text: The Kröhnke method is featured in a solvent-free synthesis of triarylpyridines that proceeds via a homo-coupling of two diaryl substituted α, β-unsaturated carbonyl compounds. This strategy offers a facile means for preparation of pyridnyl aryl systems that are important fragments of many useful drug scaffolds.
  In 1992, Robinson and co-workers developed a similar pyridine synthesis using enamino nitriles as one of the three-carbon fragments in place of an α-pyridinium methyl ketone. This improvement increases the reactivity of the system and allows for formation of fully substituted pyridines whereas use of an α-pyridinium methyl ketone requires that the 3- or 5- position on the resulting pyridine be unsubstituted. Kröhnke condensation of enamino nitrile 20 with enone 21 yielded fused pyridine 22.
  The mechanism of this Kröhnke-type reaction likely proceeds via a vinylogous cyanamide 23 which undergoes elimination of hydrocyanic acid, deprotonation to form enamine 24  and cyclization to form intermediate 25, which is then dehydrated to form the desired pyridine product.
  A clean one-pot Kröhnke method in aqueous media generates 4’-aryl-2,2’:6’, 2’’-terpyridines. Reaction of aryl aldehyde 26 with two equivalents of 2-acetylpyridine (27) yielded terpyridines of the form 28.
  In addition to variations on the original method, a number of combinatorial studies using the Kröhnke synthesis and its variations have been employed to synthesize vast libraries of highly functionalized pyridines. Janda and co-workers utilized the general Kröhnke reaction scheme to generate a 220 compound library. Various methyl ketones 29 and aldehydes 30 were coupled via aldol condensation to give enones of the form 31. These compounds were then reacted with various α-pyridinium methyl ketones 32 to give the desired tri-substituted pyridine 33.
  In 2009, Tu and coworkers developed a 3 fragment, one-pot combinatorial strategy for developing 3-cyanoterpyridines 34and 1-amino-2-acylterpyridines 35. These combinatorial variations of the Kröhnke reaction provide an efficient synthetic strategy to poly arylpyridine scaffolds. This methodology would also be advantageous for biological assays and screening experiments.