An unusual lewis acid promoted isomerization of trans-3-halo-3-phenylthio-β-lactams

Article abstract of DOI:10.3987/COM-04-10299

A method for C-3 epimerization of 3-halo-3-phenylthio-β-lactams, mediated by Lewis acids, is described. TiCl₄ promotes isomerization of trans-3-chloro-3-phenylthioazetidin-2-ones (2) to cis-3-chloro-3-phenylthioazetidin-2-ones (3). TiBr₄

Full text of DOI:10.3987/COM-04-10299

HETEROCYCLES, Vol. 68, No. 4, 2006
749
HETEROCYCLES, Vol. 68, No. 4, 2006, pp. 749 - 762. © The Japan Institute of Heterocyclic Chemistry
Received, 6th December, 2005, Accepted, 9th March, 2006, Published online, 10th March, 2006. COM-04-10299
AN UNUSUAL LEWIS ACID PROMOTED ISOMERIZATION OF
trans-3-HALO-3-PHENYLTHIO-β-LACTAMS
Shamsher S. Bari,* Paloth Venugopalan, Renu Arora, Garima Modi, and
Sachin Madan
Department of Chemistry, Panjab University, Chandigarh-160014, India
e-mail: ssbari@pu.ac.in
Abstract - A method for C-3 epimerization of 3-halo-3-phenylthio-β-lactams,
mediated by Lewis acids, is described. TiCl4 promotes isomerization of trans-3-
chloro-3-phenylthioazetidin-2-ones (2) to cis-3-chloro-3-phenylthioazetidin-2-
ones (3). TiBr4 promotes isomerization as well as substitution of chlorine with
bromine affording isomeric cis- and trans-3-bromo-3-phenylthioazetidin-2-ones
(5) and (6) respectively, while TiI4 is ineffective.
A variety of Lewis acid promoted reactions in organic chemistry are becoming valuable synthetic
processes. Moreover, the processes which convert readily available chemical entities to their less readily
accessible isomers are of a synthetic value besides being useful in mechanistic studies in organic
synthesis.1 Over the years, structural diversity of β-lactam antibiotics has led to the development of
various synthetic approaches with complete control of stereochemistry2 at C-3 and C-4 of β-lactams.
However, with the discovery of new biologically active monocyclic β-lactams, the minimum requirement
for biological activity of these heterocycles has been reduced to just suitably configured and substituted
monocyclic β-lactam ring.3-6
In the most often employed methods7-11 for β-lactam synthesis, the formation of kinetically controlled cis-
β-lactam12 is highly favoured. Leaving aside thermally induced isomerization13, all the reported
procedures for isomerization14 of cis-β-lactams to more stable trans-β-lactams require the presence of an
acid or base sensitive functionality at the site of epimerization.

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HETEROCYCLES, Vol. 68, No. 4, 2006
H
N
Cl H
1
PhS
O
1
R
R
PhS
3 4
2 1
N
O
2
2
R
R
2
Figure 1.
In continuation to our studies15 with cationic β-lactam equivalents (Figure 1), we wish to report here a
new isomerization methodology for 3-halo-3-phenylthio-β-lactams. It is now possible to isomerize
azetidin-2-ones of type (2) at C-3 by a Lewis acid such as TiCl4 or SnCl4. Thus, trans-3-chloro-3-
phenylthioazetidin-2-ones (2) on treatment with TiCl4 were transformed to cis-3-chloro-3-
phenylthioazetidin-2-ones (3) (Scheme 1). Also, cis-3-bromo- and trans-3-bromo-3-phenylthioazetidin-
2-ones (5) and (6) respectively, were obtained from 2 by in situ substitution of C-3 chlorine with
bromine using TiBr4. This may be helpful in devising new methodology for the synthesis of
therapeutically important trisubstituted β-lactams. Besides it may find application in halogen exchange as
well as halogen labelling studies using labelled titanium tetrahalide. To the best of our knowledge no such
Lewis acid promoted isomerization of azetidin-2-ones has been reported so far.
We have reported16 earlier that 3α-chloro-3-phenylthio-β-lactam substrates of type (2) undergo a
substitution at C-3 with active aromatic nucleophiles in the presence of a Lewis acid presumably via in
situ formation of cationic β-lactam synthons. Thus, trans-3-chloro-3-phenylthioazetidin-2-one (2a) (mp
166-168°C) with a confirmed stereochemistry17 at C-3, easily accessible from trans-3-phenylthioazetidin-
2-one (1a), by stereospecific SO2Cl2 chlorination underwent a facile alkylation with a number of active
aromatic nucleophiles such as anisole in the presence of Lewis acids such as SnCl4 or TiCl4 in CH2Cl2 at
0°C under nitrogen atmosphere (Scheme 1). This reaction, in effect, is equivalent to Friedel-Crafts
reaction with a very active halide. Surprisingly, this reaction failed with benzene or toluene even under
varied reaction conditions, to provide any anticipated substituted product. However, two other products
could be isolated from this reaction when carried out in the presence of TiCl4. The minor one (7 % yield)
was identified as 3,3-bis(phenylthio)-1-(4’-methoxyphenyl)-4-phenylazetidin-2-one (4a) through its
spectroscopic data. The major component (78 % yield) with Rf very close to the starting material and
having lower mp (144-146°C) than the substrate was clearly indicated to be a different product formed
during the Lewis acid treatment of 2a.

HETEROCYCLES, Vol. 68, No. 4, 2006
751
PhS
H
N
H
H
N
Cl H
Cl H
1
1
1
PhS
O
1
R
R
R
R
PhS
PhS
SO2Cl2
PhS
TiCl4
+
N
N
O
O
2
3
4
1
O
2
2
2
2
R
R
R
R
Ar H
N
Br H
Br H
1
1
1
R
R
R
PhS
PhS
Lewis Acid
PhS
TiBr4
+
X
N
N
Benzene
or
O
O
O
2
2
2
R
R
R
6
Toluene
5
1
a
b
c
d
e
f
R1
R2
-C6H5
-C6H4OCH3 (p)
-C6H4OCH3 (p)
-CH2C6H5
-C6H4OCH3 (p)
-C6H5
-C6H4Cl (p)
-C6H5
-C6H4CH3
-C6H4Br (p)
-C6H4OCH3(p)
-C(CH3)=CH-C6H5
Scheme 1.
1
The H-NMR spectral analysis of the major product showed C-4 proton resonance upfield at δ 5.18 as
compared to substrate (2a), which exhibits C-4 proton resonance at δ 5.38. There were also small changes
in the positions of the remaining proton resonances in the spectrum, compared to the resonances of
13
substrate (2a). The C-NMR spectrum also showed a similar upward shift in resonance of C-4 carbon
appearing at δ 68.83 in comparison to substrate (2a) showing it at δ 71.88. However, C-3 carbon
resonated at δ 80.1 for both isomers. The IR spectrum confirmed the presence of β-lactam carbonyl (1754
cm-1, >C=O) in it.
Keeping in view all the spectroscopic information given above, it seemed that an epimerization at C-3 of
β-lactam had taken place resulting in isomerization of β-lactam (2a). Intrigued by this transformation, this
reaction was conducted in the presence of a Lewis acid alone to evaluate the feasibility of this
transformation. The reaction indeed, proceeded equally well in the absence of anisole giving the same
product profile. To the best of our knowledge, this is the first example of epimerization of β-lactams at C-
3 effectively and efficiently by a Lewis acid. All the available spectral information was suggestive of only
structure (3a) for this product, which could be tentatively assigned to it. However, the final unequivocal

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HETEROCYCLES, Vol. 68, No. 4, 2006
confirmation of this structure was achieved through X-Ray crystal analysis18 as shown in ORTEP
diagram (Figure 2).
Figure 2. ORTEP representation of 3a
Since this kind of isomerization is unprecedented, the feasibility and generality of this reaction in terms of
various substrates and Lewis acids was evaluated. The reaction was carried out successfully with a
number of substrates (2a-f) employing TiCl4 or SnCl4 and the results are summarized in Table 1.
Table 1: Reaction of trans-3-chloro-β-lactams (2a-f) with Lewis acids in CH2Cl2
Entry
trans-3-chloro
Temp.
(oC)
Lewis Acid
Yield (%)a,b
2
cis-3-chloro 3,3-bis(phenylthio)
3
4
1
2
3
4
5
6
7
8
2a
2a
2b
2c
2c
2d
2e
2f
-78
0
SnCl4
TiCl4
TiCl4
SnCl4
TiCl4
TiCl4
TiCl4
TiCl4
55
15
78
58
72
67
62
81
82
7
17
6
-78
0
0
0
0
0
0
0
0
5
a. All new compounds have been characterized by IR, NMR spectral and CHN analysis.
b. Isolated yields after purification by chromatography on silica gel.

HETEROCYCLES, Vol. 68, No. 4, 2006
753
At this stage, it was considered important to investigate the source of halogen in the isomerized product,
which in principle can either come from the starting substrate itself or from the Lewis acid during the
course of the reaction. This information is critical in understanding the possible mechanism of this
transformation as it can suggest the role of the Lewis acid in assisting the epimerization process. This
aspect can easily be probed unequivocally, if the halogen in the substrate is different from that in the
Lewis acid. Thus, in the reaction of trans-3-chloro-3-phenylthioazetidin-2-one (2c) with TiBr4 at 0oC,
both epimerization and substitution of chlorine with bromine at C-3 occurred producing cis-3-bromo-3-
phenylthioazetidin-2-one (5c) as a major product. Here it is interesting to note that a mere substitution
product trans-3-bromo-3-phenylthioazetidin-2-one (6c) was also formed as a minor product without
undergoing epimerization. However, surprisingly no 3,3-bis(phenylthio)azetidin-2-one (4c) was formed
in this reaction (Scheme 1). The structures of cis-3-bromo- and trans-3-bromoazetidin-2-ones, (5c) and
(6c) respectively, were deduced from their spectroscopic data. The cis-isomer (5c) exhibited C-4 proton
13
resonance up field at δ 5.20 compared to C-4 proton resonance at δ 5.62 of trans-isomer (6c). The C-
NMR spectrum of cis-isomer showed upward shift in resonances of both C-3 and C-4 carbons appearing
at δ 67.3 and 71.9 in comparison to substrate (2a) showing it at δ 80.14 and 69.12. However, the final
confirmation of epimerization with substitution at C-3 was obtained from X-Ray crystal analysis19 of cis-
isomer (5c).
The feasibility of this conversion was studied by reacting a number of substrates (2a-e) with TiBr4 and the
results are summarized in Table 2. It is quite clear from the results that trans-3-chloro-3-phenylthio-β-
lactams can be effectively converted to their cis-3-bromo analogs by epimerization accompanied by
simultaneous substitution of chlorine at C-3 with bromine. In all cases, there is also the formation of a
minor substitution product, the trans-isomer that formed without undergoing epimerization. The ratio of
1
the two bromo isomeric products was ascertained from H-NMR. It seems that low temperature (-78oC)
favours the substitution with retention of stereochemistry at C-3. Interestingly, with relatively bulky TiI4
no reaction occurred.

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HETEROCYCLES, Vol. 68, No. 4, 2006
Table 2: Reaction of trans-3-chloro-3-phenylthioazetidin-2-ones (2a-e) with TiBr4
Ratio of productsa,b
Entry
trans-3-chloro-
Lewis acid
(equiv.)
(%)
Temp.(°C)
substrate
cis-3-bromo trans-3-bromo
2
isomer
5
isomer
6
1
2
3
4
5
6
7
2a
2a
2a
2b
2c
2d
2e
0
rt
1.0
1.0
1.0
1.0
1.2
1.3
1.5
66
34
62
38
-78
0
33
67
68
32
0
66
34
0
77
23
0
78
22
a. All new compounds have been characterized by IR, NMR spectral and CHN analysis.
b. Isolated yields reported in experimental after purification by chromatography.
Considering all the above noted observations, a transition state (7) in which C-3 halogen of azetidin-2-one
coordinates to the central titanium atom, can be put forward. In addition, a sulfur atom in the SPh group
could also coordinate to the central metal atom giving an octahedral or most likely a distorted octahedral
(almost like a square bipyramidal) arrangement. In such a transitory arrangement (Figure 3), the S and X
from the β-lactam ring may occupy the equatorial positions still maintaining the tetrahedral nature of C-3
carbon atom. Thus, two halogen atoms of Lewis acid marked P and Q being equatorial, either of the other
two axial halogens becomes the preferred candidate for the exchange possibly via SN2 type reaction
giving epimerization at C-3. The two different halogen exchange processes A and B can result in products
with opposite stereochemistry at C-3.
The formation of an intermediate (8) may be ruled out since the subsequent approach of the nucleophile
to the C-3 carbon from the less hindered face (R1 = H) would lead to the opposite selectivity contrary to
the observed facts in this epimerization reaction. However, further studies are required to confirm the
intermediacy of 7 or 8 in this reaction.

HETEROCYCLES, Vol. 68, No. 4, 2006
755
A
1
1
R
R
2
2
R
R
X
PX
X
Ph
3
3
R
R
N
S
N
TiX5
Ti
Q
S
X
X
Ph
O
O
B
8
7
Figure 3. Proposed transition state complex (7) and the intermediate (8)
In summary, we have reported a Lewis acid catalyzed epimerization reaction. This is potentially useful
for C-3 epimerization of trans-3-halo-3-phenylthio-β-lactams as well as for preparing trans- and cis-3-
bromo-3-phenylthio-β-lactams. Further studies using alkylthio-β-lactams and chiral Lewis acids for
asymmetric version of this isomerization are in progress in our laboratory.
EXPERIMENTAL
General experimental procedures for the starting β-lactams have previously been reported.20 1H-NMR
spectra were recorded in CDCl3 using BRUKER or JEOL 300 MHz NMR spectrometers. Chemical shifts
are given in ppm relative to TMS as an internal standard (δ = 0 ppm) for 1H-NMR and CDCl3 ( δ = 77.0
ppm) for 13C-NMR spectra. IR spectra were taken on a FTIR spectrophotometer and are reported in cm-1.
All commercially available compounds / reagents were used without further purification.
Dichloromethane distilled over P2O5 was redistilled over CaH2 before use.
General procedure for synthesis of trans-3-chloro-3-phenylthio-β-lactams: trans-1-(4’-
Methoxyphenyl)-3-chloro-3-phenylthio-4-phenylazetidin-2-one (2a): To a well stirred solution of
trans-1-(4’-methoxyphenyl)-3-phenylthio-4-phenylazetidin-2-one (1a) (360 mg, 1 mmol) in dry CH2Cl2
(5 mL) was added sulfuryl chloride (SO2Cl2) (130 mg, 1 mmol, 0.08 mL) under nitrogen atmosphere
via a syringe . The contents were stirred for additional 30 min at rt. Progress of the reaction was
monitored by TLC. After completion of the reaction, it was quenched with water, extracted with
dichloromethane (3 x 10 mL), washed with 5% NaHCO3 solution, dried over anhydrous Na2SO4 and
filtered. The residue after solvent evaporation was purified by column chromatography using silica gel
eluting with ethyl acetate-hexanes (10%). Solvent evaporation yielded trans-3-chloro-3-phenylthio-β-
lactam (2a) (370 mg, 95%) which showed following spectral data: mp 166-168oC; IR(KBr): 1754 cm-1;
1H-NMR(CDCl3)δ: 3.75(s, 3H, OCH3), 5.45(s, 1H), 6.8-7.55(m, 14H, aromatic protons); 13C-NMR
(CDCl3)δ: 55.55, 71.97, 80.14, 114.59, 119.31, 126.62, 128.33, 128.71, 129.11, 129.40, 129.81, 131.76,

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HETEROCYCLES, Vol. 68, No. 4, 2006
135.52, 156.88, 160.22; Anal. Calcd for C22H18NO2ClS: C, 66.74; H, 4.59; N, 3.54; found: C, 66.63; H,
4.51; N, 3.51.
trans-1-(4’-Methoxyphenyl)-3-chloro-3-phenylthio-4-(4’-methoxyphenyl)azetidin-2-one (2b):
1
mp 75-76oC; IR(KBr): 1764 cm-1; H-NMR(CDCl3)δ: 3.7(s, 3H, OCH3), 3.8(s, 3H, OCH3), 5.39(s, 1H),
6.81-7.5(m, 13H, aromatic protons); 13C-NMR(CDCl3)δ: 55.37, 55.48, 71.51, 80.32, 114.03, 114.48,
119.28, 123.42, 128.48, 128.7, 129.30, 129.63, 129.82, 135.35, 156.74, 160.28, 160.68; Anal. Calcd for
C23H20NO3ClS: C, 64.24; H, 4.73; N, 3.28; found: C, 64.56; H, 4.61; N, 3.14.
trans-1-Benzyl-3-chloro-3-phenylthio-4-phenylazetidin-2-one (2c):
mp 90-92oC; IR(KBr): 1776 cm-1; 1H-NMR(CDCl3)δ: 3.9(d, 1H, J = 15.1 Hz), 4.82(s,1H), 5.05(d, 1H, J =
15.0 Hz), 7.15-7.45(m, 15H, aromatic protons) ; 13C-NMR(CDCl3)δ: 44.68, 71.14, 80.90, 128.20, 128.38,
128.53, 128.65, 129.02, 129.18, 129.76, 131.81, 134.12, 135.14, 163.92; Anal. Calcd for C22H18NOClS:
C, 69.55; H, 4.78; N, 3.68; found: C, 69.47; H, 4.71; N, 3.63.
trans-1-(4’-Methylphenyl)-3-chloro-3-phenylthio-4-(4’-chlorophenyl)azetidin-2-one(2d):
mp 135-137oC; IR(KBr): 1760 cm-1; 1H-NMR(CDCl3)δ: 2.29(s, 3H, CH3), 5.35(s, 1H), 7.03-7.52(m, 13H,
aromatic protons); 13C-NMR(CDCl3)δ:21.16, 71.06, 79.93, 117.80, 128.40, 128.77, 129.36, 129.55,
129.89, 130.52, 134.13, 134.49, 135.55, 135.87, 159.7; Anal. Calcd for C22H17NOCl2S: C, 63.77; H, 4.13;
N, 3.38; found: C, 63.71; H, 4.74; N, 3.60.
trans-1-(4’-Bromophenyl)-3-chloro-3-phenylthio-4-phenylazetidin-2-one(2e):
1
mp 138-140oC; IR(CHCl3): 1762.5 cm-1; H-NMR(CDCl3)δ: 5.44(s, 1H), 7.15-7.48(m, 14H, aromatic
protons) ; 13C-NMR(CDCl3)δ: 72.0, 117.9, 119.51, 126.37, 127.53, 128.23, 128.81, 129.59, 129.89,
130.01, 131.20, 132.39, 135.62, 160.64; Anal. Calcd for C21H15NOBrClS: C, 56.71; H, 3.39; N, 3.15;
found: C, 56.59; H, 3.27; N, 3.08.
trans-1-(4’-Methoxylphenyl)-3-chloro-3-phenylthio-4-(1’-methyl-2’-phenylvinyl)azetidin-2-one(2f):
mp 176-178oC; IR(KBr): 1764 cm-1; 1H-NMR(CDCl3)δ: 2.4(s, 3H, CH3), 3.73(s, 3H, OCH3), 5.34(s, 1H),
6.74-7.52(m, 15H, aromatic protons); 13C-NMR(CDCl3)δ: 21.58, 55.21, 71.68, 80.15, 114.53, 119.17,
128.33, 128.66, 128.94, 129.10, 129.37, 130.29, 135.41, 139.43, 156.74, 159.78; Anal. Calcd for
C25H22NO2ClS: C, 68.87; H, 5.08; N, 3.21; found: C, 68.74; H, 5.01; N, 3.14.

HETEROCYCLES, Vol. 68, No. 4, 2006
757
General procedure for epimerization of trans-3-chloro-3-phenylthio-β-lactams: cis-1-(4’-
Methoxyphenyl)-3-chloro-3-phenylthio-4-phenylazetidin-2-one (3a): trans-3-Chloro-3-phenylthio-
azetidin-2-one (2a) (50 mg, 0.13 mmol) in dry CH2Cl2 (10 mL) was placed in a flame dried two necked
round bottom flask (50 mL) equipped with a magnetic stirrer under nitrogen atmosphere. The contents
were cooled to 0oC and stirred. To this TiCl4 (28 mg, 0.15 mmol, 0.016 mL) was added rapidly via a
syringe. The reaction mixture was stirred for one hour at the same temperature. The progress of the
reaction was checked by TLC, which showed the appearance of two new spots. Then the reaction mixture
was quenched with water, extracted with dichloromethane (3 x 10 mL), washed with 5% NaHCO3
solution, dried over anhydrous Na2SO4 and filtered. The residue after solvent evaporation was purified by
column chromatography using silica gel eluting with ethyl acetate-hexanes (8 %). The major component
was collected, crystallized from ethyl acetate / hexanes and identified as cis-3-chloro-3-phenylthio-β-
lactam (3a) (39 mg, 78%) on the basis of its following spectral data; mp 144-146oC; IR(KBr):1754 cm-1;
1H-NMR(CDCl3)δ: 3.72(s, 3H, OCH3), 5.18(s, 1H), 6.78-7.77(m, 14H, aromatic protons); 13C-
NMR(CDCl3)δ: 55.21, 68.83, 80.12, 114.48, 118.93, 127.83, 128.65, 129.16, 129.2, 129.28, 129.88,
130.1, 132.99, 135.45, 135.75, 156.77, 159.46; EIMS: m/z 397, 396, 395, 360, 246, 211, 196, 167, 121;
Anal. Calcd for C22H18NO2ClS: C, 66.74; H, 4.59; N, 3.54; found: C, 66.61; H, 4.52; N, 3.49.
The minor component (7%) was identified to be 1-(4’-methoxyphenyl)-3,3-bis(phenylthio)-4-
phenylazetidin-2-one (4a) on the basis of its following spectral data; mp 118-120oC; IR(KBr):1741 cm-1;
13
1H-NMR(CDCl3)δ: 3.73(s, 3H, OCH3), 5.18(s, 1H, C4-H), 6.73-7.68(m, 19H, aromatic protons); C-
NMR(CDCl3)δ: 55.42, 68.73, 72.52, 114.28, 118.90, 128.14, 128.35, 128.55, 130.13, 139.50, 132.54,
134.9, 135.75, 139.16, 139.62, 156.39, 162.79; EIMS: m/z 469(M+), 320, 223, 211, 196, 134, 121, 109;
Anal. Calcd for C28H23NO2S2: C, 71.61; H, 4.95; N, 2.98; found: C, 71.54; H, 4.90; N, 2.94.
cis-1-(4’-Methoxyphenyl)-3-chloro-3-phenylthio-4-(4’-methoxyphenyl)azetidin-2-one (3b): The major
component was crystallized from ethyl acetate/hexanes and identified as (3b) (35 mg, 58%) on the basis
1
of its spectral data; mp 154-156oC; IR(KBr):1751 cm-1; H-NMR(CDCl3)δ: 3.74(s, 3H, OCH3), 3.78(s,
13
3H, OCH3), 5.22(s, 1H, C4-H), 6.85-7.78(m, 13H, aromatic protons); C-NMR(CDCl3)δ: 55.41, 55.53,
68.78, 80.35, 114.11, 114.35, 119.26, 123.38 128.46, 128.83 129.34, 129.69, 129.84, 135.39, 156.79,
159.81, 160.88; Anal. Calcd for C23H20NO3ClS: C, 64.24; H, 4.73; N, 3.28; found: C, 64.50; H, 4.55; N,
3.15.
The other component (12 mg, 17%) was identified to be 1-(4’-methoxyphenyl)-3,3-bis(phenylthio)- 4-(4’-
methoxyphenyl)azetidin-2-one (4b) on the basis of its following spectral data; mp 123-124oC;
IR(KBr):1747 cm-1; 1H-NMR(CDCl3)δ: 3.72(s, 3H, OCH3), 3.78(s, 3H, OCH3), 5.12(s, 1H, C4-H), 6.71-
7.78(m, 18H, aromatic protons).

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HETEROCYCLES, Vol. 68, No. 4, 2006
cis-1-Benzyl-3-chloro-3-phenylthio-4-phenylazetidin-2-one (3c):
1
mp 140-142oC; H-NMR(CDCl3)δ: 3.9(d, 1H, J = 14.95 Hz), 4.67(s,1H), 4.9(d, 1H, J = 15.1 Hz), 7.01-
7.72(m, 15H, aromatic protons); 13C-NMR(CDCl3)δ: 44.38, 70.94, 80.63, 128.31, 128.49, 128.57, 128.69,
129.14, 129.30, 129.77, 131.87, 134.61, 135.28, 164.45; Anal. Calcd for C22H18NOClS: C, 69.55; H,
4.78; N, 3.68; found: C, 69.44; H, 4.69; N, 3.61.
cis-1-(4’-Methylphenyl)-3-chloro-3-phenylthio-4-(4’-chlorophenyl)azetidin-2-one (3d):
1
mp 120-121oC; IR(KBr): 1766cm-1; H-NMR(CDCl3)δ: 2.28(s, 3H, CH3), 5.17(s, 1H), 6.9-7.75(m, 13H,
aromatic protons); 13C-NMR(CDCl3)δ:21.18, 68.20, 80.2, 117.60, 129.06, 129.14, 129.27, 129.86, 130.0,
131.64, 134.20, 134.46, 135.36, 135.42, 135.9, 159.41; Anal. Calcd for C22H17NOCl2S: C, 63.77; H, 4.13;
N, 3.38; found: C, 63.63; H, 4.04; N, 3.26.
cis-1-(4’-Bromophenyl)-3-chloro-3-phenylthio-4-phenylazetidin-2-one (3e):
1
yellow oil; H-NMR(CDCl3)δ: 5.26(s, 1H), 6.68-8.0(m, 14H, aromatic protons); 13C-NMR(CDCl3)δ:
68.84, 79.64, 117.42, 119.21, 127.54, 128.31, 128.76, 129.21, 129.45, 129.97, 130.11, 131.84, 132.40,
132.46, 135.31, 135.82, 135.94, 159.91.
cis-1-(4’-Methoxyphenyl)-3-chloro-3-phenylthio-4-(1’-methyl-2’-phenylvinyl)azetidin-2-one (3f):
mp 165-169oC; IR(KBr): 1764cm-1; 1H-NMR(CDCl3)δ: 2.35(s, 3H, CH3), 3.72(s, 3H, OCH3), 5.12(s, 1H),
6.71-7.73(m, 15H, aromatic protons); 13C-NMR(CDCl3)δ: 21.33, 55.5, 69.02, 80.24, 114.46, 119.11,
127.74, 129.27, 129.36, 130.0, 135.7, 139.27, 150, 156.8; Anal. Calcd for C25H22NO2ClS: C, 68.87; H,
5.08; N, 3.21; found: C, 68.76; H, 5.01; N, 3.09.
General procedure for synthesis of trans-3-bromo- and cis-3-bromo-3-phenylthio-β-lactams:
cis-1-Benzyl-3-bromo-3-phenylthio-4-phenylazetidin-2-one
(5c)
and
trans-1-benzyl-3-bromo-3-
phenylthio-4-phenylazetidin-2-one (6c): TiBr4 (60 mg, 0.15 mmol) was transferred to a clean round
bottom flask (25 mL) using a nitrogen dry box. Dichloromethane (5 mL) was added to it and cooled to
0oC. trans-3-Chloro-3-phenylthioazetidin-2-one (2c) (50 mg, 0.14 mmol) in dry methylene chloride
(5mL) was added dropwise to this stirred solution, under nitrogen atmosphere. The reaction mixture was
allowed to stir for one hour at the same temperature and the progress of reaction was monitored by TLC,
which showed the formation of two new compounds. The reaction was quenched with water and
extracted with methylene dichloride (3 x 10 mL). The combined organic extract was washed with brine,
dried over anhydrous sodium sulfate and filtered. The residue after solvent evaporation was purified by
column chromatography using silica gel, eluting with ethyl acetate-hexanes (12%). Fast moving

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759
component (Rf 0.6) was separated and identified as trans-1-benzyl-3-bromo-3-phenylthio-4-
phenylazetidin-2-one (6c) as an oil (18 mg, 33%) on the basis of following spectral data; IR(Nujol):
1
1771cm-1; H-NMR(CDCl3)δ: 3.95(d, 1H, J=14.9 Hz), 4.96(d, 1H, J=15 Hz), 4.98 (s, 1H), 7.02-7.45, (m,
15H, aromatic protons); Anal. Calcd for C22H18NOBrS: C, 62.26; H, 4.28; N, 3.29; found: C, 62.38; H,
4.33; N, 3.37.
Slow moving component (Rf = 0.53) was isolated and crystallized from ethyl acetate-hexanes and
identified as cis-1-benzyl-3-bromo-3-phenylthio-4-phenylazetidin-2-one (5c) (36 mg, 64%) on the basis
1
of following spectral data; mp 128-130oC; IR(KBr): 1775 cm-1; H-NMR(CDCl3)δ: 3.85(d, 1H, J=15.1
Hz), 4.63 (s, 1H), 4.9(d, 1H, J=14.9 Hz), 6.97-7.69(m, 15H, aromatic protons); 13C-NMR(CDCl3)δ: 45.04,
67.40, 72.58, 127.91, 128.05, 128.38, 128.52, 128.91, 129.30, 130.03, 133.84, 135.59, 163.72. Anal.
Calcd for C22H18NOBrS: C, 62.26; H, 4.28; N, 3.29; found: C, 62.38; H, 4.23; N, 3.25.
trans-1-(4’-Methoxyphenyl)-3-bromo-3-phenylthio-4-phenylazetidin-2-one (6a):
yellow oil; 1H-NMR(CDCl3)δ: 3.73(s, 3H, OCH3), 5.62(s, 1H), 6.82-7.48(m, 14H, aromatic protons); 13C-
NMR(CDCl3)δ: 55.58, 68.21, 72.54, 114.15, 118.85, 127.36, 128.58, 129.31, 129.85, 130.20, 133.91,
135.64, 156.92, 160.11.
cis-1-(4’-Methoxyphenyl)-3-bromo-3-phenylthio-4-phenylazetidin-2-one (5a):
mp 118-120oC; 1H-NMR(CDCl3)δ: 3.75(s, 3H, OCH3), 5.20(s, 1H), 6.77-7.78(m, 14H, aromatic protons);
13C-NMR(CDCl3)δ: 55.53, 68.28, 72.27, 114.55, 119.08, 127.66, 128.61, 129.32, 129.90, 130.19, 133.96,
135.63, 156.90, 160.09; EIMS: m/z 441, 439, 292, 290, 211, 149; Anal. Calcd for C22H18NO2BrS: C,
66.01; H, 4.12; N, 3.18; found: C, 59.88; H, 4.08; N, 3.13.
trans-1-(4’-Methoxyphenyl)-3-bromo-3-phenylthio-4-(4’-methoxyphenyl)azetidin-2-one (6b):
1
yellow oil; H-NMR(CDCl3)δ: 3.79(s, 3H, OCH3), 3.82(s, 3H, OCH3), 5.58(s, 1H), 6.78-7.46(m, 13H,
aromatic protons); 13C-NMR(CDCl3)δ: 55.46, 55.54, 70.19, 72.87, 113.91, 114.39, 119.04, 125.68,
128.98, 129.11, 129.30, 134.95, 135.46, 156.81, 159.95.
cis-1-(4’-Methoxyphenyl)-3-bromo-3-phenylthio-4-(4’-methoxyphenyl)azetidin-2-one (5b):
mp 124-126oC; IR(KBr): 1760 cm-1; 1H-NMR(CDCl3)δ: 3.74(s, 3H, OCH3), 3.78(s, 3H, OCH3), 5.16(s,
1H), 6.76-7.77(m, 13H, aromatic protons); 13C-NMR(CDCl3)δ: 55.32, 55.53, 68.14, 72.92, 114.01,
114.50, 119.11, 125.78, 129.07, 129.15, 129.31, 130.09, 134.99, 135.47, 156.83, 160.33; Anal. Calcd for
C23H20NO3BrS: C, 58.72; H, 4.29; N, 2.97; found: C, 58.61; H, 4.23; N, 2.93.

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trans-1-(4’-Methylphenyl)-3-bromo-3-phenylthio-4-(4’-chlorophenyl)azetidin-2-one (6d):
mp 120-121oC; IR(KBr): 1766 cm-1; 1H-NMR(CDCl3)δ: 2.23(s, 3H, CH3), 5.48(s, 1H), 6.9-7.67(m, 13H,
aromatic protons); 13C-NMR(CDCl3)δ:21.16, 70.14, 72.13, 117.74, 128.76, 128.96, 129.36, 129.41,
129.82, 129.89, 130.16,130.64, 132.63, 133.98, 134.02, 134.6, 135.29, 135.83, 156.68; Anal. Calcd for
C22H17NOBrClS: C, 57.59; H, 3.73; N, 3.05; found: C, 57.47; H, 3.63; N, 3.01.
cis-1-(4’-Methylphenyl)-3-bromo-3-phenylthio-4-(4’-chlorophenyl)azetidin-2-one (5d):
1
yellow oil; IR(KBr): 1765.8 cm-1; H-NMR(CDCl3)δ: 2.21(s, 3H, CH3), 5.07(s, 1H), 6.87-7.67(m, 13H,
aromatic protons); 13C-NMR(CDCl3)δ:21.16, 67.35, 72.18, 117.52, 128.75, 128.95, 129.25, 129.57,
129.80, 130.06, 132.8, 134.17, 134.37, 134.94, 135.34, 135.67, 159.40.
trans-1-(4’-Bromophenyl)-3-bromo-3-phenylthio-4-phenylazetidin-2-one (6e):
1
mp 120-122oC; IR(KBr): 1768 cm-1; H-NMR(CDCl3)δ: 5.51(s, 1H), 6.94-7.67 (m, 14H, aromatic
protons) ; 13C-NMR(CDCl3)δ: 70.5, 71.95, 117.88, 119.11, 119.35, 127.61, 128.28, 128.79, 128.84,
129.27, 129.39, 129.52, 129.91, 129.94, 130.14, 131.75, 132.36, 132.43, 135.26, 135.76, 135.87, 159.87;
Anal. Calcd for C21H15NOBr2S: C, 51.55; H, 3.09; N, 2.86; found: C, 51.45; H, 3.00; N, 2.72.
cis-1-(4’-Bromophenyl)-3-bromo-3-phenylthio-4-phenylazetidin-2-one (5e):
1
mp 176-178oC; IR(KBr): 1767 cm-1; H-NMR(CDCl3)δ: 5.04(s, 1H), 6.96-7.68 (m, 14H, aromatic
13
protons); C-NMR(CDCl3)δ: 68, 71.93, 117.84, 119.08, 119.10, 127.62, 128.75, 128.8, 128.84, 129.24,
129.27, 129.44, 129.46, 130.0, 130.13, 132.34, 132.44, 133.72, 135.27, 135.74, 135.77, 135.81, 159.33;
Anal. Calcd for C21H15NOBr2S: C, 51.55; H, 3.09; N, 2.86; found: C, 51.40; H, 3.00; N, 2.68.
ACKNOWLEDGEMENT
We gratefully acknowledge the financial support for this work from Department of Science and
Technology (DST), New Delhi, Government of India (Project No. SP/S1/G-50/99).
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* Corresponding author.
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17. Structure was confirmed by X-Ray crystal analysis. Crystal data for 2a: monoclinic, P21/c, a =
11.950(1), b = 15.192(1), c = 11.062 (1) Å, β = 103.07(1)ο , V = 1956.2 (3) Å3, Z = 4, ρ calcd = 1.344
Mg/m3, µ(Mo-Kα) = 0.319 mm-1, full matrix least – square on F2, R1 = 0.0373, wR2 = 0.0932 for
2549 reflections [I>2σ (I)].
18. Crystal data for 3a: monoclinic, P21/c, a = 16.738(2), b = 5.867(1), c = 21.256 (2) Å,
β = 108.96(1)ο , V = 1974.1 (5) Å3, Z = 4, ρ calcd = 1.332 Mg/m3, µ(Mo-Kα) = 0.316 mm-1, full
matrix least – square on F2, R1 = 0.0386, wR2 = 0.0921 for 2428 reflections [I>2σ (I)].
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10.214(2), b =9.745(1), c = 20.264 (2) Å, β = 100.03(1)ο , V = 1986.2 (5) Å3, Z = 4, ρ calcd = 1.419
Mg/m3, µ(Mo-Kα) = 2.185 mm-1, full matrix least – square on F2, R1 = 0.0369, wR2 = 0.0812 for
2459 reflections [I>2σ (I)].
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