Chloroquinolines

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

Illuminati et al. have also investigated the methoxydechlorination of a series of 2-chloroquinoxahnes. Since p-values for the 2- and 4-chloroquinolines differ and since no p-values for 3-chloro compounds are available, direct calculation of bicyclic values obtained from the methoxydechlorination of the 2-chloroquinolines (cf. Table VII), which is seen to be excellently linear, with a p-value of 4.55, somewhere between the values for the 2-and 4-chloroquinoline series. From this p-value, [Pg.251]

Illuminati and Marino reported an interesting example of the dependence of solvent effects on the position of the reacting center relative to the aza group. The rate constants for the reaction of 2- and 4-chloroquinoline with piperidine were compared in three different solvents, methanol, piperidine, and toluene. These data are reported in Table III. Three main points are apparent from these data (a) the different response of the two substrates to the action of the solvent, (b) the rates for 2-chloroquinoline in the three solvents tend to cluster around the highest reactivity level shown by 4-chloroquinoline in... 

Like the chloronitrobenzenes, a chloroquinoline reacts faster with sodium p-tolylsulfide when the chloro group is para to the aza-group than when it is orthoy the factor involved being about 10. However, a strikingly different behavior is noted in the much lower BS-/ BO- ratio which is 2.5 for 4-chloroquinoline ( para isomer) and 0.24 for 2-chloroquinoline ( ortho isomer). For p-chloronitro-benzene this ratio is 38, and for 2,4-dinitrochlorobenzene it is 1950. Thus far there is no case in which the reaction of a chloronitrobenzene derivative with sodium methoxide is faster than that with sodium phenylsulfide. 

The incompleteness of the other data precludes generalization. However, a few apparent inconsistencies may be indicated to stimulate further research. Insertion of another aza group into 2-chloroquinoline causes the reactivity sequence o >m (reaction with piperidine) or, even, o reaction with CgHsO"), involving only relatively small factors and, in any case, in sharp contrast with the above-mentioned effects on 2-chloropyridine as a substrate. Further, meta-aza activation in all cases involving the ethoxide ion is fairly strong suggest-... 

Two closely related series are 2-chloroquinoline and 2-chloro-quinoxaline, and the 6- and 7-substituents in both series are of the... 

Fig. 6. The Hammett plot for the methoxy-dechlorination of meto-substituted 2-chloroquinolines.

Alkyl Groups. In the class of non-conjugative positions, the observed order of the deactivating effect of the methyl group is meta > pros (2-chloroquinoline), and the fall-off factor is 1/1.3 in this case. The fall-off factor is near unity if the effects from the meta position and the conjugative cata positions are compared (4-chloroquinoline), which indicates that the deactivating effect orders are cata > epi and amphi > pros as predicted by the benzenoid order para > meta. 

Indirect deactivation by an alkoxy group is apparent in the sluggish reaction of 4-butoxy-2-chloroquinoline with w-butylamine (EtOH, 5 hr, 180°, but not at 80°). The chloro group in 2-chloro-4-ethoxy-quinoline is more reactive than that in the 4-chloro-2-ethoxy isomer toward alkoxides or amines in spite of the usually more effective para indirect deactivation in the former. For kinetic data on quinolines see Tables X and XI, pp. 336 and 338, respectively. 

When an azine-nitrogen and a leaving group are in the 2,3-relation to each other in monoaza- and polyaza-naphthalenes, there is a dramatic effect on the reaction rate (for 3-chloroisoquLnoline lO -lO -fold less than for its 1-chloro isomer and for 2-chloroquinoline 200-400-fold less than for 2-chloropyridine) due to restrictions imposed on the resonance stabilization of charge in the transition state by the bicyclic system ... 

The monoazanaphthalenes provide a good illustration of the effect of henzo-fusion onto an azine and of the variation of the effect with the position of fusion. A benzo ring can be fused onto 2-chloro-pyridine at the 3,4- [leading to 1-chloroisoquinoline (393)], at the 4,6- [forming 3-chloroisoquinoline (394)], or at the 5,6-position [yielding 2-chloroquinoline (395)]. The first and the last fusions... 

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). 

The effect of solvent on the rate, E, and dS can be derived from the data on haloquinolines and their A-oxides (Tables X and XI), on halonitronaphthalenes (Tables XII and XIII), and on halodinitro-naphthalenes (Table XVI). Depending on the nature of the reaction, the relative reactivity of two compounds can be substantially different in different solvents. For example, piperidination of 2-chloroquinoline (Table X, lines 3 and 4) compared to 2-chloroquinoxaline (Table XV,... 

Chloroquinoline (401) reacts well with potassium fluoride in dimethylsulfone while its monocyclic analog 2-chloropyridine does not. Greater reactivity of derivatives of the bicyclic azine is evident also from the kinetic data (Table X, p. 336). 2-Chloroquinoline is alkoxylated by brief heating with methanolic methoxide or ethano-lic potassium hydroxide and is converted in very high yield into the thioether by trituration with thiocresol (20°, few hrs). It also reacts with active methylene carbanions (45-100% yield). The less reactive 3-halogen can be replaced under vigorous conditions (160°, aqueous ammonia-copper sulfate), as used for 3-bromoquino-line or its iV-oxide. 4-Chloroquinoline (406) is substituted by alcoholic hydrazine hydrate (80°, < 8 hr, 20% yield) and by methanolic methoxide (140°, < 3 hr, > 90% yield). This apparent reversal of the relative reactivity does not appear to be reliable in the face of the kinetic data (Tables X and XI, pp. 336 and 338) and the other qualitative comparisons presented here. 

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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