3-Thiolated 2-azetidinones: Synthesis and in vitro antibacterial and antifungal activities

Article abstract of DOI:10.1016/j.tet.2011.05.043

A series of 3-thiolated β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.

Full text of DOI:10.1016/j.tet.2011.05.043

Tetrahedron 67 (2011) 5832e5840
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
3-Thiolated 2-azetidinones: synthesis and in vitro antibacterial and antifungal
activities
Maaroof Zarei ,*, Masoud Mohamadzadeh b
a
a
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
Department of Biology, Faculty of Science, Islamic Azad University, Arsanjan Branch, Arsanjan, Fars Province, Iran
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-thiolated
S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio
converted to 3-(methylsulfinyl) -lactams and 3-(methylsulfonyl)
different reaction conditions. All the compounds were characterized by spectral data and elemental
analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic
strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results
indicated that some of these compounds demonstrated moderate to very good antibacterial and anti-
fungal activities.
b
-lactams were synthesized by [2þ2] keteneeimine cycloaddition reaction from
-lactams were
-lactams using m-CPBA under
Received 9 February 2011
Received in revised form 18 April 2011
Accepted 9 May 2011
b
b
b
Available online 14 May 2011
Keywords:
2
3
-Azetidinone
-Thiolated -lactam
b
Ó 2011 Published by Elsevier Ltd.
Antibacterial activity
Antifungal activity
Staudinger reaction
1
. Introduction
RCOHN
RCOHN
b-Lactam antibiotics are the most important antibacterial agents
OH
N
for human health and it began with the discovery of penicillin by
Alexander Fleming in 1928. During the late 1990s, a research group
at Schering-Plough identified a novel compound, ezetimibe, that
N
O
1
O
HO C
SO H
2
3
1
2
selectively inhibits the absorption of cholesterol and it was ap-
2
proved and marketed as Zetia in 2002. In addition,
b-lactams are
an important class of heterocyclic compounds due to their wide
3
range applications in other biological activities. The side chain of
With the alarming trends in bacterial resistance to many
b-lactam antibiotics it has become necessary to synthesize some
Taxol and related analogues (the anti-tumor agents) is preferen-
tially prepared by nucleophilic ring opening of suitably substituted
novel
for drugs with more specific antibacterial activity. Therefore, the
synthesis of the new -lactams is the subject of extensive study.
Turos and co-workers have synthesized N-thiolated -lactams
-lactam compounds have a sulfur substituent on the nitrogen
center). They have reported that N-thiolated -lactams have rep-
b-lactams for bioassay of antibacterial activity and the need
4
9
b
-lactams. They have also served as precursors to several organic
5
compounds via selective bond cleavage of the
b
-lactam nucleus.
b
The development of synthetic routes to monocyclic 2-azeti
dinones was stimulated by the observation of antibacterial activ-
b
(b
6
ity in monobactams 1 and norcardicins 2.
b
The Staudinger reaction ([2þ2] keteneeimine cycloaddition
resented a broad and growing family of bioactive molecules and the
thiol-substituent was effective at biological activities.
7
10
reaction) is regarded as one of the most fundamental and versatile
methods for the synthesis of structurally diverse 2-azetidinone
derivatives, although many synthetic methods have been
developed to date.8
Due to the adaptability, Staphylococcus aureus can easily develop
resistance to commonly used antibiotics. This resistance involves
the enzymic inactivation in resistant bacteria. Hence, there is
a great need for effective antibacterial agents against S. aureus with
11
new modes of action.
In this paper, we report the synthesis of 3-thiolated
b
-lactams
and evaluated these compounds for antibacterial and antifungal
activities.
*
Corresponding author. Tel.: þ98 761 766 0063; fax: þ98 761 667 0714; e-mail
addresses: maaroof1357@yahoo.com, mzarei@hormozgan.ac.ir (M. Zarei).
0
040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.05.043

M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
5833
2
2
. Results and discussion
Table 1
3-Thiolated
b-lactams 5aeyz
Product
R1
R2
R3
Isolated
.1. Chemistry
yield (%)
Firstly, we synthesized different Schiff bases 3aei from aliphatic
or aromatic aldehydes and amines by condensation in ethanol at
5a
4-NO
4-NO
4-NO
2
2
2
C
C
C
6
6
6
H
H
H
4
4
4
4-MeOC
6
H
4
4
C
C
C
C
C
C
6
6
6
6
6
6
H
H
H
H
H
H
5
5
5
5
5
5
91
84
79
90
83
75
94
90
81
88
86
73
86
80
71
92
82
70
93
90
74
85
84
68
93
90
72
5
5
5
5
b
c
d
e
4-ClC
Me
6 4
H
reflux or by anhydrous Na
2
SO
4
in dry dichloromethane (Scheme 1).
C
6
C
6
C
6
5
H CH
5
H CH
5
H CH
2
4-MeOC
6
H
2
2
4-ClC
Me
6 4
H
EtOH, reflux
1
2
1
R CH=NR2
5f
R CHO + R NH
2
or dry CH Cl ,
5g
5h
5i
5j
5k
5l
5m
5n
5o
4-MeOC H4
4-MeOC
4-MeOC H4
4-MeOC H4
C6H5
C H
6 5
C6H5
CH CH2
CH CH2
CH CH2
CH CH2
CH CH2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
6
6
1
1
2
2
anhydrous Na SO4
3a: R
= 4-NO C H , R
b: R = C
2
6
4
6
= 4-MeOC H4
6
H
4
4-ClC
Me
H
6 4
2
3
3
3
3
3
3
3
3
6
H
5
CH
2
, R = 4-MeOC
6
H
4
6
c: R1 = 4-MeOC
H
, R = 4-MeOC
2
H
6
4
6
4
4-NO C H
2
6
4
4
4
4-MeOC H4
6
3
3
3
3
3
1
2
d: R = 4-NO
2
C
6
H
4
, R = 4-ClC
6
H
4
4-NO C H
4-ClC H4
2
6
6
1
2
e: R = C
6
H
5
CH
f: R = 4-MeOC
g: R1 = 4-NO C H , R = Me
2
, R = 4-ClC
6
H
4
4-NO C H
Me
4-MeOC H4
2
6
1
2
6
H
4
, R = 4-ClC
6
H
4
C H CH
6
5
2
2
2
6
2
2
6
4
C H CH
6
6
5
5
4-ClC H4
6
1
2
h: R = C H CH , R = Me
6
5
2
C
H
CH
Me
4-MeOC
3
3
3
3
3
3
3
3
3
3
3
3
3
CH
CH
CH
CH
2
2
2
2
1
6 4
i: R = 4-MeOC H
, R2 = Me
5
5
5
5
5
p
q
r
s
t
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
6
H
4
H
4
H
4
H
4
4-ClC
Me
6 4
H
Scheme 1. Synthesis of Schiff bases 3aei.
4-NO
4-NO
4-NO
2
2
2
C
C
C
6
H
H
H
4
4-MeOC
6
6
4
4
4-ClC
Me
6 4
H
S-Substituted mercaptoacetic acids 4a,b were prepared by the
alkylation of corresponding thiols and chloroacetic acid. (Methyl-
thio)acetic acid 4c was synthesized from ethyl mercaptoacetate
because of difficult handling and availability of MeSH. The ethyl
mercaptoacetate reacted with methyl iodide to give ethyl 2-
5u
6
5
5
5
5
v
w
x
C
6
C
6
C
6
5
H CH
5
H CH
5
H CH
2
4-MeOC
6
2
2
4-ClC
Me
6 4
H
y
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
4-MeOC
6
5z
yz
4-ClC
Me
6 4
H
5
(
methylthio)acetate, which was hydrolyzed to (methylthio)acetic
acid 4c (Scheme 2). The IR spectra of these compounds showed the
ꢀ
1
carbonyl group, hydroxyl group of COOH at 1740e1746 cm and
ꢀ1
2
803e3336 cm (broad peak), respectively, but SH peak was not
observed.
NaOH, H O
3
2
3
R SH
+
ClCH COOH
R S-CH
2
COOH
2
rt, 8 h
3
4a: R = C H
6
5
3
4b: R = CH CH
3
2
K CO , EtOH
1. KOH, H O
2
2
3
3
HS-CH COOEt
+
MeI
MeS-CH COOEt
R S-CH COOH
2
2
2
rt, 10 h
2. HCl, H O
2
ethyl
mercaptoacetate
3
4c: R = Me
Scheme 2. Synthesis of S-substituted mercaptoacetic acids 4aec.
The Staudinger reaction was chosen for synthesis of the
-azetidinone ring. Reaction of Schiff bases 3aei and S-substituted
Next cis 3-methylthio
3-(methylsulfinyl)
sulfonyl)
(Scheme 4). Previously trans 3-sulfonyl b
b
-lactams 5veyz were converted to cis
ꢁ
2
b
-lactams 6aef at ꢀ15 C and cis 3-(methyl-
mercaptoacetic acids 4aec in the presence of the Vilsmeier re-
b
-lactams 7aef at room temperature using m-CPBA
-lactams were prepared by
several methods. The synthesized compounds were characterized
12
agent
at room temperature gave the 3-thiolated
b
-lactams
13
5
ae5yz in good to excellent yields (Scheme 3, Table 1). The IR
ꢀ
1
1
13
spectra showed the
dicated stereochemistry for these monocyclic
b
-lactam carbonyl at 1741e1755 cm . The in-
-lactams was de-
duced from analysis of their H NMR spectra. The coupling
constants of H-3 and H-4 are J¼4.3e5.1 Hz for -lactams 5ae5yz,
which are indicative of their cis stereochemistry. In addition,
NMR spectroscopic data of -lactams 5ae5yz definitely showed the
by IR, H NMR, C NMR, and elemental analysis. The IR spectra
ꢀ
1
b
showed the S]O absorption (strong peak) at 1078e1089 cm and
1
ꢀ1
O]S]O absorption (strong peak) at 1151e1161 cm
and
ꢀ
1
b
1307e1322 cm
3-(methylsulfonyl)
-lactams 6aef were obtained as a diastereomeric mixture. The
diastereomeric ratio is may be dominated by the steric hindrance of
for 3-(methylsulfinyl)
b-lactams 7aef, respectively. 3-(Methylsulfinyl)
b-lactams 6aef and
13
C
b
b
lactam CO signals at 160.5e165.3 ppm, whereas C-3 resonated at
around 60.2e62.5 ppm and C-4 at 61.3e64.2 ppm.
the starting 3-methylthio b-lactams 5veyz.
Me
Me
H
2.2. Biological activities
N
Cl
H H
R1
4
R3S
Cl
1
2
3
3
All the synthesized compounds were screened for their anti-
bacterial activity against three gram-positive bacteria S. aureus
ATCC 29737, S. aureus (Methicillin resistant strain) ATCC 33591,
Bacillus subtilis ATCC 6633, two gram-negative bacteria Escherichia
coli ATCC 25922 and Pseudomonas aeruginosa ATCC 25619. They
R CH=NR
+
R S-CH COOH
2
N
CH Cl , Et N
2
2
2
3
2 1
O R
rt, 18-24 h
3a-i
4a-c
5a-yz
Scheme 3. Synthesis of 3-thiolated b-lactams 5aeyz.

5834
M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
O H H
O
R1
H H
N
R1
H
H
N
R1
R2
Me-S
MeS
Me-S
2
eq. m-CPBA
1
eq. m-CPBA
O
N
o
rt, 2 h
R2
R2
15 C, 2 h
O
O
O
CH Cl
2
2
CH Cl
2
2
7a-f
5v-yz
6a-f
1
2
1
2
6a: R = C H CH , R = 4-MeOC H
7
7
7
a: R = C H CH , R = 4-MeOC H
6
5
2
6
4
6
5
2
6 4
1
2
1
2
6b: R = C H CH , R = 4-ClC H
6 5 2 6 4
b: R = C H CH , R = 4-ClC H
6 4
6
5
2
1
2
1
2
6c: R = C H CH , R = Me
6 5 2
c: R = C H CH , R = Me
6
5
2
1
2
1
2
6d: R = 4-MeOC H , R = 4-MeOC H
6 4 6 4
7
7
7
d: R = 4-MeOC H , R = 4-MeOC H
6
4
6 4
1
2
1
2
6e: R = 4-MeOC H , R = 4-ClC H
6 4 6 4
e: R = 4-MeOC H , R = 4-ClC H
6 4
6
4
1
2
1
2
6f: R = 4-MeOC H , R = Me
f: R = 4-MeOC H , R = Me
6
4
6
4
Scheme 4. Synthesis of 3-(methylsulfinyl)
b-lactams 6aef and 3-(methylsulfonyl)
b-lactams 7aef.
were also evaluated for their in vitro antifungal activity against
Candida albicans ATCC 10231, Aspergillus niger ATCC 1004, and Tri-
chophyton mentagrophytes (natural isolates) using the reported
method.14 The minimum inhibitory concentrations (MICs) were
defined as the lowest concentrations of the compounds that pre-
vented visible growth. It was determined that the solvent had no
antibacterial antifungal activities against any of the test
microorganisms. Standard antibacterial ciprofloxacin and penicillin
G and antifungal ciclopiroxolamine were also tested under the
similar conditions for comparison.
Firstly 3-thiolated b-lactams 5ae5yz were tested for antibacte-
rial and antifungal activities (Table 2). The best result for antibac-
3
terial and antifungal activities was found when R was methyl
(3-methylthio
b
-lactams 5seyz). Of course in the case of
Table 2
Antimicrobial activity of the synthesized compounds (MIC, mg/mL)
Comp
Bacterial strains
Fungal strains
S. aureus
S. aureus (MRSA)
B. subtilis
E. coli
P. aeruginosa
C. albicans
A. niger
T. mentagrophytes
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
7
7
7
7
7
7
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
50
100
100
25
50
100
25
25
50
25
25
50
100
50
50
50
100
25
25
25
25
25
12.5
12.5
12.5
25
12.5
6.25
25
12.5
6.25
12.5
6.25
12.5
12.5
3.125
3.125
12.5
12.5
50
25
50
100
25
25
50
25
25
25
25
50
100
25
25
50
6.25
12.5
25
6.25
6.25
12.5
6.25
6.25
12.5
3.125
6.25
12.5
25
25
50
12.5
25
25
100
100
100
100
100
100
50
100
100
50
50
50
50
100
100
50
50
50
100
100
100
50
100
50
100
100
100
100
100
100
50
100
100
50
100
100
50
50
100
25
50
50
12.5
25
50
100
50
100
50
25
50
50
25
50
50
100
50
100
50
50
100
50
100
50
100
100
50
100
100
50
100
100
50
100
100
50
100
50
50
100
50
25
100
100
12.5
100
25
12.5
25
25
12.5
25
12.5
6.25
25
12.5
6.25
25
3.125
6.25
12.5
50
25
100
25
12.5
50
6.25
3.125
12.5
3.125
3.125
6.25
d
25
50
25
25
12.5
12.5
25
6.25
6.25
25
6.25
6.25
25
6.25
12.5
12.5
3.125
3.125
12.5
25
12.5
12.5
6.25
6.25
25
25
6.25
50
12.5
6.25
12.5
6.25
3.125
12.5
50
12.5
50
12.5
12.5
50
s
t
25
50
100
25
25
50
100
25
25
50
u
v
w
x
y
z
yz
a
b
c
d
e
f
a
b
c
50
6.25
6.25
25
50
100
100
50
50
12.5
100
100
100
100
100
50
100
25
12.5
25
50
50
50
50
50
25
25
25
100
100
100
100
100
100
100
100
100
100
6.25
12.5
d
12.5
12.5
50
100
100
100
50
50
100
100
100
100
100
100
100
100
50
6.25
6.25
12.5
3.125
3.125
6.25
d
100
100
50
50
50
6.25
100
d
100
100
25
d
e
f
12.5
6.25
25
50
50
100
6.25
3.125
d
100
3.125
3.125
d
Ciprofloxacin
Penicillin G
Ciclopiroxolamine
3.125
25
d
d
6.25
3.125
6.25

M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
5835
1
3
-methylthio
b
-lactams 5seu (R ¼4-NO
2
C
6
H
4
) decrease of anti-
-lactams 5seyz
4.2. Synthesis of Schiff bases 3aei
microbial activities was seen. Then 3-methylthio
b
were selected for conversion to corresponding 3-(methylsulfinyl)
-lactams, 3-(methylsulfonyl) -lactams and the other compounds
having weak antimicrobial activities not converted. Antimicrobial
activities of 3-methylsulfinyl 6aef and 3-methylsulfonyl -lactams
aef were also investigated. The results of the antimicrobial ac-
tivities were summarized in Table 2.
From the antimicrobial studies (Table 2) we concluded that (i)
-methylthio -lactams 5seyz showed higher activity than 3-
ethylthio -lactams 5jer and 3-phenylthio -lactams 5aei. It
4.2.1. Typical procedure and synthesis of (4-nitrobenzylidene)-(4-
methoxyphenyl)amine 3a. A mixture of 4-methoxyaniline (1.23 g,
10.0 mmol) and 4-nitrobenzaldehyde (1.51 g, 10.0 mmol) was
heated to reflux in ethanol (20 mL) for 3 h. After cooling the solu-
tion, the precipitate was filtered and washed with ethanol to give
b
b
b
7
ꢁ
pure Schiff base 3a as a yellow solid (95%). Mp 125e127 C; IR (KBr,
ꢀ1
cm ): 1618 (C]N). The data for Schiff bases previously have been
8
a,12a,16
3
b
reported in the literature.
b
b
seems that these compounds could serve as alkylating agents to-
ward cellular nucleophiles, as depicted hypothetically in Ref. 10e
because attack on the carbon of the alkyl- or arylthio moiety
could be deterred by placement of bulkier groups on the sulfur
4.2.2. Synthesis of N-methyl Schiff bases 3gei. To a stirred solution
of methylamine hydrochloride (0.67 g, 10.0 mmol) in dry CH Cl
(40 mL) were successively added triethylamine (2.1 mL,
15.0 mmol), corresponding aldehydes (10.0 mmol), and a large
excess of anhydrous sodium sulfate. The resulting mixture was
stirred for 18 h at room temperature. Then the organic phase was
2
2
1
center. (ii) The R ¼4-methoxyphenyl group showed higher activity
1
than R ¼benzyl and 4-nitrophenyl group. The existence of the
methoxy group on the molecules enhances the various biological
activities.15 (iii) A methyl group at position N1 decreases activity.
2
washed with H O (25 mL) and dried over anhydrous sodium sul-
fate. After removal of the solvent N-methyl Schiff bases were
(
iv) For antibacterial activity 3-methylthio
higher activity than 3-methylsulfinyl
methylsulfonyl -lactams 7aef and 4-methoxyphenyl group at
b
-lactams 5seyz showed
obtained as a liquid, which was used for the next step without any
further purification. IR (crude) (KBr, cm ): 1626e1629 (C]N).
ꢀ1
b
-lactams 6aef, and 3-
b
position N1 increase activity. This suggests that the availability of
an electron pair on sulfur may be needed for antibacterial activity.
4.3. General procedure for the preparation of S-substituted
mercaptoacetic acids 4a,b
(
v) For antifungal activity, 3-methylsulfonyl
showed higher activity than 3-methylthio -lactams 5seyz, and
-methylsulfinyl -lactams 6aef and 4-chlorophenyl group at po-
b-lactams 7aef
b
To a stirred solution of corresponding thiols (5.0 mmol) and
chloroacetic acid (0.47 g, 5.0 mmol) in water (10 mL) was slowly
added sodium hydroxide (0.40 g, 10.0 mmol) at room temperature.
The solution was stirred for 8 h and then acidified with dilute
hydrochloric acid (2 N) to pH¼7. Then the mixture was extracted
with EtOAc (3ꢂ10 mL) and dried over anhydrous sodium sulfate.
After filtration and evaporation of the solvent under reduced
pressure, the products were obtained.
3
b
sition N1 increase activity. It can be concluded that the presence of
a chlorine atom and sulfonyl group in the azetidinone moiety en-
hanced the antifungal activity of the compounds. (vi) 3-Thiolated
b
-lactams have the same activity against b-lactamase-producing
S. aureus MRSA, in contrast to penicillin G whose inhibitory activity
is markedly diminished for MRSA. Among the synthesized com-
pound 5y showed the best antibacterial activity and compound 7e
showed the best antifungal activity, which they were comparable
or higher than with standards.
ꢁ
4.3.1. (Phenylthio)acetic acid (4a). Mp 62e64 C (lit. 62.5e
ꢁ
17
ꢀ1
63.5 C); IR (KBr, cm ): 1746 (COOH), 2803e3299 (OH).
4
.3.2. (Ethylthio)acetic acid (4b). Light yellow liquid; IR (KBr,
3
. Conclusion
ꢀ1
18
cm ): 1740 (COOH), 2831e3336 (OH).
In conclusion, we report the successful synthesis of new 3-
4
.4. Synthesis of (methylthio)acetic acid 4c
thiolated
transformed to corresponding 3-(methylsulfinyl) and 3-meth
ylsulfonyl -lactams. All the title compounds have been in-
b-lactams. Then selected 3-methylthio b-lactams were
Ethyl mercaptoacetate (0.96 g, 0.87 mL, 8.0 mmol) was dis-
b
2 3
solved in anhydrous ethanol (25 mL) and K CO (1.38 g, 10.0 mmol)
vestigated for their antimicrobial activities. Some of the synthe-
sized compounds showed significant antibacterial and antifungal
was added. Then methyl iodide (1.28 g, 0.56 mL, 9.0 mmol) was
added to the mixture and stirred at room temperature for 10 h.
Reaction mixture was filtered, and the filtrate was dried in vacuo.
KOH 3 M (30 mL, 5.0 g, 90.0 mmol) was added to residue. The
mixture is allowed to stand at room temperature for 16 h. Then the
activities. 3-Methylthio
activity and 3-methylsulfonyl
fungal activity. The 3-methylthio
marked antibacterial activity against S. aureus MRSA.
b
-lactams showed the most antibacterial
-lactams showed the most anti-
-lactams 5y and 5z displayed
b
b
ꢁ
solution of potassium salt is cooled to 0 C, and acidified with dilute
hydrochloric acid (2 N) to pH¼7. Then the mixture was extracted
4
4
. Experimental section
with EtOAc (3ꢂ15 mL) and dried over Na
2 4
SO . After filtration and
evaporation of the solvent under reduced pressure, the (methyl-
.1. Chemical reagents
thio)acetic acid 4c was obtained as a colorless liquid; IR (KBr,
ꢀ1
19
cm ): 1744 (COOH), 2828e3311 (OH).
All required chemicals were purchased from Merck, Fluka, and
Acros chemical companies. The melting points were determined on
a Buchi 535 apparatus and are uncorrected. IR spectra were mea-
sured on a galaxy series FT-IR 5000 spectrometer. NMR spectra
4.5. General procedure for the synthesis of
using the Vilsmeier reagent
b-lactams 5ae5yz
1
were recorded on a Bruker spectrophotometer ( H NMR 300 MHz,
The Vilsmeier reagent (chloromethylenedimethylammonium
chloride) was prepared according to reported procedure.
13
12a,b
C NMR 75 MHz) using tetramethylsilane as an internal standard
The
and coupling constants were given in cycles per second (Hz). Ele-
mental analyses were run on a Vario EL III elemental analyzer. Thin-
layer chromatography was carried out on silica gel 254 analytical
sheets obtained from Fluka. Column chromatography was per-
formed on silica gel 60 (Merck, 70e230 mesh).
Vilsmeier reagent (1.5 mmol) was added to a solution of the S-
substituted mercaptoacetic acids 4aec (1.5 mmol), corresponding
Schiff bases 3aei (1.0 mmol), and triethylamine (0.51 g, 0.70 mL,
2 2
5.0 mmol) in dry CH Cl (15 mL) at room temperature and the
mixture was stirred overnight (18e24 h). Then the solution was

5836
M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
washed successively with 10% HCl (20 mL), saturated NaHCO
20 mL), and brine (20 mL). The organic layer was dried (Na SO ),
filtered, and the solvent was removed under reduced pressure to
3
J¼5.6, 14.7), 2.84 (CH
2
ebenzyl, dd, 1H, J¼5.6, 14.7), 2.96 (Me, s, 3H),
(
2
4
4.22 (H-4, m, 1H), 4.64 (H-3, d, 1H, J¼5.1), 6.96e7.24 (ArH, m, 10H).
1
3
C NMR (CDCl
3
)
d
28.3 (Me), 32.1 (CH ), 61.3 (C-3), 63.7 (C-4), 117.2,
2
give the crude products.
126.9, 127.7, 129.0, 131.5, 137.4, 139.2, 144.5, (aromatic carbons),
62.2 (CO, -lactam). Anal. Calcd for C17 17NOS: C, 72.05; H, 6.05; N,
1
b
H
4
.5.1. 1-(4-Methoxyphenyl)-4-(4-nitrophenyl)-3-(phenylthio)azeti-
4.94; O, 5.65; S, 11.31. Found: C, 72.14; H, 6.18; N, 5.01.
din-2-one (5a). It was purified by crystallization from ethyl acetate.
ꢁ
White solid (0.37 g, 91%). Mp: 144e146 C. R
f
¼0.39 (7:3 hexane/
4.5.7. 1,4-Bis(4-methoxyphenyl)-3-(phenylthio)azetidin-2-one
ꢀ1
1
EtOAc); IR (KBr, cm ): 1343, 1515 (NO
NMR (CDCl
3.71 (OMe, s, 3H), 4.41 (H-4, d, 1H, J¼4.5), 4.84 (H-3,
d, 1H, J¼4.5), 6.81e7.94 (ArH, m, 13H). C NMR (CDCl
OMe), 60.2 (C-3), 62.6 (C-4), 113.8, 121.7, 126.5, 129.0, 129.4, 131.5,
2
), 1749 (CO,
b
-lactam). H
(5g). It was purified by crystallization from ethyl acetate. White
ꢁ
3
)
d
solid (0.37 g, 94%). Mp: 141e143 C. R
(KBr, cm ): 1751 (CO,
f
¼0.41 (7:3 hexane/EtOAc); IR
1
3
ꢀ1
1
3
)
d
55.8
3
b-lactam). H NMR (CDCl ) d 3.69, 3.76
(
1
b
1
(2OMe, 2s, 6H), 4.53 (H-4, d, 1H, J¼4.9), 5.01 (H-3, d, 1H, J¼4.9),
1
3
36.3, 136.9, 138.2, 141.9, 145.6, 154.4 (aromatic carbons), 163.7 (CO,
-lactam). Anal. Calcd for C22H N O S: C, 65.01; H, 4.46; N, 6.89; O,
18 2 4
5.75; S, 7.89. Found: C, 64.93; H, 4.53; N, 6.81.
6.73e7.90 (ArH, m, 13H). C NMR (CDCl
(C-3), 64.2 (C-4), 111.6, 122.9, 125.1, 125.3, 129.4, 130.1, 133.8, 134.5,
140.6, 143.1, 147.3, 157.2 (aromatic carbons), 164.4 (CO, -lactam).
Anal. Calcd for C23 S: C, 70.56; H, 5.41; N, 3.58; O, 12.26; S,
3
) d 56.1, 57.5 (OMe), 61.9
b
H
21NO
3
4
2
.5.2. 1-(4-Chlorophenyl)-4-(4-nitrophenyl)-3-(phenylthio)azetidin-
8.19. Found: C, 70.48; H, 5.49; N, 3.51.
-one (5b). It was purified by crystallization from ethyl acetate.
ꢁ
White solid (0.34 g, 84%). Mp: 123e125 C. R
f
¼0.41 (7:3 hexane/
4.5.8. 1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-(phenylthio)azeti-
din-2-one (5h). It was purified by crystallization from ethyl acetate.
ꢀ1
1
EtOAc); IR (KBr, cm ): 1349, 1519 (NO
NMR (CDCl
4.30 (H-4, d, 1H, J¼4.3), 4.86 (H-3, d, 1H, J¼4.3),
.96e8.04 (ArH, m, 13H). C NMR (CDCl
18.3,123.0,125.2,128.9,130.7,133.5,134.1,137.2,137.6,140.4,142.9,
50.6 (aromatic carbons), 161.9 (CO, -lactam). Anal. Calcd for
15ClN S: C, 61.39; H, 3.68; Cl, 8.63; N, 6.82; O, 11.68; S, 7.80.
Found: C, 61.46; H, 3.80; N, 6.90.
2
), 1742 (CO,
b
-lactam). H
ꢁ
3
)
d
White solid (0.36 g, 90%). Mp: 129e131 C. R
f
¼0.42 (7:3 hexane/
13
ꢀ1
1
6
1
1
C
3
)
d
61.1 (C-3), 63.0 (C-4),
EtOAc); IR (KBr, cm ): 1747 (CO,
3
b-lactam). H NMR (CDCl ) d 3.63
(OMe, s, 3H), 4.29 (H-4, d, 1H, J¼4.5), 4.71 (H-3, d, 1H, J¼4.5),
13
b
6.69e7.78 (ArH, m, 13H). C NMR (CDCl
62.8 (C-4), 116.2, 120.5, 121.6, 122.2, 125.8, 126.5, 132.4, 138.9, 141.3,
142.1, 146.0, 158.5 (aromatic carbons), 163.1 (CO, -lactam). Anal.
Calcd for C22 18ClNO S: C, 66.74; H, 4.58; Cl, 8.95; N, 3.54; O, 8.08;
3
) d 55.3 (OMe), 61.2 (C-3),
21
H
2 3
O
b
H
2
4
.5.3. 1-Methyl-4-(4-nitrophenyl)-3-(phenylthio)azetidin-2-one
S, 8.10. Found: C, 66.85; H, 4.72; N, 3.61.
(
5c). It was purified by crystallization from ethyl acetate. White
ꢁ
solid (0.25 g, 79%). Mp: 71e73 C. R
(
f
¼0.36 (7:3 hexane/EtOAc); IR
4.5.9. 4-(4-Methoxyphenyl)-1-methyl-3-(phenylthio)azetidin-2-one
(5i). It was purified by crystallization from ethyl acetate. White
ꢀ
1
1
KBr, cm ): 1343, 1516 (NO
2
), 1751 (CO,
b
-lactam). H NMR (CDCl
3
)
ꢁ
d
2.92 (Me, s, 3H), 4.28 (H-4, d, 1H, J¼4.8), 4.73 (H-3, d, 1H, J¼4.8),
solid (0.24 g, 81%). Mp: 63e65 C. R
f
¼0.41 (7:3 hexane/EtOAc); IR
2.98 (Me, s, 3H),
3.55 (OMe, s, 3H), 4.21 (H-4, d, 1H, J¼4.4), 4.83 (H-3, d, 1H, J¼4.4),
.62e7.89 (ArH, m, 9H). 1 C NMR (CDCl
3.8 (C-4), 117.2, 120.0, 122.8, 123.2, 127.5, 133.5, 140.3, 147.7 (aro-
-lactam). Anal. Calcd for C16 S:
3
)
d
29.7 (Me), 62.5 (C-3),
(KBr, cm ): 1750 (CO,
ꢀ1
b
-lactam). H NMR (CDCl
1
)
d
6
6
3
3
13
matic carbons), 160.5 (CO,
C, 61.13; H, 4.49; N, 8.91; O, 15.27; S, 10.20. Found: C, 61.23; H, 4.58;
N, 8.84.
b
H
14
N
2
O
3
6.75e7.63 (ArH, m, 9H). C NMR (CDCl
60.8 (C-3), 62.5 (C-4), 119.0, 122.1, 122.4, 123.4, 123.9, 136.1, 142.4,
149.6 (aromatic carbons), 161.0 (CO, -lactam). Anal. Calcd for
S: C, 68.20; H, 5.72; N, 4.68; O, 10.69; S, 10.71. Found: C,
3
) d 30.3 (Me), 56.6 (OMe),
b
17 2
C H17NO
4
.5.4. 4-Benzyl-1-(4-methoxyphenyl)-3-(phenylthio)azetidin-2-one
68.11; H, 5.84; N, 4.74.
(
5d). It was purified by crystallization from ethyl acetate. White
ꢁ
solid (0.34 g, 90%). Mp: 135e137 C. R
f
¼0.44 (7:3 hexane/EtOAc); IR
4.5.10. 3-(Ethylthio)-1-(4-methoxyphenyl)-4-(4-nitrophenyl)azeti-
din-2-one (5j). It was purified by crystallization from ethyl acetate.
ꢀ
1
1
(
(
1
6
KBr, cm ): 1746 (CO,
CH
4.5), 3.66 (OMe, s, 3H), 4.09 (H-4, m, 1H), 4.68 (H-3, d, 1H, J¼5.0),
b
-lactam).
H
NMR (CDCl
3
)
d
2.47
ꢁ
2
ebenzyl, dd, 1H, J¼5.8, 14.5), 2.94 (CH
2
ebenzyl, dd, 1H, J¼5.8,
White solid (0.32 g, 88%). Mp: 79e81 C. R
f
¼0.38 (7:3 hexane/
ꢀ
1
1
EtOAc); IR (KBr, cm ): 1347, 1528 (NO
NMR (CDCl
1.27 (Me, t, 3H, J¼6.7), 2.71 (SCH
(OMe, s, 3H), 4.38 (H-4, d, 1H, J¼4.8), 4.91 (H-3, d, 1H, J¼4.8),
2
), 1741 (CO,
b-lactam). H
13
.81e8.11 (ArH, m, 14H). C NMR (CDCl
3
)
d
37.4 (CH
2
), 56.7 (OMe),
3
)
d
2
, q, 2H, J¼6.7), 3.65
6
1
b
1.1 (C-3), 61.9 (C-4), 115.1, 123.2, 127.1, 127.6, 128.6, 128.8, 129.2,
29.7, 130.0, 131.4, 135.2, 140.7, 154.4 (aromatic carbons), 162.3 (CO,
-lactam). Anal. Calcd for C23 S: C, 73.57; H, 5.64; N, 3.73; O,
13
3 2
6.78e8.11 (ArH, m, 8H). C NMR (CDCl ) d 14.1 (Me), 29.6 (SCH ),
H21NO
2
56.3 (OMe), 60.4 (C-3), 61.8 (C-4), 115.2, 122.7, 124.0, 125.3, 130.6,
135.2, 144.9, 156.8 (aromatic carbons), 162.4 (CO, -lactam). Anal.
Calcd for C18 S: C, 60.32; H, 5.06; N, 7.82; O, 17.86; S, 8.95.
8
.52; S, 8.54. Found: C, 73.49; H, 5.79; N, 3.65.
b
18 2 4
H N O
4
.5.5. 4-Benzyl-1-(4-chlorophenyl)-3-(phenylthio)azetidin-2-one
Found: C, 60.44; H, 5.15; N, 7.90.
(
5e). It was purified by crystallization from ethyl acetate. White
ꢁ
solid (0.32 g, 83%). Mp: 126e128 C. R
f
¼0.44 (7:3 hexane/EtOAc); IR
4.5.11. 1-(4-Chlorophenyl)-3-(ethylthio)-4-(4-nitrophenyl)azetidin-
2-one (5k). It was purified by crystallization from ethyl acetate.
ꢀ
1
1
(
(
1
KBr, cm ): 1743 (CO,
CH
4.8), 4.17 (H-4, m, 1H), 4.66 (H-3, d, 1H, J¼4.8), 6.77e7.73 (ArH, m,
b
-lactam).
H
NMR (CDCl
3
)
d
2.39
ꢁ
2
ebenzyl, dd, 1H, J¼5.5, 14.8), 2.90 (CH
2
ebenzyl, dd, 1H, J¼5.5,
White solid (0.31 g, 86%). Mp: 76e78 C. R
f
¼0.39 (7:3 hexane/
ꢀ1
1
EtOAc); IR (KBr, cm ): 1341, 1532 (NO
NMR (CDCl
1.23 (Me, t, 3H, J¼6.9), 2.75 (SCH
(H-4, d, 1H, J¼5.1), 4.77 (H-3, d, 1H, J¼5.1), 6.78e8.11 (ArH, m, 8H).
2
), 1745 (CO, b-lactam). H
13
1
1
(
4H). C NMR (CDCl
3
)
d
33.7 (CH
2
), 60.8 (C-3), 62.0 (C-4), 113.7,
18.8, 127.3, 128.5, 128.8, 129.7, 130.4, 130.9, 133.1, 136.7, 143.2, 146.5
aromatic carbons), 161.5 (CO, -lactam). Anal. Calcd for
18ClNOS: C, 69.55; H, 4.78; Cl, 9.33; N, 3.69; O, 4.21; S, 8.44.
Found: C, 69.47; H, 4.86; N, 3.66.
3
)
d
2
, q, 2H, J¼6.9), 4.28
13
b
C NMR (CDCl
3
)
d
15.3 (Me), 30.3 (SCH
2
), 61.4 (C-3), 63.1 (C-4),
111.5, 119.7, 122.1, 122.7, 131.5, 133.6, 145.4, 150.4 (aromatic car-
bons), 162.9 (CO, -lactam). Anal. Calcd for C17 15ClN S: C, 56.27;
22
C H
b
H
2 3
O
H, 4.17; Cl, 9.77; N, 7.72; O, 13.23; S, 8.84. Found: C, 56.39; H, 4.25;
N, 7.77.
4.5.6. 4-Benzyl-1-methyl-3-(phenylthio)azetidin-2-one (5f). It was
purified by crystallization from ethyl acetate. White solid (0.21 g,
ꢁ
ꢀ1
7
5%). Mp: 60e62 C. R
f
¼0.43 (7:3 hexane/EtOAc); IR (KBr, cm ):
4.5.12. 3-(Ethylthio)-1-methyl-4-(4-nitrophenyl)azetidin-2-one
(5l). It was purified by column chromatography on silica gel
1
1749 (CO,
b
-lactam). H NMR (CDCl
3
)
d
2.27 (CH
2
ebenzyl, dd, 1H,

M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
5837
(
hexane/EtOAc 8:2). Colorless oil (0.19 g, 73%). R
f
¼0.41 (7:3 hexane/
(aromatic carbons), 162.4 (CO,
b
-lactam). Anal. Calcd for
ꢀ
1
1
EtOAc); IR (KBr, cm ): 1347, 1539 (NO
2
), 1752 (CO,
b
-lactam). H
C
18
H
18ClNO S: C, 62.15; H, 5.22; Cl, 10.19; N, 4.03; O, 9.20; S, 9.22.
2
NMR (CDCl
3
)
d
1.28 (Me, t, 3H, J¼7.0), 2.82 (SCH
2
, q, 2H, J¼7.0), 2.96
Found: C, 62.21; H, 5.33; N, 4.09.
(
NeMe, s, 3H), 4.41 (H-4, d, 1H, J¼4.4), 4.86 (H-3, d, 1H, J¼4.4),
13
7
.26e8.01 (ArH, m, 4H). C NMR (CDCl
3
)
d
14.7 (Me), 28.2 (SCH
8.9 (NeMe), 60.6 (C-3), 62.7 (C-4), 120.5, 128.3, 146.7, 148.2 (aro-
-lactam). Anal. Calcd for C12 S: C,
4.12; H, 5.30; N, 10.52; O, 18.02; S, 12.04. Found: C, 54.06; H, 5.38;
N, 10.47.
2
),
4.5.18. 3-(Ethylthio)-4-(4-methoxyphenyl)-1-methyl azetidin-2-one
(5r). It was purified by column chromatography on silica gel
2
matic carbons),161.7 (CO,
b
H
14
N
2
O
3
(hexane/EtOAc 9:1). Colorless oil (0.18 g, 70%). R
f
¼0.46 (7:3 hexane/
-lactam). H NMR (CDCl 1.28
, q, 2H, J¼6.7), 2.97 (NeMe, s, 3H), 3.69
OMe, s, 3H), 4.46 (H-4, d, 1H, J¼5.1), 4.87 (H-3, d, 1H, J¼5.1),
ꢀ
1
1
5
EtOAc); IR (KBr, cm ): 1753 (CO,
(Me, t, 3H, J¼6.7), 2.91 (SCH
b
3
) d
2
(
13
4
.5.13. 4-Benzyl-3-(ethylthio)-1-(4-methoxyphenyl)azetidin-2-one
6.75e7.49 (ArH, m, 4H). C NMR (CDCl
29.7 (NeMe), 56.5 (OMe), 60.9 (C-3), 62.2 (C-4), 115.9, 124.6, 125.1,
155.3 (aromatic carbons), 161.6 (CO, -lactam). Anal. Calcd for
S: C, 62.12; H, 6.82; N, 5.57; O, 12.73; S, 12.76. Found: C,
3 2
) d 15.6 (Me), 28.0 (SCH ),
(5m). It was purified by crystallization from ethyl acetate. White
ꢁ
solid (0.28 g, 86%). Mp: 64e66 C. R
f
¼0.44 (7:3 hexane/EtOAc); IR
1.24 (Me, t, 3H,
ebenzyl, dd, 1H, J¼5.8, 15.0), 2.86 (SCH , q, 2H,
ebenzyl, dd,1H, J¼5.8,15.0), 3.71 (OMe, s, 3H), 4.17
b
ꢀ
1
1
(
KBr, cm ): 1746 (CO,
J¼6.9), 2.41 (CH
J¼6.9), 2.97 (CH
H-4, m, 1H), 4.83 (H-3, d, 1H, J¼4.7), 6.90e7.74 (ArH, m, 9H).
NMR (CDCl 15.5 (Me), 29.3 (SCH ), 33.8 (CH ), 55.3 (OMe), 61.5
C-3), 62.8 (C-4), 114.3, 121.9, 126.5, 128.3, 128.7, 130.8, 144.2, 155.7
aromatic carbons), 161.9 (CO, -lactam). Anal. Calcd for
S: C, 69.69; H, 6.46; N, 4.28; O, 9.77; S, 9.79. Found: C,
b
-lactam). H NMR (CDCl
3
)
d
13 2
C H17NO
2
2
62.03; H, 6.90; N, 5.48.
2
13
(
C
4.5.19. 1-(4-Methoxyphenyl)-3-(methylthio)-4-(4-nitrophenyl)azeti-
din-2-one (5s). It was purified by crystallization from ethyl acetate.
3
)
d
2
2
ꢁ
(
(
White solid (0.32 g, 93%). Mp: 61e63 C. R
f
¼0.40 (7:3 hexane/
ꢀ1
1
b
EtOAc); IR (KBr, cm ): 1345, 1539 (NO
NMR (CDCl 2.11 (SeMe, s, 3H), 3.69 (OMe, s, 3H), 4.49 (H-4, d,
1H, J¼4.5), 4.95 (H-3, d, 1H, J¼4.5), 6.74e8.12 (ArH, m, 8H). C NMR
CDCl 16.5 (SeMe), 55.8 (OMe), 61.1 (C-3), 63.2 (C-4), 113.5,
121.8, 122.3, 127.1, 134.2, 134.8, 150.4, 156.3 (aromatic carbons),
163.0 (CO, -lactam). Anal. Calcd for C17 S: C, 59.29; H, 4.68;
2
), 1743 (CO, b-lactam). H
C
6
19
H
21NO
2
3
) d
13
9.75; H, 6.58; N, 4.21.
(
3
) d
4
.5.14. 4-Benzyl-1-(4-chlorophenyl)-3-(ethylthio)azetidin-2-one
(5n). It was purified by crystallization from ethyl acetate. White
b
16 2 4
H N O
ꢁ
solid (0.26 g, 80%). Mp: 71e73 C. R
f
¼0.43 (7:3 hexane/EtOAc); IR
1.29 (Me, t, 3H,
ebenzyl, dd, 1H, J¼5.4, 14.8), 2.81 (SCH , q, 2H,
ebenzyl, dd, 1H, J¼5.4, 14.8), 4.26 (H-4, m, 1H),
N, 8.13; O, 18.58; S, 9.31. Found: C, 59.36; H, 4.82; N, 8.05.
ꢀ
1
1
(
KBr, cm ): 1742 (CO,
b
-lactam). H NMR (CDCl
3
)
d
J¼6.7), 2.38 (CH
2
2
4.5.20. 1-(4-Chlorophenyl)-3-(methylthio)-4-(4-nitrophenyl)azeti-
din-2-one (5t). It was purified by crystallization from ethyl acetate.
J¼6.7), 2.94 (CH
2
13
ꢁ
4
.89 (H-3, d, 1H, J¼4.4), 6.97e7.69 (ArH, m, 9H). C NMR (CDCl
3
)
White solid (0.31 g, 90%). Mp: 66e68 C. R
f
¼0.39 (7:3 hexane/
ꢀ1
1
d
15.0 (Me), 28.4 (SCH
22.7, 123.4, 126.1, 129.9, 130.5, 141.6, 143.3 (aromatic carbons),
60.6 (CO, -lactam). Anal. Calcd for C18 18ClNOS: C, 65.15; H, 5.47;
Cl, 10.68; N, 4.22; O, 4.82; S, 9.66. Found: C, 65.04; H, 5.58; N, 4.27.
2
), 32.1 (CH
2
), 60.8 (C-3), 62.2 (C-4), 119.2,
EtOAc); IR (KBr, cm ): 1347, 1533 (NO
NMR (CDCl
2.09 (SeMe, s, 3H), 4.53 (H-4, d, 1H, J¼4.8), 5.05 (H-
3, d, 1H, J¼4.8), 6.89e8.15 (ArH, m, 8H). C NMR (CDCl
(SeMe), 60.5 (C-3), 62.7 (C-4), 117.9, 122.1, 122.9, 125.3, 126.0, 140.4,
49.3, 155.7 (aromatic carbons), 162.5 (CO, -lactam). Anal. Calcd
for C16 13ClN S: C, 55.09; H, 3.76; Cl, 10.16; N, 8.03; O, 13.76; S,
2
), 1744 (CO, b-lactam). H
1
1
3
) d
1
3
b
H
3
) d 16.1
1
b
4
.5.15. 4-Benzyl-3-(ethylthio)-1-methylazetidin-2-one (5o). It was
purified by column chromatography on silica gel (hexane/EtOAc
:1). Colorless oil (0.17 g, 71%). R
¼0.47 (7:3 hexane/EtOAc); IR (KBr,
H
2 3
O
9.19. Found: C, 55.19; H, 3.84; N, 8.08.
9
f
ꢀ
1
1
cm ): 1750 (CO,
J¼7.0), 2.29 (CH ebenzyl, dd, 1H, J¼5.7, 14.9), 2.78 (SCH
J¼7.0), 2.87 (CH ebenzyl, dd, 1H, J¼5.7, 14.9), 2.99 (NeMe, s, 3H),
.36 (H-4, m, 1H), 4.88 (H-3, d, 1H, J¼4.8), 7.03e7.34 (ArH, m, 5H).
b-lactam). H NMR (CDCl
3
)
d
1.22 (Me, t, 3H,
4.5.21. 1-Methyl-3-(methylthio)-4-(4-nitrophenyl)azetidin-2-one
(5u). It was purified by column chromatography on silica gel
2
2
, q, 2H,
2
(hexane/EtOAc 8:2). Colorless oil (0.19 g, 74%). R
f
¼0.40 (7:3 hexane/
ꢀ1
1
4
EtOAc); IR (KBr, cm ): 1341, 1534 (NO
NMR (CDCl 2.13 (SeMe, s, 3H), 2.96 (NeMe, s, 3H), 4.38 (H-4, d,
1H, J¼4.3), 4.72 (H-3, d, 1H, J¼4.3), 7.16e8.06 (ArH, m, 4H). C NMR
(CDCl 15.3 (SeMe), 28.9 (NeMe), 61.7 (C-3), 63.4 (C-4), 122.6,
124.8, 142.7, 151.4 (aromatic carbons), 163.8 (CO, -lactam). Anal.
Calcd for C11 S: C, 52.37; H, 4.79; N, 11.10; O, 19.03; S, 12.71.
2
), 1753 (CO, b-lactam). H
1
3
C NMR (CDCl
1.7 (C-3), 63.1 (C-4), 122.2, 123.6, 128.0, 143.7, (aromatic carbons),
-lactam). Anal. Calcd for C13 17NOS: C, 66.34; H, 7.28; N,
3
)
d
14.5 (Me), 27.7 (SCH
2
), 28.5 (NeMe), 31.3 (CH
2
),
3
) d
13
6
1
65.3 (CO,
b
H
3
) d
5
.95; O, 6.80; S, 13.62. Found: C, 66.39; H, 7.41; N, 6.03.
b
12 2 3
H N O
4
.5.16. 3-(Ethylthio)-1,4-bis(4-methoxyphenyl)azetidin-2-one
Found: C, 52.42; H, 4.90; N, 11.16.
(
5p). It was purified by crystallization from ethyl acetate. White
ꢁ
solid (0.32 g, 92%). Mp: 73e75 C. R
f
¼0.42 (7:3 hexane/EtOAc); IR
1.29 (Me, t, 3H,
, q, 2H, J¼6.9), 3.63, 3.71 (2OMe, 2s, 6H), 4.41 (H-
4.5.22. 4-Benzyl-1-(4-methoxyphenyl)-3-(methylthio)azetidin-2-one
(5v). It was purified by crystallization from ethyl acetate. White
ꢀ1
1
(
KBr, cm ): 1747 (CO,
J¼6.9), 2.79 (SCH
, d, 1H, J¼4.4), 4.96 (H-3, d, 1H, J¼4.4), 6.69e7.84 (ArH, m, 8H).
NMR 14.9 (Me), 29.3 (SCH ), 55.5, 56.2 (2OMe), 61.8 (C-3), 63.4 (C-
), 114.7, 123.2, 123.8, 128.1, 133.5, 137.0, 154.1, 156.6 (aromatic
carbons),163.7 (CO, -lactam). Anal. Calcd for C19 S: C, 66.45;
H, 6.16; N, 4.08; O, 13.98; S, 9.34. Found: C, 66.37; H, 6.24; N, 4.00.
b
-lactam). H NMR (CDCl
3
)
d
ꢁ
2
solid (0.27 g, 85%). Mp: 51e53 C. R
f
¼0.42 (7:3 hexane/EtOAc); IR
2.07 (SeMe, s,
ebenzyl, dd, 1H, J¼5.9, 14.6), 2.88 (CH ebenzyl, dd,
1H, J¼5.9, 14.6), 3.67 (OMe, s, 3H), 4.25 (H-4, m, 1H), 4.77 (H-3, d,
13
ꢀ1
1
4
C
(KBr, cm ): 1742 (CO,
3H), 2.47 (CH
3
b-lactam). H NMR (CDCl ) d
d
2
2
2
4
13
b
H21NO
3
1H, J¼4.9), 6.95e7.83 (ArH, m, 9H). C NMR (CDCl
32.5 (CH ), 56.1 (OMe), 61.3 (C-3), 63.0 (C-4), 112.8, 117.4, 127.9,
28.5, 128.9, 135.8, 146.1, 156.7 (aromatic carbons), 162.4 (CO,
-lactam). Anal. Calcd for C18 S: C, 68.98; H, 6.11; N, 4.47; O,
3
) d 15.8 (SeMe),
2
1
b
4
.5.17. 1-(4-Chlorophenyl)-3-(ethylthio)-4-(4-methoxyphenyl)azeti-
H19NO
2
din-2-one (5q). It was purified by crystallization from ethyl acetate.
10.21; S, 10.23. Found: C, 68.91; H, 6.20; N, 4.42.
ꢁ
White solid (0.29 g, 82%). Mp: 81e83 C. R
f
¼0.43 (7:3 hexane/
ꢀ1
1
EtOAc); IR (KBr, cm ): 1743 (CO,
b
-lactam). H NMR (CDCl
, q, 2H, J¼7.0), 3.66 (OMe, s, 3H), 4.50
H-4, d, 1H, J¼4.6), 4.96 (H-3, d, 1H, J¼4.6), 6.69e7.84 (ArH, m, 8H).
3
)
d
1.25
4.5.23. 4-Benzyl-1-(4-chlorophenyl)-3-(methylthio)azetidin-2-one
(
Me, t, 3H, J¼7.0), 2.86 (SCH
2
(5w). It was purified by crystallization from ethyl acetate. White
ꢁ
(
solid (0.27 g, 84%). Mp: 57e59 C. R
f
¼0.43 (7:3 hexane/EtOAc); IR
2.11 (SeMe, s,
ebenzyl, dd, 1H, J¼5.7, 15.0), 2.82 (CH ebenzyl, dd,
1
3
ꢀ1
1
C NMR (CDCl
3
)
d
14.6 (Me), 28.7 (SCH
2
), 55.9 (OMe), 60.6 (C-3),
(KBr, cm ): 1744 (CO,
3H), 2.40 (CH
3
b-lactam). H NMR (CDCl ) d
6
3.1 (C-4), 117.2, 122.7, 123.3, 127.9, 128.6, 134.1, 147.5, 155.8
2
2

5838
M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
cmꢀ1): 1085 (S]O), 1748 (CO,
(SOeMe, s, 3H, minor stereoisomer), 2.44 (SOeMe, s, 3H, major
stereoisomer), 2.52 (CH ebenzyl, m, 2H, both stereoisomers), 2.93
(CH ebenzyl, m, 2H, both stereoisomers), 3.59 (OMe, s, 3H, minor
3
b ) d 2.39
-lactam). 1H NMR (CDCl
1
(
H, J¼5.7, 15.0), 4.18 (H-4, m, 1H), 4.69 (H-3, d, 1H, J¼4.5), 6.84e7.55
ArH, m, 9H). 13C NMR (CDCl
d
14.9 (SeMe), 33.7 (CH ), 60.7 (C-3),
3
)
2
61.3 (C-4), 118.4, 120.8, 123.5, 123.7, 129.6, 131.2, 134.8, 147.5 (aro-
2
matic carbons), 160.9 (CO,
b-lactam). Anal. Calcd for C17
H16ClNOS:
2
C, 64.24; H, 5.07; Cl, 11.15; N, 4.41; O, 5.03; S, 10.09. Found: C, 64.16;
H, 5.18; N, 4.37.
stereoisomer), 3.67 (OMe, s, 3H, major stereoisomer), 4.42 (H-4, m,
1H, minor stereoisomer), 4.60 (H-4, m, 1H, major stereoisomer),
5
.09 (H-3, d, 1H, J¼4.4, minor stereoisomer), 5.18 (H-3, d, 1H, J¼4.5,
4
.5.24. 4-Benzyl-1-methyl-3-(methylthio)azetidin-2-one (5x). It was
purified by column chromatography on silica gel (hexane/EtOAc
:1). Colorless oil (0.15 g, 68%). R
¼0.45 (7:3 hexane/EtOAc); IR (KBr,
-lactam). H NMR (CDCl 2.14 (SeMe, s, 3H),
ebenzyl, dd, 1H, J¼5.7, 14.5), 2.84 (CH ebenzyl, dd, 1H,
J¼5.7, 14.5), 2.96 (NeMe, s, 3H), 4.28 (H-4, m, 1H), 4.84 (H-3, d, 1H,
major stereoisomer), 6.88e7.56 (ArH, m, 18H, both stereoisomers).
13
C NMR (CDCl
76.1 (C-3), 116.3, 119.0, 129.4, 130.5, 130.9, 138.1, 147.7, 156.0 (aro-
matic carbons), 163.3 (CO, -lactam). Anal. Calcd for C18 S: C,
3 2
) d 31.7 (SOeMe), 34.3 (CH ), 55.9 (OMe), 60.6 (C-4),
9
f
ꢀ
1
1
cm ): 1755 (CO,
.33 (CH
b
3
)
d
b
H19NO
3
2
2
2
65.63; H, 5.81; N, 4.25; O, 14.57; S, 9.73. Found: C, 65.75; H, 5.98;
N, 4.18.
1
3
J¼4.8), 7.03e7.49 (ArH, m, 5H). C NMR (CDCl
3
)
d
14.1 (SeMe), 29.7
), 61.2 (C-3), 62.9 (C-4), 121.5, 122.1, 131.7, 145.3
aromatic carbons),161.7 (CO, -lactam). Anal. Calcd for C12 15NOS:
(
(
NeMe), 33.1 (CH
2
4.6.2. 4-Benzyl-1-(4-chlorophenyl)-3-(methylsulfinyl)azetidin-2-one
(6b). White solid (0.19 g, 83%) (2.5:1 mixture of diastereomers by
b
H
ꢁ
ꢀ1
C, 65.12; H, 6.83; N, 6.33; O, 7.23; S, 14.49. Found: C, 65.22; H, 6.96;
N, 6.39.
NMR). Mp: 91e93 C. R
1088 (S]O), 1745 (CO,
f
¼0.47 (1:1 hexane/EtOAc); IR (KBr, cm ):
1
b-lactam). H NMR (CDCl
3
)
d
2.31 (SOeMe, s,
3H, minor stereoisomer), 2.42 (SOeMe, s, 3H, major stereoisomer),
4
.5.25. 1,4-Bis(4-methoxyphenyl)-3-(methylthio)azetidin-2-one
2.55 (CH ebenzyl, m, 2H, both stereoisomers), 2.83 (CH ebenzyl,
2
2
(
5y). It was purified by crystallization from ethyl acetate. White
m, 2H, both stereoisomers), 4.54 (H-4, m, 1H, minor stereoisomer),
4.68 (H-4, m, 1H, major stereoisomer), 5.08 (H-3, d,1H, J¼4.7, minor
stereoisomer), 5.20 (H-3, d, 1H, J¼4.6, major stereoisomer),
ꢁ
solid (0.31 g, 93%). Mp: 59e61 C. R
f
¼0.41 (7:3 hexane/EtOAc); IR
2.19 (SeMe, s,
H), 3.59, 3.66 (2OMe, 2s, 6H), 4.53 (H-4, d, 1H, J¼4.7), 5.03 (H-3, d,
ꢀ
1
1
(
KBr, cm ): 1745 (CO, b-lactam). H NMR (CDCl ) d
3
13
3
1
5
3
6.96e7.49 (ArH, m, 18H, both stereoisomers). C NMR (CDCl )
1
3
H, J¼4.7), 6.71e7.84 (ArH, m, 8H). C NMR (CDCl
5.9, 56.6 (2OMe), 61.8 (C-3), 63.4 (C-4), 112.4, 118.8, 123.4, 123.7,
-lactam).
S: C, 65.63; H, 5.81; N, 4.25; O, 14.57; S,
3
)
d
15.3 (SeMe),
d
32.5 (SOeMe), 36.0 (CH
133.1, 134.0, 137.4, 141.8, 150.7 (aromatic carbons), 161.5 (CO,
-lactam). Anal. Calcd for C17 16ClNO S: C, 61.16; H, 4.83; Cl, 10.62;
N, 4.20; O, 9.59; S, 9.61. Found: C, 61.07; H, 4.5; N, 4.13.
2
), 61.2 (C-4), 75.2 (C-3), 118.1, 120.5, 125.9,
1
36.9, 140.2, 152.7, 155.3 (aromatic carbons), 161.9 (CO,
b
b
H
2
Anal. Calcd for C18H19NO
3
9
.73. Found: C, 65.55; H, 5.96; N, 4.17.
4
.6.3. 4-Benzyl-1-methyl-3-(methylsulfinyl)azetidin-2-one
4
.5.26. 1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-(methylthio)aze-
(6c). Colorless oil (0.12 g, 71%) (2.5:1 mixture of diastereomers by
ꢀ1
tidin-2-one (5z). It was purified by crystallization from ethyl ace-
NMR). R
1751 (CO,
stereoisomer), 2.41 (SOeMe, s, 3H, major stereoisomer), 2.48
(CH ebenzyl, m, 2H, both stereoisomers), 2.85 (CH ebenzyl, m, 2H,
f
¼0.51 (1:1 hexane/EtOAc); IR (KBr, cm ): 1078 (S]O),
ꢁ
1
tate. White solid (0.30 g, 90%). Mp: 64e66 C. R
f
¼0.40 (7:3 hexane/
2.28
SeMe, s, 3H), 3.64 (OMe, s, 3H), 4.59 (H-4, d, 1H, J¼4.3), 5.09 (H-3,
3
b-lactam). H NMR (CDCl ) d 2.33 (SOeMe, s, 3H, minor
ꢀ
1
1
3
EtOAc); IR (KBr, cm ): 1744 (CO, b-lactam). H NMR (CDCl ) d
(
2
2
13
d, 1H, J¼4.3), 6.60e7.59 (ArH, m, 8H). C NMR (CDCl
SeMe), 56.1 (OMe), 61.3 (C-3), 62.5 (C-4), 113.3, 116.3, 122.8, 123.4,
31.7, 141.4, 146.9, 154.5 (aromatic carbons), 163.1 (CO, -lactam).
Anal. Calcd for C17 16ClNO S: C, 61.16; H, 4.83; Cl, 10.62; N, 4.20; O,
.59; S, 9.61. Found: C, 61.22; H, 4.98; N, 4.27.
3
)
d
14.7
both stereoisomers), 2.92 (NeMe, s, 3H, minor stereoisomer), 2.99
(NeMe, s, 3H, major stereoisomer), 4.59 (H-4, m, 1H, minor ste-
reoisomer), 4.66 (H-4, m, 1H, major stereoisomer), 5.14 (H-3, d, 1H,
J¼4.3, minor stereoisomer), 5.27 (H-3, d, 1H, J¼4.5, major stereo-
(
1
b
H
2
13
9
isomer), 7.01e7.38 (ArH, m, 10H, both stereoisomers). C NMR
(
CDCl
3), 119.7, 123.8, 125.6, 143.9 (aromatic carbons), 162.7 (CO,
tam). Anal. Calcd for C12 S: C, 60.73; H, 6.37; N, 5.90; O,
13.48; S, 13.51. Found: C, 60.79; H, 6.50; N, 5.83.
3
)
d
29.8 (NeMe), 31.1 (SOeMe), 33.6 (CH
2
), 61.3 (C-4), 77.5 (C-
4
.5.27. 4-(4-Methoxyphenyl)-1-methyl-3-(methylthio)azetidin-2-
b
-lac-
one (5yz). It was purified by column chromatography on silica gel
hexane/EtOAc 9:1). Colorless oil (0.17 g, 72%). R
¼0.45 (7:3 hexane/
-lactam). H NMR (CDCl 2.20
SeMe, s, 3H), 2.91 (NeMe, s, 3H), 3.58 (OMe, s, 3H), 4.44 (H-4, d,
H15NO
2
(
f
ꢀ
1
1
EtOAc); IR (KBr, cm ): 1752 (CO,
(
b
3
) d
4.6.4. 1,4-Bis(4-methoxyphenyl)-3-(methylsulfinyl)azetidin-2-one
(6d). White solid (0.18 g, 75%) (2.5:1 mixture of diastereomers by
13
1
H, J¼4.8), 4.83 (H-3, d, 1H, J¼4.8), 6.84e7.31 (ArH, m, 4H). C NMR
14.8 (SeMe), 29.7 (NeMe), 56.7 (OMe), 60.9 (C-3), 62.7 (C-
), 116.4, 125.3, 138.6, 152.5 (aromatic carbons), 162.9 (CO, -lac-
S: C, 60.73; H, 6.37; N, 5.90; O,
ꢁ
ꢀ1
(
CDCl
3
)
d
NMR). Mp: 96e98 C. R
1089 (S]O), 1745 (CO,
f
¼0.43 (1:1 hexane/EtOAc); IR (KBr, cm ):
1
4
b
b
-lactam). H NMR (CDCl
3
)
d
2.32 (SOeMe, s,
tam). Anal. Calcd for C12
H
15NO
2
3H, minor stereoisomer), 2.40 (SOeMe, s, 3H, major stereoisomer),
13.48; S, 13.51. Found: C, 60.64; H, 6.49; N, 5.86.
3.55, 3.61 (2OMe, 2s, 6H, minor stereoisomer), 3.64, 3.68 (2OMe, 2s,
6
H, major stereoisomer), 4.47 (H-4, d, 1H, J¼4.8, minor stereoiso-
4
.6. General procedure for the synthesis of 3-(methylsulfinyl)
mer), 4.59 (H-4, d, 1H, J¼4.7, major stereoisomer), 5.16 (H-3, d, 1H,
b-lactams 6aef
J¼4.8, minor stereoisomer), 5.25 (H-3, d, 1H, J¼4.7, major stereo-
13
isomer), 6.82e7.62 (ArH, m, 16H, both stereoisomers). C NMR
To a solution of 3-methylthio
b
-lactams 5veyz (0.7 mmol) in
(CDCl
114.8, 117.3, 124.6, 131.5, 132.1, 139.4, 152.2, 155.8 (aromatic car-
bons), 162.6 (CO, -lactam). Anal. Calcd for C18 S: C, 62.59; H,
3
) d 32.3 (SOeMe), 56.3, 58.0 (2OMe), 63.2 (C-4), 77.8 (C-3),
ꢁ
CH
2
Cl
2
(20 mL) at e15 C was added m-CPBA (0.12 g, 0.7 mmol).
After 2 h, a saturated solution of NaHSO
3
(10 mL) was added, and
b
H19NO
4
the mixture was allowed to warm to room temperature and then
extracted with EtOAc (2ꢂ15 mL). The organic layer was purified by
chromatography on silica gel using EtOAc/hexane (4:6) to give pure
products.
5.54; N, 4.06; O, 18.53; S, 9.28. Found: C, 62.69; H, 5.71; N, 4.13.
4.6.5. 1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-(methylsulfinyl)
azetidin-2-one (6e). White solid (0.18 g, 72%) (2.5:1 mixture of di-
ꢁ
astereomers by NMR). Mp: 99e101 C. R
f
¼0.43 (1:1 hexane/EtOAc);
ꢀ1
1
4
.6.1. 4-Benzyl-1-(4-methoxyphenyl)-3-(methylsulfinyl)azetidin-2-
IR (KBr, cm ): 1081 (S]O), 1748 (CO,
2.37 (SOeMe, s, 3H, minor stereoisomer), 2.44 (SOeMe, s, 3H,
major stereoisomer), 3.57 (OMe, s, 3H, minor stereoisomer), 3.62
3
b-lactam). H NMR (CDCl )
one (6a). White solid (0.18 g, 78%) (2.5:1 mixture of diastereomers
d
ꢁ
by NMR). Mp: 83e85 C. R
f
¼0.48 (1:1 hexane/EtOAc); IR (KBr,

M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
5839
(
OMe, s, 3H, major stereoisomer), 4.51 (H-4, d, 1H, J¼4.3, minor
(CDCl
3
)
d
29.4 (NeMe), 32.7 (CH
2
), 35.1 (SO
2
-Me), 60.3 (C-4), 81.4
stereoisomer), 4.57 (H-4, d, 1H, J¼4.6, major stereoisomer), 5.13 (H-
(C-3), 120.8, 125.3, 126.1, 143.2 (aromatic carbons), 163.4 (CO,
lactam). Anal. Calcd for C12 S: C, 56.90; H, 5.97; N, 5.53; O,
18.95; S, 12.66. Found: C, 56.82; H, 6.07; N, 5.58.
b-
3
, d, 1H, J¼4.3, minor stereoisomer), 5.17 (H-3, d, 1H, J¼4.6, major
H15NO
3
13
stereoisomer), 6.79e7.93 (ArH, m, 16H, both stereoisomers).
C
NMR (CDCl
16.2, 118.0, 122.3, 132.5, 132.8, 135.7, 142.2, 156.8 (aromatic car-
bons), 162.1 (CO, -lactam). Anal. Calcd for C17 16ClNO S: C, 58.37;
H, 4.61; Cl, 10.13; N, 4.00; O, 13.72; S, 9.17. Found: C, 58.26; H, 4.70;
N, 3.92.
3
) d 33.8 (SOeMe), 56.7 (OMe), 61.6 (C-4), 78.4 (C-3),
1
4.7.4. 1,4-Bis(4-methoxyphenyl)-3-(methylsulfonyl)azetidin-2-one
ꢁ
b
H
3
(7d). White solid (0.14 g, 80%). Mp: 111e113 C. R
f
¼0.38 (1:1 hex-
-lactam).
-Me, s, 3H), 3.53, 3.61 (2OMe, 2s, 6H),
.31 (H-4, d, 1H, J¼4.9), 5.59 (H-3, d, 1H, J¼4.9), 6.70e7.73 (ArH, m,
ꢀ1
ane/EtOAc); IR (KBr, cm ): 1159, 1313 (SO
H NMR (CDCl ) d 3.15 (SO
3 2
2
), 1756 (CO,
b
1
4
13
4
.6.6. 4-(4-Methoxyphenyl)-1-methyl-3-(methylsulfinyl)azetidin-2-
8H). C NMR (CDCl
83.5 (C-3), 115.1, 120.8, 121.3, 125.7, 129.9, 130.2, 146.1, 157.4 (aro-
matic carbons), 164.2 (CO, -lactam). Anal. Calcd for C18 S: C,
3 2
) d 32.9 (SO -Me), 56.0, 56.9 (2OMe), 61.8 (C-4),
one (6f). Colorless oil (0.13 g, 76%) (2.5:1 mixture of diastereomers
ꢀ
1
by NMR). R
755 (CO,
stereoisomer), 2.34 (SOeMe, s, 3H, major stereoisomer), 2.88
NeMe, s, 3H, minor stereoisomer), 2.96 (NeMe, s, 3H, major ste-
reoisomer), 3.63 (OMe, s, 3H, minor stereoisomer), 3.68 (OMe, s,
f
¼0.46 (1:1 hexane/EtOAc); IR (KBr, cm ): 1084 (S]O),
b
H19NO
5
1
1
b
-lactam). H NMR (CDCl
3
)
d
2.29 (SOeMe, s, 3H, minor
59.82; H, 5.30; N, 3.88; O, 22.13; S, 8.87. Found: C, 59.91; H, 5.44;
N, 3.93.
(
4.7.5. 1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-(methylsulfonyl)
ꢁ
3
H, major stereoisomer), 4.47 (H-4, d, 1H, J¼5.0, minor stereoiso-
azetidin-2-one (7e). White solid (0.13 g, 74%). Mp: 123e125 C.
ꢀ
1
mer), 4.53 (H-4, d, 1H, J¼4.8, major stereoisomer), 5.08 (H-3, d, 1H,
J¼5.0, minor stereoisomer), 5.15 (H-3, d, 1H, J¼4.8, major stereo-
R
f
¼0.40 (1:1 hexane/EtOAc); IR (KBr, cm ): 1155, 1314 (SO
2
), 1751
-Me, s, 3H), 3.54 (OMe, s,
3H), 4.36 (H-4, d, 1H, J¼4.2), 5.50 (H-3, d, 1H, J¼4.2), 6.83e7.46
1
3 2
(CO, b-lactam). H NMR (CDCl ) d 3.10 (SO
13
isomer), 6.92e7.29 (ArH, m, 8H, both stereoisomers). C NMR
13
(
(
b
1
CDCl
C-3), 116.3, 121.1, 127.5, 152.9 (aromatic carbons), 161.7 (CO,
-lactam). Anal. Calcd for C12 S: C, 56.90; H, 5.97; N, 5.53; O,
8.95; S, 12.66. Found: C, 56.97; H, 6.11; N, 5.56.
3
)
d
29.0 (NeMe), 31.8 (SOeMe), 55.4 (OMe), 61.5 (C-4), 76.9
(ArH, m, 8H). C NMR (CDCl
4), 82.8 (C-3), 116.4, 119.1, 121.8, 122.6, 125.7, 133.9, 140.4, 147.2
(aromatic carbons), 163.7 (CO, -lactam). Anal. Calcd for
16ClNO S: C, 55.81; H, 4.41; Cl, 9.69; N, 3.83; O, 17.49; S, 8.76.
3 2
) d 33.5 (SO -Me), 55.7(OMe), 62.0 (C-
H15NO
3
b
C
17
H
4
Found: C, 55.76; H, 4.50; N, 3.86.
4
.7. General procedure for the synthesis of 3-(methylsulfonyl)
b-lactams 7aef
4.7.6. 4-(4-Methoxyphenyl)-1-methyl-3-(methylsulfonyl)azetidin-2-
one (7f). Colorless oil (0.10 g, 77%). R
f
¼0.45 (1:1 hexane/EtOAc); IR
ꢀ1
1
To a solution of 3-methylthio
b
-lactams 5veyz (0.5 mmol) in
(KBr, cm ): 1151, 1307 (SO
2.90 (NeMe, s, 3H), 3.06 (SO
(H-4, d, 1H, J¼4.7), 5.57 (H-3, d, 1H, J¼4.7), 6.79e7.25 (ArH, m, 4H).
2
), 1754 (CO,
3
b-lactam). H NMR (CDCl )
CH
temperature. After 3 h, a saturated solution of NaHSO
NaHCO (20 mL) was added, and the mixture was extracted with
2
Cl
2
(20 mL) was added m-CPBA (0.2 g, 1.16 mmol) at room
d
2
eMe, s, 3H), 3.58 (OMe, s, 3H), 4.43
3
(10 mL) and
13
3
C NMR (CDCl
3 2
) d 29.5 (NeMe), 32.8 (SO -Me), 56.3 (OMe), 62.4 (C-
EtOAc (2ꢂ15 mL). The organic layer was purified by chromatogra-
4), 83.7 (C-3), 117.1, 118.9, 137.4, 155.0 (aromatic carbons), 162.6 (CO,
phy on silica gel using EtOAc/hexane (3:7) to give pure products.
b-lactam). Anal. Calcd for C12
4
H15NO S: C, 53.52; H, 5.61; N, 5.20; O,
23.76; S, 11.91. Found: C, 53.64; H, 5.77; N, 5.28.
4
.7.1. 4-Benzyl-1-(4-methoxyphenyl)-3-(methylsulfonyl)azetidin-2-
ꢁ
one (7a). White solid (0.14 g, 82%). Mp: 117e119 C. R
hexane/EtOAc); IR (KBr, cm ): 1161, 1318 (SO ), 1753 (CO, b
2
tam). H NMR (CDCl ) d 2.40 (CH
3 2
f
¼0.40 (1:1
-lac-
ebenzyl, dd, 1H, J¼5.7, 15.0), 2.79
ebenzyl, dd, 1H, J¼5.7, 15.0), 3.08 (SO -Me, s, 3H), 3.56 (OMe, s,
H), 4.19 (H-4, m, 1H), 5.52 (H-3, d, 1H, J¼4.5), 6.81e7.69 (ArH, m,
Acknowledgements
ꢀ1
1
We wish to thank the Hormozgan University Research Council
for support of this work.
(
CH
2
2
3
9
13
3 2 2
H). C NMR (CDCl ) d 32.2 (CH ), 34.0 (SO -Me), 56.7 (OMe), 60.8
Supplementary data
(
(
C
6
C-4), 81.2 (C-3), 117.6, 121.4, 123.5, 129.1, 129.7, 133.2, 148.6, 156.1
aromatic carbons), 163.9 (CO, -lactam). Anal. Calcd for
S: C, 62.59; H, 5.54; N, 4.06; O, 18.53; S, 9.28. Found: C,
b
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.05.043. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
18 4
H19NO
2.50; H, 5.67; N, 4.11.
4
.7.2. 4-Benzyl-1-(4-chlorophenyl)-3-(methylsulfonyl)azetidin-2-
ꢁ
one (7b). White solid (0.13 g, 77%). Mp: 124e126 C. R
hexane/EtOAc); IR (KBr, cm ): 1157, 1322 (SO ), 1755 (CO, b
2
tam). H NMR (CDCl ) d 2.45 (CH
3 2
f
¼0.41 (1:1
-lac-
ebenzyl, dd, 1H, J¼5.8, 14.5), 2.81
ebenzyl, dd, 1H, J¼5.8, 14.5), 3.01 (SO -Me, s, 3H), 4.13 (H-4, m,
H), 5.57 (H-3, d, 1H, J¼4.3), 6.93e7.46 (ArH, m, 9H). C NMR
31.6 (CH ), 33.3 (SO -Me), 61.3 (C-4), 81.8 (C-3), 119.9,
23.7, 123.9, 128.7, 129.4, 132.8, 141.4, 148.2 (aromatic carbons),
62.9 (CO, -lactam). Anal. Calcd for C17 16ClNO S: C, 58.37; H,
.61; Cl, 10.13; N, 4.00; O, 13.72; S, 9.17. Found: C, 58.44; H, 4.74;
ꢀ
1
References and notes
1
1. (a) Southgate, R. Contemp. Org. Synth. 1994, 1, 417e432; (b) Hwu, J. R.; Ethiraj, K.
(
CH
2
2
S.; Hakimelahi, G. H. Mini-Rev. Med. Chem. 2003, 3, 305e313; (c) De Kimpe, N. In
Comprehensive Heterocyclic Chemistry II; Katrizky, A. R., Rees, C. W., Scriven, E. F.
V., Padwa, A., Eds.; Pergamon: Oxford, 1996; Vol. 1B; p 507; (d) Koppel, G. A. In
Small Ring Heterocycles; Hasner, A., Ed.; Wiley: New York, NY, 1983; Vol. 42;
p 219.
13
1
(
1
1
4
CDCl
3
)
d
2
2
2. (a) Xu, X.; Fu, R.; Chen, J.; Chen, S.; Bai, S. Bioorg. Med. Chem. Lett. 2007, 17,
b
H
3
101e104; (b) Li, S.; Liu, G.; Jia, J.; Li, X.; Yu, C. J. Pharm. Biomed. Anal. 2006, 40,
987e992; (c) Burnett, D. A. Curr. Med. Chem. 2004, 11, 1873e1887.
N, 4.08.
3. (a) For review see: Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics,
E. Curr. Med. Chem. 2003, 10, 1741e1757; (b) Gerona-Navarro, G.; De Vega, J. P.;
Garcia-Lopez, M. T.; Andrei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E.; Gonzalez-
Muniz, R. Bioorg. Med. Chem. Lett. 2004, 14, 2253e2256; (c) Marchand-Brynaert,
J.; Dive, G.; Galleni, M.; Gerard, S. Bioorg. Med. Chem. 2004, 12, 129e138; (d)
Sutton, J. C.; Bolton, S. A.; Harti, K. S.; Huang, M. H.; Jacobs, G.; Meng, W.; Zhao,
G.; Bisacchi, G. S. Bioorg. Med. Chem. Lett. 2004, 14, 2233e2239; (e) Setti, E. L.;
Davis, D.; Janc, J. M.; Jeffery, D. A.; Cheung, H.; Yu, W. Bioorg. Med. Chem. Lett.
4
.7.3. 4-Benzyl-1-methyl-3-(methylsulfonyl)azetidin-2-one
(7c). Colorless oil (0.10 g, 79%). R
f
¼0.43 (1:1 hexane/EtOAc); IR
ꢀ1
1
(
KBr, cm ): 1155, 1308 (SO
2.48 (CH
ebenzyl, dd, 1H, J¼5.6, 14.6), 2.88 (CH
J¼5.6, 14.6), 2.97 (NeMe, s, 3H), 3.13 (SO -Me, s, 3H), 4.26 (H-4, m,
H), 5.59 (H-3, d, 1H, J¼4.7), 6.95e7.27 (ArH, m, 5H). C NMR
2
), 1752 (CO,
b
-lactam). H NMR (CDCl
3
)
d
2
2
ebenzyl, dd, 1H,
2
2005, 15, 1529e1534; (f) Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem.
2005, 13, 3611e3622; (g) Nivsarkar, M.; Thavaselvam, D.; Prasanna, S.; Sharma,
13
1

5840
M. Zarei, M. Mohamadzadeh / Tetrahedron 67 (2011) 5832e5840
M.; Kaushik, M. P. Bioorg. Med. Chem. Lett. 2005, 15, 1371e1373; (h) Zoidis, G.;
9. (a) Granados, C. A.; Cardo, D. M.; McGowan, J. E. Int. J. Antimicrob. Agents 2008,
32, 1e9; (b) Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 93e109.
Fytas, C.; Papanastasiou, I.; Foscolos, G. B.; Fytas, G.; Padalko, E.; De Clercq, E.;
Naesens, L.; Neyts, J.; Kolocouris, N. Bioorg. Med. Chem. 2006, 14, 3341e3348; (i)
Mehta, P. D.; Sengar, N. P. S.; Pathak, A. K. Eur. J. Med. Chem. 2010, 45,
10. (a) Kazi, A.; Hill, R.; Long, T. E.; Kuhn, D. J.; Turos, E.; Ping Dou, Q. Biochem.
Pharmacol. 2004, 67, 365e374; (b) Chen, D.; Falsetti, S. C.; Frezza, M.; Milacic,
V.; Kazi, A.; Cui, Q. C.; Long, T. E.; Turos, E.; Ping Dou, Q. Cancer Lett. 2008, 268,
63e69; (c) O’Driscoll, M.; Greenhalgh, K.; Young, A.; Turos, E.; Dickey, S.; Lim,
D. V. Bioorg. Med. Chem. 2008, 16, 7832e7837; (d) Abeylath, S. C.; Turos, E.;
Dickey, S.; Lim, D. V. Bioorg. Med. Chem. 2008, 16, 2412e2418; (e) Revell, K. D.;
Heldreth, B.; Long, T. E.; Jang, S.; Turos, E. Bioorg. Med. Chem. 2007, 15,
2453e2467; (f) Heldreth, B.; Long, T. E.; Jang, S.; Reddy, G. S. K.; Turos, E.;
Dickey, S.; Lim, D. V. Bioorg. Med. Chem. 2006, 14, 3775e3784; (g) Long, T. E.;
Turos, E. Curr. Med. Chem. -Anti-Infect. Agents 2002, 1, 251e268.
5
541e5560.
. (a) Ge, H.; Spletstoser, J. T.; Yang, Y.; Kayser, M.; Georg, G. I. J. Org. Chem. 2007,
2, 756e759; (b) Paik, Y.; Yang, C.; Metaferia, B.; Tang, S.; Bane, S.; Ravindra, R.;
4
7
Shanker, N.; Alcaraz, A. A.; Johnson, S. A.; Schaefer, J.; O’Connor, R. D.; Cegelski,
L.; Snyder, J. P.; Kingston, D. G. I. J. Am. Chem. Soc. 2007, 129, 361e370; (c)
Ganesh, T.; Norris, A.; Sharma, S.; Bane, S.; Alcaraz, A. A.; Snyder, J. P.; Kingston,
D. G. I. Bioorg. Med. Chem. 2006, 14, 3447e3454.
5
. (a) Ojima, I. In Advances in Asymmetric Synthesis; Hassner, A., Ed.; Jai: Green-
wich, 1995; Vol. 1, p 95; (b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev.
11. Kubo, I.; Xiao, P.; Fujita, K. Bioorg. Med. Chem. Lett. 2002, 12, 113e116.
12. (a) Jarrahpour, A.; Zarei, M. Tetrahedron 2009, 65, 2927e2934; (b) Jarrahpour,
A.; Zarei, M. Tetrahedron Lett. 2007, 48, 8712e8714; (c) Jarrahpour, A.; Fadavi,
A.; Zarei, M. Bull. Chem. Soc. Jpn. 2011, 84, 320e327.
13. (a) Gomes, L. F. R.; Trindade, A. F.; Candeias, N. R.; Veiros, L. F.; Gois, P. M. P.; Afonso,
C. A. M. Synthesis 2009, 3519e3526; (b) Zhou, F.; Rosen, J.; Zebrowski-Young, J. M.;
Freihammer, P. M.; Detty, M. R. J. Org. Chem. 1998, 63, 5403e5412; (c) Ren, X.-F.;
Konaklieva, M. I.; Shi, H.; Dickey, S.; Lim, D. V.; Gonzalez, J.; Turos, E. J. Org. Chem.
1998, 63, 8898e8917; (d) McKittrick, B. A.; Ma, K.; Huie, K.; Yumibe, N.; Davis, H.,
Jr.; Clader, J. W.; Czarniecki, M. J. Med. Chem. 1998, 41, 752e759.
2007, 107, 4437e4492; (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Synlett 2001, 1813e1826; (d) Alcaide, B.; Almendros, P.; Carrascosa, R.; Campo,
T. M. Chem.dEur. J. 2009, 15, 2496e2499; (e) Taubinger, A. A.; Fenske, D.;
Podlech, J. Synlett 2008, 539e542.
6
. (a) Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 69e92; (b) Morin, R. B.; Gorman,
M. Chemistry and Biology of
. (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51e123; (b) Jarrahpour, A.;
Motamedifar, M.; Zarei, M.; Mimouni, M. Phosphorus, Sulfur Silicon Relat. Elem.
010, 185, 287e297; (c) Keri, R. S.; Hosamani, K. M.; Shingalapur, R. V.; See-
b-Lactam Antibiotics; Academic: New York, NY, 1982.
7
2
tharama Reddy, H. R. Eur. J. Med. Chem. 2009, 44, 5123e5130; (d) Jarrahpour, A.;
Zarei, M. Molecules 2007, 12, 2364e2379; (e) Jarrahpour, A.; Zarei, M. Molecules
14. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard M7-A7;
Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2006.
2006, 11, 49e58.
8
. (a) Jarrahpour, A.; Zarei, M. Tetrahedron 2010, 66, 5017e5023; (b) Jarrahpour, A.;
Zarei, M. Tetrahedron Lett. 2009, 50, 1568e1570; (c) Fu, N.; Tidwell, T. T. Tetra-
hedron 2008, 64, 10465e10496; (d) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem.
Rev. 2008, 108, 3988e4035; (e) Vankoten, D.; Vander Steen, F. H. Tetrahedron
15. Halve, A.; Goyal, A. Orient. J. Chem. 1996, 12, 87e88.
16. Layer, R. W. Chem. Rev. 1962, 62, 489e510 and references cited therein.
17. Detty, M. R.; Wood, G. P. J. Org. Chem. 1980, 45, 80e89.
18. Lide, D. R. CRC Handbook of Chemistry and Physics, 90th ed.; CRC/Taylor and
Francis: Boca Raton, FL, 2009e2010; (Internet Version 2010), Section 3, p 254.
19. Lide, D. R. CRC Handbook of Chemistry and Physics, 90th ed.; CRC/Taylor and
Francis: Boca Raton, FL, 2009e2010; (Internet Version 2010), Section 3, p 376.
1991, 47, 7503e7524; (f) Georg, G. I. The Organic Chemistry of b-Lactams;
Chemie: New York, NY, 1993; (g) Coates, C.; Kabir, J.; Turos, E. In Science of
Synthesis; Weinreb, S. M., Ed.; 2005; Vol. 21, pp 609e646.