Thiadiazoles and Thiadiazolines

Condensed 1,3,4-Thiadiazoles. - Triazolof3,4-b][1,3,4]thiadiazoles and thiadiazolines are prepared by cyclisation of 3-mercapto-... 

A/-Chloroamidines are usehil for preparation of biocidal imidazoles (106) and thiadiazolines (107). Ai-Chloroguanidines, RNHC(=NC1)NHR, serve as starting materials for synthesis of imidazoles, oxadiazoles, and thiadiazoles (108,109). 

The thermal decomposition of some 3,5-disubstituted-l,2,4-thiadiazoles has been studied and some nonisothermal kinetic parameters have been reported <1986MI239>. Polarographic measurements of a series of methylated 5-amino-l,2,4-thiadiazoles show that thiadiazoles are not reducible in methanolic lithium chloride solution, while thiadiazolines are uniformily reduced at 0.5 = — 1.6 0.02 V. This technique has been used to assign structures to compounds which may exist theoretically as either thiadiazoles or thiadiazolines <1984CHEC(6)463>. The photoelectron spectrum for 1,2,4-thiadiazole has been published <1996CHEC-II(4)307>. 

Thiadiazolines are less stable compared to 1,2,4-thiadiazoles and this can be attributed to the loss of aromatic character. They are readily cleaved at the N-S bond under fairly mild conditions (H2S in pyridine) in some cases, the product from ring cleavage can recyclize to give new heterocyclic ring systems. The 3-imino-l,2,3-thiadiazoline 24 when reduced with H2S affords the two J-triazine derivatives 25 and 26 (Scheme 3) <1996CHEC-II(4)307>. 

The periodate oxidation of 165 and its derivatives gave 195, which could be transformed into a variety of derivatives (194 and 196) (80MI8) upon reaction with amines, hydrazines, semicarbazide, or thiosemicarbazide (Scheme 44). The thiosemicarbazones 196 were cyclized to the thiadiazoles 199 and thiadiazolines 198, which are of chemotherapeutic interest (80MI8). The aldehyde also affords the expected dimedone derivative 197. 

Clare BW, Supuran CT. Carbonic anhydrase inhibitors. Part 57 quantum chemical QSAR of a group of 1,3,4-thiadiazole- and 1,3,4-thiadiazoline disulfonamides with carbonic anhydrase inhibitory properties. Eur J Med Chem 1999 34 41-50. 

Ferric chloride 2-Amino-1,3,4-thiadiazoles and 2-imino-Zl -1,3,4-thiadiazolines from thiosemicarbazones... 

Chemical Properties.—Alkylation. Methylation of 2-amino-5-benzoyl-l,3,4-thiadiazole and its derivatives has been systematically examined. The direction of methylation, which occurs at the N-3 atom of the ring and the exocyclic amino-group, is influenced by the structure of the substrate, the nature of the reagent (Mel, Me2S04, or CH2N2), and the reaction conditions. 2-(Substituted amino)-l,3,4-thiadiazoline-5-thiones (104) are 5-methylated to (105) by one equivalent of methyl iodide, in the presence or absence of alkali. Further methylation occurs at N-3 or N-4, but may lead to mixtures, the composition of which depends on the ratio of the reactants and on the degree of substitution of the 2-amino-group in (105). At 190 C, (105 R = R = Me) isomerizes to (106) ... 

Condensed 1,3f4-Thiadiazoles. - Triazolof3,4-b][1,3,4Jthiadiazoles and thiadiazolines are prepared by cyclisation of 3-mercapto-4-amino-1,2,3-triazoles with substituted alkyl carboxylic acids or treatment with HCl followed by reflux with aldehydes. Thiazolo[4,3-b]M,3,4Ithiadiazoles (368 R=Me,Ph,H,R =Ar) result from treatment of acyl rhodanines (367) with PCl. Further reactions of the former have been reported. Imidazo [2,3-b][1,3,4]-... 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

Thiadiazole 1 was first prepared and characterized in 1955 but products containing this ring system were described as early as 1821. The 1,2,4-thiadiazole nucleus is numbered as in structure 1. The double bonds in the partially reduced rings are designated A2, A3, A4, respectively and these compounds are called thiadiazolines. The fully reduced ring is termed a thiadiazolidine. 

X-Ray crystallographic studies on 1,2,4-thiadiazoles (see Table 1) show the 1,2,4-thiadiazole ring to be essentially planar. The X-ray structure of 4-phenyl-5-(/>-nitrophenyl)-3-(/>-methoxyphenyl)-A2-l,2,4-thiadiazoline 3 shows that the 1,2,4-thiadiazoline ring has a 30° fold around the S(l)-N(4) vector atoms S-l, N-2, C-3, and N-4 are nearly coplanar <1986JCM156>. 

Methyl-4-phenyl-l,2,5-thiadiazole 1,1-dioxide 21 suffers proton abstraction in basic nonaqueous media to give a resonance stabilized anion 43, neutralization of which using anhydrous TFA gives the orange tautomer 4-methylene-3-phenyl-l,2,5-thiadiazoline 1,1-dioxide 44 (Scheme 3) <2001JP0217>. The tautomeric equilibrium is practically displaced toward 21 in acetonitrile and toward 44 in DMF. 

A difference in reactivity was observed between the phenanthro[9,10-r]- and acenaphtho[l,2-c]-l,2,5-thiadiazole 1,1-dioxides 51 and 53 when treated with thiourea. The acenaphtho derivative 53 gave the expected addition product however, the phenanthro thiadiazole 51 was reduced to the thiadiazoline 1,1-dioxide 52 (Equation 2) <2004JP01091>. The difference in reactivity was attributed to the enhanced resonance stability offered by the phenanthrene group. 

Electrochemical reduction of various 3,4-disubstituted-l,2,5-thiadiazole 1,1-dioxides (3,4-diphenyl- 10, phenanthro[9,10]- 51, and acenaphtho[l,2]- 53) gave the corresponding thiadiazoline 1,1-dioxides <1999CJC511>. Voltammetric and bulk electrolysis electroreduction of 3,4-diphenyl-l,2,5-thiadiazole 1-oxide 9 at ca. —1.5 V, in acetonitrile, gave 3,4-diphenyl-l,2,5-thiadiazole 8 (50%) and 2,4,6-triphenyl-l,3,5-triazine 54 (30%) (Equation 3) <2000TL3531>. 

The numbering of the 1,3,4-thiadiazole ring is given below. The present chapter is intended to update the previous work on the aromatic 1,3,4-thiadiazole 1, the nonaromatic A2-thiadiazolines 2, A3-thiadiazolines 3, the thiadiazoli-dines 4, the tautomeric forms 5 and 6, and the mesoionic systems 7. Reference is made to earlier chapters of CHEC(1984) and CHEC-II(1996) where appropriate. 

No examples of direct oxidation of the 1,3,4-thiadiazole ring sulfur to sulfoxide or sulfone have been reported. A3-l,3,4-Thiadiazoline 1-oxide and 1,1-dioxide, however, can be obtained by indirect methods that are reviewed in CHEC(1984) <1984CHEC(6)545>. 

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