5- Chloroquinoline

Foumeau, Trefouel, and Wancolle, Bull. aoc. chim. France, (4), 47, 742 (1930). 

One hundred and ten grams of concentrated sulfuric acid is added in small portions to a mixture of 52 g. (0.41 mole) of o-chloroaniline, 

Succinimide (4.95 g., 0.05 mole) is dissolved in a mixture of 6 ml. of glacial acetic acid and 15 ml. of water and cooled to a point until the separation of solid just starts. To this solution is added all at once 57 ml. of an 8% aqueous solution of potassium hypochlorite which has been cooled to 0°. The mixture is shaken and allowed to stand in ice water for 1 hour. The precipitated N-chlorosuccinimide is filtered off, washed with ice water, and dried in vacuum over sulfuric acid. The yield is 5.7 g., or 85%. 

Zinc dust (120 g.) is added (30 minutes) with stirring to a mixture of 72 g. (0.34 mole) of p-chlorobenzenesulfonyl chloride (p. 72), 

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A quinoline—bromine adduct in hot carbon tetrachloride containing pyridine gives a 90% yield of 3-bromoquinoline (21) 3-chloroquinoline [612-59-9] is prepared by an analogous route, but in poorer yield. A quinoline—aluminum chloride complex heated with bromine gives a 78% yield of 5-bromoquinoline [165-18-3] (22). Equal quantities of 5- and 8-bromoquinoline [16567-18-3] are formed when quinoline is treated with one equivalent of bromine in concentrated sulfuric acid containing silver sulfate (23). 

Ciamician and Dennstedt reacted the potassium salt of pyrrole with chloroform in ether and isolated, after much purification, 3-chloropyridine, which was confirmed by crystallization with platinum. While the pyrrole salt can be used as the base, the chloroform carbene is typically formed with an alkali alcohol. Forty years later, Robinson and co-workers made 3-chloroquinolines from indoles using the Ciamician-Dennstedt reaction. ... 

To a stirred solution of 2,3-dimethyl indole (6, 1.45 g, 10 mmol, 1.0 equiv) and tetra-n-butylammonium sulfate (3.40g, 10 mmol, 1.0 equiv) in chloroform (150 mL) was added potassium hydroxide (50% aqueous solution, 20 mL) over 30 minutes. The stirring was continued for six hours, at which time the mixture was extracted with chloroform, the chloroform-water mixture was washed with water, and the organic layer concentrated. Silica gel chromatography provided 2,4-dimethyl-3-chloroquinoline (7, 1.52 g, 79% yield). 

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)]. 

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). 

Chloro-2-hydroxypyridine-3-carboxylate is a terminal metabolite in the degradation of 3-chloroquinoline-8-carboxylate, but can be degraded by Mycobacterium sp. strain BA to chlorofumarate by reactions analogous to those described above for pyridine carboxylates (Figure 10.18) (Tibbies et al. 1989a). 

Tibbies PE, R Muller, F Lingens (1989b) Microbial metabolism of quinoline and related compounds. III. Degradation of 3-chloroquinoline-8-carboxylic acid by Pseudomonas spec. EKIII. Biol Chem Hoppe-Seyler 310 1191-1196. 

Indole can be reacted with dichiorocarbene to yield 3-chloroquinoline (Scheme 7.12). Initially, the carbene adds across the C-2-C-3 double bond to form a cyclopropanoindole this product then ring expands with elimination of hydrogen chloride cf. pyrrole. Section 6.1.3). 

The reaction of pyrrole with dichlorocarbene, generated from chloroform and strong base, gives a bicyclic intermediate which can be transformed to either 3-chloropyridine (155) or pyrrole-2-carbaldehyde (156). Indole gives a mixture of 3-chloroquinoline (157) and indole-3-carbaldehyde (158). The optimum conditions involve phase transfer (76S249, 76S798). Benzofuran reacts with dichlorocarbene in hexane solution to give the benzopyran (159), whereas benzothiophene fails to react. 

In addition to acyclic and monocyclic enamines, bicyclic and tricyclic enamines also undergo cycloaddition with dihalocarbenes. Endocyclic enamines , such as pyrrole and indole, add dichforocarbene and the adducts rapidly undergo ring cleavage to afford 3-chloropyridine and 3-chloroquinoline, respectively, in moderate yields (c/. Section 4.7.3.9).75-77... 

The S Ar reaction between 2-chloroquinoline 25 and trimethylstannyl sodium led to 2-trimethylstannylquinoline 41 as shown previously. Similarly, 3-trimethylstannyl quinoline 49 and 4-trimethylstannyl quinoline 51 were prepared from 3-chloroquinoline 48 and... 

Indoles show little inclination to undergo cycloadditions. The [2+1] cycloaddition with dichlorocar-bene leads to mixtures of indole-3-carbaldehyde and 3-chloroquinoline (see p 334). 

Indoles yield 3-chloroquinolines by addition of dichlorocarbene and HCl elimination (see p 101). A number of ring enlargement reactions of isatins into quinolines are known (as example, see the Pfitzinger synthesis, p 328, and [107/108]). 

The Ciamician—Dennstedt reaction involves the addition of intermediate dihalocarbene, generated from haloforms (CHX3, X = Cl, Br, or I) and a strong base, to a pyrrole (330) to form an unstable dihalogenocyclopropane, which rearranges to a 3-halogenopyridine such as 331. The reaction was expanded for indoles to provide 3-chloroquinolines. ... 

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 dropwise method gives the results as listed in TABLE VIII. In the absence of CyD, the formylation gives a considerable amount of 3-chloroquinoline as by-product. In the presence of B-CyD, indole-3-aldehyde is obtained 95% yield and 100% selectivity, [11]. 

The ternary inclusion complex of indole, 3 CyD and dichlorocarbene is probably formed in the reaction mixture as shown in Fig. 7. Dichlorocarbene attacks at 3-position to yield indole-3-aldehyde. In the absence jjCyD, dichlorocarbene adds to 2,3- double bond of pyrrole ring. Then, the five-membered ring expands to six-membered ring, resulting 3-chloroquinoline. 3-CyD inhibits sterically the 2,3-double bond addition followed by ring-expansion. 

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