Pyridine ring reductive pathway

Compared with monocyclic aromatic hydrocarbons and the five-membered azaarenes, the pathways used for the degradation of pyridines are less uniform, and this is consistent with the differences in electronic structure and thereby their chemical reactivity. For pyridines, both hydroxylation and dioxygenation that is typical of aromatic compounds have been observed, although these are often accompanied by reduction of one or more of the double bonds in the pyridine ring. Examples are used to illustrate the metabolic possibilities. 

Metabolism studies in swine showed that the drug was extensively and rapidly metabolized to at least 11 metabolites (105). The three major metabolic pathways elucidated primarily through in vitro studies were reduction of the ketone group to yield azaperol and other reduced compounds, oxidative A-deace-tylation, and hydroxylation of the pyridine ring. Apart form swine, these primary pathways were also observed in rats but there were quantitative differences between these species. 

Fig. 8.14 The coenzyme NAD accepting a hydride ion, shown in blue, from lactate. NAD -dependent dehydrogenases catalyze the transfer of a hydride ion (H ) from a carbon to NAD in oxidation reactions such as the oxidation of alcohols to ketones or aldehydes to acids. The positively charged pyridine ring nitrogen of NAD increases the electrophilicity of the carbon opposite it in the ring. This carbon then accepts the negatively charged hydride ion. The proton from the alcohol group is released into water. NADP functions by the same mechanism, but it is usually involved in pathways of reductive synthesis.

Mechanistic studies revealed a significant kinetic isotope effect (kn/ko = 4.2) which excluded an electrophUic palladation pathway (unless the deprotonation is rate-limiting). A CMD process was proposed as a plausible C—H activation route as illustrated in Scheme 36. The superior activity of pyridine over benzene is attributed to the initial coordination of the Pd metal via the N(sp ) of the pyridine ring. The authors assumed that subsequent reorientation of the pyridine to bind with its Tt-system promotes the C3-H activation via CMD (after all, the C3-position of pyridine is expected to be the most electron-rich and therefore less favorable for CMD) (2013JOC8927). An aryl-Pd species (C) is formed which undergoes oxidative addition with an aryl halide to form Pd -intermediate D. Selective C3-arylated pyridine is formed upon reductive elimination from intermediate D. 

A photolytic reduction of the 5-chloro-substituted tetrazolo[l,5- ]pyridine derivative 60 was observed by Dias et al. <1996JHC1035> (Scheme 17). These authors found that the photolysis of the starting compound 60 when carried out with unfiltered light followed an unusual pathway instead of a ring-enlargement reaction experienced with use of Pyrex filter in many cases, a photolytic reduction takes place in 44% yield, and the chlorine substituent is replaced by... 

Basolo gives a beaudfiil example of the effect of the physical blocking of the reaction pathway and thus the reduction in reactivity at the met center (5). In the series of compounds rron5-[PtCl(PEt3)2L] where L is a phenyl ring, ortho substituted, the rate of nucleophilic substitution of Cl by pyridine systematically decreases as the bulk of the ortho substituent increases ... 

The ruthenium-catalysed arylation, by aryl halides, of benzylic amines carrying a pyridine coordinating group is thought to involve a concerted metallation-deprotonation pathway to give intermediates such as (96), followed by oxidative addition of the aryl halide to ruthenium and then reductive elimination. The reaction can be successM with aryl chlorides, as well as bromides and iodides, but here there are mechanistic differences. The ability of ruthenium to activate remote ring positions to electrophilic substitution has been referred to earlier, see Ref. 97. The reaction of ruthenium-coordinated 2-pyridyl arenes (51) with secondary alkyl halides has been shown to result in the formation of metfl-alkylated products. ... 

The expected order for electrophilic attack by OH on co-ordinated and unco-ordinated pyridine derivatives is py>[Co(NH3)spy] +>Hpy+. For pyridine and isonicotinamide (ina) this order is observed and similarities in the spectra of the unstable addition products suggest that OH attacks at the same place in both bound and unbound ligands. With nicotinamide (na), reaction of the cobalt(iii) complex is faster (2.1 x 10 1 moh s at 22 C) and produces a transient spectrum which is red-shifted compared with that of the unbound ring adduct. It is suggested that in this case attack occurs not on the aromatic system but on an amide group. This behaviour may explain why the europium(ii) reduction of [Co(NH3)5(ina)] + is autocatalytic whereas the corresponding reduction of the nicotinamide complex is not. In the pulse radiolysis studies, the transient intermediate complexes decay by a second-order pathway with rate constants 1.3 x 10, 3.0 x 10 , and 6.0 x 10 1 mol for [CofNHa) sPy] , [Co(NH3) s(na)] +, and [Co(NH3)5(ina)] +respectively... 

The palladium-catalysed reaction of the pyrazolo-pyrimidine derivative (141) with 3-bromotoluene may result in arylation at the 3-position in the pyrazole ring or at an sp hybridized site in the 7-methyl side-chain depending on the base and ligands used. After initial insertion of the palladium catalyst into the aryl halide bond, palladation of (141) occurs by a concerted metalation-deprotonation pathway and is followed by reductive elimination. Concerted metalation-deprotonation is also likely in the palladium-acetate-catalysed reaction of imidazo[l,2-a]pyridines with aryl bromides to give 3-substituted derivatives such as (142). A careful mechanistic study of the arylation of pyridine A-oxide by bromotoluene, catalysed by palladium acetate and t-butylphosphine, has shown that direct reactions of an aryl palladium complex with... 

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