Convenient modular construction of medicinally important 5-acylamino-4,5-dihydroisoxazoles featuring four elements of diversity

Abstract

a b s t r a c tAn efficient modular approach toward medicinally important 5-acylamino-4,5-isoxazolines via the 1,3-dipolar cycloaddition reaction of nitrile oxides and MCR-derived enamide building blocks is described. This approach results in isoxazolines containing four elements of diversity utilizing two practically simple synthetic operations.

α-Acyl-α-diazoacetates in Transition-Metal-Free β-Lactam Synthesis

“…The apparent sensitivity of the β-lactam formation to the availability of the imine nitrogen atom for acylation (in steric as well as electronic sense) and the failure to obtain β-lactams from α-C–H imines argues for the importance of the stepwise formation of the β-lactam ring involving acylation (rather than concerted [2 + 2]-cycloaddition). Moreover, it allows drawing an almost exact analogy between the β-lactam syntheses described herein and the Castagnoli–Cushman reaction of succinic anhydride (an exemplary dicarboxylic acid anhydride), which proceeds with “nonenolizable” imines under nearly the same conditions as described herein to give γ-lactams 2a via N-acylation/intramolecular Mannich sequence and fails to give 2a with α-C–H imines, delivering enamides 14 , (similar to 12 ) instead (Scheme ).…”

“…Besides rationalizing the formation of the sole observed diastereomer of 4l , these DFT calculations reveal the following significant mechanistic clue. Oxazinones analogous to 17 are commonly isolable products in the reactions of imines with acyl ketenes derived from α-diazo-β-diketones. ,− However, their formation has never been implicated in the observed Staudinger-type reactions of imines. The mechanistic picture involving the formation of the oxazinone intermediate can potentially unify the two types of reactions, those of ketenes 7 derived from α-acyl-α-diazoacetates 8 and those of ketenes 19 formed via the Wolff rearrangement of α-diazo-β-diketones 18 .…”

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

“…In 2016, Kulyashova and Krasavin described in their article 3,5-disubstituted isoxazolines bearing acylamino substituent in position 5. Those molecules were obtained by applying 1,3-DP cycloaddition of in situ-generated nitrile oxide to N -vinyl amides— Scheme 113 [ 121 ].…”

“… Syntheses of 5-acylamino-2-isoxazolines via 1,3-DP cycloaddition of R 3 CNO to CH 2 =CHN(R 1 )COR 2 [ 121 ]. R 1 , R 2 , R 3 = Bn, Ph, Et; Bn, Ph, p -MeOC 6 H 4 Ph; Bn, Ph, 2-thienyl; 3-PyCH 2 , Ph, p -MeC 6 H 4 ; 3-PyCH 2 , Ph, 2-thienyl; and others; a = NCS, Et 3 N, PhMe or PhMe + CH 2 Cl 2 , up to rt, 2–18 h; up to 75% yield.…”