Synlett 2010(15): 2285-2288  
DOI: 10.1055/s-0030-1258030
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Tetrahydropyrrolo[1,2-a]quinoxalines and Tetrahydro­pyrido[1,2-a]quinoxalines via a One-Pot CuI-Catalyzed Aryl Amination-Hydrolysis-Condensation Process

Lanting Xua, Yongwen Jiangb, Dawei Ma*b
a Department of Chemistry, Fudan University, Shanghai 200433, P. R. of China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
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Further Information

Publication History

Received 27 May 2010
Publication Date:
19 August 2010 (eFirst)


CuI-catalyzed coupling of 2-halotrifluoroacetanilides with l-proline or pipecolinic acid in DMSO at 90-110 ˚C followed by in situ hydrolysis at 100 ˚C afforded tetrahydropyrrolo[1,2-a]quinoxalines or tetrahydropyrido[1,2-a]quinoxalines.

    References and Notes

  • 1a Tanimori S. Nishimura T. Kirihata M. Bioorg. Med. Chem. Lett.  2009,  19:  4119 
  • 1b Kher SM. Cai SX. Weber E. Keana JFW. J. Org. Chem.  1995,  60:  5838 
  • 2 Abusm Shuheil MY. Hassuneh MR. Al-Hiari YM. Qaisi AM. El-Abadelah MM. Heterocycles  2007,  71:  2155 
  • 3 Abou-Gharbia M. Freed ME. McCaully RJ. Silver PJ. Wendt RL. J. Med. Chem.  1984,  27:  1743 
  • 4a Vega MC. Montero-Torres A. Marrero-Ponce Y. Rolón M. Gómez-Barrio A. Escario JA. Arán VJ. Nogal JJ. Meneses-Marcel A. Torrens F. Bioorg. Med. Chem. Lett.  2006,  16:  1898 
  • 4b Meneses-Marcel A. Marrero-Ponce Y. Machado-Tugores Y. Montero-Torres A. Pereira DM. Escario JA. Nogal-Ruiz JJ. Ochoa C. Arán VJ. Martínez-Fernández AR. Sánchez RNG. Bioorg. Med. Chem. Lett.  2005,  15:  3838 
  • 5 Miyashiro J. Woods KW. Park CH. Liu X. Shi Y. Johnson EF. Bouska JJ. Olson AM. Luo Y. Fry EH. Giranda VL. Penning TD. Bioorg. Med. Chem. Lett.  2009,  19:  4050 
  • 6a Jamieson C. Congreve MS. Emiabata-Smith DF. Ley SV. Scicinski JJ. Org. Process Res. Dev.  2002,  6:  823 
  • 6b Chicharro R. de Castro S. Reino JL. Arán VJ. Eur. J. Org. Chem.  2003,  2314 
  • 7a Cai Q. Zou B. Ma D. Angew. Chem. Int. Ed.  2006,  45:  1276 
  • 7b Xie X. Chen Y. Ma D. J. Am. Chem. Soc.  2006,  128:  16050 
  • 7c Zou B. Yuan Q. Ma D. Angew. Chem. Int. Ed.  2007,  46:  2598 
  • 7d Liu F. Ma D. J. Org. Chem.  2007,  72:  4884 
  • 7e Chen Y. Xie X. Ma D. J. Org. Chem.  2007,  72:  9329 
  • 7f Chen Y. Wang Y. Sun Z. Ma D. Org. Lett.  2008,  10:  625 
  • 7g Yuan Q. Ma D. J. Org. Chem.  2008,  73:  5159 
  • 8a Ma D. Zhang Y. Yao J. Wu S. Tao F. J. Am. Chem. Soc.  1998,  120:  12459 
  • 8b Zhang H. Cai Q. Ma D. J. Org. Chem.  2005,  70:  5164 
  • For selected examples about heterocycle synthesis based on copper-catalyzed N-arylation, see:
  • 10a Evindar G. Batey RA. Org. Lett.  2003,  5:  133 
  • 10b Klapars A. Parris S. Anderson KW. Buchwald SL. J. Am. Chem. Soc.  2004,  126:  3529 
  • 10c Yuen J. Fang Y.-Q. Lautens M. Org. Lett.  2006,  8:  653 
  • 10d Zheng N. Buchwald SL. Org. Lett.  2007,  9:  4749 
  • 10e Yang D. Fu H. Hu L. Jiang Y. Zhao Y. J. Org. Chem.  2008,  73:  7841 
  • 10f Kim J. Lee SY. Lee J. Do Y. Chang S. J. Org. Chem.  2008,  73:  9454 
  • 10g Liu X. Fu H. Jiang Y. Zhao Y. Angew. Chem. Int. Ed.  2009,  48:  348 
  • 10h Wang H. Jiang Y. Gao K. Ma D. Tetrahedron  2009,  65:  8956 
  • 10i Reeves JT. Fandrick DR. Tan Z. Song JJ. Lee H. Yee NK. Senanayake CH. J. Org. Chem.  2010,  75:  992 
  • 10j Ma D. Geng Q. Zhang H. Jiang Y. Angew. Chem. Int. Ed.  2010,  49:  1291 

General Procedure for the Synthesis of Quinoxaline Derivatives: A Schlenk tube was charged with 2-iodo-trifluoroacetanilide (0.5 mmol), CuI (10 mg, 0.02 mmol), l-proline (or pipecolinic acid) (1.5 mmol), and K2CO3 (1.0 mmol) (for bromide, Cs2CO3 was used). The tube was evacuated and backfilled with argon. DMSO (4 mL) was added into the tube. The reaction mixture was stirred at 90 ˚C (for bromide, 110 ˚C) for 10-24 h. Then H2O (3 mL) was added and the reaction mixture was stirred at 100 ˚C for 8-12 h. After the reaction mixture was cooled, sat. NH4Cl (10 mL) solution was added. The mixture was extracted with EtOAc and the organic layer was washed with H2O, brine and dried over Na2SO4. After concentration in vacuo, the residue was purified by column chromatography on silica gel (eluting with 6:1 → 4:1 PE-EtOAc) to provide the desired product.