Synthesis of 6-methoxy-N 2,N 2,N 4,N 4,N 5,N 5-hexamethylquinoline-2,4,5-triamine - A new representative of quinoline proton sponges

Article abstract of DOI:10.1007/s10593-015-1693-6

[Figure not available: see fulltext.] We report the synthesis of 4-chloro-2-methyl-5-nitro- and 2,4-dichloro-5-nitroquinolines, containing methoxy groups at positions 6 and 8. The reaction of these compounds with dimethylamine solution in alcohol was shown to produce not only aminodehalogenation products, but also resulted in nucleophilic substitution of the methoxy groups. The reduction of 6-methoxy-N ²,N ²,N ⁴,N ⁴-tetramethyl-5-nitroquinoline-2,4-diamine with subsequent methylation gave 6-methoxy-N ²,N ²,N ⁴,N ⁴,N ⁵,N ⁵-hexamethylquinoline-2,4,5-triamine, a new representative of quinoline proton sponges.

Full text of DOI:10.1007/s10593-015-1693-6

DOI 10.1007/s10593-015-1693-6
Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
2
2
4
4
5
5
Synthesis of 6-methoxy-N ,N ,N ,N ,N ,N -hexamethylquinoline-
,4,5-triamine – a new representative of quinoline proton sponges
2
1
1
1
1
Olga V. Dyablo *, Alexander F. Pozharskii , Elena A. Shmoilova , Aleksey O. Savchenko
1
Southern Federal University, 7 Zorge St., Rostov-on-Don 344090, Russia;
е-mail: dyablo@sfedu.ru; apozharskii@sfedu.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
015, 51(3), 250–258
Submitted November 21, 2014
Accepted for publication December 15, 2014
2
We report the synthesis of 4-chloro-2-methyl-5-nitro- and 2,4-dichloro-5-nitroquinolines, containing methoxy groups at positions 6 and
. The reaction of these compounds with dimethylamine solution in alcohol was shown to produce not only aminodehalogenation products,
8
2
2
4
4
but also resulted in nucleophilic substitution of the methoxy groups. The reduction of 6-methoxy-N ,N ,N ,N -tetramethyl-
5
2
2
4
4
5
5
-nitroquinoline-2,4-diamine with subsequent methylation gave 6-methoxy-N ,N ,N ,N ,N ,N -hexamethylquinoline-2,4,5-triamine, a
new representative of quinoline proton sponges.
2
2
4
4
5
5
Keywords: 1,8-bis(dimethylamino)naphthaline, 6-methoxy-N ,N ,N ,N ,N ,N -hexamethylquinoline-2,4,5-triamine, 4-chloro-5-nitro-
quinoline, aminodehalogenation, nitration, proton sponge.
Recently we reported a synthesis of the first two
,5-bis(dimethylamino)quinolines 1а,b, which can be
Scheme 1
1,2
4
considered as quinoline analogs of 1,8-bis(dimethylamino)-
3
naphthaline (4а) (proton sponge ). Both compounds 1a,b
а
showed a lower basicity (by 0.3–1.2 рK units) than
diamine 4a, as expected due to the electron-withdrawing
nature of the aza substituent. Most remarkably, these
compounds underwent two types of protonation. While
compound 1а in solution or solid state was always
protonated as azine, forming the cation 2а (Scheme 1), the
2
derivative 1b having a 2-NMe group was protonated
simultaneously both as azine and a proton sponge. Thus, its
salts existed in solid state as the chelated cation 3b, while
both forms 2b and 3b were formed in solution, at a ratio
5
–7
effect.
Since the unusually strong basicity of proton
8
9
sponge (pK 12.10, H O; pK 18.62, MeCN ) is explained by
a
2
a
1
depending on the polarity of solvent.
the destabilization of free base by the considerable electro-
static repulsion between the lone electron pairs of peri-
dimethylamino groups, additional destabilization of the base
was proposed through introducing bulky substituents,
especially with lone electron pairs, at the ortho positions
relative to the dimethylamino groups.
The nearly half a century study of proton sponges has
been focused on searching of stronger bases and achieving
a better understanding of the relationship between their
3
,4
structure and basicity. One of the first ideas in this
direction was to take advantage of the so-called buttressing
0
009-3122/15/5103-0250©2015 Springer Science+Business Media New York
250

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
These expectations were quite justified (some excep-
15а–с in diphenyl ether resulted in the formation of
quinolones 16а–с (Scheme 3). The latter were further
treated without purification by heating with POCl ,
3
resulting in the preparation of compounds 14a–c, albeit in
yields not exceeding 31%, as calculated from the starting
methoxyanilines 13.
7
tions have been described ) in the case of 1,8-bis-
dimethylamino)-2,7-dimethoxynaphthaline (4b), the pK
value of which is 16.3 (in Н О). For a long time this was
the strongest known base among neutral organic
(
a
2
5,6
molecules.
We should note that demethylation of
compound 4b with HBr gives 2,7-binaphthol, which exists
as betaine 5 (Scheme 2). Treatment with lithium hydride in
DMSO leads only to deprotonation of a second ОН group
and the formation of dinaphtholate 6, holding a strongly
chelated proton that could not be removed even after
prolonged heating with lithium hydride.
Scheme 3
Scheme 2
H
+
H
+
Me N
NMe2
O–
Me N
NMe2
O–
2
2
HO
–O
HBr
LiH
4b
–
2MeOH
6
5
LiH
H
+
Me N
NMe2
2
Me N
NMe2
Me N
NMe2
–O
O–
2
2
BBr3
7
MeO
OMe
O
O–
8
H
9
а
The рK value of dianion 7 was estimated to be
significantly above 25, making it the strongest currently
1
0
known arylamine base. The demethylation of 4,5-di-
methoxy derivative of proton sponge 8 similarly produced
the betaine 9 (Scheme 2), featuring a symmetrical hydrogen
1
1
N–H···N bond and an asymmetric О–Н···О bond.
When taking into account all these facts, we decided to
prepare methoxy derivatives of quinoline proton sponge in
order to obtain increased basicity and to shift the
protonation towards dimethylamino groups. We should
note that the introduction of two dimethylamino groups at
the peri positions is quite difficult due to electronic
The 2,4-dichloroquinolines 14d–f were obtained
according to method proposed by Ziegler and Gelfert.
14
The reaction of anilines 13а–с with malonic acid in РОCl3
medium gave 2,4-dichloroquinolines 14d–f in 12–50%
yields (Scheme 3). In the case of ortho-anisidine (13b)
reaction with malonic acid, the malonic diamide 17 was
isolated from reaction mixture as by-product.
2
asymmetry of the quinoline system, therefore such
syntheses require many stages and seldom are selective. In
the current work, we aimed to find methods for the
synthesis of methoxy derivatives 10–12 from ortho-
anisidine (13b), para-anisidine (13a), or 2,4-di-
methoxyaniline (13c), respectively.
It is known that mononitration of quinolines with electron-
donating substituents at positions 6 or 8 occurs exclusively at
position 5. Such examples reported in the literature include
We assumed that cyclization of methoxyanilines 13а–с
12,13
15
16
17
according to the Conrad–Limpach method
would allow
6-alkyl-, 2,6-dimethyl-, 4-chloro-6-methyl-, 4-chloro-
17
17
18
to obtain 4-chloro-2-methylquinolines 14а–с. Indeed, the
condensation of methoxyanilines 13а–с with acetoacetic
ester, followed by heating of the azomethine intermediates
6-methoxy-, 4-chloro-6,8-dimethoxy-, 2-iodo-6-methoxy-,
4-chloro-8-methoxy-, and 2-cyano-8-hydroxyquinolines.
1
7
19
We performed nitration of 4-chloroquinoline methoxy
derivatives 14a–f with 10% excess of nitrating mixture at
0
–5°С and observed similar results, obtaining the respective
mononitro derivatives 18a–f in moderate to good yields (37–
7%) (Scheme 3). Only when nitrating the quinoline 14b,
,7-dinitro derivative 19 was isolated as minor product in
8
5
approximately 5% yield. The moderate yields in some
experiments correlated with the significant resinification
formation of the reaction mixture.
2
51

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
The structures of all nitro derivatives 18 were confirmed by
maintaining the reaction mixture at 5°С (Table 1,
experiment 2), trace amounts of the amine 20а were
observed by H NMR spectroscopy along with unreacted
spectral methods. In the case of 6-methoxy derivatives 18а,d,
1
1
the appearance of aromatic H NMR signals (two doublets
3
with coupling constant J = 9.4 Hz) clearly indicated the
starting material. It should be noted that the reactions with
dimethylamine were accompanied by significant formation
of intractable products, probably due to the increased
contribution of quinoid structures, caused by conjugation
of methoxy and nitro groups. This, in turn, may facilitate
the addition of dimethylamine at С(7)–С(8) or С(6)–С(7)
bonds of compounds 18а and 18b, respectively, giving
unstable adducts.
presence of nitro group at position 5. On the other hand, the
nitration products obtained from quinolines 14b,e could be
either 4-chloro-5-nitroquinolines 18b,e or the isomeric 7-nitro
1
derivatives, according to Н NMR spectra. The formation of
products due to substitution at position 5 was indirectly
1
evidenced by the significant decrease of H NMR coupling
constants of aromatic protons (8.5–8.6 Hz) compared to the
analogous coupling constants in 6-methoxy derivatives 18а,d
Depending on the reaction conditions, 2,4-dichloro-6(8)-
methoxy-5-nitroquinolines 18d,е can produce four different
products with dimethylamine, from substitution of one
chlorine atom (compounds 22, 23), from substitution of
two chlorine atoms (compound 24), as well as from
substitution of both chlorine atoms and the methoxy group
(compound 25) (Scheme 5, Table 2). 2,4-Dichloro-
6-methoxy-5-nitroquinoline (18d) forms only two of four
possible substitution products. It completely reacted with an
alcohol solution of dimethylamine over 6 days at room
temperature (Table 2, experiment 1), giving a mixture of
2,4-bis(dimethylamino)quinoline 24а and 4-chloro-2-di-
methylaminoquinoline 23а. The product resulting from
substitution of one chlorine atom was identified as structure
23а, not 22а, based on the chemical shift of dimethylamino
group signal (3.15 ppm), which is usually located at a
relatively downfield position in the case of 2-dimethyl-
amino group, compared to 4-dimethylamino group (3.23–
(
9.4 Hz). A clear indication of 5-nitro isomer was obtained
from NOЕSY spectrum of compound 18b, which contained a
cross peak between the protons of 8-ОСН group and the
3
aromatic Н-7 proton. Since the substitution in monomethoxy
derivatives occurred exclusively at position 5, the substitution
in 6,8-dimethoxyquinolines 14с,f apparently should also lead
to 5-nitro derivatives, especially since position 5 in these
compounds is sterically less crowded.
We further found that the treatment of compounds 18a–f
with dimethylamine solution in alcohol led to nucleophilic
substitution of not only chlorine atom, but also the
methoxy group, activated by nitro group and the ring
nitrogen atom. The direction of substitution here was
substantially affected by the substrate structure and the
reaction temperature. This observation was in line with a
17
previous report, where greater lability of methoxy group
compared to chlorine atom was described in the case of
20,21
4-chloro-8-methoxy-5-nitroquinoline
amination
with
3.24 ppm for 2-dimethylaminoquinoline,
3.23 ppm for
22
N,N-dimethylpropane-1,3-diamine.
compound 23b, 3.05 ppm for 4-dimethylaminoquinoline,
For example, both the chlorine atom and methoxy group in
-chloro-2-methyl-5-nitroquinolines 18а,b were easily
2.86 ppm for compound 22b). Increasing the reaction tempe-
rature (Table 2, experiment 2) shifted the product ratio in
favor of bis(dimethylamino) derivative 24а, but did not
produce even a trace of the trisubstituted product 25а. 2,4-Di-
chloro-8-methoxyquinoline (18е) completely reacted with
dimethylamine in alcohol solution at room temperature
over 3 days but formed a mixture of monosubstituted products
22b (major component) and 23b (minor component) in this
case (Table 2, experiment 3). This observation confirmed
4
substituted with dimethylamino group (Scheme 4, Table 1).
However, while the monoamination product 20b could be
isolated from the reaction of 8-methoxy derivative 18b at
room temperature (Table 1, experiment 5), the only product
from the reaction of 6-methoxy isomer 18а with dimethyl-
amine under analogous conditions was 4,6-bis(dimethyl-
amino)quinoline 21а (Table 1, experiment 3). Only after
Scheme 4
Тable 1. The reaction of 4-chloro-2-methyl-5-nitroquinolines 18a,b with dimethylamine
Yield, %
Experiment
Starting compound
Reaction conditions
2
0
21
1
2
3
4
5
6
18а
–15°С, 20 days
5°С, 20 days
No reaction
Trace
–
rt, 14 days
–
–
30
3
120–125°С, sealed ampoule, 3 h
rt, 20 days
18b
37
–
18
38
125–130°С, sealed ampoule, 7 h
2
52

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
Scheme 5
Table 2. The reaction of 2,4-dichloro-5-nitroquinolines 18d,e with dimethylamine
Yield, %
Experi-
Starting compound
Reaction conditions
ment
2
2
23
24
25
1
2
3
18d
rt., 6 days
90–95°С, scaled ampoule, 4 h
rt, 3 days
–
44
20
10
32
68
–
–
–
–
–
18е
64
4
5
6
7
70–80 °С, sealed ampoule, 1 h
110–120 °С, sealed ampoule, 3 h
140–145 °С, sealed ampoule, 2 h
140–145 °С, sealed ampoule, 7 h
Mixture of compounds 22–25 b
Trace
Trace
46
30
11
Trace
30
–
–
–
–
57
2
3
an earlier report by Italian chemists about the relatively
higher mobility of chlorine atom at position 4 in the amino-
dechlorination reaction of 2,4-dichloroquinoline. An increase
of reaction mixture temperature led to bis- and tris-
Scheme 6
(dimethylamino)quinolines 24b and 25b.
Maintaining the 6,8-dimethoxy derivatives 18c,f with
dimethylamine in alcohol at room temperature did not
produce complete conversion even after one month. TLC
analysis in this case indicated the formation of a mixture
containing at least six compounds, including the starting
materials. Both reactions were complete in 3 h with
heating, giving the 4-(dimethylamino) derivative 26а (40%)
and 2,4-bis(dimethylamino) derivative 26b (13%), respec-
tively (Scheme 6).
1
compound 10b. The H NMR spectrum of compound 10b
contained three singlets at 2.80, 2.88, and 3.11 ppm,
corresponding to the 4-, 5-, and 2-NMe groups (Fig. 1).
2
The attempts at obtaining compounds 11 and 12 from
the respective nitro derivatives 21 and 26 by analogous
procedure were not successful.
We were able to convert the obtained 6-methoxy-2,4-
bis(dimethylamino)-5-nitroquinoline (24а) in two steps to
the target 2,4,5-tris(dimethylamino)-6-methoxyquinoline
The basicity of compound 10b determined by competitive
24,25
method
а
in acetonitrile (рK 18.8) was somewhat higher
(
10b), the first representative of methoxy derivatives of
than that of the original proton sponge, compound 4а. The
reaction of a slight excess of triamine 10b with perchloric
acid gave its monoperchlorate 28. According to Н NMR
quinoline proton sponges (Scheme 7). The nitro
derivative 24а was first reduced with iron in aqueous
butanol in the presence of catalytic amount of acetic acid,
giving the amine 27. The subsequent methylation of
amine 27 with excess dimethylsulfate in methanol in the
presence of sodium carbonate led to the formation of
1
3
data, this salt existed in CD CN solution as a pair of cations
28а and 28b with a significant prevalence of the latter
(13:87). The proton chelated by peri-dimethylamino groups
(form 28b) gave an NMR signal at 17.98 ppm, while the
Scheme 7
2
53

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
1
3
Figure 1. The Н NMR spectra (CD CN): a) free base 10b, b) salt 28.
proton at heterocycle nitrogen atom (form 28а) gave a
signal at 9.49 ppm (Fig. 1).
aluminum foil backed Sorbfil silica gel plates (TU 26-11-17-
89), eluent CHCl3.
Thus, we have developed methods for preparing a range of
-dimethylamino-5-nitroquinoline methoxy derivatives –
necessary precursors in the synthesis of 4,5-bis(dimethyl-
amino)quinoline methoxy derivatives, and synthesized
,4,5-tris(dimethylamino)-6-methoxyquinoline – the first
representative of such compounds. As expected, the
introduction of even a single methoxy group at the ortho
position relative to the dimethylamino groups of quinoline
proton sponges resulted in stronger basicity and a
substantial shift of equilibrium in their salts towards the
form with proton chelated by peri-dimethylamino groups.
Preparation of 4-chloro-2-methylquinoline methoxy
derivatives 14а–c (General method). A mixture of
methoxyaniline 13a–c (40 mmol) and acetoacetic ester
(5.39 ml, 42 mmol) was maintained at room temperature
with periodic stirring for 14 days. The reaction mixture was
separated from the water that formed, and added in several
4
2
portions to refluxing Ph O (50 ml). Refluxing was
2
continued for 30 min. The obtained precipitate of quinolone
16а–с was filtered off, washed with hexane, and dried.
Compounds 16а–с were used in the next stage without
additional purification.
6-Methoxy-2,4,5-tris(dimethylamino)quinoline apparently
The obtained quinolone 16а–с was suspended in freshly
is the strongest base among all currently known quinoline
derivatives.
distilled POCl (20 ml, 214 mmol) and refluxed for 15 h.
The reaction mixture was cooled and poured in several
3
portions on ice, then neutralized with 10% NaOH solution.
The precipitate formed was filtered off, washed with ice
water, and dried, then dissolved in minimum amount of 1:1
Experimental
IR spectra were recorded on an FSM-1202 instrument in
vaseline oil. Н and С NMR spectra were recorded on a
CHCl
3
–benzene mixture and separated by chromatography
0.9. The
1
13
on alumina column, collecting the fraction with R
f
Bruker DPX-250 spectrometer (250 and 63 MHz,
solvent was removed by distillation, giving compounds
14а–с.
3
respectively) in CD CN (compounds 10b, 28) and in
CDCl (the rest of the compounds), with TMS as internal
3
4-Chloro-6-methoxy-2-methylquinoline (14а). Yield
1.87 g (23%), colorless crystals, mp 98–100°С (octane) (mp
standard. Mass spectra (EI, 70 eV) were recorded on a
Finnigan MAT INCOS 50 spectrometer. Elemental
analysis was performed by the Pregl–Dumas combustion
method. Melting points were determined in glass capillaries
on an SMP-30 instrument. The reaction progress and purity
of the obtained products was controlled by TLC on alumina
plates (activity grade IV according to Brockmann) or on
13 1
96–98°С) . H NMR spectrum, δ, ppm (J, Hz): 2.64 (3Н, s,
2-CH ); 3.91 (3Н, s, ОCH ); 7.28–7.39 (3Н, m, Н-3,5,7);
3
3
3
4
13
7.88 (1Н, dd, J = 7.9, J = 1.7, Н-8). C NMR spectrum,
δ, ppm: 25.2; 56.0; 102.2; 122.5; 123.4; 126.4; 130.9; 141.5;
145.1; 156.4; 158.5. Mass spectrum, m/z (Irel, %): 209
37
+
35
+
35
+
3
[M( Cl)] (38), 207 [M( Cl)] (100), 192 [M( Cl)–CH ] (42),
2
54

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
3
5
+
1
64 [M( Cl)–CH
Cl 17.09; N 6.76. С11
Н 4.85; Cl 17.07; N 6.74.
-Chloro-8-methoxy-2-methylquinoline (14b). Yield
.28 g (27%), beige crystals, mp 78–80°С (octane) (mp
3
–CO] (61). Found, %: С 63.60; Н 4.84;
(5%), large, pale-yellow needles, mp 163–165°С (EtOH).
–1
H
10ClNO. Calculated, %: С 63.62;
IR spectrum (KBr), ν, cm : 3319 (N–H), 1667 (С=О).
1
H NMR spectrum, δ, ppm (J, Hz): 3.55 (2H, s, CH
2
); 3.87
3
4
4
(6Н, s, 2OCH ); 6.86 (2Н, dd, J = 8.0, J = 1.4, H Ar); 6.94
3
3
4
3
2
8
(2Н, td, J = 7.7, J = 1.4, H Ar); 7.05 (2Н, td, J = 7.9,
2
6
1
4
3
4
0–82°С) . H NMR spectrum, δ, ppm (J, Hz): 2.73 (3H,
J = 1.7, H Ar); 8.33 (2Н, dd, J=7.9, J = 1.6, H Ar); 8.99
3
13
s, 2-CH
7
3
); 4.04 (3Н, s, OCH
3
); 7.04 (1Н, d, J = 7.7, Н-7);
(2Н, br. s, NH). C NMR spectrum, δ, ppm: 46.1; 56.2;
3
.38 (1Н, s, Н-3); 7.44 (1Н, t, J = 8.1, Н-6); 7.71 (1Н,
dd, J = 8.5, J = 0.9, Н-5). C NMR spectrum, δ, ppm:
110.6; 120.7; 121.3; 124.8; 127.6; 148.9; 165.4. Mass
3
4
13
+
spectrum, m/z (Irel, %): 314 [M] (75), 123 (98), 108 (100).
2
1
5.9; 56.6; 108.9; 116.1; 123.1; 126.2; 127.1; 140.9;
Found, %: С 64.94; Н 5.78; N 8.92. С17
%: С 64.96; Н 5.77; N 8.91.
2,4-Dichloro-6,8-dimethoxyquinoline (14f). Yield
2.08 g (12%), pale-yellow crystals, mp 186–187°С (benzene).
18 2 4
H N O . Calculated,
42.9; 155.3; 158.2. Mass spectrum, m/z (Irel, %): 209
3
7
+
35
+
35
+
+
[
(
(
M( Cl)] (24), 207 [M( Cl)] (73), 206 [M( Cl)–H]
100), 178 [M( Cl)–HCO] (96), 177 [M( Cl)–CH
3
5
+
35
2
O]
1
98). Found, %: С 63.61; Н 4.83; Cl 17.09; N 6.75.
10ClNO. Calculated, %: С 63.62; Н 4.85; Cl 17.07;
N 6.74.
-Chloro-6,8-dimethoxy-2-methylquinoline
Yield 2.95 g (31%), colorless crystals, mp 139–141°С
H NMR spectrum, δ, ppm (J, Hz): 3.83 (3H, s, 6-OCH
3
);
3
С
11
H
3.91 (3Н, s, 8-OCH
3
); 6.62 (1Н, d, J = 2.5, Н-7); 6.81 (1Н,
3
13
d, J = 2.5, Н-5); 7.36 (1Н, s, Н-3). C NMR spectrum, δ,
ppm: 55.8; 56.4; 93.7; 103.0; 122.9; 127.1; 136.6; 142.7;
146.1; 155.9; 159.5. Mass spectrum, m/z (Irel, %): 261
4
(14c).
1
37
+
37
35
+
35
+
(
2
(
octane). H NMR spectrum, δ, ppm (J, Hz): 2.68 (3Н, s,
-CH ); 3.90 (3H, s, 6-OCH ); 4.00 (3Н, s, 8-OCH ); 6.69
1Н, d, J = 2.5, Н-5(7)); 6.95 (1Н, d, J = 2.5, Н-7(5));
[M( Cl)] (8), 259 [M( Cl, Cl)] (48), 257 [M( Cl)] (75),
35
+
3
3
3
228 [M( Cl)–HCO] (100). Found, %: С 51.20; Н 3.50;
Cl 27.48; N 5.44. С11 Cl NO . Calculated, %: С 51.19;
Н 3.51; Cl 27.47; N 5.43.
3
3
H
9
2
2
13
7
5
1
.35 (1Н, s, Н-3). C NMR spectrum, δ, ppm: 25.5; 55.9;
6.7; 93.9; 102.3; 123.3; 126.8; 137.7; 141.5; 155.4; 156.4;
Nitration of 4-chloro-2-methylquinoline and 2,4-di-
chloroquinoline methoxy derivatives 14a–f (General
method). A solution of compound 14a–f (7.6 mmol) in
37
+
58.8. Mass spectrum, m/z (Irel, %): 239 [M( Cl)] (29), 237
35
+
35
+
[M( Cl)] (90), 236 [M( Cl)–H] (100). Found, %: С 60.65;
Н 5.10; Cl 14.94; N 5.88. С12
С 60.64; Н 5.09; Cl 14.92; N 5.89.
Preparation of 2,4-dichloroquinoline methoxy
derivatives 14d–f (General method). A mixture of
methoxyaniline 13а–с (61 mmol) and malonic acid (6.99 g,
H
12ClNO
2
. Calculated, %:
conc. H
addition of nitrating mixture prepared from fuming HNO
(0.35 ml, 8.4 mmol) and conc. H SO (0.70 ml, 16.0 mmol),
while maintaining the temperature at or below 0–5°С. The
reaction mixture was maintained at 5°С for 12 h, poured on
ice (30 g), the precipitate formed was filtered off and purified
2 4
SO (5 ml) at 0–5°С was treated by portionwise
3
2
4
67 mmol) was stirred for 40 min at 50–60°C. Freshly
distilled POCl (50 ml, 546 mmol) was added, and the
mixture was refluxed for 15 h. After cooling, the reaction
mixture was poured in several portions on ice, neutralized
3
by chromatography on alumina column (eluent CHCl
collecting the fractions with R 0.8–0.9. Removal of solvent by
distillation yielded compounds 18a–f.
3
),
f
with 10% NaОН solution, and extracted with CHCl
3
(2×50 ml).
4-Chloro-6-methoxy-2-methyl-5-nitroquinoline (18а).
Yield 0.91 g (47%), beige crystals, mp 109–111°С
(decomp., octane). H NMR spectrum, δ, ppm (J, Hz): 2.67
The solvent was removed by distillation, the residue was
dissolved in minimum amount of benzene and separated by
chromatography on alumina column, collecting the fraction
1
3 3
(3Н, s, 2-CH ); 4.02 (3Н, s, ОCH ); 7.43 (1Н, s, Н-3); 7.56
3
3
13
with R
compounds 14d–f.
,4-Dichloro-6-methoxyquinoline (14d). Yield 4.45 g
32%), pale-yellow crystals, mp 172–173°C (decomp.; 10:1
f
0.8. The solvent was removed by distillation, giving
(1Н, d, J = 9.4, Н-7); 8.14 (1Н, d, J = 9.4, Н-8). C NMR
spectrum, δ, ppm: 25.1; 57.7; 117.2; 126.3; 133.4; 133.9;
134.2; 137.3; 143.9; 150.1; 158.3. Mass spectrum, m/z (Irel, %):
2
3
7
+
35
+
+
(
254 [M( Cl)] (35), 252 [M( Cl)] (100), 217 [M–Cl] (96).
2
7
octane–benzene) (mp 170.5–171.5°C) . The spectral
Found, %: С 52.26; Н 3.60; Cl 14.04; N 11.07. С11
9 2 3
H ClN O .
characteristics of compound 14d matched those described
Calculated, %: С 52.29; Н 3.59; Cl 14.03; N 11.09.
4-Chloro-8-methoxy-2-methyl-5-nitroquinoline (18b).
The crude product was purified by silica gel column
27
in the literature .
,4-Dichloro-8-methoxyquinoline (14e). Yield 6.95 g
50%), colorless crystals, mp 136–137°C (octane) (mp
2
(
1
chromatography (eluent CHCl
with R 0.4, and the solvent was evaporated. Yield 1.23 g
(64%), beige crystals, mp 106–107°С (octane). H NMR
spectrum, δ, ppm (J, Hz): 2.77 (3H, s, 2-CH ); 4.12 (3Н, s,
); 6.99 (1Н, d, J = 8.6, Н-7); 7.54 (1Н, s, Н-3); 7.76
3
), collecting the fraction
2
8 1
27.5–128.5°C) . H NMR spectrum, δ, ppm (J, Hz): 4.02 (3Н,
f
3
4
1
s, ОCH
3
); 7.09 (1Н, dd, J = 7.9, J = 1.0, Н-7(5)); 7.47–7.54
2Н, m, Н-3,6); 7.68 (1Н, dd, J = 8.5, J = 1.1, Н-5(7)).
C NMR spectrum, δ, ppm: 56.7; 110.2; 115.9; 116.0;
3
4
(
3
1
3
3
OCH
3
3
13
1
23.1; 128.5; 140.3; 144.7; 149.3; 155.2. Mass spectrum,
(1Н, d, J = 8.6, Н-6). C NMR spectrum, δ, ppm: 25.6;
3
7
+
37
35
+
m/z (Irel, %): 231 [M( Cl)] (3), 229 [M( Cl, Cl)] (45),
2
1
57.4; 106.4; 118.5; 124.6; 126.8; 139.8; 140.5; 141.2;
35
+
35
+
37
+
27 [M ( Cl)] (75), 226 [M( Cl)–H] (92), 198 (100),
158.2; 159.9. Mass spectrum, m/z (Irel, %): 254 [M( Cl)]
35
+
+
62 (86). Found, %: С 52.63; Н 3.10; Cl.08; N 6.12.
(6), 252 [M( Cl)] (18), 217 [M–Cl] (88), 187 (100).
С
10
H
7
Cl
N 6.14.
N,N'-bis-(2-methoxyphenyl)malonodiamide (17) was
isolated from the second fraction with R 0.3. Yield 0.48 g
2
NO. Calculated, %: С 52.66; Н3.09; Cl 31.09;
Found, %: С 52.27; Н 3.60; Cl 14.05; N 11.07. С11
Calculated, %: С 52.29; Н 3.59; Cl 14.03; N 11.09.
9 2 3
H ClN O .
f
The fraction with R 0.6 contained 4-chloro-8-methoxy-
f
2-methyl-5,7-dinitroquinoline (19). Yield 0.113 g (5%),
2
55

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
1
bright-yellow crystals, mp 97–99°С (octane). H NMR
The reaction mixture was evaporated, the residue was
separated by silica gel column chromatography with CHCl
as eluent.
The following methods provided the optimum yields of
reaction products.
spectrum, δ, ppm (J, Hz): 2.80 (3H, s, 2-CH
OCH ); 7.63 (1Н, s, Н-3); 8.11 (1Н, s, Н-6). C NMR
spectrum, δ, ppm: 25.3; 65.2; 117.9; 119.9; 127.8; 139.7;
40.2; 141.2; 144.7; 153.0; 161.3. Mass spectrum, m/z (Irel, %):
3
); 4.42 (3Н, s,
3
13
3
1
2
37
+
35
+
35
+
4
4
6
6
99 [M( Cl)] (1), 297 [M( Cl)] (3), 267 [M( Cl)–CH
100). Found, %: С 44.37; Н 2.72; Cl 11.90; N 14.11.
ClN . Calculated, %: С 44.39; Н 2.71; Cl 11.91;
N 14.12.
-Chloro-6,8-dimethoxy-2-methyl-5-nitroquinoline
18c). Yield 0.79 g (37%), pale-yellow crystals, mp
2
O]
Compound 18a (253 mg, 1 mmol) gave N ,N ,N ,N ,2-
pentamethyl-5-nitroquinoline-4,6-diamine (21a) (fraction
(
С H
11 8
3
O
5
f
with R 0.4) after maintaining the reaction mixture for
14 days according to method A. Yield 83 mg (30%).
Compound 18b (253 mg, 1 mmol) gave N ,N ,N ,N ,2-
pentamethyl-5-nitroquinoline-4,8-diamine (21b) (fraction
4
4
8
8
4
(
1
1
2
6
79–181°С (benzene). H NMR spectrum, δ, ppm (J, Hz):
.70 (3Н, s, 2-CH ); 4.01 (3H, s, 8-OCH ); 4.11 (3Н, s,
-OCH ); 6.82 (1Н, s, Н-7); 7.45 (1Н, s, Н-3). C NMR
with R
trimethyl-5-nitroquinoline-4-amine (20b) (fraction with
0.2, yield 97 mg (39%)) after maintaining the reaction
f
0.4, yield 50 mg (19%)) and 8-methoxy-N,N,2-
3
3
1
3
3
R
f
spectrum, δ, ppm: 24.9; 56.9; 57.2; 95.9; 118.0; 126.7;
35.5; 137.3; 150.7; 156.7; 157.6. Found, %: С 50.97;
Н 3.94; Cl 12.53; N 9.90. С12 . Calculated, %:
С 50.99; Н 3.92; Cl 12.54; N 9.91.
,4-Dichloro-6-methoxy-5-nitroquinoline (18d). Yield
.80 g (87%), Gray-green crystals, mp 157–159°С
mixture for 20 days according to method А.
Compound 18b (252 mg, 1 mmol) gave compound 21b
f
(fraction with R 0.4) after heating the reaction mixture for
7 h at 125–130°С according to method B. Yield 104 g
(38%).
Compound 18c (283 mg, 1 mmol) gave 6,8-dimethoxy-
N,N,2-trimethyl-5-nitroquinoline-4-amine (26a) (fraction
1
H
11ClN
2
O
4
2
1
1
(
(
decomp., EtOH). H NMR spectrum, δ, ppm (J, Hz): 4.02
3
3Н, s, ОCH
3
); 7.51 (1Н, s, Н-3); 7.60 (1Н, d, J = 9.5,
f
with R 0.3) after heating the reaction mixture at 80–85°С
3
13
Н-7); 8.08 (1Н, d, J = 9.4, Н-8). C NMR spectrum, δ,
for 3 h according to method B. Yield 116 mg (40%).
Compound 18d (546 mg, 2 mmol) gave 4-chloro-
6-methoxy-N,N-dimethyl-5-nitroquinoline-2-amine (23а)
ppm: 57.3; 117.3; 117.9; 125.7; 132.9; 133.7; 138.8; 142.6;
3
7
+
1
(
[
48.8; 150.5. Mass spectrum, m/z (Irel, %): 276 [M( Cl)]
37
35
+
35
+
9), 274 [M( Cl, Cl)] (62), 272 [M( Cl)] (97), 237
M–Сl] (100). Found, %: С 43.96; Н 2.22; Cl 25.95;
(fraction with R
f
0.4, yield 248 mg (44%)) and 6-methoxy-
N ,N ,N ,N -tetramethyl-5-nitroquinoline-2,4-diamine
(24а) (fraction with R 0.2, yield 186 mg (32%)) after
+
2
2
4
4
N 10.27. С10
Cl 25.97; N 10.26.
,4-Dichloro-8-methoxy-5-nitroquinoline (18e). Yield
.22 g (59%), beige crystals, mp 153–154°С (octane).
H
6
Cl
2
N
2
O
3
. Calculated, %: С 43.98; Н 2.21;
f
maintaining the reaction mixture for 6 days according to
method А.
Compound 18e (118 mg, 0.43 mmol) gave 4-chloro-
8-methoxy-N,N-dimethyl-5-nitroquinoline-2-amine (23b)
2
1
1
H NMR spectrum, δ, ppm (J, Hz): 4.12 (3Н, s, ОCH
3
);
3
7
.07 (1Н, d, J = 8.6, Н-7); 7.66 (1Н, s, Н-3); 7.83 (1Н, d,
(fraction with R
8-methoxy-N,N-dimethyl-5-nitroquinoline-4-amine (22b)
(fraction with R 0.2, yield 78 mg (64%)) after maintaining
f
0.3, yield 12 mg (10%)) and 2-chloro-
3
13
J = 8.6, Н-6). C NMR spectrum, δ, ppm: 57.4; 107.7;
19.0; 125.7; 126.9; 140.2; 140.5; 141.7; 151.1; 157.9.
1
f
3
7
35
+
Mass spectrum, m/z (Irel, %): 274 [M( Cl, Cl)] (1), 272
the reaction mixture for 3 days according to method А.
Compound 18e (164 mg, 0.6 mmol) gave 8-methoxy-
35
+
+
[
M( Cl)] (3), 207 (38), 30 [CH
С 43.96; Н 2.20; Cl 25.94; N 10.28. С10
Calculated, %: С 43.98; Н 2.21; Cl 25.97; N 10.26.
,4-Dichloro-6,8-dimethoxy-5-nitroquinoline
Yield 0.99 g (43%), beige crystals, mp 238–239°С (n-BuOH).
2
O] (100). Found, %:
2
2
4
4
H
6
Cl
2
N
2
O
3
.
N ,N ,N ,N -tetramethyl-5-nitroquinoline-2,4-diamine
(24b) (fraction with R 0.5) after maintaining the reaction
f
2
(18f).
);
mixture at 110–120°С for 3 h according to method B. Yield
79 mg (46%).
1
H NMR spectrum, δ, ppm (J, Hz): 4.04 (3H, s, 8-OCH
.12 (3Н, s, 6-OCH ); 6.87 (1Н, s, Н-7); 7.58 (1Н, s, Н-3).
3
Compound 18e (103 mg, 0.38 mmol) gave compound
4
3
24b (fraction with R
f
0.5, yield 12 mg (11%)) and
N ,N ,N ,N ,N ,N -hexamethyl-5-nitroquinoline-2,4,8-tri-
amine (25b) (fraction with R 0.4, yield 66 mg (57%)) after
1
3
2
2
4
4
8
8
C NMR spectrum, δ, ppm: 56.9; 57.3; 96.8; 118.6; 126.6;
27.6; 134.7; 139.2; 147.8; 151.8; 157.5. Found, %: С 43.57;
1
f
Н 2.65; Cl 23.41; N 9.23. С11
С 43.59; Н 2.66; Cl 23.39; N 9.24.
Reaction of 4-chloro-5-nitroquinoline methoxy derivatives
H
8
Cl
2
N
2
O
4
. Calculated, %:
heating the reaction mixture at 140–145°С for 7 h
according to method B.
Compound 18f (300 mg, 1 mmol) gave 6,8-dimethoxy-
N ,N ,N ,N -tetramethyl-5-nitroquinoline-2,4-diamine
(26b) (fraction with R 0.4) after heating the reaction
2
2
4
4
18a–f with dimethylamine (General method).
A. A solution or suspension of compound 18a–f
f
(
2
1 mmol) and liquid Me NH (1 ml, 15 mmol) in EtOH
mixture at 140–145°С for 3 h according to method B. Yield
(5 ml) was maintained at room temperature for 3–20 days.
42 mg (13%).
The reaction mixture was evaporated, the residue was
separated by silica gel column chromatography with CHCl
as eluent.
B. A mixture of compound 18a–f (1 mmol), EtOH (3 ml),
and liquid Me NH (1 ml, 15 mmol) was sealed in an
Compound 20b. Orange crystals, mp 163–164°С (octane).
1
3
H NMR spectrum, δ, ppm (J, Hz): 2.69 (3H, s, 2-CH
3
); 2.83
(6Н, s, N(СH
3
)
2
); 4.09 (3Н, s, ОCH3
3
); 6.82 (1Н, s, Н-3); 6.89
3
13
(1Н, d, J = 8.5, Н-7); 7.79 (1Н, d, J = 8.5, Н-6). C NMR
spectrum, δ, ppm: 25.7; 42.7; 56.7; 104.6; 110.6; 113.3;
122.7; 141.8; 142.0; 155.3; 158.5; 159.5. Mass spectrum, m/z
2
ampoule. The ampoule was placed in a safety vessel and
maintained for 2–7 h at 80–145°С, then cooled and opened.
+
+
2
(Irel, %): 261 [M] (61), 215 [M–NO ] (100). Found, %:
2
56

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
С 59.74; Н 5.78; N 16.10. С13
С 59.76; Н 5.79; N 16.08.
H
15
N
3
O
3
. Calculated, %:
Compound 24b. Orange crystals, mp 182–183°С
(octane). H NMR spectrum, δ, ppm (J, Hz): 2.75 (6Н, s,
1
Compound 21a. Beige crystals, mp 127–128°С (octane).
4-N(СH
3 2 3 2 3
) ); 3.22 (6H, s, 2-N(СH ) ); 4.02 (3Н, s, OCH );
1
3
H NMR spectrum, δ, ppm (J, Hz): 2.64 (3H, s, 2-CH
3
);
6.27 (1Н, s, Н-3); 6.75 (1Н, d, J = 8.4, Н-7); 7.42 (1Н, d,
3
13
2
.65 (6Н, s, 4-N(СH ); 2.78 (6Н, s, 6-N(СH ); 6.98 (1Н,
3
)
2
3
)
2
J = 8.4, Н-6). C NMR spectrum, δ, ppm: 38.2; 43.5;
56.9; 97.7; 105.6; 110.5; 118.6; 142.5; 142.7; 157.2; 158.9.
3
3
s, Н-3); 7.61 (1Н, d, J = 9.1, Н-7); 8.01 (1Н, d, J = 9.1,
Н-8). C NMR spectrum, δ, ppm: 25.6; 45.6; 45.9; 114.9;
16.6; 124.2; 132.1; 142.5; 144.3; 147.2; 157.8; 159.9. Mass
13
+
+
Mass spectrum, m/z (Irel, %): 290 [M] (100), 275 [M–CH
(21), 214 (44). Found, %: С 57.94; Н 6.24; N 19.32.
. Calculated, %: С 57.92; Н 6.25; N 19.30.
Compound 25b. Bright-red crystals, mp 175–176°С
3
]
1
+
+
spectrum, m/z (Irel, %): 274 [M] (50), 228 [M–NO
2
] (54),
14 18 4 3
С H N O
1
С
85 (100). Found, %: С 61.34; Н 6.60; N 20.40.
1
14
H
18
N
4
O
2
. Calculated, %: С 61.30; Н 6.61; N 20.42.
(octane). H NMR spectrum, δ, ppm (J, Hz): 2.73 (6Н, s,
4 N(СH ); 3.12 (6H, s, 8-N(СH ); 3.16 (6H, s,
2-N(СH ); 6.19 (1Н, s, Н-3); 6.65 (1Н, d, J = 8.4, Н-7);
Compound 21b. Red crystals, mp 136–137°С (octane).
3
)
)
3 2
2
3 2
)
1
3
H NMR spectrum, δ, ppm (J, Hz): 2.63 (3H, s, 2-CH
3
);
3
13
2
6
.82 (6Н, s, 4-N(СH
.75 (2Н, m, Н-3,7); 7.74 (1Н, d, J = 8.5, Н-6). C NMR
3
)
2
); 3.18 (6Н, s, 8-N(СH
3
)
2
); 6.72–
7.40 (1Н, d, J = 8.4, Н-6). C NMR spectrum, δ, ppm:
38.5; 43.3; 43.9; 96.6; 110.5; 111.6; 119.5; 142.0; 143.9;
151.7; 157.3; 157.4. Mass spectrum, m/z (Irel, %): 303
3
13
spectrum, δ, ppm: 25.4; 42.4; 44.1; 109.2; 110.3; 113.6;
23.3; 140.6; 143.4; 153.7; 155.2; 156.5. Found, %: С 61.33;
+
+
1
3
[M] (100), 288 [M–CH ] (72), 241 (100), 227 (48). Found,
Н 6.59; N 20.41. С14
Н 6.61; N 20.42.
H
18
N
4
O
2
. Calculated, %: С 61.30;
%: С 59.36; Н 6.99; N 23.10. С15
С 59.39; Н 6.98; N 23.09.
21 5 2
H N O . Calculated, %:
Compound 22b. Orange crystals, mp 134–135°С
benzene). H NMR spectrum, δ, ppm (J, Hz): 2.86 (6Н, s,
Compound 26a. Orange crystals, mp 118–119°С
(decomp., octane). H NMR spectrum, δ, ppm (J, Hz): 2.66
1
1
(
N(СH
3
)
2
); 4.05 (3Н, s, OCH
3
); 6.84 (1Н, s, Н-3); 6.88 (1Н,
(6Н, s, N(СH
3
)
2
); 2.69 (3Н, s, 2-CH
3
); 3.99 (3H, s,
3
3
13
d, J = 8.6, Н-7); 7.87 (1Н, d, J = 8.6, Н-6). C NMR
spectrum, δ, ppm: 42.8; 57.1; 106.0; 109.9; 113.7; 124.4;
8-OCH ); 4.10 (3Н, s, 6-OCH
3
3
); 6.74 (1Н, s, Н-7); 7.01
13
(1Н, s, Н-3). C NMR spectrum, δ, ppm: 25.4; 44.7; 56.6;
1
41.9; 152.4; 156.9; 158.9. Mass spectrum, m/z (Irel, %): 283
57.3; 95.2; 115.1; 117.2; 136.2; 143.2; 149.6; 156.8; 157.6;
37
+
35
+
35
+
[
(
С
M( Cl)] (30), 281 [M( Cl)] (85), 235 [M( Cl)–NO
100). Found, %: С 51.17; Н 4.28; Cl 12.58; N 14.93.
. Calculated, %: С 51.17; Н 4.29; Cl 12.59;
2
]
157.8. Found, %: С 57.70; Н 5.89; N 14.43. С14
Calculated, %: С 57.72; Н 5.88; N 14.42.
17 3 4
H N O .
12
H
12ClN
3
O
3
Compound 26b. Brown crystals, mp 168–169°С.
1
N 14.92.
Compound 23a. Yellow needles, mp 173–174°С (EtOH).
H NMR spectrum, δ, ppm (J, Hz): 2.63 (6Н, s, 4-N(СH
3.20 (6Н, s, 2-N(СH ); 3.93 (3Н, s, 6-OCH ); 4.04 (3Н, s,
8-OCH ); 6.53 (1Н, s, H-3); 6.67 (1Н, s, H-7). C NMR
3 2
) );
3
)
2
3
1
13
H NMR spectrum, δ, ppm (J, Hz): 3.15 (6Н, s,
N(СH ); 3.93 (3Н, s, OCH ); 6.99 (1Н, s, Н-3); 7.36 (1Н, d,
3
)
3 2
3
spectrum, δ, ppm: 37.9; 44.7; 56.6; 57.6; 96.6; 101.5;
112.6; 128.3; 146.4; 155.8; 157.3; 158.1. Found, %:
3
3
13
J = 9.4, Н-7); 7.76 (1Н, d, J = 9.4, Н-8). C NMR spectrum,
δ, ppm: 37.8; 57.4; 111.9; 112.7; 117.0; 130.3; 134.7; 137.2;
С 56.26; Н 6.30; N 17.47. С15
С 56.24; Н 6.29; N 17.49.
6-Methoxy-N ,N ,N ,N -tetramethylquinoline-2,4,5-tri-
amine (27). A mixture of compound 24a (145 mg,
0.5 mmol), iron powder (280 mg, 5.0 mmol), n-BuOH
20 4 4
H N O . Calculated, %:
144.2; 146.3; 156.1. Mass spectrum, m/z (Irel, %): 283
37
+
35
+
35
+
2
2
4
4
[
(
M( Cl)] (35), 281 [M( Cl)] (100), 252 [M( Cl)–HCO]
31). Found, %: С 51.18; Н 4.28; Cl 12.60; N 14.90.
. Calculated, %: С 51.17; Н 4.29; Cl 12.59;
12 3 3
С H12ClN O
N 14.92.
(3 ml), H
6 h. The solution was filtered while hot, then cooled. The
precipitate formed was filtered off, dissolved in CHCl
(5 ml), and purified by chromatography on alumina column
(eluent CНCl ), collecting the fraction with R 0.3. Yield
105 mg (81%), yellowish-orange needles, mp 136–137°C
2
O (1 ml), and 5 drops of AcOH was refluxed for
Compound 23b. Yellowish-orange crystals, mp 134–135°С
1
(
isooctane). H NMR spectrum, δ, ppm (J, Hz): 3.23 (6Н, s,
3
3
N(СH
3
)
2
); 4.03 (3Н, s, OCH
3
); 6.83 (1Н, d, J= 8.5, H-7);
3
13
7
.03 (1Н, s, H-3); 7.43 (1Н, d, J=8.5, H-6). C NMR
3
f
spectrum, δ, ppm: 38.1; 57.1; 106.6; 112.7; 113.5; 119.8;
–1
1
1
39.9; 141.2; 141.7; 156.7; 157.2. Mass spectrum, m/z (Irel
,
(EtOH). IR spectrum, ν, cm : 3353, 3466 (NH
spectrum, δ, ppm (J, Hz): 2.75 (6Н, s,
4-N(СH ); 3.14 (6Н, s, 2-N(СH ); 3.87 (3Н, s, OCH );
5.63 (1Н, br. s, NH ); 6.33 (1Н, s, Н-3); 7.02 (1Н, d, J = 8.9,
2
). H NMR
3
7
+
35
+
%
): 283 [M( Cl)] (32), 281 [M( Cl)] (100), 252
35
+
[
M( Cl)–HCO] (33). Found, %: С 51.17; Н 4.27;
Cl 12.57; N 14.94. С12 . Calculated, %: С 51.17;
Н 4.29; Cl 12.59; N 14.92.
3
)
2
3
)
2
3
3
H
12ClN
3
O
3
2
3
13
Н-7); 7.14 (1Н, d, J = 8.9, Н-8). C NMR spectrum, δ,
ppm: 38.1; 45.0; 56.7; 96.4; 107.9; 113.8; 115.5; 133.1;
139.6; 145.9; 157.1; 160.5. Mass spectrum, m/z (Irel, %):
Compound 24a. Orange needles, mp 209–211°С
1
(
benzene–octane, 2:1). H NMR spectrum, δ, ppm (J, Hz):
+
+
+
2
.61 (6Н, s, 4-N(СH
3
)
2
); 3.15 (6H, s, 2-N(СH
3
)
2
); 3.90 (3Н,
260 [M] (83), 245 [M–CH
3
] (100), 230 [M–CH
2
O] (18).
O.
3
s, OCH ); 6.56 (1Н, s, Н-3); 7.28 (1Н, d, J = 9.3, Н-7);
3
Found, %: С 64.57; Н 7.75; N 21.50. С14
Calculated, %: С 64.59; Н 7.74; N 21.52.
6-Methoxy-N ,N ,N ,N ,N ,N -hexamethylquinoline-
2,4,5-triamine (10b). A solution of compound 27 (0.041 g,
20 4
H N
3
13
7
3
1
.71 (1Н, d, J = 9.3, Н-8). C NMR spectrum, δ, ppm:
8.4; 45.5; 57.8; 102.4; 112.6; 116.5; 129.8; 135.9; 145.2;
46.0; 158.1; 158.3. Mass spectrum, m/z (Irel, %): 290 [M]
2
2
4
4
5
5
+
+
+
(
100), 275 [M–CH
3
] (46), 255 (75), 244 [M–NO
2
] (82).
0.16 mmol) in MeOH (5 ml) was treated with Na
(0.450 g, 1.58 mmol) and Me SO (0.147 ml, 1.58 mmol).
The mixture was stirred at room temperature for 96 h. The
2 3 2
CO ·10H O
Found, %: С 57.90; Н 6.26; N 19.31. С14
Calculated, %: С 57.92; Н 6.25; N 19.30.
H
18
N
4
O
3
.
2
4
2
57

Chemistry of Heterocyclic Compounds 2015, 51(3), 250–258
solvent was evaporated, the residue was dissolved in a
minimum amount of 1:1 CHCl –acetone mixture and
separated by alumina column chromatography by eluting
3. Pozharskii, A. F. Russ. Chem. Rev. 1998, 67, 1. [Usp. Khim.
998, 67, 3.]
. Pozharskii, A. F.; Ozeryanskii, V. A.; Filatova, E. A. Chem.
1
3
4
Heterocycl. Compd. 2012, 48, 200. [Khim. Geterocycl.
Soedin. 2012, 208.]
with the same mixture and collecting the fraction with
1
R
f
0.3. Yield 41 mg (90%), light-brown oil. H NMR
5
. Alder, R. W.; Goode, N. C.; Miller, N.; Hibbert, F.; Hunte. K. P. P.;
spectrum (CDCl
2
3
), δ, ppm (J, Hz): 2.80 (6Н, s, 4-N(СH
.86 (6Н, s, 5-N(СH ); 3.13 (6Н, s, 2-N(СH ); 3.75 (3Н,
); 6.06 (1Н, s, Н-3); 7.14 (1Н, d, J = 9.0, Н-7);
3 2
) );
Robbins, H. J. J. Chem. Soc., Chem. Commun. 1978, 89.
6. Hibbert, F.; Hunte, K. P. P. J. Chem. Soc., Perkin Trans. 2
1983, 1895.
7. Pozharskii, A. F.; Ryabtsova, O. V.; Ozeryanskii, V. A.;
Degtyarev, A. V.; Kazheva, O. N.; Alexandrov, G. G.;
Dyachenko, O. A. J. Org. Chem. 2003, 68, 10109.
8. Hibbert, F. J. Chem. Soc., Perkin Trans. 2 1974, 1862.
3
)
2
3
)
2
3
s, OCH
3
3
1
7
.31 (1Н, d, J = 9.1, Н-8). H NMR spectrum, δ, ppm (J,
Hz): 2.80 (6Н, s, 4-N(СH ); 2.88 (6Н, s, 5-N(СH ); 3.11
6Н, s, 2-N(СH ); 3.75 (3Н, s, OCH ); 6.20 (1Н, s, Н-3);
.20 (2Н, s, Н-7,8). C NMR spectrum, δ, ppm: 38.0; 43.7;
3
)
2
3 2
)
(
3
)
2
3
1
3
7
4
1
9
. Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.;
Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
0. Ozeryanskii, V. A.; Milov, A. A.; Minkin, V. I.; Pozharskii, A. F.
Angew. Chem., Int. Ed. 2006, 45, 1453.
4.1; 58.6; 94.2; 113.6; 119.4; 121.9; 137.6; 147.5; 150.8;
57.8; 158.7. Found,%: С 66.63; Н 8.40; N 19.42.
1
16 24 4
С H N O. Calculated, %: С 66.64; Н 8.39; N 19.43.
2
2
4
4
5
5
6
-Methoxy-N ,N ,N ,N ,N ,N -hexamethylquinoline-
11. Staab, H. A.; Kriege, C.; Hieber, G.; Oberdorf, K. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1884.
2
1
,4,5-triamine perchlorate (28). A solution of quinoline
0b (28.0 mg, 0.097 mmol) in MeCN (1 ml) was treated
1
1
2. Conrad, M.; Limpach, L. Ber. 1888, 21(1), 1649.
3. Rubtsov, M. V.; Baichikov, A. G. Synthetic Chemico-
pharmaceutical Preparations; Meditsina: Moscow, 1971,
p. 222.
with a solution of 63% HClO
.8 equiv) in MeCN (1 ml). The solvent was evaporated,
the excess of base 10b was removed by extraction with
Et O (4×2 ml). Yield 27 mg (90%), beige crystals, mp
34-237°С. H NMR spectrum, δ, ppm (J, Hz) (a mixture
of forms 28а and 28b in 13:87 ratio): 2.89 (0.78H, s,
-N(CH (28a)); 3.01 (0.78H, s, 4-N(CH (28a)); 3.01
5.22H, d, J = 1.4, 4-N(CH (28b)); 3.20 (5.22H, s,
-N(CH (28b)); 3.22 (0.78H, s, 2-N(CH (28a)); 3.26
5.22H, d, J = 3.7, 5-N(CH (28b)); 3.83 (0.39H, s,
ОCH (28a)); 4.05 (2.61Н, s, ОCH (28b)); 5.79 (0.13H, s,
4
(12.3 mg, 0.077 mmol,
0
14. Ziegler, E.; Gelfert, K. Monatsh. Chem. 1959, 90, 822.
2
15. Long, R.; Schofield, K. J. Chem. Soc. 1953, 2350.
16. Bowen, D. M.; Belfit, R. W., Jr.; Walser, R. A. J. Am. Chem.
Soc. 1953, 75, 4307.
1
2
17. Denny, W. A.; Atwell, G. J.; Roberts, P. B.; Anderson, R. F.;
5
(
3
)
2
3 2
)
3
Boyd, M.; Lock, C. J. L.; Wilson, W. R. J. Med. Chem. 1992,
3 2
)
3
5, 4832.
8. Kimber, M.; Anderberg, P. I.; Harding, M. M. Tetrahedron
000, 56, 3575.
9. Noar, J. B.; Bruice, T. C. J. Org.Chem. 1987, 52, 1942.
2
(
3
)
2
3 2
)
1
1
3
3 2
)
2
3
3
Н-3 (28а)); 7.23 (0.87H, s, Н-3 (28b)); 7.32 (0.26H, s,
20. Poola, B.; Choung, W.; Nantz, M. H. Tetrahedron 2008, 64,
3
Н-7,8 (28а)); 7.57 (0.87H, d, J = 9.5, Н-7 (28b)); 7.75
10798.
3
+
2
2
2
2
1. Lundgren, R. J.; Sappong-Kumankumah, A.; Stradiotto, M.
Chem. Eur. J. 2010, 16, 1983.
2. McCurdy, A.; Jimenez, L.; Stauffer, D. A.; Dougherty, D. A.
J. Am. Chem. Soc. 1992, 114, 10314.
3. Genel, F.; Illuminati, G.; Marino, G. J. Am. Chem. Soc. 1967,
(
(
0.87H, d, J = 9.4, Н-8 (28b)); 9.49 (0.13H, br. s, N H
+
28a)); 17.98 (0.87H, br. s, N H (28b)).
This work received financial support from the Russian
Foundation for Basic Research (project No. 14-03-00010).
8
9, 3516.
4. Birchal, T.; Jolly, W. L. J. Am. Chem. Soc. 1966, 88, 5439.
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58