2-chloroquinoline oxidation

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). 

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). 

The ortho indirect deactivating effect of the two methyl groups in 2,6-dimethyl-4-nitropyridine 1-oxide (163) necessitates a much higher temperature (about 195°, 24 hr) for nucleophilic displacement of the nitro group by chloride (12iV HCl) or bromide ions N HBr) than is required for the same reaction with 4-nitropyridine 1-oxide (110°). With 5-, 6-, or 8-methyl-4-chloroquinolines, Badey observed 2-7-fold decreases in the rate of piperidino-dechlorination relative to that of the des-methyl parent (cf. Tables VII and XI, pp. 276 and 338, respectively). 

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. 

That the formation of molecular complexes (especially EDA complexes) can catalyse the decomposition of the cr-adduct has been discussed in Section n.E. Another possibility is that the substrate and catalyst (nucleophile or added base) form a complex which is then attacked by a new molecule of the nucleophile in this context catalysis need no longer be associated with proton removal. Thus, Ryzhakov and collaborators183 have recently shown that the N-oxides of 4-chloropyridine and 4-chloroquinoline act as jt-donors toward tetracyanoethylene and that the reactions of these substrates with pyridine and quinoline are strongly catalysed by the jr-acceptor. Similarly, the formation of a Meisenheimer complex between 1,3,5-trinitrobenzene and l,8-diazabicyclo[5,4,0]undec-7-ene in toluene has been assumed to take place via an association complex to explain the observed second-order in tertiary amine184. 

Hamana et al.221 have described similar reactions with 4-chloroquinoline 1-oxide, (146) which is more reactive than 4-chloropyridine 1-oxide because of the activating effect of the benzo-fused ring. 

Chloropyridine N-oxide, AD79 8-Chloroquinaldine, AQ.82 6-Chloroquinoline, AO63... 

Suzuki coupling reaction of phenylboronic acids such as 74 with 4-bromopyridine [34]. Inada and Miyuara [35] have extended the method to 2-chloroquinoline 25. Therefore, the coupling between 25 and phenylboronic acid 74 led to 2-tolylquinoline 75 in 91% yield. The catalyst was recovered with ease and used in further coupling reactions. Not surprisingly, the couplings of phenylboronic acids with electron-rich chloroarenes were ineffective due to their slow oxidative addition to the palladium(O) complex. This reaction is an example where even quinolinyl chloride is a good substrate for the oxidative addition of Pd(0) if the chlorine atom is at the activated position (a or 8). 

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. 

Syntheses. The structure (LXXXI) of ricinine has been confirmed by several sjmtheses. The anhydride of 2,3-dicarboxy-4-chloropyridine, obtained by the oxidation of 4-chloroquinoline, is converted by means of ammonia to the monoamide (LXXXII). This is converted by the Hofmann reaction to the amine (LXXXIH) from which the hydroxy compound (LXXXIV) is obtained by diazotization. The action of phosphorusi oxychloride and phosphorus pentachloride on the hydroxy compound... 

A good example of the oxidative C-H carbon functionahzation of heteroaromatic A-oxide is the reaction of 4-chloroquinoline 1-oxide with pinacolone and f-BuOK in f-BuNH2 at —10 to —15 °C, which results in the formation of 4-chloro-2-pinacolylquinoline 1-oxide in good yield (Scheme 37) [75]. 

Spath (1923) plan for ricinine benzene ring in 4-chloroquinoline is oxidatively cleaved in step 6. 

Chlorination with POCI3 gave the corresponding 4-chloroquinolines 87 and 88. Subsequent nucleophihc aromatic substitution of the chlorine in 87 and 88 with 2-pyridylacetonitrile carbanion provided 89 and 90. Oxidation of the nitrile function of 89 and 90 with H2O2/ACOH mixture afforded 2-pyridyl-4-quinolylketones 91 and 92. The final reduction of the carbonyl group and the pyridine ring in 91 and 92 resulted in the syntheses of the 6-and 7-SF5 mefloquine analogs 83 and 84 (Scheme 23). 

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