3-substituted 2-chloroquinolines

Acetanilides 92 are converted into 3-substituted 2-chloroquinolines 93 by DMF/POCI3 (Meth-Cohn synthesis [102]). The a-methylene group in the anilide 92 first undergoes a ViLSMElER reaction. This is followed by an S Ar cyclization with amine elimination to give the 2-quinolone 94 which, under the conditions of the reaction, is converted into 93 ([103], cf p 312) ... 

The Meth-Cohn quinoline synthesis provides a versatile and reliable entry in to 3-substituted 2-chloroquinolines. In several cases, the Meth-Cohn reaction plays a pivotal role for the preparation of biological important compounds as in the synthesis of E-ring modified derivatives of camptothecin or for the syntheses of selected NMDA antagonists with analgesic activity. ... 

Dichlorocarbene generated under phase transfer catalytic conditions adds to a variety of substituted indoles to give an adduct (see Sect. 2.7 and Eq. 2.25) which undergoes ring expansion resulting in the production of substituted chloroquinolines. Similar reactions with substituted pyrroles yield substituted chloropyridines. 

Amina.tlon, 2-Antinoquinoline [580-22-3] is obtained from quinoline in 80% yield by treatment with barium amide in Hquid ammonia (19). This product, as weU as 3-aminoquinoHne [580-17-6] and 4-antino quinoline [578-68-7], maybe obtained through nucleophilic substitution of the corresponding chloroquinolines with ammonia. 

The arylation of morpholinocyclohexene with 2- or 4-chloroquinoline N-oxide or 4-chloropyridine N-oxide and benzoyl chloride led to cyclohexanone a-substituted with the respective chloroquinolines or 4-chloropyridine (691). 2,4-Dinitrofluorobenzene reacted with 2-benzylidene-3-methylbenzothiazoline to give the enamine arylation product (672). 

Added in proof. To emphasize the comparisons with naphthalene, the reaction center of each series studied has been called the 1-position. For example, in the methoxy-dechlorination of substituted 4-chloroquinolines the position to which the chlorine atom is attached is the 1-position and the nitrogen atom is the 4-position this is in contrast to conventional numbering, where the nitrogen atom is always 1. 

Illuminati et al. have also investigated the methoxydechlorination of 4-substituted-2- and 2-substituted-4-chloroquinolines. The relation between the reaction site, the 2- or 4-position, and the substituent in the 4- or 2-position, respectively, is always meta. The authors found the two reaction series well correlated with one another, but diverging quite seriously from the Hammett correlation. They concluded that mesomerically electron-donating substituents, because of the importance of resonance structures like 12 and 13, are more deactivating than expected, while electron-withdrawing substituents, and even the methyl group, seem to follow normal a correlation. 

Fig. 3. Correlation of reactivity data (logfc) for the methoxy-dechlorination of meto-substituted 2- and 4-chloroquinolines.

The reactivities of 4- and 2-halo-l-nitronaphthalenes can usefully be compared with the behavior of azine analogs to aid in delineating any specific effects of the naphthalene 7r-electron system on nucleophilic substitution. With hydroxide ion (75°) as nucleophile (Table XII, lines 1 and 8), the 4-chloro compound reacts four times as fast as the 2-isomer, which has the higher and, with ethoxide ion (65°) (Table XII, lines 2 and 11), it reacts about 10 times as fast. With piperidine (Table XII, lines 5 and 17) the reactivity relation at 80° is reversed, the 2-bromo derivative reacts about 10 times as rapidly as the 4-isomer, presumably due to hydrogen bonding or to electrostatic attraction in the transition state, as postulated for benzene derivatives. 4-Chloro-l-nitronaphthalene reacts 6 times as fast with methanolic methoxide (60°) as does 4-chloroquinoline due to a considerably higher entropy of activation and in spite of a higher Ea (by 2 kcal). ... 

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. 

Alteration of the relative reactivity of the ring-positions of quinoline is expected and observed when cyclic transition states can intervene. Quinoline plus phenylmagnesium bromide (Et20,150°, 3 hr) produces the 2-phenyl derivative (66% yield) phenyllithium gives predominantly the same product along with a little of the 4-phenylation product. Reaction of butyllithium (Et 0, —35°, 15 min) forms 2-butylquinoline directly in 94% yield. 2-Aryl- or 6-methoxy-quinolines give addition at the 2-position with aryllithium re-agents, and reaction there is so favored that appreciable substitution (35%) takes place at the 2-position even in the 4-chloroquinoline 414. Hydride reduction at the 2-position of quinoline predominates. Reaction of amide ion at the 2-position via a cyclic... 

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

Electronegative groups do not invariably prevent nuclear bromination, but reaction conditions must be much more severe, and the orientation of substitution may be affected by the substituent. Thus 6-nitroquinoline was brominated in sulfuric acid at 100°C to give the 8-bromo product (71) in 51% yield 8-methyl-5-nitroquinoline gave a 69% yield of the 7-bromo derivative (72) under similar conditions, whereas 7-chloroquinoline was transformed into the 5-bromo product (93%) (88CHE892) (Scheme 35). In a sealed tube reaction with bromine, 8-nitroquinoline gave a mixture... 

Also, the influence of substituents in the meta and para positions of the benzoyl radical is in accordance with the polar character of the substituent. The rates for 4-cyanoquinoline relative to 4-chloroquinoline with meta- and para-substituted benzoyl radicals were obtained. Plots of log cn/ ci vs. a of the substituents in the benzoyl radical gave a Hammett correlation p was found to be —0.49, implying that the effect of the substituent is small, much smaller than the effect of the substituents in the heteroaromatic substrate. 

Exhaustive chlorination of quinoline over antimony pentachloride leads to fragmentation into perchlorobenzene and hexachloroethane (1882JCS412). Direct uncatalyzed chlorination of quinoline at 160-190 °C gives at least five chloroquinolines (Scheme 29) among the ten products of reaction detected by gas chromatography (70JHC171). Substitution at position... 

The trend observed with the polycyclic hydrocarbons (see preceding section), namely that the product radical anions (ArNu ) are more stable than those derived from the simple benzene analogs, is even more evident with the heteroaromatic substrates and, as a consequence, fragmentation processes are minimized.41 For example, 2-chloroquinoline is the only substrate of many studied to undergo a substitution reaction with PhCH2S- ion without fragmentation of the benzyl-S bond,103 and to react with diphenyl-arsenide ion without scrambling of the aryl moieties.25... 

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