Acylpyridinium chloride

Acetyl- 8 benzoyl- " 489-90 nd various other acylpyridinium chlorides 86-8, 491-3 sometimes of doubtful purity (because of their very ready hydrolysis or of contamination with pyridinium chloride), have been described. Salts of benzoylpyridinium with complex metal anions are also known 94. Covalent structures, with the chlorine atom at C(2) or C(4) of the pyridine ring, have been suggested for the adducts from pyridine and the nitrobenzoyl chlorides , but the ionic character of 1-acetylpyridinium chloride is affirmed by measurements of its electrical conductivity in sulphur dioxide solution . 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acyl chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acyl chloride. The conditions required for nucleophilic catalysis therefore exist, and acylation of the alcohol by acyl chloride is faster in the presence of pyridine than in its absence. Among the evidence that supports this mechanism is spectroscopic observation of the acetylpyridinium ion. An even more effective catalyst is 4-dimeftiyIaminopyridine (DMAP), which functions in the same wsy but is more reactive because of the electron-donating dimethylamino substituent. ... 

The preparation of acetylenic ketones from soluble silver acetylenides and acid chlorides was reported in 1956 (Scheme 108).512 Analogously to that report, the reaction of silver acetylenides with acylpyridinium salts was reported to proceed effectively.513 This chemistry was applied to the synthesis of cotarnine derivatives, as exemplified in Scheme lQ9.514 514a... 

Acyl chlorides are highly reactive acylating agents and react very rapidly with amines. For alcohols, preparative procedures often call for use of pyridine as a catalyst. Pyridine catalysis involves initial formation of an acylpyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, but the acylpyridinium ion reacts more rapidly with the alcohol than the acyl chloride.94 95... 

Pyridine reacts with acyl chlorides, or acid anhydrides, to form N-acylpyridinium salts, which are readily hydrolysed (Scheme 2.6a). 

A class of acylpyridinium salts that has been investigated quantitatively is the carbamoyl pyridinium compounds. Diphenylcarbamoyl-pyridinium chloride was synthesised in 1907277. l-(N,N-Dimethylcarbamoyl)-pyridinium chloride (XLVI) was found by Johnson and Rumon278 to decompose to its component parts in non-hydroxylic solvents, dielectric constants from 5 to 95, viz. 

Comins reported the regiospecific addition of hydride ion to the 4 position of 1-acylpyridinium salts in moderate yields, but with high selectivity (> 90%). The copper hydride reagent used was prepared in situ from lithium tri-trn-butoxyaluminum hydride and cuprous bromide. l-(Phenoxy-carbonyl)pyridinium chloride (97) gave the 1,4-dihydropyridine 98 exclu-... 

The first asymmetric synthesis of (+)-cannabisativine was achived by D.L. Comins et al. using the addition of metallo enolates to a chiral 1-acylpyridinium salt as one of the key steps.The amide bond was created under the Schotten-Baumann conditions from a bicyclic acid chloride and a 1,4-amino alcohol. 

The addition of nucleophiles to 1-acylpyridinium salts has surfaced as a powerful method for the synthesis of substituted pyridines. The 1-acylpyridinium salts are formed in situ by adding an acyl chloride to a pyridine in an aprotic solvent such as tetrahydrofuran. The formation of the 1-acylpyridinium salt is very rapid and will occur in the presence of various organometallics without significant competition from the reaction of the nucleophile and the acyl chloride. The addition of ethyl chloroformate to a mixture of pyridine and ethylmagnesium bromide gives 1,2- and 1-4-dihydropyridines 29 and 30 in a ratio of 64/36. Although these dihydropyridine intermediates can be aromatized with hot sulfur to 2- and 4-alkylpyridines, the poor regioselectivity makes this procedure unattractive. 

Asymmetric synthesis of dihydropyridones. 8-Phcnylmcnthol has been used frequently as a chiral auxiliary, but this derivative (1) is more effective as the chiral auxiliary for cnantioselcctivc reactions of N-acylpyridinium salts with organomctallic reagents. Thus 2, prepared by reaction of 4-methoxy-3-(triisopropylsilyl)pyridine with the chloroformate of 1 reacts with the Grignard reagent 3 to give an adduct that on acidic deprotection provides the dihydropyridone 4 in 94% dc. Conversion of the alcohol to a chloride [P(CftH5)j and NCS] followed by treatment with sodium methoxide in methanol cleaves the chiral auxiliary as the methyl carbonate (94% yield) and at the same time effects cyclization to form the chiral bicyclic dihydropyridone 5 in 84% yield. 

Acylation of amides is naturally much harder to achieve, because of their lower basicity, but it is very greatly facilitated by the presence of pyridine.583 617 618 The reason for this effect is, of course, the intermediate formation of 1-acylpyridinium salts as mentioned above.619 For instance, dibenzamide is formed almost quantitatively from benzoyl chloride and benzamide in pyridine solution even at room temperature, whereas there is no reaction in the absence of pyridine.620 Also, by the action of aromatic acid halides on aliphatic or aromatic amides in the presence of pyridine at temperatures as low as —60° to —70° Thompson617 obtained high yields of triacyl derivatives. 

Acylpyridinium ions are probably involved as intermediates in those reactions of acyl chlorides that are carried out in the presence of pyridine. 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acid chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acid chloride. The conditions required for... 

The reaction of an acyl chloride with an alcohol to form an ester occurs rapidly and does not require an acid catalyst. Pyridine is often added to the reaction mixture to react with the HCI that forms. (Pyridine may also react with the acyl chloride to form an acylpyridinium ion, an intermediate that is even more reactive toward the nucleophile than the acyl chloride is.)... 

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