6-Bromo-4-chloroquinoline

Under conditions more similar to those of the Reimer-Tiemann reaction 3-bromopyridine was obtained from pyrrole and bromo-form. Treatment of pyrrole with chloroform and aqueous alkali gave pyrrole-2-aldehyde curiously, the formation of 3-chloropyridine under these conditions does not appear to have been reported, in spite of being frequently quoted. However, indole gave both indole-3-aldehyde and 3-chloroquinoline under these conditions [Eq. (10)]. 

Finally, these reactions do not seem to be appreciably dependent on the structure of the substrate since methoxy- and ethoxy-dehalogen-ation in their respective alcohols proceed at nearly the same rate with each of the substrates, 2- and 4-chloroquinoline and 2-bromo-pyridine. ... 

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). ... 

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... 

Dilithio-fS-carboline (89), which was generated from 1-bromo-P-carboline, undergoes the Negishi coupling with 2-chloroquinoline to form the alkaloid nitramarine (90) [111]. 

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). 

A popular method to prepare haloquinolines is the halogenation of quinolones using oxyphosphorus halides, most notably POCI3. The carbonyl can be located either at the C(2) or the C(4) positions. As depicted in Scheme 1, the C(2) position of quinolone 4 was chlorinated with POCI3 to give 6-bromo-2-chloroquinoline (5) [1]. The subsequent S Ar displacement of the chlorine substituent on 5 with sodium methoxide led to 6-bromo-2-methoxyquinoline. Analogously, chlorination at the C(4) position of quinolones is exemplified by transformations 6 7 [2] and 8 9 [3]. 

Yamamoto and Yanagi [24] have prepared iodoazines through iodo-destannation of trimethylstannylazines. Trimethylstannyl sodium was prepared in situ from chlorotrimethyl-stannane and metallic sodium. Subsequent treatment of 2-chloroquinoline 25 with trimethylstannyl sodium gave 2-trimethylstannylquinoline 41. Likewise, 3- and 4-trimethyl-stannyl quinolines 42 and 44 were converted to 3- and 4-iodoquinolines 43 and 45 in 96 and 91% yield, respectively via iodo-destannation. In the same fashion, 2,4-bis (trimethylstannyl)quinoline was synthesized from 4-bromo-2-chloroquinoline using two equivalents of trimethylstannyl sodium in 65% yield. 

Bromo and 3-chloroquinolines were prepared unexpectedly when the synthesis of quinolines via the addition of an alkyl Grignard to an o-trifluoroacetylaniline was quenched with hydrohalic acid (Scheme 53). The reaction requires a copper chloride catalyst. Interestingly, both cuprous and cupric chloride worked to form the 3-chloroquinolines when mixed with 1.5 equivalents of hydrochloric acid. Anilines with different groups were tolerated well under these reaction conditions. The electronic nature... 

The known intermediate 6-bromo-2-chloroquinoline-3-carbaldehyde (17) was prepared from 4-bromoacetamilide using a modified Vilsmeier-Haack protocol. Homer-Wadsworth-Emmons olefmation of 17 with the lithium enolate of phosphonate (Et0)2P(0)CH2C02Et afforded a,P-unsaturated ester 18 in 89% yield with complete E-selectivity. 

Chandrasekhar s approach takes 10 linear steps with a 12% overall yield from the known intermediate 6-bromo-2-chloroquinoline-3-carbaldehyde (17). 

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