Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

Abstract

Reactions of β-azolyl enamines and nitrile oxides were studied by both experimental and theoretical methods. (E)-β-(4-Nitroimidazol-5-yl), (5-nitroimidazol-4-yl) and isoxazol-5-yl enamines smoothly react regioselectively at room temperature in dioxane solution with aryl, pyridyl, and cyclohexylhydroxamoyl chlorides without a catalyst or a base to form 4-azolylisoxazoles as the only products in good yields. The intermediate 4,5-dihydroisoxazolines were isolated as trans isomers during the reaction of (E)-β-imidazol-4-yl enamines with aryl and cyclohexylhydroxamoyl chlorides. Stepwise and concerted pathways for the reaction of β-azolyl enamines with hydroxamoyl chlorides were considered and studied at the B3LYP/Def2-TZVP level of theory combined with D3BJ dispersion correction. The reactions of benzonitrile oxide with both E- and Z-imidazolyl enamines have been shown to proceed stereoselectively to form trans- and cis-isoxazolines, respectively. The preference of E-isomers over Z-isomers, driven by the higher stability of the former, apparently controls the stereoselectivity of the investigated cycloaddition reaction with benzonitrilе oxide. Based on the reactivity of azolyl enamines towards hydroxamoyl chlorides, a novel, effective catalyst-free method was elaborated to prepare 4-azolyl-5-substituted isoxazoles that are otherwise difficult to obtain.

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

“…The reaction pathway corresponds to the variation of the C–C distances (2.139–2.195 Å, Table ), which are significantly shorter for 22 as compared to the C–O distance (2.528–2.697 Å). This evidences significantly asynchronous transition state of the cycloaddition step, which is consistent with previous findings . The corresponding activation energies were rather low, agreed well with proceeding the reaction under mild conditions and differed only slightly upon the variation of the EWG group (Δ G ‡ = 23.1–24.5 kcal/mol, Table ), where the lowest activation energy was inherent to EWG = NO 2 ( 22 { 18 }), and the highest one was predicted for the benzoxazole derivative ( 22 { 10 }).…”

“…The starting chloroximes 5 – 9 [both ( R )‐ and ( S )‐isomers were used in the case of chiral compounds] and enamines 10 – 18 were prepared according to the known procedures. Existing literature protocols for the [3+2] cycloaddition of halogenoximes and “push‐pull“ enamines varied in the reaction conditions, including AcOH in dioxane–H 2 O, neat Et 3 N, NaHCO 3 in EtOAc,, , and no promoter in dioxane , . In this work, we have used the conditions described in our previous works for similar transformations of the chloroximes 5 – 9 , , .…”

“…In order to discuss the effect of substituent on the reactivity of “push‐pull” enamines in the reaction with halogenoximes, quantum chemical calculations were carried out for the cyclization step at the DFT level of theory. According to the literature data, a plausible reaction mechanism includes formation of nitrile oxides from chloroximes 5 – 9 in the presence of a base (Scheme ; nitrile oxide 20 is given as an example), followed by [3+2] cycloaddition with enamines 10 – 18 to give the corresponding intermediates 21 . In the next step, elimination of dimethylamine from 21 occurs, which results in formation of the target products – 3,4‐disubstituted isoxazoles 19 .…”

“…The known methods for the synthesis of 4‐(het)arylisoxazoles include palladium‐catalyzed C–C couplings,, , various heterocyclizations and recyclizations, diazotative deamination of the corresponding 5‐aminoisoxazoles, and formal [3+2] cycloaddition of alkynes, electron‐deficient enamines or their synthetic equivalents with halogenoximes , . The latter approach can be considered as the most convenient since generally, the target products are obtained in good yields with high regioselectivity.…”

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…As Efimov and colleagues reported in 2016, 1,3-diazolyl and dimethylamine motifs bearing 2-isoxazolines were formed in the fully regio- and stereoselective 1,3-DP cycloaddition of RCNO to ( E )-(Diazolyl)CH=CHNMe 2 dipolarophiles— Scheme 213 [ 225 ].…”