Amines are a quintessential moiety in bioactive molecules, pharmaceuticals and organic materials. Transition-metal-catalysed C–N coupling of aryl electrophiles has been established as a powerful and reliable method for amine synthesis. However, the analogous C–N coupling of alkyl electrophiles is largely under-developed due to the decomposition of metal alkyl intermediates by β-hydrogen elimination and difficulty in C(sp3)–N reductive elimination. Here, we provide a general strategy for amination of alkyl electrophiles by merging photoredox and copper catalysis. Photoredox catalysis allows the use of alkyl redox-active esters, recently established as a superior class of alkyl electrophiles, whereas copper catalysis enables C(sp3)–N cross-coupling. Decarboxylative amination can be used for the synthesis of a diverse set of alkyl anilines with high chemoselectivity and functional-group compatibility. Rapid functionalization of amino acids, natural products and drugs is demonstrated.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $8.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lawrence, S. A. Amines: Synthesis Properties and Applications (Cambridge Univ. Press, Cambridge, 2004).
Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences (Wiley-VCH, Weinheim, 2008).
Edwards, M. G.et al Borrowing hydrogen: a catalytic route to C–C bond formation from alcohols.Chem. Commun. 90–91 (2004)..
Watson, A. J. A. & Williams, J. M. J. The give and take of alcohol activation. Science 329, 635–636 (2010).
Hollmann, D., Tillack, A., Michalik, D., Jackstell, R. & Beller, M. An improved ruthenium catalyst for the environmentally benign amination of primary and secondary alcohols. Chem. Asian J. 2, 403–410 (2007).
Sorribes, I., Junge, K. & Beller, M. Direct catalytic N-alkylation of amines with carboxylic acids. J. Am. Chem. Soc. 136, 14314–14319 (2014).
Yang, Q., Wang, Q. & Yu, Z. Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation. Chem. Soc. Rev. 44, 2305–2329 (2015).
Ley, S. V. & Thomas, A. W. Modern synthetic methods for copper-mediated C(aryl)–O, C(aryl)–N, and C(aryl)–S bond formation. Angew. Chem. Int. Ed. 42, 5400–5449 (2003).
Sambiagio, C., Marsden, S. P., Blacker, A. J. & McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525–3550 (2014).
Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 41, 1534–1544 (2008).
Surry, D. S. & Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide. Chem. Sci. 2, 27–50 (2011).
Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl–alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).
Hu, X. Nickel-catalyzed cross coupling of non-activated alkyl halides: a mechanistic perspective. Chem. Sci. 2, 1867–1886 (2011).
Tasker, S. Z., Standley, E. A. & Jamison, T. F. Recent advances in homogeneous nickel catalysis. Nature 509, 299–309 (2014).
Macgregor, S. A., Neave, G. W. & Smith, C. Theoretical studies on C–heteroatom bond formation via reductive elimination from group 10 M(PH3)2(CH3)(X) species (X=CH3, NH2, OH, SH) and the determination of metal–X bond strengths using density functional theory. Faraday Discuss. 124, 111–127 (2003).
Bissember, A. C., Lundgren, R. J., Creutz, S. E., Peters, J. C. & Fu, G. C. Transition-metal-catalyzed alkylations of amines with alkyl halides: photoinduced, copper-catalyzed couplings of carbazoles. Angew. Chem. Int. Ed. 52, 5129–5133 (2013).
Do, H.-Q., Bachman, S., Bissember, A. C., Peters, J. C. & Fu, G. C. Photoinduced, copper-catalyzed alkylation of amides with unactivated secondary alkyl halides at room temperature. J. Am. Chem. Soc. 136, 2162–2167 (2014).
Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016).
Zhao, W., Wurz, R. P., Peters, J. C. & Fu, G. C. Photoinduced, copper-catalyzed decarboxylative C–N coupling to generate protected amines: an alternative to the Curtius rearrangement. J. Am. Chem. Soc. 139, 12153–12156 (2017).
Cheung, C. W. & Hu, X. Amine synthesis via iron-catalysed reductive coupling of nitroarenes with alkyl halides. Nat. Commun. 7, 12494 (2016).
Gui, J. et al. Practical olefin hydroamination with nitroarenes. Science 348, 886–891 (2015).
Cornella, J. et al. Practical Ni-catalyzed aryl–alkyl cross-coupling of secondary redox-active esters. J. Am. Chem. Soc. 138, 2174–2177 (2016).
Qin, T. et al. A general alkyl–alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science 352, 801–805 (2016).
Toriyama, F. et al. Redox-active esters in Fe-catalyzed C–C coupling. J. Am. Chem. Soc. 138, 11132–11135 (2016).
Li, C. et al. Decarboxylative borylation. Science 356, eaam7355 (2017).
Fawcett, A. et al. Photoinduced decarboxylative borylation of carboxylic acids. Science 357, 283–286 (2017).
Candish, L., Teders, M. & Glorius, F. Transition-metal-free, visible-light-enabled decarboxylative borylation of aryl N-hydroxyphthalimide esters. J. Am. Chem. Soc. 139, 7440–7443 (2017).
Hu, D., Wang, L. & Li, P. Decarboxylative borylation of aliphatic esters under visible-light photoredox conditions. Org. Lett. 19, 2770–2773 (2017).
Xue, W. & Oestreich, M. Copper-catalyzed decarboxylative radical silylation of redox-active aliphatic carboxylic acid derivatives. Angew. Chem. Int. Ed. 56, 11649–11652 (2017).
Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp 3-carbons with aryl halides. Science 345, 437–440 (2014).
Zuo, Z. & MacMillan, D. W. Decarboxylative arylation of α-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J. Am. Chem. Soc. 136, 5257–5260 (2014).
Fang, Z., Feng, Y., Dong, H., Li, D. & Tang, T. Copper(i)-catalyzed radical decarboxylative imidation of carboxylic acids with N-fluoroarylsulfonimides. Chem. Commun. 52, 11120–11123 (2016).
Liu, Z. J. et al. Directing group in decarboxylative cross-coupling: copper-catalyzed site-selective C–N bond formation from nonactivated aliphatic carboxylic acids. J. Am. Chem. Soc. 138, 9714–9719 (2016).
Huihui, K. M. et al. Decarboxylative cross-electrophile coupling of N-hydroxyphthalimide esters with aryl iodides. J. Am. Chem. Soc. 138, 5016–5019 (2016).
Jamison, C. R. & Overman, L. E. Fragment coupling with tertiary radicals generated by visible-light photocatalysis. Acc. Chem. Res. 49, 1578–1586 (2016).
Okada, K., Okamoto, K., Morita, N., Okubo, K. & Oda, M. Photosensitized decarboxylative Michael addition through N-(acyloxy)phthalimides via an electron-transfer mechanism. J. Am. Chem. Soc. 113, 9401–9402 (1991).
Zhang, H., Zhang, P., Jiang, M., Yang, H. & Fu, H. Merging photoredox with copper catalysis: decarboxylative alkynylation of α-amino acid derivatives. Org. Lett. 19, 1016–1019 (2017).
Tellis, J. C., Primer, D. N. & Molander, G. A. Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 345, 433–436 (2014).
Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).
Corcoran, E. B. et al. Aryl amination using ligand-free Ni(ii) salts and photoredox catalysis. Science 353, 279–283 (2016).
Yoo, W.-J., Tsukamoto, T. & Kobayashi, S. Visible-light-mediated Chan–Lam coupling reactions of aryl boronic acids and aniline derivatives. Angew. Chem. Int. Ed. 54, 6587–6590 (2015).
Zhang, Y., Yang, X., Yao, Q. & Ma, D. CuI/DMPAO-catalyzed N-arylation of acyclic secondary amines. Org. Lett. 14, 3056–3059 (2012).
Zhou, W., Fan, M., Yin, J., Jiang, Y. & Ma, D. CuI/Oxalic diamide catalyzed coupling reaction of (hetero)aryl chlorides and amines. J. Am. Chem. Soc. 137, 11942–11945 (2015).
Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013).
Keenan, M. et al. Two analogues of fenarimol show curative activity in an experimental model of Chagas disease. J. Med. Chem. 56, 10158–10170 (2013).
This work is supported by the NoNoMeCat Marie Skłodowska-Curie training network funded by the European Union under the Horizon 2020 Programme (675020-MSCA-ITN-2015-ETN). We thank R. Scopelliti (École Polytechnique Fédérale de Lausanne) for assistance with X-ray crystallography of 9a.
The authors declare no competing financial interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Methods, Supplementary Tables 1–10, Supplementary Figures 1–100, Supplementary References.
About this article
Photoredox-catalyzed decarboxylative alkylation/cyclization of alkynylphosphine oxides: a metal- and oxidant-free method for accessing benzo[b]phosphole oxides
Chemical Communications (2019)
Copper-catalyzed ring-opening C(sp3)–N coupling of cycloketone oxime esters: access to 1°, 2° and 3° alkyl amines
Chemical Communications (2019)
Angewandte Chemie International Edition (2019)
Organic Letters (2019)