# Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines

> **NIH NIH F32** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $67,174

## Abstract

PROJECT SUMMARY/ABSTRACT
 Subtle structural modifications have the potential to dramatically alter the biological activity of small
molecules. Consequently, the development of synthetic methods that allow for selective molecular editing has
the potential to greatly accelerate the design and synthesis of novel therapeutics. Transition-metal catalyzed C–
H functionalization is a particularly compelling approach, as it circumvents the requirement for prior activation at
the site of functionalization. However, C–H activation typically requires a high degree of preorganization of the
agostic interaction between the metal and the target bond, usually through coordination of the metal to a directing
group. Unfortunately, efforts to use common functional groups and commonly used protecting groups to direct
C(sp3)–H activation have met with limited success. Instead, specially designed directing groups are often
necessary, limiting the synthetic utility of existing C–H functionalization methodologies.
 In the proposed research, ligands will be designed to enable the use of common, weakly coordinating L-type
donors, such as alcohols and carbamates, as directing groups for C(sp3)–H activation. We hypothesized that
two main factors are responsible for the failure of existing ligands to promote these reactions: the intrinsically
weak binding of these functional groups to Pd, and the focus on L,X chelates in recent ligand design efforts,
which are expected to disfavor agostic complex formation with L-type directing groups due to the lack of charge
balance within the complex. Thus, we propose to design novel bis-anionic ligands, structures that are currently
underexplored in C–H activation chemistry, containing an internal base that can participate in C–H activation via
concerted metalation-deprotonation. In order to compensate for the weak coordination of the desired directing
groups to Pd, the proposed ligands will be designed to stabilize substrate-Pd complexes through the secondary
coordination sphere by serving as H-bond acceptors or donors matched to the desired directing group. In Aim 1,
which is strongly supported by preliminary results, we will develop ligands that can enable alcohol-directed
C(sp3)–H functionalizations through two reaction manifolds: C–H dehydrogenation reactions to form allylic
alcohols, which are exceedingly versatile synthetic intermediates, and direct C(sp3)–H arylations. Aim 2 will
extend this ligand design strategy to develop α-arylations of Boc-amines, with a particular focus on methylene
C–H activation in saturated N-Boc azacycles. The successful realization of these aims will provide powerful new
synthetic methodologies, directly facilitating the design and synthesis of novel therapeutics. In addition, validation
of the underlying hypotheses and ligand design strategy will afford a conceptual advance that will contribute to
the continued development of the field of C–H activation.
 The proposed work will be carried out under t...

## Key facts

- **NIH application ID:** 10465726
- **Project number:** 1F32GM143921-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Daniel Aaron Strassfeld
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465726

## Citation

> US National Institutes of Health, RePORTER application 10465726, Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines (1F32GM143921-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465726. Licensed CC0.

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