Quinone imines with a fused azine ring: III. Synthesis and reactivity of 8-p-tolylsulfonylimino-5,8-dihydroquinolin-5-one derivatives

Article abstract of DOI:10.1007/s11178-005-0133-y

Unstable 8-p-tolylsulfonylimino-5,8-dihydroquinolin-5-one was generated by oxidation of the corresponding reduced form in acetic acid; it reacted in situ with hydrogen chloride and sodium p-toluenesulfinate to give the corresponding 6-substituted 5-hydrox

Full text of DOI:10.1007/s11178-005-0133-y

Russian Journal of Organic Chemistry, Vol. 41, No. 1, 2005, pp. 124-127. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1,
2005, pp. 124-127.
Original Russian Text Copyright Ó 2005 by Belov, Nichvoloda.
Quinone Imines with a Fused Azine Ring:
III. Synthesis and Reactivity of 8-p-Tolylsulfonylimino-
5,8-dihydroquinolin-5-one Derivatives
A. V. Belov and V. M. Nichvoloda
Ukrainian State University of Chemical Technology, pr. Gagarina 8, Dnepropetrovsk, 49005 Ukraine
Received March 23, 2004
Abstract—Unstable 8-p-tolylsulfonylimino-5,8-dihydroquinolin-5-one was generated by oxidation of the
corresponding reduced form in acetic acid; it reacted in situ with hydrogen chloride and sodium p-toluenesulfinate
to give the corresponding 6-substituted 5-hydroxy-8-aminoquinolines.
There are almost no published data on N-substituted
8-imino-5,8-dihydroquinolin-5-ones.An attempt was made
to correlate antimalarial activity of 8-amino-6-methoxy-
quinolines with their ability to undergo oxidation to 8-imino-
6-methoxy-5,8-dihydroquinolin-8-ones [1], though the
corresponding quinoid metabolites were not isolated by
independent synthesis [2] because of their instability. The
only stable compound of this series, 6-(4-methoxy-
phenylamino)-8-(4-methoxyphenylimino)-5,8-dihydro-
quinolin-5-one was obtained by treatment of 6-piperidino-
5,8-dihydroquinoline-5,8-dione with excess p-methoxy-
aniline in acetic acid [3].
hydroxyquinoline hydrochloride (VI). Oxidation of tosyl
derivative VI with (diacetoxy-l3-iodanyl)benzene in
acetic acid in the presence of an equimolar amount of
sodium acetate afforded quinone imine I as a dark green
solid material which gradually dissolved in the reaction
mixture, giving rise to a dark blue solution. We failed to
isolate quinone imine I as individual substance. Never-
theless, by treatment of the reaction mixture at the moment
of formation of quinone imine I precipitate with
hydrochloric acid or sodium p-toluenesulfinate dihydrate
we succeeded in isolating new compounds, 6-chloro-5-
hydroxy-8-p-tolylsulfonylaminoquinoline hydrochloride
(VII) and 5-hydroxy-6-p-tolylsulfonyl-8-p-tolylsulfonyl-
aminoquinoline (VIII), respectively.
In the preceding communications we reported on the
reactivity of 8-p-tolylsulfonylimino-5,8-dihydroquinolin-5-
one derivatives. We found that reactions of these com-
pounds with nucleophilic reagents are governed by the
tosylimino group rather than by the endocyclic nitrogen
atom [4, 5]. In the present work we made an attempt to
synthesize 8-arylsulfonylimino-5,8-dihydroquinolin-5-ones.
The initial model compound, 8-p-tolylsulfonylimino-5,8-
dihydroquinolin-5-one (I), and its derivatives were
synthesized following the reaction sequence shown in
Scheme 1. The reaction of 8-nitroquinoline (II) with
hydroxylamine hydrochloride in alcoholic alkali afforded
5-amino-8-nitroquinoline (III). The latter was converted
into 5-hydroxy-8-nitroquinoline (IV) by alkaline hydrolysis
according to a specially developed procedure. For this
purpose, nitro compound IV was reduced to 8-amino-5-
hydroxyquinoline dihydrochloride (V) with tin(II) chloride
in hydrochloric acid. Compound V was treated with
p-toluenesulfonyl chloride in methanol in the presence of
2 equiv of pyridine to obtain 8-p-tolylsulfonylamino-5-
The presence of a substituent in position 6 of the
quinoline ring system was proved as follows. The oxidation
of salt VII with (diacetoxy-l3-iodanyl)benzene under the
same conditions as in the generation of quinone imine I
gave unstable 6-chloro-8-p-tolylsulfonylimino-5,8-dihydro-
quinolin-5-one (IX) which was treated in situ with hydro-
chloric acid.As a result, initial compound VII wasobtained.
Compound VIII was oxidized with (diacetoxy-l3-
iodanyl)benzene in acetic acid to obtain 6-p-tolylsulfonyl-
8-p-tolylsulfonylimino-5,8-dihydroquinolin-5-one (X), and
the latter was treated with sodium p-toluenesulfinate
dihydrate. As a result, the corresponding 6,1-addition
product was isolated, 5-hydroxy-6-p-tolylsulfonyl-8-bis(p-
tolylsulfonyl)aminoquinoline (XI). The same product was
synthesized by reaction of quinone imine IX with 2 equiv
of sodium p-toluenesulfinate dihydrate. Quinone imine X
is readily soluble in acetic acid. In order to raise the yield
of tritosyl derivative XI we tested a procedure according
1070-4280/05/4101-0124Ó2005 Pleiades Publishing, Inc.

QUINONE IMINES WITH A FUSED AZINE RING: III.
125
Scheme 1.
2+
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6Q&O ꢀ+&O
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,,
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,,,
,9
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9,
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,
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;,
EXPERIMENTAL
to which sodium p-toluenesulfinate dihydrate was directly
added to the reaction mixture containing freshly prepared
compound X.
The IR spectra were recorded in KBr on a UR-20
instrument. The H NMR spectra were obtained on a
1
The structure of the newly synthesized compounds
was confirmed by their elemental analyses and 1H NMR
and IR spectra (see Experimental).
Varian VXR-200 spectrometer (199.9704 MHz) from
5% solutions in DMSO-d6; the chemical shits were
measured relative to tetramethylsilane as internal
reference. The purity of the products was checked by
TLC on Silufol UV-254 plates using the following solvent
systems: CHCl3–CH3OH–NH3, 100 : 10 : 1 (III, VI,
VIII, XI); 1-BuOH–H2O–AcOH, 5 : 4 : 1 (V–VII);
ethyl acetate (X); spots were visualized under UV light
(VI–VIII, XI).
Our results led us to conclude that the endocyclic
nitrogen atom (especially protonated) [3] and the
arylsulfonylimino group consistently affect the reactions
of 8-p-tolylsulfonylimino-5,8-dihydroquinolin-5-one with
nucleophilic reagents. We believe that the vicinity of the
endocyclic nitrogen atom possessing an unshared electron
pair to the p-tolylsulfonylimino group (which increases
the electron affinity of the quinoid ring) [6] is the main
factor responsible for kinetic instability and enhanced
reactivity of such quinone imines.
5-Amino-8-nitroquinoline (III). A hot solution of
20 g (0.30 mol) of 85% potassium hydroxide in 100 ml of
ethanol was filtered and added dropwise to a suspension
of 10.4 g (0.06 mol) of nitroquinoline II and 15 g
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

126
BELOV, NICHVOLODA
(0.22 mol) of hydroxylamine hydrochloride in 160 ml of
ethanol under stirring at 40°C. The mixture was kept for
1 h at room temperature and poured onto 200 g of crushed
ice. The precipitate was filtered off, washed with 20 ml
of cold water, and dried at 60°C. Yield 6.3 g (55%), pale
yellow powder, mp 248–50°C (from H2O, decomp.);
published data [7]: mp 252°C. 1H NMR spectrum, d, ppm:
6.65 d (1H, 6-H, J = 8.3 Hz), 8.16 d (1H, 7-H, J = 8.3 Hz),
7.51 d.d (1H, 3-H, J1 = 4.3, J2 = 8.3 Hz), 8.67 d.d (1H,
4-H, J1 = 2.1, J2 = 8.3 Hz), 8.94 d.d (1H, 2-H, J1 = 2.1,
J2 = 4.3 Hz), 7.34 s (2H, NH2).
was stirred for 30 min, and the precipitate was filtered
off, washed with 10–15 ml of methanol, and dried. Yield
3.1 g (89%), lemon-yellow finely crystalline substance,
mp 232–233.5°C (from acetic acid, decomp.). IR
–1
spectrum, n, cm : 1376, 1172 (SO2). 1H NMR spectrum,
d, ppm: 2.39 s (3H, CH3), 7.08 d (1H, 6-H, J = 8.7 Hz),
7.22 d (1H, 7-H, J = 8.7 Hz), 7.27 d (2H, C6H4, J =
8.8 Hz), 7.56 d (2H, C6H4, J = 8.8 Hz), 7.75 d.d (1H,
3-H, J1 = 4.8, J2 = 7.9 Hz), 8.87 d.d (1H, 4-H, J1 = 2.2,
J2 = 7.9 Hz), 8.98 d.d (1H, 2-H, J1 = 2.2, J2 = 4.8 Hz),
9.89 s (1H, NH), 11.42 s (1H, OH). Found, %: N 7.89;
S 9.07. C16H14N2O3S · HCl. Calculated, %: N 7.98;
S 9.14.
5-Hydroxy-8-nitroquinoline (IV). A suspension of
1.1 g (5.8 mmol) of aminonitroquinoline III in 130 ml of
water containing 1.1 g (20.0 mmol) of 85% potassium
hydroxide was heated at the boiling point until it turned
homogeneous and ammonia no longer evolved. The
resulting hot solution was treated with charcoal and
filtered, and the filtrate was acidified with acetic acid
and cooled under stirring. The precipitate was filtered
off, washed with 10 ml of water on a filter, and dried at
65–70°C. Yield 0.85 g (77%), orange finely crystalline
substance, mp 260–261°C (decomp.); published data [8]:
mp 258–261°C. 1H NMR spectrum, d, ppm: 6.81 d (1H,
6-H, J = 9.3 Hz), 8.23 d (1H, 7-H, J = 9.3 Hz), 7.61 d.d
(1H, 3-H, J1 = 4.8, J2 = 8.2 Hz), 8.67 d.d (1H, 4-H, J1 =
2.1, J2 = 8.2 Hz), 8.96 d.d (1H, 2-H, J1 = 2.1, J2 =
4.8 Hz).
Generation of 8-p-tolylsulfonylimino-5,8-
dihydroquinolin-5-one (I) from hydrochloride VI.
(Diacetoxy-l3-iodanyl)benzene, 1 g (3.1 mmol), was
added to a suspension of 1.1 g (3.1 mmol) of salt VI and
0.26 g (3.1 mmol) of sodium acetate in 10 ml of glacial
acetic acid, and the mixture was stirred for 10–15 min.
6-Chloro-5-hydroxy-8-p-tolylsulfonylamino-
quinoline hydrochloride (VII). Concentrated hydro-
chloric acid, 3 ml, was added to a mixture containing
quinone imine I (see above), and the mixture was stirred
for 10 min. The precipitate was filtered off, washed on
a filter with 5 ml of glacial acetic acid, thoroughly squeezed,
and dried at 65–70°C. Yield 0.95 g (79% calculated on
hydrochloride VI), brownish–yellow finely crystalline
substance, mp 159–161°C (from acetic acid, decomp.).
8-Amino-5-hydroxyquinoline dihydrochloride
(V). Nitro compound IV, 12.3 g (0.065 mol), was added
to a hot freshly prepared solution of tin(II) chloride in
hydrochloric acid, which was prepared from 32 g
(0.26 mol) of tin and 120 ml of concentrated hydrochloric
acid. The mixture was stirred for 3 h on heating at the
boiling point and was then kept for 24 h at room
temperature. The precipitate was filtered off and
dissolved in 600 ml of warm water, and a stream of
hydrogen sulfide was passed through the solution while
stirring. The mixture was filtered, and the filtrate was
evaporated to dryness under reduced pressure. The
residue was recrystallized from 17% hydrochloric acid
to obtain 10.3 g (68%) of compound V as a lemon-yellow
crystalline substance with mp 252–254°C (decomp.);
published data [9]: mp 252–255°C.
–1
IR spectrum, n, cm : 1368, 1164 (SO2); 3448 (NH, OH).
1H NMR spectrum, d, ppm: 2.26 s (3H, CH3), 7.54 s
(1H, 7-H), 7.23 d (2H, C6H4, J = 8.8 Hz), 7.65 d (2H,
C6H4, J = 8.8 Hz), 7.58 d.d (1H, 3-H, J1 = 4.4, J2 =
8.3 Hz), 8.55 d.d (1H, 4-H, J1 = 2.6, J2 = 8.3 Hz),
8.79 d.d (1H, 2-H, J1 = 2.6, J2 = 4.4 Hz), 9.83 s (1H,
NH), 10.38 s (1H, OH). Found, %: N 7.22; S 8.26.
C16H13ClN2O3S · HCl. Calculated, %: N 7.27; S 8.32.
5-Hydroxy-6-p-tolylsulfonyl-8-p-tolylsulfonyl-
aminoquinoline (VIII). Sodium p-toluenesulfinate
dihydrate, 1.1 g (5.1 mmol), was added to a mixture con-
taining quinone imine I (see above), and the mixture was
stirred for 10 min. The precipitate was filtered off, washed
with 10 ml of glacial acetic acid, squeezed, and dried at
65–70°C. Yield 1.2 g (82% calculated on hydrochloride
VI), yellowish–pink finely crystalline substance, mp 219–
–
5-Hydroxy-8-p-tolylsulfonylaminoquinoline
hydrochloride (VI). A solution of 1.7 g (0.02 mol) of
freshly distilled pyridine in 5 ml of methanol was added
dropwise under stirring to a suspension of 2.3 g
(0.01 mol) of dihydrochloride V and 1.9 g of p-tolu-
enesulfonuyl chloride in 10 ml of methanol. The mixture
220°C (from acetic acid, decomp.). IR spectrum, n, cm
1: 1339, 1172 (SO2); 3240 (OH, NH). 1H NMR spectrum,
d, ppm: 2.26 s (3H, CH3C6H4N), 2.33 s (3H,
4-CH3C6H4SO2C), 7.26 d (2H, CH3C6H4SO2C, J =
8.1 Hz), 7.38 d (2H, 4-CH3C6H4SO2N, J = 8.1 Hz),
7.65 d (2H, 4-CH3C6H4SO2N, J = 8.1 Hz), 7.74 d (2H,
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

QUINONE IMINES WITHAFUSEDAZINE RING: III.
127
4-CH3C6H4SO2C, J = 8.1 Hz), 7.59 d.d (1H, 3-H, J1 =
4.0, J2 = 7.6 Hz), 8.04 s (1H, 7-H), 8.61 d.d (1H, 4-H,
J1 = 1.8, J2 = 7.6 Hz), 8.88 d.d (1H, 2-H, J1 = 1.8, J2 =
4.0 Hz), 9.82 s (1H, NH), 11.15 s (1H, OH). Found, %:
N 5.93; S 13.57. C23H20N2O5S2. Calculated, %: N 5.98;
S 13.69.
dihydrate, 0.5 g (2.3 mmol), was added to a mix-
ture containing quinone imine X prepared from 0.4 g
(0.85 mmol) of compound VIII, and the mixture was
stirred for 10 min. The precipitate was filtered off, washed
on a filter with 2 ml of glacial acetic acid, squeezed, and
dried at 65–70°C. Yield 0.3 g (79% calculated on VIII),
pale pink finely crystalline substance, mp 221–222°C
(from acetic acid, decomp.).
Generation of 6-chloro-8-p-tolylsulfonylimino-
5,8-dihydroquinolin-5-one (IX) from hydrochloride
VII. (Diacetoxy-l3-iodanyl)benzene, 0.48 g (1.5 mmol),
was added to a suspension of 0.6 g (1.5 mmol) of
hydrochloride VII and 0.12 g (1.5 mmol) of sodium
acetate in 3 ml of glacial acetic acid, and the mixture
was stirred for 10–15 min.
b. Sodium p-toluenesulfinate dihydrate, 1.0 g
(4.6 mmol), was added to a mixture containing quinone
imine IX, and the mixture was stirred for 10 min. The
product was isolated and purified as described above in
a. Yield 0.7 g (76% calculated on hydrochloride VII),
yellowish–pink finely crystalline substance, mp 220.5–
222°C (decomp.). No depression of the melting point was
observed on mixing with a sample prepared from quinone
Reduction of quinone imine IX with hydrogen
chloride. Concentrated hydrochloric acid, 1.5 ml, was
added to a mixture containing quinone imine IX (see
above), and the mixture was stirred for 10 min. The
precipitate was filtered off, washed with 3 ml of glacial
acetic acid on a filter, thoroughly squeezed, and dried at
65–70°C. The product was recrystallized from acetic acid
to obtain an orange–yellow finely crystalline substance
which showed no depression of the melting point on
mixing with hydrochloride VII.
–1
imine X. IR spectrum, n, cm : 1361, 1175 (SO2); 3276
1
(OH). H NMR spectrum, d, ppm: 2.37 s (3H,
4-CH3C6H4SO2C), 2.43 s (6H, 4-CH3C6H4SO2N),
7.45 d (2H, 4-CH3C6H4SO2C, J = 8.7 Hz), 7.45 d (4H,
4-CH3C6H4SO2N, J = 8.7 Hz), 7.62 s (1H, 7-H),
7.58 d.d (1H, 3-H, J1 = 4.9, J2 = 8.6 Hz), 7.76 d (4H,
4-CH3C6H4SO2N, J = 8.7 Hz), 7.76 d (2H,
4-CH3C6H4SO2C, J = 8.7 Hz), 8.70 d.d (1H, 4-H, J1 =
1.2, J2 = 8.6 Hz), 8.79 d.d (1H, 2-H, J1 = 1.2, J2 =
4.9 Hz). Found, %: N 4.45; S 15.39. C30H26N2O7S3.
Calculated, %: N 4.50; S 15.45.
6-p-Tolylsulfonyl-8-p-tolylsulfonylimino-5,8-
dihydroquinolin-5-one (X). (Diacetoxy-l3-iodanyl)-
benzene, 0.27 g (0.85 mmol), was added under stirring to
a suspension of 0.4 g (0.85 mmol) of quinoline VIII in
3 ml of acetic acid. The mixture was stirred for 1 h, and
the precipitate was filtered off, washed with acetic acid
and hexane, and dried in air. Yield 0.3 g (77%), mustard-
yellow needles with mp 224–225°C (from toluene,
decomp.). The product is stable within a week since
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..
..
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–1
isolation. IR spectrum, n, cm : 1328, 1164 (SO2); 1668
1
(C=O, C=N). H NMR spectrum, d, ppm: 2.33 s (3H,
4-CH3C6H4SO2C), 2.38 s (6H, 4-CH3C6H4SO2N),
7.34 d (2H, 4-CH3C6H4SO2C, J = 8.1 Hz), 7.46 d
(2H, 4-CH3C6H4SO2N, J = 8.1 Hz), 7.69 d (2H,
4-CH3C6H4SO2N, J = 8.1 Hz), 7.72 s (1H, 7-H),
7.62 d.d (1H, 3-H, J1 = 5.4, J2 = 8.1 Hz), 8.93 d (2H,
4-CH3C6H4SO2C, J = 8.1 Hz), 8.28 d.d (1H, 4-H, J1 =
2.2, J2 = 8.1 Hz), 9.01 d.d (1H, 2-H, J1 = 2.2, J2 =
5.4 Hz). Found, %: N 5.93; S 13.68. C23H18N2O5S2.
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