2, 5 - D I A L K Y L - 1 , 3, 4 - O X A D I A Z O L E S

M. S. S k o r o b o g a t o v a , Y a . /~. L e v i n , a n d O. A. R a e v s k i i

UDC 547.793

A single stage method has been developed for the prepara t ion of 2, 5-dialky-1, 3, 4- oxadiazoles f rom aliphatie carboxylic acids, by boiling with hydrazine hydrochlor ide in phosphoryl chloride. A mechanism for the synthesis is suggested. The oxadiazoles are charac ter ized , and the group ref rgc t iv i ty of the 1, 3, 4-oxadiazole r ing has been de t e r - mined.

1, 3, 4-Oxadiazoles are usually p repa red f rom carboxylic acids and hydrazides . All the reac t ions in these mult is tage syntheses are condensations, leading to activation of the acid molecules , and fur ther r e a c - tion of the active species with hydrazine at both nitrogen atoms, followed by in t ramolecular se l f -condensa- tion to give the oxadiazole. It is of course desi rable , therefore , that conditions are se lected which are sui t- able for each stage, and to c a r r y out the synthesis in such a way that it is not neces sa ry to isolate the var ious in termedia te products . A number of papers have appeared which are devoted to the synthesis of 2, 5-diaryl -1 , 3, 4-oxadiazoles by indirect methods f rom carboxylic acids [1-3].

We have repor ted previously [4] on the possibil i ty, in principle, of a s ingle-s tage prepara t ion of the hi therto di f f icul t ly-access ible 2, 5-dialkyl-1, 3, 4-oxadiazoles . It seemed that it would be possible to use phosphoryl chloride as the overal l condensing agent. The use of polyphosphoric acid [1, 3] or sulfur t r ioxide [2] was contraindicated by the need to t r ea t the reac t ion mixture with water if these reagents were used, whereas the use of phosphoryl chloride makes it possible to isolate the oxadiazo!es by distillation, which is pa r t i cu la r ly valuable in the case of the read i ly -hydro lyzed lower homologs [5]. The reac t ion wa~ successful when normal and iso-acids , f rom propionic upwards, were used, and also using mixed acids. In the la t te r case, a mixture of the two symmet r i ca l and the unsymmet r i ca l oxadiazoles was obtained. Halosubstituted and dibasic acids did not give oxadiazoles under these conditions.

In o rde r to obtain sa t i s fac tory yields, it was found neces sa ry to t r ea t the react ion mixture, af ter completion of the main react ion, with phosphorus pentachloride in o rd e r to convert the non-volat i le hydro- lys is products of phosphoryl chloride which were formed in the react ion (chloropolyphosphoric acid, CPPA) into phosphoryl chloride. This t rea tment proved par t icu lar ly valuable in the prepara t ion of oxadiazoles, bear ing substitutents f rom butyl upwards.

Bearing in mind the possibil i ty of activating carboxylie acids by the format ion of both the i r acid chlo- r ides and the aeylphosphoryl dichlorides, the single stage synthesis of I may be r ep resen ted by the following scheme:

RCOOH + POCI 3 +N2H 4. 2 HCI + RCOCI(RCOOPOCI2)

--CPPA, HC1 RCOCI(RCOOPOCI2) --HCI(POCI3) RCONHNH2 --HCI(POCI~) +

+ POCi 3 N ~ N N - - N H Cl-- - coN.N.co

I II

Arbuzov Institute of Organic and Physica l Chemistry, Academy of Sciences of the USSR. Trans la ted f rom Khimiya Geterots ikl ieheskikh Soedinenii, No. 9, pp. 1171-1175, September, 1970. Original ar t ic le sub- mit ted January 14, 1969.

�9 1973 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without permission of the publisher. A copy of this article is available from the publisher for $15.00.

1092

In the case of capronyl chloride, we showed that the fo rmat ion of the oxadiazole p roceeded in the same way if, instead of the acid, the acylchlor ide was used; the acid chloride could t he re fo re be an i n t e r - media te in the one - s t age synthes is . However, this does not exclude a pa raUe l course for the reac t ion via the acylchlorophosphate . The double reac t ion of hydrazine dihydrochloride with capronyl chlor ide also indi- ca tes the poss ib i l i ty of such a p roce s s , although s im i l a r reac t ions , as pointed out by Grekov [6], do not occur , in pa r t i cu l a r the reac t ion of acylhydrazine hydrochlor ides with benzoyl chlor ide in benzene solution. We have obse rved no reac t ion of hydrazine dihydrochloride with phosphoryl chloride, even on boiling.

It has been found that, in o rde r to avoid the format ion of oily impur i t i es , i t is n e c e s s a r y to add the acid and the hydrazine hydrochlor ide at the same t ime, which r e su l t s in the immedia te reac t ion of the acid chlor ide or acyldichlorophosphate as it is fo rmed, thus prevent ing the development of this p r o c e s s .

On dis t i l la t ion of the reac t ion mix tures , there was isola ted in every case as by-produc t the hydro- chloride of the oxadiazole (II), in addition to I. In o rder to conf i rm the s t ruc tu re of II, the hydrochlor ide of 2, 5-diethyl-1, 3, 4-oxadi~zole was p r e p a r e d by sa tura t ing the l a t t e r with hydrogen chlor ide. The sa l t - l ike s t ruc tu re of these compounds was indicated by the p r e s e n c e in the IR spec t rum of a broad, intense band at

+ 1850 cm -i, a t t r ibuted to deform~t ional v ibra t ion of the = N - - H 7 group [7].

I

The compounds obtained could, in addition to II, be ass igned s eve ra l s t ruc tu res , both cyclic and acyclic, with covalent chlor ine bonds, which could not be ruled out on the bas i s of the i r IR spec t ra . However, the absence of s ignals in the NQR C13~ spec t rum of these compounds is in ag reemen t with s t ruc tu re II alone, in which the chlor ide is p r e s e n t as the anion.

The II were obtained as e x t r e m e l y hygroscopic , low-melt ing, eas i ly -d i s t i l l ed compounds which d eco m- posed comple te ly in contact with water . On heating in vacuo, they los t hydrogen chloride with the fo rmat ion of I.

The s ing le - s t age synthes is of 2, 5-d imethyl -1 , 3, 4-oxadiazole d i rec t ly f rom acet ic acid was not ve ry successful , owing pa r t ly to the high volat i l i ty of acetyl chloride, entraining hydrogen chloride, and to the volat i l i ty of the oxadiazole hydrochlor ide in compar i son with that of the base . Bet ter y ie lds were obtained by us ing NN' -d iace ty lhydraz ine , but mos t sa t i s f ac to ry was the use of acetic anhydride and hydrazine d ihydro- chlor ide .

The 2, 5-dia lkyl-1 , 3, 4 -oxadiazo les were liquids with weak, noncharac te r i s t i c odors, readi ly misc ib le with organic solvents . The lower m e m b e r s were readi ly soluble in water , but the solubili ty dec rea sed with inc reas ing size of the alkyl r ad ica l s . 2 -E t hy l -5 -hexy l - and 2 - i sop ropy l -5 -hexy l -1 , 3-, 4-oxadiazole were insoluble in water . The lower I were read i ly hydrolyzed in neut ra l aqueous solution. Hydro lys i s of d ie thyl - oxadiazole with an equ imola r amount of water led to the rapid fo rmat ion of NN' -d iprop ionyl -hydraz ine , whilst 2, 5-dipentyl -1 , 3, 4 -oxadiazole exhibited cons iderable hydrolyt ic s tabil i ty.

The NMR s pec t rum of 2, 5-d imethyl -1 , 3 ,4-oxadiazole exhibits a single peak at 5 = 2.40 ppm, which fal ls in the range between the value fo r the group 6cH,-c= in dimethyl de r iva t ives of c a r b o - and he t e ro -

I cyc les [8], and d i f fe rs f r o m dimethyl ketazine: 2.00 and 1.82 [9]. This emphas izes the a roma t i c s t ruc tu re of the 1, 3, 4 -oxadiazo les .

The IR spec t rum of 2, 5-diethyl-1, 3, 4-oxadiazole in the mult iple bond v ibra t iona l region shows two s t rong bands with f requenc ies 1562 and 1593 cm -1, which are probably due to v ibra t ion of the oxadiazole r ing. These bands are shifted substant ia l ly towards lower f requencies in compar i son with azines [10], which is also a consequence of the a romat ic i ty of the oxadiazole ring. It is in te res t ing that, in the Raman spec t rum, both v ibra t ions a re active, although at shor t wavelength and much reduced in intensity. The oxa- d iazoles a re also dist inguished f r o m the re la ted azines [10], in the II~ spec t r a of which only ~ a s is active, whilst in the Raman spec t ra , v s is act ive. It i s suggested that this difference is connected with the cons ide r - able d i f fe rences in the nature of the osci l la t ing groups, in our case being concerned with a roma t i c r ing v ibra t ions .

The group r e f r ac t iv i t y for the 1, 3, 4-oxadiazole r ing was de te rmined by calculat ion f rom the ob- s e rved m o l a r r e f r ac t ion values for the group r e f r ac t ions of the two alkyl groups. The mean value for the group re f rac t ion for the 1, 3, 4 -oxadiazole ring, obtained by the l e a s t - s q u a r e s method, was 12.57 ~= 0.04,

1093

which is the same, within the l imi t s of expe r imen ta l e r r o r , with the value calculated by the additive method, us ing a r e f r ac t iv i ty for the ni t rogen a tom de te rmined f r o m i m i n o e s t e r s [11].

E X P E R I M E N T A L

2, 5-Dialkyl-1, 3, 4 -oxad iazo les . All the 1, 3, 4-oxadiazoles , with the exception of 2, 5-dimethyl-1 , 3, 4-oxadiazole , were obtained by the following method. A mix tu re of 0.4 mole of the carboxyl ic acid {or 0.2 mole of each acid in the synthes is of u n s y m m e t r i c a l oxadiazoles) , 0.2 mole of hydrazine hydrochloride, and 1.8 mole of phosphoryl chloride was heated at 60-80 ~ for 1-2 h, then boiled until the hydrazine sa l t had d i s - solved, and evolution of hydrogen chloride had ceased (6-8 hr) . To the cooled reac t ion mix tu re was added 0.6 mole of phosphorous pentachlor ide , and the mix tu re was boiled for a fu r the r 7-9 h. The phosphoryl chloride was then dist i l led in vaeuo, and the res idue was t r ea t ed with 100 ml of dry ch lo ro fo rm or benzene. The insoluble impur i t i e s were f i l te red off, the solvent removed, and the product red is t i l led in vaeuo. The 2, 5-dialkyl-1, 3, 4 -oxadiazo les thus obtained were contaminated with salt . This mix tu re was kept fo r 1-2 h in vacuo at a t e m p e r a t u r e somewhat lower than the bp of the oxadiazole, then slowly disti l led, which in mos t c a s e s gave the pure oxadiazole: the p rocedure was r epea ted if n e c e s s a r y . For final purif ication, the oxadi- azoles were dis t i l led again in vacuo (Table 1).

Reaction of Capronyl Chloride with Hydrazine Hydrochlor ide in Phosphoryl Chloride. A por t ion of capronyl chlor ide [46.27 g (0.344 mole)] and 1 8 . 0 5 g (0.172 mole) of hydrazine hydrochlor ide were boiled in phosphoryl chloride for 10 h. The mix tu re was f rac t iona ted to give 67.8% of 2, 5-dipentyl-1, 3, 4-oxadiazole .

2, 5-Dimethyl -1 , 3, 4-oxadiazole . a) F r o m NN' -Diace ty lhydraz ine in Phosphoryl Chloride, followed by T r e a t m e n t with Phosphorus Pentaehlor ide . A mix tu re of 5.00 g (0.043 mole) of N N ' - d i a c e t y l h y d r a z i n e and 20 ml (0.219 mole) of phosphoryl chloride was heated. At 70-77 ~ rapid solution Of the solid took place. accompanied by rapid evolution of hydrogen chlor ide. The solution was boiled for 1 h, cooled, and t r ea t ed with 9.9 g (0.048 mole) of phosphorus pentachlor ide . After boiling for a fu r the r 2 h, the mix tu re was d i s - t i l led in vaeuo to give a yield of 85.8%.

b) F r o m NN' -d iaee ty lhydraz ine and Thionyl Chloride in Dioxane. A mix tu re of 5.00 g (0.043 mole) of NN' -d iace ty lhydraz ine , 4 ml ofthionyl chloride, and 50 ml of dioxane was heated. The reac t ion p roceeded s i m i l a r l y to that desc r ibed above. After boiling for 3 h, the mix tu re was f rac t ionated in vacuo to give 1.1 g (21%) of 2, 5-dimethyl-1 , 3, 4-oxadiazole , identical with that obtained by method a).

c) F r o m Acetic Acid and Anhydrous Hydrazine . To 5 ml (5 g, 0.157 mole) of hydrazine was added dropwise with s t i r r ing and wate r cooling a solution of 18 m l (0.315 mole) of acet ic acid in 50 ml of dioxane fo l lowedby 35 ml (0.436 mole) of thionyl chloride. The mix tu re was kept at 50 ~ for 1 h, then boiled until evolution of hydrogen chlor ide ceased (4 h). A smal l quantity of so l idwas f i l te red off, and the f i l t ra te was dis t i l led in vacuo to give 1.8 g (11.7%) of the oxadiazole, having the same constants as the product of r e a c - t ion a).

d) F r o m Acetic Anhydride andHydraz ine Hydrochlor ide . A mix tu re of 21 g (0.2 mole) of hydraz ine hydrochlor ide and 61.26 g (0.6 mole) of acet ic anhydride was boiled until the solid had d isso lved completely , and the evolution of hydrogen chloride had ceased (9 h). The mix tu re was boiled for a fu r the r h, cooled, and subjected to slow f rac t iona l dist i l lat ion at a tmospher i c p r e s s u r e . The f rac t ion boiling at 150-250 ~ was r e - dis t i l led s e v e r a l t imes to give 6.1 g (31%) of product ident ical with that obtained by method a).

2, 5 -D ime thy ! - i , 3, 4-Oxadiazole Hydrochlor ide . A por t ion of acet ic acid [36 m l (0.57 mole)], 26.1 g (0.25 mole) of hydrazine hydrochloride, and 136 m l (0.53 mole) of phosphoryl chlor ide were heated with s t i r r ing at 68-75 ~ for 2 h, then boiled for 3 h 30 min. The reac t ion mix tu re was cooled, and 120 g (0.57 mole) of phosphorus pentachlor ide was added. The mix tu re was boiled for a fu r the r 4 h, then dist i l led in vacue to give 4.66 g of the oxadiazole salt, which was pur i f ied for analys is by subl imation in vacuo at 10 m m (Table 2).

2, 5-Diethyl-1, 3 ,4-Oxadiazole Hydrochlor ide , a) Dry hydrogen chlor ide was pa s sed through 3.26 g (0.027 mole) of 2, 5-diethyl-1, 3, 4-oxadiazole , the t e m p e r a t u r e r i s ing rapidly to 144 ~ The v iscous m a s s was c rys ta l l i zed in vaeuo at 10 mm, without heating above 35 ~ The c rys ta l l ine product was t r ea t ed with n-pentane, f i l te red off, and dr ied to give 3.1 g (70%) of product .

b) Obtained together with the oxadiazole by reac t ion of propionie acid with hydrazine hydrochlor ide followed by dist i l lat ion of the reac t ion mix tu re . After washing with n-hexane under dry carbon dioxide, the product was ident ical with the sa l t obtained by method a).

1094

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2, 5-Dipentyl-1, 3, 4-oxadiazole hydrochloride was obtained together with the free oxadiazole, and was isolated as described above.

Decomposition of 2,5-Diethyl-l,3,4-oxadiazole Hydrochloride. A portion of the salt [1.62 g (0.01 mole)] was heated at 60-70 ~ for 4 h under a vacuum of 10 mm, hydrogen chloride being evolved from the melt. The temperature was then raised to 95 ~ and 0.51 g (40~ of 2, 5-diethyl-1, 3, 4-oxadiazole was dis- tilled off.

Hydrolysis of 2, 5-dialkyl-1, 3, 4-oxadiazoles. A mixture of 1 g (0.008 mole) of 2, 5-diethyl-1, 3, 4- oxadiazole and 0.14 g (0.008 mole of water was converted into a colorless crystalline mass on standing for two days at room temperature. Recrystallization from light petroleum gave NN'-dipropionylhydrazine, mp 134-135 ~ [12].

Under similar conditions, and on boiling an aqueous alcoholic solution of 2, 5-dipentyl-1, 3,4-oxadi- azole, no hydrolysis occurred, but on standing in contact with atmospheric moisture for several months, crystals of NN'-dicapronylhydrazine, mp 157.5 ~ were formed (according to [13], mp 159~

IR spectra were recorded on a UR-10 instrument. The compounds were trapped as drops between KBr discs, so that the layer thicknesses were not known. The recording rate was 150 cm- l /min using a re ta rder . The spectral slit width was varied in the spectral range under investigation according to pro gramme 4.

The Raman spectra were obtained in the liquid phase on an ISP-51 instrument, with a photoelectric recorder . The spectral slit width was ~4-5 cm-1. Toluene was used as standard.

11. 12. 13.

L I T E R A T U R E C I T E D

1. CIBA Ltd., British Patent 896219 {1962); C. A., 5_.88, 12574 (1963). 2. A . P . Grekov, KhGS, 352 {1966). 3. Ya. A. Levin and M. S. ~korobogatova, KhGS, 1114 (1967). 4. Ya. A. Levin and M. S. Skorobogatova, KhGS, 1128 {1967). 5. Y. Iwakura, K. Uno, and S. Hara, Maeromol. Chem.,9_44, 103 (1966). 6. A . P . Grekov and M. S. Marakhova, Collection: Scintillators and Scintillating Materials [in Russian],

3, 24 (1963). 7 A: Bellamy, The Infrared Spectra of Complex Molecules [Russian translation], Moscow, 355 (1963). 8 Varian catalog of NMR-Speetra, vols. 1, 2. 9. Yu. Yu. Samitov, in: Some Problems in Organic Chemistry [in Russian], KGU, Kazan, 221 {1964).

10. Yu. P. Kitaev, L. E. Nivorozhkin, S. A. Flegontov, O. A. Raevskii, and Z. S. Titova, DAN 178, 1328 (1968). B. V. Ioffe, Handbook of Refractometry for Chemists [in Russian], izd. LGU, 177 (1956). Beilst. 2, 247. Beilst. 2, 324.

1096