Halogenation of Quinolines

Finally, photolysis of 5-azidoquinoline (22) in hydrobromic acid resulted in the formation of both 6-bromo-5-aminoquinoline (23) and 8-bromo-5-aminoquinoline (24) in a 1 1 ratio (82H1043), The conversion may involve interesting intermediates such as an azirine and/or azacycloheptatetraene. 

Despite being activated by the nitrogen atom, 2-chloroquinoline (25) is still a poor substrate for the Stille cross-coupling reactions, though yields are usually improved under Negishi conditions. For instance, the coupling of 

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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. 

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. 

Halogenation. Direct halogenation of quinoline proceeds at the 2-position. Fluorination and bromination are known, but they proceed using forcing conditions (eqs 24 and 25). lodination proceeds under milder conditions, but requires an additional titanium-based reagent (eq 26). Chlorination of quinoline without prior activation has not been reported. 

Since various substituents are tolerated, the Friedlander reaction is of preparative value for the synthesis of a large variety of quinoline derivatives. The benzene ring may bear for example alkyl, alkoxy, nitro or halogen substituents. Substituents R, R and R" also are variable. The reaction can be carried out with various carbonyl compounds, that contain an enolizable a-methylene group. The reactivity of that group is an important factor for a successful reaction. 

Variable results have been reported for the halogenation of thieno[2,3-6]quinoline (123). Initial attack was mainly at the 3-position, but it was difficult to avoid the formation of 2,3-dihalogenated products, even when only 1 mol of halogen was used (predictions are for 2- and 3-substitution [77ZN(B)1331]). Bromine buffered in chloroform gave the 3-monobromo derivative, but analogous chlorination gave a mixture that included some... 

Halogen-metal exchange reactions in the carbocyclic rings of quinolines have also successfully been achieved, and all four possible types of lithio... 

Table 10 Halogenation of Amino-, Oxo- and Hydroxy-pyridines and -quinolines...

Iodoquinol (diiodohydroxyquin) is a halogenated hydroxy-quinoline. It is an effective luminal amebicide that is commonly used with metronidazole to treat amebic infections. Its pharmacokinetic properties are poorly understood. Ninety percent of the drug is retained in the intestine and excreted in the feces. The remainder enters the circulation, has a half-life of 11-14 hours, and is excreted in the urine as glucuronides. 

The direct halogenation of furan is unsatisfactory on a preparative scale, and halofurans are more conveniently prepared by the following methods (B-79M131200). Decarboxylation of halofurancarboxylic acids is usually carried out with copper and quinoline at 150-230 °C to yield the corresponding halofuran, which can be removed by distillation. 

The first step constitutes a che mo selective radical bromination of the methyl group in quinoline 10 using A-bromosuccinimide (33), leading to compound 34. Here benzoyl peroxide (32) acts as the radical initiator. A rule of thumb for chemoselectivity states that heat and light produce side-chain halogenation, whereas cold and catalysis favor halogenation of the aromatic nucleus. 

The multi-functionalized ketone A in Scheme 82 is reduced with an excellent ketone-selectivity with (R,R)-39 and a formic acid-(C2H5)3N mixture, affording (R)-B with 92% ee [321], The olefin, halogen atom, quinoline ring, and ester group are left intact. This product is a key intermediate in the synthesis of L-699,392 (LTD4 antagonist) [323],... 

To substantiate this mechanism, haloquinolines (75) were used. The strategy was to hinder sterically the addition of superoxide. In the case of 6-chloroquinoline, the products were the same as those formed from quinoline, except that they were chlorinated, which was expected because position 6 is not involved in either mechanism. Halogen substitution on the pyridine moiety in part directed oxygen addition to the benzene moiety, which was consistent with superoxide addition onto the more accessible positions on the benzene ring of the halogenated radical cation. This result supports the fact that a cycloaddition mechanism can take place in the photocatalytic degradation of quinoline. This mechanism has been proposed in the case of other aromatics, such as 4-chlorophenol (76) and 4-chloro-catechol (77). 

The nuclear-substituted halogens of aromatic /V-hetereocycles may also be susceptible to hydrogenolysis. In particular, those at the 2 and 6 positions of pyridines and at the 2 and 4 positions of quinolines are readily hydrogenolyzed, as shown in eqs. 13.129— 13.131. In the example shown in eq. 13.131, it was noticed that the rate of hydrogenolysis of the 4-chlorine was considerably greater than that of the 7-chlorine in the presence of an excess of alkali, and the selective dechlorination of the 4-chlorine was successful in an alcoholic solution containing 1.25 equiv of potassium hydroxide at room temperature and atmospheric pressure.240... 

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