Amide linkages are present in key natural products and in many biologically active molecules. Therefore, the formation of amide bonds is important to both synthetic chemists and biologists. Approximately 66% of all preliminary screening reactions in industrial medicinal chemistry laboratories involve amide formation. Although many methods have been developed for amide synthesis, a procedure for the direct coupling of amines with an acid in the presence of coupling agents without prior activation would be useful for building small-molecule libraries and for key steps in total syntheses. Condensing agents such as carbodiimides or other activating agents are generally employed under dry conditions. However, the condensing agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4methylmorpholium chloride (DMT-MM) can be used to prepare carboxamides in alcohol or water. This reaction is technically simple and relatively easy to implement, requiring only a mixing of acids, amines, and DMTMM in MeOH or H2O. The synthesis of DMT-MM is also relatively simple, and it can be prepared from CDMT (2chloro-4,6 dimethoxy-1,3,5-triazine) and N-metheylmorphorine (NMM) in THF. The current report describes the application of microwave-induced acceleration to further improve the reaction conditions for amide synthesis using DMT-MM. Highspeed synthesis using microwave technology has attracted considerable attention in organic chemistry. Microwave irradiation provides advantages over conventional heating for chemical transformations, including accelerated reaction rates (and consequently reduced reaction times), higher yields, and cleaner reactions. These advantages led us to evaluate the use of microwave irradiation for amidation reactions involving less reactive secondary and primary amines with acid in the presence of DMT-MM. We also compared the effectiveness of dicyclohexylcarbodiimide (DCC), a well-known condensing reagent, when coupled with microwave irradiation versus classical thermal methods. The reactions were performed by dissolving amines, carboxylic acids, and the condensing agent in solvent, followed by irradiation in a temperature-controlled microwave oven. For comparison, the same reactions were carried out under conventional heating conditions. The amidation of 2-phenylethylamine (a primary amine) with substituted benzoic acid in the presence of DMT-MM in MeOH gave a yield of over 90% products within 25 min at 110 C with microwave irradiation. The reaction time with conventional heating was seven times that with microwave irradiation, and the yield was less than 10-20% of the yield with the microwave-assisted method. The reaction of piperidine (a secondary amine) with benzoic acid afforded a 91% yield within 30 min at 150 C with microwave irradiation; note the higher reaction temperature and longer reaction time compared with those of the primary amine reaction. Amidation of piperidine with substituted benzoic acid in the presence of DCC with pyridine in THF yielded more than 60% products within 25 min at 120 C with microwave irradiation. Thus, DMT-MM was a much more effective coupling agent than DCC. Further increases in reaction temperature were limited by the potential of solvents for producing an explosive atmosphere within the micro-
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