Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles.

The reaction of 6-chloro-1-methylpyrazin-2(1 H)-one with Grignard reactants followed by quenching with different electrophiles gave access to a variety of 3,6-difunctionalized 1-methylpyrazin-2(1 H)-ones. This regioselective three-component reaction represents the first example of a tele-nucleophilic substitution of hydrogen (S) in which the anionic σ adduct is quenched by electrophiles (other than a proton) before elimination takes place. Quenching the reaction with iodine (I) or bromine (Br) provides an alternative reaction pathway, yielding a 3-functionalized 6-chloro-1-methylpyrazin-2(1 H)-one or 5-bromo-6-chloro-1-methylpyrazin-2(1 H)-one, respectively.

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen.

The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papaverine.

Mechanism of the Cu-catalyzed benzylic oxygenation of (aryl)(heteroaryl)methanes with oxygen.

A mechanistic study of the copper-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes was performed. Initial reaction rates were measured making use of IR reaction monitoring and a kinetic analysis of the reaction was executed. The reaction proved to be first order in oxygen concentration.

Synthesis of aryl(di)azinyl ketones through copper- and iron-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes.

Sustainable Oxidations: an oxidation method to transform aryl(di)azinylmethanes into aryl(di)azinyl ketones is described. Base metals (copper and iron) as catalysts in combination with O(2) as the oxidant are used, which makes this method sustainable. The utility of this method is illustrated by the synthesis of 6-(4-methylbenzoyl)pyridine-2-carbaldehyde, which is an intermediate in the preparation of the drug Acrivastine.