Acylpyridinium salts, formation

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). 

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 enhanced activity of 1 and 2 over pyridine is not a result of increased basicity (DMAP, pK = 9.70 Py, pK = 5.29), but is due at least in part to the formation of high concentrations of N-acylpyridinium salts, which are very effective acylating reagents. 

King, J. A., Jr. Nucleophilic versus general base catalysis in carbonyl substitution reactions the influence of acylpyridinium/acylammonium salt formation on the observed reaction rate. Trends in Organic Chemistry QQ7, 6, 67-89. 

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. 

The yield was still low however, the authors then reported the total synthesis of Erythonolide A by the macrocyclisation of a slightly different substrate, 7.11 The excellent yield was attributed to a suitable conformation of 7 and a more efficient formation of the acylpyridinium salt. A more detailed study on the macrocyclisation of such substrates by employing different conditions discusses different coupling reagents and varying equivalents of triethylamine.12 It is demonstrated that the Yamaguchi reaction can be carried as a one-pot procedure. 

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. 

Highly nucleophilic aromatic compounds are capable of arylating acyl-pyridinium salts. The first example of this striking reaction was described by Koenigs and Ruppelt s ho observed the formation of 4-(/>-dimethyl-aminophenyl) pyridine from pyridine, benzoyl chloride and dimethyl-aniline in the presence of copper. Benzaldehyde is also formed s, 736 and the copper is not necessaryThe dihydropyridine (105) is probably an intermediate. Other examples of the reaction are known s, 493 but attempts to isolate the intermediates have failed , though that from dimethyl-m-toluidine may have been obtained. In contrast, the dihydropyridines (106) were isolated when indole was the nucleophile. Skatole reacted similarly, at the 2-position of the indole nucleus, giving the fully aromatic 3-methyl-2-(4 -pyridyl)indole. These reactions failed with 2- and 4-picoline . Similar reactions occur between acylpyridinium salts and pyrroles (p. 71). 

The acylating power of acylpyridinium salts has been mentioned already (p. 195). It is probable that in the formation of phenol esters, arylation of the 2-position in the pyridinium salt is an essential step ... 

The reaction between ethyl Hthiopropiolate and the N-acylpyridinium salt formed by reaction of 4-methoxy-3-methyl-5-(triisopropylsilyl)pyridine 2363 with (+)-frafis-2-(a-cumyl)-cyclohexyl chloroformate (TCC chloro-formate) was the starting point in the synthesis of (-l-)-aUopumihotoxin 267A (1718) by Comins et al. (Scheme 301). The dihydropyridone product (—)- 2364 was obtained diastereoselectively (>96%) before hydrogenation to the saturated ester (+)-2365. However, some epimerization of the methyl substituent was apparent after cleavage of the TCC carbamate with lithium methoxide and cyclization to the indolizidinone (—)-2366 (dr 8 1). Acetoxylation at C-8 with lead tetraacetate was stereoselective, and introduced the acetate from the axial direction, possibly by stereoelec-tronicaUy-controUed intramolecular transfer of acetate from a lead—enol intermediate. The acetoxy product (—)-2367 was protodesilylated with formic acid, after which a one-pot tandem reduction with K-Selectride followed by hthium aluminum hydride gave diol (- -)-2368 with complete... 

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