Pyrroles formation from pyridines

The formation of some pyrroles, pyrrolines, pyrrolidines, pyridines, and tetra-hydropyridines were considered above. Next come the pyrazines, a very important group of odorants. Pyrazines have been reviewed periodically by Maga.231-233 Vemin and Parkanyi216 have tabulated 26 pyrazines, as well as 11 6,7-dihydro-(5//)-cyclopentapyrazines and 9 5,6,7,8-tetrahydroquinoxalines from 15 systems. 

In 1895 Am6 Pictet (1857-1937) published the first nicotine synthesis. [529,530] Key steps are the formation of 3-(lff-pyrrol-l-yl)-pyridine from 3-aminopyridine and mucic acid and its rearrangement to 3-(l//-pyrrol-2-yl)-pyridine at high temperatures. N-Methylation and sequential reduction give eventually racemic nicotine, which can be separated with tartaric acid into its enantiomers. 

Interestingly, this Heck-type palladium-catalyzed oxidative addition/insertion manifold can also be applied to the actual formation of the carbon-heteroatom bond. This was illustrated by Narasaka in the reaction of olefin-tethered oxime derivatives. This chemistry can be considered to arise from oxidative addition of the N—O bond to palladium (30) followed by the more classical olefin insertion and (3-hydride elimination, ultimately allowing the assembly of pyrroles (Scheme 6.58) [79]. The nature of the OR unit was found to be critical in pyrrole formation, with the pentafluorobenzoylimine leading to selective cyclization and rearrangement to the aromatic product. An analogous approach has also been applied to pyridines and imidazoles [80]. 

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). 

SCHEME 1.96 Formation of a complex of 2,6-di(pyrrol-2-yl)pyridine with DMSO from 2,6-diacetylpyridine dioxime and acetylene in the LiOH/DMSO system. 

Extrusion of CO from the pyrrolinediones 298 is followed by ketene cyclization to give quinolones 299 (Scheme 60 2002JCS(P1)1232). Unexpected formation of pyridine products is observed from pyrolytic decarboxylation of isoxazolone-containing cinnamic acid derivatives such as 300 the ethyl ester gives 301 (X = OEt), in addition to a pyrrole product (see... 

Ciamician reported the formation of 3-halogenopyridines in low yield from the reaction of pyrryl potassium with chloroform, or bromo-form, in ether. Similar reactions of pyrrole with benzal chloride and methylene iodide gave 3-phenylpyridine and traces of pyridine, respectively. These reactions were later reinvestigated by Alexander... 

Formation of a central pyridine ring can also be effected by reaction of 2-(pyrrol-2-yl)imidazoles with ethyl bromoacetate <1999TL8157>. Kandeel et al. also synthesized angular systems in this manner from the thioxo-pyranopyrazole precursor <2002H(57)1121>. 

Carbon and nitrogen are the most common elements from the first row of the periodic table to form aromatic compounds, characterized by cyclic electron delocalization. The bonding of these elements in the conjugated systems shows a large variety. Carbon can be a divalent (carbene), sp carbon with one jT-electron, but also sp carbon can be part of hyperconjugate aromatic systems, provided that it is properly substituted. The pyrrole- and pyridine-type nitrogens also allow the formation of cyclic electron delocalization in a large variety of aromatic systems. 

This near-thermoneutrality gives confidence in both values of the oxime enthalpies of formation, the salicylaldoxime some 50 years old and the pyridine-2-carboxaldoxime within a year from when the chapter was submitted. Consider now the formal solid phase reaction 25 involving the some decades older pyrrole-2-carbaldoxime. ... 

We can now make sensible guesses as to the order of rate constant for water replacement from coordination complexes of the metals tabulated. (With the formation of fused rings these relationships may no longer apply. Consider, for example, the slow reactions of metal ions with porphyrine derivatives (20) or with tetrasulfonated phthalocyanine, where the rate determining step in the incorporation of metal ion is the dissociation of the pyrrole N-H bond (164).) The reason for many earlier (mostly qualitative) observations on the behavior of complex ions can now be understood. The relative reaction rates of cations with the anion of thenoyltrifluoroacetone (113) and metal-aqua water exchange data from NMR studies (69) are much as expected. The rapid exchange of CN " with Hg(CN)4 2 or Zn(CN)4-2 or the very slow Hg(CN)+, Hg+2 isotopic exchange can be understood, when the dissociative rate constants are estimated. Reactions of the type M+a + L b = ML+(a "b) can be justifiably assumed rapid in the proposed mechanisms for the redox reactions of iron(III) with iodide (47) or thiosulfate (93) ions or when copper(II) reacts with cyanide ions (9). Finally relations between kinetic and thermodynamic parameters are shown by a variety of complex ions since the dissociation rate constant dominates the thermodynamic stability constant of the complex (127). A recently observed linear relation between the rate constant for dissociation of nickel complexes with a variety of pyridine bases and the acidity constant of the base arises from the constancy of the formation rate constant for these complexes (87). 

This order of base activity corresponds almost exactly to that observed in the formation of pyrroles from ketoximes and acetylene, evidently for the same causes. The failure of trimethylbenzylammonium hydroxide to catalyze the reaction of vinylation is believed (59MI1 66MI1) to be caused by its lack of coordination. Along with inhibition of the reaction with water, pyridine, o-phenanthroline, and diketones, this indicates the reaction occurs by complex ionic mechanisms in which the participation of the complex ion as an intermediate is possible. 

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