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Alcohols as alkylating agents in heteroarene C–H functionalization

Nature volume 525, pages 87–90 (2015)Cite this article

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Abstract

Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage1. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of ‘spin-centre shift’2, during which an alcohol C–O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides3,4,5,6,7, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.

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Figure 1: Bio-inspired alkylation process using alcohols as spin-centre shift equivalents via a dual catalytic platform.
Figure 2: Proposed mechanism for the direct alkylation of heteroaromatic C–H bonds via photoredox organocatalysis.
Figure 3: Substrate scope for the alkylation of heteroaromatic C–H bonds with alcohols via the dual photoredox organocatalytic platform.
Figure 4: Mechanistic studies support spin-centre shift elimination pathway.

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Acknowledgements

Financial support was provided by NIHGMS (R01 GM103558-03), and gifts from Merck and Amgen. J.J. thanks J. A. Terrett for assistance in preparing this manuscript.

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Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, 08544, New Jersey, USA

    Jian Jin & David W. C. MacMillan

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  1. Jian Jin
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  2. David W. C. MacMillan
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Contributions

J.J. performed and analysed experiments. J.J. and D.W.C.M. designed experiments to develop this reaction and probe its utility, and also prepared this manuscript.

Corresponding author

Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

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This file contains Supplementary Text and Data 1-5, Supplementary Figures 1-13 and NMR Spectras (see Contents for details). (PDF 29916 kb)

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Jin, J., MacMillan, D. Alcohols as alkylating agents in heteroarene C–H functionalization. Nature 525, 87–90 (2015). https://doi.org/10.1038/nature14885

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