1.2.5- Thiadiazoles 2,4-dihydro— from

As mentioned previously, 2,5-dihydro-l,3,4-thiadiazoles obtained from aromatic thioketones and diazomethane readily eliminate N2 at -45 °C. (53-Methylides... 

Table 13 3,6-Disubstituted 5,6-dihydro[l,2,4]triazolo[3,4-()][l,3,4]thiadiazoles (111) from the reaction of 4-amino-5-sulfonyl-4//-[l,2,4]triazoles (105) with aldehydes.

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. 

Thiadiazolines were also obtained by a 1,5-dipolar ring reconstruction of mesoionic ylides. The bromine adduct of 2,3-diphenyltetrazolium-5-thiolate (181) reacts with the sodium salt of diethyl malonate to yield as the only product 5,5-bis(ethoxycarbonyl)-4-phenyl-2-phenylazo-2,3-dihydro-1,3,4-thiadiazole (182) (Scheme 33). The same type of product was obtained from reactions with ethyl cyanoacetate and ethyl acetoacetate <88BCJ2979>. 

In some instances, sterically encumbered 2,5-dihydro-l,3,4-thiadiazoles do not eliminate nitrogen. Instead, cycloreversion leading to the starting materials or a new pair of diazo- and thiocarbonyl compounds was reported. Thus, a crystalline product of type 20, obtained from di(ferf-butyl)diazomethane and 2-benzyl-4,4-dimethyl-l,3-thiazole-5(477)-thione, was found to dissociate in solution to give the starting materials (42). In the case of (ferf-butyl)(trimethylsilyl)thioketone and... 

Acidic compounds of type R—XH, which are able to protonate thiocarbonyl ylides, also undergo 1,3-addition leading to products of S,S-, S,0-, or 5,A-acetal type (Scheme 5.20). Thiophenols and thiols add smoothly to thiocarbonyl ylides generated from 2,5-dihydro-l,3,4-thiadiazoles (36,38,86,98,99). Thiocamphor, which exists in solution in equilibrium with its enethiol form, undergoes a similar reaction with adamantanethione (5)-methylide (52) to give dithioacetal 53 (40) (Scheme 5.21). Formation of analogous products was observed with some thiocarbonyl functionalized NH-heterocycles (100). 

The preparation of thiiranes is most conveniently performed in solution. However, there are also protocols reported for reaction in the gas and solid phase. By using diazo and thiocarbonyl compounds in ether as solvent, both alkyl and aryl substituted thiiranes are accessible. As indicated earlier, aryl substituents destabilize the initially formed 2,5-dihydro-1,3,4-thiadiazole ring and, in general, thiiranes are readily obtained at low temperature (13,15,35). On the other hand, alkyl substituents, especially bulky ones, enhance the stability of the initial cycloadduct, and the formation of thiiranes requires elevated temperatures (36 1,88). Some examples of sterically crowded thiiranes prepared from thioketones and a macro-cyclic diazo compound have been published by Atzmiiller and Vbgtle (106). Diphenyldiazomethane reacts with (arylsulfonyl)isothiocyanates and this is followed by spontaneous N2 elimination to give thiirane-2-imines (60) (107,108). Under similar conditions, acyl-substituted isothiocyanates afforded 2 1-adducts 61 (109) (Scheme 5.23). It seems likely that the formation of 61 involves a thiirane intermediate analogous to 60, which subsequently reacts with a second equivalent... 

Numerous examples involving the preparation of tetrahydrothiophenes via [3 + 2] cycloaddition of thiocarbonyl ylides with electron-poor alkenes have been reported. Thiobenzophenone (5)-methylide (16), generated from 2,5-dihydro-1,3,4-thiadiazole (15) and analogous compounds, react with maleic anhydride, N-substituted maleic imide, maleates, fumarates, and fumaronitrile at —45°C (28,91,93,98,128,129). Similar reactions with adamantanethione (5)-methylide (52) and 2,2,4,4-tetramethyl-3-thioxocyclobutanone (5)-methylide (69) occur at ca. +45°C and, generally, the products of type 70 were obtained in high yield (36,94,97,130) (Scheme 5.25). Reaction with ( )- and (Z)-configured dipolaro-philes stereospecifically afford trans and cis configured adducts. 

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). 

Similar results were encountered in the reaction of 69 (generated thermally from the corresponding 2,5-dihydro-1,3,4-thiadiazole) with benzylidene malonodinitrile or a-cyano-substituted cinnamates (97). In these cases, seven-membered lactams or... 

Thioxanthione and thiobenzophenone 3 -methylide, obtained by the elimination of N2 from 2,5-dihydro-2,2-diphenyl-l,3,4-thiadiazole at —45°, give the spiro[thioxanthene-9,4 -[l,3]dithiolane] 355 through a 1,3-dipolar cycloaddition (Equation 78) <2000EJ01695>. 

Of the various heterocycles discussed in this chapter, the pyridofuroxans show the least aromatic character. In Section 7.10.5.4, subtle differences in aromaticity between the [l,2,5]thiadiazolo[3,4-c]pyridines and the [l,2,5]oxadiazolo[3,4-c]pyridines are apparent from their dissimilar reactivity towards various reducing agents. In contrast to the former where desulfurization of the thiadiazole ring or substituent reduction occur, the latter heterocycles undergo initial reduction of the C=N bond to form the 4,5-dihydro[l,2,5]oxadiazolo[3,4-c]pyridines (120) with sodium borohydride at ambient temperature (Scheme 19). However, at 80 °C, the oxadiazole moiety is preferentially reduced... 

Azine approach. Fused 1,2,3-thiadiazoles are often conveniently prepared from vicinal aminomercaptoarenes by a diazotization reaction the mercapto group adds to the initially formed diazonium group to form the ring. So far this reaction has not been reported in this series, but a mechanistically similar reaction results when l,4-dihydro-7H-t>-triazolo[4,5-h]pyridine-7-thione (655 R = H) is heated in ethanol to furnish the 1,2,3-thiadiazole (657). Heating the latter under alkaline conditions reverses the reaction with... 

Azole approach. 3,4-Diamino-l,2,5-thiadiazole reacts with 1,2-dicarbonyl compounds to form pyrazines (747) (76JHC13). From the reaction of 1,2,5-thiadiazole 1,1-oxides such as (748) with o-phenylenediamine, the l,3-dihydro[l,2,5]thiadiazolo[3,4-Z>]quinoxaline 2,2-dioxide (749) is formed. To understand this reaction it is pointed out that the 1,2,5-thiadiazole 1,1-dioxide ring is to be regarded as alicyclic rather than aromatic and is strongly 7r-electron deficient. Substituents with leaving properties in the 3,4-positions are therefore readily displaced as in the reaction of (748) (75JOC2743). 

Fig.33 Alignment and superposition models of 5-[l-aryl-l,4-dihydro-6-methylpyridazin-4-one-3-yl]-2-arylamino-l,3,4-thiadiazoles and corresponding oxadiazoles in CoMFA. (Reprinted with permission from [194]. Copyright 2002 American Chemical Society)...

Diastereomeric 2,3-dihydro-l, 3,4-thiadiazole 5-oxides 6 have also been prepared by [2 + 3] dipolar cycloaddition of thioketone 5-oxides 5 to nitrilimines81,82. The reaction of diphenylni-trilimine [generated in situ from A,-(a-chlorobenzylidene)-A"-phenylhydrazine and triethylamine] with a series of the pure ( > and (Z)-isomers of unsymmetrical thioketone 5-oxides gives either the same single diastereomeric adduct or a mixture of both diastereomers. 

Some interesting spiro jS-lactams (22) are obtained from the reaction of 2-imino-2,5-dihydro-l,3,4-thiadiazoles and ketones. The products presumably arise via a [27t + 27t] cycloaddition followed by elimination of a molecule of nitrogen. 

A synthesis of (25) (Table 3) has been reported from pyrazolidine (177) through the intermediacy of l,3-dithioxo-6,7-dihydro-5//-pyrazolo[l,2-c][l,3,4]thiadiazole (178) (Scheme 16) <92PHA416>. 

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