Synthesis of trans-1,2-bis(2-R-amino-1,3,4-thiadiazol-5-yl)ethene and trans-1,2-bis[3-(4-substituted-[delta]2-1,2,4-triazoline-5-thione)]ethene - Biblioteka UMCS

ANNALES

U N I V E R S I T A T I S MARIAE C U R I E - S K Ł O D O W S K A

LUBLIN — POLONIA

VOL. L/LI,6 SECTIO AA 1995/1996

School of Medicine, Lublin

MARIA DOBOSZ * . MONIKA WUJEC * . MONIKA PITUCHA *

Synthesis of trans- 1,2-bis(2-R-amino-l,3,4-

-thiadiazol-5-yl)ethene and trans-l,2-bis[3-(4- -substituted-A 2 -1,2,4-triazoline-5-thione)] ethene

Synteza trans-1,2-bis(2-R-amino-1,3,4-tiadiazol-5-yl)etenu i trans-1,2-bis[3-(4-podstawionych-A2-1,2,4-triazolino-5-tionu)]etenu

INTRODUCTION

Depending on the nature of substituents the derivatives of 1 ,2,4-triazole and 1,3,4-thiadiazole can show various pharmacological activity. There are known drugs containing the 1 ,2,4-triazole group e.g. Triazolam [1], Alprazolam [2], Etizolam [3], Furacrylin [4] and drugs containing 1,3,4-thiadiazole'group e.g.

Acetazolamide [5], Benzolamide [6], Methazolamide [7], Furidazine [8]. De­

rivatives of the 1,2,4-triazole and 1,3,4-thiadiazole could be prepared in the cyclization of acyl derivatives of thiosemicarbazide. The reactions were carried out in acidic media. Cyclization of alkaline medium leads to 1 ,2,4-triazole sys­

tem [9-14] and in the acidic medium 1,3,4-thiadiazole were obtained [13,14].

In the previous papers [15-18] it was stated that the reaction of cyclization was affected not only by pH of the medium but also by the substituents in thio­

semicarbazide derivatives.

Cyclization of thiosemicarbazide derivatives containing the substituents of acidic nature led with good yield to 1,3,4-thiadiazole and with lower yield to 1 ,2,4-triazole system [15,16] .Cyclization of thiosemicarbazide derivatives con-

Chair and Department of Organic Chemistry, Pharmaceutical Faculty, Akademia Medyczna,

20-081 Lublin, ul. Staszica 6.

taining the substituents of alkaline nature wither in alkaline or in acidic media led to 1,2,4-triazole system with good yield [15,17,18].

It has been found that the direct cyclization of hydrazides acids with iso­

thiocyanates to 1,2,4-triazole and 1,3,4-thiadiazole system is possible as well.

This fact has been unknown in literature up to now. The direction of these reac­

tions depended on the substituents in acyl group of hydrazides acids. The ob ­ taining of 1 ,2,4-triazole and 1,3,4-thiadiazole derivatives was possible from hydrazides acids too. The conditions of reaction of hydrazides acids with iso­

thiocyanates were established experimentally. Derivatives of 1,2,4-triazole and 1,3,4-thiadiazole were obtaining not in each case. In this paper there are shown the results of studies on the reaction of cyclization of fumaroil thiosemicarba­

zide derivatives in alkaline and acidic media and possibility of cyclization of hydrazide fumaric acid with isothiocyanates.

INVESTIGATIONS, RESULTS AND DISCUSSION

Thiosemicarbazide derivatives were obtained in the reaction of the hy­

drazide of fumaric acid with isothiocyanates. The reactions were carried out by heating substrates in the alloy for 10h at the temperature of 100°C. The reac­

tions of cyclization of thiosemicarbazide derivatives in alkaline media run ac ­ cording to the scheme 1.

Cyclization of thiosemicarbazide derivatives obtained from hydrazide of fumaric acid and aromatic isothiocyanates (I-VI) in this medium led to forma ­ tion of the mixture containing derivatives of 1,3,4-thiadiazole (high yield 65-70 % ) and l,2,4-triazoline-5-thione (low yield 16-25 %). The cyclization of the same thiosemicarbazide derivatives in acidic medium led only to formation of 1,3,4-thiadiazole (yield 30-42 %). Cyclization of thiosemicarbazide deriva­

tives obtained from hydrazide of fumaric acid and ethyl and ethoxycarbonyl­

methyl isothiocyanates (VII, VIII ) in alkaline medium led only to formation of derivatives of 1 ,2,4-triazole system. During cyclization of thiosemicarbazide derivatives with ethoxycarbonylmethyl group, hydrolysis of ester group took place as well. The same compounds were obtained also in the reaction of cycli­

zation performed in acidic medium. The derivatives of 1,3,4-thiadiazole (IX-

XIV) were obtained also by the heating of hydrazide of fumaric acid with

aromatic isothiocyanates in alloy for 10h at the temperature of 140°C and in

N,N-dimethylacetamide at boiling point. The structure of obtained products in

Synthesis of trans-l,2-bis(2-R-amino-l,3,4-thiadiazoI-5-yl)ethene and ... 69

the paper was confirmed by elemental analysis as well as by IR and 'H NMR spectra.

CH-CO-NH-NH-Ç-NH-R CH-CO-NH-NH-Ç-NH-R II ś

R = с6н5 , p - och 3 c 6 h 4 , 2- ch 3 c 6. h 4 , з-сн3сбн4 , 4- ch 3 c 6 h 4 ,

p-BrC6H4 , C2H5 ( VII,XXI ) , CH2C00C2H5 ( VIII ) , СН2С00Н (XXII )

In IR spectra of thiosemicarbazide derivatives I-VIII the characteristic ab­

sorption bands were observed: 1668-1685 cm'1 corresponding to CH=CH group of isomer trans, 1670-1720 cm'1 corresponding to C=O group and 3180- 3360 cm 1 corresponding to NH group.

'H NMR spectra of thiosemicarbazide derivatives I-VIII have 3 protons signals, typical of NH group in the range from S 8.0-10.0.

In the IR spectra with 1 ,3,4-thiadiazole IX-XIV there were observed the ab­

sorption bands for NH group 3200-3300 cm' 1 , absorption bands for CH=CH

group of isomer trans 1614-1680 cm' 1 and absorption bands for C-S-C group of thiadiazole 710-750 cm'1 [19].

In 'H NMR spectra of this compounds IX-XIV have the proton signals typi­

cal of NH group in the range from 5 8.9-10.1.

In the cyclic compounds containing 1,2,4-triazole system XV-XXII in IR spectra there were observed the absorption bands of group C-N 1540- -1560 cm' 1, C=N 1610-1640 cm'1 [20-22] and CH=CH of isomer trans 1646- -1684 cm' 1. In ‘ H NMR spectra of 1,2,4-triazole derivatives XV-XXII proton signals for N ^C=S group in the range from 5 13.1-13.5 were observed. The

HN

'HNMR spectra derivatives of thiosemicarbazide, 1,3,4-thiadiazole and 1,2,4- triazoline-5-thione have the proton signals typical of CH=CH group in the range from ô 6.1-8.0.

The investigations described in this paper have shown that the presence of CH=CH group in the molecules of hydrazide and thiosemicarbazide of fumaric acid promotes significantly cyclization to derivatives of 1,3,4-thiadiazole sys­

tem. In the reactions of cyclization of hydrazide of fumaric acid with aromatic isothiocyanates only 1,3,4-thiadiazole system was obtained. The same deriva ­ tives also with good yield were obtained in the reaction cyclization derivatives of thiosemicarbazide formed from hydrazide fumaric acid and aromatic isothio ­ cyanates. Derivatives of 1,2,4-triazole system were obtained with low yield by cyclization of fumaroil thiosemicarbazides.

The results of these investigations confirm our earlier suppositions relating to the effect of substituents present in molecules of thiosemicarbazide deriva­

tives on the course of cyclization of acyl thiosemicarbazide derivatives to 1,3,4- thiadiazole and 1,2,4-triazole system.

EXPERIMENTAL

Melting points were determined in Fischer-Johns block and presented with ­

out any corrections. IR spectra were recorded in KBr Perkin Elmer FT 1725 X

spectrophotometer. The 'H NMR spectra were recorded on Tesla BS-567 A

spectrometer (100Hz) in DMSO-d6 with TMS as internal standard.

Synthesis of trans- l,2-bis(2-R-amino-l,3,4-thiadiazol-5-yl)ethene and ... 71

1. Fumaroil thiosemicarbazides (I-VIII)

The 0.01 mole of hydrazide of fumaric acid and 0.02 mole isothiocyanates was mixed carefully and then placed in round-bottomed flask, and heated on oil bath at temperature of 35-100 °C for 8h.

Then the product of the reaction was washed with ethyl ether in order to remove the unreacted isothiocyanate and then with water to remove the unre­

acted hydrazide. The product was filtered and dried and then crystallized from ethanol.

The data relating to the compounds I-VIII are listed in Table 1.

2. Trans /,2-bis(2-R-amino-I ,3 ,4-thiadiazol-5-yl)ethene (IX-XIV) and trans 1,2-bis[3-(4-substituted-A2-1,2,4-triazoline-5-thione)l ethene (XV-XXII)

Method A

The 0.01 mole thiosemicarbazide derivatives (I-VIII) was placed in a (round-bottomed flask equipped with reflux and 10cm of 2% solution of so ­ dium hydroxide was added. The flask was heated for 2h. Hot solution was fil­

tered and the obtained derivatives of 1,3,4-thiadiazole (IX-XIV) were crystal ­ lized from ethanol. The data relating to these compounds are listed in Table 2.

After the cooling the filtrate was neutralized with diluted hydrochloric acid.

The precipitated compound was filtered and crystallized from ethanol. The data related to the l,2,4-triazoline-5-thione derivatives (XV-XXII) are listed in Ta ­ ble 3.

Method В (IX-XIV)

The mixture of 0.01 mole of hydrazide of fumaric acid and 0.02 mole of

isothiocyanate was heated in a round-bottomed flask on oil bath for 10h at the

temperature of 140°C. The product of reaction was washed with ethyl ether to

remove the unreacted isothiocyanate and then with water to remove the unre ­

acted hydrazide. The residue solid was crystallized from ethanol. The same

products as in the method A were obtained.

Method C (IX-XIV)

The 0.01 mole of hydrazide of fumaric acid and 0.02 mole of isothiocyanate in 10cm3 of the N,N-dimethylacetamide was heated in a round-bottomed flask at boiling point for 10h. After cooling the solution 40cm 3 of water was added.

Precipitated compound was filtered, washed carefully with the ethyl ether and water, dried and crystallized from ethanol.

The same products as in the method A and В were obtained.

Method D (IX-XIV)

The 0.01 mole of thiosemicarbazide derivatives (I-VI) and 10cm 3 3N HO was refluxed for 2h. The mixture was kept for 24h at the room temperature. The precipitated product was filtered, dried and crystallized from ethanol. Mixed melting points have not shown any variations. IR and 'H NMR spectra the com­

pounds by the method A,B,C,D are identical.

3. Trans 1 ,2-bis[3-(4-substituted-A: -l,2,4-triazoline-5-thione)/ethene

Method В (XXI, XXII)

The 0,01 mole of thiosemicarbazide derivatives (VII, VIII) and 10cm3 3N HC1 was refluxed for 2h. The mixture was kept for 24h at the room temperature.

The precipitated product was filtered, dried and crystallized from ethanol. The same products as in the method A were obtained. Yield of reactions: 14-15 %.

REFERENCES

[1] Brucato A., Coppola A., Gianguzza S., Provenzano P.M., Ital. Biol.

Sper., 54, 1051, (1978).

[2] С о f f e n D.L., Fryer R.I., Pat. USA Chem. 3849434 (1975), Chem. Abstr., 82,730044v (1975).

[3] Shiroki M., Tahara T., Araki К., Jap. Pat. 75100096 (1975), Chem. Abstr., 84, 59588k (1976).

[4] P о V e I i t s a F.D., G u r a 1 A.G., Antibiotiki (Moscow) 18, 71 (1973).

[5] Fremont P., Riverin H., Frenette J., Rogers P.A., Cote C., Am. J.

Physiol., 260 (3,Pt,.2), R615-R621 (1991).

Synthesis of trans-l,2-bis(2-R-amino-1,3,4-thiadiazol-5-yl)ethene and ... 73

[6] Kenny A.D., Pharmacology, 31 (2), 97 (1985).

[7] Preston W.A., Doyon D.l.Simmons S.P., USA Pat., 410, 709 (1989).

[8] Cohen S.M., Ertruk E., V о n Esch A.M., C r о v e 11 i A.J., Bryan G.T., J. Natl. Cancer. Inst., 54, 841 (1975).

[9] Ainsworth C., J о n e s R.G., J. Am. Chem. Soc., 76, 5651 (1955).

[10] Jones R.G., Ainsworth C.,J. Am. Chem. Soc., 77, 1538 (1955).

[11] Hogarth E„ J. Chem. Soc., 1163 (1949).

[12] Fry D.J., Lambie A.J., Brit. Pat. 741228, (1955).

[13]

[14]

[15]

[16]

[17]

[18]

[19]

Godfrey L.E.A., Kurzer F., J. Chem. Soc., 5137 (1961).

Kurzer F., C a n e 11 e J., Tetrahedron, 19, 1603 (1963).

Dob Dob Dob Dob Dobosz

о о о о

s z s z s z s z

M., P i t u c h а М., Wujec М., Acta Polon. Pharm., 52, No 2, 103 (1995).

M., Pachuta-Stec A., Acta Polon. Pharm., 52, No 2, 103 (1995).

M., Sikorska M., Acta Polon. Pharm., 51, 369 (1994).

M., Maliszewska-Guz A., Ann. UMCS, Sec. AA, 46/47,50 (1991/1992).

M., Pachuta-Stec A., Acta Polon. Pharm., 51, 457 (1994).

[20] Mohan J., Anjaneyulu G.S.R., Polish J. Chem., 61, 545 (1987).

[21 ] Wiles D.M., Suprunchuk T., Can. J. Chem., 46, 701 (1968).

[22] K r a e b e 1 C.M.. Davis S.M., London M.J., Spectrochini. Acta, 23 A, 2541 (1967).

STRESZCZENIE

Reakcje pochodnych tiosemikarbazydowych kwasu fumarowego w środowisku zasadowym prowadziły do otrzymania pochodnych 1,3,4-tiadiazolu i l,2,4-triazolino-5-tionu. Cyklizacja pochodnych tiosemikarbazydowych kwasu fumarowego, otrzymanych z izotiocyjanianów aro­

matycznych w środowisku kwasowym, prowadziła tylko do pochodnych 1,3,4-tiadiazolu. Te same pochodne 1,3,4-tiadiazolu otrzymano również przez ogrzewanie hydrazydu kwasu fumarowego z izotiocyjanianami aromatycznymi w stopie lub w N,N-dimetyloacetamidzie.

Przeprowadzone badania wskazują, że obecność grupy CH=CH w cząsteczce hydrazydu lub

tiosemikarbazydu kwasu fumarowego sprzyja cyklizacji, w wyniku której otrzymujemy pochodne

1,3,4-tiadiazolu. Pochodne 1,2,4-triazolu zostały otrzymane z małą wydajnością przez cyklizację

pochodnych tiosemikarbazydowych kwasu fumarowego.

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