Theoretical understanding mechanisms and stereoselectivities of [2+2] cycloaddition of ketenes with ketimines catalyzed by bifunctional N-heterocyclic carbene

  • Nan He
  • Zhenhua Zhu
  • Fangfang Li
  • Yanyan ZhuEmail author
  • Lingbo QuEmail author
  • Hongsheng ChenEmail author
Original Research


Reaction mechanism of NHC-catalyzed asymmetric [2+2] cycloaddition reaction between ketenes and isatin-derived ketimines for the formation of spirocyclic indolo-β-lactams has been investigated using density functional theory (DFT). The catalytic cycle for the title reaction included three possible mechanisms: the “ketene preferential mechanism” (mechanism A) and the “imine preferential mechanism” (mechanisms B and C). They have three similar steps: the first step is the nucleophilic attack of the NHC catalyst, the second one is ring-closure proceed, and the last one is catalyst regeneration and product formation. This work adopted the two different N-heterocyclic carbene catalysts (named as NHC-I and NHC-II) involved in experiment. The calculated results indicate that the Gibbs free energy barriers of mechanism A are remarkably lower than those of mechanisms B and C, and the reaction pathway leading to the SS-configured product has the lowest Gibbs free energy barrier, which agrees with the experiments. It is worth noting that in mechanism A, NHC-I has a free-rotating hydroxyl group which can form a hydrogen bond and ketene, which greatly reduces the energy of the enolate intermediate and affects the cycloaddition process, improving the stereoselectivity of the reaction. Furthermore, the special role of the catalysts and origin of stereoselectivity of the title reaction were also identified by global reactivity index and frontier molecular orbital analyses. The new insights obtained in this study might provide clues for understanding the reaction mechanism of the high stereoselective reaction catalyzed by bifunctional N-heterocyclic carbene catalysts.


N-Heterocyclic carbene (NHC) Density functional theory (DFT) [2+2] Cycloaddition Reaction mechanism 


Funding information

The authors received financial support from the National Natural Science Foundation of China (Grant Nos. 21001095 and J120062), China Scholarship Council (Grant Nos. 201807045019 and 201808230086), and the University Key Research Programs of Education Department in Henan Province (Grant No. 15A150082).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

This article does not contain any studies with animals performed by any of the authors.

Supplementary material

11224_2019_1389_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 20 kb)


  1. 1.
    Fleming A (1980) On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae. Rev Infect Dis 2:129–139CrossRefGoogle Scholar
  2. 2.
    Kobayashi Y, Uchida H, Kawakami Y (1992) Synergy with aztreonam and arbekacin or tobramycin against Pseudomonas aeruginosa from blood. J Antimicrob Chemother 30:3828–3831CrossRefGoogle Scholar
  3. 3.
    Oost T, Backfisch G, Bhowmik S, van Gaalen MM, Geneste H, Hornberger W, Lubisch W, Netz A, Unger L, Wernet W (2011) Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties. Bioorg Med Chem Lett 21:3828–3831CrossRefGoogle Scholar
  4. 4.
    Anthoni U, Bock K, Chevolot L (1987) Marine alkaloids. 13. Chartellamide A and B, halogenated β-lactam indole-imidazole alkaloids from the marine bryozoan Chartella papyracea. J Org Chem 52:5638–5639CrossRefGoogle Scholar
  5. 5.
    Kumar R, Giri S, Nizamuddin (1989) Synthesis of some 1′-(substituted phenyl)spiro [indole-3,4′- azetidine]-2(3H),2′-diones as potential fungicides. J Agric Food Chem 37:1094–1096CrossRefGoogle Scholar
  6. 6.
    Singh GS, Luntha P (2009) Synthesis and antimicrobial activity of new 1-alkyl/cyclohexyl-3,3-diaryl-1′-methylspiro[azetidine-2,3′-indoline]-2′,4-diones. Eur J Med Chem 44:2265–2269CrossRefGoogle Scholar
  7. 7.
    Zhang HM, Gao ZH, Ye S (2014) Bifunctional N-heterocyclic carbene-catalyzed highly enantioselective synthesis of spirocyclic oxindolo-beta-lactams. Org Lett 16:3079–3081CrossRefGoogle Scholar
  8. 8.
    Xu JF, Yuan SR, Peng JY, Miao MZ, Chen ZK, Ren HJ (2017) Enantioselective [2+2] annulation of simple aldehydes with isatin-derived ketimines via oxidative N-heterocyclic carbene catalysis. Chem Commun 53:3430–3433CrossRefGoogle Scholar
  9. 9.
    Palomo C, Aizpurua JM, Ganboa I, Oiarbide M (2004) Asymmetric synthesis of β-lactams through the Staudinger reaction and their use as building blocks of natural and nonnatural products. Curr Med Chem 11:1837–1872CrossRefGoogle Scholar
  10. 10.
    Staudinger H (1907) Zur kenntniss der ketene. diphenylketen. Justus Liebigs Ann Chem 356:51–123CrossRefGoogle Scholar
  11. 11.
    Sun C, Lin X, Weinreb SM (2006) Explorations on the total synthesis of the unusual marine alkaloid chartelline A. J Org Chem 71:3159–3166CrossRefGoogle Scholar
  12. 12.
    Zhang WJ, Zhu YY, Wei DH, Li YX, Tang MS (2012) Theoretical investigations toward the [4+2] cycloaddition of ketenes with N-benzoyldiazenes catalyzed by N-heterocyclic carbenes: mechanism and enantioselectivity. J Org Chem 77:10729–10737CrossRefGoogle Scholar
  13. 13.
    Lv H, Jia WQ, Sun LH, Ye S (2013) N-heterocyclic carbene catalyzed [4+3] annulation of enals and o-quinone methides: highly enantioselective synthesis of benzo-epsilon-lactones. Angew Chem Int Ed 52:8607–8610CrossRefGoogle Scholar
  14. 14.
    Baran PS, Shenvi RA, Mitsos CA (2005) A remarkable ring contraction en route to the chartelline alkaloids. Angew Chem Int Ed 44:3714–3717CrossRefGoogle Scholar
  15. 15.
    Mahatthananchai J, Bode JW (2014) On the mechanism of N-heterocyclic carbene-catalyzed reactions involving acyl azoliums. Acc Chem Res 47:696–707CrossRefGoogle Scholar
  16. 16.
    Ryan SJ, Candish L, Lupton DW (2013) Acyl anion free N-heterocyclic carbene organocatalysis. Chem Soc Rev 42:4906–4917CrossRefGoogle Scholar
  17. 17.
    Bode JW (2013) Carbene catalysis: an internal affair. Nat Chem 5:813–815CrossRefGoogle Scholar
  18. 18.
    Guo C, Schedler M, Daniliuc CG, Glorius F (2014) N-heterocyclic carbene catalyzed formal [3+2] annulation reaction of enals: an efficient enantioselective access to spiro-heterocycles. Angew Chem Int Ed 53:10232–10236CrossRefGoogle Scholar
  19. 19.
    Guo C, Schedler M, Daniliuc CG, Glorius F (2014) Durch N-heterocyclische carbene katalysierte formale [3+2]-Anellierungen von Enalen: enantioselektiver Zugang zu Spiroheterocyclen. Angew Chem 126:10397–10401CrossRefGoogle Scholar
  20. 20.
    Lin L, Yang Y, Wang M, Lai L, Guo Y, Wang R (2015) Oxidative N-heterocyclic carbene catalyzed stereoselective annulation of simple aldehydes and 5-alkenyl thiazolones. Chem Commun 51:8134–8137CrossRefGoogle Scholar
  21. 21.
    Xu JF, Yuan SR, Miao MZ (2016) N-Heterocyclic carbene catalyzed [4+2] annulation reactions with in situ generated heterocyclic ortho-quinodimethanes. Org Lett 18:3822–3825CrossRefGoogle Scholar
  22. 22.
    Zhang YR, He L, Wu X, Shao PL, Ye S (2008) Chiral N-heterocyclic carbene catalyzed Staudinger reaction of ketenes with imines: highly enantioselective synthesis of N-boc β-lactams. Org Lett 10:277–280CrossRefGoogle Scholar
  23. 23.
    Duguet N, Campbell CD, Slawin AM, Smith AD (2008) N-Heterocyclic carbene catalysed beta-lactam synthesis. Org Biomol Chem 6:1108–1113CrossRefGoogle Scholar
  24. 24.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2010) Gaussian 09, Revision C.01. Gaussian Inc., WallingfordGoogle Scholar
  25. 25.
    Qiao Y, Zhao JM, Chang JB, Wei DH (2019) Insights into the oxidative palladium-catalyzed regioselective synthesis of 3-arylindoles from N-Ts-anilines and styrenes: a computational study. ChemCatChem 11:780–789CrossRefGoogle Scholar
  26. 26.
    Sun K, Li SJ, Chen XL, Liu Y, Huang XQ, Wei DH, Qu LB, Zhao YF, Yu B (2019) Silver-catalyzed decarboxylative radical cascade cyclization toward benzimidazo[2,1-a]isoquinolin-6(5H)-ones. Chem Commun 55:2861–2864CrossRefGoogle Scholar
  27. 27.
    Wang Y, Du C, Wang YY, Guo XK, Fang L, Song MP, Niu JL, Wei DH (2018) High-valent cobalt-catalyzed C–H activation/annulation of 2-benzamidopyridine 1-oxide with terminal alkyne: a combined theoretical and experimental study. Adv Synth Catal 360:2668–2677CrossRefGoogle Scholar
  28. 28.
    Liu CH, Han PL, Xie ZZ, Xu ZH, Wei DH (2018) Insights into Ag(I)-catalyzed addition reactions of amino alcohols to electron-deficient olefins: competing mechanisms, role of catalyst, and origin of chemoselectivity. RSC Adv 8:40338–40346CrossRefGoogle Scholar
  29. 29.
    Wei D, Huang X, Qiao Y, Rao J, Wang L, Liao F, Zhan CG (2017) Catalytic mechanisms for cofactor-free oxidase-catalyzed reactions: reaction pathways of uricase-catalyzed oxidation and hydration of uric acid. ACS Catal 7:4623–4636CrossRefGoogle Scholar
  30. 30.
    Wei DH, Lei BL, Tang MS, Zhan CG (2012) Fundamental reaction pathway and free energy profile for inhibition of proteasome by epoxomicin. J Am Chem Soc 134:10436–10450CrossRefGoogle Scholar
  31. 31.
    Zhang QC, Li X, Wang XH, Li SJ, Qu LB, Lan Y, Wei DH (2019) Insights into highly selective ring expansion of oxaziridines under Lewis base catalysis: a DFT study. Org Chem Front 6:679–687CrossRefGoogle Scholar
  32. 32.
    Li X, Li SJ, Wang Y, Wang Y, Qu LB, Li ZJ, Wei DH (2019) Insights into NHC-catalyzed oxidative α-C(sp3)-H activation of aliphatic aldehydes and cascade [2+3] cycloaddition with azomethine imines. Catal Sci Technol 9:2514–2522CrossRefGoogle Scholar
  33. 33.
    Li X, Duan R, Wang Y, Qu LB, Li Z, Wei D (2019) Insights into N-Heterocyclic carbene-catalyzed oxidative alpha-C(sp(3))-H activation of aliphatic aldehydes and cascade [2+2] cycloaddition with ketimines. J Organomet Chem 84:6117–6125CrossRefGoogle Scholar
  34. 34.
    Wang Y, Wu QY, Lai TH, Zheng KJ, Qu LB, Wei DH (2019) Prediction on the origin of selectivities of NHC-catalyzed asymmetric dearomatization (CADA) reactions. Catal Sci Technol 9:465–476CrossRefGoogle Scholar
  35. 35.
    Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Accounts 120:215–241CrossRefGoogle Scholar
  36. 36.
    Zhao Y, Truhlar DG (2008) Density functionals with broad applicability in chemistry. Acc Chem Res 41:157–167CrossRefGoogle Scholar
  37. 37.
    Mennucci B, Tomasi J (1997) Continuum solvation models: a new approach to the problem of solute’s charge distribution and cavity boundaries. J Chem Phys 106:5151–5158CrossRefGoogle Scholar
  38. 38.
    Barone V, Cossi M (1998) Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent Model. J Phys Chem 102:1995–2001CrossRefGoogle Scholar
  39. 39.
    Gonzalez C, Schlegel HB (1989) An improved algorithm for reaction path following. J Chem Phys 90:2154–2161CrossRefGoogle Scholar
  40. 40.
    Gonzalez C, Schlegel HB (1990) Reaction path following in mass-weighted internal coordinates. J Phys Chem 94:5523–5527CrossRefGoogle Scholar
  41. 41.
    Xu H, Zhu ZH, Guo YE, Liu CM, Zhang WJ, Zhu YY, Wang YL, Tang MS (2018) A DFT study on N-heterocyclic carbene catalyzed [4+2] annulation reaction with in situ generated heterocyclic ortho-quinodimethane: mechanism, origin of enantioselectivity and role of catalyst. Tetrahedron 74:1009–1015CrossRefGoogle Scholar
  42. 42.
    Sun DZ, Zhu YY, Wei DH, Zhang C, Zhang WJ, Tang MS (2010) Insight into the multicomponent reaction mechanisms of prop-2-en-1-amine and ethyl propiolate with alloxan derivative: a density functional theory study. Chem Phys Lett 495:33–39CrossRefGoogle Scholar
  43. 43.
    Xu H, Zhu YY, Guo P, Liu CM, Shan JK, Tang MS (2018) Mechanisms of phosphine-catalyzed [4+3] annulation of allenoates with C, N-cyclic azomethine imines: a DFT investigation. Int J Quantum Chem 118:e25626CrossRefGoogle Scholar
  44. 44.
    Zhang C, Zhu YY, Wei DH, Sun DZ, Zhang WJ, Tang MS (2010) Theoretical study on the reaction mechanism between 6-benzyl-6-azabicyclo[2.2.1]hept-2-ene and benzoyl isocyanate to urea and isourea. J Phys Chem A 114:2913–2919CrossRefGoogle Scholar
  45. 45.
    Xu H, Li Y, Zhu YY, Shang XC, Zhu ZH, Tang MS (2017) A theoretical study on synthesis mechanisms of α,β-unsaturated carbon γ-amino ester catalyzed by PPh3. Struct Chem 28:1959–1968CrossRefGoogle Scholar
  46. 46.
    Li Y, Li FF, Zhu YY, Li X, Zhou ZY, Liu CM, Zhang WJ, Tang MS (2016) DFT study on reaction mechanisms of cyclic dipeptide generation. Struct Chem 27:1165–1173CrossRefGoogle Scholar
  47. 47.
    Li YX, Zhu YY, Zhang WJ, Wei DH, Ran YY, Zhao QL, Tang MS (2014) A DFT study on the reaction mechanism of dimerization of methyl methacrylate catalyzed by N-heterocyclic carbene. Phys Chem Chem Phys 16:20001–20008CrossRefGoogle Scholar
  48. 48.
    Parr RG, Pearson RG (1983) Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Soc 105:7512–7516CrossRefGoogle Scholar
  49. 49.
    Domingo LR, Aurell MJ, Perez P, Contreras R (2002) Quantitative characterization of the global electrophilicity power of common diene/dienophile pairs in Diels–Alder reactions. Tetrahedron 58:4417–4423CrossRefGoogle Scholar
  50. 50.
    Domingo LR, Saez JA, Zaragoza RJ, Arno M (2008) Understanding the participation of quadricyclane as nucleophile in polar [2σ+2σ+2π] cycloadditions toward electrophilic π molecules. J Organomet Chem 73:8791–8799CrossRefGoogle Scholar
  51. 51.
    Domingo LR, Saez JA (2009) Understanding the mechanism of polar Diels-Alder reactions. Org Biomol Chem 7:3576–3583CrossRefGoogle Scholar
  52. 52.
    Domingo LR, Picher MT, Saez JA (2009) Toward an understanding of the unexpected regioselective Hetero-Diels-Alder reactions of asymmetric tetrazines with electron-rich ethylenes: A DFT Study. J Org Chem 74:2726–2735CrossRefGoogle Scholar
  53. 53.
    Sham LJ, Kohn W (1966) One-particle properties of an inhomogeneous interacting electron gas. Phys Rev 145:561–567CrossRefGoogle Scholar
  54. 54.
    Yepes D, Murray JS, Perez P, Domingo LR, Politzer P, Jaque P (2014) Complementarity of reaction force and electron localization function analyses of asynchronicity in bond formation in Diels-Alder reactions. Phys Chem Chem Phys 16:6726–6734CrossRefGoogle Scholar
  55. 55.
    Domingo LR, Chamorro E, Pérez P (2008) An understanding of the electrophilic/nucleophilic behavior of electro-deficient 2,3-disubstituted 1,3-butadienes in polar Diels-Alder reactions. A density functional theory study. J Phy Chem A 112:4046–4053CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Chemistry and Molecular EngineeringZhengzhou UniversityZhengzhouPeople’s Republic of China
  2. 2.College of Food ScienceHeilongjiang Bayi Agricultural UniversityDaqingPeople’s Republic of China

Personalised recommendations