Catalysis by pyridine

The scope of this reaction is similar to that of 10-21. Though anhydrides are somewhat less reactive than acyl halides, they are often used to prepare carboxylic esters. Acids, Lewis acids, and bases are often used as catalysts—most often, pyridine. Catalysis by pyridine is of the nucleophilic type (see 10-9). 4-(A,A-Dimethylamino)pyridine is a better catalyst than pyridine and can be used in cases where pyridine fails. " Nonbasic catalysts are cobalt(II) chloride " and TaCls—Si02. " Formic anhydride is not a stable compound but esters of formic acid can be prepared by treating alcohols " or phenols " with acetic-formic anhydride. Cyclic anhydrides give monoesterified dicarboxylic acids, for example,... 

An observation that the oxidation is subject to marked catalysis by pyridine was later refuted i °. ... 

The general chemistry of acylpyridinium salts (181) and their role in the nucleophilic catalysis by pyridine of carbonyl substitution reactions have been reviewed and compared with the role of acylammonium salts (182). ... 

Reeves and Hilbrich288 have reported the catalysis by pyridines of benzyl ketone alkylation they are less efficient than aliphatic trialkylamines. Reeves and White289 have also described the reaction of alkyl bromides with sodium cyanide, where pyrazine is a better catalyst (99% yield) compared to pyridine (12% yield). Isakawa et al.289 have also carried out addition of dichloro-carbene to cyclohexene under biphasic conditions, using heterocyclic amines as catalysts (e.g., iV-butylpiperidine gives 76% yield). 

A similar substitution on anilines causes the reverse effect. Nitro groups in ortho position either in the isocyanate or the aniline lower the reactivity by steric hindrance. These authors also reported that the reaction is subject to catalysis by pyridine, tertiary bases, and certain carboxylic acids but is unaffected by water, inorganic acids, bases, or salts. Relative rates for the reactions of some primary aliphatic amines with phenyl isocyanates have been determined by Davis and Ebersole (52). 

It is interesting that, in contrast to nearly all nucleotidyltransferase reactions, most nonenzymic reactions that are used for synthesizing phosphoanhydrides and phosphodiesters are best carried out in nucleophilic solvents or in reaction media containing nucleophilic catalysts. In one case stereochemical evidence has been advanced as evidence for nucleophilic catalysis by pyridine used as the solvent in the synthesis of a thiophosphoanhydride (60). While many of these nonen-... 

Variation of A in Zn(II) complexes has recently been studied by Hambright (11), whereas previous scattered data refer mostly to solvated ions. The same rate laws are found for the reaction of Zn2+ and Cu2+ with TMPyP in alkali nitrate solutions at pH <4, but the corresponding rate constants are about 50 times smaller for Zn +. The complications pointed out in Sections 2.2 and 2.3.3 arise at pH >4 when buffers have to be introduced. In NaNOa 1 M, the 2,6-lutidine buffer enhances the rates, and the parameters kg increase when the pH is raised. Catalysis by pyridine has been analyzed (11) in terms of the rate law... 

In Chapter 10 we used pyridine as a catalyst in carbonyl substitution reactions, even though it is only a weak base. Catalysis by pyridine involves two mechanisms, and is discussed on p. 200.Acetate ion is another weak base which can catalyse the formation of esters from anhydrides ... 

Acyl transfer from an acid anhydride to an alcohol is a standard method for the preparation of esters. The reaction is subject to catalysis by either acids (H2SO4) or bases (pyridine). 

In this solvent the reaction is catalyzed by small amounts of trimethyl-amine and especially pyridine (cf. 9). The same effect occurs in the reaction of iV -methylaniline with 2-iV -methylanilino-4,6-dichloro-s-triazine. In benzene solution, the amine hydrochloride is so insoluble that the reaction could be followed by recovery. of the salt. However, this precluded study mider Bitter and Zollinger s conditions of catalysis by strong mineral acids in the sense of Banks (acid-base pre-equilibrium in solution). Instead, a new catalytic effect was revealed when the influence of organic acids was tested. This was assumed to depend on the bifunctional character of these catalysts, which act as both a proton donor and an acceptor in the transition state. In striking agreement with this conclusion, a-pyridone is very reactive and o-nitrophenol is not. Furthermore, since neither y-pyridone nor -nitrophenol are active, the structure of the catalyst must meet the conformational requirements for a cyclic transition state. Probably a concerted process involving structure 10 in the rate-determining step... 

Kishimoto et al. (1974, 1981) found a general acid catalysis by protonated pyridines in coupling reactions of the 1-naphthoxide ion if weakly electrophilic diazonium ions were used. In this case it is likely that the general acid protonates the carbonyl oxygen of the o-complex, with a concerted or stepwise deprotonation at the 4-position (transition stage 12.150). 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

Kinetic Studies. The pioneering work of Hierl et al. (8) and Delaney et al. (9) had established that hydrolysis of jr-nitro-phenylcarboxylates was an excellent means of observing the nucleophilic catalysis by 4-(dialkylamino) pyridine functionalized polymers. Hydrolysis of p-nitrophenylacetate in a buffer at pH 8.5 showed that the polymer was a slightly better catalyst than the monomeric analog PPY (Table II). However, preliminary results indicate that the polymer bound 4-(dialkylamino) pyridine is more effective as a catalyst than the monomeric analog in the hydrolysis of longer carbon chain p-nitrophenylcarboxylates, such as p-nitrophenylcaproate. 

A recent method for the synthesis of the indolizine skeleton is represented by a three-component reaction between a-bromo ketones 16, pyridine 17, and ethyl propiolate or diethyl acetylenedicarboxylate. These three reagents, under microwave irradiation and catalysis by basic alumina, afforded a good variety of 3-aroyl indolizines 18 <20030L435> (Scheme 4). 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

The Glaxo synthesis of zanamivir (2) started with the esterification of commercially available A-acetyl-neuraminic acid (88) with methanolic HCl to give the methyl ester as shown in Scheme 7.14 (Chandler and Weir, 1993 Chandler et ah, 1995 Patel, 1994 Weir et al., 1994). Global acetylation of all the hydroxyl groups with acetic anhydride in pyridine with catalysis by 4-(dimethylamino)pyridine (DMAP) led to the penta-acetoxy compound 89. Treatment of 89 with trimethylsilyl triflate in ethyl acetate at 52°C introduced the oxazoline as well as the 2,3-double bond to provide 86. Addition of trimethysilyl azide to the activated allylic oxazoline group led to the stereoselective introduction of azide at the C-4 position to afford 83 as in Scheme 7.13. 

There are many reactions in which pyridines are used as bases. However in a large number of reactions only pyridine itself is reactive. a-Substituted pyridines behave differently, e.g. in the catalysis of acylation reactions with acyl chlorides or anhydrides [45]. The sterical hinderance of the a-substituents decelerates reactions in which a pyridine reacts as a nucleophile. A reaction which can be base-catalyzed by a-substituted pyridines is the addition of alcohols to hetero-cumulenes such as ketenes and isocyanates. Therefore this reaction was investigated as a model reaction for base catalysis by concave pyridines. 

In a general base catalysis, the pyridine forms a hydrogen bond to an alcohol function (56). This causes a polarization and increases the nucleophi-licity of the alcohol oxygen thus accelerating the reaction [46c]. The second mechanism postulates a betain intermediate 57 which is formed by a nucleophilic attack of the pyridine on the ketene 59 [46d]. 

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