Reduced Pyridines

Reduced Pyridines. - Recent calculations (ab initio and semi-empirical) on the relative stabilities of the five dihydropyridines give results which vary markedly according to the method used, with the two enaminic isomers (1,2-and 1,4-dihydro) predicted to be either more or less stable than the three imino forms  

Bbhm and J. Kuthan, Collect. Czech. Chem. Commun., 1981,46, 2068. 

Improved methods for preparing l-aryl-4-piperidones have been reported. Formation of a piperidine A-oxide was shown to take place with 

Imanishi, N. Yagi, H. Shin, and M. Hanaoka, Tetrahedron Lett., 1981, 22, 4001. 

The conversion of acetanilides into 2-dialkylamino-quinolines has been carried out by a high-temperature (250 °C) reaction with a mixture of NN- 

Reduced Pyridines.—An important new method for synthesizing unstable 1-alkyl-1,2-dihydropyridines (74) involves thermolysis of the stable bicyclic precursor (73). Compound (73) is obtained by alkylation of 2-azabicyclo- 

Bonini, E. Maccagnani, G. Mazzanti, and P. Pedrini, Tetrahedron Lett., 1979, 1799. 

1-Methyl-1,2-dihydropyridine behaves as an enamine rather than as a diene at — 10°C in its primary cycloaddition reactions with alkenes and alkynes. At higher temperatures, the [2 -I- 2] cyclo-adducts, e.g. (79), are unstable, and the more thermodynamically stable Diels-Alder endo- and exo-adducts, e.g. (80) and (81), are formed.  

The 2-substituted-l,2-dihydropyridines (82) form bicyclic products (83) by addition of cyanogen azide to the 5,6-double bond these aziridines are readily 

Natsume, Y. Sekine, M. Ogawa, H. Soyagimi, and Y. Kitagawa, Tetrahedron Lett., 1979, 3473. L.-F. Tietze and K. Briiggermann, Angew. Chem., Int. Ed. Engl., 1979,18, 540. 

If R = benzyl, this substituent can be hydrogenoiysed after, or as a part of, the hydrogenation procedure [i.B- without the isolation of the intermediate N-alkylpiperidine). 

In this case the aqueous conditions permit protonation at C-5 after the first hydride addition, thereby setting up the next hydride transfer. The reduction stops before the ring is fully saturated, however, as the lone pair electrons on the N atom of the 1,2,5,6-tetrahydropyridine are not conjugated with the C=C double bond i.e. further activation by protonation is not possible). 

Reduction of 1,2,5,6-tetrahydropyridines to A-alkylpiperidines requires catalytic hydrogenation. 

Conversely, NADH is one of the important natural reductants, and in yeast cells, for example, it reduces acetaldehyde to ethanol  

Piperidine is obtained commercially by the catalytic hydrogenation of pyridine over a nickel catalyst at about 200 C. A-Substituted derivatives are formed by reduction of the corresponding pyridinium salts. 

Multidrug resistance, where a tumor becomes immune to a broad range of compounds without regard to their mechanism of action, comprises one 

The design of the peptidomimetic antiviral agent (Chapter 1) ultimately traces back to the fact that structures of these protease inhibitors in some way act as surrogates for the natural substrate enzyme. The recent protease 

Reaction of this intermediate with base leads the anion of the newly revealed hydroxyl group to attack with the carhoxylate in what amounts to an internal transesterification. This step forms the cyclic ester and thus the requisite pyranone ring (50). Catalytic hydrogenation of 50 results in reduction of the nitro group to yield 51. Acylation of the newly formed amine with 5-trifluoromethylpyridinium-2-sulfonyl chloride affords 52.  

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Partially reduced derivatives have been obtained from o-aminopyridinemethanors (218 219) (75JAP(K)75157394), and partially reduced pyridines e.g. 220) have also furnished this type of derivative in reactions with formamide, guanidine and imidates <72JHC1113, 72JHC1123, 78CB2297). 

The formation of cotar none from cotar nine methine methiodide by the action of potash (IX—X) led Roser to represent cotarnine and its salts by the following formulae, the loss of a molecule of water in the formation of cotarnine salts being explained by the production of a partially reduced pyridine ring, which is fully hydrogenated in the reduction of cotarnine to hydrocotarnine. In the reverse process, oxidation of liydrocotarnine to cotarnine, Roser assumed the scission of the ring at the point indicated, with the formation of a hydration product, and oxidation of the latter to cotarnine thus —... 

Bland, Perkin and Robinson have shown that oxyberberine is converted by hydrochloric acid into sooxyberberine (XI) by the opening of the reduced pyridine ring. 

Indium metal reduces the pyridine ring in quinoline in aqueou sethanol solution.Samarium iodide (Sml2) reduces pyridine in aqueous THF ° and phenol in MeOH/KOH. ... 

Reduction of aromatic rings with lithium or calcium " in amines (instead of ammonia—called Benkeser reduction) proceeds further and cyclohexenes are obtained. It is thus possible to reduce a benzene ring, by proper choice of reagent, so that one, two, or all three double bonds are reduced. Lithium triethylborohy-dride (LiBEtsH) has also been used, to reduce pyridine derivatives to piperidine derivatives." ... 

B. Nicotinamide and Flavin Coenzymes.—High-frequency (220 MHz) H n.m.r. spectroscopy shows that there are differences in conformation between oxidized and reduced pyridine coenzymes. A preliminary report on the P n.m.r. spectra of NAD+ and NADH confirms these observations, as the spectrum of NAD+ consists of an AB quartet while there is only a single resonance discernible in the spectrum of NADH. 

Nitrosoarenes are readily formed by the oxidation of primary N-hydroxy arylamines and several mechanisms appear to be involved. These include 1) the metal-catalyzed oxidation/reduction to nitrosoarenes, azoxyarenes and arylamines (144) 2) the 02-dependent, metal-catalyzed oxidation to nitrosoarenes (145) 3) the 02-dependent, hemoglobin-mediated co-oxidation to nitrosoarenes and methe-moglobin (146) and 4) the 0 2-dependent conversion of N-hydroxy arylamines to nitrosoarenes, nitrosophenols and nitroarenes (147,148). Each of these processes can involve intermediate nitroxide radicals, superoxide anion radicals, hydrogen peroxide and hydroxyl radicals, all of which have been observed in model systems (149,151). Although these radicals are electrophilic and have been suggested to result in DNA damage (151,152), a causal relationship has not yet been established. Nitrosoarenes, on the other hand, are readily formed in in vitro metabolic incubations (2,153) and have been shown to react covalently with lipids (154), proteins (28,155) and GSH (17,156-159). Nitrosoarenes are also readily reduced to N-hydroxy arylamines by ascorbic acid (17,160) and by reduced pyridine nucleotides (9,161). 

The combination of PhMeSiH2 (or Ph2SiH2) and Cp2TiMe2 (10 mol%) reduces pyridines to N-silylated-di- or tetrahydropyridines or the N-silylated piperidines.264,265 With quinoline, only the pyridine ring is reduced preferentially to the benzene ring (Eq. 121). 

The carbonyl reductases catalyze reduction of aldehydes and ketones by reduced pyridine nucleotides (NADH and/or NADPH). As mentioned earlier, alcohol dehydrogenase can perform this function in the presence of a high ratio of NADH to NAD+. Other enzymes capable of carbonyl reduction include the aldehyde and ketone reductases. The aldehyde and ketone reductases have a ubiquitous species distribution, with the enzymes present in organisms ranging from bacteria to vertebrates. The mammalian carbonyl reductases have been extensively reviewed (101). 

Indicine IV-oxide (169) (Scheme 36) is a clinically important pyrrolizidine alkaloid being used in the treatment of neoplasms. The compound is an attractive drug candidate because it does not have the acute toxicity observed in other pyrrolizidine alkaloids. Indicine IV-oxide apparently demonstrates increased biological activity and toxicity after reduction to the tertiary amine. Duffel and Gillespie (90) demonstrated that horseradish peroxidase catalyzes the reduction of indicine IV-oxide to indicine in an anaerobic reaction requiring a reduced pyridine nucleotide (either NADH or NADPH) and a flavin coenzyme (FMN or FAD). Rat liver microsomes and the 100,000 x g supernatant fraction also catalyze the reduction of the IV-oxide, and cofactor requirements and inhibition characteristics with these enzyme systems are similar to those exhibited by horseradish peroxidase. Sodium azide inhibited the TV-oxide reduction reaction, while aminotriazole did not. With rat liver microsomes, IV-octylamine decreased... 

Figure 4 summarizes the direct oxidative pathway with its relations to (a) the gycolytic route of G-6-P utilization, (b) the reduction of pyridine nucleotides, and (c) the influences on some reactions depending on reduced pyridine nucleotides. 

The reactions in Eqs. (10) and (11) indicate the links with glucose metabolism, the former to the direct oxidative pathway, the latter to the glycolytic route. The essential link in the reduction of MHb is the generation of reduced pyridine nucleotides (B14, R12, S10). The... 

Methemoglobinemia arises from poisoning with MHb-forming substances and from the hereditary deficiency of an enzyme system which either provides reduced pyridine nucleotides for MHb reduction or is involved itself in the MHb reduction mechanism (e.g., electron transport system). (See Section II of the Addendum, page 280.)... 

Indirect Electrochemical Activation of Reducing Enzymes without Reduced Pyridine Nucleotides... 

Also, the carboxylation of oxoglutaric acid to form isocitric acid catalyzed by isocitric acid dehydrogenase (ICDH) can be driven electrochemically using methyl viologen as mediator without reduced pyridine nucleotides as cofactors. Thus, electrolysis at — 0.95 V vs SCE of a 0.2 M tris buffer solution (pH 7.7)... 

Flavoprotein dehydrogenases usually accept electrons from reduced pyridine nucleotides and donate them to a suitable electron acceptor. The oxidation-reduction midpoint potential of the FAD of the oxidase has been determined by ESR spectroscopy and shown to be -280 mV. The NADP+/ NADPH redox potential is -320 mV and that of the cytochrome b is -245 mV hence, the flavin is thermodynamically capable of accepting electrons from NADPH and transferring them to cytochrome b. As two electrons are transferred from NADPH, although O2 reduction requires only one electron, the scheme of electron transfer shown in Figure 5.8 has been proposed by Cross and Jones (1991). 

Intracellular reduced pyridine nucleotides NAD(P)H are the primary suppliers of reducing power to anabolic and catabolic pathways. They can be measured because of their fluorescent properties.<16) The fluorescence is caused by the presence of the reduced forms of the pyridine nucleotides NADH and NADPH (jointly referred to as NAD(P)H). These fluorophores absorb light in a wide band around 340 nm, and reemit, or fluoresce, light in a wide band around 460 nm. The phosphorylated and nonphos-phorylated nucleotides have essentially equivalent fluorescence properties while the oxidized forms of these nucleotides are nonfluorescent. 

B. Chance, B. Schoener, and S. Elsaesser, Control of the waveform of oscillations of the reduced pyridine nucleotide level in a cell-free extract. Proc. Natl. Acad. Sci. USA 52, 337-341 (1964). 

In view of the oxidant nature of ozone, a number of investigators have evaluated its effects on intracellular compounds that are normally active in cellular redox reactions. Attention has focused particularly on reduced pyridine nucleotides—reduced nicotinamide adenine dinudeotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH)— and on sulfhydryl compounds, specifically reduced glutathione (GSH). 

Mudd, Mudd et Menzel, and Nasr et have reported that ozonization of aqueous solutions of NADH or NADPH results in their oxidation. However, there is a difference in their findings as to whether the resulting product is a biologically active oxidized pyridine nudeotide (NAD or NADP), as suggested by Menzel, or is molecularly disrupted to the extent that it is unable to participate in enzymatic processes. Inasmuch as more drastic effects are likely to be observed in vitroy it is more likely that oxidation of intracellular reduced pyridine nucleotides proceeds mainly to NAD or NADP after ozone inhalation but further resolution of this question would be of value. 

Mudd, J. B., and W. M. Dugger, Jr. The oxidation of reduced pyridine nucleotides by peroxyacyl nitrates. Arch. Biochem. Biophys. 102 52-58, 1%3. 

The work by Scott and Lee 165) on the isolation of a crude enzyme system from a callus tissue culture of C. roseus was followed by studies of Zenk et al. on an enzyme preparation from a cell suspension system which produced indole alkaloids 166). The cell-free preparation was incubated with tryptamine and secologanin (34) in the presence of NADPH to afford ajmalicine (39), 19-epiajmalicine (92), and tetrahydroalstonine (55) in the ratio 1 2 0.5. No geissoschizine (35) was detected. In the absence of NADPH, an intermediate accumulated which could be reduced with a crude homogenate of C. roseus cells in the presence of NADPH to ajmalicine (39). Thus, the reaction for the formation of ajmalicine is critically dependent on the availability of a reduced pyridine nucleotide. 

Note the way we can refer to the unsaturated heterocycle hy considering it as a reduced pyridine, e.g. a... 

The pyridine nucleotides NAD and NADP always function in unbound form. The oxidized forms contain an aromatic nicotinamide ring in which the positive charge is delocalized. The right-hand example of the two resonance structures shown contains an electron-poor, positively charged C atom at the para position to nitrogen. If a hydride ion is added at this point (see above), the reduced forms NADH or NADPH arise. No radical intermediate steps occur. Because a proton is released at the same time, the reduced pyridine nucleotide coenzymes are correctly expressed as NAD(P)H+HT... 

These kinetic experiments were carried out in microcuvettes at 25°C, which contained 25 nmoi reduced pyridine nucieotide, 50 nmoi potassium ferricyanide (added at zero time as the eiectron acceptor), 1 nmoi reductase in 0.2 ml 0.1 M Tris-acetate (pH 8.1) containing 1 mM EDTA. 

The adsorption microcalorimetry has been also used to measure the heats of adsorption of ammonia and pyridine at 150°C on zeolites with variable offretite-erionite character [241]. The offretite sample (Si/Al = 3.9) exhibited only one population of sites with adsorption heats of NH3 near 155 kJ/mol. The presence of erionite domains in the crystals provoked the appearance of different acid site strengths and densities, as well as the presence of very strong acid sites attributed to the presence of extra-framework Al. In contrast, when the same adsorption experiments were repeated using pyridine, only crystals free from stacking faults, such as H-offretite, adsorbed this probe molecule. The presence of erionite domains in offretite drastically reduced pyridine adsorption. In crystals with erionite character, pyridine uptake could not be measured. Thus, it appears that chemisorption experiments with pyridine could serve as a diagnostic tool to quickly prove the existence of stacking faults in offretite-type crystals [241]. 

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