Journal of Chemical Sciences

, 130:120 | Cite as

Regioselective synthesis of pyrrole and indole-fused isocoumarins catalysed by N\(^\wedge \)O chelate ruthenium(II) complex

  • Keisham S SinghEmail author
  • Sneha G Sawant
  • Werner Kaminsky
Regular Article


Heterocyclic compounds containing pyrrole and indole-fused isocoumarins were obtained from a one-pot synthesis via annulations of N-heterocyclic carboxylic acids and alkynes with N\(^\wedge \)O chelate ruthenium(II) complex, [RuCl(\(\hbox {PySO}_{3})(p\)-cymene)] (\(\hbox {PySO}_{3}\) = 2-pyridinesulfonate) in the presence of Cu(OAc)\(_{2}\hbox {H}_{2}\)O. The reaction proceeds efficiently in DMF but can also be performed in other solvents such as dichloroethane, \(^{t}\)AmOH, and water. The annulations reaction is regioselective when performed 1-methylpyrrole-2-carboxylic acid with 1-phenyl-1-propyne.


Abstract Pyrrole and indole-fused isocoumarins are obtained from a one-pot synthesis via annulations of heterocyclic acids and alkynes with N\(^\wedge \)O chelate ruthenium(II) complex, [RuCl(\(\hbox {PySO}_{3})(p\)-cymene)](\(\hbox {PySO}_{3}\) = 2-pyridinesulfonate) in the presence of Cu(OAc)\(_{2}\hbox {H}_{2}\)O. The annulation reaction is regioselectively performed with 1-methylpyrrole-2-carboxylic acid and 1-phenyl-1-propyne in DMF.


Annulation reaction isocoumarins alkynes ruthenium(II) catalyst regioselection 



KSS thanks the Department of Science and Technology, India for financial support and the Director, CSIR-NIO for providing necessary facilities.

Supplementary material

12039_2018_1519_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (pdf 1222 KB)


  1. 1.
    Bhardwaj V, Gumber D, Abbot V, Dhiman S and Sharma P 2015 Pyrrole: a resourceful small molecule in key medicinal hetero-aromatics RSC Adv. 5 15233CrossRefGoogle Scholar
  2. 2.
    Kaushik N K, Kaushik N, Attri P, Kumar N, Kim C H, Verma A K and Choi E H 2013 Biomedical Importance of Indoles Molecules 18 6620PubMedGoogle Scholar
  3. 3.
    Olgen S, Altanlar N, Karatayli E and Bozdayi M 2008 Antimicrobial and antiviral screening of novel indole carboxamide and propanamide derivatives Z. Naturforsch C 63 189CrossRefPubMedGoogle Scholar
  4. 4.
    Fatahala S S, Shalaby E A, Kassab S E and Mohamed M S A 2015 promising anti-cancer and anti-oxidant agents based on the pyrrole and fused pyrrole: synthesis, docking studies and biological evaluation Anticancer Agents Med. Chem. 15 517CrossRefPubMedGoogle Scholar
  5. 5.
    Mitchell A, Tsueng G, Rheingold A, White D J, Grodberg J, Lam K S and Potts B C 2008 Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete J. Nat. Prod. 71 1732CrossRefPubMedGoogle Scholar
  6. 6.
    Copp B R, Ireland C M and Barrows L R 1991 Wakayin: a novel cytotoxic pyrroloiminoquinone alkaloid from the ascidians Clavelina species J. Org. Chem. 56 4596CrossRefGoogle Scholar
  7. 7.
    Hamid H A, Ramli A N M and Yusoff M M 2017 Indole alkaloids from plants as potential leads for antidepressant drugs: A mini review Front. Pharmacol. 8 1CrossRefGoogle Scholar
  8. 8.
    Littke A F and Fu G C 1998 A Convenient and general method for Pd-catalyzed Suzuki cross-couplings of aryl chlorides and arylboronic acids Angew. Chem. 37 3387CrossRefGoogle Scholar
  9. 9.
    Gong B, Shi J, Wang X, Yan Y, Li Q, Meng Y, Xu H E and Yi W 2014 Rhodium (III)-catalyzed regioselective direct C-2 alkenylation of indoles assisted by the removable N-(2-pyrimidyl) group Adv. Synth. Catal. 356 137CrossRefGoogle Scholar
  10. 10.
    Chinnagolla R K and Jeganmohan M 2012 Regioselective synthesis of isocoumarins by ruthenium-catalyzed aerobic oxidative cyclization of aromatic acids with alkynes Chem. Commun. 48 2030CrossRefGoogle Scholar
  11. 11.
    Beck E M and Gaunt M J 2010 Pd-catalyzed C-H bond functionalization on the indole and pyrrole nucleus Top. Curr. Chem. 292 85CrossRefPubMedGoogle Scholar
  12. 12.
    Pinxterhuis E B, Giannerini M, Hornillos V and Feringa B L 2016 Fast, greener and scalable direct coupling oforganolithium compounds with no additional solvents Nature Commun. 7 1CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Padala K and Jeganmohan M 2011 Ruthenium-catalyzed ortho-alkenylation of aromatic ketones with alkenes by C-H bond activation Org. Lett. 13 6144CrossRefPubMedGoogle Scholar
  14. 14.
    Singh K S and Dixneuf P H 2012 Ruthenium(II)-catalysed alkenylation of ferrocenyl ketones via C-H bond Activation Organometallics 31 7320CrossRefGoogle Scholar
  15. 15.
    Boele M D K, van Strijdonk G P F, de Varies A H M, Kamer P C J, de Varies J G and van Leeuwen P W N M 2002 Selective Pd-catalyzed oxidative coupling of anilides with olefins through C-H bond activation at room temperature J. Am. Chem. Soc. 124 1586CrossRefPubMedGoogle Scholar
  16. 16.
    Ueyama T, Mochida S, Fukutani T, Hirano K, Satoh T and Miura M 2011 Ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes via regioselective C-H bond cleagave Org. Lett. 13 706CrossRefPubMedGoogle Scholar
  17. 17.
    Hashimoto Y, Ortloff T, Hirano K, Satoh T, Bolm C and Miura M 2012 Ru/Ag-catalyzed oxidative alkenylation of benzamides and phenylazoles through regioselective C-H bond cleavage Chem. Lett. 41 151CrossRefGoogle Scholar
  18. 18.
    Ackermann L, Wang L, Wolfram R and Lygin A V 2012 Ruthenium-catalyzed oxidative C-H alkenylations of anilides and benzamides in water Org. Lett. 14 728CrossRefPubMedGoogle Scholar
  19. 19.
    Chen X, Engle K M, Wang D H and Yu J Q 2009 Palladium(II)-catalyzed C-H activation/C-C cross-coupling reactions: versatility and practicality Angew. Chem. Int. Ed. Engl. 48 5094CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Caron L, Campeau L C and Fagnou K 2008 Palladium-catalyzed direct arylation of nitro-substituted aromatics with aryl halides Org. Lett. 10 4533CrossRefPubMedGoogle Scholar
  21. 21.
    Hull K L, Lanni E L and Sanford M S 2006 Highly regioselective catalytic oxidative coupling reactions: synthetic and mechanistic investigations J. Am. Chem. Soc. 128 14047CrossRefPubMedGoogle Scholar
  22. 22.
    Yan T, Chen L, Bruneau C, Dixneuf P H and Doucet H 2013 Synthesis of heteroarylated polyfluorobiphenyls via Palladium-catalyzed sequential \(\text{ sp }^{2}\) C–H bonds functionalizations J. Org. Chem. 78 4177CrossRefPubMedGoogle Scholar
  23. 23.
    Shimizu M, Hirano K, Satoh T and Miura M 2009 Waste-free synthesis of condensed heterocyclic compounds by rhodium-catalyzed oxidative coupling of substituted arene or heteroarene carboxylic acids with alkynes J. Org. Chem. 74 3478CrossRefPubMedGoogle Scholar
  24. 24.
    Delord J W, Nimphius C, Patureau F W and Glorius F 2012 [\(\text{ Rh }^{III}\)Cp*]-catalyzed dehydrogenative aryl-aryl bond formation Angew. Chem. 51 2247CrossRefGoogle Scholar
  25. 25.
    Arockiam P B, Fischmeister C, Bruneau C and Dixneuf P H 2010 C-H bond functionalization in water catalyzed by carboxylato ruthenium (II) systems Angew. Chem. Int. Ed. 122 6779CrossRefGoogle Scholar
  26. 26.
    Singh K S and Dixneuf P H 2013 Direct C-H bond arylation in water promoted by (O, O) and (O, N) chelate ruthenium(II) catalysts ChemCatChem. 5 1313CrossRefGoogle Scholar
  27. 27.
    Arockiam P B, Fischmeister C, Bruneau C and Dixneuf P H 2013 Ruthenium(II)-catalyzed selective monoarylation in water and sequential functionalisations of C-H bonds Green Chem. 15 67CrossRefGoogle Scholar
  28. 28.
    Arockiam P, Poirier V, Fischmeister C, Bruneau C and Dixneuf P H 2009 Diethyl carbonate as a solvent for ruthenium catalysed C–H bond functionalization Green Chem. 11 1871Google Scholar
  29. 29.
    Ackermann L, Pospech J, Graczyk K and Rauch K 2012 Synthesis of isocoumarins and\(\alpha \)-pyrones by ruthenium-catalyzed oxidative C-H/O-H bond cleavages Org. Lett. 14 930CrossRefPubMedGoogle Scholar
  30. 30.
    Hung C H, Gandeepan P and Cheng C H 2014 Ruthenium(II)-catalyzed C-H bond activation: An efficient route toward indenamines ChemCatChem. 6 2692CrossRefGoogle Scholar
  31. 31.
    Lin H, Li S S and Dong L 2015 Synthesis of indoles and polycyclic amides via ruthenium (II)-catalyzed C-H activation and annulation Org. Biomol. Chem. 13 11228CrossRefPubMedGoogle Scholar
  32. 32.
    Singh K S, Sawant S G and Dixneuf P H 2016 Ruthenium (II) catalysed synthesis of pyrrole and indole fused isocoumarins via C-H bond activation in DMF and water ChemCatChem. 8 1046CrossRefGoogle Scholar
  33. 33.
    Ackermann L 2014 Carboxylate-assisted ruthenium-catalyzed alkyne annulations by C-H/Het-H bond functionalizations Acc. Chem. Res. 47 281CrossRefPubMedGoogle Scholar
  34. 34.
    Villuendas P and Urriolabeitia E P 2013 Primary amines as directing groups in the Ru-catalyzed synthesis of isoquinolines, benzoisoquinolines, and thienopyridines J. Org. Chem. 78 5254CrossRefPubMedGoogle Scholar
  35. 35.
    Banerjee A, Santra S K, Mohanta P R and Patel B K 2015 Ruthenium (II) Catalyzed Regiospecific C-H / O-H Annulations of Directing Arenes via Weak Coordination Org. Lett. 17 5678CrossRefPubMedGoogle Scholar
  36. 36.
    Guo X X 2013 Synthesis of isocoumarin derivatives by copper-catalyzed addition of o-halobenzoic acids to active internal alkynes J. Org. Chem. 78 1660CrossRefPubMedGoogle Scholar
  37. 37.
    Zhao P, Chen D, Song G, Han K and Li X 2012 Palladium-catalyzed cascade cyclization-oxidative olefination of tert-butyl 2-alkynylbenozates J. Org. Chem. 77 1579CrossRefPubMedGoogle Scholar
  38. 38.
    Mishra N K, Park J, Choi M, Sharma S, Jo H, Jeong T, Han S, Kim S and Kim I S 2016 Synthesis of phthalides through tandem rhodium-catalyzed C-H olefination and annulation of benzamides Eur. J. Org. Chem. 3076Google Scholar
  39. 39.
    Gupta S, Han J, Kim Y, Lee S W, Rhee Y H and Park J 2014 C-H activation guided by aromatic N-H ketimines: synthesis of functionalized isoquinolines using benzyl azides and alkynes J. Org. Chem. 79 9094CrossRefPubMedGoogle Scholar
  40. 40.
    Kudo E, Shibata Y, Yamazaki M, Masutomi K, Miyauchi Y, Fukui M, Sugiyama H, Uekusa H, Satoh T, Miura M and Tanaka K 2016 Oxidative annulation of arenecarboxylic and acrylic acids with alkynes under ambient conditions catalyzed by an electron-deficient rhodium(III) complex Chem. Eur. J. 22 14190CrossRefPubMedGoogle Scholar
  41. 41.
    Arockiam P B, Bruneau C and Dixneuf P H 2012 Ruthenium (II)-catalyzed C-H bond activation and functionalization Chem. Rev. 112 5879CrossRefPubMedGoogle Scholar
  42. 42.
    Pozgan F and Dixneuf P H 2009 Ruthenium (II) acetate catalyst for direct functionalization of \(\text{ sp }^{2}\)-C-H bonds with aryl chlorides and access to tris-heterocyclic molecules Adv. Synth. Catal. 351 1737CrossRefGoogle Scholar
  43. 43.
    Ackerman L 2011 Carboxylate-assisted transition-metal-catalyzed C-H bond functionalizations: mechanism and scope Chem. Rev. 111 1315CrossRefGoogle Scholar
  44. 44.
    Sundararaju B, Achard M, Sharma G V M and Bruneau C 2011 \(\text{ sp }^{3}\) C-H bond activation with ruthenium(II) catalysts and C(3)-alkylation of cyclic amines J. Am. Chem. Soc. 133 10340CrossRefPubMedGoogle Scholar
  45. 45.
    Bennett M A and Smith A K 1974 Arene ruthenium(II) complexes formed by dehydrogenation of cyclohexadienes with ruthenium(III) trichloride J. Chem. Soc. Dalton Trans. 233Google Scholar
  46. 46.
    Altomare A, Burla C, Camalli M, Cascarano G L, Giacovazzo C, Guagliardi A, Moliterni A G G, Polidori G and Spagna R 1999 SIR97: a new tool for crystal structure determination and refinement. J. Appl. Cryst. 32 115CrossRefGoogle Scholar
  47. 47.
    Sheldrick G M 1997 SHELXL-97: Program for the Refinement of Crystal Structures University of Göttingen, GermanyGoogle Scholar
  48. 48.
    Flegeau E F, Bruneau C, Dixneuf P H and Jutand A 2011 Autocatalysis for C-H bond activation by ruthenium(II) complexes in catalytic arylation of functional arenes J. Am. Chem. Soc. 133 10161CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  • Keisham S Singh
    • 1
    Email author
  • Sneha G Sawant
    • 1
  • Werner Kaminsky
    • 2
  1. 1.Bioorganic Chemistry LaboratoryCSIR-National Institute of OceanographyDona PaulaIndia
  2. 2.Department of ChemistryUniversity of WashingtonSeattleUSA

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