Pyridines acylating agents

While pyridine N-oxide does not react with enaniines in the absence of an acylating agent, other nitrone systems have formed adducts (615,616). 

The Boekelheide reaction and related reactions involves treating pyridine N Oxides 1 with acylating agents to afford rearranged products 2. Traditionally, the rearrangement occurs at the a-position but variations andyor side-products of this reaction afford y-position modification. 

Preparation of Nicergoline To a solution of 1-methyl lumilysergol-10-methyl ether in pyridine, 5-bromonicotinyl chloride is used as an acylating agent at room temperature. 

The ring contraction of 3//-azepines is also promoted by acylating agents,54 35 and by arenesulfonyl halides.34 For example, in refluxing acetic anhydride A,-phenyl-3//-azepin-2-amine yields 2-acetamidodiphenylamine (22% mp 121-122°C),34 whereas A,A,-diethyl-3/7-azepin-2-amine (30) with 4-nitrobenzoyl chloride in pyridine yields the benzanilide 31.35... 

Acyl chlorides are highly reactive acylating agents and react very rapidly with alcohols and other nucleophiles. Preparative procedures often call for use of pyridine as a catalyst. Pyridine catalysis involves initial formation of an acyl pyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, but the acyl pyridinium ion reacts more rapidly with the alcohol than the acyl chloride.103... 

Pyrazolo[l,5-fc]-l,2,4-triazole 154 " and l,2,4-triazolo[l,5-a]pyridine 156 ring systems were successfully obtained from the corresponding formamidoximes or related ami-doximes 153 and 155, respectively, and acylating agent (TsCl or TFAA) (equations 67 and 68). Similarly, l,2,4-triazolo[l,5-a]pyrimidines were obtained from pyrimidine formamidoximes . 

A general procedure for acylation of 2-aryl-5(4//)-oxazolones using an acylating agent in the presence of 4-(dimethylamino)pyridine and triethylamine has been described.The resulting products are useful intermediates for agrochemicals and drugs. 

Clay den et al. [115] have reported the synthesis of spirocyclic p-lactams 176 (Scheme 41) by exo-cyclization of lithiated pyridine and quinoline carboxamides. The reaction of isonicotinamide or chlorinated isonicotinamide 175 with LDA at -40°C with addition of methyl chloroformate led to the formation of spirocyclic p-lactams 176 in good yields. Benzyl chloroformate, benzoyl chloride, methyl triflate can also be used as the effective acylating agents. In these type of reactions, lithiation of /V-benzyl pyridine and quinoline carboxamides to nitrogen provided... 

Regioselective reactions in systems which contain multiple functional groups are an area ideally suited for biocatalysis. Linhardt and co-workers at the University of Iowa s Division of Medicinal and Natural Products Chemistry recently published the synthesis of a series of 1 -O-acyl sucrose derivatives [31], Using Chiro-CLEC -BL (the CLC of subtilisin) and vinyl esters of the acylating agent in pyridine as solvent, the authors prepared l -O-lauryl sucrose, l -O-myristyl sucrose, and l -O-stearyl sucrose in 80-90% yield (Fig. 9). Their method represents a green alternative to the tin chemistry previously used [32],... 

The 6th rank in terms of acylation reactivity that is attributed to the acyl imidazolides in Table 6.1 (entry 10) is also plausible. In the acyl imidazolides, the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the -electron sextet, which makes the imidazole ring an aromatic compound. This is why acyl imidazolides, in contrast to normal amides (entry 2 in Table 6.1) can act as acylating agents. Nevertheless, acyl imidazolides do not have the same acylation capacity as acylpyridinium salts because the aromatic stabilization of five-mem-bered aromatic compounds—and thus of imidazole—is considerably smaller than that of six-membered aromatic systems (e. g., pyridine). This means that the resonance form of the acyl imidazolides printed red in Table 6.1 contributes to the stabilization of the C=0 double bond. For a similar reason, there is no resonance stabilization of the C=0 double bond in N-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

The nitroalcohols are esterified by the usual acylating agents in the presence of acidic catalysts. With the nitroglycols of the sugar series, acetic anhydride containing a trace of sulfuric acid gives rapid and complete acetylation. Basic acetylation catalysts, such as pyridine or sodium acetate, are not satisfactory, presumably due to interaction with the nitro group. 

This is how the N-Boc pyrrole was made for use in the synthesis of epibatidine. The base used was the pyridine derivative DMAP, which you met earlier in the chapter. It has a p Tan of 9.7 and so produces small, equilibrating amounts of the anion as well as acting as a nucleophilic catalyst. Boc anhydride is used as the acylating agent. 

A particularly interesting nucleophilic substitution occurs when quinoline N-oxide is treated with acylating agents in the presence of nucleophiles. These two examples show that nucleophilic substitution occurs in the 2-position and you may compare these reactions with those of pyridine Af-oxide. The mechanism is similar. 

In many cases, the trimethoxybenzoyl group has been introduced into synthetic methyl reserpate as the last or second-to-last step. An optimal yield of 72% of reserpine is reported if a 50% excess of the acid chloride is used (190, 193), the yield diminishing as the amount of acylating agent is increased. In the French synthesis, acylation is carried out with tri-methoxybenzoic anhydride in triethylamine and pyridine (185). 

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