Synthesis of unexpected novel bis-coumarin derivatives via three component reactions of 4-hydroxycoumarin, aldehydes and cyclic secondary amines. Conformation in the solid state and pharmacological evaluation

Article abstract of DOI:10.1515/znb-2017-0066

A series of unexpected bis-coumarins have been synthesized by multicomponent reactions of 4-hydroxycoumarin, aldehydes, and cyclic secondary amines in ethanol at room temperature. The chemical structures of new compounds were identified by ¹H, ¹³C NMR, and mass spectrometry. Furthermore, the molecular structure of the solid-state adduct of 3,3′-[(4-methoxyphenyl)-methylene] bis(4-hydroxy-2H-chromen-2-one) with morpholine (1:1) has been confirmed by single-crystal X-ray diffraction. The cytotoxicity of the new coumarin derivatives against MCF7 breast cancer cells was evaluated. A docking study of the new products was carried out to assess the molecular affinity between the tested compound and Topoisomerase IIa.

Full text of DOI:10.1515/znb-2017-0066

Z. Naturforsch. 2017; 72(10)b: 705–716
Fatma A. El-Samahy*, Hayam A. Abd El Salam, Naglaa F. El-Sayed, Elsayed M. Shalaby
and Mahmoud F. Dondeti
Synthesis of unexpected novel bis-coumarin derivatives via three
component reactions of 4-hydroxycoumarin, aldehydes and
cyclic secondary amines. Conformation in the solid state and
pharmacological evaluation
https://doi.org/10.1515/znb-2017-0066
to the combination of more than two components in the
generation of new products in one-pot reactions; these
types of reactions are extremely economical. Also, the
development of new multicomponent reactions and the
improvement of known ones constitute an area of consid-
erable current interest [1–5]. Coumarin scaffolds and their
derivatives are the key structural feature of a wide range
of synthetic and biologically active natural products [6,
Received April 13, 2017; accepted June 22, 2017
Abstract: A series of unexpected bis-coumarins have been
synthesized by multicomponent reactions of 4-hydroxy-
coumarin, aldehydes, and cyclic secondary amines in
ethanol at room temperature. The chemical structures of
new compounds were identified by H, C NMR, and mass
spectrometry. Furthermore, the molecular structure of the
solid-state adduct of 3,3′-[(4-methoxyphenyl)-methylene]
bis(4-hydroxy-2H-chromen-2-one) with morpholine (1:1)
has been confirmed by single-crystal X-ray diffraction. The
cytotoxicity of the new coumarin derivatives against MCF7
breast cancer cells was evaluated. A docking study of the
new products was carried out to assess the molecular affin-
ity between the tested compound and Topoisomerase IIa.
1
13
7
]. They show a wide range of biological activities such
as anti-HIV, antimalarial as insecticides, and antioxidants
8–10]. Among various derivatives of 4-hydroxylcoumarin,
[
3
-substituted-4-hydroxy coumarins have been used in
important clinical applications (Scheme 1) [11–14].
α-Aminobenzyl-4-hydroxycoumarin derivatives
6
have high biological activity and a number of synthetic
protocols have been reported for their synthesis by the
Keywords: aldehydes; cyclic secondary amines; cytotoxic- reaction of 4-hydroxycoumarin with aromatic aldehydes
ity; docking; 4-hydroxycoumarin; multicomponent reac- and secondary amines [15–19]. Recently, we have reported
tions; single crystal X-ray diffraction.
that morpholine and piperidine-containing compounds
possess promising biological activities. The behavior of
morpholine and piperidine with different groups have
been studied [20–23].
1
Introduction
Herein, we explored ways of combining the hydroxy
Multicomponent reactions have been shown to be particu- coumarin 1 with aldehydes 2a–d, in the presence of cyclic
larly useful methods in organic synthetic chemistry due amines such as morpholine and piperidine to synthesize
novel α-aminobenzyl-4-hydroxycoumarin derivatives 6
and to evaluate them as antitumor agents against MCF7
breast cancer cells (Scheme 2). In the course of these
*
Corresponding author: Fatma A. El-Samahy, Department of
studies, we obtained the unexpected bis-coumarin prod-
ucts 4 and 5 instead. The crystal and molecular structure
of compound 4m has been confirmed by single crystal
X-ray studies (Scheme 2).
Green Chemistry, Chemical Industries Research Division, National
Research Centre, El Buhouth St., P.O. 12622, Dokki, Giza, Egypt,
e-mail: samahyf@hotmail.com
Hayam A. Abd El Salam: Department of Green Chemistry, Chemical
Industries Research Division, National Research Centre, El Buhouth
St., P.O. 12622, Dokki, Giza, Egypt
Naglaa F. El-Sayed: Department of Organometallic and
Organometalloid, Chemical Industries Research Division, National
Research Centre, El Buhouth St., P.O. 12622, Dokki, Giza, Egypt
Elsayed M. Shalaby: X-Ray Crystallography Laboratory, Solid State
Physics Department, Physics Division, National Research Centre,
El Buhouth St., P.O. 12622, Dokki, Giza, Egypt
2
Results and discussion
2
.1 Chemistry
Mahmoud F. Dondeti: Molecular Biology Department, Genetic
Engineering and Biotechnology Research Division, National
Research Centre, El Buhouth St., P.O. 12622, Dokki, Giza, Egypt
Initially, the reaction of 4-hydroxycoumarin 1 and ben-
zaldehydes 2a–d in the presence of the cyclic secondary
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06ꢀꢀꢀꢀꢁꢀF.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactions
6
was not formed (Scheme 2). The crystal and molecular
structures of compound 4m as an example have been con-
firmed by single-crystal X-ray diffraction.
O
O
OH
O
The two products were separated by column chro-
matography and/or by crystallization and the assigned
structures were based on correct elemental and spectral
analyses. The IR spectrum of 4a, taken as an example,
showed absorption bands at 3382 (OH), 3147 (NH),
OH
O
Coumatetralyl
Difenacoum
O
O
−1
1
1
672, and 1668 (2 CO) cm . The H NMR of compound
4
–
–
a showed two triplets at δꢀ=ꢀ3.11 (t, 4 H, J ꢀ=ꢀ6.8 Hz,
HH
OH
O
CH NCH ) and at δꢀ=ꢀ3.75 ppm (t, 4 H, J ꢀ=ꢀ6.8 Hz,
2
2
HH
OH
O
CH OCH ). Moreover, it also showed the three singlets at
2
2
δꢀ=ꢀ6.28, 7.36, and 17.59 ppm attributed to CH, NH, and 2
O
OH, respectively. The phenyl protons appeared as a mul-
Warfaren
Phenprocoumon
1
3
tiplet at 7.02–7.83 ppm (m, 13 ArH). The C NMR showed
Scheme 1:ꢀBiologically active 3-substituted coumarins.
signals with chemical shifts δꢀ=ꢀ36.2 (CH), 42.9 and 63.3
(
CH NCH , CH OCH ), and 103.4 ppm (C-3), respectively.
2 2 2 2
The aromatic carbons signals appeared at δꢀ=ꢀ115.4, 122.8,
amines 3a–d in ethanol at room temperature, surprisingly, 124.1, 124.8, 126.6, 127.6, 128.2, and 130.8 ppm (8 CH) and
led to the formation of novel bis-coumarins 4a–p as major the quaternary carbons at δꢀ=ꢀ119.9, 142.3, 152.5, 164.7, and
products and trace amounts of 5a–d, whereas compound 167.8 ppm. Additional evidence supporting this structure
X
O
H
OH
O
H
N
OH
O
N
EtOH
RT
+
+
X
O
O
R
R
3
a, X = O
1
6
2
a, R = H
b, R = Cl
c, R = F
b, X = CH2
c, X = NH
d, X = NMe
d, R = OMe
R
R
H
O
OH
OH
O
+
H
O
O
O
O
O
O
O
O
H
N
X
5
a, R = H
4
a, R = H, X = O; b, R = H, X = CH ; c, R = H, X = NH; d, R = H, X
2
b, R = Cl
c, R = F
=
NMe; e, R = Cl, X = O; f, R = Cl, X = CH ; g, R = Cl, X = NH; h,
2
R = Cl, X = NMe; i, R = F, X = O; j, R = F, X = CH ; k, R = F, X =
d, R = OMe
2
NH; l, R = F, X = NMe; m, R = OMe, X = O; n, R = OMe, X = CH2;
o, R = OMe, X = NH; p, R = OMe, X = NMe
Scheme 2:ꢀThe synthesis of bis-coumarins 4 and 5.
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F.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactionsꢂꢁꢀꢀꢀꢂ707
was obtained by mass spectrum, which gave a molecu-
2
.2 Description of the molecular structure
of 4m in the crystal
+
lar ion at m/zꢀ=ꢀ499 [M] . The IR spectrum of 5a showed
absorption bands at 3426 (OH), 1672, and 1669 (2 C=O)
−1
1
cm and its H NMR spectrum showed characteristic An Ortep view of the molecular structure of compound
signals at δꢀ=ꢀ6.28 (CH), 17.59 (OH) ppm, and at δꢀ=ꢀ 7.0 2– 4m in the crystal is shown in Fig. 1. It crystallizes as a
1
3
7
.83 ppm for the aromatic protons. The C NMR spectrum 1:1 adduct with morpholine in the monoclinic space
of 5a showed signals at δꢀ=ꢀ36.2 (CH), 103.3 (C3), 142.3, group P2 /n with four molecules in the unit cell and
1
1
52.5 (2 COH), and 164.7, 167.8 (2 C=O) ppm. Additional one molecule per asymmetric unit. It consists of two
confirmation-supported structures of compound 5a were 4-hydroxycoumarin moieties and a methoxyphenyl
obtained by mass spectrum, which gave the molecular moiety all connected at C9 as well as at a separate mor-
ion at m/zꢀ=ꢀ412.
pholine ring. The two coumarins as well as the phenyl
were found to exhibit planar configuration; however,
the morpholine ring exhibits chair conformation as
expected. The two coumarins make a dihedral angle of
5
9.10° with each other. The phenyl ring makes a dihedral
angle of 78.11° with one coumarin and 67.02° with the
other. Generally, bond lengths and angles of compound
4
m are in good agreement with previously determined
similar structures [24–29]. Bond lengths and bond angles
are summarized in Tables 1 and 2. The structure is stabi-
lized by set of intra- and intermolecular hydrogen bonds
(
Table 3), which in turn form a supramolecular assem-
bly (Fig. 2) linking inter alia the morpholine molecule
with the bis-coumarin as shown in Scheme 2. The crystal
structure of compound 4m has been validated using dis-
persion-corrected density functional theory (DFT) mini-
mization arrangement (d-DFT). Global comparisons were
performed by superimposing the molecular skeletons
obtained from X-ray diffraction with the correspond-
ing ones of the d-DFT optimization method (Fig. 3). The
values of the root-mean-square deviations (0.0363 Å) and
the maximum deviations (0.1208 Å) indicate the correct-
ness of the determined structure (values of RMS up to
Fig. 1:ꢀOrtep view of compound 4m in the crystal with atom
numbering scheme adopted. Displacement ellipsoids are
drawn at the 30% probability level, H atoms as spheres with arbi-
trary radii.
0
.25 Å indicate that the structures are correct [30]). These
observations support the accuracy of the experimental
crystal structure.
Table 1:ꢀBond lengths (Å) for compound 4m.
Oꢃ–Cꢄ
Oꢃ–Cꢆ
Cꢄ–Cꢅ
Cꢄ–Cꢅꢅ
Cꢅ–C4
Cꢅ–Cꢅꢈ
C4–Oꢇ
C4–Cꢉ
Cꢉ–Cꢆ
Cꢉ–C9
Cꢆ–O8
ꢃ.ꢅꢆ8(ꢇ)
ꢃ.ꢅ9ꢇ(ꢇ)
ꢃ.ꢅ8ꢉ(ꢉ)
ꢃ.ꢅꢆ8(ꢉ)
ꢃ.4ꢇ4(ꢉ)
ꢃ.ꢅ94(ꢉ)
ꢃ.ꢅꢄꢉ(4)
ꢃ.ꢅꢇ9(ꢇ)
ꢃ.4ꢅ8(ꢇ)
ꢃ.ꢇꢄꢄ(ꢇ)
ꢃ.ꢄꢄꢃ(ꢇ)
C9–Cꢃꢈ
C9–Cꢃ8
ꢃ.ꢇ4ꢄ(ꢇ)
ꢃ.ꢇꢄꢆ(ꢇ)
ꢃ.ꢅꢆꢆ(ꢇ)
ꢃ.49ꢈ(ꢆ)
ꢃ.ꢅ8ꢈ(ꢇ)
ꢃ.ꢅ9ꢈ(ꢉ)
ꢃ.ꢅꢆꢆ(ꢉ)
ꢃ.ꢅ8ꢄ(ꢇ)
ꢃ.ꢅꢆꢅ(ꢉ)
ꢃ.4ꢈꢈ(ꢉ)
ꢃ.ꢅ84(ꢉ)
Cꢃ8–Cꢃ9
Cꢃ8–Cꢄ8
Cꢃ9–Oꢄꢈ
Cꢃ9–Cꢄꢃ
Cꢄꢃ–Cꢄꢄ
Cꢄꢃ–Cꢄꢉ
Cꢄꢄ–Cꢄꢅ
Cꢄꢅ–Cꢄ4
Cꢄ4–Cꢄꢇ
Cꢄꢇ–Cꢄꢉ
Cꢄꢉ–Oꢄꢆ
ꢃ.ꢅꢆꢇ(ꢇ)
ꢃ.4ꢅꢄ(ꢉ)
ꢃ.ꢄ94(4)
ꢃ.4ꢉꢄ(ꢇ)
ꢃ.ꢅꢆꢃ(ꢉ)
ꢃ.ꢅ8ꢅ(ꢉ)
ꢃ.ꢅ8ꢃ(ꢉ)
ꢃ.ꢅ84(ꢆ)
ꢃ.ꢅꢆꢅ(ꢆ)
ꢃ.4ꢈꢉ(ꢉ)
ꢃ.ꢅꢆꢄ(ꢇ)
Oꢄꢆ–Cꢄ8
Cꢄ8–Oꢄ9
Cꢅꢈ–Cꢅꢃ
Cꢅꢃ–Cꢅꢄ
Cꢅꢄ–Cꢅꢅ
Oꢅ4–Cꢅꢇ
Oꢅ4–Cꢅ9
Cꢅꢇ–Cꢅꢉ
Cꢅꢉ–Nꢅꢆ
Nꢅꢆ–Cꢅ8
ꢃ.ꢅ9ꢄ(ꢇ)
ꢃ.ꢄꢃꢆ(ꢇ)
ꢃ.ꢅꢆ9(ꢉ)
ꢃ.ꢅ8ꢄ(ꢆ)
ꢃ.ꢅꢆ9(ꢆ)
ꢃ.4ꢃꢃ(ꢉ)
ꢃ.4ꢈ4(ꢉ)
ꢃ.ꢇꢃꢉ(ꢆ)
ꢃ.4ꢉꢇ(ꢇ)
ꢃ.48ꢅ(ꢇ)
Cꢃꢈ–Cꢃꢃ
Cꢅ8–Cꢅ9
Cꢃꢈ–Cꢃꢆ
Cꢃꢃ–Cꢃꢄ
Cꢃꢄ–Cꢃꢅ
Cꢃꢅ–Oꢃ4
Cꢃꢅ–Cꢃꢉ
Oꢃ4–Cꢃꢇ
Cꢃꢉ–Cꢃꢆ
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08ꢀꢀꢀꢀꢁꢀF.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactions
Table 2:ꢀBond angles (deg.) for compound 4m.
Cꢄ–Oꢃ–Cꢆ
Oꢃ–Cꢄ–Cꢅ
ꢄOꢃ–Cꢄ–Cꢅꢅ
Cꢅ–Cꢄ–Cꢅꢅ
Cꢄ–Cꢅ–C4
Cꢄ–Cꢅ–Cꢅꢈ
C4–Cꢅ–Cꢅꢈ
Cꢅ–C4–Oꢇ
Cꢅ–C4–Cꢉ
Oꢇ–C4–Cꢉ
C4–Cꢉ–Cꢆ
C4–Cꢉ–C9
Cꢆ–Cꢉ–C9
Cꢉ–Cꢆ–Oꢃ
Cꢉ–Cꢆ–O8
Oꢃ–Cꢆ–O8
Cꢉ–C9–Cꢃꢈ
Cꢉ–C9–Cꢃ8
Cꢃꢈ–C9–Cꢃ8
Cꢄꢄ–Cꢄꢃ–Cꢄꢉ
ꢃꢄꢃ.ꢃ(ꢅ)
ꢃꢄꢃ.ꢄ(4)
ꢃꢃꢉ.ꢅ(4)
ꢃꢄꢄ.ꢇ(4)
ꢃꢃ8.ꢃ(4)
ꢃꢃ8.ꢈ(4)
ꢃꢄꢅ.9(4)
ꢃꢃꢅ.8(4)
ꢃꢄꢈ.9(4)
ꢃꢄꢇ.ꢅ(4)
ꢃꢃ9.ꢉ(4)
ꢃꢄ4.ꢄ(4)
ꢃꢃꢉ.ꢄ(4)
ꢃꢃ9.ꢃ(4)
ꢃꢄꢉ.ꢉ(4)
ꢃꢃ4.ꢅ(4)
ꢃꢃꢅ.ꢅ(ꢅ)
ꢃꢃ4.ꢉ(ꢅ)
ꢃꢃ4.8(ꢅ)
ꢃꢃ8.ꢅ(4)
C9–Cꢃꢈ–Cꢃꢃ
C9–Cꢃꢈ–Cꢃꢆ
Cꢃꢃ–Cꢃꢈ–Cꢃꢆ
Cꢃꢈ–Cꢃꢃ–Cꢃꢄ
Cꢃꢃ–Cꢃꢄ–Cꢃꢅ
Cꢃꢄ–Cꢃꢅ–Oꢃ4
Cꢃꢄ–Cꢃꢅ–Cꢃꢉ
Oꢃ4–Cꢃꢅ–Cꢃꢉ
Cꢃꢅ–Oꢃ4–Cꢃꢇ
Cꢃꢅ–Cꢃꢉ–Cꢃꢆ
Cꢃꢉ–Cꢃꢆ–Cꢃꢈ
C9–Cꢃ8–Cꢃ9
C9–Cꢃ8–Cꢄ8
Cꢃ9–Cꢃ8–Cꢄ8
Cꢃ8–Cꢃ9–Oꢄꢈ
Cꢃ8–Cꢃ9–Cꢄꢃ
Oꢄꢈ–Cꢃ9–Cꢄꢃ
Cꢃ9–Cꢄꢃ–Cꢄꢄ
Cꢃ9–Cꢄꢃ–Cꢄꢉ
Cꢄꢃ–Cꢄꢄ–Cꢄꢅ
ꢃꢄꢄ.ꢈ(4)
ꢃꢄꢈ.ꢆ(4)
ꢃꢃꢆ.ꢃ(4)
ꢃꢄꢄ.ꢅ(4)
ꢃꢃ9.ꢃ(4)
ꢃꢄ4.4(4)
ꢃꢃ9.ꢆ(4)
ꢃꢃꢇ.9(4)
ꢃꢃ8.ꢈ(4)
ꢃꢄꢈ.ꢈ(4)
ꢃꢄꢃ.ꢆ(4)
ꢃꢄ4.4(4)
ꢃꢃꢇ.4(ꢅ)
ꢃꢄꢈ.ꢄ(4)
ꢃꢄꢈ.9(4)
ꢃꢃ9.9(4)
ꢃꢃ9.ꢄ(4)
ꢃꢄ4.ꢃ(4)
ꢃꢃꢆ.ꢉ(4)
ꢃꢄꢃ.ꢃ(ꢇ)
Cꢄꢅ–Cꢄ4–Cꢄꢇ
Cꢄ4–Cꢄꢇ–Cꢄꢉ
Cꢄꢇ–Cꢄꢉ–Cꢄꢃ
Cꢄꢇ–Cꢄꢉ–Oꢄꢆ
Cꢄꢃ–Cꢄꢉ–Oꢄꢆ
Cꢄꢉ–Oꢄꢆ–Cꢄ8
Cꢃ8–Cꢄ8–Oꢄꢆ
Cꢃ8–Cꢄ8–Oꢄ9
Oꢄꢆ–Cꢄ8–Oꢄ9
Cꢅ–Cꢅꢈ–Cꢅꢃ
Cꢅꢈ–Cꢅꢃ–Cꢅꢄ
Cꢅꢃ–Cꢅꢄ–Cꢅꢅ
Cꢅꢄ–Cꢅꢅ–Cꢄ
Cꢅꢇ–Oꢅ4–Cꢅ9
Oꢅ4–Cꢅꢇ–Cꢅꢉ
Cꢅꢇ–Cꢅꢉ–Nꢅꢆ
Cꢅꢉ–Nꢅꢆ–Cꢅ8
Nꢅꢆ–Cꢅ8–Cꢅ9
Cꢅ8–Cꢅ9–Oꢅ4
Cꢄꢄ–Cꢄꢅ–Cꢄ4
ꢃꢄꢃ.ꢈ(ꢇ)
ꢃꢃꢆ.ꢆ(ꢇ)
ꢃꢄꢄ.ꢈ(4)
ꢃꢃꢇ.ꢉ(4)
ꢃꢄꢄ.4(4)
ꢃꢄꢈ.ꢆ(4)
ꢃꢃ9.ꢈ(4)
ꢃꢄꢆ.8(4)
ꢃꢃꢅ.ꢄ(4)
ꢃꢄꢈ.ꢄ(ꢇ)
ꢃꢄꢈ.ꢅ(ꢇ)
ꢃꢄꢈ.ꢉ(ꢇ)
ꢃꢃ8.4(ꢇ)
ꢃꢈ9.ꢄ(4)
ꢃꢃꢈ.9(4)
ꢃꢈ9.ꢆ(4)
ꢃꢈ9.9(4)
ꢃꢃꢃ.ꢈ(4)
ꢃꢃꢃ.4(ꢇ)
ꢃꢃ9.9(ꢇ)
Table 3:ꢀInter- and intramolecular hydrogen bond parameters and
a
nonbonding contacts (Å, deg.) of compound 4m.
D–Hꢁ·ꢁ·ꢁ·ꢁA
D–H
Hꢁ·ꢁ·ꢁ·ꢁA
Dꢁ·ꢁ·ꢁ·ꢁA
D–Hꢁ·ꢁ·ꢁ·ꢁA
Oꢇ–Hꢇꢃꢁ·ꢁ·ꢁ·ꢁOꢄꢈ
Oꢄꢈ–Hꢄꢈꢃꢁ·ꢁ·ꢁ·ꢁNꢅꢆ
Nꢅꢆ–Hꢅꢆꢃꢁ·ꢁ·ꢁ·ꢁOꢄ9
Cꢅꢉ–Hꢅꢉꢃꢁ·ꢁ·ꢁ·ꢁO8
Cꢅꢉ–Hꢅꢉꢄꢁ·ꢁ·ꢁ·ꢁOꢃ4
ꢈ.8ꢃ
ꢈ.8ꢃ
ꢈ.94
ꢈ.9ꢆ
ꢈ.9ꢆ
ꢃ.ꢆꢇꢇ
ꢄ.ꢃ8
ꢃ.8ꢅ
ꢄ.ꢇꢃ
ꢄ.ꢉꢈ
ꢄ.49ꢃ (ꢅ)
ꢄ.ꢆꢈꢇ (ꢇ)
ꢄ.ꢆꢅꢃ (ꢇ)
ꢅ.ꢃꢉ9 (ꢉ)
ꢅ.ꢄꢈ8 (ꢉ)
ꢃꢇꢈ
ꢃꢄꢄ
ꢃꢉꢈ
ꢃꢄꢇ
ꢃꢄꢃ
i
ii
ii
iii
X–Hꢁ·ꢀ·ꢀ·ꢁCg
X–H
Hꢀ·ꢀ·ꢀ·ꢀCg
Xꢀ·ꢀ·ꢁ·ꢁCg
X–Hꢀ·ꢀ·ꢀ·ꢀCg
iii
Cꢅꢈ–Hꢅꢈꢃꢁ·ꢁ·ꢁ·ꢁCgꢄ
Cꢅ8–Hꢅ8ꢄꢁ·ꢁ·ꢁ·ꢁCg4
ꢈ.9ꢉ
ꢈ.9ꢉ
ꢄ.9ꢈ
ꢄ.8ꢆ
ꢅ.ꢆ9ꢇ (ꢇ)
ꢅ.ꢉ44 (ꢉ)
ꢃꢇ8
ꢃꢅꢆ
iv
Symmetry codes: (i) 1/2ꢁ+ꢁx, 1/2ꢁ−ꢁy, −1/2ꢁ+ꢁz; (ii) 1ꢁ−ꢁx, 1ꢁ−ꢁy,
ꢁ−ꢁz; (iii) 3/2ꢁ−ꢁx, −1/2ꢁ+ꢁy, 1/2ꢁ−ꢁz; (iv) −1/2ꢁ+ꢁx, 1/2ꢁ−ꢁy, 1/2ꢁ+ꢁz;
1
Cg2 (center of gravity) of O27–C26–C21–C1ꢊ–C1ꢋ–C2ꢋ; Cgꢌ:
C10–C11–C12–C13–C16–C17.
Fig. 3:ꢀOverlay diagram of compound 4m; red (X-ray structure),
green (DFT).
2
.3 Biological evaluation
2.3.1 Cytotoxicity screening
Cancer is one of the diseases with a high mortality rate
[31]. Coumarin derivatives have received considerable
Fig. 2:ꢀUnit cell contents of structure 4m showing different intermo-
lecular hydrogen bond interactions as dashed lines.
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Table 4:ꢀThe IC valued of the bis-coumarin derivatives used in the
potential antitumor activity and it is suggested to be used
in trials on breast cancer. Interestingly, structures con-
taining N-methyl piperazine moiety enhance cytotoxic
activities compared with the same structures containing
morpholine, piperidine, and piperazine moiety. However,
unexpected results were observed for compound 4e
5
0
treatment of MCF-7.
Compound ꢂ MCFꢃ ICꢄꢅ (μg mL ) ꢂ Compoundꢂ MCFꢃ IC (μg mL−ꢆ)a
−ꢆ a
ꢄꢅ
Doxorubicinb ꢍ
ꢅꢍ ꢇi
ꢄ4.ꢇꢍ ꢇj
ꢄꢄꢍ ꢇk
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢃꢉ.ꢄ
ꢃꢆ
ꢄꢃ.ꢇ
ꢄꢈ
ꢃꢆ.ꢇ
ꢇa
ꢇb
ꢇc
ꢇd
ꢇe
ꢇf
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
ꢍ
(
lowest IC ), which contained a morpholine ring. The
50
ꢄꢃꢍ ꢇl
−1
growth inhibition IC50 values in μg mL of the coumarin
ꢃꢄ.ꢇꢍ ꢇm
ꢃꢄ.ꢃꢍ ꢇn
ꢄꢈ.ꢇꢍ ꢇo
ꢃ9.ꢇꢍ ꢇp
ꢃꢅ.ꢉꢍ
ꢃꢄ.ꢉ derivatives 4a–p on MCF-7 (human breast cancer cells) are
ꢄꢆ shown in Fig. 4.
ꢇg
ꢇh
ꢃꢄ.9
aIC value was defined as the concentration at which 50% survival
of cells was observed; Doxorubicin was used a reference drug;
DMSO was used as a negative control.
50
2
.3.2 In silico docking studies for novel bis-coumarin
b
derivatives
Docking studies were performed to assess the molecular
attention owing to their chemotherapeutic potentials affinity between the prepared compounds and the target
including their versatile anticancer activities [32–34], protein [38]. Determination of the consistent receptor was
especially in the treatment of breast carcinoma cell line based on previous studies [39–41]. The crystallographic
(
MCF7) [35, 36], the current study was focused to screen structure of the protein (PDBs) was obtained from the
in vitro cytotoxic and growth-inhibitory activities of the protein data bank. Macromolecule file (PDB code: 4r1f)
newly synthesized bis-coumarin compounds on human was modified using the ADT package. The compounds
breast carcinoma cell line (MCF7). MCF7 cells were cul- 4a, 4d, 4e, and 4o were studied regarding their affinity to
tured as monolayers and treated with our compounds for the Topoisomerase IIa cell proteins as the Topoisomerase
4
8 h. The rate of proliferation was assessed by the sulfo- II alpha. All the docking was performed by the auto-dock
rhodamine B assay [37]. From the current data (Table 4), it tool. The current docking results showed that the com-
can be deduced that compounds 4e, 4d, and 4n have the pounds 4e and 4d have the highest affinity to the Topoi-
−1
most potent inhibition of tumor cells compared with the somerase IIa as they were −4.4 and −4.8 kcal mol for
other derivatives with IC values of 12.1, 12.5, and 12.6 μg compounds 4d and 4e, respectively. Although compounds
5
0
−1
mL , respectively, which places them with high antitumor 4a and 4o have the lowest binding affinity with −11.5 and
−1
activity. On the other hand, compound 4a has the highest −11.7 kcal mol , respectively, this is congruent with the IC
5
0
−1
IC of 24.5 μg mL value, which reveals that it is the least values. The docking studies show that there are interac-
50
effective derivative. Therefore, compound 4e may have tions between the coumarin nucleus of compound 4e and
−1
Fig. 4:ꢀThe growth inhibition IC50 values (μg mL ) of the coumarin derivatives 4a–p on MCF-7 (human breast cancer cells).
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7
10ꢀꢀꢀꢀꢁꢀF.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactions
Fig. 5:ꢀThe docking studies show that there are interactions between the coumarin nucleus of compound 4e and Topoisomerase IIa protein.
the Thr193 residue through hydrogen bonds via the amino spectrometer (JEOL, Japan) or on Varian Mercury VX-300
group. The presence of glycine (Gly191) and phenylalanine (at 300 MHz) spectrometer using tetramethylsilane as an
1
13
(
Phe308) suggests the stabilization of the protein–ligand internal reference. H and C NMR spectra were recorded
complex. The compound binding is near the active site of in deuterated dimethylsulfoxide ([D ]DMSO) and chemical
6
the protein, which suggests its potential effect. Therefore, shifts (δ) are given in ppm. Mass spectra (EI-MS) were deter-
compound 4e may have the most potential anti-tumor mined at 70 eV on a Finnigan MAT SSQ 7000 spectrometer.
activity and it can be used in trials on breast cancer. Very Elemental analyses (C/H/N) were carried using elementary
good agreement between predicted and experimentally Analysen-Systeme GmbH-Vario EL III Element Analyzer,
measured antitumor activities was observed for the tested Germany, and the method for determining halogens was
compounds (Fig. 5).
by oxygen flask method. Commercial 4-hydroxycoumarin,
substituted aromatic aldehydes, and secondary amines
(morpholine, piperidine, piperazine, and 1-methylpipera-
zine) were used without further purification and solvents
were dried using standard techniques. TLC: Merck 0.2 mm
silica gel 60 F154 anal aluminum plates. Column chroma-
tography: silica gel (Kieselgel 60 mesh, particle size 0.2–
3
Conclusion
In conclusion, the multicomponent method was used for
the synthesis of novel and biologically significant bis-cou-
marins 4a–p with 5a–d from 4-hydroxycoumarin, aromatic
aldehydes, and secondary cyclic amines (morpholine,
piperidine, piperazine, and N-methylpiperazine) in ethanol
0.5 mm; E. Merck, Darmstadt, Germany).
at room temperature. The advantages of the proposed pro- 4.2 Crystal structure determination
cedure include simplicity, short reaction time, easy work-
up, and high yield. The cytotoxic activity of bis-coumarin
and validation of compound 4m
derivatives against MCF7 breast cancer cell lines was evalu- X-ray diffraction data for compound 4m has been
ated. The results showed that compound 4e increased the recorded in the rotation mode using the φ and ω scan
cytotoxic efficacy in breast cancer cells (MCF7), which was technique with θmaxꢀ=ꢀ 3 7.43 ° at room temperature (298 K)
in agreement with the molecular docking results for com- on an Enraf-Nonius 590 diffractometer with a Kappa CCD
pounds with Topoisomerase IIa protein.
detector using graphite-monochromatized MoKα radia-
tion (λꢀ=ꢀ0.71073 Å) [42]. Data were corrected for absorp-
tion effects using the multiscan method (Sadabs [43]). The
crystal structure was solved using Superflip [44] imple-
mented in the crystals program suit [45]. The refinement
was carried out by full-matrix least-squares methods with
anisotropic displacement parameters for all nonhydrogen
4
Experimental section
4
.1 Chemistry
2
atoms based on F using crystals. The hydrogen atoms
Melting points were determined on an electrical digital were positioned geometrically in their idealized positions
melting point apparatus (Stuart/melting point SMP 30) and [46]. The general-purpose crystallographic tool Platon [47]
uncorrected. IRspectrawererecordedonaJASCOFT-IR6100 was used for the structure analysis and presentation of the
using KBr disc (JASCO, Japan). NMR spectra were measured results. Ortep-3 for Windows [48] and Mercury [49] were
13
1
with a JEOL E.C.A-500 MHz ( C: 125.4 MHz, H: 500.7 MHz) used for molecular graphics representations. Crystal data
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F.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactionsꢂꢁꢀꢀꢀꢂ711
Table 5:ꢀCrystal data and data collection and structure refinement
CCDC 1523251 contains the supplementary crystallo-
graphic data for this article. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
parameters of compound 4m.
Crystal data
ꢂChemical formula
C H NO
ꢅꢈ ꢄꢆ
ꢇꢄ9.ꢇꢇ
8
ꢂMr
ꢂCrystal system, space group
Monoclinic, Pꢄ /n
ꢄ98
ꢃ
ꢂTemperature, K
ꢂa, Å
4.3 General procedure for the synthesis
of compounds (4a–p) and 5a–d
ꢃꢅ.ꢃ49 (ꢅ)
ꢃꢃ.ꢉ9ꢈ (ꢄ)
ꢃꢆ.ꢄꢃꢉ (ꢅ)
9ꢄ.ꢈ84 (ꢆ)
ꢄꢉ44.ꢉ (9)
4
ꢃꢃꢃꢄ
ꢈ.ꢈ9ꢆ
Cube, colorless
ꢈ.ꢅꢄꢁ×ꢁꢈ.ꢄꢉꢁ×ꢁꢈ.ꢄꢅ
ꢃ.ꢅꢅ
ꢂb, Å
ꢂc, Å
A mixture of 4-hydroxycoumarin (1) (0.5 mmol), aldehydes
(2) (0.5 mmol) and secondary amines (3) (0.5 mmol) was
stirred at room temperature in ethanol absolute. After the
completion of the reaction (monitored using TLC), the vol-
atile materials were evaporated and the residue separated
on column chromatography using silica gel and petro-
leum ether b.p. 60°C–80°C and ethyl acetate as eluent or
by crystallization. The products were isolated and recrys-
tallized by suitable solvents to give pure products 4 and
ꢂβ, deg
ꢂV, Åꢅ
ꢂZ
ꢂF(ꢈꢈꢈ), e
−
ꢃ
ꢂμ, mm
ꢂCrystal shape, color
ꢂCrystal size, mmꢅ
ꢂCalculated density, g cm−
ꢅ
Data collection
ꢂRadiation type
ꢂMonochromator
ꢂScan type
MoKα
Graphite
5
at a ratio of approximately 4:1. The isolated compounds
ϕ and ω scans
ꢃ.9–ꢅꢆ.4
ꢈ.8ꢇꢇ
Multiscan
ꢈ.98/ꢈ.98
899ꢆ/ꢅꢃꢄꢆ/ꢃ9ꢉꢇ
were characterized by mp, elemental analysis (C, H and
ꢂθ range, deg
1
13
N), IR, H NMR, C NMR, and crystal structure determina-
tion (compound 4m).
ꢂ((sinθ)/λ)max, Å−ꢃ
ꢂAbsorption correction
ꢂTmin/Tmax
ꢂRefl. total/unique/obs. with Iꢁ>ꢁꢄ.ꢈ σ(I)
Refinement
4
.4 3,3′-(Phenylmethylene)bis(4-hydroxy-
H-chromen-2-one) compound with
morpholine (1:1) (4a)
ꢂNo. of reflections
ꢃ9ꢉꢇ
ꢃꢄꢆ
2
ꢂNo. of ref. parameters
ꢄ
ꢄ
ꢄ
ꢂR/wR(F )/S [F ꢁ>ꢁꢄ σ(F )]
ꢈ.ꢈ4ꢉꢅ/ꢈ.ꢃꢈ84/ꢃ.ꢈꢈꢈꢇ
ꢈ.ꢄꢇ/−ꢈ.ꢃ8
−
ꢅ
ꢂΔρmax/min, e Å
The residue was triturated and treated with boiling ethanol,
the soluble major fraction is 4a, which, after cooling, gave
and numbers pertinent to data collection and refinement colorless crystals. Yield: 1.74 g (70%); m.p. 244°C–246°C.
are given in Table 5.
– Analysis calcd. for C H NO : C 69.73, H 5.04, N 2.80;
29 25 7
The structure obtained from X-ray single crystal data found C 69.79, H 5.11, N 2.88%. – IR (KBr): νꢀ=ꢀ3382 (OH),
−1
1
of compound 4m was compared with the one computed 3147 (NH), 1672, 1668 (C=O), and 1614 (C=C) cm . – H
by dispersion-corrected quantum-mechanical DFT. DFT NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ3.11 (t, J ꢀ=ꢀ6.8 Hz, 4H,
6
HH
calculations have been introduced as an important check –CH NCH –), 3.75 (t, J ꢀ=ꢀ6.8 Hz, 4H, –CH OCH –), 6.28 (s,
2
2
HH
2
2
on the accuracy of structures derived from single crystal 1 H, CH), 7.02–7.83 (m, 13 ArH), 7.36 (s, 1H, NH), and 17.59
1
3
data [30, 47]. The DFT program Castep [50] as integrated (s, 2 OH) ppm. – C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ36.2
6
into the Accelrys Materials Studio 6.1 package, was used (CH), 42.9, 63.3 (–CH NCH –, –CH OCH –), 103.3 (C), 115.4
2
2
2
2
with the PBE functional [51] plane-wave energy cutoff of (CH), 119.9 (C), 122.8 (CH), 124.1 (CH), 124.8 (C), 126.6 (CH),
5
20 eV, and includes dispersion interactions via the TS 127.6 (CH), 128.2 (CH), 130.8 (CH), 142.3, 152.5 (2 COH),
scheme [52]. The Materials Studio ‘Ultrafine’ geometry 164.7, and 167.8 (2 C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ499
+
+
optimization convergence criteria was adopted, with a (10) [M] , (20) 412 [M-morpholine] , 335 (11), 252 (35), 223
final Cartesian displacement of less than 5ꢀ×ꢀ10 Å, a (23), 162 (83), 120 (100), 92 (95), 87 (26), and 57 (55).
−4
−1
maximum force of 0.01 eV Å and maximum energy differ-
ence of 5ꢀ×ꢀ10 eV per atom. The unit cell parameters were
−
6
fixed at the experimental values. Optimizing the crystal 4.5 3,3′-(Phenylmethylene)bis(4-hydroxy-
structures starting from the final model from the diffrac-
2
H-chromen-2-one) (5a)
tion data led to a d-DFT-minimized arrangement, which
was then compared with the X-ray structure by overlaying The insoluble fraction is 5a as colorless crystals. Yield
corresponding molecules using Mercury [49]. (10%); m.p. 233°C–235°C [53]. – Analysis calcd. for C H O :
2
5
16
6
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12ꢀꢀꢀꢀꢁꢀF.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactions
C 72.81, H 3.91; found C 72.90, H 3.98%. – IR (KBr): νꢀ=ꢀ3426 (100), 92 (35), and 57 (45). The second fraction (85%, ethyl
−
1
1
(
OH), 1672, 1669 (C=O), and 1611 (C=C) cm . – H NMR acetate) yielded colorless crystals of 5a.
(
500 MHz, [D ]DMSO): δꢀ=ꢀ6.28 (s, 1 H, CH), 7.02–7.83 (m,
6
13
1
3 ArH), and 17.59 (s, 2 OH) ppm. – C NMR (125.4 MHz,
4
.8 3,3′-(Phenylmethylene)bis(4-hydroxy-
H-chromen-2-one) compound with
-methylpiperazine (1:1) (4d)
[
D ]DMSO): δꢀ=ꢀ36.2 (CH), 103.3 (C), 115.4 (CH), 119.9 (C),
6
2
1
22.8 (CH), 124.1 (CH), 124.8 (C), 126.6 (CH), 127.6 (CH), 128.2
1
(
CH), 130.8 (CH), 142.3, 152.5 (2 COH), 164.7, and 167.8 (2
+
C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ412 (10) [M] , 335 (21),
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4d, which, after
cooling, gave colorless crystals. Yield: 1.66 g (65%); m.p.
2
52 (25), 223 (20), 162 (43), 120 (100), 92 (25), and 57 (35).
2
50°C–253°C (EtOH). – Analysis calcd. for: C H N O :
30 28 2 6
4
.6 3,3′-(Phenylmethylene)bis(4-hydroxy-
H-chromen-2-one) compound with
piperidine (1:1) (4b)
C 70.30, H 5.51, N 5.47; found C 70.37, H 5.58, N 5.53%. –
2
IR (KBr): vꢀ=ꢀ3461 (OH), 3190 (NH), 1666 (C=O), and 1602
−1
1
(
C=C) cm . – H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ2.15 (s, 3H,
6
NMe), 2.87, 3.09 (2 m, 4 CH , piperazine ring), 3.21, 6.23,
2
The residue was triturated and treated with boiling ethanol,
the soluble major fraction is 4b, which, after cooling, gave
colorless crystals. Yield: 1.79 g (72%); m.p. 340°C–342°C. –
Analysis calcd. for: C H NO : C 72.42, H 5.47, N 2.82; found
1
7.57 (3s, NH, CH, 2 OH), and 7.13–7.58 (m, NH, 13 ArH) ppm;
1
3
C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ43.7 (CH), 45.3, 50.5,
6
5
2.8, 69.2, 94.0, 116.4, 121.7, 123.2, 123.4, 124.8, 128.2, 129.4,
30
27
6
1
29.7, 130.0, 131.7, 154.1, 163.3, and 173.4 ppm. – MS (70 eV):
C 72.49, H 5.53, N 2.90%. – IR (KBr): vꢀ=ꢀ3430 (OH), 3145
+
+
m/z (%)ꢀ=ꢀ512 (8) [M] , 412 (35) [M-methylpiperazine] , 335
−1
1
(
[
NH), 1671 (C=O), and 1611 (C=C) cm . – H NMR (500 MHz,
(
(
22), 252 (29), 223 (16), 162 (27), 120 (100), 92 (55), and 57
15). The insoluble fraction is 5a as colorless crystals.
D ]DMSO): δꢀ=ꢀ0.82, 1.23 (m, 3 CH at positions 3, 4, 5 of
6
2
the piperidine ring), 3.36 (m, 2 CH at positions 2 and 6
2
of the piperidine ring), 4.10, 6.23 (2s, NH, CH), 7.05–7.24
13
(
m, 13 ArH), and 17.60 (s, 2 OH) ppm; C NMR (125.4 MHz, 4.9 3,3′-[(4-Chlorophenyl)methylene]bis(4-
[
D ]DMSO): δꢀ=ꢀ23.7, 28.9 (–CH CH CH –), 40.2 (CH), 67.9
6
2
2
2
hydroxy-2H-chromen-2-one) compound
(
–CH NCH –), 103.9 (C3), 116.0 (CH), 120.4 (C), 123.4 (C),
2
2
with morpholine (1:1) (4e)
1
24.6 (CH), 125.4 (CH), 127.1 (C), 127.2 (CH), 128.2 (CH), 131.5
(
CH), 142.8, 153.0 (2 COH), 165.1, and 168.2 (2 C=O) ppm. – Theresiduewastrituratedandtreatedwithboilingethanol,
+
+
MS (70 eV): m/z (%)ꢀ=ꢀ497 (5) [M] , 412 (20) [M-piperidine] , the soluble major fraction is 4e, which, after cooling, gave
35 (32), 252 (15), 223 (26), 162 (25), 120 (100), 92 (65), and 57 colorless crystals. Yield: 1.78 g (67%); m.p.: 245°C–247°C.
35). The insoluble fraction is 5a (colorless crystals). – Analysis calcd. for C H ClNO : C 65.23, H 4.53, Cl 6.64,
3
(
2
9
24
7
N 2.62; found C 65.30, H 4.59, Cl 6.71, N 2.69%. – IR (KBr):
−1
3
443 (OH), 3155 (NH), 1674 (C=O), and 1609 (C=C) cm .
1
4
.7 3,3′-(Phenylmethylene)bis(4-hydroxy-
H-chromen-2-one) compound with
piperazine (1:1) (4c)
– H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ3.06 (t, J ꢀ=ꢀ6.8 Hz,
6
HH
4
H, –CH NCH –), 3.71 (t, J ꢀ=ꢀ6.8 Hz, 4H, –CH OCH –), 6.19
2
2 2 HH 2 2
(
s, 1H, CH), 7.16–7.24 (m, NH, 12 ArH), and 17.50 (1H, 2 OH)
1
3
ppm. – C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ36.7 (CH), 43.8,
6
The first fraction (80% ethyl acetate) gave 4c as colorless 63.5 (–CH NCH –, –CH OCH –), 102.9 (C), 114.8 (CH), 119.7
2
2
2
2
crystals. Yield: 1.71 g (68%); m.p. 228°C–230°C (ethyl ace- (C), 123.1 (CH), 124.3 (CH), 124.4 (C), 126.2 (CH), 127.8 (CH),
tate-petroleum ether b.p. 60°C–80°C). – Analysis calcd. 128.5 (CH), 131.5 (CH), 141.9, 152.7 (2 COH), 164.9, and 167.5
+
for: C H N O : C 69.87, H 5.26, N 5.62; found C 69.94, H (2 C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ534 (15) [Mꢀ+ꢀ1] , 446
29
26
2
6
5
1
.34, N 5.70%. – IR (KBr): vꢀ=ꢀ3424, 3378 (OH), 3188 (NH), (100), 404 (10), 382 (12), 325 (15), 283 (30), 249 (23), 200
−1
1
671 (C=O), and 1611 (C=C) cm . – H NMR (500 MHz, [D ] (18), 161 (15), 96 (15), and 87 (10).
6
DMSO): δꢀ=ꢀ1.35, 2.82 (2 m, 4 CH , piperazine ring), 2.86,
2
6
.20, 17.57 (3s, NH, CH, 2 OH), and 7.04–7.23 (m, NH,
3 ArH) ppm; 1 C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ26.8 4.10 3,3′-[(4-Chlorophenyl)methylene]bis(4-
3
1
6
(
CH NHCH ), 36.6 (CH NCH ), 43.5 (CH), 103.9, 116.0, 120.4,
2
2
2
2
hydroxy-2H-chromen-2-one) (5b)
1
1
23.4, 124.6, 125.3, 127.2, 128.2, 131.4, 142.8, 153.0, 165.1, and
+
68.2 ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ498 (13) [M] , 412 (36) The insoluble fraction is 5b as colorless crystals. Yield:
+
[
M-piperazine] , 335 (22), 252 (23), 223 (16), 162 (18), 120 (10%); m.p. 256°C–258°C [54]. – Analysis calcd. for
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F.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactionsꢂꢁꢀꢀꢀꢂ713
C H ClO : C 67.20, H 3.38, Cl 7.93; found C 67.29, H 3.45, 128.2 (CH), 129.1 (C), 129.9 (CH), 131.6 (CH), 142.0, 153.1 (2
2
5
15
6
Cl 8.00%. – IR (KBr): vꢀ=ꢀ3427 (OH), 1675 (C=O), and 1615 COH), 165.0, and 168.3 (2 C=O) ppm. – MS (70 eV): m/z
−
1
1
+
(
C=C) cm . – H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ6.06 (s, (%)ꢀ=ꢀ533 (15) [Mꢀ+ꢀ1] , 492 (8), 463 (25), 402 (30), 377 (55),
6
1
3
CH), 7.16–8.10 (m, 12 ArH), and 17.51 (s, 2 OH) ppm. – C 360 (45), 335 (40), 275 (45), 250 (20), 195 (30), 153 (100), 120
NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ35.8 (CH), 103.7 (C), 115.7, (15), and 92 (10). The second fraction (85%, ethyl acetate)
6
1
1
16.0 (CH), 120.3 (C), 123.5 (C), 124.7 (CH), 128.2 (CH), yielded colorless crystals of 5b.
28.2 (CH), 129.1 (C), 131.6 (CH), 149.2, 153.0 (2 COH), 165.1,
and 168.4 (2 C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ448 (20)
+
[
(
Mꢀ+ꢀ1] , 402 (25), 377 (30), 360 (100), 335 (37), 316 (15), 275
4
.13 3,3′-[(4-Chlorophenyl)methylene]bis(4-
hydroxy-2H-chromen-2-one) compound
with 1-methylpiperazine (1:1) (4h)
82), 255 (17), 191 (25), 153 (35), 115 (15), and 91 (15).
4
.11 3,3′-[(4-Chlorophenyl)methylene]bis(4-
hydroxy-2H-chromen-2-one) compound
with piperidine (1:1) (4f)
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4h after cooling
gave colorless crystals. Yield: 1.72 g (63%); m.p. >350°C.
–
Analysis calcd. for C H ClN O : C 65.87, H 4.98, Cl 6.48,
30 27 2 6
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4f, which, after
cooling, gave colorless crystals. Yield: 1.72 g (65%); m.p.
N 5.12; found C 65.96, H 5.07, Cl 6.55, N 5.19%. – IR (KBr):
−1
vꢀ=ꢀ3443 (OH), 3230 (NH), 1659 (C=O), and 1613 (C=C) cm .
1
–
H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ1.82, 2.23 (2m, 4 CH2
6
2
42°C–244°C. – Analysis calcd. for C H ClNO : C 67.73, H
30 26 6
of piperazine ring), 3.14 (s, 3H, NMe), 6.20 (s, CH), 7.07–
4
.93, Cl 6.66, N 2.63; found C 67.80, H 4.98, Cl 6.72, N 2.68%.
1
3
7
(
.86 (m, NH, 12 ArH), and 17.51 (s, OH) ppm. – C NMR
–
IR (KBr): vꢀ=ꢀ3433 (OH), 3145 (NH), 1672 (C=O), and 1610
125.4 MHz, [D ]DMSO): δꢀ=ꢀ40.1 (CH), 41.4, 54.2, 64.7,
−1
1
6
(
C=C) cm . – H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ1.49 (m,
6
1
1
03.7, 116.3, 120.7, 123.1, 1243.9, 128.2, 128.6, 129.0, 129.9,
2
2
2
H, CH at position 4 of the piperidine ring), 1.58 (m, 4H,
2
31.4, 142.3, 153.2 (2 COH), 165.3, and 168.5 (2 C=O) ppm. –
CH at positions 3 and 5 of the piperidine ring), 2.96 (m,
2
+
MS (70 eV): m/z (%)ꢀ=ꢀ548 (24) [Mꢀ+ꢀ1] , 448 (25), 412 (20),
CH at positions 2 and 6 of the piperidine ring), 6.20
2
3
(
77 (35), 360 (33), 335 (22), 275 (15), 250 (34), 195 (32), 153
100), 120 (25), and 92 (50). The insoluble fraction is 5b as
colorless crystals.
(
s, CH), 7.05–7.77 (m, 12 ArH), 8.21 (s, NH), and 17.49 (s, 2
13
OH) ppm. – C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ22.1, 22.7
6
(
–CH CH CH –), 39.2 (C), 49.1 (–CH NCH –), 103.6 (C), 116.0
2 2 2 2 2
(
CH), 120.4 (C), 123.4 (C), 124.6 (CH), 128.2 (CH), 129.1 (CH),
1
29.9 (C), 131.6 (CH), 142.0, 153.0 (2 COH), 165.0, and 168.3
+
(
(
(
2 C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ532 (15) [Mꢀ+ꢀ1] , 446 4.14 3,3′-[(4-Florophenyl)methylene]bis(4-
100), 404 (15), 375 (13), 325 (20), 298 (13), 283 (80), 249
hydroxy-2H-chromen-2-one) compound
61), 227 (10), 164 (8), 120 (11), and 85 (8). The insoluble
with morpholine (1:1) (4i)
fraction is 5b as colorless crystals.
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4i after cooling gave
4
.12 3,3′-[(4-Chlorophenyl)methylene]bis(4- colorless crystals; yield: 1.80 g (70%); m.p. 194°C–196°C.
–
Analysis calcd. for C H FNO : C 67.31, H 4.67, F 3.67,
29 24 7
hydroxy-2H-chromen-2-one) compound
N 2.71; found C 67.38, H 4.76, F 3.74, N 2.77%. – IR (KBr):
with piperazine (1:1) (4g)
−1
1
vꢀ=ꢀ3436 (OH), 3125 (NH), 1672 (C=O), 1611 (C=C) cm . – H
The first fraction (80% ethyl acetate) gave 4g as colorless NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ2.82 (t, J ꢀ=ꢀ6.8 Hz, 4H,
6
HH
crystals. Yield: 1.72 g (65%); m.p. >350°C (EtOH). – Analy- –CH NCH –), 3.68 (t, J ꢀ=ꢀ6.8 Hz, 4H, –CH OCH –), 5.30 (s,
2
2
HH
2
2
sis calcd. for C H ClN O : C 65.35, H 4.73, Cl 6.65, N 5.26; NH), 6.21 (s, CH), 7.14–7.85 (m, 12 ArH), and 17.57 (OH) ppm.
29
25
2
6
1
3
found C 65.42, H 4.78, Cl 6.73, N 5.34%. – IR (KBr): vꢀ=ꢀ3430 – C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ43.8 (CH), 50.9, 64.7
6
−1
1
(
OH), 3330 (NH), 1660 (C=O), and 1610 (C=C) cm . – H (–CH NCH –, –CH OCH –), 103.7 (C), 115.9 (CH), 116.1 (C),
2 2 2 2
NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ2.87 (m, 4 CH of piperazine 116.5 (CH), 121.6 (C), 123.2 (CH), 124.8 (CH), 131.7 (CH), 133.5
6
2
ring), 2.95 (s, NH) 6.19 (s, CH), 7.05–7.76 (m, NH, 12 ArH), (C), 154.1, 163.3 (2 COH), 164.6, and 172.9 (2 C=O) ppm. – MS
13
+
and 17.45 (s, 2 OH) ppm. – C NMR (125.4 MHz, [D ]DMSO): (70 eV): m/z (%)ꢀ=ꢀ518 (35) [Mꢀ+ꢀ1] , 500 (20), 485 (50), 453
6
δꢀ=ꢀ39.5 (CH), 40.4 (–CH NHCH –), 64.9 (–CH NCH –), 103.6 (53) 414 (40), 384 (55), 326 (82), 286 (47), 262 (90), 185 (70),
2
2
2
2
(
C), 116.0 (CH), 120.3 (C), 123.5 (C), 124.7 (CH), 128.0 (CH), 146 (100), 105 (54), and 85 (37).
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14ꢀꢀꢀꢀꢁꢀF.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactions
4
.15 3,3′-[(4-Fluorophenyl)methylene]bis(4-
hydroxy-2H-chromen-2-one) (5c)
8H, 4 CH of piperazine ring), 6.20 (s, CH), 6.93–7.78 (m, NH,
2
13
1
2 ArH), and 17.55 (s, OH) ppm. – C NMR (125.4 MHz, [D ]
6
DMSO): δꢀ=ꢀ39.5 (CH), 40.4 (–CH NHCH –), 64.9 (–CH NCH –
2
2
2
2
The insoluble fraction is 5cas colorless crystals; yield (13%); ), 103.6 (C), 116.0 (CH), 120.3 (C), 123.5 (C), 124.7 (CH), 128.0
m.p.: 213°C–215°C [54]. – Analysis calcd. for C H FO : C (CH), 128.2 (CH), 129.1 (C), 129.9 (CH), 131.6 (CH), 142.0, 153.1
2
5
15
6
6
9.77, H 3.51, F 4.41; found C 69.85, H 3.59, F 4.50%. – IR (2 COH), 165.0, and 168.3 (2 C=O) ppm. – MS (70 eV): m/z
−1
1
+
+
(
KBr): vꢀ=ꢀ3427 (OH), 1665 (C=O), and 1608 (C=C) cm . – H (%)ꢀ=ꢀ518 (45) [Mꢀ+ꢀ1] , 467 (65), 432 (35) [M-piperazine] , 414
NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ6.21 (s, CH), 7.14–7.85 (m, (20), 361 (30), 322 (75), 309 (100), 281 (35), 266 (43), 208 (32),
6
13
1
2 ArH), and 17.57 (OH) ppm. – C NMR (125.4 MHz, [D ] 178 (25), 132 (19), and 99 (42). The second fraction (85%,
6
DMSO): δꢀ=ꢀ36.8 (CH), 103.7 (C3), 115.9 (CH), 116.1 (C), 116.5 ethyl acetate) yielded colorless crystals of 5c.
(
CH), 121.6 (C), 123.2 (CH), 124.8 (CH), 131.7 (CH), 133.5 (C),
1
54.1, 163.3 (2COH), 164.6, and 172.9 (2 C=O) ppm. – MS (70
+
eV): m/z (%)ꢀ=ꢀ431 (20) [Mꢀ+ꢀ1] , 384 (25), 326 (42), 286 (57), 4.18 3,3′-[(4-Florophenyl)methylene]bis(4-
2
62 (30), 185 (44), 146 (100), 105 (24), and 85 (57).
hydroxy-2H-chromen-2-one) compound
with 1-methylpiperazine (1:1) (4l)
4
.16 3,3′-[(4-Florophenyl)methylene]bis(4-
hydroxy-2H-chromen-2-one) compound
with piperidine (1:1) (4j)
The residue was triturated and treated with boiling ethanol,
the soluble major fraction is 4l, which, after cooling, gave
colorless crystals. Yield: 1.91 g (72%); m.p. >350°C. – Analy-
sis calcd. for C H FN O : C 67.92, H 5.13, F 3.58, N 5.28; found
30
27
2
6
The residue was triturated and treated with boiling C 67.99, H 5.19, F 3.67, N 5.35%. – IR (KBr): vꢀ=ꢀ3429 (OH), 3123
−1
1
ethanol, the soluble major fraction is 4j, which, after (NH), 1671 (C=O), and 1605 (C=C) cm . – H NMR (500 MHz,
cooling, gave colorless crystals. Yield: 1.67 g (65%); m.p.: [D ]DMSO): δꢀ=ꢀ1.73 (s, 3H, NMe), 2.18, 3.60 (2 m, 8H, 4 CH2
6
2
47°C–249°C (EtOH). – Analysis calcd. for C H FNO : C of piperazine ring), 6.20 (s, CH), 6.93–7.79 (m, NH, 12 ArH),
30 26 6
13
6
9.89, H 5.08, F 3.69, N 2.72; found C 69.96, H 5.16, F 3.77, and 17.55 (s, OH) ppm. – C NMR (125.4 MHz, [D ]DMSO):
6
N 2.78%. – IR (KBr): vꢀ=ꢀ3438 (OH), 3220 (NH), 1650 (C=O), δꢀ=ꢀ23.9 (NMe), 36.1 (CH), 55.5, 103.9 (C), 114.7, 114.9, 115.7,
−1
1
and 1608 (C=C) cm . – H NMR (500 MHz, [D ]DMSO): 116.0, 120.4, 123.5, 124.7, 1249, 128.8, 131.2, 131.5, 138.6, 153.0,
6
δꢀ=ꢀ1.49 (m, 2H, CH at position 4 of the piperidine ring), 159.7, 161.6 (2 COH), 165.1, and 168.4 (2 C=O) ppm. – MS (70
2
+
1
.59 (m, 4H, 2 CH at positions 3 and 5 of the piperidine eV): m/z (%)ꢀ=ꢀ531 (23) [Mꢀ+ꢀ1] , 467 (65), 446 (15) [M-methyl-
2
+
ring), 2.96 (m, 4H, 2 CH at positions 2 and 6 of the piperi- piperazine] , 414 (33), 361 (26), 322 (25), 309 (100), 281 (37),
2
dine ring), 6.20 (s, CH), 6.94–7.78 (m, NH, 12 ArH), and 17.53 266 (21), 208 (55), 178 (19), 132 (39), and 99 (60). The insolu-
13
(
s, OH) ppm. – C NMR (125.4 MHz, [D ]DMSO): δꢀ=ꢀ22.1, ble fraction is 5c as colorless crystals.
6
2
2.7 (–CH CH CH –), 36.2 (C), 44.3 (–CH NCH –), 103.9 (C),
2 2 2 2 2
1
14.7 (C), 114.9 (CH), 116.0 (CH), 120.4 (C), 123.5 (CH), 124.6
(
CH), 128.8 (CH), 131.5 (CH), 138.7, 153.0 (2 COH), 165.1, and 4.19 3,3′-[(4-Methoxyphenyl)methylene]
+
1
68.3 (2 C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ516 (15) [Mꢀ+ꢀ1] ,
bis(4-hydroxy-2H-chromen-2-one)
+
4
30 (100) [M-piperidine,] , 412 (10), 383 (11), 309 (20), 281
compound with morpholine (1:1) (4m)
(
(
15), 267 (53), 239 (12), 183 (10), 162 (14), 120 (19), and 92
22). The insoluble fraction is 5c as colorless crystals.
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4m which after
cooling gave colorless crystals. Yield: 1.85 g (70%); m.p.
233°C–235°C (EtOH). – Analysis calcd. for C H NO : C
4
.17 3,3′-[(4-Florophenyl)methylene]bis(4-
hydroxy-2H-chromen-2-one) compound
with piperazine (1:1) (4k)
30
27
8
6
8.04, H 5.14, N 2.65; found C 68.12, H 5.21, N 2.73%. –
IR (KBr): vꢀ=ꢀ3436 (OH), 3135 (NH), 1675 (C=O), and 1610
−
1
1
(C=O) cm . – H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ3.06 (t,
6
The first fraction (80%, ethyl acetate) gave 4k as colorless J , 6.2 Hz, 4H, –CH NCH –), 3.64 (s, 3H, OMe), 3.70 (t,
HH
2
2
crystals. Yield: 1.63 g (63%); m.p. 293°C–295°C (EtOH). – J , 6.2 Hz, 4H, –CH OCH –), 6.16 (s, 1H, CH), 6.68–7.76
HH
2
2
13
Analysis calcd. for C H FN O : C 67.43, H 4.88, F 3.68, N 5.42; (m, 12 ArH), 8.63 (s, NH), and 17.61 (s, OH) ppm. – C NMR
29
25
2
6
found C 67.49, H 4.95, F 3.76, N 5.49%. – IR (KBr): vꢀ=ꢀ3434 (125.4 MHz, [D ]DMSO): δꢀ=ꢀ37.3 (CH) 46.8 (OMe), 55.4, 63.8
6
−1
1
(
OH), 3195 (NH), 1660 (C=O), 1611 (C=C) cm . – H NMR (–CH NCH –, –CH OCH –), 104.2 (C), 113.6 (CH), 115.8 (CH),
2 2 2 2
(
500 MHz, [D ]DMSO): δꢀ=ꢀ1.95 (s, 1H, NH), 2.07, 2.96 (2m, 116.0 (CH), 120.5 (C), 123.4 (CH), 124.6 (CH), 128.1 (CH),
6
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F.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactionsꢂꢁꢀꢀꢀꢂ715
1
31.4 (CH), 134.5 (C), 153.0, 157.3 (2COH), 165.1, and 168.2 – Analysis calcd. for C H N O : C 68.17, H 5.34, N 5.30;
3
0
28
2
7
+
(
2C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ529 (5) [M] , 442 (10) found C 68.25, H 5.41, N 5.37%. – IR (KBr): vꢀ=ꢀ3466, 3327
+
−1
1
[
M-morpholine] , 306 (10), 279 (25), 249 (20), 240 (11), 162 (OH), 3230 (NH), 1644 (C=O), and 1606 (C=C) cm . – H
(
19), 145 (8), 120 (25), 92 (36), 87 (65), and 57 (100).
NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ2.82, 3.68 (2m, 8H, pipera-
6
zine ring), 3.82 (s, 3H, OMe), 6.17 (s, 1H, CH), 6.68–7.83 (m,
1
3
1
2 ArH), 9.83 (s, NH), and 17.60 (s, OH) ppm. – C NMR
4
.20 3,3′-[(4-Methoxyphenyl)methylene]
bis(4-hydroxy-2H-chromen-2-one) (5d)
(125.4 MHz, [D ]DMSO): δꢀ=ꢀ37.3 (CH), 46.8 (OMe), 51.1, 56.2
piperazine ring), 104.2 (C), 113.6, 114.3, 115.0, 116.0, 120.5,
23.4, 124.6, 128.1, 130.0, 130.1, 131.4, 132.3, 153.0, 157.3 (2
6
(
1
The insoluble fraction gave colorless crystals. Yield 9%; COH), 165.2, and 168.2 (2 C=O) ppm. – MS (70 eV): m/z
m.p. 246°C–248°C [54]. – Analysis calcd. for C H O : C (%)ꢀ=ꢀ528 (15) [M] , 442 (20) [M-piperazine] , 439 (45), 320
+
+
2
6
18
7
7
0.58, H 4.10; found C 70.68, H 4.19%. – IR (KBr): vꢀ=ꢀ3422 (100), 279 (53), 249 (42), 207 (75), 180 (52), 136 (47), 88
−1
1
(
OH), 1667 (C=O), and 1604 (C=C) cm . – H NMR (500 MHz, (40), and 68 (77). The second fraction (85%, ethyl acetate)
[
D ]DMSO): δꢀ=ꢀ3.64 (s, 3H, OMe), 6.17 (CH), 6.64–7.80 (m, 12 yielded colorless crystals of 5d.
6
13
ArH), and 17.59 (OH) ppm. – C NMR (125.4 MHz, [D ]DMSO):
6
δꢀ=ꢀ36.8 (CH), 55.4 (OMe), 104.2 (C3), 113.6, 115.9, 116.2, 120.5,
1
(
23.4, 124.6, 128.1, 131.4, 134.5, 153.0 (2 COH), 165.2, and 168.2 4.23 3,3′-[(4-Methoxyphenyl)methylene]
+
2 C=O) ppm. – MS (70 eV): m/z (%)ꢀ=ꢀ442 (100) [M] , 320
bis(4-hydroxy-2H-chromen-2-one)
(10), 279 (83), 249 (52), 237 (15), 162 (16), 119 (17), and 92.
compound with 1- methylpiperazine
(
1:1) (4p)
4
.21 3,3′-[(4-Methoxyphenyl)methylene]
bis(4-hydroxy-2H-chromen-2-one)
compound with piperidine (1:1) (4n)
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4p which after
cooling gave colorless crystals. Yield: 1.76 g (65%); m.p.
>
350°C (EtOH). – Analysis calcd. for C H N O : C 68.62,
31 30 2 7
The residue was triturated and treated with boiling
ethanol, the soluble major fraction is 4n, which, after
cooling, gave colorless crystals. Yield: 1.76 g (67%); m.p.
H 5.57, N 5.16; found C 68.61, H 5.65, N 5.22%. – IR (KBr):
−1
vꢀ=ꢀ3433 (OH), 3134 (NH), 1669 (C=O), and 1603 (C=C) cm .
1
–
H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ2.05, 3.23 (2m, 8H of
6
>
350°C (EtOH). – Analysis calcd. for C H NO : C 70.58,
31 29 7
piperazine ring), 3.61 (OMe), 6.22 (s, CH), 6.92–7.79 (m,
H 5.54, N 2.65; found C 70.66, H 5.61, N 2.72%. – IR (KBr):
1
3
1
2 ArH), 8.56 (s, NH), and 17.55 (s, OH) ppm. – C NMR
−1
vꢀ=ꢀ3450 (OH), 3230 (NH), 1664 (C=O), and 1608 (C=C) cm .
(
125.4 MHz, [D ]DMSO): δꢀ=ꢀ37.5 (CH), 49.0 (–CH NHCH –),
– 1
6
2
2
H NMR (500 MHz, [D ]DMSO): δꢀ=ꢀ1.49 (m, 2H, CH at
6
2
6
3.7 (–CH NCH –), 103.5, 116.0, 120.3, 123.5, 124.7, 128.0,
2 2
position 4 of the piperidine ring), 1.59 (m, 4H, 2 CH at
2
1
28.2, 129.1, 129.9, 131.6, 142.0, 153.1, 165.0, and 168.3 ppm.
positions 3 and 5 of the piperidine ring), 2.96 (m, 4H, 2
+
–
MS (70 eV): m/z (%)ꢀ=ꢀ542 (32) [M] , 442 (40) [M-methyl-
CH at positions 2 and 6 of the piperidine ring), 3.64 (s, 3
2
+
piperazine] , 322 (90), 299 (90), 273 (35), 237 (26), 194 (91),
H, OMe), 6.17 (s, CH), 6.70–7.78 (m, 12 ArH), 8.23 (s, NH),
1
67 (42), 135 (72), 127 (100), 110 (52), 85 (25), and 62 (47).
13
and 17.60 (s, OH) ppm. – C NMR (125.4 MHz, [D ]DMSO):
6
The insoluble fraction is 5d as colorless crystals.
δꢀ=ꢀ22.1, 22.7 (–CH CH CH –), 35.9 (CH), 44.3 (–CH NCH –),
2
2
2
2
2
5
5.4 (OMe), 104.2 (C), 113.6, 116.0, 120.5, 123.4, 124.6, 128.1,
Acknowledgment: The authors thank the National
1
31.4, 134.6, 153.0, 157.4, 165.1, and 168.2 ppm. – MS (70 eV):
Research Centre for financial support (project number
+
+
m/z (%)ꢀ=ꢀ527 (33) [M] , 442 (100) [M-piperidine] , 320 (10),
79 (83), 249 (52), 237 (15), 162 (16), 119 (17), and 92. The
insoluble fraction is 5d as colorless crystals.
11090305).
2
References
4
.22 3,3′-[(4-Methoxyphenyl)methylene]
bis(4-hydroxy-2H-chromen-2-one)
compound with piperazine (1:1) (4o)
[
[
[
[
1] I. Ugi, C. Steinbrückner, Chem. Ber. 1961, 94, 73ꢌ.
2] A. Dömling, Chem. Rev. 2006, 106, 17.
3] D. M. D’Souza, T. J. Müller, Chem. Soc. Rev. 2007, 36, 10ꢊ5.
ꢌ] C. C. A. Cariou, G. J. Clarkson, M. Shipman, J. Org. Chem. 2008,
The first fraction (80% ethyl acetate) gave 4o as color-
7
3, ꢊ762.
less crystals. Yield: 1.87 g (71%); m.p. >350°C (EtOH). [5] G. H. Posner, Chem. Rev. 1986, 86, ꢋ31.
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7
16ꢀꢀꢀꢀꢁꢀF.A. El-Samahy et al.: Synthesis of unexpected novel bis-coumarin derivatives via three component reactions
[
6] R. D. H. Murray, Nat. Prod. Rep. 1995, 12, ꢌ77.
[32] A. Thakur, R. Singla, V. Jaitak, Eur. J. Med. Chem. 2015, 101,
ꢌ76.
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