3- Hydroxy-1,2,4-thiadiazoles synthesis

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

Examples of the Dimroth rearrangement (Section IV, F) include several s3mtheses of monocyclic triazoles from other heterocyclic systems (cf. Scheme 25). Triazole-5-thiols can be prepared by treatment of 5-amino-l,2,3-thiadiazoles with bases.A similar base-induced rearrangement of sydnoneimines provides a synthesis of 4-hydroxy-triazoles. ... 

Due to the lack of suitable aliphatic starting materials, the synthesis of aromatic forms of monocyclic 1,2,5-thiadiazoles was not accomplished for more than 70 years after the first report of the benzo analogues. General synthetic methodology for monocyclic 1,2,5-thiadiazoles was devized which readily leads to a variety of substituted derivatives, alkyl, aryl, halo, hydroxy, alkoxy, cyano, and amino as well as the parent system. A general model for substrates applicable in these syntheses... 

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)... 

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... 

Grantham RK, Meth-Cohn O (1968) The synthesis of meso-ionic anhydro-2-hydroxy-l,3,4-thiadiazolium hydroxides and the rearrangement of meso-ionic 1,3,4-oxadiazoles to meso-ionic 1,3,4-thiadiazoles. Chem Commun 9 500-502. doi 10.1039/ C19680000499... 

The successful synthesis of stable 4-hydroxy-3-thiosemicarbazides (90)" has opened the way to novel, substituted, 2-hydroxyamino-l,3,4-thiadiazoles (91), by their conventional condensation with imino-esters" or with acid halides R COCl and subsequent dehydrative cyclization. ... 

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