Regiospecific Synthesis of Novel 6-Amino-5-hydroxypyridazin-3(2H)-ones

Abstract

The synthesis of a novel class of 6-amino-5-hydroxy­pyridazin-3(2H)-ones (3-oxo-2,3-dihydropyridazines) is described. These compounds also contain an ethoxycarbonyl moiety at the 4-position of the pyridazinone ring. They are prepared in good to moderate yields (30-72%) by the condensation of disubstituted amines with (alkylhydrazono)- or (arylhydrazono)(chloro)acetates followed by subsequent acylation with ethyl malonyl chloride and Dieckmann cyclization. An initial assessment of the scope and limitations of the new methodology is described along with the novel synthesis of several (alkylhydrazono)(chloro)acetate substrates utilized in the pyridazinone preparations.

Key words

pyridazin-3(2H)-ones - Dieckmann cyclization - hydrazones - amino- and chloro(hydrazono)acetates - heterocycles

References

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11

Unless otherwise noted, all hydrazones described in this work were isolated and characterized as single isomers. No attempt was made to assign hydrazone stereochemistry (E or Z) or to rigorously identify any minor amounts of alternate isomers that may have been formed during a given synthetic transformation.

12

Reversing the order of the chlorination and Boc-deprotection steps also afforded 3a, but in significantly lower yield.

13

The major amino(hydrazono)acetate acylation products described in this work are inferred to be those depicted in Scheme [1] (structure 5) by their successful conversion into 6-aminopyridazin-3(2H)-ones in reasonable yields (Scheme [1] , structure 6). Significant amounts of alternate acylation products were not detected by LCMS analysis of the reaction mixtures and no other attempts were made to identify and/or quantify such entities.

14

The reaction was performed in an open flask. We have observed that the chlorination rate and yield can vary with the source of the N-chlorosuccinimide employed in the reaction.