A general and versatile synthesis of 3-phenylthio β-lactams as lead molecules for 3-methyl-2-azetidinones

Article abstract of DOI:10.1002/jhet.5570440523

(Chemical Equation Presented) Ketene-imine cycloaddition using phosphorus oxychloride and benzenesulfonyl chloride under the described reaction conditions yielded trans 3-phenylthio 2-azetidinones in good yields. Desulfurization using Raney nickel and alk

Full text of DOI:10.1002/jhet.5570440523

Sep-Oct 2007
A General and Versatile Synthesis of 3-Phenylthio ꢀ-Lactams as
1121
Lead Molecules for 3-Methyl-2-Azetidinones
Seema Kanwar and S. D. Sharma*
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India.
E mail: sdsharmapu@yahoo.com ; Phone: 91-172-2541435; Fax: 91-172-2545074
Received December 4, 2006
2
R
H
N
R
2 5 3
POCl3 / (C H ) N
H
2
C
6
H
5
S
R
-
+
or
Cl / (C
DCM
+
6
C H
SCHCO
2
K
5
C
6
H
5
SO
2
2 5 3
H ) N
N
1
1
R
R
O
R
Ni [H]
Acetone
Reflux / 3 h
or
3
Bu SnH / AIBN
H
H
R
H
(
(CH
3
)
2
CH)
n-BuLi
CH
2
NH
R2
R1
R2
H
3
H C
N
3
I
N
R1
O
O
Ketene-imine cycloaddition using phosphorus oxychloride and benzenesulfonyl chloride under the
described reaction conditions yielded trans 3-phenylthio 2-azetidinones in good yields. Desulfurization
using Raney nickel and alkylation finally afforded trans 3-methyl-2-azetidinones in a stereoselective
manner.
J. Heterocyclic Chem., 44, 1121 (2007).
INTRODUCTION
equivalents with imines (a variant of the Staudinger
Reaction [7]) has proved to be a convenient procedure for
the construction of 2-azetidinone ring. This strategy is
potentially quite versatile since the needed substrates,
acetic acids and Schiff bases are easily accessible, and as
a result a number of ꢀ-lactams with latent functional
group at the three positions can be prepared. Although
from this method the steric course of the ꢀ-lactam
formation does not appear to be predictable, it can be
controlled by the experimental conditions used [8,9] and
by the choice of Schiff bases with bulky substitutents
The synthesis of ꢀ-lactams has witnessed a resurgence
of interest since the discovery that several representatives
of this class of compounds can effectively inhibit proteases
[
1,2]. In particular azetidinone 1 was identified [3] as a
powerful and selective inhibitor of thrombin, a serine
protease involved in both venous and arterial thrombotic
episodes [4]. More recently, ꢀ-lactam 2 was found to
display inhibition of tryptase at the subnanomolar level
and suppress induced inflammation in animal lungs [5] and
3
as cholesterol absorption inhibitor (Figure 1).
[
10].
-Unsubstituted ꢀ-lactams can serve as synthons for 3-
ꢁ
F
NH
OH
alkylazetidin-2-ones antibiotics. ꢀ-Lactams of this type
have a single chiral center at C-4 and the question of cis
and trans isomers is absent. The activated methylene
group at C-3 can undergo base catalyzed alkylation and
condensation reactions, the steric course of which is
usually controlled by the bulk of the substituents at C-4.
These 3-unsubstituted 2-azetidinones, therefore, can
undergo a variety of chemical transformations of immense
interest [11].
CO R
2
H N
N
2
H
Ph
N
N
R1
O
O
1
2
R = CH ; R1 = H, CO CH , Tos
3
2
3
F
3
R = H; R1
=
C
O
N
NCONHBut
(
Figure 1)
The utility of the ꢁ-bromoester-imine condensation to
the synthesis of appropriately substituted 3-alkyl ꢀ-
lactams had been reported by Palomo et al in 1989 [12].
Among many other methods for the synthesis of
monocyclic ꢀ-lactams [13], however, the direct
preparation of 3-alkyl ꢀ-lactams from monoalkylketenes,
generated from their corresponding acid chlorides, is
often limited in scope [14]. Although some exception has
appeared [15], no general method to the synthesis of 3-
The structural features of these new types of ꢀ-lactams
are (a) the presence of an alkyl group at the C - 3 position
of the ꢀ-lactam ring; (b) the presence of diverse substitu-
tents at C - 4 and N - 1; and (c) the relative stereo-
chemistry at C - 3 and C - 4 positions. Among numerous
methods for the synthesis of substituted monocyclic ꢀ-
lactams [6], the annulation of acid chlorides or

1
122
S. Kanwar and S. D. Sharma
Vol 44
alkyl ꢀ-lactam from the ketene-imine approach has been
described. Given the strategic and tactical significance of
(phenylthio)ketene. Even the ꢀ-thiophenoxy ester-
enolates react with N-trimethylsilylimines to afford
mixture of stereoisomeric ꢀ-lactams [20,21].
3
-unsubstituted ꢀ-lactams, it was imperative to secure an
efficient and highly stereoselective synthetic route to
prepare these compounds. The fulcrum of our synthetic
plan was a stereoselective synthesis of 3-phenylthio-2-
In the present work, we have substantially improved the
synthesis of 3-phenylthio-2-azetidinones and shown that
these reagents (POCl and PhSOCl ) under the described
3
2
Scheme 1
azetidinones derived from Schiff bases and phenylthio-
acetic acids using readily available benzenesulfonyl
chloride and phosphorus oxychloride as the acid
activating agents for the construction of ꢀ-lactam ring
which in analogous systems, is well-precedented in the
literature employing Staudinger reaction between appro-
priately substituted acid chloride and imines [16].
reaction conditions undergo clean and efficient cyclo-
addition to provide a concise, high yielding and stereo-
selective synthesis of trans 3-phenylthio-2-azetidinones.
The thiophenoxyacetic acid after converting to its potas-
sium salt was reacted with a variety of imines in presence
of benzenesulfonyl chloride as well as phosphorous oxy-
chloride and triethylamine to yield the corresponding
trans ꢀ-lactams in good yields which were purified using
column chromatography. In all of these ꢀ-lactams the 2
Hz coupling constant between the C-3 and C-4 protons
were indicative of the trans stereochemistry.
RESULTS AND DISCUSSION
Though we have already reported the use of PhSO Cl as
2
well as POCl [17] for the synthesis of ꢀ-lactams, we have
3
observed that these reagents work in a cleaner fashion
when potassium salts of the requisite acid components
were used instead of the acids themselves. A large
number of 3-phenylthio ꢀ-lactams were prepared using
this technique as precursors of 3-unsubstituted ꢀ-lactams
No trace of cis isomer was detected by NMR
spectroscopy. This method display a general scope since
various carboxylic acids, as their potassium salt and
imines were readily cyclized to their corresponding
ꢀ-lactams yields being in the range 75-80% (Table 1). To
explain the stereoselectivity associated with the reaction
involving imines and aryl/alkyl thioacetic acids using
C H SO Cl/(C H ) N and POCl /(C H ) N it seems quite
(
Scheme 1). Synthesis of such ꢀ-(phenylthio) azetidine-2-
ones as an isomeric mixture of cis and trans have already
been reported [18,19] in the literature using methyl-
6
5
2
2
5
3
3
2
5 3

Sep-Oct 2007
3-Phenylthio ꢀ-Lactams as Lead Molecules for 3- alkyl-2-azetidinones
1123
S
R
N
R
H
R
H
L
L
L
H
(
a)
con
a)
S
R
S
(
(
C
N
C
N
+
O
-O
R'
O
R'
R'
(
c) Nuc-
R' = Ph
b) R = Ph, OMe, SMe
Nuc
H
R
H
+
N
L
L
S
S
C
C
N
-O
R'
-O
R'
H
R
H
N
S
L
con
L
R
S
C
N
-O
+
O
R'
R'
9
Scheme 2
probable that the groups on the bond forming carbons C-3
and C-4 orient themselves on the diene dipolar inter-
mediates 9 as shown in Scheme 2. This intermediate is the
as these last are recognized as valuable starting materials
for the introduction of several groups at the ꢁ-position of
the ꢀ-lactam carbonyl [22]. The phenylthio group at C-3
of the ꢀ-lactam ring is chosen as a convenient vehicle for
introducing the alkyl group. Cleavage of the C - S bond
has been most conveniently done under mild conditions
using desulfurization reaction with Raney nickel chem-
isorbed with hydrogen [23], the reaction is generally
performed in ethanol or acetone. Thus when the 3-thio-
favored one due to absence of any interaction of C -SPh
3
2
vs C –R . Conrotation of the overlapping orbitals for bond
4
formation leads to the exclusive formation of the trans
ꢀ
-lactams.
A key feature of these ꢀ-lactams is shown by their use
as potential precursors of 3-unsubstituted ꢀ-lactams where
Table 1
Characterization Data of 3-Phenylthio-2-azetidinones
Molecular
formula
Analytical data
Spectral data
FT-IR (NaCl plates, ꢂ, cm )
H NMR (300 MHz, CDCl , ꢃ, ppm)
-
1
Yield
%)
mp
Found (calculated) (%)
Compd.
1
(
(°C)
(molecular
weight)
3
C
H
N
1
3
3
C NMR (300 MHz, CDCl , ꢃ,ppm)
6a
6b
6c
70
72
70
67-68
C
21
H
17NOS
75.92
(75.73)
5.12
(5.24)
4.41
(4.22)
1750
4.44 (d, 1H, C
(
331)
3
H, J = 1.6 Hz), 4.85 (d, 1H, C H, J = 1.6 Hz),
4
7
5
1
.01-7.72 (m, 15H, ArH)
2.2, 61.9, 120.4, 124.9, 126.6, 127.1, 128.7, 135.6, 140.8,
42.4, 170.9
175-
C
22
H
17NO
3
S
S
70.20
(70.40)
4.49
(4.53)
3.86
(3.73)
1760
1
76
(375)
3 4
4.25 (d, 1H, C H, J = 2.2 Hz), 4.65 (d, 1H, C H, J = 2.2 Hz), 6.85
2
(s, 2H, OCH O) 7.31-7.82 (m, 13H, ArH)
5
1
3.2, 62.2, 91.5, 112.1, 115, 120, 124, 126.6, 128.7, 135, 140.8,
45.6, 147.4, 170.9
Oil
C
23
H
21NO
3
70.49
5.01
3.71
1747
(
391)
(70.59)
(5.27)
(3.58)
3.79 (s, 3H, OCH ), 3.85 (s, 3H, OCH ), 4.21 (d, 1H, C H, J =
3
3
3
2
7
5
1
4
.2 Hz), 4.71 (d, 1H, C H, J = 2.2 Hz), 6.76-7.62 (m, 8H, ArH),
.35 (s, 5H, ArH)
.
5.33, 55.41, 61.4, 63.01, 114.3, 114.63, 118.7, 127.42, 127.82,
28.19, 129.17, 130.70, 131.99, 132.52, 156.28, 160.06, 162.81
6
d
69
141-
C
22
H
19NO
2
S
72.92
5.17
3.91
1743
1
42
(361)
(72.73)
(5.26)
(3.88)
3 3
3.75 (s, 3H, OCH ), 4.27 (d, 1H, C H, J = 2.3 Hz), 4.79 (d, 1H,
4
C H, J = 2.3 Hz), 6.75-7.66 (m, 14H, ArH)
5
1
5.46, 61.52, 63.17, 114.33, 118.68, 126.12, 128.05, 128.55,
29.26, 130.58, 132.30, 132.60, 134.93, 136.38, 156.43, 162.79

1
124
S. Kanwar and S. D. Sharma
Vol 44
Table 1 (continued)
Molecular
formula
(molecular
weight)
Analytical data
Found (calculated) (%)
Spectral data
FT-IR (NaCl plates, ꢁ, cm )
H NMR (300 MHz, CDCl , ꢂ, ppm)
3
C NMR (300 MHz, CDCl , ꢂ,ppm)
-
1
Yield
%)
mp
(°C)
Compd.
1
(
3
C
H
N
13
6
e
75
127-
C
24
H
(387)
21NO
2
S
74.20
(74.42)
5.29
(5.43)
3.75
(3.62)
1752, 1600
3.87 (s, 3H, OCH
H, J = 7.0, 2.0 Hz), 6.32 (dd, 1H, NCHCH, J = 15.0, 7.0 Hz),
.79 (d, 1H, CHC , J = 15 Hz), 6.81-7.72 (m, 14H, ArH)
1.5, 56.0, 59.5, 114, 121.4, 123.3, 124.9, 126.6, 127.7, 128.4,
33.1, 134, 135.6, 157.6, 170.9
1
28
3 3
), 4.99 (d, 1H, C H, J = 2 Hz), 5.47 (dd, 1H,
C
4
6
5
1
6 5
H
6
f
73
71
140-
42
C
23
H
(405)
19NO
4
S
S
68.00
(68.15)
4.51
(4.69)
3.75
(3.56)
3200, 1755, 1600
3 3
3.81 (s, 3H, OCH ), 4.21 (d, 1H, C H, J = 1.8 Hz), 4.72 (d, 1H,
C H, J = 1.8 Hz), 6.65-7.00 (m, 13H, Ar-H)
4
1
5
1
2.2, 56.0, 61.9, 113.9, 120.3, 122.5, 124.0, 125.1, 126.6, 128.7,
30.3, 133.9, 134.7, 135.6, 142.2, 160.0, 170.9, 172.0
6
6
g
157-
53
C
24
H
(389)
23NO
2
73.99
(73.84)
5.89
(5.91)
3.89
(3.60)
1756
1
2.89 (t, 2H, CH
2
C
6
H
5
), 3.60 (t, 2H, NCH
H, J = 2.0 Hz), 4.61 (d, 1H, C
.85 (m, 14H, ArH)
2
), 3.92 (s, 3H, OCH
3
),
4
7
2
1
.32 (d, 1H, C
3
4
H, J = 2 Hz), 6.85-
5.0, 48.8, 56.0, 59.8, 113.9, 124.9, 125.7, 126.4, 127.9, 128.7,
29.5, 135.6, 140.7, 160.3, 173.6
h
68
72
130-
32
C
19
H
(343)
21NO
3
S
S
66.23
(66.47)
6.09
(6.12)
4.11
(4.08)
3460, 1756
1
1.32 (d, 3H, CH
3
, J = 7 Hz), 3.25 (m, 1H, CHOH), 3.53 (m, 2H,
), 4.19 (d, 1H, C H, J = 1.5 Hz), 4.23
4
H, J = 1.5 Hz), 6.85-7.73 (m, 9H, ArH)
NCH
2
), 3.88 (s, 3H, OCH
3
3
(d, 1H, C
2
1
0.4, 52.6, 56.5, 60.1, 67.6, 113.9, 124.9, 126.6, 128.7, 129.5,
35.6, 160.3, 173.6
6
i
125-
27
C
20
H
(339)
21NO
2
69.99
(69.81)
6.00
(6.19)
4.27
(4.13)
3381, 1739, 1650
1.23 (d, 3H, CH
1
3
, J = 7.0 Hz), 3.25 (m, 1H, CHOH), 3.45 (m,
), 4.09 (d, 1H, C H, J = 1.8 Hz), 4.23 (dd, 1H, C H, J =
.0, 1.8 Hz), 6.25 (dd, 1H, NCHCH, J = 14.0, 6.0 Hz), 6.75 (d,
H, CHC , J = 14.0 Hz), 7.41 and 7.51 (s each, 10H, ArH)
0.4, 50.5, 57.0, 57.7, 67.7, 123.3, 124.9, 126.2, 127.7, 128.4,
34.0, 135.6, 173.6
2
6
1
2
1
H, NCH
2
3
4
6
H
5
6
j
60
62
Oil
C
19
H
19NO
4
S
S
63.75
(63.87)
5.30
(5.42)
4.01
(3.92)
1756, 1731
(
357)
1.32 (t, 3H, CH
2
CH
3
,), 3.81 (s, 3H, OCH
H, J = 2.2 Hz), 4.85 (d, 1H, C
.2 Hz), 6.85-7.73 (m, 9H, ArH)
3.6, 45.2, 56.0, 59.5, 62.2, 114.3, 121.4, 124.9, 126.6, 128.7,
33.1, 135.6, 137.6, 170.0, 172.0
3
), 4.25 (q, 2H,
CH
2
CH
3
), 4.41 (d, 1H, C
3
4
H, J =
2
1
1
1
7
6
k
121-
C
22
H
19NO
2
73.01
5.19
3.95
1745
1
22
(361)
(73.13)
(5.26)
(3.88)
3 3
3.77 (s, 3H, OCH ), 4.05 (d, 1H, C H, J = 2.0 Hz), 4.08 (d, 1H,
4
C H, J = 2.0 Hz), 6.80-7.41 (m, 14H, ArH)
phenoxy ꢀ-lactams 6a-k were refluxed with freshly
prepared Raney nickel in acetone furnished the corre-
sponding ꢀ-lactams 7a-k in good yields. The characteri-
zation data of all the compounds prepared is given in
Table 2.
the preparation of different ꢀ-lactam synthons. However,
the chemistry involving the anionic ꢀ-lactam equivalents
has not been extensively studied. Hence, our attention was
focused on the use of anionic ꢀ-lactam equivalent type a.
If the C substitution is bulky, the trans ꢀ-lactam is often
4
Transformation at the C - 3 carbon of ꢀ-lactams
leading to the formation of diverse molecules involving
anionic and cationic ꢀ-lactam equivalents a and b
respectively (Figure 2) are an important area of research
the only substitution product and that is essential for the
molecule to show antimicrobial property.
Thus, when we subjected the anion, generated in situ
from 3-unsubstituted ꢀ-lactam 7a-k and LDA, to
alkylation with methyl iodide, and obtained exclusively
the trans 3-methyl ꢀ-lactam 8a-k in high yields.
Significantly, no bis-methylated lactam or cis isomer was
detected in the reaction. The structure was confirmed by
analytical as well as spectral data (Table 3). As a model for
our work the synthesis of 7b was studied first. The
starting material, Schiff base 4b was prepared by the
reaction of aniline and piperonal in refluxing methylene
[
24,25]. The potential of the cationic ꢀ-lactam equivalent
of type b has been explored by many groups [26-28] for
H
N
H
N
R
O
R +
-
R2
R2
R1
O
R1
Type a
Type b
Figure 2

Sep-Oct 2007
3-Phenylthio ꢀ-Lactams as Lead Molecules for 3- alkyl-2-azetidinones
1125
Table 2
Characterization data of 3-Unsubstituted-2-Azetidinones
Compd.
Yield
%)
mp
(°C)
Molecular
formula
Analytical data
Found (calculated) (%)
Spectral Data
FT-IR (NaCl plates, ꢁ, cm )
H NMR (60 MHz, CDCl , ꢂ, ppm)
3
-
1
(
1
(molecular
C
H
N
weight)
7
7
a
62
59
61
67-68
145
C
15
H
223)
13NO
80.52
(80.72)
5.70
(5.83)
6.35
(6.27)
1751
2.82 (dd, 1H, C
12.9, 5.1 Hz), 4.41 (dd, 1H, C
.5 (m, 10H, ArH)
1757
3.22 (dd, 1H, C
5, 4.5 Hz), 4.52 (dd, 1H, C
H, OCH O), 6.52-6.91 (m, 8H, ArH)
1750
2.85 (dd, 1H, C
14.1, 5.0 Hz), 3.71 (s, 3H, OCH
.85 (dd, 1H, C H, J = 5.0, 2.5 Hz), 6.73 and 6.85 (d each,
H, ArH, J = 9.1 Hz), 7.16 and 7.35 (d each, 4H, ArH, J
9.3 Hz)
1745
3.15 (dd, 1H, C
(
3
H, J = 12.9, 2.4 Hz), 3.35 (dd, 1H, C
3
H, J
=
7
4
H, J = 5.1, 2.4 Hz), 7.01-
b
C
16
H
13NO
3
3
71.80
(71.91)
4.75
(4.87)
5.31
(5.24)
(
267)
3
H, J = 15, 2.7 Hz), 3.40 (dd, 1H, C
3
H, J =
1
2
4
H, J = 4.5, 2.7 Hz), 5.99 (s,
2
7
c
134-
C
17
H
17NO
71.99
(72.08)
5.81
(6.00)
4.99
(4.95)
1
36
(283)
3
H, J = 14.1, 2.5 Hz), 3.55 (dd, 1H, C
3
H, J
),
=
4
4
=
3
), 3.78 (s, 3H, OCH
3
4
7
d
60
61
Oil
C
16
H
15NO
2
2
75.71
(75.89)
6.01
(5.93)
5.62
(5.53)
(
253)
3
H, J = 15.2, 3.0 Hz), 3.23 (dd, 1H, C
15.2, 5.5 Hz), 3.75 (s, 3H, OCH ), 4.52 (dd, 1H, C
5.5, 3.0 Hz), 6.91-7.52 (m, 9H, ArH)
3
H, J
H, J
=
=
3
4
7
e
134-
C
18
H
17NO
77.20
(77.40)
6.00
(6.13)
5.21
(5.01)
1750
2.81 (dd, 1H, C
=
=
1
36
(279.3)
3
H, J = 14.1, 2.5 Hz), 3.23 (dd, 1H, C
14.1, 5.0 Hz), 3.76 (s, 3H, OCH ), 4.63 (dd, 1H, C
5.0, 2.5 Hz), 6.04 (dd, 1H, C HC=, J = 15.3, 2.5 Hz),
3
H, J
4
H, J
3
4
6.61 (d, 1H, CH=CHPh, J = 15.3 Hz) 6.88 and 7.35 (d
each, 4H, ArH, J = 9.4 Hz), 6.73 and 6.85 (d each, 4H,
ArH, J = 9.1 Hz), 7.16 and 7.35 (d each, 4H, ArH, J = 9.3
Hz), 7.20 – 7.40 (m, 5H, ArH)
7
f
55
57
77 - 79
89 - 91
C
(
17
H
15NO
4
68.47
(68.68)
4.91
(5.09)
4.50
(4.71)
1752
297.31)
2.27 (dd, 1H, C
3
H, J = 15.2, 2.7 Hz), 2.95 (dd, 1H, C
15.2, 5.7 Hz), 3.75 (s, 3H, OCH ), 5.07 (dd, 1H, C
3.0, 2.70 Hz), 6.84 and 7.25 (d each, 4H, ArH, J = 8.4
3
H, J
4
H, J
=
=
3
Hz), 7.27–7.96 (m, 4H, ArH)
1748
7
g
C
18
H
19NO
2
76.66
6.70
4.71
(
281.35)
(76.84)
(6.81)
(4.98)
2.75 (dd, 1H, C
.23 (m, 1H, NHCH
Hz), 3.45 (m, 1H, NHCH
H, C H, J = 3.0, 2.7 Hz), 6.85 and 7.24 (d each, 4H,
3
H, J = 15, 2.2 Hz), 2.89 (m, 2H, CH
), 3.30 (dd, 1H, C H, J = 15, 5.1
), 3.76 (s, 3H, OCH ), 5.10 (dd,
2
Ph),
3
2
3
2
3
1
4
ArH, J = 8.5 Hz), 7.20 – 7.50 (m, 5H, ArH)
1751
7
h
56
54
101 -
C
13
H
17NO
3
66.15
(66.36)
7.0
(7.28)
5.85
(5.95)
1
03
(237.29)
1.21 (d, 3H, CHCH
4.0, 2.2 Hz), 3.05 (dd, 1H, NCHCH, J = 13.3, 3.6 Hz), 3.1
dd, 1H, C H, J = 14.0, 5.1 Hz), 3.47 (dd, 1H, NCHCH, J =
3.3, 8.6 Hz), 3.76 (s, 3H, OCH ), 3.83 (m, 1H, CHOH),
.22 (dd, 1H, C H, J = 5.10, 2.2 Hz), 4.36 (br s, 1H, OH),
.86 and 7.24 (d each, 4H, ArH, J = 8.5 Hz )
1751
1.22 (d, 3H, CHCH
4.9, 4.4 Hz), 2.82 (dd, 1H, NCHCH, J = 13.3 3.6 Hz),
.16 (dd, 1H, C H, J = 14.9, 4.4 Hz), 3.22 (dd, 1H,
NCHCH, J = 13.3, 8.6 Hz), 3.95 (m, 1H, CHOH), 4.15 (m,
H, C H), 4.36 (br s, 1H, OH), 6.46 (dd, 1H, >CH-CH=, J
15.3, 7.6 Hz), 6.58 (d, 1H, =CHPh, J = 15.3 Hz ),
.16 – 7.27 (m, 5H, ArH)
1751
1.27 (t, 3H, CH
Hz), 3.34 (dd, 1H, C
OCH ), 4.16 (q, 2H, CH
.6, 2.6 Hz), 6.88 and 7.32 (d, 4H, ArH, J = 9.40 Hz)
1753
2.88 (dd, 1H, C
J = 15.2, 5.7 Hz), 3.72 (s, 3H, OCH
3 3
, J = 6.60 Hz), 2.52 (dd, 1H, C H, J =
1
(
3
1
3
4
4
6
7
i
77 - 79
C
14
H
17NO
2
72.60
(72.70)
7.21
(7.41)
6.26
(6.06)
(
231.29)
3 3
, J = 6.7 Hz), 2.76 (dd, 1H, C H, J =
1
3
3
1
4
=
7
7
j
58
59
72 - 74
81 - 83
C
13
H
15NO
4
62.44
(62.64)
6.27
(6.07)
5.82
(5.62)
(
249.26)
2
CH
3
), 3.04 (dd, 1H, C
H, J = 14.6, 4.6 Hz), 3.73 (s, 3H,
CH ), 4.68 (dd, 1H, C H, J =
3
H, J = 14.6, 2.6
3
3
2
3
4
4
7
k
C
16
H
15NO
2
75.69
(75.87)
5.81
(5.97)
5.41
(5.53)
(
253.29)
3
H, J = 15.2, 2.7 Hz), 3.55 (dd, 1H, C
), 4.99 (dd, 1H, C
3
H,
H,
3
4
J = 2.7, 5.7 Hz), 6.93 and 7.16 (d each, 4H, ArH, J = 9.4
Hz), 7.28 – 7.41 (m, 5H, ArH)

1
126
S. Kanwar and S. D. Sharma
Vol 44
Table 3
Characterization data of 3-Methyl-2-Azetidinones prepared
Molecular
Analytical data
Found (calculated) (%)
Spectral Data
IR (NaCl plates, ꢀ, cm )
H NMR (60 MHz, CDCl , ꢁ, ppm)
Yield
%)
mp
(°c)
formula
(molecular
weight)
-1
Compd.
(
1
3
C
H
N
8
a
62
61
59
99-
C
16
H
(237)
15NO
79.89
(81.01)
6.13
(6.33)
5.89
(5.91)
1
1
748
.25 (d, 3H, CH
H, J = 2 Hz), 6.95-7.45 (m, 10H, ArH)
1
00
3
3
, J = 7.2 Hz), 3.21 (m, 1H, C H), 4.30
(d, 1H, C
4
8
b
130-
35
C
17
H
15NO
3
3
72.38
(72.60)
5.22
(5.34)
4.87
(4.98)
1750
1
(281)
1.32 (d, 3H, CH
d, 1H, C H, J = 2.1 Hz), 6.01 (s, 2H, OCH
.12 (m, 8H, ArH)
1750
1.30 (d, 3H, CH
s, 3H, OCH ), 3.82 (s, 3H, OCH
3
3
, J = 6.5 Hz), 3.35 (m, 1H, C H), 4.42
(
7
4
2
O), 6.69-
8
c
122-
24
C
18
H
19NO
72.51
(72.73)
6.28
(6.39)
4.69
(4.71)
1
(297)
3
, J = 7.0 Hz), 3.30 (m, 1H, C
3
H), 3.75
H,
(
3
3
), 4.51 (d, 1H, C
4
J = 2.2 Hz), 6.63-7.30 (m, 8H, ArH)
8
d
58
60
110-
12
C
17
H
(267)
17NO
2
2
76.38
(76.40)
6.35
(6.37)
5.11
(5.24)
1755
1
1.39 (d, 3H, CH
3
, J = 6.5 Hz), 3.21 (m, 1H, C
), 4.50 (d, 1H, C H, J = 2.3 Hz), 7.00-7.60
m, 9H, ArH)
3
H), 3.75
(
(
s, 3H, OCH
3
4
8
e
101-
04
C
19
H
19NO
77.58
(77.79)
6.42
(6.53)
4.82
(4.77)
1750
1
(293.36)
1.17 (d, 3H, CHCH
3
, J = 7.42 Hz), 3.16 (m, 1H, C
), 4.88 (dd, 1H, C H, J = 2.3, 8.3
Hz), 6.46 (dd, 1H, >C-CH=, J = 8.3, 16.0 Hz), 6.57 (d,
H, =CHPh, J = 16.0 Hz), 6.82 & 7.26 (d each, 4H,
3
H),
3
.77 (s, 3H, OCH
3
4
1
ArH, J = 9.40 Hz), 7.19–7.35 (m, 5H, ArH)
1754
8
f
57
61
112-
14
C
18
H
17NO
4
69.27
(69.44)
5.35
(5.50)
4.31
(4.50)
1
(311.33)
1.04 (d, 3H, CHCH
.76 (s, 3H, OCH ), 4.95 (d, 1H, C
and 6.95 (d each, 4H, ArH, J = 8.48 Hz), 7.41 and 8.00
d each, 4H, ArH, J = 8.7 Hz), 12.19 (br s, 1H, COOH)
3
, J = 7.5 Hz), 3.32 (m, 1H, C
3
H),
3
3
4
H, J = 2.3 Hz), 6.90
(
8
g
89 -
C
19
H
21NO
2
77.11
7.29
4.53
1752
9
1
(295.38)
(77.26)
(7.17)
(4.74)
3 2
1.01 (d, 3H, CHCH , J = 7.5 Hz), 2.89 (t, 2H, CH Ph),
3
.26 (m, 1H, C
NCH), 3.76 (s, 3H, OCH
Hz), 6.92 and 6.99 (d each, 4H, ArH, J = 8.5 Hz), 7.08-
.41 (m, 5H, ArH)
3
H), 3.28 (m, 1H, NCH), 3.50 (m, 1H,
3
), 4.13 (d, 1H, C H, J = 2.3
4
7
8
h
56
95 -97
C
14
H
19NO
3
67.27
7.51
5.50
1755
(
249.31)
(67.45)
(7.68)
(5.62)
3
1.04 (d, 3H, CHCH , J = 7.5 Hz), 1.22 (d, 3H,
HC(OH)CH
3.3 and 3.6 Hz), 3.10 (m, 1H, C
NHCH, J = 13.3 and 8.6 Hz), 3.76 (s, 3H, OCH
dd, 1H, CHOH, J = 8.6 and 3.6 Hz), 4.10 (d, 1H, C
J = 2.1 Hz), 4.36 (br s, 1H, OH), 6.91 and 6.99 (d each,
H, ArH, J = 8.5 Hz)
3
, J = 6.6 Hz), 3.03 (dd, 1H, NHCH, J =
H), 3.45 (dd, 1H,
), 4.00
H,
1
3
3
(
4
4
8
i
57
107 -
08
C
15
H
19NO
2
73.30
(73.44)
7.60
(7.81)
5.61
(5.71)
1750
1
(245.32)
3
1.13 (d, 3H, CHCH , J = 7.4 Hz), 1.25 (d, 3H,
HC(OH)CH
3.3 and 3.6 Hz), 3.14 (m, 1H, C
NHCH, J = 13.3 and 8.6 Hz), 4.00 (dd, 1H, CHOH, J =
.6 and 3.6 Hz), 4.36 (br s, 1H, OH), 4.42 (dd, 1H,
H, J = 8.3 and 2.3 Hz), 6.49 (d, 1H, =CHPh, J =
3
, J = 6.6 Hz), 2.98 (dd, 1H, NHCH, J =
1
3
H), 3.38 (dd, 1H,
8
C
4
1
7
6.0 Hz), 6.56 (dd, 1H, CHCH=, J = 16.0 and 8.3 Hz),
.16–7.35 (m, 5H, ArH)
8
j
60
58
125 -
27
C
14
H
17NO
4
63.61
(63.87)
6.40
(6.51)
5.11
(5.32)
1751
1.26 (t, 3H, CH
1
(263.29)
2
CH
3
), 1.31 (d, 3H, HCCH
), 3.70 (s, 1H, OCH
), 4.59 (d, 1H, C H, J = 2.3 Hz), 6.85
3
, J = 7.5
Hz), 3.54 (m, 1H, CHCH
q, 1H, CH CH
3
3
), 4.15
(
2
3
4
and 7.33 (d each, 4H, ArH, J = 9.4 Hz)
1754
8
k
130 -
32
C
17
H
17NO
2
76.18
(76.38)
6.20
(6.41)
5.01
(5.24)
1
(267.32)
1.04 (d, 3H, CHCH
HCCH ), 3.70 (s, 1H, OCH
.25 Hz), 6.89 and 7.16 (d each, 4H, ArH, J = 9.4 Hz),
.95–7.32 (m, 5H, ArH)
3
, J = 7.5 Hz), 3.38 (m, 1H,
3
3
), 4.82 (d, 1H, C H, J =
4
2
6

Sep-Oct 2007
3-Phenylthio ꢀ-Lactams as Lead Molecules for 3- alkyl-2-azetidinones
1127
chloride. Compound 4b was then treated with the
potassium salt of thiophenoxy acetic acid 5b and triethyl-
amine followed by POCl and PhSO Cl to yield 6b in 72
Finally, these trans ꢀ-lactam compounds can be further
elaborated according to the known methodology to give
the corresponding trans PS-5 and trans PS-6 precursors. It
is interesting to note that this procedure only leads to
trans isomers. Therefore, it appears to be superior to the
earlier route in terms of overall yield and stereocontrol.
This synthesis of trans 3-alkyl-2-azetidinones, alongside
previous known routes, represents a useful application of
the [2+2] cycloaddition reaction and illustrates the value
of phosphrous oxychloride and benzenesulfonyl chloride
as efficient and readily available reagents.
3
2
%
yield. Treatment of 6b with Raney nickel in refluxing
acetone resulted in desulfurization yielding the expected
-unsubstituted product 7b in 59% yield. Compound 7b
3
could also be obtained in high yield from 6b when treated
with a slight excess of tributyltin hydride with azoisobuty-
ronitrile (AIBN) catalyst [29] in refluxing toluene for 3
hours, to efficiently produce 7b in 80% yield. Although
both methods were successful, the first one proved to be
more convenient and less expensive. Finally, methylation
of 3-unsubstituted ꢀ-lactam 7b using methyl iodide
yielded the corresponding trans 3-methyl ꢀ-lactam 8b in
EXPERIMENTAL
6
1% yield.
All melting points (mp, °C) are uncorrected. The FT-IR
spectra were calibrated against polystyrene. Only the principal
We would like to describe here another very interesting
reaction of the ꢀ-lactam enolate 10 with the Schiff base 4e
in a manner similar to an ester enolate-imine condensation
in the hope of getting a new ꢀ-lactam structure. Below is
given the probable two-step course of the reaction, which
can lead to the product 12 or the desired 3-alkylated ꢀ-
lactam 13 via 11 (Scheme 3).
-1
1
peaks of interest are reported and expressed in cm . H NMR
chemical shifts are expressed as ꢁ values (ppm) downfield from
tetramethylsilane (TMS). Thin layer chromatography was
performed using TLC grade silica gel (G) and was developed in
an atmosphere of iodine vapors. The characterization data are
given in Table 1-3.
H
H
(
(CH ) CH) NH
3 2 2
H
C H
6 5
Ph
Ph
n-BuLi
C
N
+
N
N
O
C H OCH -p
O
C H OCH -p
C H OCH -p
6 4 3
6
4
3
6
4
3
7
k
10
4e
H
H
C H
6
5
C H
6
5
-
p-H COC H N
3
6
4
N
O
C H OCH -p
6 4 3
1
1
H+
a
b
H
O
H
H
O
H
H
H
C H
C H
6
6
5
C H
6 5
5
C H
4
6
5
4
NHC H OCH -p
p-H COC H HN
6
4
3
3
6 4
N
N
p-H COC H
6 4
C H OCH -p
3
6
4
3
13
1
2
Scheme 3
Compound 12 could not be obtained in pure form and
General Procedure for the Formation of 3-Phenyl
sulfanyl-2-azetidinones 6. Phosphorous oxychloride or
benzenesulfonyl chloride (0.1 mmol) in dry dichloromethane (6
mL) was added dropwise to a well stirred solution of potassium
salt of thiophenoxyacetic acid (0.12 mmol), appropriate Schiff
base (0.1 mmol) and triethylamine (0.2 mmol) in dry
dichloromethane (10 mL) at 0-5 °C and the reaction mixture was
then stirred overnight at 25 – 30 °C. The mixture was washed
with dilute hydrochloric acid (10 mL), followed by brine (10
mL) and water (10 mL). The organic layer was dried over
therefore a tentative assignment had to be gleaned from
1
the crude product. The FT-IR and H NMR data
1
undoubtly confirmed the product to be 12. H NMR
showed the C - 4 proton as doublet with J = 2 Hz,
indicating the trans orientation of ꢀ-lactam protons. In the
alternative structure 13 this proton should have shown a
double doublet due to coupling with adjacent C - 3 and
cinnamyl proton.

1
128
S. Kanwar and S. D. Sharma
Vol 44
anhydrous sodium sulfate and the solvent removed under
vacuum to obtain the final 2-azetidinones which were purified
by recrystallization from suitable solvents or through column
chromatography using 15% ethyl acetate in hexane as eluent.
Preparation of Raney Nickel Catalyst. To an aqueous
solution of sodium hydroxide (0.1 M; 2 mL), 0.6 g of Ni-Al alloy
was added in fractions maintaining the temperature up to 20 °C
and the contents digested for 1 h at 60 °C, cooled and allowed to
settle. The water was decanted off and the residue washed several
times with water. It was filtered through G-4 sintered glass
crucible and finally washed with alcohol (5 mL ꢀ 3) to drain off
the moisture and used instantly for desulfurization reactions.
General Procedure for Desulfurization of 3-Phenylthio 2-
azetidinones 7. Using Raney Nickel: A solution of appropriate
phenylthio 2-azetidinone (0.1 mmol) in acetone (10 mL) was
stirred and heated under reflux for 3 h with four teaspoons of
Raney nickel catalyst. The catalyst was filtered and washed with
acetone (2 mL). Removal of solvent from the filtrate afforded
was quenched with saturated ammonium chloride solution (8
mL) and extracted with ether (10 mL). The organic layer was
separated, washed with water (5 mL) and brine (5 mL). The
-1
solvent was removed to afford crude 12. FT-IR (CHCl , ꢀ, cm ):
3
1
3
3
3
=
200, 1748, and 1630. H NMR (300 MHz, CDCl , ꢁ, ppm):
3
.23 (dd, 1H, NHCH, J = 7, 6 Hz), 3.75 (s, 3H, OCH ), 3.81 (s,
3
H, OCH ), 4.32 (dd, 1H, C H, J = 7, 2 Hz), 4.95 (d, 1H, C H, J
3
3
4
2 Hz), 6.25 (dd, 1H, CHCHC H , J = 14, 6 Hz), 6.73 (d, 1H,
6
5
CHC H , J = 14 Hz), 6.95-7.52 (m, 18H, ArH).
6
5
Acknowledgement. The authors are grateful to CSIR (New
Delhi, India) for financial assistance.
REFERENCES
[1] Wilmouth, R. C.; Kassamally, S.; Westwood, N. J.;
Sheppard, R. S.; Claridge, T. D. W.; Aplin, R. T.; Wright, P. A.;
Pritchard, G. J.; Schofield, C. J. Biochemistry 1999, 38, 7989.
[2] Yoakim, C.; Ogitive, W. W.; Cameron, D. R.; Chabot, C.;
the final compound as
a thick oily liquid, which was
Guse, I.; Hache, B.; Naud, J.; O’Meara, J. A.; Plante, R.; Deziel, R. J. Med.
Chem. 1998, 41, 2882.
chromatographed over neutral alumina using petroleum ether as
eluent and was then crystallized from n-hexane.
[3] Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Federici, M. E.;
Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem. 1995, 3, 1123.
Using Bu SnH/AIBN: To
a solution of phenylthio-2-
3
[4] Talbot, M. D.; Butler, K. D. Drugs News Perspect. 1992, 3,
azetidinone (5.96 mmol) in THF (30 mL) under nitrogen
3
57.
atmosphere was added Bu SnH (3.0 mL; 11.15 mmol; 1.9
3
[5] Qian, X.; Zheng, B.; Burke, B.; Saindane, M. T.; Kronental,
equiv.). The reaction mixture was heated to reflux to get a clear
homogenous solution. The reaction mixture was then cooled
slightly and AIBN (300 mg) was added. The mixture as then
cooled to 25 °C and concentrated to give a residue. The residue
was purified by silica gel column chromatography (Silica gel 60,
D. R. J. Org. Chem. 2002, 67, 3595.
[
[
[
6] Mukerjee, K.; Singh, A. K. Tetrahedron, 1978, 34, 1731.
7] Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
8] Bose, K.; Anjaneyulu, B.; Bhattacharya, S. K.; Manhas, M.
S. Tetrahedron 1967, 23, 4769.
2
30 – 400 mesh, using ethyl acetate/hexane as eluent) or by
[9] Bose, K.; Chiang, Y. H.; Manhas, M. S. Tetrahedron Lett.
1972, 4091.
hexane trituration to afford final product 7.
General Procedure for the Preparation of 3-Methyl-2-
azetidinone 8. To diisopropylamine (0.18 mmol) in dry THF (9
mL) under nitrogen atmosphere was added n-BuLi in hexane
[10] Arrieta, R.; Lecea, B.; Palomo, C. J. Chem. Soc., Perkin
Trans. 1 1987, 845.
[
11] Williams, D. R.; Donnell, A. F.; Kammler, D. C.
Heterocycles 2004, 62, 167.
12] Cossio, F. P.; Odriozola, J. M.; Oiarbide, M.; Palomo, C. J.
Chem. Soc. Chem. Commun. 1989, 74.
(0.18 mmol, 0.5 N) at –78 °C and the solution was stirred for 15
[
min. This was followed by the addition of the 3-unsubstituted-2-
azetidinone (0.15 mmol) in THF (9 mL) at such a rate that the
temperature did not exceed –60 °C. The solution was stirred at
the same temperature for 50 min followed by the addition of the
methyl iodide (0.20 mmol) in THF (5 mL). The mixture was
stirred at –78 °C for 1 h, the cold bath was removed and the
mixture was warmed to 25 – 30 °C and was stirred for additional
[
13] Isaacs, N. S. Chem. Soc. Rev. 1976, 76, 181.
[14] McCarney, C. C.; Ward, R. S. J. Chem. Soc.; Perkin Trans.
1
975, 1600.
[15] Shaken, M.; Fuentes, L. M.; Lynch, J. L.; Laswell, W. L.;
Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 29, 2779.
[16] Bose, K.; Manhas, M. S.; Chib, J. S.; Chawla, H. P. S.;
Dayal, B. J. Org. Chem. 1974, 39, 2877.
1
4-16 h. The reaction progress was monitored by TLC. The
[17] Sharma, S. D.; Kaur, V.; Saluja, A. Indian J. Chem. 1994,
reaction mixture was quenched with saturated ammonium
chloride solution (6 mL) and extracted with ether (15 mL). The
organic layer was separated, washed with water (7 mL) and
brine (7 mL). The solvent was removed to afford the crude
product that was purified by chromatography using light
petroleum ether:ethyl acetate (4:1) to obtain pure 3-methyl 2-
azetidinone.
3
3B, 624.
[18] Bari, S. S.; Sharma, A. K.; Sethi, M. K. Indian J. Chem.
1
988, 37B, 1114.
[19] Minami, T.; Ishida, M.; Agawa, T. J. Chem. Soc. Chem.
Commun. 1978, 12.
[20] Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T. –K. J. Org. Chem.
1983, 48, 289.
Reaction of 3-Unsubstituted-2-Azetidinone 7k with Schiff
Base 4e. To diisopropylamine (0.18 mmol) in dry THF (5 mL)
under nitrogen atmosphere was added n-BuLi in hexane (0.18
mmol, 0.5 N) at –78 °C and the solution was stirred for 15 min.
This was followed by the addition of the 3-unsubstituted-2-
azetdidinone (0.15 mmol) in THF (5 mL) at such a rate that the
temperature did not exceed –60 °C. The solution was stirred at
the same temperature for 50 min followed by the addition of the
Schiff base (0.20 mmol) in THF (5 mL). The mixture was stirred
at –78 °C for 1 h, the cold bath was removed and the mixture
was warmed to 25 – 30 °C and stirred for additional 48 h. The
reaction progress was monitored by TLC. The reaction mixture
[21] Ha, D. C.; Hart, D. J.; Yang, T. -K. J. Am. Chem. Soc. 1984,
106, 4819.
22] Ogilvie, W. W.; Durst, T. Can. J. Chem. 1988, 66, 304.
23] Wolf, S.; Hasan, S. K. Chem Commun. 1970, 833.
24] Wild, H. The Organic Chemistry of ꢂ-Lactam, Georg, G. I.
[
[
[
Ed, VCH, New York, 1992, pp 53-64.
[25] O’Donnell, M. J.; Bennett, W. D. Tetrahedron 1988, 44, 389.
[26] Bellettini, J. R.; Miller, M. J. J. Org. Chem. 1996, 61, 7959.
[27] Teng, M.; Miller, M. J. J. Am. Chem. Soc. 1993, 115, 548.
[28] Madan, S.; Arora, R.; Venugopalan, P.; Bari, S. S. Tetrahedron
Lett. 2000, 41, 5577.
[29] Gutierrez, C. G.; Summernays, L. R. J. Org. Chem. 1984, 49,
5206.