1.2.4- Thiadiazoles, halo-, synthesis

Electrophilic substitution reactions on the carbon atoms of 1,3,4-thiadiazoles are rare due to the low electron density of ring carbons. G-Acylation can be accomplished via rearrangement of intermediate W-acylthiadiazolium salts while radical halogenation can give chlorinated or brominated 2-halo-5-substituted thiadiazoles. Examples can be found in CHEC(1984) <1984CHEC(6)545> and in Houben-Weyls Science of Synthesis <2004HOU(13)349>. 

Nucleophilic reactions at the carbon atoms of 1,3,4-thiadiazoles occur readily owing to the electron-deficient nature of this ring. Halo-substituted thiadiazoles are therefore highly activated and react with a wide range of nucleophiles. Carbon-based nucleophiles such as malonates have been used in the synthesis of 2-substituted thiadiazoles. When chlorothiadiazole 52 was treated with ethyl acetate in the presence of NaHMDS, the 2-phenyl-1,3,4-thiadiazol-5-ylacetic ester 53 was obtained (Equation 6) <20060L1447>. 

A useful method for the synthesis of 5-chloro-l,2,4-thiadiazoles (206) is the reaction of amidines with trichloromethylsulfenyl chloride (see Equation (30)). 3-Halo derivatives (349) (X = Cl, Br, I) (Equation (57)) have been obtained in moderate yields from the corresponding amines (348) via the Sandmeyer-Gatterman reaction <84CHEC-I(6)463>. 3-Chloro-l,2,4-thiadiazolin-5-ones (350) and (351) can be prepared by reacting chlorocarbonylsulfenyl chloride with carbodiimides or cyanamides respectively (Scheme 79) <84CHEC-I(6)463>. 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel rafts reaction, thiadiazole acetic acid derivatives, and halo ketones via the Arndt Eistert synthesis and carbinols by hydride reduction <68AHC(9)107>. The dialkylcadmium conversion of acid chlorides into ketones fails in the 1,2,5-thiadiazole series. The major product is either a tertiary carbinol or the corresponding dehydration product, by virtue of the high reactivity of the intermediate ketone. 

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... 

A new approach to the synthesis of the fused 1,2,3-thiadiazolo ring systems, for example (81) and (82), has been studied by Dehaen and coworkers. Displacement of 5-halo-l,2,3-thiadiazoles (77) with sodium salts of malononitrile has led to the formation of the intermediate (78) which upon treatment with alkali gave the pyrano fused system (81) via the intermediate carboxylate anion (79). Alternatively, reaction of (78) with methylamine or with hydrazine furnished the fused pyridinone (82) via the amide (80) <97JCR(S)396>. 

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