Isoquinoline halogenation

Isoquinolines halogenated in the 1-position are particularly reactive towards S Ar replacement. For instance, 1,3-dichloroisoquinoline is selectively substituted in the 1-position by methoxide to form the 1-methoxy compound 8. Reductive dehalogenation also removes the 1-halogen substituent and produces 3-chloroisoquinoline 9 which, by a SnAt reaction with methoxide, yields 10 ... 

Although, in most cases, iodine is a fairly inert halogen (in contrast to bromine) and does not normally react with the substances that have been chromatographed there are, nevertheless, examples where chemical changes have been observed. Oxidations can evidently take place (e.g. aromatic hydrocarbons and isoquinoline alkaloids [252,253]) and additions and substitutions have also been observed. Pale zones then appear on a brown background. 

Halogenations of quinoline, isoquinoline, acridine, and phenanthridine will be discussed here. Reaction usually occurs in a homocyclic fused ring rather than in the 7r-deficient pyridine moiety, especially in acidic media. Relatively mild conditions suffice, but under more vigorous regimes radical involvement can result in heteroring halogenation. Substituents are able to modify reactivity and regiochemistry. 

Kobayashi and co-workers have described a new synthesis of a range of 1,4-disubstituted isoquinoline derivatives 117 <06S2934>. Initially, a lithium halogen exchange of 118 was performed to form 119, followed by treatment with a variety of nitriles 120 resulting in 1,4-disubstituted isoquinolines 117. 

The oxidative degradations of binuclear azaarenes (quinoline, isoquinoline, and benzodrazines) by hydroxyl and sulfate radicals and halogen radicals have been studied under both photochemical and dark-reaction conditions. A shift from oxidation of the benzene moiety to the pyridine moiety was observed in the quinoline and isoquinoline systems upon changing the reaction from the dark to photochemical conditions. The results were interpreted using frontier-orbital calculations. The reaction of OH with the dye 3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-(l,8)(2//,5//)-acridinedione has been studied, and the transient absorption bands assigned in neutral solution.The redox potential (and also the pA a of the transient species) was determined. Hydroxyl radicals have been found to react with thioanisole via both electron transfer to give radical cations (73%) and OH-adduct formation (23%). The bimolec-ular rate constant was determined (3.5 x lO lmoU s ). " ... 

Method of Nys and Rekker The Nys and Rekker method [53,54] has been developed for mono- and di-substituted benzenes. The substituents considered are halogen atoms and hydroxyl, ether, amino, nitro, and carboxyl groups, for which contributions have been calculated by multiple regression analysis (s = 0.106, r = 0.994, F = 1405). Rekker discusses the extension of his approach to other compound classes, such as PAHs, pyridines, quinolines, and isoquinolines. 

A variety of N-, 0- and 5-heterocyclic halides have been found to undergo the palladium-catalyzed al-kene substitution reaction. Halogen derivatives of furan, thiophene, pyridine, pyrazine, uracil, indole, quinoline and isoquinoline, for example, undergo the reaction. Iodoferrocene also reacts normally. 

The cathodic removal of one halogen radical from perhalogenated quinolines and isoquinolines 450) occurs with high selectivity ... 

For instance, both quinoline and isoquinoline undergo the Chichibabin reaction (with formal hydride elimination, see Chapter 5) to give 2-aminoquinoline 6.23 and 1-aminoisoquinoline 6.24 respectively. Halogen substituents ortho to the nitrogen atoms are easily displaced, as in the preparations of 6.25 and 6.26. 

The halogen atom of 2-(w-haloalkyl)-l,3,4,6,ll,lla-hexahydro-2//-pyrazino[l,2-fi]isoquinoline-l,3-diones was replaced by 4-substituted piperazines (88EUP2%048 90EUP378468). 

Microbiological transformation of laudanosine by the micro-organism Cunninghamella blakesleeana is accomplished by selective demethylation, to give i/f-codamine (19).29 Isoquinoline alkaloids that can be selectively halogenated can readily be converted into hydroxy-compounds by lithiation of the bromo-... 

Consideration of the halogenation of quinoline and isoquinoline is complicated by uncertainties relating to the mechanisms of reaction of the free base this applies particularly to quinoline. 

Under neutral conditions, the positional reactivity order for the halogenation of quinoline appears to be 3 > 6 > 8, whereas isoquinoline gives mainly 4-substitution. For isoquinoline, the fact that reaction occurs on the free base is adequate explanation for the change in orientation, since, contrary to common belief, the 4-position is shown by calculations and gas-phase studies of reactivity to be the most reactive in the neutral isoquinolines (see Section U.G.) indeed, more reactive than benzene. 

The reactions of the 4-halopyridines parallel those of the corresponding 2-isomers, with the exception that 4-halopyridines polymerize much more readily (e.g., to 923) because the pyridine nitrogen atom is not sterically hindered and is more nucleophilic (cf. Section 3.2.1.3.4). A halogen at the isoquinoline 1-position is more reactive than one at the 3-position thus, mild treatment of 1,3-dichloroisoquinoline with sodium ethoxide gives 924. Halogens at the 9-position of acridine are more reactive, e.g., 925 926, 927. 

The very fast metal-halogen exchange allows intramolecular cyclization reactions, which are known as Parham cyclizations171. The potential of Parham cyclizations as a useful stereoselective cyclization procedure has proven to be extremely interesting172. Thus, it has been recently demonstrated that iodinated IV-phenethylimides tolerate iodine-lithium exchange, giving rise to the isoquinoline nucleus 304, via a Parham-... 

This tends to weaken the hypothesis that halogenation at C-3 of quinoline and at C-4 of isoquinoline involves covalent intermediates of the type shown in 13 and 14. No spectral evidence for these hypothetical adducts has as yet been obtained for the parent heterocycles and the assumption that pyridinoid methiodides may involve covalent species86 has now been shown to be mistaken.26 The spectral shifts seem best explained by charge-transfer ion pairs [Eq. (18)] ... 

---