A Practical Synthesis of 2-Aroylindoles from N-(2-Formylphenyl)trifluoro­acetamides in PEG-400

Abstract

A one-pot and environmentally benign approach to the synthesis of highly functionalized 3-unsubstituted 2-aroylindoles is described. Moderate to good yields were obtained through the reaction of easily accessible N-(2-formylphenyl)trifluoroacetamides and α-bromoacetophenones in the presence of K₂CO₃. PEG-400 was found to be an efficient and reusable solvent in the process.

Key words

2-aroylindoles - PEG-400 - N-(2-formylphenyl)trifluoro­acetamides - heterocycles - cyclization

References

• 1 Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
• 2a Romagnoli R. Baraldi PG. Sarkar T. Carrion MD. Cara CL. Cruz-Lopez O. Preti D. Tabrizi MA. Tolomeo M. Grimaudo S. Di Cristina A. Zonta N. Balzarini J. Brancale A. Hsieh H.-P. Hamel E. J. Med. Chem.  2008,  51:  1464 
• 2b Mahboobi S. Pongratz H. Hufsky H. Hockemeyer J. Frieser M. Lyssenko A. Paper DH. Bürgermeister J. Böhmer F.-D. Fiebig H.-H. Burger AM. Baasner S. Beckers T. J. Med. Chem.  2001,  44:  4535 
• 2c Beckers T. Reissmann T. Schmidt M. Burger AM. Fribig HH. Vanhoefer U. Pongratz H. hufsky H. Hockemeyer J. Frieser M. mahboobi S. Cancer Res.  2002,  62:  3113 
• 2d Brancale A. Silvestri R. Med. Res. Rev.  2007,  27:  209 
• 3 Mahboobi S. Sellmer A. Höcher H. Garhammer C. Pongratz H. Maier T. Ciossek T. Beckers T. J. Med. Chem.  2007,  50:  4405 
• 4 Mahboobi S. Teller S. Pongratz H. Hufsky H. Sellmer A. Botzki A. Uecker A. Beckers T. Baasner S. Schächtele C. Uberall F. Kassack MU. Dove S. Böhmer F.-D. J. Med. Chem.  2002,  45:  1002 
• 5 Willson TM. Brown PJ. Sternbach DD. Henke BR. J. Med. Chem.  2000,  43:  527 
• 6 Cruz-López O. Díaz-Mochón JJ. Campos JM. Entrena A. Núñez MT. Labeaga L. Orjales A. Gallo MA. Espinosa A. ChemMedChem  2007,  2:  88 
• 7a Saulnier MG. Gribble GW. J. Org. Chem.  1982,  47:  757 
• 7b Katritzky AR. Akutagawa K. Tetrahedron Lett.  1985,  26:  5935 
• 7c Takeda Y. Kikuchi A. Terashima M. Heterocycles  1993,  35:  573 
• 7d Kazunari N, William SR, Kiyoshi K, Chikara U, Hiroki K, and Stephane C. inventors; PCT Int. Appl. WO  9935130. 
• 7e Thomas B, Siavosh M, Herwig P, Markus F, Harald H, Jörg H, and Udo V. inventors; PCT Int. Appl. WO  2003037861. 
• 8a Arthuis M. Pontikis R. Florent J.-C. Org. Lett.  2009,  11:  4608 
• 8b Abbiati G. Casoni A. Canevari V. Nava D. Rossi E. Org. Lett.  2006,  8:  4839 
• 8c Labadie SS. Teng E. J. Org. Chem.  1994,  59:  4250 
• 8d Cenini S. Bettettini E. Fedele M. Tollari S. J. Mol. Catal. A: Chem.  1996,  111:  37 
• 9a Black DSt. C. Wong LCH. Chem. Commun.  1980,  4:  200 
• 9b Jones AW. Purwono B. Bowyer PK. Mitchell PSR. Kumar N. Nugent SJ. Jolliffe KA. Black DSt. C. Tetrahedron  2004,  60:  10779 
• 10a Jones CD. Suarez T. J. Org. Chem.  1972,  37:  3622 
• 10b Shiang J, Litz K, Celia JA, Chichak KS, and Ye Q. inventors; PCT Int. Appl. WO  2008014037. 
• 12 Clark MP, Brugel TA, Sabat M, Golebiowski A, Bookland RG, and De B.. inventors; PCT Int. Appl. US 2008  0139588. 
• For representative papers, see:
• 13a Chandrasekhar S. Reddy NR. Sultana SS. Narsihmulu C. Reddy KV. Tetrahedron  2006,  62:  338 
• 13b Namboodiri VV. Varma RS. Green Chem.  2001,  3:  146 
• 15 Han R. Chen S. Lee SJ. Qi F. Wu X. Kim BH. Heterocycles  2006,  68:  1675 
• 16 Murakami Y. Heterocycles  1984,  22:  1211 

11

The only reaction condition reported by Jones’ group was that DMF was used as the solvent. We examined different solvents including acetone, acetonitrile, toluene, DMF and PEG-400, and different bases including NaHCO₃, Na₂CO₃, K₂CO₃ and Et₃N. Only a trace amount of 2-aroylindole was obtained.

14

No attempt was made to free the PEG-400 of salts because the salts did not hamper the rate of the reaction