One-pot synthesis and radical scavenging activity of novel polyhydroxylated 3-arylcoumarins

Article abstract of DOI:10.1016/j.ejmech.2014.03.053

An unexpected domino rearrangement brought about the development of a novel one-pot procedure for synthesis of coumarins. This protocol allowed the gram-scale synthesis of a variety of polyhydroxylated derivatives 3a-p, from readily available starting materials at a low cost. Based on two proven intermediates, a probable mechanism consisting of boron tribromide induced demethylation/lactone ring opening/elimination/isomerization/lactone ring closure reaction sequence of in situ formed 3-aryl-3,4-dihydroisocoumarin-4- carboxylic acids was deduced. Compared to the common methods, used for the synthesis of coumarins, the proposed herein possesses great advantages, such as mild conditions, good yields for short reaction time, simple work-up procedure and easy isolation of the final products. The structure of the newly synthesized compounds 3a-p was established by spectroscopic methods (¹H NMR, ¹³C NMR, IR, MS and HRMS) and their radical scavenging activity was evaluated in vitro against 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH). The results obtained show that compounds 3g-p posses higher radical scavenging activity (3.16 SC;bsubesub[μM] ; 6.82) than well-known antioxidants such as trolox, protocatechuic acid, caffeic acid and gallic acid (SC₅₀ [μM] = 9.34, 8.83, 9.48, 5.33, respectively), which is a precondition for promising antioxidant activity of these compounds to be expected.

Full text of DOI:10.1016/j.ejmech.2014.03.053

European Journal of Medicinal Chemistry 78 (2014) 198e206
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
One-pot synthesis and radical scavenging activity of novel
polyhydroxylated 3-arylcoumarins
*
Ivan Svinyarov, Milen G. Bogdanov
Faculty of Chemistry and Pharmacy, University of Sofia “St. Kl. Ohridski”, 1, James Bourchier Blvd., 1164 Sofia, Bulgaria
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected domino rearrangement brought about the development of a novel one-pot procedure for
synthesis of coumarins. This protocol allowed the gram-scale synthesis of a variety of polyhydroxylated
derivatives 3aep, from readily available starting materials at a low cost. Based on two proven in-
termediates, a probable mechanism consisting of boron tribromide induced demethylation/lactone ring
opening/elimination/isomerization/lactone ring closure reaction sequence of in situ formed 3-aryl-3,4-
dihydroisocoumarin-4-carboxylic acids was deduced. Compared to the common methods, used for the
synthesis of coumarins, the proposed herein possesses great advantages, such as mild conditions, good
yields for short reaction time, simple work-up procedure and easy isolation of the final products. The
structure of the newly synthesized compounds 3aep was established by spectroscopic methods (1H
NMR, 13C NMR, IR, MS and HRMS) and their radical scavenging activity was evaluated in vitro against 1,1-
diphenyl-2-picrylhydrazyl free radical (DPPHꢀ). The results obtained show that compounds 3gep posses
Received 17 December 2013
Received in revised form
14 March 2014
Accepted 16 March 2014
Available online 19 March 2014
Keywords:
One-pot reactions
Anhydrides
Oxygen heterocycles
DPPH radical
Antioxidant
higher radical scavenging activity (3.16 ꢁ SC50
protocatechuic acid, caffeic acid and gallic acid (SC50
a precondition for promising antioxidant activity of these compounds to be expected.
Ó 2014 Elsevier Masson SAS. All rights reserved.
[
m
M] ꢁ 6.82) than well-known antioxidants such as trolox,
[m
M] ¼ 9.34, 8.83, 9.48, 5.33, respectively), which is
1. Introduction
thus their large scale production from natural sources is unreliable.
To overcome this, various synthetic approaches for the synthesis of
coumarins have been developed [27e49]. One of the main strate-
gies is based on condensationecyclization-type transformations
employing the well-known Perkin, Pechmann or Knoevenagel re-
actions [27e35] as a key step for the coumarin backbone formation.
An alternative strategy consists in the direct 3-arylation of the
coumarin scaffold by metal cross-coupling reactions [36e42]
leading to diversely substituted coumarin derivatives. All these
methods, however, possess some drawbacks that hinder their
benefits from an applied standpoint. In particular, the requirement
of strong acids, high temperatures and prolonged reaction times in
the classical condensation methods and the expensive, toxic, and
sensitive to moisture catalysts in the case of metal cross-coupling
reactions. Furthermore, these methods are of limited applicability
for the direct synthesis of hydroxylated coumarins, and thus, in
order polyhydroxylated derivatives to be synthesized, one should
follow multistep approach including sequential protection,
condensation, and deprotection steps. This sequence is necessary
due to the extreme susceptibility of the hydroxyl function towards
oxidation and polymerization, but results in a low overall product
yields. Therefore, the need for improved methodologies for the
synthesis of coumarin derivatives can be put forward [43e51]. In
Coumarins are a large class of oxygenated heterocyclic second-
ary metabolites, that are biosynthesized by plants and fruits de novo
[1]. They serve as phytoalexins which are directly formed as a
defence response to stress (drought and cold), wound, viral infec-
tion or invasion by bacterial or fungal pathogens [2,3]. Natural
coumarins display a wide range of biological activities [4e7] such as
anti-inflammatory, anticoagulant, anticancer, vasorelaxant, and
antiviral, to name just a few. In addition, several synthetic coumarin
derivatives, particularly 3-aryl substituted ones (see Fig. 1), proved
to be efficient antioxidants [8e11], that inhibit variety of enzymes
[12e20], possess anti-HIV [21], anticancer [22e24] and vaso-
relaxant activities [25], and are antagonists of certain receptors
[26]. Thus, due to their widespread pharmacological properties,
coumarins occupy an important place in the realm of medicinal
chemistry. Despite their remarkable medical benefits, it is note-
worthy that the coumarins bioavailability is dependent to a large
extent on the environmental conditions and seasonal changes, and
* Corresponding author.
E-mail address: mbogdanov@chem.uni-sofia.bg (M.G. Bogdanov).
http://dx.doi.org/10.1016/j.ejmech.2014.03.053
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
199
Scheme 1. Initial synthesis of coumarins. Reagents and conditions: (i) DMAP/CH2Cl2,
10 min, rt, then (ii) BBr3/CH2Cl2, rt, 1 or 4 h.
arylcoumarins are normally synthesized under harsh conditions,
and that the common methods used for the coumarin scaffold
formation are of limited applicability for the direct synthesis of
hydroxylated derivatives. So, the above transformation can be
considered as attractive for further investigation. We were further
delighted to find that the yield of 3i increases with the time,
reaching its maximum in 4 h, and then staying intact even after
12 h. Thus 3i was obtained in nearly twofold higher yield (78%)
compared to the initial conditions (44%). It is noteworthy, that 3i
was isolated as a crystalline product in a high purity, simply by
filtration of the worked up reaction mixture, and that some quan-
tities of E-4a were always present in the filtrate. This shows, on the
one hand, that E-4a could be considered as an intermediate for the
synthesis of 3i, and on the other, that equilibrium between 3i and E-
4a, in favour of the target coumarin could be assumed. To check
this, an isolated E-4a was reacted at the same conditions and the
reaction outcome was monitored by means of TLC. As a result, the
expected transformation of E-4a into 3i was observed, thus proving
the participation of E-4a as an intermediate in the reaction scheme
to 3i and suggesting some hints regarding the probable reaction
mechanism (see below). In addition, when E-4a was put to crys-
tallize in ethyl acetate, a spontaneous reaction occurs and pre-
cipitates of 3i appear with the time, showing that the lactonization
is the thermodynamically favoured process, which proceeds
spontaneously to give the more stable product 3i. In contrary, when
3i was put under the reaction conditions, no formation of the
stilbene E-4a was observed, thus rejecting the hypothesis for the
existing equilibrium between both compounds. The above
reasoning, however, suggests the promising potential of the
approach under study for the facile synthesis of hydroxylated
coumarins in a one-pot manner, from commercially available re-
agents. Considering this as a great advantage, we were further
interested to check the applicability of our methodology by reacting
Fig. 1. Structure of some biologically active 3-arylcoumarins.
this context, in continuation of an ongoing in our laboratory project
on anhydride-based syntheses of biologically active compounds
[52e59], herein we report the synthesis of
a series of 3-
arylcoumarins by means of a novel one-pot procedure, including
initial Perkin-like reaction between commercially available homo-
phthalic anhydrides and 2-methoxybenzaldehydes, followed by
treatment with BBr3. This straightforward procedure allows the
room-temperature gram-scale production of polyhydroxylated
coumarins in good yields for short reaction times, and provides an
easy isolation of the final products. Furthermore, in order for the
influence of the number and position of the hydroxyl groups in the
3-arylcoumarin scaffold on the radical scavenging activity of the
synthesized compounds to be established, an in vitro differentiating
screening against 1,1-diphenyl-2-picrylhydrazyl free radical
(DPPHꢀ) was performed.
2. Results and discussion
2.1. Chemistry
In a recent article of ours [52], we have demonstrated that
diastereomeric mixture of methoxylated cis- and trans-3-aryl-3,4-
dihydroisocoumarin-4-carboxylic acids undergoes simultaneous
demethylation and lactone-ring opening reaction in presence of
BBr3. This finding resulted in the development of a novel one-pot
procedure for the synthesis of polyhydroxylated cis-restricted stil-
benes possessing a triple biological action as potent antioxidants,
antifungal agents and tyrosinase inhibitors. The proposed method
consists of sequential reaction between homophthalic anhydrides
and aromatic aldehydes to produce diastereomeric mixture of the
corresponding 3-aryl-3,4-dihydroisocoumarin-4-carboxylic acids,
which, after treatment with BBr3, give the target polyhydroxylated
stilbenes in short reaction times (10e60 min) [52]. In continuation
of this study, in order a more complete series of compounds to be
synthesized, we were interested to perform reactions between
two homophthalic anhydrides with
a
series of 2-
methoxybenzaldehydes. The reaction scheme and conditions are
depicted in Scheme 2, and yields and products substitution pattern
are given in Table 1. In brief, the obtained by a reaction of the
corresponding anhydrides 1a,b and aldehydes 2aeh in presence of
DMAP/CH2Cl2 diastereomeric mixtures of cis- and trans-5 [52e
54,59] were further successfully converted without isolation into
3aep by direct addition of BBr3/CH2Cl2 solution at room tempera-
ture. After 4 h, the reaction was terminated by pouring over ice,
stirred for additional 30 min for hydrolysis of the boron esters
formed, and the target coumarins 3aep were then isolated simply
by filtration. It is noteworthy that the obtained in this way com-
pounds do not need further chromatographic purification, which is
a necessary step for isolation of other polyhydroxylated derivatives
[12,16,25]. Furthermore, as mentioned above, additional quantities
of 3 could be obtained by slow precipitation of the corresponding
filtrates, mainly containing stilbenes of type 4. The structures of
3aep were elucidated by means of spectral methods. In case of 1H
NMR, 13C NMR and IR methods, the spectra were taken for the
homophthalic
anhydrides
and
a
series
of
2-
methoxybenzaldehydes.
Surprisingly, when 3,4-dimethoxyhomophthalic anhydride (1b)
and 2-methoxybenzaldehyde (2a) were subjected to the reaction
conditions depicted in Scheme 1, a by-product, whose structure
was latter established as the coumarin 3i, was isolated in quantity
comparable with that of the desired at this stage stilbene E-4a. This
result intrigued us, since, to the best of our knowledge, the syn-
thesis of coumarins according such a protocol is not known.
Moreover, a short retrospection of the literature showed that 3-

200
I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
Scheme 2. One-pot synthesis of polyhydroxylated coumarins. Reagents and conditions: (i) DMAP/CH2Cl2, 10e15 min, rt, then (ii) BBr3/CH2Cl2, rt, 4 h.
synthesized compounds, while their mass spectra (both MS and
HRMS) were obtained after derivatization with diazomethane
ethereal solution prior to analysis. However, the data obtained is in
agreement with that previously reported for similar compounds
[60,61], thus allowing us to assign unequivocally their structures
(cf. Supporting information). Summarizing, if one follows the one-
pot procedure under consideration, polyhydroxylated 3-
arylcoumarins are readily available from commercial starting ma-
terials in less than 5 h. Compared to the common methods, used for
synthesis of coumarins, our method possesses advantages, such as
mild conditions, good yields in short reaction time, simple work-up
procedure and easy final product isolation. Furthermore, the syn-
thesized herein coumarins bear a carboxylic substituent in their
structure, which can be considered as a precondition for increased
water solubility of these compounds. On the other hand, it provides
the possibility for further modifications to other functional groups,
thus broadening the scope of the proposed method.
means of NMR analysis as E-4b and mixture of cis-/trants-6a (cf.
Supporting information). To prove their participation as in-
termediates, E-4b and 6a were further subjected independently to
the reaction conditions and the reaction outcome was monitored
by means of TLC. As a result, the expected transformation of both
compounds into 3l was observed. It was monitored that E-4b un-
dergoes direct transformation to 3l, whereas in case of 6a, simul-
taneous formation of both 3l and E-4b was detected. It is
noteworthy, that in the former case E-4b also disappeared with the
time, which suggests 6a as an intermediate towards its formation.
Consequently, taking into account the above reasoning, and based
on previously described by us results [52,53,59], a probable reac-
tion mechanism, whose second part mimics the coumarin
biosynthesis [3,62,63] could be proposed (Scheme 3). In brief, in the
first part, homophthalic anhydride reacts in a Perkin-like reaction
with an aldehyde to give in 10 min a mixture of cis- and trans-3-aryl
substituted
3,4-dihydroisocoumarin-4-carboxylic
acids
5
Let us discuss the mechanistic aspects of the current approach.
Considering the particular structure of both starting and target
[52,53,59]. Demethylation of 5 in the next step can be considered as
a beginning of the second part, which starts a domino process
affording the target coumarins 3. This part consists of four
sequential steps, including lactone ring opening, elimination,
isomerization and lactone ring closure reactions. In the first step, as
was discussed above, the demethylated intermediate 6 undergoes
concomitant lactone ring opening and elimination reaction to
produce E-4. Such a reaction was also documented in a recent study
of ours [52], where we have shown, that the rate of formation of E-4
from 5 depends on the number of methoxyl groups that have to be
demethylated, and that the highly substituted representative (5
groups) reacts quantitatively in 1 h. It is noteworthy that the
compounds,
dimethoxyhomophthalic
we
studied
reaction
between
and
6,7-
2,3-
anhydride
(1b)
dimethoxybenzaldehyde (2b) in more details. This reaction was
selected because the performed shortly after the BBr3 addition TLC
analysis showed presence of additional compounds in the reaction
mixture, which disappear with the time. The latter suggests that
they could be considered as intermediates in the reaction scheme.
Thus, after flash chromatography of the worked up reaction
mixture, we were able to isolate two other compounds beside the
coumarin 3l. The structure of the unknowns was elucidated by
Table 1
Yields, substitution patterns, number of hydroxyl groups and DPPHꢀ scavenging activity (SC50) of compounds 3aep and standard antioxidants.
Compd.
Yielda [%]
R1
R2
R3
R4
R5
R6
OH groups (total)
DPPHꢀ EC50 M]b
[m
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
72
49
50
63
72
80
72
66
78
77
44
70
65
44
55
72
H
H
H
H
OH
H
H
H
H
H
OH
H
H
H
H
H
H
OH
H
Br
OH
H
H
OH
H
H
H
Br
OH
H
H
H
OH
H
H
H
OH
H
H
H
H
H
OH
H
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
OH
0
1
1
1
1
0
2
2
2
3
3
3
3
2
4
4
1
2
2
3
nac
nac
nac
nac
nac
H
nac
OH
OH
H
H
H
H
OH
H
OH
OH
5.32 ꢂ 0.05
3.59 ꢂ 0.16
5.14 ꢂ 0.11
3.17 ꢂ 0.06
6.86 ꢂ 0.16
4.09 ꢂ 0.12
6.02 ꢂ 0.15
4.02 ꢂ 0.09
5.30 ꢂ 0.03
3.39 ꢂ 0.05
9.34 ꢂ 0.07
9.48 ꢂ 0.17
8.83 ꢂ 0.62
5.34 ꢂ 0.34
H
H
3p
OH
Trolox
CAd
PCAd
GAd
a
Yields refer to isolated crystalline products.
b
c
Results are presented as a mean ꢂ SD, n ¼ 3.
Not active up to concentration 100 mM.
d
CA, PCA and GA refer to caffeic acid, protocatechuic acid and gallic acid, respectively.

I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
201
other coumarins [8e11]. Therefore, this method was employed to
assess the radical scavenging activity of the synthesized by us
compounds 3aep. The analysis was performed in methanol and the
activity was expressed as SC50 (mM) e the concentration able to
scavenge 50% of DPPHꢀ. For comparison purpose, well-known an-
tioxidants such as Trolox, protocatechuic acid (PCA), caffeic acid
(CA) and gallic acid (GA) were used as reference compounds. The
results obtained are presented in Table 1 and Fig. 2. In general, the
compounds tested can be split into two groups: 3aee e not active
up to concentration 100
mM; and 3gep e highly active, with
SC50 ꢁ 6.82 M. These results suggest that the number of OH groups
m
play an important role in triggering the scavenging activity, since
the lack of activity of 3aee at the concentration measured could be
attributed to the absence or presence of only one OH group into the
3-arylcoumarin backbone. The other group (3gep) shows compa-
rable, even higher radical scavenging activity than the standards
used, as can be seen from the following scavenging activity order:
CA < Trolox < PCA < 3k < 3m < GA z 3g z 3i z 3l <
3n < 3h z 3p z 3o z 3j. Taking into account the substitution
pattern, it could be concluded that the main factor for the apparent
activity is the presence of a catechol fragment, regardless in which
aromatic ring it is. It is noteworthy that CA and PCA also possess
such a fragment, but except 3k and 3m, all other compounds are at
least twofold more active. This could be attributed to the presence
Scheme 3. Probable reaction pathway for the proposed one-pot synthesis of
coumarins.
of an extended
p-conjugated system providing better delocaliza-
tion, and thus stabilization, of the radicals formed. Consequently,
compounds 3gep can be considered attractive targets for further
detailed studies of their antioxidant activity, since it is well known
that one of the main characteristics responsible for the antioxidant
activity of phenolic compounds is their ability to scavenge free
radicals. Moreover, the observed short range regarding SC50 values
presence of hydroxyl groups in the 3-aryl substituent in 6, partic-
ularly in para-position, accelerates the lactone ring opening reac-
tion by its positive mesomeric effect [52,64], and thus poses
difficulties in isolation and structural characterization of these in-
termediates. The latter also suggests that the formation of E-4 is not
the rate limiting step in the synthetic sequence. Further, in order for
the coumarin scaffold to be formed, E-4 should isomerise to its Z-
form, which happens in the next step. This sequence seems to be
not illogical, since it mimics the coumarin biosynthetic pathway
[63] from trans-cinnamic acid, via ortho-hydroxylation, trans-cis
isomerisation of the side chain double bond and further lactoni-
sation. Moreover, some papers [65e67] reported the synthesis of
coumarins by cyclisation of obtained in advance E-ortho-methox-
ycinnamates under similar to the reported herein conditions e
boron tribromide in dichloromethane. It is noteworthy that these
results regard cinnamic acid analogues that always exist as an
equilibrium mixture of the corresponding E- and Z-isomers. In our
case, compounds 4 are entirely in their E-configuration. This was
comprehensively studied and reported in recent studies [52,53],
where we have used different NMR techniques and X-ray analysis
to show that the incorporated trans-cinnamic acid fragment in 4
ensures cis-orientation of the phenyl substituents and prevents
further isomerization along the carbonecarbon double bond.
Nevertheless, despite that the E-isomers of 4 are proved to be
preferred [52,53], they should isomerize somehow prior to cycli-
sation to 3. We believe that the substituents electronic effects are
implicated in this process, but in order for the above speculations to
be converted into a more conclusive interpretation additional work
including detailed reaction progress evaluation by NMR, kinetics
measurements and quantum-chemical computations is needed.
(3.16 ꢁ SC50
[
m
M] ꢁ 6.82), shows that the activity of 3gep is nearly
independent on the number and position of the hydroxyl groups.
The latter suggests that evaluation of other biological activities, in
order for double or triple action to be established for these com-
pounds, is worth performing.
3. Conclusions
In summary, we have developed a concise method for the syn-
thesis of coumarins via boron tribromide induced demethylation/
lactone ring opening/elimination/isomerization/lactone ring
closure
reaction
sequence
of
in
situ
formed
3,4-
dihydroisocoumarin-4-carboxylic acids. This novel one-pot
2.2. Biological activity
The DPPHꢀ radical is one of the commercially available stable
organic nitrogen radicals, which does not have to be generated
prior to analysis. The analysis whit it is easy to perform, highly
reproducible, comparable with other methods and has been suc-
cessfully applied for evaluation of the radical scavenging activity of
Fig. 2. A comparison of the radical scavenging activity of compounds 3gep and
standard antioxidants.

202
I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
procedure allows the gram-scale synthesis of a variety of poly-
hydroxylated coumarin derivatives from readily available starting
materials at a low cost. The method proposed provides good yields
for short reaction time, which, in combination with both simple
work-up procedure and final products isolation in a purity level
without the need for any further purification, shows its promising
potential for the synthesis of a series of coumarins useful for their
biological activity. The performed in vitro DPPHꢀ assay show that
compounds 3gep posses both higher and nearly independent on
the substitution pattern radical scavenging activity than well-
known antioxidants such as Trolox, protocatechuic acid, caffeic
acid and gallic acid, which is a precondition for promising antiox-
idant activity of these compounds to be expected. The latter also
suggests that evaluation of other activities of 3gep, in order for
multiple biological actions to be established for these compounds,
is worth performing. In this direction, work on the synthesis of
particular value added coumarins, as well as work on the biological
activity evaluation of the synthesized herein new compounds 3aep
is currently ongoing in our laboratory and the results will be pub-
lished in due course.
solvent was evaporated under reduced pressure. The residue was
further dissolved in ethyl acetate. After few days, additional
quantities from coumarins 3aep could be obtained by filtration.
4.2.1.1. 2-(2-Oxo-2H-chromen-3-yl)benzoic acid (3a). From reaction
of homophthalic anhydride (1a) (1.08 g, 6.71 mmol), 2-
methoxybenzaldehyde (2a) (0.91 g, 6.71 mmol), 4-
dimethylaminopyridine (0.82 g, 6.71 mmol), boron tribromide
(33.5 mL, 53.64 mmol) in 20 mL dichloromethane. Yield: 1.30 g
(72%), white solid, mp 259e260 ꢃC; 1H NMR (600.13 MHz, DMSO-
d6),
d
¼ 12.90 (bs, 1H, COOH), 8.02 (s, 1H, ]CHe), 7.95 (dd,
3JH,H ¼ 7.8, JH,H ¼ 1.2 Hz, 1H, ArH), 7.76 (dd, JH,H ¼ 7.7,
4
3
4JH,H ¼ 1.5 Hz, 1H, ArH), 7.69 (dt, 3JH,H ¼ 7.5, 4JH,H ¼ 1.4 Hz; 1H, ArH),
3
4
7.63 (ddd, JH,H ¼ 8.4, 7.4, JH,H ¼ 1.6 Hz, 1H, ArH), 7.57 (dt,
3JH,H ¼ 7.6, JH,H ¼ 1.3 Hz, 1H, ArH), 7.50 (dd, JH,H ¼ 7.6,
4
3
4JH,H ¼ 1.0 Hz, 1H, ArH), 7.45 (d, JH,H ¼ 8.3 Hz, 1H, ArH), 7.39 (dt,
3
3JH,H ¼ 7.5, 4JH,H ¼ 1.1 Hz, 1H, ArH); 13C NMR (150.92 MHz, DMSO-
d6)
d
¼ 167.7 (COCOOH), 159.7 (COlactone), 152.8, 138.5, 135.8, 132.1,
131.3, 131.2, 130.8, 130.1, 129.7, 128.7, 128.3, 124.5, 119.4, 115.9; IR
(Nujol)
281.1(18), 280.0(100), 254.0(25), 249.0(76), 235.0(13), 221.0(61),
220.0(19), 193(12), 165.0(17), 163.0(12); HRMS (EI): m/z calculate:
280.07356, found: 280.07314 for C17H12O4.
n
¼ 3600e3050 (OH), 1720, 1670 (C]O) cmꢄ1; MS (EI) m/z:
4. Experimental section
4.1. General remarks
4.2.1.2. 2-(8-Hydroxy-2-oxo-2H-chromen-3-yl)benzoic acid (3b).
From reaction of homophthalic anhydride (1a) (0.99 g, 6.09 mmol),
2,3-dimethoxybenzaldehyde (2b) (1.01 g, 6.09 mmol), 4-
dimethylaminopyridine (0.74 g, 6.09 mmol), boron tribromide
(34.3 mL, 54.83 mmol) in 20 mL dichloromethane. Yield: 0.84 g
(49%), brown solid, mp 305e306 ꢃC; 1H NMR (600.13 MHz, DMSO-
All chemicals used in this study were purchased from Sigmae
Aldrich (FOT, Bulgaria). Melting points were determined on a Kofler
microscope Boetius PHMK 0.5. The reactions were monitored by
thin layer chromatography (TLC) on pre-coated polyesters sheets
POLIGRAMÒ SIL G/UV254; spots were visualised with UV light. The
IR spectra were acquired in Nujol on a Specord 75 and are reported
in reciprocal centimetres. NMR spectra were recorded on a Bruker
Avance spectrometer at 600 MHz/150 MHz for 1H and 13C,
d6),
d
¼ 12.87 (bs, 1H, COOH), 10.24 (bs, 1H, OH), 7.94 (s, 1H, ]CHe),
3
4
3
7.93 (dd, JH,H ¼ 7.9, JH,H ¼ 1.2 Hz, 1H, ArH), 7.68 (dt, JH,H ¼ 7.5,
4JH,H ¼ 1.4 Hz, 1H, ArH), 7.56 (dt,, 3JH,H ¼ 7.6, 4JH,H ¼ 1.3 Hz, 1H, ArH),
7.49 (dd, 3JH,H ¼ 7.6, 4JH,H ¼ 1.0 Hz, 1H, ArH), 7.19e7.14 (m, 2H, ArH),
7.10 (dd, 3JH,H ¼ 6.8, 4JH,H ¼ 2.7 Hz, 1H, ArH); 13C NMR (150.92 MHz,
respectively, using DMSO-d6 as a solvent. The chemicals shifts (d)
are given in ppm relative to tetramethylsilane as an internal stan-
dard and coupling constants (J) values are reported in Hz. The exact
mass of compounds 3aep was determinate by HRMS analyses on
DFS High Resolution GC/MS (Thermo), after derivatization with
diazomethane. The mass spectra were obtained after preliminary
GC separation on Trace GC (Thermo Electron) instrument equipped
with a quadruple MS detector DSQ (Thermo Electron). The sepa-
ration was carried out on DB-5 MS column. The mass spectrometer
operates in scan-mode (70 eV ionization potential). The radical
scavenging activity was assessed by UVeVIS spectrophotometer
Thermo Evolution 60S.
DMSO-d6)
d
¼ 167.9 (COCOOH), 159.8 (COlactone), 144.5, 141.6, 139.0,
136.1, 132.2, 131.4, 131.0, 130.1, 129.8, 128.8, 124.6, 120.5, 118.4, 117.8;
IR (Nujol)
311.1(20), 310.1(100), 282.1(19), 279.1(57), 278.1(40), 265.1(13),
251.1(53), 208(16), 207.0(25), 165.0(20), 152.0(25), 151.0(18),
139.0(14), 125.0(15), 76.0(19); HRMS (EI): m/z calculate: 310.08412,
found: 310.08392 for C18H14O5.
n
¼ 3400 (OH), 1705, 1670 (C]O) cmꢄ1; MS (EI) m/z:
4.2.1.3. 2-(7-Hydroxy-2-oxo-2H-chromen-3-yl)benzoic acid (3c).
From reaction of homophthalic anhydride (1a) (0.99 g, 6.09 mmol),
2,4-dimethoxybenzaldehyde (2c) (1.01 g, 6.09 mmol), 4-
dimethylaminopyridine (0.74 g, 6.09 mmol), boron tribromide
(34.3 mL, 54.83 mmol) in 20 mL dichloromethane. Yield: 0.86 g
(50%), beige solid, mp 255e256 ꢃC; 1H NMR (600.13 MHz, DMSO-
4.2. Chemistry
4.2.1. General procedure for one-pot synthesis of polyhydroxy
coumarins 3aep
d6),
d
¼ 12.78 (bs,1H, COOH), 10.56 (bs, 1H, OH), 7.90 (dd, 3JH,H ¼ 7.4,
3
An equimolar mixture of the corresponding homophthalic anhy-
dride (1a,b), an aldehyde 2aeh and DMAP was stirred at room tem-
perature in dry dichloromethane (20 mL). The consumption of the
reagents was monitored by TLC. At the end of the reaction (10e
15 min), boron tribromide (1.6 M solution in dichloromethane) was
slowly added (one equivalent per heteroatom), and after 4 h stirring
thereactionmixturewaspouredovergrindedice(50g)andstirredfor
additional30min. Thecrystallizedcoumarins3aepwere then filtered
off, washed with deionised water and dried at 100 ꢃC under reduced
pressure. The obtained in this way coumarins 3aep were recrystal-
lized from acetic acid/water prior to spectral characterization.
Additional quantities of 3 could be obtained from the filtrates as
follows: the corresponding filtrate was saturated with NaCl and
extracted with ethyl acetate. The organic phase was washed with
brine to a constant pH, dried over anhydrous Na2SO4 and the
4JH,H ¼ 1.5 Hz, 1H, ArH), 7.89 (s, 1H, ]CHe), 7.65 (dt, JH,H ¼ 7.5,
4JH,H ¼ 1.4 Hz, 1H, ArH), 7.57 (d, JH,H ¼ 8.5, 1H, ArH), 7.52 (dt,
3
3JH,H ¼ 7.6, JH,H ¼ 1.3 Hz, 1H, ArH), 7.45 (dd, JH,H ¼ 7.6,
4JH,H ¼ 1.0 Hz,1H, ArH), 6.83 (dd, 3JH,H ¼ 8.5, 4JH,H ¼ 2.3 Hz,1H, ArH),
6.76 (d, 4JH,H ¼ 2.3 Hz, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
4
3
d
¼ 167.9 (COCOOH), 160.8 (COlactone), 160.1, 154.7, 139.2, 136.1, 131.9,
131.4, 130.8, 2 ꢅ 129.6, 128.3, 125.4, 113.1, 111.8, 101.8; IR (Nujol)
n
¼ 3500e3000 (OH), 1705, 1670 (C]O) cmꢄ1; MS (EI) m/z:
311.1(20), 310.1(100), 282.1(30), 279.0(50), 267.0(22), 251.0(27),
235.0(9), 223.1(7); HRMS (EI): m/z calculate: 310.08412, found:
310.08285 for C18H14O5.
4.2.1.4. 2-(6-Hydroxy-2-oxo-2H-chromen-3-yl)benzoic acid (3d).
From reaction of homophthalic anhydride (1a) (0.99 g, 6.09 mmol),
2,5-dimethoxybenzaldehyde (2d) (1.01 g, 6.09 mmol), 4-

I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
203
dimethylaminopyridine (0.74 g, 6.09 mmol), boron tribromide
(34.3 mL, 54.83 mmol) in 20 mL dichloromethane. Yield: 1.08 g
(63%), white solid, mp 251e252 ꢃC; 1H NMR (600.13 MHz, DMSO-
7.04 (s, 1H, ArH), 6.76 (s, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
¼ 168.1 (COCOOH), 160.5 (COlactone), 150.0, 147.9, 143.0, 139.4, 136.4,
d
132.0, 131.7, 131.0, 129.6, 128.3, 125.6, 112.4, 111.5, 102.4; IR (Nujol)
d6),
d
¼ 12.86 (bs, 1H, COOH), 9.76 (bs, 1H, OH), 7.92 (dd, 3JH,H ¼ 7.7,
n
¼ 3550e2500 (OH), 1700, 1660 (C]O) cmꢄ1; MS (EI) m/z:
4JH,H ¼ 1.2 Hz, 1H, ArH), 7.92 (s, 1H, ]CHe), 7.66 (dd, JH,H ¼ 7.5,
4JH,H ¼ 1.4 Hz, 1H, ArH), 7.57 (dt, 3JH,H ¼ 7.6, 4JH,H ¼ 1.3 Hz, 1H, ArH),
7.47 (dd, 3JH,H ¼ 7.6, 4JH,H ¼ 1.0 Hz, 1H, ArH), 7.28 (d, 3JH,H ¼ 8.9, 1H,
341.2(20), 340.2(100), 309.2(45), 281.1(10), 265.1(14), 237.1(18),
209.1(9), 194.0(10); HRMS (EI): m/z calculate: 340.09469, found:
340.09415 for C19H16O6.
3
4
3
ArH), 7.07 (d, JH,H ¼ 2.9 Hz, 1H, ArH), 7.03 (dd, JH,H ¼ 8.9,
4JH,H ¼ 2.9 Hz, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
d
¼ 167.9
4.2.1.8. 2-(7,8-Dihydroxy-2-oxo-2H-chromen-3-yl)benzoic acid (3h).
From reaction of homophthalic anhydride (1a) (0.91 g, 5.58 mmol),
2,3,4-trimethoxybenzaldehyde (2h) (1.09 g, 5.58 mmol), 4-
dimethylaminopyridine (0.68 g, 5.58 mmol), boron tribromide
(35.0 mL, 55.81 mmol) in 20 mL dichloromethane. Yield: 1.10 g
(66%), beige solid, mp 285e286 ꢃC; 1H NMR (600.13 MHz, DMSO-
(COCOOH), 160.1 (COlactone), 153.9, 146.3, 138.6, 136.1, 132.2, 131.5,
131.0, 130.2, 129.7, 128.8, 120.1, 119.3, 116.9, 112.5; IR (Nujol)
n
¼ 3500e3000 (OH), 1710, 1680 (C]O) cmꢄ1; MS (EI) m/z:
311.2(23), 310.2(100), 279.1(51), 278.1(42), 263.1(15), 251.1(32),
207.1(25), 152.1 (14), 139.0(8), 126.0(10), 76.1(8); HRMS (EI): m/z
calculate: 310.08412, found: 310.08394 for C18H14O5.
d6),
d
¼ 12.64 (bs, 1H, COOH), 10.11 (bs, 1H, OH), 9.41 (bs, 1H, OH),
7.89 (dd, 3JH,H ¼ 7.8, 4JH,H ¼ 1.2 Hz,1H, ArH), 7.84 (s,1H, ]CHe), 7.64
3
4
3
4.2.1.5. 2-(5-Hydroxy-2-oxo-2H-chromen-3-yl)benzoic acid (3e).
From reaction of homophthalic anhydride (1a) (0.49 g, 3.01 mmol),
2,6-dimethoxybenzaldehyde (1e) (0.50 g, 3.01 mmol), 4-
dimethylaminopyridine (0.37 g, 3.01 mmol), boron tribromide
(16.9 mL, 27.08 mmol) in 10 mL dichloromethane. Yield: 0.61 g
(72%), orange solid, mp 285e286 ꢃC; 1H NMR (600.13 MHz, DMSO-
(dt, JH,H ¼ 7.5, JH,H ¼ 1.4 Hz, 1H, ArH), 7.51 (dt, JH,H ¼ 7.6,
4JH,H ¼ 1.3 Hz, 1H, ArH), 7.45 (dd, 3JH,H ¼ 7.6, 4JH,H ¼ 1.0 Hz, 1H, ArH),
7.06 (d, 3JH,H ¼ 8.5, 1H, ArH), 6.83 (d, 3JH,H ¼ 8.4, 1H, ArH); 13C NMR
(150.92 MHz, DMSO-d6)
d
¼ 168.1 (COCOOH), 160.2 (COlactone), 149.3,
143.2, 139.8, 136.4, 132.0, 132.0, 131.6, 131.0, 129.7, 128.4, 125.4,
118.8, 112.7, 112.6; IR (Nujol)
n
¼ 3550e2400 (OH), 1695 (C]O)
d6),
d
¼ 12.84 (bs, 1H, COOH), 10.80 (bs, 1H, OH), 7.92 (dd, 3JH,H ¼ 7.7,
cmꢄ1; MS (EI) m/z: 341.1(22), 340.1(100), 309.1(45), 297.1(22),
281.1(21), 269.1(32), 237.1(14), 223.0(16), 183.0(14), 167.0(12),
139.0(21), 127.0(11); HRMS (EI): m/z calculate: 340.09469, found:
340.09421 for C19H16O6.
4JH,H ¼ 1.2 Hz, 1H, ArH), 7.92 (s, 1H, ]CHe), 7.66 (dt, JH,H ¼ 7.5,
4JH,H ¼ 1.4 Hz, 1H, ArH), 7.54 (dt, 3JH,H ¼ 7.6, 4JH,H ¼ 1.3 Hz, 1H, ArH),
7.48 (dd, 3JH,H ¼ 7.6, 4JH,H ¼ 1.0 Hz, 1H, ArH), 7.45 (t, 3JH,H ¼ 8.3, 1H,
3
3
3
ArH), 6.85 (d, JH,H ¼ 8.3, 1H, ArH), 6.80 (dd, JH,H ¼ 8.2,
4JH,H ¼ 0.8 Hz, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
d
¼ 168.0
4.2.1.9. 4,5-Dihydroxy-2-(2-oxo-2H-chromen-3-yl)benzoic acid (3i).
From reaction of 6,7-dimetoxihomophthalic anhydride (1b) (1.24 g,
5.58 mmol), 2-methoxybenzaldehyde (2a) (0.76 g, 5.58 mmol), 4-
dimethylaminopyridine (0.68 g, 5.58 mmol), boron tribromide
(35.0 mL, 55.81 mmol) in 20 mL dichloromethane. Yield: 1.31 g
(78%), beige solid, mp 283e284 ꢃC; 1H NMR (600.13 MHz, DMSO-
(COCOOH), 160.0 (COlactone), 154.9, 154.2, 136.2, 133.4, 132.2, 132.2,
131.5, 131.0, 129.8, 128.7, 127.8, 110.1, 108.8, 106.5; IR (Nujol)
n
¼ 3500e3000 (OH), 1705, 1680 (C]O) cmꢄ1; MS (EI) m/z:
311.2(22), 310.2(100), 282.2(28), 279.1(74), 251.1(48), 236.1(22),
207.1(11), 180.1(7), 152.1(14), 139.1(8); HRMS (EI): m/z calculate:
310.08412, found: 310.08382 for C18H14O5.
d6),
d
¼ 12.30 (bs, 1H, COOH), 9.84 (bs, 1H, OH), 9.62 (bs, 1H, OH),
7.82 (s, 1H, ]CHe), 7.71 (dd, 3JH,H ¼ 7.7, 4JH,H ¼ 1.4 Hz, 1H, ArH), 7.57
(ddd, 3JH,H ¼ 8.7, 7.5, 4JH,H ¼ 1.6 Hz, 1H, ArH), 7.40 (d, 3JH,H ¼ 8.4, 1H,
ArH), 7.39 (s, 1H, ArH), 7.35 (dt, 3JH,H ¼ 7.6, 4JH,H ¼ 1.0, 1H, ArH), 6.76
4.2.1.6. 2-(6-Bromo-2-oxo-2H-chromen-3-yl)benzoic
acid
(3f).
From reaction of homophthalic anhydride (1a) (0.86 g, 5.30 mmol),
5-bromo-2-methoxybenzaldehyde (2f) (1.140 g, 5.30 mmol), 4-
dimethylaminopyridine (0.60 g, 5.30 mmol), boron tribromide
(30.0 mL, 47.72 mmol) in 20 mL dichloromethane. Yield: 1.46 g
(80%), white solid, mp 259e260 ꢃC; 1H NMR (600.13 MHz, DMSO-
(s, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
160.0 (COlactone), 152.9, 149.0, 145.1, 137.5, 131.1, 130.9, 128.8, 128.2,
d
¼ 167.4 (COCOOH),
124.5,121.6,119.7,118.1,117.6,116.0; IR (Nujol)
n
¼ 3550e2400 (OH),
1670 (C]O) cmꢄ1; MS (EI) m/z: 341.3(20), 340.2(100), 325.2(5),
312.2 (13), 309.2(50), 281.2(45), 265.2(20), 253.2(8), 237.2(11),
195.1(7), 139.1(10), 69.4(5); HRMS (EI): m/z calculate: 340.09469,
found: 340.09435 for C19H16O6.
d6),
d
¼ 12.97 (bs, 1H, COOH), 8.00 (d, 4JH,H ¼ 2.4 Hz, 1H, ArH), 7.96
(s, 1H, ]CHe), 7.95 (dd, 3JH,H ¼ 7.7, 4JH,H ¼ 1.2 Hz, 1H, ArH), 7.77 (dd,
3JH,H ¼ 8.8, JH,H ¼ 2.4 Hz, 1H, ArH), 7.69 (dt, JH,H ¼ 7.5,
4JH,H ¼ 1.4 Hz, 1H, ArH), 7.58 (dt, 3JH,H ¼ 7.6, 4JH,H ¼ 1.3 Hz, 1H, ArH),
7.47 (dd, 3JH,H ¼ 7.6, 4JH,H ¼ 1.1 Hz, 1H, ArH), 7.44 (d, 3JH,H ¼ 8.8, 1H,
4
3
4.2.1.10. 4,5-Dihydroxy-2-(6-hydroxy-2-oxo-2H-chromen-3-yl)ben-
zoic acid (3j). From reaction of 6,7-dimetoxihomophthalic anhy-
dride (1b) (1.14 g, 5.15 mmol), 2,5-dimethoxybenzaldehyde (2d)
(0.86 g, 5.15 mmol), 4-dimethylaminopyridine (0.63 g, 5.15 mmol),
boron tribromide (35.4 mL, 56.65 mmol) in 20 mL dichloro-
methane. Yield: 1.25 g (77%), beige solid, mp 212e213 ꢃC; 1H NMR
ArH); 13C NMR (150.92 MHz, DMSO-d6)
d
¼ 167.7 (COCOOH), 159.4
(COlactone), 152.0, 137.2, 135.7, 133.8, 132.4, 131.4, 131.2, 130.9, 130.4,
129.9, 129.1, 121.4, 118.4, 116.2; IR (Nujol)
n
¼ 1730, 1680 (C]O)
cmꢄ1; MS (EI) m/z: 361.0(18), 360.0(96), 359.0(22), 358.0(100),
330.0(38), 329.0(64), 328.0(34), 327.0(66), 302.0(250), 301.0(63),
300.0(58), 299.0(98), 298.0(44), 220.0(28), 192.0(12), 164.0(14),
(600.13 MHz, DMSO-d6),
d
¼ 12.29 (bs, 1H, COOH), 9.81 (bs, 1H, OH),
163.0(28); HRMS (EI): m/z calculate: 357.98407, found: 357.98473
9.69 (bs, 1H, OH), 9.56 (bs, 1H, OH), 7.73 (s, 1H, ]CHe), 7.37 (s, 1H,
79
for C
H BrO4.
ArH), 7.23 (d, 3JH,H ¼ 8.9, 1H, ArH), 7.03 (d, 4JH,H ¼ 2.9, 1H, ArH), 6.98
17 11
3
4
(dd, JH,H ¼ 8.9, JH,H ¼ 2.9, 1H, ArH), 6.73 (s, 1H, ArH); 13C NMR
4.2.1.7. 2-(6,7-Dihydroxy-2-oxo-2H-chromen-3-yl)benzoic acid (3g).
From reaction of homophthalic anhydride (1a) (0.91 g, 5.58 mmol),
2,4,5-trimethoxybenzaldehyde (2g) (1.09 g, 5.58 mmol), 4-
dimethylaminopyridine (0.68 g, 5.58 mmol), boron tribromide
(35.0 mL, 55.81 mmol) in 20 mL dichloromethane. Yield: 1.20 g
(72%), beige solid, mp 290e291 ꢃC; 1H NMR (600.13 MHz, DMSO-
(150.92 MHz, DMSO-d6)
d
¼ 167.4 (COCOOH), 160.2 (COlactone), 153.8,
148.9, 146.2, 145.0, 137.4, 130.9, 128.9, 121.6, 120.2, 118.8, 118.1, 117.6,
116.8, 112.3; IR (Nujol)
n
¼ 3550e2400 (OH), 1700, 1670 (C]O)
cmꢄ1; MS (EI) m/z: 371.2(25), 370.2(100), 339.2(40), 338.2(55),
323.1(39), 211.2(35), 295.2(25), 267.1(22), 239.2(7), 225.1(7); HRMS
(EI): m/z calculate: 370.10525, found: 370.10483 for C20H18O7.
d6),
d
¼ 12.74 (bs, 1H, COOH), 10.19 (bs, 1H, OH), 9.44 (bs, 1H, OH),
7.87 (dd, 3JH,H ¼ 7.8, 4JH,H ¼ 1.2 Hz,1H, ArH), 7.83 (s,1H, ]CHe), 7.63
4.2.1.11. 4,5-Dihydroxy-2-(5-hydroxy-2-oxo-2H-chromen-3-yl)ben-
zoic acid (3k). From reaction of 6,7-dimetoxihomophthalic anhy-
dride (1b) (0.67 g, 3.01 mmol), 2,6-dimethoxybenzaldehyde (2e)
3
4
3
(dt, JH,H ¼ 7.5, JH,H ¼ 1.4 Hz, 1H, ArH), 7.50 (dt, JH,H ¼ 7.6,
4JH,H ¼ 1.3 Hz, 1H, ArH), 7.43 (dd, 3JH,H ¼ 7.6, 4JH,H ¼ 1.0 Hz, 1H, ArH),

204
I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
(0.50 g, 3.01 mmol), 4-dimethylaminopyridine (0.37 g, 3.01 mmol),
boron tribromide (20.7 mL, 33.11 mmol) in 10 mL dichloromethane.
4.2.1.15. 2-(6,7-Dihydroxy-2-oxo-2H-chromen-3-yl)-4,5-
dihydroxybenzoic acid (3o). From reaction of 6,7-
Yield: 0.42
g
(44%), pink solid, mp 278e279 ꢃC; 1H NMR
dimetoxihomophthalic anhydride (1b) (1.06 g, 4.78 mmol), 2,4,5-
trimethoxybenzaldehyde (2g) (0.94 g, 4.78 mmol), 4-
dimethylaminopyridine (0.58 g, 4.78 mmol), boron tribromide
(36.0 mL, 57.36 mmol) in 20 mL dichloromethane. Yield: 0.87 g
(55%), yellow solid, mp 290e291 ꢃC; 1H NMR (600.13 MHz, DMSO-
(600.13 MHz, DMSO-d6),
d
¼ 12.29 (bs, 1H, COOH), 10.70 (bs, 1H,
OH), 9.82 (bs, 1H, OH), 9.54 (bs, 1H, OH), 7.74 (s, 1H, ]CHe), 7.37 (s,
1H, ArH), 7.36 (t, 3JH,H ¼ 8.2, 1H, ArH), 6.82 (d, 3JH,H ¼ 8.3, 1H, ArH),
6.76 (dd, 3JH,H ¼ 8.2, 4JH,H ¼ 0.7, 1H, ArH), 6.74 (s, 1H, ArH); 13C NMR
(150.92 MHz, DMSO-d6)
d
¼ 167.4 (COCOOH), 160.0 (COlactone), 154.6,
d6),
d
¼ 12.20 (bs, 1H, COOH), 10.10 (bs, 1H, OH), 9.75 (bs, 1H, OH),
154.0, 148.9, 145.0, 132.2, 131.7, 129.0, 128.5, 121.6, 118.1, 117.6, 110.0,
9.49 (bs, 1H, OH), 9.36 (bs, 1H, OH), 7.67 (s, 1H, ]CHe), 7.34 (s, 1H,
108.9, 106.4; IR (Nujol)
n
¼ 3600e2400 (OH), 1695, 1680 (C]O)
ArH), 7.00 (s, 1H, ArH), 6.74 (s, 1H, ArH), 6.69 (s, 1H, ArH); 13C NMR
cmꢄ1; MS (EI) m/z: 371.3(20), 370.2(100), 342.2(21), 339.2 (40),
327.2(10), 211.2(40), 295.2(20), 267.1(10), 253.1(10), 225.1(13),
210.1(7). 139.0(7), 126(9), 58.9(8); HRMS (EI): m/z calculate:
370.10525, found: 370.10476 for C20H18O7.
(150.92 MHz, DMSO-d6)
148.8, 147.7, 144.7, 142.9, 138.2, 129.3, 126.4, 121.8, 118.2, 117.6, 112.3,
d
¼ 167.5 (COCOOH), 160.7 (COlactone), 149.5,
111.6, 102.4; IR (Nujol)
n
¼ 3550e2400 (OH), 1670 (C]O) cmꢄ1; MS
(EI) m/z: 401.3(22), 400.3(100), 385.2(12), 369.3(30), 353.2(20),
341.2(15), 325.2(12), 297.2(15); HRMS (EI): m/z calculate:
400.11582, found: 400.11526 for C21H20O8.
4.2.1.12. 4,5-Dihydroxy-2-(8-hydroxy-2-oxo-2H-chromen-3-yl)ben-
zoic acid (3l). From reaction of 6,7-dimetoxihomophthalic anhy-
dride (1b) (1.14 g, 5.15 mmol), 2,3-dimethoxybenzaldehyde (2b)
(0.86 g, 5.15 mmol), 4-dimethylaminopyridine (0.63 g, 5.15 mmol),
boron tribromide (35.4 mL, 56.65 mmol) in 20 mL dichloro-
methane. Yield: 1.14 g (70%), pink solid, mp 313e314 ꢃC; 1H NMR
4.2.1.16. 2-(7,8-Dihydroxy-2-oxo-2H-chromen-3-yl)-4,5-
dihydroxybenzoic
acid
(3p). From
reaction
of
6,7-
dimetoxihomophthalic anhydride (1b) (1.06 g, 4.78 mmol), 2,3,4-
trimethoxybenzaldehyde (2h) (0.94 g, 4.78 mmol), 4-
dimethylaminopyridine (0.58 g, 4.78 mmol), boron tribromide
(36.0 mL, 57.36 mmol) in 20 mL dichloromethane. Yield: 1.14 g
(72%), beige solid, mp 290e291 ꢃC; 1H NMR (600.13 MHz, DMSO-
(600.13 MHz, DMSO-d6),
d
¼ 12.25 (bs, 1H, COOH), 10.15 (bs, 1H,
OH), 9.81 (bs, 1H, OH), 9.56 (bs, 1H, OH), 7.74 (s, 1H, ]CHe), 7.39 (s,
1H, ArH), 7.21e6.98 (m, 3H, ArH), 6.75 (s, 1H, ArH); 13C NMR
(150.92 MHz, DMSO-d6)
d
¼ 167.4 (COCOOH), 159.9(COlactone), 149.0,
d6),
d
¼ 12.23 (bs, 1H, COOH), 10.01 (bs, 1H, OH), 9.78 (bs, 1H, OH),
145.0, 144.4, 141.5, 137.9, 130.7, 128.9, 124.4, 121.6, 120.6, 118.2, 118.1,
9.50 (bs, 1H, OH), 9.35 (bs, 1H, OH), 7.65 (s, 1H, ]CHe), 7.36 (s, 1H,
¼ 3600e2400 (OH), 1680 (C]O) cmꢄ1; MS
ArH), 7.01 (d, 3JH,H ¼ 8.5, 1H, ArH), 6.79 (d, 3JH,H ¼ 8.5, 1H, ArH), 6.71
117.7, 117.5; IR (Nujol)
n
(s, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
d
¼ 167.5 (COCOOH),
(EI) m/z: 371.2(20), 370.1(100), 338.1(27), 323.1 (25), 311.1(37),
295.1(20), 283.1(10), 267.1(15), 225.1(13), 226.0(10), 58.9(8); HRMS
(EI): m/z calculate: 370.10525, found: 370.10486 for C20H18O7.
160.3 (COlactone), 148.9, 148.8, 144.7, 143.0, 138.7, 132.0, 129.3, 126.1,
121.7,118.5,118.2,117.6,112.7,112.5; IR (Nujol)
n
¼ 3550e2400 (OH),
1685, 1650 (C]O) cmꢄ1; MS (EI) m/z: 401.3(22), 400.1(100),
369.2(30), 357.2(17), 341.2(20), 325.1(13), 309.1(10); HRMS (EI): m/
z calculate: 400.11582, found: 400.11538 for C21H20O8.
4.2.1.13. 4,5-Dihydroxy-2-(7-hydroxy-2-oxo-2H-chromen-3-yl)ben-
zoic acid (3m). From reaction of 6,7-dimetoxihomophthalic anhy-
dride (1b) (1.14 g, 5.15 mmol), 2,4-dimethoxybenzaldehyde (2c)
(0.86 g, 5.15 mmol), 4-dimethylaminopyridine (0.63 g, 5.15 mmol),
boron tribromide (35.4 mL, 56.65 mmol) in 20 mL dichloro-
methane. Yield: 1.05 g (65%), pink solid, mp 266e268 ꢃC; 1H NMR
4.2.1.17. (E)-2-(1-carboxy-2-(2-hydroxyphenyl)vinyl)-4,5-
dihydroxybenzoic
acid
(E-4a). From
reaction
of
6,7-
dimetoxihomophthalic anhydride (1b) (1.24 g, 5.58 mmol), 2-
methoxybenzaldehyde (2a) (0.76 g, 5.58 mmol), 4-
dimethylaminopyridine (0.68 g, 5.58 mmol), boron tribromide
(35.0 mL, 55.81 mmol) in 20 mL dichloromethane. Yield: 0.71 g
(40%), yellow solid, mp 214e216 ꢃC; 1H NMR (600.13 MHz, DMSO-
(600.13 MHz, DMSO-d6),
d
¼ 12.22 (bs, 1H, COOH), 10.44 (bs, 1H,
OH), 9.75 (bs, 1H, OH), 9.49 (bs, 1H, OH), 7.70 (s, 1H, ]CHe), 7.52 (d,
3JH,H ¼ 8.5, 1H, ArH), 7.39 (s, 1H, ArH), 6.79 (dd, JH,H ¼ 8.4,
3
4JH,H ¼ 2.2, 1H, ArH), 6.74 (s, 2H, ArH); 13C NMR (150.92 MHz,
DMSO-d6)
d
¼ 167.6 (COCOOH), 160.6 (COlactone), 160.5, 154.7, 148.9,
d6),
d
¼ 11.69 (bs, 2H, COOH), 9.70 (bs, 1H, OH), 9.38 (bs, 1H, OH),
144.8, 138.2, 129.4, 129.2, 126.4, 121.8, 118.2, 117.7, 113.1, 112.1, 102.0;
IR (Nujol)
371.2(20), 370.1(100), 342.1(13), 339.1(35), 327.1(13), 311.2(35),
311.1(20), 295.1(15); HRMS (EI): m/z calculate: 370.10525, found:
370.10473 for C20H18O7.
¼ 3550e2400 (OH), 1680 (C]O) cmꢄ1; MS (EI) m/z:
9.09 (bs, 1H, OH), 7.80 (s, 1H, ]CHe), 7.43 (s, 1H, ArH), 7.03e6.98
n
3
3
(m, 1H, ArH), 6.82 (d, JH,H ¼ 7.7, 1H, ArH), 6.54 (dd, JH,H ¼ 7.9,
4JH,H ¼ 1.4, 1H, ArH), 6.46 (q, 3JH,H ¼ 7.5, 1H, ArH), 6.31 (s, 1H, ArH);
13C NMR (150.92 MHz, DMSO-d6)
d
¼ 168.2 (COCOOH), 167.1
(COCOOH), 156.3, 148.9, 144.0, 133.4, 131.1, 130.3, 129.4, 129.3, 123.1,
121.6, 118.3, 117.9, 117.7, 115.4; IR (Nujol)
¼ 3550e2400 (OH), 1670
(C]O) cmꢄ1
HRMS (EI): m/z calculate: 386,13655, found:
n
4.2.1.14. 2-(6-Bromo-2-oxo-2H-chromen-3-yl)-4,5-dihydroxybenzoic
acid (3n). From reaction of 6,7-dimetoxihomophthalic anhydride
(1b) (1.02 g, 4.57 mmol), 5-bromo-2-methoxybenzaldehyde (2f)
(0.98 g, 4.57 mmol), 4-dimethylaminopyridine (0.56 g, 4.57 mmol),
boron tribromide (28.6 mL, 4.57 mmol) in 20 mL dichloromethane.
Yield: 0.75 g (44%), white solid, mp 269e270 ꢃC; 1H NMR
;
386,13592 for C21H22O7.
4.2.2. Isolation of intermediates E-4b and cis-/trans-6
Compounds E-4b and cis-/trans-6 were isolated from reaction of
6,7-dimetoxihomophthalic anhydride (1b) (1.14 g, 5.15 mmol), 2,3-
dimethoxybenzaldehyde (2b) (0.86 g, 5.15 mmol), 4-
dimethylaminopyridine (0.63 g, 5.15 mmol) and boron tribromide
(35 mL, 56.65 mmol) in 20 mL dichloromethane, stirred for 30 min
and worked up as described in 4.2.1. After isolation of the corre-
sponding coumarin 3l, the residue was immediately subjected to
separation by means of column chromatography (Mobile phase:
49% acetone/50% cyclohexane/1% HCOOH). Compound 6 was iso-
lated as yellow foam (yield: 0.53 g (17%)), and as diastereomeric
mixture of the corresponding cis-/trans- isomers in a ratio 15/85
(1H NMR) [56,57].
(600.13 MHz, DMSO-d6),
d
¼ 12.38 (bs, 1H, COOH), 9.89 (bs, 1H, OH),
9.63 (bs, 1H, OH), 7.97 (d, 4JH,H ¼ 2.4, 1H, ArH), 7.78 (s, 1H, ]CHe),
7.72 (dd, 3JH,H ¼ 8.8, 4JH,H ¼ 2.4, 1H, ArH), 7.04 (s, 1H, ArH), 7.39 (d,
3JH,H ¼ 8.8, 1H, ArH), 6.75 (s, 1H, ArH); 13C NMR (150.92 MHz,
DMSO-d6)
d
¼ 167.3 (COCOOH), 159.5 (COlactone), 151.9, 149.0, 145.3,
136.1, 133.4, 132.0, 130.2, 128.4, 121.6, 121.5, 118.3, 118.0, 117.7, 116.1;
IR (Nujol)
n
¼ 3550e2400 (OH), 1690, 1670 (C]O) cmꢄ1; MS (EI) m/
z: 421.1(23), 420.0(99), 419.0(24), 418.0(100), 390.0(16), 389.0(32),
388.0(21), 387.0(33), 361.0(36), 359(36), 354.0(17), 339.0(17);
HRMS (EI): m/z calculate: 418.00520, found: 418.00469 for
79
C
H BrO6.
19 15

I. Svinyarov, M.G. Bogdanov / European Journal of Medicinal Chemistry 78 (2014) 198e206
205
4.2.2.1. (E)-2-(1-carboxy-2-(2,3-dihydroxyphenyl)vinyl)-4,5-
dihydroxybenzoic acid (E-4b). Yield: 0.53 g (31%), beige solid, mp
University Fund (project 029/2013) is greatly acknowledged by the
authors. The authors are also thankful to Mrs. Silviya Stoykova for
performing MS analyses.
228e230 ꢃC; 1H NMR (600.13 MHz, DMSO-d6),
d
¼ 12.07 (bs, 2H,
COOH), 9.55 (bs, 1H, OH), 9.43 (bs, 1H, OH), 9.25 (bs, 1H, OH), 8.75
(bs, 1H, OH), 7.80 (s, 1H, ]CHe), 7.41 (s, 1H, ArH), 6.61 (d,
1H, 3JH,H ¼ 7.4, ArH), 6.32 (s, 1H, ArH), 6.29 (t, 3JH,H ¼ 7.9, 1H, ArH),
Appendix A. Supplementary data
3
5.98 (d, JH,H ¼ 7.8, 1H, ArH); 13C NMR (150.92 MHz, DMSO-d6)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.03.053.
d
¼ 168.6 (COCOOH), 167.3 (COCOOH), 149.1, 145.2, 145.0, 144.2, 133.4,
131.5, 130.8, 122.9, 121.5, 120.1, 118.3, 118.0, 117.9, 115.2; IR (Nujol)
n
¼ 3550e2400 (OH), 1670 (C]O) cmꢄ1
.
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.
ꢁ
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