3- Amino-1.2.5-thiadiazole, chlorination

Amino-l,2,5-thiadiazole is chlorinated or brominated at the 4-position at 20°C in acetic acid. 3-Methyl-l,2,5-thiadiazole can also be chlorinated in the 4-position (68AHC(9)107). Bromination of 2-amino-l,3,4-thiadiazole succeeds in the 5-position (65ACS2434). 

JME538, 1997CH739>. The main thiadiazole product 185, however, suffered chlorination in the a-position. The isolation of 2-amino acrylonitrile 184 from the reaction mixture supported decomposition of the 2-oximino acetonitrile 183 furthermore, treatment of the pure acrylonitrile under typical reaction conditions gave exclusively ot-chloro-3-chloro-l,2,5-thiadiazole 185 (Scheme 27 Table 11). Mechanisms explaining the formation of both thiadiazoles were proposed <1998H(48)2111>. 

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

Sulfur-linked substituents are usually prone to oxidation by halogens. In aqueous solution, chlorine converted 5-amino-3-benzylthio-1,2,4-thiadiazole successively into sulfoxide and sulfone, but in glacial acetic... 

The sulfur in alkylthio groups of 1,2,4-thiadiazoles may be oxidized successively to the sulfoxide and sulfone stage. Thus, 5-amino(or anilino)-3-alkylthio- 1,2,4-thiadiazoles (321 R = NH2 or PhNH)85,133 and 3-alkylthio-1,2,4-thiadiazoles (321 R = H),90 on treatment with one or two moles of monoperphthalic acid, yield the appropriate oxidation products (322 and 323). Hydrogen peroxide or chlorine may replace the less convenient per-acid as the oxidizing reagent.86 By careful... 

The 5-position in 1,2,4-thiadiazoles is most reactive in nucleophilic substitution reactions. Chlorine, for example, may be displaced by nucleophiles (Nu) such as fluoride, hydroxide, thiol, amino, hydrazino, sulfite and azido groups (Scheme 11). Active methylene compounds such as malonic, acetoacetic and cyanoactic esters as their sodio derivatives also displace the 5-halo substituent (65AHC(5)ll9). The reaction follows second-order kinetics, the rate determining step being addition of the nucleophile at C-5 followed by rapid elimination of X. 

Nucleophilic displacements on the sp2 carbon atom at C-5 of 1,2,4-thiadiazole (155 X = Cl) are plentiful. Chlorine, for example, may be displaced by fluoride, hydroxy, amino,... 

A modification of the reaction of a-aminoacetonitrile (37a) has been developed which leads to 3,4-dichloro-l,2,6-thiafiiazole (39) in over 80% yield. The action of commercial sulfur dichloride on 37a produces a 1-1 mixture of 3-chloro- and 3,4-dichloro-l,2,5-thiadiazole, (38 and 39). However, if excess chlorine is added to the reaction mixture the dichloro compound forms exclusively in 82 % yield. It was shown that the dichloro compound does not form via chlorination of 3-chloro-1,2,5-thiadiazole. Therefore, either chlorination takes place on one of the intermediates prior to aromatization or the amino-acetonitrile is oxidized by the chlorine-sulfur dichloride mixture to cyanogen which is known to react with the sulfur chlorides to form 39 (see Section II,B,4). 

Finally, in order to confine the reactions of the cyanodithioimidocarbon-ates (280) to one Section, their participation in a synthesis of type E is now included the reaction concerned is their condensation with N-chloroamino compounds. Potassium S-alkylcyanodithioimidocarbonates (280) react with chloramine itself (produced in situ from aqueous ammonia and chlorine) to afford good yields of 3-amino-5-alkylthio-l,2,4-thiadiazoles (284).223,224... 

Reaction between hydrazine hydrate and ammonium thiocyanate yields 1,1-his (thiocarbamoyl) hydrazine which on treatment with phosgene undergoes molecular rearrangement through loss of ammonia to yield 5-amino-2-mercapto-l, 3, 4-thiadiazole. This on acylation gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. The final step essentially consists of amidation by treatment with ammonia. 

An alkaline soln. of NaOCl prepared from chlorine and 2 N NaOH mixed at -5 with 1 N NH OH-soln., the resulting soln. of chloramine cooled and treated drop-wise with a cooled aq. soln. of potassium benzyl cyaniminodithiocarbonate with stirring, which is continued for 3 hrs. -> 3-amino-5-benzylthio-l,2,4-thiadiazole. Y 90%. F. e. and relating ring closure s. W. Walek, M. Pallas, and M. Augustin, Tetrahedron 32, 623 (1976). 

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