1,2,3-Thiadiazole Subject

Isothiazoles are reductively desulfurized by Raney nickel, e.g. as in Scheme 31 (72AHC(l4)l). 1,2,5-Thiadiazoles are subject to reductive cleavage by zinc in acid, sodium in alcohol, or Raney nickel, e.g. Scheme 32 (68AHC(9)107). 

The 1,2,3-thiadiazole literature was extensively reviewed in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) <84CHEC-I(6)447>. It covered the literature up to 1981 and cited many excellent previous references to 1,2,3-thiadiazoles. A further review on the chemistry of 1,2,3-selenadiazoles and 1,2,3-thiadiazoles, while comparing and contrasting these heterocycles, focused more on the former <90HACl >. Another short review of 1,2,3-thiadiazoles addressed their rearrangement products <92PHC(4)128>. This review (second edition) covers the 1,2,3-thiadiazole literature up to the early part of 1994. It includes some references to CHEC-I when no reference to a particular subject is available between 1982 and 1994. 

Thiadiazole has been subjected to AMI calculations <90JPR885>. The results were used to predict the degree of aromatic character of the heterocycle. Some energetic and magnetic parameters were also calculated. Electrostatic potentials at N-2 and N-4 have been calculated for 3,5-dimethyl-... 

Herz salts (89) made from 3-aminopyrazoles (Section 4.11.8.5) give pyrazolo[3,4-r/]-l,2,3-thia-diazoles (90) when subjected to reduction by sodium dithionite followed by nitrozation (Equation (12)) <84JOCl224>. If the reduction is carried out in an inert atmosphere the disulfide (91) is formed which upon nitrozation gives (90) in 63% yield. Notably, benzo-fused Herz salts give benzo-1,2,3-thiadiazoles simply on treatment with nitrozating mixture <84CHEC-I(6)916>. 

Diazotization of aminothiophene and the Hurd-Mori reaction <1955JA5359> are two popular methods for synthesis of thieno[2,3- -l,2,3-thiadiazoles. Amine 128 gave only a poor yield of methyl thieno[2,3-/7]-l,2,3-thiadiazole-6-carbox-ylate 131a when subjected to acidic diazotization conditions (Scheme 14). The fully substituted thiophenes 129 and 126 underwent cyclization in much greater yields under similar conditions <1999M573>. Protected amines 127 and 130 also gave a better yield of the cyclized product than the unprotected amine 128 <1999JHC761>. 

The carbon-poor sulfur-nitrogen bicyclic [l,2,5]thiadiazolo[3,4-f][l,2,5]thiadiazole 6, its radical anion 7, and its dianion 8 have been the subject of a number of theoretical studies <1997JP033, 2004JA11202, 2005IC7194>. 

Because of the greater-than-average difficulties encountered in the study of these heterocycles, the older literature is unusually confused and controversial, a fact that is clearly apparent from Bambas s review1 of this subject published in 1952. In another survey2 of this field, the literature is covered up to 1956. It is probably true that the most rapid and significant progress dates from about 1954. In the present review, an attempt is therefore made to provide a comprehensive account of the development of the chemistry of the 1,2,4-thiadiazoles during the last ten years. To put the advances into perspective, and for the sake of completeness, the older work is very briefly summarized, chiefly in form of references. 

The preparations of 1,2,4-thiadiazoles and 1,2,4-thiadiazolidines from thioureas are well known and have been summarized in three reviews those of Bambas,188 Sherman,189 and Kurzer.170 Contained in these reviews are discussions of the controversies that surrounded some of the products, notably Hector s bases, which resulted from oxidation of substituted thioureas.171,172 Subjects covered in the above reviews, but too extensive to outline in detail here, are the oxidation of amidinothioureas to 3,5-diamino-1,2,4-thiadiazoles (71),173,174 the oxidation of phenylthiourea175 and of substituted amidinothioureas176 to 3,5-diimino-l,2,4-thiadiazolidines (72, Hector s bases), the reaction of thiopseudoureas with trichloromethanesulfenyl chloride to form 3-alkylthio-5-chloro-l,2,4-thiadiazoles (73),177 the reaction of thiopseudoureas with sodium thiocyanate and bromine178 and the oxidation... 

Binding affinity data of thiazoles and thiadiazoles at the hA3 AR have been subjected to QSAR analysis (Bhattacharya et al. 2005). This study disclosed the importance of molecular electrostatic potential surface (Wang-Ford charges) in correspondence of atoms C2, C5, C7, X8 and S9 (Fig. 7.6), the last two playing the most important roles. Furthermore, the A3 binding affinity increases with decrease of lipophilicity of the compounds and in the presence of short alkyl chains (Me or Et) at the R position. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

The skeletal structure of 3-hydroxy-l,2,5-thiadiazole was determined through reductive desulfurization with Raney nickel in ethanol which formed A, A-diethylaminoacetamide, Eq. (6). The same product was obtained by subjecting the proposed intermediate, glycinamide, to the same reaction conditions. The aryl-substituted thiadiazoles (64) were reduced to a-diamines with sodium and alcohol. 

The mono- and dicarboxylic acids and their derivatives were among the earliest available thiadiazoles and have been the subject of a considerable amount of investigation. The acids are readily converted to reactive esters, acid chlorides, amides, hydrazides, and nitriles ... 

Ohta et aiy subjected 2-phenyl-l,3,4-thiadiazole to a mixture of concentrated nitric and sulfuric acids at 0° and obtained a mixture of the three isomeric 2-nitrophenyl-l,3,4-thiadiazoles in the ratio p m o = 2 3 l, but no 2-phenyl-5-nitro-1,3,4-thiadiazole. The products were identified by oxidation to the corresponding nitro-benzoic acids. 

Potential 2-hydroxy- and 2-mercapto-l,3,4-thiadiazoles have been examined both by infrared and by ultraviolet spectra in the solid state and in solution by Sheinker et They concluded that these compounds exist in the 2-oxo and 2-thione forms, respectively. To 2,5-dimercapto-l,3,4-thiadiazole the 2-mercapto-5-thione structure (155) was given. The structure of this compound has been the subject of some controversy. Stanovnik and TiSler have added some valuable arguments to the discussion. They measured the pKfl values of 155, its iV-methyl, iV -phenyl, and iV -phenyl-/S-methyl derivatives (156), and of the conjugate acids of these and the S-methyl derivative (pKn ) (Table III). In all compounds 156 with R = H, the infrared spectrum showed an absorption band near 2300 cm characteristic of the SH group. They also had pK i values near —1.5, Avhich in connection with the infrared evidence was taken as characteristic of an SH group in this situation. Since the 2,5-dithiol structure is excluded by ultraviolet spectral evidence, the 2-mercapto-5-thione structure (155) seems rather well established. It has previously been shown bj Thorn to predominate in chloroform solution, whereas he concluded that the dithione form (157) should predominate in ethanol solution. However, the pK i value for 155, — 1.36, makes it rather probable that Thorn used the monoanion of 155 instead of the acid itself for spectral comparison, and in that case his conclusions have a very weak foundation. 

Hydroxy-4-cyano-l,2,5-thiadiazole 22 was subjected to thiocarbamoy-lation and subsequent thermal rearrangement for the production of the nitrile intermediate, which upon hydrolysis gave 3-thiolate-4-amide-1,2,5-thiadiazole 25 (Scheme 16) [50],... 

A mixture of 2-methyl-2,3,5-triphenyl-2,3-dihydro-l,3,4-thiadiazole i-oxide (21 0.4g, 1.16 mmol) and AcjO (12 mL) in benzene was heated at reflux for 6 h. The solvent was distilled off and the residue subjected to chromatography (prep TLC, development with benzene, elution with EtzO) to give 25a yield 0.3 g (70%) mp 129-130°C. 

The period covered by this review has seen a spectacular rise in the importance of physical techniques in the study of organic reactions. Its influence has been felt in the chemistry of 1,2,4-thiadiazoles no less than in other branches of the subject. 

By far the greatest number of monoazo dyes of this type are based on diazotized 5-amino-3-phenyl-l,2,4-thiadiazole. A great variety of examples, their structure and properties modulated by a suitable choice of couplers are the subject of numerous, often very substantial3928 patent specifications.393-424 An example of more than ordinary interest is (3-phenyl-1,2,4-thiadiazol-5-yl)- [4-(4,7,10,13-tetraoxa-1 -azacyclopentadecyl)phenyl] diazen... 

The remarkable pestiddal properties of 1,2,4-thiadiazole derivatives, especially of organophosphorus compounds, and of 5-ethoxy-3-trichloro-methyl-1,2,4-thiadiazole and its analogs are the subject of brief separate Sections. Screening programs and individual studies continue3 to reveal a variety of other biological activities of 1,2,4-thiadiazoles. 

Volume 32 consists of five chapters. Of these, that by Kurzer on 1,2,4-Thiadiazoles updates his own contribution on this subject which appeared in 1965 in Volume 5. 

Reactivity towards nucleophilic reagents is not very high. 1,2,5-Oxadiazoles, and 1,2,3- and 1,2,4-thiadiazoles are subject to ring cleavage. Halogenated compounds such as 5-chloro-1,2,4-thiadiazole, 3(5)-chloro-1,2,4-triazole and 5-chlorotetrazole undergo nucleophilic substitution reactions. 

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