SYNTHESIS OF SOME NEW HETEROCYCLIC COMPOUNDS …

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Tamara et al. World Journal of Pharmacy and Pharmaceutical Sciences

SYNTHESIS OF SOME NEW HETEROCYCLIC COMPOUNDS

DERIVED FROM 2-NAPHTHOIC ACID AND 4-METHYL BENZOIC

ACID

Tamara T. Fatah* and Amal N. Ali

*Department of Chemistry, College of Education for Pure Science, University of Mosul.

ABSTRACT

In this paper, the acid hydrazides (2-naphthohydrazide,4-methyl

benzohydrazide) is converted into substituted 1, 3, 4-oxadiazole-

2(3H)-one (1, 2) when treated with ethyl chloroformate in n-butanol

and then these compounds are converted to substituted 4-amino-2H-1,

2, 4-triazole-3(4H)-one (3, 4) when treated with hydrazine hydrate in

n-butanol, and then hydrazides are converted to substituted potassium

hydrazine-1-carbothioate (5, 6) by reaction with carbone disulfide and

potassium hydroxide which is converted to substituted 1, 3, 4-

thiadiazole-2 (3H)-thione (7, 8) and substituted 1, 3, 4-oxadiazole-

2(3H)-thione (9,10) by treated with concentrated sulfuric acid and

hydrochloric acid in absolute ethanol respectively. The two compounds 2-amino-5-

substituted-1, 3, 4-thiadiazole (11, 12) which are prepared by treated substituted

thiosemicarbazides with concentrated sulfuric acid converted to some substituted schiff bases

(13-18) by reaction with benzaldehyde derivatives in ethanol and added drops of glacial

acetic acid, the schiff bases derivatives product then converted to 2-(substituted)-3 (5-(4-

methyl benzyl or naphthalene-2-yl)-1, 3, 4-thiadiazol-2-yl) thiazoliden-4-one (19-24) when

treated with thioglycolic acid in presence of anhydrous zinc chloride in methanol. The

structures of the synthesized compounds have been confirmed by physical and spectral data.

KEYWORDS: 1, 3, 4-thiadiazole, 1, 2, 4-triazole, Schiff bases, thiazoliden.

INTRODUCTION

Many years ago, there had been tremendous growth in the study of heterocyclic compounds

containing nitrogen and sulfur due to their importance and entry into various applications

such as medicines, fuel, explosives and fireworks.[1]

where 1, 2, 4-triazole and 1, 3, 4-

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 8, Issue 10, 1165-1177 Research Article ISSN 2278 – 4357

Article Received on

19 August 2019,

Revised on 09 Sept. 2019,

Accepted on 29 Sept. 2019,

DOI: 10.20959/wjpps201910-14852

*Corresponding Author

Tamara T. Fatah.

Department of Chemistry,

College of Education for

Pure Science, University of

Mosul.


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thiadiazole compounds show biological importance which act as an analgesic[2]

,

anticonvulsant[3]

, antiviral[4]

, antifungal[5]

, antibacterial[6]

, antihypertensive[7]

and

antidepressant.[8]

A large number of ring systems containing triazoles and thiadiazoles have

been incorporated into a wide range of therapeutically interesting drugs such as alprazolam[9]

,

etizolam[10]

, vorozole[11]

, letrozole[12]

and others. The present research also dealt with schiff

bases, which is one of the widespread compounds, which are organic compounds containing

in the composition of the group azomethin (CH=N) attended by the German scientist Schiff

for the first time in 1864 through a simple condensing reaction which is the interaction of

primary aromatic and aliphatic amines with aldehydes or ketones. These compounds contain

the N or C groups that increase their stability and keep them from decomposing.[13]

Schiff

bases are obtained during the condensation between the carbonyl group and the primary

amines, as the mono alkyl amine (R-NH2) or the mono aryl amine (Ar-NH2) is added to the

carbon of carbonyl group following aldehyde or ketone and is composed of an intermediate

compound, followed by a molecular loss water to form (N-Substituted imine), which

represents the schiff base of the final product.[14,15]

EXPERIMENTAL

HNMR spectra has been recorded on nucleic magnetic resinous model 400MHz Bruker

Analytische Messtechnik GmbH, using DMSO-d6 as solvent. Infrared Spectrophotometer

Model Tensor 27, Bruker Co. Germany and Shimadzu-8400S was used to record IR spectra

using KBr dises. Melting point data was measured using electro thermal 1A 9100 melting

points apparatus type (not corrected).

Synthesis of 5-substituted-1, 3, 4-oxadiazole-2(3H)-one (1, 2)[16]

A mixture of acid hydrazide (0.02mole) and ethyl chloroformate (0.02mole) in n-butanol

(20ml) was refluxed with stirring for 20 hours, then the reaction mixture was cooled. The


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resulting solid was filtered and washed with ethanol, dried and re-crystallized from acetic

acid. The chemical and spectra data of the compounds (1) and (2) are given in table 1 and 4.

Synthesis of 4-amino -5-substituted-2H-1, 2, 4-triazole-3(4H)-one (3, 4)[17]

A mixture oxadiazole (1, 2) (0.02mole) and hydrazine hydrate (0.02mole) in n-butanol

(20ml) was refluxed with stirring for 15 hours, then the product was cooled. The resulting

solid was filtered and washed with ethanol, dried and re-crystallized from ethanol. The

chemical and spectra data of the compounds (3) and (4) are given in table 1and 4.

Synthesis of potassium-2-(Substituted) hydrazine-1-carbodithioate (5, 6)[18]

Carbon disulfide (0.02 mole) was added drop wise to an ice cooled solution of (2g) KOH in

ethanol (20ml) containing the acid hydrazide (0.02mole), the reaction mixture was stirred at

room temperature 12 hours. After dilution with ethanol the solid precipitated was washed

twice with ether. The chemical and spectra data of the compounds (5) and (6) are given in

table 1.

Synthesis of 5-substituted 1, 3, 4-thiadiazole-2(3H)-thione (7, 8)[19]

A cold solution of the carbodithioate (5, 6) (1g) was added dropwise to ice cold concentrated

H2SO4 (10ml) with continuous stirring 24 hours, then added to cruched ice. The solid

separated was washed with water, filtered and dried then re-crystallized from ethanol. The

chemical and spectra data of the compounds (7) and (8) are given in table 1and 4.

Synthesis of 5-substituted-1, 3, 4-oxadiazole-2(3H)-thione (9, 10)[20]

A cold solution of the carbodithioate (5, 6) (0.003 mole, 1g) dissolved in absolute ethanol (20

ml), was refluxed for 10hours. The reaction mixture was concentrated, dissolved in water,

then after acidification with conc. HCl the solid separated was washed with water, filtered,

dried and re- crystallized from ethanol. The chemical and spectra data of the compounds (9)

and (10) are given in table 1.

Synthesis of 2-amino-5- (substituted)-1, 3, 4-thiadiazole (11, 12)[21]

First method

A concentrated H2SO4 (10 ml) was added to (0.002mole) substituted thiosemicarbazide, the

mixture was stirred at room temperature 1 hour, then heated on water bath with stirring for 2

hours at (90 C°), then added to cruched ice and equivalent by using concentrated ammonium


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hydroxide, the product filtered, washed with water, dried and re-crystallized from ethanol.

The chemical and spectra data of the compounds (11) and (12) are given in table 1.

Second method

A carboxylic acid (0.5mole) dissolved in (20ml) concentrated H2SO4 with stirred, then added

(0.5mole,4.6 g) of thiosemicarbazide, the mixture heated on steam bath for 8 hours, the solid

separated then added to cruched ice and equivalent by using concentrated ammonium

hydroxide, filtered, and re- crystallized from ethanol.

Synthesis of Schiff bases (13-18)

First method[22,23]

To the solution of benzaldehyde derivatives (0.01 mole) in (20ml) ethanol added (1-2 drop)

glacial acetic acid, then the amine (11,12) is added, the mixture stirring for 4 hours. The

chemical and spectra data of the compounds (13-18) are given in table 2 and 4.

Second method[24]

To the solution of benzaldehyde derivatives (0.001mole) in (5ml) ethanol was added with

stirring the amine (11,12), and the mixture was refluxed for 4 hours. The product filtered off,

washed with water, dried and re-crystallized from ethanol.

Synthesis of 2-(Substituted)-3-(5-(4-methyl benzyl or naphthalen-2-yl)-1, 3, 4-thiadiazol-

2-yl) thiazoliden-4-one (19-24)[25]

To the Schiff bases (13-20) (0.004mole) and (0.1g) anhydrous zinc chloride in (30ml)

methanol added (0.004 mole, 0.368g) thioglycolic acid. This mixture was refluxed for 10

hours, then equivalent by using sodium bicarbonate, the product filtered and re-crystallized

from ethanol. The chemical and spectra data of the compounds (19-24) are given in table 3

and 4.

RESULTS AND DISCUSSION

The compounds 5-substituted-1, 3, 4-oxadiazole-2(3H)-one were synthesized by the reaction

of hydrazide derivatives with ethyl chloroformate in n-butanol.[16]

The IR spectra of these

compounds showed absorption at 3425-3434 cm-1

for the N-H group and at 1639-1660 cm-1

which is attributed to carbonyl group and absorption at 1610-1632 cm-1

for the C=N group

while this peak did not appear in hydeazide. The 1HNMR spectrum of compound (1) shows a

singlet at δ 9.33(s,1H,N-H) and δ8.30-7.58 (m,7H,Ar-Ar) and 1HNMR spectrum of


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compound (2) shows a singlet at δ 9.14 (s,1H,N-H) and multiple at 7.76-7.28 (m,4H,Ar-CH3)

and singlet at δ2.35 (s,3H,CH3), these values are consistent with the literature.[26]

(table 4).

4-amino -5-substituted-2H-1,2,4-triazole-3(4H)-one(3,4) compounds were synthesized by the

reaction of compounds (1,2) with hydrazine hydrate in n-butanol.[17]

The IR spectra of these

compounds showed absorption at 3301-3340 cm-1

for N-H group and carbonyl group at 1650-

1666 cm-1

and at 1618-1648 cm-1

attributed to C=N, Two peak were observed while one with

oxadiazole.

The two compounds potassium-2-(substituted) hydrazine-1-carbodithioate (5,6) per formed

by the reaction of acid hydrazide with carbon disulfide and potassium hydroxide with

stirrer.[18]

The IR spectra of these compounds showed NH stretching bands absorption at

3380-3162cm-1

and absorption C=O at 1626-1601 cm-1

and at 1108-1113cm-1

for C=S group

for two compounds respectively and these values are consistent with the literature.[27]

(table1). These compounds (5,6) are used to synthesized 5-substituted 1, 3, 4-thiadiazole-

2(3H)-thione (7, 8) by stirring with concentrated H2SO4.[19]

The IR spectra showed absorption

N-H group at 3213-3427 cm-1

and absorption for C=N at 1635-1679 cm-1

while disappeared

in compounds (5,6), and absorption C=S at 1168-1180 cm-1

and these values are consistent

with the literature.[28]

1HNMR spectrum of compound (8) showed a singlet at δ 7.88 (s,1H,N-

H) and multiple at δ 7.81-7.30 (m,4H,Ar-CH3) and a singlet at δ 2.36 (s,3H,CH3).

The compounds (5, 6) were given 5-substituted-1, 3, 4-oxadiazole-2(3H)-thione (9,10) by

treated with absolute ethanol.[20]

IR spectra of these compounds showed absorption at 3370-

3320 cm-1

attributed to N-H group and absorption C=N at 1618-1611 cm-1

and absorption

C=S at 1128-1175 cm-1

and a new peak appeared at 1085-1067 in which attributed to C-O-C

group for two compounds respectively. The two compounds 2-amino-5- (substituted)-1, 3, 4-

thiadiazole (11, 12) were synthesized by the reaction of thiosemicarbazide derivatives with

concentrated H2SO4.[29]


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The IR spectra of these compounds showed absorption N-H at 3284-3376 cm-1

and

absorption C=N at 1631-1662 cm-1

and absorption C-S-C at 1027-1058 cm-1

while carbonyl

peak were disappeared. New Schiff bases (13-18) were synthesized by reaction of substituted

amino thiadiazole (11, 12) with substituted benzaldehyde in ethanol and some drops of

glacial acetic acid as the mechanism.[30]

The IR spectra of these compounds showed absorption C=N at 1615-1691 cm-1

and at 1343-

1571 cm-1

attributed to C=C group (table 2). 1HNMR spectrum of compound (14) showed

multiple at δ 8.92-8.50 (m,7H,Ar-Ar) and multiple at δ 8.34-8.18 (m,4H,Ar-Cl) and a singlet


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at δ 8.09 (s,1H,N=CH). and 1HNMR spectrum of compound (18) a singlet at δ8.04

(s,1H,N=CH) and multiple at δ7.68-7.61 (m,4H,Ar-O-CH3) and multiple at δ7.35-7.27

(m,4H,Ar-CH3) and singlet at δ 3.34 (s,3H,O-CH3) and singlet at δ2.33 (s,3H,Ar-CH3) and

these values are consistent with the literature.[31]

(table 4).

While reaction of compounds (13-18) with thioglycolic acid and anhydrous zinc chloride in

methanol give 2-(Substituted)-3-(5-(4-methyl benzyl or naphthalen-2-yl)-1, 3, 4-thiadiazol-2-

yl) thiazoliden-4-one (19-24) as the mechanism.[25]

The IR spectra of these compounds showed absorption C=O at 1677-1695 cm-1

and

absorption C=N at 1622-1645 cm-1

and absorption C-S-C at 1001-1058 cm-1

and these values

are consistent with the literature.[32]

(table 3). 1

HNMR spectrum of compound (22) showed

multiple at δ7.71-7.57 (m,4H,Ar-NO2) and multiple at δ 7.44-7.19 (m,4H,Ar-CH3) and

singlet at δ 6.97 (s,1H,CH-Ar-NO2) and doublet at δ 4.41 (d,2H,CO-CH2) and singlet at δ

2.33 (s,3H,CH3) (table 4).

The IR and 1HNMR of These compound are listed in table 1, 2, 3 and 4.


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Table 1: Physical and IR Spectral of Compounds (1-12).

Others C=S C=N C=O N-H Colour Molecular

Formula

Yield

%

M.

pC°

Com

p. No.

C-O-C asym.1298

C-O-C sym. 1043 --- 1632 1660 3434 White C12H8N2O2 65 177-178 1

C-O-C asym.1267

C-O-C sym.1037 --- 1610 1639 3425

Light

White C9H8N2O2 62 140-142 2

--- --- 1648 1666 3340,

3280

Pale

Brown C12H10N4O 83 108-110 3

--- --- 1618 1650 3301,

3228

Dark

Brown C9H10N4O 49 68-69 4

--- 1108 --- 1626 3380,

3252 Yellow C12H9KN2OS2 78 250-253 5

--- 1113 --- 1601 3332,

3162

Greenish

White C9H9KN2OS2 87 293-295 6

--- 1168 1635 --- 3427 Pale

Brown C12H8N2S2 83 98-100 7

--- 1180 1679 --- 3213 Yellow C9H8N2S2 65 102-104 8

C-O-C asym. 1255

C-O-C sym. 1085 1128 1618 --- 3320 White C12H8N2OS 66 202-204 9

C-O-C asym.1280

C-O-C sym. 1067 1175 1611 --- 3370 White C9H8N2OS 86 206-208 10

C-S-C 1027 --- 1662 --- 3376 Brown C12H9N3S 88 88-90 11

C-S-C 1058 --- 1631 --- 3284 Greenish

Brown C9H9N3S 91 170-172 12


Others C=N C=C Colour Molecular

Formula

Yield

%

M. p

C°

Comp.

No.

N-Oasym. 1531

N-O sym. 1343

C-S-C 1073

1684 1509,

1343 Yellow C19H12N4O2S 49 93-95 13

C-Cl 786

C-S-C 1029 1691

1521,

1433 Yellow C19H22ClN3S 81 98-100 14

C-O 1114

C-S-C 1055 1615

1560,

1439

Yellowish

Brown C20H15N3OS 83

118

decompose 15

N-O asym. 1543

N-O sym. 1338

C-S-C 1057

1625 1508,

1463

Yellowish

Brown C16H12N4O2S 79 153-155 16

C-Cl 754

C-S-C 1064 1629

1510,

1450 Yellow C16H12ClN3S 85 155-158 17

C-O 1178

C-S-C 1060 1633

1571,

1471

Yellowish

white C17H15N3OS 93 184-186 18


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Other C-S-C C=N C=O Colour Molecular

Formula

Yield

%

m. p

C°

Comp.

No.

N-O asym. 1568

N-O sym. 1354

C-N 1280

1001 1643 3961 Pale

Yellow C21H14N4O3S2 71

256-260

decompose 19

C-N 1212

C-Cl 780 1001 1634 3911 Orange C21H14ClN3OS2 82

244-248

decompose 20

C-N 1276

C-O 1126 1052 1639 3969

Turbid

Yellow C22H17N3O2S2 70

250-253

decompose 21

N-O asym. 1519

N-O sym. 1359

C-N 1263

1058 1622 1695 Yellowis

h white C18H14N4O3S2 88 163-165 22

C-Cl 771

C-N 1265 1056 1631 3916 Yellow C18H14ClN3OS2 87 162-164 23

C-N 1267

C-O 1178 1058 1645 1691 White C19H17N3O2S2 82 240-241 24

Table 4: 1HNMR data of some Compounds.

1HNMR(ppm)-DMSO-d6 Comp. No.

9.33(s,1H,N-H), 8.30-7.58 (m,7H,Ar-Ar) 1

9.14 (s,1H,N-H), 7.76-7.28 (m,4H,Ar-CH3), 2.35 (s,3H,CH3) 2

7.88 (s,1H,N-H), 7.81-7.30 (m,4H,Ar-CH3), 2.36 (s,3H,CH3) 8

8.92-8.50 (m,7H,Ar-Ar), 8.34-8.18 (m,4H,Ar-Cl), 8.09

(s,1H,N=CH) 14

8.04 (s,1H,N=CH), 7.68-7.61 (m,4H,Ar-O-CH3), 7.35-7.27

(m,4H,Ar-CH3),3.34 (s,3H,O-CH3),2.33 (s,3H,Ar-CH3). 18

7.71-7.57 (m,4H,Ar-NO2),7.44-7.19 (m,4H,Ar-CH3), 6.97

(s,1H,CH-Ar-NO2),4.41 (d,2H,CO-CH2), 2.33 (s,3H,CH3) 22

Scheme 1: Illustrates the prepared compounds (1-10).


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Scheme 2: illustrates the prepared compounds (11-24).

CONCLUSION

Preparation and study of new substitutes for 1, 3, 4-thiadiazole, 1, 3, 4-oxadiazole and 1, 2, 4-

triazole are derived from various materials and converted some substituted 1,3,4-thiadiazole

into schiff bases and then combined with five membered heterocyclic rings by converting

them into thiazolidine derivatives.

Figure (1): 1HNMR spectrum of the compound 1.


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Figure (2): 1HNMR spectrum of the compound 14.

Figure (3): 1 HNMR spectrum of the compound 22.


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SYNTHESIS OF SOME NEW HETEROCYCLIC COMPOUNDS …