Catalyst- and Additive-Free C(sp³)–H Functionalization of (Thio)barbituric AcidsviaC-5 Dehydrogenative Aza-Coupling Under Ambient Conditions

Abstract

A one-pot room-temperature-based three-component reaction strategy has been accomplished to access a new series of bio-relevant barbituric/2-thiobarbituric acid hydrazones from the reaction between barbituric/2-thiobarbituric acids, primary aromatic amines, and tert -butyl nitrite in an acetonitrile solvent, without the aid of any catalysts/additives. The ambient reaction conditions can efficiently implement the C(sp 3 )–H functionalization of barbituric/2-thiobarbituric acids via C-5 dehydrogenative aza-coupling. The process does not require column chromatographic purification; pure products are obtained by simple filtration of the resulting reaction mixture, followed by washing the crude residue with distilled water. The catalyst-free ambient reaction conditions, operational simplicity, broad substrate scope and tolerance for various functional groups, no need for chromatographic purification, good to excellent yields of products within reasonable reaction times in minutes, clean reaction profile, and gram-scale synthetic applicability make this procedure attractive, green, and cost-effective.

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“…Recently, Brahmachari and his group 61 accomplished an efficient and straightforward practical method for accessing a new series of diversely functionalised hydrazone molecular hybrids, such as 5-(2-arylhydrazono)pyrimidine-2,4,6(1 H ,3 H ,5 H )-triones ( 95 )/5-(2-arylhydrazono)-2-thioxodihydropyrimidine-4,6(1 H ,5 H )-diones ( 96 ), from a one-pot three-component reaction between barbituric acids ( 64 )/2-thiobarbituric acids ( 65 ), primary aromatic amines ( 2 ) and tert -butyl nitrite ( 43 ) in acetonitrile solvent under ambient conditions without the aid of any catalysts/additives (Scheme 37).…”