Synthesis of secondary amides from N-substituted amidines by tandem oxidative rearrangement and isocyanate eliminationAdvanced synthesis and catalysis -

The use of amidines for the tandem or one pot synthesis of guanidines is reported. Guanidines are obtained by oxidative rearrangement of readily available and stable amidines into carbodiimides, followed by in situ reaction with amines. The protocol can be executed under mild reaction conditions (30°C), in a green solvent (dimethyl carbonate). The amine scope is broad, including sterically hindered, oxidation sensitive and chiral amines. Examples for the synthesis of both acyclic and cyclic guanidines are provided. 2-PrOPhI byproduct, generated from the oxidant 2-PrOPhINTs, can be isolated in high yields making regeneration of the hypervalent iodine reagent possible. The utility and greenness of the synthetic method is demonstrated by a new route towards the antihypertensive drug Pinacidil. The Process Mass Intensity (PMI) of the new route is only 24% of the classical one.

The potential of halogen-magnesium exchange reactions, followed by quenching with electrophiles, for the functionalization of the pyridazin-3(2H)-one core was investigated. 2-Benzyl-4-bromo-5-methoxy- (1), 2-benzyl-5-bromo-4-methoxy- (4), and 2-benzyl-4,5-dibromopyridazin-3(2H)-one (10) were selected as readily available model substrates. While 1 and 10 gave exclusively C-4 metalation, a tandem reaction involving nucleophilic substitution via addition elimination and bromine-magnesium exchange was observed with 4.

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Elimination. -This new, efficient tandem process for the transformation of N-substituted amidines into secondary amides is applicable for aliphatic and (hetero)aromatic compounds. It is also effective for bulky and electron-deficient substituents. The pharmaceutically interesting boscalid (XVIII) is also synthesized. -(DEBNATH, P.; BAETEN, M.; LEFEVRE, N.; VAN DAELE, S.; MAES*, B. U. W.; Adv. Synth. Catal. 357 (2015) 1, 197-209, http://dx.