A Decade of Development of Ethylidenethiosemicarbazides as Building Blocks for Synthesis of Azoles and Azines (A Review)

Abstract

This survey represents synthesis of ethylidenethiosemicarbazides, with aryl or heterocyclic moieties, and its utility as building blocks for construction of different heterocyclic compounds such as; thiazoles, thiazolidinones, [1,3,4]thiadiazoles, [1,3,4]triazoles, [1,3]thiazines, pyrimidines, thiazolo[5,4-b]quinoxalines, bis-thiazoles, and bis-pyrazoles. Also, the pharmaceutical applications of ethylidenethiosemicarbazides have been demonstrated.

Introduction

Ethylidenethiosemicarbazides [(ethylidene)hydrazine carbothioamides) are a class of organic compounds with general structure [Ar(CH₃)C=N-NH-CS-NH₂]. Variation of substituents on thioamide nitrogen (A), sulfur atom (B), and hydrazone nitrogen (C) led to developing an array of ethylidenethiosemicarbazides with structural diversity and broad spectrum of biological activities (Fig. 1).

Figure 1: Representative derivatives of ethylidenethiosemicarbazides

Recently, ethylidenethiosemicarbazides have been used as effective pharmacophoric agents in medicinal chemistry such as; antitumor¹, anti-tubercular², anti-amoebic³, anti-fungal⁴, antiviral⁵, antimicrobial⁶, antioxidant⁷, anticonvulsant⁸, and anti-trypanosomal^9,10. Also, these compounds were prescribed for treatment of hypertension as calcium channel blockers¹¹. The biological activity of ethylidenethiosemicarbazides is related to their chelating ability with metal ion through either thione or thiolate sulfur and one of the hydrazone-nitrogen atoms¹². Furthermore, ethylidenethiosemicarbazides have been used as a reactive building blocks for synthesis of different azoles such as, bis-thiazoles¹³, [1,3,4]thiadiazoles¹⁴, [1,3,4]oxadiazoles¹⁵, thiazolidin-4-ones¹⁶, imidazolinones¹⁷, and thiazoles^18,19. In this survey, we represent three approaches about ethylidenethiosemicarbazides, with different aryl or heterocyclic moieties, including synthesis, reactivity, and their biological activities.

Synthesis of Ethylidenethiosemicarbazides

Ethylidenethiosemicarbazides with aryl group (compound 3) or heterocyclic moiety (compound 5) were prepared through condensation reactions of thiosemicarbazide (1) with acetylarene 2 or heterocyclic ethanone 4, respectively [Scheme 1 & Tables 1,2].

Scheme 1: Synthesis of ethylidenethiosemicarbazides

Table 1: 1-(1-arylethylidene)thiosemicarbazide derivatives

Table 2: Ethylidenethiosemicarbazides with heterocyclic moiety

Reactions of Ethylidenethiosemicarbazides

Reaction with a-Ketohydrazonoyl Halides

5-Arylazothiazoles 7 were synthesized via reactions of ethylidenehydrazine-1-carbothioamides 3 or 5 with a-ketohydrazonoyl halides 6 [N-aryl 2-oxopropanehydrazonoyl chlorides or N-aryl 2-substituted-acetohydrazonoyl bromides] under thermal conditions^{6,7,18,19,42,43,53,57,70,80-86} (Scheme 2).

Scheme 2: Reaction of ethylidenehydrazine-1-carbothioamides with a-ketohydrazonoyl halides

By analogous method, ethylidenehydrazine-1-carbothioamides 3 or 5 reacted with ethyl N-aryl-2-chloro-2-hydrazono acetate 8 under reflux conditions in dioxane, containing catalytic amount of triethyl amine and afforded arylhydrazothiazolone^81,85 derivatives 9 (Scheme 3).

Scheme 3: Reaction of ethylidenehydrazine-1-carbothioamides with ethyl N-aryl-2-chloro-2-hydrazono acetate

The reactivity of thiosemicarbazones 3 or 5 towards N-aryl carbohydrazonoyl chlorides 10, without keto group, has been reported^18,19,84 under thermal^19,84 or microwave irradiation and using grafted chitosan¹⁸ or triethylamine^19,84 as basic catalyst. These reactions have been established to give [1,3,4]thiadiazoles 11 (Scheme 4).

Scheme 4: Reaction of thiosemicarbazones with N-aryl carbohydrazonoyl chlorides

Reaction with bis-hydrazonoyl Chlorides

Two equivalents of thiosemicarbazones 3 or 5 were reacted with bis-[a-ketohydrazonoyl chlorides] 12 in dioxane, in the presence of catalytic amount of triethylamine, to furnish the corresponding bis-(hydrazonothiazoles)⁸⁷ 13 (Scheme 5).

Scheme 5: Reaction of thiosemicarbazones with bis-[a-ketohydrazonoyl chlorides]

By the same manner, bis-hydrazonothiazoles 15, containing sulfonyl group, were synthesized via reaction of thiosemicarbazones 3 or 5 with sulfonyl bis-[a-ketohydrazonoyl chlorides] 14 in a molar ratio (2:1), respectively⁸⁷ (Scheme 6).

Scheme 6: Reaction of thiosemicarbazones with sulfonyl bis-[a-ketohydrazonoyl chlorides]

Reaction with a-halocarbonyl Compounds

Treatment of 2-[(1-arylethylidene)hydrazine]-1-carbothioamides 3 with 1-aryl-2-bromoethanone 16 under thermal conditions gave the respective 2-[2-(1-arylethylidene)hydrazono]-4-arylthiazoles^{6,10,19,21,29,42,43,49,83,88-90} 17 (Scheme 7).

Scheme 7: Reaction of arylethylidenehydrazine-1-carbothioamides with 1-aryl-2-bromoethanone

Also, refluxing of thiosemicarbazones 5, with heterocyclic moiety, with 1-aryl-2-substituted (unsubstituted)-2-bromoethanone 18 afforded 2-hydrazono-4-arylthiazoles^{49,52,55,74,76,80,84,88-93} 19 (Scheme 8).

Scheme 8: Reaction of thiosemicarbazones with 1-aryl-2-substituted (unsubstituted)-2-bromoethanone

Conversion of ethylidenehydrazine-1-carbothioamides 3 or 5 into 2-hydrazonothiazoles with coumarin moiety 21 was achieved through their reactions with 3-(2-bromoacetyl)-2H-chromen-2-one (20) in ethanol^{7,21,23,71,84,86,94,95} (Scheme 9).

Scheme 9: Synthesis of 4-(coumarin-3-yl)-2-hydrazonothiazoles

2-Arylhydrazono-5-(2-fluorophenyl)thiazoles 23 were synthesized from the reaction of 1-(1-arylethylidene)thiosemicarbazides 3 with a-bromoketone 22 in ethanolic solution containing triethylamine as a basic catalyst³⁰ (Scheme 10)

Scheme 10: Reaction of arylethylidenethiosemicarbazides with a-bromoketone

Thiosemicarbazones 3 or 5 were reacted with 1,4-bis-(2-bromoacetyl)benzene (24) under thermal condition to give 1,4-phenylene-bis-thiazolyl derivatives¹³ 25 (Scheme 11).

Scheme 11: Reaction of thiosemicarbazones with 1,4-bis-(2-bromoacetyl)benzene

The reactivity of thiosemicarbazones 3 or 5 towards other a-haloketones was investigated. Thus, treatment of 3 or 5 with chloroacetone 26 furnished the corresponding 4-methyl-2-hydrazonothiazoles 27^{6,10,19,42,53,78,80,83} (Scheme 12).

Scheme 12: Reaction of thiosemicarbazones with chloroacetone

Reaction with Chloroethanoic acid or ethyl α-haloalkanoate

Cyclocondensation of ethylidenehydrazine-1-carbothiamides 3 or 5 with chloroethanoic acid (28) in ethanolic solution, containing anhydrous sodium acetate afforded thiazole-4(5H)-one derivatives^{7,8,26,45,57,60} 29 (Scheme 13).

Scheme 13: Synthesis of thiazole-4(5H)-one derivatives

Refluxing of chloroethanoic acid (28) with ethylidenehydrazine-1-carbothiamides 30a or 30b, in ethanolic solution containing sodium acetate, led to formation of tricyclic compounds [2,4,6,7-tetraazabicyclo[7.3.1]trideca-1(13),3,5,7,9,11-hexaen-5-yl]thioethanoic acid (33) or [2,4,6,7-tetraazabicyclo[7.2.2]trideca-1(11),3,5,7,9,12-hexaen-5-yl]thioethanoic acid (34), respectively⁹⁶ (Scheme 14). The reactions proceeded by nucleophilic substitution and intramolecular condensation of amino group of thiourea residue and carbonyl of amide linkage.

Scheme 14: Synthesis of tricyclic compounds from ethylidenehydrazine-1-carbothiamides

Cyclocondensation of bis-oxyphenylthiosemicarbazones 35 with two equivalent of chloroethanoic acid (28) gave the respective bis-[2-(4-oxybenzylidene) hydrazono)-thiazol-4(5H)-one]²⁶ 36 (Scheme 15).

Scheme 15: Synthesis of bis-thiazol-4(5H)-one derivatives

Treatment of ethylidenehydrazine-1-carbothioamide 5 with chloroethanoic acid or ethyl chloroethanoate gave 2-hydrazonothiazolidin-4-one⁷² (37) (Scheme 16).

Scheme 16: Reaction of ethylidenehydrazine-1-carbothioamide with chloroethanoic acid or ethyl chloroethanoate

Conduction of 1-(1-arylethylidene)thiosemicarbazides 3 with ethyl 2-chloro-2-phenylacetate (38) under reflux conditions gave the respective 2-[2-(1-arylethylidene) hydrazono]-5-phenyl-thiazol-4(5H)-ones¹⁶ 39 (Scheme 17).

Scheme 17: Synthesis of 5-phenyl-thiazol-4(5H)-ones

Similarly, reaction of ethylidenehydrazine-1-carbothioamides 3 or 5 with ethyl bromoethanoate (40) under reflux condition in an anhydrous potassium carbonate ethanolic solution afforded 4-thiazolidenones^{42,43,76,78,90,97} 41(Scheme 18).

Scheme 18: Synthesis of 2-hydrazono-4-thiazolidenones

Cyclocondensation of ethylidenehydrazine-1-carbothioamide 5 with ethyl bromoethanoate (40) in an equal molar ratio, in ethanolic solution containing catalytic amount of fused sodium acetate, afforded thiazole-5(4H)-one derivative 41. However, reaction of two moles of ethyl bromoethanoate with one mole of compound 5 gave N-ethoxycarbonylthiazole-5(4H)-one derivative^6,53,78 42, which was obtained from treatment of 40 with 41 (Scheme 19)

Scheme 19: Reaction of ethylidenehydrazine-1-carbothioamide with ethyl bromoethanoate

Treatment of arylethylidenethiosemicarbazide 3 with ethyl 2-bromopropanoate (43) under reflux condition in absolute ethanol/piperidine mixture furnished 5-methyl-4-thiazolidenone⁴³ 44 (Scheme 20).

Scheme 20: Reaction of arylethylidenethiosemicarbazide with ethyl 2-bromopropanoate

Reaction with Chloroacetonitrile

Reaction of chloroacetonitrile with 1-[1-(2-naphthyl)ethylidene]thiosemicarbazide (3) in ethanol/triethylamine mixture, under reflux condition, underwent cyclization to give the respective 2,5-dihydro-4-aminothiazole derivative⁴² 45 (Scheme 21).

Scheme 21: Reaction of thiosemicarbazone with chloroacetonitrile

Reaction with α-halo dicarbonyl Compounds

Refluxing of ethylidenehydrazine-1-carbothioamides 3 or 5 with a-halo dicarbonyl compounds such as; chloroacetylacetone (46), ethyl chloroacetoacetate (47), and chloroacetoacetanilide (48) gave the respective 2-hydrazono-4-methylthiazoles^{20,42,43,52,57} 49a-c (Scheme 22).

Scheme 22: Reaction of ethylidenehydrazine-1-carbothioamides with a-halo dicarbonyl compounds

Conventional thermal heating or microwave irradiation of a mixture of ethylidenehydrazine-1-carbothioamides 3 or 5 and ethyl bromopyruvate (50) gave 4-ethoxycarbonylthiazole derivatives⁹⁸ 51 (Scheme 23).

Scheme 23: Reaction of ethylidenehydrazine-1-carbothioamides with ethyl bromopyruvate

Reaction with Dihalo Compounds

Treatment of ethylidenehydrazine-1-carbothioamide 5 with 2,3-dichloroquinoxaline (52) in absolute ethanol, under reflux condition gave ethylidenehydrazonothiazolo[5,4-b]quinoxaline⁷ 53 (Scheme 24).

Scheme 24: Reaction of ethylidenehydrazine-1-carbothioamide with 2,3-dichloroquinoxaline

Reaction with Aldehydes

Condensation of 1-[1-(9-arylidene-3-methyl-5-phenyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[3,4-b]quinazolin-1(5H)-yl)ethylidene]thiosemicarbazide (5) with 2-chlorobezaldehyde (54) gave the respective Schiff’s base compound⁹⁹ 55 (Scheme 25).

Scheme 25: Preparation of Schiff's base

Reaction with a,b-unsaturatednitrile Compounds

The response of ethylidenehydrazine-1-carbothioamide 5 towards different acrylonitrile derivatives was investigated^52,57. Thus, reaction of 5 with arylidenemalononitriles 56, 2-cyano-N,3-diphenylacrylamide (57), and 3-aryl-2-cyano-prop-2-enethioamide (58), in dioxane under microwave irradiation⁵² or methanol under thermal conditions⁵⁷ furnished the respective 1,3-thiazine derivatives^52,57 60a-c (Scheme 26).

Scheme 26: Reaction of ethylidenehydrazine-1-carbothioamide with acrylonitrile derivatives

Similarly, reaction of ethylidenehydrazine-1-carbothioamide 5 with ethoxymethylenemalononitrile (61) in refluxing methanol afforded 4-amino-2-hydrazono-1,3-thiazine-5-carbonitrile⁵⁷ 63 via non-isolable intermediate 62 (Scheme 27).

Scheme 27: Reaction of ethylidenehydrazine-1-carbothioamide with ethoxymethylenemalononitrile

Treatment of an equimolar amounts of 2-[1-(2-pyridyl)ethylidene]hydrazine-1-carbothioamide (5) with arylmethylenemalononitriles 56 in pyridine solution gave 2-hydrazono-4-aryl-2,3-dihydrothiazole-5-carbonitriles¹⁰⁰ 64 (Scheme 28).

Scheme 28: Synthesis of 2,3-dihydrothiazole-5-carbonitriles

On the other hand, reactions of 1-[1-(2-naphthyl)ethylidene]thiosemicarbazide (3) with benzylidenemalononitrile 56 or ethoxymethylenemalononitrile (61) afforded amino-pyrimidinethione derivative (67) or imino-pyrimidinethione derivative⁴² (68), respectively (Scheme 29).

Scheme 29: Synthesis of pyrimidinethione derivatives

A mixture of 2-arylhydrazono-4-amino-1,3-thiazine-5,6,6-tricarbonitriles 72 and 6-amino-2-thioxo-2,3-dihydropyrimidine-4,5-dicarbonitriles 73 was obtained¹⁰¹ from the reactions of thiosemicarbazones 3 or 5 with tetracyanoethylene (69) (Scheme 30).

Scheme 30: Reaction of thiosemicarbazone with tetracyanoethylene

Reaction with anhydrides

Cyclocondensation of ethylidenethiosemicarbazides 3 or 5 with acetic anhydride (74) led to formation of 3,5-di(N-acetylamino)-[1,3,4]thiadiazole derivatives^59,102,103 77. The isolable products were formed via acetylation of primary nitrogen of thiourea residue (intermediate 75), intramolecular cyclization of thiol group into imino group (intermediate 76), and acetylation of NH group of [1,3,4]thiadiazole ring (Scheme 31).

Scheme 31: Reaction of thiosemicarbazone with acetic anhydride

Treatment of ethylidenehydrazine-1-carbothioamides 3 or 5 with maleic anhydride (78) gave 2-[2-hydrazono-4-oxo-4,5-dihydrothiazol-5-yl]ethanoic acid derivatives^8,43 79 through thia-Michael reaction (Scheme 32).

Scheme 32: Reaction of ethylidenehydrazine-1-carbothioamides with maleic anhydride

Treatment of thiosemicarbazone (5), containing indole moiety, with maleic anhydride (78) or phthalic anhydride (80) in boiling ethanol gave 2-[2-hydrazono-4-oxo-4,5-dihydrothiazol-5-yl]ethanoic acid derivative (81) or N- substituted phthalimide derivative (82), respectively⁸⁴ (Scheme 33).

Scheme 33: Reactions of thiosemicarbazone with maleic anhydride and phthalic anhydride

Reaction With Hydrochloric and Sulfuric Acids

Refluxing of thiosemicarbazone (5), containing benzofuran moiety, with methanol/hydrochloric acid mixture furnished [1,2,4]triazoline-3-thione derivative⁶⁸ 83 (Scheme 34).

Scheme 34: Reaction of thiosemicarbazone with hydrochloric acid

[1,2,4]Triazepino[6,5-c]quinolin-6(7H)-one (84) was prepared through dehydration of ethylidenehydrazine-1-carbothioamide (5), containing hydroxyquinolone moiety, by sulfuric acid at room temperature⁷⁴ (Scheme 35).

Scheme 35: Dehydration of ethylidenehydrazine-1-carbothioamide

Reaction with dialkyl but-2-ynedioate

Refluxing of ethylidenehydrazine-1-carbothioamides 3 or 5 with dimethyl but-2-ynedioate or diethyl but-2-ynedioate in methanol afforded the respective alkyl 2-[2-hydrazono-4-oxothiazol-5(4H)-ylidene] ethanoate derivatives^{42,52,57,84,100,104,105} 88a,b (Scheme 36).

Scheme 36: Reaction of ethylidenehydrazine-1-carbothioamides with dialkyl but-2-ynedioate

Self-Condensation Reaction

Microwave irradiation of ethylidenehydrazine-1-carbothioamides 3 or 5 led to self-condensation and give 3,4-diazahex-2,4-diene derivatives 89¹⁵ (Scheme 37).

Scheme 37: Microwave irradiation of ethylidenehydrazine-1-carbothioamides

Vilsmeier-Haack Reaction

Treatment of bis-thiosemicarbazones 90 with Vilsmeier-Haack reagent furnished the respective 6,8-bis-pyrazolylcoumarine derivative¹⁰⁶ 92 (Scheme 38).

Scheme 38: Reaction of bis-thiosemicarbazone with Vilsmeier-Haack reagent

Biological Activity

Antimicrobial Activity

Ethylidenethiosemicarbazide 3 or 5 were proclaimed to display a wide range of antibacterial and antifungal activities with different pharmacophore moieties^{4,6,7,25,39,58,64,65,67,68,72} (Chart 1).

Graph 1: Ethylidenethiosemicarbazide having antimicrobial activity

Antiviral Activity

Ethylidenethiosemicarbazide with aryl or benzimidazole substituents were evaluated as antiviral agents and showed moderate activity in most cases^5,33,107,108 (Chart 2).

Graph 2: Ethylidenethiosemicarbazide having antiviral activity

Anticancer Activity

Different alicyclic, aryl, or heterocyclic moieties introduced to thiosemicarbazone scaffolds 3 or 5 led to strengthen the anticancer activities against different cell lines^{1,7,18,31,47,48,51,73,75,85,96} (Chart 3).

Graph 3: Ethylidenethiosemicarbazide having anticancer activity

Anticonvulsant Activity

Thiosemicarbazones are promising anticonvulsant candidates⁸ that contain non-polar groups (aryl or heteroaryl) and thiourea residue (polar group which is responsible for hydrogen bonding) (Chart 4).

Graph 4: Ethylidenethiosemicarbazide having anticonvulsant activity

Antiparasitic Activity

Recent research focuses on developing new drugs for Chagas diseases, caused by the protozoan parasite Trypanosoma Cruzi. Ethylidenethiosemicarbazides were evaluated and displayed higher activity against T. Cruzi^9,10,24,38 (Chart 5).

Graph 5: Ethylidenethiosemicarbazide having antiparasitic activity

Miscellaneous

Other pharmaceutical applications of ethylidenethiosemicarbazides such as; Tyrosinase inhibitors⁵¹, antihypertensive⁶⁶, antioxidant³⁶, antiamoebic³, and antitubercular agents² have been reported (Chart 6).

Graph 6: Miscellaneous activities of Ethylidenethiosemicarbazide

Acknowledgment

The authors represent their glory to King Abdulaziz University for funding our research project (grant No: 1-17-01-006-0001).

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