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Alcohols as alkylating agents in heteroarene C–H functionalization

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.

References

  1. Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 4th edn (Oxford Univ. Press, 2007)

    Google Scholar 

  2. Wessig, P. & Muehling, O. Spin-center shift (SCS) – a versatile concept in biological and synthetic chemistry. Eur. J. Org. Chem. 2219–2232 (2007)

  3. Minisci, F., Vismara, E. & Fontana, F. Homolytic alkylation of protonated heteroaromatic bases by alkyl iodides, hydrogen peroxide, and dimethyl sulfoxide. J. Org. Chem. 54, 5224–5227 (1989)

    CAS  Article  Google Scholar 

  4. Molander, G. A., Colombel, V. & Braz, V. A. Direct alkylation of heteroaryls using potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–1855 (2011)

    CAS  Article  Google Scholar 

  5. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011)

    ADS  CAS  Article  Google Scholar 

  6. Antonchick, A. P. & Burgmann, L. Direct selective oxidative cross-coupling of simple alkanes with heteroarenes. Angew. Chem. Int. Edn Engl. 52, 3267–3271 (2013)

    CAS  Article  Google Scholar 

  7. DiRocco, D. A. et al. Late-stage functionalization of biologically active heterocycles through photoredox catalysis. Angew. Chem. Int. Edn Engl. 53, 4802–4806 (2014)

    CAS  Article  Google Scholar 

  8. Eklund, H., Uhlin, U., Färnegårdh, M., Logan, D. T. & Nordlund, P. Structure and function of the radical enzyme ribonucleotide reductase. Prog. Biophys. Mol. Biol. 77, 177–268 (2001)

    CAS  Article  Google Scholar 

  9. Schönherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Edn Engl. 52, 12256–12267 (2013)

    Article  Google Scholar 

  10. Minisci, F., Bernardi, R., Bertini, F., Galli, R. & Perchinunno, M. Nucleophilic character of alkyl radicals–VI: A new convenient selective alkylation of heteroaromatic bases. Tetrahedron 27, 3575–3579 (1971)

    CAS  Article  Google Scholar 

  11. Duncton, M. A. J. Minisci reactions: versatile CH-functionalizations for medicinal chemists. Med. Chem. Commun. 2, 1135–1161 (2011)

    CAS  Article  Google Scholar 

  12. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011)

    CAS  Article  Google Scholar 

  13. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013)

    CAS  Article  Google Scholar 

  14. Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014)

    Article  Google Scholar 

  15. Qvortrup, K., Rankic, D. A. & MacMillan, D. W. C. A general strategy for organocatalytic activation of C–H bonds via photoredox catalysis: direct arylation of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014)

    CAS  Article  Google Scholar 

  16. Hager, D. & MacMillan, D. W. C. Activation of C–H bonds via the merger of photoredox and organocatalysis: a coupling of benzylic ethers with Schiff bases. J. Am. Chem. Soc. 136, 16986–16989 (2014)

    CAS  Article  Google Scholar 

  17. Cuthbertson, J. D. & MacMillan, D. W. C. The direct arylation of allylic sp3 C–H bonds via organic and photoredox catalysis. Nature 519, 74–77 (2015)

    ADS  CAS  Article  Google Scholar 

  18. Jin, J. & MacMillan, D. W. C. Direct α-arylation of ethers through the combination of photoredox-mediated C–H functionalization and the Minisci reaction. Angew. Chem. Int. Edn Engl. 54, 1565–1569 (2015)

    CAS  Article  Google Scholar 

  19. Ochiai, M. & Morita, K. A novel photo-induced methylation of pyrimidines and condensed pyrimidine compounds. Tetrahedr. Lett. 8, 2349–2351 (1967)

    Article  Google Scholar 

  20. Stermitz, F. R., Wei, C. C. & Huang, W. H. Imine photoalkylations: quinolone and isoquinoline. Chem. Commun. (Lond.) 1968, 482–483 (1968)

    Article  Google Scholar 

  21. Sugimori, A. et al. Radiation-induced alkylation of quinoline derivatives with alcohol. Bull. Chem. Soc. Jpn. 59, 3905–3909 (1986)

    CAS  Article  Google Scholar 

  22. Slinker, J. D. et al. Efficient yellow electroluminescence from a single layer of a cyclometalated iridium complex. J. Am. Chem. Soc. 126, 2763–2767 (2004)

    CAS  Article  Google Scholar 

  23. Shaidarova, L. G., Ziganshina, S. A. & Budnikov, G. K. Electrocatalytic oxidation of cysteine and cystine at a carbon-paste electrode modified with ruthenium(IV) oxide. J. Anal. Chem. 58, 577–582 (2003)

    CAS  Article  Google Scholar 

  24. Escoubet, S. et al. Thiyl radical mediated racemization of nonactivated aliphatic amines. J. Org. Chem. 71, 7288–7292 (2006)

    CAS  Article  Google Scholar 

  25. Berkowitz, J., Ellison, G. B. & Gutman, D. Three methods to measure RH bond energies. J. Phys. Chem. 98, 2744–2765 (1994)

    CAS  Article  Google Scholar 

  26. Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–35 (1999)

    CAS  Article  Google Scholar 

  27. Cai, Y. & Roberts, B. P. Radical-chain racemization of tetrahydrofurfuryl acetate under conditions of polarity-reversal catalysis: possible implications for the radical-induced strand cleavage of DNA. Chem. Commun. (Camb.) 1998, 1145–1146 (1998)

    Article  Google Scholar 

  28. McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011)

    ADS  CAS  Article  Google Scholar 

Download references

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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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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