Synthesis and antimicrobial activity of some novel derivatives of benzofuran: Part 2. The synthesis and antimicrobial activity of some novel 1-(1-benzofuran-2-yl)-2-mesitylethanone derivatives

Article abstract of DOI:10.1016/j.ejmech.2007.03.023

The reaction of salicylaldehyde with 1-chloro-3-mesitylacetone (2) and potassium carbonate was used to prepare 1-(1-benzofuran-2-yl)-2-mesitylethanone (4) for the starting reagent purposes. 1-(1-Benzofuran-2-yl)-2-mesitylethanoneoxime (5) was synthesized by the reaction of the compound (4) with hydroxylamine. New derivative of 1-(1-benzofuran-2-yl)-2-mesitylethanoneoxime (5) as 1-(1-benzofuran-2-yl)-2-mesitylethanonesemicarbazone (7) was obtained in very high yields. Alkyl substituted N-oxime ethers (8a-d) were obtained by the reaction compound 5 and various halogen contained compounds. The compounds 9a-d were synthesized by the reaction of the compound (5) and four different acyl chlorides. Some of the synthesized compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 25922 and Candida albicans ATCC 10231. Among the synthesized compounds (E)-1-(1-benzofuran-2-yl)-2-mesitylethanone-O-benzoyloxime (9b) was found the most active derivative against S. aureus ATCC 6538 and E. coli ATCC 25922. The other compounds exhibited moderate activity against the other test microorganisms.

Full text of DOI:10.1016/j.ejmech.2007.03.023

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 300e308
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial activity of some novel derivatives of
benzofuran: Part 2. The synthesis and antimicrobial activity of
some novel 1-(1-benzofuran-2-yl)-2-mesitylethanone derivatives
a
a
a
Cumhur Kirilmis a, , Misir Ahmedzade , Suleyman Servi , Murat Koca ,
*
¨
Ahmet Kizirgil b, Cavit Kazaz c
a Firat University, Faculty of Science and Arts, Department of Chemistry, 23169 Elazig, Turkey
b Firat University, School of Medicine, Department of Clinical Microbiology, 23169 Elazig, Turkey
c Ataturk University, Faculty of Science and Arts, Department of Chemistry, Erzurum, Turkey
Received 18 November 2006; received in revised form 6 March 2007; accepted 19 March 2007
Available online 7 April 2007
Abstract
The reaction of salicylaldehyde with 1-chloro-3-mesitylacetone (2) and potassium carbonate was used to prepare 1-(1-benzofuran-2-yl)-2-
mesitylethanone (4) for the starting reagent purposes. 1-(1-Benzofuran-2-yl)-2-mesitylethanoneoxime (5) was synthesized by the reaction of
the compound (4) with hydroxylamine. New derivative of 1-(1-benzofuran-2-yl)-2-mesitylethanoneoxime (5) as 1-(1-benzofuran-2-yl)-2-mesi-
tylethanonesemicarbazone (7) was obtained in very high yields. Alkyl substituted N-oxime ethers (8aed) were obtained by the reaction com-
pound 5 and various halogen contained compounds. The compounds 9aed were synthesized by the reaction of the compound (5) and four
different acyl chlorides. Some of the synthesized compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC
6538, Escherichia coli ATCC 25922 and Candida albicans ATCC 10231. Among the synthesized compounds (E )-1-(1-benzofuran-2-yl)-2-me-
sitylethanone-O-benzoyloxime (9b) was found the most active derivative against S. aureus ATCC 6538 and E. coli ATCC 25922. The other
compounds exhibited moderate activity against the other test microorganisms.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Antimicrobial activity; Mesitylene; Benzofuran; Ketoxime
1. Introduction
benzofurans are amiodarone, angelicin xanthotoxin, bergapten,
nodekenetin and usnic acid compounds (Fig. 1). The benzofu-
ran ring system is the basic skeleton of numerous compounds
possessing cardiovascular activities [4]. Amiodarone, an iodin-
ated lipophilic benzofuran derivative, is widely used in the
treatment of ventricular tachyarrhythmia and atrial fibrillation
[5,6]. Initially marketed as an antianginal agent, amiodarone
possesses coronary and peripheral vasodilator effects and ex-
erts a negative chronotropic and dromo-tropic influence on
the sinoatrial and atrioventricular nodes, respectively [7].
Benzofuran containing structures have been found among
naturally occurring furocoumarins, such as psoralen and me-
thoxalen isolated from the seed of Ammi majus L. and used
for the treatment of psoriasis and other dermal diseases [8,9].
Psoralen is structurally related to coumarin by the addition of
Benzofuran derivatives are an important class of heterocy-
clic compounds that are known to possess important biological
properties. Substituted benzofurans find application such as of
fluorescent sensor [1], oxidant [2], antioxidants, brightening
agents, a variety of drugs and in other field of chemistry and
agriculture [3].
Benzofurans occur in a great number of natural products.
Many of the natural benzofurans have physiological, pharma-
cological and toxic properties. The most recognized of the
* Corresponding author. Tel.: þ90 424 237 0000; fax: þ90 424 233 0062.
E-mail address: ckirilmis@firat.edu.tr (C. Kirilmis).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.03.023

C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
301
CH3
O
O
O
OH
O
O
O
O
O
O
O
Angelicin
Bergapten
I
Nodakenetin
N
CH3 OH
CH3
O
O
CH3
O
O
CH3
OH
(+) Usnic acid
Fig. 1. Benzofuran containing some biological molecules.
O
OH
O
O
O
CH3
I
O
H3C
O
O
CH3
-
Amiodarone
Xanthotoxin
a fused furan ring, and may be considered as a derivative of um-
belliferone. Some important psoralen derivatives are impera-
torin, xanthotoxin, bergapten and nodekenetin. One of the
most important applications of psoralen is in the field of photo
chemotherapy, where psoralens are capable of undergoing
photo addition with thymine units present in DNA [10].
Usnic acid is one of the most common and abundant lichen
metabolites, well known as an antibiotic, but also endowed
with several other interesting properties. Both the (þ) and
(ꢀ) enantiomers of usnic acid are effective against a large va-
riety of Gram-positive bacterial strains, including strains from
clinical isolates, irrespective of their resistant phenotype. Of
particular relevance is the inhibition of growth of multi-
resistant strains of Staphylococcus aureus, enterococci and
mycobacteria. The (þ)-usnic acid enantiomer appears to be se-
lective against Streptococcus mutans without inducing perturb-
ing side effects on the oral saprophyte flora [11]. This
compound inhibits bacterial as well as eukaryotic cell prolifer-
ation in vitro. Its antimitotic and antiproliferative action was
shown in a variety of biological systems including higher plant
cells. Also, the pharmacological potential of usnic acid has
been evaluated in the control of tumor proliferation [12].
The spread of multi drug-resistant strains of fungus and
bacteria the reduced number of drugs available, makes it nec-
essary to discover new classes of antifungal and antibacterial
compounds that inhibit these resistant mechanisms. This has
led to a search for therapeutic alternatives, particularly among
medicinal plants and compounds isolated from them, used for
their empirically antimicrobial properties.
against S. aureus [15]. Encouraged by the good results ob-
tained from that work, we planned to prepare 1-(1-benzofu-
ran-2-yl)-2-mesitylethanone derivatives (5e11) and perform
antimicrobial activity tests.
In this study, the starting material, 1-chloro-3-mesitylpro-
pane-2-ol (1) was synthesized from the reaction of mesitylene
and 1-chloro-2,3-epoxypropane according to cited Ref. [16]
and it was characterized by using spectroscopic methods.
1-(1-Benzofuran-2-yl)-2-mesitylethanone (4) was obtained by
the reaction of salicylaldehyde with 1-chloro-3-mesitylacetone
(2) in presence of potassium carbonate. (E,Z )-1-(1-Benzofu-
ran-2-yl)-2-mesitylethanoneoxime (5) was synthesized from
the reaction of the compound (4) with hydroxylamine hydro-
chloride. The derivatives of compound 5, such as, 8aed,
9aed, 10 and 11 were obtained in good yields and these com-
pounds were synthesized for the first time and characterized in
the present study. Some of the synthesized compounds were
tested in vitro for their antimicrobial activities. Melting points
and yields of the obtained compounds are given in Section 4.
2. Chemistry
In the first part of the study, 1-chloro-3-mesitylpropane-2-ol
(1) was synthesized from FriedeleCrafts alkylation reaction
with mesitylene and epichlorohydrine by using AlCl3 as cata-
lyst at ꢀ5 ꢁC [16]. 1-Chloro-3-mesitylacetone (2) was pre-
pared by oxidation reaction of the compound 1 and Jones
reagent at room temperature. 3-Mesityl-1-thiocyanateacetone
(3) was obtained from the SN reaction of 1-chloro-3-mesityla-
cetone (2) and SCNꢀ.
1-(1-Benzofuran-2-yl)-2-mesitylethanone (4) was synthe-
sized from the reaction of the compound 2 and salicylaldehyde
with K2CO3 in acetone. Structure of this compound was charac-
terized by using FT-IR, 1H NMR, 13C NMR and X-ray data [17].
In order to improve yields of this compound, many reactions
were performed with various bases (NaH, KOH, Na2CO3 and
K2CO3, etc.) and solvents (acetonitrile, acetone, ethanol, ben-
zene and THF, etc.) at various temperatures. When K2CO3
and acetone were used for the synthesis of 1-(1-benzofuran-2-
yl)-2-mesitylethanone (4), maximum yield was obtained. The
Previously, our group reported the synthesis and antimi-
crobial activity of some bis-(benzofuran-2-yl)methanone and
cyclobutane substituted benzofuran derivatives. Bis-(benzofu-
ran-2-yl)methanone exhibited activity towards all the microor-
ganisms studied, but its derivatives generally showed moderate
activity at the higher concentrations towards many of the bac-
teria and the fungus tested [13,14], but cyclobutane substituted
benzofuran derivatives exhibited very strong antimicrobial
effect against Candida albicans and (benzofuran-2-yl)(3-ph-
enyl-3-methylcyclobutyl)-O-[2-hydroxy-3-(N-methylpiperazi-
no)]propylketoxime was found to be the most active derivative

302
C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
CH3
CH3
CH3
CH3
AlCl3
Na2Cr2O7
H2SO4
Cl
Cl
+
O
KSCN
CH3
CH3
Cl
SCN
O
O
CH3
CH3
CH3
CH3
OH
CH3
CH3
3
1
2
H3C
O
CH3
CH3
K2CO3
H
Cl
+
O
O
O
OH
CH3
CH3
CH3
2
4
Scheme 1. Synthesis of 3-mesityl-1-thiocyanateacetone (3) and 1-(1-benzofuran-2-yl)-2-mesitylethanone (4).
most relevant temperatures were determined as boiling points of
the solvents [15]. The synthesis of compounds 1e11 is pre-
sented in Schemes 1 and 2.
(E,Z )-1-(1-Benzofuran-2-yl)-2-mesitylethanoneoxime (5)
was synthesized by reflux of compound 4 with NH2OH$HCl
and natrium acetate in ethanol. 1-(1-Benzofuran-2-yl)-2-mesi-
tylethanole (6) was prepared from the reaction of compound 4
and NaBH4. 1-(1-Benzofuran-2-yl)-2-mesitylethanonesemi-
carbazone (7) was synthesized from the reaction of compound
4 and semicarbazide hydrochloride.
The synthesis of compounds 8aed was carried out by the
SN reaction of compound 5 and different alkyl halogens with
potassium carbonate in acetone. Compounds 9aed were syn-
thesized by O-acylation reaction of compound 5 and four dif-
ferent acyl chlorides such as, acetyl chloride, benzoyl chloride,
4-methoxybenzoyl chloride and phenyl acetyl chloride, after
neutralizing the reaction mixture with 5% ammonia solutions.
(E,Z )-[1-(1-Benzofuran-2-yl)-2-mesityl-ethylideneaminooxy]
acetic acid hydrazide (10) was obtained by reflux of the com-
pound 8d with hydrazine monohydrate (99%) in ethanol. The
synthesis of (E,Z )-[1-(1-benzofuran-2-yl)-2-mesityl-ethyli-
deneaminooxy]acetic acid (11) was performed with NaOH
and the compound 8d, after the reaction mixture neutralized
with dilute HCl.
Compounds 3e7, 8aed, 9aed, 10 and 11 were first time
synthesized and characterized in this study. For compounds
8aed and 9b, only the E isomer was isolated, whereas the
compounds 9a, 9c, 9d, 10 and 11 were obtained as the mixture
of E and Z isomers. The isomer rates were calculated by the
1H NMR integrals and these values are shown in Table 1.
Some of the synthesized compounds were tested in vitro for
their antimicrobial activities.
Mes
NH2NH2
O
N
O
Mes
O
8d
N
10
O
Mes
OH
HN NH2
O
R1
O
8a-d
Mes
NaOH
6
N
O
O
R1-X
NaBH4
O
11
OH
Mes
Mes
NH2OH
CH3
N
HO
O
O
O
Mes =
5
4
H3C
CH3
R2C(O)-Cl
NH2NHC(O)NH2
Mes
R
1
8a CH3-,
8b CH3CH2 -
8c
X=I
X=Br
X=Cl
Mes
N
C6H5CH2 -
8d
C H OC(O)CH -
X=Br
2
5
2
N
O
O
O
HN
R
C2H3-,
R2
O
NH2
9a
O
9b C6H5-
9c
C6H5CH2 -
7
9a-d
9d
(p-OCH3)C6H5-
Scheme 2. Synthesis of 1-(1-benzofuran-2-yl)-2-mesitylethanone (4), 1-(1-benzofuran-2-yl)-2-mesitylethanoneoxime (5) and their derivatives.

C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
303
Table 1
E and Z isomer rates of 1-(1-benzofuran-2-yl)-2-mesitylethanoneoxime (5)
and its derivatives
Table 2
Antimicrobial activities of compounds (1e7, 8a, 8d, 9b, 9c and 10) against
S. aureus, E. coli and C. albicans
Compound no.
E isomers (%)
Z isomer (%)
Compound no.
MIC values (mg/ml)
5
65
100
100
100
100
50
35
e
e
S.a.
E.c.
C.a.
8a
8b
8c
8d
9a
9b
9c
9d
10
11
1
128
16
64
64
32
16
2
e
3
256
128
128
128
256
256
4
256
128
128
64
32
e
5
128
64
50
e
6
100
64
7
8a
64
64
36
38
38
66
128
256
32
62
62
8d
9b
256
64
34
9c
10
256
256
1
128
64
128
32
Meropenem
Fluconazole
0.125
e
3. Result and discussion
e
e
0.25
S.a., Staphylococcus aureus ATCC 6538; E.c., Escherichia coli ATCC 25922;
C.a. Candida albicans ATCC 10231.
The structures of the synthesized compounds were verified
by using 1H, 13C NMR and FT-IR spectroscopic methods. Melt-
ing points and yields of the compounds are given in Section 4.
In the IR spectra of (E,Z )-1-(1-benzofuran-2-yl)-2-mesity-
lethanoneoxime (5) was displayed broad OH absorption peak
between 3429 and 3199 cmꢀ1 and NeO (stretching) absorption
peak at 995 cmꢀ1. As is known, oxime can be found in two
different isomeric structures namely, the syn (Z ) and anti (E )
configurations [18,19]. It was expected that 1-(1-benzofuran-
2-yl)-2-mesitylethanoneoxime (5) shows two different iso-
meric structures. When the 1H NMR spectra were investigated
for the compound 5 and its derivatives (9a, 9c, 9d, 10 and 11)
two different proton signals were observed for E and Z isomers,
whereas only E isomer was isolated for compounds 8aed and
9b. It might be as a result of the crystallization technique [15].
When the E and Z isomers were separately isolated, E isomer
was appeared at lower frequency than Z isomer [20e24]. In
spite of our all efforts, E and Z isomers belonging to com-
pounds 5, 9a, 9c, 9d, 10 and 11 could not be separated by using
column chromatography. E and Z isomer rates of these com-
pounds were calculated from integrated height in the 1H
NMR spectra and these values are given in Table 1.
of the selected microorganisms in vitro showing MIC values
between 4 and 256 mg/ml.
Because the compounds (5, 9a, 9c, 9d and 10) weren’t
able to purified with chromatographic and crystallographic
methods, these compounds were obtained as E and Z isomer
mixture (Table 1) and their antimicrobial activity results are
given as isomer mixture in Table 2.
Among the synthesized compounds, (E )-1-(1-benzofuran-
2-yl)-2-mesitylethanone-O-benzoyloxime (9b) was found to
be the most active derivative against S. aureus and E. coli at
MIC values of 4 and 32 mg/ml, respectively. Compound 2
showed the best activity against C. albicans (16 mg/ml) but
the compounds 1, 3 and 10 also showed a good activity with
MICs of 32 mg/ml. Also, the other compounds exhibited mod-
erate activity against the other test microorganisms.
4. Experimental
4.1. Chemistry
1
In the H NMR spectra (E,Z )-1-(1-benzofuran-2-yl)-2-me-
All of the reagents were obtained from commercial sources.
Solvents were dried and purified with known conventional
methods. Melting points (uncorrected) were determined on
a Gallenkamp apparatus. The IR spectra were measured on
a Mattson 1000 FT-IR spectrophotometer (potassium bromide
disks). The 1H NMR spectra were recorded on a Varian-Gem-
ini 200 MHz spectrometer and are reported in ppm (d) relative
to tetramethyl silane (TMS) as the internal standard and 13C
NMR (50.34 MHz) is referenced to deutero-chloroform
(CDCl3). Elemental analyses were determined by a LECO
CHNSO-932 auto elemental analysis apparatus. Analyses
(TLC) were performed on recoated 0.2 mm Merck Kieselgel
60 F254 plates. Column chromatography was performed using
Merck silica gel, 70e230 mesh.
sitylethanoneoxime (5) signals belonging to ]NeOH ap-
peared at 8.69 (for Z isomer) and 9.88 (for E isomer) ppm.
In the 13C NMR spectra of compound 5, C]N signal was dis-
played at d 156 ppm while the C]O signal disappeared.
3.1. Biological evaluation
We have designed and synthesized novel compounds of
mesitylene substituted benzofuran class, in order to investigate
antimicrobial activity. The compounds (1e7, 8a, 8d, 9b, 9c
and 10) were tested for antimicrobial activity against S. au-
reus, Escherichia coli and C. albicans.
The minimal inhibitory concentration (MIC) of the synthe-
sized compounds was determined against S. aureus, E. coli
and C. albicans using a standard broth dilution technique.
All the MIC results are presented in Table 2. The obtained
data reported that compounds were able to inhibit the growth
4.1.1. Synthesis of 1-chloro-3-mesitylpropane-2-ol (1)
Mesitylene (1700 mL, d: 0.864 g/cm3, 12.21 mol) and dry
AlCl3 (305.2 g, 2.29 mol) were placed in a 5 L two-necked

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C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
flask. Epichlorohydrine (175 mL, d: 1.18 g/cm3, 2.23 mol) was
added drop wise at 15 ꢁC and the reaction mixture was stirred
at room temperature for 2 h. The mixture was hydrolyzed with
15% HCl solution and then neutralized with a 5% solution of
NaOH. The residue was extracted with diethyl ether and the
ether phase dried over MgSO4. After the residue was distil-
lated in vacuum at 145e148 ꢁC (5 mmHg), the following
product was obtained.
65.28; H, 5.69; N, 6.33; S, 13.54. Yield %: 85.55. M.p.
125e126 ꢁC.
4.1.4. Synthesis of 1-(1-benzofuran-2-yl)-2-
mesitylethanone (4)
Salicylaldehyde (82.5 mL, d: 1.146 g/cm3, 24 mmol), dry
K2CO3 (4.91 g, 35.6 mmol) and dry acetone (200 mL) were
placed in a 500 mL flask with a reflux condenser. The mix-
ture was stirred at room temperature for 1 h. To the mixture,
compound 2 (23.73 mmol, 5.0 g) was added and refluxed for
3 h. The reaction mixture was cooled, and then water was
added. The solid filtrated off, dried and the compound (4)
was recrystallized from ethanol. The following product was
obtained.
4.1.1.1. 1-Chloro-3-mesitylpropane-2-ol (1). IR (KBr) (n,
cmꢀ1), 3593e3284 (OeH stretching), 1028 (CeO stretching),
1
852 (CeCl stretching); H NMR (CDCl3, 200 MHz) d (ppm),
2.38 and 2.44 (s, 9H, 3CH3), 2.97 (d, J ¼ 6.0 Hz, 2H, eCH2e
CHe), 3.62e3.76 (m, 3H, eCH2eCHeCH2eCl), 4.06e4.08
(broad, 1H, OH ), 6.98 (s, 2H, aromatic protons); 13C NMR
(CDCl3) d: 22.51 (2C), 22.95, 36.12, 51.84, 73.77 (CHe
OH), 131.38 (2C), 133.36, 138.04, 139.14 (2C). Anal. Calcd.
for C12H17ClO: C, 67.76; H, 8.06. Found: C, 67.25; H, 7.96.
Yield %: 64.21.
4.1.4.1. 1-(1-Benzofuran-2-yl)-2-mesitylethanone (4). IR (KBr)
(n, cmꢀ1), 1680 (C]O stretching), 1161 (CeOeC stretching),
1059 and 758 (]CH benzofuran out of plane ring bending);
1H NMR (CDCl3, 200 MHz) d (ppm), 2.23 and 2.29 (s, 9H,
3CH3), 4.38 (s, 2H, Ar-CH2e), 6.95 (s, 2H, mesitylene ring
protons), 7.57 (s, 1H, furan ring), 7.28e7.78 (m, 4H, benzofu-
ran ring protons); 13C NMR (CDCl3) d: 22.36 (2C), 22.95,
41.83, 114.47 (2C), 125.30, 125.92, 129.14, 130.18, 130.39,
130.92 (2C), 138.60, 139.05 (2C), 154.65, 157.55, 190.92
(C]O). Anal. Calcd. for C19H18O2: C, 81.99; H, 6.52. Found:
C, 81.23; H, 6.58. Yield %: 69.84. M.p. 172e173 ꢁC.
4.1.2. Synthesis of 1-chloro-3-mesitylacetone (2)
Compound
1 (9.5 g, 8.04 mmol), Na2Cr2O7 (7.0 g,
26.71 mmol) and H2O (7.3 mL) were placed in a 100 mL
two-necked flask with a reflux condenser. H2SO4/H2O (7.5/
3.0 mL) solution was added drop wise to the reaction mixture
at 27 ꢁC for 8 h. The mixture was extracted with diethyl ether
and ether phase dried with MgSO4. After filtration and re-
moval of the solvent under reduced pressure, the compound
2 was recrystallized from ethanol. The following product
was obtained.
4.1.5. Synthesis of 1-(benzofuran-2-yl)-
2-mesitylethanoneoxime (5)
Compound 4 (3.0 g, 10.77 mmol), NH2OH$HCl (0.83 g,
12.0 mmol) and 25 mL pyridine were placed in a 100 mL flask
with a reflux condenser. The reaction mixture was refluxed for
2 h. The mixture was cooled, and water was added drop wise.
The solid was filtrated off, dried and the compound 5 was re-
crystallized from acetone. The following product was
obtained.
4.1.2.1. 1-Chloro-3-mesitylacetone (2). IR (KBr) (n, cmꢀ1),
1727 (C]O stretching), 750 (CeCl stretching); 1H NMR
(CDCl3, 200 MHz) d (ppm), 2.24 and 2.30 (s, 9H, 3CH3),
3.95 (s, 2H, Ar-CH2e), 4.13 (s, 2H, C(O)eCH2eCl), 7.28
(s, 2H, aromatic protons); 13C NMR (CDCl3) d: 22.33 (2C),
22.88, 43.13, 49.84, 129.62, 131.17 (2C), 138.76 (2C),
138.95, 202.04 (C]O). Anal. Calcd. for C12H15ClO: C,
68.40; H, 7.18. Found: C, 67.20; H, 6.98. Yield %: 69.75.
M.p. 69e70 ꢁC.
4.1.5.1. (E,Z )-1-(1-Benzofuran-2-yl)-2-mesitylethanoneoxime
(5). IR (KBr) (n, cmꢀ1), 3429e3199 (OeH stretching),
1613 (C]N stretching), 1169 (CeOeC stretching), 1065
(]CH benzofuran out of plane ring bending), 995 (NeO
1
4.1.3. Synthesis of 3-mesityl-1-thiocyanateacetone (3)
stretching); H NMR (CDCl3, 200 MHz) d (ppm), 2.34 and
The compound 2 (2.1 g, 10 mmol), KSCN (0.19 g, 2 mmol)
and absolute ethanol (50 mL) were placed in a 100 mL flask
with a reflux condenser. The reaction mixture was refluxed for
12 h. After the mixture was cooled, water was added drop
wise. The solid was filtrated off, dried and the compound 3 was
recrystallized from ethanol. The following product was obtained.
2.37 (s, 9H, 3CH3), 4.22 (s, 2H, Ar-CH2e), 6.23 for Z isomer
and 6.95 for E isomer (s, 1H, furan ring), 7.01 (s, 2H, mesity-
lene ring protons), 7.21e7.78 (m, 4H, benzofuran ring pro-
tons), 8.69 for Z isomer and 9.88 for E isomer (s, 1H, Ne
OH); 13C NMR (CDCl3) d: 22.03 (2C), 22.31, 33.23,
113.35, 115.84, 124.35, 125.29, 128.19, 130.94 (2C),
131.21, 132.25, 139.00 (2C), 146.93, 151.56, 155.49, 156.41
(C]NeOH). Anal. Calcd. for C19H19NO2: C, 77.79; H,
6.53; N, 4.77. Found: C, 76.60; H, 6.99; N, 4.54. Yield %:
97.91. M.p. 189e191 ꢁC.
4.1.3.1. 3-Mesityl-1-thiocyanateacetone (3). IR (KBr) (n,
1
cmꢀ1), 2153 (C^N stretching), 1708 (C]O stretching); H
NMR (CDCl3, 200 MHz) d (ppm), 2.23 and 2.29 (s, 9H,
3CH3), 3.87 (s, 2H, Ar-CH2e), 3.96 (s, 2H, C(O)eCH2e
SCN), 6.91 (s, 2H, aromatic protons); 13C NMR (CDCl3) d:
22.38 (2C), 22.91, 44.94, 45.58, 113.39 (SeC^N), 128.95,
131.51 (2C), 138.66 (2C), 139.52, 201.54. Anal. Calcd. for
C13H15NOS: C, 66.92; H, 6.48; N, 6.00; S, 13.74. Found: C,
4.1.6. Synthesis of 1-(1-benzofuran-2-yl)-
2-mesitylethanole (6)
Compound 4 (1.0 g, 3.59 mmol) and NaBH4 (0.14 g,
3.70 mmol) in 1,4-dioxane (50 mL) were placed in a 100 mL

C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
305
flask. The reaction mixture was stirred at room temperature for
24 h and then to the mixture, water was added drop wise. The
solid was filtrated, dried and the compound 6 was recrystal-
lized from ethanol. The following product was obtained.
200 MHz) d (ppm), 2.28 and 2.34 (s, 9H, 3CH3), 3.95 (s,
3H, OeCH3), 4.12 (s, 2H, Ar-CH2e), 6.86 (s, 2H, mesitylene
ring protons), 7.26e7.66 (m, 5H, benzofuran ring protons);
13C NMR (CDCl3) d: 22.30, 22.88 (2C), 33.66, 64.64
(CH3e), 113.42, 124.60, 124.13, 125.11, 127.94, 130.42,
130.58 (2C), 133.09, 137.52, 139.23 (2C), 146.66, 148.62,
155.29. Anal. Calcd. for C20H21NO2: C, 78.15; H, 6.89; N,
4.56. Found: C, 78.10; H, 6.75; N, 3.98. Yield %: 74.64.
M.p. 86e87 ꢁC.
4.1.6.1. 1-(1-Benzofuran-2-yl)-2-mesitylethanole (6). IR (KBr)
(n, cmꢀ1), 3375 (OeH stretching), 1072 and 1027 (CeOeC
1
stretching); H NMR (CDCl3, 200 MHz) d (ppm), 2.28 and
2.33 (s, 9H, 3CH3), 3.29 (d, J ¼ 5.7 Hz, 2H, eCHeCH2e),
5.01 (t, J ¼ 3.1 Hz, 1H, eCH2eCHeO), 6.64 (s, 1H, furan
ring), 6.89 (s, 2H, mesitylene ring protons), 7.26e7.53 (m,
4H, benzofuran ring protons); 13C NMR (CDCl3) d: 22.26
(2C), 22.83, 37.69, 70.41 (CHeOH), 104.50, 113.26,
123.02, 124.78, 126.13, 130.20, 131.22 (2C), 133.02,
138.10, 139.37 (2C), 156.80, 161.03. Anal. Calcd. for
C19H20O2: C, 81.40; H, 7.19. Found: C, 80.21; H, 6.41. Yield
%: 90.45. M.p. 75e76 ꢁC.
4.1.8.2. (E )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-ethyl-
oxime (8b). IR (KBr) (n, cmꢀ1), 1138 (CeOeC benzofuran
ring stretching), 977 (NeO stretching); 1H NMR (CDCl3,
200 MHz) d (ppm), 1.29 (t, J ¼ 7.0 Hz, 3H, eOeCH2e
CH3), 2.28 and 2.34 (s, 9H, CH3), 4.12 (s, 2H, Ar-CH2),
4.18 (q, J ¼ 7.0 Hz, 2H, OeCH2eCH3), 6.86 (s, 2H, mesity-
lene ring protons), 7.22e7.69 (m, 5H, benzofuran ring pro-
tons); 13C NMR (CDCl3) d: 16.80 (CH3e), 22.28, 22.89
(2C), 33.71, 72.43, 113.41, 115.13, 124.12, 125.08, 127.87,
130.48, 130.55 (2C), 133.20, 137.44, 139.22 (2C), 146.30,
148.83, 155.27. Anal. Calcd. for C21H23NO2: C, 78.48; H,
7.21; N, 4.36. Found: C, 78.00; H, 7.68; N, 3.52. Yield %:
73.26. M.p. 74e75 ꢁC.
4.1.7. Synthesis of 1-(1-benzofuran-2-yl)-
2-mesitylethanonesemicarbazone (7)
Compound 4 (7.18 mmol, 2.00 g), semicarbazide hydrochlo-
ride (10 mmol, 1.11 g), natrium acetate (10 mmol, 1.36 g) and
ethanol/water (80/20 mL) were placed in a 250 mL flask with
a reflux condenser. The reaction mixture was refluxed for
12 h. The reaction mixture was cooled, and then water was
added drop wise. The solid was filtrated off, dried and the com-
pound 7 was recrystallized from ethanol. The following product
was obtained.
4.1.8.3. (E )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-ben-
zyloxime (8c). IR (KBr) (n, cmꢀ1), 1170 and 1113 (CeOeC
1
benzofuran ring stretching), 991 (NeO stretching); H NMR
(CDCl3, 200 MHz) d (ppm), 2.27 and 2.31 (s, 9H, 3CH3),
4.12 (s, 2H, Ar-CH2), 5.16 (s, 2H, Ar-CH2eO), 6.87 (s, 2H,
mesitylene ring protons), 7.22e7.70 (m, 10H, benzofuran
and phenyl ring protons); 13C NMR (CDCl3) d: 22.19 (2C),
22.90, 33.67, 79.08 (PheCH2e), 113.42, 115.45, 124.21,
125.12, 127.98, 129.78 (2C), 130.24 (2C), 130.33, 130.47
(3C), 133.06, 137.46, 139.22 (2C), 139.84, 146.95, 148.70,
155.34. Anal. Calcd. for C26H25NO2: C, 81.43; H, 6.57; N,
3.65. Found: C, 80.95; H, 6.12; N, 3.02. Yield %: 83.07.
M.p. 94e95 ꢁC.
4.1.7.1. 1-(1-Benzofuran-2-yl)-2-mesitylethanonesemicarba-
zone (7). IR (KBr) (n, cmꢀ1), 3464e3388 (NeH stretching),
1706 (C]O stretching), 1581 (CeN stretching), 1142e1048
1
(CeOeC stretching); H NMR (CDCl3, 200 MHz) d (ppm),
2.26 and 2.30 (s, 9H, 3CH3), 3.96 (s, 2H, Ar-CH2e), 5.47e
5.51 (broad, 2H, C(O)eNH2), 6.89 (s, 2H, mesitylene ring
protons), 7.16 (s, 1H, furan ring), 7.33e7.70 (m, 4H, benzofu-
ran ring protons), 9.85 (s, 1H, NeNHe); 13C NMR (CDCl3) d:
22.09 (2C), 22.60, 35.51, 82.45 (2C), 110.89, 113.83, 124.06,
126.07, 128.63, 128.75, 130.62 (2C), 132.84, 137.94, 151.96,
156.55 (NeCOeN), 159.34, 159.41. Anal. Calcd. for
C20H21N3O2: C, 71.62; H, 6.31; N, 12.53. Found: C, 71.55;
H, 6.12; N, 12.55. Yield %: 78.55. M.p. 206e208 ꢁC.
4.1.8.4. (E )-[1-(1-Benzofuran-2-yl)-2-mesityl-ethylidineami-
nooxy]acetic acid ethylester (8d). IR (KBr) (n, cmꢀ1), 1752
(C]O stretching), 1165 and 1098 (CeOeC benzofuran ring
stretching), 1024 (NeO stretching); 1H NMR (CDCl3,
200 MHz) d (ppm), 1.31 (t, J ¼ 7.0 Hz, 3H, eOeCH2e
CH3), 2.27 and 2.31 (s, 9H, 3CH3), 4.21 (s, 2H, Ar-CH2),
4.27 (q, J ¼ 7.0 Hz, 2H, eOeCH2eCH3), 4.88 (s, 2H, Ne
OeCH2), 6.19 (s, 1H, furan ring), 6.85 (s, 2H, mesitylene
ring protons), 7.09e7.47 (m, 4H, benzofuran ring protons);
13C NMR (CDCl3) d: 16.18, 22.31 (2C), 22.84, 29.54, 62.94,
73.45, 109.77, 113.46, 123.49, 124.85, 127.51 (3C), 131.10
(3C), 132.52, 138.19, 139.17 (2C), 152.87, 171.52 (C]O).
Anal. Calcd. for C23H25NO4: C, 72.80; H, 6.64; N, 3.69.
Found: C, 72.50; H, 6.44; N, 3.19. Yield %: 54.26. M.p.
130e132 ꢁC.
4.1.8. General method for the synthesis
of compounds (8aed)
To a solution of compound 5 (1.0 g, 3.4 mmol) in dry acetone
(150 mL) was added K2CO3 (0.48 g, 3.50 mmol) and was
stirred at room temperature for 1 h. Different alkyl halogens
(3.5 mmol) were added drop wise to the reaction mixture and
were refluxed for 8 h. The reaction mixture was cooled, and
then water was added drop wise. The solid was filtrated off,
dried and then the compounds 8aed were crystallized from ac-
etone/ethanol (3/1). The following products were obtained.
4.1.8.1. (E )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-meth-
4.1.9. General method for the synthesis of compounds 9aed
Compound 5 (1.0 g, 3.40 mmol) and dry acetone (50 mL)
were placed in a 100 mL two-necked flask with a reflux
yloxime (8a). IR (KBr) (n, cmꢀ1), 1083 (CeOeC benzofuran
1
ring stretching), 1023 (NeO stretching); H NMR (CDCl3,

306
C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
condenser. The mixture was cooled to ꢀ5 ꢁC and then acyl
chloride (3.5 mmol) was added drop wise and the reaction
was maintained at room temperature for 2 h. After the reaction
mixture was cooled, it was neutralized with NH3 solution and
the resulting precipitate was filtrated and washed with water.
Compounds 5aec were recrystallized from ethanol. The fol-
lowing product was obtained.
(s, 2H, Ar-CH2), 6.95 (s, 1H, furan ring), 6.96 (s, 2H, mesi-
tylene ring protons), 7.26e7.93 (m, 6H, benzofuran and phe-
nyl ring protons), 8.06e8.13 (m, 2H, phenyl ring protons).
Anal. Calcd. for C27H25NO4: C, 75.86; H, 5.89; N, 3.28.
Found: C, 75.10; H, 5.41; N, 3.12. Yield %: 87.58. M.p.
96e98 ꢁC.
4.1.10. Synthesis of (E,Z )-[1-(1-benzofuran-2-yl)-2-mesityl-
ethylideneaminooxy]acetic acid hydrazide (10)
4.1.9.1. (E,Z )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-ace-
tyloxime (9a). IR (KBr) (n, cmꢀ1), 1777 (C]O stretching),
1173 (CeOeC benzofuran ring stretching), 1004 (NeO
Compound 8d (0.70 g, 1.84 mmol) and hydrazine monohy-
drate (0.97 mL, d: 1.06 g/cm3, 2 mmol, 99%) in ethanol (98%)
were placed in a 100 mL flask with a reflux condenser. The re-
action mixture was refluxed for 3 h. The mixture was cooled,
and then water was added drop wise. The solid was filtrated
off, dried and compound 10 was crystallized from ethanol.
The following product was obtained.
1
stretching); H NMR (CDCl3, 200 MHz) d (ppm), 2.17 for Z
isomer and 2.20 for E isomer (s, 3H, C(O)eCH3), 2.26 for Z
isomer and 2.28 for E isomer (s, 3H, CH3), 2.30 and 2.36 (s,
6H, 2CH3), 4.21 for Z isomer and 4.26 for E isomer (s, 2H,
Ar-CH2), 6.70 (s, 1H, furan ring), 6.87 (s, 2H, mesitylene
ring protons), 7.20e7.74 (m, 4H, benzofuran ring protons).
Anal. Calcd. for C21H21NO3: C, 78.15; H, 6.89; N, 10.41.
Found: C, 76.24; H, 6.47; N, 10.55. Yield %: 80.70. M.p.
89e91 ꢁC.
4.1.10.1. Synthesis of (E,Z )-[1-(1-benzofuran-2-yl)-2-mesityl-
ethylideneaminooxy]acetic acid hydrazide (10). IR (KBr) (n,
cmꢀ1), 3479e3288 (NeH stretching), 1666 (C]O stretch-
ing), 1169e1145 (CeOeC benzofuran ring stretching),
1049 (NeO stretching); 1H NMR (CDCl3, 200 MHz)
d (ppm), 2.28 and 2.30 (s, 9H, 3CH3), 3.68e3.73 (broad,
2H, eNHeNH2), 4.09 for Z isomer and 4.15 for E isomer
(s, 2H, Ar-CH2), 4.75 for Z isomer and 4.97 for E isomer (s,
2H, OeCH2), 6.42e6.44 (broad, 1H, eC(O)eNHeNH2),
6.82 (s, 2H, mesitylene ring protons), 6.91 (s, 1H, furan
ring), 7.23e7.70 (m, 4H, benzofuran ring protons); 13C
NMR (CDCl3) d: 22.17, 22.89 (2C), 33.75, 75.36, 109.71,
113.63, 123.67, 124.45, 125.55, 128.79, 130.76 (2C),
132.13, 137.97, 138.86 (2C), 149.71, 153.29, 156.59, 172.06
(C]O). Yield %: 66.67. M.p. 114e115 ꢁC.
4.1.9.2. (E )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-ben-
zoyloxime (9b). IR (KBr) (n, cmꢀ1), 1747 (C]O stretching),
1176 and 1078 (CeOeC benzofuran ring stretching), 1050
(NeO stretching); 1H NMR (CDCl3, 200 MHz) d (ppm),
2.29 and 2.32 (s, 9H, 3CH3), 4.35 (s, 2H, Ar-CH2), 6.72 (s,
1H, furan ring), 6.88 (s, 2H, mesitylene ring protons), 7.17e
7.95 (m, 7H, benzofuran and phenyl ring protons), 8.12 (d,
J ¼ 4.9 Hz, 2H, phenyl ring protons); 13C NMR (CDCl3) d:
22.55 (2C), 22.86, 31.27, 112.22, 113.91, 116.70, 123.90,
125.21, 128.44 (2C), 129.62 (2C), 130.48 (2C), 130.72 (2C),
131.04, 131.76, 135.42, 138.85, 139.40, 151.18, 156.91,
159.04, 165.42 (C]O). Anal. Calcd. for C26H23NO3: C,
78.57; H, 5.83; N, 3.52. Found: C, 77.48; H, 5.16; N, 3.57.
Yield %: 70.37. M.p. 110e112 ꢁC.
4.1.11. Synthesis of (E,Z )-[1-(1-benzofuran-2-yl)-2-mesityl-
ethylideneaminooxy]acetic acid (11)
4.1.9.3. (E,Z )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-(2-
phenylacetyl)oxime (9c). IR (KBr) (n, cmꢀ1), 1761 (C]O
stretching), 1108 (CeOeC benzofuran ring stretching), 939
(NeO stretching); 1H NMR (CDCl3, 200 MHz) d (ppm),
2.26 and 2.35 (s, 9H, 3CH3), 3.73 for Z isomer and 3.83
for E isomer (s, 2H, C(O)eCH2), 4.15 for Z isomer and
4.25 for E isomer (s, 2H, Ar-CH2), 6.69 (s, 1H, furan ring),
6.88 (s, 2H, mesitylene ring protons), 7.13e7.58 (m, 9H, ben-
zofuran and phenyl ring protons); 13C NMR (CDCl3) d:
22.33, 22.88, 34.24, 42.24, 113.62, 117.84, 124.67, 125.53,
129.07, 129.27 (2C), 129.84, 130.67 (2C), 130.92 (2C),
131.28 (2C), 131.52, 131.66 (2C), 138.17, 139.25, 146.83,
155.06, 158.75, 171.47 (C]O). Yield %: 62.59. M.p. 117e
119 ꢁC.
Compound 8d (0.70 g, 1.84 mmol) and powder NaOH
(0.11 g, 2.76 mmol) in ethanol (98%) were placed in a two-
necked flask with a condenser. The reaction mixture was re-
fluxed for 1 h. The mixture was cooled and then water was
added drop wise and was neutralized with dilute HCl. The
solid was filtrated, dried and compound 11 was recrystallized
from ethanol. The following product was obtained.
4.1.11.1. (E,Z )-[1-(1-Benzofuran-2-yl)-2-mesityl-ethylidenea-
minooxy]acetic acid (11). IR (KBr) (n, cmꢀ1), 1725 (C]O
stretching), 1175e1102 (CeOeC benzofuran ring stretching),
1048 (NeO stretching); 1H NMR (CDCl3, 200 MHz) d (ppm),
2.29 and 2.33 (s, 9H, 3CH3), 4.18 for Z isomer and 4.23 for E
isomer (s, 2H, Ar-CH2), 4.75 for Z isomer and 4.97 for E iso-
mer (s, 2H, NeOeCH2), 6.20 and 6.88 (s, 2H, mesitylene ring
protons), 7.14e7.82 (m, 5H, benzofuran ring protons), 10.21e
10.23 (broad, 1H, OH); 13C NMR (CDCl3) d: 22.37 (2C),
22.92, 29.72, 72.87, 110.22, 113.55, 116.70, 124.49, 128.48,
130.40 (2C), 131.22, 132.40, 138.37, 139.16 (2C), 149.31,
153.53, 156.55, 176.94 (C]O). Anal. Calcd. for C21H21NO4:
4.1.9.4. (E,Z )-1-(1-Benzofuran-2-yl)-2-mesitylethanone-O-(4-
methoxybenzoyl)oxime (9d). IR (KBr) (n, cmꢀ1), 1789 and
1747 (C]O stretching), 1164 (CeOeC benzofuran ring
stretching), 1040 (NeO stretching); 1H NMR (CDCl3,
200 MHz) d (ppm), 2.26 for Z isomer and 2.31 for E isomer
(s, 3H, CH3), 2.45 (s, 6H, 2 CH3), 3.90 (s, 3H, OCH3), 4.34

C. Kirilmis et al. / European Journal of Medicinal Chemistry 43 (2008) 300e308
307
C, 71.78; H, 6.02; N, 3.99. Found: C, 70.54; H, 5.68; N, 3.57.
Yield %: 82.81. M.p. 143e144 ꢁC.
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tion (FUBAP 866) for financial support of this work.

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