SYNTHESIS OF SOME NEW NITROGEN SULPHUR LIGANDS AND THEIR INTERACTION WITH METALS

Abstract

Among the various branches of organic sulphur chemistry, the chemistry of thiocarbamides occupies a position of importance. This is mainly due to the remark able pharmacological activity and industrial application of many thiocarbamide derivatives. The chemistry of thiocarbomides is about a century old and although various methods have been developed by many workers for the synthesis of thiocarbamide derivatives, very few of these can be claimed to be of general application. Even today a number of thiocarbamide derivatives are obtained by tedious pro cesses and in not too good yields. It is then obvious that simplified procedures and novel methods for the preparation of thiocarbamides will be welcome. With this background, the author has tried to elaborate some of the available methods, as well as to introduce novel procedures for the thiocarbamylation of amines. The already known reaction of benzoyl isothiocyanate with amines has been extended to the preparation of aliphatic and heterocyclic thiocarbamides. Further, the reaction of various amino compounds with tert-butyl isothiocyanates have been investigated in detail with fruitful results. Thiocarbamides are also known as thioureas and both the terms are in current usage. However, the author has 2 preferred the name 'thiocarbamide' and it is used. The term thiocarbamylation implies the introduction of N-C-S group into any system. The discovery of thiocarbamides1 by Reynolds in the year 1869 opened a new chapter in the chemistry of organic compounds. Subsequently, various N-substituted-thiocarbamides containing aliphatic or aromatic or mixed substituents have been prepared. Apart from the simple thiocarbamides of the type mentioned above, complex heterocyclic systems are also known. Several hundreds, perhaps, thousands of thiocarbamides are known at the present time. Though thiocarbamide itself has not found any large scale industrial applications, it has been proved that the group >N-C-N< is of considerable Chemotherapeutic interest S and systematic researches with derivatives of thiocarbamide have opened new vistas in medicinal chemistry. Among the most important pharmacological activities of thiocarbamides may be mentioned, antituberculous, antithyroid, hypnotic, anasthetic, anthelmintic, antibacterial and antispasmodic 2 3 activities. • Some of the derivatives are of interest as insecticides and rodenticides. Recently, antiviral5' and 7 antiradiation activities have also been observed in some of the derivatives. Apart from their pharmacological applications, 3 many thiocarbamide derivatives have been found to be of interest as rubber vulcanization accelerators and in plastic, varnish and adhesive industries and also in photography.2 There are a number of methods available for the pre paration of thiocarbamides. The following account is a brief critical review of these. 1# Isomeric change of ammonium or amine thiocyanates1 R\ NH, HSCN > R^\N-J-NH2 R^ RX S Where R = hydrogen, alkyl or aryl. This is still used for the preparation of the parent thiocarbamide and some of its 1-mono and 1,1-disubstltuted derivatives. 2. Addition of ammonia or amines to isothiocyanates9"' Hi Rl R-NCS + J^NH » R-NH-C-N^ *2 § N*2 Where R a alkyl or aryl, Ri = hydrogen, alkyl or aryl and R2 = hydrogen, alkyl, aryl, HgN-, ^N-^, heterocycle etc. NH The method is suitable for the preparation of aliphatic, aromatic, mixed aliphatic aromatic and mixed aromatic hetero cyclic thiocarbamides.9"14 It is applicable for the preparation 4 of 1-monosubstituted, 1,3-disubstituted and 1,1,3-trisubstituted thiocarbamides. Hydrazine reacts with isothiocyanates to form hydrazine 11 12 dithioamides. ' The latter are formed in presence of excess of isothiocyanate. R-NCS +H2N-NH2-» R-NH-C-NH-NH2R"NC) R-NH-g-NH-NR-fl-NH-R S S S 1 R 1 fi Hydroxylamine yields hydroxy thiocarbamides » which then cyclize into oxadiazoles.1^ 2R-NCS + 2H2N-0H—» 2ZR-NH-g-NH-oH_7—> R-NH-fl-g-NH-R + 2H20 + 2S S N H o Guanidines on reaction with isothiocyanates afford 18 J?7 substituted amidinothiocarbamides. R-NCS + R'-NH-g-NH2 > R-NH-g-NH-g-NH-R' NH S NH Where R and R' = alkyl or aryl. Sulphonamides of primary amines reacts with isothio cyanates in aqueous alkali solution to form sulphothiocarbamides. R-NCS + NaNH-So2-R' > R-NH-C-N-S02-R,H—» R-NH-C-NH-S02-R' SNa S Cyanamide in aqueous alkaline media reacts with alkyl isothiocyanates to afford cyanothiocarbamides. " R-NCS ♦ HsB-CN ^^ H-NH-0-HH-CN s 5 The aromatic derivatives, however, cannot be prepared by this method. 3. Addition of hydrogen sulphide to cvanamides 5 RX R\ Nf-C =N+h2s —• /N-g-NH2 R^ K S Where R = hydrogen, alkyl or aryl. The method consists in passing hydrogen sulphide for a long time through an ammonical solution of the cyanamide. Theoretically, the method is applicable for the preparation of all type of 1-mono and 1,1-disubstituted thiocarbamides. 4. Reaction of carbon disulphide with primary amines36"40 Carbon disulphide exhibits marked differences in its reaction with aromatic and aliphatic primary amines when aromatic amine is heated with carbon disulphide especially in presence of alkali and catalysts like iodine,37 hydrogen peroxide ' or sulphur, hydrogen sulphide is eliminated and a 1,3-diaryl thiocarbamide is formed. 2 Ar-NH2 + CS2 • Ar-NH-C-NH-Ar + H2S 8 With aliphatic amines they react with carbon disulphide, usually in the cold, to give the corresponding dithiocarbamic acid which combines with more of the amine to form a salt.36'38 R-NH2 + CS2 >/R-NH-C-SH_7R"NH3 >R-NH-C-SH3N-R s s unstable 6 The amine dithiocarbamates when heated eliminate hydrogen sulphide and afford the corresponding 1,3-dialkyl 38 thiocarbamides. _ + R-NH-C-SH3N-R > R-NH-C-NH-R + H2S S S 41-45 5. Reaction of potassium ethylxanthate with amines The reaction of potassium ethylxanthate with aromatic primary amines41'42 has been developed lately.43,44,4S The symmetrical 1,3-diaryl thio-carbamides obtained by this method. 2 Ar-NH2 + EtO-C-SK » Ar-NH-C-NH-Ar + EtOH + KSH S S The method, however, is not useful for the preparation of 1,3-dialkyl thiocarbamides. 6. Aminolysis or ammonolysis of thiourethanes46 Ammonia and amines react with thiourethanes when mixtures of the reactants are heated, especially, in presence of catalysts like P2O5J affording 1-substituted and 1,3- disubstituted thiocarbamides. tj H^J-C-OEt + C6H5-NH2 • HgN-C-NH-CgHg + EtOH S S H2N-g-NH-C6H5 + C6H5-NH2 • C6H5-NH-g-NH-C6H5 + NH3 S S 7 47 7. Action of ammonia or amines on thioallophanates NHo e.g. HgN-C-NH-C-OR—2+ HgN-C-NHg + HgN-C-OR S o aq- S o The reaction has not been studied in any detail and does not appear to have found practical application. 8. Reaction of amines on trithiocarbonates Heavy metal or alkali metal trithiocarbonates on reaction with amines give the corresponding 1,3-disubstituted thiocarbamides. MCS3 + R-NH2 • R-NH-C-NH-R + MS + H2S S M = heavy metals or alkali metal; R = alkyl or aryl. 9. Thermolysis of bis(thiocarbamyl) disulphide49-51 Rv /R R\ /R N-C-S-S-C-K » N-c-r + cs2 + s R£ 8 S \Rl K{ • XRX This method offers scope for the preparation of a variety of 1,3-disubstituted and 1,1,3,3-tetrasubstituted thiocarbamides in practice it is found applicable only for the preparation of tetra alkyl thiocarbamides. 10. Reaction of amines with thiophosgene52"56 R. R^ vB Rv 4 NH + Cl-C-Cl y ^N-C-N + 2 ^NH,HC1 y » S II \ y * s *r s \ r 8 The method is applicable to the preparation of all types of N-substituted thiocarbamides but the practical difficulties are considerable. As a modification of the thiophosgene reaction, the reaction of disubstituted thiocarbamyl chloride with amines can be used for the preparation of thiocarbamides. R\ R\ >-fi-Cl + HgN-R]. • N-C-NH-R-l / S / S R K R\ ^Ri R\ yRi N-c-r • % —• / r\ ^n-c-ci + hn: R' S NR2 R XR2 11. Indirect method using acyl isothiocyanates * The method consists in the reaction of a suitable acyl isothiocyanate, such as benzoyl isothiocyanate, with amines leading to the formation of acyl thiocarbamides which are then hydrolysed to the free thiocarbamides. C6H5-C-NCS + R-NH2—> R-NH-C-NH-C-C6H5^ R-NH-C-NH2 +C6H5-C00H o so s The method has so far been used only for the preparation of 1-aryl thiocarbamides. 12. Reaction of silicon tetraisothiocyanate with amines59*60 The reaction of silicon tetraisothiocyanates with amines leading to silicon thiocarbamides has been used very 9 recently for a high yield synthesis of thiocarbamides.60 RX A A NH + Si(NCS)^—^ Si(HH-C-H( )4 » 4 HJJ-C-< + Sioo ^ S \Ri ^5 J \Ri 2 Where R = hydrogen, alkyl etc. Rl= alkyl, aryl, heterocycle etc. It is obvious that although a number of methods for the preparation of thiocarbamide derivatives have been developed from time to time, most of them have limited applicability. Anumber of thiocarbamides which are important intermediates in heterocyclic syntheses can be obtained by tedious processes and in low yields only. Further many types of thiocarbamides remain to be prepared. Evidently, an investigation directed to the introduction of noval and convenient methods as well as the simplification of available procedure for thiocarbamylation of amino compounds appeared to be of great interest. The benzoyl isothiocyanate reaction for the preparation of 1-aryl thiocarbamides has now been successfully extended to the preparation of certain other type of thiocarbamides. The second approach was to introduce noval procedures for thio carbamylation purposes, with this object in view, investigations were carried out with tert-butyl isothiocyanate with a variety of amino compounds. Some of these methods, especially, the tert-butyl isothiocyanate reactions have enabled a facile and high yield synthesis of a number of thiocarbamides. 10 The occurrence of antimalarial activity in certain substituted diguanides61 stimulated the search for other therapeutically useful members of this series and in due course led to the discovery of high antibacterial activity more especially among a series of bis-diguanides. One such compound l,6-di-(N -p-chlorophenyl-N'-diguanide)-hexane62 has recently been introduced into medicinal and veterinary practice under the common name Chlorohexidine B.P.C. Dyer and Johnson ' have prepared a series of nitro and amino derivatives of triphenylguanidine and their pharmacolo gical study in the chemotherapy of tuberculosis was reported. In view of the great therapeutic activities of substi tuted thioureas and guanidine derivatives as mentioned above it seemed desirable to synthesise some thioureas and guanidines with various cyclic modifications of the parent structure.