6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, a red compound class with solvent and pH independent green fluorescence maxima

Article abstract of DOI:10.1002/jhet.1758

The sodium p-toluenesulfinate mediated reaction of potassium cyanide with 4-chlorocarbostyrils 8, 16, 18, and 23 gave in all cases the highly fluorescent and stable 6-methoxy-2-oxoquinoline-3,4-dicarbonitrile 9 (λ_exc 460 nm and λ_em 545 nm). This is remarkable, because starting carbostyrils 8, 16, 18, and 23 had a chloro substituent, a nitro substituent, an acetylamino substituent, or a piperidinyl substituent in position 3. Hence, we observed not only a substitution of the 4-chloro and expected 3-chloro substituents by the cyanide nucleophile but also an exchange of a nitro substituent, an acetylamino substituent, and a piperidinyl substituent in position 3. The multistep insertion of substituents leading to 8, 16, 18, and 23 started from 4-hydroxy-6-methoxyquinolone 4, easily obtained from p-anisidine and malonic acid. Substitutions in position 3 gave 4-hydroxy-3-nitro and 3-chloro intermediates, which were converted to 3,4-dichlorocarbostyril 8 and 4-chloro-3-nitrocarbostyril 16. Reduction of the 3-nitro intermediate led to the 3-acetylamino analog and subsequent chlorination led to 3-acetylamino-4- chlorocarbostyril 18. 4-Chloro-3-piperidinylcarbostyril 23 was obtained from intermediate 3,3-dichloroquinolinedione by subsequent amination, reduction and chlorination. Further, 3-acetylamino-4-chlorocarbostyril 18 gave with lithium p-toluenesulfinate highly fluorescent 3-amino-6-methoxy-4-p- tolylsulfonylquinolone 19.

Full text of DOI:10.1002/jhet.1758

492
6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, A Red
Compound Class with Solvent and pH Independent Green
Fluorescence Maxima
Vol 51
*
G. C. Enoua, G. Lahm, G. Uray, and W. Stadlbauer
Department of Chemistry, Organic Synthesis Group, Karl-Franzens University of Graz,
Heinrichstrasse 28, A-8010 Graz, Austria
*
E-mail: wolfgang.stadlbauer@uni-graz.at
Received February 25, 2012
DOI 10.1002/jhet.1758
Published online 20 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
CN
CN
MeO
KCN
OH
Cl
p-MePhSO2Na
MeO
N
H
O
X
MeO
9
N
H
O
p-MePhSO2Li
N
H
O
O
4
8: X = Cl
16: X = NO2
18: X = NH-Ac
X = NH-Ac
S
O
MeO
NH2
O
23: X = 1-piperidinyl
N
H
19
The sodium p-toluenesulfinate mediated reaction of potassium cyanide with 4-chlorocarbostyrils 8,
16, 18, and 23 gave in all cases the highly fluorescent and stable 6-methoxy-2-oxoquinoline-3,4-dicarbonitrile
9 (lexc 460 nm and lem 545 nm). This is remarkable, because starting carbostyrils 8, 16, 18, and 23 had a
chloro substituent, a nitro substituent, an acetylamino substituent, or a piperidinyl substituent in position 3.
Hence, we observed not only a substitution of the 4-chloro and expected 3-chloro substituents by the cyanide
nucleophile but also an exchange of a nitro substituent, an acetylamino substituent, and a piperidinyl
substituent in position 3. The multistep insertion of substituents leading to 8, 16, 18, and 23 started from
4-hydroxy-6-methoxyquinolone 4, easily obtained from p-anisidine and malonic acid. Substitutions in posi-
tion 3 gave 4-hydroxy-3-nitro and 3-chloro intermediates, which were converted to 3,4-dichlorocarbostyril
8 and 4-chloro-3-nitrocarbostyril 16. Reduction of the 3-nitro intermediate led to the 3-acetylamino analog
and subsequent chlorination led to 3-acetylamino-4-chlorocarbostyril 18. 4-Chloro-3-piperidinylcarbostyril
23 was obtained from intermediate 3,3-dichloroquinolinedione by subsequent amination, reduction and
chlorination. Further, 3-acetylamino-4-chlorocarbostyril 18 gave with lithium p-toluenesulfinate highly
fluorescent 3-amino-6-methoxy-4-p-tolylsulfonylquinolone 19.
J. Heterocyclic Chem., 51, 492 (2014).
INTRODUCTION
containing a variety of substituents in position 3 to
study the influence of donor and acceptor groups on the
electronic spectra.
In earlier investigations, we have shown that
6,7-dimethoxy-4-trifluoromethylcarbostyrils [1] and 4-cyano-
6,7-dimethoxycarbostyrils [2] are highly fluorescent
compounds with emission values up to 440 nm, and high
quantum yields up to 0.6. Together with further properties
such as a high thermal and photochemical stability and no
oxygen quenching make them very useful as new fluorophors
(e.g. shown in Ref. [3]) suitable to outclass similar and
wide-used coumarin derivatives [4]. In a recent project, we
reported about the interesting fluorescence properties of
3-aryl-4-cyano-6-methoxycarbostyrils [5] with excitation
wavelengths above 400 nm and emission wavelengths above
500 nm, with quantum yields of about Φ = 0.23. Attempts for
a fine tuning of these values with donor and acceptor substi-
tuents at the aryl nucleus in position 3 showed no significant
effect (the emission values range between 503 and 510nm).
In this communication, we report about our investigation on
the synthesis of derivatives of 4-cyano-6-methoxycarbostyrils
RESULTS AND DISCUSSION
Synthesis. 4-Hydroxy-6-methoxy-2-quinolone (4) serves
as starting compound for the planned multistep syntheses
of the desired fluorescent 4-cyano-6-methoxycarbostyrils. In
the literature, several syntheses for quinolone 4 are
published, starting from p-anisidine (1) that cyclized to the
quinoline nucleus either with diethylmalonate [6], malonic
acid [7], or Meldrum’s acid [8]; another approach to 4 was
reported starting from 5-methoxy-nitrobenzoyl chloride and
diethyl malonate followed by reduction [9]. Our approach
started from p-anisidine (1) and malonic acid (2) using
phosphoryl chloride as cyclization agent similar as described
in Refs. [7,10]. Phosphoryl chloride is reported to act in two
© 2013 HeteroCorporation

March 2014
6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, A Red Compound Class
with Solvent and pH Independent Green Fluorescence Maxima
493
steps, first to convert malonic acid (2) to a reactive malonic-
halfamide intermediate, and then as cyclocondensation agent
for the acylation at the reactive aromatic amine 1. In the
literature [7,10], quinolone 4 was obtained in 63% yield;
and as by-product, N,N0-bis(4-methoxyphenyl)malonamide
(3) was obtained in 32% yield. Optimization attempts by
changing the ratio of p-anisidine, malonic acid, and
phosphoryl chloride, reaction time and work-up gave best
results when only a small excess of phosphoryl chloride and
a reaction temperature of 90–95 ꢀC for 90 min were used,
then pouring the mixture onto ice water and doing work-up
by dissolving the crude material in a large excess of 1 M
sodium hydroxide solution. In this case, 4 was obtained in
73% yield together with 19% of the dianilide 3 as by-
product. Scheme 1.
In order to introduce electron acceptor substituents in
position 3 of quinolone 4, two approaches were chosen:
chlorination and nitration. Electrophilic chlorination with
sulfuryl chloride provides a Cl+ source known to give in
similar systems 3,3-dichloroquinolinediones [11]; a radical
process can be ruled out because all requirements for this
reaction type such as high temperature, radical starters,
or light irradiation were missing. In contrast, reactive
4-hydroxyquinolones and similar systems are known to need
cooling to avoid multi-chlorination [11]. The chlorination
of 4 was carried out in dioxane keeping the temperature
at 40–50 ꢀC by dropwise addition of sulfuryl chloride.
The reaction temperature must be kept below 60 ꢀC be-
cause otherwise many unwanted by-products were
formed—mainly chlorinations at the reactive benzene
nucleus [11]—which were difficult to separate. As product,
3,3-dichloro-6-methoxyquinolinedione 5 was isolated in
73% yield, showing two expected carbonyl signals
at 1725 and 1688 cmꢁ1. Reduction of 5 with zinc dust
in refluxing ethanolic acetic acid gave a selective removal
of one chloro substituent to form 3-chloro-4-hydroxy-6-
methoxyquinolone 6 in an excellent yield of 89%. The
end of the monodechlorination is shown when the yellow
color of the reaction mixture changes to a greenish color.
This must be observed carefully because otherwise the
addition of more zinc dust results in the removal of the
second chloro substituent, and the pre-starting material,
4-hydroxyquinolone 4, is formed back.
The next step in the reaction sequence was the exchange
of the rather inreactive hydroxy group in position 4 against
a better leaving group. Our earlier investigations revealed
that a 4-chloro group would be the best choice, both in
synthesis, stability and then in further exchange reactions
[2,5]. The transformation of 6 to the intended reactive
4-chloroquinolone 8 needed two steps, because a single
regioselective substitution of the 4-hydroxy group of 6
could not be performed: with phosphoryl chloride, the
completion of the reaction resulted in the formation of
2,3,4-trichloroquinoline 7 in excellent yields, confirmed by
the lack of the carbonyl function at position 2 in the IR spectra.
In order to obtain a regioselective hydrolysis of the
chlorine at position 2 of the quinoline nucleus in acidic
media such as methanesulfonic acid, a number of solvents
had to be tested to form 3,4-dichloroquinolone 8. The
conditions we have described for similar systems [2] using
ethanol as the solvent gave here a mixture of compounds.
Among a series of solvents, we found that refluxing 1-
butanol revealed the best results in yields and purity for
3,4-dichloroquinolone 8, whereas higher boiling
solvents (e.g. DMF or dodecanol) caused a partial hydro-
lysis of both chloro substituents back to its oxygen
origins. Methanesulfonic acid in 1-butanol [5] attacked
regioselectively the 2-chloro function to form back the
2-oxo function producing 3,4-dichloroquinolone 8 in
Scheme 1
OMe
O
N
COOH
H
H
COOH
N
O
2
1
excellent yields (IR: C═O at 1657 cmꢁ1, H NMR: NH
OMe
3 (19%)
MeO
POCl3
at 12.47 ppm). 3,4-Dichloroquinolone 8 served now as
reactive starting material for the introduction of the
cyano substituent in position 4. Scheme 2
+
NH2
95°C
OH
1
MeO
Recently, we were able to show that the introduction of cy-
ano substituents into 4-chloroquinolones was performed with
best results from potassium cyanide using p-toluenesulfinate
as catalyst, forming reactive intermediates [2, and references
cited therein].
N
H
O
4 (73%)
SO2Cl2
Other approaches described in the literature such as the re-
action with copper(II) cyanide according to the Rosenmund–
Brown aromatic cyanation gave low yields and impure
products [2, and references cited therein]; the use of crown
ethers gave no products. The treatment of 3,4-dichloroquino-
lone 8 with dry potassium cyanide in the presence of dry
sodium p-toluenesulfinate in dry dimethylformamide gave at
dioxane
60°C
73 %
Zn
AcOH
EtOH
reflux
OH
O
Cl
Cl
O
MeO
MeO
Cl
O
N
H
88 %
N
H
6
5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

494
G. C Enoua, G. Lahm, G. Uray, and W. Stadlbauer
Vol 51
Scheme 2
dichloroquinolone 8 with iodomethane, and then reacting
the N-methyl derivative 11 with potassium cyanide, or in
a reversed order, by alkylation of dicyanoquinolone 9
with iodomethane. The result was that the reaction of the
N-alkylated dichloroquinolone 11 obtained from 8 with
iodomethane and sodium carbonate in dimethylformamide
gave with potassium cyanide only mixtures, whereas
N-alkylation of dicyanoquinolone 9 produced in excellent
yields N-methylquinolone 10. In the same manner, the
alkylation of dicyanoquinolone 9 with ethyl bromoacetate
gave in excellent yields ethyl (3,4-dicyano-2-oxoquinolin-
1-yl)acetate 12. On the other hand, alkylation of dicyanoqui-
nolone 9 with benzylchloride attacked under similar
conditions the tautomeric 2-oxo/2-hydroxy group and gave
the isomeric product, 2-benzyloxy-6-methoxyquinoline-
3,4-dicarbonitrile (13); no N-benzyl product could be
detected.
Cl
OH
POCl3
reflux
Cl
Cl
MeO
Cl
O
MeO
N
N
H
89%
7
6
MeSO3H
1-BuOH
reflux
88%
KCN
p-MePh-SO2Na
DMF
140 °C
CN
Cl
CN
MeO
Cl
O
MeO
N
H
O
N
H
72%
Pathway A
9
8
MeI/Na2CO3
DMF, 120 °C
MeI/Na2CO3
DMF, 120°C
78%
80%
Another well-known electrophilic substitution at position
3 of hydroxyquinolone 4 is the nitration reaction, because
the products reveal many biological activities [8,12]. The
nitration was performed under mild reaction conditions at
room temperature with nitric acid in acetic acid using sodium
nitrite as catalyst [13], which prevents by-products such as
benzo-nitrated quinolones formed with higher reaction
temperatures. 4-Hydroxy-3-nitroquinolone 14 was obtained
in a pure form and in good yields by this method. The reac-
tion with phosphoryl chloride gave again a bis-chlorination
and yielded the dichloroquinoline 15. The addition of
triethylamine both accelerated the reaction and increased
the yield obviously because hydrogen bondings between
the 4-hydroxy and the 3-nitro group were destructed. Similar
as described for compound 8, 4-chloro-3-nitroquinolone
16 was obtained by regioselective hydrolysis at position 2
with methanesulfonic acid in 1-butanol. Scheme 3.
The reaction of the 16 with dry potassium cyanide in the
presence of dry sodium p-toluenesulfinate in dry dimethyl-
formamide gave at 140 ꢀC already after 2–3 h reaction
time, a single product with strong green fluorescence prop-
erties. After work-up and interpretation of the spectra, it
was obvious that again the same product as obtained
from 8, namely 6-methoxy-2-oxo-1,2-dihydroquinoline-
3,4-dicarbonitrile (9) was isolated in excellent yields. This
fact means that again also the substituent in position 3, the
nitro group, was exchanged against the cyano substituent.
Both investigated electron-withdrawing substituents in
position 3, the 3-chloro and the 3-nitro group, did not allow
us to perform the introduction of a single cyano group in
position 4. However, on the other hand, we fortunately
obtained in this way a 4-cyano compound having addition-
ally the 3-cyano group that allowed us to study the effect of
a strong electron withdrawing group in ortho neighborhood.
In the next step, we planned the synthesis of 6-methoxy-
2-quinolones having an electron-donor group in position 3.
The first reaction sequence started from 4-hydroxy-3-
CN
Cl
CN
MeO
Cl
O
MeO
N
O
N
CH3
CH3
11
10
PhCH2Cl
K2CO3, DMF
110°C
61%
BrCH2COOEt
Na2CO3
DMF, 90°C
CN
CN
MeO
CN
N
O
CN
MeO
84 %
OEt
OCH2Ph
N
O
12
13
140 ꢀC after some hours a mixture of fluorescent compounds.
Prolongation of the reaction time resulted in the formation of
one single compound showing a strong fluorescence in the
green region. Surprisingly, after work-up and analytical
evaluation, we found that not only the chloro substituent in
position 4 but also the chloro substituent in position 3 was
exchanged against a cyano group to yield 6-methoxy-2-oxo-
1,2-dihydroquinoline-3,4-dicarbonitrile (9). The IR spectra
of 9 showed the cyano signal at 2228 cmꢁ1 and the lactam
carbonyl signal at 1650 cmꢁ1. In the 13C NMR spectra, a sig-
nal for the cyano group at 118.8 ppm with intensity of signals
twice the usual size was visible. Mass spectra gave a molecu-
lar mass of 225 and also elemental analysis gave the correct
values for 9.
In a further continuation of this project, the introduction of
linker groups into compound 9 at N-1 is planned, similar to
earlier investigations [1,2]. As model compounds for
testing the reaction conditions and fluorescence properties
of N-alkylated derivatives of 9, we selected two path-
ways: either performing the alkylation step at precursor
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, A Red Compound Class
with Solvent and pH Independent Green Fluorescence Maxima
495
Scheme 3
Scheme 4
OH
Zn
HNO3/NaNO2
AcOH, rt
OH
OH
OH
Ac2O/AcOH
reflux
H
N
MeO
NO2
O
MeO
MeO
NO2
O
MeO
74 %
O
N
H
O
N
H
N
H
N
H
O
85%
4 (73%)
14
14
17
POCl3/Et3N
reflux
80%
POCl3/Et3N
reflux
89%
Cl
NO2
Cl
MeO
Cl
H
N
MeO
N
O
N
H
O
15
MeSO3H
1-BuOH
110°C
18
74%
KCN
p-MePh-SO2Na
DMF, 140°C
p-MePh-SO2Li
DMF, reflux
KCN
p-MePh-SO2Na
DMF, 70-140 °C
73 %
CN
Cl
97 %
Pathway C
CN
O
MeO
NO2
O
MeO
O
N
H
N
H
92 %
S
O
Pathway B
CN
9
16
MeO
NH2
O
CN
O
MeO
N
H
N
H
nitroquinolone 14, where the 3-nitro group was reduced
with zinc in acetic acid as mild reduction agent. Other
agents such as sodium dithionite gave no satisfying results
[14]. The resulting 3-amino group is not very stable
and was therefore stabilized by acetylation [15] to give
in excellent yields 3-acetylamino-4-hydroxyquinolone
17. Chlorination with phosphoryl chloride using again
triethylamine as catalyst gave surprisingly only a selective
monochlorination in position 4 probably caused by hydro-
gen bondings between the acetyl and the hydroxy group.
A dichlorination at the 2- and 4-position as observed
with 3-nitroquinolone 14 did not take place. As product,
3-acetylamino-4-chloroquinolone 18 was obtained in
excellent yield. Scheme 4.
The reaction of 4-chloroquinolone 18 with dry potassium
cyanide in the presence of dry sodium p-toluenesulfinate in
dry dimethylformamide gave again at 140 ꢀC after 45 h re-
action time 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-
dicarbonitrile (9) in excellent yields by cleavage of the
acetylamino group. Shorter reaction time or lower tempera-
tures resulted in a mixture of a number of fluorescent
compounds, with 18 as the main product (65–86%).
Recently, we found in first experiments that quinoline-
tosylates and quinoline-sulfones are a new class of fluorescent
compounds [16]. Attempts to produce that class of com-
pounds from nitro derivatives such as 2,4-dichloroquinoline
15 or 4-chloroquinolone 16 with sodium p-toluenesulfinate
were unsuccessful because no reaction was observed. When
lithium p-toluenesulfinate was used in this reaction, a mixture
19
9
of fluorescent compounds was produced; however, we could
not isolate a pure product because of persistent co-crystalliza-
tion and the almost equal chromatographic properties. The
reaction of hydroxy-nitroquinolone 14 or acetylamino-
hydroxyquinolone 17 with tosylchloride gave mixtures
of several ditosylates that could not be isolated in a pure form;
similar results were obtained in the reaction of 14 or 17
with methylbenzenesulfonyl chloride [17]. 3-Acetylamino-4-
chloroquinolone 18 reacted with lithium p-toluenesulfinate
in refluxing dry dimethylformamide in good yields to the
sulfone 19 by cleavage of the acetyl group. This compound
showed as expected a strong fluorescence already visible
during TLC detection. The structural elucidation by IR and
1H NMR spectra gave the expected signals of lactam,
methoxy and NH groups. The 13C NMR spectra favor
the sulfone structure (and not the possible sulfinyloxy deriv-
ative) because only two signals can be assigned to a C–O
bonding: 156.2 ppm (2-CO) and 155.1 ppm (6-O). A third
C–O signal supporting the structure of a 4-sulfinyloxy deriv-
ative is missing. This result is supported by findings in the
literature, which favor the formation of sulfones from
arylsulfinates and activated halogenoarenes. [18].
A further approach to obtain a 4-cyanoquinolone with an
electron-donor group in position 3 was planned via a 3-N,N-
disubstituted aminoquinolone. Adapting a literature-known
reaction sequence for the introduction of piperidinyl
Journal of Heterocyclic Chemistry
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496
G. C Enoua, G. Lahm, G. Uray, and W. Stadlbauer
Vol 51
substituents [19], we started from dichloroquinolinedione 5,
which gave by reaction with piperidine already at 0 ꢀC
3,3-dipiperidinylquinolinedione 20. Reductive cleavage of
one piperidinyl substituent with sodium dithionite gave
4-hydroxy-3-piperidinylquinolone 21. The reaction with
phosphoryl chloride formed—similar as observed in 6 and
14—the 2,4-dichloro-3-piperidinylquinoline 22, which was
regioselectively hydrolyzed with methanesulfonic acid to
4-chloro-3-piperidinylquinolone 23. Scheme 5
When 4-chloro-3-piperidinylquinolone 23 reacted
with dry potassium cyanide in the presence of dry sodium
p-toluenesulfinate in dry dimethylformamide at 140–150 ꢀC,
after a reaction time of several days, a mixture of a number
of fluorescent and decomposition products was obtained.
Among them again quinoline-3,4-dicarbonitrile 9 could be
isolated in 65% yield; a further very strong fluorescent
product was isolated via HPLC separation, which showed
very interesting fluorescence properties, with again an
absorption maximum at 450 nm and an emission maximum
at 570 nm, and an excellent quantum yield of Φ = 0.79.
However, separation of a sufficiently pure product and
structural elucidation was not successful.
position 3 and 4 causes a strong red shift compared with
analogs we have investigated in recent years [1,2,5], which
makes this structure very interesting for fluorescence
investigations. The fluorescence measurement with an
excitation wavelength of
lexc = 460 nm produces an
emission wavelength of lem = 545nm, which means a
further red shift of about 40–50nm compared with our
most long-wave fluorescent compounds, 3-aryl-4-cyano-6-
methoxycarbostyrils [5]. The quantum yield, however,
gave a value of ΦF = 0.13, which is no improvement
compared with the recently investigated compounds. N-
Alkyl derivatives of the dicyanocarbostyril, such as N-
methylquinolone 10 and quinolinyl-N-acetate 12, showed
similar values of 543 and 535 nm, however, with similar
low quantum yields. These results show that the intended
use of N-alkyl linkers do not influence the photophysical
properties. Further investigations on photophysical
properties revealed that in structures 9, 10, and 12 there is
nearly no solvent dependance visible (e.g. lem = 535 nm in
dimethylsulfoxide and lem = 550 nm in acetonitrile for 12)
and also no pH dependance and oxygen quenching was
observed. 3-Amino-4-p-tolylsulfonylquinolone 19 shows a
blue shifted fluorescence maximum at 455 nm, together
with a comparable quantum yield of ΦF = 0.10. The blue
shift seems to be caused at least in part by the 3-amino
group as donor substituent [16].
Electronic spectra. 6-Methoxy-2-oxo-1,2-dihydroquinoline-
3,4-dicarbonitrile (3,4-dicyano-6-methoxycarbostyril) (9)
is our hitherto most advanced push–pull substituted
fluorescent carbostyril. The single methoxy group in 6-
position in combination with the 2 cyano groups in
CONCLUSIONS
Scheme 5
Quinoline-4-carbonitriles with different electron acceptor
and donor substituents in position 3 for comparison of the
fluorescence properties were not obtained, because in all cases
not only the substituent in 4-position but also the substituent in
3-position were exchanged during the reaction with potassium
cyanide and toluenesulfinate against a further cyano
substituent. So in all cases, quinoline-3,4-dicarbonitrile 9
was obtained as the main product. Milder reaction conditions
resulted only in mixtures of intermediate compounds.
The fluorescent properties show in both compounds a
dramatic red shift up to the green area of 560 nm influenced
by the 3-cyano substituent, however, accompanied with
a rather low quantum yield of max. ΦF = 0.13. With lithium
p-toluenesulfinate we obtained from 4-chloro substituted 18,
a new representative of push–pull substituted fluorescent
carbostyrils, 4-p-tolylsulfonylquinolone 19, which will be
further investigated.
O
O
Cl
Cl
HN
DMF, 0°C
N
MeO
MeO
N
N
O
N
H
O
H
78%
20
5
Na2S2O4
EtOH/H2O
reflux
94%
OH
Cl
POCl3
110°C
N
O
MeO
N
MeO
N
H
47%
N
Cl
22
21
MeSO3H
n-BuOH
reflux
53%
Method A
POCl3
80-90°C
82%
Method B
EXPERIMENTAL
Cl
N
MeO
General. Melting points were determined in open capillary
tubes using a Stuart SMP3 Melting Point Apparatus (Bibby
Scientific Limited, Stone, Staffordshire, UK). IR spectra were
recorded either with a Mattson Galaxy Series FTIR 7020
instrument (Mattson Instruments, Ltd. Milton Keynes, England) in
potassium bromide disks, or with a Bruker Alpha-P (Bruker
KCN, p-MePh-SO2Na
DMF, 140 °C
N
O
H
9
23
65%
Pathway D
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, A Red Compound Class
with Solvent and pH Independent Green Fluorescence Maxima
497
GmbH, Karlsruhe, Germany) with Attenuated Total Reflectance
(ATR) measurement, using a reflexion method. NMR spectra were
recorded either on a Bruker AMX 360 instrument (Bruker GmbH,
vigorous stirring, sulfuryl chloride (60.0 g, 0.44 mol) was
added dropwise keeping the temperature between 50–60 ꢀC.
The reaction mixture was then cooled to 20 ꢀC and filtered.
The filtrate was poured onto ice/water (1.5 L) under stirring,
and the precipitate filtered by suction, washed with water and
dried at 40 ꢀC under reduced pressure. The product was pure
enough for further reactions. The yield was 34.96 g (73%),
yellow prisms, mp 219–223 ꢀC (ethanol), lit. mp 215–216 ꢀC [7].
IR (KBr): 3434 m, 3198 m, 3076 m, 2976 m, 2915 m, 1725 s,
1
Karlsruhe, Germany) (360 MHz H, 90 MHz 13C), or on a Bruker
Avance III instrument (Bruker GmbH, Karlsruhe, Germany)
(300 MHz 1H), or on a Bruker Avance DRX 500 instrument
(Bruker GmbH, Karlsruhe, Germany) (500 MHz 1H, 125 MHz
13C). Chemical shifts are given in parts per million (d) from the
internal TMS standard. Elemental analyses were performed at the
Microanalytical Laboratory of the University of Vienna, Austria.
Mass spectra were obtained from an HP 1100 LC/MSD mass
spectral instrument (Agilent Technologies, Santa Clara, California,
USA) (either positive or negative atmospheric pressure chemical
ionization (APCI) ion source, 50–200 V, nitrogen, or atmospheric
pressure-electrospray (AP–ES) electrospray method). UV/Vis
1688 s, 1622 m cmꢁ1 1H NMR (360 MHz, DMSO-d6): d 3.79
.
(s, 3H, MeO), 7.07 (d, J = 8.5 Hz, 1H, 8-H), 7.28 (d,
J = 2.8 Hz, 1H, 5-H), 7.30 (dd, J = 8.6 + 2.9 Hz, 7-H), 11.27
(s, 1H, NH).
3-Chloro-4-hydroxy-6-methoxyquinolin-2(1H)-one (6). To a
solution of 3,3-dichloroquinolinedione 5 (5.25 g, 20.2 mmol) in
ethanol (50 mL) and acetic acid (25 mL), zinc-dust (5.23 g,
80 mmol) was added in small portions, whereas the solution was
kept to boiling. The yellow solution got decolorized (from
yellow to gray-greenish), which indicated the end of reaction. The
solution was cooled to room temperature and filtered from
insoluble zinc reagents. To the filtrate, ice/water (500mL) was
added. The colorless precipitate was filtered by suction, washed
with water, and dried at 40ꢀC under reduced pressure. The yield
was 4.02 g (88%), colorless powder, mp 270–273 ꢀC (ethanol). IR
spectra were recorded with
a Shimadzu UV/Vis scanning
spectrophotometer UV-2101 PC (Shimadzu Corp., Kyoto, Japan);
concentration: 1 ꢂ 10ꢁ4 M. Fluorescence data: excitation and
emission spectra were recorded with a Perkin–Elmer LS50B
luminescence spectrometer (Perkin Elmer Corp., Waltham,
Massachusetts, USA). Determination of quantum yields: emission
signals were set in relation to the known area of the emission
signal of quinine sulfate at pH = 1. Corrections were made for other
2
solvents by using the factor (nwater/nsolvent
)
[4c,d]. Analytical
(KBr): 3432 m, 1633 w, 1586 s cmꢁ1 1H NMR (360MHz,
.
HPLC was performed on a Shimadzu LC 20 system (Shimadzu
Corp., Kyoto, Japan) equipped with a diode array detector (215
and 254 nm) on a Pathfinder AS reversed phase (4.6150 mm,
5 mm) column, running mainly in acetonitrile/water gradient
(30–100% acetonitrile). Dry column flash chromatography [20]
was carried out on silica gel 60 H (5–40mm) (Merck, Darmstadt,
Germany). All reactions were monitored by thin layer
chromatography on 0.2 mm silica gel F 254 plates using UV light
(254 and 366nm) for detection. Common reagent-grade chemicals
are either commercially available and were used without further
purification or prepared by standard literature procedures.
DMSO-d6): d 3.68 (s, 3H, MeO), 7.00 (dd, J = 8.7 + 2.6 Hz, 1H,
7-H), 7.12 (d, J = 8.8 Hz, 1H, 8-H), 7.41 (d, J = 2.5 Hz, 1H, 5-H ),
10.84 (s, 1H, NH). Anal. Calcd. for C10H8ClNO3 (225.63): C,
53.23; H, 3.57; N, 6.21. Found: C, 53.47; H, 3.29; N, 5.98.
2,3,4-Trichloro-6-methoxyquinoline (7).
A solution of 3-
chloroquinolone 6 (6.00 g, 26.6 mmol) in phosphoryl chloride
(40.0 g, 0.26 mol) was heated under reflux for 8 h. The excess of
phosphoryl chloride was removed under reduced pressure, the
residue poured onto ice/water (300 mL) and brought to pH = 4–6
with aq. sodium hydroxide (5 M). The precipitate was filtered by
suction and washed with water and the solid dried at 40 ꢀC
under reduced pressure. The yield was 6.24 g (89%), beige
powder, mp 276–279 ꢀC (toluene). IR (ATR): 3012 w, 2944 w,
N,N0-Bis(4-methoxyphenyl)malonamide (3). This compound
was obtained as insoluble solid by-product during the work-up of 4-
hydroxyquinolone 4. The solid was recrystallized from acetic acid/
methanol (1:3). The yield was 9.21 g (19%), gray prisms, mp 228–
231 ꢀC (acetic acid/methanol), lit. mp 226–240 ꢀC [6a,7,21]. IR
1
1619 m, 1546 m cmꢁ1. H NMR (300 MHz, DMSO-d6): d 3.97
(s, 1H, MeO), 7.40 (d, J = 2.8 Hz, 1H, 5-H), 7.57 (dd,
J = 9.2 + 2.7 Hz, 1H, 7-H), 7.96 (d, J = 9.2 Hz, 1H, 8-H). Anal.
Calcd for C10H6Cl3NO (262.52): C, 45.75; H, 2.30; N, 5.34.
Found: C, 45.71; H, 2.44; N, 5.27.
1
(KBr): 3435 m, 1655 w, 1620 s, 1588 s cm1. H NMR (360 MHz,
CDCl3): d 3.49 (s, 2H, CH2), 3.81 (s, 6H, 2 MeO), 6.88 (d,
J= 8.8 Hz, 4H, ArH), 7.45 (d, J= 8.8 Hz, 4H, ArH), 8.64 (s, 2H, NH).
3,4-Dichloro-6-methoxyquinolin-2(1H)-one (8). A solution
4-Hydroxy-6-methoxyquinolin-2(1H)-one (4).
A mixture
of trichloroquinoline
7
(6.50 g, 24.8 mmol) and 70%
of p-anisidine (1) (19.00 g, 154 mmol) and dry malonic acid (2)
(23.0 g, 220 mmol) in phosphoryl chloride (40.0 g, 260 mmol) was
heated under stirring for 90 min in an open flask to 95ꢀC, then
cooled to 20 ꢀC, poured onto ice/water (500 mL) and filtered by
suction. The precipitate was dissolved in aq. sodium hydroxide (1 L,
1M) at 60ꢀC. The remaining insoluble N,N0-bis(4-methoxyphenyl)
malonamide (3) was filtered off. To the alkaline filtrate, concentrated
hydrochloric acid was added until pH = 1–2 was reached, the
precipitate filtered by suction, washed with water and dried at 40 ꢀC
under reduced pressure. The yield was 21.55 g (73%), yellow
prisms, mp 324–328 ꢀC (methanol), lit. mp 298–320 ꢀC [6–9]. IR
(ATR): 3434 m, 3290 s, 1663 w, 1642 s, 1616 w, 1602 w cmꢁ1. 1H
NMR (300 MHz, DMSO-d6): d 3.77 (s, 3H, MeO), 5.79 (s, 1H,
3-H), 7.14 (dd, J = 8.9 + 2.7 Hz, 1H, 7-H), 7.20 (d, J = 8.8 Hz,
1H, 8-H), 7.21 (d, J = 2.8 Hz, 1H, 5-H), 11.08 (s, 1H, NH).
3,3-Dichloro-6-methoxyquinoline-2,4(1H,3H)-dione (5). A
suspension of 4-hydroxyquinolone 4 (35.00 g, 183 mmol) in
dioxane (400 mL) was warmed to 40–50 ꢀC; and then under
methanesulfonic acid (10.0 g, 0.07mol) in 1-butanol (130 mL)
was heated under reflux for 45 h. The mixture was cooled to
20ꢀC, poured onto ice/water (50 mL), brought to pH= 4–6 with
aq. sodium hydroxide (2 M) and filtered by suction. The solid was
washed with water and dried at 40ꢀC under reduced pressure. The
yield was 5.33 g (88%), beige prisms, mp 264–265 ꢀC (xylene). IR
(KBr): 3467 m, 2840 m, 1657 s, 1599 s cmꢁ1. 1H NMR (360 MHz,
DMSO-d6): d 3.83 (s, 3H, MeO), 7.25 (d, J= 2.2 Hz, 1H, 5-H),
7.30 (dd, J= 8.9 + 2.4 Hz, 1H, 7-H), 7.36 (d, J= 8.9 Hz, 1H, 8-H),
12.47 (s, 1H, NH). Anal. Calcd for C10H7Cl2NO2 (244.08): C,
49.21; H, 2.89; N, 5.74. Found: C, 49.24; H, 2.83; N, 5.68.
6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (9).
Pathway A: A mixture of 3,4-dichloroquinolone 8 (619 mg,
2.54 mmol), sodium p-toluenesulfinate (950 mg, 5.34 mmol), and
potassium cyanide (410 mg, 6.35 mmol) in dry dimethylformamide
(15 mL) was heated to 140 ꢀC for 46 h with vigorous stirring. The
resulting solution was cooled to 20 ꢀC and poured onto ice/water
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

498
G. C Enoua, G. Lahm, G. Uray, and W. Stadlbauer
Vol 51
(500 mL). The obtained solid was filtered by suction, washed with
water, and dried at 40 ꢀC under reduced pressure. The yield was
408 mg (72%), red prisms, mp 302–306 ꢀC (acetone).
1-methylquinoline-3,4-dicarbonitrile 10. The yield was 798 mg
(80%), light yellow prisms, mp 170–179 ꢀC (methanol). IR
(ATR): 2998 w, 1644 s, 1585 w cmꢁ1 1H NMR (300 MHz,
.
Pathway B: A mixture of 4-chloro-3-nitroquinolone 16 (32 mg,
0.13 mmol), potassium cyanide (30 mg, 0.46 mmol), and sodium
p-toluenesulfinate (50 mg, 0.28mmol) in dry dimethylformamide
(1mL) was heated to 140 ꢀC for 2.5 h and worked up using the
procedure described for pathway A. The yield was 26 mg (92%),
red prisms, mp 301–304 ꢀC (acetonitrile).
Pathway C: A mixture of N-(4-chloroquinolin-3-yl)acetamide
18 (1.67 g, 6.6 mmol), potassium cyanide (1.02 g, 15.7mmol), and
sodium p-toluenesulfinate (2.34g, 13.1mmol) in dry
dimethylformamide (38 mL) was heated to 140 ꢀC for 45 h
with vigorous stirring and worked up using the procedure
described for pathway A. The yield was 1.37 g (97%), red prisms,
mp 300–302 ꢀC (acetonitrile).
Pathway D: A mixture of 4-chloro-3-piperidinylquinolone 23
(340mg, 1.16 mmol), sodium p-toluenesulfinate (440 mg,
2.47 mmol), and potassium cyanide (200 mg, 3.07mmol) in dry
dimethylformamide (7mL) was heated to 140 ꢀC for 5 days with
vigorous stirring and worked up using the procedure described for
pathway A. The yield was 171mg (65%), red-green prisms, mp
297–300 ꢀC (acetonitrile).
IR (KBr): 2972–2742 w, br, 2228 w, 1650 s, 1615 w, 1555 w
cmꢁ1. 1H NMR (300 MHz, DMSO-d6): d 3.88 (s, 3H, MeO), 7.12
(d, J = 2.7 Hz, 1H, 5-H), 7.42 (d, J = 9.2 Hz, 1H, 8-H), 7.52 (dd,
J = 9.2 + 2.7 Hz, 1H, 7-H), 13.08 (s, 1H, NH). 13C NMR
(90 MHz, DMSO-d6): d 56.3 (MeO), 106.5 (3-C), 113.4 (8-C),
114.6 (10-C), 116.7 (5-C), 118.8 (3-CN, 4-CN), 126.4 (7-C),
129.5 (9-C), 135.8 (4-C), 156.1 (6-C), 157.0 (2-C═O). UV
(DMSO): l (e, Mꢁ1cmꢁ1) = 319, 460 (7310, 4760) nm. Fluores-
cence (DMSO): l (ΦF) = 545 (0.13). MS (API-ESI neg): m/z
(%) = 225 (15, M), 224 (100, M ꢁ 1), 209 (6, M ꢁ 16). MS
(API–ESI pos): m/z (%) = 264 (17, M + K), 248 (100 M + Na),
226 (8, M + 1). Anal. Calcd for C12H7N3O2 (225.21): C, 64.00;
H, 3.13; N, 18.66. Found: C, 63.70; H, 3.00; N, 18.33.
DMSO-d6): d 3.67 (s, 3H, NMe), 3.85 (s, 3H, MeO), 7.31
(d, J = 2.7 Hz, 1H, 5-H), 7.36 (dd, J = 9.2 + 2.7 Hz, 1H, 7-H),
7.57 (d, J = 9.2 Hz, 1H, 8-H). 13C NMR (75 MHz, DMSO-d6):
d 31.5 (NMe), 56.1 (MeO), 107.7 (ArC), 117.7 (ArC), 118.8
(ArC), 121.1 (ArC), 126.1 (ArC), 132.5 (ArC), 139.8 (4-C),
155.5 (6-C), 156.2 (2-C═O). Anal. Calcd. for C11H9Cl2NO2
(258.11): C; 51.19 H, 3.51; N, 5.43. Found: C, 51.06; H,
3.37; N, 5.41.
Ethyl (3,4-Dicyano-6-methoxy-2-oxoquinolin-1(2H)-yl)-acetate
(12).
A mixture of quinoline-3,4-dicarbonitrile 9 (500 mg,
2.22 mmol), ethyl bromoacetate (910 mg, 5.4 mmol), and dry
sodium carbonate (710 mg, 6.7 mmol) in dry dimethylformamide
(15mL) was heated to 90ꢀC for 15 min. The solution was cooled
to room temperature and poured onto ice/water (5 mL). The
resulting precipitate was filtered by suction, washed with water,
and dried at 40 ꢀC under reduced pressure. The yield was 579 mg
(84%), yellow prisms, mp 216ꢁ219 ꢀC (ethanol). IR (KBr): 3143
w, 2230 w, 1746 s, 1656 s, 1557 s cmꢁ1 1H NMR (300 MHz,
.
DMSO-d6): d 1.22 (t, J= 7.0 Hz, 3H, Me), 3.92 (s, 3H, MeO),
4.17 (q, J= 7.0 Hz, 2H, CH2), 5.20 (s, 2H, NCH2), 7.26 (d,
J= 2.7 Hz, 1H, 5-H), 7.60 (dd, J= 9.4 + 2.8 Hz, 1H, 7-H), 7.73 (d,
J= 9.5 Hz, 1H, 8-H). 13C NMR (90 MHz, DMSO-d6): d 14.5
(Me), 45.6 (NCH2), 56.4 (MeO), 62.1 (OCH2), 108.5 (ArC), 112.0
(ArC), 113.2 (ArC), 114.2 (ArC), 117.4 (CN), 118.6 (CN), 125.9
(ArC), 129.8 (ArC), 135.9 (4-C), 156.2 (6-C), 156.6 (2-C═O),
167.6 (ester-C═O). UV (DMSO): l (e, Mꢁ1cmꢁ1) = 321, 451
(10000, 9440) nm. Fluorescence (DMSO): l (ΦF) = 535 (0.15).
UV (MeCN): l (e, Mꢁ1cmꢁ1) = 319, 455 (9440, 5400) nm.
Fluorescence (MeCN): l (ΦF) = 550 (0.02). MS (API–ESI pos):
m/z (%) = 305 (51, M + K), 334 (100, M + Na), 312 (62, M + 1).
Anal. Calcd for C16H13N3O4 (311.30): C, 61.73; H, 4.21; N,
13.50. Found: C, 61.48; H, 4.06; N, 13.34.
2-Benzyloxy-6-methoxyquinoline-3,4-dicarbonitrile (13).
A mixture of quinoline-3,4-dicarbonitrile 9 (900 mg, 4.00 mmol),
potassium carbonate (750mg, 5.4 mmol), and benzylchloride
(880 mg, 6.8 mmol) in dry dimethylformamide (65 mL) was
heated slowly to 80ꢀC, then the mixture was kept at this
temperature for 3 h until TLC showed no more starting material.
Then the temperature was raised to 110 ꢀC for 2 h. The solution
was filtered while still hot and the solvent removed under reduced
pressure. A thick brown oil was obtained, which crystallized after
standing overnight. The solid was purified by dry flash column
chromatography using toluene/dichloromethane (3:1) as eluent.
The yield was 768 mg (61%), yellow prisms, mp 318–323 ꢀC
(toluene/dichloromethane 3:1). IR (KBr): 3435 s, 2924 w, 2231
6-Methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile
(10).
A mixture of quinoline-3,4-dicarbonitrile 9 (421 mg,
1.87 mmol), iodomethane (685 mg, 4.83 mmol), and dry sodium
carbonate (590mg, 5.56mmol) in dry dimethylformamide
(17 mL) was heated to 120 ꢀC for 25 min. The solution was
cooled to 20 ꢀC and poured onto ice/water (50 mL). The obtained
solid was filtered by suction, washed with water, and dried at
40ꢀC under reduced pressure. The yield was 347 mg (78%), red
prisms, mp 219–223 ꢀC (ethanol). IR (KBr): 3459–3438 w, br,
3026 w, 2238 w, 1657 s, 1586 w cmꢁ1 1H NMR (300 MHz,
.
DMSO-d6): d 3.70 (s, 3H, NMe), 3.91 ( s, 3H, MeO), 7.21 (d,
J = 2.3 Hz, 1H, 5-H), 7.61 (dd, J = 9.4 + 2.5 Hz, 1H, 7-H), 7.76
(d, J = 9.4 Hz, 1H, 8-H). 13C NMR (75 MHz, DMSO-d6): d 31.5
(NMe), 56.1 (MeO), 107.29 (ArC), 112.5 (ArC), 113.3 (ArC),
114.6 (ArC), 117.3 (CN), 118.9 (CN), 125.8 (ArC), 128.5 (ArC),
136.5 (ArC), 155.9 (6-C), 156.7 (2-C═O). UV (DMSO): l
w, 1620 w, 1584 m cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d 3.98 (s, 3H, MeO), 5.61 (s, 2H, CH2), 7.30–7.55 (m, 5H, PhH),
7.58 (d, J = 1.6 Hz, 1H, 5-H), 7.70 (dd, J = 9.3 + 2.8 Hz, 1H, 7-H),
7.96 (d, J = 9.2 Hz, 1H, 8-H). Anal. Calcd. for C19H13N3O2
(315.33): C, 72.37; H, 4.16; N, 13.33. Found: C, 72.58; H,
(e,
M
ꢁ1cmꢁ1) = 321, 459 (8600, 5720) nm. Fluorescence
(DMSO): l (ΦF) = 543 (0.08). MS (API–ESI pos): m/z (%) = 278
(11, M + K), 262 (100, M + Na), 240 (47, M + 1). Anal. Calcd for
C13H9N3O2 (239.24): C, 65.27; H, 3.79; N, 17.56. Found: C,
65.10; H, 3.59; N, 17.17.
4.01; N, 13.67.
4-Hydroxy-6-methoxy-3-nitroquinolin-2(1H)-one (14). To a
mixture of 4-hydroxyquinolone 4 (17.40 g, 90.9 mmol) in glacial
acetic acid (200 mL) at room temperature, a mixture of
concentrated nitric acid (20 mL) and sodium nitrite (0.85 g,
12.32 mmol, 0.14 eq.) was added within 2 min. A strong
exothermic reaction started and the starting material dissolved,
followed immediately by precipitation of the product. The
mixture was stirred for 45 min at ambient temperature and then
3,4-Dichloro-6-methoxy-1-methylquinolin-2(1H)-one (11). A
mixture of 3,4-dichloroquinolone
8 (945mg, 3.87 mmol),
iodomethane (1.60 g, 11.3 mmol), and dry sodium carbonate
(1.03 g, 9.7mmol) in dry dimethylformamide (20 mL) was heated
to 120ꢀC for 25min, and worked up as described for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, A Red Compound Class
with Solvent and pH Independent Green Fluorescence Maxima
499
1
poured onto ice/water (1.5 L), stirred, filtered by suction, and the
precipitate washed with water. The solid was dried at 40 ꢀC under
reduced pressure and then recrystallized from methanol. The yield
was 16.01 g (74%), orange prisms, mp 254–257 ꢀC (methanol).
IR (KBr): 3001 m, 2896 m, 2847 m, 1668 s, 1636 w, 1609
m, 2913 m, 2837 m, 1654 w, 1640 w, 1615 s cmꢁ1. H NMR
(300 MHz, DMSO-d6): d 2.24 (s, 3H, Me), 3.79 (s, 3H, MeO),
7.13 (dd, J= 9.0 + 2.7 Hz, 1H, 7-H), 7.22 (d, J=9.0Hz, 1H, 8-H),
7.27 (d, J = 2.7 Hz, 1H, 5-H), 9.73 (s, 1H, NHAc), 11.74 (s,
1H, NH), 11.98 (s, 1H, OH). Anal. Calcd for C12H12N2O4
(248.24): C, 58.06; H, 4.87; N, 11.28. Found: C, 57.92; H,
4.62; N, 11.01.
1
s cmꢁ1. H NMR (360 MHz, DMSO-d6): d 3.81 (s, 3H, MeO),
7.28 (d, J = 8.9 Hz, 1H, 8-H), 7.31 (dd, J = 9.1 + 2.5 Hz, 1H, 7-
H), 7.49 (d, J = 2.2 Hz, 1H, 5-H), 11.89 (s, 1H, NH). Anal.
Calcd. for C10H8N2O5 (236.19): C, 50.85; H, 3.41; N, 11.86.
N-(4-Chloro-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)
acetamide (18).
To a solution of N-(4-hydroxyquinolinyl)
acetamide 17 (5.50 g, 22.2 mmol) in phosphoryl chloride
(45.0 g, 0.29 mmol), dry triethylamine was added (2.70 g,
26.6 mmol), then the solution was heated under reflux for 1 h.
The excess phosphoryl chloride was removed under reduced
pressure, the residue poured onto ice/water (400 mL) and
brought to pH = 4–6 with sodium hydroxide (2 M). The
mixture was filtered by suction, the solid washed with water,
and dried at 40 ꢀC under reduced pressure. The yield was 5.25 g
(89%), dark-brown powder, mp 283–285 ꢀC (dioxane). IR
(ATR): 3435 m, 3225 m, 3010 w, 2937 w, 1651 s, 1620
Found: C, 50.63; H, 3.67; N, 12.02.
2,4-Dichloro-6-methoxy-3-nitroquinoline (15). A solution
of 3-nitroquinolone 14 (3.63 g, 15.37 mmol) and dry
triethylamine (2.52 mL) in phosphoryl chloride (18.9 mL) was
heated under reflux for 2 h. The excess phosphoryl chloride was
removed under reduced pressure. The residue was poured onto
ice/water (400 mL) and the solution brought to pH = 4–6
with aqueous sodium hydroxide (5 M). The residue was
filtered by suction, washed with water, and the remaining solid
dried at 40 ꢀC under reduced pressure. The yield was 3.34 g
(80%), brown prisms, mp 195–196 ꢀC (dioxane). IR (ATR):
1
m cmꢁ1. H NMR (300 MHz, DMSO-d6): d 2.05 (s, 3H, Me),
3120 w, 3077 w, 2971 w, 2936 w, 1680 sh, 1616 m cmꢁ1. H
1
3.84 (s, 3H, MeO), 7.25 (d, J = 2.4 Hz, 1H, 5-H), 7.31–7.35 (m,
2H, 7-H and 8-H), 9.60 (s, 1H, NHAc), 12.18 (s, 1H, NH). MS
(APCI pos): m/z (%) = 269 (30, M + 3), 268 (12, M + 2 ), 267
(100, M + 1), 225 (8, M ꢁ 42), Anal. Calcd for C12H11ClN2O3
(266.69): C, 54.05; H, 4.16; N, 10.50. Found: C, 54.30; H,
3.97; N, 10.46.
NMR (360 MHz, DMSO-d6): d 4.01 (s, 3H, MeO), 7.52 (d,
J = 2.6 Hz, 1H, 5-H), 7.73 (dd, J = 9.4 + 2.5 Hz, 1H, 7-H), 8.10
(d, J = 9.4 Hz, 1H, 8-H). Anal. Calcd. for C10H6Cl2N2O3
(273.08): C, 43.98; H, 2.21; N, 10.26. Found: C, 44.27; H,
2.50; N, 10.02.
3-Amino-6-methoxy-4-[(4-methylphenyl)sulfonyl]quinolin-2
4-Chloro-6-methoxy-3-nitroquinolin-2(1H)-one (16).
A
(1H)-one (19).
To a solution of N-(4-chloroquinolin-3-yl)
solution of 2,4-dichloroquinoline 15 (5.10 g, 18.67 mmol) and
70% methanesulfonic acid (15.0 g, 0.11 mol) in 1-butanol
(100 mL) was heated to 110 ꢀC for 20 h. The mixture
was cooled to room temperature and the solid (mainly 4-
hydroxyquinolone 14) was filtered off. The filtrate was poured
onto ice/water (300 mL), the solution brought to pH = 4–6 with
aq. sodium hydroxide (2 M), the precipitate filtered by suction,
washed with water, and dried at 40 ꢀC under reduced pressure.
The remaining solid was purified by dry flash column
chromatography using ethyl acetate as eluent. The yield was
3.52 g (74%), yellow prisms, mp 274–276 ꢀC (chloroform/
acetone 3:7). IR (KBr): 3437 m, 2866 m, 1663 s, 1626 w, 1596
acetamide 18 (150 mg, 0.56 mmol) in dry dimethylformamide
(11 mL), lithium p-toluenesulfinate (140 mg, 0.88 mmol) was
added and the reaction mixture heated under reflux for 16 h,
then cooled to room temperature and poured onto ice/water
(50 mL). The obtained solid was filtered by suction, washed
with water, and dried. The remaining solid was purified by dry
flash column chromatography using chloroform/acetone (8:2) as
eluent. The yield was 140 mg (73%), yellow prisms, mp 245–
247 ꢀC (toluene). IR (ATR): 3475 s, 3360 s, 2837 s, br, 1671 s,
1593 s, sh, 1572 s cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
.
2.33 (s, 3H, Me), 3.66 (s, 3H, MeO), 6.80 (dd, J = 9.0 + 2.4 Hz,
1H, 7-H), 7.13 (d, J = 9.9 Hz, 1H, 8-H), 7.38 (d, J = 8.1 Hz,
w cmꢁ1 1H NMR (360 MHz, DMSO-d6): d 3.87 (s, 3H,
.
0
2HBB , Ar–H ), 7.44 (d, J = 2.4 Hz, 1H, 5-H), 7.82 (d, J = 8.4 Hz,
MeO), 7.33 (d, J = 2.4 Hz, 1H, 5-H), 7.44–7.47 (m, 2H, 7-H and
8-H), 12.97 (s, 1H, NH). MS (APCI pos): m/z (%) = 257 (30,
M + 3), 256 (10, M + 2), 255 (100, M + 1). MS (APCI neg): m/z
(%) = 255 (34, M + 1), 254 (10, M), 253 (100, M ꢁ 1). Anal.
Calcd. for C10H7ClN2O4 (254.63): C, 47.17; H, 2.77; N, 11.00.
2 HAA , Ar–H), 12.27 (s, 1H, NH). 13C NMR (75MHz,
0
DMSO-d6): d 21.5 (Me), 55.7 (MeO), 106.2 (3-C), 106.8 (5-C),
113.1 (7-C), 117.1 (ArC), 117.1 (8-C), 124.9 (ArC), 126.5
0
0
(2 ꢂ ArCBB ), 130.5 (2 ꢂ ArCAA ), 139.6 (ArC), 141.8 (ArC),
144.9 (ArC), 155.1 (6-C), 156.2 (2-C═O). UV (ethanol): l (e,
Found: C, 47.26; H, 2.62; N, 10.87.
N-(4-Hydroxy-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)
M
ꢁ1cmꢁ1) = 356 (14500) nm. Fluorescence (ethanol): l (ΦF)=455
(0.10). UV (DMSO): l (e, Mꢁ1cmꢁ1) = 354 nm. MS (API–ESI
pos): m/z (%) = 377 (95, M + 33), 367 (100, M + Na). MS (API–ESI
neg): m/z (%) = 452 (35, M + 108), 343 (100, M –1). Anal. Calcd.
for C17H16N2O4S (344.38): C, 59.29; H, 4.68; N, 8.13. Found: C,
acetamide (17). To a solution of 3-nitroquinolone 14 (1.50 g,
6.48 mmol) in acetic acid (50 mL), zinc-dust (2.60g, 38.90 mmol,
6 eq.) was added in portions until the yellow colored mixture was
decolorized. The reaction mixture was then heated under reflux
for 15 min. Acetic anhydride (33 mL) was now added, and the
mixture heated under reflux for further 15 min. The formed
zinc salt was filtered off by suction while hot, and the filtrate
taken to dryness under reduced pressure. The remaining
residue was dissolved in aq. sodium hydroxide (100 mL, 1 M)
and stirred for 10 min at room temperature. The solution was
filtered and the filtrate acidified with conc. hydrochloric acid
to pH = 1–2 under stirring. The precipitate was filtered
by suction, washed with water, and dried at 40 ꢀC under
reduced pressure. The yield was 1.37 g (85%), beige prisms,
mp 304–306 ꢀC (toluene). IR (ATR): 3434 m, 3326 m, 2964
59.69; H, 4.46; N, 7.99.
6-Methoxy-3,3-di(piperidin-1-yl)quinoline-2,4(1H,3H)-dione
(20). To a solution of 3,3-dichloroquinolinedione 5 (4.60 g,
17.7 mmol) in dry dimethylformamide (20 mL), piperidine
(10.0 g, 117 mmol) was added at 0 ꢀC, which gave a dark
colored mixture. The temperature raised to 35 ꢀC, and piperidine
hydrochloride precipitated. The mixture was stirred for 30 min,
cooled to 0 ꢀC, and water (80 mL) was added dropwise to give a
precipitate, which was filtered by suction. The solid was washed
with water and dried at 40 ꢀC under reduced pressure. The
yield was 4.92 g (78%), yellow-green prisms, mp 162–164 ꢀC
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

500
G. C Enoua, G. Lahm, G. Uray, and W. Stadlbauer
Vol 51
(ethanol). IR (KBr): 3435 s, 3202 m, 2932 s, 2851 m, 1688 s,
1657 s, 1616 w cmꢁ1 1H NMR (360 MHz, CDCl3): d 1.47–
1.54 (m, 12H, piperidine-CH2), 2.62–2.64 (m, 8H,
Acknowledgment. This research was supported by a PhD
scholarship from the Austrian Exchange Service/Academic
Cooperation and Mobility Unit (G.C.E.).
.
6
4
piperidine-N–CH2), 3.86 (s, 3H, MeO), 6.82 (d, J = 8.7 Hz, 1H,
8-H ), 7.11 (dd, J = 8.7 + 2.7 Hz, 1H, 7-H), 7.39 (d, J = 2.7 Hz,
1H, 5-H), 8.36 (s, 1H, NH). Anal. Calcd. for C20H27N3O3
(357.46): C, 67.20; H, 7.61; N, 11.76. Found: C, 67.59; H,
7.23; N, 11.39.
4-Hydroxy-6-methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one
REFERENCES AND NOTES
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Stadlbauer, W. Eur J Org Chem 2006, 2715; (b) Uray, G.; Badgujar, N. S.;
Kovácková, S.; Stadlbauer, W. J Heterocyclic Chem 2008, 45, 165; (c)
Stadlbauer, W.; Avhale, A. B.; Badgujar, N. S.; Uray, G.; J Heterocyclic
Chem 2009, 46, 415;
ꢀ
(21). To
a
refluxing solution of 3,3-di(piperidinyl)
quinolinedione 20 (2.00 g, 5.60 mmol) in water/ethanol (1:1,
32 mL), sodium dithionite (2.00 g, 11.5 mmol) was added and
the mixture stirred and heated for 30 min under reflux, then
cooled to 5 ꢀC and kept 2 h at this temperature. The product
precipitated, was filtered by suction, washed with water and
dried at 40 ꢀC under reduced pressure. The product was
sufficient pure for further reactions. The yield was 1.44 g
(94%), beige prisms, mp 228–231ꢀC. IR (KBr): 3439 m,
ꢀ
ꢀ
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2991 m, 2952 m, 2851 m, 1638 s, 1597 s cmꢁ1 1H NMR
.
(360 MHz, DMSO-d6): d 1.50–1.52 (m, 2 H, 1 piperidine-
CH2), 1.70–1.80 (m, 4H, 2 piperidine-CH2), 3.39 (s, 3H,
MeO), 3.73–3.76 (m, 4H, 2 piperidine-N–CH2), 7.04 (dd,
J = 8.8 + 2.8 Hz, 1H, 7-H), 7.10 (d, J = 8.8 Hz, 1H, 8-H), 7.28
(d, J = 2.7 Hz, 1H, 5-H), 10.66 (s, 1H, NH). MS (APCI neg):
m/z (%) = 274 (5, M), 273 (100, M – 1). MS (APCI pos):
m/z (%) = 276 (18, M + 2), 275 (100, M + 1). Anal. Calcd. for
C15H18N2O3 (274.32): C, 65.68; H, 6.61; N; 10.21. Found: C,
65.67; H, 6.37; N, 10.22.
2,4-Dichloro-6-methoxy-3-(piperidin-1-yl)quinoline (22). A
solution of 4-hydroxy-3-piperidinylquinolone 21 (905 mg,
3.30 mmol) in phosphoryl chloride (15.0 g, 96.5 mmol) was
heated under reflux for 8 h and worked up as described for
trichloroquinoline 7. The yield was 482 mg (47%), brown
prisms, mp 182–185 ꢀC (methanol). IR (KBr): 3433 m, 2932 m,
2847 w, 1620 s, 1556 w cm–1. 1H NMR (360 MHz, CDCl3):
d 1.66–1.81 (m, 6H, 3 piperidine-CH2), 3.23–3.25 (m, 4H,
2
piperidine-N–CH2), 3.97 (s, 3H, MeO), 7.30 (dd,
J = 9.1 + 2.6 Hz, 1H, 7-H), 7.39 (d, J = 2.4 Hz, 1H, 5-H), 7.86
(d, J = 9.2 Hz, 1H, 8-H). Anal. Calcd. for C15H16Cl2N2O
(311.21): C, 57.89; H, 5.18; N, 9.00. Found: C, 57.76; H, 5.34;
N, 9.18.
4-Chloro-6-methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one
(23).
Method A:
A solution of 2,4-dichloro-3-(piperidin-1-yl)
quinoline 22 (2.00 g, 6.43 mmol) and 70% methanesulfonic
acid (1.5 g, 10.9mmol) in 1-butanol (15 mL) was heated under
reflux for 48h and worked up as described for dichloroquinolone
8. The yield was 997 mg (53%), pale green prisms, mp
210–214 ꢀC (ethanol).
Method B:
A
solution of 4-hydroxy-3-(piperidin-1-yl)
quinolone 21 (1.00 g, 3.65 mmol) in phosphoryl chloride
(13.0 g, 84 mmol) was heated at 80 ꢀC for 25 min and
worked up as described for trichloroquinoline 7 to form
directly 4-chloroquinolone 23. The yield was 875 mg (82%),
pale green prisms, mp 213–216 ꢀC (ethanol). IR (KBr): 3454 s,
2840 m, 1643 s, 1599 w cmꢁ1. 1H NMR (360 MHz, DMSO-d6): d
1.56–1.60 (m, 6H, 3 piperidine-CH2), 3.12–3.14 (m, 4H, 2
piperidin-N–CH2), 3.82 (s, 3H, MeO), 7.11 (dd, J=8.8+2.7Hz,
1H, 7-H), 7.22 (d, J = 8.9 Hz, 1H, 8-H), 7.26 (d, J = 2.7 Hz, 1H,
5-H), 11.83 (s, 1H, NH). MS (APCI pos): m/z (%) = 295 (33,
M + 3), 294 (20, M + 2), 293 (100, M + 1). C15H17ClN2O2 (292.77):
C, 61.54; H, 5.85; N, 9.57. Found: C, 61.23; H, 5.98; N, 9.75.
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6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitriles, A Red Compound Class
with Solvent and pH Independent Green Fluorescence Maxima
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