Thiadiazoles quaternization

Thiadiazoles are quaternized to give 3- or mixtures of 2- and 3-alkyl quaternary salts. In 5-amino-1,2,4-thiadiazole, quaternization takes place at the 4-position (90) (64AHC(3il). 1-Substituted 1,2,4-triazoles are quaternized in the 4-position (91), and 4-substituted 1.2,4-triazoles are quaternized in the 1- or the 2-position (92) 64AHC(3)l). 

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). 

When the N-3 atom is quaternized, as is the case of 4,5-diphenyl-3-trimethylsilylmethyl-l,2,3-thiadiazol-3-ium triflate, there is a large upfield shift for the N-3 atom of 160ppm, and a smaller shift is also observed for the N-2 atom of 25 ppm in the 15N NMR spectrum <1999J(P1)1415>. 

Alkylation of 3,5-diaryl-l,2,4-thiadiazoles 22 with trimethylsilylmethyl triflate, in contrast to methyl iodide, occurs at N-2 to afford the salt 23 (Equation 5) and the quaternization at N-2 was confirmed by analysis of the 1SN NMR spectrum <1999J(P1)1709>. 

As a rule, the annular nitrogen atoms in 1,3,4-thiadiazoles are very reactive towards electrophiles as shown by facile alkylation reactions and quaternary salt formation. A thorough study on the quaternization of 2,5-disubstituted thiadiazoles, and its comparison with pyridazines has been published <84CHEC-i(4)545>. Electrophilic attack by benzyl chloride on 2-aminothiadiazole to give (44) in a regiospecific manner was utilized in the synthesis of an antiviral candidate <92MI 4io-oi>. 

Thiadiazoles (see Section VI,F,1). Disubstituted thiadiazoles (68) react with Mel at N-3 and/or N-4 steric and electronic factors have been implicated. Thus, when R, is Me and R2 is NH2, 76% reaction occurs at N-3, while when R, is Me and R2 is MeCONH, only 37% quaternization takes place at N-3.33 Similarly, for compounds where R, is MeS, predominant reaction takes place at N-3 when R2 is NH2 but not when R2 is larger, the morpholino substrate favoring alkylation at N-4.176 The situation becomes complicated when R, is MeS and R2 is Me2N. In this case, the N-3 product is favored about 2 1 over the N-4 isomer when one equivalent of Mel is employed. However, the ratio changes to 1 5.6 when an excess of Mel is used.176... 

A kinetic study of the quaternization of (1), (2) and (3) and related heterocycles with dimethyl sulfate (74AJC1917, 65JCS6769) showed the order of activation by the heteroatom in benzazoles to be Se>NMe>S>0 (74AJC1917). Benzo fusion has very little effect on the rate of quaternization of thiadiazole, implying that development of benzenoid character in the product (9) is relatively unimportant as a driving force for the reaction (see Section 4.26.2.9). 

Thiadiazoles undergo a facile reaction with electrophiles on the annular nitrogen atoms. In an extensive study, the quaternization of 2,5-disubstituted 1,3,4-thiadiazoles with methyl iodide was compared with quaternization in the pyridazine series. The influence of the alkyl substituents on product-distribution was less in the thiadiazole series than in the pyridazine series, probably due to the difference in geometry of the two compounds. The conditions chosen for the quaternization were such that the reaction was irreversible and the product distribution therefore kinetically controlled. Some of the results obtained are summarized in Table 13 (73ACS391). NMR data on these compounds are presented in Section 4.27.2.3.4. 

Diazoles are in principle capable of forming diquaternary salts without loss of aromaticity however, it is difficult to introduce the second alkyl group, probably because quaternization of one ring nitrogen reduces the nucleophilidty of the other. Diquatemary salts of thiadiazoles of type 373... 

Quaternization of 3,5-dimethyl- and 3,5-diphenyl-l,2,4-thiadiazole with methyl fluorosulfate produces, in the former case, the 4-methyl salt (375, Y = S03F, 60%), in the latter a mixture of the 4- and 2-methyl isomers (376,377 Y = S03F 9 and 34%). The quaternization sites were established both by chemical and X-ray techniques. The predominant 2-quaternization in 377 is ascribed to the electronic and steric effects of the two phenyl groups flanking N4 in 377.283... 

Thiadiazoles are weak bases. On quaternization, for example, with dimethyl sulfate, mixtures of 2- and 3-methyl-l,2,3-thiadiazoles are formed. Electrophilic substitution (SEAr) at the C-atoms has not been observed. 

Chemical Properties.—The rates of quaternization of 1,2,5-thiadiazole, 2,1,3-benzothiadiazole, and the corresponding selenium heterocycle have been examined by a competition method, using dimethyl sulphate in sulpholane, ... 

A study of the quaternization of 2-alkyl- and 2,4-dialkyl-thiazoles and 2-alkyl-l,3,4-thiadiazoles has served to elucidate the applicability of the Taft steric parameters, E,. It appears that E, values from the Taft scale will correlate structural or reactivity data, provided that the groups concerned are in a structural environment which does not induce a significant conformational preference of the group. ... 

The quaternization by methyl iodide of a series of 2-alkyl-5-methyl-1,3,4-thiadiazoles has been studied quantitatively by a spectrometric method. The product distribution due to quaternization at N-3 and N-4 in a series of 2,5-disubstituted 1,3,4-thiadiazoles has been determined. The observed influence of alkyl substituents on product distribution is almost the same as in comparable thiazoles, but is less pronounced than in the pyridazine series, probably owing to differences in the geometry of their respective transition states. ... 

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