Molecular Diversity

, Volume 18, Issue 4, pp 787–796 | Cite as

Synthesis of benzimidazole[2.1-b][1,3]oxazine spirooxindoles via three-component reaction of N-benzylbenzimidazole, acetylenedicarboxylates, and N-alkylisatins

  • Li-Juan Zhang
  • Chao-Guo Yan
Full-Length Paper


The three-component reaction of \(N\)-benzylbenzimidazole, dialkyl acetylenedicarboxylate, and \(N\)-alkylisatins in tetrahydrofuran at room temperature afforded the novel functionalized benzimidazole[2.1-b][1,3]oxazine spirooxindoles in good yields. \({}^{1}\)H NMR spectra indicated that two diastereoisomers with a ratio of 1:3–1:6 exist in the obtained spirooxindole derivatives.

Graphic Abstract


Multicomponent reaction Spirooxindole Isatin Benzimidazole Electron-deficient alkyne MRC 



This work was financially supported by the National Natural Science Foundation of China (Grant No. 21172189) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We thank the Analysis and Test Center of Yangzhou University for providing instruments for analysis.


  1. 1.
    Huisgen R, Morikawa M, Herbig K, Brunn E (1967) 1.4-Dipolare Cycloadditionen, II. Dreikomponenten-Reaktionen des Isochinolins mit Acetylendicarbonsäureester und verschiedenen Dipolarophilen. Chem Ber 100:1094–1106. doi: 10.1002/cber.19671000406 CrossRefGoogle Scholar
  2. 2.
    Huisgen R (1968) Synthese von Heterocyclen mit 1,4-Dipolaren Cycloadditionen. Z Chem 8:290–298. doi: 10.1002/zfch.19680080803 CrossRefGoogle Scholar
  3. 3.
    Lu XY, Zhang CM, Xu ZR (2001) Reactions of electron-deficient alkynes and allenes under phosphine catalysis. Acc Chem Res 34:535–544. doi: 10.1021/ar000253x PubMedCrossRefGoogle Scholar
  4. 4.
    Nair V, Rajesh C, Vinod AU, Bindu S, Sreekanth AR, Mathen JS, Balagopal L (2003) Strategies for heterocyclic construction via novel multicomponent reactions based on isocyanides and nucleophilic carbenes. Acc Chem Res 36:899–907. doi: 10.1021/ar020258p PubMedCrossRefGoogle Scholar
  5. 5.
    Nair V, Menon RS, Sreekanth A, Abhilash N, Biju AT (2006) Engaging Zwitterions in carbon-carbon and carbon-nitrogen bond-forming reactions? A promising synthetic strategy. Acc Chem Res 39:520–530. doi: 10.1021/ar0502026 PubMedCrossRefGoogle Scholar
  6. 6.
    Kielland N, Lavilla R (2010) Recent developments in Reissert-Tipe multicomponent reactions. Top Heterocycl Chem 25:127–168. doi: 10.1007/7081_2010_42
  7. 7.
    Shaabani A, Rezayan AH, Sarvary A (2011) Recent progress of isocyanide-based multicomponent reactions in Iran. Mol Divers 15:41–68. doi: 10.1007/s11030-010-9258-1 PubMedCrossRefGoogle Scholar
  8. 8.
    Nair V, Deepthi A, Ashok D, Raveendran AE, Paul RR (2014) 1,4-Dipolar cycloadditions and related reactions. Tetrahedron 70:3085–3105. doi: 10.1016/j.tet.2014.03.014 CrossRefGoogle Scholar
  9. 9.
    Yavari I, Mirzaei A, Moradi L, Khalili G (2010) Diastereoselective synthesis of spiro-functionalized tetraalkyl benzoisoquinopyrrolonaphthyridine-tetracarboxylates from isoquinoline, dialkyl acetylenedicarboxylates, and indane-1,3-dione. Tetrahedron Lett 51:396–398. doi: 10.1016/j.tetlet.2009.11.040 CrossRefGoogle Scholar
  10. 10.
    Yavari I, Seyfi S, Hossaini Z (2010) Formation of trialkyl quinoline-2,3,4-tricarboxylates by reaction of isatin, dialkyl acetylenedicarboxylates, and sodium \(O\)-alkyl carbonodithioates. Tetrahedron Lett 51:2193–2194. doi:  10.1016/j.tetlet.2010.02.107 CrossRefGoogle Scholar
  11. 11.
    Yadav JS, Reddy BVS, Yadav NN, Gupta MK, Sridhar B (2008) Gold(III) chloride-catalyzed three-component reaction: a facile synthesis of alkynyl derivatives of 1,2-dihydroquinolines and isoquinolines. J Org Chem 73:6857–6859. doi: 10.1021/jo8007034 PubMedCrossRefGoogle Scholar
  12. 12.
    Ding HF, Zhang YP, Bian M, Yao WJ, Ma C (2008) Concise assembly of highly substituted furan-fused 1,4-thiazepines and their Diels-Alder reactions with benzynes. J Org Chem 73:578–584. doi: 10.1021/jo702299m PubMedCrossRefGoogle Scholar
  13. 13.
    Çavdar H, Saraçoglu N (2006) Synthesis of new 2-vinylation products of indole via a Michael-type addition reaction with dimethyl acetylenedicarboxylate and their Diels-Alder reactivity as precursors of new carbazoles. J Org Chem 71:7793–7799. doi: 10.1021/jo061336f PubMedCrossRefGoogle Scholar
  14. 14.
    Teimouri MB, Abbasi T (2010) Facile synthesis of oxaspirobicyclic butenolides via a domino Michael addition/aldol reaction/\(\gamma \)-lactonization sequence. Tetrahedron 66:3795–3800. doi:  10.1016/j.tet.2010.03.058 CrossRefGoogle Scholar
  15. 15.
    Zewge D, Chen CY, Deer C, Dormer PG, Hughes DL (2007) A mild and efficient synthesis of 4-quinolones and quinolone heterocycles. J Org Chem 72:4276–4279. doi: 10.1021/jo070181o PubMedCrossRefGoogle Scholar
  16. 16.
    Liu WB, Jiang HF, Huang LB (2010) One-pot silver-catalyzed and PIDA-mediated sequential reactions: synthesis of polysubstituted pyrroles directly from alkynoates and amines. Org Lett 12:312–315. doi: 10.1021/ol9026478 PubMedCrossRefGoogle Scholar
  17. 17.
    Shen YX, Jiang HF, Chen ZW (2010) \(PdCl_{2}(\text{ HNMe }_{2})_{2}\)-catalyzed highly selective cross [2 + 2 + 2] cyclization of Alkynoates and alkenes under molecular oxygen. J Org Chem 75:1321–1324. doi:  10.1021/jo902636g PubMedCrossRefGoogle Scholar
  18. 18.
    Sun J, Sun Y, Gong H, Xie YJ, Yan CG (2012) Facile synthesis of dispirooxindole-fused heterocycles via domino 1,4-dipolar addition and Diels-Alder reaction of in situ generated Huisgen 1,4-dipoles. Org Lett 14:5172–5175PubMedCrossRefGoogle Scholar
  19. 19.
    Han Y, Sun Y, Sun J, Yan CG (2012) Efficient synthesis of pentasubstituted pyrroles via one-pot reactions of arylamines, acetylenedicarboxylates, and 3-phenacylideneoxindoles. Tetrahedron 68:8256–8260Google Scholar
  20. 20.
    Sun J, Zhu D, Gong H, Yan CG (2013) The molecular diversity of three-component reactions of 4-dimethylamino- or 4-methoxypyridine with acetylenedicarboxylates and arylidene cyanoacetates. Tetrahedron 69:10565–10572Google Scholar
  21. 21.
    Valizadeh H, Shomali A, Gholipour H (2011) A facile and efficient addition reaction of nitrogen-containing heterocyclic compounds with DMAD under neat conditions. J Heterocycl Chem 48:1440–1444. doi: 10.1002/jhet.763 CrossRefGoogle Scholar
  22. 22.
    Shaabani A, Safaei HR, Bijanzadeh HR (2001) Reaction of 2-aminobenzimidazol: a simple synthesis of stable hetereocyclic phosphorus ylides. Synth Commun 31:2639–2644. doi: 10.1081/SCC-100105390 CrossRefGoogle Scholar
  23. 23.
    Kawahara N, Nakajima T, Itoh T, Ogura H (1982) Addition reactions of condensed azole derivatives with dimethyl acetylenedicarboxylate III. Heterocycles 19:1623–1626. doi: 10.3987/R-1982-09-1623 CrossRefGoogle Scholar
  24. 24.
    Latham DWS, Meth-Cohn O, Suschitzky H, Herbert JA (1977) Benzofurazan N-oxides as synthetic precursors. Part 2. Conversion of benzofurazan N-oxides into 2H-benzimidazoles and some unusual reactions of 2H-benzimidazoles. J Chem Soc Perkin Trans 1:470–478. doi: 10.1039/P19770000470 CrossRefGoogle Scholar
  25. 25.
    Acheson RM, Wallis John D (1981) Addition reactions of heterocyclic compounds. Part 74. Products from dimethyl acetylenedicarboxylate with thiourea, thioamide, and guanidine derivatives. J Chem Soc Perkin Trans 1:415–422. doi: 10.1039/P19810000415 CrossRefGoogle Scholar
  26. 26.
    Nagarajan K, Nair MD, Desai JA (1979) Addition products of benzimidazole-2 (2H)-thione and acetylene dicarboxylic esters. Tetrahedron Lett 20:53–56. doi: 10.1016/S0040-4039(01)85879-2 CrossRefGoogle Scholar
  27. 27.
    McKillop A, Bellinger GCA, Preston PN, Davidson A, King TJ (1978) Reaction of benzimidazole-2(2H)-thione with dimethyl acetylenedicarboxylate. Tetrahedron Lett 19:2621–2624. doi: 10.1016/S0040-4039(01)94845-2 CrossRefGoogle Scholar
  28. 28.
    Acheson RM, Foxton MW, Abbot PJ, Mills KR (1967) Addition reactions of heterocyclic compounds. Part XXVI. Dimethyl acetylenedicarboxylate with imidazoles and benzimidazoles. J Chem Soc (C):882–887. doi: 10.1039/J39670000882
  29. 29.
    Abbot PJ, Acheson RM, Eisher U, Watkin DJ (1975) Structures of 2:1 molar adducts from dimethyl acetylenedicarboxylate with thiazoles and related heterocycles. J Chem Soc Chem Commun 155–156. doi: 10.1039/C39750000155
  30. 30.
    Abbot PJ, Acheson RM, Eisher U (1976) Addition reactions of heterocyclic compounds. Part LXIII. New structures for some 2:1 molar adducts from dimethyl acetylenedicarboxylate with thiazoles and benzo-imidazoles, -oxazoles, and -thiazoles formed by novel rearrangement. Crystal and molecular structure determinations for tetramethyl 3,8a-dimethylpyrido[2,1-b]thiazole-5,6,7,8-tetracarboxylate and tetramethyl 5-methylpyrido[2,1-b]thiazole-6,7,8,8a-tetracarboxylate. J Chem Soc Perkin Trans 1:1269–1278. doi: 10.1039/P19760001269 CrossRefGoogle Scholar
  31. 31.
    Varlamov AV, Savitkina EA, Krapivko AP, Chernyshev AI, Levov AN (2005) Cleavage of 7- and 8-nitropyrido[1,2-a]benzimidazoles on treatment with dimethyl acetylenedicarboxylate. Mendeleev Commun 15:127–128. doi: 10.1070/MC2005v015n03ABEH001955 CrossRefGoogle Scholar
  32. 32.
    Terzidis MA, Stephanidou-Stephanatou J, Tsoleridis CA (2009) Engaging a thiazole-DMAD zwitterion in novel one-pot multicomponent reactions involving chromones. Expeditious synthesis of thiazolo- and chromenothiazolopyridines. Tetrahedron Lett 50:1196–1198. doi: 10.1016/j.tetlet.2008.12.106 CrossRefGoogle Scholar
  33. 33.
    Mloston G, Gendeka T, Heimgartner H (2000) Reactions of 2-unsubstituted 1H-imidazole 3-oxides with heterocumulenes and dimethyl acetylenedicarboxylate. Tetrahedron 56:5405–5412. doi: 10.1016/S0040-4020(00)00449-X CrossRefGoogle Scholar
  34. 34.
    Adib M, Mollahosseini M, Yavari H, Sayahi MH, Bijanzadeh HR (2004) Efficient one-pot three-component synthesis of 7-oxo-1,7,8,8a-tetrahydroimidazo[1,2-a]pyrimidines. Synlett:1086–1088. doi: 10.1055/s-2004-820056
  35. 35.
    Yavari I, vHosseinpour R, Pashazadeh R, Skoulika S (2012) Novel synthesis of functionalized indolizine derivatives from Huisgen’s Zwitterions and 1-methylimidazole/dichloroketene adduct. Synlett 23:2103–2105. doi: 10.1055/s-0031-1290447 CrossRefGoogle Scholar
  36. 36.
    Zhang JH, Cheng Y (2009) The [3 + 2] cycloaddition reaction of thiazole carbene-derived C-C-Se 1,3-dipoles: a concise and highly efficient strategy for the construction of multifunctional dihydroselenophenes and selenopheno[2,3-b]pyrazines. Org Biomol Chem 7:3264–3270. doi: 10.1039/B904575A PubMedCrossRefGoogle Scholar
  37. 37.
    Nair V, Sreekanth AR, Abhilash N, Biju AT, Devi BR, Menon RS, Rath NP, Srinivas R (2003) Novel pyridine-catalyzed reactionof dimethyl acetylenedicarboxylate with aldehydes and N-Tosylimines: efficient synthesis of 2-benzoylfumarates and 1-azadienes. Synthesis 12:1895–1902. doi: 10.1055/s-2003-41000
  38. 38.
    Yavari I, Hossaini Z, Sabbaghan M, Ghazanfarpour-Darjani M (2007) Reaction of N-heterocycles with acetylenedicarboxylates in the presence of N-alkylisatins or ninhydrin. Efficient synthesis of spiro compounds. Monatsh Chem 138:677–681. doi: 10.1007/s00706-007-0662-x CrossRefGoogle Scholar
  39. 39.
    Adib M, Sheibani E, Mostofi M, Ghanbarya K, Bijanzadeh HR (2006) Efficient highly diastereoselective synthesis of 1,8a-dihydro-7H-imidazo[2,1-b][1,3]oxazines. Tetrahedron 62: 3435–3438. doi: 10.1016/j.tet.2006.01.048 CrossRefGoogle Scholar
  40. 40.
    Yavari I, Hossaini Z, Souri S, Seyfi S (2009) Diastereoselective synthesis of fused [1,3]thiazolo[1,3]oxazins and [1,3]oxazino[2,3-b][1,3]benzothiazoles. Mol Divers 13:439–443. doi: 10.1007/s11030-009-9128-x PubMedCrossRefGoogle Scholar
  41. 41.
    Nair V, Sreekanth AR, Biju AT, Rath NP (2003) The reaction of isoquinoline and dimethyl acetylenedicarboxylate with 1,2- and 1,4-benzoquinones: a novel synthesis of spiro[1,3]oxazino[2,3-a]isoquinolines. Tetrahedron Lett 44:729–732. doi: 10.1016/S0040-4039(02)02649-7 CrossRefGoogle Scholar
  42. 42.
    Nair V, Devipriya S, Suresh E (2008) Construction of heterocycles via 1,4-dipolar cycloaddition of quinoline-DMAD zwitterion with various dipolarophiles. Tetrahedron 64:3567–3577. doi: 10.1016/j.tet.2008.01.106
  43. 43.
    Yavari I, Mirzaei A, Hossaini Z, Souri S (2010) Diastereoselective synthesis of fused [1,3]oxazines from ethyl pyruvate, activated acetylenes and N-heterocycles. Mol Divers 14:343–347. doi: 10.1007/s11030-009-9174-4 PubMedCrossRefGoogle Scholar
  44. 44.
    Yavari I, Mirzaei A, Hossaini Z, Seyfi S (2010) Diastereoselective synthesis of fused [1,3]thiazolo[1,3]oxazins and [1,3]oxazino[2,3-b][1,3]benzothiazoles. Mol Divers 13:343–347. doi: 10.1007/s11030-009-9174-4
  45. 45.
    Adib M, Sheibani E, Mostofi M, Ghanbary K, Bijanzadeh HR (2006) Efficient highly diastereoselective synthesis of 1,8a-dihydro-7H-imidazo[2,1-b][1,3]oxazines. Tetrahedron 62:3435–3438. doi: 10.1016/j.tet.2006.01.048 CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.College of Chemistry & Chemical EngineeringYangzhou UniversityYangzhou China

Personalised recommendations