One-pot synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates and arylmethylene-bis-3,3′-quinoline-2-ones

Article abstract of DOI:10.1007/s11696-018-0561-0

Abstract: In this investigation an efficient synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinic acid derivatives was achieved by one-pot reaction of one equivalent of aromatic amines with two equivalents of diethyl malonate in dipheny

Full text of DOI:10.1007/s11696-018-0561-0

Chemical Papers
https://doi.org/10.1007/s11696-018-0561-0
ORIGINAL PAPER
One‑pot synthesis
of 2,3‑bis‑(4‑hydroxy‑2‑oxo‑1,2‑dihydroquinolin‑3‑yl)succinates
and arylmethylene‑bis‑3,3′‑quinoline‑2‑ones
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Ashraf A. Aly · Essmat M. El‑Sheref · Aboul‑Fetouh E. Mourad · Momtaz E. M. Bakheet · Stefan Bräse ·
Martin Nieger3
Received: 27 April 2018 / Accepted: 24 July 2018
©
Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
In this investigation an efcient synthesis oꢀ 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinic acid derivatives
was achieved by one-pot reaction oꢀ one equivalent oꢀ aromatic amines with two equivalents oꢀ diethyl malonate in diphenyl
ether and catalyzed with triethylamine. In case oꢀ applying the previous condition with aromatic amines and diethyl malonate
1
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in a ratio oꢀ 2:1, no quinolone structure was obtained, whereas N ,N -bis(4-bromophenyl)malonamide, as an example, was
obtained in 95% yield. Under the same previous condition, arylmethylene-bis-3,3′-quinoline-2-ones were in one pot syn-
thesized via the reaction oꢀ equal equivalents oꢀ aromatic amines and diethyl malonate together with halꢀ equivalent oꢀ the
corresponding aromatic aldehydes. The structure oꢀ the obtained compounds was proved by IR, NMR and mass spectra and
X-ray structure analyses.
Graphical abstract
Extended author inꢀormation available on the last page oꢀ the article
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Keywords Bis-(quinolin-3-yl)succinates · N ,N -bis(4-bromophenyl)malonamide arylmethylene-bis-3,3′-quinoline-2-ones ·
One-pot synthesis · X-ray
Introduction
Results and discussion
2
-Quinolones (Chen et al. 2001) have showed consider-
To our delight, mixing oꢀ one molar proportion oꢀ aromatic
amines 1a–d to two molar equivalents oꢀ diethyl malonate
(2) in diphenyl ether catalyzed with ꢀew drops oꢀ triethyl-
able interest because oꢀ their pharmacological importance
(
Abass et al. 2015) and various biological activities (Abass
and Mostaꢀa 2005). Various quinolones are described to
have antimicrobial (Al-Trawneh et al. 2010; Eswaran et al.
amine (Et N) and when the mixture was heated at 180 °C
3
ꢀor 4 h, the reaction gave 2,3-bis-(4-hydroxy-2-oxo-1,2-di-
hydroquinolin-3-yl)succinic acid.bis(triethylamine) deriva-
tives 3a–d in 79–84% yields (Scheme 1). The structures oꢀ
2
010), antiꢀungal (Musiol et al. 2006), enzyme inhibi-
tory (Slater and Cerami 1992), anti-HIV (Ahmed et al.
010) , anti-oxidant (Sankaran et al. 2010) and cytotoxic
1
13
2
the products were ꢀully consistent with their H NMR,
C
activities (Ma et al. 2004). The quinolones are also occur-
ring in natural products (Junichiro et al. 2012), mainly in
alkaloids (Michael 2005). As ꢀor example, quinine is a qui-
noline-based alkaloid structure isolated ꢀrom the bark oꢀ
cinchona tree (Igarashi and Kobayashi 2005) and is used ꢀor
the treatment oꢀ Malaria. Luotonin A (Cagir et al. 2003)
is a cytotoxic alkaloid as a cytotoxic alkaloid drug, which
is used in treatment oꢀ rheumatism and inꢁammation. Qui-
narcine (Thi et al. 2008) drug is oꢀ an acridine-based alka-
loid structure which has been used as an antimalarial agent.
Kynurenic acid (Turski et al. 1988) is oꢀ quinolone structure
that can be used ꢀor the normal metabolism oꢀ amino acids
and reveals neuro active activity. Interestingly, antimalarial
drugs consist oꢀ amino quinoline skeletons (primaquine)
and are used ꢀor the treatment oꢀ Malaria (Turski et al.
NMR, IR and mass spectra, elemental analyses and X-ray
structure analysis as well. We choose compound 3a, as an
example, to conꢂrm the structures. According to elemental
analysis, the compound 3a would be in accordance to the
molecular weight equals 638.75. In the mass spectrum oꢀ
3a, the molecular peak is the base peak and corresponding
to the molecular weight oꢀ m/z 436. One can then conclude
the presence oꢀ the two molecules oꢀ Et N in its crystal lat-
3
tice, which was not noticed in mass spectrum. The latter
was conꢂrmed by the NMR spectra oꢀ 3a. The IR spectrum
revealed bands at ν 3400, 3210, 1720 and 1680, correspond-
ing to OH, NH, carbonyl-acid and 2-carbonyl-quinolone
groups. Figure 1 illustrates the NMR spectroscopic data oꢀ
1
compound 3a, where the H NMR spectrum indicates three
singlets, each ꢀor the two protons at δ 14.10 (COOH), 13.20
(OH), and 11.80 (NH). A quartet resonated at δ 3.17 ꢀor the
1
988).
Synthesis oꢀ bis-quinolones has recently attracted much
12 CH protons oꢀ the two triethylamine units, and a triplet
2
attention due to prospective high biological and pharma-
ceutical activities (Tarushi et al. 2011). For example, ꢀunc-
tionalized 4,4′-bisquinolones were synthesized by micro-
wave-assisted Pd(0)-catalyzed one-pot borylation/Suzuki
cross-coupling reactions or via Ni(0)-mediated homocou-
plings oꢀ 4-chloroquinolin-2(1H)-one precursors (Hashim
et al. 2006). Bis-conjugates oꢀ quinine with quinolone anti-
biotics and amino acid linkers retain in vitro antimalarial
activity with IC values ranging ꢀrom 12 to 207 μM, simi-
at δ 1.30 ꢀor the 18 CH protons oꢀ the same units (see the
3
“Experimental”). The two adjacent methine protons were
1
resonated in the H NMR spectrum as a singlet at δ 3.72.
1
3
1
The C NMR spectrum conꢂrmed the H NMR spectral
data by showing the carbonyl-acid and carbonyl-quinolone
carbon signals at δ 164.8 and 160.1, respectively. The CH -
2
and CH -Et N appeared at δ = 50.0 and 13.7, whereas the
3
3
ethano-carbons oꢀ succinic acid appeared at δ 38.2. In case
1
oꢀ 3d, the H NMR spectral data revealed the presence oꢀ
5
0
lar to quinine itselꢀ (Panda et al. 2012). Recently, we have
two molecules oꢀ Et N in its crystal lattice structure as a
3
synthesized spiro(indoline-3,4′-pyrano[3,2-c]quinoline)-
quartet at δ 3.20 ꢀor 18 protons and a triplet at δ 1.15 ꢀor
3
2
′-carbonitriles ꢀrom reaction oꢀ quinoline-2,4-diones with
12 protons. Another two ethyl protons oꢀ N-1 ꢀor quinolone
1
-(2-oxo-1,2-dihydroindol-3-ylidene)malononitrile (Aly
moiety appeared in the H NMR spectrum as a quartet and
et al. 2018). We also reacted quinolinediones and diethyl
acetylenedicarboxylate to give pyranoquinoline-4-carboxy-
lates and (quinolin-3-yl)ꢀumarates in good yields (El-Shereꢀ
et al. 2018). Considering the importance oꢀ the interesting
chemical behavior oꢀ quinolones, and in view oꢀ the prom-
ising aspects and making a ꢀurther step ꢀorward, we report
herein on the application oꢀ the one-pot technique in synthe-
sis oꢀ the title compounds.
triplet at δ 3.15 and 1.17, respectively (“Experimental” Sec-
1
tion). The H NMR spectrum showed also the two methine
protons as a singlet at δ 3.70. The structure oꢀ 3d was then
totally proved by X-ray structure analysis (Fig. 2).
Since the structures oꢀ compounds 3a–d involve two ste-
reogenic centers, in principle two diastereoisomers should
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Scheme 1 One-pot synthesis oꢀ 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates 3a–d, N ,N -bis(4-bromophenyl)malonamide (4)
and arylmethylene-bis-3,3′-quinoline-2-ones 6a–e
be obtained. One oꢀ these stereoisomers is the anti-ꢀorm.
Interestingly, the reaction proceeded to give only one dias-
tereomers. Two types oꢀ hydrogen bonds were ꢀormed; one
was held between the oxygen oꢀ the carboxylic-OH and
the hydrogen atom oꢀ the hydroxyl group oꢀ 4-hydroxyqui-
nolone. The other hydrogen bond was held between the
nitrogen lone pair in triethylamine and the hydrogen atom
oꢀ the ꢀree carboxylic-OH. Formation oꢀ such two types oꢀ
hydrogen bonds would be expected to stabilize the anti-ꢀorm
structure oꢀ 3a–d as shown in Scheme 1. The X-ray structure
analysis conꢂrmed the meso (R, S) conꢂguration oꢀ com-
pounds 3a–d, as shown in Fig. 2.
water to 9 would then give intermediate 10, which was in
equilibrium with its tautomer (Scheme 2). Finally, autoxida-
tion oꢀ the α-ketonic acid 10 accompanied with elimination
oꢀ CO and rearrangement would then give salt 11. Further
2
oxidation oꢀ two molecules oꢀ 11 would produce target mol-
ecule 3 (Scheme 2). To ensure the reaction pathway, we also
heat compound 9 in diphenyl ether at 180 °C ꢀor 3 h and
successꢀully obtain 3.
Interestingly, when we carried out the reaction between
1 and 2 in a molar ration oꢀ 2:1, we could not separate any
quinolonoyl structure and we obtained malonamide 4 (Chat-
taway and Mason 1910; Vennerstrom and Holmes 1987)
(Scheme 1). X-ray structure analysis oꢀ 4 is as shown in
Fig. 3.
It is well known that both ester enolates and carboxylic
acid dianions can be used ꢀor oxidative homocoupling. The
reaction mechanism can be explained as due to condensation
between 1 and 2, which would ꢀorm 2-quinolone 8. Subse-
quently, condensation between 8 and another molecule oꢀ 2
would give the ꢀused α-pyranone 9 (Scheme 2). Addition oꢀ
Inspired by the above results, we extended our studies to
react aromatic amines 1a–d with diethyl malonate (2) and
aromatic aldehydes 5a–c in a molar ratio oꢀ 2:2:1 and under
the condition mentioned above (Scheme 1). We surprisingly
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derivatives under solvent- and catalyst-ꢀree reaction condi-
tions at 80 °C. The reactants underwent a cascade Kno-
evenagel–Michael reaction to yield other derivatives 6 in
good yields (Bhat and Trivedi 2014). The main diꢃerence
between our method and the previous method is that we
prepared compounds 6 in one step in relatively good yields.
Moreover, no literatures have discussed the regio-structure
oꢀ 6 (Madhu et al. 2017), whether it is in anti- or syn ꢀorm.
To the best oꢀ our knowledge, NMR spectral data oꢀ 6a–e
derivatives have not reported yet. NMR spectral data oꢀ the
product 6b (Fig. 4), as an example, which was obtained ꢀrom
the reaction oꢀ 4-methylaniline (1b), diethyl malonate (2)
and 4-methylbenzaldehyde (5b) were illustrated in Table 1.
In 6b; the two quinolinone rings are spectroscopically non-
equivalent, although some oꢀ their signals co-resonate; the
simplest explanation is that their rotation is hindered so that
the compound does not possess a σ plane. The 6H methyl
singlet at δ 2.38 must be H-6a; its attached carbon appears at
δ 20.64. H-6a gives HMBC correlation with carbon signals
at δ 131.91 and 122.03; these are assigned as C-7 and C-5
in that order, because the downꢂeld oꢀ the two gives HSQC
correlation with a 2H doublet at δ 7.42 and the upꢂeld signal
correlates with the nonequivalent 1H singlets at δ 7.79 and
Fig. 1 NMR spectroscopic data some distinctive hydrogen protons
and carbons oꢀ compound 3a
7
.69. C-7 also gives HMBC correlation with a 2H doublet
obtained arylmethylene-bis-3,3′-quinoline-2-ones 6a–e in
good yields as shown in Scheme 1. Previously, another deriv-
ative oꢀ 6 (Bhat and Trivedi 2014) was obtained by reacting
at δ 7.33, assigned as H-8; its attached carbon appears at δ
115.34 grounds as C-2,2′,4,4′.
The p-tolyl group is assigned similarly: the 3H methyl
singlet at δ 2.26 must be H-3ꢀ and gives HSQC correlation
4-hydroxy-N-methylquinolin-2(1H)-ones with benzaldehyde
Fig. 2 Molecular structure
analysis oꢀ compound 3d (dis-
placement parameters are drawn
at 50% probability level)
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Scheme 2 Proposed mechanism describes the ꢀormation oꢀ 3
Fig. 3 Molecular structure
analysis oꢀ compound 4 (dis-
placement parameters are drawn
at 50% probability level)
to a carbon at δ 20.02. C-3ꢀ gives HMBC correlation to a
6e was obtained aꢀter recrystallization ꢀrom N,N-dimethyl-
ꢀormamide and ethanol; the structure showed the inclusion
oꢀ a molecule oꢀ DMF (Fig. 5).
2
H doublet at δ 7.05, assigned as H-3d; its attached car-
bon appears at δ 128.14. H-3d gives COSY correlation
with the remaining 2H doublet at δ 6.96; its attached car-
bon appears at δ 125.66. H-3c, H-3d, and C-3c also give
HMBC correlation with the 1H singlet at δ 6.10, assigned
as H-3a; its attached carbon appears at δ 34.43. The ꢀour
lines between δ 166–160 give HMBC correlation with
H-3a and are assigned on chemical-shiꢀt. The remaining
The mechanism can be explained as due to ꢀormation
oꢀ 2-quinolone 8 by the same previous steps mentioned in
Scheme 2. Compound 8 would then condense with alde-
hyde 5 to give intermediate 12 (Scheme 3). Elimination
oꢀ water molecule ꢀrom 12 would enable the ꢀormation
oꢀ 13. Addition oꢀ another one molecule oꢀ 8–13 would
ultimately give 6 (Scheme 3).
1
3
C lines are assigned on chemical shiꢀts as shown in the
Table 1. Finally, an X-ray structure analysis oꢀ compound
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Chemical Papers
with a FT device, Minia University. NMR spectra were
measured in DMSO-d on a Bruker AV-400 spectrometer
6
1
13
(
400 MHz ꢀor H, 100 MHz ꢀor C, and 40.55 MHz ꢀor
1
5
N); chemical shiꢀts are expressed in δ (ppm), versus
1
13
internal tetramethylsilane (TMS) = 0 ꢀor H and C, and
1
5
external liquid ammonia = 0 ꢀor N. Coupling constants
1
are stated in Hz. Correlations were established using H-
1
1
13
1
15
H COSY, and H- C and H- N HSQC and HMBC
experiments. Mass spectra were recorded on a Finnigan
Fab 70 eV, Institute oꢀ Organic Chemistry, Karlsruhe Uni-
versity, Karlsruhe, Germany. TLC was perꢀormed on ana-
lytical Merck 9385 silica aluminum sheets (Kieselgel 60)
with Pꢀ indicator; TLCs were viewed at λ = 254 nm.
2
54
max
Elemental analyses were carried out at the Microanalytical
Center, Cairo University, Egypt.
Fig. 4 Magnetically inequivalent carbons oꢀ compound 6b
General procedure describes the formation of com‑
Experimental
pounds 3a–d
Melting points were determined using open glass capillar-
ies on a Gallenkamp melting point apparatus (Weiss–Gal-
lenkamp, Loughborough, UK) and are uncorrected. The
IR spectra were recorded ꢀrom potassium bromide disks
A mixture oꢀ aromatic amines 1a–d (1 mmol) and 2
(2 mmol) in 50 mL oꢀ diphenyl ether and 0.5 mL oꢀ Et3N
was heated at 180 °C ꢀor 4 h. The ꢀormed resulting white
precipitate was leꢀt to cool ꢀor 24 h. The precipitate was
Table 1 NMR spectral data oꢀ compound 6b
1H NMR
1
1
H- HCOSY
Assignment
1
1
7
7
7
7
6
6
2
2
3.18 (s; 1H), 12.73 (s; 1H)
2.21 (s; 1H), 12.10 (s; 1H)
.79 (s; 1H), 7.69 (s; 1H)
.42 (d, J=8.0; 2H)
.33 (d, J=8.4; 2H)
.05 (d, J=7.2; 2H)
.96 (d, J=7.6; 2H)
.10 (s; 1H)
OH
NH
H-5,5′
H-7
H-8
H-3d
H-3c
H-3a
H-6a
H-3ꢀ
7.42,7.33,2.38
7.79,7.69,7.33,2.38
7.79, 7.69, 7.42
6.96, 6.10, 2.26
7.05, 6.10
7.05, 6.96, 2.26
7.79, 7.69, 7.42
7.05, 6.10
.38 (s; 6H)
.26 (s; 3H)
1
3
C NMR
HSQC
6.10
HMBC
6.10
Assignment
1
1
1
1
1
1
1
1
1
1
1
3
2
2
65.87, 164.17
61.64, 160.69
34.56, 134.14, 134.05
31.91
31.24
28.14
25.66
22.03
15.99
15.34
C-2,2′
C-4,4′
C-3b,4a,6
C-7
C-8a
C-3d
C-3c
C-5
C-3e
C-8
C-3,3′
C-3a
C-6a
C-3ꢀ
7.42,7.05, 6.96, 6.10, 2.26
7.42
7.33, 2.38
7.05
6.96
7.79, 7.69
7.05, 2.26
6.96, 6.10
7.42, 2.38
7.33
6.96
6.10
2.38
2.26
7.33
10.85, 109.22
4.43
0.64
6.96
7.42
7.05
0.02
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Fig. 5 Molecular structure oꢀ
compound 6e (displacement
parameters are drawn at 50%
probability level)
Scheme 3 Suggested mecha-
nism describes the ꢀormation
oꢀ 6
collected by ꢂltration, then was washed with 200 mL oꢀ
EtOH and then dried well. The ꢀormed product was then
recrystallized ꢀrom stated solvents.
IR (KBr): ῡ = 3400 (OH), 3210 (NH), 3030–3000
−
1
(Ar–CH), 2980–2670 (Aliph–CH), 1720, 1680 cm (CO);
1
H NMR (400 MHz, DMSO-d ): δ=14.10 (s, 2H, 2COOH),
6
1
3.20 (s, 2H, 2OH), 11.80 (s, 2H, 2NH), 8.08 (dd, 2H,
(
2R,3S)‑2,3‑bis(4‑hydroxy‑2‑oxo‑1,2‑dihydro‑quino‑
J = 1.0, 0.8 Hz), 7.60–7.56 (m, 2H), 7.40–7.33 (m, 4H),
lin‑3‑yl)succinate. bis(triethylammonium) salt (3a)
3.72 (s, 2H), 3.17 (q, 12H, 6CH –NEt ), 1.30 ppm (t, 18H,
2
3
1
3
6
CH –2NEt ); C NMR (100 MHz, DMSO-d ): δ=164.8
3 3
6
Yellow crystals (DMF), 0.35 g (80%), m.p. 340–2 °C
(2CO-acid), 160.1 (2CO-quinolone), 158.0 (Ar–2C–OH),
146.7 (Ar–2C), 133.6, 122.9, 122.8, 116.8 (Ar–2H), 111.7,
(
decomp).
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Chemical Papers
1
1
05.4 (Ar–2C), 50.0 (6CH –NEt ), 38.2 (Aliph–2CH),
(2R,3S)‑2,3‑bis(1‑ethyl‑4‑hydroxy‑2‑oxo‑1,2‑dihyd‑
roquinolin‑3‑yl)succinate. bis(triethylammonium)
salt (3d)
2
3
3.7 ppm (6CH –NEt ).
3
3
MS (70 eV, %): m/z=436 (M–2Et N, 100), 306 (30), 282
3
(
52), 153 (92), 136 (65), 106 (25).
Anal ꢀor C H N O (638.75): Calcd. 63.93; H, 7.26; N,
Yellow crystals (AcOEt), 0.41 g (82%), m.p.>350 °C.
3
4
46
4
8
8
.77. Found: C, 64.00; H, 7.30; N, 8.80.
IR (KBr): ῡ=3450–3360 (OH), 3220 (NH), 3060–3020
−1
(
Ar–CH), 2960–2810 (Aliph–CH), 1716, 1665 cm (CO).
1
(
2R,3S)‑2,3‑bis(4‑hydroxy‑6‑methyl‑2‑oxo‑1,2‑di‑
H NMR (400 MHz, DMSO-d ): δ=14.20 (s, 2H, COOH),
6
hydroquinolin‑3‑yl)‑succinate. bis(triethyl‑ammo‑
13.30 (s, 2H, 2OH), 7.40–7.35 (m, 4H), 7.25–7.22 (m,
nium) salt (3b)
4H), 3.70 (s, 2H), 3.20 (q, 12H, 6CH –NEt ), 3.15 (q, 4H,
2
3
2
CH –NEt ), 1.17 (t, 6H, 2CH –Et N), 1.15 ppm (t, 18H,
2 3 3 3
Yellow crystals (DMF/EtOH), 0.39 g (84%), m.p. 350–2 °C.
6CH –Et N).
3 3
13
IR (KBr): ῡ = 3460 (OH), 3230 (NH), 3060–3030
C NMR (100 MHz, DMSO-d ): couldn’t be resolved due
6
−
1
(
Ar–CH), 2970–2890 (Aliph–CH), 1718, 1682 cm (CO).
to bad solubility.
1
+
H NMR (400 MHz, DMSO-d ): δ = 14.20 (s, 2COOH),
MS (70 eV, %): m/z=492 (M , 35), 472 (40), 306 (42),
153 (100), 136 (72).
6
1
3.20 (s, 2H, 2OH), 11.20 (s, 2H, 2NH), 8.15 (d, 2H,
J=0.7 Hz), 7.77–7.74 (m, 2H), 6.80 (dd, 2H, J=1.1 Hz),
Anal ꢀor C H N O (694.86): Calcd. 65.68; H, 7.83; N,
38
54
4
8
3
1
.75 (bs, 2H), 3.20 (q, 12H, 6CH ), 2.20 (s, 6H, 2CH ),
8.06. Found: C, 65.80; H, 7.70; N, 8.15.
2
3
.20 ppm (t, 18H, CH ).
3
1
3
C NMR (100 MHz, DMSO-d ): δ=165.6 (2CO–ester),
Preparation of compound 4
6
1
1
62.3 (2CO–quinolone), 158.4 (Ar–2C–OH), 147.2,
37.2, 133.3 (Ar–2C), 126.8, 123.4 (Ar–2H), 112.4, 106.0
On repeating the previous procedure, a mixture oꢀ aromatic
(
(
Ar–2C), 50.0 (6CH –Et N), 37.4 (Aliph–2CH), 21.0
amine 1e (340 mg, 2 mmol) and 2b (160 mg, 1 mmol) in
2
3
2CH ) 14.4 ppm (2CH –ester).
15 mL oꢀ diphenyl ether and 0.5 mL oꢀ Et N was heated at
3
3
3
+
MS (70 eV, %): m/z=465 (M–2Et N , 100), 442 (18).
180 °C ꢀor 4 h. The resulting pale-yellow precipitate was leꢀt
3
Anal ꢀor C H N O (660.80): Calcd. 64.84; H, 7.56; N,
to cool. The ꢀormed product was then recrystallized.
3
6
50
4
8
1
3
8
.40. Found: C, 64.80; H, 7.60; N, 8.76.
N ,N -bis(4-bromophenyl)malonamide (4). Pale yellow
crystals (MeOH), 0.40 g (95%), m.p. 330–2 °C (lit (Venner-
strom and Holmes 1987), 332 °C).
(
2R,3S)‑2,3‑bis(6‑chloro‑4‑hydroxy‑2‑oxo‑1,2‑di‑
hydro‑quinolin‑3‑yl)succinate. Bis(triethyl‑ammo‑
IR (KBr): ῡ=3230 (NH), 3090–3030 (Ar–CH), 2970–2820
−1
nium) salt (3c)
(Aliph–CH), 1685 cm (CO).
+2
+
MS (70 eV, %): m/z=414 (M , 18), 412 (M , 30), 239
Yellow crystals (DMF/EtOH), 0.40 g (79%), m.p. 310–2 °C.
(40), 172 (100).
IR (KBr): ῡ = 3400 (OH), 3220 (NH), 3060–3030
−
1
(
(
Ar–CH), 2970–2890 (Aliph–CH), 1715, 1672 cm
General procedure describes the formation of com‑
pounds 6a–e
1
CO). H NMR (400 MHz, DMSO-d ): δ = 14.20 (s, 2H,
6
2
COOH), 13.20 (s, 2H, 2OH), 11.80 (s, 2H, 2NH), 7.80
(
(
d, 2H, J = 0.7 Hz), 7.40 (dd, 2H, J = 1.2, 0.8 Hz), 7.15
On repeating the procedure, a mixture oꢀ aromatic amines
dd, 2H, J=1.1, 0.7 Hz, Ar–H), 3.80 (s, 2H), 3.20 (q, 12H,
1a–d (2 mmol), 2b (320 mg, 2 mmol) and aromatic aldehydes
CH –Et N), 1.20 ppm (t, 18H, CH –NEt ).
5a–c (1 mmol) in 70 mL oꢀ diphenyl ether and 0.5 mL oꢀ Et N
2
3
3
3
3
1
3
C NMR (100 MHz, DMSO-d ): δ=168.2 (2CO–acid),
was ꢀused at 180 °C ꢀor 4 h. The resulting white precipitate was
6
1
1
62.0 (2CO–quinolone), 157.6 (Ar–2C–OH), 141.6,
leꢀt to cool and then poured in ice-cold saturated solution oꢀ
35.6, 133.2 (Ar–2C), 128.6, 127.4 (Ar–2H), 113.4, 101.4
NaHCO . The ꢀormed precipitate was kept standing up at room
3
(
(
Ar–2C), 50.0 (6CH –NEt ), 38.0 (Aliph–2CH), 13.0 ppm
temperature ꢀor 24 h. The precipitate which was collected by
2
3
6CH –ester).
ꢂltration was washed with about 200 mL oꢀ H O. The ꢀormed
3
2
+
MS (70 eV, %): m/z=505 (M , 15), 153 (37), 135 (25),
product was then washed again with 200 mL oꢀ EtOH and
dried well. The ꢀormed product was then recrystallized ꢀrom
stated solvents.
1
01 (100).
Anal ꢀor C H Cl N O (707.64): Calcd. 57.71; H, 6.27;
3
4
44
2
4
8
N, 7.92. Found: C, 57.80; H, 6.30; N, 8.00.
1
3

Chemical Papers
3
,3′‑(Phenylmethylene)bis(4‑hydroxyquino‑
Anal ꢀor C H N O (424.45): Calcd. C, 73.57; H, 4.75;
26 20 2 4
lin‑2(1H)‑one (6a)
N, 6.60. Found: C, 73.65; H, 4.71; N, 6.51.
Yellow crystals (DMF/EtOH), 0.360 g (88%), m.p.
3,3′‑((4‑chlorophenyl)methylene)
3
35–7 °C.
bis(4‑hydroxy‑6‑methylquinolin‑2(1H)‑one) (6d)
IR (KBr): ῡ = 3390 (OH), 3230 (NH), 3070 (Ar–CH),
−
1
1
2
970 (Aliph–CH), 1650 (CO), 1605, 1580 cm (C=C); H
Yellow crystals (DMF/EtOH), 0.32 g (68%), m.p. 280–2 °C.
NMR (400 MHz, DMSO-d ): δ=13.17 (s; 1H, OH), 12.70
IR (KBr): ῡ = 3385 (OH), 3210 (NH), 3077 (Ar–CH),
6
−
1
1
(
s, 1H, OH), 12.22 (s, 1H, NH), 12.11 (s, 1H, NH), 7.80 (d
H, H-5,5′), 7.67 (m 2H, H-6,6′), 7.44 (m 2H, H-7,7′), 7.30
d 2H, H-8,8′), 7.05–6.96 (m 5H, Ph-H), 6.11 ppm (s; 1H,
H-3a).
2980 (Aliph-CH), 1646 (CO), 1605, 1588 cm (C=C). H
2
NMR (400 MHz, DMSO-d ): δ=13.21 (s, 1H, OH), 12.70
6
(
(s; 1H, OH), 12.21 (s, 1H, NH), 12.08 (s, 1H, NH), 7.77
(s, 2H, H-5,5′), 7.40 (d, J = 7.80 Hz, 2H, H-7), 7.03 (d,
J=7.0 Hz, 2H, H-3d), 6.97 (d, J=7.2 Hz, 2H, H-3c), 6.10
(s, 1H, H-3a), 2.33 ppm (s, 6H, H-6a).
1
3
C NMR (100 MHz, DMSO-d ): δ = 165.71, 164.11
6
(
(
(
C-2,2′), 161.33, 160.77 (C-4,4′), 135.60 (C-3b), 134.11
C-4a), 131.22 (C-7), 130.89 (C-8a), 122.89, 122.86, 116.78
Ph-CH), 115.11 (C-3,3′), 34.32 ppm (C-3a).
1
3
C NMR (100 MHz, DMSO-d ): δ = 165.67, 164.20
6
(C-2,2′), 161.66, 160.13 (C-4,4′), 135.54 (C-3b), 134.18
(C-4a), 134.09 (C-6), 131.87 (C-7), 131.11 (C-8a), 130.32
(C-3e), 128.22 (C-3d), 125.18 (C-3c), 122.32 (C-5), 115.48
(C-8), 110.90, 109.66 (C-3,3′), 34.30 (C-3a), 20.55 ppm
(C-6a).
+
MS (70 eV, %): m/z=410 (M , 34), 333 (100), 161 (55),
7
7 (66).
Anal ꢀor C H N O (410.42): Calcd. C, 73.16; H, 4.42;
2
5
18
2
4
N, 6.83. Found: C, 73.22; H, 4.36; N, 6.95.
+
MS (70 eV, %): m/z=472 (M , 71), 361 (100), 187 (67),
3
,3′‑(4′‑Methylphenyl‑methylene)
111 (43), 77 (65).
bis(4‑hydroxy‑6‑methyl‑quinolin‑2(1H)‑one (6b)
Anal ꢀor C H ClN O (472.92): Calcd. C, 68.57; H,
2
7
21
2
4
4
.48; Cl, 7.50; N, 5.92. Found: C, 68.65; H, 4.55; N, 6.11.
Yellow crystals (DMF/EtOH), 0.365 g (80%), m.p.
3
58–60 °C.
3,3′‑(p‑Tolylmethylene)bis(1‑ethyl‑4‑hydroxy‑quino‑
lin‑2(1H)‑one (6e)
IR (KBr): ῡ = 3410 (OH), 3222 (NH), 3045–3020
−
1
(
(
Ar–CH), 2989 (Aliph-CH), 1646 (CO), 1610, 1590 cm
C=C).
Yellow crystals (DMF/EtOH), 0.400 g (83%), m.p.
312–4 °C.
NMR (400 MHz, DMSO-d ) (Table 1).
6
+
MS (70 eV, %): m/z=452 (M , 38), 361 (100), 187 (24),
IR (KBr): ῡ = 3390 (OH), 3220 (NH), 3052 (Ar–CH),
−
1
9
1 (66).
2988 (Aliph–CH), 1649 (CO), 1600, 1580 cm (Ar–C=C).
+
Anal ꢀor C H N O (452.50): Calcd. C, 74.32; H, 5.35;
MS (70 eV, %): m/z=480 (M , 71), 389 (100), 189 (32),
2
8
24
2
4
N, 6.19. Found: C, 74.22; H, 5.43; N, 6.35.
91 (43), 77 (50).
Anal ꢀor C H N O (480.55): Calcd. C, 74.98; H, 5.87;
3
0
28
2
4
3
,3′‑(4′‑Methylphenyl‑methylene)bis(4‑hydroxy‑qui‑
N, 5.83. Found: C, 75.15; H, 5.75; N, 6.01.
nolin‑2(1H)‑one (6c)
Supporting information
Yellow crystals (DMF/EtOH), 0.360 g (88%), m.p.>360 °C.
IR (KBr): ῡ = 3405 (OH), 3225 (NH), 3091 (Ar–CH),
Crystal structure determinations
−
1
1
2
956 (Aliph–CH), 1648 (CO), 1600, 1590 cm (C=C). H
NMR (400 MHz, DMSO-d ): δ=13.11 (s 1H, OH), 12.78
The single-crystal X-ray diꢃraction studies were carried
out on a Bruker D8 Venture diꢀꢀractometer with Pho-
ton100 detector at 123(2) K using Cu-Kα radiation (3d,
6e, λ=1.54178 Å) or Mo-Kα radiation (4, λ=0.71073 Å).
Direct Methods (3d, 6e, SHELXS-97) (Sheldrick 2008) or
dual space methods (4, SHELXT ꢀor 5a) (Sheldrick 2015)
were used ꢀor structure solution and reꢂnement was car-
ried out using SHELXL-2014 (ꢀull-matrix least-squares on
6
(
(
s 1H, OH), 12.20 (s 1H, NH), 11.99 (s 1H, NH), 7.81, 7.76
m, 2H, H-5,5′), 7.42 (m 2H, H-7), 7.03 (d J=7.1 Hz, 2H,
H-3d), 6.98 (m 2H, H-3c), 6.12 (s, 1H, H-3a), 2.23 ppm (s,
3
H, H-3ꢀ).
1
3
C NMR (100 MHz, DMSO-d ): δ = 165.80, 164.21
6
(
(
(
(
C-2,2′), 161.63, 159.97 (C-4,4′), 135.55 (C-3b), 134.18
C-4a), 132.01 (C-8a), 128.66 (C-6), 128.21 (C-3d), 125.08
C-3c), 123.11 (C-5), 115.78 (C-3e), 115.55 (C-8), 110.99
C-3,3′), 34.33 (C-3a), 20.10 ppm (C-3ꢀ).
2
F ) (Sheldrick 2015). Hydrogen atoms were localized by
diꢃerence electron density determination and reꢂned using
a riding model (H(O, N) ꢀree). Semi-empirical absorption
corrections were applied. For 4 and 6e an extinction oꢀ
+
MS (70 eV, %): m/z=424 (M , 40), 333 (100), 161 (67),
7
7 (77).
1
3

Chemical Papers
corrections was applied. In 6e one NEt-group is disordered.
The absolute structure oꢀ 4 was determined by reꢂnement
oꢀ Parsons’ x-parameter (Parson et al. 2013).
Al-Trawneh SA, Zahra JA, Kamal MR, El-Abadelah MM, Zani
F, Incerti M, Cavazzoni A, Alꢂeri RR, Petronini PG, Vicini
P (2010) Synthesis and biological evaluation oꢀ tetracy-
clic ꢁuoroquinolones as antibacterial and anticancer agents.
Bioorg Med Chem 18:5873–5884. https://doi.org/10.1016/j.
bmc.2010.06.098
2
−
+
3
d: colorless crystals, C H N O
∙ 2(C H N) ,
2
6
22
2
8
6
16
M =694.85, crystal size 0.18×0.14×0.12 mm, monoclinic,
r
Aly AA, El-Shereꢀ EM, Mourad Aboul-Fetouh E, Brown AB, Bräse
S, Bakheet ME, Nieger M (2018) Synthesis oꢀ spiro[indoline-
space group P2 /c (No. 14), a=9.9912(3) Å, b=10.7399(3)
1
Å, c = 16.4621(4) Å, β = 94.647(1)°, V = 1760.65(8)
3
,4′-pyrano[3,2-c]quinolone]-3′-carbonitriles. Monatsh Chem
3
−3
−1
Å , Z = 2, ρ = 1.311 Mg/m , µ(Cu-K ) = 0.747 mm ,
149(149):635–644. https://doi.org/10.1007/s00706-017-2078-6
Bhat SI, Trivedi DR (2014) A highly efcient and green cascade
synthesis oꢀ 3-methyl-substituted-4- hydroxy-1-methylquinolin-
α
F(000) = 748, 2θ = 144.2°, 17106 reꢁections, oꢀ which
max
3
467 were independent (Rint = 0.025), 232 parameters, 2
2
(1H)-ones under solvent- and catalyst-ꢀree conditions. RSC Adv
restraints, R =0.039 (ꢀor 3201 I>2σ(I)), wR =0.106 (all
1
2
4:11300–11304. https://doi.org/10.1039/C3RA45208E
Cagir A, Jones SH, Gao R, Eisenhauer BM, Hecht SM, Luotonin A
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ja0368857
−3
data), S=1.03, largest diꢃ. peak/hole=0.303/−0.237 e Å .
4
: colorless crystals, C H Br N O , M = 412.02,
1
5
12
2
2
2
r
crystal size 0.28 × 0.14 × 0.05 mm, orthorhombic, space
group Pca2 (No. 29), a = 9.5819(4) Å, b = 18.4026(7) Å,
1
Chattaway FD, Mason FA (1910) XXXVIII.—Halogen derivatives oꢀ
malonanilide, ethyl malonanilate, and malonanilic acid. J Chem
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El-Shereꢀ EM, Aly AA, Mourad Aboul-Fetouh E, Brown AB, Bräse
S, Bakheet ME (2018) Synthesis oꢀ pyrano[3,2-c]quinoline-
3
c = 16.9824(7) Å, V = 2994.5(2) Å , Z = 8, ρ = 1.828 Mg/
−
3
−1
m , µ(Mo-K )=5.419 mm , F(000)=1616, 2θ =55.4°,
α
max
1
04279 reꢀlections, oꢀ which 6908 were independent
(
R =0.048), 392 parameters, 5 restraints, R =0.028 (ꢀor
int
1
6
424 I>2σ(I)), wR =0.063 (all data), S=1.08, largest diꢃ.
2
−
3
peak/hole=0.754/−0.420 e Å , x=0.000(6).
4
-carboxylates and 2-(4-oxo-1,4-dihydroquinolin-3-yl)ꢀuma-
6
e: colorless crystals, C H N O ∙ C H NO,
3
0
28
2
4
3
7
rates. Chem Pap 72:181–190. https://doi.org/10.1007/s1169
6-017-0269-6
M =553.64, crystal size 0.38×0.30×0.24 mm, monoclinic,
r
space group P2 /c (No. 14), a=11.4000(5) Å, b=11.1444(5)
Eswaran S, Adhikari AV, Chowdhury LH, Pal NK, Thomas KD (2010)
New quinoline derivatives: synthesis and investigation oꢀ antibac-
terial and antituberculosis properties. Eur J Med Chem 45:3374–
1
Å, c = 22.8990(9) Å, β = 103.551(2)°, V = 2828.2(2)
3
−3
−1
Å , Z = 4, ρ = 1.300 Mg/m , µ(Cu-K ) = 0.711 mm ,
α
3
383. https://doi.org/10.1016/j.ejmech.2010.04.022
F(000)=1176, 2θ =144.0°, 25228 reꢁections, oꢀ which
max
Hashim J, Glasnoc TN, Kremsner JM, Kappe CO (2006) Symmetrical
bisquinolones via metal catalyzed cross-coupling and homocou-
pling reactions. J Org Chem 71:1707. https://doi.org/10.1021/
jo052283p
5
552 were independent (R = 0.023), 379 parameters, 8
int
restraints, R =0.037 (ꢀor 5095 I>2σ(I)), wR =0.101 (all
1
2
−3
data), S=1.05, largest diꢃ. peak/hole=0.270/−0.245 e Å .
CCDC 1824942 (3d), 1827436 (4), and 1824943 (6e)
contain the supplementary crystallographic data ꢀor this
paper. These data can be obtained ꢀree oꢀ charge ꢀrom The
Cambridge Crystallographic Data Centre via http://www.
ccdc.cam.ac.uk/data_request/ciꢀ.
Igarashi J, Kobayashi Y (2005) Improved synthesis oꢀ quinine alkaloids
with the Teoc protective group. Tetrahedron Lett 46:6381–6384.
https://doi.org/10.1016/j.tetlet.2005.06.171
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zation: emerging synthetic tools ꢀor natural products and phar-
maceuticals. Angew Chem Int Ed 51:8960–9009. https://doi.
org/10.1002/anie.201201666
Ma Z, Hano Y, Nomura T, Chen Y (2004) Novel quinazoline–quino-
line alkaloids with cytotoxic and DNA topoisomerase II inhibi-
tory activities. Bioorg Med Chem Lett 14:1193–1196. https://doi.
org/10.1016/j.bmcl.2003.12.048
Acknowledgements Authors thank the DFG-ꢀunded Transregio 3MET
(
TRR88), Karlsruhe Institute oꢀ Technology; Karlsruhe, Germany ꢀor
1
month oꢀ ꢂnancial support ꢀor Proꢀessor Aly to enable him to carry
out the analyses.
Madhu B, Sekar BR, Reddy CH, Dubey PK (2017) Eꢃect oꢀ heter-
ocyclic ring system on ꢀormation oꢀ dimeric quinolones under
catalyst-ꢀree conditions: a green approach. Res Chem Intermed
4
3:6993–7012. https://doi.org/10.1007/s11164-017-3032-2
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(
Aꢀliations
1
1
1
1
2
Ashraf A. Aly · Essmat M. El‑Sheref · Aboul‑Fetouh E. Mourad · Momtaz E. M. Bakheet · Stefan Bräse ·
Martin Nieger3
2
*
Ashraꢀ A. Aly
Institute oꢀ Organic Chemistry, Karlsruhe Institute
oꢀ Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe,
Germany
ashraꢀaly63@yahoo.com; ashraꢀ.shehata@mu.edu.eg
1
Chemistry Department, Faculty oꢀ Science, Minia
University, 61519 El-Minya, Egypt
3
Department oꢀ Chemistry, University oꢀ Helsinki,
P.O. Box55, A. I. Virtasenaukio I, 00014 Helsinki, Finland
1
3