Synthesis of 4-alkoxy-8-hydroxyquinolines

Article abstract of DOI:10.1021/jo062175i

(Chemical Equation Presented) Quinolines with a hydroxyl group at the 8-position and an alkoxy group at the 4-position are rare compounds. In this paper the synthesis of five 4-alkoxy-8-hydroxyquinolines is reported. The key reaction in the synthetic rout

Full text of DOI:10.1021/jo062175i

Synthesis of 4-Alkoxy-8-hydroxyquinolines†
Juha P. Heiskanen, Walaa A. E. Omar, Mari K. Ylikunnari, Kirsi M. Haavisto,
Maria J. Juan, and Osmo E. O. Hormi*
Department of Chemistry, UniVersity of Oulu, P.O. Box 3000, 90014 Oulu, Finland
osmo.hormi@oulu.fi
ReceiVed October 19, 2006
Quinolines with a hydroxyl group at the 8-position and an alkoxy group at the 4-position are rare
compounds. In this paper the synthesis of five 4-alkoxy-8-hydroxyquinolines is reported. The key reaction
in the synthetic route is a selective protection of the hydroxyl group at C-atom 8 in 4,8-dihydroxyquinoline
with a tosyl group and the hydrolytic removal of the protective group after the alkylation. The tosyl
group is stable during the alkylations with various alkylating agents in the presence of sodium hydride.
Introduction
shown that the 8-hydroxyl group of 4,8-dihydroxylquinoline can
be alkylated prior to the alkylation of the hydroxyl group at the
4-position. The yield of the alkylated compound was low, and
moreover it was not proven that the alkyl group at 8-position
can be removed without a simultaneous removal of the alkyl
group at 4-position. In this paper, we describe a selective
protection of the 8-hydroxyl group in 4,8-dihydroxyquinoline
with an easily removable tosyl group. The protected compound
can be synthesized in an almost quantitative yield and was
found to be stable enough in the consequent alkylation step.
The stability of the tosyl group in 4-hydroxy-8-tosyloxyquinoline
can be utilized to produce 4-alkoxy-8-tosyloxyquinolines that
undergo hydrolysis in an alkaline environment readily to afford
4-alkoxy-8-hydroxyquinolines. Potentially, 4-hydroxy-8-tosyl-
oxyquinoline can also serve as a starting material in the synthe-
sis of other 4-position heteroatom functionalized 8-tosyl-
oxyquinolines and their derivatives.7
Substituted quinoline compounds can be found in many
applications. In medicine they have attracted interest as anti-
malarial drugs1 and therapeutic drugs for inflammatory diseases.2
Quinolobactin, a naturally occurring quinoline, has been identi-
fied as a siderophore that pseudomonas produce to complex
iron.3
Other important applications of 8-hydroxyquinolines deriva-
tives such as tris(8-hydroxyquinoline) aluminum (Alq3) exploit
their unique electronic characteristics, and considerable attention
has recently been focused on their potential utility as electron
transporter and light-emitting layer in organic light-emitting
devices (OLEDs).4 A computer simulations for Alq3 has
predicted that its optical properties can be modified by changing
the substitution pattern of 8-hydroxyquinoline. Particularly, an
electron-donor group at C-atom 4 of 8-hydroxyquinoline
increases the intrinsic luminescence yield.5
Protection of the functional group is required frequently when
a chemical reaction is to be carried out selectively at one reactive
site in a multifunctional compound. Previously6 it has been
Results and Discussion
The commercially available xanthurenic acid 1 was decar-
boxylated to give 4,8-dihydroxyquinoline 2 in a excellent (96%)
yield8 (Scheme 1).
The hydroxyl group at the 8-position was easily deprotonated
by using a 1:1 molar ratio of NaOH to the diol 2. The tosyl
† Contribution from the Empart group of Infotech Oulu.
(1) Novak, I.; Kovac, B. J. Org. Chem. 2004, 69, 5005.
(2) Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.; Asano,
M.; Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. J. Med. Chem. 2004, 47,
2853.
(3) (a) Pierre, J.; Baret, P.; Serratrice, G. Curr. Med. Chem. 2003, 10,
1077. (b) Mossialos, D.; Meyer, J. M.; Budzikiewicz, H.; Wolff, U.;
Koedam, N.; Baysse, C.; Anjaiah, V.; Cornelis, P. Appl. EnViron. Microbiol.
2000, 66, 487.
(5) Curioni, A.; Andreoni, W. IBM J. Res. DeV. 2001, 45, 101.
(6) Dempcy, R. O.; Kutyavin, I. V.; Mills, A. G.; Lukhtanov, E. A.;
Meyer, R. B. Nucleic Acids Res. 1999, 27, 2931.
(7) Synthetic procedure to produce other 4-position-substituted 8-tosyl-
oxyquinoline, and its derivatives will be published during our future work.
(4) Tang, C. W.; Van Slyke, S. A. Appl. Phys. Lett. 1987, 51, 913.
10.1021/jo062175i CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/04/2007
920
J. Org. Chem. 2007, 72, 920-922

Synthesis of 4-Alkoxy-8-hydroxyquinolines
SCHEME 1
SCHEME 4
SCHEME 2
the amount of alkylating reagent or solvent was changed. Both
alkylated products could be separated by flash chromatography.
The other alkoxylated tosyloxyquinolines 4b-e were also
prepared by using the NaH deprotonation of the tosylated
quinolinol 3 followed by subsequent treatment of the sodium
salt with alkyl halides in DMF (Scheme 3) to afford the products
4b-d in good yields (74-78%) and 4e in a moderate 56% yield.
The formation of any N-alkylated products could not be detected
in the reactions between the bulky alkyl halides and the sodium
salt of 3. An excess of alkyl halide was found to be necessary
in order to obtain a time efficient alkylation.
SCHEME 3
Treatment of 4-alkoxy-8-tosyloxyquinolines 4a-e with so-
dium hydroxide in a water/alcohol mixture followed by neu-
tralization with hydrochloric acid gave the final 4-alkoxy-8-
hydroxyquinolines 5a-e (Scheme 4) in good yields (72-79%).
group was then attached to the monosodium salt of the diol 2
in 95% yield by using p-toluenesulfonyl chloride in a water/
acetone solution9 (Scheme 2). The protection reaction was found
to be easily scaled up. The structure of the protected compound
4-hydroxy-8-tosyloxyquinoline 3 was actually found to be 3b
Conclusions
Commercially available xanthurenic acid can be effectively
decarboxylated to give 4,8-dihydroxyquinoline. Selective pro-
tection of the 8-hydroxyl group with p-toluenesulfonyl chloride
gives 4-hydroxy-8-tosyloxyquinoline in a high yield, and the
compound can be used as a starting material to produce
4-alkoxy-8-tosyloxyquinolines. The protective tosyl group can
easily be removed by hydrolysis to afford 4-alkoxy-8-hydroxy-
quinolines in good yields.
1
instead of 3a. The H NMR spectrum of 3 showed clearly a
coupling between the N-H proton and the proton at C-2.
The next step in our synthetic scheme was the alkylation of
the compound 3 with various alkylating agents. NaH was used
as a base to deprotonate the 4-hydroxyl group of the quinoline
(Scheme 3).10
To produce 4a, tosylated quinoline 3 was reacted with NaH
to afford the corresponding sodium salt of 3. Methyl trifluo-
romethanesulfonate was then added to the salt to give the
O-methylated quinoline 4a in a moderate 47% yield. Also the
N-methylated quinoline 4f was formed during the treatment of
the sodium salt with methyl trifluoromethanesulfonate. Attempts
to increase the amount of O-alkylated product 4a by changing
the solvent from DMF to the nonpolar cyclohexane gave rise
to the formation of the N-methylated quinoline exclusively.11
In DMF the ratio between the N-methylated quinoline 4f and
the O-methylated quinoline 4a was 1:10, varying slightly when
Experimental Section
4,8-Dihydroxyquinoline (2). Xanthurenic acid 1 (15.0 g, 73.1
mmol) was added to diphenylether (150 mL) at 235 °C. The mixture
was stirred at 240-250 °C under N2 for 2.5 h. The mixture was
cooled and diluted with high-boiling petroleum ether (180 mL).
The precipitate was filtered and washed with petroleum ether to
provide 2 (11.3 g, 96%) as a crude product, which was used in the
next step without further purification. For analysis a small amount
of the crude product was recrystallized from ethanol. Mp: 321 °C12.
IR (KBr): ν 3400, 3345, 3043, 2957, 2461 (br), 1788, 1623 cm-1
.
1H NMR (400 MHz, DMSO-d6): δ 6.06 (1H, d, J ) 7.3 Hz), 7.07-
7.15 (2H, m), 7.56 (1H, dd, J ) 7.9 Hz), 7.78 (1H, d, J ) 7.0 Hz),
10.88 (1H, br s), 11.39 (1H, br s). 13C NMR (100 MHz, DMSO-
d6): δ 109.1, 114.7, 115.2, 123.5, 127.4, 131.0, 139.3, 147.2, 177.4.
HRMS: calcd for C9H8NO2 ([M + H]+) 162.0555, found 162.0567.
4-Hydroxy-8-tosyloxyquinoline (3). 4,8-Dihydroxyquinoline 2
(7.00 g, 43.4 mmol) was dissolved in sodium hydroxide solution
(1 M, 45.9 mL, 45.9 mmol). The clear solution was cooled to room
temperature, and p-toluenesulfonyl chloride (8.28 g, 43.4mmol) in
(8) Our initial route to prepare 2 involved the use of the Gould-Jacobs
reaction of substituted anilines with diethyl ethoxymethylenemalonate.
Unfortunately, cyclization led to less than 30% yield, and all attempts to
improve the yield were unsuccesful. For a review of Gould-Jacobs reaction,
see: Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890.
(9) (a) Morita, J.-I.; Nakatsuji, H.; Misaki, T.; Tanabe, Y. Green Chem.
2005, 7, 711. (b) Ouchi, M.; Inoue, Y.; Liu, Y.; Nagamune, S.; Nakamura,
S.; Wada, K.; Hakushi, T. Bull. Chem. Soc. Jpn. 1990, 63, 1260.
(10) Our initial effort to alkylate tosylated quinoline 3 involved the use
of potassium carbonate, potassium iodide, and alkyl halide according to
the general method of the Claisen O-alkylation. With that method, alkylation
products 4b,d were obtained in moderate yields.
(12) Grandjean, D.; Dhimane, H.; Pommelet, J.-C.; Chuche, J. Bull. Soc.
Chim. Fr. 1989, 5, 657 reports a melting point of 197 °C; however, the
melting point differs strongly from our melting point, 320 °C, which is
much closer to the melting point of 2,4-dihydroxyquinoline, 355 °C: CRC
Handbook of Chemistry and Physics, 62nd ed.; Weast, R. C., Ed.; CRC
Press Inc.: Boca Raton, FL, 1982.
(11) An opposite effect of solvents is seen in alkylation of 2-pyridone:
Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. J. Org.
Chem. 1967, 32, 4040.
J. Org. Chem, Vol. 72, No. 3, 2007 921

Heiskanen et al.
acetone (15 mL) was slowly added to the solution. The mixture
was stirred for 3 h. Water (50 mL) was added, and the precipitate
was filtered off and washed with water (80 mL) and acetone
(80 mL). The title compound 3 (13.0 g, 95%) was obtained as a
powder. The crude product was used directly in the next step
without further purification. For analysis a small amount was
recrystallized from ethanol as white crystals. Mp: 237 °C. IR
132.9, 142.3, 145.2, 145.8, 152.6, 161.8. HRMS: calcd for C17H16-
NO4S ([M + H]+) 330.0800, found 330.0799.
N-Methyl-8-tosyloxyquinolin-4-one (4f). In the described reac-
tion above the title compound formed in the ratio 1:10 to
O-alkylated product. For analysis a small amount was purified with
flash chromatography (10 mL methanol/1.5 L 1:1 acetone/n-
1
hexane). Mp: 156 °C. IR (KBr): ν 3068, 2965, 1627 cm-1. H
(KBr): ν 3052, 2941, 2883, 1644 cm-1 1H NMR (200 MHz,
.
NMR (400 MHz, DMSO-d6): δ 2.42 (3H, s), 3.91 (3H, s), 6.06
(1H, d, J ) 7.8 Hz), 7.20 (1H, dd, J ) 7.8 Hz), 7.30 (1H, t, J )
7.9 Hz), 7.48 (2H, d, J ) 8.4 Hz), 7.75 (2H, d, J ) 8.3 Hz), 7.82
(1H, d, J ) 7.8 Hz), 8.14 (1H, dd, J ) 8.0 Hz). 13C NMR (100
MHz, DMSO-d6): δ 21.7, 45.3, 109.7, 123.6, 125.7, 127.1, 128.9
(2C), 129.7, 130.9 (2C), 131.3, 135.3, 138.3, 147.1, 148.3, 175.5.
HRMS: calcd for C17H15NO4NaS ([M + Na]+) 352.0619, found
352.0652.
DMSO-d6): δ 2.38 (3H, s), 6.05 (1H, d, J ) 7.5 Hz), 7.28 (1H, t,
J ) 7.9 Hz), 7.39-7.45 (3H, m), 7.73 (1H, t, J ) 6.6 Hz), 7.81
(2H, d, J ) 8.3 Hz), 8.00 (1H, dd, J ) 7.9 Hz), 11.50 (1H, d, J )
4.9 Hz). 13C NMR (100 MHz, DMSO-d6): δ 21.6, 109.8, 123.0,
124.3, 124.4, 127.7, 129.2 (2C), 130.5 (2C), 131.0, 133.6, 138.5,
140.4, 146.8, 177 (carbonyl C-atom signal in the 13C NMR spectrum
is visible in its 2D HMBC spectrum). HRMS: calcd for C16H14-
NO4S ([M + H]+) 316.0644, found 316.0648.
General Procedure for Synthesis of 4-Alkoxylated 8-Hydroxy-
quinoline. Preparation of 4-Methoxy-8-hydroxyquinoline (5a).
4-Methoxy-8-tosyloxyquinoline 4a (819 mg, 2.49 mmol), sodium
hydroxide (1 M, 7.50 mL, 7.50 mmol), and methanol (15 mL) were
refluxed for 4 h.14 The solution was cooled to room tempetature,
and the pH was adjusted with hydrochloric acid (1 M) to 7.2. The
mixture was concentrated in vacuo, and water (20 mL) was added.
The precipitate was filtered and washed with water. Recrystalli-
zation from ethanol gave the product 5a (325 mg, 75%) as off-
white crystals. Mp: 118 °C. IR (KBr): ν 3262 (br), 3023, 2938,
2841 cm-1. 1H NMR (200 MHz, DMSO-d6): δ 4.00 (3H, s), 6.99-
7.09 (2H, m), 7.36 (1H, t, J ) 8.0 Hz), 7.52 (1H, dd, J ) 8.2 Hz),
8.66 (1H, d, J ) 5.2 Hz), 9.62 (1H, br s). 13C NMR (50 MHz,
DMSO-d6): δ 56.9, 102.2, 112.0, 112.4, 122.3, 127.4, 140.1, 150.0,
154.0, 162.6. HRMS: calcd for C10H10NO2 ([M + H]+) 176.0712,
found 176.0690.
General Procedure for Synthesis of 4-Alkoxylated 8-Tosyl-
loxyquinoline with NaH as Base. Synthesis of 4-Methoxy-8-
tosyloxyquinoline (4a). NaH (176 mg, 7.33 mmol) in 60% oil
dispersion was washed with cyclohexane or n-pentane (5 mL), and
4-hydroxy-8-tosyloxyquinoline 3 (1.50 g, 4.76 mmol) in dimeth-
ylformamide (30 mL) was added. The mixture was stirred at room
temperature until H2 evolution was completed, and methyl trifluo-
romethanesulfonate (0.78 mL, 7.11 mmol) was slowly added under
N2. After 2 h the reaction mixture was poured into water (200 mL)
and allowed to stand at room temperature overnight. The precipitate
was collected by filtration and washed with water. The final
purification by flash chromatography13 (10 mL methanol/1.5 L 1:1
acetone/n-hexane) afforded the title compound (738 mg, 47%) as
off-white crystals. Mp: 127 °C. IR (KBr): ν 3029, 2954, 2849
1
cm-1. H NMR (400 MHz, DMSO-d6): δ 2.37 (3H, s), 4.02 (3H,
Acknowledgment. The authors thank Mrs. Pa¨ivi Joensuu
for high-resolution mass spectrometric data.
s), 7.05 (1H, d, J ) 5.5 Hz), 7.40 (2H, d, J ) 8.4 Hz), 7.47-7.55
(2H, m), 7.82 (2H, d, J ) 8.4 Hz), 8.06 (1H, dd, J ) 8.4 Hz), 8.66
(1H, d, J ) 5.2 Hz). 13C NMR (100 MHz, DMSO-d6): δ 21.6,
56.8, 102.4, 121.3, 122.7, 122.8, 125.7, 128.8 (2C), 130.3 (2C),
Supporting Information Available: Experimental procedures
and spectroscopic data of compounds 4b-e and 5b-e and IR, 1H
NMR, 13C NMR, and high resolution mass spectra for all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) Silica gel with 0.040-0.063 mm particle size was used as a support
in every flash chromatography purification procedures.
(14) In other hydrolysis reactions ethanol was used instead of methanol
to help dissolution.
JO062175I
922 J. Org. Chem., Vol. 72, No. 3, 2007