Hydrazinecarbothioamide group in the synthesis of heterocycles

The review summarizes recent literatures dealing with hydrazinecarbothioamide group in thiocarbohydrazides and other derivatives including their physical and chemical properties along with their applications in the synthesis of heterocycles


Introduction
Carbohydrazide and thiocarbohydrazide are hydrazine derivatives of carbonic and thiocarbonic acids.Although in general thiocarbohydrazides are more widely used in heterocyclic synthesis than thioureas, both types contain the functional group RNHCSNHR.Substituted thiobiureas (RNHCONHNHCSNHR) are key to the synthesis of many organic heterocyclic ring systems.Several authors have investigated under various conditions the heterocyclization of 1acylthiobiurea, 1 1,6-disubstituted 2,5-dithiobiureas, 2 and 1-aryl/alkyl-2-thiobiureas. 3 Also, the heterocyclization of compounds having an extended urea-like chain such as 1,4-and 2,4disubstituted thiosemicarbazides have been reported. 4,5Thiocarbohydrazide derivatives have attracted much attention in recent years due to their applications in the synthesis of heterocyclic compounds, 6 synthesis of transition metal complexes, 7,8 and pharmacological studies. 3Moreover, carbohydrazide derivatives were widely used as an oxygen scavenger (metal passivator) for water treatment systems, particularly for boiler-feed systems. 9The chemistry of carbohydrazides has grown fast, and has not been reviewed in more than three decades.Accordingly, it is important to shed more light on the recent literature dealing with that chemistry, especially in the field of heterocycles.

Synthesis of Thiocarbohydrazides
Syntheses of carbohydrazide and thiocarbohydrazide of preparative value are exclusively variations of one basic reaction, viz. the hydrazinolysis of carbonic and thiocarbonic acid derivatives.The individual variants of this general synthesis differ from one another in their applicability and relative merit and are discussed separately below.

Hydrazinolysis of carbon disulfide
The reaction of hydrazine with carbon disulfide is no doubt the cheapest and most useful method for the preparation of thiocarbohydrazide (2) in quantity. 11S 2 + 2NH 2 NH 2 → NH 2 NHCSNHNH 2 (2)+ H 2 S

Hydrazinolysis of dialkyl xanthates
The hydrazinolysis of dialkyl xanthates 3 is a possible route to thiocarbohydrazide (2).By warming the two reactants, high yields of thiocarbohydrazide are claimed to be obtainable; the effluent gases, ethanol and ethanethiol, are ignited as they leave the reaction vessel (Scheme 2).Scheme 2 1.4.General procedure for the preparation of 1,5-diacyl thiocarbohydrazides Thiocarbohydrazide (2) was dissolved in aqueous NaOH solution, which was added dropwise to a solution of acid chloride in tetrahydrofuran at 0-5 o C. The reaction mixture was then stirred at room temperature for 2 h to give products 4 in 71-80% yield (Scheme 3). 14

From acid hydrazides
Varma 15 reported the synthesis of benzamidothiosemicarbazides (N-aroyl thiocarbohydrazides) 5 by treating successively the acid hydrazides prepared by the hydrazinolysis of the acid methyl ester with carbon disulphide, sodium monochloroacetate and hydrazine hydrate (Scheme 4). 15RKIVOC 2009 (i) 150 Scheme 5

Biological activities of thiocarbohydrazide derivatives
Thiocarbohydrazide is the closest structural analog of thiosemicarbazide, derivatives of which are recommended as effective antitubercular 18,19 and antiviral preparations. 20Thiocarbazides of the aromatic series also exhibit high antiviral 21 and antimicrobial activity. 22Macrocycles synthesized in the reactions of thiocarbohydrazide (2) with polycarbonyl compounds and their complexes with the salts of divalent metals are effective fungistatic agents, 23 while the cytotoxicity of the carbohydrazones and thiocarbohydrazones of some ketones is commensurable with or even exceeds the cytotoxicity of the well-known product melphalan. 24

Thermolysis of thiocarbohydrazides
Thermolysis of dithiocarbohydrazides offers monomeric and dimeric aliphatic and aromatic Nisothiocyanatoamines.An example is shown in Scheme 8.

Scheme 9
The structure of the compounds 11 so obtained demonstrated that the process takes place selectively through the intermediate formation of the enamine A, which is in tautomeric equilibrium with the hydrazone form B; at the second stage of the reaction attack by the amide nitrogen atom on the electron-deficient carbonyl carbon atom is accompanied by closure of the pyrazoline ring (Scheme 9). 26By contrast, 1-acetyl-2-phenylacetylene 10c reacted with thiocarbohydrazide (2) in (i) DMSO or (ii) AcOH at room temperature only through the carbonyl moiety to furnish N 2 -(Z-s-trans)-and N 3 -(Z-s-cis)-bis(1-methyl-3-phenyl-2-propynylidene)carbonothioic dihydrazides 12 in 76 or 92% yield, respectively (Scheme 10). 27
Radiosterilization of 58 in the dry state proves to be applicable (retaining their structures unchanged up to 40 kGy). 49he s-triazolosulfonamide derivatives 60 were obtained in good yields by fusion of the tosyl amino acid derivatives 59 with 2 in an oil bath at 180 o C (Scheme 32). 50 Solvents affect the cyclized products resulting from the reaction of thiocarbohydrazide (2) with carbon disulfide.In pyridine, reaction of 2 with carbon disulfide afforded the salts 75 and 76. 56 In DMF, compound 2 reacted with carbon disulfide and KOH to afford the salt 77 which can be cyclized on warming to give the corresponding 1,3,4-thiadiazoline-2-thione (Scheme 38). 56

Scheme 55
However, the reaction of the starting materials under microwave irradiation afforded the same products in higher yields within a few minutes. 76 N-Imidoylthioureas (133, analogous to thiocarbohydrazides) reacted with DMAD (128) to form 1,3,5-thiadiazepines 134a-e (Scheme 57). 77The reaction mechanism can be simply described as due to sulfur atoms attacking the triple bond of DMAD in conjugate fashion, followed by proton transfer and nucleophilic attack of the amidine group on the double bond in 128 to form the intermediates 135. 77Thereafter a nucleophilic attack of the amidine-like nitrogen on the ethylenic-ester would form the salt 136.Aromatization of 136 is accompanied by the extrusion of a hydrogen molecule to produce the stable compounds 134a-e (Scheme 57). 77A similar observation was reported by Alajarín and his group.[1,3,4]triazines 155 were discovered as activators of caspases and inducers of apoptosis so they may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs; accordingly, they may be used as therapeutic anti-cancer agents. 82eaction of 3,5-dimethoxybenzoic acid (148) with thiocarbohydrazide ( 2

Heterocycles via Metal Complexation
A series of complexes 218 of the type [M(TML)X 2 ]; where TML is Tetradentate Macrocyclic Ligand; M = Co(II), Ni(II), Cu(II), Zn(II)or Cd(II); X = Cl, CH 3 COO or NO 2 have been synthesized by template condensation of glyoxal and compound 2 in the presence of divalent metal salts in methanolic medium (Scheme 79). 95The procedure can be summarized as follows: to a stirring methanolic solution (50 mL) of 2 (10 mmol) was added a divalent cobalt, nickel, copper, zinc or cadmium salt (5 mmol) dissolved in a minimum quantity of methanol (20 mL).The resulting solution was refluxed for 0.5 h.After that glyoxal (10 mmol) dissolved in 20 mL methanol was added to the refluxing mixture and refluxing continued for 6-10 h, depending upon the metal salt.The mixture was concentrated to half of its volume and kept in desiccators for 2 d.The complexes 218 were filtered, washed with methanol, acetone and ether and dried in vacuo: yield 40%.The complexes are soluble in DMF and DMSO, but are insoluble in common organic solvents and water. 95he triple Cu(II) thiocarbohydrazide-2,3-butanedione system in the Cu(II) hexacyanoferrate gelatin immobilized matrix (219 and 220) has been prepared.The similar process in the nickel(II)hexacyanoferrate(II) matrices does not occur under such conditions (Scheme 80).

in the synthesis of heterocycles 4 . 1 .
Scheme 10