1,2,3-Thiadiazoles, solution-phase

As a member of the thiadiazole family, which is a privileged structure for the generation of drug-like libraries, 1,2,4-thiadiazoles have been used as the basic framework for substances of interest in numerous therapeutic areas Recently, we reported the results of a study that led to the development of a solution-phase parallel synthesis of various drug-like 5-amino-1,2,4-thiadiazoles via a three-component nucleophiUc substitution reaction between carbon disulhde, benzamidine, and benzyl chloride, using a key cyclization reaction of a carboxamidine dithiocarbazate induced by TsCl. We also developed a simple and efficient solid-phase parallel synthetic method capable of facilitating the... 

The preparation of thiiranes is most conveniently performed in solution. However, there are also protocols reported for reaction in the gas and solid phase. By using diazo and thiocarbonyl compounds in ether as solvent, both alkyl and aryl substituted thiiranes are accessible. As indicated earlier, aryl substituents destabilize the initially formed 2,5-dihydro-1,3,4-thiadiazole ring and, in general, thiiranes are readily obtained at low temperature (13,15,35). On the other hand, alkyl substituents, especially bulky ones, enhance the stability of the initial cycloadduct, and the formation of thiiranes requires elevated temperatures (36 1,88). Some examples of sterically crowded thiiranes prepared from thioketones and a macro-cyclic diazo compound have been published by Atzmiiller and Vbgtle (106). Diphenyldiazomethane reacts with (arylsulfonyl)isothiocyanates and this is followed by spontaneous N2 elimination to give thiirane-2-imines (60) (107,108). Under similar conditions, acyl-substituted isothiocyanates afforded 2 1-adducts 61 (109) (Scheme 5.23). It seems likely that the formation of 61 involves a thiirane intermediate analogous to 60, which subsequently reacts with a second equivalent... 

The synthesis of hybrid solution/solid-phase small arrays of 1,2,3-thiadiazoles, L20 and L21, has also been described (239). An SP strategy was first set up (Fig. 8.43) based on commercially available PS-sulfonyl hydrazide resin that was reacted with a small set of commercially available ketones (step a) to form intermediate resin-bound sulfonyl hydrazones 8.84, then submitted to cyclative cleavage to form the thiadiazoles L22 (step b) with good yields (84-99%) and GC purities (94-99%). 

Thiadiazoles. Sulfonyl hydrazide resin 74 could also serve as a sulfone linker in SPS. Porco and coworkers have demonstrated the use of resin 74 for the preparation of sulfonylhydrazone resin 112, which was subsequently applied to the synthesis of 1,2,3-thiadiazoles 113 (Scheme 12.27a).Resin 74 has also been efficiently employed in the resin capture of ketones in a hybrid solution/solid-phase synthesis of 1,2,3-thiadiazoles (Scheme 12.27b). The resin-bound sulfonylhydrazones with aryl halide substituents 112a could be subjected to Stille reaction for the generation of more diverse thiadiazole structures 113a. 

---