2.1.3- Benzothiadiazole ring

Perfluorination of the benzothiadiazole ring results in a dramatic change in the electronic nature of the system. N NMR of the 4,5,6,7-tetrafluoro analogue (10) shows strong shielding of the nitrogens (320.1 ppm) versus the parent benzothiadiazole (1) (332.9 ppm) <83JFC(22)23l>. 

Alkylation of the benzothiadiazole ring nitrogen will provide an ammonium halide (64) which is readily hydrolyzed to an unsymmetrically substituted 1,2-benzenediamine (65). Subsequent treatment with formic acid allows access to iV-alkylbenzimidazoles (66) (Scheme 13) <89SC1381>. 

Figure 4.4 Replacing the benzodioxole ring by a benzothiadiazole ring results in affinity increases in two endothelin ETa receptor antagonist series [49],...

Another approach involves utilization of the amines for addition of a fused pyridine ring to the benzothiadiazole skeleton. The Gould-Jacobs reaction of 4-amino-2,l,3-benzothiadiazole 60 with diethyl ethoxymethylenemalonate gave the substitution product, and, after thermal cyclization in diphenyl ether, afforded the... 

Compounds of special interest whose preparation is described include 1,2,3-benzothiadiazole 1,1-dioxide (a benzyne precursor under exceptionally mild conditions), bis(l,3-diphenylimida-zolidinylidene-2) (whose chemistry is quite remarkable), 6- di-melhylamino)julvene (a useful intermediate for fused-ring non-benzenoid aromatic compounds), dipkenylcyclopropenone (the synthesis of which is a milestone in theoretical organic chemistry), ketene di(2-melhoxyethyl) acetal (the easiest ketene acetal to prepare), 2-methylcyclopenlane-l,3-dione (a useful intermediate in steroid synthesis), and 2-phenyl-5-oxazolone (an important intermediate in amino acid chemistry). 

Benzothiadiazole 3, when heated in the presence of sulfur, first loses nitrogen and then reacts with sulfur to form benzopentathiepin 32 C1984JOC1221 >. This method has been extended to the synthesis of several heterocyclic ring compounds fused to pentathiepin starting from the corresponding 1,2,3-thiadiazolo heterocycle (Equation 4) <1985JA3871>. 

The naphthalene-like, aromatic stmcture of 1,2,3-benzothiadiazole imparts stability to the system that survives exposure to 20% potassium hydroxide at 150°C or 27% sulfuric acid at 200 °C. It is not oxidized by potassium permanganate, potassium ferricyanide, chromic acid, or dilute nitric acid <1996CHEC-II(4)289>. Electrophilic substitution occurs in the benzo ring, predominantly at the 4-position. Chlorine in the 6-position is displaced by a variety of nucleophiles <1975SST670>. 

No significant developments have appeared since CHEC-II(1996). Diels-Alder reactions involving the fused benzene ring of benzothiadiazoles have, however, been reported (see Section 5.09.7.1). 

In 2-heterosubstituted benzo derivatives (Scheme 51), the effect of the heteroatom X on the ring is similar to the azole series above, and the decreasing scale of aromaticity is 2,1,3-benzoselenadiazole (118)-> 2,1,3-benzothiadiazole (119) > 2,1,3-benzoxadiazole (120).111... 

Chlorination of 2,1,3-benzothiadiazoles can take place either by addition or substitution, depending on the reaction conditions, the nature of the substituents in the benzene ring, and the catalyst employed. The uncatalyzed reaction of (1) with chlorine is exothermic and produces an isomeric mixture of tetrachloro addition products, which form 4,7-dichloro-2,l,3-benzothiadiazole on treatment with base <70RCR923>. In the presence of an iron catalyst, chlorine substitution in the 4,7-positions predominates. 

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. 

Linear thieno[c J]benzothiadiazoles dimerize by linking at the carbocyclic peri positions <75ACR139>. While most [c] fused heterocycles add dienophiles across the heterocyclic ring, the thieno[l,2-c 4,5-c ]benzisothiazole (21) added ethyl azodicarboxylate across the benzenoid ring <86CB3158>. 

The first 1,2,3-thiadiazole synthesized, 1,2,3-benzothiadiazole, was prepared by diazotiz-ation of o-aminothiophenol with nitrous acid (equation 31) (B-61MI42400), and recently sodium nitrite-acetic acid has been substituted for nitrous acid (B-79MI42400),. Another modification, thermal decomposition of diazonium acetate (34), affords benzothiadiazole in good yield in contrast to the variable yields usually experienced in the diazotization of o-aminothiophenols (equation 32) (78SST(5)43l). Benzothiadiazoles are also available directly from aromatic amines (equation 33) (70JCS(C)2250). Sulfur monochloride reacts with the amine to form a benzothiazothiolium salt which reacts with nitrous acid to yield a chlorinated 1,2,3-benzothiadiazole (35). This process, depending on the aromatic ring substitution, may afford a number of products, and yields are variable. 

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