Quaternary salts, of pyridines

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. 

The reaction of alkyl quaternary salts of pyridine and its benzo analogues with cyanide ion and subsequent loss of the alkyl substituent is known as the Reissert-Kaufmann reaction (Scheme 112). It is not of as much importance for heterocyclic cyanations or alkylations as the other reactions described in this section, chiefly because the N- substituent is such a poor leaving group. 

Reaction of the quaternized salts of 4-ethoxycarbonyl-3,5-dimethyl-f-phenylpyttolo(furo or thieno)[2,3-c]pyrazole 34 with the iodomethane quaternary salts of pyridine, quinoline, and isoquinoline in ethanol with catalytic piperidine gave 3-[4(f)]-monomethine cyanine dyes (e.g., 35). Additionally, 3-[2(4)]-trimethine cyanine dyes and 4-[2(4)]-di-3[2(4)]-tri-mixed methine cyanine dyes (e.g., 36 and 37, respectively) were similarly prepared from the intermediates derived by reaction of 34 with triethyl orthoformate in the presence of piperidine (Scheme 8) <2002CCS106f>. 

One-third of all pyridine electrochemical citations deal with the electrolysis of quaternary salts of pyridines two out of five cathodic reports are concerned with them. Moreover, the products of reduction and the salts themselves are commercially valuable. A whole class of biochemical transformations depends on the reactivity of pyridinium ions. Agricultural products are also derived from these salts, and the value of bipyridiniiim herbicides is directly linked to their redox chemistry. 

Reduction of quaternary salts of aromatic heterocyclic bases occurs much more readily. Quaternary salts of pyridine are reduced preponderantly to 1,2-dihydro derivatives 408 with sodium amalgam and to 1,4-dihydro derivatives409 with sodium hydrosulfite. Potassium... 

Reduction of both the free bases and their quaternary salts proceeds by similar mechanisms. In pyridine and its quaternary salts, a hydride ion, or its equivalent, attacks a position of a low electron density, i.e. the 2- or 4-position. The mechanism of the reduction of quaternary salts of pyridine and its homologs (LukeS and Ferles414) has been elucidated using deuterated formic acid.415 The hydride ion attack in position 2 is followed by addition of a proton to the enamine grouping with the formation of A 3-piperideines (124). If the reduction commences with attack in the 4-position, a saturated base (125) is the final product. In agreement, a-picoline methobromide yields 1,2-dimethyl-... 

Cyanide ion does not react with pyridine iV-oxide nor does this substance undergo the Reissert reaction. 4-Halopyridine iV-oxides are exceptional in reacting with cyanide ion in the presence of benzoyl chloride, giving the 2-cyano-4-halopyridines (149).350 In contrast to this, N-alkoxy-quaternary salts of pyridine have been found to yield... 

In Lukes reductions of quaternary salts of pyridine homologs, the ratio of the tetrahydro to the hexahydro product is strongly dependent of the position and bulkiness of the substituent on the pyridine ring. Only the tetrahydro base is obtained from 4-methylpyridine metho-bromide.83 On the other hand, both the tetrahydro and hexahydro bases (in the ratio 1 1) result from the reduction of 3-methylpyridine methobromide.82 The LukeS reductions of 2-methylpyridine metho-bromide and 2,6-dimethylpyridine methobromide (80) are accompanied by formation of by-products (81-83) due to reductive cleavage... 

Quaternary salts of pyridines also add nucleophiles. The reaction with metallic hydroxides has found special value as an entry to the family of N-alkylpyridones (Scheme 6.19). Note that the initial hydroxy adduct 6.9 has no NH bond and therefore cannot tautomerize. The adducts are easily oxidized to form the carbonyl group of the pyri-done. 

Of practical importance are the reactions of the quaternary salts of pyridine 1-oxides with aqueous potassium cyanide. The 1-methoxypyridinium methosulphates have usually been used, and with aqueous potassium cyanide, 2- and 4-cyanopyridine result [Table 5.25), the 2-position being somewhat favoured. A 3-substituent usually, but not always, causes 2-substitution to predominate over 6-substitution. The quaternary function is eliminated as an alcohol its presence probably determines the preference for 2- over 4-substitution, and its ready elimination makes the reaction a practicable source of cyanopyridines, in contrast to the case of other quaternary pyridinium salts (see above) with which reaction stops at the addition stage. These reactions are nucleophilic replacements not of hydride but of alkoxyl ... 

Examples are the 2-substitution and loss of the oxide function in the reaction between pyridine, acetic anhydride and ethyl cyanoacetate (p. 206), and the chlorination of pyridine 1-oxides with sulphuryl chloride, though in the latter example the mechanistic necessity for loss of the oxide function is not established. Quaternary salts of pyridine oxides react at C(2) with Grignard reagents and alkoxide ion is eliminated (p. 201), but in the related reaction with cyanide, ion substitution at both C(2) and C(4) can occur (p. 225). 

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 intermediacy of an anhydro base (57) was referred to in Scheme 46. Analogous anhydro bases (pyridone methides) can be formed by deprotonation of quaternary salts of 2- and 4-benzylpyridines and the like. The pyridone methides are usually highly reactive and not readily isolable some stable examples are shown in Scheme 49. Pyridine methides are intermediates in the base-catalyzed alkylation and acylation reactions of pyridinium salts at the exocyclic carbon. Compounds of type (60) have been estimated to have 25-30% dipolar character. Protonation of (60) occurs at the 2 - and 3 -positions in the ratio 4 1 respectively (70JCS(C)800). 

All presently known phosphamethin-cyanines were prepared according to our original procedure (1964) in which two quaternary salts of a heterocyclic base (e. g. 4) are condensed with tris-hydroxymethyl-phosphine 5 in the presence of a proton-abstracting base The preparation ofbis-[N-ethyl-benzothiazole(2)]-phosphamethin-cyanine-tetrafluoroborate 6 illustrates the synthetic sequence. A mixture of 2 moles of N-ethyl-2-chlorobenzothiazolium-tetrafluoroborate 4 and 1 mole of tris-hydroxymethyl-phosphine 5 in dimethylformamide is slowly reacted with ethyl-di-isopropylamine or pyridine at 0 °C. Addition of water immediately affords the crystalline cyanine dye 6 in ca. 45% yield ... 

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. 

Intramolecular substitution of chlorine in 3-[iV-alkanesulfonyl-iV-alkyl)-amino-2-chloropyridines 455 affords pyridosultams 456 (see Section 4.05.6.3.2) <2000EJ01263, 1997TL4667>. The application of intramolecular vicarious nucleophilic substitution of hydrogen in A -oxides and quaternary salts of chloromethansulfonamides 457 (R =0, Me R = R = H) afforded isothiazolo[4,3-/ ]pyridines 458 and 459. Starting from 3-aminoquinoline 457 (R -R = -CH=CH-CH=CH-), the corresponding compounds 458 and 459 were obtained <2001T5009>. 

In the quaternary salts of alkyl-pyridines, the side-chain hydrogens are considerably more acidic and condensations can be brought about under quite mild conditions, the reactive species being a dienamine. " Dienamides are the reacting nucleophiles in aldol-type condensations bronght abont with acetic anhydride or in side-chain trifluoroacetylation of 2-picoline. ... 

The presence of a phenolic group was indicated by a positive ferric chloride test and by methylation to ether 31, which showed reactions typical of quaternary salts of the O-methylbalfourodinium type. Thus, heating O-methylribalinium iodide in pyridine furnished the 4-quinolone (32), which was reconverted into the quaternary salt by methyl iodide. The structures of 30 and 32 were confirmed by NMR and mass spectrometry. 

Anions of CH-acidic compounds add to pyridinium ions mainly at C-4. Substituents already present on pyridine can bring about interesting reaction sequences. This is exemplified by the formation of the 2,7-naphthyridine derivative 53 from the quaternary salt of the nicotinic acid amide 52 and malonic... 

These compounds all closely resemble the corresponding benzene compounds in their reactivity because the carbonyl group cannot interact mesomerically with the ring nitrogen. The pyridine 2- (picolinic), 3- (nicotinic), and 4- (isonicotinic) acids exist almost entirely in their zwitterionic forms in aqueous solution they are slightly stronger acids than benzoic acid. Decarboxylation of picolinic acids is relatively easy and results in the transient formation of the same type of ylide which is responsible for specific proton a-exchange of pyridine in acid solution (see section 5.1.2. ). This transient ylide can be trapped by aromatic or aliphatic aldehydes in a reaction known as the Hammick reaction. As implied by this mechanism, quaternary salts of... 

The reduction of quaternary salts of 2-aza-IcP, i.e. triazolo[4,5-c]pyridine, for example 552, by sodium borohydride gives 2-aza-SpA derivative 553 (94ZOR440, 94KFZ58). 

Although many phenylacetamides were successfully alkylated with 2-bromo-pyridine, the corresponding thioamides were not. The pyrrolidone XI-14was employed as the active methylene compound in a condensation with 2-bromopyridines. ° Treatment of quaternary salts of halo- or alkoxy-pyridines... 

Aminopyridine gives, with benzoquinone, the cyclic product (72). When reactive methylene compounds are also present, further reaction can occur, as in the formation of (73) from benzoquinone, pyridine and acetylacetone 4 and of (74) from a-naphthoquinone, pyridine and aceto-acetic ester s. 1,4-Naphthoquinonedibenzenesulphonimide behaves like naphthoquinone in forming a quaternary salt with pyridine and hydrochloric acid " . 

Similarly, the reaction of Grignard reagents with quaternary salts from pyridine 1-oxides promises to be of practical value i. Thus, 1-ethoxypyri-dinium bromide reacts with ethyl magnesium bromide to give 78 per cent of 2-ethylpyridine. The picoline 1-oxide quaternary salts react equally efficiently in the case of l-ethoxy-3-methylpyridinium bromide, the product is almost exclusively the 2-alky 1-3-methylpyridine. The reaction probably proceeds as shown, but a side-reaction always generates some of the parent base ... 

Baumgarten 80, 1204 showed the pyridine-sulphur trioxide complex to be converted rapidly by alkali into the yellow compound (144). This could be hydrolysed to glutacondialdehyde, and as a source of this compound the reaction has found synthetic use os, xhe quaternary salt from pyridine and ethyl chlorosulphonate is similarly split by alkali, to glutacondialdehyde and sulphamic acid oe. 

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