4-Bromo-7- thiadiazole

Unsymmetrical 3,4-dihalo-l,2,5-thiadiazoles 118 and 119 were prepared from 3-amino-4-chloro-l,2,5-thiadiazole 117 via a Sandmeyer-like reaction involving successively tert-butyl nitrite and either copper bromide or copper iodide in anhydrous acetonitrile (Scheme 17) <2003H(60)29>. The bromo and iodo thiadiazoles 118 and 119 undergo selective Stille and Suzuki C-C coupling chemistry (see Section 5.09.7.6). 

Chlorophenyl)-4-phenyl-l,2,5-thiadiazole 128 was prepared from 3-trifluoromethylsulfonyloxy-4-phenyl-1,2,5-thiadiazole 127 by palladium-catalyzed cross-coupling reaction with the tributyl(4-chlorophenyl)stannane (Equation 20) <1996H(43)2435>. The addition of lithium chloride improves the yield. The 3-chloro- and 3-bromo-l,2,5-thiadiazole derivatives were also reactive, but only the bromo compound gave the product in comparable yield (see Section 5.09.7.6). 

Heating to reflux a pyridine solution of 3-substituted-5-(l-aroyl-l-bromo)methylthio-4-phenylamino-4//-[l,2,4]tria-zoles 81 (available from the corresponding 1,2,4-triazoles with phenacyl bromides and subsequent ultraviolet (UV) light-induced bromination) affords 3-substituted-6-aroyl-5,6-dihydro-5-phenyl[l,2,4]triazolo[3,4-6][l,3,4]thiadiazoles 82 (Equation 19) <1993IJH135>. 

The pronounced electron-withdrawing nature of the 1,2,5-thiadiazole system is also evidenced by strong carbonyl electrophilic activation and by enhancement of carboxy acidity. The acid dissociation constants of thiadiazole acids, discussed in Section 4.09.4.1, fall in the range 1.5-2.5. The 1,2,3-thiadiazole carboxylic acids are easily decarboxylated at 160-200 °C. This reaction has been used for the synthesis of monosubstituted derivatives as well as the parent ring and deuterated derivatives <68AHC(9)107>. An efficient bromo-decarboxylation of 3-amino-1,2,5-thiadiazole-carboxylic acid has also been reported <70BRP1190359>. 

The electrophilic substitution of the 3-aryl compounds (265, R = Ar, R = H) exemplified by the formation of 5-bromo- (265, R = Ar, R = Br) and 5-nitro derivatives (265, R = Ar, R = NOj) has been put forward as evidence against the meso-ionic formulation 265. lliis approach is unacceptable since ground state charge distribution cannot be deduced from reaction products. The aluminum-amalgam reduction of meso-ionic l,2,3-thiadiazol-4-ones (265) yields either N-mercaptoacetyl-A-arylhydrazines or Ar-acyl-A-arylbydrazines. Triethyl-oxonium tetrafluoroborate and meso-ionic l,2,3-thiadiazol-4-ones (265) yield 1,2,3-thiadiazolium tetrafluoroborates (267). The effect of solvent on the ultraviolet spectra of meso-ionic l,2,3-thiadiazol-4-ones (265) has been reported. ... 

Chloro- and bromo-l,3,4-thiadiazoles are usually prepared by nucleophilic processes, e.g., Sandmeyer reactions of diazonium salts [56CB1534 68AHC(9)165 86CHE1148], and reactions of thiadiazolinones with phosphorus halides [68AHC(9)165]. The halogeno derivatives are important... 

Subtle reactivity differences are also found in the reaction of 6-bromo[l,2,5]thia- (or selena) diazolo[3,4-/)]pyridines (92) with morpholine and cuprous cyanide which afford the C(7)-amine (94) and C(6)-nitrile (95), respectively (Scheme 15). Under identical reaction conditions, 6-bromo-benzo[l,2,5]thiadiazole affords exclusive C(6)-amination and C(6)-cyanation. The anomalous regio-chemistry in the formation of (94) is attributed to initial formation of a hetaryne intermediate (93), which adds morpholine at the more electron-deficient C-7 position <79IJC(B)13,86IJC(B)500>. 

Bromo-l,2,4-thiadiazole (225) is reduced to the parent heterocycle by H2 and Raney nickel (Scheme 79) (56CB1534). 

Due to the low electron density at the carbon atoms in 1,3,4-thiadiazole, such reactions as nitration, sulfonation, acetylation, halogenation, etc. normally do not take place. However, 2-amino-substituted 1,3,4-thiadiazoles (73a-i) react with bromine in acetic acid to give the 5-bromo derivatives (74a-i). Similarly, the thiadiazolines (75b) and (75d-f) yield the corresponding 5-bromo derivatives (76b) and (76d-f). The thiadiazoline (75a), however,... 

Chloro-substituted thiazoles can be prepared by the reaction of phosphorus oxychloride with the corresponding 4-hydroxythiazoles. This method is also applicable for the preparation of 4-bromo-2-phenylthiazole. Conversion of 3-hydroxy-l,2,5-thiadiazoles into the bromo compounds can be achieved using phosphorus oxybromide, but vigorous conditions are required <1996H(43)2435>. 

They can be replaced with hydrogen atoms by catalytic (Pd, Ni, etc.) or chemical reduction (HI or Zn/H2S04). For example, halopyrazoles with HI and red phosphorus at 150C give pyrazoles, and 5-bromo-l,2,4-thiadiazole is reduced by Raney nickel to the parent heterocycle. 2-Bromothiazole can be reduced electrochemically. 

The unsubstituted 1,3,4-thiadiazole (3, R = H) was described in 1956 by Goerdeler et al. They transformed 2-amino-1,3,4-thiadiazole (4, R = H) into the 2-bromo compound (5, R = H) by a Sandmeyer reaction, and by hydrogenation of the latter with Adams catalyst the parent compound of the series was obtained as a colorless solid, m.p. 42-43°, b.p. 204-205°. Jensen and Pedersen prepared the same... 

Due to the electronegativity of the two nitrogen atoms in the ring, the carbon atoms have a low electron density, and, consequently, halogeno-l,3,4-thiadiazoles are important intermediates, in which the halogen atom is readily displaced by nucleophiles. The general way of preparing chloro- and bromo-l,3,4-thiadiazoles is by Sandmeyer... 

Bromo-1,3,4-thiadiazoles can be transformed to the corresponding 2-fluoro compounds by treatment with silver fluoride, but the yield is low and the reaction attended with considerable decomposition. 

Method (c) was employed by Goerdeler et al., who obtained 1,3,4-thiadiazoline-2(3)-thione from 2-bromo-l,3,4-thiadiazole (5, R = H)... 

However, a 2-amino group does activate the ring towards electrophilic agents, since Bak et al. could prepare 2-amino-5-bromo-1,3,4-thiadiazole by bromination of 2-amino-l,3,4-thiadiazole in 40% hydrobromic acid. The product was not isolated but was diazotized in situ to give 2,5-dibromo-l,3,4-thiadiazole. 

A symmetrical tricyclic 1,3,6-thiadiazepine derivative 152 (Scheme 48) has been synthesized [68,69] in 54% yield starting from 5-bromo-thiadiazole derivative 144 and 1,2-diaminobenzene 145. The synthesis embraces two types of molecular rearrangements Smiles and Dimroth s. 

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