Synthesis and antimicrobial activity of some novel derivatives of benzofuran: Part 1. Synthesis and antimicrobial activity of (benzofuran-2-yl)(3- phenyl-3-methylcyclobutyl) ketoxime derivatives

Article abstract of DOI:10.1016/j.ejmech.2005.07.004

The reaction of salicylaldehyde with 1-phenyl-1-methyl-3-(2-chloro-1- oxoethyl) cyclobutane (1) and potassium carbonate was used to prepare (benzofuran-2-yl)(3-methyl-3-phenylcyclobutyl) methanone (2) for the starting reagent purposes. (benzofuran-2-yl)(3

Full text of DOI:10.1016/j.ejmech.2005.07.004

European Journal of Medicinal Chemistry 40 (2005) 1351–1358
www.elsevier.com/locate/ejmech
Short communication
Synthesis and antimicrobial activity of some novel derivatives
of benzofuran: part 1. Synthesis and antimicrobial activity
of (benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl) ketoxime derivatives
Murat Koca a,*, Süleyman Servi a, Cumhur Kirilmis a, Misir Ahmedzade a, Cavit Kazaz b,
Berna Özbek c, Gülten Ötük c
a Department of Chemistry, Faculty Science-Art, Firat University, 23169 Elazig, Turkey
b Chemistry Department, Faculty of Arts and Sciences, Ataturk University, Erzurum, Turkey
c Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
Received 9 May 2005; received in revised form 30 June 2005; accepted 6 July 2005
Available online 29 August 2005
Abstract
The reaction of salicylaldehyde with 1-phenyl-1-methyl-3-(2-chloro-1-oxoethyl) cyclobutane (1) and potassium carbonate was used to
prepare (benzofuran-2-yl)(3-methyl-3-phenylcyclobutyl) methanone (2) for the starting reagent purposes. (benzofuran-2-yl)(3-phenyl-3-
methyl cyclobutyl) ketoxime (3) was synthesized from the reaction of the compound (2) with hidroxylamine. New derivatives of (benzofuran-
2-yl)(3-phenyl-3-methyl cyclobutyl) ketoxime (3) such as, O-glycidylketoxime (4) and O-phenylacylketoxime (5a–c) were obtained very
high yields. Alkyl, allyl and aryl substituted N-oxime ethers (6a–e) were obtained from the reaction compound 3 and various halogen con-
tained compounds. The syntheses of the compounds (7a–f) were carried out from the reaction of the compound (4) and different amines such
as, isopropyl amine, natrium azide, morpholine and piperazine. All of the synthesized compounds were tested for antimicrobial activity
against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae
ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albi-
cans ATCC 10231. Among the synthesized compounds (benzofuran-2-yl)(3-phenyl-3-methyl cyclobutyl)-O-[2-hydroxy-3-(N-
methylpiperazino)] propylketoxime (7d) was found the most active derivative against S. aureus ATCC 6538. The compounds 2, 5b, 6b, 6c, 7b
and 7f showed very strong and the same antimicrobial effect against C. albicans ATCC 10231. Similarly (benzofuran-2-yl)(3-phenyl-3-
methylcyclobutyl)-O-benzylketoxime 6a showed good antimicrobial effect against C. albicans ATCC 10231. None of the other compounds
exhibited activity against the other test microorganisms.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Benzofuran; Cyclobutane; Ketoxime; Antimicrobial activity
1. Introduction
related benzofuran ring structures, which are particularly iso-
lated from Machilus glaucescens, Ophryosporus charua,
Ophryosporus lorentzii, Krameria ramosissima, and Zan-
thoxylum ailanthoidol [1]. The most recognized benzofurans
are ailanthoidol, amiodarone and bufuralol compounds
(Scheme 1). Ailanthoidol, a neolignan with a 2-arylbenzofuran
skeleton, was isolated from the Chinese herbal medicine Zan-
thoxylum ailanthoides. It has been reported that neolignans
and lignans possess a variety of biological activities such as
anticancer, antiviral, immunosuppressive, antioxidant, anti-
fungal and antifeedant activities [2]. Amiodarone is a highly
effective antiarrhythmic agent with class III activity accord-
ing to the classification ofVaughan-Williams. It is used in the
Widespread interest in the chemistry of benzofurans in a
large number of natural products has attracted due to their
biological activities and their potential applications as phar-
macological agents. Several benzofuran ring systems bear-
ing various substituents at the C-2 position are widely distrib-
uted in nature. There are well known natural products having
* Corresponding author. Tel.: +90 424 237 0000; fax: +90 424 233 0062.
E-mail address: rmkoca@yahoo.com (M. Koca).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.07.004

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M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
Scheme 1. Benzofuran containing some biological molecules.
treatment and prophylaxis of both ventricular and supraven-
tricular arrhythmias, in particular in patients with heart insuf-
fucuency, because it has no significant negative inotropic
effect [3]. Bufuralol is a nonselective b-adrenoceptor antago-
nist developed by Hoffman-La Roche. Bufuralol is a chiral
molecule having an asymmetric carbon in its ethanol amine
side chain, yielding the enantiomer 1′R-Bufuralol and 1′S-
Bufuralol, and the b-adrenoceptor blocking activity resides
mainly in 1′S-Bufuralol. This compound is a good substrate
of cytochrome P450 (CYP) and undergoes enantioselective
and regioselective oxidations in liver [4].
2. Chemistry
(Benzofuran-2-yl)(3-methyl-3-phenylcyclobutyl) metha-
none (2) was prepared from the reaction of the 1-phenyl-1-
methyl-3-(2-chloro-1-oxoethyl) cyclobutane (1) and salicyla-
ldehyde with K2CO3 in acetone/acetonitrile solvent mixture.
Structure of this compound was characterized by using FT-IR,
-NMR (1H and 13C) and X-ray data [7–9].
In order to improve yields of compound 2, many reactions
were performed with various bases (NaH, KOH, Na2CO3 and
K2CO3, etc.) and the solvents (acetonitrile, acetone, ethanol,
benzene and THF, etc.) at various temperatures. When K2CO3
base and acetonitrile/acetone solvents were used for synthe-
sis of the compound 2, maximum yield was obtained. The
most relevant temperatures were determined as boiling points
of the solvents [8,9].
The syntheses of compounds 2, 3, 4, 5a–c, 6a–e and 7a–f
were presented in Schemes 2 and 3. (Benzofuran-2-yl)(3-
phenyl-3-methylcyclobutyl) ketoxime (3) was synthesized by
reflux of (benzofuran-2-yl)(3-methyl-3-phenylcyclobutyl)
methanone (2) with hydroxylamine hydrochloride and
natrium acetate in ethanol. (benzofuran-2-yl)(3-phenyl-3-
methylcyclobutyl)-O-glycidyl ketoxime 4 was obtained from
the reaction of (benzofuran-2-yl)(3-phenyl-3-methylcyclo-
butyl) ketoxime (3) and epichlorohydrine and potassium
hydroxide in acetone. Compound 5a–e was obtained by reflux
of (benzofuran-2-yl) (3-phenyl-3-methylcyclobutyl) ketoxime
(3) with various acyl chlorides in acetone. The products 5a, b
was obtained, after the reaction mixture neutralizing with 5%
ammonia solutions. In order to synthesize 5c, acetic anhy-
dride was used instead of acyl chloride. Sodium bicarbonate
was used for neutralizing the reaction mixture in this reac-
tion. Compounds 6a–e were synthesized by the reaction of
compound 3 and different alkyl halogens and potassium car-
bonate in acetone.
The incidence of fungal infection has increased signifi-
cantly in the past 25 years. The growing number of immuno-
compromised patients as a result of cancer chemotherapy,
organ transplantation, and HIV infection are the major fac-
tors contributing to this incidence. Since Candida albicans
(C. albicans), and Aspergillus fumigatus (A. fumigatus) are
the main causative fungi of the systemic mycosis, antifungal
drugs for treating patients of deep mycosis should have a broad
antifungal spectrum including at least these microorganisms.
Currently, only four classes of antifungal drugs, polyene mac-
rolides (amphotericin B), azoles (fluconazole, miconazole,
itraconazole and voriconazole), flucytosine, and candins
(caspofungin acetate and micafungin), are available for treat-
ment of systemic mycoses. Unfortunately, none of them is
ideal in terms of efficacy, antifungal spectrum or safety.
Although amphotericin B is efficacious against both candidi-
asis and aspergillosis, it shows severe renal toxicity [5].
In this study, as the starting material, 1-phenyl-1-methyl-
3-(2-chloro-1-oxoethyl) cyclobutane (1) was synthesized
according to the cited reference [6]. (Benzofuran-2-yl)(3-
methyl-3-phenylcyclobutyl) methanone (2) was obtained by
reaction of salicylaldehyde with 1-phenyl-1-methyl-3-(2-
chloro-1-oxoethyl) cyclobutane (1) in presence of potassium
carbonate. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)
ketoxime (3) was obtained from the reaction of the com-
pound (2) with hidroxylamine hydrochloride (NH2OH·HCl).
By using the compound 3, its derivatives such as, 4, 5a–c,
6a–e and 7a–f were synthesized in good yields.
Compounds 7a–f were synthesized by nucleophilic sub-
stitution reaction of (benzofuran-2-yl)-(3-phenyl-3-methyl-
cyclobutyl)-O-glycidylketoxime (4) and different amines such
as, isopropyl amine, piperidine, morpholine, piperazine and
sodium azide.
3, 4, 5a–c, 6a–e and 7a–f were first time synthesized and
characterized in this present study. Melting points and yields
of obtained compounds are presented in Table 2. The synthe-
sized all compounds were tested in vitro for their antimicro-
bial activity.
This article reports the first synthesis of compounds 3, 4,
5a–c, 6a–e and 7a–f. So far, antimicrobial activity of cyclobu-
tane substituted benzofuran derivatives has not been investi-
gated.

M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
1353
Scheme 2. Synthesis of (benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl) ketoxime(3) derivatives.
Scheme 3. Synthesis of (benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-gylcidylketoxime derivatives (7a–f).
3. Result and discussion
to cyclobutane ring was observed at d 3.9 ppm integrating for
one proton as pentet. This signal was attributed to cis isomer
for all of synthesized compounds. This is appropriate with
cited references [6,8,9].
In the IR spectra of (benzofuran-2-yl)(3-methyl-3-
phenylcyclobutyl) methanone (2) showed C=O absorption
(stretching), which is adjacent to benzofuran ring, at
1689 cm−1 and the signals belonging to furan ring absorption
were observed at 1562 and 1257 cm−1. In 13C-NMR spectra
of this compound the signal belonging to C=O appeared at d
194 ppm.
We have synthesized novel compounds of cyclobutane sub-
stituted benzofuran class in this work. It was expected that
synthesized compounds should have two different isomers in
the cis and trans configurations, due to the methyl and phe-
nyl groups on the cyclobutane ring. In fact, the starting mate-
rial, 3-phenyl-3-methyl-1-(2-chloro-1-oxoethyl) cyclobutane
itself is an 85:15 mixture of cis and trans isomeric structures.
Unfortunately, only cis isomer was isolated. It might be as a
result of the crystallization technique. CH proton belonging

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M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
Table 1
In the IR spectra of (benzofuran-2-yl)(3-phenyl-3-
Antimicrobial activity results (MIC values in mg ml–1) of synthesized com-
pounds
methylcyclobutyl) ketoxime (3) display ed broad OH absorp-
tion peak between 3276 and 3185 cm−1 and N–O (stretching)
Sample
2
5b
S.a.
C.a.
1
absorption peak at 985 cm−1. In H-NMR spectra of com-
–
0.625
0.625
2.5
pound 3 showed at d 12 ppm (N–OH controlled by changing
with D2O). In 13C-NMR spectra this compound C=N signal
appeared d 135 ppm while the signal belonging to C=O (d
195 ppm) disappeared. As is known, oximes can be found in
two different isomeric structures namely, the syn and anti con-
figurations [10,11]. It was expected that compound 3 shows
two different isomeric structures. Unfortunately, only
E-isomer was isolated. It might be as a result of the crystal-
lization technique. d 12 ppm (1H-NMR) and d 135 ppm (13C-
NMR) signals were attributed to E-isomer of compound 3 of
N–OH and C=N, respectively.
–
6a
–
6b
6c
7d
–
0.625
0.625
–
–
0.039
7b
7f
–
–
0.625
0.625
S.a.: S. aureus ATCC 6538, C.a.: C. albicans ATCC 10231.
Among the synthesized compounds (benzofuran-2-yl)(3-
phenyl-3-methylcyclobutyl)-O-[2-hydroxy-3-(N-
methylpiperazino)] propylketoxime 7d was found the most
active derivative at an MIC value of 0.039 mg ml–1 against S.
aureus. Chemically similar compounds (7c, 7e and 7f) did
not at all show antimicrobial activity for resembling test
microorganisms as S. epidermidis. The compounds 2, 5b,
6b, 6c, 7b and 7f showed the same antimicrobial effect against
C. albicans (0.625 mg ml–1). Similarly (benzofuran-2-yl)(3-
phenyl-3-methylcyclobutyl)-O-benzyl ketoxime 6a showed
good antimicrobial effect against C. albicans (2.5 mg ml–1).
Also, none of the other compounds exhibited activity against
test microorganisms.
In the IR spectra of compound 4, 5a–c and 6a–e displayed
no signal belonging to OH group; instead, =N–O–C stretch-
ing appeared at 1040 cm−1 for compound 4. In the IR spectra
of compound 5a–c, C=O absorption of ester was displayed at
1
1447, 1756 and 1774 cm−1, respectively. In H- and 13C-
NMR spectra of compound 4 the signal belonging to 2,3-
epoxipropane are appropriate with cited reference for similar
to compounds [12]. In the 1H-NMR spectra compounds 5a–c,
the signal belonging to CH2, which is between phenyl and
ester groups, were observed at 3.35 ppm as singlet. CH3 pro-
tons were appeared at d 3.2 ppm, as singlet for 5c compound.
In 13 C-NMR of compounds 5a–c, C=O signals appeared d
158, 170 and 170 ppm, respectively.
In IR spectra of compounds 6c–e were observed C=O
absorption at 1702 cm−1 for 6c, =CH2 plane out of plane bend-
ing at 990–919 cm−1 for 6d and C=O absorption at 1753 cm−1.
1H-NMR spectra of compounds 6a–e were observed at
5.40 ppm (CH2CO for 6a), 4.1 (OCH3 for 6b), 5.41 (CH2CO
for 6c), 4.7–6.1 (allylic protons for 6d) and 4.3 and 1.3 (OCH2
and OCH3 for 6e, respectively).
4. Experimental
4.1. Chemistry
All chemicals were reagent grade as received from com-
mercial sources (Sigma–Aldrich and Fluka). 1-Phenyl-1-
methyl-3-(2-chloro-1-oxoethyl) cyclobutane (1) [6] and
(benzofuran-2-yl)(3-methyl-3-phenylcyclobutyl) methanone
(2) were prepared following literature procedures [8,14–16].
Melting points (uncorrected) were determined with a Gallen-
kamp apparatus. The IR spectra were measured with Mattson
1000 FT-IR spectrophotometer (potassium bromide disks).
In IR spectra of compounds 7a–f were appeared broad OH
absorption (stretching) at 3115 and 3448 cm−1. The IR spec-
tra 7b compound showed additional peak at 2099 cm−1 due
to absorption N3. In the 1H-NMR spectra of compounds 7a–f
signals belonging to CH2CH (OH) CH2 are suitable with cited
1
1
The H-NMR spectra were recorded on a Varian-Gemini
reference [12,13]. In the H-NMR spectra of compound 7f
200 MHz spectrometer and are reported in ppm (d) relative
to tetramethylsilane (TMS) as the internal standard and 13C-
NMR (50.34 MHz) is referenced to deuterochloroform
(CDCl3). Elemental analyses were determined on a LECO
CHNSO-932 auto elemental analysis apparatus.
showed no signal belonging to OH group due to effect of
solvent.
3.1. Biological evaluation
In order to investigate the relationships between antimi-
crobial activity and structure, we have designed and synthe-
sized novel compounds of cyclobutane substituted benzofu-
ran class. The minimum inhibitory concentration (MIC) of
the synthesized compounds was determined against the bac-
teria and the yeast C. albicans using a standard broth dilution
technique. All the MIC results are presented in Table 1. The
obtained data reported that compounds were able to inhibit
the growth of the selected micro-organisms in vitro showing
MIC values between 2, 5 and 0.039 mg ml–1.
4.1.1. Synthesis of (benzofuran-2-yl)(3-phenyl-3-methylcy-
clobutyl) ketoxime (3)
A mixture of the compound 2 (10 mmol, 2.9 g),
NH2OH·HCl (14 mmol, 0.973 g), Na+CH3COO– (14 mmol,
1.148 g) and ethanol/water (100:50 ml) were placed one-
necked flask, which was refluxed for 12 h. The reaction mix-
ture was cooled, and then water was added drop wise. The
solid was filtrated off, dried and the compound 3 was crystal-
lized from ethanol. The following product was obtained.

M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
1355
Table 2
Melting points, yields (%) and crystallization solvents of synthesized compounds
R1
R2
m.p. (°C)
200–201
159–160
119–120
144–145
134–135
166–168
132–133
154–155
140–142
155–156
119–120
94–95
Yield (%)
94
Solvent
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
acetone
acetone
ethanol
ethanol
3
4
–
–
–
–
87
5a
5b
5c
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
Ph–
–
77
Ph–CH2–
–
82
CH3–
–
89
–
–
–
–
–
–
–
–
–
Ph–CH2–
89
CH3–
77
Ph–C(O)CH2–
72
CH2=CHCH2–
85
C2H5OC(O)CH2–
91
–
–
–
–
63
91
170–171
143–145
96–97
79
89
65
103–104
63
4.1.1.1. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)
ketoxime (3). IR (KBr) (t, cm−1), 3276–3185 (OH stretch-
ing), 1450 (C=N stretching) 1257 (C–O–C benzofuran stretch-
ing), 985 (N–O stretching); 1H-NMR (DMSO-d6, 200 MHz)
d (ppm), 1.6 (s, 3H, CH3), 2.4–2.6 (m, 4H, cyclobuta ne CH2),
3.9 (p, 1H, cyclobutane CH2), 7.0−7.7 (m, 10H, aromatic pro-
tons), 11.82 (s, 1H, N–OH); 13C-NMR (DMSO-d6) d: 32.20,
40.20, 40.40, 40.70, 40.90, 113.00, 114.10 , 123.90, 124.00,
126.20, 126.90 (2C), 127.70 (2C), 129.90 (2C), 148.50,
149.00, 153.70, 154.50.Anal. Calc. for C20H19NO2: C, 78.66;
H, 6.27; N, 4.59. Found: C, 78.69; H, 6.29; N, 5.61.
128.30, 130.20 (2C), 148.40, 151.39, 154.50, 155.50. Anal.
Calc. for C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found: C,
76.48; H, 6.45; N, 3.91.
4.1.3. A general method for the syntheses of compounds
5a–c
The compound 3 (1 mmol, 0.305 g) and THF (40 ml) were
placed in a 250 ml one-necked flask with a reflux condenser.
1.1 mmol acyloyl chloride was added and refluxed for 16 h.
After the reaction mixture was cooled, it was neutralized with
NH3 solution. Occurred precipitate was filtrated off and
washed with water. Compounds 5a–c was crystallized from
ethanol. The following product was obtained.
4.1.2. Synthesis of (benzofuran-2-yl)-(3-phenyl-3-methylcy-
clobutyl)-O-glycidylketoxime (4)
The compound 3 (1 mmol, 0.305 g) and dry acetone
(150 ml) were placed in a 250 ml two-necked flask with a
reflux condenser. 3 mmol powder KOH (0.168 g) was added
and stirred for 4 h at room temperature. To the mixture,
epichlorohydrine (3.18 mmol, 0.25 ml, d = 1.18 gcm−3) was
added drop wise and refluxed for 8 h. The solvent was then
removed under reduced pressure, the residue extracted with
diethyl ether and the ether phase dried over MgSO4. After
filtration and removal of the solvent under reduced pressure,
the compound 3 was crystallized from ethanol. The follow-
ing product was obtained.
4.1.3.1. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
benzoylketoxime (5a). IR (KBr) (t, cm−1), 1747 (C=O stretch-
ing), 1605 (C=C stretching), 1483 (C=N stretching) 1249
1
(ester C–O stretching), 998 (N–O stretching); H-NMR
(CHCl3-d, 200 MHz) d (ppm), 1.7 (s, 3H, CH3), 2.6–2.8 (m,
4H, cyclobutane CH2), 3.9 (p, 1H, cyclobutane CH), 7.1–8.1
(m, 15H, aromatic protons); 13C-NMR (CDCl3) d: 32.20,
33.40 40.50 (2C), 41.40, 113.70, 117.80, 124.50, 125.80,
126.70, 127.40, 128.10 (2C), 130.10, 130.20 (2C), 130.70
(2C), 131.20, 131.80 (2C), 135.30, 147.50, 153.70, 154.10,
156.00, 158.00.Anal. Calc. for C27H23NO3: C, 79.20; H, 5.66;
N, 3.42. Found: C, 79.22; H, 5.69; N, 3.49.
4.1.2.1. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
glycidylketoxime (4). IR (KBr) (t, cm−1), 2976–2862 (ali-
phatic C–H stretching), 1493 (C=N stretching), 1253 (epoxide
ring symmetric bending), 1098 (C–ON stretching), 940–917
4.1.3.2. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
phenylacetylketoxime (5b). IR (KBr) (t, cm−1), 1756 (C=O
stretching), 1597 (C=C stretching), 1493 (C=N stretching),
1235 (ester C–O stretching), 1007 (N–O stretching), 1H-NMR
(CHCl3-d, 200 MHz) d (ppm), 1.6 (s, 3H, CH3), 2.5–2.8 (m,
4H, cyclobutane CH2), 3.7–4.0 (m, 3H, cyclobutane CH and
ester CH2), 7.1–7.8 (m, 15H, aromatic protons); 13C-NMR
(CDCl3) d: 32.30, 34.00, 40.30 (2C), 41.40, 42.70, 113.60,
117.80, 124.50, 126.70 (2C), 127.30, 128.40 (2C), 128.70,
130.20 (2C), 131.70 (3C), 135.20, 148.00, 153.70, 155.80,
1
(epoxide ring asymmetric bending); H-NMR (CHCl3-d,
200 MHz) d (ppm), 1.7 (s, 3H, CH3), 2.5–2.9 (m, 4H, cyclobu-
tane CH2), 2.9 (m, 2H, epoxide ring CH2) 3.4 (m, 1H, epoxide
ring CH) 3.9 (p, 1H, cyclobutane CH), 4.3 (dd, 2H, N–O–
CH2) 7.2–7.8 (m, 10H, aromatic protons); 13C-NMR (CDCl3)
d: 33.40, 40.58 (2C), 41.23, 41.53, 46.90, 52.20, 77.70,
113.60, 116.60, 124.30, 126.80 (2C), 127.30 (2C), 128.10,

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M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
158.80, 170.00.Anal. Calc. for C28H25NO3: C, 79.41; H, 5.95;
N, 3.31. Found: C, 79.44; H, 5.91; N, 3.36.
1070 (ether C-O stretching), 1006 (N–O stretching); 1H-NMR
(CHCl3-d, 200 MHz) d (ppm), 1.6 (s, 3H, CH3), 2.4–2.7 (m,
4H, cyclobutane CH2), 3.9 (p, 1H, cyclobutane CH), 5.4 (s,
2H, O–CH2–C=0), 7.1–7.9 (m, 15H, aromatic protons); 13C-
NMR (CDCl3) d: 32.30, 33.20, 40.40 (2C), 41.40, 58.10,
113.40, 116.80, 124.40, 126.70 (2C), 127.20, 128.10, 128.50
(2C), 128.80 (2C), 130.10 (2C), 130.70 (2C), 135.40, 137.70,
148.12, 152.20, 154.20, 155.50, 197.20. Anal. Calc. for
C28H25NO3: C, 79.41; H, 5.95; N, 3.31. Found: C, 79.43; H,
5.96; N, 3.38.
4.1.3.3. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
acetylketoxime (5c). IR (KBr) (t, cm−1), 1774 (C=O stretch-
ing), 1604 (C=C stretching), 1492 (C=N stretching), 1246
1
(ester C–O stretching), 980 (N–O stretching); H-NMR
(CHCl3-d, 200 MHz) d (ppm), 1.6 (s, 3H, CH3), 2.3 (s, 3H,
CH3) 2.6–2.8 (m, 4H, cyclobutane CH2), 3.9 (p, 1H, cyclobu-
tane CH), 7.1–7.7 (m, 15H, aromatic protons); 13C-NMR
(CDCl3) d: 21.80, 32.30, 34.10, 40.50 (2C), 41.40, 113.70,
117.70, 124.50, 125.50, 126.70, 127.40, 128.00 (2C), 128.70,
130.20 (2C), 147.20, 151.10, 153.70, 157.40, 170.00. Anal.
Calc. for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C,
76.10; H, 6.12; N, 4.08.
4.1.4.4. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
allylketoxime (6d). IR (KBr) (t, cm−1), 1644 (C=C stretch-
ing), 1493 (C=N stretching), 1030 (ether C–O stretching),
1010–919 (=CH plane out bending), 990 (N–O stretching);
1H-NMR (CHCl3-d, 200 MHz) d (ppm), 1.6 (s, 3H, CH3),
2.5–2.8 (m, 4H, cyclobutane CH2), 3.9 (p, 1H, cyclobutane
CH), 4.7 (d, 2H,=CH2), 5.3 (dd, 2H, allylic CH2), 6.1 (m,
1H,=CH), 7.1–7.9 (m, 10H, aromatic protons); 13C-NMR
(CDCl3) d: 32.40, 33.40, 40.50 (2C), 41.20, 77.80, 113.40,
115.50, 118.70, 124.10, 125.40, 126.80, 127.20, 127.80 (2C),
130.10, 131.10 (2C), 136.00, 148.60, 150.80, 154.30, 155.40.
Anal. Calc. for C23H23NO2: C, 79.97; H, 6.71; N, 4.05. Found:
C, 79.99; H, 6.68; N, 4.13.
4.1.4. A general method for the syntheses of compounds
6a–e
K2CO3 (0.276 g) and different alkyl halogens (2 mmol)
was added to a 50 ml solution of the compound 3 (1.0 mmol,
0.305 g) in acetone while stirring at room temperature. The
reaction mixture was refluxed for 12 h. After the solvent was
removed by using rotary evaporator, the residue extracted with
diethyl ether and ether phase dried over MgSO4. After filtra-
tion and removal of the solvent by under reduced pressure,
the compounds (6a–e) were crystallized from ethanol. The
following products were obtained.
4.1.4.5. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
carbetoxymethylketoxime (6e). IR (KBr) (t, cm–1); 1753
(C=O stretching), 1601 (C=C stretching), 1493 (C=N stretch-
ing), 1126 (ether C–O stretching), 1021 (N–O stretching),
1H-NMR (CHCl3-d, 200 MHz) d (ppm), 1.2 (t, 3H, C–CH3),
1.6 (s, 3H, CH3), 2.4−2.7 (m, 4H, cyclobutane CH2), 3.9 (p,
1H, cyclobutane CH), 4.2 (q, 2H, O–CH2–C), 4.8 (s, 2H,
O–CH2–C=O), 7.1–7.8 (m, 15H, aromatic protons); 13C-
NMR (CDCl3) d: 18.16, 32.30, 33.20, 40.50 (2C), 41.13,
62.85, 73.60, 113.40, 118.40, 124.30, 125.10, 126.70, 127.20,
128.10, 130.10 (2C), 130.30 (2C), 148.10, 152.20, 154.20,
155.50, 171.50.Anal. Calc. for C24H25NO4: C, 73.64; H, 6.44;
N, 3.58. Found: C, 73.66; H, 6.48; N, 3.61.
4.1.4.1. (Benzofuran-2-yl) (3-phenyl-3-methylcyclobutyl)-
O-benzylketoxime (6a). IR (KBr) (t, cm−1); 1610 (C=C
stretching), 1492 (C=N stretching), 1117 (ether C–O stretch-
ing), 1009 (N–O stretching); 1H-NMR (CHCl3-d, 200 MHz)
d (ppm), 1.6 (s, 3H, CH3), 2.4–2.7 (m, 4H, cyclobuta ne CH2),
3.9 (p, 1H, cyclobutane CH), 5.3 (s, 2H, Ph–CH2), 6.9–7.6
(m, 15H, aromatic protons); 13C-NMR (CDCl3) d: 32.00,
33.30, 40.90 (2C), 41.70, 78.80, 104.40, 113.20, 115.30,
124.40, 126.70, 127.10, 129.60 (2C), 130.00 (2C), 130.20
(6C), 130.40, 139.40, 148.80, 150.10, 154.50, 155.50. Anal.
Calc. for C27H25NO2: C, 82.00; H, 6.37; N, 3.54. Found: C,
82.03; H, 6.38; N, 3.49.
4.1.5. A general method for the syntheses of compounds
7a–f
4.1.4.2. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
methylketoxime (6b). IR (KBr) (t, cm−1); 1598 (C=C stretch-
ing), 1492 (C=N stretching), 1137 (ether C–O stretching),
The compound 4 (1 mmol) and 2 mmol secondary amines
(or NaN3 for 7b) were placed one-necked flask with a reflux
condenser. The reaction mixture was refluxed with 50 ml
appropriate solvent for 4 h (with water for 7a, acetone for
7b–d and THF for 7e, f). The excess of secondary amine was
removed by under reduced pressure. After filtration and
removal of the solvent by using rotary evaporator, the com-
pounds (7a–f) were crystallized from appropriate the sol-
vent. The following products were obtained.
1
992 (N–O stretching), H-NMR (CHCl3-d, 200 MHz) d
(ppm), 1.6 (s, 3H, CH3), 2.5–2.8 (m, 4H, cyclobutane CH2),
3.9 (p, 1H, cyclobutane CH), 4.1 (s, 3H, OCH3), 7.1–7.8 (m,
10H, aromatic protons); 13C-NMR (CDCl3) d: 32.40, 33.30,
40.40 (2C), 41.40, 64.50, 115.40, 124.10, 125.00, 125.10,
127.20, 127.80 (2C), 128.00, 128.10, 130.10, 130.30, 148.60,
150.40, 154.40, 155.40.Anal. Calc. for C21H21NO2: C, 78.97;
H, 6.63; N, 4.39. Found: C, 78.94; H, 6.59; N, 4.42.
4.1.5.1. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
(2-hydroxy-3-izopropylamino) propyl ketoxime (7a). IR (KBr)
(t, cm−1); 3475–3200 (OH stretching), 1610 (C=C stretch-
ing), 1449 (C=N stretching), 1580 (N–H bending), 1114–
4.1.4.3. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
phenylacylketoxime (6c). IR (KBr) (t, cm−1); 1703 (C=O
stretching), 1598 (C=C stretching), 1491 (C=N stretching),
1
1099 (C–N stretching), 997 (N–O stretching); H-NMR

M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
1357
(CHCl3-d, 200 MHz) d (ppm), 1.1 (d, 6H, CH3), 1.6 (s, 3H,
CH3), 2.3 (broad, 2H, OH and NH), 2.4–2.8 (m, 7H, cyclobu-
tane 2 × CH2, CH2 and CH), 3.8–4.1 (m, 2H, cyclobutane CH
and CH–O), 4.3 (d, 2H, O–CH2–CH), 7.1–7.81(m, 10H, aro-
matic protons); 13C-NMR (CDCl3) d: 25.00 (2C), 33.20, 40.60
(2C), 40.70, 41.20, 50.80, 51.30, 71.50, 78.90, 113.40, 115.70,
124.20, 125.10, 126.70, 127.30, 128.00, 130.10, 130.20 (2C),
130.50, 148.40, 151.30, 154.20, 155.50. Anal. Calc. for
C26H32N2O3: C, 74.26; H, 7.67; N, 6.66. Found: C, 74.31; H,
7.69; N, 6.69.
4.1.5.5. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
[2-hydroxy-3-(N-phenylpiperazino)] propylketoxime (7e). IR
(KBr) (t, cm−1), 3300 (broad OH stretching), 1620 (C=C
stretching), 1496 (C=N stretching), 1285 (Ar–N piperazine
ring stretching), 1234 (broad, OH bending), 1151–1082 (C–N
piperazine ring stretching), 996 (N–O stretching); 1H-NMR
(CHCl3-d, 200 MHz) d (ppm), 1.6 (s, 3H, CH3), 2.4–2.8 (m,
7H, cyclobutane 2 × CH2, CH2–N and OH), 3.0–3.2 m, 8H,
piperazine CH2), 3.9 (p, 1H, cyclobutane CH), 6.8–7.7 (m,
15H, aromatic protons); 13C-NMR (CDCl3) d: 32.40, 33.30,
41.20, 40.80 (2C), 51.20, 52.40 (2C), 55.40 (2C), 62.70,
68.40, 113.40, 115.80, 118.10 (4C), 120.70, 124.20, 125.20,
126.70, 127.30, 128.10, 130.20 (2C), 131.30 (2C), 148.40,
151.20, 153.20, 154.30, 155.50.Anal. Calc. for C33H37N3O3:
C, 75.69; H, 7.12; N, 8.02. Found: C, 75.71; H, 7.15; N, 7.98.
4.1.5.2. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
(3-azido-2-hidroxy) propylketoxime (7b). IR (KBr) (t, cm−1);
3423 (broad OH stretching), 2099 (N3 asymmetric stretch-
ing), 1620 (C=C stretching), 1493 (C=N stretching), 1302
(N3 symmetric stretching), 1112 (C–N stretching), 980 (N–O
stretching); 1H-NMR (CHCl3-d, 200 MHz) d (ppm), 1.6 (s,
3H, CH3), 2.4 (d, 2H, CH2N3) 2.4–2.6 (m, 4H, cyclobutane
CH2), 3.2 broad, 1H, OH), 3.9 (p, 1H, cyclobutane CH),
4.1(m, 1H, CH–OH), 4.3 (d, 2H, OCH2), 7.1–7.7 (m, 10H,
aromatic protons); 13C-NMR (CDCl3) d: 32.40, 33.40, 40.50
(2C), 41.30, 55.30, 72.00, 77.30, 113.50, 116.50, 124.30,
125.30, 126.70, 127.40 (2C), 128.40, 130.10, 130.20 (2C),
148.00, 152.20, 154.00, 155.00 .Anal. Calc. for C23H24N4O3:
C, 68.30; H, 5.98; N, 13.85. Found: C, 68.33; H, 5.99; N,
13.87.
4.1.5.6. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
(2-hydroxy-3-morfolino)propylketoxi me (7f). IR (KBr) (t,
cm−1), 3448 (broad OH stretching), 1600 (C=C stretching),
1493 (C=N stretching), 1297 (broad, OH bending), 1038
(C–O morpholine), 997 (N–O stretching); 1H-NMR
(CHCl3-d, 200 MHz) d (ppm) 1.6 (s, 3H, CH3), 2.3–2.9 (m,
14H cyclobutane 2 × CH2, morpholine 4 × CH2 and CH2),
3.9 (p, 1H, cyclobutane CH), 4.2 (m, 1H, CH–OH), 4.3 (d,
2H, OCH2), 7.1–7.8 (m, 10H, aromatic protons); 13C-NMR
(CDCl3) d: 32.40, 33.30, 40.50 (2C), 41.10, 55.80 (2C), 63.20,
63.30, 68.80 (2C), 78.40, 113.40, 115.50, 115.80, 124.20,
125.10, 126.70, 127.30, 128.10, 130.20 (4C), 148.30, 151.20,
154.20. Anal. Calc. for C27H32N2O4: C, 72.30; H, 7.19; N,
6.25. Found: C, 72.26; H, 7.24; N, 6.28.
4.1.5.3. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
(2-hydroxy-3-piperidino) propyl ketoxime (7c). IR (KBr) (t,
cm−1), 3411(broad OH stretching), 1640 (C=C stretching),
1460 (C=N stretching), 1112–1110 (C–N piperidine ring),
987 (N–O stretching); 1H-NMR (CHCl3-d, 200 MHz) d (ppm)
1.4–1.6 (m, 6H), 1.6 (s, 3H,CH3), 2.3–2.7 (m, 10H), 3.4
(broad, 1H, OH), 3.9 (p, 1H, cyclobutane CH), 4.1–4.3 (m,
3H, OCH2OH), 7.1–7.7 (m, 10H, aromatic protons); 13C-
NMR (CDCl3) d: 25.80, 27.50 (2C), 32.30, 33.30, 40.60 (2C),
41.10, 56.80 (2C), 63.60, 67.90, 78.20, 113.40, 115.70,
124.20, 125.00, 126.70, 127.20, 127.30, 127.90, 130.10,
130.30 (2C), 148.50, 151.10, 154.30, 155.50. Anal. Calc. for
C28H34N2O3: C, 75.31; H, 7.67; N, 6.27. Found: C, 75.32; H,
7.68; N, 6.25.
4.2. Biological activity studies
4.2.1. Antimicrobial activity
Disk diffusion method was used for antimicrobial activity.
Antimicrobial activity against Staphylococcus aureus ATCC
6538, Staphylococcus epidermidis ATCC 12228, Escheri-
chia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352,
Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shi-
gella flexneri, Proteus mirabilis ATCC 14153 were investi-
gated. Mueller–Hinton agar (Difco, Detroit, USA) for all bac-
terial strains were used. The media were melted at 100 °C
and after cooled to 50 °C were poured into plates of 9 cm
diameter in quantities of 20 ml, and left on a flat surface to
solidify and the surface of media was dried at 37 °C. Then,
the inoculum was prepared using a 4–6 h Mueller–Hinton
broth adjusted to a turbidity equivalent to a 0.5 McFarland
standard (108 cfu ml–1). A sterile cotton swab was dipped in
the inoculum and the surfaces of the Mueller–Hinton agar
were inoculated by streaking the swab over the surface. The
surface of the media was allowed to dry 3–5 min at room
temperature. The 10 mg ml–1 (in DMSO, E. Merck), com-
pound impregnated disks were applied to the surface of inocu-
lated plates .The Mueller–Hinton agar plates were incubated
at 35 °C for 18–24 h. The plates were examined and the diam-
eter of the inhibition zone was measured [18].
4.1.5.4. (Benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-
[2-hydroxy-3-(N-methylpiperazino)] propylketoxime (7d). IR
(KBr) (t, cm−1), 3135 (broad OH stretching), 1603 (C=C
stretching), 1493(C=N stretching), 1153–1085 (C–N pipera-
zine ring stretching), 981 (N–O stretching); 1H-NMR
(CHCl3-d, 200 MHz) d (ppm), 1.6 (s, 3H, CH3), 2.3 (s, 3H,
piperazine CH3), 2.4−2.8 (m, 14H, cyclobutane 2 × CH2, pip-
erazine CH2 and CH2), 3.5 (broad, 1H, OH), 3.9 (p, 1H,
cyclobutane CH), 4.1 (m, 1H, CH–OH), 4.3 (d, 2H, OCH2),
7.1−7.6 (m, 10H, aromatic protons) 13C-NMR (CDCl3) d:
32.30, 33.30, 40.50 (2C), 41.10, 47.90, 55.30 (2C), 57.10
(2C), 62.60, 68.40, 79.30, 113.30, 115.70, 124.10, 125.00,
126.70 (2C), 127.20, 128.00 (2C), 130.10, 130.30, 148.50,
151.10, 154.30, 155.50. Anal. Calc. for C28H35N3O3: C,
72.86; H, 7.64; N, 9.10. Found: C, 72.89; H, 7.66; N, 9.11.

1358
M. Koca et al. / European Journal of Medicinal Chemistry 40 (2005) 1351–1358
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found effective against the strains, were selected in order to
determine the minimum inhibitory concentrations (MIC).
4.2.1.1. Determination of the MICs. MIC was determined by
micro broth dilutions technique using Mueller–Hinton broth
for bacteria, RPMI-1640 medium for yeast strain. Serial two-
fold dilutions ranging from 5000 to 0.031 mg ml–1 were pre-
pared in media. The inoculum was prepared using a 4–6 h
broth culture of each bacteria and 24 h culture of yeast strains
adjusted to a turbidity equivalent to a 0.5 Mc Farland stan-
dard, diluted in broth media to give a final concentration of
5 × 105 cfu ml–1 for bacteria and 0.5 × 103–2.5 × 103 cfu ml–1
for yeast in the test tray. The trays were covered and placed in
plastic bags to prevent evaporation. The trays containing
Mueller–Hinton broth were incubated at 35 °C for 18–20 h
and the trays containing RPMI-1640 medium were incu-
bated at 35 °C for 46–50 h. The MIC was defined as the low-
est concentration of compound giving complete inhibition of
visible growth [17,19].
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Acknowledgments
We are indebted to the Firat University Research Founda-
tion (FÜBAP 643) for financial support of this work.
[14] Sq. Demirayak, U. Ucucu, K. Renkli, N. Gundogdu-Karaburun,
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