Functionalized 4-hydroxy coumarins: Novel synthesis, crystal structure and DFT calculations

Article abstract of DOI:10.3390/molecules16010384

A novel short-step methodology for the synthesis in good yields of functionalized coumarins has been developed starting from an activated precursor, the N-hydroxysuccinimide ester of O-acetylsalicylic acid. The procedure is based on a tandem C-acylation-c

Full text of DOI:10.3390/molecules16010384

Molecules 2011, 16, 384-402; doi:10.3390/molecules16010384
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Functionalized 4-Hydroxy Coumarins: Novel Synthesis, Crystal
Structure and DFT Calculations
Valentina Stefanou 1,2, Dimitris Matiadis 2, Georgia Melagraki 2, Antreas Afantitis 2,
Giorgos Athanasellis 2, Olga Igglessi-Markopoulou 2, Vickie McKee 3 and John Markopoulos 1,*
1
Laboratory of Inorganic Chemistry, Department of Chemistry, University of Athens, Panepistimio-
polis, Athens 15771, Greece; E-Mail: stef-valentin@windowslive.com (V.S.)
2
Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University
of Athens, Zografou Campus, Athens 15773, Greece; E-Mails: dmatiadis@yahoo.gr (D.M.);
georgiamelagraki@gmail.com (G.M.); afantitis@novamechanics.com (A.A.);
g_athanasellis@yahoo.com (G.A.); ojmark@chemeng.ntua.gr (O.I.-M.)
3
Chemistry Department, University of Loughborough, Leicestershire, LE113TU, UK;
E-Mail: v.mckee@lboro.ac.uk (V.M.)
* Author to whom correspondence should be addressed; E-Mail: jmmarko@chem.uoa.gr;
Tel.: +30-210-7274450; Fax: +30-210-7723072.
Received: 22 November 2010; in revised form: 20 December 2010 / Accepted: 27 December 2010 /
Published: 7 January 2011
Abstract: A novel short-step methodology for the synthesis in good yields of
functionalized coumarins has been developed starting from an activated precursor, the
N-hydroxysuccinimide ester of O-acetylsalicylic acid. The procedure is based on a tandem
C-acylation-cyclization process under mild reaction conditions. The structure of
3-methoxycarbonyl-4-hydroxy coumarin has been established by X-ray diffraction analysis
and its geometry was compared with optimized parameters by means of DFT calculations.
Keywords: coumarins; N-hydrocysuccinimide ester; C-acylation; β,β΄-dicarbonyl system;
cyclization; DFT

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Molecules 2011, 16
1. Introduction
The 4-hydroxy-3-substituted coumarin moiety (Figure 1) is a common fused heterocyclic nucleus
found in many natural products of medicinal importance. Several of these natural products exhibit
exceptional biological and pharmacological activities such as antibiotic, antiviral, anti-HIV,
anticoagulant and cytotoxicity properties [1-8]. Additionally, coumarin derivatives have been used as
food additives, perfumes, cosmetics, dyes and herbicides [9,10]. Recently, Supuran et al. reported that
coumarin derivatives constituted a totally new class of inhibitors of the zinc metalloenzyme carbonic
anhydrase [11]. Additionally, two new series of 4-hydroxycoumarin analogues have been synthesized
as inhibitors of the enzyme of human NAD(P)H quinine oxidoreductase-1 (NQO1), which is expressed
in several types of tumor cells [12,13]. A series of coumarins bearing different groups on the aromatic
ring were synthesized and tested as caspase activators and apoptosis inducers [14], showing that these
compounds can be used to induce cell death in a variety of conditions in which uncontrolled growth
and spread of abnormal cells occurs.
Figure 1. 4-Hydroxy-3-substituted coumarins.
OH
Y
O
O
Moreover, coumarin dyes have attracted much interest owing to their application in organic
light-emitting diodes (OLEDs). As a result of showing a wide range of size, shape and hydrophobicity,
coumarins are used as sensitive fluorescent probes of systems including homogeneous solvents and
mixtures and heterogeneous materials [15]. In addition, they form host-guest inclusion complexes with
cage-like molecules such as cyclodextrins [16] and cucurbiturils [17].
The interest in the biological activity of 4-hydroxycoumarins continues nowadays, with warfarin
and acenocoumarol being two of these derivatives which have been marketed as drugs [18,19].
Warfarin has been the mainstay of anticoagulation therapy worldwide for over 20 years, therefore a
series of similar derivatives have been synthesized and tested as anticoagulant agents [20,21].
Acenocoumarol acts in the same way, therefore several 4-hydroxy coumarin derivatives have been
synthesized and their pharmacological activity was tested [22-26].
A number of 4-hydroxy coumarins have been isolated from Ferula sp. The first ones were the toxic
3-fernesyl coumarin [27] and ferulenol [28] from Ferula communis. Many ferulenol derivatives
followed [29-33] and the most recent ones are ε-hydroxy ferulenol (I) and ferulenoxyferulenol (II)
(Figure 2). On the other hand, a number of sesquiterpenecoumarins have been isolated from Ferulla
pallid [34]. Two new compounds (Figure 3) were isolated and their biosynthetic pathway was
studied [35]. The synthesis of many compounds containing the 4-hydroxycoumarin nucleus showing
antibacterial, insecticidal and activity against helminths has been reported [36]. A review article has
been presented concerning the anti-HIV1 protease inhibition of a number of 4-hydroxycoumarins

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Molecules 2011, 16
concluding that this inhibition is strongly dependent to the group attached at position 3 of the coumarin
nucleus [37].
Figure 2. ε-Hydroxy ferulenol (I) and ferulenoxyferulenol (II).
Me
OH
Me
Me
Me
HO
O
O
I
Me
OH
Me
Me
Me
O
O
O
CH2
OH
Me
Me
Me
O
O
II
Figure 3. Sesquiterpenecoumarins.
Coumarins and coumarin analogues have attracted the attention of many synthetic chemists since
the late 1800s. Methods for their synthesis have been presented in the literature. Methodologies such
as the Pechmann [38], Suzuki [8], Wittig [39] and Knoevenagel [40] condensation are well known. In
addition, there have been reports for their synthesis using epoxides [41-43] or arylcarbamides as
starting materials [44] or finally by intramolecular nucleophilic attack of β-ketoesters [45]. In this
paper we used suitably functionalized salicylic acids as starting materials, as it has been reported in the
literature [46,47].
2. Results and Discussion
As part of our program studying the chemistry of fused heterocyclic systems with specific
functional groups [47-51] we wish to report herein an extended methodology for the synthesis of

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Molecules 2011, 16
3-functionalized-4-hydroxycoumarin-2-ones, applying as alternative and ultimate scaffold, the
N-hydroxysuccinimide ester of O-acetylsalicylic acid, for the “coupling reaction” with an active
methylene compound. The chemistry proceeds via a tandem intermolecular nucleophilic coupling of
the N-hydroxysuccinimide ester of O-acetylsalicylic acid 2 with an active methylene compound, and
the subsequent intramolecular cyclization of the intermediate 3a-d to a stable six-membered ring
system, the coumarin nucleus 4a-d, as shown in Scheme 1.
Scheme 1. Synthesis of 3-functionalized-4-hydroxycoumarin-2-ones.
O
O
OH
O
OH
OSu
ii
R2
i
O
O
COOR1
OAc
OAc
OAc
R2
OR1
1
2
R1 = Me, Et
R2 = OMe, OEt, Ph
3a-c
O
ii
iii
CN
EtO
OH
O
OH
O
R2
OEt
CN
OAc
O
O
3d
iv
4a-c
OH
CN
O
O
4d
Reagents and conditions: (i) DCC, NHS, THF, r.t; (ii) NaH, THF, 0 °C → r.t.; (iii) NaOEt,
EtOH, r.t.; (iv) HCl 10%, MeOH, r.t.
This approach would provide an alternative general method for the synthesis of coumarins and
other similar organic molecules containing the benzopyranone ring system. The proposed protocol
involves the following steps: a) the deprotonation of an active methylene compound; b) the
nucleophilic attack at the carbonyl of the N-hydroxysuccinimide ester; c) the in situ intramolecular
cyclization of the “intermediate” precursor affording the functionalized heterocycles bearing
the coumarin nucleus. The key control element of this approach is the utilization of the
N-hydroxy-succinimide ester of O-acetylsalicylic acid 2. This acylating agent was synthesized by
condensation of equimolar amounts of O-acetyl-protected salicylic acid 1 and N-hydroxysuccinimide
(NHS) in the presence of 1.2 equiv. of dicyclohexylcarbodiimide (DCC) in anhydrous tetrahydrofuran
at 0 °C. This excellent activating synthon 2 was isolated in good yields as a white solid and was used
in the next step without further purification. The C-acylation protocol involved the reaction of 2 equiv.
of an active methylene compound with 2 equiv. of sodium hydride in anhydrous tetrahydrofuran at

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Molecules 2011, 16
0 °C. After 1 hour of continuous stirring, 1 equiv. of the N-hydroxysuccinimide ester 2 was added and
the mixture was stirred for 2 hours, at room temperature. In consequence, the solvent was removed
under reduced pressure, the gummy solid was diluted with water, washed with diethyl ether and the
aqueous layer was acidified with aq. solution of hydrochloric acid 10%, to give after extraction with
dichloromethane, the intermediates 3a-d as oily products. Cyclization of these C-acylation compounds
was affected by refluxing them with two-fold excess amount of sodium ethoxide in ethanol for 24 h or
by mixing them with aq. solution of hydrochloric acid 10% in methanol for 48 h at room temperature.
Several features of the proposed methodology make it synthetically useful: the starting materials are
inexpensive and stable; the yields are good; the reactions are relatively rapid and proceed at ambient
temperature or under mild and easily controlled conditions. Furthermore, the methodology can be
expanded to other heterocyclic systems bearing different heteroatoms or functions on the heterocyclic
and/or aromatic ring.
2.1. X-ray Crystallographic Analysis
The crystal of this compound belongs to the monocyclic space group P2(1)/c. The data were
collected at 150(2) K on a Bruker Apex II CCD diffractometer using MoKα radiation (λ = 0.71073 Å).
The structure was solved by direct methods and refined on F2 using all the reflections [52]. Parameters
for data collection and refinement are summarized in Table 1.
Table 1. Crystal data and structure refinement for 4-hydroxy-3-methoxycarbonyl coumarin.
Empirical formula
Formula weight
Temperature
C11H8O5
220.17
150(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Monoclinic
P2(1)/c
Unit cell dimensions
a = 3.802(3) Å
b = 21.945(15) Å; β= 90.097(10)°.
c = 11.352(8) Å
947.1(11) Å3
Volume
Z
4
Density (calculated)
Absorption coefficient
F(000)
1.544 Mg/m3
0.124 mm−1
456
Crystal size
0.44 × 0.10 × 0.07 mm3
colourless block
0.93 to 25.00°.
−4 ≤ h ≤ 4, −25 ≤ k ≤ 26, −13 ≤ l ≤ 13
7326
Crystal description
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 25.00°
Absorption correction
Max. and min. transmission
1686 [Rint = 0.0758]
100.0%
Semi-empirical from equivalents
0.9914 and 0.9474

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Table 1. Cont.
Refinement method
Full-matrix least-squares on F2
Data / restraints / parameters
Goodness-of-fit on F2
1686 / 0 / 149
1.028
Final R indices [I > 2sigma(I)]
R indices (all data)
R1 = 0.0662, wR2 = 0.1633
R1 = 0.0984, wR2 = 0.1897
0.348 and -0.399 × 10−3 Å
Largest diff. peak and hole
Crystallographic data of 4-hydroxy-3-methoxycarbonyl- coumarin 4a and selected bond lengths and
angles are given in Tables 2 and 3. The crystal structure and packing diagram of this compound are
given in Figures 4 and 5 respectively.
The structure resembles that of tautomer a (Scheme 2) with a double bond character in C(8)-C(9)
(1.37 Å) (Figure 4) and the bond C(8)-O(3) distinctly longer than the conventional carbonyl distance
for C(1)-O(1) (1.31 Å and 1.19 Å respectively). The molecules show π-π stacking principally with a
planar distance of 3.9 Å. Figure 5 shows this weak intermolecular π-π stacking interactions between
molecules in crystal lattice.
Figure 4. X-ray structure and numbering scheme of compound 4a.
Figure 5. Packing diagram of 4-hydroxy-3-methoxycarbonyl coumarin 4a.

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Table 2. Bond lengths [Å] and angles [°] for 3-methoxy-4-hydroxy coumarin.
C(1)-O(1)
1.199(4)
1.378(5)
1.450(5)
1.371(5)
1.374(6)
1.384(6)
1.376(6)
1.387(6)
1.372(6)
1.398(6)
1.435(6)
1.310(5)
1.375(5)
1.457(6)
1.232(5)
1.317(5)
1.441(5)
115.0(3)
127.8(4)
117.2(3)
122.4(3)
O(2)-C(2)-C(3)
O(2)-C(2)-C(7)
C(3)-C(2)-C(7)
C(2)-C(3)-C(4)
C(3)-C(4)-C(5)
C(6)-C(5)-C(4)
C(5)-C(6)-C(7)
C(2)-C(7)-C(6)
C(2)-C(7)-C(8)
C(6)-C(7)-C(8)
O(3)-C(8)-C(9)
O(3)-C(8)-C(7)
C(9)-C(8)-C(7)
C(8)-C(9)-C(1)
C(8)-C(9)-C(10)
C(1)-C(9)-C(10)
O(4)-C(10)-O(5)
O(4)-C(10)-C(9)
O(5)-C(10)-C(9)
C(10)-O(5)-C(11)
116.7(4)
121.9(4)
121.4(4)
118.9(4)
120.6(4)
120.5(4)
119.3(4)
119.3(4)
117.3(3)
123.4(4)
123.3(4)
115.6(3)
121.1(3)
120.0(3)
118.3(3)
121.7(3)
121.8(4)
121.9(4)
116.3(3)
116.4(3)
C(1)-O(2)
C(1)-C(9)
O(2)-C(2)
C(2)-C(3)
C(2)-C(7)
C(3)-C(4)
C(4)-C(5)
C(5)-C(6)
C(6)-C(7)
C(7)-C(8)
C(8)-O(3)
C(8)-C(9)
C(9)-C(10)
C(10)-O(4)
C(10)-O(5)
O(5)-C(11)
O(1)-C(1)-O(2)
O(1)-C(1)-C(9)
O(2)-C(1)-C(9)
C(2)-O(2)-C(1)
Table 3. Hydrogen bonds for 4-hydroxy-3-methoxycarbonyl coumarin [Å and °].
D-H...A
d(D-H)
0.84
d(H...A)
1.77
D(D...A)
2.512(4)
<(DHA)
146.6
O(3)-H(3A)...O(4)
2.2. Quantum Chemical Calculations
The structure of 3-substituted-4-hydroxy coumarin consists of a benzene ring fused with a pyrone
ring. The carbonyl group is attached at C-2 position, substitution group in position 3 and hydroxyl
group in position 4. Three major tautomeric forms of 3-substituted-4-hydroxy coumarin can be formed
and are presented in the following scheme (Scheme 2) [53,54].
Various quantum chemical calculations for coumarins have been previously reported in
literature [55-59]. In order to predict the equilibrium molecular geometries of the possible tautomers of
3-methoxycarbonyl-4-hydroxy coumarin we have used the Density Functional Theory (DFT) hybrid
method with the Becke’s three-parameter exchange functional and gradient-corrected functional of
Lee, Yang and Parr (B3LYP) [60-62].
Scheme 2. Tautomeric forms of 3-substituted-4-hydroxy coumarin.

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Molecules 2011, 16
The geometries were fully optimized, with tight convergence criteria (Opt = Tight) using the
following standard basis set: 6–311++G(d,p), valence triple zeta plus diffuse and polarization functions
of d and p type. It is generally recognized that for an accurate description of hydrogen bonds at least
double zeta quality basis augmented with a set of polarization and diffuse functions set is needed.
Therefore a somewhat better geometry description is expected with 6–311++G(d,p) standard basis set.
All geometry optimization were followed by calculations of frequencies in order to identify
obtained structures as energy minima (no imaginary frequencies). All minima for the three tautomeric
forms were verified by establishing that the matrix of energy second derivatives (Hessian) has only
positive eigenvalues (all vibrational frequencies real). HOMO and LUMO frontier orbitals of the
molecule were also computed at the same level of theory. All calculations were carried out with the
Gaussian 09W program [63].
2.3. Computational Studies
DFT calculations have been performed for the tautomers of 3-methoxycarbonyl-4-hydroxy
coumarin. Optimized molecular structures of the most stable tautomers are depicted in Figure 6. Their
calculated energies and relative energies are presented in Table 4.
Figure 6. Optimized structures for the tautomers of 3-methoxycarbonyl-4-hydroxy
coumarin using DFT.
Tautomeric form a.
Tautomeric form b.
Tautomeric form c.
Table 4. Total Energy (a.u.) and relative energy for the four tautomers.
Total Energy (kcal/mol)
502236.25
ΔΕ
0
14.21
14.92
Tautomer a
Tautomer b
Tautomer c
502222.04
502221.33
The optimized structure of compound 4a which expected to be the predominant structure is shown
in Figure 6 (Tautomer a) and it is close to the crystal structure given in the crystallographic analysis.

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Molecules 2011, 16
As listed in Table 2 for selected bond and angles, it was found that the B3LYP/6–311++G(d,p)
optimized structure is in good agreement with the X-ray crystallographic data as listed in Table 5.
Therefore, the results using density functional theory (DFT) B3LYP/6–311++G(d,p) level is
creditable. The average discrepancy of the selected bond lengths between theoretical and experimental
data is less than ±0.02 Å and the average discrepancy of the selected bond angles is less than ±1.1°.
Table 5. Comparison of bond lengths and angles.
Bonds (Å)
C(1)-O(1)
X-ray
1.199
1.310
1.232
1.371
1.317
1.450
1.457
1.375
X-ray
115
DFT
1.198
1.319
1.238
1.356
1.323
1.463
1.469
1.394
DFT
C(8)-O(3)
C(10)-O(4)
O(2)-C(2)
C(10)-O(5)
C(1)-C(9)
C(9)-C(10)
C(8)-C(9)
Angles (°)
O(1)-C(1)-O(2)
C(9)-C(10)-O(5)
C(10)-O(5)-C(11)
115.9
116.3
116.6
116.3
116.3
The predominant tautomer a is coplanar. Major variation in geometry of different tautomeric forms
are at C8-O3, C9-C10, C10-O4, C1-O1, O5-C11, C10-O5 bonds and hydrogen bonds at O1, O3 and
O5 atoms (O1-H, O3-H, O5-H). The remainder of the bonds and angles in the three tautomeric forms
do not change significantly. Bond distances in the three tautomers indicate a more double bond
character or a more single bond character as shown in Figure 6. According to the single-crystal
structure distance shown in Table 2 predominance of tautomer a is confirmed.
Molecular orbital calculations provide a detailed description of orbitals including spatial
characteristics, nodal patterns and individual atom contributions. The contour plots of the frontier
orbitals for the ground state of 3-methoxycarbonyl-4-hydroxy coumarin are shown in Figure 7
including the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular
Orbital (LUMO). It is interesting to see that both orbitals are substantially distributed over the
conjugation plane. The HOMO and LUMO orbitals resemble those obtained for unsubstituted
coumarin and therefore the substitution has only a small impact in the present case [64].
Figure 7. HOMO and LUMO orbitals of 3-methoxycarbonyl-4-hydroxy coumarin.
LUMO
HOMO

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The orbital energy levels of HOMO, second HOMO (HOMO-1), LUMO and second LUMO
(LUMO+1) of 3-methoxy-4-hydroxy coumarin were deduced using the DFT/6–311++G(d,p) method
and are presented in Table 6. It can be seen that HOMO and LUMO energies are −0.25767 eV and
−0.09207 eV respectively. The energy gap between HOMO and LUMO is about 0.1656 eV.
Table 6. Orbital Energies.
Orbital
LUMO+3
LUMO+2
LUMO+1
LUMO
Energy (eV)
−0.01268
−0.01715
−0.03766
−0.09207
−0.25767
−0.27303
−0.28980
−0.30505
HOMO
HOMO-1
HOMO-2
HOMO-3
Table 7. Total Energy and relative energy for the four tautomers after single point
PCM calculations.
Total Energy (kcal/mol)
502251.36
ΔΕ
0
Tautomer a
Tautomer b
Tautomer c
502236.36
15.00
15.28
502236.08
On top of our gas phase geometries we have also performed single-point C-PCM (Conductor like
Polarized Continuum Model) calculations using CH2Cl2 as the solvent. Results for relative energies
and HOMO and LUMO orbitals are presented below in Table 7 and Figure 8 respectively.
Figure 8. HOMO (−0.25988eV) and LUMO (−0.09171eV) orbitals of 3-methoxycarbonyl-
4-hydroxy coumarin after single point PCM calculations.
LUMO
HOMO
3. Experimental
3.1. General
All reagents were purchased from Aldrich, Fluka and Acros and used without further purification.
Dry THF was distilled from Na/Ph2CO. Melting points were determined on a Gallenkamp MFB-595

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melting point apparatus and are uncorrected. IR spectra were recorded on a Jasco 4200 FTIR
spectrometer. NMR spectra were recorded on a Varian Gemini-2000 300 MHz spectrometer operating
at 300 MHz (1H) and 75 MHz (13C). Chemical shifts δ are reported in ppm relative to DMSO-d6
(1H: δ = 2.50, 13C: δ = 39.52) and CDCl3 (1H: δ = 7.26, 13C: δ = 77.16). J values are given in Hz.
3.1.1. General Procedure for the Synthesis of the N-hydroxysuccinimide Ester of O-acetylsalicylic
Acid (2)
O-acetylsalcylic acid (1, 10 mmol, 1.8 g) was treated under argon with N-hydroxysuccininimide
(10 mmol, 1.16 g) in anhydrous THF (11.5 mL), and a solution of DCC (12 mmol, 2.47 g) in
anhydrous THF (8.5 mL) was added dropwise at 0 °C. The reaction mixture was allowed to stir at 0 °C
for 2 h. The resulting suspension was refrigerated overnight at 3-5 °C. The precipitated solid (DCCU)
was filtered off and the filtrate was evaporated under reduced pressure and dried in vacuo to afford the
N-hydroxysuccinimide ester of the corresponding O-acetylsalicylic acid as a white solid. Yield 2.4 g,
1
87%, mp 80 °C (lit. mp 87-89 °C [65]). H-NMR (DMSO-d6): δ 2.28 (s, 3H, COCH3), 2.88 (s, 4H,
COCH2CH2CO), 7.39-7.42 (d, 1H, aromatic protons), 7.54 (pt, 1H, aromatic protons), 7.85 (pt, 1H,
aromatic protons), 8.07-8.11 (d, 1H, aromatic protons).
3.1.2. General Procedure for the Synthesis of 3-Substituted-4-Hydroxycoumarins
Sodium hydride (60% in oil, 20 mmol, 0.8 g) was added in anhydrous THF (65 mL) at 0 °C and the
resulting mixture was stirred under argon for 15 min at room temperature. The appropriate active
methylene compound (ethyl benzoylacetate, diethyl malonate, dimethyl malonate, ethyl cyanoacetate
(20 mmol) was then added at 0 °C, and the resulting mixture was stirred at room temperature for 1h.
The N-hydroxysuccinimide ester of acetylsalicylic acid 2 (10 mmol) was added at 0 °C and the
reaction mixture was stirred at r.t for 2h and then concentrated in vacuo. The obtained gum was diluted
with H2O (10 mL) and washed with Et2O (10 mL). The aqueous extract was acidified with aqueous
HCl (10%) in an ice-water bath to afford an oily product, which was extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated under
reduced pressure and dried in vacuo to give the oily residue, which was treated either with method
A or B.
Method A: The C-acylation compound (10 mmol) was added to a solution of sodium (0.46 g,
20 mmol) in absolute ethanol and stirred at room temperature for 24 h. The solvent was evaporated in
vacuo and the residue was diluted with H2O and washed with Et2O, and the aqueous layer was
acidified with 10% HCl at 0 °C to afford the desired coumarins as solid products.
Method B: The C-acylation compound (10 mmol) was dissolved in MeOH (20 mL) and treated with
aqueous HCl (10%, 20 mL) for 48 h at room temperature to afford a gummy solid which was extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were dried with Na2SO4, concentrated under
reduced pressure and dried in vacuo to afford the desired coumarins as solid products.
4-Hydroxy-3-methoxycarbonylcoumarin (4a): According to method A. White solid (1.41 mg, 64%),
1
mp: 139-140 °C (lit. mp 139-140 °C [47]), IR (KBr) 1730,1640 (C=O), 1615 (C=C) cm−1; H-NMR
(CDCl3): δ 4.02 (s, 3H, COOCH3), 7.30-7.38 (pt and dd, 2H, H-6, H-8), 7.65 (pt J = 8.1 Hz, 1H, H-7),

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13
8.00 (d J = 8.1 Hz, 1H, H-5), 14.55 (s, 1H, OH); C-NMR (CDCl3): δ 53.1 (COOCH3), 93.2 (C-3),
114.6 (C-4a), 117.1 (C-8), 124.4 (C-6), 125.0 (C-5), 135.8 (C-7), 154.5 (C-8a), 157.6 (C-2),
172.5 (C-4), 175.7 (COOCH3).
3-Ethoxycarbonyl-4-hydroxycoumarin (4b): According to method A. White solid (1.23 mg, 53%), mp
1
98.5-100 °C (lit. mp 100-101 °C [47]), IR (KBr) 1730,1638 (C=O), 1616 (C=C) cm−1; H-NMR
(CDCl3): δ 1.43 (t J = 6.9 Hz, 3H, COOCH2CH3), 4.50 (q J = 6.9 Hz, 2H, COOCH2CH3),
7.28-7.36 (pt and dd, 2H, H-6, H-8), 7.67 (pt J = 8.1 Hz, 1H, H-7), 8.00 (dd J = 8.1/1.8 Hz, 1H, H-5),
14.73 (s, 1H, OH); 13C-NMR (CDCl3): δ 14.1 (COOCH2CH3), 62.9 (COOCH2CH3), 93.0 (C-3),
114.5 (C-4a), 116.8 (C-8), 124.2 (C-6), 125.0 (C-5), 135.5 (C-7), 154.2 (C-8a), 157.4 (C-2),
172.0 (C-4), 175.5 (COOCH2CH3).
3-Benzoyl-4-hydroxycoumarin (4c): According to method A. White solid (1.83 mg, 69%),
mp 115-116 °C (lit. mp 116-117 °C [47]), IR (KBr) 1722 (C=O), 1614 (C=C) cm−1; 1H-NMR (CDCl3):
δ 7.30-7.70 (m, 8H, aromatic ring protons), 8.10 (dd J = 7.8/1.2 Hz, 1H, H-5), 16.72 (s, 1H, OH);
13C-NMR (CDCl3): δ 100.5 (C-3), 115.3 (C-4a), 117.4 (C-8), 124.6 (C-6), 125.7 (C-5), 128.1 (C-c),
128.5 (C-b), 132.7 (C-d), 136.3 (C-7), 137.8 (C-a), 155.2 (C-8a), 159.7 (C-2), 178.2 (C-4), 201.0
(COPh).
3-Cyano-4-hydroxycoumarin (4d): According to method B. White solid (0.60 mg, 35%), mp
252-254 °C (lit. mp 250-251 °C [47]), IR (KBr) 2247 (CN), 1717 (C=O), 1602 (C=C) cm−1; 1H-NMR
(DMSO-d6): δ 7.23 (pt, 2H, H-6, H-8), 7.54 (pt J = 8.1 Hz, 1H, H-7), 7.81 (d J = 8.1 Hz, 1H, H-5);
13C-NMR (DMSO-d6): δ 75.0 (C-3), 116.3 (C-4a), 119.1 (C-8), 120.9 (CN), 123.0 (C-5), 124.9 (C-6),
132.6 (C-7), 153.5 (C-8a), 163.1 (C-2), 176.3 (C-4).
3.2. Crystal Structure Determination of 4a
Compound 4a: C11H8O5, monoclinic, P2 (1)/c, α = 3.802(3), b = 21.945(15), c = 11.352(8) A’,
β= 90.097(10)°, V= 947,1(11) A’3, T=150(2) K, λ=0.71073 A’, Z = 4, 7326 reflections measured,
1686 unique (Rint = 0.0758), wR2 = 0.1897 (all data), R1 = 0.0662 (I > 2σ(Ι). Data were collected on a
Bruker APEX II diffractometer. The structure was solved by direct methods and refined on F2 using all
the reflections [60]. All the non-hydrogen atoms were refined using anisotropic atomic displacement
parameters and hydrogen atoms bonded to carbon were inserted at calculated positions using a riding
model. The hydrogen bonded to O3 was located from difference maps and refined with thermal
parameter riding on that of the carrier atom. Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no CCDC 790977.
4. Conclusions
In summary, we have successfully synthesized a range of functionalized 4-hydroxycoumarins using
the N-hydroxysuccinimide ester of acetylsalicylic acid as a new efficient precursor (scaffold). The
structure of 3-methoxy-4-hydroxy coumarin has been determined by single-crystal X-ray diffraction

396
Molecules 2011, 16
and its geometry was compared with optimized parameters obtained by means of Density Functional
Theory calculations at B3LYP/6-311++(d,p) level. A good agreement between theory and X-ray
diffraction was found. The HOMO and LUMO levels and the lowest energy tautomer of
3-methoxy-4-hydroxy coumarin have been studied with DFT at B3LYP/6–311++G(d,p) level. Further
work in the benzopyranone series and the application of N-hydroxysuccinimide methodology towards
the synthesis of more complex substrates with various substituents to explore potential biological
applications will be reported in due course.
Acknowledgements
J. M. would like to thank the National and Kapodistrian University of Athens for financial support
(special account for research grant No. 70/4/3337). D. M. is grateful to the Research Committee of the
National Technical University of Athens for financial support. A. A. wishes to thank the Cyprus
Research Promotion Foundation (Grant 0308/20) for financial support.
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Supporting Information
Table S1. XYZ coordinates for tautomer a.
Center
Atomic
Atomic
Coordinates (Angstroms)
Number Number
Type
0
X
−3.863365
−4.135989
−3.107716
−1.785738
−1.495749
−2.552628
−0.806136
0.568307
0.902676
−0.105367
0.138342
2.292934
3.231744
4.599130
1.315559
2.573797
−4.677724
−5.163665
−3.298328
−2.316874
1.136344
5.197386
4.798717
4.798710
Y
Z
1
6
6
6
6
6
6
8
6
−1.026907
0.349539
1.279694
0.829994
−0.540269
−1.468517
1.767112
1.458477
0.034388
−0.929393
−2.225277
−0.439924
0.492372
0.032938
2.394467
−1.645763
−1.740938
0.694595
2.345344
−2.524743
−2.329785
0.940375
−0.564118
−0.564134
0.000004
0.000006
0.000004
0.000001
−0.000001
0.000001
−0.000002
−0.000005
−0.000002
−0.000003
−0.000005
−0.000002
0.000011
0.000012
−0.000013
−0.000009
0.000006
0.000009
0.000005
0.000000
−0.000006
0.000023
−0.890153
0.890168
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
6
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6
8
6
8
6
8
8
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

401
Molecules 2011, 16
Table S2. XYZ coordinates for tautomer b.
Atomic Atomic Coordinates (Angstroms)
Number Number Type Z
Center
X
−3.618148
−3.998088
−3.047740
−1.709017
−1.304270
−2.281357
−0.810933
0.524803
1.041859
0.131388
0.488894
2.457879
3.172725
3.217744
2.764139
1.214329
−4.368400
−5.042901
−3.318669
−1.954487
2.597225
3.683895
2.043747
2.328808
Y
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6
6
6
6
6
6
8
6
6
6
8
6
8
8
6
8
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
−1.245874 −0.007977
0.078140
1.089629
0.761144
−0.549857 −0.147866
−1.553277 −0.207628
0.245068
0.295254
0.096863
1.805230
0.121572
1.604765 −0.018278
0.251884 −0.085742
−0.866082 −0.340040
−1.980777 −0.710457
0.140135 −0.089479
−0.945992
1.187155 −0.227783
−2.092598 0.836929
2.624762 −0.071247
−2.026310 −0.049685
0.322058
2.122060
−2.565527 −0.411849
1.992583 −0.271100
−2.441204
−1.791336
−2.843394
0.051319
0.399237
0.476953
1.303092
1.597193
0.186302
Table S3. XYZ coordinates for tautomer c.
Atomic Atomic Coordinates (Angstroms)
Center
Number Number
Type
X
Y
Z
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6
6
6
6
6
6
8
6
6
6
8
6
8
8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3.625545
3.991918
3.030236
1.698956
1.303332
2.293164
0.776087
−0.522396
−1.048824
−0.132598
−0.480906
−2.523855
−3.193606
−1.227759
−1.219490
0.105914
1.105326
0.755070
−0.553836
−1.543919
1.783523
1.518830
0.229110
−0.880766
−1.995785
0.155251
1.163428
2.608730
−0.028375
0.240048
0.304629
0.102571
−0.159337
−0.230248
0.141362
0.014305
−0.096703
−0.357093
−0.729157
−0.147462
−0.399711
0.006259

402
Molecules 2011, 16
15
16
17
18
19
20
21
22
23
24
8
6
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
−3.196434
−2.723093
4.385801
5.034104
3.287543
1.978969
−2.176000
−3.600399
−1.956518
−2.326874
−0.963313
−2.031505
−1.989630
0.359492
2.138811
−2.557818
2.299376
−2.352457
−1.673761
−2.836595
0.091663
0.940363
−0.080094
0.394986
0.499467
−0.445769
−0.206636
1.500562
1.628696
0.329283
Sample Availability: Samples of the compounds 2, 3a-c, 4a-d are available from the authors.
© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).