Improved synthesis and characterisation of 1,3,4-oxadiazole

Synthetic approaches to 1,3,4-oxadiazole have been investigated and an improved method involving dehydration of N,N' -diformylhydrazine with P 2 O 5 in polyphosphoric acid is described. The 13 C NMR spectrum of this compound is reported for the first time including determination of 1 J C–H and 3 J C–H .


Introduction
In the context of recent experimental and computational studies on the high resolution vibrational spectra of some fundamental heterocyclic compounds, [1][2][3][4][5][6] we needed to prepare 1,3,4oxadiazole 1. 7 Although this simple compound was first reported in 1965, 8 only one method has ever been described for its preparation, 9 and this involves thermal elimination of ethanol from compound 2, itself formed by reaction of N-formylhydrazine with triethyl orthoformate (Scheme 1).We have found this method to be unsatisfactory in various ways.The preparation of 2 must be carefully controlled to avoid formation of a 1,2,4-triazole byproduct, 9 it exists as a mixture of different E/Z isomers leading to complex, and as yet unexplained, NMR spectra and problems in obtaining it in pure crystalline form, and the final thermolysis reaction, reported to proceed in "about 50% yield", 9 was found to be unpredictable and to give yields in our hands ranging from 0-10%.We therefore set out to develop a more convenient synthesis and describe here the results.

Results and Discussion
We first re-examined the literature method in an attempt to overcome the problems encountered.In our hands, heating the solid compound 2 above its melting point under atmospheric pressure and collecting the liquids which distilled off afforded mainly ethanol and ethyl formate with <1% yield of 1.The use of various methods that would favour the intramolecular cyclisation with loss of EtOH as opposed to intermolecular reactions leading to polymerisation was attempted.Moving to vacuum distillation and mixing the compound 2 with an inert solid such as SiO2 was of little benefit.Flash Vacuum Pyrolysis (FVP), which involves passing the substrate through a furnace in a flow system under high vacuum, is well known as a method for clean and efficient extrusion reactions where polymerisation is to be avoided.This did result in a significant improvement with 1 being obtained in a reproducible 10% yield upon FVP at 600-700 °C, but the yield was still disappointing so attention was turned to alternative methods avoiding 2.

Scheme 1
An attractive alternative approach involves the cyclodehydration of the readily available N,N'-diformylhydrazine 3 but, although this is a well known route to oxadiazoles in general, 10 it does not seem to have been reported for the parent heterocycle.Exposure of compound 3, 11 to a variety of standard dehydration reagents and conditions showed that the desired transformation was not easily achieved (Table 1, entries 1-12).Part of the problem was that the methods tried for dehydrative cyclisation frequently involved acidic conditions under which the target product would be protonated.A basic work up followed by extraction was therefore used but this sometimes resulted in hydrolysis of the compound.The first sign of success came from treatment with P2O5 in toluene (entry 13).By moving to polyphosphoric acid, a much better result was achieved (entry 14), but we were concerned to find that repeating this reaction with newly purchased polyphosphoric acid gave no product (entry 15).The problem was eventually traced to the fact that the original polyphosphoric acid was dehydrated with a crust of solid around the bottle and this effect could be duplicated by addition of 10% w/w of P2O5 to new polyphosphoric acid (entry 16).Even with this reagent, the reaction time proved to be critical with too long a reaction time again leading to no product (entry 17).The other important aspect was found to be the work-up.Initially we neutrallised the reaction mixture with aqueous NaOH before extracting with CH2Cl2 but it was later found to be better to use the milder base NaHCO3 to minimise losses through hydrolytic breakdown of product 1.By using these conditions we have been able to prepare multi-gram quantities of 1,3,4oxadiazole as required for spectroscopic investigation, and the high-resolution vibrational spectra have already been published. 7Compound 1 is a colourless liquid with bp 150 °C and shows a 1 H NMR signal in CDCl3 at H 8.52 (Lit., 8 8.73).We were surprised to discover that, despite detailed studies of the 15 N and 14 N NMR spectra having been reported some time ago, 12,13 the 13 C NMR spectrum of this fundamental heterocyclic compound has apparently remained unreported until now.The observed chemical shift of C 152.7 is in good agreement with values reported for similar compounds such as C-2 of oxazole (C 151.2) 14 and thiazole (C 152.8). 14By recording the undecoupled 13 C NMR spectrum, the C-H coupling constants were determined as 1 JC-H = 234 Hz and 3 JC-H = 5 Hz.
Finally, we were attracted by the recent reports of Ramazani and Souldozi, 15,16 that aromatic carboxylic acids may be converted directly into 2-aryl-1,3,4-oxadiazoles under mild conditions by treatment with isocyanoiminotriphenylphosphorane, Ph3P=N-N=C:.This phosphinimine was readily prepared, 17 but unfortunately attempts to react it with formic acid under a wide variety of conditions gave no trace of 1,3,4-oxadiazole 1.

Experimental Section
General.NMR spectra were obtained for 1 H at 300 MHz and for 13 C at 75 MHz using a Bruker AM300 instrument.All spectra were run on solutions in CDCl3 with internal Me4Si as reference.Chemical shifts are reported in ppm to high frequency of the reference and coupling constants J are in Hz.N-Formylhydrazine was prepared from ethyl formate and hydrazine hydrate using the reported method 18 and converted into compound 2 as described. 9N,N'-Diformylhydrazine 3 was prepared from hydrazine sulfate and sodium formate using the literature method. 113,4-Oxadiazole (1).Polyphosphoric acid (18.0 g) was stirred at 80-100 °C while P2O5 (2.0 g) was added, followed after 15 min by N,N'-diformylhydrazine 3 (2.0 g, 35.7 mmol).The mixture was stirred at 100 °C for 4 h and then added to ice (100 g).The resulting mixture was neutrallised by addition of NaHCO3 (13.8 g) and then extracted with CH2Cl2 (3  50 cm 3 ).Drying and evaporation of the extract gave the product (0.42 g, 30%) as a colourless liquid, bp ~150 °C; H 8.52 (2 H, s); C 152.7; C (undecoupled) 152.7 (dd, J 234, 5) ; HRMS (CI) Calcd.