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Hydroacylation of α,β-unsaturated esters via aerobic C–H activation

Abstract

The development of methods for carbon–carbon bond formation under benign conditions is an ongoing challenge for the synthetic chemist. In recent years there has been considerable interest in using selective C–H activation as a direct route for generating reactive intermediates. In this article, we describe the use of aldehyde auto-oxidation as a simple, clean and effective method for C–H activation, resulting in the generation of an acyl radical. This acyl radical can be used for carbon–carbon bond formation and herein we describe the application of this method for the hydroacylation of α,β-unsaturated esters without the requirement of additional catalysts or reagents. This methodology generates unsymmetrical ketones, which have been shown to have broad use in organic synthesis.

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Figure 1: Auto-oxidation of aldehydes generates acyl radicals, which can be intercepted to generate carbon–carbon bonds.
Figure 2: Proposed mechanism for the aerobic hydroacylation of alkenes.

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References

  1. Anastas, P. T. & Kirchhoff, M. M. Origins, current status, and future challenges of green chemistry. Acc. Chem. Res. 35, 686–694 (2002).

    Article  CAS  Google Scholar 

  2. Arndtsen, B. A., Bergman, R. G., Mobley, T. A. & Peterson, T. H. Selective intramolecular carbon–hydrogen bond activation by synthetic metal complexes in homogenous solution. Acc. Chem. Res. 28, 154–162 (1995).

    Article  CAS  Google Scholar 

  3. Hartwig, J. F. Carbon-heteroatom bond formation catalysed by organometallic complexes. Nature 455, 314–322 (2008).

    Article  CAS  Google Scholar 

  4. Herrerias, C. I., Yao, X. Q., Li, Z. P. & Li, C. J. Reactions of C–H bonds in water. Chem. Rev. 107, 2546–2562 (2007).

    Article  CAS  Google Scholar 

  5. Motherwell, W. B. & Crich, D. Free Radical Chain Reactions in Organic Synthesis. (Elsevier, 1992).

    Google Scholar 

  6. Rowlands, G. J. Radicals in organic synthesis. Part 1. Tetrahedron 65, 8603–8655 (2009).

    Article  CAS  Google Scholar 

  7. Rowlands, G. J. Radicals in organic synthesis. Part 2. Tetrahedron 66, 1593–1636 (2010).

    Article  CAS  Google Scholar 

  8. Barton, D. H., Beaton, J. M., Geller, L. E. & Pechet, M. M. A new photochemical reaction. J. Am. Chem. Soc. 83, 4076–4083 (1961).

    Article  CAS  Google Scholar 

  9. Curran, D. P., Kim, D., Liu, H. T. & Shen, W. Translocation of radical sites by intramolecular 1,5-hydrogen atom transfer. J. Am. Chem. Soc. 110, 5900–5902 (1988).

    Article  CAS  Google Scholar 

  10. Hofmann, A. W. Über die Einwirkung des Broms in alkalischer Lösung auf die Amine. Berichte der deutschen chemischen Gesellschaft 16, 558–560 (1883).

    Article  Google Scholar 

  11. Löffler, K. Über eine neue Bildungsweise von N-alkylierten Pyrrolidinen. Berichte der deutschen chemischen Gesellschaft 42, 3427–3431 (1909).

    Article  Google Scholar 

  12. Julia, M. et al. Cyclisations radicalaires - XXV: Inhibition sterique de la formation du cycle a six carbones dans la cyclisation de radicaux δ, ϵ ethyleniques. Tetrahedron 31, 1737–1744 (1975).

    Article  CAS  Google Scholar 

  13. Chatgilialoglu, C., Crich, D., Komatsu, M. & Ryu, I. Chemistry of acyl radicals. Chem. Rev. 99, 1991–2069 (1999).

    Article  CAS  Google Scholar 

  14. Curran, D. P. The design and application of free-radical chain reactions in organic synthesis 1. Synthesis, 417–439 (1988).

    Article  Google Scholar 

  15. McNesby, J. R. & Heller, C. A. Oxidation of liquid aldehydes by molecular oxygen. Chem. Rev. 54, 325–346 (1954).

    Article  CAS  Google Scholar 

  16. Walling, C. in Active Oxygen in Chemistry (eds C. S. Foote, J. S. Valentine, A. Greenberg & J. F. Liebman) 24–65 (Blackie, 1995).

    Book  Google Scholar 

  17. Tsujimoto, S., Sakaguchi, S. & Ishii, Y. Addition of aldehydes and their equivalents to electron-deficient alkenes using N-hydroxyphthalimide (NHPI) as a polarity-reversal catalyst. Tetrahedron Lett. 44, 5601–5604 (2003).

    Article  CAS  Google Scholar 

  18. Esposti, S., Dondi, D., Fagnoni, M. & Albini, A. Acylation of electrophilic olefins through decatungstate-photocatalyzed activation of aldehydes. Angew. Chem. Int. Ed. 46, 2531–2534 (2007).

    Article  CAS  Google Scholar 

  19. Recupero, F. & Punta, C. Free radical functionalization of organic compounds catalyzed by N-hydroxyphthalimide. Chem. Rev. 107, 3800–3842 (2007).

    Article  CAS  Google Scholar 

  20. Protti, S., Ravelli, D., Fagnoni, M. & Albini, A. Solar light-driven photocatalyzed alkylations. Chemistry on the window ledge. Chem. Commun. 7351–7353 (2009).

  21. Cauquis, G., Sillion, B. & Verdet, L. Addition of aldehyde to olefin in presence of silver salts. Tetrahedron Lett. 27–30 (1977).

  22. Shapiro, N. & Vigalok, A. Highly efficient organic reactions “on water”, “in water”, and both. Angew. Chem. Int. Ed. 47, 2849–2852 (2008).

    Article  CAS  Google Scholar 

  23. Tada, N., Okubo, H., Miura, T. & Itoh, A. Metal-free epoxidation of alkenes with molecular oxygen and benzaldehyde under visible light irradiation. Synlett 3024–3026 (2009).

  24. Jarboe, S. G. & Beak, P. Mechanism of oxygen transfer in the epoxidation of an olefin by molecular oxygen in the presence of an aldehyde. Org. Lett. 2, 357–360 (2000).

    Article  CAS  Google Scholar 

  25. Fitzmaurice, R. J., Ahern, J. M. & Caddick, S. Synthesis of unsymmetrical ketones via simple C-H activation of aldehydes and concomitant hydroacylation of vinyl sulfonates. Org. Biomol. Chem. 7, 235–237 (2009).

    Article  CAS  Google Scholar 

  26. Chudasama, V., Fitzmaurice, R. J., Ahern, J. M. & Caddick, S. Dioxygen mediated hydroacylation of vinyl sulfonates and sulfones on water. Chem. Commun. 46, 133–135 (2010).

    Article  CAS  Google Scholar 

  27. Vinogradov, M. G., Kereselidze, R. V., Gachechiladze, G. G. & Nikishin, G. I. Addition of aldehydes to unsaturated compounds induced by autooxidation. Russ. Chem. Bull. 18, 276–281 (1969).

    Article  Google Scholar 

  28. Hirano, K., Biju, A. T., Piel, I. & Glorius, F. N-Heterocyclic carbene-catalyzed hydroacylation of unactivated double bonds. J. Am. Chem. Soc. 131, 14190–14191 (2009).

    Article  CAS  Google Scholar 

  29. Christmann, M. New developments in the asymmetric Stetter reaction. Angew. Chem. Int. Ed. 44, 2632–2634 (2005).

    Article  CAS  Google Scholar 

  30. Shibata, Y. & Tanaka, K. Rhodium-catalyzed highly enantioselective direct intermolecular hydroacylation of 1,1-disubstituted alkenes with unfunctionalized aldehydes. J. Am. Chem. Soc. 131, 12552–12553 (2009).

    Article  CAS  Google Scholar 

  31. Osborne, J. D. & Willis, M. C. Rhodium-catalysed hydroacylation or reductive aldol reactions: a ligand dependent switch of reactivity. Chem. Commun. 5025–5027 (2008).

  32. Srikanth, G. S. C. & Castle, S. L. Advances in radical conjugate additions. Tetrahedron 61, 10377–10441 (2005).

    Article  CAS  Google Scholar 

  33. Lederer, P., Lunak, S., Macova, E. & Vepreksiska, J. Oxidation of benzaldehyde by dioxygen—thermal reaction. Collect. Czech. Chem. Commun. 47, 392–402 (1982).

    Article  CAS  Google Scholar 

  34. Lunak, S., Lederer, P., Stopka, P. & Vepreksiska, J. Oxidation of benzaldehyde by dioxygen—photoinitated reaction. Collect. Czech. Chem. Commun. 46, 2455–2465 (1981).

    Article  CAS  Google Scholar 

  35. Cai, Y. D. & Roberts, B. P. The mechanism of polarity-reversal catalysis as involved in the radical-chain reduction of alkyl halides using the silane-thiol couple. J. Chem. Soc. Perkin Trans. 2 1858–1868 (2002).

  36. Dang, H. S., Roberts, B. P. & Tocher, D. A. Selective radical-chain epimerisation at electron-rich chiral tertiary C–H centres using thiols as protic polarity-reversal catalysts. J. Chem. Soc. Perkin Trans. 1 2452–2461 (2001).

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Acknowledgements

We thank A.G. Davies and K.U. Ingold for helpful discussions. We gratefully acknowledge EPSRC, BBSRC, MRC, GSK, UCL and CEM UK for support of our program. We also thank the EPSRC Mass Spectrometry Service for provision of mass spectra.

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S.C., R.J.F. and V.C. conceived the experiments. V.C. performed the laboratory experiments and analysed the data. V.C., R.J.F. and S.C. wrote the paper.

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Correspondence to Stephen Caddick.

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Chudasama, V., Fitzmaurice, R. & Caddick, S. Hydroacylation of α,β-unsaturated esters via aerobic C–H activation. Nature Chem 2, 592–596 (2010). https://doi.org/10.1038/nchem.685

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