From alkylarenes to anilines via site-directed carbon–carbon amination

An Author Correction to this article was published on 08 November 2018

This article has been updated


Anilines are fundamental motifs in various chemical contexts, and are widely used in the industrial production of fine chemicals, polymers, agrochemicals and pharmaceuticals. A recent development for the synthesis of anilines uses the primary amination of C–H bonds in electron-rich arenes. However, there are limitations to this strategy: the amination of electron-deficient arenes remains a challenging task and the amination of electron-rich arenes has a limited control over regioselectivity—the formation of meta-aminated products is especially difficult. Here we report a site-directed C–C bond primary amination of simple and readily available alkylarenes or benzyl alcohols for the direct and efficient preparation of anilines. This chemistry involves a novel C–C bond transformation and offers a versatile protocol for the synthesis of substituted anilines. The use of O2 as an environmentally benign oxidant is demonstrated, and studies on model compounds suggest that this method may also be used for the depolymerization of lignin.

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Fig. 1: Efficient synthesis of anilines.
Fig. 2: Synthetic applications of the site-directed C–C amination.
Fig. 3: Mechanistic experiments.

Data availability

Full experimental procedures and spectral data for all the new compounds as well as computational details are included in the Supplementary Information and are available from the corresponding authors on request.

Change history

  • 08 November 2018

    The version of this Article originally published online did not include a caution statement relating to safety concerns over some of the reagents used. All versions of the Article now have the following text included at the start of the Methods section “Caution: Sodium azide (NaN3) is highly toxic and also a potential explosion hazard; it can also react with organohalides to form explosive organic azides. Under acidic conditions, sodium azide can form hydrazoic acid (HN3) which is highly toxic. Considering these hazards, appropriate safety precautions should be taken when undertaking the C–C amination reactions reported in this Article.” Furthermore, in Fig. 2a, in the reaction conditions on the first equation it should have read DDQ not DDG; this has also been amended.


  1. 1.

    Lawrence, S. A. Amines: Synthesis, Properties and Applications (Cambridge Univ. Press, Cambridge, 2004).

    Google Scholar 

  2. 2.

    Newhouse, T., Baran, P. S. & Hoffmann, R. W. The economies of synthesis. Chem. Soc. Rev. 38, 3010–3021 (2009).

    CAS  Article  Google Scholar 

  3. 3.

    Trost, B. M. Atom economy—a challenge for organic synthesis: homogeneous catalysis leads the way. Angew. Chem. Int. Ed. 34, 259–281 (1995).

    CAS  Article  Google Scholar 

  4. 4.

    Booth, G. Nitro Compounds, aromatic. In Ullmann’s Encyclopedia of Industrial Chemistry (Wiley-VCH, Weinheim, 2005).

    Google Scholar 

  5. 5.

    Hartwig, J. F. Carbon–heteroatom bond-forming reductive eliminations of amines, ethers, and sulfides. Acc. Chem. Res. 31, 852–860 (1998).

    CAS  Article  Google Scholar 

  6. 6.

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

    CAS  Article  Google Scholar 

  7. 7.

    Surry, D. S. & Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination. Angew. Chem. Int. Ed. 47, 6338–6361 (2008).

    CAS  Article  Google Scholar 

  8. 8.

    Surry, D. S. & Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide. Chem. Sci. 2, 27–50 (2011).

    CAS  Article  Google Scholar 

  9. 9.

    Klinkenberg, J. L. & Hartwig, J. F. Catalytic organometallic reactions of ammonia. Angew. Chem. Int. Ed. 50, 86–95 (2011).

    CAS  Article  Google Scholar 

  10. 10.

    Gao, H. et al. Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds. Nat. Chem. 9, 681–688 (2017).

    CAS  Article  Google Scholar 

  11. 11.

    Tezuka, N. et al. Direct hydroxylation and amination of arenes via deprotonative cupration. J. Am. Chem. Soc. 138, 9166–9171 (2016).

    CAS  Article  Google Scholar 

  12. 12.

    Zhou, Z. et al. Non-deprotonative primary and secondary amination of (hetero)arylmetals. J. Am. Chem. Soc. 139, 115–118 (2017).

    CAS  Article  Google Scholar 

  13. 13.

    Morofuji, T., Shimizu, A. & Yoshida, J. Electrochemical C–H amination: synthesis of aromatic primary amines via N-arylpyridinium ions. J. Am. Chem. Soc. 135, 5000–5003 (2013).

    CAS  Article  Google Scholar 

  14. 14.

    Romero, N. A., Margrey., K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C–H amination via photoredox catalysis. Science 349, 1326–1330 (2015).

    CAS  Article  Google Scholar 

  15. 15.

    Zheng, Y.-W. et al. Photocatalytic hydrogen-evolution cross-couplings: benzene C–H amination and hydroxylation. J. Am. Chem. Soc. 138, 10080–10083 (2016).

    CAS  Article  Google Scholar 

  16. 16.

    Paudyal, M. P. et al. Dirhodium-catalyzed C–H arene aminaton using hydroxylamines. Science 353, 1144–1147 (2016).

    CAS  Article  Google Scholar 

  17. 17.

    Jones, W. D. The fall of the C–C bond. Nature 364, 676–677 (1993).

    Article  Google Scholar 

  18. 18.

    Gozin, M., Weisman, A., Ben-David, Y. & Milstein, D. Activation of a carbon–carbon bond in solution by transition-metal insertion. Nature 364, 699–701 (1993).

    CAS  Article  Google Scholar 

  19. 19.

    Fumagalli, G., Stanton, S. & Bower, J. F. Recent methodologies that exploit C–C single-bond cleavage of strained ring systems by transition metal complexes. Chem. Rev. 117, 9404–9432 (2017).

    CAS  Article  Google Scholar 

  20. 20.

    Murakami, M., Amii, H. & Ito, Y. Selective activation of carbon–carbon bonds next to a carbonyl group. Nature 370, 540–541 (1994).

    CAS  Article  Google Scholar 

  21. 21.

    Masarwa, A. et al. Merging allylic carbon–hydrogen and selective carbon–carbon bond activation. Nature 505, 199–203 (2014).

    CAS  Article  Google Scholar 

  22. 22.

    Murphy, S. K., Park, J.-W., Cruz, F. A. & Dong., V. M. Rh-catalyzed C–C bond cleavage by transfer hydroformylation. Science 347, 56–60 (2015).

    CAS  Article  Google Scholar 

  23. 23.

    Xia, Y., Lu, G., Liu, P. & Dong, G. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016).

    CAS  Article  Google Scholar 

  24. 24.

    Bender, M., Turnbull, B. W. H., Ambler, B. R. & Krische, M. J. Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C–C bonds: entry to type II polyketides. Science 357, 779–781 (2017).

    CAS  Article  Google Scholar 

  25. 25.

    Murakami, M. & Ishida, N. Potential of metal-catalyzed C–C single bond cleavage for organic synthesis. J. Am. Chem. Soc. 138, 13759–13769 (2016).

    CAS  Article  Google Scholar 

  26. 26.

    Hock, H. & Lang, S. Autoxydation von Kohlenwasserstoffen, IX. Mitteil.: Über Peroxyde von Benzol-Derivaten. Ber. Dtsch. Chem. Ges. B77, 257–264 (1944).

    Article  Google Scholar 

  27. 27.

    McMillen, D. F. & Golden, D. M. Hydrocarbon bond dissociation energies. Ann. Rev. Phys. Chem. 33, 493–532 (1982).

    CAS  Article  Google Scholar 

  28. 28.

    Brocks, J. J. et al. Estimation of bond dissociation energies and radical stabilization energies by ESR spectroscopy. J. Org. Chem. 63, 1935–1943 (1998).

    CAS  Article  Google Scholar 

  29. 29.

    Jun, C.-H. Transition metal-catalyzed carbon–carbon bond activation. Chem. Soc. Rev. 33, 610–618 (2004).

    CAS  Article  Google Scholar 

  30. 30.

    Park, Y. J., Park, J.-W. & Jun, C.-H. Metal–organic cooperative catalysis in C–H and C–C bond activation and its concurrent recovery. Acc. Chem. Res. 41, 222–234 (2008).

    CAS  Article  Google Scholar 

  31. 31.

    Goossen, L. J., Rodríguez, N. & Goossen, K. Carboxylic acids as substrates in homogeneous catalysis. Angew. Chem. Int. Ed. 47, 3100–3120 (2008).

    CAS  Article  Google Scholar 

  32. 32.

    Chen, F., Wang, T. & Jiao, N. Recent advances in transition-metal-catalyzed functionalization of unstrained carbon–carbon bonds. Chem. Rev. 114, 8613–8661 (2014).

    CAS  Article  Google Scholar 

  33. 33.

    Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition to transition metals. Chem. Rev. 115, 9410–9464 (2015).

    CAS  Article  Google Scholar 

  34. 34.

    Dong, G. C–C Bond Activation (Topics in Current Chemistry 346, Springer, Berlin, 2014).

  35. 35.

    Tobisu, M. & Chatani, N. Catalytic reactions involving the cleavage of carbon–cyano and carbon–carbon triple bonds. Chem. Soc. Rev. 37, 300–307 (2008).

    CAS  Article  Google Scholar 

  36. 36.

    Morioka, T., Nishizawa, A., Furukawa, T., Tobisu, M. & Chatani, N. Nickel-mediated decarbonylation of simple unstrained ketones through the cleavage of carbon–carbon bonds. J. Am. Chem. Soc. 139, 1416–1419 (2017).

    CAS  Article  Google Scholar 

  37. 37.

    Ye, J. et al. Remote C–H alkylation and C–C bond cleavage enabled by an in situ generated palladacycle. Nat. Chem. 9, 361–369 (2017).

    CAS  Article  Google Scholar 

  38. 38.

    Rahimi, A., Ulbrich, A., Coon, J. J. & Stahl, S. S. Formic-acid-induced depolymerization of oxidized lignin to aromatics. Nature 515, 249–252 (2014).

    CAS  Article  Google Scholar 

  39. 39.

    Rahimi, A., Azarpira, A., Kim, H., Ralph, J. & Stahl, S. S. Chemoselective metal-free aerobic alcohol oxidation in lignin. J. Am. Chem. Soc. 135, 6415–6418 (2013).

    CAS  Article  Google Scholar 

  40. 40.

    Qin, C., Shen, T., Tang., C. & Jiao, N. FeCl2-promoted cleavage of the unactivated C–C bond of alkylarenes and polystyrene: direct synthesis of arylamines. Angew. Chem. Int. Ed. 51, 6971–6975 (2012).

    CAS  Article  Google Scholar 

  41. 41.

    Wang, T. & Jiao, N. TEMPO-catalyzed aerobic oxygenation and nitrogenation of olefins via C=C double bond cleavage. J. Am. Chem. Soc. 135, 11692–11695 (2013).

    CAS  Article  Google Scholar 

  42. 42.

    Shen, T., Wang., T., Qin, C. & Jiao, N. Silver-catalyzed nitrogenation of alkynes: a direct approach to nitriles through C≡C bond cleavage. Angew. Chem. Int. Ed. 52, 6677–6680 (2013).

    CAS  Article  Google Scholar 

  43. 43.

    Fu, N., Sauer, G. S., Saha, A., Loo, A. & Lin, S. Metal-catalyzed electrochemical diazidation of alkenes. Science 357, 575–579 (2017).

    CAS  Article  Google Scholar 

  44. 44.

    Bharadwaj, S. K., Boruah, P. K. & Gogoi, P. K. Phosphoric acid modified montmorillonite clay: a new heterogeneous catalyst for nitration of arenes. Catal. Commun. 57, 124–128 (2014).

    CAS  Article  Google Scholar 

  45. 45.

    Torker, S., Müller, A. & Chen, P. Building stereoselectivity into a chemoselective ring-opening metathesis polymerization catalyst for alternating copolymerization. Angew. Chem. Int. Ed. 49, 3762–3766 (2010).

    CAS  Article  Google Scholar 

  46. 46.

    Wang, P.-C., Yao, K. & Lu, M. Preparation of heteropoly acid based amphiphilic salts supported by nano oxides and their catalytic performance in the nitration of aromatics. RSC Adv. 3, 2197–2202 (2013).

    CAS  Article  Google Scholar 

  47. 47.

    Schweighauser, L., Strauss, M. A., Bellotto, S. & Wegner, H. A. Attraction or repulsion? London dispersion forces control azobenzene switches. Angew. Chem. Int. Ed. 54, 13436–13439 (2015).

    CAS  Article  Google Scholar 

  48. 48.

    Song, S. et al. Study on the design, synthesis and structure–activity relationships of new thiosemicarbazone compounds as tyrosinase inhibitors. Eur. J. Med. Chem. 139, 815–825 (2017).

    CAS  Article  Google Scholar 

  49. 49.

    West, J. D., Stafford, S. E. & Meter, M. P. A mechanistic probe for asymmetric reactions: deuterium isotope effects at enantiotopic groups. J. Am. Chem. Soc. 130, 7816–7817 (2008).

    CAS  Article  Google Scholar 

  50. 50.

    Mou, J., Park, A., Cai, Y., Yuan, J. & Yuan, C. Structure–activity relationship study of E6 as a novel necroptosis inducer. Bioorg. Med. Chem. Lett. 25, 3057–3061 (2015).

    CAS  Article  Google Scholar 

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Financial support from the National Basic Research Program of China (973 Program) (no. 2015CB856600), the National Natural Science Foundation of China (nos 21632001 and 21772002) and Peking University Health Science Center (no. BMU20160541) are appreciated.

Author information




J.L. and N.J. conceived and designed the experiments; J.L., X.Q. and C.Z. carried out most of experiments; J.L., X.Q., X.L., J.W., J.P. and N.J. analysed data; J.L., X.Q., X.H., J.W., J.P., Y.L., Y.Z., Q.Q., S.S. and N.J. participated in discussion and co-wrote the paper; N.J. directed the project.

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Correspondence to Ning Jiao.

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Supplementary information

Supplementary Information

General information, optimization data, substrate synthesis, general procedures, synthetic application, mechanistic experiments, additional references and characterization data

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Liu, J., Qiu, X., Huang, X. et al. From alkylarenes to anilines via site-directed carbon–carbon amination. Nature Chem 11, 71–77 (2019).

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