Halogeno-l,2,4-thiadiazoles

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

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... 

Halogeno-l,2,4-thiadiazol-5-yl sulphenyl chlorides (50) react rapidly and exothermally at — 40 °C with olefins to yield adducts [e.g. (51) from butene]. The addition proceeds stereospecifically, probably by a mechanism... 

Several papers report on the nucleophilic reactivity of dithiocarbamate ions towards alkyl halides, 1,2-dibromoalkyl compounds, alkyl and aryl chloroformates, chloroacetic acid, chloroacetates, 3-halo-genophthalides, sulphenyl chlorides, sultones, and trialkylam-monium compounds. Examples of a similar reactivity of dithiocarbazate anions have also appeared. " A series of papers deal with addition or addition-elimination reactions of dithiocarbamate - or dithiocarbazate anions with w-nitrostyrene, 2-thioxo-, 2-oxo-, and 2-imino-5-methoxycarbonylmethylidene-4-thiazolidones, dimethyl acetylenedicar-boxylate, and NN -dialkyl phenylpropiolamidines. S-Monoalkylated N-cyanodithioimidocarbonates (492) underwent oxidative ring-closure to give 3-halogeno-l,2,4-thiadiazole sulphides (493) on treatment with halogenating agents. ... 

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. 

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). 

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... 

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). 

Yoon SC, Cho J, Kim K (1998) Reactions of l-aryl-2,2-dihaloethanone oximes with tetrasulfur tetranitride (S4N4) a general method for the synthesis of 3-aryl-4-halogeno-l,2,5-thiadiazoles. J Chem Soc Perkin Trans 1 109-116... 

Nucleophilic Substitution. A study of the kinetics of the nucleophilic replacement of halogen by methoxide in four halogeno-l,3,4-thiadiazoles and two 1,2,3-isomers has provided values for the pseudo-first-order rate constants and activation energies of these reactions. A mechanism consistent with the observations... 

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

Amino-2,1,3-benzothiadiazole (237) is convertible into its anthranilic acid derivative (238), which is cyclized by phosphorus oxychloride to 6-chloro-[l,2,5]thiadiazolo[3,4-c]acridine (239). Replacement of its 6-halogeno-substituent produces derivatives such as (240). An analogous series of reactions provides 7,8,9,10-tetrahydro-analogues. The condensation of (237) and alkyl 2-oxocyclopentanecarboxylate yields derivatives of the [1,2,5]-thiadiazolo[3,4-h]quinoline ring system such as (241)—(243). Electrophilic substitutions of naphtho[l,2-d][2,l,3]thiadiazole (244) have been studied in some detail. Nitration produces a mixture of the 6- and... 

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