Download PDF
Synlett 2009(12): 2010-2016  
DOI: 10.1055/s-0029-1217535
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Polycyclic Indolone and Pyrroloindolone Heterocycles via the Annulation of Indole- and Pyrrole-2-Carboxylate Esters with Arynes

Robert D. Giacometti, Yeeman K. Ramtohul*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd., P.O. Box 1005, 16711 Trans Canada Highway, Kirkland, Quebec, H9H 3L1, Canada
Fax: +1(514)4284900; e-Mail: yeeman_ramtohul@merck.com;
Further Information

Publication History

Received 8 April 2009
Publication Date:
01 July 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

A mild and general method for the synthesis of a variety of polycyclic indolone and pyrroloindolone heterocycles via the reaction of indole- and pyrrole-2-carboxylate esters with arynes has been developed.

Keywords

arynes - indolones - pyrroloindolones - pyrroloindoles - indoles - annulation reactions

    References and Notes

  • 1a Gul W. Hamann MT. Life Sci.  2005,  78:  442 
    Google Scholar
  • 1b Pindur U. Lemster T. Curr. Med. Chem.  2001,  8:  1681 
    Google Scholar
  • 1c Fan H. Peng J. Hamann MT. Hu J.-F. Chem. Rev.  2008,  108:  264 
    Google Scholar
  • 1d Gupton JT. Topics in Heterocyclic Chemistry   Vol. 2:  Lee M. Springer; Berlin / Heidelberg: 2006.  p.53-92  
    Google Scholar
  • 1e Galm U. Hager MH. Van Lanen SG. Ju J. Thorson JS. Shen B. Chem. Rev.  2005,  105:  739 
    Google Scholar
  • 1f Lisowski V. Léonce S. Kraus-Berthier L. Santos JS.-d O. Pierré A. Atassi G. Caignard D.-H. Renard P. Rault S. J. Med. Chem.  2004,  47:  1448 
    Google Scholar
  • 2a Abbiati G. Casoni A. Canevari V. Nava D. Rossi E. Org. Lett.  2006,  8:  4839 
    Google Scholar
  • 2b Hwang SJ. Cho SH. Chang S. J. Am. Chem. Soc.  2008,  130:  16158 
    Google Scholar
  • 2c Campo MA. Larock RC. J. Org. Chem.  2002,  67:  5616 
    Google Scholar
  • 2d Ren h. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  3462 
    Google Scholar
  • For reviews on the use of arynes in organic synthesis, see:
  • 3a Peña D. Pérez D. Guitián E. Angew. Chem. Int. Ed.  2006,  45:  3579 
    Google Scholar
  • 3b Kessar SV. Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.483-515  
    Google Scholar
  • 4a For the application of arynes in total synthesis, see: Allan KA. Stoltz BM. J. Am. Chem. Soc.  2008,  130:  17270 
    Google Scholar
  • 4b Tambar UK. Ebner DC. Stoltz BM. J. Am. Chem. Soc.  2006,  128:  11752 
    Google Scholar
  • 4c Sato Y. Tamura T. Mori M. Angew. Chem. Int. Ed.  2004,  43:  2436 
    Google Scholar
  • For selected examples of aryne reactions with nucleophiles, see:
  • 5a Liu ZJ. Larock RC. J. Org. Chem.  2006,  71:  3198 ; and references therein
    Google Scholar
  • 5b Yoshida H. Watanabe M. Ohshita J. Kunai A. Chem. Commun.  2005,  3292 
    Google Scholar
  • 5c Tambar UK. Stoltz BM. J. Am. Chem. Soc.  2005,  127:  5340 
    Google Scholar
  • 5d Gilmore CD. Allan KM. Stoltz BM.
    J. Am. Chem. Soc.  2008,  130:  1558 
    Google Scholar
  • 5e Bronner SM. Bahnck KB. Garg NK. Org. Lett.  2009,  11:  1007 
    Google Scholar
  • 6 Zhao J. Larock RC. J. Org. Chem.  2007,  72:  583 
    CrossrefPubMedGoogle Scholar
  • 7a Ramtohul YK. Chartrand A. Org. Lett.  2007,  9:  1029 
    Google Scholar
  • 7b Blackburn T. Ramtohul YK. Synlett  2008,  1159 
    Google Scholar
  • 8 Bailey AS. Scott PW. Vandrevala MH. J. Chem. Soc., Perkin Trans. 1  1980,  97 
    CrossrefGoogle Scholar
  • 9 Yoshihara T. Druzhinin SI. Zachariasse KA. J. Am. Chem. Soc.  2004,  126:  8535 
    CrossrefPubMedGoogle Scholar
  • 10 Himeshima Y. Sonoda T. Kobayashi H. Chem. Lett.  1983,  1211 
    CrossrefGoogle Scholar
  • 11a Yoshida H. Shirakawa E. Honda Y. Hiyama T. Angew. Chem. Int. Ed.  2002,  41:  3247 
    Google Scholar
  • 11b Yoshida H. Fukushima H. Ohshita J. Kunai A. J. Am. Chem. Soc.  2006,  128:  11040 
    Google Scholar
12

Representative Experimental Procedure - 5 H -Indolo[1,2- a ]indol-5-one (10a)
To a solution of ethyl 1H-indole-2-carboxylate 9a (76 mg, 0.40 mmol) and TMAF (94 mg, 1.0 mmol) in THF (4 mL) was added 2-(trimethylsilyl)phenyl trifluoromethane-sulfonate (2a, 107 µL, 0.44 mmol) in an oven-dried 8 mL glass vial. The reaction mixture was stirred at r.t. for 1 h, monitored by TLC. The solvent was evaporated, the residue was diluted with H2O (2 mL) and extracted with CH2Cl2 (3 × 2 mL; the organic phase was separated using an organic phase separator cartridge). The solvent was evaporated and the product was purified by Combi-flash (ISCO) on silica gel column (10 g) using a gradient elution of 0-2% EtOAc-hexanes over 3 min, followed by 2-4% EtOAc-hexanes over 25 min) to afford the title product (66 mg, 75% yield) as a solid. ¹H NMR (500 MHz, acetone-d 6): δ = 7.80 (d, 1 H, J = 8.4 Hz), 7.74 (d, 1 H, J = 8.1 Hz), 7.70 (d, 1 H, J = 7.9 Hz), 7.66-7.60 (m, 2 H), 7.50-7.44 (m, 1 H), 7.21 (s, 1 H), 7.19 (d, 1 H, J = 7.3 Hz), 7.18-7.13 (m, 1 H). ¹³C NMR (126 MHz, acetone-d 6): δ = 181.5, 146.3, 136.7, 136.5, 135.0, 133.6, 130.0, 128.9, 125.7, 125.4, 124.9, 122.9, 112.8, 112.5, 108.0. HRMS (ESI, MH+): m/z calcd for C15H10NO: 220.0757; found: 220.0755.