1- Halo isoquinolines

Again the Sandmeyer reaction is frequently used to convert amino- to halo-isoquinolines. The diazonium salt of 5-amino-8-isoquinolinol (14) on treatment with potassium iodide and iodine gives the 5-iodophenol (15). Iodination of the hydrochloride of (15) with iodine monochloride in ethanol gives (16 Scheme 9) (66JMC46). 

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. 

A significant difference in this typical behaviour applies to the isoquinoline 3-position - the special reactivity that the discussion above has developed for positions a to pyridine nitrogen, and that also applies to the isoquinofine 1-position, does not apply at C-3. In the context of nucleophilic displacements, for example, an intermediate for reaction of a 3-halo-isoquinoline cannot achieve delocalisation of negative charge onto the nitrogen unless the aromaticity of the benzene ring is disrupted. Therefore, such intermediates are considerably less stabilised and reactivity considerably tempered. 

The main principle here is that halogen on the homocychc rings of quinoline and isoquinoline, and at the quinoline-3- and the isoquinohne-4 positions, behaves as would a halo-benzene. In contrast, 2- and 4-halo-quinolines and 1-halo-isoquinohnes have the same susceptibility as a- and y-halopyridines (see 8.3.2). 3-Halo-isoquinolines are intermediate in their reactivity to nucleophiles. ... 

An apparent exception to the relative unreactivity of 3-halo-isoquinolines is provided by the reaction of 3-bromoisoquinoline with sodium amide. Here, a different mechanism, known by the acronym ANRORC (Addition of Nucleophile, Ring Opening and Ring Closure), leads to the product, apparently of direct displacement, but in which a switching of the ring nitrogen to become the substituent nitrogen, has occurred. 

The carbonyl tautomers deprotonate at N-H, generating ambident anions that can react at either oxygen or nitrogen, depending on the exact conditions for example 0-alkylation can be achieved with silver carbonate. They are converted, as with the pyridones, into halo-quinolines and halo-isoquinolines by reaction with phosphorus halides. 

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... 

Pyrazolo[3,4-d][l,2]diazepines synthesis, 7, 597 Pyrazolop, 4- 6][ 1,4]diazepines synthesis, 5, 272 Pyrazolo[l, 4]diazepinones as anticonvulsant, 1, 170 Pyrazolo[2,3-e]diazepinones synthesis, 5, 272 1 H-Pyrazolo[l,5-6]imidazoles synthesis, 6, 992 Pyrazolo[2,3-a]imidazoles biological activity, 6, 1024 Pyrazolo[2,3-c]imidazoles reactions, 6, 1041 synthesis, 6, 1047 Pyrazolo[2,3-imidazoles synthesis, 6, 991 Pyrazolo[3,2- njisoquinolines synthesis, 5, 339 Pyrazolop, 4-c]isoquinolines synthesis, 5, 273 Pyrazolonaphthyri dines synthesis, 5, 339 Pyrazolone, diazophotolysis, 5, 252 Pyrazolone, 4,4-dihalo-rearrangements, 5, 250 Pyrazolone, ethoxy-hydrazinolysis, 5, 253 Pyrazolone, 4-halo-... 

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 halo-2-nitronaphthalenes (Table XIII) enable one to draw tentative conclusions about intranitclear and internitclear activation in the isoquinolines for which data are not available. These compounds are numbered so as to show their relation to their isoquinoline analogs. The relative rates are summarized in the following tabulation along with the ratio of the rates of piperidino-debromination to that of the appropriate bromonaphthalene (res. = resonance activation, ind. = inductive activation). 

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). 

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

The palladium-catalyzed intramolecular annulation of alkynes and /i r7-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals to produce isoquinoline and quinolines has been reported <2001JOG8042>. 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

Azine approach. Oxazolo[3,2-a]pyridinium salts (210) were first obtained from the cyclodehydration reaction of l-phenacyl-2(lii)-pyridinone in sulfuric acid (67JHC66). These salts can also be prepared from 2-halo-l-phenacylpyridinium derivatives (211) by treatment with a base which causes ylide formation and hence cyclization by intramolecular substitution (69JOC2129, 76CB3646). It is recommended that a bulky tertiary amine is used as base in order to avoid opening of the ring or substitution of the 2-halo substituent in the starting material (211). Isoquinoline and quinoline analogues have also been prepared by these methods. 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids. Aside from 5-chloro- and 3-acetylaminomethylquinoline and a few halo, methyl, and carbomethoxyisoquinolines, all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline... 

According to their IR and UV spectra, l-halo-3-hydroxyisoquinolines exist in the solid state predominantly in the lactim form. 1-Unsubstituted 3-hydroxyisoquino-lines exist in methanolic solution at 20 °C in the lactim-lactam equilibrium with 48-58% of the lactam form (74LA1802). l-Alkyl-3-oxo-6,7-dimethoxy-7V-(2 -ami-nophenyl)isoquinoline perchlorates 33 were found to exist in the lactim form shown with a hydrogen bond between the amino and hydroxy groups (76KG238). 

The t-butylimines of o-iodobenzaldehydes and 3-halo-2-alken-l-ones can be reacted with terminal alkynes in the presence of a Pd/Cu catalyst to afford isoquinolines and pyridines in a process which apparently involves aryl alkyne formation, followed by cyclization with fragmentation of the f-butyl group (Eq. 18) [51,52]. 

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