Amidinothiourea

Another antiulcer histamine Hj receptor antagonist containing a thiazole moiety is zalb-dine (131) Its synthesis can be accomplished readily by brominating 4 acetyl 2 methylimidazole (129) to give haloketone 130 Displacement with amidinothiourea completes the synthesis of zaltidme (131) via a displacement cyclodehydration sequence [45]... 

One of the most successful approaches to the synthesis of metalla-supramolecular systems has been by templated self-assembly processes. Most of the templating agents used by synthetic chemists are either cationic or neutral species. Anions, on the other hand, have only fairly recently been successfully utilized as templates. The new metalla-macrocycles [Pd2Ni2(atu)4(PPh3)4X]3+ (atu = deprotonated amidinothiourea, X = C1, Br, I) have been prepared using anion templated syntheses. Only in the presence of each of these three halides are the metalla-macrocycles... 

A variation using thioacylguanidines affords 5-substituted-3-amino-l,2,4-thiadiazoles. If an amidinothiourea is oxidized, 5-amino-l,2,4-thiadiazoles are obtained. A recent example of this type of synthesis has been reported the amidinothiourea 87 was oxidized to the 1,2,4-thiadiazolium salt 88 on treatment with bromine (Equation 25) <2003SC2053>. 

The oxidative cyclization of amidinothioureas, which is probably the most frequently used variation of this synthesis, provides 3,5-diamino-1,2,4-thiadiazoles with varying degrees of substitution. 

The oxidation of amidinothioureas by a range of oxidizing agents to give 3,5-diimino derivatives is still one of the most versatile methods for the synthesis of N-linked derivatives (see Section 5.08.9.4). An alternative method which gives symmetrical derivatives is the oxidation of A-arylthioureas to produce Hector s bases which readily isomerize to give 3,5-diamino-l,2,4-thiadiazoles (see Section 5.08.9.2). 

An obvious approach to biguanides is the ammonolysis or aminolysis of the sulphm--function in amidinothioureas (IX), and their S-alkyl-deriv-atives (XIV). An early example of this reaction is due to Bamberger 30). 

Reactions of 1,2,4-thiadiazoles with radicals and electron-deficient species are virtually unknown. Catalytic and dissolving metal reductions usually cleave the nucleus at its N—S bond by a reaction that may be regarded as the reverse of its synthesis by the oxidative cyclization of amidinothiono structures (Section 4.08.9.4). For example, reduction of the diamino compound (37) gives the amidinothiourea (38) from which it may be prepared by oxidation (Equation (8)). 

The reaction of arylisothiocyanates with guanidines (233) affords amidinothioureas (234), which can be converted into 3,5-diarylimino-l,2,4-thiadiazolines (235) directly on treatment with bromine in ethanol. Alternatively, (234) can be alkylated with benzyl chloride to give the S-benzyl derivative (236) which on treatment with bromine in chloroform gives (235) (Scheme 51) <87JIC675>. 

An alternative synthesis of amidinothioureas involves the reaction of a-chloroformamidines (237)... 

Amidinothioureas (342) are oxidized by a range of oxidizing agents to give 3,5-diimino derivatives (343) (Equation (54) see also Schemes 51 and 52) <81ijc(B)825, 87JIC675>. 

Reduction. The near-quantitative reduction of Hector s bases to s-diarylguanidines under various conditions34-30 53, 55 is well established. Milder reduction, by hydrogen sulfide at 26°, gives excellent yields of A-aryl-A-arylamidinothioureas (28),54a obviously by the familiar preferential fission of the heterocycle at the S—N(2) bond (see Section III,D,1) since these amidinothioureas (28) are cleaved to s-diarylguanidines and thiocyanic acid under the mildest hydrolytic conditions,54 their primary formation in aM reductions of Hector s bases is probable.54 ... 

Treatment of amidinothiourea (82) with acidified hydrogen peroxide affords the parent compound (83) in excellent yield.110 At higher... 

Di(alkyl or aryl)amino-l,2,4-thiadiazoles (90 R,R = alkyl or aryl) are similarly obtainable in 60-85% yields from the appropriate disubstituted amidinothioureas (89 R,R = alkyl or aryl).56,57 The preparation of the latter from monosubstituted guanidines (87) and isothiocyanate esters (88) might conceivably yield the isomeric ami-... 

Amongst oxidizing reagents, arylsulfonyl chlorides in pyridine simultaneously cyclize and acylate amidinothiourea (and its 2V-phenyl and AT -diphenylhomologs), producing moderate yields of sulfonyl derivatives of 3,5-diamino-l,2,4-thiadiazoles in one step.116... 

Monosubstituted amino groups (e.g. anilino) in amidinothioureas can participate in this cyclization, as shown by the ready oxidation of l-(2V,jV -diphenylamidino)-3-phenylthiourea (98 R = H, Ar = Ph) (and its analogs) to 5-anilino-2-phenyl-3-phenylimino-AM,2,4-thia-diazoline (99 R = H, Ar = Ph).116 This reaction, in which the alternative cyclization to benzothiazoles might be expected to predominate,68... 

The trisubstituted amidinothioureas (98) required as precursors of the thiadiazolines are obtained by the interaction of isothiocyanate esters and s-diarylguanidines,115 or by the action of aromatic amines on dithiazolidines (102).117 The former reaction might conceivably yield the isomeric amidinothioureas (98a) instead if so, however, oxidation and isomerization would give rise to a 2-(diphenylguanidino)benz-thiazole (100a) isomeric with, but different from, the product (100) actually obtained. The structure of this product is confirmed by synthesis from 2-aminobenzthiazole (101) and carbodiimides.115... 

The oxidative cyclization of amidinothioureas has been utilized in the preparation of further examples of 1,2,4-thiadiazole derivatives 38.112,113.118-122... 

The structure of a considerable number of alleged substituted amidinothioureas and their acetyl derivatives obtained by the above... 

Arylamino-3-nitroamino-l,2,4-thiadiazoles are crystalline solids which explode at their melting points. They are monobasic acids, remarkably stable to alkalis and to the action of boiling sodium plumbite. Mild reduction by sulfur dioxide reconverts 5-anilino-3-nitroamino-l,2,4-thiadiazole into its parent amidinothiourea from which it arises by oxidation. Attempts to reduce 3-nitroamino compounds to the corresponding 3-hydrazines were not successful.141... 

The intermediate A-anilinoamidino-2-thioureas, which result from the treatment of 3,5-diimino-l,2,4-dithiazolines (thiurets) with phenyl-hydrazine, were reported by Fromm64-88 to cyclize to 3,5-diamino-1,2,4-triazoles. Kurzer and co-workers, who had earlier reported the cyclization of amidinothioureas to 1,2,4-triazoles,67 extended this work to l,3-bis(isopropylideneimino)-2-arylthiocarbamoylguanidines (35),... 

The preparations of 1,2,4-thiadiazoles and 1,2,4-thiadiazolidines from thioureas are well known and have been summarized in three reviews those of Bambas,188 Sherman,189 and Kurzer.170 Contained in these reviews are discussions of the controversies that surrounded some of the products, notably Hector s bases, which resulted from oxidation of substituted thioureas.171,172 Subjects covered in the above reviews, but too extensive to outline in detail here, are the oxidation of amidinothioureas to 3,5-diamino-1,2,4-thiadiazoles (71),173,174 the oxidation of phenylthiourea175 and of substituted amidinothioureas176 to 3,5-diimino-l,2,4-thiadiazolidines (72, Hector s bases), the reaction of thiopseudoureas with trichloromethanesulfenyl chloride to form 3-alkylthio-5-chloro-l,2,4-thiadiazoles (73),177 the reaction of thiopseudoureas with sodium thiocyanate and bromine178 and the oxidation... 

Reaction of RuC13 xH20 with JV-amidinothiourea (Hatu) or W-methylamidinothiourea (HNmatu) (412) in the presence of NO gives [RunCl2(atu)(0H2)N0] 2H20 and [RuC12-(Nmatu)(OH2)(NO)] -H20 respectively. Further reaction with aqueous NaOH produces the corresponding nitro complexes [RuII(N02)atu(0H2)3]2551 etc. 

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