Synthesis of 8-hydroxyquinolines with amino and thioalkyl functionalities at position 4

Article abstract of DOI:10.1002/jhet.5570450247

(Chemical Equation Presented) Six 8-hydroxyquinolines with amino and thioalkyl functionalities at position 4 have been prepared. The synthesis starts with chlorination of the readily available 4-hydroxy-8-tosyloxyquinoline to give 4-chloro-8-tosyloxyquinoline in 94% yield. Treatment of the 4-chloro-8-tosyloxyquinoline with sulphur and nitrogen nucleophiles produces the target 4-amino and 4-thioalkyl-8-hydroxyquinolines in more than 70% yield. In case of sulphur nucleophiles and pyrrolidine, the removal of the protecting tosyl group at position 8 occurs simultaneously with the substitution of chlorine at position 4.

Full text of DOI:10.1002/jhet.5570450247

Mar-Apr 2008
593
Synthesis of 8-Hydroxyquinolines with Amino and Thioalkyl
Functionalities at Position 4
Walaa A. E. Omar, Juha P. Heiskanen and Osmo E. O. Hormi∗
Department of Chemistry, University of Oulu P. O. Box 3000, 90014 Oulu, Finland
Osmo.hormi@oulu.fi
Received April 17, 2007
Cl
N
R
N
N
N
R =
N
N
,
,
,
,
N
CH3
OTs
OH
S-n-Pr
S-i-Pr ,
S-n-Bu
Six 8-hydroxyquinolines with amino and thioalkyl functionalities at position 4 have been prepared. The
synthesis starts with chlorination of the readily available 4-hydroxy-8-tosyloxyquinoline to give 4-chloro-
8-tosyloxyquinoline in 94% yield. Treatment of the 4-chloro-8-tosyloxyquinoline with sulphur and
nitrogen nucleophiles produces the target 4-amino and 4-thioalkyl-8-hydroxyquinolines in more than 70%
yield. In case of sulphur nucleophiles and pyrrolidine, the removal of the protecting tosyl group at position
8 occurs simultaneously with the substitution of chlorine at position 4.
J. Heterocyclic Chem., 45, 593 (2008).
INTRODUCTION
After chlorination of 1 [11], 4-chloro-8-tosyloxy-
quinoline 2 was allowed to react with different nitrogen
and sulphur nucleophiles.
The reaction between 2 and pyrazole or 3-methyl-
pyrazole in toluene produced 4-pyrazolyl-8-tosyloxyquin-
oline 4 in 83% yield and 4-(3-methylpyrazolyl)-8-tosyl-
oxyquinoline 5 in 81% yield respectively (Scheme 2).
Quinoline derivatives are widely used in many
applications, in medicine they are used in the treatment of
inflammatory diseases [1] and also are very well known as
antimalarial drugs [2-5].
8-Hydroxyquinolines are also involved in the structures
of some electrically important materials, such as Alq3,
which is commonly used as an emitter in OLED’s due to
its excellent electronic properties [6-10].
Scheme 2. General route for the synthesis of
4-pyrazolyl -8-hydroxyquinolines.
In our previous work [11], we succeeded to produce 4-
alkoxy-8-hydroxyquinolines from 4,8-dihydroxyquinol-
ine by protecting the hydroxyl group at position 8 and
carrying out the desired alkylation reactions on position 4
to give 4-alkoxy-8-tosyloxyquinoline.
In our present work we have chlorinated 4-hydroxy-8-
tosyloxyquinoline and reacted the chlorinated product
with various nitrogen and sulphur nucleophiles to produce
rare 8-hydroxyquinolines with amino or thioalkyl groups
at position 4.
R
R
N
Cl
N
N
N
N
N
N
N
R
H
N
(1)NaOH
(2)HCl
Toluene
OTs
OH
OTs
2
6, R = H
7, R = Me
4, R = H
5, R = Me
RESULTS AND DISCUSSION
4-Pyrazolyl-8-hydroxyquinoline 6 and 4-(3-methyl-
pyrazol)yl-8-hydroxyquinoline 7 were produced from 4
and 5 by hydrolysis using sodium hydroxide in aqueous
ethanol followed by acidification of the alkaline reaction
mixture with hydrochloric acid (Scheme 2). The products
were formed in 79 and 77% yields respectively.
4-hydroxy-8-tosyloxyquinoline 1 was chlorinated with
phosphorus oxychloride to give 4-chloro-8-tosyloxyquin-
oline 2 in an excellent yield (94%), the chlorination could
easily be performed in a large scale (10 g). 4-Chloro-8-
tosyloxyquinoline could be hydrolyzed to give 4-chloro-
8-hydroxyquinoline 3 in a 79%yield (Scheme 1) [12].
The reaction between 4-chloro-8-tosyloxyquinoline 2
and pyrrolidine in toluene produced 4-pyrrolidinyl-8-
hydroxyquinoline 8 together with N-tosyl-pyrrolidine 9
(Scheme 3) [13]. Compound 8 could be separated from 9
by addition of hot ethyl acetate to the mixture. Compound
9 was separated by filtration, and after cooling to room
temperature 8 appeared from the filtrate as bright yellow
crystals in 62%.
Scheme 1. Synthesis and hydrolysis of 2.
OH
O
Cl
N
Cl
POCl3
(1)NaOH
(2)HCl
N
N
N
OTs
OTs
OH
OTs
3
1
2

594
W. Omar, J. Heiskanen and O. Hormi
Vol 45
General procedure for the synthesis of 4-amino-8-
tosyloxyquinolines. 4-chloro-8-tosyloxyquinoline (1
Scheme 3. Synthesis of 8.
2
equivalent) was refluxed with the amine derivative (5
equivalents) in toluene for 5 hours, the reaction mixture was
then concentrated and allowed to cool to room temperature. The
crystals formed were collected by filtration and recrystalized
from the proper solvent.
Cl
N
N
O
S
H
N
N
Me
+
Toluene
Synthesis of 4-pyrazolyl-8-tosyloxyquinoline (4). The title
compound was prepared by the previous procedure by reacting 2
(3.3 g, 10 mmol) and pyrazole (3.36 g, 49 mmol) in toluene (25
mL), the white crystals formed (3 g, 83%) were recrystalized
from ethanol, mp 146 °C; ir (KBr): 3275, 3105, 3055, 2959,
1594, 1506, 1437, 1371 cm-1; 1H nmr (200 MHz, CDCl3): δ 2.36
(3H, s), 6.55 (1H, t, J = 2.6 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.40
(1H, d, J = 4.8 Hz), 7.49-7.62 (2H, m), 7.80-7.89 (4H, m), 8.22
(1H, dd, J = 8.5 Hz), 8.80 (1H, d, J = 4.8 Hz); 13C nmr (50
MHz, CDCl3): δ 22.0, 108.7, 116.3, 123.3, 123.8, 124.3, 127.2,
129.1 (2C), 129.9 (2C), 131.7, 133.2, 142.9, 143.6, 144.3, 145.7,
145.9, 151.1; hrms calcd for C19H16N3O3S ([M+H]+) 366.0912,
found 366.0919.
N
O
OH
8
OTs
9
2
The substitution reactions involving the sulphur
nucleophiles needed a strong base [14]. NaH was used to
deprotonate the thiols. The resulting sodium thiolates
from n-butanethiol and n-propanethiol were refluxed with
4-chloro-8-tosyloxyquinoline 2 in butanol to produce n-
propylthio-8-hydroxyquinoline 10 and 4-n-butylthio-8-
hydroxyquinoline 11 in good yields (70 and 71% yield
respectively) (Scheme 4). Similarly to the reaction
between pyrrolidine and 2, the reaction between sodium
thiolates and 2 produced the deprotected 8-hydroxy-
quinolines 10 and 11 directly by a simultaneous removal
of the protecting tosyl group. The reaction between 2 and
isopropanethiol was performed in t-amyl alcohol in the
presence of DMF to afford 4-isopropylthio-8-hydroxy-
quinoline 12 in a good yield (77%) (Scheme 4).
Synthesis of 4-(3-methylpyrazole)yl-8-tosyloxyquinoline
(5). The title compound was prepared by the previous procedure
by reacting 2 (3.3 g, 10 mmol) and 3-methylpyrazole (4 mL, 49
mmol) for 5 hours. The yellowish white crystals formed (3 g,
81%) were collected by filtration and recrystalized from ethanol;
mp 145 °C; ir (KBr): 3110, 3056, 2928, 1741, 1594, 1506, 1431,
1
1372, 1171 cm-1; H nmr (200 MHz, CDCl3): δ 2.34 (3H, s),
2.38 (3H, s), 6.32 (1H, d, J = 2.6 Hz), 7.22 (2H, d, J = 8.4 Hz),
7.33 (1H, d, J = 4.7 Hz), 7.52-7.61 (2H, m), 7.76-7.82 (3H, m),
8.23-8.28 (1H, dd, J = 8.6 Hz), 8.75 (1H, d, J = 4.8 Hz); 13C nmr
(50 MHz, CDCl3): δ 14.1, 22.0, 108.9, 115.9, 123.3, 123.9,
124.2, 127.0, 129.1 (2C), 129.9 (2C), 132.4, 133.2, 143.7, 144.4,
145.6, 146, 151.0, 152.6; hrms calcd for C20H17N3O3NaS
([M+Na]+) 402.0888, found 402.0871.
General procedure for the cleavage of the tosyl group. The
4-amino-8-tosyloxyquinoline derivative (1 equivalent) was
refluxed with NaOH (5 equivalents) in aqueous ethanol for 1
hour, diluted with water and neutralized with HCl to pH 7. The
powder formed was collected by filtration and recrystalized
from the proper solvent.
Synthesis of 4-chloro-8-hydroxyquinoline (3). The previous
procedure was followed by reacting (1 g, 3.0 mmol) of 2 and (2
M, 7.5 mL, 15 mmol) NaOH in ethanol (10 mL), after
neutralization the powder formed was recrystalized from ethanol
to give light yellow needles (0.85 g, 79%) [15], mp 145-146 °C ,
mp (lit. [12] 145-146°C ); ir (KBr): 3186 (br), 1625, 1571, 1502,
1400, 1263 cm-1; 1H nmr (200 MHz, DMSO-d6): δ 7.15 (1H, t, J
= 4.5 Hz), 7.55 (2H, d, J = 4.7 Hz), 7.73 (1H, d , J = 4.7 Hz), 8.
74 (1H, d, J = 4.7 Hz), 10.15 (1H, br s); 13C nmr (50 MHz,
DMSO-d6): δ 113.5, 114.1, 122.8, 127.3, 129.9, 140.2, 142.1,
148.6, 154.7; hrms calcd for C9H7NOCl ([M+H]+) 180.0216,
found 180.0206.
Scheme 4. General route for the synthesis of 4-
thioalkyl-8-hydroxyquinolines
SR
N
Cl
RSH/NaH
Butanol or
t-amyl alcohol/ DMF
N
OH
OTs
2
10, R = n-Pr
11, R = n-Bu
12, R = i-Pr
EXPERIMENTAL
Synthesis of 4-chloro-8-tosyloxyquinoline (2). 4-Hydroxy-8-
tosyloxyquinoline 1 [11], (3.15 g, 10 mmol) and phosphorus
oxychloride (25 mL) was refluxed for 1 hour. After cooling to
room temperature, the reaction mixture was poured into an ice-
NH4OH mixture with stirring. The precipitate formed was
collected by filtration and washed with water to give the title
compound (3.13 g, 94%). Recrystalization from toluene gave
yellowish white crystals of Mp 141-142 °C; ir (KBr): ν 3052,
Synthesis of 4-pyrazolyl-8-hydroxyquinoline (6). The tosyl
group in 4 was cleaved by reacting (1 g, 2.7 mmol) of 4 and
NaOH (2 M, 6.75 mL, 13.5 mmol) The precipitate formed was
collected and recrystalized from methanol to give the title
compound as yellowish white crystals (1.37 g, 79%). mp 105 °C;
2362, 1585, 1493, 2461, 1372, 1174 cm-1; H nmr (200 MHz,
1
DMSO-d6): δ 2.34 (3H, s), 7.35 (2H, d, J = 8.2 Hz), 7.61 (1H,
dd, J = 7.6Hz), 7.68-7.80 (4H, m), 8.08 (1H, dd, J = 8.4 Hz),
8.74 (1H, d, J = 4.7 Hz); 13C nmr (50 MHz, DMSO-d6): δ 21.9,
123.4, 123.9, 124.1, 127.8, 128.7, 129.2 (2C), 130.7 (2C), 132.9,
142.1, 142.6, 145.8, 146.5, 151.7; hrms: calcd for
C16H12NO3NaSCl ([M+Na]+) 356.0124, found 356.0133.
1
ir (KBr): 3312, 3049, 1942, 1746, 1590, 1515, 1407 cm-1; H
nmr (200 MHz, CDCl3): δ 6.56 (1H, t, J = 2.4 Hz ), 7.20-7.24
(1H, dd, J = 7.6 Hz), 7.43-7.51 (2H, m), 7.74-7.86 (1H, dd, J =
8.6 Hz), 7.87 (1H, d, J = 1.5 Hz),7.93 (1H, D, J = 2.4 Hz), 8.68
(1H, br s), 8.77 (1H, d, J = 8.7 Hz); 13C nmr (50 MHz, CDCl3): δ

Mar-Apr 2008
Synthesis of 8-hydroxyquinolines with amino and thioalkyl functionalities
595
108.5, 111.2, 114.4, 116.4, 122.9, 129.1, 131.6, 140.4, 142.7,
144.8, 148.2, 152.9; hrms calcd for C12H10N3O ([M+H]+)
212.0824, found 212.0827.
Synthesis of 4-(3-methylpyrazol)yl-8-hydroxyquinoline (7).
The title compound was prepared by refluxing (1 g, 2.6 mmol)
and NaOH (2 M, 6.5 mL, 13 mmol) in ethanol.
d, J = 4.7 Hz), 9.80 (1H, br s); 13C nmr (50 MHz, DMSO-d6): δ
13.5, 21.5, 32.0, 111.8, 113.1, 116.6, 126.6, 127.7, 137.7, 147.2,
147.2, 154.0; hrms calcd for C12H14NOS ([M+H] +) 220.0796,
found 220.0791.
Synthesis of 4-n-butylthio-8-hydroxyquinoline (11). The
title compound was prepared by using the previous procedure
from NaH (218 mg, 9.08 mmol), 1-butanethiol (0.83 ml, 7.50
mmol) and 4-chloro-8-tosyloxyquinoline 2 (500 mg, 1.50
mmol). Recrystallization from aqueous ethanol afforded 11 (249
mg, 71%) as light brown crystals. mp 121°C; ir (KBr): 3275
(br), 2955, 2922, 2862, 1622 (m), 1559 cm-1; 1H nmr (200 MHz,
DMSO-d6): δ 0.91 (3H, t, J = 7.2 Hz), 1.45 (2H, sextet, J = 7.2
Hz), 1.69 (2H, quintet, J = 7.2 Hz), 3.16 (2H, t, J = 7.2 Hz),
7.04-7.13 (1H, m), 7.39-7.45 (3H, m), 8.64 (1H, d, J = 4.8 Hz),
9.80 (1H, br s); 13C nmr (50 MHz, DMSO-d6): δ 13.7, 21.8,
29.9, 30.0, 111.8, 113.1, 116.6, 126.6, 127.7, 137.7, 147.2,
147.3, 154.0; hrms: calcd for C13H16NOS ([M+H] +) 234.0953,
found 234.0967.
Synthesis of 4-isopropylthio-8-hydroxyquinoline (12). NaH
(216 mg, 9.00 mmol), 2-methyl-2-butanol (10 mL) and 2-
propanethiol (0.72 mL, 7.48 mmol) were stirred together. After 1
½ h. 4-chloro-8-tosyloxyquinoline 2 (500 mg, 1.50 mmol) and
DMF (5 ml) were added. The reaction mixture was refluxed for
24 h. The product was recrystalized from aqueous ethanol to give
12 (253 mg, 77%) as light brown crystals. mp 125°C; ir (KBr): ν
3319 (br), 2969 (m), 2923 (m), 2866 (w), 1621 (m), 1556 (s) cm-
1; 1H nmr (200 MHz, DMSO-d6): δ 1.39 (6H, d, J = 6.5 Hz), 3.85
(1H, septet, J = 6.4 Hz), 7.07-7.11 (1H, m), 7.39-7.48 (3H, m),
9.81 (1H, br s); 13C nmr (50 MHz, DMSO-d6): δ 23.3, 35.6, 112.5,
113.9, 118.6, 127.5, 128.3, 138.6, 147.1, 147.8, 154.6; hrms calcd
for C12H14NOS ([M+H]+) 220.0796, found 220.0828.
After acidification the powder formed (0.45 g, 79%) was
recrystalized from methanol to give 7 as light yellow crystals of
mp 99-100 °C; ir (KBr): 3335, 3114, 2929, 1921, 1587, 1519,
1418 cm-1; 1H nmr (200 MHz, CDCl3): δ 2.44 (3H, s), 6.38 (1H,
d, J = 2.4 Hz), 7.21-7.25 (1H, dd, J = 7.6 Hz), 7.46-7.54 (2H,
m), 7.76-7.81 (1H, dd, J = 8.6 Hz), 8.87 (1H, d, J = 2.4 Hz),
8.44 (1H, br s), 8.81 (1H, d, J = 4.7 Hz); 13C nmr (50 MHz,
CDCl3): δ 14.2, 108.7, 110.8, 114.5, 116.0, 122.7, 128.9, 132.3,
140.5, 144.8, 148.2, 152.4, 152.8; hrms calcd for C13H12N3O
([M+H]+) 226.0980, found 226.0961.
Synthesis of 4-pyrrolidinyl-8-hydroxyquinoline (8). The
title compound was prepared by refluxing 2 (3.3 g, 10 mmol)
and pyrrolidine (4 mL, 49 mmol) in toluene for 9 hours. After
cooling the resulting mixture of products was boiled in ethyl
acetate and filtered. The precipitate was found to be N-tosyl-
pyrrolidine 9. Cooling the filtrate to room temperature produced
bright yellow crystals of the titled compound (1.3 g, 62%). mp
141-142 °C; ir (KBr): 3277, 2967, 2852, 1520, 1417, 1347 cm-1;
1H nmr (200 MHz, CDCl3): δ 2 (4H, quintet), 3.71 (4H, t, J = 6.2
Hz), 6.43 (1H, d, J = 5.3 Hz), 6.65 (1H, s), 7.09 (1H, d, J = 7.5
Hz), 7.18-7.26 (1H, t, J = 8.6 Hz), 7.73 (1H, dd, J = 8.7 Hz),
8.36 (1H, d, J = 5.5 Hz); 13C nmr (50 MHz, DMSO-d6): δ 26.3
(2C), 52.6 (2C), 104.0, 110.1, 116.0, 121.5, 124.3, 140.9, 148.2,
152.8, 153.4; hrms calcd for C13H15N2O ([M+H]+) 215.1184,
found 215.1172.
N-tosyl-pyrrolidine (9). Mp 123 °C, mp (lit. [13] 122-123
°C); 1H nmr (200 MHz, CDCl3): δ 1.73 (4H, quintet, J = 3.3
Hz), 3.21 (4H, t, J = 6.6 Hz), 7.32 (2H, d, J = 7.6 Hz), 7.72 (2H,
d, J = 8.2 Hz); hrms calcd. for C13H15NO2NaS ([M+Na]+)
248.0721, found 248.0718.
General procedure for the preparation of 4-thioalkyl-8-
hydroxyquinolines. NaH in 60% oil dispersion in paraffin oil (6
equivalent) washed with n-hexane (5 mL), and the thiol
derivative (5 equivalent) were stirred vigorously and 4-chloro-8-
tosyloxyquinoline 2 (1 equivalent) dissolved in 1-butanol or tert-
amyl alcohol (10 mL) was added. The reaction mixture was
refluxed under N2 atmosphere for 28 h. The solvent was
removed by evaporation and water (15 mL) was added. The pH
was adjusted with hydrochloric acid (1 M) to 7.1-7.2. The
residue was kept in an ice bath for 10 minutes, filtered and
washed with water (50 mL) and recrystalized from the proper
solvent.
REFERENCES AND NOTES
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[15] This compound is prepared in a better yield using the tosyl
protecting group during the synthetic route, see reference 12.
Synthesis of 4-n-propylthio-8-hydroxyquinoline (10). The
titled compound was prepared by the previous procedure by
reacting NaH (216 mg, 9.00 mmol) and 1-propanethiol (0.69
mL, 7.53 mmol). 4-Chloro-8-tosyloxyquinoline 2 (500 mg, 1.50
mmol) dissolved in 1-butanol (10 mL) was added. The product
formed was recrystalized from aqueous ethanol to give light
brown crystals. mp 101°C; ir (KBr): 3280 (br), 2960, 2924,
2868, 1619 (m), 1558 (s) cm-1; 1H nmr (200 MHz, DMSO-d6): δ
1.05 (3H, t, J = 7.3 Hz), 1.74 (2H, sextet, J = 7.3 Hz), 3.16 (2H,
t, J = 7.2 Hz), 7.03-7.12 (1H, m), 7.40-7.45 (3H, m), 8.64 (1H,