Hydroxy-l,2,5-thiadiazoles

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>. 

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

More recently, some AMPA agonists showing unusual stereostructure-activity have been compared using the commercial docking package Glide (21). These include the enantiomers of 2-amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid (TDPA) and 2-amino-3-hydroxy-5-phenyl-4-isoxazolyl propionic acid (APPA) (28), as well as 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA). 

Fig. 12. (S)- and t/G-isomers of 2-amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid (TDPA) docked to iGluR2 (28). 

When treated with either sulfur monochloride or thionyl chloride, AAs and 2,3-diaminopropionic acid afforded neither l,2,5-thiadiazole-3-carboxylic acid or 3-alkyl-4-hydroxy-l,2,5-thiadiazoles in fair to low yields (66JOC1964 67JOC2823). 

Morpholino-4-hydroxy-l,2,5-thiadiazole Maleic acid Sodium borohydride... 

Thiadiazole - The l-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-l,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)-l,2,5-thiadiazole. 

Hydroxythiadiazoles exhibit marked acid properties (see Section 4.26.2.8) and exist essentially in the hydroxy form (68AHC(9)107). Alkylation with alkyl halides or sulfates and base in dipolar aprotic solvents usually forms ethers. In media where the oxygen atom is screened by solvation or by formation of ion pairs, mixtures of N- and O -alkylation products are formed. The reaction of 3-chloro-4-hydroxy-l,2,5-thiadiazole with epichlorohydrin catalyzed by piperidine in the absence of a solvent gave a mixture of N- and O-alkylated products in about equal amounts (72JMC651). Treatment of 3 - hydroxy-4-(A - morpholino) -... 

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>. 

From a.-Amino Acid Amides and Amidines a-Amino acid amides, which fall into the amine-imine class according to the general model (beginning of Section II,B), are converted to 3-alkyl-4-hydroxy-l,2,5-thiadiazoles by reaction with sulfur mono-chloride, thionyl chloride, or thionyl aniline. A large number of -amino acid amides were employed in the synthesis (see Table I)... 

Cyanoformamide (40), formed in quantitative yield by the acid-catalyzed reaction of cyanogen with water, is converted into 3-chloro-4-hydroxy-l,2,5-thiadiazole (41) by reaction with sulfur monochloride.Prior conversion of 40 to the imino ether (42) leads to 3-ethoxy-4-hydroxy-l,2,5-thiadiazole (43). 

Ross and Smith prepared 3-cyano-4-hydroxy-l,2,5-thiadiazole (48) by the reaction of isonitrosocyanoacetamide (47) with sulfur dichloride. (X-Dioximes were also shown to enter the 1,2,5-thiadiazole... 

The skeletal structure of 3-hydroxy-l,2,5-thiadiazole was determined through reductive desulfurization with Raney nickel in ethanol which formed A, A-diethylaminoacetamide, Eq. (6). The same product was obtained by subjecting the proposed intermediate, glycinamide, to the same reaction conditions. The aryl-substituted thiadiazoles (64) were reduced to a-diamines with sodium and alcohol. 

Thiazolidinediones are another class of heterocyclic carboxylic acid surrogates commonly used for peroxisome prohferator-activated receptors (PPAR) agonists, as potent antihyperglycemic and lipid activity modulators. Other interesting, but less studied heterocyclic surrogates are 3,5-dioxo-l,2,4-oxadiazolidine," 3-hydroxy-l,2,5-thiadiazoles, l,2,4-oxadiazole-5(4//)-ones, 1,2,4-thiadi-azole-5(4/7)-ones , 3,5-difluoro-4-hydroxyphenyl, and 3-hydroxy-7-pyrones. ... 

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