Synthesis of Functionalized Pyridines by Substitution of Hetarenium-Activated­ Pentachloropyridine with Bisnucleophiles

Abstract

Pyridines, acting as heteroaromatic N-nucleophiles, 4-aminopyridine as an N,N-bisnucleophile, and 3,4-diaminopyridine as an N,N,N-trisnucleophile, all reacted with 4-(dimethylamino)-1-(2,3,5,6-tetrachloropyridin-4-yl)pyridinium chloride to give trispyridinio-substituted 3,5-dichloropyridines. Reaction of the same pyridinium chloride with O,O-bisnucleophiles such as 1,3-propanediol, hydroquinone, and resorcine, or the O,O,O-nucleophile phloroglucine, formed new Cl 2 ,Cl 3 ,O 4 ,Cl 5 ,Cl 6 and O 2 ,Cl 3 ,O 4 ,Cl 5 ,Cl 6 -substituted pyridines. S,O-Bisnucleophiles, such as 2-sulfanylethanol or 3-sulfanylpropionic acid gave the corresponding S-substituted pyridines (x-ray analysis). The (pyridin-4-yl)propionic acid was converted into bis(pyridinio)pyridine-4-thiol, an example of the rare class of N 2 ,Cl 3 ,S 4 ,Cl 5 ,N 6 -substituted pyridines.4-(Dimethylamino)pyridine (DMAP) and other nucleophilic heteroaromatics such as 4-(pyrrolidin-1-yl)pyridine and 1-methylimidazole are very valuable tools in organic synthesis. They play important roles as catalysts of organic reactions, as stabilizing substituents, and as activating groups for subsequent chemical reactions. Since Steglich and Höfle reported that DMAP effectively catalyzes acylation reactions, 1 its application for acylations of a broad variety of alcohols, amines, phenols, and enolates, 2,3 Baylis-Hillman 4 and Dakin-West reactions, 5 protection of amines, 6 C-acylations, 7 silylations, 3 and many other reactions have been described. Moreover, activation through a combination of DMAP and N,N¢-dicyclohexylcarbodiimide (DCC) was developed as an efficient method for esterifications, 8 nucleophilic asymmetric catalysis, 9 and reactions with polymeric DMAP reagents. 10 Streitwieser and co-workers reported that 4-(dimethylamino)pyridinium and other hetarenium substituents are able to stabilize reactive species such as the allyl anion 11 and the allyl radical. 12 We described stabilized uracilates, 13 pyrimidinium-olates, 14 pyrimidinium-aminides 15 and pyridinium-olates, 16 as well as hetarenium-substituted heteroaromatics which delocalize up to ten positive charges within a common p-electron system. 17 The activation of perhalogenated heteroaromatics by hetarenium substituents can be employed for the preparation of otherwise unavailable substituted heteroaromatics. As depicted in Scheme 1 for pyridines, 4-(dimethylamino)-1-(2,3,5,6-tetrachloropyridin-4-yl)pyridinium chloride (2a), readily available in almost quantitative yield from pentachloropyridine (1), 17 can be used to prepare Cl 2 ,Cl 3 ,O 4 ,Cl 5 ,Cl 6 -and O 2 ,Cl 3 ,O 4 ,Cl 5 ,Cl 6 -pentasubstituted pyridines 18 as well as their sulfur analogs. 19 Similarly, hitherto unavailable O 2 ,Cl 3 ,O 4 ,Cl 5 ,O 6 -16 and biologically interesting S 2 ,Cl 3 ,S 4 ,Cl 5 ,S 6 -pentasubstituted pyridines, 19 as well as a broad variety of symmetric and non-symmetric O 2 ,Cl 3 ,S 4 ,Cl 5 ,O 6 -pentasubstituted pyridines are available starting from 1. The procedure can be extended to the synthesis of the first representativ...

Regioselective Addition of Mesitol to a 2,4-Dichloropyridine

“…The beneficial effect of pyridine, either as a ligand or as solvent, has been well-demonstrated in nonpyridyl Ullmann couplings, but this example appears to be unique, since the pyridine appears to play a role even in the absence of copper. It is possible that pyridine is adding to form a transient pyridinium species, but literature precedent suggests that such activation would occur at C-4, and would be more likely to enhance the electrophilicity of that carbon rather than block it. One reaction was run in which collidine was substituted for pyridine, and in that instance, almost no conversion was observed after extensive reaction times.…”