Pyridine quaternary salts

The general principle that activation of para substitution is greater than of ortho substitution holds true also for an azinium moiety in the one instance studied. Thus, the activation energy for the 4-chloropyridine quaternary salt 280 (Table II, line 9) is 1 kcal lower than that for the 2-isomer (line 5). The rate relation (2- > 4-isomer) is controlled by the entropies of activation in this reaction due to electrostatic attraction in the transition state (281). The reverse rate relation (4- > 2-position) is predicted for aminations of such quaternary compounds due to electrostatic repulsion (282) plus the difference in E. A kinetic study of the 2- and 4-pyridine quaternary salts... 

Pyridine quaternary salts, uses for, 22 121 Pyridine ring syntheses, 22 108-112 from nonheterocyclic compounds, 22 108-110... 

Thieno[3,4-d]azocine (78JHC193) 152 is formed as a result of intramolecular cyclization of 2-thienyltetrahydropyridine 151 produced by the interaction of pyridine quaternary salts 149 and thienylmagnesiumbromide with subsequent reduction. Under the action of the cyanogenbromide thienoazocines 152 are converted into their NH derivatives 153, subsequent alkylation allows the introduction of pharmacophoric substituents into the molecule (Scheme 41). 

Although this method is rarely used because of the poor yields often associated with it, acetic and other anhydrides have been shown to promote the formation of indolizines from pyridine quaternary salts in a cyclization reaction in which the 2,3-bond of the indolizines is formed.3141-45 This route starts from a quaternary salt of general formula 11 which is acylated and dehydrobrominated in one step to give 12. Heating 12 under reflux with acetic anhydride gives the indolizine 13a or 13b (Method A) (see Scheme 4).31 Alternatively, the quaternary salt can be converted directly into the indolizine by employing triethylamine (Method B).41 Some idea of the scope of the reaction can be gained from Table I. 

Pyridines, quaternary salts (descending) Whatman 1 Ac/w or AmS04/Ph buffer (pH = 6.8)/n-PrOH(2%) or n-PrOH 75... 

A comparison of the effect of the 3-benzoyl group and the reported ineffectiveness of the 3-acetyl group, of equally strong electron withdrawing power, on selective reduction of the pyridine ring of pyridine quaternary compounds causes speculation. It would be of interest to determine whether the effect is steric by comparison with a pyridine quaternary salt containing the 3-COC(CH3)3 group. 

Activation in terms of Ea is in the order 4- > 2- > 3-position for the methoxy-dechlorination of chloro-pyridines, -p3rridine A-oxides, and -pyridine quaternary salts (Table II). In methoxylation and piperidination of the 2-, 3- and 4-chloro derivatives of pyridine, nitrobenzene (Table VIII), pyridine A-oxide, and 1-methylpyridinium cation, the activation in terms of is in the order benzene C—<... 

Girard s reagent P , C5H5NCH2C0NHNH2 C1. In a 1-htre threenecked flask, equipped as in the previous preparation, place 200 ml. of absolute ethyl alcohol, 63 g. (64 -5 ml.) of pure anhydrous pyridine and 98 - 5 g. (84 5 ml.) of ethyl chloroacetate. Heat the mixture under reflux for 2-3 hours until the formation of the quaternary salt is complete acidify a small test-portion with dilute sulphuric acid it should dissolve completely and no odour of ethyl chloroacetate should be apparent. Cool the mixture in ice and salt. Replace the thermometer by a dropping funnel, and add a solution of 40 g. of 100 per cent, hydrazine hydrate in 60 ml. of absolute ethanol all at once. A vigorous exothermic reaction soon develops and is accompanied by vigorous effervescence. The pro duct separates almost immediately. When cold, filter with suction, wash... 

The easier elimination of pyridine compared to quinoline-4 may be related to the pK value of 4-methylthiazole, which is between those of lepidine and 2-picoline (25. 55). This reaction explains also why a neutrodimethine cyanine is obtained with such good yields when reacting together a quaternary salt, ketomethylene, and o-ester in a basic medium. As the reaction proceeds, the trimethine cyanine is attacked by the ketomethylene. The resulting 2-methyl quaternary salt is transformed into trimethine cyanine, consuming the totality of the ketomethylene (1, p. 512 661). The mesosubstituted neutrodimethine cyanine is practically pure. 

Carbocyanines with three methine groups can be prepared using Pvo equivalents of selenazolium quaternary salt and one equivalent of ethyl orthoformate in pyridine solution (53). 

Nucleophilic Attack at Carbon or Hydrogen. Only the strongest of nucleophiles (eg, —NH2) can replace a hydrogen in pyridine. However, N-oxides and quaternary salts rapidly undergo addition, followed by subsequent transformations (12). 

Most of them are generally classified as poisons. Exceptions to this rule are known. A notable one is 4-dimethyl aminopyridine (DMAP) (24), which is widely used in industry as a superior acylation catalyst (27). Quaternary salts of pyridines are usually toxic, and in particular paraquat (20) exposure can have fatal consequences. Some chloropyridines, especially polychlorinated ones, should be handled with extra care because of their potential mutagenic effects. Vinylpyridines are corrosive to the skin, and can act as a sensitizer for some susceptible individuals. Niacin (27), niacinamide (26), and some pyridinecarbaldehydes can cause skin flushing. 

Amino and sulfur analogues of pyrazolones also yield the aromatic quaternary salt (231 X = NH or S). If the pyrazole bears a substituent with a second pyridine-like nitrogen atom, an intramolecular bridge can be formed by reaction with a dihalogenoalkane. Thus pyrazol-I -ylpyridines react with 1,2-dibromoethane to form (233) (81JHC9). 

The formation of quaternary salts from benzyl halides and related compounds occurs readily and has been known for many years. More recently, Krohnke and co-workers, who have studied the reactions of many heterocyclic quaternary salts, reported the formation of 5 from pyridine and benzylidene dibromide on heating the reactants together for 1 hr at 100°. The salt is sufficiently stable to be recrystallized from methanol containing a trace of hydrogen bromide. Isoquinoline gives a similar salt. 

Chloromethylbenzo-l,2,4-thiadiazine 1,1-dioxide forms quaternary salts, e.g. 8 (n = 1), with pyridine, 2- and 3-picolines, and iso-quinoljne, but the 3-(2 -chloroethyl) compound gives a lower yield of the salt, e.g. 8 (% = 2), because some of the halogen derivative is converted into the 3-vinyl compound. ... 

Heterocyclic bases which readily form quaternary salts with the more usual reagents will also react with suitably activated aryl and heterocyclyl halogen compounds, the classic case being the salt formed from pyridine and l-chloro-2,4-dinitrobenzene. Reactions of this type have been studied by Chapman et Salt formation between... 

Most N-phenyl quaternary salts are not prepared by direct quater-nization but rather by introducing the nitrogen substituent before ring closure. It has recently been found that diphenyl iodonium boro-fluoride reacts smoothly with pyridine the phenyl carbonium ions formed give the 1-phenylpyridinium ion good yield. ... 

The introduction of a nitrogen atom into the benzene ring of indole affords a center, not present in indole itself, at which quaternary salt formation occurs readily, and the base 95 is converted into a quaternary salt (96) on the pyridine-type nitrogen atom. ... 

The corresponding [5,4-6]-compound (107) was prepared similarly and treated with methyl iodide to give a quaternary salt which was shown to have structure 108, because mild alkaline hydrolysis gave 3-acetamido-l-methyl-2-pyridone. Again, quaternization took place on the pyridine-nitrogen, which is different from the behavior of the corresponding 1,4-diazaindene mentioned above. 

The quaternary salt from 2-methylthiothiazolo[4,5-c]pyridine (111 Y = SMe) has been described but no structure has been advanced. Again the Russian workers report that a bis-etho-toluene- -sulfonate... 

The only examples of ring oxidation are the one-electron anodic oxidation of Nl-aryl[l,2,4]triazolo[4,3-a]pyridines such as compound 143 to give quaternary salts (88ZC187), and the voltammetric oxidation of the anti-depressant Trazodone (Section V.A) (87MI1). 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

Quatemization of the isoxazole nitrogen atom makes the ring particularly susceptible toward nucleophilic attack there is a certain analogy here with pyridine. The cleavage of the ring proceeds extremely readily in quaternary salts of isoxazole, even occurring by the action of such weak nucleophilic agents as the anions of carboxylic acids. 

The effectiveness of ylides in the field of polymer science was first described in 1966 by George et al. [11] who felt that 3- and 4-(bromo acetyl) pyridines, which contain both the a-haloketone and the pyridine nucleus in a single molecule, could be quaternized to polymeric quaternary salts and finally to polymeric ylides Schemes 9 and 10 by treating these polymeric salts with a base. 

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