Pyridazines quaternization

On boiling the methiodide with 70% sulfuric acid an N-methyl-oxo derivative was obtained, and this in turn gave 3-amino-2-phenyl-quinoline, methylamine, and ammonia on fusion with soda lime. The bulk of the evidence therefore favors quaternization at N-2 (cf, 154), in which case the acid-hydrolysis product is 155. Quaternization at N-2 would be expected because of the steric influence of the 10-phenyl group and the influence of the 4-amino group (cf. 4-hydroxy-pyridazine ) in the pyridazine-type ring, although the partial double-bond character of that ring is probably different from that in pyridazine itself. 

The mesomeric effect of the C=S linkage is very pronounced and is responsible for the facile quaternization of heterocyclic N-alkylated thiones (159) this effect is operative even when such a shift does not increase the aromaticity of the ring. Thione derivatives of pyridazine, benzothiazole, quinazoline, 1,3-thiazine, triazole,and isoindole are examples of compounds which readily form quaternary salts. 

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>. 

Pyridazines (see Sections II, IV, V,C,1, and V,D-G). Product ratios for the quaternization of 3- and 4-methylpyridazines and their NMR spectra have been reported.155 Betaine (49) is prepared by heating 3(2//)-pyridazinone (50) with methyl tosylate to 130° in kerosene followed by deprotonation of the resultant cation with an exchange resin. Interestingly, both Mel and methyl sulfate react under alkaline conditions with the pyridazinone at the other annular nitrogen atom.156... 

Quaternization of various pyridazinethiones and pyridazinyl sulfides is dependent on the substituents attached to the pyridazine ring. For example, 3-methylthiopyridazine and 6-methyl-3-methylthiopyridazine react with methyl iodide to form the corresponding 1-methyl-3-methylthio and l,6-dimethyl-3-methylthio derivatives (85). On the other hand, if a larger group, such as methoxy or phenyl, is attached at the 6-position, quaternization takes place at position 2 to give 6-substituted 2-methyl-3-methylthiopyridazines (86 Scheme 24). 

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. 

The aza substituent constants (vide supra) reflect the fact that electron-withdrawing annular nitrogens decrease the reactivity of any other ring nitrogen in the order ortho meta < para. For this reason, pyrazines should quaternize more readily than pyrimidines and pyridazines, and all three diazines should react faster than triazines. When the diazines are included in a Hammett plot for the methylation of substituted pyridines (p = —2.3), the positive deviations showed that they were all more reactive than indicated by their pK values. Relative rates compared with pyridine were pyridazine, 0.25 pyrimidine, 0.044 and pyrazine, 0.036 (72JA2765). Pyridazine in particular appears to be much more reactive than one would expect. (See Section III, A below). 

Quaternization of Substituted Pyridazines with Methyl Iodide... 

The tendency for larger alkylating agents to attack the less hindered nitrogen is demonstrated by the orientation of quaternization in a series of 3-methyl-6-R-substituted pyridazines. The percentages of N-l substitution observed using methyl, ethyl, and isopropyl iodides in turn were 72,80, and 90... 

The isomer ratios estimated for a series of pyrazines, pyridazines, and pyrimidines are in good agreement with experiment (72T1983) they provide not only reasonable predictions of isomer ratios of quaternization products but also a method for rectifying many of the previously contradictory statements in the literature. 

Quaternization of pyridazine derivatives is described. Methyl iodide in acetonitrile gave in most cases a mixture of isomers. The composition of the quaternization mixture is determined mainly by sterie and inductive effects. ... 

A new approach for introducing a carbon side-chain at position 3 in the pyridazine ring is displacement of a methylthio group of quaternized py-ridazine with reactive methylene compounds to give 77 (79TL4837). Alternatively, a 3-chloropyridazine reacts with dimethylsulfoxonium methylide... 

Based on available herbicide data for related Cyanamid pyridazines and patented compounds, the following structural modifications were proposed 1) substitution of the chlorine at the 3-position 2) replacement or derivatization of the 4-methyl group 3) introduction of substituents at the 5-position 4) alternate substitution in the 6-phenyl ring as well as reduction to the corresponding cyclohexyl derivatives and replacement of the phenyl by heterocycles and 5) oxidation and quaternization of the nitrogens at positions 1 and 2. 

Ionization constants of hydroxy- and mercaptopyridazines, ° of amino- and diaminopyridazines and their quaternization products,of methylsulfinylpyridazines," and of pyridazinium ylides have been recorded. The basicities of a series of pyridazines have been determined and correlated with substituent constants using the Hammett free-energy relationship. The magnetic susceptibility of pyridazine was measured, and the rate constant for the reaction of hydrogen atoms with pyridazine was determined. The experimental dipole moment, Kerr constant, and molar Cotton-Mouton constant, obtained at 298 K and 633 nm, are reported. The magnetic circular dichroism spectrum of pyridazine has been measured. ... 

The reaction rates for quaternization of pyridazines provide a measure of the steric effect of alkyl groups.269 Rates for 3,6-dialkylpyridazines with methyl iodide show that the product distribution is kinetically controlled and is solvent dependent. Moreover, steric effects of substituents prevail... 

Relative rates have been determined for the competitive methylations and also acetylations of azines. Pyridazine reacts faster than pyridines in both reactions this is interpreted in terms of pair-pair electron repulsion and the a-effect.272 An additivity approach provides reasonable predictions of isomer ratios of quaternization products of pyridazine and other azines.273 Reinvestigation of the quaternization of various amino- and diamino-pyridazines with methyl iodide shows that both 1- and 2-methyl derivatives were usually formed.274 3-Amino-6-chloropyridazine forms /V2-quaternary salts with a- and / -halo esters and 1,4-dibromobutane, but with 1,2-dibromo-ethane or 1,3-dibromopropane bicyclic products, are formed.275 Protonation and quaternization of 1,4,5,6-tetrahydropyridazines takes place at position 1, this being the more basic nitrogen.276... 

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