1,2,5-Thiadiazoles, halogeno

Azido-1,3,4-thiadiazoles (87) can be prepared by reaction of hydra-zinothiadiazoles (86) with nitrous acid, and by reaction of halogeno-thiadiazoles with sodium azide. Like similar heterocyclic azides - they may exist as true azides (87) or as tetrazolothiadiazoles (88). Kanaoka prefers the bicyclic formulation when R = Ph, but Bacchetti et al. have shown that in the solid state the compound... 

In the 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than at the 3-position, and this affects substituent reactions. 5-Halogeno derivatives, for example, approach the reactivity of 4-halogenopyrimidines. The 1,2,4-oxadiazole ring shows a similar difference between the 3- and 5-positions. 

There are many related examples which are now known as the general Dimroth rearrangement. For example, 3-ethylamino-l,2-benzisothiazole (419) is in equilibrium in aqueous solution with the 2-ethyl-3-imino isomer (420) <72AHCf 14)43). Dimroth rearrangements are known in the 1,2,4-thiadiazole series (421- 422), and in the 1,3,4-thiadiazole series as products of reactions of halogeno-l,3,4-thiadiazoles see Section 4.02.3.9.1 <68AHC(9)165). For a similar example in the 1,2,3,4-thiatriazole series, see Section 4.02.3.1.9. 

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

Halogeno-substituted imidazo[2,l-h][l,3,4]thiadiazoles lOS are accessible from 104 with phosphorus oxytrihalides (toluene, heat) (88JOU1177, 88ZOR1306 90MI3). 

Aiyl-l,2,5-thiadiazoles or 3-aryl-4-halogeno-l,2,5-thiadiazoles can be readily prepared from l-aryl-2-haloethanone or 1-aryl-2,2-dihalogenoethanone oximes and tetrasul-fur tetranitride ". For instance, interaction of dichloroacetophenone oxime 280 with S4N4/dioxane at reflux afforded 3-phenyl-4-chloro-l,2,5-thiadiazole 281 in 98% yield (equation 121). 

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... 

Halogeno-l,2,4-thiadiazoles are destroyed fairly rapidly by zinc and hydrochloric acid, with evolution of hydrogen sulfide.88,91... 

The replacement of the reactive 5-chloro by a sulfonamido group in 1,2,4-thiadiazoles affords a convenient synthesis of the 5-sulfonamido heterocycles.92- 3,168-172 173 Thus, 5-halogeno compounds (171), on treatment with p-acetamidobenzenesulfonamide and potassium carbonate in diphenyl ether at 200°, afford the sulfonamido derivatives (170) in 70 % yields. Nitrobenzenesulfonamides do not react. This route is valuable, because the products are obtainable with difficulty by sulfonylation of the parent amine (see Section III,D, 1,A).8-8S-86-87 The superiority of route 171 -> 170 over route 169-y 170, though unusual in the heterocyclic field, recalls similar observations made in the synthesis of sulfonamidotriazines.174... 

In alkaline media, 3-halogeno compounds appear to be less stable 3-chloro-5-phenyl-l,2,4-thiadiazole is decomposed completely by 1 Jf-alcoholic potassium hydroxide and by hydrazine.178 Nucleophilic substitution of the 3-halogen atom by alkoxy groups can be achieved, however, by means of sodium alkoxide in the appropriate alcohol 3-methoxy-, 3-benzyloxy-, and 3-(2 -hydroxyethoxy)-5-phenyl-l,2,4-thiadiazole are obtainable by this route in good yield.178... 

Substituted l,2,4-thiadiazol-5-yl diazonium tetrafluoroborates (314) react with potassium halides in acetonitrile in the absence of catalysts to afford the corresponding 5-halogeno compounds (315) in excellent yields.169 The isomeric 5-phenyl-l,2,4-thiadiazol-3-yl diazonium salts, however, resist substitution by this procedure, except with iodide ions by taking advantage of the catalytic effect of copper... 

Fungicidal properties are exhibited by 3-methyl-209 and 3-methyl-thio-5-arylsulfonyl-l,2,4-thiadiazoles,210 5-substituted 3-trichloro-methyl-1,2,4-thiadiazoles,97 2,4-dimethyl-3-thiono-l,2,4-thiadiazoli-din-5-one,164,166,211 and 2,4-dimethyl-l,2,4-thiadiazolidine-3,5-dithi-one.165,166 5-Halogeno-3-halogenoalkyl-l,2,4-thiadiazoles are active against Rhizoctonia aolani,9B... 

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... 

As has been mentioned previously, the reactivity of halogeno- and methylsulfonyl-l,3,4-thiadiazoles toward nucleophilic reagents is in agreement with the low electron density on the carbon atoms in the ring. The high coupling activity of the diazonium salts can be ascribed to the same cause. 

Hydroxy-l,2,4-thiadiazoles readily form esters with phosphoric acid and its various analogs. Because of the pesticidal properties of these organo-phosphorus compounds, and their reported relatively low toxicity to warmblooded animals, a large volume of preparative work has been undertaken. The patent literature exemplifies almost the full range of possible phosphoric and phosphonic acid derivatives, and their thio analogs. For their production, a hydroxy-1,2,4-thiadiazole is condensed with the phosphoro- or phosphono-chloridic ester (426 or 429), in the presence of a base.332-336 Alternatively, a halogeno-1,2,4-thiadiazole is allowed to react with the appropriate free acid (424 or 427).337-341 The use of mercapto-l,2,4-thiadiazoles, or of the... 

Phosphoro and phosphono thioates and dithioates which are formally derived from mercapto-l,2,4-thiadiazoles, but are usually prepared from the halogeno compounds, are described together with their oxygen analogs (see Section IV.C). 

Halogeno-l,2,4-thiadiazol-5-yl sulfenyl chlorides (455) react rapidly with olefins at — 40°C to yield adducts (e.g., 456 from butene). The stereospecific mechanism of the exclusive trans addition probably involves epi-sulfonium ions as intermediates. Thus, erythro adducts arise from trans-2-buteneand threo adducts from ds-2-butene terminal olefins (e.g., isobutylene, 3,3-dimethylbut-l-ene) produce single products, the assigned structures of which (Markovnikov or otherwise) are consistent with their H NMR spectra.209... 

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