Reaction of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via Intramolecular N–O Bond Formation

Abstract

An efficient new synthesis of 3,5-bis­(het)­arylisoxazoles, involving the reaction of 1,3-bis­(het)­arylmonothio-1,3-diketones with sodium azide in the presence of IBX catalyst, has been reported. The reaction proceeds at room temperature in high yields and is applicable to a broad range of substrates including the synthesis of 5-methyl-3-arylisoxazoles, a key subunit present in several β-lactamase-resistant antibiotics. A probable mechanism for the formation of isoxazoles has been suggested. A few of the 5-styryl/arylbutadienyl-3-(het)­arylisoxazoles have also been synthesized by reacting the corresponding 1-(het)­aryl-1-(methylthio)-4-(het)­arylidene-but-1-en-3-ones with sodium azide at higher temperatures. The reaction of β-ketodithioesters with sodium azide is shown to furnish β-ketonitriles in good yields.

A review of recent synthetic strategies and biological activities of isoxazole

“…Mary Antony P. et al have reported the synthesis of 3‐(Het)aryl‐5‐(het)aryl/alkylisoxazoles 5 starting from acetone. Prior to it, unsymmetrically substituted 1,3‐bis(het)‐arylmonothio‐1,3‐diketones of the general structure 2 , a new class of versatile organosulfur synthons, was yielded by base‐mediated condensation of active methylene ketones with (het)aryldithioesters 1 which further treated in DMF with a solution of IBX with sodium azide gave isoxazole derivatives 3 as shown in Scheme 42 [63]. Using another route, 3‐(Het)aryl‐5‐styryl/ aryldienyl Isoxazoles 5 have also been synthesized by the reaction of β ‐(methylthio)‐ β ‐(het)aryl‐3‐styrl/aryldienyl‐1‐propen‐3‐ones 4 in DMSO with sodium azide at 100°C for 12 h.…”

“…The 3-amino-5-(methyl/t-butyl)isoxazoles 1 were utilized as key starting materials for the synthesis of the new compounds. The isoxazole-thiazolone derivatives 2 were synthesized by heating compound 1 with S C H E M E 4 0 Synthesis of diverse ß/ ɷ-isoxazole aldehydes/ketones derivatives [61] S C H E M E 4 1 Synthesis of isoxazole under TEMPO-catalyzed aerobic conditions [62] S C H E M E 4 2 Synthesis of 3, 5-(bis)isoxazole via intramolecular N-O bond formation [63] S C H E M E 4 3 An intramolecular Wittig approach for the synthesis of isoxazoles [64] S C H E M E 4 4 An intramolecular cyclization approach for the synthesis of isoxazoles [65] ammonium thiocyanate in refluxing ethanol. The reaction of 2 with aromatic aldehydes in presence of an ethanolic solution of sodium hydroxide gave the corresponding 5-arylidenethiazolone-isoxazole derivatives 3 as depicted in Scheme 49.…”

Synthesis of 3,5-Disubstituted-1,2,4-thiadiazoles via NaH–DMF-Promoted Dehydrogenative Intramolecular N–S Bond Formation

“…Five-membered nitrogen heterocycles, containing heteroatom–heteroatom bonds, play an important role in pharmaceutical chemistry, as well as in material science. − Therefore, much efforts have been directed toward their synthesis, especially via intramolecular construction of the N–heteroatom bond. , Among these subunits, 3,5-disubstituted-1,2,4-thiadiazoles, bearing a N–S bond, represent an important class of five-membered heterocyclic frameworks, , which are associated with diverse biological profiles. − Thus, polycarpathiamine A I , recently isolated from marine organism ascidian Polycarpa aurata, displays significant cytotoxic effect against the L5178Y murine lymphoma cell line (IC 50 = 0.41 μM, Figure ). , Among synthetic analogues, compound II displays good β-secretase inhibitory activity and is a potential drug candidate for Alzheimer’s disease .…”

Synthesis of Substituted Benzo[b]thiophenes via Base-Promoted Domino Condensation–Intramolecular C–S Bond Formation

“…The advent of transition metal (TM) free C–C − and C–heteroatom − bond-forming reactions resulted in the synthesis of several five- and six-membered benzo heterocycles in efficient manner. In continuation of our efforts toward TM-free synthesis of heterocycles employing organosulfur reagents, , herein we report the synthesis of 2,3-substituted benzo­[ b ]­thiophenes from in situ generated thioenolates (Scheme , eq 5).…”