Microwave-assisted preparation and antimicrobial activity of O-alkylamino benzofurancarboxylates

Article abstract of DOI:10.1007/s00706-013-1067-7

A series of derivatives of 2 and 3-benzofurancarboxylates were synthesized under microwave-assisted conditions. Their in-vitro antimicrobial properties were assessed. Inhibition by the compounds of the growth of antibiotic- susceptible standards and clinically isolated strains of Gram-positive and Gram-negative bacteria, yeasts, and a human fungal pathogen was moderate to significant. Methyl 5-bromo-7-[2-(N,N-diethylamino)ethoxy]-6-methoxy-2- benzofurancarboxylate hydrochloride was identified as the most active compound (MIC 3-12 9 10^-3 μmol/cm³ against Gram-positive bacteria; MIC 9.4 9 10^-2 μmol/cm³ against Candida and Aspergillus brasiliensis). The molecular and crystal structures of 2-(N,N-diethylamino)ethyl 6-acetyl-5-hydroxy-2-methyl-3-benzofurancarboxylate were established by single-crystal X-ray diffraction. Springer-Verlag Wien 2013.

Full text of DOI:10.1007/s00706-013-1067-7

Monatsh Chem (2013) 144:1679–1689
DOI 10.1007/s00706-013-1067-7
ORIGINAL PAPER
Microwave-assisted preparation and antimicrobial activity
of O-alkylamino benzofurancarboxylates
•
Kinga Ostrowska Elzbieta Hejchman Irena Wolska
•
•
_
Hanna Kruszewska Dorota Maciejewska
•
Received: 16 February 2013 / Accepted: 17 July 2013 / Published online: 16 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract A series of derivatives of 2 and 3-benzofuran-
carboxylates were synthesized under microwave-assisted
conditions. Their in-vitro antimicrobial properties were
assessed. Inhibition by the compounds of the growth of
antibiotic-susceptible standards and clinically isolated
strains of Gram-positive and Gram-negative bacteria,
yeasts, and a human fungal pathogen was moderate to
significant. Methyl 5-bromo-7-[2-(N,N-diethylamino)eth-
oxy]-6-methoxy-2-benzofurancarboxylate hydrochloride
was identified as the most active compound (MIC
3–12 9 10-3 lmol/cm3 against Gram-positive bacteria;
MIC 9.4 9 10-2 lmol/cm3 against Candida and Asper-
gillus brasiliensis). The molecular and crystal structures of
2-(N,N-diethylamino)ethyl 6-acetyl-5-hydroxy-2-methyl-3-
benzofurancarboxylate were established by single-crystal
X-ray diffraction.
Introduction
The benzofuran system, an important pharmacophore, is
present in numerous compounds isolated from natural
sources and in synthetic products. These heterocyclic
compounds have a variety of pharmacological properties,
and changes of their structure result in high diversity that
has proved useful in the search for new therapeutic agents.
It is widely known that numerous compounds containing
the benzo[b]furan system, both synthetic and isolated from
natural sources, have antimicrobial activity [1].
Eight flavaglines and six cyclopenta[b]benzofurans iso-
lated from Aglaia odorata, Aglaia elaeagnoidea, and
Aglaia edulis (Meliaceae) have been tested for antifungal
properties against the three plant pathogens Pyricularia
grisea, Fusarium auenaceum, and Alternaria citri. P. gri-
sea, responsible for rice blast disease, was the fungus most
susceptible to all the benzofurans, with rocaglaol the most
active compound [2]. Thirteen compounds based on the
benzofuran structure bearing aryl substituents at the C-3
position through a methanone linker have been synthesized
and screened for antibacterial and antifungal activity
against four bacteria: Escherichia coli, Staphylococcus
aureus, Methicillin-resistant S. aureus, and Bacillus sub-
tilis, and a fungus Candida albicans. Four hydrophobic
benzofuran analogs were found to have favorable anti-
bacterial activity better than that of control drugs [3].
It has been shown that esters and amides of 4-substituted
2-benzofurancarboxylic acids may act as inhibitors of
fungal N-myristoyltransferase [4–8]. Mild to significant
inhibition of the growth of an antibiotic-susceptible stan-
dard, clinically isolated strains of Gram-positive and Gram-
negative bacteria, and human fungal pathogens was
observed for a series of 2-substituted and three new dia-
cetyl benzofurans. Different substitution of the benzofuran
Keywords Heterocycles ꢀ Alkylation ꢀ
Phase-transfer catalysis ꢀ X-ray structure determination ꢀ
Drug research
K. Ostrowska (&) ꢀ E. Hejchman ꢀ D. Maciejewska
Department of Organic Chemistry, Faculty of Pharmacy,
Medical University of Warsaw,
1 Banacha, 02097 Warsaw, Poland
e-mail: kostrowska@wum.edu.pl
I. Wolska
Department of Crystallography, Faculty of Chemistry,
Adam Mickiewicz University, Grunwaldzka 6,
60780 Poznan, Poland
H. Kruszewska
Department of Antibiotics and Microbiology,
National Medicines Institute, 30/34 Chełmska,
00725 Warsaw, Poland
123

1680
K. Ostrowska et al.
moiety and subsequent antimicrobial screening identified
the C-3-acetyl functionality as a new structural alternative
for optimum antimicrobial activity in the benzofuran class
of compounds [9]. Substituted 3-methyl-2-benzofur-
ancarbohydrazides had moderate activity against S. aureus
and B. subtilis [10]. Similarly, 2-(1-benzofuran-2-yl-)-5-
propyl-4,5-diphenyl-4,5-dihydrofuran-3-carbonitrile had
average antimicrobial activity against S. aureus, B. subtilis,
Pseudomonas aeruginosa, Micrococcus luteus, E. coli,
Salmonella enteritidis, and Listeria monocytogenes [11].
Methyl esters of 4-bromo-6-(dibromoacetyl)-5-hydroxy-2-
methyl-1-benzofuran-3-carboxylic acid (I), 6-(dibromo-
acetyl)-5-methoxy-2-methyl-1-benzofuran-3-carboxylic acid
(II), and 4-chloro-6-(dichloroacetyl)-5-hydroxy-2-methyl-
1-benzofuran-3-carboxylic acid (III) had antimicrobial
activity against Gram-positive bacteria and compounds
I and III had antifungal activity against Candida albicans
and C. parapsilosis [12].
The X-ray structure of 2-(N,N-diethylamino)ethyl 6-acetyl-
5-hydroxy-2-methyl-3-benzofurancarboxylate (1c) is pre-
sented, with inter and intramolecular interactions in the
solid state.
Results and discussion
Our strategy was based on preparation of a series of
derivatives of 2 and 3-benzofurancarboxylic acids (Fig. 1).
Acids 1–6 were prepared as described elsewhere [15] and
converted to their ammonium salts to improve solubility in
polar solvents. Acids 1–4 and 6 were esterified with meth-
anol to protect the carboxyl group against O-alkylation.
As the first step of our research we obtained O-alkyl-
amino derivatives of methyl benzofurancarboxylates 1b–
4b and 6b by microwave-assisted O-alkylation of the
appropriate esters (compounds 1a–4a, 6a, Scheme 1,
routes i and ii, Fig. 2), using 2-chloroethyl-N,N-diethyl-
amine hydrochloride as alkylating agent.
Surprisingly, no recently synthesized chloro and bromo
derivatives of methyl 5-methoxy-2-methyl-3-benzofur-
ancarboxylate had any antimicrobial activity [13].
The syntheses were performed in acetone under phase-
transfer conditions, using anhydrous potassium carbonate
as a base and Aliquat 336 (N-methyl-N,N-dioctyloctan-1-
ammonium chloride) as phase-transfer catalyst (PTC).
Preparation of hydrochloride salts of the resulting bases
was necessary to prevent decomposition and improve their
solubility in polar solvents. These compounds were previ-
ously synthesized conventionally [15]. Microwave
assistance resulted in reduced reaction time (from 16 to
20 h to 24 min); however, we did not notice any mean-
ingful increase in product yield.
As we have reported elsewhere, aminoalkylation the OH
group of 7-hydroxycoumarin derivatives resulted in prod-
ucts with better antibacterial activity than the starting
compounds [14]. Encouraged by this, and in continuation
of our research, we designed the synthesis of a series of
benzofurancarboxylates bearing O-aminoethyl substituents
and assayed their antimicrobial activity. In this study we
report their microwave-assisted preparation and discuss the
advantages of this technique compared with synthesis
under conventional conditions, described elsewhere [15].
Fig. 1 Structures of 2 and
3-benzofurancarboxylic acids
H
C
H
COO
H
C
3
3
H
3CO
H
O
H
COO
H
C
H
COO
3
O
O
O
H
O
H
3COC
H
O
H
COC
H
COC
3
3
1
2
3
H
C
3
H
C
3
H
COO
H
COO
O
H
3CO
O
H
O
H
COC
3
5
O
r
B
H
COO
H
COO
H
3CO
O
O
H
3CO
4
H
OC
H
O
3
7
6
123

Microwave-assisted preparation and antimicrobial activity
1681
Scheme 1
H
COOC
3
3
ii
H
COO
H
O
H
O
i
H
C
H
C
3
O
H
3COC
O
H
3COC
a
1
1
H
H
3C 2C
H
COOC
3
NH
H
2C 2CO
ii
H
H
3C 2C
H
C
3
O
H
3COC
1b
H H
C 2C
3
H
H N
COOC 2C
2
H
O
H H
C 2C
3
H
C
3
O
H
3COC
+
13
C
4
1
c
1
H
H
2C
3
14'' 13''
9
11 12
H
H
3C 2C
H
H N
COOC 2C
2
12' 11'
2C 2CO
4
NH
H
H
2C
H
3
C
a
3
3
5
6
13' 14'
H
H
3C 2C
H
C
3
2
14'''
13'''
8
a
7
O
H
3COC
7
15 10
1d
Benzofurancarboxylic acids 1–4, 6, and 7 reacted with
2-chloroethyl-N,N-diethylamine under similar conditions.
Microwave-assisted alkylation of these compounds resul-
ted in a mixture of two products. An example of this
synthetic route (for compound 1) is presented in Scheme 1,
route ii. Separation by column chromatography on silica
gel yielded the product of esterification 1c and the product
of O-alkylation and esterification 1d. The isolated com-
pounds 1c, 1d, 3c, 4c, 6c, and 7c (Fig. 2) were converted to
compounds 1bꢀHCl–4bꢀHCl and 6bꢀHCl is summarized in
Table 1.
The results show that the pattern of substitution of the
benzofuran moiety is important to the activity. The most
potent compound is 6bꢀHCl; at concentrations in the range
3–12 9 10-3 lmol/cm3 it inhibits growth of Gram-posi-
tive bacteria strains. Given its structure, we may speculate
that the 2-(N,N-diethylamino)ethoxy function at C-7, the
bromine substituent at C-5, and the methoxy group at C-6
are responsible for the high activity. The isomeric com-
pound 6cꢀHCl is, however, less active; exchanging the
positions of the 2-(N,N-diethylamino)ethoxy and methoxy
functions results in reduction of both antibacterial and
antifungal activity.
1
their hydrochloride salts. Spectroscopic data (IR, H and
13C NMR, and MS) confirmed the structures of all the
products.
In this investigation eighteen derivatives of 2 and
3-benzofurancarboxylic acids were assayed for in-vitro
antimicrobial activity. The ammonium salts of benzofu-
rancarboxylic acids 1–7 (Fig. 1) were also tested. They did
not inhibit the growth of any of the microorganisms
(MIC [ 30 lmol/cm3). Methyl esters 1a–7a of the acids
[15] were not tested for antimicrobial activity.
It is worth noting that the derivative of the substituted
3-benzofurancarboxylic acid 1bꢀHCl is more active against
Gram-positive bacteria strains than compounds 2bꢀHCl,
3bꢀHCl, and 4bꢀHCl, obtained from the substituted 2-ben-
zofurancarboxylic acids. Introducing the lipophilic
methoxy group at the C-5 position resulted in increased
antimicrobial activity (compound 3bꢀHCl is more active
then 2bꢀHCl). Similarly, the 7-(p-methoxycinnamoyl)
group increases the activity of 4bꢀHCl compared with
2bꢀHCl against Gram-positive bacteria (Table 1). The
Alkylation of hydroxyl groups in the molecules of
methyl esters 1a–4a and 6a gave five 2-(N,N-diethyl-
amino)ethoxy derivatives 1b–4b and 6b (Fig. 2;
Scheme 1). All were evaluated microbiologically as
hydrochloride salts. The in-vitro antimicrobial activity of
123

1682
K. Ostrowska et al.
Fig. 2 Structures of the esters
of benzofurancarboxylic acids
H
C
CH3
3
H
3CO
H
COOCH3
O
COOC
3
O
(
C2
)
(
)
(
) (
)
2
H5 2N H
2C O
C2H5 2N H2C O
2
H
COC
COCH3
3
2b
3b
r
B
H
C
3
H
COOC
3
O
H
3CO
H
COOC
3
(
)
( )
H5 2
C2
H
N
O C
2 2
O
(
C2
)
(
)
2
H5 2N H
2C O
6b
O
8
H
C
3
15
3CO
13
14
4
H
a
3
H
H
2C
3
C
3
11
12
5
H
H N
COOC 2C
2
2
H
3CO
4b
9
6
O
a
7
H
H
3
C
2C
H
O
7
13' 14'
c
H
COC
3
3
10 16
8
C
H
3
4
13
14
a
3
3
C
H
2C
H
3
3
5
12
11
9
H
H N
COOC 2C
2
2
6
a
7
O
H
H
C
2C
H
O
7
13'
14'
10
15
16
17
O
4
13 14
3
a
3
H
H
C
2C
18'
5
6
3
11 12
9
19
20
H
H N
COOC 2C
2
2
O
a
7
CH2CH3
18
7
13'
14'
c
4
H
3CO
19
H
OC
21
3
c
7
10
4
13
C
14
r
B
3
a
a
3
H
H
2C
3
8
12
11
5
H
H N
COOC 2C
2
2
7
H
C
H
2C
O
6
3
H
3CO
7
13'
14'
9
H
OC
3
c
6
10
2-(N,N-diethylamino)ethyl esters 1cꢀHCl, 3cꢀHCl, and
4cꢀHCl, with unsubstituted phenolic groups, are more
active against Gram-positive bacteria but less active
against Gram-negative bacteria than 1bꢀHCl, 3bꢀHCl, and
4bꢀHCl (Table 2). It is worth noticing that compound
4cꢀHCl is the most active against yeast strains. Compound
7cꢀHCl was inactive in our assay.
compound crystallizes in the monoclinic space group P 21/n
with one molecule in the asymmetric unit. Selected bond
lengths, bond angles, and torsion angles are listed in
Table 3. The benzofuran moiety is nearly planar with a
˚
maximum deviation of 0.020(1) A for C3a. The C8, C9,
C10, O16, O17, and O18 atoms are almost coplanar with
the two-ring framework (the appropriate torsion angles are
given in Table 3). The orientation of the substituent at C3
relative to the benzofuran ring can be described by the
torsion angle C2–C3–C9–O19 of -0.2(3)°. For the (N,N-
diethylamino)ethyl fragment we observed structural disor-
der as a result of conformational freedom and from X-ray
data we found alternative positions of the C12 and C13
atoms. Strong intramolecular hydrogen bonding is present
between O16 and O17 atoms (Fig. 3; Table 4). The angle
X-ray structure analysis
The molecular and crystal structure of 1c in the solid state
were analyzed by single-crystal X-ray diffraction. The
molecular structure with the atomic numbering scheme is
illustrated in Fig. 3 (the drawings were performed with
Mercury software [16]). The results indicate that the
123

Microwave-assisted preparation and antimicrobial activity
1683
Table 1 Antimicrobial activity of hydrochlorides of methyl benzofurancarboxylate O-alkylamino derivatives (minimum inhibitory concen-
tration, lmol cm-3
)
1bꢀHCl
2bꢀHCl
3bꢀHCl
4bꢀHCl
6bꢀHCl
Micrococcus luteus
ATCC 9341
0.05
0.75
0.05
0.04
0.003
Bacillus cereus
0.05
0.05
0.05
0.10
0.05
0.39
6.51
13.02
0.78
0.39
0.39
NT
1.49
1.49
1.49
3.11
3.11
3.11
12.44
NA
0.36
0.18
0.18
0.18
0.18
0.36
6.04
NA
0.30
0.04
0.04
0.15
0.15
0.60
NA
0.012
0.012
0.012
0.012
0.012
0.012
1.50
ATCC 11178
Bacillus subtilis
ATCC 6633
Staphylococcus epidermidis
ATCC 12228
Staphylococcus aureus
ATCC 6538
Staphylococcus aureus
ATCC 6538 P
Enterococcus hirae
ATCC 10541
Escherichia coli
ATCC 8739
Pseudomonas aeruginosa
ATCC 15442
NA
3.12
Candida albicans
ATCC 10231
1.49
1.49
1.49
NT
0.36
0.36
0.72
NT
4.98
4.98
0.2987
NT
0.09
Candida albicans
ATCC 2091
0.09
Candida parapsilosis
ATCC 22019
0.094
0.187
0.023
0.094
Saccharomyces cerevisiae
ATCC 9763
Zygosacharomyces rouxi
ATCC 28253
0.39
0.78
NT
0.36
0.72
NT
Aspergillus brasiliensis
ATCC 16404
1.49
1.19
NA not assayed [0.3 lmol/cm3, NT not tested
between the best planes of the benzofuran moiety and the
C5/O17/H17A/O16/C10/C6 ring is only 1.56(6)°. More-
over the weak C4–H4AꢀꢀꢀO18 and C11–H11ꢀꢀꢀO18
interactions stabilize the conformation of the molecule.
The packing of the molecules viewed down the a axis
(Fig. 4) shows that the molecules are stacked in blocks
with partly overlapping benzofuran systems and an inter-
Experimental
Reagents of the highest grade available were purchased
from Aldrich and used without further purification. Sol-
vents were used as received from commercial suppliers,
and no further attempts were made to purify or dry them.
Melting points were determined with an ElectroThermal
9001 digital melting point apparatus (ElectroThermal,
Essex, UK). A Plazmatronika 1,000-W microwave oven
equipped with a single mode cavity suitable for microscale
synthesis and microwave choked outlet connected to an
external condenser set to 30 % power was used (http://
www.plazmatronika.com.pl). High-resolution mass spectra
˚
layer spacing of ca. 3.5 A. The molecules are linked by
C7–H7AꢀꢀꢀO18, C11–H11A(D)ꢀꢀꢀO1 hydrogen bonds
forming infinite chains along the a axis. These chains
interact via C13D–H13GꢀꢀꢀO17, C15–H15CꢀꢀꢀC9, C8–
H8BꢀꢀꢀC10 contacts and pꢀꢀꢀp stacking forces to create the
blocks mentioned above. The bulky aminoethyl substitu-
ents are oriented outside these blocks and connect them via
C13C–H13FꢀꢀꢀO16 hydrogen bonds. Geometric data for all
intra and intermolecular interactions are given in Table 4.
were recorded on a Quattro LCT (TOF). H NMR, 13C
1
NMR, HSQC, and HMBC spectra in solution were recor-
ded at 25 °C with Varian NMRS-300 or a Varian Unity
123

1684
K. Ostrowska et al.
Table 2 Antimicrobial activity of hydrochlorides of 2-(N,N-diethylamino)ethyl benzofurancarboxylates (minimum inhibitory concentration,
lmol cm-3
)
1cꢀHCl
3cꢀHCl
4cꢀHCl
6cꢀHCl
1dꢀHCl
7cꢀHCl
Micrococcus luteus
ATCC 9341
0.01
0.01
0.01
0.09
0.04
15.28
Bacillus cereus
0.10
0.01
NA
0.05
0.09
0.19
0.19
0.09
0.75
NA
0.04
0.04
0.01
0.01
0.04
0.08
NA
0.71
0.35
0.09
0.09
0.18
NA
0.04
0.04
0.04
0.04
0.07
0.30
0.59
NA
15.28
15.28
ATCC 11778
Bacillus subtilis
ATCC 6633
Staphylococcus epidermidis
ATCC 12228
15.28
Staphylococcus aureus
ATCC 6538
1.62
0.41
NA
15.28
Staphylococcus aureus
ATCC 6538P
15.28
Enterococcus hirae
ATCC 10541
[30.56
[30.56
30.56
Escherichia coli
ATCC 8739
NA
NA
Pseudomonas aeruginosa
ATCC 15442
NA
NA
NA
NA
Candida albicans
ATCC 10231
1.62
0.41
NA
NA
0.32
0.08
0.15
0.08
0.04
NA
5.91
NA
2.47
4.96
4.96
4.96
0.59
4.96
[30.56
[30.56
[30.56
15.28
Candida albicans
ATCC 2091
NA
Candida parapsilosis
ATCC 22019
NA
NA
Saccharomyces cerevisiae
ATCC 9763
1.62
NA
3.13
NA
1.42
5.91
NA
Zygosacharomyces rouxi
ATCC 28253
[30.56
15.28
Aspergillus brasiliensis
ATCC 16404
NA
NA
NA not assayed [0.3 lmol/cm3; NT not tested
Fig. 3 Schematic diagram of
molecule 1c showing the
labeling scheme and the
disordered 2-(N,N-
diethylamino)ethyl substituent
plus-500 spectrometers, and standard Varian software was
used (Varian, Palo Alto, CA, USA). Calculated shielding
constants were used as an aid to assignment of resonances
of 13C atoms. The CPHF-GIAO approach was used for
computation of NMR shielding constants using Gaussian
09 software [17]. Chemical shifts (d, ppm) were referenced
123

Microwave-assisted preparation and antimicrobial activity
1685
to TMS. The notation used for detailed description of NMR
resonances is given in Scheme 1 and Fig. 2. IR spectra
were recorded on a Perkin Elmer FT IR Spectrum 2000
instrument. TLC was performed on silica gel 60 F254 sheets
(Merck, Darmstadt, Germany), spots were visualized by
UV at 254 and 365 nm. Silica gel 60 was used for column
chromatography. Preparation of compounds 1b–6b has
been described elsewhere [15].
monomode microwave oven for 24 min. The reaction was
monitored by TLC. After completion of the reaction inor-
ganic salts were removed by filtration. The solvent was
evaporated. The residue was purified by column chroma-
tography on silica gel, eluent: CHCl3–MeOH 50:1. The
base was dissolved in methanol saturated with gaseous HCl.
The hydrochloride was precipitated by addition of diethyl
ether. The crude product was crystallized from methanol–
diethyl ether.
General procedure for microwave-assisted preparation
of hydrochlorides of methyl [2-(N,N-diethylamino)-
ethoxy]-substituted benzofurancarboxylates
Methyl 6-acetyl-5-[2-(N,N-diethylamino)ethoxy]-2-methyl-
3-benzofurancarboxylate (1b, C19H25NO5)
1H NMR (300 MHz, CDCl3): d = 1.11 (t, J = 7.2 Hz, 6H,
H-14,140), 2.69 (s, 3H, H-16), 2.70 (m, 4H, H-13,130), 2.77
(s, 3H, H-8), 2.99 (t, J = 6.3 Hz, 2H, H-12), 3.96 (s, 3H,
H-15), 4.25 (t, J = 6.3 Hz, 2H, H-11), 7.49 (s, 1H, H-4),
7.82 (s, 1H, H-7) ppm; 13C NMR (125 MHz, CDCl3):
d = 11.66 (C-14,140), 15.10 (C-8), 32.16 (C-16), 47.92
(C-13), 51.81 (C-15), 52.02 (C-12), 67.45 (C-11), 104.70 (C-
4), 109.25 (C-3), 112.51 (C-7), 125.88 (C-6), 131.05 (C-3a),
148.20 (C-7a), 155.68 (C-5), 164.62 (C-9), 167.40 (C-2),
199.34 (C-10) ppm.
A mixture of the appropriate methyl benzofurancarboxylate
(2 mmol), N,N-diethyl-2-chloroethylamine hydrochloride
(6 mmol), anhydrous potassium carbonate (23 mmol), and
Aliquat 336 (0.25 mmol) in 10 cm3 anhydrous acetone was
placed in the microwave flask and heated under reflux in the
˚
Table 3 Selected bond lengths/A and angles/°, and selected torsional
angles/° for 1c
O1–C2
1.309(2)
1.384(2)
1.351(2)
1.331(2)
1.433(3)
1.477(2)
108.6(1)
112.5(1)
123.2(2)
177.1(2)
179.0(2)
178.8(2)
-178.3(2)
-178.1(2)
179.6(2)
1bꢀHCl (C19H26ClNO5)
O1–C7a
1H NMR (300 MHz, CDCl3): d = 1.48 (t, J = 6.9 Hz, 6H,
H-14,140), 2.62 (s, 3H, H-16), 2.71 (m, 4H, H-13,130), 2.79
(br.s, 3H, H-8), 3.21 (m, 4H, H-13, 130), 3.55 (m, 2H,
H-12), 3.98 (s, 3H, H-15), 4.71 (br.s, 2H, H-11), 7.55 (s,
1H, H-4), 7.74 (s, 1H, H-7), 12.47 (br.s, 1H, NH) ppm.
C5–O17
C3a–C7a
C6–C10
C2–C8
C2–O1–C7a
C3–C9–O19
C6–C10–O16
C3a–C3–C2–C8
C7–C6–C5–O17
C2–C3–C9–O18
O1–C2–C3–C9
C7–C6–C10–O16
C4–C5–C6–C10
Methyl 7-acetyl-6-[2-(N,N-diethylamino)ethoxy]-3-methyl-
2-benzofurancarboxylate hydrochloride
(2bꢀHCl, C19H26ClNO5xH2O),
methyl 7-acetyl-6-[2-(N,N-diethylamino)ethoxy]-5-
methoxy-3-methyl-2-benzofurancarboxylate
hydrochloride (3bꢀHCl, C20H28ClNO6),
methyl 6-[2-(N,N-diethylamino)ethoxy]-7-
(p-methoxycinnamoyl)-3-methyl-2-benzofurancarboxylate
hydrochloride (4bꢀHCl, C27H32ClNO6),
˚
Table 4 Intra and intermolecular interactions in crystals of 1c (A, °)
D-HꢀꢀꢀA
D-H
HꢀꢀꢀA
DꢀꢀꢀA
\(D-HꢀꢀꢀA)
O17–H17AꢀꢀꢀO16
C4–H4AꢀꢀꢀO18
C11–H11DꢀꢀꢀO18
C7–H7AꢀꢀꢀO18a
C11–H11AꢀꢀꢀO1b
C13D–H13GꢀꢀꢀO17c
C13C–H13FꢀꢀꢀO16d
C8–H8BꢀꢀꢀC10e
C15–H15CꢀꢀꢀC9f
a
0.82
0.93
0.97
0.93
0.97
0.97
0.97
0.96
0.96
1.70
2.54
2.28
2.53
2.53
2.71
2.67
2.85
2.84
2.433(2)
3.011(2)
2.637(3)
3.313(2)
3.166(2)
3.415(3)
3.435(5)
3.661(3)
3.558(3)
148
111
101
179
123
130
136
143
133
b
c
d
e
f
Symmetry codes: 1 ? x, y, z; -1 ? x, y, z; -x, 1 - y, -z; -0.5 ? x, 1.5 - y, 0.5 ? z; 1 - x, 1 - y,-z; 1 - x, 2 - y, -z
123

1686
K. Ostrowska et al.
Fig. 4 Projection of the crystal
structure of 1c viewed along the
a axis, showing molecular
blocks
Table 5 Crystal data, data collection, and structure refinement for 1c
General procedure for microwave-assisted preparation
of hydrochlorides of 2-(N,N-diethylamino)ethyl
benzofurancarboxylates
Compound
1c
Empirical formula
Formula weight
T/K
C18H23NO5
333.37
The appropriate benzofurancarboxylic acid (0.3 mmol),
N,N-diethyl-2-chloroethylamine hydrochloride (1.5 mmol),
anhydrous potassium carbonate (10.2 mmol), and Aliquat
336 (0.25 mmol) in 8 cm3 anhydrous acetone were placed
in the microwave flask. The mixture was heated under
reflux in the monomode microwave oven: 4–8 cycles:
heating 6 min, cooling 2 min. TLC monitoring on silica gel
plates (mobile phase CHCl3–MeOH 10:1) indicated com-
plete disappearance of the substrate. The inorganic salts
were removed by filtration, then the solvent was evapo-
rated. The residue was purified by column chromatography
on silica gel 230–400 mesh, eluent: CHCl3–MeOH 50:1.
One or two basic products were isolated. The bases were
converted into their hydrochlorides as described above.
293(2)
˚
Wavelength/A
1.54178
Crystal system, space group
Unit cell dimensions
Monoclinic, P 2(1)/n
˚
a/A
8.1681(1)
7.4276(1)
27.3017(3)
94.218(1)
1,651.89(4)
4, 1.340
˚
b/A
˚
c/A
b/°
Volume/A
3
˚
Z, Dx/mg m-3
l/mm-1
0.805
F(000)
712
h range for data collection/°
hkl range
5.55–88.24
-10 B h B 10
-9 B k B 7
-33 B l B 33
2-(N,N-Diethylamino)ethyl 6-acetyl-5-hydroxy-2-methyl-3-
benzofurancarboxylate (1c, C18H23NO5)
Yield 61 %; m.p.: 101–103 °C; Rf = 0.69; 1H NMR
(300 MHz, CDCl3): d = 1.10 (t, 6H, J = 7.2 Hz,
H-14,140), 2.67 (t, 4H, J = 7.2 Hz, H-13,130), 2.68 (s,
3H, H-15), 2.79 (s, 3H, H-8), 2.91 (t, 2H, J = 6.5 Hz,
H-12), 4.45 (t, 2H, J = 6.5 Hz, H-11), 7.49 (s, 1H, H-4),
7.77 (s, 1H, H-7), 12.17 (1H, OH) ppm; 13C NMR
(125 MHz, CDCl3): d = 11.74 (C-14,140), 15.13 (C-8),
26.94 (C-16), 47.82 (C-13,130), 51.36 (C-12), 62.28 (C-11),
109.37 (C-3), 109.46 (C-4), 111.97 (C-7), 116.45 (C-6),
134.08 (C-3a), 146.77 (C-7a), 159.45 (C-5), 163.83 (C-9),
Reflections
Collected
17,343
Unique (Rint
)
3,523 (0.021)
3,324
Observed (I [ 2r(I))
Data/restraints/parameters
Goodness-of-fit on F2
R(F) [I [ 2r(I)]
3,523/0/236
1.007
0.0629
wR(F2) (all data)
0.1921
-3
˚
Max/min. Dqe/A
0.323/–0.278
ꢀ
169.56 (C-2), 203.88 (C-10) ppm; IR (CHCl3): m = 3,417
methyl 5-bromo-7-[2-(N,N-diethylamino)ethoxy]-6-
methoxy-2-benzofurancarboxylate hydrochloride
(6bꢀHCl, C17H22BrNO5)
(mOH), 3,076 (m ), 2,963, 2,926 (m ), 2,852
CꢁHarom
CꢁHasym
(m
), 1,703 (mC¼O), 1,621, 1,587 (mC¼C), 1,423 (dOH),
CꢁHsym
Analytical data (1H NMR data and m.p.) for compounds
2b–4b and 6b were in agreement with the data reported in
our paper [15].
1,318, 1,260 (m
), 1,176, 1,092 (m
), 979,
887, 863, 799 (cCꢁH) cm-1; MS (TOF-ES?): [M ? H]?
calcd for C18H24NO5 334.1654, found 334.1654.
CꢁOꢁCasym
CꢁOꢁCasym
123

Microwave-assisted preparation and antimicrobial activity
1687
1cꢀHCl (C18H24ClNO5)
3cꢀHCl (C19H26ClNO6)
IR (CHCl3): 3,424 (mOH), 2,954, 2,926 (mCꢁH ), 2,855
1H NMR (300 MHz, CDCl3): d = 1.46 (t, 6H, J = 7.2 Hz,
H-14,140), 2.79 (s, 3H, H-8), 2.69 (s, 3H, H-16), 3.25 (m,
4H, H-13,130), 3.46 (m, 2H, H-12), 4.94 (t, 2H,
J = 5.4 Hz, H-11), 7.35 (s, 1H, H-4), 7.80 (s, 1H, H-7)
ppm, 12.17 (1H, OH) ppm; 13C NMR (125 MHz, CDCl3):
d = 8.87 (C-14,140), 15.41 (C-8), 26.98 (C-16), 47.52 (C-
13,130), 50.13 (C-12), 58.57 (C-11), 108.37 (C-3), 108.90
(C-4), 112.33 (C-7), 116.70 (C-6), 133.43 (C-3a), 146.75
(C-7a), 159.61 (C-5), 163.21 (C-9), 170.51 (C-2), 203.86
(C-10) ppm.
asym
(mCꢁH ), 2,485 (m
tertiary amine salt), 1,716 (mC¼O),
asym
NꢁH
1,610, 1,584 (mC¼C), 1,428 (dOH), 1,316, 1,260
(m ), 1,148, 1,097 (m ), 977, 934, 848,
CꢁOꢁCasym
CꢁOꢁCasym
799, 769 (cCꢁH) cm-1
2-(N,N-Diethylamino)ethyl 6-hydroxy-7-
.
(p-methoxycinnamoyl)-3-methyl-2-benzofurancarboxylate
(4c, C26H29NO6)
Yield 65 %; m.p.: 104–106 °C; Rf = 0.59; 1H NMR
(300 MHz, CDCl3): d = 1.08 (t, 6H, J = 7.2 Hz,
H-14,140), 2.57 (s, 3H, H-8), 2.67 (m, 4H, H-13,130),
2.96 (t, 2H, J = 6.5 Hz, H-12), 3.88 (s, 3H, H-21), 4.53 (t,
2H, J = 6.5 Hz, H-11), 6.97 (m, 4H, H-18,180,19,190), 7.65
(d, 1H, J = 8.7 Hz, H-5), 7.75 (d, 1H, J = 8.7 Hz, H-4),
7.99 (d, 1H, J = 15.3 Hz, H-16), 8.34 (d, 1H,
J = 15.1 Hz, H-15), 14.06 (br.s, 1H, OH) ppm; 13C
NMR (125 MHz, CDCl3): d = 9.40 (C-14,140), 11.96 (C-
8), 29.91 (C-16), 47.81 (C-13,130), 51.51 (C-12), 55.69 (C-
21), 62.86 (C-11), 107.35 (C-3), 114.79 (C-19,190), 116.03
(C-5), 121.64 (C-7), 122.69 (C-4), 127.92 (C-17), 128.35
(C-3a), 131.11 (C-18, 180), 140.19 (C-7a), 145.94 (C-15),
153.59 (C-20), 160.01 (C-6), 162.36 (C-9), 166.54 (C-2),
2-(N,N-Diethylamino)ethyl 6-acetyl-5-
[2-(N,N-diethylamino)ethoxy]-2-methyl-3-
benzofurancarboxylate (1d, C24H36N2O5)
Yield 71 %; m.p.: 101–103 °C; Rf = 0.75; 1H NMR
(300 MHz, CDCl3): d = 1.068, 1.072 (t, 6H, J = 7.2 Hz;
t, 6H, J = 7.8 Hz; H-14,140,1400,14000), 2.64 (q, 8H,
J = 7.2 Hz, H-13, 130, 1300,13000), 2.70 (s, 3H, H-15),
2.77 (s, 3H, H-8), 2.87 (t, 2H, J = 6.3 Hz, H-120), 2.95 (t,
2H, J = 6.3 Hz, H-12), 4.20 (t, 2H, J = 6.3 Hz, H-110),
4.44 (t, 2H, J = 6.3 Hz, H-11), 7.54 (s, 1H, H-4), 7.83
(s,1H, H-7) ppm; MS (TOF-ES?): [M ? H]? calcd for
C24H37N2O5 433.2702, found 433.2702.
ꢀ
191.85 (C-10) ppm; IR (CHCl3): m = 3,400 (mOH), 2,965,
1dꢀ2HCl (C24H38Cl2N2O5)
2,925 (mCꢁH ), 2,851 (mCꢁH ), 1,712 (mC¼O), 1,635,
asym
asym
1H NMR (300 MHz, CDCl3): d = 1.44 (t, 6H,
J = 7.2 Hz), 1.47 (t, 6H, J = 7.8 Hz, H-14,140), 2.63 (s,
3H, H-16), 2.79 (s, 3H, H-8), 3.35 (m, 8H, H-13, 130,
1300,13000), 3.61 (t, 2H, J = 5.1 Hz, H-120), 3.72 (m, 2H,
H-12), 4.86 (t, J = 4.8 Hz, 2H, H-110), 4.98 (t, J = 4.8 Hz,
2H, H-11), 7.69 (s, 1H, H-4), 7.76 (s, 1H, H-7), 11.92,
1,593 (mC¼C), 1,424 (dOH), 1,259 (m
), 1,172, 1,085
), 983, 869, 829, 764 (cCꢁH) cm21; MS (TOF-
CꢁOꢁCasym
(m
CꢁOꢁCasym
ES?): [M ? H]? calcd for C26H30NO6 452.3222, found
452.3222.
2-(N,N-Diethylamino)ethyl 5-bromo-6,7-dimethoxy-2-
benzofurancarboxylate (6c, C17H22BrNO5)
ꢀ
12.04 (br.s, 2 NH) ppm; IR (CHCl3): m = 2,981, 2,955,
This compound was prepared in accordance with the
general procedure, except acetone–methanol 9:10 was used
instead of anhydrous acetone. Yield 48 %; m.p.: 61–63 °C;
2,927 (m ), 2,855 (m ), 2,489 (m tertiary
amine salt), 1,713 (mC¼O), 1,623, 1,588 (mC¼C), 1,440
CꢁHasym
CꢁHasym
NꢁH
(d
), 1,250, 1,227 (m
), 1,182, 1,090
CꢁHasym
CꢁOꢁCasym
1
(mCꢁOꢁC ), 979, 892, 847, 780 (cCꢁH) cm-1
.
Rf = 0.52; H NMR (300 MHz, CDCl3): d = 1.11 (t, 6H,
sym
J = 7.2 Hz, H-14,140), 2.75 (q, 4H, J = 7.2 Hz, H-13,130),
3.00 (t, 2H, J = 6.3 Hz, H-12), 3.92 (s, 3H, H-10), 3.95 (s,
3H, H-9), 4.44 (t, 2H, J = 6.3 Hz, H-11), 7.12 (s, 1H,
3-H), 7.46 (s, 1H, 4-H) ppm; MS (TOF-ES?): [M ? H]?
calcd for C17H23NO5Br79 400.0753, found 400.1958;
C17H23NO5Br81 402.0733, found 402.2709.
2-(N,N-Diethylamino)ethyl 7-acetyl-6-hydroxy-5-methoxy-
3-methyl-2-benzofurancarboxylate (3c, C19H25NO6)
Yield 55 %; m.p.: 61–63 °C; Rf = 0.16; 1H NMR
(300 MHz, CDCl3): d = 1.12 (t, 6H, J = 7.2 Hz,
H-14,140), 2.57 (s, 3H, 8-H), 2.72 (q, 4H, J = 7.2 Hz,
H-13,130), 2.95 (s, 3H, H-16), 2.94 (t, 2H, J = 6.0 Hz,
H-12), 3.98 (s, 3H, H-15), 4.93 (t, 2H, J = 6.0 Hz, H-11),
7.15 (s, 1H, H-4), 13.61 (br.s, 1H, OH) ppm; 13C NMR
(125 MHz, CDCl3): d = 9.55 (C-8), 11.72 (C-14,140),
31.76 (C-16), 47.85 (C-13,130), 51.19 (C-12), 56.85 (C-15),
62.71 (C-11), 106.93 (C-7), 107.64 (C-4), 119.74 (C-3a),
126.80 (C-3), 140.32 (C-2), 146.97 (C-6), 147.99 (C-5),
156.37 (C-7a), 160.00 (C-9), 203 (C-10) ppm; MS (TOF-
ES?): [M ? H]? calcd for C19H26NO6 362.1760, found
364.1760.
6cꢀHCl (C17H23BrClNO5)
1H NMR (300 MHz, CDCl3): d = 1.14 (t, 6H, J = 7.5 Hz,
H-14,140), 2.82 (m, 2H, H-13,130), 3.05 (m, 2H, H-12),
3.92 (s, 3H, H-10), 3.95 (s, 3H, H-9), 4.62 (t, 2H,
J = 6.3 Hz, H-11), 7.13 (s, 1H, 3-H), 7.46 (s, 1H, 4-H)
ꢀ
ppm; IR (CHCl3): m = 2,967, 2,932 (mCꢁH ), 2,848
asym
(mCꢁH ), 1,731 (mC¼O), 1,619, 1,581, 1,502 (mC¼C),
asym
1,262 (m
764 (cCꢁH) cm-1
), 1,122 (m
), 982, 914, 834,
CꢁOꢁCasym
CꢁOꢁCasym
.
123

1688
K. Ostrowska et al.
2-(N,N-Diethylamino)ethyl 7-methoxy-2-
Crystallography
benzofurancarboxylate (7c, C16H21NO4)
1
Yield 55 %; oil; Rf = 0.86; H NMR (300 MHz, CDCl3):
Crystals of 1c suitable for X-ray analysis were grown by
slow evaporation of a solution in toluene–isopropanol
(1:1). Diffraction data were collected on an Oxford Dif-
fraction SuperNova diffractometer using CuKa radiation at
room temperature. Data reduction was performed with
SuperNova software [20]. The unit cell parameters were
determined by least-squares treatment of setting angles of
the highest-intensity reflections chosen from the whole
experiment. The structure was solved by direct methods, by
use of SHELXS-97 software, and refined on F2 by the full-
matrix least-squares method, again by use of SHELXL97
software [21]. Two reflections were excluded from the
d = 1.09 (t, 6H, J = 7.2 Hz, H-14,140), 2.66 (q, 4H,
J = 6.9 Hz, H-13,130), 2.89 (t, 2H, J = 6.3 Hz, H-12),
4.02 (s, 3H, H-10), 4.58 (t, 2H, J = 6.3 Hz, H-11), 6.92
(dd, 1H, J = 7.2 Hz, 1.5 Hz, H-5), 7.24 (m, 2H, H-4, H-6),
7.51 (s, 1H, H-3) ppm; MS (TOF-ES?): [M ? H]? calcd
for C16H22NO4 292.1555, found 292.1549.
7cꢀHCl (C16H22ClNO4)
ꢀ
IR (CHCl3): m = 2,979, 2,950 (mCꢁH ), 2,843 (mCꢁH ),
asym
asym
2,485 (m
tertiary amine salt), 1,727 (mC¼O), 1,622,
NꢁH
1,594 (mC¼C), 1,366, 1,307, 1,271 (m
), 1,185,
2
2
CꢁOꢁCasym
reflection file because of their large ðjF j ꢁjFcj Þ differ-
ꢀ
ꢁ o
2
1,093 (m
), 972, 914, 850, 800, 780, 732 (c
)
2
2
CꢁOꢁCasym
CꢁH
ences. The function Rw jFoj ꢁjFcj
was minimized
cm-1
.
2
2
with wꢁ1 ¼ ½r2ðFoÞ þð0:1234PÞ þ0:3568Pꢂ, where P ¼
À
Á
Fo2 þ 2Fc2 =3.
Non-hydrogen atoms were refined with anisotropic ther-
Microbiology
mal data and the atoms of O-aminoethyl substituent were
found to be disordered. So, the C12, C13A, and C13B atoms
were located in two alternative positions and their occu-
pancies were refined to 0.487(5) for C12A/C13A/C13B and
0.513(5) for C12B/C13C/C13D. The coordinates of the
hydrogen atoms were generated geometrically and refined
‘‘riding’’ on their parent atoms with Uiso set at 1.2 (1.5 for
methyl group) times Ueq of the appropriate carrier atom. All
details concerning data collection, crystal data, and structure
refinement are given in Table 5. The supplementary infor-
mation in the CIF form is available from Cambridge
Crystallographic Database Centre, no. CCDC-949328.
The following microbial strains with different cell wall
structures were chosen:
–
Gram-positive bacteria: Micrococcus luteus ATCC
9341, B. cereus ATCC 11778, B. subtilis ATCC 6633,
S. epidermidis ATCC 12228, S. aureus ATCC 6538, S.
aureus ATCC 6538P, E. hirae ATCC 10541;
Gram-negative bacteria: E. coli ATCC 8739, P. aerugin-
osa ATCC 15442; and
–
–
fungal strains: Aspergillus brasiliensis ATCC 16404,
C. albicans ATCC 10231 and ATCC 2091, C.
parapsilosis ATCC 22019, S. cervisiae ATCC 9763,
Z. rouxi ATCC 28253.
Acknowledgments The project was supported by the Medical
University of Warsaw, Faculty of Pharmacy, Grant FW 24/PM1/11.
The cylinder-plate method was used in the preliminary
antimicrobial activity tests [18]. A suspension of the tested
compound (20 mg/cm3, 0.05 cm3, in 0.08 M phosphate
buffer, pH 7.0, containing 10 % DMSO) was placed in the
cylinder. The cylinders were placed on a Muller–Hinton 2
or Sabouraud agar plate inoculated with one of the tested
strains. The bacterial strains were incubated at 37 °C for
24 h and the fungal strains at 30 °C for 48 h. Minimal
inhibitory concentration (MIC) was obtained by mixing
with 19 cm3 Mueller–Hinton 2 agar and cooling to 56 °C
with 1 cm3 of the appropriate dilution of the tested com-
pound. Then, 2 9 10-3 cm3 of a particular cell suspension
of optical density 0.5 unit on the McFarland scale was
applied to the surface of the agar. The lowest concentration
of tested compound which totally inhibited growth of the
examined strain was evaluated as MIC value [19]. For
control samples, MIC values of ciprofloxacin ranged
between 0.14 and 0.37 9 10-3 lmol/cm3 for bacterial
strains and MIC values of fluconazole ranged between
3.9 9 10-4 and 8.4 9 10-1 lmol/cm3 for yeast strains.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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