Heterocyclic alkyl quaternary salts

The heterocyclic alkyl quaternary salts used for preparing spiropyrans are usually obtained by N-alkylating the heterocyclic bases by standard methods. The common bases having an active methyl group of the indolenine, benzothiazole, benzoxazole, and quinoline series some of their substitution products, and a few of their quaternary salts are commercially available. The pyrylium, thiopyrylium, 2-azaazulenium and bcnz[c,d]indolenium salts needed for potentially infrared-absorbing spiropyrans are not (as of the time of writing). 

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. 

In the case of the bases derived from quaternary heterocyclic ammonium salts, the carbinolamines (5) can react as cyclic aldehyde-ammonias with many reagents with which the amino-aldehyde (7) could react. However, reactions of the carbinolamines which are not characteristic of amino-aldehydes are also known. Carbinolamines can easily be reconverted into the quaternary salts by the action of dilute acids, and they form alkyl ethers very easily with alcohols. If these last reactions do not occur, then this is convincing evidence for the base possessing the amino-aldehyde structure. However, if these reactions do occur this does not provide unambiguous confirmation of the carbinolamine structure. They are also given by the bi-molecular ethers (8), and, in the case of a tautomeric equilibrium... 

By far the commonest reagents for the formation of heterocyclic quaternary salts are the alkyl halides, and, indeed, methiodides out-... 

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. 

A characteristic feature of picolines and many azoles is the well-known ability of methyl (and corresponding methylene) groups to undergo condensation of the aldol, crotonic, and Michael type. This is especially pronounced in the quaternary salts of these heterocycles where it occurs under comparatively mild conditions. Such condensations are not unknown for alkylisoxazoles. Lampe and Smolinska were the first to describe the condensation of the quaternary alkyl iodides of 3,5-dimethyl- (96) and 3-methyl-5-phenylisoxazole with... 

Quaternary salts are obtained by alkylation of selenazole bases, the heterocyclic nitrogen atom playing the role of nucleophile with regard to the electrophilic carbon of the alkylating agent. 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

A7-Acyl derivatives of heterocycles can often be quatemized by hard alkylating agents, such as trialkyloxonium fluoroborates406 or methyl fluorosulfonate.364 The quaternary salt is not usually isolated, but N-alkylated derivatives are obtained whose structures are generally different from those obtained by alkylation of anions (Sections IV,C,2). This method, due to Olofson and Kendall,406 has been used with success in azapentalenes [Eqs. (34) and (35)1, where the products 384 and 385 are different from those obtained by alkylation of the anions 361 and 364, respectively (Scheme 16). 

Azalene salts 90 and 92 are obtained by quaternization of the corresponding heterocyclic bases with alkyl halides or tosylates. If the heterocyclic base contains several nitrogen atoms, alkylation can produce different quaternary salts. Quaternization, however, is surprisingly selective if certain conditions are met.205 Pyrrolo- and indolopyridines containing one pyridine-and one pyrrole-type nitrogen atom in their molecular lattice are (in aprotic solvents) almost exclusively alkylated at the nitrogen atom of the pyridine... 

If the heterocyclic base contains several pyridine-type nitrogens select can also be observed. Indeno[l,2-b]quinoxalines, for example, are quaternized at the N-10 atom.110 The alkylation of heterocycles conta one pyrrole-type nitrogen and several pyridine-type nitrogens is appar selective (e.g., indolo[2,3-b]quinoxaline).201 The yields of quaternary however, are extremely low,201 even if phenacyl halides or a-halo ester used.207 Perhaps the resultant quaternary salts are dealkylated.200,207... 

In many alkylations other side reactions can contribute to losses in yields of quaternary salts 90 and 92. Preferably, the quaternization is carr out in aprotic solvents because in protic solvents the heterocyclic base cl give rise to deprotonation of these salts (especially if Y = CH).58,59 Then, through substitution reactions the desired pseudoazulene products can produce substances with the quaternary salts that harden in the reaction medium (Eq. 1). 

Reduction of aromatic heterocyclic bases and their quaternary salts is of particular interest. Reduction of pyridine with lithium aluminum hydride gives the unstable 1,2-dihydro derivative,403 whereas sodium in 95% ethanol yields 1,4-dihydropyridine. The latter is readily hydrolyzed with the formation of glutaric dialdehyde.404 Reduction of pyridine and its homologs with sodium in butanol affords a mixture of saturated and unsaturated bases d3-piperideines are formed405 only from those pyridine homologs which possess alkyl groups in positions 3 and 4. Electrolytic reduction always gives a mixture of both bases.406 A3-Piperideines have been obtained by reduction with a mixture of lithium aluminum hydride and aluminum chloride.407... 

Thieno[2,3-c]isothiazole-3-carboxylic acid was the compound obtained by the reaction of ethyl 3-cyano-5,5-diethoxy-2-oxopentanoate with phosphorus pentachloride in refluxing toluene, previously assumed (55JA4069) to yield thieno[3,4-c ]isothiazole-4-carboxylic acid. The proposed mechanism involves the cyclization of the intermediate 3-cyano-2,5-dithioxopentanoate as shown in Scheme 20. The parent heterocycle, which is a weak base and fails to give quaternary salts with alkyl halides, was obtained by decarboxylation of the acid and also by independent synthesis (82AJC385). 

The first method is perhaps the most common, and is exemplified by the condensation shown in Scheme 3 of a 2-alkyl heterocyclic quaternary salt or the corresponding methylene base with a 2-hydroxy unsaturated aldehyde grouping (which usually is part of an aromatic ring, as in salicylaldehyde). These intermediates have given a broad assortment of spiropyran classes. The ready availability of 1.2.3.3.-tetraalkyl-3/f-indoleninium salts and salicylaldehydes has led to a large number of spiro-(2i/-l-benzopyran-2,2 -indolines) [this name will be used in preference to the correct T,3 -dihydrospiro(2//-l-bcnzopyran-2,2 -(2 //(-indole)]. A common acronym for this class, BIPS, will be used in this chapter as both singular and plural. 

Tertiary Mannich bases having a halogen atom in position 4 with respect to the amino group (Fig. 127) can give cyclic products by intramolecular N-alkylation, with formation of the heterocyclic quaternary salts 330, as shown by the N-Mannich bases of chloroacctohydrazidc and by some brominated O-Mannich bases. ... 

With sodium in ethanol pyridazine is reduced to hexahydropyrida-zine 1,4-diaminobutane is also obtained.It can form quaternary salts, but no bisquaternization was found. A survey of the quarternization of pyridazines and other heterocycles is given in Volume 3, Chapter 1 of this Series. For alkylation and arylation of pyridazine see Section IV of the present chapter. 

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