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Transition-metal-free chemo- and regioselective vinylation of azaallyls


Direct C(sp3)–C(sp2) bond formation under transition-metal-free conditions offers an atom-economical, inexpensive and environmentally benign alternative to traditional transition-metal-catalysed cross-coupling reactions. A new chemo- and regioselective coupling protocol between 3-aryl-substituted-1,1-diphenyl-2-azaallyl derivatives and vinyl bromides has been developed. This is the first transition-metal-free cross-coupling of azaallyls with vinyl bromide electrophiles and delivers allylic amines in excellent yields (up to 99%). This relatively simple and mild protocol offers a direct and practical strategy for the synthesis of high-value allylic amine building blocks that does not require the use of transition metals, special initiators or photoredox catalysts. Radical clock experiments, electron paramagnetic resonance studies and density functional theory calculations point to an unprecedented substrate-dependent coupling mechanism. Furthermore, an electron paramagnetic resonance signal was observed when the N-benzyl benzophenone ketimine was subjected to silylamide base, supporting the formation of radical species upon deprotonation. The unique mechanisms outlined herein could pave the way for new approaches to transition-metal-free C–C bond formations.

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Figure 1: Overview of allylic amines synthesis and vinylation reactions.
Figure 2: Overview of reaction scope.
Figure 3: Overview of mechanistic study.
Figure 4: Computed free-energy profile for nucleophilic vinyl substitution of azaallyl anion A1 and vinyl bromide 2a.
Figure 5: Overview of possible radical mechanism.


  1. 1

    Negishi, E. Magical power of transition metals: past, present, and future (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6738–6764 (2011).

    CAS  Google Scholar 

  2. 2

    Suzuki, A. Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6722–6737 (2011).

    CAS  Google Scholar 

  3. 3

    Sun, C. L. & Shi, Z. J. Transition-metal-free coupling reactions. Chem. Rev. 114, 9219–9280 (2014).

    CAS  PubMed  Google Scholar 

  4. 4

    Petranyi, G., Ryder, N. & Stutz, A. Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 224, 1239–1241 (1984).

    CAS  PubMed  Google Scholar 

  5. 5

    Roggen, M. & Carreira, E. M. Stereospecific substitution of allylic alcohols to give optically active primary allylic amines: unique reactivity of a (P,alkene)Ir complex modulated by iodide. J. Am. Chem. Soc. 132, 11917–11919 (2010).

    CAS  PubMed  Google Scholar 

  6. 6

    Yamashita, Y., Gopalarathnam, A. & Hartwig, J. F. Iridium-catalyzed, asymmetric amination of allylic alcohols activated by Lewis acids. J. Am. Chem. Soc. 129, 7508–7509 (2007).

    CAS  PubMed  Google Scholar 

  7. 7

    Patel, S. J. & Jamison, T. F. Asymmetric catalytic coupling of organoboranes, alkynes, and imines with a removable (trialkylsilyloxy)ethyl group—direct access to enantiomerically pure primary allylic amines. Angew. Chem. Int. Ed. 43, 3941–3944 (2004).

    CAS  Google Scholar 

  8. 8

    Shi, X., Kiesman, W. F., Levina, A. & Xin, Z. Catalytic asymmetric petasis reactions of vinylboronates. J. Org. Chem. 78, 9415–9423 (2013).

    CAS  PubMed  Google Scholar 

  9. 9

    Overman, L. E. A general method for the synthesis of amines by the rearrangement of allylic trichloroacetimidates. 1,3 Transposition of alcohol and amine functions. J. Am. Chem. Soc. 98, 2901–2910 (1976).

    CAS  Google Scholar 

  10. 10

    Ngai, M.-Y., Barchuk, A. & Krische, M. J. Enantioselective iridium-catalyzed imine vinylation: optically enriched allylic amines via alkyne–imine reductive coupling mediated by hydrogen. J. Am. Chem. Soc. 129, 12644–12645 (2007).

    CAS  PubMed  Google Scholar 

  11. 11

    Skucas, E., Kong, J. R. & Krische, M. J. Enantioselective reductive coupling of acetylene to N-arylsulfonyl imines via rhodium catalyzed C–C bond-forming hydrogenation: (Z)-dienyl allylic amines. J. Am. Chem. Soc. 129, 7242–7243 (2007).

    CAS  PubMed  Google Scholar 

  12. 12

    Li, M., Berritt, S. & Walsh, P. J. Palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides. Org. Lett. 16, 4312–4315 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Li, M. et al. Palladium-catalyzed C–H arylation of α,β-unsaturated imines: catalyst-controlled synthesis of enamine and allylic amine derivatives. Angew. Chem. Int. Ed. 128, 2875–2879 (2016).

    Google Scholar 

  14. 14

    Li, M., Yucel, B., Adrio, J., Bellomo, A. & Walsh, P. J. Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions. Chem. Sci. 5, 2383–2391 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Li, M . et al. Umpolung synthesis of diarylmethylamines via palladium-catalyzed arylation of N-benzyl aldimines. Adv. Synth. Catal. 358, 1910–1915 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Wu, Y., Hu, L., Li, Z. & Deng, L. Catalytic asymmetric Umpolung reactions of imines. Nature 523, 445–450 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Burger, E. C. & Tunge, J. A. Synthesis of homoallylic amines via the palladium-catalyzed decarboxylative coupling of amino acid derivatives. J. Am. Chem. Soc. 128, 10002–10003 (2006).

    CAS  PubMed  Google Scholar 

  18. 18

    Fields, W. H. & Chruma, J. J. Palladium-catalyzed decarboxylative benzylation of diphenylglycinate imines. Org. Lett. 12, 316–319 (2009).

    Google Scholar 

  19. 19

    Niwa, T., Yorimitsu, H. & Oshima, K. Palladium-catalyzed benzylic arylation of N-benzylxanthone imine. Org. Lett. 10, 4689–4691 (2008).

    CAS  PubMed  Google Scholar 

  20. 20

    Zhu, Y. & Buchwald, S. L. Ligand-controlled asymmetric arylation of aliphatic α-amino anion equivalents. J. Am. Chem. Soc. 136, 4500–4503 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Liu, Y. E. et al. Enzyme-inspired axially chiral pyridoxamines armed with a cooperative lateral amine chain for enantioselective biomimetic transamination. J. Am. Chem. Soc. 138, 10730–10733 (2016).

    CAS  PubMed  Google Scholar 

  22. 22

    Ankner, T., Cosner, C. C. & Helquist, P. Palladium- and nickel-catalyzed alkenylation of enolates. Chem. Eur. J. 19, 1858–1871 (2013).

    CAS  PubMed  Google Scholar 

  23. 23

    Grigalunas, M., Ankner, T., Norrby, P. O., Wiest, O. & Helquist, P. Palladium-catalyzed alkenylation of ketone enolates under mild conditions. Org. Lett. 16, 3970–3973 (2014).

    CAS  PubMed  Google Scholar 

  24. 24

    Hardegger, L. A., Habegger, J. & Donohoe, T. J. Modular synthesis of highly substituted pyridines via enolate alpha-alkenylation. Org. Lett. 17, 3222–3225 (2015).

    CAS  PubMed  Google Scholar 

  25. 25

    Padilla-Salinas, R., Walvoord, R. R., Tcyrulnikov, S. & Kozlowski, M. C. Nitroethylation of vinyl triflates and bromides. Org. Lett. 15, 3966–3969 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Piers, E. & Marais, P. C. A new five-membered ring annulation method based on palladium(0)-catalyzed intramolecular coupling of vinyl iodide and enolate anion functions. J. Org. Chem. 55, 3454–3455 (1990).

    CAS  Google Scholar 

  27. 27

    Solé, D., Peidró, E. & Bonjoch, J. Palladium-catalyzed intramolecular coupling of vinyl halides and ketone enolates. synthesis of bridged azabicyclic compounds. Org. Lett. 2, 2225–2228 (2000).

    PubMed  Google Scholar 

  28. 28

    Yang, X., Kim, B. S., Li, M. & Walsh, P. J. Palladium-catalyzed selective alpha-alkenylation of pyridylmethyl ethers with vinyl bromides. Org. Lett. 18, 2371–2374 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Niwa, T., Suehiro, T., Yorimitsu, H. & Oshima, K. Carbon–carbon bond formations at the benzylic positions of N-benzylxanthone imines and N-benzyldi-1-naphthyl ketone imine. Tetrahedron 65, 5125–5131 (2009).

    CAS  Google Scholar 

  30. 30

    Tang, S., Park, J. Y., Yeagley, A. A., Sabat, M. & Chruma, J. J. Decarboxylative generation of 2-azaallyl anions: 2-iminoalcohols via a decarboxylative Erlenmeyer reaction. Org. Lett. 17, 2042–2045 (2015).

    CAS  PubMed  Google Scholar 

  31. 31

    Yeagley, A. A., Lowder, M. A. & Chruma, J. J. Tandem C–C bond-forming processes: interception of the Pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with activated olefins. Org. Lett. 11, 4022–4025 (2009).

    CAS  PubMed  Google Scholar 

  32. 32

    Kauffmann, T., Berger, D., Scheerer, B. & Woltermann, A. Anionic 3+2 cycloaddition of a 1,2-diazaallyllithium compound. Angew. Chem. Int. Ed. 9, 961–962 (1970).

    CAS  Google Scholar 

  33. 33

    Pandiancherri, S. & Lupton, D. W. Preparation of 2-azaallyl anions and imines from N-chloroamines and their cycloaddition and allylation. Tetrahedron Lett. 52, 671–674 (2011).

    CAS  Google Scholar 

  34. 34

    Taber, D. F., Sahli, A., Yu, H. & Meagley, R. P. Efficient intramolecular C–H insertion by an alkylidene carbene generated from a vinyl chloride. J. Org. Chem. 60, 6571–6573 (1995).

    CAS  Google Scholar 

  35. 35

    Taber, D. F., Sikkander, M. I. & Storck, P. H. Enantioselective synthesis of (+)-majusculone. J. Org. Chem. 72, 4098–4101 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Bernasconi, C. F. & Rappoport, Z. Recent advances in our mechanistic understanding of SNV reactions. Acc. Chem. Res. 42, 993–1003 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Rappoport, Z. Nucleophilic vinylic substitution. A single- or a multi-step process? Acc. Chem. Res. 14, 7–15 (1981).

    CAS  Google Scholar 

  38. 38

    Rappoport, Z. The rapid steps in nucleophilic vinylic addition–elimination substitution. Recent developments. Acc. Chem. Res. 25, 474–479 (1992).

    CAS  Google Scholar 

  39. 39

    Bach, R. D., Baboul, A. G. & Schlegel, H. B. Inversion versus retention of configuration for nucleophilic substitution at vinylic carbon. J. Am. Chem. Soc. 123, 5787–5793 (2001).

    CAS  PubMed  Google Scholar 

  40. 40

    Castro, E. A., Gazitua, M. & Santos, J. G. Kinetics and mechanism of the anilinolysis of aryl 4-nitrophenyl carbonates in aqueous ethanol. J. Org. Chem. 70, 8088–8092 (2005).

    CAS  PubMed  Google Scholar 

  41. 41

    Castro, E. A., Ramos, M. & Santos, J. G. Concerted pyridinolysis of aryl 2,4,6-trinitrophenyl carbonates. J. Org. Chem. 74, 6374–6377 (2009).

    CAS  PubMed  Google Scholar 

  42. 42

    Williams, A. Concerted mechanisms of acyl group transfer reactions in solution. Acc. Chem. Res. 22, 387–392 (1989).

    CAS  Google Scholar 

  43. 43

    Fernandez, I., Bickelhaupt, F. M. & Uggerud, E. Reactivity in nucleophilic vinylic substitution (SNV): SNVπ versus SNVσ mechanistic dichotomy. J. Org. Chem. 78, 8574–8584 (2013).

    CAS  PubMed  Google Scholar 

  44. 44

    Baum, A. A. & Karnischky, L. A. Photochemical formation of oxazolidines from aryl ketones and aliphatic imines. J. Am. Chem. Soc. 95, 3072–3074 (1973).

    CAS  Google Scholar 

  45. 45

    Dannenberg, J. J. & Tanaka, K. Theoretical studies of radical recombination reactions. 1. Allyl and azaallyl radicals. J. Am. Chem. Soc. 107, 671–674 (1985).

    CAS  Google Scholar 

  46. 46

    Malassa, A., Agthe, C., Görls, H., Friedrich, M. & Westerhausen, M. Deprotonation and dehydrogenation of di(2-pyridylmethyl)amine with M[N(SiMe3)2]2 (M=Mn, Fe, Co, Zn) and Fe(C6H2-2,4,6-Me3)2 . J. Organomet. Chem. 695, 1641–1650 (2010).

    CAS  Google Scholar 

  47. 47

    Pallagi, I., Toró, A. & Horváth, G. Mechanism of the Gibbs reaction. Part 4.1 Indophenol formation via N-chlorobenzoquinone imine radical anions. The Aza-SRN2 chain reaction mechanism. Chain initiation with 1,4-benzoquinones and cyanide ion. J. Org. Chem. 64, 6530–6540 (1999).

    CAS  PubMed  Google Scholar 

  48. 48

    Giese, B. The stereoselectivity of intermolecular free radical reactions [New Synthetic Methods (78)]. Angew. Chem. Int. Ed. 28, 969–980 (1989).

    Google Scholar 

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The authors acknowledge the National Science Foundation (CHE-1464744 to P.J.W. and CHE-1464778 to M.C.K.) and the National Institutes of Health (GM-104349 to P.J.W. and GM-087605 to M.C.K.) for financial support. J.A. acknowledges support from Ministerio de Educación, Cultura y Deporte, Subprograma Estatal de Movilidad, Salvador de Madariaga. Computational support was provided by XSEDE on SDSC Gordon (TG-CHEM120052). This work was also financially supported by a SICAM Fellowship by Jiangsu National Synergetic Innovation Center for Advanced Materials. The authors thank S. Montel of UPenn and K. Scheidt of Northwestern University for discussions.

Author information




M.L. and P.J.W. conceived and designed the experiments. M.L., S.B., A.P.-E., A.Y., X.Y., J.A. and G.H. performed the research. O.G. and M.C.K. designed and performed the DFT computational study. M.L. and E.N.-O. performed the EPR study. M.L., O.G., M.C.K. and P.J.W. wrote the paper.

Corresponding authors

Correspondence to Marisa C. Kozlowski or Patrick J. Walsh.

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The authors declare no competing financial interests.

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Li, M., Gutierrez, O., Berritt, S. et al. Transition-metal-free chemo- and regioselective vinylation of azaallyls. Nature Chem 9, 997–1004 (2017).

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