From Other Heterocyclic Substrates

This general approach to 1,5-naphthyridines has seldom been used, but classified examples follow. 

9-Dihydroxybenzo b -l, 5-naphthyridin-10(5//)-one (66), easily made by fusion of 3-aminopicolinic acid with phloroglucinol, underwent oxidation to 4-oxo-1,4-dihydro-l,5-naphthyridine-2,3-dicarboxylic acid (67) [HNO3 (d. 1.5), 20°C, then 95°C, 40 min %, after separation from a byproduct].17 

5-Diamino-2,7-bis(l,3-dioxolan-2-yl)-4,5-dimethyloctane (68) [a bis(cycloa-cetal) of the corresponding dialdehyde] gave 2,4a,6,8a-tetramethyl-3,4,4a,7,8,8a-hexahydro-l,5-naphthyridine (69) (1M H2SO4 no details).196 

6-Diphenyl-3-[3-(2-phenylimidazol-l-yl)propyl]-l,2,4-triazine (70) underwent thermal intramolecular addition (with loss of nitrogen) to give the tricyclic intermediate (71) and thence (by loss of benzonitrile) 2,3-diphenyl-5,6,7,8-tetrahydro-l,5-naphthyridine (72) [substrate, antioxidant (2,6-di-terf-butyl-4-methylphenol), l,3,5-Pr 3C6H3, reflux, 3 h 92%] that could be aromatized to 2,3-diphenyl-1,5-naphthyridine (73) (l,3,5-Pr 3C6H3, reflux, air, 24h 91%) the latter product (73) was also made directly from the triazine (70) (neat substrate, Se, 330°C, 10 h 85%) analogs likewise.137,522 

This chapter covers information on the preparation, physical properties, and reactions of 1,5-naphyhyridine and its C-alkyl, C-aryl, /V-alkyl, and /V-aryl derivatives as well as their respective ring-reduced analogs. In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into 1,5-naphthyridines already bearing substituents and the reactions specific to the alkyl or aryl groups in such compounds. For simplicity, the term alkyl-l,5-naphthyridine in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, aralkyl-, and cycloalkyl-1,5-naphthyridines likewise, aryl-l,5-naphthyridine includes both aryl-and heteroaryl-1,5-naphthyridines. 

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The primary synthesis of 1,5-naphthyridines may be accomplished by double cyclization of appropriate aliphatic substrates by cyclization of appropriately substituted pyridines by cyclocondensation of pyridine substrates with one or more aliphatic synthons or from other heterocyclic substrates by degradation, rearrangement, or the like. Partially or fully reduced 1,5-naphthyridines are often made by somewhat similar procedures such cases are usually illustrated toward the end of each subsection. Some reviews of naphthyridine chemistry contain material on the primary synthesis of 1,5-naphthyridines49 52 61 231 265 670 1260 1273 1430 1432... 

The primary synthesis of 1,6-naphthyridines has been accomplished by condensation of two or more aliphatic substrates by cycbzation of a single pyridine substrate by condensation of a pyridine substrate with an aliphatic synthon that provides one, two, three, or even four ring atoms by condensation of a pyridine substrate with two or more synthons or from other heterocyclic substrates by degradation, rearrangement, or other elaborative processes. 

Like the primary syntheses of other naphthyridines, the primary synthesis of 1,8-naphthyridines may be done by cyclization of appropriate aliphatic substrates, with or without auxiliary synthons, by cyclization of appropriately substituted pyridines with or without synthons, or from other heterocyclic substrates by several processes. 

Such syntheses may be classified into four main categories from nonhetero-cyclic precursors from single pyridine substrates, from pyridine substrates with ancillary synthons, and from other heterocyclic substrates. 

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

There is clearly enormous potential using other cis dihydrodiols produced from benzocyclo-alkenes, or from the numerous dihydrodiols produced from polycyclic carbocyclic and heterocyclic substrates. 

In agreement with what has been observed in animals, the level of aldehyde oxidase activity present in human liver is also markedly dependent on the substrate employed, the analytical method used to evaluate the substrate, and most importantly, the intrinsic activity of the preparation (Beedham et al. 1992). For N-1-methylnicotinamide oxidase activity, the rank order was cynomolgus monkey > rat > beagle dog > human liver (Rodrigues 1994). The relative levels of aldehyde oxidase activity may help determine the relative extent of lactim formation from N-heterocyclic compounds such as N-1-methylnicotinamide. Of course, formation of lactim metabolites from iminium ions can also be coordinately regulated by other enzyme activities including cytochromes P-450. Thus, formation of... 

During nearly forty years of study, the photocycloaddition of 2-pyri-dones has consistently exhibited versatile and reliable [4+4] reactivity. When dimerization is not desired, intramolecular reactions efficiently steer two pyridones to react. Alternatively, intermolecular cross reaction with an excess of another four-electron reactant can be extended to other heterocycles and to simple 1,3-dienes. It is perhaps surprising how few photoreactions of 2-pyridone fail to yield [4+4] products. Failure of the [4+4] reaction can result from a tethering unit that prevents the normal head-to-tail reactivity and introduces strain (Figures 14 and 22) or from steric hindrance caused by excessive substitution at the reacting carbons (Figure 23). A 4-alkoxy substrate shuts down the normally dominant photodimerization reaction and provides opportunities for other [4+-2] or [4+4] reactions (Figures 6 and 7). 

The ability of A -heterocyclic carbenes to activate a,p-unsaturated carbonyl compounds via the formation of the corresponding Breslow intermediate, which plays the role of a homoenolate nucleophile, has also been applied to a cascade process involving a formal intramolecular Michael reaction/oxidation/ lactonization, leading to the formation of complex tricyclic carbon frameworks starting from a bifunctional substrate containing an enone and an a,p-unsa-turated aldehyde side chain linked to each other via a benzene tether (Scheme 7.82). The reaction involved a complex multistep mechanism which started with the activation of the enal by the catalyst, forming the Breslow intermediate, which subsequently underwent intramolecular Michael reaction and next the generated enol-type intermediate reacted intramolecularly with the... 

Xanthina oxidase, xanthine dehydrogenase, Schardtnger enzyme an enzyme of aerobic purine degradation, which catalyses the oxidation of hypoxan-thine to xanthine, and xanthine to uric acid Hypox-anthine + HjO + 62 -> Xanthine -h H2O2 Xanthine + H2O -H O2 -> Uric acid + H2O2. It is a dimeric enzyme, M, 275,000, pH-optimum 4.7, pi 5.35, containing 2 FAD, 2 Mo and 8 Fe (data for the enzyme from milk). The substrate specificity is low it catalyses the oxidation of other purines (e. g. adenine), aU-phatic and aromatic aldehydes, pyrimidines, pteri-dines and other heterocyclic compounds. 

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