1,2,4-Thiadiazoles, hydroxy

Hydroxy-1,2,4-thiadiazoles are generally distinctly acidic. 3-Ethyl-5-hydroxy-1,2,4-thiadiazole, for example, is more acidic than nitrophenol and 4-hydroxypyrimidine, but less so than 2,4-dinitrophenol. 3-Hydroxy-1,2,4-thiadiazoles fail to afford ketonic derivatives and give red to purple colors with iron(III) chloride, indicating their phenolic nature <65AHC(5)119>. Their IR spectra in... 

Chloroamine reacts with both (266) and ethoxycarbonylthioiminocarbonates (267) to give 3-amino and 3-hydroxy-1,2,4-thiadiazoles (260) (Equation (38)) <84CHEC-I(6)463>. 

By taking advantage of the well-known conversion of the cyano into the carbamoyl group under the influence of alkaline hydrogen peroxide, A-aryl-A -cyanoisothioureas (120) (as their stable sodio derivatives) are directly cyclizable, in approximately 50% yield, to 5-arylamino-3-hydroxy-1,2,4-thiadiazoles (119) in one stage.130... 

The ultraviolet absorption spectrum122 of 5-anilino-3-hydroxy-1,2,4-thiadiazole closely resembles that of the 3-amino analog, for which the 3-enamine configuration seems most likely (see Section... 

Acylation of 3-hydroxy-l,2,4-thiadiazoles (184) by the usual procedures yields monosubstitution products that are formulated as phenolic esters (e.g. 185 R = Ph R = Ac, Bz, or p-MeC6H4S02)178 (see also ref. 130). 5-Anilino-3-hydroxy-1,2,4-thiadiazole affords diacetyl and dibenzoyl derivatives one acyl residue being assumed to enter the hydroxyl group, the possible structures of the derivatives are 186a-c.130... 

The position of equilibrium in the tautomers of 3-hydroxy-1,2,4-thiadiazoles (Scheme 9) is not conclusively known. The existing chemical evidence suggests that the OH form (13) predominates. However, a UV spectral study was interpreted to suggest that the lactam NH form (14a) contributed substantially to the tautomeric equilibrium in ethanol <76AHC(S1)266, p. 377). 

The synthesis of an interesting 1,2,4-thiadiazole nucleoside has been achieved by the following route 5-amino-3-hydroxy-1,2,4-thiadiazole, in which the substituents are blocked (418) by silylation,329 is condensed with l,2,3,5-tetra-0-acetyl-/ -D-ribofuranose (419), in 1,2-dichloroethane in the... 

A reinvestigation of the reactions of 3,4-dichloro- and 3-chloroH-hydroxy thiadiazoles with a variety of acetylene nucleophiles (NaC=CNa, I, iC=C-TMS, LiC=C-SnM e3) showed consumption of the starting thiadiazoles with no significant higher molecular weight products being formed <2004TL5441>. 

Aminoacid amides are suitable synthons for transformation to 3-hydroxy-thiadiazoles 25 (1967JOC2823, 1984WOP8402525) in moderate yields (Scheme 14). Clycinamide gave 4-chloro-l,2,5-thiadiazol-3-ol (1993JPP05140133) in a reaction with sulfur monochloride. 

A number of other heterocycHc diazo components such as thiazole, iadazole, thiophenes, and thiadiazole types (see Fig. 1), as well as heterocycHc couplers, ie, 6-hydroxy-2-pyridinone [626-06-2] barbituric acid [67-52-7] and tetrahydroquiaoline [25448-04-8] h.2L e been cited ia the Hterature (90,91). Reviews on disperse dyes have been pubUshed (92,93). 

Pyrazblin-5-one, 3-alkyl-(l,2,4-thiadiazol-5-yl)-reactions, 6, 483 2-Pyrazolin-5-one, 3-amino-tautomerism, 5, 215 2-Pyrazolin-5-one, 4,4-diazido-rearrangement, 5, 720 2-Pyrazolin-5-one, 3-hydroxy-tautomerism, 5, 215 2-Pyrazolin-5-one, 3-methyl-1 -phenyl-reactions, 5, 252... 

Step C Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Oxopropoxy)-1,2,5-Thia-diazole — The 1-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane, prepared as described in Step B, (11 mols) is added to 0.80 N methanolic sodium methoxide (15 ml) at 0°C. The mixture is stirred for 15 minutes at 0° to 5°C, treated with 3-morpholino-4-hydroxy-1,2,5-thiadiazole (4.29 grams) and then refluxed for 16 hours. The solvent is evaporated in vacuo and the residue is treated with excess potassium carbonate to provide 3-morpholino-4-(3-butylamino-2-oxopropoxy)-1,2,5-thiadiazole. 

Step D Chemical Reduction Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Hydroxy-propoxyl-l,2,5-Thiadiazole — The 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride). 

In Section 3.4 we discussed the problem of reversibility of diazotization of aromatic and heteroaromatic amines. Simple stoichiometric considerations indicate that the reverse reaction (ArNJ -> ArNH2) may take place under strongly acidic conditions. Experimentally the reverse reaction was found only with heteroaromatic diazonium salts (Kavalek et al., 1989). Reaction conditions of hydroxy-de-diazonia-tion are comparable to those used for the reverse reactions of diazotization (e.g., 10 m H2S04, but at 0°C for the formation of 2-amino-5-phenyl-l,3,4-thiadiazol from the corresponding diazonium salt, Kavalek et al., 1979). So far as we know, however, amines have never been detected in aromatic hydroxy-de-diazoniations, not even in small amounts. 

Hydroxy-l,2,4-thiadiazoles can exist in 3-tautomeric forms (Scheme 1). Chemical evidence suggests that the OH form 4 predominates however, UV data suggest that the lactam form 5 is the major tautomer in ethanol <1996CHEC-II(4)307>. 

Hydroxy-l,2,4-thiadiazoles are acidic compounds that are generally more acidic than nitrophenol but less acidic than 2,4-dinitrophenol. 

In general, 3-hydroxy-l,2,4-thiadiazoles react with hard nucleophiles (acid chlorides, sulfonyl chlorides) at the oxygen atom, whereas soft nucleophiles (isocyanates, acid anhydrides) react at the N-2 position yielding 1,2,4-thiadiazolin-3-ones. Nucleophiles react at the N-4 position of 5-hydroxy-l,2,4-thiadiazoles <1996CHEC-II(4)307>. There have been no new publications on O-linked substituents since the publication of CHEC-II(1996). 

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>. 

In this method, the 1,2-N-S bond and the 2,3-N-C bond are formed. This is a useful method for the preparation of 3-hydroxy- or 3-amino-5-substituted-l,2,4-thiadiazoles starting from either an ethoxycarbonyl or a cyano thioimino-carbonate. Thus the condensation reaction of the ethoxycarbonyl thioiminocarbonate 100 with chloramine at low temperatures affords 3-hydroxy-5-substituted-l,2,4-thiadiazoles 100 (Equation 28) <2004HOU277>. 

CR y)-2-Amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid 42 was resolved into the (—)- and (+)-enantiomers using a semipreparative Crownpak CR(+)-column (150 x 10mm2) equipped with a Crownpak CR(+) guard column (10 x 4.0 mm2) (Daicel). The column was eluted at 0 °C (ice bath) with aqueous trifluoroacetic acid (TFA) (pH 2.0) at 1.5 mlmin-1. After removal of the acidic mobile phase, the pure enantiomers could be crystallized as zwitterions with high ee (99.9%) <2002BMC2259>. The first eluted (—)-enantiomer has the ////-configuration as proved by an X-ray crystallographic analysis. 

Addition reactions such as A-alkylation do not occur readily, and trimethylsilylmethylation of 3,4-diphenyl-l,2,5-thiadiazole 8 with trimethylsilylmethyl trifluoromethanesulfonate at 80°C occurred at N-2 < 1999J(P1) 1709>. The electron-rich 3-hydroxy-l,2,5-thiadiazole can be preferentially methylated on N-2 using trimethyl orthoacetate in toluene to afford the 2-methyl-l,2,5-thiadiazol-3-one in 69% yield <2002EJ01763>, although a mixture of 3-hydroxythiadiazole and neat trimethyl orthoacetate showed a 20 80 ratio of N- versus 0-alkylation products by H NMR. Treatment of 3-hydroxy-l,2,5-thiadiazole with /-butyl acetate under acid catalysis (Amberlyst 15) gave almost exclusively the A-alkylated compound <2002BMC2259>. 

The preparation of the 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 via oxidative elimination of the thioether 111 according to the published procedure <1966JOC1964> gave unsatisfactory results leading the authors to develop a one-pot procedure for the preparation of the vinylthiadiazole (Equation 19) <2004TL5441>. 

The olefin metathesis of 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 and a McMurry coupling reaction (Ti3+ under reductive conditions) of the aldehyde 114 were both unsuccessful <2004TL5441>. An alternative approach via a Wittig reaction was successful. With the use of the mild heterogenous oxidant 4-acetylamino-2,2,6,6-tetramethyl-piperidine-l-oxoammonium perfluoroborate (Bobbitt s reagent), the alcohol 113 was converted into the aldehyde 114. The phosphonium salt 115 also obtained from the alcohol 113 was treated with the aldehyde 114 to give the symmetrical alkene 116 (Scheme 16) <2004TL5441>. 

Bromination of 3-hydroxy-l,2,5-thiadiazoles 129 was achieved using phosphorus oxybromide however, vigorous conditions are required (Equation 21) <1996H(43)2435>. 

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