Cyclodehydration aminoketone

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

The frequently reported dimerization of 1-azirines to 3,6-dihydro-pyrazines probably involves initial hydrolysis to the aminoketone which then undergoes a cyclodehydration to the dihydropyrazine, rather than a direct dimerization of the 1-azirine. Catalytic amounts of water absorbed on the acid surface of the glass are probably responsible for this reaction. 

Many modified Marckwald procedures are available to prepare structurally diverse imidazoles most of them are focused on the preparation of an oe-aminoketone or its equivalents. For example, a regiospecific synthesis of trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266 will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) <2005TL7315>. 

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