Thiophene-1,3,4-thiadiazole

The aromatic character of 1,3,4-thiadiazole can be demonstrated with the aid of micro-wave spectroscopy. Using the differences between the measured bond lengths and covalent radii, aromaticity, as shown by 7r-electron delocalization, diminishes in the order 1,2,5-thiadiazoles > thiophene > 1,3,4-thiadiazole > 1,2,5-oxadiazole (66JSP(19)283). The micro-wave spectrum was further refined by later workers (7lJST(9)l63). 

Microwave spectroscopy on related heterocycles like 1,2,5-oxa-diazole and 1,3,4-thiadiazole has led to an interesting ranking of these molecules in order of decreasing aromaticity as 1,2,5-thiadiazole > thiophene > 1,3,4-thiadiazole > 1,2,5-oxadiazole. The almost normal O—N bond distance in the oxadiazole indicates this molecule to consist essentially of an ordinary system of two conjugated double bonds without any sizable degree of aromaticity. This is further borne out by a comparison of the C—N bond lengths of the two molecules (see Table V). 

Fig. 1-6). The structure obtained for thiazoie is surprisingly close to an average of the structures of thiophene (169) and 1,3,4-thiadiazole (170) (Fig. 1-7). From a comparison of the molecular structures of thiazoie, thiophene, thiadiazole. and pyridine (171), it appears that around C(4) the bond angles of thiazoie C(4)-H with both adjacent C(4)-N and C(4)-C(5) bonds show a difference of 5.4° that, compared to a difference in C(2)-H of pyridine of 4.2°, is interpreted by L. Nygaard (159) as resulting from an attraction of H(4) by the electron lone pair of nitrogen. 

Rg. 1-7. Molecular structures of thiophene and 1,3,4-thiadiazole bond lengths in A (left), bond angles in degrees (right). 

A number of other heterocycHc diazo components such as thiazole, iadazole, thiophenes, and thiadiazole types (see Fig. 1), as well as heterocycHc couplers, ie, 6-hydroxy-2-pyridinone [626-06-2] barbituric acid [67-52-7] and tetrahydroquiaoline [25448-04-8] h.2L e been cited ia the Hterature (90,91). Reviews on disperse dyes have been pubUshed (92,93). 

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. 

A thiophene-annelated thiadiazole has been prepared from hydrazone 47, which was obtained from the thiolactone 46. Reaction of the hydrazone at room temperature with thionyl chloride resulted in an 8 1 mixture of 48 and 49. Heating the reaction to 80°C in dichloroethane provided 48 exclusively. ... 

Reaction of /3-carbonyl amides with the Lawesson s reagent under microwave irradiation gave thiazoles in acceptable yields [37]. The reaction was the same one previously reviewed for the synthesis of thiophenes and was also employed for the preparation of thiadiazoles (Scheme 10, X = NH, Y = CH). 

The 2,5-dihydro-l,3,4-thiadiazole 79 reacts with a range of acetylenic dipolarophiles to afford the 2,5-dihydrothio-phenes 80 in 25-75% yields (Equation 19) <2002HCA451>. The thermal extrusion of dinitrogen from the thiadia-zole affords a thiocarbonyl ylide, which reacts with the dipolarophiles to form the thiophenes. 

Thiophene-1-oxide and 1 -substituted thiophenium salts present reduced aromaticity.144 A variety of aromaticity criteria were used in order to assess which of the 1,1-dioxide isomers of thiophene, thiazole, isothiazole, and thiadiazole was the most delocalized (Scheme 46).145 The relative aromaticity of those molecules is determined by the proximity of the nitrogen atoms to the sulfur, which actually accounts for its ability to participate in a push-pull system with the oxygen atoms of the sulfone moiety. The relative aromaticity decreases in the series isothiazole-1,1-dioxide (97) > thiazole-1,1 -dioxide (98) > thiophene-1-dioxide (99) then, one has the series 1,2,5 -thiadiazole-1,1 -dioxide (100) > 1, 2,4-thiadiaz-ole-1,1-dioxide (101) > 1,2,3-thiadiazole-1,1 -dioxide (102) > 1,3,4-thiadiazole-l,1-dioxide (103) in the order of decreasing aromaticity. As 1,2,5-thiadiazole-1,1-dioxide (100) was not synthesized, the approximations used extrapolations of data obtained for its 3,4-dimethyl-substituted analogue 104 (Scheme 46). 

Microwave spectroscopy indicates that aromaticity diminishes in the order 1,2,5-thia-diazole > thiophene > l,3,4-thiadiazole> l,2,5-oxadiazole> 1,2,4-oxadiazole <84CHEC-1(4)545, B-85MI 410-01>. The aromaticity of heterocycles has been discussed by Katritzky and Barczynski (90JPR885) and by Bird <94H(37)249>. The thermal stability of 2,5-substituted thiadiazoles (23) was studied by differential scanning calorimetry and shown to increase as the rt-contribution of the substituents becomes greater <89MI410-01>. 

Thiadiazoles having one or two thio groups in the 2- and/or 5-positions react with metals to form bidentate ligands they are widely used as antioxidants. An interesting reaction of mesoionic (95) with acetylene dicarboxylate is the formation of thiophene (97) via the intermediate (96) (Scheme 15) <84CHEC-I(4)545>. 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

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>. 

As in the synthesis of thieno[2,3-,7]-l,2,3-thiadiazoles, thieno[3,2-.7 -l,2,3-thiadiazoles are made using diazotization of aminothio-substituted thiophenes and by Hurd-Mori reaction of hydrazones. Diazotization of compound 134 with NaN02 in AcOH/HCl at 0°C produced methyl thieno[3,2- / -l,2,3-thiadiazole-5-carboxylate 135 but in only low yield. Hydrazone tautomer 136 treated with excess SOCI2 in CH2CI2 at room temperature gave dimethyl thieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 137 and dimethyl 5,6-dihydrothieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 138 in a ratio of 3 2 (Equations 20 and 21) <1998H(48)259>. 

The structural indices of aromaticity, I, of oxadiazoles (145-148), thiadiazoles (150-153) and selenadiazoles (155, 156) are compared with that of the parent furan (144), thiophene (149) and selenophene (154) (Scheme 11). 1,2,3-Oxadiazole (145) is the least stable among them since all attempts to synthesize this compound were unsuccessful, most likely because of its easy isomerization to the acyclic isomer. At the same time its sulfur analogue (150) possesses good stability and has been synthesized. Its 2,4-diaza- (151), 3,4-diaza- (152) and 2,5-diaza-(153) isomers demonstrate even more the extent of n-electron delocalization. There exists a well-known tendency of decreasing aromaticity depending on the type of pyrrole-like heteroatom S > Se > O. However, there is no uniformity in the change in aromaticity in the horizontal rows, i. e., dependence on heteroatom disposition. 

Another useful source of the CS fragment in this synthesis scheme is dichlorosulfine. It has been shown to react with diaryldiazomethanes to yield 2-chlorobenzo[h]thiophene 1-oxides in reasonable yields (72RTC1345). The reaction is quite successful when X = H, 4-Me, 4-C1 or 3-OMe (Scheme 20) but failed when X = 4-OMe. The reaction presumably proceeds by a [3 + 2] cyclization to form an intermediate thiadiazole derivative, which loses nitrogen to give an episulfoxide that can rearrange to the final product (Scheme 20). Since benzothiophene sulfoxides are easily reduced, this constitutes a new thiophene synthesis. 

The photolysis of 1,2,3-thiadiazoles also leads to the evolution of nitrogen, but the unstable thiirene is not obtained. 1,2,3-Thiadiazole itself yields nitrogen, acetylene, and polymer.96 In the presence of perfluorobut-2-yne, however, 2,3-bis(trifluoromethyl)thiophene is... 

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