Study on DDQ ‐ promoted synthesis of 2,5 ‐ disubstituted 1,3,4 ‐ oxadiazoles from acid hydrazides and aldehydes

A facile stepwise synthesis of 2,5 ‐ disubstituted 1,3,4 ‐ oxadiazoles proceeding via oxidative cyclization of N ‐ acylhydrazones is reported. The reaction is efficiently promoted by 2,3 ‐ dichloro ‐ 5,6 ‐ dicyano ‐ 1,4 ‐ benzoquinone (DDQ) to afford the desired products mostly in high yields and in relatively short times. The final 1,3,4 ‐ oxadiazole derivatives are also synthesized directly from acid hydrazides and aldehydes in a one ‐ pot procedure. The substrate scope and limitations of the reported transformation are discussed in detail

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][74][75][76][77][78][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. 80We 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 1,3,4oxadiazole derivatives.These compounds were obtained from their respective carboxylic acids according to a two-step synthetic procedure described in literature. 81The starting acids were esterified with methanol in the presence of catalytic H 2 SO 4 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 Nacylhydrazones 3a-s precipitated immediately after mixing the reagents and were recrystallized from ethanol according to a well-known literature protocol. 82The structure of the synthesized compounds 3a-s were identified by elemental analysis and spectroscopic methods ( 1 H and 13 C NMR, MS, UV, IR).However, Nacylhydrazones 3t-v containing aliphatic chains were not isolated from the post-reaction mixture due to the presence of numerous by-products and problematic separation.Their presence and yields were confirmed by NMR studies.
The resulting series of N-acylhydrazones 3a-v was subjected to heating at reflux with equimolar amounts of DDQ in toluene in order to determine the scope of their oxidative cyclization.To our satisfaction, the reaction exhibited a broad substrate scope, high functional group tolerance and proceeded smoothly to give a wide range of 2,5-disubstituted 1,3,4-oxadiazoles 4a-v, mostly in good yields (Table 1).It should be mentioned that the great advantage of the methodology using DDQ is the fact that the reduced by-product (DDQ-H 2 ) could be readily removed by filtration and oxidized with MnO 2 in order to recycle back into DDQ.Our initial investigations of the substrate scope were conducted with N-acylhydrazones 3a-c originating from benzhydrazide (1a) and various benzaldehydes.The results shown in Table 1, demonstrated that this methodology displayed excellent compatibility with a variety of functional groups on the benzene ring of the precursor aldehyde.However, N-benzoylhydrazones derived from benzaldehydes bearing an electron-donating group, such as the methoxy-containing example 3b, gave a higher yield of the desired product in comparison to the substrate with an electron-withdrawing group, such as the nitrocontaining species 3c, due to the resonance stabilization involving the methoxy group.These promising results encouraged us to further studies with polycyclic aromatic and heterocyclic aldehydes.5-Phenyl-1,3,4oxadiazoles containing furan and thiophene rings 4d-e, were successfully obtained in high yields (80-90%, Table 1).N'-(9-Anthrylmethylene)benzhydrazide (3f) also reacted smoothly under the typical reaction conditions to afford the desired product 4f in 72% yield.
To explore the generality and scope of this reaction further, we tested various N-benzoylhydrazones 3ho derived from meta-and para-substituted benzhydrazides possessing different groups such as OMe, NO 2 , Cl.All these substrates 3h-o underwent oxidative cyclization to give the corresponding 1,3,4-oxadiazoles 4h-o in yields ranging from 61 to 91%.We noticed that this synthetic method was also compatible with various substituents on the aromatic ring of the benzhydrazide.However, N-benzoylhydrazones subsituted with an electron-donating group 3h-k reacted faster giving higher yields of the final products compared to those bearing an electron-withdrawing group 3l-o.This observation in the trend of yields is due to the fact that an electron-donating substituent stabilizes the oxygen-centred radical formed in the reaction of an Nacylhydrazone with DDQ.
This methodology was also successful for N-furoylhydrazones 3d',p derived from 2-furancarbohydrazide (1f).These substrates 3d',p were smoothly converted into the corresponding products 4d',p in high yields (86-94%, Table 1).The best result was obtained in the reaction conducted with N'-(2-thienylmethylene)-2furancarbohydrazide (3p, 94%) due to the fact that heterocyclic rings such as furan and thiophene are found to be stable under the reaction conditions.As shown in Table 1, higher yields were observed in the final 1,3,4oxadiazoles containing heterocycles.A similar trend of yields was also noticed for the formation of the acyclic N-acylhydrazones 3a-s.
Additionally, aliphatic hydrazides and aliphatic aldehydes were also subjected to the protocol in order to investigate the scope of the protocol further.Among the tested compounds were N-acylhydrazones 3q-v derived from hydrazides such as phenylacetic acid hydrazide, heptanoic acid hydrazide or palmitic acid hydrazide and aldehydes such as benzaldehyde or propionaldehyde.Initially, N'-benzylidene-2phenylacetohydrazide (3q) was heated with DDQ and afforded the final product 4q in satisfactory yield (52%, Table 1).However, when the benzene ring of the precursor aldehyde was replaced with an aliphatic chain (e.g.R' = Et), the reactivity of the substrate greatly decreased and 2-ethyl-5-(phenylmethyl)-1,3,4-oxadiazole (4r) was produced only in low yield (27%).Further, aliphatic hydrazides were also investigated in this reaction.N-Acylhydrazone 3s originating from palmitic acid hydrazide and benzaldehyde underwent oxidative cyclization to form the coresponding product 4s in only 18% yield.The results shown in Table 1 demonstrate that this methodology works well when both of the counterparts are aromatic (R = R' = Ar).When both of the counterparts were aliphatic (R = C 15 H 31 , C 6 H 13 ; R' = Et), the studied DDQ-promoted oxidative cyclization was not successful.The transformations with N-acylhydrazones 3t-v containing aliphatic chains required long reaction times and gave trace amounts of the desired 1,3,4-oxadiazoles 4t-v.This observation in the trend of yields is due to the decomposition of these acyclic substrates during the reaction and the formation of numerous unidentified by-products.
It should be noted that the final products can be synthesized via two alternative pathways, that utilize different substrates.As shown in Scheme 2, 2-(2-furyl)-5-phenyl-1,3,4-oxadiazole (4d) was obtained from N'-(2-furylmethylene)benzhydrazide (3d, Path A) or N'-benzylidene-2-furancarbohydrazide (3d', Path B).While Path B gave a slightly better result in terms of both yield and time in comparison to Path A, based on the above observations, we concluded that there is no significant correlation between the type of starting substrate and the reaction yield.In addition, the synthesis of the final 1,3,4-oxadiazoles 4a-s could be performed as a one-pot procedure without isolation and purification of the intermediate N-acylhydrazones 3a-s.For this purpose, the starting acid hydrazides 1a-i were heated at reflux with the appropriate aldehydes 2a-h in dry toluene, in the presence of catalytic p-TsOH and DDQ.To our delight, all substrates underwent smooth oxidative cyclization to form 2,5-disubstituted 1,3,4-oxadiazoles 4a-s, mostly in good yields (22-95%, Table 2).The one-pot procedure proved to be useful and effective, giving the desired products in yields comparable to results obtained using a two-step reaction sequence.It is also worth noting that the one-pot synthetic methodology saves time, energy and the excessive usage of solvents by eliminating the isolation of the intermediates.
The structures of all the synthesized 1,3,4-oxadiazoles 4a-v were confirmed by elemental analyses and spectroscopic methods.To confirm the structures of the final products 4, an X-ray analysis was also performed on a typical example.The molecular structure of 2-(3-chlorophenyl)-5-(2-furyl)-1,3,4-oxadiazole (4l), with the atomic numbering scheme, is depicted in Figure 1.There are very few structures of unsymmetrically substituted 1,3,4oxadiazoles with 2-furyl and phenyl substituents in The Cambridge Crystallographic Database 2015 (Figure 2, JUGZIU, 83 LODZUZ, 84 PODZIR 85 and for comparison a symmetrical structure NAXDOF 86 ).However, all of them have the same opposite, trans conformation of the C-O bonds in the oxadiazole and furan rings.Although, the molecules express a high degree of planarity, not exceeding 13 o (there is a perpendicular benzene ring in PODZIR due to another azole fragment in the R group), 4l belongs to the most planar structures within this small family (the plane of the furyl ring forms a 5.20 o (0.23) angle with the oxadiazole ring, while the latter is twisted out 4.57 o (0.20) from the plane of the phenyl ring).A weak C-H…N intermolecular interaction (2.748 Å) is found between a furan fragment and another oxadiazole moiety.We have demonstrated the general utility and application of DDQ for the synthesis of 2,5-disubstituted 1,3,4oxadiazoles.We have reported that the formation of such heterocycles proceeded smoothly via intermediate N-acylhydrazones or directly from acid hydrazides and aldehydes in a one-pot procedure.The studied DDQpromoted oxidative cyclization was successful especially for the conjugated arrangements.This methodology is a promising alternative for the preparation of a variety of 1,3,4-oxadiazole derivatives due to compatibility with a wide range of substrates, good functional group tolerance, short reaction times, high yields, the use of easy accessible, non-toxic reagents and the possibility of regeneration of the oxidizing agent.

Experimental Section
General.All solvents and reagents were purchased from commercial sources and used without further purification.Melting points were determined on a Stuart SMP3 melting point apparatus without corrections.1 H and 13 C NMR spectra were recorded on an Agilent 400-MR spectrometer using DMSO-d 6 or CDCl 3 as the solvent and TMS as the internal standard.Elemental analyses were performed with a VarioEL analyser.FT-IR spectra were recorded between 4000 and 650 cm -1 on an FT-IR Nicolet 6700 apparatus with a Smart iTR accessory.UV-Vis spectra were recorded on a Jasco V-650 spectrophotometer.High-resolution mass spectra were obtained on a Waters ACQUITY UPLC/Xevo G2QTof instrument.Thin-layer chromatography was performed on silica gel 60 F 254 (Merck) TLC plates using benzene/EtOAc (3:1 v/v) as the mobile phase.Column chromatography was carried out using Merck silica gel (200-300 mesh) and benzene/EtOAc (3:1 v/v) as the eluent.
The 1 H NMR spectroscopic studies proved the successful DDQ-promoted oxidative cyclization of N-acylhydrazones 3a-v by the disappearance of peaks corresponding to CH=N and NH protons.Additionally, we observed the disappearance of signals belonging to CH=N and C=O carbon atoms in the 13 C NMR spectra.The diagnostic signals corresponding to two ring carbon atoms C2 and C5 were seen in the range of 157-169 ppm.The chemical shifts of these carbon atoms were dependent on the substituents at the 2-and 5-positions of the 1,3,4-oxadiazole ring.