Naphthalene and isoquinoline

The reaction of nitronaphthalenes and nitroisoquinolines with dimethyl phosphite in MeONa/MeOH (equation 27), proceeded via nucleophilic substitution of hydrogen according to a redox stoichiometry and gave substituted dimethyl naphthalene- and isoquinoline-phosphonates and benzazepines.214... 

As mentioned, naphthylisoquinoline alkaloids are structurally unusual on account of the methyl group at the 3-position and oxygenation at the 8- and/or 6-position of the isoquinoline ring which points to a polyketide origin. This postulate has been supported by extensive studies conducted by Btingmann on the in vitro biomimetic synthesis of the naphthalene and isoquinoline portions of these compounds (ref. 13,14) and this work is worth briefly mentioning in a discussion on the total synthesis of these compounds. 

It was proposed that both the naphthalene and isoquinoline moieties of these compounds could arise from a common polyketide precursor 9 (Scheme I). Aldol condensation of 9 could provide diketone 10 or a reduction/aldol sequence could provide the C-6 deoxygenated analogue... 

Additional strong evidence of the chemical plausibility of joint in vivo formation of both naphthalenes and isoquinolines from common p-polycarbonyl precursors was obtained from the in vitro imitation of the proposed biosynthetic pathway in the laboratory. These model reactions, which simultaneously allowed first total syntheses of naphthyl isoquinoline alkaloids, are depicted in Section V. 

Following the postulated biogenetic pathway (see Scheme 3), a chemical in vitro imitation, aiming at a biomimetic first synthesis of naphthyl isoquinoline alkaloids, had to consist of essentially four crucial steps (1) synthesis of suitable P-polycarbonyl precursors, (2) their primary cyclization to monocyclic diketones like 31 or 32, (3) the further differentiation to naphthalenes and isoquinolines, and (4) their mixed coupling to the complete natural alkaloids. 

C. Naphthalenes and Isoquinolines from Joint Biosynthetic Precursors... 

Replacing one carbon atom of naphthalene with an a2omethene linkage creates the isomeric heterocycles 1- and 2-a2anaphthalene. Better known by their trivial names quinoline [91-22-5] (1) and isoquinoline [119-65-3] (2), these compounds have been the subject of extensive investigation since their extraction from coal tar in the nineteenth century. The variety of studies cover fields as diverse as molecular orbital theory and corrosion prevention. There is also a vast patent Hterature. The best assurance of continuing interest is the frequency with which quinoline and isoquinoline stmctures occur in alkaloids (qv) and pharmaceuticals (qv), for example, quinine [130-95-0] and morphine [57-27-2] (see Alkaloids). 

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

Both of these approaches have been attempted, and both are substantially equivalent for heterocyclic (e.g. quinoline and isoquinoline) and homocyclic (naphthalene) systems. Consequently, in the subsequent discussion it is fruitful to include the available work on naphthalene derivatives. In the case of the fused six-membered rings, Eq. (3) is not applied because it does not permit treatment of the 5- and 8-positions, and the available series as a whole are too short to make this treatment useful. 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

The rate of amination and of alkoxylation increases 1.5-3-fold for a 10° rise in the temperature of reaction for naphthalenes (Table X, lines 1, 2, 7 and 8), quinolines, isoquinolines, l-halo-2-nitro-naphthalenes, and diazanaphthalenes. The relation of reactivity can vary or be reversed, depending on the temperature at which rates are mathematically or experimentally compared (cf. naphthalene discussion above and Section III,A, 1). For example, the rate ratio of piperidination of 4-chloroquinazoline to that of 1-chloroisoquino-line varies 100-fold over a relatively small temperature range 10 at 20°, and 10 at 100°. The ratio of rates of ethoxylation of 2-chloro-pyridine and 3-chloroisoquinoline is 9 at 140° and 180 at 20°. Comparison of 2-chloro-with 4-chloro-quinoline gives a ratio of 2.1 at 90° and 0.97 at 20° the ratio for 4-chloro-quinoline and -cinnoline is 3200 at 60° and 7300 at 20° and piperidination of 2-chloroquinoline vs. 1-chloroisoquinoline has a rate ratio of 1.0 at 110° and 1.7 at 20°. The change in the rate ratio with temperature will depend on the difference in the heats of activation of the two reactions (Section III,A,1). 

Hiickel 4n -r 2 rule and, 523-524 imidazole and, 529 Indole and. 533 ions and,525-527 isoquinoline and, 533 naphthalene and, 532 polycyclic aromatic compounds and,531-532 purine and, 533... 

Nitrogen. Pyridine is one of the most important heterocycles. The aromaticity of pyridine was intensively connected to structural considerations and chemical behavior. The relative difference between the aromaticity of benzene and pyridine is controversial generally calculations give similar orders of magnitude and differences depend on the criterion of aromaticity considered and the mode of calculation used. A comprehensive review on the theoretical aspects in connection with the aromaticity of pyridine was published.191 Pyridine is about as aromatic as benzene according to theoretical calculations and to experimental data, while quinoline is about as aromatic as naphthalene and more aromatic than isoquinoline.192193 The degrees of aromaticity of pyridine derivatives strongly depend on their substituents. 

Based on the carbon shifts of naphthalene as reference, nitrogen increments can be derived for quinoline and isoquinoline as is shown in Table 4.84. These increments are... 

Table 4.84. Nitrogen Increments in Quinoline and Isoquinoline Relative to Naphthalene [73] (a) Application of these increments to Quinazoline (b) and 2,7-Naphthyridine (c).

Benzo[6]thiophene forms continuous solid solutions with molecules of similar molecular geometry (e.g., indene, indole, or isoquinoline), but eutectics with molecules of significantly different geometry (e.g., 3-methylisoquinoline, 2-methyl- and 2,6-dimethylnaphthalene, or dibenzothiophene).197,198 Naphthalene and benzo[6]thiophene form a system of limited solid solutions,54,199 which accounts for the difficulties encountered in their separation (see Section II, B). 

Heterocyclic systems. Pyridine exhibits an absorption spectrum very similar to that of benzene with an additional absorption band at 270 nm which is assigned to the transition involving the nitrogen lone pair. Similarly quinoline and isoquinoline have spectral profiles closely analogous to naphthalene. 

Quinoline and isoquinoline can also be viewed as being formally derived from naphthalene... 

The importance of steric strain arising from benzo fusion in pyridines was first estimated by Packer and Wong (58JA905) in quaternization of methyl-substituted quinolines and isoquinolines. They used the strained homo-morph concept of Brown (53JA1) to approximate strains existing in naphthalene compounds of similar geometry (e.g., 1-methylquinoline and 1-methylnaphthalene) (Scheme 8). 

Scheme 11.5. Net deactivation at the nonconjugated positions of quinoline and isoquinoline relative to naphthalene, in terms of a values.

Fluorescence spectra of analytical and pharmaceutical interest arise from functionally substituted aromatic molecules, particularly those derived from benzene, naphthalene, and anthracene or their heteroaromatic analogs pyridine, quinoline, isoquinoline, and acridine. 

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