Isoquinolines nucleophilic substitution

Chemical Properties. The presence of both a carbocycHc and a heterocycHc ring faciUtates a broad range of chemical reactions for (1) and (2). Quaternary alkylation on nitrogen takes place readily, but unlike pyridine both quinoline and isoquinoline show addition by subsequent reaction with nucleophiles. Nucleophilic substitution is promoted by the heterocycHc nitrogen. ElectrophiHc substitution takes place much more easily than in pyridine, and the substituents are generally located in the carbocycHc ring. 

Isoquinoline, l-(dimethylamino)-methylation, 2, 179 Isoquinoline, halo-lithium derivatives, 2, 363 Isoquinoline, 3-halo-nucleophilic substitution, 2, 59 Isoquinoline, l-halo-3-hydroxy-synthesis... 

Chichibabin reaction, 5, 409-410 UV spectra, 5, 356 Naphthimidazoles, 2-amino-tautomerism, 5, 368 Naphth[2,3-h]imidazoles oxidation, 5, 405 Naphth[l,2-d]imidazolium salts nucleophilic substitution, 5, 412 Naphth[l, 2-h]isoquinolines... 

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. 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

Nucleophilic substitution occurs exclusively at position 1 in isoquinoline the alternative position C-3 is quite unreactive. This is explained by the loss of... 

Several further publications report on the (—)-sparteine-mediated addition of alkyl-or aryllithium onto imines or the C=N bond of isoquinolines . Usually, the achieved enantiomeric excesses are low and, sometimes, other chiral ligands serve better. As reported by Muller and coworkers, the nucleophilic substitution of arenecarbaldehyde dialkyl acetals by o-substituted aryllithium reagents is an alternative . 

Nucleophilic substitutions Nucleophilic substitutions in quinoline and isoquinoline occur on the pyridine ring because a pyridine ring is more... 

Electron density calculations suggest that electrophilic attack in pyridine (42) is favored at C-3, whereas nucleophilic attack occurs preferentially at C-2 and to a lesser extent at C-4. Cytochrome P-450 mediated ring hydroxylation of pyridine would, therefore, be expected to occur predominantly at C-3, the most electron-rich carbon atom. Although 3-hydroxypyridine is an in vivo metabolite in several species, the major C-oxidation product detected in the urine of most species examined was 4-pyridone (82MI10903). The enzyme system catalyzing the formation of this latter metabolite may involve the molybdenum hydroxylases and not cytochrome P-450 (see next paragraph). In the related heterocycle quinoline (43), positions of high electron density are at C-3, C-6 and C-8, while in isoquinoline (44) they are at C-5, C-7 and C-8. Nucleophilic substitution predictably occurs... 

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... 

Quinoline and isoquinoline undergo nucleophilic substitution reactions, like pyridine. 

This type of chemistry is also observed with 1-methyl isoquinoline 6.28. However 3-methyl isoquinoline is much less activated because delocalisation of charge in 6.29a,b involves disruption of aromaticity of the benzenoid ring. This phenomenon is closely related to the reluctance of 3-halo isoquinolines to undergo nucleophilic substitution. 

Again, as expected, pyridine A-oxides are very susceptible to nucleophilic attack. Unlike the situation usually prevalent with the quaternary pyridinium salts, the elimination stage of the two-step nucleophilic substitution can occur with relative ease, the oxide grouping serving as a good sink for the leaving hydride ion electron-pair and being itself eliminated in the process. Considerably more work has been carried out on quinoline and isoquinoline A-oxides than on pyridine A-oxide derivatives. 

Quinoline forms part of quinine (structure at the head of this chapter) and isoquinoline forms the central skeleton of the isoquinoline alkaloids, which we will discuss at some length in Chapter 51. In this chapter we need not say much about quinoline because it behaves rather as you would expect—its chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring. So nitration of quinoline gives two products—the 5-nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinoline. 

Af-Methyl-jV-(l-methylpropyl)-l(2-fluoro-5-nitrophenyl)isoquinoline-3-carboxamide, 323, possessing high affinity and selectivity for PBBS (peripheral-type benzodiazepine binding sites)312 in living man, has been labelled313 with n.c.a. fluorine-18, obtained via lsO(p, n)18F nuclear reaction, by an aromatic nucleophilic substitution process (equation 139). (n.c.a. = no carrier added)... 

Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles with activated pyridines [69, 70]. The first examples of this chemistry involved either 77-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal alkynes as activating agents in a one-step protocol. The reaction proceeds under mild conditions that include AI2O3 catalysis. Quinolines 1 and chloroformates afford the expected adducts 68. The latter structures can be easily oxidized with O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates obtained this way have been used in Wittig-Homer chemistry. The whole sequence offers ready access to alkyl substituted isoquinolines [71]. Analogously, sUyl substituents have been introduced into A-acylated pyridines by using silylcuprates [72]. 

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