Acylpyridinium intermediates

Fig. 2.4 Reaction pathways in caibodiimide mediated polyesterification. 1 O-acylisourea intermediate, 2 urea, 3 acid anhydride, 4 N-acylpyridinium intermediate, and 5 TV-acyl urea side product Adapted from Ref. [18]...

First, the acid anhydride is produced by the reaction of the free acid with DCC. NucleophiUc attack by 4-pyrroUdinonepyridine on the anhydride results in the corresponding, highly reactive acylpyridinium carboxylate this leads to the formation of cellulose ester, plus a carboxylate anion. The latter imdergoes a DCC-mediated condensation with a fresh molecule of acid to produce another molecule of anhydride. N,N-carbonyldiimidazole (CDl) may substitute DCC for acid activation, the intermediate being N-acyhmidazol,... 

The intermediate N-acylpyridinium salt is highly stabilized by the electron donating ability of the dimethylamino group. The increased stability of the N-acylpyridinium ion has been postulated to lead to increased separation of the ion pair resulting in an easier attack by the nucleophile with general base catalysis provided by the loosely bound carboxylate anion. Dialkylamino-pyridines have been shown to be excellent catalysts for acylation (of amines, alcohols, phenols, enolates), tritylation, silylation, lactonization, phosphonylation, and carbomylation and as transfer agents of cyano, arylsulfonyl, and arylsulfinyl groups (lj-3 ). 

Pyridine has another useful attribnte, in that it behaves as a nncleophilic catalyst, forming an intermediate acylpyridinium ion, which then reacts with the nucleophile. Pyridine is more nucleophilic than the carboxylate anion, and the acylpyridinium ion has an excellent leaving group (pATa pyridinium 5.2). The reaction thus becomes a double nucleophilic substitution. 

Treatment of pyridines with acyl halides or anhydrides gives AT-acylpyridinium salts (76). They are isolable, though highly reactive, and are postulated as intermediates in acylations in pyridine solution (Scheme 72). They are rapidly hydrolyzed by moisture. The benzo analogues of pyridine behave similarly. 

Since formamide is a weak nucleophile, the use of imidazole or 4-dimethylaminopyridine (DMAP) is necessary for acyl transfer to formamide via an activated amide (imidazolide) or acylpyridinium ion. As Scheme 22 illustrates, the reaction starts with the oxidative addition of aryl bromide 152 to Pd(0) species, followed by CO insertion to form acyl-Pd complex 154. Imidazole receives the aroyl group to form imidazolide 155 and liberates HPdBr species. Then, imidazolide 155 reacts with formamide to form imide 156. Finally, decarbonylation of imide 156 gives amide 157. In fact, the formations of imidazolide intermediate 155 and imide 156 as well as the subsequent slow transformation of imide 156 to amide 157 by releasing CO were observed. This mechanism can accommodate the CO pressure variations observed during the first few hours of aminocarbonylation. When the reaction temperature (120 °C) was reached, a fast drop of pressure occurred. This corresponds to the formation of the intermediary imide 156. Then, the increase of pressure after 3 h of reaction was observed. This phenomenon corresponds to the release of CO from imide 156 to form amide 157. ... 

Expanding on established chemistry using iV-acylpyridinium salts as intermediates for the preparation of iV-acyldihydropyridines and dihydropyridones, Wanner and co-workers examined a method using a bicyclolactone... 

Porphobilinogen and Studies of Its Biosynthesis, ft. Neier. Synthesis and Cycloaddition Reactions of Iso-Condensed Heteroaromatic Pyrroles, C. K. Sha. Azacyclopentadienyl Metal Compounds Historical Background and Recent Advances, C. Janiak and N. Kuhn. Recent Developments in the Synthesis of Marine Pyridoacridine Alkaloids, A. M. Echavar-ren. Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates, D. L. Comins and S. P. Joseph. Index. S S... 

Cyclization occurs directly through catalysis by the acid liberated when a pyridine-2(lH)-thione is heated with an a-halo acid ester. The most convenient method for preparing the thiazole, however, seems to be the cyclization of (2-pyridinethio)acetic acids in acetic anhydride in the presence of pyridine. Without base catalysis the reaction is slow, which suggests a mixed anhydride intermediate. Mixed anhydride formation with ethyl chlorofor-mate in pyridine, or carboxyl activation by DCC in pyridine, gives the mesoionic product. The cyclization reaction and the chemical stability of the thiazole are adversely affected by a pyridine 6-substituent. The initially formed acylpyridinium salt (407) undergoes rapid tautomerization to the aromatic thiazole form equilibrium between the forms (407) and (408) is verified by rapid deuteration at C-2 (R1 = H) in AcOH-d (81H(15)1349). 

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. 

Pyridinium salt 72 is generated by the treatment of the amide 71 with triflic anhydride in the presence of pyridine followed by treatment with the lithium enolate. Intermediate 72 was used to synthesize tetraponerine T4 in four steps in 38% overall yield. Comins and co-workers used addition of a zinc enolate to an Al-acylpyridinium salt in the synthesis of (+)-hyperaspine <05OL5227>. Additionally, they have studied cuprate addition to A/ -acyl pyridinium salts of nicotine, where addition occurs selectively at the 4-position <050L5059>. 

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. 

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