6-Methoxyquinoline 1-oxide

A soln. of 6-methoxyquinoline 1-oxide hydrate in chloroform dried with Na-sulfate, filtered, coned, to ca. half its volume, cooled, henzoyl chloride followed by AgGN added with water-cooling and stirring, which is continued 4 hrs. at room temp., then refluxed 1 hr. on a water bath 2-cyano-6-methoxyquinoline. Y 84%. F. e. s. G. Kaneko, E. Ochiai et al., Ghem. Pharm. Bull. 8, 487, 286 (I960). 

A soln. of 4-picolinoyl-6-methoxyquinoline 1-oxide in anhydrous chloroform satd. with dry HCl-gas, POCI3 added, and heated 1.5 hrs. at 73-75 under anhydrous conditions 2-chloro-4-picolinoyl-6-methoxyquinoline (Y 96%) suspended in 15%-H2S04, and refluxed 3.5 hrs. 4-picolinoyl-6-methoxy-carbostyril (Y 93%). F. e. s. M. Takahashi, Chem. Pharm. Bull. 14, 1144 (1966). 

Methoxyquinoline is regioselectively oxidized at the methyl group by a chelate-directed palladium-catalyzed C-H bond activation <2004JA2300>. 8-Methylquinoline is selectively oxidized at the methyl position on treatment with palladium(ll) acetate followed by the oxidant phenyliodinium diacetate in acetic acid. The reaction proceeds via formation of a palladacycle (Scheme 4). Performing the reaction in methanol leads to isolation of 8-(methoxy-methyl)quinoline in 77% yield. 

The preparation of 3,1-benzoxazepines by photochemical isomerization of quinoline A-oxides constitutes a rather general entry into this class of seven-membered heterocycles. Since the structure of the photoisomer of 2-phenylquinoline A-oxide was first recognized as 2-pheny 1-3,1-benzoxazepine by Buchardt et al.,3 the scope of this method for oxidative ring expansion of six-membered heterocyclic A-oxides to 1,3-oxazepines has been extensively explored.4 For example, irradiation of 2-cyano-, 2-phenyl-, and 2-methoxyquinoline A-oxides affords the corresponding 2-substituted 3,1-benzoxazepines in 70-90% yield.5 However, isolation of the moisture-sensitive parent compound was only recently accomplished in the submitters laboratories.6... 

Disposition in the Body. Readily absorbed after oral administration. It is extensively metabolised by oxidation to carboxyprimaquine which is the major plasma metabolite. Other reactions which may occur are demethylation and oxidation to the 5,6-diol, which is then converted to an active quinone, V-dealkylation to 8-amino-6-methoxyquinoline, and iV-acetyla-tion. Less than 5% of a dose is excreted in the urine unchanged in 24 hours. 

Narasimhan et al. (194) instituted a new approach to the synthesis of furoquinoline alkaloids by introducing a C2 side chain into a preformed quinoline nucleus. Lithiation of 2,4-dimethoxyquinoline, 2,4,6-tri-methoxyquinoline, and 2,4,8-trimethoxyquinoline with n-butyllithium in ether and subsequent reaction with ethylene oxide furnished hydroxyethyl derivatives 237, which with 20% hydrochloric acid were converted into dihydrodictamnine (239), dihydropteleine (240), and dihydro-y-fagarine... 

On treatment of both quinoline and pyridine /V-oxides with bromine and thallium(iil) acetate, y-bromo-derivatives are formed pyridine JV-oxides are the less reactive substrates/ The reaction of 8-methoxyquinoline iV-oxide with acetic anhydride and methanol yields 84% of 2,8-dimethoxyquinoline. Similarly, the reaction of the 6-methoxy-iV-oxide and ethanol and acetic anhydride gives 2-ethoxy-6-methoxyquinoline, but, under the same conditions, the 7-methoxy-N-oxide is unchanged/ The Reissert compounds (149) derived from substituted quinolines, on treatment with thallium(lll) nitrate and trimethyl orthoformate, undergo either smooth ring-contraction or oxidative debenzoyl-ation, depending on the substitution pattern in the aromatic ring (Scheme 61)/ ... 

II), and also its isomer (III), but foimd that neither substance was identical with galipine. Moreover, neither 7-methoxyquinoline-4-car-boxylic acid (I) nor the -2-carboxylic acid was identical with the oxidation product CiiH(OtN. 

In seeking a further clue to the structure of the alkaloids, Sp th and Brunner recognized the significance of the isomerization of cusparine and galipine by methyl iodide. This type of rearrangement is characteristic of 2- and 4-methoxyquinolines (4, 25). The oxidation product ci galipine was not identical with the known 2-methoxyquinoline-4-... 

Methoxyquinoline 77-oxide and 3-bromoquinoline 77-oxide were reacted with phenylacetylene under the same reaction conditions to give the desired ethynylquinoline derivatives in 84% and 47% yields, respectively. The reaction of isoquinoline 77-oxide with phenylacetylene gave 1 -phenylethynylisoquinoline in 70% yield. The interaction of 4-phenylpyridine 77-oxide with phenylacetylene also proceeded smoothly to give 2-phenylethynyl derivative in 77% yield (Scheme 32) [72]. 

Dowers TS, Jones JP (2006) Kinetic isotope effects implicate a single oxidant for cytochrome P450-medi-ated O-dealkylation, N-oxygenation, and aromatic hydroxylation of 6-methoxyquinoline. Drug Metab Dispos 34 1288-1290... 

Methoxyquinoline-W-oxide, owing to the 7T-donating substituent, undergoes H/D exchange readily giving deuteration at the 5- and 7-positions. ... 

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. ... 

Quinoline-A/-oxides can be readily converted to 2-aikoxyquinolines or 2-quinalones. 6-Methoxyquinoline-A/-oxide readily furnishes 2-ethoxyquinoline in the presence of acetic anhydride and ethanol (eq A) The 2-quinolone can be readily obtained by conducting the reaction in the presence of f-butyl alcohol and subsequent hydrolysis under acidic conditions or by quenching with ammonium hydroxide (eq 5). 6-Methoxyquinoline-Al-oxide is considerably less reactive than unsubstituted quinolines. 

Similarly, amines can be installed at the 2-position of 6-methoxyquinoline-iV-oxide. Addition of t-butylamine in the presence of toluenesulfonic anhydride furnishes 2-substituted quinoline, which can be converted to the primary amine by treat-... 

P5Tidine-A-oxides and their derivatives have recently been shown to undergo direct alkylation under paUadiumcatalysis when treated with alkyl bromides. 6-Methoxyquinoline-lV-oxide coupled efficiently to furnish the 2-cyclohexyl-substituted product (eq S)P... 

A related copper-catalyzed dehydrogenative coupling of amines and quinoline-lV-oxides has recently been described. Interestingly, no added oxidant was required to affect the transformation and oxygen from the atmosphere was proposed to act as a terminal oxidant (eq 11). 6-Methoxyquinoline-lV-oxide proved to be a challenging substrate for this reaction, giving the desired product in 27% yield. 

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