Thiadiazole aromaticity

The precise geometrical data obtained by microwave spectroscopy allow conclusions regarding bond delocalization and hence aromaticity. For example, the microwave spectrum of thiazole has shown that the structure is very close to the average of the structures of thiophene and 1,3,4-thiadiazole, which indicates a similar trend in aromaticity. However, different methods have frequently given inconsistent results. 

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). 

In Section 3.4 we discussed the problem of reversibility of diazotization of aromatic and heteroaromatic amines. Simple stoichiometric considerations indicate that the reverse reaction (ArNJ -> ArNH2) may take place under strongly acidic conditions. Experimentally the reverse reaction was found only with heteroaromatic diazonium salts (Kavalek et al., 1989). Reaction conditions of hydroxy-de-diazonia-tion are comparable to those used for the reverse reactions of diazotization (e.g., 10 m H2S04, but at 0°C for the formation of 2-amino-5-phenyl-l,3,4-thiadiazol from the corresponding diazonium salt, Kavalek et al., 1979). So far as we know, however, amines have never been detected in aromatic hydroxy-de-diazoniations, not even in small amounts. 

Equimolar amounts of aromatic aldehydes, thioglycolic acid and thionohydrazides in sulphuric acid at room temperature afforded 2-methylthio-5-aryl-5ff-thiazolo[4,3-h]-l,3,4-thiadiazoles in a one pot procedure <96HC243>. 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

The 1,2,3-thiadiazole 1 possesses three contiguous heteroatoms in a five-membered ring and exists as a remarkably stable neutral aromatic compound. It is isomeric with the ring-opened a-diazothioketone 2 (Equation 1) although there is evidence that it reacts through this intermediate, all structural methods, including X-ray diffraction, point to 1 as the structure for a 1,2,3-thiadiazole. 

Benzothiadiazoles 3 have been extensively studied. Fully aromatic mesoionic compounds such as 4 continue to be synthesized. A number of examples of 4,5-dihydro-l,2,3-thiadiazole derivatives such as compound 5 <1993JOC82> and more recently the phenyl derivative 6 <2003RJ01501> have been reported. The corresponding 2,3-dihydro-l,2,3-thiadiazoles have also been reported and Hurd and Mori reported the N-Z phenylsulfonyl derivative 7. The electron spin... 

Proton nuclear magnetic resonance (NMR) chemical shifts of 1,2,3-thiadiazoles give another indication of the aromatic character of these compounds. Compiled in Table 4 are a number of examples of proton chemical shifts for ring-substituted 1,2,3-thiadiazoles. 

Rings incorporating [4 +2] rt-electrons are aromatic according to the Hiickel definition and on this basis 1,2,3-thiadiazoles can be considered as aromatic. This is supported by 13C and 111 NMR chemical shifts. In 1990, the aromaticities of some five- and six-membered ring heterocycles including 1,2,3-thiadiazole were studied by computational methods and found to correlate well with their chemical natures <1990JPR885>. 

Chloro-l,2,3-thiadiazole-4-carboxamides 38 react with the sodium salt of diethyl malonate to give the corresponding malonic acid derivatives 39. The yield in these reactions falls as the electron-releasing properties of the 4-substituents in the aromatic ring increase (Equation 8) <1997JCM396>. 

As mentioned earlier, 1,2,4-thiadiazoles are generally quite stable to heat due to the aromatic nature of the ring. Irradiation of 3-phenyl-l,2,4-thiadiazole 11, however, resulted in the formation of benzonitrile in 74% yield <2003JOC4855>. 

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>. 

Condensations of 5-methyl-substituted 1,2,4-thiadiazoles with aromatic aldehydes lead to 5-styrylthiadiazoles. With carboxylic acid esters, ethoxalyl derivatives are formed, and isoamyl nitrite produces the corresponding oximes <1982AHC285>. These reactions are restricted exclusively to the 5-methyl-substituted 1,2,4-thiadiazoles reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

Studies on the statistical deviation from an ideal bond order support the relatively high aromaticity of 1,2,5-thiadiazole (Table 7). The harmonic oscillator model of aromaticity (HOMA) value for 1,2,5-thiadiazole has not yet been reported. 

Table 7 Aromaticity based on geometric criteria (TDA=thiadiazole)...

Analogous studies on 1-monoxides and 1,1-dioxides support the nonaromaticity of these derivatives. The. /(C—C) spin-spin coupling between 13C nuclei has been determined for 1,2,5-thiadiazole (48.1 Hz) and correlated to bond length and tentatively to aromaticity <1994MRC62>. Based on this, a low aromaticity was assigned to 1,2,5-thiadiazole similar to furan and isoxazole while a high aromaticity assignment was made for 1,2,3-thiadiazole, contrary to that reported by Bird. 

Table 9 Aromaticity based on magnetic criteria (TDA=thiadiazole) <2002JOC1333>...

Thiadiazoles undergo substitution reactions reflecting their relatively high aromatic character but in contrast the 1,2,5-thiadiazole 1-oxides and 1,1-dioxides suffer addition chemistry supporting their non- or antiaromatic characters. 

The relatively high aromaticity of the parent 1,2,5-thiadiazole renders it good thermal stability (stable up to 220 °C) despite this, 3,4-diphenyl-l,2,5-thiadiazole 8 suffers slow photochemical degradation to give benzonitrile and sulfur. The low basicity of 1,2,5-thiadiazole indicates a relatively high electron density in the Jt-orbital and corresponding low electron density of the nitrogen lone pairs. Addition reactions such as Walkylation do not occur readily. A-Oxidation is... 

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. 

The thiadiazole thione 112 was treated with an alkyl halide in sodium hydroxide to afford the thiadiazole derivatives 113 in 35-92% yields (Equation 35, Table 3) < 1999JME1161 >. This reaction results in the aromatization of the reduced thiadiazoline ring (see Section 5.10.9.5.1). The 2-(methylsulfanyl)-l,3,4-thiadiazoles can be S-demeth-ylated to afford 1,3,4-thiadiazole-2-thiones <1994JHC1439>. 

The mechanism of formation of various 1,2,4-thiadiazoles by self condensation of aromatic thioamides and of TV-substituted thioureas was studied by Forlani et al. Typically, condensations were performed in the presence of DMSO and an acid such as hydrochloric acid <00JHC63>. 

Tetramethylthiuram disulphide (TMTD) has proved to be a useful reagent for the thiocarbamoylation of amine containing compounds. Thus, reaction of a series of hydrazones of aromatic aldehydes with TMTD in a 1 1 ratio gave amongst other products, 4,4-dimethylthiosemicarbazide 86 and 5-dimethylamino-l,3,4-thiadiazole-2-thiol 85. It was confirmed that 86 was an intermediate in the synthesis of 85 as treatment of 86 with TMTD gave 85 in 85% yield <00RCB344>. 

When solutions of iminophosphorane 366 in anhydrous DMF are treated with an aromatic isocyanate at room temperature, 2-arylamino-imidazo[2,TA][l,3,4]thiadiazol-5(67/)-ones 135 are isolated (Equation 70) <2004S1067>. 

The first single-crystal structure was reported for 6-methyl-3-phenyl-.r-triazolo[3,4-3]-l,3,4-thiadiazole in which the nucleus of the triazolothiadiazole system was planar confirming the aromatic character of the lOn-electron system <1974CSC7>. This is generally the case for the entire series of 5,5-fused heterocycles. 

Reaction of 218 with aromatic aldehydes to give the ring-closed product 220 takes place in boiling ethanol in excellent yield (Scheme 44) <2001PHA376>. The transformation obviously proceeds via formation of a dihydro thiadiazole 219, as also suggested for the transformation of 218 under microwave irradiation in the presence of montmorillonite <2002PS2399>. 

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