Synthesis of isoxazolylpyrrolones by three-component reaction of α-ketoglutaric acid or its diethyl ester with 3-amino-5-methylisoxazole and aromatic aldehydes

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones

“…We suppose that such inaction of compound 1a in the reaction with cyclohexylamine could be explained by the fact that the desired transformation proceeded via the participation of the corresponding HDP A in keto form, which underwent a condensation reaction with amine to afford the target 3-amino derivative of HDP B ( Scheme 4 ) [ 12 ]. Compound 1a ( Scheme 4 , structure A , R 2 + R 3 = spiro) had less conformational flexibility and less propensity for tautomerization to its keto form due to the influence of the rigid spiro-substituent at the C 5 position of the pyrrol-2-one moiety than the previously reported [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ] non-spiro HDPs bearing hydrogen and a substituent at the C 5 position ( Scheme 4 , structure A , R 2 = H, R 3 = Alk, Ar, H).…”

“…Then, we performed a series of reactions of compound 1a with cyclohexylamine ( Table 1 ) in order to obtain the required cyclohexylamino derivative 3a . The examined conditions ( Table 1 ) were selected according to the previously reported substitution reactions of hydroxyl groups in various non-spiro HDPs (bearing hydrogen and a substituent at the C 5 position) with amines [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ]. Although the examined conditions were productive in the reported cases [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], in our study, none of them led to the desired results ( Table 1 ).…”

“…The examined conditions ( Table 1 ) were selected according to the previously reported substitution reactions of hydroxyl groups in various non-spiro HDPs (bearing hydrogen and a substituent at the C 5 position) with amines [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ]. Although the examined conditions were productive in the reported cases [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], in our study, none of them led to the desired results ( Table 1 ). We observed that the reaction mixtures contained unconverted compound 1a (93–99%), cyclohexylamine and small quantities of unidentified side products.…”

“…There are three universal strategies towards ADPs enabling their synthesis with a wide range of substituents ( Scheme 1 ). These strategies are the substitution of hydroxyl groups in the corresponding HDPs via their reactions with amines (pathway a ) [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], the multicomponent reactions of amines and aldehydes with pyruvic acid derivatives (pathway b ) [ 13 , 14 ] or acetylenedicarboxylates (pathway c ) [ 15 , 16 ] ( Scheme 1 ).…”

“…As a part of our long-standing interest in the synthesis of spiro compounds bearing the HDP moiety [ 17 ], we wanted to prepare their 3-amino analogs. However, we were unable to synthesize the desired compounds from HDPs and amines [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], and therefore, herein, we report an alternative approach to ADPs ( Scheme 2 ).…”