2-Chloroquinoline nucleophilic substitution

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 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). ... 

Photoassisted heteroaromatic nucleophilic substitution reactions of various carbanion nucleophiles with 2-bromopyridine, iodobenzene, bromobenzene, bromomesitylene, and 2-chloroquinoline in KNH2-liquid NH3 have also been compared.27... 

Nucleophilic substitution most readily occurs at the 2- and 4-position of the more electron-deficient heterocyclic ring of quinolines. However, SNAr reactions at the carbocyclic ring can occur, mainly at positions 5 and 7. 5,7-Dibromo-8-hydroxyquinoline, 5-bromo-8-hydroxyquinoline, and 7-bromo-8-hydroxy-5-methylquinoline undergo conversion to the corresponding chloroquinolines on treatment with neat pyridine hydrochloride at 220 °C in a process that is postulated to proceed via the formation of stabilized Meisenheimer complexes <1996TL6695> (Equations 20 and 21). 

The halogen atom in 4-chloroquinoline-N-oxides is highly activated toward nucleophilic substitution. From the only examples reported for the thienopyridine analog81 (64), it is clear that reaction does not occur particularly readily it seems likely that electron release from the thiophene ring reduces the activating influence of the N-oxide group. 

Turning to bicyclic systems, and a study of reaction with ethoxide, a small increase in the rate of reaction relative to pyridines was found for chloroquinolines at comparable positions.In the bicyclic compounds, quaternisation again greatly increases the rate of nucleophilic substitution, having a larger effect ( 10 ) at C-2... 

Likewise, 2-chloroquinoline reacts considerably faster than 4-chloro-quinoline in nucleophilic substitution reactions, and Illuminati and his colleagues ( ) refer to this phenomenon as the a-aza effect. 

Hamana, M., Iwasaki, G., and Saeki, S., Nucleophilic substitution of 4-chloroquinoline 1-oxide and related compounds by means of hydride elimination. Heterocycles, 17, 177, 1982. 

With Me3Sn ion, only compounds in which chloride is the leaving group, like p-chloroanisole, 1-chloronaphthalene, /7-dichlorobenzene and 2-chloroquinoline, do not react by an HME mechanism. They react by the S l mechanism to give good yields (70-100%) of substitution products (equation 115). 2-chloroquinoline reacts in the dark in a reaction which is partially inhibited by /7-DNB. /7-Bromoanisole and presumably all the aryl bromides and iodides react with this nucleophile by an HME mechanism. 

Enolate ions derived from /3-dicarbonyl compounds are unreactive toward 2-chloroquinoline even under photolytic conditions.10 However, the dilithium salt of benzoylacetone does react by an SrnI mechanism with 2-chloroquinoline. The less substituted carbon atom of the dianion is the nucleophilic site 43 forms.109 ... 

Nucleophilic aromatic substitution of 4-chloroquinolines is known to proceed in the... 

Table 19. Relative rates in homolytic t-butylation of 3-(a)- and 4-(b)-X-substituted pjrridines, in nucleophilic methoxydechlorination of 4-(c)-X-substituted-2-chloroquinoline and amination of l-Cl-2-N02-4-(d)- and 5-(e)-X-benzenes with piperidine...

The potential advantage of the Sr I mechanism is that it is not particularly sensitive to the nature of other aromatic ring substituents, although electron-attracting substituents favor the nucleophilic addition step. For example, chloropyridines and chloroquinolines are also excellent reactants. A variety of nucleophiles undergo the reaction, although not always in high yield. The nucleophiles that have been found to participate in Sr I substitution include ketone enolates, 2,4-pentanedione dianion, amide enolates, pentadienyl... 

As is t) ical with heterocyclic A -oxides, 6-methoxyquinoline-A -oxide reacts with nucleophiles under acidic conditions to give substitution at the 2- or 4-position. One of the earlier examples of this reactivity is the chlorination with POCI3 (or SO2CI2). 6-Methoxyquinoline-W-oxide furnishes 2- and 4-chloroquinoline in a 1 0.63 ratio (eq 2), with lower selectivity than electron-deficient quinoline-A -oxides, which favor the 4-position. ... 

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