2- Halo-1,3,4-thiadiazoles

There are examples of nucleophilic displacement of halide from halo-1,2,5-thiadiazoles by ammonia, primary alkylamines, secondary alkylamines, arylamines, sulfonamides, and phthalimide <1984CHEC(6)513, 1996CHEC-II(4)355>, but the reactions often require high temperatures and excess of the nucleophile. 

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>. 

The a-halo ketone has also been prepared in situ (NBS, benzoyl peroxide, light) [89IJC(B)500]. Similarly, imidazo[2,l-b][l,3,4]thiadiazoles are accessible from 2-amino-l,3,4-thiadiazoles and acetophenones in the presence of hydroxy(tosyloxy)iodobenzene (HTIB). This latter method has been proposed as more convenient and versatile than the reaction of 2-amino-1,3,4-thiadizoles with a-halo ketones [94IJC(B)686, 94JCR(S)38, 94MI5],... 

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... 

Unsubstituted thiadiazole is unstable under basic conditions, and will decompose. 2-Amino-thiadiazole derivatives (45) react with amines to yield triazolinethiones (46). 2-Amino-5-halo-thia-diazole reacts with hydrazine to give a mixture of (47) and (48). 2,5-Dihalo and 2,5-dithio-thiadiazoles yield only (48) under the same conditions. Even a weaker nucleophile such as aniline... 

In the 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than at the 3-position, and this affects substituent reactions. 5-Halo derivatives, for example, approach the reactivity of 4-halopyrimidines. The 1,2,4-oxadiazole ring shows a similar difference between the 3-and 5-positions. 

The 5-position in 1,2,4-thiadiazoles is most reactive in nucleophilic substitution reactions. Chlorine, for example, may be displaced by nucleophiles (Nu) such as fluoride, hydroxide, thiol, amino, hydrazino, sulfite and azido groups (Scheme 11). Active methylene compounds such as malonic, acetoacetic and cyanoactic esters as their sodio derivatives also displace the 5-halo substituent (65AHC(5)ll9). The reaction follows second-order kinetics, the rate determining step being addition of the nucleophile at C-5 followed by rapid elimination of X. 

Aminothiadiazoles also react with halo aldehydes and halo ketones in a bidentate fashion to give imidazo[2,1-b ][1,3,4]thiadiazoles (145). The NMR properties, aromatic character, basicity and crystal structure data are available (80JCS(P2)42l). Aminothiadiazoles also react with trichloromethanesulfenyl chloride to give the sulfenamide (146) which in the presence of an aromatic amine cyclizes to 3//- [1,3,4]thiadiazolo[2,3-c ][1,2,4]thiadiazole (147) (75JOC2600). 

Reaction of 5-halo-l,2,3-thiadiazoles with 1,3-diaminopropane leads to bis(l,2,3-triazolyl-l,2,3-thiadiazolyl)sulfide 105. Further intramolecular cyclization affords bis-[l,2,3]triazolo[l,3,7]thiadiazocine ring system 106 in 79% yield (Scheme 25 <20030BG4030>). The role of the ester groups on both the 1,2,3-triazole and 1,2,3-thiadiazole rings in the formation of the final product is essential. 

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