1.3.4- Thiadiazolo 3,2-a pyrimidines

Table 11 Novel transformations to [1,3,4]thiadiazolo[3,2-a]pyrimidine and its benzologues by using old methodologies...

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... 

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... 

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

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). 

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>. 

Representatives of the l,2,4-thiadiazolo[3,2-b]thiazole (101), 1,2,4-thia-diazolo[2,3-a]pyridine (102), and l,2,4-thiadiazolo[2,3-a]pyrimidine (103) ring-system are accessible in high yield by the action of bromine in chloroform on the appropriate heterocyclic thiourea, e.g. (100). ... 

The fusion of the 1,2,5-thiadiazole or selenadiazole system to a heterocyclic nucleus greatly enhances the electrophilicity 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-d]pyrimidines was studied in detail by Shealy and coworkers and previously discussed (68AHC(9)107). 

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. 

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