Pyridine ethers electrophilic substitution

Electrochemical fluorination of pyridine in the presence of a source of fluoride ion gave 2-fluoropyridine in 22% yield (85M11). With xenon difluoride, pyridine formed 2-fluoropyridine (35%), 3-fluoropyridine (20%), and 2,6-difluoropyridine (11%) in a reaction unlikely to be a conventional electrophilic substitution. Xenon hexafluoride has also been used (76JFC179). With cesium fluoroxysulfate at room temperature in ether or chloroform, the major product was 2-fluoropyridine (61 and 47%, respectively). Some 2-chloropyridine was also formed in chloroform solution. In methanol the entire product was 2-methoxypyridine (90TL775). Fluorine, diluted with argon in acetic acid, gave a 42% yield of the 5-fluoro derivative of l-methyl-2-pyridone [82H( 17)429],... 

Electrophilic substitution is difficult with electron-deficient heteroatomic compounds such as pyridine and quinoline. However, an electrophile can be readily introduced when the heterocycles have an effective ortho-directing group such as a sulfamoyl moiety. Lithiation of the 2-pyridinesulfonamide (51) was performed at low temperature by using 2 equivalents of LDA in ether at —78 °C for 1.5 h (equation 27). Addition of benzophenone to the solution of 52 gave the adduct in high yield38. Metallation of the 4-pyr-idinesulfonamide 53 with 3 equivalents of LDA, followed by reaction with benzaldehyde, afforded the 3,5-disubstituted pyridine 54 (equation 28). 

Comparatively little is known about other electrophilic substitution reactions of pyridine. Exceptions are activated systems, e.g. 3-hydroxypyridine 23 which undergoes azo-coupling, carboxylation and hydroxymethylation. Its 0-ethyl ether 24 can be ring-alkylated by a Friedel-Crafts method [49] ... 

Simple 2,2-dibutyl-l,3,2-dioxastannolanes form solid complexes of monomer units with certain nucleophiles, such as pyridine and dimethyl sulfoxide, that have 1 1 stoichiometry and pentacoordinate tin atoms.62 Such complexes are less stable for more-substituted stannylene acetals, such as those derived from carbohydrates.62 Unfortunately, the precise structures of these complexes have not yet been defined. Addition of nucleophiles to solutions of stannylene acetals in nonpolar solvents has been found to markedly increase the rates of reaction with electrophiles,63 and transient complexes of this type are likely intermediates. Similar rate enhancements were observed in reactions of tributylstannyl ethers.57 Tetrabu-tylammonium iodide was the nucleophile used first,57 but a wide variety of nucleophiles has been used subsequently tetraalkylammonium halides, jV-methylimidazole,18 and cesium fluoride64,65 have been used the most. Such nucleophilic solvents as N,N-dimethylformamide and ethers probably also act as added nucleophiles. As well as increasing the rates of reaction, in certain cases the added nucleophiles reverse the regioselectivity from that observed in nonpolar solvents.18,19... 

Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-(3-substituted tetrahydro-pyridines 272-274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits M-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi-Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. 

Benzyl bromide is a good electrophile and it reacts well with alkoxides to make ethers. With neutral alcohols however the substitution is very slow, so only the more nucleophilic (and more basic) pyridine nitrogen is attacked, to make a pyridinium salt. 

The preparation and use of these nucleophilic organometallic reagents in the presence of electrophilic fluorinated olefins was a surprising result and prompted us to explore theoretical support for their stability. Upon calculating (at the ab initio level) deprotonation energies of trifluorovinyloxy substituted benzene and pyridine model compounds vs. the corresponding methyl ether, we found that perfluorovinyl... 

The electrophilic behavior of these carbene intermediates is also shown by their reactions with pyridine and with cyclic ethers as electron donors. Pyridine forms betaines of the type 11, which are strongly colored. In 1956, Sirs noted the formation of strongly colored photoproducts with pyridine but assumed these to be C-substituted rather than N-substituted pyridines. Reaction with tetrahydrofuran produces a 1 1 copolymer, which probably arises by the mechanism shown in Scheme 9. The photopolymerization... 

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