The significance of amides as a component of biomolecules and synthetic products has triggered the development of catalytic direct amidation methods 1,2,3 which involve reaction of a carboxylic acid and amine to form an amide with water as the only by-product. These methods evade the need for stoichiometric activation or coupling reagents and hence, are important green chemical processes 1,2. The present study involved the development a mild reaction conditions for the direct amidation reaction where known arylboronic acid catalysts 1,2,3,4,5 were employed in two different model reactions and compared with both reported 6,7and potential organometallic catalysts (Zr and Fe based).After a systematic evaluation of solvent, temperature and catalyst, ambient reaction conditions were applied in the direct amidation of amino-acid derivatives in order to exploit these more economical reagents for peptide synthesis. Protected amino acid derivatives showed slow reactivity compared to simple amine-carboxylic acid combinations though did proceed at 65~68 �C generally avoiding racemization.3,4,5-Trifluorophenylboronic acid and o-nitrophenylboronic acid were found to be the best catalysts, though for this sluggish reaction, high catalyst loadings were required. However, an interesting synergistic catalytic effect was observed during dipeptide formation using 'Co-Catalyst' (mixture of o-nitrophenyl boronic acid and o-methylphenylboronic acid (1:1)) in the direct amidation reaction at lower temperatures, although the process was particularly slow. Driven by this impressive result, the effect of cooperative catalysts, particularly, on the less reactive acid-amine combination (which was found to be inert at low temperature with single catalysts) was tried to explore. As a consequence, some commercially important synthesis has been reviewed through some lucrative novel cooperative catalysts to ensure their real applicability in industries.References:C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005  , 61, 10827�10852.K. Ishihara, S. Ohara, H. Yamamoto, J. Org. Chem., 1996  , 61, 4196-4197.a) K. Arnold, B. Davies, R. Giles, C. Grosjean, G. Smith, A. Whiting, Adv. Synth. Catal., 2006  , 348, 813-820; b) H. Charville, D. Jackson, G. Hodges, A. Whiting, M. R. Wilson, Eur. J. Org. Chem. 2011, 5981�5990K. Arnold, B. Davies, D. H�rault, A. Whiting, Angew. Chem. Int. Ed., 2008  , 47, 2673-2676.P. Tang, Org. Synth., 2005  , 81, 262-272.P. Starkov, T.D. Sheppard, Org. Biomol. Chem.,2011  , 9, 1320-1323.C. Liana Allen, A. R. Chhatwal and J. M. J. Williams, Chem. Commun., 2012  , 48, 666-668.

Novel approaches towards green catalytic direct amide bond formation

247th National Meeting (2014)

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