Synthesis of Quaternary Ammonium Salts

It is noteworthy that this protocol was applied to a concise synthesis of S-HTg-receptor antagonist 103 on a gram scale (Eq. (5.98)). 

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The amino functional group is not commonly encountered in steroid synthesis except perhaps in steroidal alkaloids. However, certain elimination reactions have been shown to have theoretical and limited preparative importance, largely due to the efforts of McKenna and co-workers. The Hofmann rule for 2 elimination predicts that alkaline elimination of quaternary ammonium salts will occur towards the carbon carrying the most hydrogen atoms cf. the converse Saytzeff orientation, above). In cyclohexyl systems, the requirement for diaxial elimination appears to be important, as in other 2 eliminations, and the Hofmann rule frequently is not obeyed [e.g., (116) (117)]. 

In our previous works[8,9] on the synthesis of various 5-membered cyclic carbonate, quaternary ammonium salts such as tetrabutylammonium halides showed excellent catalytic activities in relatively mild reaction conditions, under atmospheric pressure and below 140 U. hi this work, several kinds of quaternary ammonium salts have been used for the transesterification reactions of the ethylaie carbonate with methanol to DMC and ethylene glycol. 

The early work by CM Starks at the Continental Oil Co., Ponca City, USA showed the versatility of quaternary ammonium salts as phase-transfer catalysts in organic synthesis. 

The cleavage of resin-bound peptides, produced in the Merrifield synthesis, is aided by the addition of quaternary ammonium salts to the basic medium [17, 18]. In many cases, cleavage is 100% effective and rarely less than 70%. 

From Catechol. Several routes have recently been developed for the synthesis of heliotropin from catechol. In one such route, catechol is converted into 3,4-dihydroxymandelic acid with glyoxylic acid in an alkaline medium in the presence of aluminum oxide. 3,4-Dihydroxymandelic acid is oxidized to the corresponding keto acid (e.g. with copper-(II) oxide), which is decarboxylated to 3,4-dihydroxybenzaldehyde [176]. The latter product is converted into heliotropin, for example, by reaction with methylene chloride in the presence of quaternary ammonium salts [177]. 

Furthermore, investigations of template decomposition in zeolites upon calcination of the as-synthesized materials have received much attention by researchers (248-250). However, the decomposition mechanisms of quaternary ammonium salts, which are commonly used as templates for zeolite synthesis, are still not well understood. Thus, MAS NMR investigations of the decomposition of quaternary ammonium ions in zeolites bear the potential of significantly improving the understanding of these processes (243,251). For this purpose, a general method was developed for the synthesis of... 

Ellis, K. O., R. L. White, G. C. Wright, and F. L. V fessels. 1980. Synthesis and skeletal muscle relaxant activity of quaternary ammonium salts of dantrolene and clodanolterf iarm. Sci69 327-331. 

The synthesis of DOTMA was performed first using D-mannitol-3,4-acetonide as a starting material (Figure 15.2). This tedious procedure was improved for the synthesis of a variety of DOTMA related cationic lipids (Bennett et al., 1995). Their synthesis was accomplished using a simplified synthetic approach also suitable for the synthesis of DOTMA (Figure 15.3). This procedure allowed access to quaternary ammonium esters with less toxicity and to a variety of quaternary ammonium salts (Figure 15. 4) with improved transfection efficacy. 

Thermal decomposition of quaternary ammonium salts and bases is most valuable in structural investigations of amines, particularly heterocyclic secondary amines (Hofmann exhaustive methylation). The course of the elimination (A or B) is determined by the nature of the four alkyl groups on the nitrogen atom. The reaction has found little use in the synthesis of pure olefins. The yields are low even when three of the alkyl groups are methyl radicals. Carbon-skeleton rearrangement does not occur. Thus, the only olefin obtained by pyrolysis of pinacolyltri-methylammonium hydroxide, (CHj),CCH(CHj)N(CHj)j OH, is /-butylethylene (50%). ... 

The synthesis of p-aminophenol was accomplished by the platinum catalyzed hydrogenation of nitrobenzene in aqueous sulfuric acid with concomitant acid catalyzed rearrangement of the intermediate phenylhydroxylamine (Scheme 19.2).3 The addition of quaternary ammonium salts or DMS0 -33 decreased the rate of phenylhydroxylamine hydrogenolysis to give more time for the rearrangement to take place. 

We have already encountered alkylation of amines as a side reaction in the preparation of primary amines by the ammonolysis of halides (Sec. 22.10), and as a method of synthesis of secondary and tertiary amines (Sec. 22.13). Let us look at one further aspect of this reaction, the formation of quaternary ammonium salts. 

The synthesis of stereodefined acyclic alkenes via 3-elimination reactions—such as (1) dehydration of alcohols, (2) base-induced eliminations of alkyl halides or sulfonates (tosyl or mesyl esters), and (3) Hofmann eliminations of quaternary ammonium salts—often suffers from a lack of regio- and stereoselectivity, producing mixtures of isomeric alkenes. 

The synthesis of aromatic azides (Scheme 37) from aryl halides with azide ions (SxAr) is particularly successful with systems that carry an activating substituent, an electron-withdrawing group, either in the ortho or the para position relative to the potential leaving group." -" A table with numerous examples can be found in the literature." Fluoride ion as a leaving group is superior to the other halides. Dipolar aprotic solvents, such as DMF for instance, have their special merits in these transformations, too. The reaction of 2,4- or 2,6-dinitroaryl halides with azide ions was shown to be accelerated in micelles or in the presence of quaternary ammonium salts." ... 

On the other hand, A-tosylated aza-crowns were formed in good yields (50-94%) from the reaction of the bis-sulfonamides with dibromides or di-tosylates in aqueous alkali-toluene or benzene mixtures in the presence of quaternary ammonium salt phase-transfer catalysts. Some cyclizations did not depend on alkali concentration, but for the tri- or tetraaza-crowns, 50% alkali solutions were preferred. In the synthesis of A,jV -ditosyldiaza-18-crown-6 via the interaction of the bis-sulfonamide with a dibromide, dichloride, diiodide, or ditosylate using 50% aqueous sodium hydroxide-toluene or benzene solution in the phase-transfer reaction, the cyclization rate varied according to the leaving group, Br > OTs > I > Cl. In dilute alkaline solution (7.5%), the diiodide was more reactive than the ditosylate. This could be a result of the greater activity of water in the solution so that hydrolysis of the tosylate is more rapid and, therefore, there would be less tosylate to react with the amide (Bogatskii et al., 1984 Lukyanenko et al., 1987, 1988). 

Most interest in biological activity has been centered on 4,5,6,7-tetra-hydrothieno 2,3-c, - or - 3,2-c pyridines. A considerable number of derivatives of these systems have been prepared by the sodium borohy-dride reduction of quaternary ammonium salts,90,91 or by reaction of the 4,5,6,7-tetrahydro base with a suitable halide,9,I°4 tosyl derivative,105 epoxide,106 or activated alkene.107 An alternative, and very convenient, synthesis of 2-amino-3,6-substituted 4,5,6,7-tetrahydrothieno[2,3-c[-pyridincs (89), used mostly by Nakanishi and his co-workers, involves reaction of an N-substituted 4-piperidone, a compound of the type 88 and sulfur, in the presence of morpholine. The group X can be CN,... 

Hofmann elimination Alkene synthesis from quaternary ammonium salts, used to determine the structure of amines. 

Quaternisation improves the mucoadhesive properties of CS, the extent of which depends on the degree of quaternisation, which makes this CS derivative a good candidate for gene delivery. Jia and co-workers reported the synthesis and antibacterial activities of quaternary ammonium salts of CS including N,N,N-trimethyl CS,... 

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