Unusual Formation of 1,2,4-Oxadiazine Core in Reaction of Amidoximes with Maleic or Fumaric Esters

Abstract

We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. Different products can be synthesized selectively in good yields depending on the base used and the ratio of reactants: substituted (1,2,4-oxadiazin-6-yl)acetic acids, corresponding methyl esters, or hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4H-1,2,4-oxadiazin-5(6H)-ones. The reaction is tolerant to substituents' electronic and steric effects in amidoximes. As a result, a series of 2-(5-oxo-3-(p-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazin-6-yl)acetic acids, their methyl esters, and 1,2,4-oxadiazoles based on them were prepared and characterized by HRMS, ¹H, and ¹³C NMR spectroscopy. The structures of three of them were elucidated with X-ray diffraction.

Keywords: amidoximes; basic medium; cyclization; esters; heterocycles; nucleophilic addition.

Scheme 1

Previously known reactions of amidoximes with carboxylic acid derivatives (A), α,β–unsaturated carbonyl compounds (B), and vicinal bis-electrophiles (C).

Scheme 2

Reaction of amidoximes 1 with 2a in NaOH–DMSO medium. Reaction conditions: 1 (2 mmol), 2 (4 mmol), NaOH (4 mmol), DMSO (3 mL), RT, 18 h. Isolated yields are presented.

Scheme 3

Reactions of amidoximes 1 with 2a in t-BuONa–DMSO medium. Reaction conditions: (left) 1 (2 mmol), 2 (4 mmol), t-BuONa (2 mmol), DMSO (3 mL), RT, 4 h; (right) 1 (5 mmol), 2 (2 mmol), t-BuONa (4 mmol), DMSO (3 mL), RT, 18 h. Isolated yields are presented.

Figure 1

Hydrogen-bonded dimers in crystals of 4d (A), 5b (B), and 5f (C).

Scheme 4

Plausible mechanism of 1,2,4-oxadiazine ring formation.