Synthesis 2009(11): 1846-1850  
DOI: 10.1055/s-0028-1088071
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical Synthesis of Indole-Based Heterocycles Using an Amidoaluminum-Mediated Strategy

Robert Todd, M. Mahmun Hossain*
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer, Milwaukee, WI 53211, USA
e-Mail: [email protected];
Further Information

Publication History

Received 5 December 2008
Publication Date:
27 April 2009 (online)

Abstract

A large number of biologically active compounds consist of an indole scaffolding. Because of this, chemists are continually searching for more efficient means through which to successfully synthesize the required alkaloids. In our recent effort to synthesize indole-based p38 inhibitors and gramines, we found that a series of indole-based indole-3-carboxamides could be efficiently synthesized from various indole-3-carboxylates using an amidoaluminum-mediated strategy. The treatment of ethyl indole-3-carboxylates bearing a range of substitution patterns on the indole ring with various amidoaluminum complexes, led to the corresponding 1H-indole-3-carboxamides in yields up to 75%. Reduction by diisobutylaluminum hydride afforded the corresponding gramines in 63-85% yield. This is the first reported example of amidoaluminum complexes of type Al2(CH3)4(NR2)2 promoting facile amidation of relatively inert indole esters. This particularly promising approach has resulted in the first strategy for generating medicinally important alkaloids of this type.

    References

  • 1 Mavunkel BJ. Chakravarty S. Perumattam JJ. Luedtke GR. Xi L. Lim D. Xu Y. Laney M. Liu DY. Schreiner GF. Lewicki JA. Dugar S. Bioorg. Med. Chem. Lett.  2003,  13:  3087 
  • 2a Saxton JE. The Alkaloids   The Chemical Society; London: 1971. ; Specialist Periodical Reports:
  • 2b Saxton JE. Nat. Prod. Rep.  1989,  6: 
  • 2c Hesse M. Alkaloid Chemistry   Wiley; New York: 1978. 
  • 2d Cordell GA. Introduction to Alkaloids: A Biogenetic Approach   Wiley; New York: 1981. 
  • 2e Gilchrist TL. Heterocyclic Chemistry   Pitman; London: 1981. 
  • 2f Pindur AR. J. Heterocycl. Chem.  1988,  25:  1 
  • 3a Joule JA. Mills K. Heterocyclic Chemistry   University Press; Cambridge: 2000. 
  • 3b Sundberg RJ. The Chemistry of Indoles   Academic Press; New York: 1970.  p.142 
  • 3c Jones AR. Comprehensive Heterocyclic Chemistry   Vol. 4:  Katrizky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.334 
  • 3d Gupta RR. Heterocyclic Chemistry   Vol. 2:  Springer Publishing; New York: 1999.  p.199 
  • 3e Nakazaki M. Yamamoto K. J. Org. Chem.  1976,  41:  1877 
  • 4 Islam M. Brennan C. Wang Q. Hossain MM. J. Org. Chem.  2006,  71:  4675 
  • 5a Basha A. Lipton M. Weinreb SM. Tetrahedron Lett.  1977,  48:  4171 
  • 5b Ko D. Kim KH. Ha D. Org. Lett.  2002,  4:  3759 
  • 6 Lindsay FB. Ferrando F. Christensen KL. Overgaard J. Roca T. Bennasar ML. Skrydstrup T. J. Org. Chem.  2007,  72:  4181 
  • 7 Germain C. Bourdais J. J. Heterocycl. Chem.  1976,  13:  1209 
  • 8 Collman JP. Hegedus LL. Norton JR. Finke RG. Principles and Applications of Organotransition Metal Chemistry   University Science Books; Mill Valley, CA: 1987. 
  • 9 Orth RE. Bennett JW. Ma OH. Young L. J. Pharm. Sci.  1968,  57:  1814