1.3.4- Thiadiazole ring synthesis

Perhaps the earliest reported method for the synthesis of the 1,2,3-thiadiazole ring system was the one described by Pechmann and Nold in which diazomethane was reacted with phenyl isothiocyanate. Of the four possible isomers that could be obtained from the reaction, 5-anilino-l,2,3-thiadiazole 62 (R1 Ph, R2 = H) was the only product formed (Equation 16) <1896CB2588>. This method continues to be used as a route to 5-amino substituted 1,2,3-thiadiazoles. 4,5-Disubstituted 1,2,3-thiadiazoles have been produced in excellent yield by reaction of l,l -thiocar-bonyl diimidazole with ethyl diazoacetate <1988SUL155>. 

There are three classical methods for the synthesis of the 1,2,5-thiadiazole ring system. They are characterized by the combination of atom fragments necessary to form the ring [4 + 1], [3 + 2] (type A), and [3 + 2] (type B) (Figure 3). These methods will be reviewed in the subsequent sections (Sections 4.09.9.1.1 and 4.09.9.1.2). The synthesis of aromatic and azaaromatic fused 1,2,5-thia-diazole has been reviewed <83H(20)7l). 

The syntheses from [4+1] atom fragments, in which the Group 16 heteroatom is introduced between two nitrogen atoms, are the most widely applicable and versatile methods available for construction of the 1,2,5-thiadiazole ring system. These methods have been applied to the synthesis of monocyclic and polycyclic aromatic forms of these ring systems in addition to the direct formation of 1-oxides and 1,1-dioxides, 2-oxides, quaternary salts, and reduced forms. The earliest use of the [4+ 1] synthesis dates back to 1889 when Hinsburg prepared 2,1,3-benzothiadiazole (I) from o-phenylenediamine and sodium bisulfite. 

RING SYNTHESIS BY TRANSFORMATION OF ANOTHER RING 4.09.10.1 Synthesis of 1,2,5-Thiadiazole Rings... 

Ring Synthesis by Transformation of Another Ring System 10.03.10.1 Thieno[2,3-d]-1,2,3-thiadiazoles... 

Thiadiazolidines cannot be prepared by catalytic or chemical reductions. Reagents vigorous enough to reduce the double bonds in a 1,2,4-thiadiazole ring also cleave the ring (see Section 4.25.3.1.8). No other synthesis of 1,2,4-thiadiazolidines has been reported. 

Amino-l,2,4-thiadiazoles (16) readily yield monoacylated derivatives of type (129) under the usual conditions whereas both monoacyl and diacyl derivatives (130 and 131, respectively) are easily obtained from the 3-amino isomers (65AHC(5)119, 70CB1805). In a similar manner the 3-amino-l,2,4 thiadiazoles produce mono- and di-sulfenamide derivatives when treated with sulfenyl halides. In general, the reactions of 3-amino- and 5-amino-1,2,4-thiadiazoles with sulfonyl halides under basic conditions produce only low yields of the desired derivatives. Sulfonamides of type (132) are best prepared by ring synthesis methods as illustrated in Scheme 55 (75LA1961). 

In certain bicyclic and polycyclic thiadiazoles the ring can be hydrolytically cleaved to an o-diamine and sulfur dioxide. This process is a reversal of the reaction pathway involved in the synthesis of thiadiazoles from o -diamines and thionyl chloride or iV-sulfinylaniline under anhydrous conditions (see Section 4.26.5.1.1), and is analogous to, but much slower than, the hydrolysis of sulfurdiimides. In contrast to (1), which steam distilled without decomposition, steam distillation of [l,2,5]thiadiazolo[3,4-c][l,2,5]thiadiazole (21) produced only oxamide. Under milder conditions (75 °C, 12 h) a mixture of the diamine (22), oxamide and elemental sulfur was obtained (75JOC2749). Similar hydrolytic instability was observed in thiadiazole rings angularly joined to an anthraquinone (70RCR923) and ben-zofuroxan (78CPB3896). 

The thiadiazole ring was employed as a diamine protecting group in a synthesis which led to the unambiguous formation of the 9-substituted adenine arprinocid (24) (78JOC960). The thiadiazole (23) readily underwent amine replacement, formylation, and reduction with Raney nickel to produce (24 Scheme 5). 

In Chapter 43 we also gave the structure of timolol, a thia diazole-based [3-blocker drug for reduction of high blood pressure. This compound has an aromatic 1,2,5-thiadiazole ring system and a saturated morpholine as well as an aliphatic side chain. Its synthesis relies on ring formation by rather a curious method followed by selective nucleophilic substitution, rather in the style of the last synthesis. The aromatic ring is made by the action of S2CI2 on cyanamide . 

The ease with which two molecules of thioureas are joined by an S—S link to form dithioformamidine salts (37) under the influence of the most diverse oxidizing agents3,34 makes it plausible that these disulfides (37) are the primary products of most, if not all, oxidation processes. Moreover, the disulfides (37) yield, on further oxidation, the same 1,2,4-thiadiazole derivatives as the thioureas from which they are derived.3 Their role as the initial intermediates in the synthesis of the 1,2,4-thiadiazole ring system from thioureas is therefore generally accepted. In solution, dithioformamidine salts deposit elementary sulfur spontaneously and produce monothioformamidines (38) or amidinothioureas (39). The latter tend to predominate, and to become the sole products under more stringent conditions (e.g., on boiling). These amidinothioureas and the final 1,2,4-thiadiazoles are reversibly con-... 

The new synthesis of 9-substituted adenines elaborated in Scheme 60 is worthy of mention, as all steps proceed under relatively mild conditions and in >90% yield. ° Briefly, the process involves transamination of 7-amino-l,2,5-thiadi-azolo[3,4-rf]pyrimidine (255) with, for example, 2-fluoro-6-chlorobenzylamine, followed successively by formylation of the resulting benzylamine (256 R = H) and ring cleavage of the thiadiazole ring to give the triaminopyrimidine (257), which cyclizes in situ to the 9-substituted adenine (258), which is a highly active coccidiostat. 

The synthesis has been described mainly by building the thiadiazole onto a triazine ring. However, one report has used thiadiazole 981 as starting material. Reaction of 981 with ethyl pyruvate gave 982 that was... 

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