Chemoselective Tertiary C−H Hydroxylation for Late-Stage Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis

Rachel K. Chambers; Jinpeng Zhao; Connor P. Delaney; M. Christina White

doi:10.1002/adsc.201901472

Chemoselective Tertiary C−H Hydroxylation for Late-Stage Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis

Rachel K. Chambers, Jinpeng Zhao, Connor P. Delaney, M. Christina White

Research output: Contribution to journal › Article › peer-review

Abstract

Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP) catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C(sp³)−H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10–15% higher isolated yields on these substrates and is uniquely effective for remote C(sp³)−H hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic acid C(sp³)−H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery processes via late-stage functionalization. (Figure presented.).

Original language	English (US)
Pages (from-to)	417-423
Number of pages	7
Journal	Advanced Synthesis and Catalysis
Volume	362
Issue number	2
DOIs	https://doi.org/10.1002/adsc.201901472
State	Published - Jan 23 2020

Keywords

C−H hydroxylation
chemoselective
late stage functionalization
oxidation
site-selective

ASJC Scopus subject areas

Catalysis
Organic Chemistry

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title = "Chemoselective Tertiary C−H Hydroxylation for Late-Stage Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis",

abstract = "Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP) catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C(sp3)−H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10–15% higher isolated yields on these substrates and is uniquely effective for remote C(sp3)−H hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic acid C(sp3)−H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery processes via late-stage functionalization. (Figure presented.).",

keywords = "C−H hydroxylation, chemoselective, late stage functionalization, oxidation, site-selective",

author = "Chambers, {Rachel K.} and Jinpeng Zhao and Delaney, {Connor P.} and White, {M. Christina}",

note = "Funding Information: The authors thank L. Zhu and D. Olsen for assistance with NMR spectroscopy, D. Gray and T. Woods for X‐Ray crystallographic studies. Funding Sources : Financial Support for this work was provided by the NIH NIGMS Maximizing Investigator's Research Award MIRA (R35 GM122525). RKC was partially funded by a Sir Keith Murdoch Scholarship from the American Australian Association. Competing Interest : The University of Illinois has filed a patent application on the Mn(CF 3 ‐PDP) catalyst for C−H oxidation in aromatic molecules. ",

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language = "English (US)",

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AU - Zhao, Jinpeng

AU - Delaney, Connor P.

AU - White, M. Christina

N1 - Funding Information: The authors thank L. Zhu and D. Olsen for assistance with NMR spectroscopy, D. Gray and T. Woods for X‐Ray crystallographic studies. Funding Sources : Financial Support for this work was provided by the NIH NIGMS Maximizing Investigator's Research Award MIRA (R35 GM122525). RKC was partially funded by a Sir Keith Murdoch Scholarship from the American Australian Association. Competing Interest : The University of Illinois has filed a patent application on the Mn(CF 3 ‐PDP) catalyst for C−H oxidation in aromatic molecules.

PY - 2020/1/23

Y1 - 2020/1/23

N2 - Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP) catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C(sp3)−H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10–15% higher isolated yields on these substrates and is uniquely effective for remote C(sp3)−H hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic acid C(sp3)−H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery processes via late-stage functionalization. (Figure presented.).

AB - Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP) catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C(sp3)−H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10–15% higher isolated yields on these substrates and is uniquely effective for remote C(sp3)−H hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic acid C(sp3)−H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery processes via late-stage functionalization. (Figure presented.).

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