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3-Nitro-, 4-nitro-, 7-nitro-, 5,7-dinitro-, and 6,8-dinitroquinoline react with the carbanion of chloromethyl phenyl sulfone to give products of substitution of hydrogen at positions 4, 3, 8, 6,8, and 5,7, respectively. The reactions are found by quantum chemical calculations to be controlled by the interactions of the HOMO of the nucleophile with the LUMO of the substrate. The σ adducts 4-(methylsulfonylphenyl)-3-nitroquinoline and 3-(methylsulfonylphenyl)-4-nitroquinoline are detected by 1H-NMR spectroscopy. In addition, heats of formation of the intermediary σ adducts 2a–d, f, h, and i are calculated.

The reaction of 3-chloro-6-phenyl-1,2,4-triazine 1a with carbon nucleophiles 2ad bearing a cyano substituent at a carbanionic center has been studied. In all reactions the formation of the corresponding 3-aminopyridazines 3ad takes place via ANRORC mechanism involving addition of the nucleophile at position 5 in compound 1a, ring opening with breaking of the N4C5 bond and intramolecular ring closure of the resulting open-chain intermediate. A 15N study with labeled phenylacetonitrile 2a* has shown that the nitrogen atom of the exocyclic amino group of 3-amino-4,6-diphenylpyridazine 3a was originally present in phenylacetonitrile.

In this review attention is paid to two topics, which were of great interest to us during 30 years of studies in pyrimidine chemistry in our laboratory: first, the development of our concepts of the AIYRORC processes, which occur in ring transformation reactions; second, the intra- and intermolecular inverse Diels-Alder reactions in which the pyrimidine ring acts as the electron poor diazadiene system. Their use in synthetic chemistry is illustrated and evidence is presented, based on experiments and molecular mechanics calculations, that in intermolecular Diels-Alder reactions the geometry of the side-chain plays a vital role.

Computational studies (MNDO/PM3 and MMX) were performed towards the selectivity and reactivity of the ringtransformation reactions of the 5-(1-propynyloxyethyl)pyrimidine derivatives A1 -8. Determination of the energy and dipole moments of the transition states of the different possible reaction pathways revealed that the ratio of the product formation was determined by the polarity of the transition states, as expressed by their dipole moments, in combination with the dipole moment of the reaction medium. Also the reactivity of the compounds under study appeared to depend on the polarity of the transition state of the initial Diels-Alder reaction. The differences in dipole moments of the different TS's are ascribed to the geometry of the molecules in the TS's. Furthermore, a comparison of the heats of activation of the initial Diels-Alder reaction and the subsequent retro Diels-Alder reaction showed that the first one is the rate determining step.

Intramolecular Diels-Alder reactions of (2-alkynylphenyl-X)-pyrazines (X = O, NAc, S) under neutral and acidic conditions are described. The isomer distribution of the resulting tricyclic b - and c -annelated pyridines is discussed.

Publisher Summary The chemistry of naphthyridines has developed significantly since the late 1970s. Many compounds containing the naphthyridine ring system show interesting and useful chemical and biological properties and are applied in medical treatment. This chapter reviews naphthyridines that are characterized as π-deficient systems. Introduction of an electron-withdrawing group such as the nitro group further depletes the ring of its π-electrons and lowers its electron density. Because of this low electron density, nitronaphthyridines show a high reactivity to nucleophilic reagents and low reactivity to electrophiles; several characteristic examples of this behavior are explained in the chapter. The chapter reviews the chemistry of the nitro-1,5-, -1,6-, -1,7-, and -1,8-naphthyridines with special attention to the results obtained in the laboratories. The chapter mainly refers to the synthesis and reactivity of the nitronaphthyridines along with their physical and spectroscopic properties and biological activity.

The methoxo-oxomolybdenum(V), diperoxomolybdenum(VI) and cis-dioxomolybdenum(VI) derivatives of 5,15-diphenyl-2,8,12,18-tetra-n-butyl-3,7,13,17-tetramethylporphyrin (4a, 5c, 6a) have been prepared and characterized by uv, ir, pmr, mass and esr spectra. The structure of the molybdenum(V) porphyrin was confirmed by X-ray analysis.

The 5-propynyloxycycloalkane pyrimidines IIIA (17 – 20), IIIB (21 – 24), and IIIC (25, 26) and the 5-(1-propynyloxyethyl) pyrimidines IIID (27,28), easily undergo intramolecular Diels-Alder reactions with inverse electron demand and a subsequent retro Diels-Alder reaction in which R1CN (R1 = H, Me) or X-CH2CN (X = −CH2, −CH2CH2, −H) is expelled. For the compounds IIIA and IIIB the extrusion of X-CH2CN is favoured, yielding 3-(3-cyanopropyl)-1,3 dihydro-6-phenyl-R1-R2-furo[3,4- c ]pyridines (29 – 36). The compounds 17 and 21 also yielded 4-phenyl-2H-6,7,8,8a-tetrahydro-furo[4,3,2- de ]quinoline (38), by expulsion of HCN or MeCN respectively, which constitute a new class of heterocyclic compounds. For the compounds IIIC and IIID the extrusion of HCN is favoured as compared to the extrusion of X-CH2CN. In case of IIIC this also gives a hitherto unknown class of heterocyclic ring systems namely 2H- 1,6,7,8,9,9a-hexahydro-4-phenyl-9a-R1-5-aza-1-oxo-benz[ c , d ]azulenes (39, 40). The reactivity of the compounds III towards the cycloaddition appears to be strongly influenced by the nature of the substituent R2 if R1 = H. However, if R1 = Me the effect of R2 on the reactivity was very small. The ratio of the products V and VI appears to depend mainly on the nature of -X-.

Pyridines being substituted at position 2 or 3 with a silylated propynyloxymethyl side-chain undergo a thermolytic intramolecular Diels-Alder reaction with formation of dihydroisobenzofurans. The 3-substituted pyridines are found to be more reactive than the 2-substituted ones. Substitution of both hydrogens in the methylene group at the (α-position of this side-chain by one methyl as well as one phenyl substituent leads to a considerable increase of the reaction rate. In a similar way, from the N-acetyl derivative of 3-trimethylsilyl-propynylaminomethylpyridine, the isoindoline system is formed. The rate of the reaction is considerably lower than that of the corresponding propynyloxymethyl derivative.

Quaternization of 3-(3-butynylthio) and 3-(4-pentynyltio) substituted 1,2,4-triazines with triethyloxonium tetrafluoroborate in CH2Cl2 at room temperature occurs exclusively at N-1 yielding 3-alkynylthio-1-ethyl-1,2,4-triazinium salts, as unequivocally shown by the 13C NMR and X-ray crystallographic data. 3-Alkynylthio-1-ethyl-5-phenyl-1,2,4-triazinium salts undergo the intramolecular Diels-Alder reaction into the corresponding thieno [2,3-b]- and thiopyrano [2,3-b]pyridines under considerably milder conditions than the corresponding neutral 1,2,4-triazines.

Milk xanthine oxidase was immobilized by covalent attachment to CNBr-activated Sepharose 4B and by adsorption to n-octylamine-substituted Sepharose 4B. The amounts of activity immobilized for the two preparations were 30 and 90%, respectively. The pH optima for free and adsorbed xanthine oxidase were at 8.6 and 8.2, respectively. Both free and immobilized xanthine oxidase show substrate inhibition. The apparent inhibition constant (Ki′) found for adsorbed xanthine oxidase with xanthine as substrate was higher than the Ki for the free enzyme, which was shown to be due to substrate diffusion limitation in the pores of the carrier beads (internal diffusion limitation). Higher substrate concentrations, as desirable for practical application in organic synthesis, can therefore be used with the immobilized enzyme without decreasing the rate. As a result of the internal diffusion limitation the apparent Michaelis constant (Km′) for adsorbed xanthine oxidase was also higher than the Km for the free enzyme. Immobilized xanthine oxidase was more stable than the free enzyme during storage at 4 and 30°C. Both forms rapidly lost activity during catalysis. The loss was proportional to the amount of substrate converted. Coimmobilization of xanthine oxidase with superoxide dismutase and catalase improved the operational stability, suggesting that O2− and H2O2 side-products of the enzymatic reaction were involved in the inactivation. Coimmobilization with albumin also had some stabilizing effect. Complete surrounding of xanthine oxidase by protein, however, by means of etrapment in a glutaraldehyde-crosslinked gelatin matrix, considerably enhanced the operational half-life. This system was less efficient than the Sepharose preparations either because much activity was lost during the immobilization procedure and/or because it had poor flow properties. Xanthine (15 mg)was converted by an adsorbed xanthine oxidase preparation and product (uric acid) was isolated in high yield (84%).

Rate and equilibrium constants for the dissociation of cyanide ion from 1-benzyl-4-cyano-1,4-dihydronicotinamide (BNA-CN) in acetonitrile at 25°C have been evaluated. Compared to water as the solvent, the dissociation constant in acetonitrile, K diss = 3.9(±0.6) × 10 −7 m , is approximately a factor 10 6 lower. This reduction is brought about by a nearly 10 2 slower rate of dissociation ( k 1 = 2.6 × 10 −4 s −1 ) and a 10 4 faster rate of addition of cyanide ion in acetonitrile. Addition of zinc salts, like zinc perchlorate, zinc bromide, and zinc iodide, induce cyanide ion dissociation by both entrapment of cyanide ion and efficient promotion of the cyanide ion expulsion. Remarkably, the latter effect is dependent on the nature of the zinc counterion and increases in the order ClO 4 − − − . It is concluded that the zinc-promoted cyanide expulsion is preceded by complex formation of zinc species with BNA-CN and that both Zn 2+ and monoionized Zn X + species are active. A transition state model for the reaction is proposed.

Several 4-R-1,4(or 3,4)-dihydropyrimidines (R = 2- or 3-thienyl, 2-furyl, 1-methylpyrrol-2-yl, and 3-pyridyl), containing heteroaryl vinyl methane units were shown to undergo photochemical rearrangement into 5-R-1,2(or 2,3)-dihydropyrimidines. These compounds were oxidized to yield 5-heteroarylpyrimidines. The chemical yields of the photorearrangement were found to be strongly dependent on the nature of the heteroaryl group.

Thermally induced intramolecular Diels-Alder cyclisations of (alkynyloxyalkyl)pyrazines to dihydropyranopyridines have been studied in the solvent undecane. The introduction of a phenyl group in the α-position of the 3-butynyloxymethyl side chain leads to a 3–4 fold increase of the reaction rate, while the influence of a γ-phenyl group on the rate is negligible. The (3-butynyloxymethyl)pyrazine reacts about 7 times slower than the (3-propynyloxyethyl)pyrazine, the presence of a trimethylsilyl group at the terminus of the alkyne decreases in general the rate of the intramolecular cyclisations. The mechanisms are discussed.

A facile synthesis of 2,6-naphthyridine is described. Both 2,6- and 2,7-naphthyridine undergo with potassium amide under kinetically and thermodynamically controlled conditions σ-adduct formation at position 1. Chichibabin amination of 2,6-naphthyridine yields 1-amino-2,6-naphthyridine in 54% yield.

The reaction of 5-aminopyrimidine with benzenediazonium chloride, p-methylbenzenediazonium chloride and p-bromobenzenediazonium chloride is described. The reaction leads to a mixture of compounds, i.e. 1-aryl-3-(pyrimidin-5-yl)triazene (6), 5-amino-4-aryl-6-arylazopyrimidine (7) and 4-aryl-6-arylazo-5-hydroxypyrimidine (8). The yields are found to be strongly dependent on the substituent present in the diazonium salt. Attempts to rearrange 1-(p-bromophenyl)-3-(pyrimidin-5-yl)triazene (6c) under basic and acidic conditions into a 1,2,3-triazole derivative failed.

5-Nitropyrimidine undergoes inverse Diels-Alder cycloadditions with ketene_N,N-, -O,O- acetals and enamines resulting in pyridine derivatives. The 1H NMR evidence for the 1 -N,N-diethyl-aminopropyne cycloadduct formation is presented.

A special section of the SNHreaction, notably Chichibabin aminations has been reviewed involving KNH2/NH3/KlVIn04system as an reagent for amino-dehydrogenation

Phosphitylation of the allylic hydroxy group in 9-tetrahydropyranyltrans-zeatine with salicyl chlorophosphite gives the allyl phosphonate monoester 5, which can be readily converted into the corresponding phosphate 7, methylphosphate 8 or thiophosphate 9. After cleavage of the tetrahydropyranyl group under mild acidic condition allylic phosphate derivatives of trans-zeatin are obtained.

Zinc 1-(α-2-methyl-1,10-phenanthroline)-1,4-dihydronicotinamide has been synthetized as a model for the enzyme-coenzyme complex of NADH-alcohol dehydrogenase. The model forms with 2-pyridinecarboxaldehyde a ternary complex in which the phenanthroline-bound zinc ion activates the aldehyde group for reduction. Transfer of a hydride equivalent in this complex occurs in an orientation in which the dihydronicotinamide ring lies over the carbonyl group with the carbonyl oxygen pointing to the ring nitrogen. Kinetic data for the reaction are given.

Prolonged illumination of 8-X-5-deazaflavins (X = C1, N(CH3)2, NH2, p-NH2-C6H4) in the presence of an electron donor leads to the formation of a 5,5′-dimer and/or a 6,7-dihydro compound. The course and rate of these photoreductions were established and discussed in terms of electronic and steric effects, exerted by the substituent at position 8 and the electron donor. Pseudo first-order kinetics were found to apply to the photoreduction of 8-X-5-deazaflavins (X = Cl, NH2, p-NH2-C6H4) while the rate of the photoreduction of 8-X-5-deazaflavin (X = N(CH3)2) appeared to contain an autocatalytic element. The catalytic effect of 8-X-5-deazaflavins in the photoreduction of methyl viologen by EDTA was investigated. The substituent effect on the rate of the 8-X-5-deazaflavin mediated photoreduction of methyl viologen by EDTA was found to be comparable with that on the photoreduction rate of 8-X-5-deazaflavin in the presence of EDTA with the exception of 8-X-5-deazaflavin (X = N(CH3)2), which showed a remarkable relative enhancement of the reactivity towards methyl viologen photoreduction.