Acylation of pyridines

Free radical acylation of pyridines generally results in predominant or exclusive formation of the 2- and 4-substituted isomers, and carbamoylation, carboxylation and halogenation show similar product distributions. In certain of these reactions, most notably carbamoylation, synthetically significant yields of substitution products can be realized, but in many cases while quoted yields can look impressive, actual conversions can be very low <74AHC(16)123>. 

Direct selective acylation of pyridine was achieved by use of olefins and CO, with Ru3(CO)12 as catalyst, as shown in Scheme 1 [2], Reaction of pyridine 1 with CO and 1-hexene in the presence of Ru3(CO)12 gave hexanoylpyridine 2 with a 93 7 ratio of linear and branched isomers. Use of 2-hexene or 3-hexene in place of 1-hexene also gave 2 with exactly the same linear/branched product ratio as in the reaction with 1-hexene. 

The search for new reactivity and new reactions is an important target in homogeneous catalysis. A declared goal is the selective activation of C-H bonds under mild conditions. Although there are numerous examples of stoichiometric C-H bond oxidative additions to transition metal centers, successful examples regarding catalytic functionalization of C-H bonds have been made only during the last five years. Notable advances have been achieved by Moore and coworkers who described in 1992 the ortAo-acylation of pyridine with olefins and carbon monoxide. The cluster compound triruthenium dodecacarbonyl has been used as catalyst (Scheme 10). 

FormylatioH and acylation of pyridine. Direct formylation and acylation at the )S-position of pyridine is possible by reaction with phenyllithium and then with Fe(CO)s. The reactions are formulated in scheme (I). 2-Phenylpyridine is also obtained in these reactions. Halide exchange of 3-bromopyridine with n-butyl-lithium to give 3-pyridinyllithium followed by reaction with Fe(CO)5 gives only a 5% yield of 3-pyridinectu boxaldehyde. ... 

The direct formylation and acylation of pyridine has been achieved using [Fe(CO)s]-PhLi. Depending on the work-up conditions a variety of products can be obtained in reasonable yield (Scheme 1). ... 

In addition to palladium catalysts, ruthenium catalysts were applied in carbonylative C-H activation reactions as well. Moore and colleagues described the first ruthenium-catalyzed carbonylative C-H activation reaction in 1992 [52], Orf/io-acylation of pyridine and other nitrogen-containing aromatic compounds can be carried out with olefins and CO, using Ru3(CO)i2 as the catalyst (Scheme 6.16). Interestingly, internal olefins, such as cis- and frawi-2-hexene, yield the same linear/branched product ratio as terminal olefins. 

The quaternary ammonium urethanes produced by iV-acylation of pyridines " and isoquinolines " with chloroformates react with trialkylphos-phites to give the phosphonates (153) and (154), respectively. Wittig-Homer reaction with aldehydes and subsequent re-aromatization then gives the corresponding alkylated heterocycles. 

O-Acylation of pyridine-N-oxide is brought about by add anhydrides it is accompanied by addition of carboxylate to the 2-position of the O-acyl-N-oxide (e.g., with AC2O —> 93) and elimination of carboxylic acid (e.g., 93 —> 94). The resulting (2-acyloxy)pyridine (e.g., 94) hydrolyzes to 2-pyridone. 

Electrophilic C-acylation of pyridine is practically unknown. The exception is the surprising report that pyridine reacts with V-methylformanilide and phosphoryl chloride to give a small yield of pyridine-2-aldehydei30. Xhe reported orientation makes the report suspect. The Friedel-Crafts method fails, presumably because the acylium cation is not active enough to attack the pyridine nucleus deactivated by coordination with aluminium chloride (cf the case of chlorination below). Even the much more reactive 2 hydroxy-pyridine cannot be C-acylated, though 2-pyridyl benzoate gives a trace of 5-benzoyl-2-hydroxypyridine in the Fries rearrangementi i. 

Acid 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-catalyzed acylations probably usually involve initial acylation of pyridine followed by reaction with the alcohol. Pyridine is a better nucleophile... 

FormyUuion and Acylation of Pyridine. Direct formylation and acylation at the p-position of pyridine is possible by reaction with phenyllithium and then with Fe(CO)5. 2-Phenylpyridine is also formed in these reactions. ... 

Selenazolidines are acylated on carbon without ring rupture when the reaction is carried out in benzene in the presence of pyridine (73),... 

Esterification with acyl chlorides (Section 15 8) Acyl chlorides react with alcohols to give esters The reaction is usually carried out in the presence of pyridine... 

Acid anhydrides react with alcohols to form esters The reaction may be carried out in the presence of pyridine or it may be catalyzed by acids In the example shown only one acyl group of acetic anhydride becomes incorporated into the ester the other becomes the ac yl group of an acetic acid molecule... 

Norethindrone may be recrystakhed from ethyl acetate (111). It is soluble in acetone, chloroform, dioxane, ethanol, and pyridine slightly soluble in ether, and insoluble in water (112,113). Its crystal stmcture has been reported (114), and extensive analytical and spectral data have been compiled (115). Norethindrone acetate can be recrystakhed from methylene chloride/hexane (111). It is soluble in acetone, chloroform, dioxane, ethanol, and ether, and insoluble in water (112). Data for identification have been reported (113). The preparation of norethindrone (28) has been described (see Fig. 5). Norethindrone acetate (80) is prepared by the acylation of norethindrone. Norethindrone esters have been described ie, norethindrone, an appropriate acid, and trifiuoroacetic anhydride have been shown to provide a wide variety of norethindrone esters including the acetate (80) and enanthate (81) (116). 

Most of them are generally classified as poisons. Exceptions to this rule are known. A notable one is 4-dimethyl aminopyridine (DMAP) (24), which is widely used in industry as a superior acylation catalyst (27). Quaternary salts of pyridines are usually toxic, and in particular paraquat (20) exposure can have fatal consequences. Some chloropyridines, especially polychlorinated ones, should be handled with extra care because of their potential mutagenic effects. Vinylpyridines are corrosive to the skin, and can act as a sensitizer for some susceptible individuals. Niacin (27), niacinamide (26), and some pyridinecarbaldehydes can cause skin flushing. 

Acylation of pyridazinones and related compounds in the presence of weakly basic catalysts such as pyridine or sodium acetate produces IV-acylated products, while O-acylated products are obtained under strongly basic conditions. However, the reaction between 6-chloropyridazin-3(2//)-one with chlorocarbonates and that of maleic hydrazide with unsaturated acid chlorides or chloromethylsulfonyl chloride gives preferentially N-substituted products. 

The most useful general method for the C-acylation of pyrroles is the Vilsmeier-Haack procedure in which pyrrole is treated with the phosphoryl chloride complex (55a, b) of an AiA-dialkylamide (54). The intermediate imine salt (56) is hydrolyzed subsequently under mildly alkaline conditions to give the acylated pyrrole (57). On treatment of the imminium salt (56 R =H) with hydroxylamine hydrochloride and one equivalent of pyridine and heating in DMF, 2-cyanopyrrole (58) is formed (80CJC409). 

Isomerization of 3-cephems (27) to 2-cephems (28) takes place in the presence of organic bases (e.g. pyridine) and is most facile when the carboxyl is esterified. Normally an equilibrium mixture of 3 7 (3-cephem/2-cephem) is reached. Since the 2-cephem isomers are not active as antibacterial agents, the rearrangement proved to be an undesirable side reaction that complicated acylation of the C-7 amine under certain conditions. A method for converting such mixtures to the desired 3-cephem isomer involves oxidation with concomitant rearrangement to the 3-cephem sulfoxide followed by reduction. Additions... 

ACOCH2CCI3, pyridine, porcine pancreatic lipase, 85% yield.These studies examined the selective acylation of carbohydrates. Mannose is acy-lated at the 6-position in 85% yield in one example. 

Acylation of alcohols is often performed in the presence of an organic base such as pyridine. The base serves two purposes. It neutralizes the protons generated in the reaction and prevents the development of high acid concentrations. Pyridine also becomes directly involved in the reaction as a nucleophilic catalyst (see Section 8.5). 

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. ... 

II. The replacement of the benzene residue by that of pyridine in the acyl group of a mydriatic tropeine does not cause the activity to vanish. 

The sulfonating actions of pyridine-sulfur trioxide, pyridine-bis sulfur trioxide and dioxane sulfur trioxide on 2,5-dimethyIthiophene have been compared. Yields of 95% monosulfonic acid were obtained with the latter two reagents, whereas pyridine sulfur trioxide yielded only 75%. 2-Methyl-3,5-diphenylthiophene resists formylation and SnCl4 Catalyzed acylation in contrast to 2,3,5-trimethylthiophene, which is formylated and acylated quite easily. 

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