Thiadiazoles 1,2,51 thiadiazolo pyrimidines

Treatment of 5,7-diamino-l,3,4-thiadiazolo[3,2-n]pyrimidinium ehloride (25) with Vilsmeier reagent gave the 7-formamido-l,2,4-triazolo[l,5-c]pyrimidin-5-one (27) (90JHC851) (Seheme 42). Compound 27 has presumably been formed via rupture of the 1,3,4-thiadiazole ring of 25 and... 

Heating the 5-isocyano-l,3,4-thiadiazolo[3,2- ]pyrimidin-5-one 115 with 10% hydrochloric acid gave a mixture of the 5-imino-l,3,4-thiadiazolo[3,2- ]pyrimidin-7-one 116 (10%) and the l,2,4-triazolo[l,5-c]pyrimidine-5,7-dione 117 (35%) (91JHC489). Formation of 117 probably occurred through thiadiazole ring rupture of 116 and recyclizatioii with its imino function together with desulfurization (Scheme 43). 

When 7r-deficient thiadiazoles are fused to an azine, electrophilic substitution is possible only in the presence of strongly electron-donating substituents (74BCJ2813) (Scheme 56). Some [l,3,4]thiadiazolo[3,2-a]pyrimidin-5-ones were brominated next to the oxo group (90DOK743). 

Very many fused 1,2,5-thiadiazoles, and some fused 1,2,3-thiadiazoles, have been prepared the two typical reactions are illustrated (Scheme 8). The first is exemplified by the synthesis of numerous benzo- and hetero-fused 1,2,5-thiadiazoles by Carmack and co-workers,68 and by Hartman s group 69 an example of the second is the preparation of l,2,3-thiadiazolo[4,5-d]-pyrimidines.70... 

Amino-5-mercapto-l,3,4-thiadiazole was reacted with EMME in boiling DMF for 16 hr to afford thiadiazolo[3,2,-n]pyrimidine-6-carboxylate (1131, X = S, R = SH) in 80% yield [85EUP150507]. 

Amino-3-methyl-l,2,4-thiadiazole was reacted with EMME in boiling trichlorobenzene to give 1,2,4-thiadiazolo[4,5-a]pyrimidine-6-carboxylate (1132) (59JOC779). 

The fusion of the 1,2,5-thiadiazole system to a heterocyclic nucleus greatly enhances the elec-trophilicity of the substituted ring. These properties are manifested in increased rates of hydrolysis and more facile displacement, Diels-Alder, and cycloaddition reactions. The synthetically useful nucleophilic cleavage of the pyrimidine ring of l,2,5-thiadiazolo[3,4- /]pyrimidines was studied in detail by Shealy and co-workers and previously discussed <68ahc(9)107>. 

Tsuji obtained two isomeric l,3,4-thiadiazolo[3,2-a]pyrimidino compounds by changing the pH (Scheme 13) <91JHC489>. Thus treatment of 2-amino-5-substituted-thiadiazoles (82) with ethyl cyanoacetate (83) in the presence of sodium methoxide gave the 2-substituted 5-imino-6//-[ 1,3,4]-thiadiazolo[3,2-a]pyrimidine-7-one (84). When the same reaction was carried out in the presence of P2O5 and CH3SO3H instead of sodium methoxide, 7-amino[l,3,4]thiadiazolo[3,2-a]pyrimidine-5-one... 

Reaction of the amino-1,3.4-thiadiazole 86 with a series of benzaldehydes gave the arylidene amines 87 which when treated with arylacetyl chlorides and triethylamine gave 5-substituted l,3,4-thiadiazolo[3,2-fc]pyrimidin-6-ones 88 in good yields (75-95%). The reaction was thought to proceed by a (4+2) cycloaddition reaction between 87 and the ketene which was produced in situ by the interaction of arylacetyl chlorides and triethylamine <99JCR(S)36>. 

The novel derivative 56 (m.p. 127-128 °C) has been prepared in high yield by reaction of the 1,2,5-thiadiazole 55 with thionyl chloride (Scheme 3) <2000JHC1269>. The intermediate 55 is made by alkaline hydrolysis of 4,6-dimethyl[l,2,5]thiadiazolo[3,4-,7 pyrimidine-5,7(4//,6//)-dione 54 <2000JHC1269>. 

Addition of nucleophiles to cyanothiadiazole under basic conditions takes place with unusual ease. Hydrolysis to the amide, for example, can be effected at 0 °C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-1,2,5-thiadiazole into the [l,2,5]thiadiazolo[3,4-d]pyridazines <7iJHC44l>. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine and thiazole (77H(6)1985). 

In 7-amino[l,2,5]thiadiazolo[3,4-d]pyrimidine the N—S bond (1.622 A) is substantially shorter than the N—S single bond (1.735 A) whereas the C—N bonds in the thiadiazole ring are shorter than the corresponding bonds in 9-methyladenine. Comparisons of bond lengths indicate that double bond character of the C—N bond is about 50% in the fused thiadiazole, which indicates an efficient electron delocalization between the ring as opposed to the finding for the oxadiazole analogue when a 75% C—N double bond character is indicated. 

Condensed 1,3,4-Thiadiazoles. The preparation of 7-oxo-7//-l,3,4-thiadia-zolo[3,2-a] pyrimidine-5-carboxylic compounds has been mentioned above. 1-(Acylamino)-l,2,3,4-tetrahydropyrimidine-2-thiones react with H2SO4 to give IH-1,3,4-thiadiazolo [3,2-c] pyrimidine-6-methanesulphonic acids. Cyclo-condensation of derivatives of l-aminopyrimidine-2-thione with RCO2H gives 2,7-disubstituted 5/f-1,3,4-thiadiazolo [3,2-<7] pyrimidin-5-... 

The addition of chlorothioformyl chloride to a-amino-N-heterocycles can clearly take place in the opposite sense, the sulfur atom appearing adjacent to the exocyclic nitrogen of the starting material. This occurs when 2-aminothiazole or 2-amino-A2-thiazoline react in ethanol-free chloroform, resulting in thiazolo[2,3-c]-l,2,4-thiadiazol-3-one (186) or its 5,6-dihydro analog. The structure of the latter has been confirmed by X-ray analysis. 2-Amino- (and 4-amino-2,6-dimethyl)pyrimidine similarly afford 1,2,4-thiadiazolo[4,3-a]pyrimidin-3-one (187, R = H, 34%) and 5,7-dimethyl-l,2,4-thiadiazolo[4,3-c]pyrimidin-3-one (39%), respectively. Possible mechanisms of the reactions have been discussed.164... 

The Wittig-type reactions of iminophosphoranes with isocyanates and related compounds have also been extensively used in heterocyclic synthesis. Examples include the preparations of the mesoionic [l,3,4]thiadiazolo[2,3-c][l,2,4]triazines (210) from (209), 0 bicyclic guanidines, e.g. (212), from (211), naphthypyridines (215), (216), and (217) from (213) and (214), 2 pyrido[l,2-f]pyrimido-[4,5-d)pyrimidines (218), 7H-pyrido-[4,3-c]- (219) and 10H-pyrido[3,4-b]- (220) carbazoles, tricyclic fused 2,4-diimino-l,3-diazetidines (222) from the bisiminophosphorane (221), benzotriazepines (225) from (223) and (224), 6 and mesoionic thiazolo-[2,3-b]-1,3,4-thiadiazoles (227) and N,N-bisheteroarylamines from the iminophosphorane (226), derived from 3-amino-4-phenylthiazole-2(3H)-thione. The carbodiimides (229), prepared from the iminophosphorane (228), can be converted into quinolines or a-carboline derivatives depending on the nature of the isocyanate used in the reaction with (228) and the reactions of iminophosphoranes (230) and (231) with aryl and styryl isocyanates provide one-pot syntheses of quinoline, a-carboline, and quinindoline derivatives. 9... 

A soln. of 7-amino 1,2,5-thiadiazolo [3,4-d] pyrimidine in HCl-dioxane-water heated 4 hrs. at 82-85° under Ng 4-amino-l,2,5-thiadiazole-3-carboxamidine hydrochloride. Y 81%. — Similarly 7-Amino-u-triazolo[4,5-d]pyrimidine 5-amino-y-triazole-4-carboxamidine hydrochloride. Y 89%. F. e. s. Y. F. Shealy and C. A. O Dell, J. Org. Chem. 30, 2488 (1965). 

A-Thiadiazolo[3,2-a.]pyrimidines. 2,5-Diamino-l,3,4-thiadiazole (217) reacts with ethyl acetoacetate, yielding 2-amino 5-oxo-7-methyI-5//-1,3,4-thiadiazolo[3,2-a]pyrimidine (219) (19% after boiling for 80 h in ethanol, 90% in the absence of solvent), presumably by way of the jS-aminocrotonic ester (218). The action of diketen on (217) in aqueous solution at room temperature affords a monoacetoacetyl derivative (221) which is ring-closed quantitatively to the same bicyclic product (219), The intermediate (221) is... 

The general synthesis of l,3>4-thiadiazolo[3,2-a]pyrimidines from 2-amino-l,3>4-thiadiazoles has been varied by the use of 2,3-dichloroacryl-oyl chloride the intermediate (206) is cyclized thermally to the final product (207) in 35% yield. A similar route [to (208)] is the condensation of 2-amino-l,3 4-thiadiazoles with the appropriate 3-diketones. 

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