1.2.5- Thiadiazole, 3-methyl-, ring

Certain 1,2,4-thiadiazoles undergo ring expansion on treatment with dialkyl acylphosphonates. Thus, the action of diethyl acetyl(or benzoyl)-phosphonates (383, R = Me, Ph) on 4-benzyl-3-methyl-l,2,4-thiadiazolium bromide (382) produces substituted 1,2,4-thiadiazines (384), albeit in low yield. The pyrimidyl analog (385, formally comparable with thiamin) behaves similarly, but a cyclization (to 387) competes with the ring expansion (to 386). The structure of these and other complex products, and the mechanism of their formation, were discussed in detail.286... 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

Reaction of the pyridine-2-thiol (109) with ketones and with triethyl orthoformate has led to A(5-acetals (112) and 1,3,4-thiadiazoles (110) which on methylation and subsequent ring opening gave two new pyridine derivatives (113) and (111) <96JPR516>. 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

Substituents on the ring nitrogen can often cyclize to afford fused 1,3,4-thiadiazoles (see also Volume 9). The N-substituent on the l-(2-amino-5-methyl-3-[l,3,4]thiadiazolyl)acetone 49 was annulated on the ring when treated with HBr (Equation 38) <2000AF550>. 

Iwakawa et al. studied the reaction of 3-acetonyl-5-cyano-l,2,4-thiadiazole 72 with a series of 4-substituted phenylhydrazine hydrochlorides. When electron-donating substituents were used (e.g., methyl and methoxy) in the phenyl ring of the hydrazine, the reaction proceeded via a Fischer-indole mechanism to give indoles 73 as the sole product. In contrast, reaction of 72 with phenylhydrazine and 4-chlorophenylhydrazine gave only small amounts of indole 72, but much higher yields of the pyrazole 74. The authors described in detail the respective reaction mechanisms... 

Whereas methyl 5-(3-methyl[l,2,4]thiadiazolyl)diazoacetate 56 shows no tendency to cyclize to 7-methoxycarbonyl-3-methyl[l,2,3]triazolo[3,4-A][l,2,4]thiadiazole 57, the 5-(l-diazoalkyl)substituted [l,3,4]thiadiazoles 58 are in equilibrium with the fused bicyclic form, the [l,2,3]triazolo[5,l-A]][l,3,4]thiadiazoles 59 <1988BSB795, 1992JHG713>. The latter ring-closed form 59 prevails in the solid state as indicated by infrared (IR KBr disk). The chain/ring equilibrium of the diazoimine/triazole forms is shifted toward the open-chain diazo form 58 by raising the temperature and by using less polar solvents (Equations 8 and 9). 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

Nucleophilic attack at the C-5 carbon atom of 1,2,4-thiadiazoles has been proposed as a reaction mechanism for many of the ring transformations described throughout this chapter. Thus, 2-methyl-3,5-diphenyl-1,2,4-thiadiazolium fluorosulfate (33) is cleaved by alkoxide giving the benzimidate (34) in the case of hydroxide ions, reaction continues to the benzoylamidine stage (35) (Scheme 10) <82AHC(32)285>. 

Fusion with a pyrazine ring gives an interesting 12 rr-electron system (6) which is completely planar except for the C—H bonds of methyl substituents <90AG(E)643>. Even fusion with a 1,4-diazepine has only minimal effects on the 1,2,5-thiadiazole ring (7) <93MI 409-01 >. 

The corresponding ethylation proceeds in lower yields, and may be suppressed entirely by the presence of substituents elsewhere in the nucleus (e.g. 192 R = Ph).171 The attempted introduction of higher alkyl, allyl, and benzyl residues also failed.171 The derivative (204) obtained with phenacyl bromide is readily ring-closed to the diheterocycle 205.171 Diphenyl- and triphenyl-methyl halides, on the other hand, alkylate 5-amino-1,2,4-thiadiazoles in the exocyclic amino group,171 as shown by the lower basicity of the resulting products (e.g. 202). 

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