Pyridines hindered, 4-acylation

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-methylamino)pyridine has been recommended (DMAP G. Hdfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

Additional acceleration of acylation can be obtained by inclusion of cupric salts, which coordinate at the pyridine nitrogen. This modification is useful for the preparation of highly hindered esters.122 Pyridine-2-thiol esters can be prepared by reaction of the carboxylic acid with 2,2 -dipyridyl disulfide and triphenylphosphine123 or directly from the acid and 2-pyridyl thiochloroformate.124... 

More stable iV-acylpyridinium salts can be formed by using 4-(Ar,Ar-dialkyl-amino)pyridines. The salts are less readily hydrolyzed and are effective in the acylation of sterically hindered alcohols (72S619) and in the formation of iV-f-butoxycarbonyl derivatives of a-amino acids in aqueous alkali, for use in peptide synthesis (71CC267). 

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 general reaction of an alcohol with the appropriate anhydride or acid chloride in pyridine at 0-20 JC is sufficient. In the case of tertiary alcohols, acylation is very slow in which case a catalytic amount of 4-dimethylaminopyridine (DMAP) can be added to speed up the reaction by a factor of 10,000. Reaction of polyols with acyl chlorides (1.2 equiv) in the presence of hindered bases (2.0equiv) such as 2,4,6-collidine, diisopropylethylamine or 1,2,2,6,6-penta-methylpiperidine in dichloromethane at -78 °C leads to selective acylation of a primary alcohol. Primary alcohols can also be acylated selectively with isopro-penyl acetate or acetic anhydride in the presence of a catalytic amount of 1,3-dichlorotetrabutyldistannoxane 325.1 [Scheme 4.325].602 The catalyst 325.1 is available commercially or can be easily prepared by simply mixing dibutyltin oxide and dibutyldichlorostannane. No aqueous workup is necessary since the catalyst can be removed by simple chromatography. 

Benzoylation. This acyl triflate is particularly useful for benzoylation of hindered secondary hydroxyl groups and, in combination with pyridine, tertiary hydroxyl groups. Acetals and ketals, if present, are converted into carbonyl groups. Epoxides also react, generally to give a mixture of products. 

These two compounds are superior to pyridine as catalysts for acylation of alcohols, particularly for tertiary and sterically hindered alcohols. Even axial lljS-hydroxyl groups of steroids can be acetylated in yields as high as 80%. Several useful C-acylations have been reported. The reagents catalyze the transformation of amino acids into or-acylamino ketones (equation II). They are superior to pyridine for reaction of isocyanates and carboxylic acids to form amides (equation III). 

The steric requirements of such a complex would amply account for the low reactivity of axial and other hindered alcohols. The alternative stepwise formation of an alkoxide anion followed by its attack upon the acylating reagent seems unlikely in view of the weakly basic character of pyridine. 

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

The reaction of acid chlorides with tetramethylguanidinium azide also proceeds under very mild con-ditions. Using this technique even r-alkyl azidoformates may be prepared (Scheme 38). Quantitative yields of acyl azides (in solution) are reported for the interaction of acid chlorides in toluene with HNs/pyridine at 0 °C. Even sterically hindered educts are smoothly converted into acyl azides. If tetraalicylammonium azides are used, the use of hazardous hydrazoic acid is avoided. ... 

Acylation catalyst.2 4-Pyrrolidinopyridine (1), like N,N-dimethyl-4-pyridinamine (3, 118-119), is a very effective catalyst for acylation of sterically hindered alcohols. In a typical procedure, the alcohol is treated with a carboxylic acid anhydride and an equimolar amount of the dialkylaminopyridine at room temperature. In preparations on a larger scale, 1 eq. of triethylamine is added to bind the acid formed in the acylation. For example, methyl cholate is converted into the triacetate at room temperature within 2 hr. using 4-pyrrolidinopyridine as catalyst. Acetylation with Ac20/pyridine at room temperature affords only the 3,7-diaeetate (the 12a-hydroxyl group is axial).3 4-Dialkylaminopyridines are particularly useful catalysts for acylation of add-sensitive tertiary alcohols such as linalool (2), which can be acetylated in 80% yield by this new procedure. 

Acid anhydrides, with or without pyridine, bring about A-acylation of benzimidazoles, A-l-acylation of indazoles, and 1,3-diacylation of benzimidazol-2-one. A-2-Acylation of indazole can be achieved in the presence of a hindered base. ... 

The reactions of iV-alkoxycarbonylimines with acetylenedicarboxylic esters146 are summarized in Scheme 14. A-Imines unsubstituted in the 2,6-positions furnish pyrazqlo-pyridine only in low yield, the acyl residue of the imino group also being cleaved during the rearomatization. 2,6-Disubstituted imines in which the mesomerism between the imino group and the pyridine ring is hindered yield the normal addition products and vinylpyridine derivatives in various amounts. 

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