A diastereoselective synthesis of pyrano fused coumarins via organocatalytic three-component reaction

Article abstract of DOI:10.1039/c2ob26203g

A new method for the synthesis of pyran fused coumarins by 3-bromo-4-hydroxycoumarins as cyclic α-halo ketones based on an organocatalyst assisted three-component tandem reaction is investigated. To the best of our knowledge, cyclic α-halo ketones have not yet been used for the synthesis of pyran fused coumarins.

Full text of DOI:10.1039/c2ob26203g

Organic &
Biomolecular
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A diastereoselective synthesis of pyrano fused
coumarins via organocatalytic three-component
reaction†
Cite this: Org. Biomol. Chem., 2013, 11,
279
Somayeh Ahadi, Mahdi Zolghadr, Hamid Reza Khavasi and Ayoob Bazgir*
Received 24th June 2012,
A new method for the synthesis of pyran fused coumarins by 3-bromo-4-hydroxycoumarins as cyclic
α-halo ketones based on an organocatalyst assisted three-component tandem reaction is investigated. To
the best of our knowledge, cyclic α-halo ketones have not yet been used for the synthesis of pyran fused
coumarins.
Accepted 7th November 2012
DOI: 10.1039/c2ob26203g
www.rsc.org/obc
(Fig. 1). These various biological activities of pyranocoumarins
encourage researchers to introduce new methodologies for
Introduction
Multicomponent reactions (MCRs) have proved to be very synthesizing novel biologically active pyranocoumarins.27 One
influential and efficient bond-forming tools in organic, combi- of the most utilized among these various methods is the for-
natorial and medicinal chemistry.1 In addition to the funda- mation of a pyran ring starting from hydroxycoumarins.28,29
mental atom economy and selectivity underlying such
Recently, the reaction of acyclic α-halo ketones, aldehydes,
reactions, simpler procedures, equipment, time, and energy and C–H acids has been shown to be powerful methods for the
savings, as well as environmental friendliness have all led to a synthesis of polycyclic heterocycles.30 In 2009, Chao-Guo Yan
sizable effort to design and execute MCRs in both academia and coworkers reported the synthesis of furano fused cou-
and industry.2
marins by the reaction of 4-hydroxy coumarin, aromatic alde-
In recent years, the study of the biological activities of chro- hydes and p-nitrobenzyl bromide or α-phenacyl bromide in the
mene and coumarin derivatives has been the aim of many presence of pyridine (Scheme 1).30a
scientists.3–7 These compounds have been reported to possess
As part of our continuing efforts for the synthesis of hetero-
a wide spectrum of biological activities like antibacterial, anti- cycles using cyclic α-halo ketones,31 herein, we wish to report a
coagulant, hypothermal, anti-helminthic, and vasodilatory
properties.8–14 Coumarin is a useful building block in many
natural products with remarkable biological activities and
unique physical properties.15 Coumarin and its derivatives
inhibit prostaglandin biosynthesis, which involves fatty acid
hydroperoxy intermediates.16 In particular among heterocycle-
fused coumarins, pyranocoumarins are an important class of
heterocycles in natural compounds with broad pharmacologi-
cal activities such as anti-cancer,17 anti-hepatitis B virus,18
anti-HIV-1,19 anti-inflammatory,20 antinociceptive,21 anti-
microbial and antiproliferative22 activity. In addition they are
inhibitors of measles virus replication23 and gained impor-
Fig. 1 Biologically active pyranocoumarins.
tance as photoactive drugs for skin disorders.24 Pyranocoumar-
ins A are used as anti-hyperglycemic and anti-dyslipidemic
agents25 and compound B is an antidiabetic natural product26
Shahid Beheshti University, Tehran, Islamic Republic of Iran.
E-mail: a_bazgir@sbu.ac.ir
†Electronic supplementary information (ESI) available. CCDC 876614. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob26203g
Scheme 1 Synthesis of furano fused coumarins by Chao-Guo Yan and co-
workers.30a
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Table 2 Synthesis of pyranocoumarins 4a–l
Product 4
RCHO
Yield (%)a
a
b
c
d
e
f
g
h
i
PhCHO
p-NO2C6H4CHO
p-ClC6H4CHO
85
87
75
73
95
75
60
65
79
70
96
75
p-BrC6H4CHO
p-HO2CC6H4CHO
p-OHC6H4CHO
p-OMeC6H4CHO
p-MeC6H4CHO
m-NO2C6H4CHO
m-BrC6H4CHO
Thiophene-2-carbaldehyde
HO2CCHO
j
k
l
Scheme 2 Model of the reaction.
a Isolated yields.
new method for the diastereoselective synthesis of pyrano
fused coumarins by the reaction of 4-hydroxy coumarin 1,
aldehydes 2 and 3-bromo-4-hydroxycoumarin 3, a cyclic α-halo
ketone, via an organocatalytic three-component reaction
(Scheme 2). It was interesting that based on recent reports,30
the desired spiro furo fused coumarins 5 were not detected at
all, while pyrano fused coumarins 4 were obtained in good
yields.
Results and discussion
Initially, the three-component reaction of 4-hydroxy coumarin
1 (1 mmol), 4-nitrobenzaldehyde 2b (1 mmol) and 3-bromo-4-
hydroxycoumarin 3 (1 mmol) in the presence of various bases
and solvents was investigated (Table 1). As shown in Table 1,
the use of acetic acid at 100 °C in the presence of DBU (30%)
allowed the formation of pyranocoumarin 4b in 87% yield
(Table 1, entry 7). It was found that when increasing the
amount of DBU from 10 to 20, and 30 mol%, the isolated yield
increased from 70 to 74 and 87%, respectively, and more
amounts of the DBU did not improve the yield (entry 10). It
should be mentioned that when the reaction was carried out
in the absence of DBU the yield of the product was low (entry
Scheme 3 Synthesis of bis(pyranocoumarins).
12). To study the effect of temperature on the reaction, we also
performed the reaction at a lower temperature. It was observed
that a lower reaction temperature leads to a lower yield
(entry 11).
According to the optimized conditions, various aldehydes
2a–l were selected to react with 4-hydroxy coumarin 1 and
3-bromo-4-hydroxycoumarins 3 under the optimal conditions
(Table 2). The yield of the product seems to be affected by the
nature of the substituents on the aldehyde, and increases
when electron-withdrawing substituents are present. Reason-
able yields were obtained using aromatic aldehydes carrying
electron-donating or electron-withdrawing substituents.
Heterocyclic aldehydes such as thiophene-2-carbaldehyde
afforded a high yield of product (4k) and even for glyoxylic
acid, the corresponding pyranocoumarin was obtained in 75%
yield (4l).
To further explore the potential of this protocol for new
pyrano fused coumarin synthesis, we investigated a reaction
involving terephthalaldehyde 6a or isophthalaldehyde 6b and
obtained the corresponding bis(pyranocoumarins) 7a,b in
good isolated yields (Scheme 3). The mass spectrum of
product 7 displayed a molecular ion peak at 748 m/z, which
Table 1 Optimization for synthesis of 4b
Entry
Solvent
Base (mol%)
Yield (%)a
1
2
3
CH3CN (reflux)
EtOH (reflux)
H2O (reflux)
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (20)
DBU (10)
DBU (40)
DBU (30)
—
K2CO3 (30)
CsCO3 (30)
NEt3 (30)
NaOAc (30)
NH4OAc (30)
65
45
60
50
30
50
87
74
70
88
71
47
55
60
60
65
62
4
5
DMF (100 °C)
THF (reflux)
6
7
8
9
10
11
12
13
14
15
16
17
Toluene (reflux)
HOAc (100 °C)
HOAc (100 °C)
HOAc (100 °C)
HOAc (100 °C)
HOAc (80 °C)
HOAc (100 °C)
HOAc (100 °C)
HOAc (100 °C)
HOAc (100 °C)
HOAc (100 °C)
HOAc (100 °C)
a Reaction time = 24 h.
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was consistent with the proposed 2 : 2 : 1 adduct of 4-hydroxy conditions. The pyranocoumarins 4a,b were not detected at
coumarin 1, 3-bromo-4-hydroxycoumarin 3 and aldehyde 6. all, while biscoumarin salts 10a,b were obtained in <30% yield
The chromone scaffold forms the nucleus of flavonoids that (Scheme 5). When this reaction was carried out with equimolar
are found naturally in fruits, vegetables, nuts, seeds, flowers, amounts of the DBU salts 10a,b were obtained in moderate
and barks.32 Chromone is also part of the pharmacophores of yields.
a large number of molecules of medicinal significance33
When we introduced the reaction of salicylaldehyde 11a
including anticancer agents such as psorospermin and plura- with 4-hydroxy coumarin 1 and 3-bromo-4-hydroxycoumarin 3
mycin A.34 Considering the very important biological activities under the same reaction conditions, it was interesting that the
of molecules containing a chromone scaffold, we hypothesize desired pyranocoumarin 13 was not observed, while 7-(4-
that the integration of a chromone moiety with a pyranocou- hydroxy-2-oxo-2H-chromen-3-yl)chromeno[4,3-b]chromen-6-
marin may result in the discovery of novel drug candidates (7H)-one 12a was obtained in 60% yield (Scheme 6). It was
with unknown biological activities. So, we investigated the found when the reaction was carried out in refluxing acetic
reaction of 4-oxo-4H-chromene-3-carbaldehydes 8a–c with acid that the product 12a was obtained in 75% yield after 30 h.
4-hydroxy coumarin
1
and 3-bromo-4-hydroxycoumarin
3
Therefore, the reaction of various 2-hydroxybenzaldehydes
under same reaction conditions and obtained the desired pyra- 11a–f, 4-hydroxycoumarin 1 and 3-bromo-4-hydroxy coumarin
nocoumarins 9a–c containing chromone moiety in good iso- 3 in the presence of DBU (30%) in refluxing acetic acid affords
lated yields (Scheme 4).
7-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno[4,3-b]chromen-
It is notable that two pairs of diastereomers may be formed 6(7H)-ones 12a–f in good isolated yields (Table 3).
in the reaction. The 1H-NMR spectra of the crude reaction
The structures all of the products were deduced from their
mixture without any purification reveals a combination of two IR, 1H, and 13C NMR spectra and elemental analysis. The
diastereomers. The trans-diastereoisomer is the major isomer structure of 12f was confirmed by single-crystal X-ray analysis
and the cis-diastereoisomer is in trace amounts that can be (Fig. 2).
removed by purification; therefore the reaction is diastereo-
It is known that DBU promotes sequential Michael, aldol,
selective. The expected trans-stereochemistry of the major dia- dehydration and dealkoxycarbonylation.35 Also, DBU in acidic
stereomer was established by the analysis of vicinal coupling conditions, facilitates Knoevenagel condensation via hydrogen
constants of the two methine hydrogens as well as by NOE bonding to aldehydes.36 There are some examples of DBU
difference spectroscopy. In the major isomer of 4g and 9a, hydrogen bonding to substrates and some examples of the use
irradiation of one of the methine hydrogens gave no enhance- of DBU as a nucleophile.37 Catalysis employing hydrogen
ment of the other methine hydrogen.
bonding for substrate activation has been shown to be an
To demonstrate the key role of 3-bromo-4-hydroxycoumar- effective and versatile strategy in a wide variety of transfor-
ins 3 in the reaction, we investigated the reaction of 4-hydroxy mations.38 Therefore, the plausible mechanism for the for-
coumarin 1 with aromatic aldehydes 2a,b in the same reaction mation of products 4 and 12 are depicted in Scheme 7. First,
Scheme 4 Synthesis of pyranocoumarins containing a chromone moiety 9.
Scheme 6 Synthesis of 7-(2-oxo-2H-chromen-3-yl)chromeno[4,3-b]chromen-6-
(7H)-one 12a.
Table 3 Synthesis of 7-(2-oxo-2H-chromen-3-yl)chromeno[4,3-b]chromen-ones
12
Product 12
X
Yield (%)
a
b
c
d
e
H
5-Br
4-OMe
5-OMe
3-OH
75
65
69
85
50
Scheme 5 Synthesis of biscoumarin salt 10.
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in which purification via chromatography and recrystallization
can be avoided, and the pure products were obtained simply
by washing the crude products with methanol.
Experimental section
General methods
Melting points were determined on a melting point apparatus
and are uncorrected. IR spectra were taken with a FTIR spec-
1
trophotometer. H NMR spectra were recorded on a 300 MHz
spectrometer. Chemical shifts are expressed in parts per
million downfield from tetramethylsilane as an internal stan-
dard. 13C NMR spectra were recorded on a 70 MHz spec-
trometer using broadband proton decoupling. Chemical shifts
are expressed in parts per million using the middle resonance
of DMSO as an internal standard. Mass spectra were recorded
on a JEOL MAT312 mass spectrometer or Agilent 5973 network
mass selective detector operating at an ionization potential of
70 eV. Elemental analyses for C, H and N were performed
using a Heraeus CHN–O– Rapid analyzer.
Fig. 2 ORTEP diagram of product 12f.
All chemicals were purchased from Merck or Aldrich and
were used without further purification. Known 3-bromo-4-
hydroxycoumarin was prepared by the procedure reported
previously.39
General procedures for the synthesis of 4a–4l
A mixture of aldehyde (1.0 mmol), 4-hydroxy coumarin (0.16 g,
1.0 mmol), 3-bromo-4-hydroxycoumarin (0.24 g, 1 mmol) in
HOAc (2 mL) in the presence of DBU (0.05 g, 30 mol%) was
heated at 100 °C for 24 h. After completion of the reaction
(TLC), the reaction mixture was cooled to room temperature.
Then, the precipitated product was filtered and washed with
methanol (5 ml) to afford the pure product 4.
Scheme 7 Proposed mechanism.
salt 15 is formed in situ by the acid–base reaction of DBU and
HOAc. Then a hydrogen bond is formed between the aldehyde
2 and 15. This activated aldehyde reacts with 4-hydroxy cou-
marin 1 by Knoevenagel condensation. Then Michael addition
of 3-bromo-4-hydroxycoumarin 3 to intermediate 16 affords
intermediate 17. Finally, nucleophilic attack of DBU on 17, fol-
lowed by cyclization produces the corresponding pyranocou-
marin 4. The formation of product 12 can be rationalized by
enolization of 17, followed by elimination of one molecule of
H2O (Scheme 7).
3-(2-Hydroxybenzoyl)-4-phenyl-3,4-dihydropyrano[3,2-c]-
chromene-2,5-dione (4a)
White powder (85%); mp 215–217 °C. IR (KBr) (νmax/cm−1):
1
3049, 1716, 1637, 1613. H NMR (300 MHz, DMSO-d6): δH 4.54
(1H, bs, CH), 6.56 (1H, bs, CH), 6.91–7.88 (13H, m, H–Ar),
10.93 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC 49.4, 93.6,
105.5, 112.1, 117.2, 117.8, 119.9, 120.3, 123.5, 125.0, 127.7,
127.9, 129.1, 131.0, 133.8, 136.4, 141.2, 155.1, 158.7, 159.6,
166.8, 194.9. MS, m/z: 412 (M+). Anal. Calcd for C25H16O6: C,
72.81; H, 3.91. Found: C, 72.70; H, 3.84.
Conclusions
In this paper for the first time, the three-component reaction
of 3-bromo-4-hydroxycoumarins as a cyclic α-bromo ketone,
aldehydes and 4-hydroxy coumarin using a DBU/HOAc system
3-(2-Hydroxybenzoyl)-4-(4-nitrophenyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione (4b)
for the diastereoselective synthesis of pyrano fused coumarins Cream powder (87%); mp 210–212 °C. IR (KBr) (νmax/cm−1):
1
is reported. Reaction of 3-bromo-4-hydroxycoumarins with sali- 3073, 1721, 1646, 1606. H NMR (300 MHz, DMSO-d6): δH 4.76
cylaldehydes and 4-hydroxycoumarins resulted in the for- (1H, d, J = 3.54 Hz, CH), 6.62 (1H, d, J = 3.69 Hz, CH),
mation of 7-(2-oxo-2H-chromen-3-yl)chromeno[4,3-b]chromen- 6.94–8.22 (12H, m, H–Ar), 10.86 (1H, s, OH). MS, m/z: 457
one derivatives. Prominent among the advantages of this new (M+). Anal. Calcd for C25H15NO8: C, 65.65; H, 3.31; N, 3.06.
method are novelty, operational simplicity, good yields and the Found: C, 65.57; H, 3.37; N, 3.14. (Due to very low solubility of
easy work-up procedures employed. This synthesis serves as a the product 4b, we cannot report the 13C NMR date for this
nice addition to group-assistant-purification (GAP) chemistry product).
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4-(4-Chlorophenyl)-3-(2-hydroxybenzoyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione (4c)
442 (M+). Anal. Calcd for C26H18O7: C, 70.58; H, 4.10. Found:
C, 70.45; H, 4.01.
White powder (75%); mp 191–193 °C. IR (KBr) (νmax/cm−1):
3055, 1722, 1647, 1605. H NMR (300 MHz, DMSO-d6): δH 4.56
3-(2-Hydroxybenzoyl)-4-p-tolyl-3,4-dihydropyrano[3,2-c]-
chromene-2,5-dione (4h)
1
(1H, bs, CH), 6.55 (1H, d, J = 3.72 Hz, CH), 6.92–7.88 (12H, m,
H–Ar), 10.89 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC
48.8, 93.5, 105.2, 112.0, 117.2, 117.8, 119.7, 120.4, 123.6, 125.1,
129.0, 129.7, 131.0, 132.4, 133.9, 136.4, 140.3, 155.1, 158.7,
159.6, 167.0, 194.4. MS, m/z: 446 (M+). Anal. Calcd for
C25H15ClO6: C, 67.20; H, 3.38. Found: C, 67.13; H, 3.30.
White powder (65%); mp 199–201 °C. IR (KBr) (νmax/cm−1):
3055, 1721, 1643, 1607. H NMR (300 MHz, DMSO-d6): δH 3.73
1
(3H, s, CH3), 4.48 (1H, d, J = 3.57 Hz, CH), 6.52 (1H, d, J =
3.75 Hz, CH), 6.88–7.88 (12H, m, H–Ar), 10.93 (1H, s, OH). 13C
NMR (75 MHz, DMSO-d6): δC 48.9, 55.5, 93.7, 105.6, 112.1,
113.6, 114.5, 117.2, 117.8, 119.9, 120.2, 123.5, 125.0, 128.8,
131.0, 133.1, 133.8, 136.4, 155.1, 159.0, 159.7, 195.2. MS, m/z:
426 (M+). Anal. Calcd for C26H18O6: C, 73.23; H, 4.25. Found:
C, 73.30; H, 4.19.
4-(4-Bromophenyl)-3-(2-hydroxybenzoyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione (4d)
White powder (73%); mp 216–218 °C. IR (KBr) (νmax/cm−1):
1
3049, 1714, 1646, 1604. H NMR (300 MHz, DMSO-d6): δH 4.54
3-(2-Hydroxybenzoyl)-4-(3-nitrophenyl)-3,4-dihydropyrano-
(1H, bs, CH), 6.55 (1H, d, J = 3.09 Hz, CH), 6.91–7.88 (12H, m,
H–Ar), 10.88 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC
48.9, 93.4, 105.2, 112.0, 117.2, 117.8, 119.9, 120.4, 121.0, 123.6,
125.1, 130.1, 131.0, 131.9, 133.9, 136.4, 140.8, 155.1, 158.7,
159.6, 167.0, 194.4. MS, m/z: 492 (M+, 81Br), 490 (M+, 79Br).
Anal. Calcd for C25H15BrO6: C, 61.12; H, 3.08. Found: C, 61.01;
H, 2.96.
[3,2-c]chromene-2,5-dione (4i)
Cream powder (79%); mp 206–208 °C. IR (KBr) (νmax/cm−1):
1
3079, 1718, 1646, 1607. H NMR (300 MHz, DMSO-d6): δH 4.81
(1H, bs, CH), 6.63 (1H, d, J = 3.61 Hz, CH), 6.93–8.18 (12H, m,
H–Ar), 10.82 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC
48.8, 93.4, 104.9, 112.0, 117.2, 117.7, 119.9, 120.5, 122.8, 123.6,
125.1, 130.7, 131.1, 134.0, 134.6, 136.4, 143.6, 148.3, 155.2,
158.7, 159.5, 167.3, 193.9. MS, m/z: 457 (M+). Anal. Calcd for
C25H15NO8: C, 65.65; H, 3.31; N, 3.06. Found: C, 65.73; H, 3.23;
N, 3.17.
4-(3-(2-Hydroxybenzoyl)-2,5-dioxo-2,3,4,5-tetrahydropyrano-
[3,2-c]chromen-4-yl)benzoic acid (4e)
White powder (95%); mp 250–252 °C. IR (KBr) (νmax/cm−1):
1
3192, 1726, 1680, 1637. H NMR (300 MHz, DMSO-d6): δH 4.64 4-(3-Bromophenyl)-3-(2-hydroxybenzoyl)-3,4-dihydropyrano-
(1H, d, J = 3.24 Hz, CH), 6.56 (1H, d, J = 3.51 Hz, CH), [3,2-c]chromene-2,5-dione (4j)
6.92–7.94 (12H, m, H–Ar), 10.88 (1H, s, OH), 12.93 (1H, bs, OH
Cream powder (70%); mp 148–150 °C. IR (KBr) (νmax/cm−1):
exchange with solvent). 13C NMR (75 MHz, DMSO-d6): δC 49.3,
93.2, 105.2, 112.0, 117.2, 117.8, 119.9, 120.4, 123.6, 125.1,
128.1, 129.1, 130.2, 130.3, 131.1, 133.9, 136.4, 146.2, 155.1,
158.7, 159.6, 167.1, 167.5, 194.3. MS, m/z: 456 (M+). Anal.
Calcd for C26H16O8: C, 68.42; H, 3.53. Found: C, 68.51; H, 3.45.
1
3048, 1728, 1652, 1609. H NMR (300 MHz, DMSO-d6): δH 4.61
(1H, d, J = 3.99 Hz, CH), 6.61 (1H, d, J = 4.11 Hz, CH),
6.92–7.88 (12H, m, H–Ar), 10.93 (1H, s, OH). 13C NMR
(75 MHz, DMSO-d6): δC 48.9, 93.3, 105.1, 112.1, 117.2, 117.5,
117.8, 119.9, 120.4, 122.3, 123.5, 123.6, 125.1, 126.9, 130.5,
130.8, 131.1, 133.9, 136.4, 143.9, 155.1, 158.7, 159.6, 167.1,
194.4. MS, m/z: 492 (M+, 81Br), 490 (M+, 79Br). Anal. Calcd for
C25H15BrO6: C, 61.12; H, 3.08. Found: C, 61.20; H, 3.15.
3-(2-Hydroxybenzoyl)-4-(4-hydroxyphenyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione (4f)
Cream powder (75%); mp 263–265 °C. IR (KBr) (νmax/cm−1):
1
3-(2-Hydroxybenzoyl)-4-(thiophen-2-yl)-3,4-dihydropyrano-
3279, 1688, 1646, 1605. H NMR (300 MHz, DMSO-d6): δH 4.42
[3,2-c]chromene-2,5-dione (4k)
(1H, bs, CH), 6.49 (1H, bs, CH), 6.71–7.94 (12H, m, H–Ar), 9.44
(1H, s, OH), 10.96 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6):
δC 49.0, 93.8, 105.7, 112.1, 115.8, 117.2, 117.8, 119.8, 120.2,
123.5, 125.0, 128.7, 131.0, 131.3, 133.7, 136.4, 155.1, 157.2,
158.7, 159.7, 162.7, 166.5, 195.4. MS, m/z: 428 (M+). Anal.
Calcd for C25H16O7: C, 70.09; H, 3.76. Found: C, 70.22; H, 3.69.
Cream powder (96%); mp 210–212 °C. IR (KBr) (νmax/cm−1):
1
3049, 1721, 1637, 1603. H NMR (300 MHz, DMSO-d6): δH 4.90
(1H, d, J = 2.31 Hz, CH), 6.56 (1H, d, J = 2.43 Hz, CH),
6.92–7.87 (11H, m, H–Ar), 11.07 (1H, s, OH). 13C NMR
(75 MHz, DMSO-d6): δC 44.5, 93.6, 105.0, 111.9, 117.3, 117.8,
119.9, 120.3, 123.6, 125.1, 125.8, 127.6, 131.1, 134.1, 136.4,
143.8, 155.1, 158.6, 159.7, 166.9, 194.3. MS, m/z: 418 (M+).
Anal. Calcd for C23H14O6S: C, 66.02; H, 3.37. Found: C, 65.91;
3-(2-Hydroxybenzoyl)-4-(4-methoxyphenyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione (4g)
White powder (60%); mp 198–200 °C. IR (KBr) (νmax/cm−1): H, 3.28.
1
3059, 1720, 1644, 1610. H NMR (300 MHz, DMSO-d6): δH 3.73
3-(2-Hydroxybenzoyl)-2,5-dioxo-2,3,4,5-tetrahydropyrano[3,2-c]-
chromene-4-carboxylic acid (4l)
(3H, s, CH3), 4.47 (1H, bs, CH), 6.53 (1H, d, J = 3.57 Hz, CH),
6.88–7.88 (12H, m, H–Ar), 10.94 (1H, s, OH). 13C NMR
(75 MHz, DMSO-d6): δC 48.9, 55.5, 93.7, 105.6, 112.1, 114.5, Cream powder (75%); mp 254–256 °C. IR (KBr) (νmax/cm−1):
1
117.2, 117.8, 119.9, 120.2, 123.5, 125.0, 128.8, 131.0, 133.1, 3178, 1729, 1698, 1647. H NMR (300 MHz, DMSO-d6): δH 4.07
133.8, 136.4, 155.1, 158.7, 159.0, 159.7, 166.6, 195.2. MS, m/z: (1H, d, J = 3.99 Hz, CH), 6.69 (1H, d, J = 3.99 Hz, CH),
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6.94–7.83 (8H, m, H–Ar), 11.28 (1H, s, OH), 13.13 (1H, s, OH). 3-(2-Hydroxybenzoyl)-4-(6-methyl-4-oxo-4H-chromen-3-yl)-3,4-
13C NMR (75 MHz, DMSO-d6): δC 49.0, 90.7, 100.9, 111.7, dihydropyrano[3,2-c]chromene-2,5-dione (9c)
117.3, 117.8, 120.0, 120.2, 123.5, 125.2, 131.0, 134.3, 136.5,
White powder (70%); mp 267–269 °C. IR (KBr) (νmax/cm−1):
3045, 1710, 1631. H NMR (300 MHz, DMSO-d6): δH 2.49 (3H,
155.0, 158.3, 159.5, 168.0, 172.0, 193.1. MS, m/z: 380 (M+).
Anal. Calcd for C20H12O8: C, 63.16; H, 3.18. Found: C, 63.10;
H, 3.24.
1
s, CH3), 4.64 (1H, d, CH, J = 4.86 Hz), 6.64 (1H, d, CH, J =
5.25 Hz), 6.93–6.96 (2H, m, H–Ar), 7.43–7.84 (9H, m, H–Ar),
8.39 (1H, s,vCH), 10.93 (1H, s, OH). 13C NMR (75 MHz,
DMSO-d6): δC 20.4, 41.8, 89.6, 101.5, 111.7, 116.7, 117.4, 118.2,
119.5, 120.1, 121.2, 122.9, 123.1, 124.2, 124.5, 130.9, 133.3,
135.2, 135.3, 136.1, 154.1, 154.6, 155.3, 158.4, 159.4, 167.0,
175.6, 195.5. MS, m/z: 494 (M+). Anal. Calcd for C29H18O8: C,
70.44; H, 3.67. Found: C, 70.37; H, 3.63.
4,4′-(1,4-Phenylene)bis(3-(2-hydroxybenzoyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione) (7a)
Cream powder (69%); mp 210–212 °C. IR (KBr) (νmax/cm−1):
1
3079, 1721, 1648, 1602. H NMR (300 MHz, DMSO-d6): δH 4.56
(2H, bs, CH), 6.46–6.55 (2H, bs, CH), 6.96–7.85 (20H, m, H–
Ar), 10.95 (1H, s, OH), 11.01 (1H, s, OH). MS, m/z: 748 (M+).
MS, m/z: 746 (M+). Anal. Calcd for C44H26O12: C, 70.78; H, 3.51.
Found: C, 70.67; H, 3.57. (Due to very low solubility of the
product 7a, we cannot report the 13C NMR date for this
product).
2,3,4,5,7,8,9,10-Octahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium
3-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-nitrophenyl)methyl)-2-
oxo-2H-chromen-4-olate (10a)
White powder (55%); mp 128–130 °C. IR (KBr) (νmax/cm−1):
1
3436, 2936, 1686, 1648. H NMR (300 MHz, DMSO-d6): δH 1.61
(6H, bs, CH2), 1.89 (2H, bs, CH2), 2.60 (2H, bs, CH2), 3.22 (2H,
bs, CH2), 3.45 (2H, bs, CH2), 3.51 (2H, bs, CH2), 3.91 (1H, bs,
NH overlap with solvent), 6.34 (1H, bs, CH), 7.24–8.07 (12H,
m, H–Ar), 9.46 (1H, bs, OH). Anal. Calcd for C34H31N3O8: C,
66.99; H, 5.13. N, 6.89. Found: C, 66.86; H, 5.21; N, 6.78.
4,4′-(1,3-Phenylene)bis(3-(2-hydroxybenzoyl)-3,4-dihydropyrano-
[3,2-c]chromene-2,5-dione) (7b)
Cream powder (48%); mp 216–218 °C. IR (KBr) (νmax/cm−1):
1
3065, 1710, 1645. H NMR (300 MHz, DMSO-d6): δH 4.59 (2H,
d, CH, J = 3.84 Hz), 6.49 (2H, d, CH, J = 3.87 Hz), 6.88–7.09
(6H, m, H–Ar), 7.19–7.22 (2H, m, H–Ar), 7.33–7.84 (16H, m,
H–Ar), 10.89 (2H, s, OH). MS, m/z: 746 (M+). Anal. Calcd for
C44H26O12: C, 70.78; H, 3.51. Found: C, 70.65; H, 3.45. (Due to
very low solubility of the product 7b, we cannot report the 13C
NMR date for this product).
2,3,4,5,7,8,9,10-Octahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium
3-((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)-2-oxo-
2H-chromen-4-olate (10b)
White powder (50%); mp 123–125 °C. IR (KBr) (νmax/cm−1):
1
3434, 2936, 1684, 1645. H NMR (300 MHz, DMSO-d6): δH 1.62
(5H, bs, CH2), 1.76 (2H, bs, CH2), 2.62 (3H, bs, CH2), 3.22 (2H,
bs, CH2), 3.45 (2H, bs, CH2), 3.51 (2H, bs, CH2), 3.91 (1H, bs,
NH overlap with solvent), 6.34 (1H, bs, CH), 7.24–8.07 (12H,
m, H–Ar), 9.46 (1H, OH). Anal. Calcd for C34H32N2O6: C, 72.32;
H, 5.71. N, 4.96. Found: C, 72.20; H, 5.64; N, 4.87.
3-(2-Hydroxybenzoyl)-4-(4-oxo-4H-chromen-3-yl)-3,4-
dihydropyrano[3,2-c] chromene-2,5-dione (9a)
White powder (93%); mp 247–249 °C. IR (KBr) (νmax/cm−1):
1
3055, 1710, 1638. H NMR (300 MHz, DMSO-d6): δH 4.65 (1H,
d, J = 4.59 Hz, CH), 6.66 (1H, d, δH 4.65 Hz, CH), 6.93–8.04
(13H, m, H–Ar), 8.44 (1H, s,vCH), 10.96 (1H, s, OH). 13C NMR
(75 MHz, DMSO-d6): δC 42.3, 89.9, 101.9, 112.2, 117.2, 117.8,
118.9, 119.9, 120.5, 121.8, 123.8, 125.0, 125.4, 126.0, 131.3,
133.7, 134.8, 136.6, 155.0, 155.9, 156.2, 158.8, 159.9, 167.5,
176.1, 195.8. MS, m/z: 480 (M+). Anal. Calcd for C28H16O8: C,
70.00; H, 3.36. Found: C, 70.09; H, 3.31.
General procedures for the synthesis of 12a–12e
A mixture of salicylaldehyde (1.0 mmol), 4-hydroxy coumarin
(0.16 g, 1.0 mmol), 3-bromo-4-hydroxycoumarin (0.25 g,
1 mmol) in HOAc (3 mL) in the presence of DBU (0.05 g,
30 mol%) was refluxed in HOAc for 30 h. After completion of
the reaction (TLC), the reaction mixture was cooled to room
temperature. Then, the precipitated product was filtered and
washed with methanol (5 ml).
4-(6-Chloro-4-oxo-4H-chromen-3-yl)-3-(2-hydroxybenzoyl)-3,4-
dihydropyrano[3,2-c]chromene-2,5-dione (9b)
7-(4-Hydroxy-2-oxo-2H-chromen-3-yl)chromeno[4,3-b]chromen-
6(7H)-one (12a)
White powder (78%); mp 260–262 °C. IR (KBr) (νmax/cm−1):
1
3065, 1710, 1645. H NMR (300 MHz, DMSO-d6): δH 4.65 (1H, White powder (75%); mp 247–249 °C. IR (KBr) (νmax/cm−1):
1
d, CH, J = 5.13 Hz), 6.64 (1H, d, CH, J = 4.71 Hz), 6.93–6.96 3256, 1718, 1700, 1633. H NMR (300 MHz, DMSO-d6): δH 5.72
(2H, m, H–Ar), 7.45–7.52 (3H, m, H–Ar), 7.72–7.90 (5H, m, H– (1H, s, CH), 7.13–8.05 (12H, m, H–Ar), 12.18 (1H, s, OH). 13C
Ar), 7.97 (1H, s, H–Ar), 8.49 (1H, s,vCH), 10.93 (1H, s, OH). NMR (75 MHz, DMSO-d6): δC 29.6, 114.2, 116.5, 116.6, 116.9,
MS, m/z: 514 (M+). Anal. Calcd for C28H15ClO8: C, 65.32; H, 122.6, 123.0, 124.0, 124.1, 124.2, 124.3, 124.9, 125.7, 128.7,
2.94. Found: C, 65.43; H, 2.87. (Due to very low solubility of the 129.0, 132.6, 132.9, 149.5, 152.4, 152.6, 156.6, 160.8, 161.1. MS,
product 4b, we cannot report the 13C NMR date for this m/z: 410 (M+). Anal. Calcd for C25H14O6: C, 73.17; H, 3.44.
product).
Found: C, 73.09; H, 3.37.
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Paper
9-Bromo-7-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno[4,3-b]-
chromen-6(7H)-one (12b)
X-ray data for 12f
C29H16O7(DMSO), M = 538.56 g mol−1, triclinic system, space
White powder (65%); mp > 260 °C. IR (KBr) (νmax/cm−1): 3276, group P1, a = 10.399(3), b = 11.235(3), c = 13.089(3) Å, β =
ˉ
1
1710, 1674, 1629. H NMR (300 MHz, DMSO-d6): δH 3.23–3.51 101.40(2)°, V = 1277.6(6) Å3, Z = 2, Dc = 1.400 g cm−3, μ(Mo–
(1H, bs, OH), 5.70 (1H, s, CH), 7.30–8.07 (11H, m, H–Ar). 13C Kα) = 0.177 mm−1, crystal dimension of 0.20 × 0.16 × 0.15 mm.
NMR (75 MHz, DMSO-d6): δC 29.6, 114.0, 116.6, 116.8, 116.9, The structure was solved by using SHELXS. The structure
117.0, 119.0, 123.0, 124.4, 124.5, 125.0, 125.3, 131.2, 131.6, refinement and data reduction was carried out with SHELXL
132.7, 133.0, 149.0, 152.3, 152.7, 156.4, 160.6, 161.7, 161.7. MS, of the X-STEP32 suite of programs. The non-hydrogen atoms
m/z: 489 (M+, 81Br), 487 (M+, 79Br). Anal. Calcd for C25H13BrO6: were refined anisotropically by full matrix least-squares on F2
C, 61.37; H, 2.68. Found: C, 61.25; H, 2.73.
values to final R1 = 0.1168, wR2 = 0.2969 and S = 1.006 with 356
parameters using 5003 independent reflection (θ range =
1.74–26.00°). Hydrogen atoms were located from expected geo-
metry and were not refined.
7-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-10-methoxychromeno-
[4,3-b]chromen-6(7H)-one (12c)
The X-ray diffraction measurements were made on a STOE
IPDS-II diffractometer with graphite monochromated Mo–Kα
radiation. Cell constants and an orientation matrix for data
collection were obtained by least-squares refinement of the
diffraction data from 5003 unique reflections. Data were col-
lected at a temperature of 298(2) K to a maximum 2θ value of
52.00° and in a series of ω scans in 1° oscillations and inte-
grated using the Stoe X-AREA40 software package. The numeri-
cal absorption coefficients, μ, for Mo–Kα radiation is
0.177 mm−1. A numerical absorption correction was applied
using X-RED41 and X-SHAPE42 software. The data were cor-
rected for Lorentz and polarizing effects. The structure was
solved by direct methods and refined on F2 by a full-matrix
least-squares procedure. All hydrogen atoms were added at
ideal positions and constrained to ride on their parent atoms,
with Uiso(H) = 1.2Ueq. All refinements were performed using
the X-STEP32 crystallographic software package.43 Complete
crystallographic data for compound 12f has been deposited
with the Cambridge Crystallographic Data Center as sup-
plementary publication No. CCDC 876614.
White powder (69%); mp 262 °C. IR (KBr) (νmax/cm−1): 3212,
1736, 1674. 1H NMR (300 MHz, DMSO-d6): δH 3.61 (1H, bs,
OH), 5.66 (1H, s, CH), 6.71–8.41 (11H, m, H–Ar), 12.01 (1H, bs,
OH). 13C NMR (75 MHz, DMSO-d6): δC 28.61, 55.90, 101.7,
112.3, 114.2, 114.3, 116.6, 116.9, 117.0, 123.0, 124.1, 124.3,
124.9, 129.6, 132.5, 132.9, 150.2, 152.4, 152.6, 156.6, 159.5,
160.9. MS m/z 440 (M+). MS, m/z: 440 (M+). Anal. Calcd for
C26H16O7: C, 70.91; H, 3.66. Found: C, 70.80; H, 3.58.
7-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-9-methoxychromeno-
[4,3-b]chromen-6(7H)-one (12d)
White powder (85%); mp > 260 °C. IR (KBr) (νmax/cm−1): 3064,
1
1703, 1666, 1608. H NMR (300 MHz, DMSO-d6): δH 3.78 (1H,
bs, OH), 5.69 (1H, s, CH), 6.66–8.08 (11H, m, H–Ar), 12.16 (1H,
bs, OH). MS, m/z: 440 (M+). Anal. Calcd for C26H16O7: C, 70.91;
H, 3.66. Found: C, 70.84; H, 3.61. (Due to very low solubility of
the product 12d, we cannot report the 13C NMR date for this
product).
11-Hydroxy-7-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno-
[4,3-b]chromen-6(7H)-one (12e)
Acknowledgements
White powder (50%); mp 247–249 °C. IR (KBr) (νmax/cm−1):
3404, 1683, 1607. H NMR (300 MHz, DMSO-d6): δH 3.40 (1H,
bs, OH overlap with solvent), 5.70 (1H, s, CH), 6.61–8.32 (11H,
m, H–Ar), 9.85 (1H, s, OH), 12.13 (1H, bs, OH). MS, m/z: 426
(M+). Anal. Calcd for C25H14O7: C, 70.42; H, 3.31. Found: C,
70.52; H, 3.25. (Due to very low solubility of the product 12e,
we cannot report the 13C NMR date for this product).
We gratefully acknowledge financial support from the
Research Council of Shahid Beheshti University and the
Iranian National Science Foundation (Proposal No: 90002265).
1
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