Cycloaddition, 1,3-dipolar 1.2.3- thiadiazoles

Reaction of lithium trimethylsilyldiazomethane (TMSC(Li)N2) with thiocarbonyl compounds has proved to be a convenient method for the preparation of 5-substituted 1,2,3-thiadiazoles. This reaction is very similar to the Pechmann-Nold reaction but probably does not proceed through a dipolar cycloaddition pathway. A number of examples of this type of reaction were described in CHEC-II(1996). More recently, it was reported that TMSCN2Li also reacts with diethylaminothiocarbonyl chloride to afford a mixture of 1,2,3-thiadiazoles 66 and 67 (Equation 19) <1997BSB533>. 

Imino-1,2,4-thiadiazoles such as 27 react with electron-deficient alkynes to afford arylimino thiazoles such as 28. There has been some speculation as to the mechanism of this reaction, which may involve a 1,3-dipolar cycloaddition or a stepwise nucleophilic addition (Equation 6) <1996CHEC-II(4)307>. 

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>. 

An alternative route to C-linked derivatives involves the 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles which yields 3,5-disubstituted-l,2,4-thiadiazoles of unequivocal structure (see Section 5.08.9.8). 

Bistrifluoromethyl-l,3,4-thiadiazole 71 undergoes a Diels-Alder reaction with norbornadiene under high pressure to give the unstable cycloadduct 72 which rapidly loses dinitrogen forming the 1,3-dipolar intermediate 73. The [4+2] cycloaddition of the intermediate 73 with a second alkene affords product 74 in 29% yield (Scheme 5) <1997SL196>. 

The 5-thio-substituted l,3,4-thiadiazole-2(377)-thiones 75 react with iV-methyl-C-phenylnitrilimine in a regiospe-cific 1,3-dipolar cycloaddition to form not the expected cycloadducts 76 but rather the rearranged products 77 and 78 in 16-28% yields (Scheme 6) <1998AJC499>. 

When planning reactions of thiocarbonyl compounds with electrophilic carbene complexes it should be taken into aceount that thiocarbonyl compounds can undergo uncatalyzed 1,3-dipolar cycloaddition with acceptor-substituted diazomethanes to yield 1,3,4-thiadiazoles. These can either be stable or eliminate nitrogen to yield thiiranes or other products similar to those resulting from thiocarbonyl ylides [1338]. 

A very similar reaction to that of Pechmann and Nold but which probably does not proceed through a dipolar cycloaddition manifold is the formation of 1,2,3-thiadiazole (6) via a thionoester and lithium trimethylsilyldiazomethane (Equation (17)) <86H(24)589>. Lithium trimethylsilyl-diazomethane also reacts with thioketones to produce 1,2,3-thiadiazoles <87H(26)1467>. 

No proven 1,3-dipolar cycloaddition reactions of 1,2,4-thiadiazoles have been reported. For proposals related to these transition states see Section 4.08.6.1 and Scheme 13. 

As reported before (see Section 4.14.6.1, Scheme 19), thermolysis of oxathiazolines (169) proceeds via a retro 1,3-dipolar cycloaddition to produce the carbonyl compound and the nitrile sulfide intermediate. Trapping reactions have been carried out with DMAD, ECF (ethyl cyano formate), and benzonitrile to give respectively isothiazoles (170) and thiadiazoles (171) and (172). However in two particular cases (R = 4-MeOC6H4, 4-ClCgH4, thermolysis in the presence of benzonitrile gives (172) and the thiadiazole (173) in very low yields. It has been suggested that the latter arises... 

Amino-l,2,4-thiadiazoles 191 are obtained when ether is used (249), while 5-alkylthio-1,2,3-triazoles 192 result when the reaction is carried out in THF (250). Reaction of 3 with carbon disulfide leads to 5-alkylthio-l,2,3-thiadiazoles 193 (251). While 3 can act as a synthetic equivalent of the RC—N—N synthon (R = H, SiMea) in all these reactions, it should be emphasized that it does not react by a concerted 1,3-dipolar cycloaddition but rather by a stepwise polar mechanism. The highly nucleophilic character of 3 can account for why diazomethane and... 

Electron-poor nitriles react with compound 87 and its derivatives to form the 5-amino-l,2,4-thiadiazole derivatives 104 <1985JOC1295>. Therefore, the formation of product 94 (see Scheme 21) may be explained alternatively by the addition of amidonitrile 93 to compound 90. The mechanism of the formation of product 104 was discussed in detail in CHEC-II(1996) <1996CHEC-II(4)691> but most probably the steps involved are (1) reaction of the electrophilic nitrile with the exocyclic nitrogen of compound 87 or its derivatives (2) loss of nitrogen similarly to the previous reactions and formation of an imine 103 (3) masked 1,3-dipolar cycloaddition/elimination reaction of the nitrile to the imine 103. Since the same nitrile is expelled in the elimination step, only 1 equiv of reagent is needed (Scheme 24). 

Partially and perfluorinated thioketones and thioaldehyde were stabilized as anthracene adducts (70). The adducts (70) were prepared in moderate yield from the corresponding carbonyl compounds with P4S10 or Lawesson s reagent in the presence of anthracene under toluene reflux. The generated thiocarbonyl compounds are not accessible in bulk due to their tendency towards polymerization. By thermolysis of the anthracene adducts (70) in the presence of C,N-bis(triisopropylsilyl)nitrilimine (NI), 1,3,4-thiadiazole derivatives (71) were obtained. Also, 1,3-dipolar cycloaddition with bis(trimethylstannyl)diazomethane (BTSD) to give consecutive products (72) from a 1,2-metallotropic migration of primary adducts was discussed. [95LA95]... 

A study of the 1,3-dipolar cycloaddition of pyrazines, pyrimidines and l//-pyrimidinthiones with nitrilimines (80), generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides (79), was carried out. Reaction of pyrimidine-2( l//)-thiones (81) and -4(l//)-thiones with nitrilimines in benzene at reflux gave spiro[pyrimidine-2(l//), 2 (3 f/)-[ 1,3,4]thiadiazoles... 

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>. 

Heteropentalenes with a nonclassical ring structure have been observed to partake in interesting dipolar cycloaddition reactions <75ACR139,77T3203). It is believed that by increasing the number of heteroatoms in the ring the resultant chemical reactivity decreases as a consequence of increased stability of the system. This hypothesis was reinforced when no evidence was found for cycloaddition of dipolarophiles to 6-methyl-4-phenylpyrazolo[3,4-c][l,2,5]thiadiazole (24a) <8UOC4065>. 

Alkyl azides readily undergo 1,3-dipolar cycloaddition to arylsulfonyl isothiocyanates (375) to yield thiatriazolines (376). Thermolysis of (376) in the presence of isocyanates or carbodiimides produces 1,2,4-thiadiazole derivatives (378) and (379), respectively. The intermediate formation of a thiaziridinimine (377) has been postulated as indicated in Scheme 137 (75JOC1728, 75S52). The use of isothiocyanates as dipolarophiles produces dithiazolidines (380) instead of the thiadiazole derivatives. In these reactions the intermediate thiazirine (377) functions as a 1,3-dipole with the positive charge primarily localized on sulfur. It was recently proposed that the reaction of oxaziridines (381) with isothiocyanates produces a similar thiazirine intermediate (382) which reacts in a different regiospecific manner with isothiocyanates to produce 1,2,4-thiadiazole derivatives (383) and (384 Scheme 138) (74JOC957). 

The synthesis of 1,3,4-thiadiazoIes is discussed in terms of the number of bonds being formed and by ring transformation. Thiadiazole synthesis by one-bond formation is exemplified by the cyclization of an acylated thiosemicarbazide as shown in Scheme 16. The most common two bond formation takes place via 1,3-dipolar cycloadditions presented in Scheme 23. 

Azine approach. 1 -Pyridinimines undergo 1,3-dipolar cycloaddition reactions with thiones. In the reaction between 2-isoquinolinimine and carbon disulfide the mesoionic thiadiazole (716) is formed the formation of (716) involves a secondary dehydrogenation of the initial adduct. With diphenyl thionocarbonate, phenoxy group expulsion is succeeded by cyclization leading to the adduct (717) (62TL387). 

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. 

The dipolar 1,3-cycloaddition reaction of thiocarbonyl ylides to thiones can be a source of 1,3-dithiolanes. Its regioselectivity depends on the nature of substituents in the substrates. Thus, the. J-methylide 589, generated in situ by thermal decomposition of the corresponding l,5-dihydro-l,3,4-thiadiazoles, was reacted with the trithiocarbonate 588 to give a labile 4,4,5,5-tettasubstituted-l,3-dithiolane 590, which easily isomerized to an open-chain compound 591 in the presence of acids in solution (Scheme 84) <2000EJ01695>. 

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