Reactions of 4-dimethylamino-3-quinolinyl sulfides with nitrating mixture and transamination of 4-dimethylamino-3-methylsulfinyl-6-nitroquinoline

Article abstract of DOI:10.1002/jhet.5570450436

(Chemical Equation Presented) 4-Amino-3-quinolinyl sulfides 4d-e and 7a-c were prepared by amination of 4-chloro-3-quinolinyl sulfides 4c or 1c, respectively, in methanol (140-160°C) or in boiling phenol with yields up to 95 %. Reaction of 4-dimethylamino

Full text of DOI:10.1002/jhet.5570450436

Jul-Aug 2008
1171
Reactions of 4-Dimethylamino-3-quinolinyl Sulfides with Nitrating
Mixture and Transamination of
4-Dimethylamino-3-methylsulfinyl-6-nitroquinoline
Elwira Chrobak and Andrzej Maꢀlankiewicz*
Department of Organic Chemistry, The Medical University of Silesia, 4 Jagielloꢁska, 41-200 Sosnowiec, Poland.
e-mail: maslankiewicz@slam.katowice.pl
Received January 24, 2008
N(CH3)2
SCH3
N(CH3)2
S(O)CH3
NHR
N
O2N
O2N
S(O)CH3
a)
b)
N
N
a) nitrating mixture , 0 oC
b) NH3 or alkyl-NH2, 140 o
C
4-Amino-3-quinolinyl sulfides 4d-e and 7a-c were prepared by amination of 4-chloro-3-quinolinyl
sulfides 4c or 1c, respectively, in methanol (140-160 ºC) or in boiling phenol with yields up to 95 %.
Reaction of 4-dimethylamino-3-quinolinyl sulfides 7c and 4e with nitrating mixture proceeded
simultanously as oxidation of the methylthio group to the methylsulfinyl one and as C6-nitration to form 6-
nitro-ꢀ-quinolinyl sulfoxides 9c or 10b, respectively. 4-Dimethylamino-3-methylsulfinyl-6-nitroquinoline
9c underwent acid catalysed transamination when reacting with primary aliphatic amines and ammonia.
J. Heterocyclic Chem., 45, 1171 (2008).
INTRODUCTION
Scheme 1
X
O
ꢀ-Quinolinyl sulfides of types 1-6 (n=0) were
previously subjected to reaction with nitrating mixture. In
all instances it led primarily to the formation of the
respective ꢀ-quinolinyl sulfoxides 1-6 (n=1) [1-7]. Under
further treatment with nitrating mixture (0-5 °C) some of
X
S(O)CH3
O
S(O)nCH3
S(O)nCH3
6
4
N
N
N
8
CH3
R(CH3 or H)
1
2
3
X=OCH3, SCH3, Cl
them (2-6, n=1) underwent nitration at the 6quinolinyl
,
O
N
X
8quinolinyl [1,3] and even 5quinolinyl positions [4], but
4-alkylthio derivatives of type 4 (X=SR) and 3 (X=SCH3)
were oxidized to the respective 4-alkylsulfinylquinolines
of type 4 [X=S(O)R] or 3 [X=S(O)R], respectively [6,7]
(Scheme 1). However, 4-methoxy- and 4-chloro-3-
methylsulfinylquinolines 1, (n=1) did not undergo any
further transformation with nitrating mixture at 0-5 °C.
To complete the set of 4-substituted ꢀ-quinolinyl
sulfides, we turned to 4-dimethylamino derivatives 7c and
4e [X=N(CH3)2, R=CH3, n=0]. Treatment with nitrating
mixture converted them to ꢀ-methylsulfinyl-6-nitro-
derivatives 9c, or 10a and 10b, respectively. Even a first
insight into the structure of 4-dimethylamino-3-methyl-
sulfinyl-6-nitroquinoline 9c indicates that 4-dimethyl-
amino substituent is strongly influenced by three electron-
withdrawing groups: endocyclic nitrogen-ring atom (i.e.
by aza-activation), ortho 3-methylsulfinyl group and
6-nitro qroup [8]. This induced a study on nucleophilic
displacement of 4-dimethylamino substituent in 9c as a
source of other 4-aminoquinolines as well as other
quinoline derivatives.
5
6
S
N
6
S
N
N
S(O)nR
S(O)nR
8
8
CH3 (H)
4
X=OCH3, SCH3, Cl
5
S
6a =CH2-CH2,
S(O)n
N
6b
=
6b
=
N
N
4-chloroquinolines was a matter of broad and numerous
studies [9,12] due to potent biological activities of
4-aminoquinolines e.g. as antimalarial, [9] antirheumatic
and antiinflammatory [10] or antiviral agents [11].
Some of literature indications were applied for
preparation of 4-aminoquinolines (7a,b,c) from 4-chloro-
quinoline (1c) (see Schemes 2 and 3, Table 1). Best
results with yields up to 95 % were obtained when
treating chloroquinoline (1c) or (4c) with methanolic
solution of amine in autoclave (140-160 ºC) in the
presence of hydrochloric acid. (Table 1, entries 5-9). As
methylsulfinyl group activates the ortho chlorine
substituent towards nucleophilic displacement, amination
of chloro-sulfoxide 1d to 8a and 8b could be effectively
RESULTS AND DISCUSSION
Synthesis of 4-amino-ꢀ-quinolinyl sulfides (7) and
(4e). Direct and indirect amino-de-chlorination of

1172
E. Chrobak, A. Maꢀlankiewicz
Vol 45
Scheme 2
Scheme 3
Cl
N
Cl
N
NR1R2
SR
Cl
SCH3
SR
R1R2NH
N
S
1c
N
N
SCH3
4c
1c, R=CH3
7b, 7c (Table 1, entries 5,6)
4d, 4e (Table 1, entries 7,8)
(CH3)2NH2,
boil.phenol, 1 h
4c, R=3-methylthio-4-quinolinyl
NH3,
boil.phenol, 0.5 h
Cl
NR
CH3
S(O)CH3
S(O)CH3
CH3NHR
N(CH3)2
SCH3
NH2
O
S
S
N
SCH3
N
N
SCH3
1d
8a, 8b (Table 1, entries 9,10)
N
N
N
N
UHP
7c, 37 %
11a, 33 %
7c
8b
6b, (n=0), 80 %
7a, 90 %
performed at a lower temperature (Table 1, entries 9 and
10). Amination of 4-chloroquinoline 1c in boiling phenol
with ammonia led to the expected 4-amino-quinoline (7a)
but that with dimethylamine yielded the 4-dimethyl-
aminoquinoline (7c), which was accompanied by
substantial amounts of 4-phenoxy-3-methylthio-quinoline
(11a). Reaction of 4-chloro-3,4'-diquinolinyl sulfide (4c)
with aqueous ammonia proceeded with breaking of the
4'-quinolinyl sulfur bond to give 7a, which were
potassium methoxide for 4e and potassium phenoxide for
10b, as presented on Scheme 4
Table 1
Amination of 4-chloroquinolines 1cb, 1d and 4c
according to systems [a] or [b].
Entry
Substrate
Reaction
conditions
NH3, [a],
30 min
(CH3)2NH, [a],
60 min
Results, products
[%]
1
2
3
4
1c, X=Cl,
R=CH3, n=0
1c
7a,
R1=R2=H, 96 %
7c,R1=R2=CH3, 37
% and 11a, 33 %
7a, R1=R2=H, 90 %
and 6b (n=0), 80 %
7c, R1=R2=CH3 , 60
% or 48 %
accompanied
by
thioquinanthrene
(6b)
(n=0).
4-Dimethylamino-3-methylsulfinylquinoline (8b) could
be also prepared by oxidation of 7c with urea/hydrogen
peroxide system (UHP).
4c, R=3-CH3S-4- NH3, [a],
quinolinyl, n=0
1c
30 min
DMF/KOH, [c]
or boil. DMF,
18 h
(CH3)2NH,[b],
150 °C, 6 h
CH3NH2, [b]
140 °C, 6 h
CH3NH2, [b]
160 °C, 6 h
Scheme 4
5
6
7
1c
1c
4c
7c, R1=R2=CH3 , 95
%, ref.[4].
N(CH3)2
Y
7b, R1=H, R2=CH3,
51 %
S
N
N
4d, R1=H, R2=CH3,
R=3'- CH3S-4-
quinolinyl,
S(O)nCH3
4e, Y=H, n=0
10b, Y=NO2, n=1
n=0, 64 %
ROK / DMSO
r.t., 30 min
8
4c
(CH3)2NH,[b],
4e, R1=R2=
160 °C, 6 h
CH3, R=3'-CH3S-4-
quinolinyl,
n=0, 79 %
8a,R=H, 80 %
OR
N(CH3)2
SCH3
N(CH3)2
9
1d
1d
CH3NH2, [b]
100 °C, 6 h
(CH3)2NH,[b],
70 °C, 6 h
_
S(O)nCH3
S
Y
Y
CH3I
_
10
8b, R=CH3, 80 %
OH
N
N
N
1a, Y=H, n=0, R=CH3
or
11b, n=1, R=C6H5
7c, Y=H,
(from 4e and CH3OK),
7e, Y=NO2,
[a] boiling phenol, [b] autoclave, methanol, HClaq.;[c] prepared as
decribed for 4-chloroquinoline- ref [13].
(from 10b and C6H5OK)
Reactions of 4-dimethylamino-ꢀ-quinolinyl sulfides
(7c) and (4e) with nitrating mixture. As discussed
above (Scheme 1), action of nitrating mixture usually
converts ꢀ-quinolinyl sulfides stepwise via ꢀ-quinolinyl
Dimethylamino-3-methylthioquinoline (7c) and its
6-nitroderivative (7e) (required for the transamination
study presented below) were prepared from
3,4'-diquinolinyl sulfides (4e) or (10b) and ROK reagents:

Jul-Aug 2008
Reactions of 4-Dimethylamino-3-quinolinyl Sulfides with Nitrating Mixture
1173
sulfoxides to nitro-ꢀ-quinolinyl sulfoxides. Similarly,
reaction of 4-dimethylamino-3-methylthioquinoline (7c)
with 3 mol. eqv. of HNO3 (used in form of nitrating
mixture) gave 4-dimethylamino-3-methylsulfinylo-6-
nitroquinoline (9c) (93 %) but the same reaction
performed even with use of 0.8 mol. eqv. of HNO3 at 0 °C
led to a mixture of 9c, 4-dimethylamino-3-methyl-
sulfinylquinoline (8b) and non-converted substrate 7c in
ratio 1:2:1. This may be due to high electron-donating
properties of the 4-amino group, which significantly
quinoline (9c) is strongly affected by three electron-
withdrawing groups: endocyclic nitrogen-ring atom, ortho
3-methylsulfinyl group and 6-nitro qroup [8]. All these
groups strongly enhance susceptibility of 4-dimethyl-
amino substituent towards nucleophilic displacement with
the dimethylamino group acting as a leaving group.
Although various nucleofuges have been used in activated
aromatic [15-17] and heteroaromatic nucleophilic
substitution reactions [18-19], the dialkylamino group has
seldom been considered and is considered as a poor
leaving group [18]. In spite of this, amine-amine group
exchange, i.e. transamination, was observed in the
reactions of 1-dialkylamino-2,4-dinitronaphtalenes with
primary and secondary amines, in the case of
1-dimethylamino-2,4-di(trifluoroacetyl)naphthalene, [15-
17] and also in the case of aza-aromatic systems e.g. for
2-dimethylaminoquinoline [18-19].
activate
4-aminoquinolines
towards
electrophilic
substitution. Similarly, reaction of 4-dimethylamino-3'-
methylthio-3,4'-diquinolinyl sulfide (4e) with nitrating
mixture containing 3 molar eqv. of HNO3 gave nitro-
sulfoxide (10b) (70 %) accompanied by its N-demeth-
ylated analog 10a (8 %) and two unidentified products
with lower Rf values. As nitration of 4-aminoquinolines
was mentioned several times [14], 4-methylaminoquino-
line (4d) was also subjected to the reaction with nitrating
mixture, but it led to a multicomponent mixture of
unstable products. IR spectra proved for the presence of
sulfinyl groups and nitro groups in the molecules of 9c
and 10a,b. Positioning of the nitro group in 9c and 10a,b
was estabilished from 1H NMR spectra based on coupling
constant values JH,H and nitro group substituent effects,
both being very close to data reported previously for 6-
nitro-3-quinolinyl sulfides [1]. Structure of 10b was
additionally confirmed by its reaction with potassium
phenoxide (Scheme 4).
Scheme 6
N(CH3)2
O2N
S(O)CH3
N
9c
RNH2
O
NHR
O2N
S(O)CH3
S(O)CH3
O2N
N
H
N
2c
9a,b,d,e,f
Scheme 5
80 % AcOH
N(CH3)2
S(O)CH3
N(CH3)2
SCH3
9c
2c
O2N
HNO3 (3 mol.eqv.)
H2SO4, 0 oC
N(CH3)2
N
N
Y
Y=H or NO2
S(O)nCH3
9c, 93 %
7c
N
7e or 8b
N(CH3)2
CH3NH2
S
N
N
O
CH
S
3
N(CH3)2
SCH3
4e
O2N
SCH3
O2N
HNO3 (3 mol.eqv.)
H2SO4, 0 oC
N
H
N
from 7e
2b
7d
O
NHCH3
S(O)CH3
S(O)CH3
N(CH3)2
N(CH3)2
O2N
O2N
S
S
N
N
N
H
N
N
N
2a
(O)CH
S
from 8b
(O)CH
S
8a
3
3
10a, 8 %
10b, 70 %
Our study showed that the dimethylamino group in 9c
is readily replaced (aqueous methanol, 140-150 ºC) with
methylamine and ammonia and then with butylamine
Transamination. 4-Dimethylamino substituent in the
molecule of 4-dimethylamino-3-methylsulfinyl-6-nitro-

1174
E. Chrobak, A. Maꢀlankiewicz
Vol 45
(Table 2). Acid catalysis accelerates transamination
reactions of 9c, however, since this reaction produces
hydrogen chloride, the same yield of transamination
product was obtained for both acid catalysed and non-
catalysed reactions. The exchange of dimethylamino
group is strongly affected by steric effects at the
introductory amino group. We found for the case of
primary alkylamines with some slightly bulkier isopropyl
and cyclopropyl groups that the yields of transamination
products 9d or 9e decrease to 30-38 % and that the
transamination product is accompanied by a substantial
amount of non-converted substrate (25-31 %) as well as
by 6-nitro-3-methylsulfinyl-4(1H)-quinolinone (2c) (8-30
%). The latter could be also prepared by hydrolysis of 9c
with 80 % acetic acid. The same reactivity relative to
amines was observed for the reaction of 4-dimethylamino-
2,4-dinitronaphtalene [15].
6-Nitro-4-aminoquinolines are most often prepared from
the respective 4-chloroquinolines[9,12,21] and to less
extent by nitration of 4-aminoquinolines.[14] Our approach
open the third route to 6-nitro-4-aminoquinolines, via
transamination of 4-dimethylamino-3-methylsulfinyl-6-
nitroquinoline (9c) with primary aliphatic amines and
ammonia leading to nitro derivatives of type 9 with amino
and alkylamino groups at C4. It may be of interest as
introduction of nitro group to the molecules of 4-
aminoquinolines open access to numerous biologically
active amino- and nitroquinoline derivatives [21].
EXPERIMENTAL
Melting points were taken in open capillary tubes and are
uncorrected. 1H NMR spectra were recorded on a Bruker
spectrometer at 400 MHz in deuterochloroform or in
hexadeuterodimethyl sulfoxide solutions with tetramethylsilane
(ꢁ 0.0 ppm) as internal standard. IR spectra were recorded with a
Magma – IR 500 (Nicolet) spectrometer in potassium bromide
pellets. TLC analyses were performed employing Merck’s
silicagel 60 F254 plates and a solution of chloroform-ethanol
Table 2
Transamination of dimethylaminoquinolines 9c, 8b and 7e.
(Scheme 6) [a].
(19:1, v/v) as an eluent (system I) or
a mixture of
No Substrate
Amine
NH3
Products / Recovered substrate
CH2Cl2/ethanol, (19:1, v/v) (system II) and Merck’s aluminium
oxide 60 F254 neutral (type E) plates using mixture of chloroform
– ethanol (19:1, or 10 : 1, v/v) as an eluent (system III).
Preparation of 4-aminoquinolines 7b, 7c, 4d, 4e, 8a, 8b by
amination of 4-chloroquinolines 1c, 4c and 1d in autoclave
(Table 1, entries 5-10). The procedure described previously [6]
was modified as follows:
4-Chloroquinoline (5 mmol), 15 mL of methanol, 4 mL of
20% aqueous methylamine or dimethylamine and one drop of
conc. hydrochloric acid were placed in a steel autoclave. It was
heated as described in Table 1. Volatile compounds were
evaporated under vacuum at 50 ꢂC and the residue was alkalized
(if necessery) with few drops of 10% aqueous sodium
hydroxide. 3,4'-Diquinolinyl sulfides 4d, 4e were isolated by
filtration and then recrystallized from ethanol.
1
9c
9a, R=NH2, 75 % / 9c, 11 %.
2
3
9c
9c
MeNH2
iPrNH2
9b, R=NH-Me, 90 % / 9c, 0 %.
9d, R=NH-iPr, 30 %; 2c, 30 %
/ 9c, 30 %.
9e, R=NH-cPr, 39 %; 2c, 8 %
/ 9c, 31 %.
9f, R=NH-n-Bu, 60 %; 2c, 18 %
/ 8b, 13 %.
8a, R=NH-Me, 25 %; 2a, 16 %
/ 8b, 46 %.
4
5
6
7
9c
9c
cPrNH2
n-BuNH2
MeNH2
MeNH2
8b, R=
N(Me)2
7e, R=
N(Me)2
7d, R=NH-Me, 31 %; 2b, 22 %
/ 7e, 31 %.
[a] Abbreviations: Me=methyl, iPr=isopropyl, cPr=cyclopropyl, n-Bu =
n-butyl.
4-Amino-3-thioquinolines 7b, 7c, 8a, 8b were isolated by
extraction with methylene chloride (4 x 5 mL). Extracts were
evaporated to dryness and the residue was recrystallized as
indicated below. Properties of 7b and 7c were the same as
reported previously [22,6].
To compare the activating effect of 3-methylsulfinyl
and 6-nitro groups, respective desoxy derivative 7e
(Y=NO2, n=0) and desnitro derivative 8b (Y=H, n=1)
were subjected to reaction with methylamine. It indicates
that activating effect of 6-nitro group is stronger for
nucleophilic displacement of dimethylamino group at C4
in 9c than that of the 3-methylsulfinyl one.
4-Methylamino-3'-methylthio-3,4'-diquinolinyl sulfide
(4d). This compound was obtained as bright yellow plates
1
(ethanol), mp 173-175 °C; H NMR (CDCl3), ꢁ: 2.69 (s, 3H,
CH3S), 3.41 (d, J=5.4 Hz, 3H, CH3NH), 6.20-6.70 (broad, 1H,
NH), 7.39-7.44 (m, 1H, Harom), 7.58-7.68 (m, 3H, 3 x Harom),
8.06-8.08 (m, 2H, 2 x Harom), 8.13-8.16 (m, 1H, Harom), 8.48-8.51
(m, 1H, Harom), 8.68 (s, 1H, H-2), 8.79 (s, 1H, H-2'). Anal. Calcd.
for C20H17N3S2: C, 66.08; H, 4.71; N, 11.56. Found: C, 65.80; H,
4.65 ; N, 11.29.
CONCLUSIONS
Reactions of 4-dimethylamino-ꢀ-quinolinyl sulfides
(4e) and (7c) with nitrating mixture (3 molar eqv.) led
directly to 4-dimethylamino-ꢀ-quinolinyl-6-nitro sulf-
oxides (10b) and (9c). Nitration of 3,4'-diquinolinyl
sulfide (4e) proceeded in the ‘left’ quinoline unit being
activated towards nitration by the 4-dimethylamino group.
4-Dimethylamino-3-methylsulfinyl-6-nitroquinoline (9c)
underwent acid-catalysed transamination in the reaction
with primary aliphatic amines and ammonia.
4-Dimethylamino-3'-methylthio-3,4'-diquinolinyl sulfide
(4e). This compound was obtained as bright yellow plates
(ethanol), mp 94-96 °C; 1H NMR (CDCl3), ꢁ: 2.60 (s, 3H,
SCH3), 3.27 (s, 6H, N(CH3)2), 7.51-7.53 (m, 2H, Harom), 7.57-
7.59 (m, 1H, Harom), 7.65-7.67 (m, 1H, Harom), 7.92-7.95 (m, 1H,
H
arom), 7.93 (s, 1H, H-2), 8.03-8.06 (m, 1H, Harom), 8.10-8.12 (m,
1H, Harom), 8.34-8.36 (m, 1H, Harom), 8.83 (s, 1H, H-2'). Anal.

Jul-Aug 2008
Reactions of 4-Dimethylamino-3-quinolinyl Sulfides with Nitrating Mixture
1175
Calcd. for C21H19N3S2: C, 66.81; H, 5.07; N, 11.13; S, 16.99.
Found: C, 66.48; H, 5.11; N, 11.12; S, 16.69.
h. Then 6 mL of water was added and the mixture was extracted
with chloroform (4 x 5 mL). The extracts were dried with
anhydrous sodium sulfate and evaporated to dryness. The
residue (190 mg, an oil containing the product 8b and the
substrate 7c) was subjected to chromatographic separation
(Al2O3 neutral, chloroform:ethanol, 30:1, v/v), which gave 0.03
g of substrate 7c (the fraction with upper Rf value) and 0.16 g of
product 8b. The later was recrystallized from ethyl acetate to
give 0.15 g (64 %) of pure 8b with mp 142-143 °C being
identical with the product prepared from amination od 1d (Table
1, entry 10).
4-Methylamino-3-methylsulfinylquinoline (8a). This
compound was obtained as white plates (ethanol), mp 165-167
1
°C; H NMR (CDCl3), ꢀ: 2.96 (s, 3H, S(O)CH3), 3.48-3.49 (d,
J=5.6 Hz, 3H, N(CH3), 7.42-7.46 (m, 1H, Harom), 7.67-7.71 (m,
1H, Harom), 7.87 (broad s, 1H, NH), 7.95-7.98 (m, 1H, Harom),
8.27-8.29 (m, 1H, Harom), 8.44 (s, 1H, H-2). IR (KBr pellet):
ꢁS=O=1003 cm-1. Anal. Calcd. for C11H12N2OS: C, 59.97; H, 5.49;
N, 12.72; S, 14.56. Found: C, 59.52; H, 5.91; N, 12.51; S, 14.61.
4-Dimethylamino-3-methylsulfinylquinoline (8b). This
compound was obtained as white plates (ethyl acetate), mp 141-
Reaction of 3,4'-diquinolinyl sulfides (4e) or (10b) with
ROK reagents (Scheme 4). 3,4'-Diquinolinyl sulfide (1 mmol)
was added at rt to 8 mL of DMSO and then on stirring, 3 mmol
of ROK reagents [potassium methoxide for sulfide (4e) or
potassium phenoxide for sulfide (9b)] was introduced in one
portion. The mixture was stirred for 30 min at rt and then poured
into 15 mL of 5% aqueous sodium hydroxide. 4-Phenoxy-3-
methylsulfinylquinoline (11b) was filtered off and the residual
part of 11b was extracted with chloroform (3 x 5 mL), but 4-
methoxy-3-methylthioquinoline (1a) was isolated by extraction
(as above) only. The solid and extracts were combined (for 11b),
the solution was dried with anhydrous Na2SO4. The solvent was
then distilled off to give crude 11b or 1a. 11b was recrystallized
from ethanol but 1a was purified from impurities by extraction
with hot hexane [23,5].
1
143 °C; H NMR (CDCl3), ꢀ: 2.84 (s, 3H, S(O)CH3), 3.16 (s,
6H, N(CH3)2), 7.57-7.59 (m, 1H, Harom), 7.55-7.77 (m, 1H,
H
arom), 8.05-8.07 (m, 1H, Harom), 8.15-8.18 (m, 1H, Harom), 9.30
(s, 1H, H-2). IR (KBr pellet): ꢁS=O=1047 cm-1. Anal. Calcd. for
C12H14N2OS: C, 61.51; H, 6.02; N, 11.96. Found: C, 61.25; H,
6.01; N 12.01.
Amination in boiling phenol. Ammonia or dimethyl amine
was passed through a mixture of phenol (5 g), 4-chloroquinoline
1c or 4c (5 mmol) and one crystal of ammonium chloride at 200
°C for 2 h. The mixture was then cooled down to rt, treated with
15 mL of 5 % aqueous sodium hydroxide and stirred with 15 mL
of methylene chloride for 10 min. Further work-up depends on
the products composition.
In the case of the reaction of 1c with ammonia (Table 1, entry
1), organic layer was separated and dried over anhydrous
Na2SO4. The solvent was then distilled off to give crude 7a
(~100 %) with mp. 123-125 °C. It was recrystallized from
aqueous ethanol to results in product with mp. 124-126 °C.
In the case of the reaction of 1c with dimethylamine (Table 1,
entry 2), organic layer was worked-up as above to give a
solution containing 4-dimethylamino-3-methylthioquinoline (7c)
and 4-phenoxy-3-methylthioquinoline (11a). It was shaken with
5 mL of 5 % hydrochloric acid. The aqueous layer was washed
twice with 5 mL of methylene chloride. The organic layers were
combined, dried with anhydrous Na2SO4 and evaporated to
dryness to give 0.44 g (33 %) of 11a with mp 139-141 °C, ref.
[23], mp 139-140 °C. Aqueous layer was alkalized with 5 %
aqueous NaOH and extracted with chloroform (3 x 5 mL).
Extracts were combined, dried and evaporated as above to give
0.40 g of 7c with mp 86-88 °C, ref. [6], mp 86-88 °C.
In the case of the reaction of 4c with ammonia (Table 1, entry
3) the solid [thioquinanthrene (6b)]) was collected by filtration.
The solid was washed with water and dried on air to give 0.63 g
(80 %) of the chromatographically homogenous yellow material
with mp 314-315 °C being identical with thioquinanthrene (6b),
ref. [24], mp 314-315 °C. Further work-up of organic layer gave
crude 7a (0.85 g, 100 %).
Aqueous DMSO solution was methylated on stirring (30 min)
with 0.066 mL (1.1 mmol) of methyl iodide. 4-Dimethylamino-
3-methylthioquinoline (7c) was extracted with chloroform (3 x 5
mL) and then isolated and purified as described previously [6].
4-Dimethylamino-3-methylthio-6-nitroquinoline
isolated and purified in the same manner.
(7e)
was
4-Dimethylamino-3-methylthio-6-nitroquinoline (7e). This
compound was obtained as yellow plates (ethanol), mp 120-122
°C; 1H NMR (CDCl3), ꢀ: 2.56 (s, 3H, SCH3), 3.22 (s, 6H,
N(CH3)2), 8.11-8.13 (d, J=8.8 Hz, 1H, H-8), 8.34-8.37 (dd,
J=8.82 Hz, J=2.4 Hz, 1H, H-7), 8.86 (s, 1H, H-2), 9.02-9.023
(d, J=2.4 Hz, 1H, H-5). IR (KBr pellet): ꢁNO2=1337 cm-1 and
1505 cm-1. Anal. Calcd. for C12H13N3O2S: C, 54.74; H, 4.98; N,
15.96. Found: C, 54.4; H, 5.12; N, 16.04.
Reactions of 3-methylthioquinolines (7c) and (4e) with
nitrating mixture. The described procedure [6] was modified as
follows:
3-Methylthioquinoline (5 mmol) was dissolved upon strirring
in conc. sulfuric acid (11 mL) at 10 °C and the solution was
cooled down to – 5 °C. Then, 1.25 mL of nitrating mixture
(prepared from 1 mL of fuming nitric acid and 1 mL of conc.
sulfuric acid) was added dropwise at -5 °C and kept at -5 °C for
15 min. The reaction mixture was poured on 110 g of crushed
ice and then neutralized at 0 °C with conc. aqueous ammonia up
to pH 6. The solid product was filtered off and dried on air. 4-
Dimethylamino-3-methylsulfinyl-6-nitroquinoline (8c) was
recrystallized from ethanol. Reaction products from 4e were
separated by column chromatography (silicagel 60, a mixture
CH2Cl2/ethanol, 19:1 , v/v) to afford 10b (Rf=0.32, system II),
1.54 g (70 %), 10a (Rf=0.22, system II), 0.17 g (8 %).
4-Amino-3-methylthioquinoline (7a). This compound was
1
obtained as white plates (aqueous ethanol), mp 124-126 °C; H
NMR (benzene-d6) 1.79 (s, 3H, SCH3), 4.75 (s, 2H, NH2), 7.03 –
7.11 (m, 2H, Harom), 7.28-7.34 (m, 1H, Harom), 8.24-8.27 (m, 1H,
Harom), 8.97 (s, 1H, H-2). Anal. Calcd. for C10H10N2S: C, 63.13;
H, 5.30; N, 14.72; S, 16.85. Found: C, 63.09; H, 5.28; N, 14.58;
S 16.75.
4-Dimethylamino-3-methylsulfinyl-6-nitroquinoline (9c).
This compound was obtained as yellow plates (ethanol), mp
160-162 °C; H NMR (CDCl3), ꢀ: 2.85 (s, 3H, S(O)CH3), 3.27
(s, 6H, N(CH3)2), 8.23-8.25 (d, J=9.2 Hz, 1H, H-8), 8.47-8.49
(dd, J=9.2 Hz, J=2.4 Hz, 1H, H-7), 9.04-9.05 (d, J=2.4 Hz, 1H,
Oxidation of 4-dimethylamino-3-methylthioquinoline (7c)
to 4-dimethylamino-3-methylsulfinylquinoline (8b) by means
of UHP. Sulfide (7c) (0.22 g, 1 mmol) was added to a solution
of UHP (i.e. urea-hydrogen peroxide complex [25], 0.55 g, 6
mmol) in 3 mL of methanol. The mixture was stirred at rt for 48
1

1176
E. Chrobak, A. Maꢀlankiewicz
Vol 45
H-5), 9.42 (s, 1H, H-2). IR (KBr pellet): ꢀS=O=1041 cm-1,
ꢀNO2=1343 cm-1 and 1504 cm-1. Anal. Calcd. for C12H13N3O3S: C,
51.60; H, 4.69; N, 15.04; S, 11.48. Found: C, 51.26; H, 4.71; N,
14.81; S, 11.16.
8.45 (s, 1H, H-2), 8.78-8.84 (d, J=2.4 Hz, 1H, H-5). IR (KBr
pellet): ꢀS=O=1019 cm-1, ꢀNO2=1336 cm-1 and 1499 cm-1. Anal.
Calcd. for C10H9N3O3S: C, 47.80; H, 3.61; N, 16.72. Found:
C, 47.42; H, 3.70; N, 16.32.
4-Methylamino-3-methylsulfinyl-6-nitroquinoline (9b).
This compound was obtained as yellow solid (ethanol), mp 210-
212 °C; H NMR (CDCl3), ꢁ: 3.00 (s, 3H, S(O)CH3), 3.59-3.60
4-Methylamino-3'-methylsulfinyl-6-nitro-3,4'-diquinolinyl
sulfide (10a). This compound was obtained as yellow solid
(ethanol), mp decomposition from 189-193 °C; 1H NMR
(CDCl3), ꢁ: 2.86 (s, 3H, S(O)CH3), 3.57 (d, J=5.4 Hz, 3H,
NHCH3), 6.41 (broad doublet, 1H, NHCH3), 7.65-7.70 (m, 1H,
Harom), 7.81-7.86 (m, 1H, Harom), 7.96-7.99 (m, 1H, Harom), 8.21-
8.24 (m, 1H, Harom), 8.36-8.39 (m, 1H, Harom),8.45-4.48 (m, 1H,
Harom), 8.68 (s, 1H, H-2), 9.18-9.19 (m, 1H, Harom.), 9.39 (s, 1H,
H-2'). IR (KBr pellet): ꢀS=O=1035 cm-1, ꢀNO2=1336 cm-1 and 1590
cm-1. Anal. Calcd. for C20H16N4O3S2: C, 56.59; H, 3.80; N,
13.20. Found: C, 56.24; H, 4.03; N, 12.84.
1
(d, J=5.6 Hz, 3H, NHCH3), 8.01-8.03 (d, J=9.2 Hz, 1H, H-8),
8.42-8.45 (dd, J=9.2 Hz, J=2.4 Hz, 1H, H-7), 8.46 (s, 1H, H-2),
8.63 (1H, broad, NH), 9.35-9.36 (d, J=2.4 Hz, 1H, H-5). IR
(KBr pellet): ꢀS=O=1031 cm-1, ꢀNO2=1335 cm-1 and 1557 cm-1.
Anal. Calcd for C11H11N3O3S: C, 49.80; H, 4.18; N, 15.84.
Found: C, 49.52; H, 4.30; N, 15.58.
4-Isopropylamino-3-methylsulfinyl-6-nitroquinoline (9d).
This compound was obtained as yellow solid (ethyl acetate), mp
156-158 °C; 1H NMR (CDCl3), ꢁ: 1.47-1.49 (m, 3H, CH3), 1.54-
1.56 (m, 3H, CH3), 2.99 (s, 3H, S(O)CH3), 4.39-4.48 (m, 1H,
CH), 8.02-8.04 (d, J=9.2 Hz, 1H, H-8), 8.14 (broad s, 1H, NH),
8.42-8.45 (dd, J=9.2 Hz, J=2.4 Hz, 1H, H-7), 8.51 (s, 1H, H-2),
9.16-9.17 (d, J=2.4 Hz, 1H, H-5). IR (KBr pellet): ꢀS=O=1053
cm-1, ꢀNO2=1340 cm-1 and 1503 cm-1. Anal. Calcd for
C13H15N3O3S: C, 53.23; H, 5.15; N, 14.32. Found: C, 53.48; H,
4.97; N, 14.25.
4-Cyclopropylamino-3-methylsulfinyl-6-nitroquinoline (9e).
This compound was obtained as yellow solid (ethanol), mp 153-
155 °C; 1H NMR (CDCl3), ꢁ: 0.87-0.95 (m, 2H, CH2), 1.19-1.29
(m, 2H, CH2), 2.97 (s, 3H, S(O)CH3), 3.24-3.33 (m, 1H, CH),
8.01-8.02 (d, J=9.2 Hz, 1H, H-8), 8.42 (s, 1H, H-2), 8.43-8.46
(dd, J=9.2 Hz, J=2.4 Hz, 1H, H-7), 8.98 (broad s, 1H, NH),
10.07-10.08(d, J=2.4 Hz, 1H, H-5). IR (KBr pellet): ꢀS=O=1011
cm-1, ꢀNO2=1348 cm-1 and 1498 cm-1. Anal. Calcd. for
C13H13N3O3S: C, 53.60; H, 4.50; N, 14.42; S, 11.01. Found: C,
53.41; H, 4.42; N, 14.12.
4-Butylamino-3-methylsulfinyl-6-nitroquinoline (9f). This
compound was obtained as yellow solid (ethanol), mp 108-110
°C; 1H NMR (CDCl3), ꢁ: 1.03-1.06 (m, 3H, CH3), 1.59-1.63 (m,
2H, CH2), 1.86-1.90 (m, 2H, CH2), 3.01 (s, 3H, S(O)CH3), 3.90-
3.95 (m, 2H, CH2), 8.01-8.03 (d, J=9.2 Hz, 1H, H-8), 8.41-8.44
(dd, J=9.2 Hz, J=2.4 Hz, 1H, H-7), 8.46 (broad s, 1H, NH), 8.47
(s, 1H, H-2), 9.26-9.27 (d, J=2.4 Hz, 1H, H-5). IR (KBr pellet):
ꢀS=O=1011 cm-1, ꢀNO2=1323 cm-1 and 1504 cm-1. Anal. Calcd for
C14H17N3O3S: C, 54.71; H, 5.57; N, 13.67. Found: C, 54.72; H,
5.62; N, 13.60.
4-Dimethylamino-3'-methylsulfinyl-6-nitro-3,4'-diquinol-
inyl sulfide (10b). This compound was obtained as yellow
1
plates (ethanol), mp 218-220 °C; H NMR (CDCl3), ꢁ: 2.91 (s,
3H, S(O)CH3), 3.38 (s, 6H, N(CH3)2), 7.59-7.64 (m, 1H, Harom),
7.83-7.89 (m, 1H, Harom), 8.03-8.06 (m, 1H, Harom), 8.06 (s, 1H,
H-2), 8.20-8.23 (d, J=9 Hz, 1H, H-8), 8.27-8.30 (m, 1H, Harom),
8.36-8.40 (dd, J=9 Hz, J=2.7 Hz, 1H, H-7), 9.02 (d, J=2.7 Hz,
1H, H-5), 9.51 (s, 1H, H-2'). IR (KBr pellet): ꢀS=O=1057 cm-1,
ꢀNO2=1339 cm-1 and 1576 cm-1. Anal. Calcd. for C21H18N4O3S2:
C, 57.52; H, 4.14; N, 12.78. Found: C, 57.44; H, 4.23; N, 12.54.
4-Methylamino-3-methylthio-6-nitroquinoline (7d). This
compound was obtained as yellow plates (ethanol), mp 106-108
1
°C; EIMS (70 eV) m/z: 249 (100, M+). H NMR (CDCl3), ꢁ:
2.33 (s, 3H, SCH3), 3.59-3.60 (d, J=6 Hz, 3H, NCH3), 6.58
(broad, 1H, NH), 7.99-8.01 (d, J=9.3 Hz, 1H, H-8), 8.35-8.38
(dd, J=9.3 Hz, J=2.4 Hz, 1H, H-7), 8.78 (s, 1H, H-2), 9.29-9.3
(d, J=2.4 Hz, 1H, H-5). IR (KBr pellet): ꢀNO2=1330 cm-1 and
1504 cm-1. Anal. Calcd. for C11H11N3O2S: C, 53.00; H, 4.45; N,
16.86. Found: C, 52.86; H, 4.25; N, 16.68.
Transamination of 4-dimethylamino-3-methylsulfinyl-6-
nitroquinoline (9c). 4-Dimethylaminoquinoline 9c (0.28 g, 1
mmol), 16 mL of methanol, 3 mL of water, alkylamine (6 mmol)
or 0.8 mL of 25 % aqueous ammonia or methylamine and one
drop of conc. hydrochloric acid was placed in a steel autoclave.
It was heated in an oil bath as described in Table 1. The volatile
compounds were evaporated under vacuum at 80 °C up to
volume of 3 mL and the residue was cooled down to rt. The
solid was filtered off and the filtrate was extracted with CHCl3
or CH2Cl2 (3 x 4 mL). The solid and the extracts were
combined, dried with anhydrous Na2SO4. The solvent was
distilled off. The residue was either recrystallized from ethanol
(for 9a and 9b) or subjected to chromatographic separation
(Al2O3, CH2Cl2 /ethanol, 35:1, v/v) (for the other experiments,
Table 2, entries 3-5). The later give fractions of: transamination
product 9d,e,f (upper Rf value), substrate 9c (middle Rf value),
and 4(1H)-quinolinone 2c (lower Rf value). Properties of 2c
were the same as described below.
Hydrolysis of sulfoxide 9c to quinolinone 2c. Sulfoxide 9c
(0.28 g, 1 mmol) and 80 % acetic acid (3 mL) were stirred at 70
°C for 6 h. Volatile components were evaporated to dryness
from water bath at vacuum. The residue was cooled to rt and
mixed with 2 mL of water and then treated with saturated
NaHCO3. The solid was collected by filtration and dried on air.
The resulted material was refluxed with the mixture of
methylene chloride/ethanol (10-1, v/v) and quinolinone 2c with
mp 236-238 °C (0.176 g, 70 %) was hot filtered off. The filtrate
was evaporated to dryness to give unreacted substrate (0.084 g,
30 %) Crude 2c was recrystallized from DMF to yield the solid
with mp 242-243 °C; lit. [5], mp 242-243 °C.
In the same manner were performed transamination of 8b and
7e with methylamine (Table 2, entries 6,7).
Properties of 3-methylsulfinyl-4(1H)-quinolinone (2a) and
3-methylthio-6-nitro-4(1H)-quinolinone (2b) were the same as
described earlier [5,23].
REFERENCES AND NOTES
4-Amino-3-methylsulfinyl-6-nitroquinoline (9a). This
compound was obtained as yellow solid (ethanol), mp 227-
228 °C (decomp); 1H NMR (CDCl3), ꢁ: 2.97 (s, 3H,
S(O)CH3), 6.9-7.05 (broad s, 2H, NH2), 8.01-8.03 (d, J=9.2
Hz, 1H, H-8), 8.41-8.44 (dd, J=9.2 Hz, J=2.4 Hz, 1H, H-7),
[#] Part CV in the Series of Azinyl Sulfides
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