Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones

Article abstract of DOI:10.1016/j.tet.2006.06.062

A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of α-chlorosulfide-β-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl₂ in the presence of molecular

Full text of DOI:10.1016/j.tet.2006.06.062

Tetrahedron 62 (2006) 8291–8302
Facile stereoselective synthesis of cis- and
trans-3-alkoxyazetidin-2-ones
y
*
Aman Bhalla, Paloth Venugopalan and Shamsher S. Bari
Department of Chemistry, Panjab University, Chandigarh (UT) 160014, India
Received 29 March 2006; revised 31 May 2006; accepted 15 June 2006
Available online 7 July 2006
Abstract—A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of
˚
a-chlorosulfide-b-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl2 in the presence of molecular sieves (3–4 A) leads
to cis-3-alkoxy-3-phenyl/benzylthio-b-lactams whereas treatment of potassium 2-alkoxy-2-phenylthioethanoate with appropriate Schiff’s
base using POCl3 in the presence of triethylamine leads to the formation of trans-3-alkoxy-3-phenylthioazetidin-2-ones as major products.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
alkoxy-b-lactams in the preparation of the Taxol C-13 side
chain has also been well documented.15 More recently,
a novel 3-methoxy-b-lactam 1 (Fig. 1) has been found to
have apoptotic activity against human leukaemia, breast,
prostate and head–neck cancer cells, thus exhibiting antitu-
mour activity.16 Besides this, 3-methoxy spiro-b-lactam 2
(Fig. 1) has also been found to be an inhibitor of both polio-
virus and human rhinovirus 3C-proteinases.17
Apart from being the sub-structure of widely used anti-
biotics1–3 such as penicillins, cephalosporins and mono-
bactams, b-lactams have emerged as an important class of
heterocycles. There is a considerable activity directed at
the stereocontrolled synthesis of this heterocycle.4 Besides
this, the unique feature of these strained molecules is that
these heterocycles are also important building blocks for
the stereoselective synthesis of a variety of biologically
important compounds.5 For example, suitably substituted
hydroxy b-lactams have been used in the semi-synthesis of
paclitaxel (Taxol) and docetaxel (Taxotere).6 The need for
potent effective b-lactam antibiotics as well as new b-lacta-
mase inhibitors has motivated synthetic organic and medi-
cinal chemists to design new functionalized azetidin-2-ones.
Some of the synthetic azetidin-2-ones are reported to be
biologically active as inhibitors of cholesterol acyl transfer-
ase,7 thrombin,8 human cytomegalovirus protease,9 human
leukocyte elastase10 and cysteine protease.11
Cl
H
H
H
H3C
O
O
H3C
N
O
N
CH3
N
S
S
O
O
O2
CH3
1
2
Figure 1. Biologically active 3-methoxyazetidin-2-ones.
The biological activity of the particular b-lactam ring is
influenced by the type of substitution attached to the basic
nucleus.6–17 So, keeping in view the importance of relation-
ship between biological activity and structural diversity as
an essential component, we wish to report here a stereoselec-
tive synthesis of cis- and trans-3-alkoxyazetidin-2-ones.
Synthesis of cis-3-alkoxy-3-phenyl/benzylthio-b-lactams
has been achieved via transformation at C-3 of cationic
b-lactam equivalents 3 using Lewis acid catalyzed reaction
of various alcohols in the presence of silica gel and zinc
chloride. However, both trans- and cis-3-alkoxy-3-phenyl-
thio-b-lactams are obtained via direct annelation of potas-
sium 2-alkoxy-2-phenylthioethanoate (11) with appropriate
Schiff’s base (12) using POCl3 as the condensing reagent
in the presence of triethylamine.
Further interest in the development of synthetic methodol-
ogy for 3-alkoxy-b-lactams was sparked by the discoveries
of 2-isocephem,12 2-oxa-isocephem,12 7-methoxycephalo-
sporins13 and PS-5,14 possessing an alkoxy group at the
C-3 position of azetidin-2-ones. The potential use of cis-3-
Keywords: Azetidin-2-ones; cis-3-Alkoxy-b-lactams; trans-3-Alkoxy-b-
lactams; Lewis acid catalysis; Ethyl 2-alkoxy-2-phenylthioethanoate;
Potassium 2-alkoxy-2-phenylthioethanoate.
* Corresponding author. Tel.: +91 172 2534405/2541435; fax: +91 172
2545074; e-mail addresses: venu@krist.unibe.ch; ssbari@pu.ac.in
Present address: Laboratorium fuer chem., und min. Kristallographie,
y
Universitaet Bern, Freiestrasse 3, CH-3012 Bern, Switzerland. Tel.: +41
31 631 42 72.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.062

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A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
˚
sieves (3–4 A) to the reaction mixture, containing anhydrous
2. Results and discussion
ZnCl2, alcohol and SiO2 in chloroform prior to the addition
of substrate b-lactam (3) produced very satisfactory results
and provided cis-3-alkoxy-3-phenyl/benzylthioazetidin-2-
ones (4) in very high yields (Scheme 1, Table 1).
2.1. cis-3-Alkoxy-3-phenyl/benzylthio-b-lactams
In continuation of our efforts towards the synthesis of C-3
substituted b-lactams,18–20 we became interested in studies
towards the synthesis of C-3 alkoxy-b-lactams. Our earlier
study, reporting21 the preparation of a-methoxy-b-lactams
was re-examined with a view to using it for the synthesis
of other cis-3-alkoxy-b-lactams. We report here a modifica-
tion of this procedure, which has now been successfully em-
ployed for the synthesis of various cis-3-alkoxy-b-lactams.
Initial studies were carried out by treating 3a with absolute
ethyl alcohol as the nucleophile in the presence of dry
˚
molecular sieves (3–4 A), SiO2 and a sub-stoichiometric
amount of anhydrous ZnCl2 in refluxing chloroform. This re-
action resulted in the exclusive formation of cis-3-ethoxy-3-
phenylthioazetidin-2-one (4b) in quantitative yield (Scheme
1). The reaction was carried out successfully with a number
of substrates (3a–e) using various alcohols (R4OH) and the
results are summarized in Table 1. However, this reaction
failed to give the anticipated products with benzyl alcohol
and chiral alcohols such as (R)-(+)-sec-phenethyl alcohol.
Lewis acids such as TiCl4 and SnCl4 were found to give
unsatisfactory results. Only anhydrous ZnCl2 brought about
this transformation effectively.
The starting substrates, trans-3-chloro-3-phenyl/benzyl-
thioazetidin-2-ones (3a–e) were prepared from trans-3-
phenyl/benzylthioazetidin-2-ones according to the procedure,
reported in our earlier publication.20 The reported reaction
conditions,21 when applied for the synthesis of other 3-alk-
oxy-b-lactams using various alcohols, invariably failed to
produce the desired products. In some cases, the reaction
did not even take place, whereas in others, it produced
some amount of 3-keto-b-lactams (5)22 only (Scheme 1).
However, it was found that the addition of dry molecular
The structures of these cis-3-alkoxy-b-lactams 4 were con-
firmed on the basis of their spectral data (IR, H NMR and
1
H
O
H
R4O
H
Cl
H
N
R1S
R1S
R1S
R2
R2
R3
R2
R3
R4OH, ZnCl2 SiO2
H2O, ZnCl2 SiO2
CHCl3, Reflux
N
N
CHCl3, Reflux
Mol. Sieves (3-4)A
R3
R1SH
O
O
O
3a-e
4a-p
_
H
R2
R3
O
N
O
5
Scheme 1. Synthesis of cis-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones 4a–p.
Table 1. cis-3-Alkoxy-3-phenyl/benzylthio-b-lactams 4a–p
Entry
1
3 (substrate)
R4OH (nucleophile)
CH3OH
R1
R2
R3
Product 4 (% yield)a
4a (91)
3a
C6H5
C6H5
C6H4OCH3(p)
2
3
3a
3a
OH
OH
C6H5
C6H5
C6H5
C6H5
C6H4OCH3(p)
C6H4OCH3(p)
4b (83)
4c (76)
4
3a
3a
3a
3b
3b
3b
3b
3b
OH
OH
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
4d (74)
4e (64)
4f (78)
4g (81)
4h (80)
4i (70)
4j (66)
4k (61)
5
C6H5
6
C6H5
OH
7
CH3OH
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
8
OH
OH
OH
OH
9
10
11
12
13
3c
3d
CH3OH
CH3OH
C6H5
CH2C6H5
C6H5
C6H5
CH2C6H5
C6H4OCH3(p)
4l (89)
4m (90)
14
15
3d
3e
3e
OH
CH3OH
OH
CH2C6H5
CH2C6H5
CH2C6H5
C6H5
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
4n (81)
4o (79)
4p (63)
C6H4OCH3(p)
C6H4OCH3(p)
16
a
Yields quoted are for the isolated products.

A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
8293
In an effort to demonstrate the synthetic potential of this
reaction and versatility of the products, the cis-3-alkoxy-3-
phenyl/benzylthioazetidin-2-ones were subjected to a desul-
furization reaction. Initially, tri-n-butyltinhydride reduction
of 4a, catalyzed by AIBN in toluene at reflux temperature,
ledto stereoselectivedesulfurizationto afford cis-3-methoxy-
azetidin-2-one (6a) (Scheme 3).
R4O
O
H
N
H
H
N
R1S
R2
R3
R4O
R2
R3
n-Bu3SnH, AIBN
Toluene , Reflux
O
4
6
Scheme 3. n-Bu3SnH desulfurization of cis-3-alkoxy-3-phenyl/benzylthio-
b-lactams 4.
Figure 2. ORTEP diagram for compound 4b.
The cis stereochemistry of the product 6a was assigned
on the basis of coupling constant (J¼5.1 Hz, C3–H and
13C NMR). The stereochemistry at C-3 of cis-3-alkoxy-b-
lactams was established through single crystal X-ray crystal-
lographic studies of 4b23 (Fig. 2) and 4m24 (Fig. 3).
1
C4–H) in the H NMR spectrum.20,25 The reaction was
found to be general with several substrates and the results
are summarized in Table 2. The exclusive formation of the
cis product is due to the donation of hydrogen from the
less hindered face of the intermediate radical.
Table 2. cis-3-Alkoxyazetidin-2-ones 6
Entry
4 (substrate)
Product 6 (% yield)a
1
2
3
4
5
6
4a
4b
4c
4g
4m
4o
6a (88)
6b (83)
6c (72)
6g (71)
6a (81)
6g (74)
a
Yields quoted are for the isolated products.
The stereospecific Raney-nickel desulfurization26 of cis-3-
alkoxy-3-phenyl/benzylthioazetidin-2-ones (4) was carried
out in different solvents to ascertain its effect on the product
stereochemistry. Initially, treatment of 4a with Raney-nickel
in refluxing ethanol resulted in the exclusive formation of
cis-3-methoxyazetidin-2-one (6a). However, when desulfur-
ization was performed in acetone, it produced a mixture of
two compounds, which were separated by column chromato-
graphy and identified as trans-3-methoxyazetidin-2-one (7a)
and cis-3-methoxyazetidin-2-one (6a), respectively, in the
ratio of 3:1 on the basis of their spectroscopic data (Scheme
4, Table 3).
Figure 3. ORTEP diagram for compound 4m.
In order to propose a plausible explanation forthe transforma-
tion of trans-3-chloro-3-phenyl/benzylthioazetidin-2-ones
(3) into cis-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones
(4), a schematic reaction pathway is shown in Scheme 2.
It is likely that the reaction first involves the co-ordination by
chlorine at C-3 to ZnCl2 and the latter being a Lewis acid, it
results in the formation of intermediate carbocation at C-3,
which is further resonance stabilized by lone pair of elec-
trons on sulfur. Subsequent approach of the nucleophile
(R4OH) to this carbocation from the side of hydrogen
atom at C-4, which is less hindered, results in the formation
of cis-b-lactam 4.
Thereafter, the reaction was carried out successfully with
a number of substrates using different solvents and the
results are summarized in Table 3. Variable ratio of trans-
3-alkoxyazetidin-2-ones (7) and cis-3-alkoxyazetidin-2-
ones (6) was observed when desulfurization was performed
_
_
..
HOR4
ZnCl3
ZnCl3
..
Cl
H
N
H
N
H
N
R4O
O
H
N
..
R1S
R1S
R2
R3
R2
R3
R2
R3
R1S
R1S
R2
R3
R4OH
ZnCl2
O
O
O
3
4
A (Carbocation)
Scheme 2. Plausible reaction pathway for the formation of cis-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones (4).

8294
A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
H
H
N
R4O
H
N
H
H
N
H
H
N
R1S
R2
R4O
R4O
R2
R3
R2
R2
R4O
Raney-Ni
Ethanol
Raney-Ni
Acetone
+
R3
O
R3
O
R3
O
O
6
4
7
6
Major
trans-β-lactam
Minor
cis-β-lactam
Scheme 4. Raney-nickel desulfurization of cis-3-alkoxy-3-phenyl/benzylthio-b-lactams 4.
Table 3. Raney-nickel desulfurization of azetidin-2-ones 4
Entry 4 (substrate) Solvent
Products of type (% yield)a
7 (trans-b-lactam) 6 (cis-b-lactam)
2.2. trans-3-Alkoxy-3-phenylthio-b-lactams
Our interest in the stereodivergent construction of the b-lac-
tam ring with alkoxy substituents at C-3 led us to examine the
preparation of trans-3-alkoxy-3-phenylthio-b-lactams (13)
also. A convenient procedure for the synthesis of the b-lac-
tam ring skeleton is the [2+2] cyclocondensation of ketenes
to imines, a process known as the Staudinger reaction.28,29
In particular, this method has provided useful and economic
entries to b-lactams, mainly due to ready availability of both
Schiff’s bases and ketenes. It was envisaged to study the syn-
thesis of trans-3-alkoxy-b-lactams via direct annelation of
alkoxy-substituted potassium phenylthioacetate (11) with
appropriate Schiff’s base (12) using phosphorus oxychloride
(POCl3) as the condensing reagent in the presence of triethyl-
amine. The desired substrates 11(a–d) were prepared from
ethyl 2-chloro-2-phenylthioethanoate (9) (Scheme 5). To
the best of our knowledge, no such alkoxy-substituted phe-
nylthioacetates have been reported so far.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4g
4m
4a
4b
4c
4d
4g
4m
4n
4o
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Acetone 7a (63)
Acetone 7b (55)
Acetone 7c (49)
Acetone 7d (65)
Acetone 7g (46)
Acetone 7a (52)
Acetone 7c (53)
Acetone 7g (43)
—
—
—
—
—
—
6a (79)
6b (74)
6c (69)
6d (70)
6g (75)
6a (68)
6a (20)
6b (28)
6c (30)
6d (22)
6g (27)
6a (16)
6c (21)
6g (24)
9
10
11
12
13
14
a
Yields quoted are for the isolated products.
in acetone. The spatial juxtaposition of the C3–H and C4–H
was assigned cis in product 6 and trans in product 7 on the
basis of coupling constant values (J¼4.8–5.1 Hz, C3–H
and C4–H) and (J¼1.8–2.1 Hz, C3–H and C4–H), respec-
The reaction of ethyl chloroacetate with thiophenol in the
presence of sodium in toluene at refluxing temperature gave
a quantitative yield of thiophenoxy ethylacetate (8). This es-
ter was further treated with 1 equiv of SO2Cl2 in methylene
chloride at 0 ꢀC, to yield ethyl 2-chloro-2-phenylthioetha-
noate (9). Treatment of ethyl 2-chloro-2-phenylthioethanoate
1
tively, in H NMR spectrum.20,25 The structures of these
3-alkoxy-b-lactams (6 and 7) were confirmed on the basis
of their spectral data (IR, 1H NMR and 13C NMR).
Cl
SO2Cl2
CH2Cl2,0oC
Na
+
PhSH ClCH2COOC2H5
PhSCH2COOC2H5
PhSCHCOOC2H5
9
Toluene
8
R4OH, ZnCl2 SiO2
CHCl3, Reflux
Mol. Sieves (3-4)A
R4O
PhSCHCOO_K+
11a-d
R4O
KOH / MeOH
PhSCHCOOC2H5
10a-d
Scheme 5. Synthesis of potassium 2-alkoxy-2-phenylthioethanoate 11a–d.
The variation in the stereochemistry of 3-alkoxy-b-lactams
formed with Raney-nickel desulfurization in acetone or
ethanol can be rationalized on the basis of the availabil-
ity of surface hydrogen on the catalyst. Thus, the greater
the hydrogen availability, the greater is the tendency for
an inversion27 to take place at C-3. Retention of config-
uration at C-3 in acetone solvent may be attributed to
depletion in the supply of surface bound hydrogen due
to the reducible character of the carbonyl function of ace-
tone. In contrast, ethanol as a solvent enhances the sup-
ply of surface hydrogen due to its capability of initiating
dehydrogenation in the presence of Raney-nickel under
reflux conditions and thus favours the inversion of con-
figuration at C-3.
(9) with various alcohols catalyzed by ZnCl2–SiO2, resulted
in the formation of ethyl 2-alkoxy-2-phenylthioethanoate
(10a–d) efficiently and the results are summarized in Table 4.
Ethyl 2-alkoxy-2-phenylthioethanoate (10a–d) on hydrolysis
Table 4. Ethyl 2-alkoxy-2-phenylthioethanoate 10a–d
Entry
R4OH (nucleophile)
Product 10 (% yield)a
10a (90)
1
2
3
CH3OH
OH
10b (87)
OH
10c (81)
4
OH
10d (84)
a
Yields quoted are for the isolated products.

A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
8295
using KOH in methanol afforded potassium 2-alkoxy-2-
phenylthioethanoate (11a–d).
important role in the stereochemical outcome of the Stau-
dinger reaction.30,31 The formation of trans- and cis-3-alk-
oxy-b-lactams in this case can be rationalized on the basis
of the mechanism, which is presented in Scheme 7.
Initial studies were carried out by treating 11a with appropri-
ate Schiff’s base (12) using methylene chloride at 0 ꢀC. This
reaction resulted in the exclusive formation of trans-3-
methoxy-3-phenylthioazetidin-2-one (13a) in quantitative
yield (Scheme 6). The reaction was carried out successfully
with a number of substrates 11b–d and the results are sum-
marized in Table 5. Interestingly, all the substrates produced
exclusively trans-3-alkoxy-3-phenylthio-b-lactams.
Here, first an active ester B is formed by the reaction
of potassium 2-alkoxy-2-phenylthioethanoate (11) and
POCl3, which furnishes the ketene C by undergoing elimina-
tion under the influence of a base. It has been postulated that
LUMO of the ketene carbonyl group, which is coplanar to
the substituents of the ketene, is attacked by imine in an
R4O
H
PhS
CH2Cl2
0oC
N
R4O
PhSCHCOO_K+
11a-d
O
OCH3
POCl3
13a-d
+
trans-β-lactam
Et3N
N
R4O
PhS
H
N
H
N
R4O
O
PhS
H3CO
12
C6H6
Reflux
+
O
OCH3
OCH3
13a-d
4a-d
Major
trans-β-lactam
Minor
cis-β-lactam
Scheme 6. Synthesis of trans- and cis-3-alkoxy-3-phenylthioazetidin-2-ones.
orthogonal approach.30 E imines gave preferentially cis-b-
lactams and Z imines gave predominantly the corresponding
trans-b-lactams.31 The literature studies reveal that most of
the starting acyclic imines employed in the Staudinger reac-
tion exist in E configuration exclusively.31,32 Considering
this, the formation of trans-b-lactams can be proposed
initially by the exo attack of the E imine to the ketene C,
generating the zwitterionic intermediate D. Further, the
isomerization of the E imine to less favoured Z imine gives
the zwitterionic intermediate E, which, on conrotatory elec-
trocyclization generates the thermodynamically more stable
trans-3-alkoxy-b-lactams (13). The literature findings con-
clude that the reaction of ketene with cyclic imines also gives
trans-b-lactams exclusively.31 Since the cyclic imines
cannot undergo the isomerization in the reaction,30,31,33
the possibility of formation of trans-b-lactams through
isomerization of the E imine moiety to less favoured Z imine
or reaction with inversion of imine configuration is not fea-
sible. So, in this case, it is believed that the attack of the E
imine on the face of the ketene C brings the PhS group clo-
sure to imine, thus generating the zwitterionic intermediate
F, which on direct ring closure or conrotatory electrocycliza-
tion produces exclusively the trans-3-alkoxy-b-lactams
(13).34 It has been proposed that the competition between
the direct ring closure and the isomerization controls the rel-
ative stereoselectivity of b-lactam formation, which can be
further explained in terms of rate constant. It has been re-
ported31 that the lower rate constant for direct ring closure
process is the real reason for the exclusive formation of
the trans-b-lactams. The rate constant of the direct ring clo-
sure process has been found to be quite small when the R1 in
ketene C is PhS.31 This can also be rationalized through the
experimental classification as proposed by Georg and Ravi-
kumar.30 ‘Moore ketenes’ possessing very weak electron-
donating substituents R1 (such as S-alkyl, S-aryl, alkyl and
Table 5. Synthesis of trans-3-alkoxy-3-phenylthio-b-lactams (13a–d) using
CH2Cl2 at 0 ꢀC
Entry
11 (substrate)
Product 13 (% yield)a
1
2
3
4
11a
11b
11c
11d
13a (85)
13b (80)
13c (71)
13d (74)
a
Yields quoted are for the isolated products.
On the other hand, when this reaction was performed in
refluxing benzene (Scheme 6), instead of leading to the
exclusive formation of the expected trans-3-methoxy-3-
phenylthioazetidin-2-one (13a), a mixture of trans- and
cis-3-alkoxy-b-lactams was formed in a ratio of 3:1, respec-
tively, and the b-lactams were separated by column chroma-
tography. The reaction was found to be general for various
substrates (11b–d) and the results are summarized in Table
6. The structures of these trans-3-alkoxy-b-lactams (13a–
d) and cis-3-alkoxy-b-lactams (4a–d) were confirmed on
the basis of their spectral data (IR, 1H NMR and 13C NMR).
A variety of factors, such as structure and size of the substit-
uents of the acid and imine components, sequence of addi-
tion of reactants, nature of solvent and temperature play an
Table 6. Synthesis of trans- and cis-3-alkoxy-3-phenylthio-b-lactams using
C6H6 at reflux temperature
Entry
11 (substrate)
Products of type (% yield)a
13 (trans-b-lactam) 4 (cis-b-lactam)
1
2
3
4
11a
11b
11c
11d
13a (69)
13b (60)
13c (54)
13d (57)
4a (21)
4b (18)
4c (15)
4d (17)
a
Yields quoted are for the isolated products.

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A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
OR4
OR4
O
PhS
H
PhS
OR4
PhS
O
P
O
P
Base
Et3N
Cl
Cl
+
Cl
Cl
P
Cl
Cl
C
O
+
+
K
O
O
O
O
HO
Cl
11
B
C
PhS
PhS
R2
OR4
R2
OR4
R2
R4O
H
H
OR4
H
PhS
PhS
C
O
C
N
+
N
+
O
R3
R3
N
O
R3
cis-β-lactam
+
O
R2
D
4
H
.
.
N
R2
OR4
OR4
H
R2
R3
H
R3
PhS
PhS
12
R4O
R2
N
+
N
+
R3
O
O
PhS
H
E
R4O
SPh
N
R3
C
R2
13
R2
O
R4O
O
SPh
H
R4O
H
O
C
trans-β-lactam
SPh
R3
+
R2
H
N
N
O
+
R3
+
.
.
N
F
R3
12
Scheme 7. A plausible mechanism for the formation of trans- and cis-3-alkoxy-3-phenylthioazetidin-2-ones.
aryl) have a strong preference for trans-b-lactam formation
due to small rate constant of the direct ring closure (k1,
rel<1). However, the formation of almost 30% cis-3-alk-
oxy-b-lactams (4) at high temperature in refluxing benzene
indicates the involvement of high energy zwitterionic inter-
mediate D as shown, which undergoes further conrotatory
electrocyclization to form cis-b-lactam.
Table 7. Reductive desulfurization of trans-3-alkoxy-3-phenylthio-b-lac-
tams 13
Entry 13 (substrate) Solvent
Products of type (% yield)a
6 (cis-b-lactam) 7 (trans-b-lactam)
1
2
3
4
5
6
7
8
13a
13b
13c
13d
13a
13b
13c
13d
Acetone 6a (85)
—
—
—
—
7a (75)
7b (72)
7c (63)
7d (68)
Acetone 6b (82)
Acetone 6c (78)
Acetone 6d (81)
The trans-3-alkoxy-3-phenylthioazetidin-2-ones (13a–d)
were also subjected to stereospecific Raney-nickel desulfur-
ization25 in different solvents. When 13a was treated with
Raney-nickel in refluxing acetone, cis-3-methoxyazetidin-
2-one 6a was formed exclusively, whereas, it undergoes
reductive desulfurization with inversion of configuration
in ethanol, leading to the exclusive formation of trans-3-
methoxyazetidin-2-one 7a (Scheme 8). The reaction was
found to be general with several substrates (13b–d) and the
results are summarized in Table 7.
Ethanol
Ethanol
Ethanol
Ethanol
—
—
—
—
a
Yields quoted are for the isolated products.
configurational assignment is provided by taking into con-
sideration the comparison of spectroscopic data of 13a and
4a. The stereochemistry of 4a was confirmed by single crys-
tal X-ray crystallographic studies of 4b23 (Fig. 2) and 4m24
(Fig. 3) and further, the comparison of spectroscopic data of
13a with 4a, confirmed the stereochemistry of 13a as well.
The methoxy group in trans-b-lactam 13a, in which, it is
cis to phenyl group, resonates at higher field (3.41 ppm)
than the methoxy group in cis-b-lactam 4a, in which, it is
trans to phenyl group, resonating at 3.77 ppm (Fig. 4).
The assignment of stereochemistry to trans- and cis-3-alk-
oxy-b-lactams is also based on 1H NMR spectroscopy.
The alkoxy signal in the H NMR spectrum of trans-3-
1
alkoxy-b-lactams is shifted to higher field by about
0.35–0.50 ppm as compared to cis-3-alkoxy-b-lactams.21
This upfield shift is due to the shielding effect of the cis-4-
phenyl group on the 3-alkoxy protons. Support for this
H
H
N
R4O
PhS
H
H
H
N
R4O
R4O
Raney-Ni
Ethanol
Raney-Ni
Acetone
N
O
O
O
OCH3
OCH3
OCH3
6a-d
13a-d
7a-d
Scheme 8. Raney-nickel desulfurization of trans-3-alkoxy-3-phenylthio-b-lactams 13a–d.

A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
8297
H3CO
PhS
H
N
H
H3CO
PhS
was purified by silica gel column chromatography (10%
EtoAc/hexane).
N
4.2.1. cis-1-(40-Methoxyphenyl)-3-methoxy-3-phenyl-
thio-4-phenylazetidin-2-one (4a). Colourless crystalline
solid (0.045 g, 91%); mp 141–142 ꢀC [Found: C, 70.49; H,
5.36; N, 3.52. C23H21NO3S requires C, 70.57; H, 5.40; N,
3.58%]; IR (cmꢂ1, KBr): 1755 (C]O); dH (300 MHz,
CDCl3) 7.33–6.76 (14H, m, Ph), 5.10 (1H, s, C4-H), 3.77
(6H, s, 2ꢁOCH3); dC (75 MHz, CDCl3) 160.8, 156.4,
133.7, 132.2, 130.6, 130.5, 128.6, 128.3, 128.2, 128.1,
127.2, 118.9, 114.3, 99.9, 68.5, 55.1, 53.4.
O
O
OCH3
OCH3
13a
4a
Figure 4. trans- and cis-3-Methoxy-azetidin-2-ones (13a and 4a).
3. Conclusion
In conclusion, it is thus possible to achieve the stereoselec-
tive synthesis of cis-3-alkoxy-3-phenyl/benzylthioazetidin-
2-ones by reacting trans-3-chloro-3-phenyl/benzylthio-
azetidin-2-ones (3a–e) with various alcohols in silica gel
mediated by Lewis acid such as ZnCl2 using molecular sieves
4.2.2. cis-1-(40-Methoxyphenyl)-3-ethoxy-3-phenylthio-
4-phenylazetidin-2-one (4b). Colourless crystalline solid
(0.042 g, 83%); mp 113–114 ꢀC [Found: C, 71.05; H,
5.67; N, 3.34. C24H23NO3S requires C, 71.09; H, 5.71; N,
3.45%]; IR (cmꢂ1, KBr): 1757 (C]O); dH (300 MHz,
CDCl3) 7.65–6.75 (14H, m, Ph), 5.15 (1H, s, C4-H), 4.16
(1H, m, OCHaHb), 4.05 (1H, m, OCHaHb), 3.71 (3H, s,
OCH3), 1.35 (3H, t, CH3); dC (75 MHz, CDCl3) 162.0,
156.4, 132.9, 130.3, 128.6, 128.4, 128.2, 128.1, 127.5,
119.1, 114.3, 96.7, 68.4, 61.7, 55.4, 14.9.
˚
(3–4 A) in refluxing chloroform. The X-ray crystallographic
analysis of compounds 4b and 4m allowed establishment
of the stereochemistry at C-3 of cis-3-alkoxy-b-lactams 4.
Additionally, we have also shown that direct annelation of
potassium 2-alkoxy-2-phenylthioethanoate (11a–d) and
appropriate Schiff’s base (12) using phosphorous oxy-
chloride (POCl3) as condensing reagent in the presence of
triethylamine as the base provides an easy access to trans-
3-alkoxy-3-phenylthioazetidin-2-ones. Further elaboration
of these products to potentially useful building blocks is
underway in our laboratory.
4.2.3. cis-1-(40-Methoxyphenyl)-3-isopropyloxy-3-
phenylthio-4-phenylazetidin-2-one (4c). Colourless crys-
talline solid (0.040 g, 76%); mp 112–113 ꢀC [Found: C,
77.54; H, 6.03; N, 3.24. C25H25NO3S requires C, 77.57; H,
6.00; N, 3.33%]; IR (cmꢂ1, KBr): 1750 (C]O); dH
(300 MHz, CDCl3) 7.23–6.61 (14H, m, Ph), 5.00 (1H, s,
C4-H), 4.52 (1H, m, OCH), 3.62 (3H, s, OCH3), 1.23 (3H,
d, J 6.0 Hz, CH3), 1.13 (3H, d, J 6.0 Hz, CH3); dC
(75 MHz, CDCl3) 161.7, 156.4, 133.2, 132.1, 131.4, 130.5,
128.6, 128.4, 128.2, 127.9, 126.5, 119.0, 114.3, 98.9, 70.0,
69.8, 55.1, 23.8, 23.7.
4. Experimental
4.1. General
General experimental has been described previously.20 Crys-
tallographic data (excluding structure factors) of compounds
4b23 and 4m24 in CIF format have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the
data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
(internet.) +44 1223/336 033; e-mail: deposit@ccdc.cam.
ac.uk]. All other relevant information regarding the data
and supplementary publication CCDC number is presented
in respective references.
4.2.4. cis-1-(40-Methoxyphenyl)-3-propyloxy-3-phenyl-
thio-4-phenylazetidin-2-one (4d). White crystalline solid
(0.039 g, 74%); mp 114–116 ꢀC [Found: C, 77.52; H,
5.91; N, 3.24. C25H25NO3S requires C, 77.57; H, 6.00; N,
3.33%]; IR (cmꢂ1, KBr): 1756 (C]O); dH (300 MHz,
CDCl3) 7.25–6.69 (14H, m, Ph), 5.05 (1H, s, C4-H), 4.01
(1H, m, OCHaHb), 3.89 (1H, m, OCHaHb), 3.71 (3H, s,
OCH3), 1.67 (2H, m, CH2CH3), 0.91 (3H, t, CH3); dC
(75 MHz, CDCl3) 161.2, 156.4, 133.2, 132.5, 130.9, 130.6,
128.6, 128.2, 128.1, 127.8, 118.9, 114.3, 99.0, 68.5, 67.7,
55.1, 22.9, 10.9.
Compounds 3a–e20 were prepared by the procedures de-
scribed in the cited reference. The spectroscopic data of
compounds 3a–e20 were also reported in the cited reference.
4.2. General procedure for the synthesis of cis-3-alkoxy-
3-phenyl/benzylthio-b-lactams (4a–p)
4.2.5. cis-1-(40-Methoxyphenyl)-3-butyloxy-3-phenyl-
thio-4-phenylazetidin-2-one (4e). Yellow solid (0.035 g,
64%); mp 72–74 ꢀC [Found: C, 71.95; H, 6.24; N, 3.17.
C26H27NO3S requires C, 72.03; H, 6.27; N, 3.23%]; IR
(cmꢂ1, CHCl3): 1757 (C]O); dH (300 MHz, CDCl3)
7.25–6.69 (14H, m, Ph), 5.04 (1H, s, C4-H), 4.04 (1H, m,
OCHaHb), 3.92 (1H, m, OCHaHb), 3.70 (3H, s, OCH3),
1.61 (2H, m, OCH2CH2), 1.39 (2H, m, CH2CH2CH3), 0.91
(3H, t, CH3); dC (75 MHz, CDCl3) 161.2, 156.4, 133.2,
132.4, 130.9, 130.6, 128.6, 128.3, 128.2, 128.1, 127.0,
118.9, 114.3, 99.0, 68.5, 65.9, 55.1, 31.7, 19.4, 14.1.
A mixture containing silica gel (1.00 g, 100–200 mesh),
alcohol (4.68 mmol), anhydrous chloroform (10 mL),
˚
molecular sieves (3–4 A) and anhydrous zinc chloride
(0.03 mmol) was stirred for 25–30 min, followed by the ad-
dition of a solution of trans-3-chloro-3-phenylthio-b-lactam
(3) (0.13 mmol) in 1 mL of CHCl3. The reaction mixture
was refluxed for 2 h with constant stirring. The progress of
the reaction was monitored by TLC. Disappearance of the
starting b-lactam was considered as the completion of the
reaction. The reactants were filtered, washed with water
(2ꢁ5 mL) and extracted with CH2Cl2 (3ꢁ10 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4
and filtered. The residue after solvent evaporation in vacuo,
4.2.6. cis-1-(40-Methoxyphenyl)-3-(prop-2-ynyloxy)-
3-phenylthio-4-phenylazetidin-2-one (4f). Yellow oil
(0.041 g, 78%) [Found: C, 72.24; H, 5.02; N, 3.31.

8298
A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
C25H21NO3S requires C, 72.27; H, 5.09; N, 3.37%]; IR
(cmꢂ1, CHCl3): 1758 (C]O); dH (300 MHz, CDCl3) 7.25–
6.69 (14H, m, Ph), 5.27 (1H, s, C4-H), 4.87 (1H, dd, J 2.4,
2.4 Hz, OCHaHb), 4.57 (1H, dd, J 2.4, 2.4 Hz, OCHaHb),
3.71 (3H, s, OCH3), 2.47 (1H, t, HC^); dC (75 MHz,
CDCl3) 160.3, 156.5, 133.0, 132.9, 132.9, 130.4, 129.8,
128.7, 128.4, 128.3, 128.2, 127.5, 119.1, 119.0, 114.4,
99.2, 79.4, 75.4, 68.4, 55.1, 53.9; dC (DEPT-135) (75 MHz,
CDCl3) 133.0 (+), 132.9 (+), 132.9 (+), 128.7 (+), 128.4
(+), 128.3 (+), 128.2 (+), 127.5 (+), 119.1 (+), 119.0 (+),
114.4 (+), 79.4 (+), 75.4 (+), 68.4 (+), 55.1 (+), 53.9 (ꢂ).
4.2.7. cis-1-(40-Methoxyphenyl)-3-methoxy-3-phenyl-
thio-4-(40-methoxyphenyl)azetidin-2-one (4g). Yellow-
ish-brown oil (0.040 g, 81%) [Found: C, 68.36; H, 5.40; N,
3.28. C24H23NO4S requires C, 68.39; H, 5.49; N, 3.32%];
IR (cmꢂ1, CHCl3): 1745 (C]O); dH (300 MHz, CDCl3)
7.49–6.60 (13H, m, Ph), 4.98 (1H, s, C4-H), 3.76 (3H, s,
OCH3), 3.71 (3H, s, OCH3), 3.70 (3H, s, OCH3); dC
(75 MHz, CDCl3) 161.2, 159.8, 156.2, 132.5, 130.9, 130.5,
129.2, 128.1, 127.0, 124.7, 118.9, 114.5, 113.7, 98.8, 68.1,
55.0, 54.7, 52.8.
2.93. C27H29NO4S requires C, 69.96; H, 6.30; N, 3.02%];
IR (cmꢂ1, CHCl3): 1756 (C]O); dH (300 MHz, CDCl3)
7.21–6.60 (13H, m, Ph), 4.92 (1H, s, C4-H), 3.94 (1H, m,
OCHaHb), 3.83 (1H, m, OCHaHb), 3.69 (3H, s, OCH3),
3.63 (3H, s, OCH3), 1.55 (2H, m, OCH2CH2), 1.31 (2H,
m, CH2CH2CH3), 0.84 (3H, t, CH3); dC (75 MHz, CDCl3)
161.4, 160.0, 156.3, 132.4, 131.1, 130.6, 129.3, 128.2,
127.0, 125.0, 119.0, 114.3, 113.6, 99.3, 68.2, 65.8, 55.1,
55.0, 31.7, 19.4, 14.1.
4.2.12. cis-1-Benzyl-3-methoxy-3-phenylthio-4-phenyl-
azetidin-2-one (4l). Colourless crystalline solid (0.044 g,
89%); mp 101–102 ꢀC [Found: C, 73.55; H, 5.64; N, 3.70.
C23H21NO2S requires C, 73.57; H, 5.63; N, 3.73%]; IR
(cmꢂ1, KBr): 1752 (C]O); dH (300 MHz, CDCl3) 7.22–
6.94 (15H, m, Ph), 4.87 (1H, d, J 15.0 Hz, CHaHbPh), 4.40
(1H, s, C4-H), 3.83 (1H, d, J 14.7 Hz, CHaHbPh), 3.54
(3H, s, OCH3); dC (75 MHz, CDCl3) 164.5, 135.0, 133.3,
132.4, 130.6, 128.9, 128.6, 128.5, 128.2, 128.1, 127.9,
127.1, 100.6, 67.7, 53.4, 44.1.
4.2.13. cis-1-(40-Methoxyphenyl)-3-methoxy-3-ben-
zylthio-4-phenylazetidin-2-one (4m). Colourless crystal-
line solid (0.044 g, 90%); mp 128–129 ꢀC [Found: C,
71.05; H, 5.62; N, 3.41. C24H23NO3S requires C, 71.09; H,
5.71; N, 3.45%]; IR (cmꢂ1, KBr): 1762 (C]O); dH
(300 MHz, CDCl3) 7.39–6.74 (14H, m, Ph), 5.13 (1H, s,
C4-H), 4.02 (1H, d, J 12.0 Hz, CHaHbS), 3.77 (1H, d,
J 12.0 Hz, CHaHbS), 3.75 (3H, s, OCH3), 3.56 (3H, s,
OCH3); dC (75 MHz, CDCl3) 161.1, 156.4, 137.6, 133.2,
130.6, 129.2, 128.8, 128.5, 128.3, 128.0, 126.9, 118.9,
114.4, 97.8, 67.9, 55.1, 52.5, 32.2.
4.2.8. cis-1-(40-Methoxyphenyl)-3-ethoxy-3-phenylthio-
4-(40-methoxyphenyl)azetidin-2-one (4h). Colourless
crystalline solid (0.040 g, 80%); mp 114–115 ꢀC [Found:
C, 68.91; H, 5.71; N, 3.19. C25H25NO4S requires C, 68.95;
H, 5.78; N, 3.22%]; IR (cmꢂ1, KBr): 1756 (C]O); dH
(300 MHz, CDCl3) 7.31–6.65 (13H, m, Ph), 4.99 (1H, s,
C4-H), 4.09 (1H, m, OCHaHb), 3.99 (1H, m, OCHaHb),
3.73 (3H, s, OCH3), 3.66 (3H, s, OCH3), 1.23 (3H, t,
CH3); dC (75 MHz, CDCl3) 161.3, 159.9, 156.2, 132.5,
130.9, 130.5, 129.3, 128.2, 127.0, 124.8, 118.9, 114.2,
113.5, 99.3, 68.1, 61.5, 55.0, 54.9, 15.1.
4.2.14. cis-1-(40-Methoxyphenyl)-3-isopropyloxy-3-
benzylthio-4-phenylazetidin-2-one (4n). Colourless crys-
talline solid (0.043 g, 81%); mp 115–116 ꢀC [Found: C,
72.10; H, 6.24; N, 3.20. C26H27NO3S requires C, 72.13; H,
6.27; N, 3.22%]; IR (cmꢂ1, KBr): 1760 (C]O); dH
(300 MHz, CDCl3) 7.35–6.70 (13H, m, Ph), 5.04 (1H, s,
C4-H), 4.46 (1H, m, OCH), 3.96 (1H, d, J 12.0 Hz,
CHaHbS), 3.71 (3H, s, OCH3), 3.51 (1H, d, J 12.0 Hz,
CHaHbS), 1.36 (3H, d, J 6.0 Hz, CH3), 1.31 (3H, d,
J 6.0 Hz, CH3); dC (75 MHz, CDCl3) 162.1, 156.3, 137.0,
133.4, 130.6, 129.2, 128.9, 128.5, 128.4, 128.3, 127.0,
118.9, 114.3, 97.6, 69.4, 69.1, 55.1, 32.5, 24.0, 23.8.
4.2.9. cis-1-(40-Methoxyphenyl)-3-isopropyloxy-3-
phenylthio-4-(40-methoxyphenyl)azetidin-2-one (4i). Col-
ourless crystalline solid (0.037 g, 70%); mp 87–88 ꢀC
[Found: C, 69.50; H, 6.01; N, 3.07. C26H27NO4S requires
C, 69.47; H, 6.05; N, 3.12%]; IR (cmꢂ1, CHCl3): 1755
(C]O); dH (300 MHz, CDCl3) 7.29–6.59 (13H, m, Ph),
4.99 (1H, s, C4-H), 4.57 (1H, m, OCH), 3.73 (3H, s,
OCH3), 3.70 (3H, s, OCH3), 1.29 (3H, d, J 6.0 Hz, CH3),
1.19 (3H, d, J 6.0 Hz, CH3); dC (75 MHz, CDCl3) 161.6,
159.9, 156.3, 132.3, 131.3, 130.6, 129.5, 128.1, 126.5,
124.9, 119.1, 114.3, 113.5, 99.1, 69.9, 69.4, 55.1, 54.9,
23.8, 23.6.
4.2.15. cis-1-(40-Methoxyphenyl)-3-methoxy-3-ben-
zylthio-4-(40-methoxyphenyl)azetidin-2-one (4o). Colour-
less crystalline solid (0.039 g, 79%); mp 101–102 ꢀC
[Found: C, 68.90; H, 5.77; N, 3.19. C25H25NO4S requires
C, 68.95; H, 5.78; N, 3.22%]; IR (cmꢂ1, KBr): 1762
(C]O); dH (300 MHz, CDCl3) 7.12–6.62 (13H, m, Ph),
4.92 (1H, s, C4-H), 3.86 (1H, d, J 12.3 Hz, CHaHbS), 3.68
(3H, s, OCH3), 3.64 (3H, s, OCH3), 3.63 (1H, d, J
12.6 Hz, CHaHbS), 3.42 (3H, s, OCH3); dC (75 MHz,
CDCl3) 162.0, 160.0, 156.3, 137.6, 130.5, 129.2, 128.3,
126.9, 124.7, 118.9, 114.3, 113.8, 98.6, 67.3, 55.1, 54.9,
52.4, 32.2.
4.2.10. cis-1-(40-Methoxyphenyl)-3-propyloxy-3-phenyl-
thio-4-(40-methoxyphenyl)azetidin-2-one (4j). White solid
(0.035 g, 66%); mp 75–76 ꢀC [Found: C, 69.39; H, 6.00; N,
3.05. C26H27NO4S requires C, 69.47; H, 6.05; N, 3.12%]; IR
(cmꢂ1, CHCl3): 1756 (C]O); dH (300 MHz, CDCl3) 7.27–
6.66 (13H, m, Ph), 4.99 (1H, s, C4-H), 3.95 (1H, m,
OCHaHb), 3.86 (1H, m, OCHaHb), 3.74 (3H, s, OCH3),
3.70 (3H, s, OCH3), 1.65 (2H, m, CH2CH3), 0.92 (3H, t,
CH3); dC (75 MHz, CDCl3) 161.4, 160.0, 156.3, 132.4,
131.1, 130.6, 129.3, 128.2, 127.0, 124.9, 119.0, 114.3,
113.6, 99.3, 68.1, 67.6, 55.1, 55.0, 22.9, 10.8.
4.2.16. cis-1-(40-Methoxyphenyl)-3-isopropyloxy-3-ben-
zylthio-4-(40-methoxyphenyl)azetidin-2-one (4p). Yellow
oil (0.033 g, 63%) [Found: C, 69.92; H, 6.27; N, 2.99.
C27H29NO4S requires C, 69.96; H, 6.30; N, 3.02%]; IR
4.2.11. cis-1-(40-Methoxyphenyl)-3-butyloxy-3-phenyl-
thio-4-(40-methoxyphenyl)azetidin-2-one (4k). Yellow-
ish-brown oil (0.033 g, 61%) [Found: C, 69.91; H, 6.22; N,

A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
8299
(cmꢂ1, CHCl3): 1764 (C]O); dH (300 MHz, CDCl3) 7.25–
6.70 (13H, m, Ph), 4.90 (1H, s, C4-H), 4.43 (1H, m, OCH),
4.00 (1H, d, J 12.0 Hz, CHaHbS), 3.77 (3H, s, OCH3), 3.72
(3H, s, OCH3), 3.57 (1H, d, J 12.0 Hz, CHaHbS), 1.35
(3H, d, J 6.0 Hz, CH3), 1.25 (3H, d, J 6.0 Hz, CH3); dC
(75 MHz, CDCl3) 160.1, 156.3, 137.9, 130.8, 129.6, 129.3,
129.2, 128.4, 128.3, 126.9, 125.0, 119.0, 118.9, 114.3,
113.9, 113.8, 98.0, 67.7, 60.9, 55.1, 55.0, 32.4, 24.0, 23.8.
4.4. General procedure for Raney-nickel desulfurization
Compounds 6 and 720 were prepared by the procedure
described in the cited reference.
4.4.1. cis-1-(40-Methoxyphenyl)-3-propyloxy-4-phenyl-
azetidin-2-one (6d). Colourless crystalline solid (0.026 g,
70%); mp 112–113 ꢀC [Found: C, 73.18; H, 6.82; N, 4.43.
C19H21NO3 requires C, 73.29; H, 6.89; N, 4.49%]; IR
(cmꢂ1, CHCl3): 1760 (C]O); dH (300 MHz, CDCl3)
6.85–6.21 (9H, m, Ph), 4.61 (1H, d, J 4.8 Hz, C3-H), 4.34
(1H, d, J 4.8 Hz, C4-H), 3.21 (3H, s, OCH3), 2.89 (1H, m,
OCHaHb), 2.56 (1H, m, OCHaHb), 0.82 (2H, m, CH2CH3),
0.52 (3H, t, CH3); dC (75 MHz, CDCl3) 163.7, 156.3,
133.7, 130.7, 128.5, 128.4, 128.1, 118.7, 114.3, 83.8, 72.5,
62.2, 55.3, 22.5, 10.2.
4.3. General procedure for n-Bu3SnH reduction
n-Bu3SnH (0.14 mmol) was added dropwise via a syringe in
the mixture of 4 (0.13 mmol) and catalytic amount of AIBN
in toluene (4 mL). The reaction mixture was refluxed for 1 h.
The progress of the reaction was checked by TLC. After the
completion of reaction, the solvent was evaporated in vacuo.
The residue was redissolved in methylene chloride (20 mL),
washed with water (2ꢁ5 mL) and dried over anhydrous
Na2SO4. The residue after solvent evaporation in vacuo,
was purified by silica gel column chromatography (8%
EtOAc/hexane).
4.4.2. trans-1-(40-Methoxyphenyl)-3-methoxy-4-phenyl-
azetidin-2-one (7a). Yellow oil (0.019 g, 63%) [Found: C,
85.60; H, 7.11; N, 5.81. C17H17NO3 requires C, 85.68; H,
7.18; N, 5.87%]; IR (cmꢂ1, CHCl3): 1757 (C]O); 1H
NMR (CDCl3) d: 7.36–6.45 (9H, m, Ph), 4.80 (1H, d, J
1.8 Hz, C3-H), 4.31 (1H, d, J 1.8 Hz, C4-H), 3.71 (3H, s,
OCH3), 3.57 (3H, s, OCH3); dC (75 MHz, CDCl3) 168.3,
156.3, 136.6, 130.7, 129.2, 128.7, 127.9, 126.0, 118.8,
114.3, 91.3, 63.2, 58.0, 55.3.
4.3.1. cis-1-(40-Methoxyphenyl)-3-methoxy-4-phenyl-
azetidin-2-one (6a). Colourless crystalline solid (0.027 g,
88%); mp 165–166 ꢀC [Found: C, 85.62; H, 7.14; N, 5.84.
C17H17NO3 requires C, 85.68; H, 7.18; N, 5.87%]; IR
(cmꢂ1, KBr): 1747 (C]O); dH (300 MHz, CDCl3) 7.35–
6.68 (9H, m, Ph), 5.09 (1H, d, J 5.1 Hz, C3-H), 4.73 (1H,
d, J 5.1 Hz, C4-H), 3.73 (3H, s, OCH3), 3.22 (3H, s,
OCH3); dC (75 MHz, CDCl3) 163.5, 156.3, 133.5, 130.7,
128.6, 128.5, 128.0, 118.7, 114.3, 84.8, 61.8, 58.3, 55.3.
4.4.3. trans-1-(40-Methoxyphenyl)-3-ethoxy-4-phenylaze-
tidin-2-one (7b). Colourless oil (0.020 g, 55%) [Found: C,
72.58; H, 6.39; N, 4.61. C18H19NO3 requires C, 72.71; H,
6.43; N, 4.71%]; IR (cmꢂ1, CHCl3): 1761 (C]O); dH
(300 MHz, CDCl3) 7.33–6.56 (9H, m, Ph), 5.10 (1H, d, J
4.8 Hz, C3-H), 4.76 (1H, d, J 4.8 Hz, C4-H), 3.68 (1H, m,
OCHaHb), 3.62 (3H, s, OCH3), 3.57 (1H, m, OCHaHb),
1.06 (3H, t, CH3); dC (75 MHz, CDCl3) 163.7, 156.2,
133.4, 130.5, 129.1, 128.4, 128.0, 125.3, 118.7, 114.2,
80.2, 69.3, 61.8, 55.3, 14.9.
4.3.2. cis-1-(40-Methoxyphenyl)-3-ethoxy-4-phenyl-
azetidin-2-one (6b). White solid (0.030 g, 83%); mp 127–
128 ꢀC [Found: C, 72.60; H, 6.37; N, 4.65. C18H19NO3
requires C, 72.71; H, 6.43; N, 4.71%]; IR (cmꢂ1, KBr):
1757 (C]O); dH (300 MHz, CDCl3) 7.29–6.63 (9H, m,
Ph), 5.04 (1H, d, J 4.8 Hz, C3-H), 4.79 (1H, d, J 4.8 Hz,
C4-H), 3.63 (3H, s, OCH3), 3.39 (1H, m, OCHaHb), 3.10
(1H, m, OCHaHb), 0.82 (3H, t, CH3); dC (75 MHz, CDCl3)
163.5, 156.2, 133.6, 130.7, 128.4, 128.3, 128.0, 118.6,
114.2, 83.6, 66.2, 62.0, 55.2, 14.7.
4.4.4. trans-1-(40-Methoxyphenyl)-3-isopropyloxy-4-
phenylazetidin-2-one (7c). Pinkish-yellow oil (0.018 g,
49%) [Found: C, 77.16; H, 6.66; N, 4.38. C19H21NO3 re-
quires C, 73.29; H, 6.79; N, 4.49%]; IR (cmꢂ1, CHCl3):
1759 (C]O); dH (300 MHz, CDCl3) 6.96–6.29 (14H, m,
Ph), 4.35 (1H, d, J 2.1 Hz, C3-H), 4.01 (1H, d, J 1.8 Hz,
C4-H), 3.43 (1H, m, OCH), 3.29 (3H, s, OCH3), 0.89 (3H,
d, J 6.0 Hz, CH3), 0.77 (3H, d, J 6.0 Hz, CH3); dC
(75 MHz, CDCl3) 164.2, 156.2, 133.0, 132.7, 131.2, 130.3,
128.6, 128.4, 128.2, 126.7, 126.1, 119.1, 114.3, 89.1, 70.1,
64.9, 55.3, 24.8, 24.6.
4.3.3. cis-1-(40-Methoxyphenyl)-3-isopropyloxy-4-
phenylazetidin-2-one (6c). Colourless crystalline solid
(0.026 g, 72%); mp 122–123 ꢀC [Found: C, 77.21; H,
6.72; N, 4.43. C19H21NO3 requires C, 73.29; H, 6.79; N,
4.49%]; IR (cmꢂ1, KBr): 1750 (C]O); dH (300 MHz,
CDCl3) 7.28–6.65 (14H, m, Ph), 5.03 (1H, d, J 4.5 Hz,
C3-H), 4.90 (1H, d, J 4.8 Hz, C4-H), 3.65 (3H, s, OCH3),
3.39 (1H, m, OCH), 1.03 (3H, d, J 6.0 Hz, CH3), 0.60 (3H,
d, J 6.0 Hz, CH3); dC (75 MHz, CDCl3) 164.2, 156.2,
134.5, 130.8, 128.4, 128.3, 118.4, 114.3, 82.1, 72.7, 62.6,
55.3, 22.1, 21.3.
4.4.5. trans-1-(40-Methoxyphenyl)-3-propyloxy-4-
phenylazetidin-2-one (7d). Colourless oil (0.024 g, 65%)
[Found: C, 73.15; H, 6.78; N, 4.37. C19H21NO3 requires C,
73.29; H, 6.89; N, 4.49%]; IR (cmꢂ1, CHCl3): 1767
(C]O); dH (300 MHz, CDCl3) 7.28–6.66 (9H, m, Ph),
4.77 (1H, d, J 4.8 Hz, C3-H), 4.41 (1H, d, J 4.8 Hz, C4-
H), 3.74 (1H, m, OCHaHb), 3.62 (3H, s, OCH3), 3.54 (1H,
m, OCHaHb), 1.62 (2H, m, CH2CH3), 0.91 (3H, t, CH3);
dC (75 MHz, CDCl3) 163.9, 156.3, 133.9, 130.8, 128.5,
128.1, 126.0, 118.8, 114.3, 90.4, 72.7, 63.7, 55.3, 23.0, 10.5.
4.3.4. cis-1-(40-Methoxyphenyl)-3-methoxy-4-(40-
methoxyphenyl)azetidin-2-one (6g). Colourless oil (0.026 g,
71%) [Found: C, 68.81; H, 5.98; N, 4.38. C18H19NO4
requires C, 68.99; H, 6.10; N, 4.47%]; IR (cmꢂ1, CHCl3):
1751 (C]O); dH (300 MHz, CDCl3) 7.37–6.71 (8H, m,
Ph), 4.78 (1H, d, J 5.1 Hz, C3-H), 4.41 (1H, d, J 5.1 Hz,
C4-H), 3.72 (3H, s, OCH3), 3.68 (3H, s, OCH3), 3.31 (3H, s,
OCH3).
4.4.6. trans-1-(40-Methoxyphenyl)-3-methoxy-4-(40-
methoxyphenyl)azetidin-2-one (7g). Brownish-yellow oil

8300
A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
(0.017 g, 46%) [Found: C, 68.83; H, 5.95; N, 4.36.
C18H19NO4 requires C, 68.99; H, 6.10; N, 4.47%]; IR
(cmꢂ1, CHCl3): 1762 (C]O); dH (300 MHz, CDCl3)
7.37–6.51 (8H, m, Ph), 4.43 (1H, d, J 2.1 Hz, C3-H), 4.15
(1H, d, J 2.1 Hz, C4-H), 3.70 (3H, s, OCH3), 3.66 (3H, s,
OCH3), 3.55 (3H, s, OCH3).
4.7.3. Ethyl 2-isopropyloxy-2-phenylthioethanoate (10c).
Yellow oil (0.044 g, 81%) [Found: C, 61.03; H, 7.05.
C13H18O3S requires C, 61.14; H, 7.12%]; IR (cmꢂ1
,
CHCl3): 1756 (C]O); dH (300 MHz, CDCl3) 7.40–7.20
(5H, m, Ph), 5.07 (1H, s, CH), 4.21 (2H, q, OCH2), 4.07
(1H, m, OCH), 1.14 (3H, t, CH3), 1.07 (3H, d, J 6.0 Hz,
CH3), 0.97 (3H, d, J 6.0 Hz, CH3).
4.5. General procedure for the preparation of
ethyl 2-phenylthioethanoate (8)
4.7.4. Ethyl 2-propyloxy-2-phenylthioethanoate (10d).
Yellow oil (0.046 g, 84%) [Found: C, 61.09; H, 7.14.
A mixture of thiophenol (27.50 g, 250 mmol) and molecu-
larized sodium (5.75 g, 250 mmol) in toluene (250 mL)
was refluxed for 10 h. To the resulting sodium thiophenoxide
(33.00 g, 250 mmol) was added dropwise ethyl chloro-
acetate (33.68 g, 275 mmol) and the reaction mixture was
refluxed. Progress of the reaction was monitored by TLC.
The reaction mixture was washed with water and dried
over anhydrous Na2SO4. After evaporation of the solvent
in vacuo, the residue was vacuum distilled to furnish the title
compound 8 (41.45 g, 85%) as colourless oil [Found: C,
61.12; H, 2.51. C10H12O2S requires C, 61.20; H, 2.58%];
IR (cmꢂ1, CHCl3): 1755 (C]O); dH (300 MHz, CDCl3)
7.37–7.13 (5H, m, Ph), 4.14 (2H, q, OCH2), 3.54 (2H, s,
CH2), 1.19 (3H, t, CH3); dC (75 MHz, CDCl3) 166.8,
133.7, 132.1, 128.8, 128.7, 128.2, 128.1, 84.6, 61.0, 14.1.
C13H18O3S requires C, 61.14; H, 7.12%]; IR (cmꢂ1
,
CHCl3): 1753 (C]O); dH (300 MHz, CDCl3) 7.46–7.21
(5H, m, Ph), 5.09 (1H, s, CH), 4.11 (2H, q, OCH2), 3.85
(1H, m, OCHaHb), 3.47 (1H, m, OCHaHb), 1.70 (2H, m,
CH2CH3), 1.18 (3H, t, CH3), 0.95 (3H, t, CH3); dC
(75 MHz, CDCl3) 167.1, 133.7, 132.0, 128.8, 128.7, 128.3,
128.2, 84.7, 61.7, 61.2, 22.5, 14.1, 10.7.
4.8. General procedure for the synthesis of trans-3-
alkoxy-3-phenylthio-b-lactams (13a–d)
Compounds 13a–d were prepared by using the same proce-
dure as for trans-3-phenyl/benzylthioazetidin-2-ones,20
reported in cited reference, starting from potassium 2-alk-
oxy-2-phenylthioethanoate (11a–d).
4.6. General procedure for the synthesis of
ethyl 2-chloro-2-phenylthioethanoate (9)
4.8.1. trans-1-(40-Methoxyphenyl)-3-methoxy-3-phenyl-
thio-4-phenylazetidin-2-one (13a). White solid (0.042 g,
85%); mp 112–114 ꢀC [Found: C, 70.52; H, 5.32; N, 3.54.
C23H21NO3S requires C, 70.57; H, 5.40; N, 3.58%]; IR
(cmꢂ1, KBr): 1755 (C]O); dH (300 MHz, CDCl3) 7.49–
6.73 (14H, m, Ph), 4.97 (1H, s, C4-H), 3.64 (3H, s,
OCH3), 3.41 (3H, s, OCH3); dC (75 MHz, CDCl3) 160.6,
156.4, 133.6, 133.5, 131.9, 130.7, 128.9, 128.6, 128.3,
128.1, 118.8, 114.3, 97.2, 69.1, 55.1, 53.7.
This compound was prepared by using the same method
as for 3a–c, starting from ethyl 2-phenylthioethanoate (8).
Colourless oil (0.044 g, 75%) [Found: C, 51.96; H, 4.77.
C10H11O2SCl requires C, 52.04; H, 4.80%]; IR (cmꢂ1
,
CHCl3): 1744 (C]O); dH (300 MHz, CDCl3) 7.51–7.27
(5H, m, Ph), 5.39 (1H, s, CH), 4.14 (2H, q, OCH2), 1.19
(3H, t, CH3); dC (75 MHz, CDCl3) 165.4, 134.1, 133.2,
130.8, 129.4, 129.3, 129.2, 129.1, 65.5, 62.5, 14.0.
4.8.2. trans-1-(40-Methoxyphenyl)-3-ethoxy-3-phenyl-
thio-4-phenylazetidin-2-one (13b). White solid (0.040 g,
80%); mp 114–115 ꢀC [Found: C, 71.06; H, 5.74; N, 3.50.
C24H23NO3S requires C, 71.09; H, 5.71; N, 3.45%]; IR
(cmꢂ1, KBr): 1754 (C]O); dH (300 MHz, CDCl3) 7.56–
6.66 (14H, m, Ph), 4.98 (1H, s, C4-H), 3.92 (1H, m,
OCHaHb), 3.67 (3H, s, OCH3), 3.62 (1H, m, OCHaHb),
0.93 (3H, t, CH3); dC (75 MHz, CDCl3) 161.2, 156.3,
133.4, 133.1, 131.7, 130.5, 128.9, 128.7, 128.2, 118.9,
114.1, 98.9, 68.7, 61.7, 55.0, 14.7.
4.7. General procedure for the synthesis of ethyl
2-alkoxy-2-phenylthioethanoate (10a–d)
Compounds 10a–d were prepared by using the same method
as for 4, starting from ethyl 2-chloro-2-phenylthioethanoate
(9).
4.7.1. Ethyl 2-methoxy-2-phenylthioethanoate (10a). Col-
ourless oil (0.044 g, 90%) [Found: C, 58.35; H, 6.18.
C11H14O3S requires C, 58.39; H, 6.23%]; IR (cmꢂ1
,
4.8.3. trans-1-(40-Methoxyphenyl)-3-isopropyloxy-3-
phenylthio-4-phenylazetidin-2-one (13c). White solid
(0.037 g, 71%); mp 115–116 ꢀC [Found: C, 77.51; H,
5.91; N, 3.28. C25H25NO3S requires C, 77.57; H, 6.00; N,
3.33%]; IR (cmꢂ1, KBr): 1757 (C]O); dH (300 MHz,
CDCl3) 7.08–6.18 (14H, m, Ph), 4.52 (1H, s, C4-H), 4.39
(1H, m, OCH), 3.57 (3H, s, OCH3), 1.17 (3H, d, J 6.0 Hz,
CH3), 0.87 (3H, d, J 6.0 Hz, CH3).
CHCl3): 1755 (C]O); dH (300 MHz, CDCl3) 7.39–7.16
(5H, m, Ph), 4.96 (1H, s, CH), 4.03 (2H, q, OCH2), 3.45
(3H, s, OCH3), 1.09 (3H, t, CH3); dC (75 MHz, CDCl3)
166.3, 133.5, 131.7, 128.5, 128.3, 128.1, 128.0, 86.2, 60.8,
55.2, 14.0.
4.7.2. Ethyl 2-ethoxy-2-phenylthioethanoate (10b). Col-
ourless oil (0.045 g, 87%) [Found: C, 59.91; H, 6.63.
C12H16O3S requires C, 59.98; H, 6.70%]; IR (cmꢂ1
,
4.8.4. trans-1-(40-Methoxyphenyl)-3-propyloxy-3-
phenylthio-4-phenylazetidin-2-one (13d). White solid
(0.039 g, 74%); mp 118–119 ꢀC [Found: C, 77.50; H,
6.03; N, 3.29. C25H25NO3S requires C, 77.57; H, 6.00; N,
3.33%]; IR (cmꢂ1, KBr): 1753 (C]O); dH (300 MHz,
CDCl3) 7.13–6.25 (14H, m, Ph), 4.58 (1H, s, C4-H), 3.39
(1H, m, OCHaHb), 3.26 (3H, s, OCH3), 3.17 (1H, m,
CHCl3): 1753 (C]O); dH (300 MHz, CDCl3) 7.42–7.19
(5H, m, Ph), 5.05 (1H, s, CH), 4.08 (2H, q, OCH2), 3.97
(1H, m, OCHaHb), 3.53 (1H, m, OCHaHb), 1.25 (3H,
t, CH3), 1.15 (3H, t, CH3); dC (75 MHz, CDCl3) 167.1,
133.8, 131.9, 129.9, 128.8, 128.3, 84.8, 61.8, 61.2, 14.7,
14.1.

A. Bhalla et al. / Tetrahedron 62 (2006) 8291–8302
8301
11. (a) Zhou, N. E.; Guo, D.; Thomas, G.; Reddy, A. V. N.; Kaleta,
J.; Purisima, E.; Menard, R.; Micetich, R. G.; Singh, R. Bioorg.
Med. Chem. Lett. 2003, 13, 139–141; (b) Setti, E. L.; Davis, D.;
Chung, T.; McCarter, J. Bioorg. Med. Chem. Lett. 2003, 13,
2051–2053.
OCHaHb), 0.91 (2H, m, CH2CH3), 0.23 (3H, t, CH3); dC
(75 MHz, CDCl3) 161.6, 156.4, 133.3, 133.2, 131.6, 130.5,
128.9, 128.6, 128.2, 128.1, 128.0, 118.9, 114.3, 96.3, 69.2,
67.8, 55.3, 22.5, 10.5.
12. Barton, D. H. R.; Anaya, J.; Gateau-Olesker, A.; Gero, S. D.
Tetrahedron Lett. 1992, 33, 6641–6642.
Acknowledgements
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N.; Oiarbide, M. Tetrahedron Lett. 1990, 31, 6425–6428; (b)
Palomo, C.; Cossio, F. P.; Ontoria, M.; Odriozola, J. M.
Tetrahedron Lett. 1991, 321, 3105–3108.
15. Palomo, C.; Arrieta, A.; Cossio, F. P.; Aizpurua, J. M.; Mielgo,
A.; Aurrekoetxea, N. Tetrahedron Lett. 1990, 31, 6429–6432.
16. Smith, D. M.; Kazi, A.; Smith, L.; Long, T. E.; Heldreth, B.;
Turos, E.; Dou, Q. P. Mol. Pharmacol. 2002, 01, 1348–1358.
17. Skiles, J. W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277–
7280.
We gratefully acknowledge the financial support for this
work from Council of Scientific and Industrial Research,
New Delhi and Department of Science and Technology
(DST), New Delhi, Government of India (Project No. SP/
S1/G-50/99).
References and notes
18. Madan, S.; Arora, R.; Venugopalan, P.; Bari, S. S. Tetrahedron
Lett. 2000, 41, 5577–5581.
19. Bari, S. S.; Venugopalan, P.; Arora, R. Tetrahedron Lett. 2003,
44, 895–897.
20. Bhalla, A.; Madan, S.; Venugopalan, P.; Bari, S. S. Tetrahedron
2006, 62, 5054–5063.
21. van der Veen, J. M.; Bari, S. S.; Krishnan, L.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1989, 54, 5758–5762.
22. Manhas, M. S.; Bari, S. S.; Bhawal, B. M.; Bose, A. K.
Tetrahedron Lett. 1984, 42, 4733–4736.
1. For reviews on b-lactam antibiotics, see: (a) Durckheimer, W.;
Blumbatch, J.; Lattrell, R.; Scheunrmann, K. H. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 180–202; (b) Chu, D. T. W.; Plattner,
J. J.; Katz, L. J. Med. Chem. 1996, 39, 3853–3874; (c)
Chemistry and Biology of b-Lactam Antibiotics; Morin,
R. B., German, M., Eds.; Academic: New York, NY, 1982;
(d) Coulton, S.; Hunt, E. Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products;
Lukaes, G., Ed.; Springer: Berlin, 1993; p 621; (e) Southgate,
R. Contemp. Org. Synth. 1994, 1, 417–432.
˚
23. Crystal data for 4b: monoclinic; P21/n; a¼12.7209(2) A,
2. The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992.
ꢀ
ꢀ
˚
˚
b¼10.0018(2) A, c¼17.7900(3) A; a¼90 , b¼110.1480(10) ,
g¼90 ꢀC; V¼2124.95(6) A ; Z¼4; rcalcd¼1.267 mg/m3;
3
˚
3. For comprehensive general reviews, see: (a) de Kimpe, N.
Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.;
Elsevier: Oxford, UK, 1996; pp 536–575; (b) Koppel, G. A.
Chemistry of Heterocyclic Compounds—Small Ring
Heterocycles; Hassner, A., Ed.; Wiley: New York, NY, 1983;
p 219.
4. Ojima, I.; Georg, G. I. The Organic Chemistry of b-Lactams;
Georg, G. I., Ed.; VCH: New York, NY, 1993; pp 197–255.
5. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbid, M.
Enantioselective Synthesis of Beta-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, NY, 1997; p 279.
m(Mo Ka)¼0.177 mmꢂ1; full matrix least-square on F2;
R1¼0.0456, wR2¼0.1239 for 2805 reflections [I>2s (I)];
T¼293(2) K; GOF¼1.042. Crystallographic data (excluding
structure factors) for the structure 4b in this paper has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 292949.
˚
24. Crystal data for 4m: monoclinic; P21/c; a¼10.2813(4) A,
ꢀ
ꢀ
˚
˚
b¼18.5745(8) A, c¼11.9227(5) A; a¼90 , b¼110.335(2) ,
g¼90 ; V¼2134.98(15) A ; Z¼4; rcalcd¼1.262 mg/m3; m(Mo
3
ꢀ
˚
Ka)¼0.176 mmꢂ1
;
full matrix least-square on F2;
R1¼0.0480, wR2¼0.1066 for 2447 reflections [I>2s (I)];
T¼293(2) K; GOF¼1.011. Crystallographic data (excluding
structure factors) for the structure 4m in this paper has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 292948.
25. (a) Kagan, H. B.; Basselier, J. J.; Luche, J. L. Tetrahedron Lett.
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