures. While C–H bonds proximate to
coordinating groups have been successfully activated through its directing effect to form a wide
range of C–C and C–X bonds, the majority of C–H bonds in a given molecule are incompatible
with this conventional approach. The limitation arises from two factors: 1) distance - the directing
effect of a coordinating group diminishes at distances greater than six bonds, and 2) geometry -
meta and para positions on arenes are geometrically inaccessible, which greatly restricts the utility
of C–H activation in synthesis. These widely recognized challenges escalate with heterocyclic
substrates, as heteroatoms coordinate strongly to metal catalysts. This strong binding interaction
either limits the utility of C–H activation to proximate sites, or leads to deleterious catalyst
poisoning. Therefore, the development of new approaches to achieve selective functionalization
of these previously inaccessible C–H bonds is of great value to drug discovery.
 To achieve the goal of site-selective remote C–H functionalizations of arenes and
hetereocycles, we propose three complementary approaches to overcome the two
aforementioned challenges. These are 1) the use of transient and catalytic templates, 2) the use
of ligand-promoted site-selective C–H activation, and 3) employing a norbornene-mediated relay
strategy to expand the first two methods to more distal sites. The first strategy features the use of
novel transient directing templates for amine and ketone substrates, as well as employing
reversible bifunctional bimetallic directing templates for heterocycles. The second approach is
based on our previous finding that phenanthroline-type ligands can promote C-3 selective C–H
activation of pyridines, albeit requiring super-stoichiometric amounts of starting material. We
propose to redesign this ligand by using additional weak interactions to stabilize the transition
states, thereby accelerating the C–H activation reaction. Finally, we propose to utilize
norbornenes as a transient mediator to relay the initial remote C–H palladation from the first two
approaches to an adjacent, more distal position. The multi-pronged approach presented here fills
a major gap in current synthetic methodology. To achieve this overall goal, novel templates,
ligands and reagents will be invented. These remote site-selective C–H activation reactions of
arenes and heteroarenes will be applied to expedite drug discovery and chemical biology
programs in collaboration with the Cravatt and Kelly labs, as well as with Bristol-Myers Squibb.

## Key facts

- **NIH application ID:** 10254416
- **Project number:** 5R01GM102265-10
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Jin-Quan Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,617
- **Award type:** 5
- **Project period:** 2012-09-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254416

## Citation

> US National Institutes of Health, RePORTER application 10254416, Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes (5R01GM102265-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10254416. Licensed CC0.

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