Salts quaternaries

Benzo-l,3-azolium salts are susceptible to nucleophilic addition at C-2, for example, they are converted into the corresponding ortfto-substituted benzene, with loss of C-2, by aqueous base, a process that must involve addition of hydroxide at C-2 as an initiating step.  

By a sequence involving 2-lithiation of benzothiazole, then reaction with an aldehyde, quatemisation, C-2-addition of an alkyllithium, and finally silver-promoted ring cleavage of fhe resulting dihydro- 

Reissert-type adducts (cf. 9.13) can be obtained from benzothiazole, benzoxazole and indazole, as 

As in the case of pyridine (185), the quaternization of thiazole induces a bathochromic shift of the ultraviolet absorption spectrum in ethanol the long wavelength maximum at 232.3 nm (3900) for thiazole moves to 240 nm (4200) for 3-methylthiazolium tosylate (186) (Table 1-19). 

As in the case of the free bases, the substitution of a nuclear hydrogen atom by a methyl group induces a bathochromic shift that decreases in the order of the position substituted 4- 5- 2- Ferre et al. (187) have proposed a theoretical model based on the PPP (tt) method using the fractional core charge approximation that reproduces quite correctly this Order of decreasing perturbation. 

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The Formaldehyde-Formic Acid Method, This method applies to primary and secondary amines, which when boiled with a formalin-formic acid mixture undergo complete methylation to the corresponding tertiary amine. This method has the advantage over the dimethyl sulphate method in that quaternary salts clearly cannot be formed. 

Dissolve 2-3 g. of methyl p-toluenesnlphonate in 10 ml. of dry benzene, add 1 g. of the amine, and boU the mixture for 20-30 minutes. Cool, and filter the precipitated quaternary salt. Recrystallise by dissolving the solid in the minimum volume of boiling ethyl alcohol and then adding ethyl acetate until crystallisation commences. Filter the cold mixture, dry rapidly on a porous plate, and determine the m.p. immediately. 

The benzyl chloride quaternary salts RR R"NC3HsCH2 +Cl are prepared similarly 3 g. of redistilled benzyl chloride replaces the methyl p-toluenesulphonate. 

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... 

For this series of compounds qualitative information is quite extensive. Application of the criteria discussed in 8.2, in particular comparison with the corresponding methyl quaternary salt, establishment of the rate profile for nitration in sulphuric acid, and consideration of the encounter rate and activation parameters, shows that 2,4,6-collidine is nitrated as its cation. The same is true for the 3-nitration of 2,4- ... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Recently, a new synthesis of 2-aminothiazo es has been proposed it involves the reaction between quaternary salts of 2-aikylthiothiazo es and the appropriate amine (1566). 

Quaternary salts (33) obtained from aminothiazole derivatives liberate 2-imino-4-thiazolines in basic medium (Scheme 24). This reaction is general and independent of the nature of R in 33 (160-167). The same result was found when 2-propynylbromide (168) or 3-chloropropionic acid (169) were the quaternizing reagents. This method is particularly... 

Alkv lation of the appropriate 2-aminothiazole in neutral medium (46, 173, 263 i followed by liberation of the free base from the quaternary salt is also used. The quaternary salt (365) is the starting material for the... 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

Other quaternary salts may provide the starting material (24, 25). A-4-Thiazoline-2-thiones (25) may be used as starting material they react... 

Few examples of reactivity involving the electrophilic character of the Cn atom are reported. In some cases, a catalyst or reagent convens the neutral thione into a quaternary- salt (Scheme 40), the Ct of which is clearly electrophilic (205. 206), The mechanism of Raney Ni desul-... 

It is noteworthy that some catalysts convert thioethers to quaternary salts where the reactive electrophilic center is no longer one of the two C centers but the C sp center of the thiazolium salt (284. 285). Thus... 

One may find many publications in the literature on the theoretical aspects of thiazolium quaternary salts, because of the biological importance of thiamine and their use as catalysts for benzoin condensation. 

This section is restricted to the general properties and chemical behavior of quaternary salts chiefly when they are used as dye intermediates (Tables IX-1-3, IX-4abc, IX-5) . 

Besides the well-known lower basicity of ethanol, these data illustrate the greater acidity of benzoxazolium compared with benzothiazolium. The relative pK. values of the quaternary salts obtained in acetonitrile when treated with tetrabutylammonium hydroxide are 18.3 and 17.6, respectively (25). Those of 2-methyl 4-phenyl thiazolium and 2.4-dimethyl thiazolium are 20.5 and 21.8 under the same conditions (25). 

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

In 1923, Mills introduced thiazole for the first time in the synthesis of methine dyes through a somewhat indirect route. In order to demonstrate the 2,4 -cyanine mechanism of formation by quinoline and quinaldine quaternary salts reacting together, Mills used other pairs of quaternary salts as 2-methylthiazolium with either quinolinium or benzothiazolium (42, 43). 

Even if the specific role attributed to benzothiazolium was not confirmed later (24), all these syntheses account for the significant and common behavior of quaternary salts, carbocations giving either symmetrical or asymmetrical reactive anhydrobases. They constitute the mam step in cyanine dye formation. 

A sufficient concentration of base B is necessary for the removal of a proton of the CH, group. In a first step, the equilibrium in Scheme 20 results, in which the monomeric anhydrobase Bi constitutes the conjugated base of the quaternary salt A,. As has been shown for other rings (24). the equilibrium depends upon the concentration of the different species and the relative strength of the bases B and Bj, and depends also upon the nature of X. 

Many monomeric heterocyclic anhydrobases can be isolated now using specific methods (44), but application of these methods to thiazole ring did not succeed however, appropriate conditions lead to the separation of a dimer, the structure of which has been established by its NMR Spectra and chemical reactivity (26). The most probable mechanism of its formation appears identical with the one previously described in the benzothiazolium series (24). A second molecule of quaternary salt A3... 

Possibility of making 2-methyl benzothiazolium either bt reaction of the benzothiazolium quaternary salt on the anhydrobase (24) or by reaction of o-methylaminothiophenol on the same anhydrobase (26). 

Melting of a quaternary salt with an arylformamidine (method A. Scheme 32). 

Mixing of quaternary salt, aniline, and ethylorthoformate (method B. Scheme 33). 

Styry] Dyes result from the condensation of benzaldehyde or p-dialkylaminobenzaldehyde with quaternary salts of 2-methylthiazole. either in acetic anhydride or in a solvent with a base as catalyst. 

The methine chain is obtained by reacting ethyl o-formate (method A ) or ethylisoformanilide (method B) with a bis quaternary salt of bis-(2-thiazolyllbutane. Concerning dyes with fused thiazolo rings pyrrolo[2. lb]thiazoIe. thiazolo[2.3a]indole. thiazolo[2.3c]1.4-benzox-azine. the a carbon directly linked to the carbon 2 of the thiazoJe ring is also responsible for the classical syntheses giving trimethine or penta-methine dyes. 

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