1.2.4- Thiadiazole pyrimidine

Similar effects, although with rather subtle differences, are also observed in the furazan and thiadiazole pyrimidine derivatives (91) and (92). These two molecules have quite different chemical properties, as evidenced both by the extremely facile nucleophilic substitution of the amino-group in (91), which is less easy in (92), and also by the ready photoaddition to the... 

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). 

Formation of the outer pyrimidine ring, by a different route, is also the final step in the synthesis of the benzothi-azolopyrimidopyrimidine 264 (Equation 82) <1997JIC818>, and similarly the outer six-membered ring is formed in the final step which leads to the thiadiazole-fused compounds 265 and 266 (Scheme 64) <1995RCB1957,1999RCB364>. 

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... 

Ring opening of the tricyclic thiadiazoloquinazolone derivative 84 was described by Santagati et al. <1994PHA880> the transformation is shown in Scheme 10. When this compound was heated with sodium hydroxide in a mixture of ethanol and dioxane, the central pyrimidine ring underwent hydrolytic ring opening, and the substituted thiadiazole derivative 85 was formed. 

The reactions of 2-amino-1,3,4-thiadiazoles and diethyl 1-ethoxyethyli-denemalonate in diglyme at 140°C for 20 hr gave 7-methyl-1,3,4-thiadia-zolo[3,2-a]pyrimidine-6-carboxylates (672) in 14-25% yields after column chromatography (86FES737). Reactions in ethanol or dimethylacetamide were unsuccessful. 

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>. 

The facile hydrolysis of a pyrimidine ring fused to a 1,2,5-thiadiazole (52) allowed the use of... 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). 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-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. 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>. 

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>. 

Treatment of the symmetrical triaminopyrimidine (50-1) with sulfuryl chloride ties up the two adjacent amines in a thiadiazole ring, protecting those groups from attacks in subsequent reactions. Reaction of the product (50-2) with ortho difluorinated benzylamine (50-3) results in the replacement of the pyrimidine amino group by that in the reagent most hkely by an addition-elimination sequence to afford (50-4). That amino group is then converted to the formamide (50-5) with formic acid. Exposure of the product to Raney nickel leads to a loss of sulfur and the formation of the transient intermediate (50-6). This cyclizes to a purine... 

Renewed interest in 1,2,4-thiadiazoles is not merely part of the general intensive activity in contemporary heterocyclic chemistry. It is obviously desirable to compare this ring system with closely related important heterocycles (including thiazoles, oxazoles, pyrimidines, etc.), the chemistry of which is known in much greater detail. The iso-steric relationship between pyrimidine and 1,2,4-thiadiazole (but not with any of its isomers) foreshadows similarities in certain physical properties of the two series. The question of the biochemical function and physiological activity of heterocyclic compounds of this general pattern has also served to reinforce interest in the 1,2,4-thiadiazoles. 

As may be expected from the isosteric relationship between the two ring-systems, 1,2,4-thiadiazoles and the corresponding pyrimidine derivatives show certain similarities in their physical properties. Thus, the boiling points of the parent compounds are strikingly similar5 (see Table V). 

Oxazines and 1,3-thiazines are converted into pyrimidine derivatives by ammonia. For the conversion of 1,2,4-thiadiazoles into pyrimidines see Section 3.4.1.6.5.i. 

A study of the 1,3-dipolar cycloaddition of pyrazines, pyrimidines and l//-pyrimidinthiones with nitrilimines (80), generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides (79), was carried out. Reaction of pyrimidine-2( l//)-thiones (81) and -4(l//)-thiones with nitrilimines in benzene at reflux gave spiro[pyrimidine-2(l//), 2 (3 f/)-[ 1,3,4]thiadiazoles... 

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