Arkivoc 2017, (ii), 87‐106
Jasiak, K. et al
The first synthesis of 1,3,4‐oxadiazoles was reported by Ainsworth in 1954.34 The most popular method for preparation of these heterocyclic compounds involves oxidative cyclization of N‐acylhydrazones with various oxidizing agents such as ceric ammonium nitrate,35 potassium permanganate,36 ferric chloride,37 tetravalent lead reagents,38 mercuric oxide/iodine,39 bromine/sodium acetate,40 chloramine T41, hypervalent iodine reagents,42‐47 iodine/hydrogen peroxide48 or cross‐linked poly[styrene(iodoso diacetate)].49 Electrooxidative cyclization of N‐acylhydrazones have also been reported.50 Another common synthetic route comprises dehydrative cyclization of N,N'‐diacylhydrazines utilizing reagents such as polyphosphoric acid,51 sulfuric acid,52 thionyl chloride,53‐54 phosphorus oxychloride,55‐56 phosphorus pentoxide,57 triflic anhydride,58 boron trifluoride diethyl etherate59 and the Burgess reagent.60 Besides these methods, 2,5‐disubstituted 1,3,4‐ oxadiazoles have also been synthesized by photoisomerization of 1,2,4‐oxadiazoles,61 heterocyclization of semicarbazide, thiosemicarbazide and selenosemicarbazide derivatives,62‐64 as well as N‐acylation and subsequent ring opening/closing of starting tetrazoles.65‐66 In recent years, one‐pot syntheses of these compounds from acid hydrazides with carboxylic acids,67 aromatic aldehydes35 or orthoesters68‐70 have also been described in the literature. 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) has attracted significant attention since it was first synthesized by Thiele and Günther in 1906.71 DDQ is a highly effective oxidizing agent and has been successfully utilized for various organic transformations, including aromatization, deprotection of functional groups, dehydrogenation and potential applications for the formation of carbon‐carbon bonds.72‐79 Our previous studies on oxidative cyclization of a narrow group of N‐aroylhydrazones demonstrated the effectiveness and selectivity of DDQ for the synthesis of 1,3,4‐oxadiazoles conjugated via an ethenyl linker to benzene, thiophene and furan rings.80 We reported that the formation of such heterocycles could proceed via intermediate N'‐(arylmethylidene)‐3‐arylacrylohydrazides or directly from α,β‐unsaturated acid hydrazides and aromatic aldehydes in a one‐pot procedure. The examined compounds possessed an unsaturated C=C double bond, that was prone to oxidation. The obtained results encouraged us to investigate further the general utility and application of DDQ for the preparation of 2,5‐disubsituted 1,3,4‐oxadiazoles. The present work was undertaken to explore the possibility of oxidative cyclization of a wide variety of saturated both aromatic and aliphatic N‐acylhydrazones without an ethenyl linker. This approach seemed to be quite promising due to high reactivity, commercial availability and recyclability of DDQ. Results and Discussion Hydrazides of aromatic and aliphatic carboxylic acids 1a‐j served as precursors for the synthesis of 1,3,4‐ oxadiazole derivatives. These compounds were obtained from their respective carboxylic acids according to a two‐step synthetic procedure described in literature.81 The starting acids were esterified with methanol in the presence of catalytic H2SO4 to form the appropriate methyl esters, which were treated with excess hydrazine hydrate, yielding the desired hydrazides in satisfactory yields (73‐89%). Our studies on the synthesis of the title 1,3,4‐oxadiazoles began with a stepwise pathway proceeding via N‐acylhydrazones. These acyclic intermediates 3a‐v were easily prepared by HCl‐catalyzed condensation of acid hydrazides 1a‐j with the selected aromatic and aliphatic aldehydes 2a‐h in ethanol. The obtained N‐ acylhydrazones 3a‐s precipitated immediately after mixing the reagents and were recrystallized from ethanol according to a well‐known literature protocol.82 The structure of the synthesized compounds 3a‐s were identified by elemental analysis and spectroscopic methods (1H and 13C NMR, MS, UV, IR). However, N‐ acylhydrazones 3t‐v containing aliphatic chains were not isolated from the post‐reaction mixture due to the
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