Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-β-lactams and their C–3 functionalization

Article abstract of DOI:10.1016/j.tet.2019.07.001

A stereoselective synthesis and C–3 functionalization of a long series of novel hybrid 4-(thiophenyl)pyrazolyl-β-lactams have been carried out. The divergent substrate scope and mechanistic insights were examined to delineate the generality of reaction that favored trans-β-lactams 4a-q almost exclusively in all cases. The C–3 functionalization was achieved by Lewis acid assisted nucleophilic substitution reaction of cis-3-chloro-β-lactams 6a-e to afford cis-3-monosubstituted-β-lactams 7a-e. The cis stereochemistry of β-lactams 7a-e was further established by stereospecific desulfurization with Raney-nickel, in representative cases (7a,b), leading to the formation of cis-β-lactams 8a,b. The structures and stereochemical assignments for synthesized β-lactams have been unambiguously confirmed using FT-IR, 1D NMR (¹H and ¹³C), 2D NMR (¹H–¹H COSY, ¹H–¹³C HSQC and ¹³C DEPT–135), elemental analysis (CHN), mass spectrometry (ESI-MS) and single crystal X-ray crystallography, in representative cases (4b,e). The cis and trans configuration of the hydrogen/chloro/nucleophile substituent at C–3 was assigned with respect C4–H of the β-lactam ring.

Full text of DOI:10.1016/j.tet.2019.07.001

Accepted Manuscript
Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-
β-lactams and their C–3 functionalization
Preety Saini, S.S. Bari, Subash C. Sahoo, Sadhika Khullar, Sanjay K. Mandal, Aman
Bhalla
PII:
S0040-4020(19)30732-X
https://doi.org/10.1016/j.tet.2019.07.001
TET 30443
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 March 2019
Revised Date: 21 June 2019
Accepted Date: 1 July 2019
Please cite this article as: Saini P, Bari SS, Sahoo SC, Khullar S, Mandal SK, Bhalla A, Stereoselective
synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-β-lactams and their C–3
functionalization, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.07.001.
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Stereoselective synthesis and characterization of novel
trans-4-(thiophenyl)pyrazolyl-β-lactams and their
C–3 functionalization
Leave this area blank for abstract info.
Preety Sainia, S. S. Baria, Subash C. Sahooa, Sadhika Khullarb, Sanjay K. Mandalc, Aman Bhallaa,*
S
S
S
R
N
N
N
N
What affects
the relative
Stereoselectivity ?
N
Stereospecific
"C-3 Functionalization"
NuH
N
H
H
N
N
Stereospecific
H
H
N
N
Z
Z
Nu
Z
"Desulfurization"
+
N
Raney-Ni, Ethanol
Reflux
Solvent
1) NCS, CHCl3, r.t.
2) Nu, Lewis acid, Solvent
O
X
N
O
R
O
R
O
R
S
Steric bulk
cis-β-Lactams
cis-β-Lactams
trans-β-Lactams
Temperature
X = -OH, -Cl
OCH3
Z = -Cl, -OCOCH3, -OCH3, -OC6H5, -SC6H5, -SCH2C6H5, -SeCH2C6H5
,
,
O
,
OCH3 H3CO
OCH3
Nu =
,
,
,
Cl
OCH3
CH3
R =

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-
β-lactams and their C–3 functionalization
Preety Sainia, S. S. Baria, Subash C. Sahooa, Sadhika Khullarb, Sanjay K. Mandalc, Aman Bhallaa,
aDepartment of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India
bDepartment of Chemistry, Dr. B. R. Ambedkar National Institute of Technology, Jalandhar 144011, Punjab, India
cDepartment of Chemical Sciences, Indian Institute of Science Education and Research, Sector 81, S.A.S. Nagar, Mohali 140306, Punjab, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A stereoselective synthesis and C–3 functionalization of a long series of novel hybrid 4-
(thiophenyl)pyrazolyl-β-lactams have been carried out. The divergent substrate scope and
mechanistic insights were examined to delineate the generality of reaction that favored trans-β-
lactams 4a-q almost exclusively in all cases. The C–3 functionalization was achieved by Lewis
acid assisted nucleophilic substitution reaction of cis-3-chloro-β-lactams 6a-e to afford cis-3-
monosubstituted-β-lactams 7a-e. The cis stereochemistry of β-lactams 7a-e was further
established by stereospecific desulfurization with Raney-nickel, in representative cases (7a,b),
leading to the formation of cis-β-lactams 8a,b. The structures and stereochemical assignments
for synthesized β-lactams have been unambiguously confirmed using FT-IR, 1D NMR (1H and
Available online
Keywords:
β-Lactams
1
13C), 2D NMR (1H–1H COSY, H–13C HSQC and 13C DEPT–135), elemental analysis (CHN),
Stereoselective
(Thiophenyl)pyrazolyl
C–3 Functionalization
mass spectrometry (ESI-MS) and single crystal X-ray crystallography, in representative cases
(4b,e). The cis and trans configuration of the hydrogen/chloro/nucleophile substituent at C–3
was assigned with respect C4–H of the β-lactam ring.
2009 Elsevier Ltd. All rights reserved
.
with phenyl, pyrazole and pyrimidine and many more15 have
been diarized, addressing great emphasis on their synthesis,
spectroscopic proofs, X-ray diffraction studies and biological
evaluation. Distinguishably, thiophene shows bioisosterism to
benzene ring and, therefore, is an interesting template as
replacement of choice to mimic the analogues of previously
synthesized benzene derivatives.16
1. Introduction
β-Lactams, 4-membered ring aza-heterocycles, are valuable
due to their synthetic utility as building blocks in organic
chemistry and versatile applications in medicinal field.1,2 The
reactivity of β-lactams strongly swivel around peripheral
substitution pattern, and the substituents at C–3 and C–4 are
crucial for the stereocontrolled outcome.3 The task of ensuring
selectivity in this 4-membered strained aza-heterocycle is by far
more troublesome. So far, the existing approaches to monocyclic
β-lactams have mainly careened on the Staudinger cycloaddition,
where the use of hindered substrates (ketene/imine) offer
increased/improved diastereoselectivity.4 Notwithstanding that
these cycloadditions are known over a century, its mechanism is
still under investigation as it sometimes leads to an unpredictable
output.
HO
O
HO
O
H
N
H
N
OCH3
N
CH3
CH3
S
S
O
O
S
S
N
CH3
OH
CH3
OH
O
O
I
II
O
O
H
N
H
N
S
S
NO2
S
S
O
O
S
O
N
O
O
N
CH3
N
O
O
O
OH
O
OH
3S
NO2
For a practical method aimed at improving the biological
potentials of β-lactams, the functionalization5 is pivotal that
involves the linking of two or more biologically active
heterocycles either via direct covalent linkage of various
heterocycles or using a linker (aryl/heteroaryl).6-9 In this context,
quite recently, the groups of Zigheimat,10 Mortazavi11 and
Jorrahpour12 have independently documented the stereoselective
formation of heterocyclic hybrids of trans-β-lactams. Recently,
novel functionalized thiophenes13 as organic functionals, most
III
IV
H
N
H
N
OCH
N
S
S
O
N
O
O
NH2
O
O
O
O
O
OH
V
VI
Figure 1. Biologically active thiophene anchored β-lactams I-VI.
The importance of thiophene ring in relation to β-lactam can
be traced from its obligatory presence, in the appended C–3 side
commonly of carbonyl compounds,14 and hybrids (fused/isolated)
———
Corresponding author. Tel.: +91-172-253-4417; fax: +91-172-254-5074; e-mail: amanbhalla@pu.ac.in (A. Bhalla)

2
Tetrahedron
ACCEPTED MANUSCRIPT
chain via amide linker (heteroalkyl), for the antibiotic activity
Schiff’s bases 3a-d were then treated with a broad range of 2-
of established β-lactams, such as, ticarcillin I and temocillin II
(penicillin derivative), cephalothin III, nitrocefin IV,
cephaloridine V and cefoxitine VI (cephalosporin derivatives)
(Fig. 1).17 This seminal work hugely stimulated the chemists into
further extensions of stereodivergent cycloadditions to produce
novel hybrid β-lactams. Our group has been actively involved in
the development of expedient methodologies to expand β-lactam
armamentarium 4-pyrazolyl spirocyclic-β-lactams,18a 3-allylidene
-β-lactams,18b chiral 3-acetoxy/methoxy/phthalimido-β-lactams18c
and functionalized 3-sulfonyl-β-lactams.18d
Therefore, in continuation to our research interest and further
encouraged by the diffuse applications of thiophenes19 and
pyrazoles,20 herein we intrigue to expose the stereochemical
outcome of Staudinger cycloaddition reaction by selecting
thiophene as the component of choice for the appended C–4 side
chain of β-lactams using pyrazole as heteroaryl linker. Moreover,
these β-lactams were subjected to Lewis acid mediated
functionalization to furnish C–3 mono/disubstituted β-lactams.
The stereochemistry of these C–3 monosubstituted β-lactams was
established through their stereospecific reductive desulfurization
with Raney-nickel, in representative cases. DFT calculation
uncovered that the favorable selectivity was originated mainly
due to presence of appended C–4 (thiophenyl)pyrazolyl moiety in
the β-lactam structure.
substituted ethanoic acids/acid chlorides using Et3N or
POCl3/Et3N to access novel trans- and/or cis-β-lactams 4 and/or
5 (Scheme 2). The initial reaction was carried out by the
dropwise addition of 2-chloroethanoyl chloride in dry methylene
chloride to a stirred solution of N-[(1ʹ-phenyl-3ʹ-(thiophen-2ʹʹ-yl)-
1H-pyrazol-4ʹ-yl)methylene]-4-methoxybenzenamine 3a and
triethylamine in dry methylene chloride at 0 ºC. However, the
reaction failed to afford the target β-lactam (Table 2, entry 1).
Thereafter, performing this reaction in refluxing chloroform
(CHCl3), tetrahydrofuran (THF), 1,4-dioxane and toluene
furnished the exclusive formation of trans-β-lactam 4a in
excellent yields (67-94%) (Table 2, entries 2-5). Delightfully,
toluene was found to be the most promising solvent and the
substrate scope was illustrated to deliver a series of 4-
(thiophenyl)pyrazolyl-β-lactams 4a-q in excellent yields (Table
2). The reaction was found to be stereospecific, giving trans
isomer in all cases.
General Bose-Evans rule22 suggests that ketenes having O-
alkyl and O-aryl groups bear cis stereoselectivity. To get a deeper
insight, the reaction of 2-phenoxyethanoic acid with 3a was
performed in dry methylene chloride (at 0 °C)/toluene (under
refluxing condition). Surprisingly, no product was formed in dry
methylene chloride (Table 2, entry 17). However, exclusive
formation of trans-β-lactam 4m occurred in refluxing toluene
(Table 2, entry 18). Further, the reaction of 2-acetoxyethanoyl
chloride yielded only cis-3-acetoxy-β-lactam 5n in dry methylene
chloride (Table 2, entry 19) and trans-3-acetoxy-β-lactams 4n,o
in refluxing toluene (Table 2, entries 20 and 21).
On the other hand, 2-methoxyethanoic acid afforded the
diastereomeric mixture of trans- and cis-3-methoxy-β-lactams
i.e. 4p and 5p, respectively in dry methylene chloride, albeit in
lower yields (Table 2, entry 22) and exclusively trans-3-
methoxy-β-lactams 4p,q in refluxing toluene (Table 2, entries 23
and 24).
All the synthesized β-lactams were quantitatively recovered
indicating their high thermal stability and were purified by
column chromatography (EtOAc–n-hexane). Their structures
were established using FT-IR, NMR (1H, 13C, 1H–1H COSY, 1H–
13C HSQC and 13C DEPT–135), elemental analysis (CHN) and
mass spectrometry (ESI-MS), in representative cases. The spatial
juxtaposition of the C3–H and C4–H was assigned trans in
products 4a-q and cis in products 5n,p on the basis of coupling
2. Results and discussion
2.1 Synthesis and mechanistic aspects for trans- and cis-4-
(thiophenyl)pyrazolyl-β-lactams (4 and 5)
The study commenced with the initial preparation of 1-phenyl
-3-(1ʹ-thiophen-2ʹ-yl)-1H-pyrazole-4-carbaldehyde 2 from 1-[1ʹ-
(thiophen-2ʹʹ-yl)ethylidene]-2-phenylhydrazine 1 by following
reported method21 with slight modifications (temperature: 60 °C
and the precipitates of 2 appeared directly by pouring into ice
cold distilled water) (Scheme 1). The isolated carbaldehyde 2
was reacted with selected aromatic amines to deliver (thiophenyl)
pyrazole substituted Schiff’s bases 3a-d in good yields (Table 1)
and were characterized by FT-IR, NMR (1H and 13C)
spectroscopy and elemental analysis (CHN).
CH3
H
H
N
CH3
O
N
.
HCl CH3COONa (anhy.)
EtOH, Reflux
NH2
N
+
S
S
1
constant values of C3–H and C4–H protons in the respective H
Phenylhydrazine
hydrochloride
1
2-Acetylthiophene
NMR spectra. In general, all these β-lactams 4a-q and 5n,p were
air and moisture stable and soluble in solvents such as methylene
chloride, chloroform, acetone, toluene and ethyl acetate. Most of
the compounds were obtained as stable solids (4a-e,h,m-p),
except a few (4f,g,i-l,q and 5n,p) as semi-solids or viscous oils.
The crystal structure of representative β-lactams 4b23 (Fig. 2)
and 4e24 (Fig. 3) depicted the trans-stereochemical assignment at
C–3 and C–4 stereocenters. Further, it showed that no classical
hydrogen bond is present despite the presence of heteroatoms and
established the cis form of thiophene with respect to pyrazole
ring in the novel synthesized β-lactams 4/5.
POCl3, DMF
60 o
C
R
N
O
H
o
N
N
N
R
NH2, MS (4 A)
N
CH2Cl2, r.t.
S
S
3a-d
2
,
,
,
Cl
OCH3
CH3
R =
Scheme 1. Synthesis of (thiophenyl)pyrazole substituted Schiff’s bases 3a-d.
On the basis of preliminary results (Table 2) together with the
previous related literature,22 a reasonable mechanism for the
formation of β-lactams 4/5 has been proposed in Supporting
Information. As per general Bose-Evans rule 22 the ketenes with
O-alkyl and O-aryl groups bear cis stereoselectivity. However,
the formation of minor cis diastereomers 5n,p (Table 2, entries
19 and 22) only for O-alkyl groups (Z = -OCOCH3 and -OCH3),
and not for O-aryl groups (Z = -OC6H5), implies that this reaction
does not follow this rule strictly. Therefore, the mechanistic
aspects were further investigated by density functional theory
(DFT)25,26 (see the Supporting Information).
Table 1
Synthesis of (thiophenyl)pyrazole substituted Schiff’s bases 3a-d.
Entry
1
R
Product 3
Yielda (%)
85
OCH3
CH3
Cl
3a
2
3
4
3b
3c
3d
82
87
79
a Yield of pure, isolated product with correct analytical and spectral data.

3
R
ACCEPTED MANUSCRIPT
N
S
S
N
N
POCl3, Et3N
H H
N
N
H H
or
Et3N
Z
Z
N
Z
N
and/or
+
S
Toluene, Reflux
N
N
O
X
O
R
O
R
2-Substituted ethanoic acid
or acid chloride
5n,p
3a-d
4a-q
cis-β-Lactams
trans-β-Lactams
X = -OH, -Cl
Z = -Cl, -OCOCH3, -OCH3, -OC6H5, -SC6H5, S-CH2C6H5, -SeCH2C6H5
,
,
,
Cl
OCH3
CH3
R =
Scheme 2. Synthesis of trans- and/or cis-4-(thiophenyl)pyrazolyl-β-lactams 4a-q and/or 5n,p.
Table 2
Synthesis of trans- and cis-4-(thiophenyl)pyrazolyl-β-lactams 4a-q and 5n,p.
Products of type (yield %)a
Entry
1
Z
X
Substrate 3
R
Solvent
CH2Cl2
trans-β-Lactams 4 cis-β-Lactams 5
Temperature (°C)
Cl
-Cl
3a
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
0 to rt
–
–
2
Cl
-Cl
3a
3a
3a
3a
3b
3c
3d
3a
3b
3c
3d
3a
3c
3a
3c
3a
3a
3a
3a
3b
3a
3a
3b
CHCl3
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
0 to rt
4a (67)
4a (72)
4a (91)
4a (94)
4bb (91)
4c (93)
4d (89)
4ec(92)
4f (90)
4g (87)
4h (89)
4i (91)
4j (81)
4k (88)
4l (78)
–
–
3
Cl
-Cl
THF
–
4
Cl
-Cl
1,4-Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
Toluene
CH2Cl2
Toluene
Toluene
–
5
-Cl
-Cl
–
6
-Cl
-Cl
–
7
-Cl
-Cl
Cl
–
8
-Cl
-Cl
–
9
-SC6H5
-SC6H5
-SC6H5
-SC6H5
-SCH2C6H5
-SCH2C6H5
-SeCH2C6H5
-SeCH2C6H5
-OC6H5
-OC6H5
-OCOCH3
-OCOCH3
-OCOCH3
-OCH3
-OCH3
-OCH3
-OH
-OH
-OH
-OH
-OH
-OH
-OH
-OH
-OH
-OH
-Cl
OCH3
CH3
Cl
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
–
–
–
OCH3
Cl
–
–
OCH3
Cl
–
–
OCH3
OCH3
OCH3
OCH3
CH3
–
Reflux
0 to rt
4m (92)
–
–
5n (25)
-Cl
Reflux
Reflux
0 to rt
4n (89)
4o (71)
4p (26)
4p (84)
4q (73)
–
-Cl
–
-OH
-OH
-OH
OCH3
OCH3
CH3
5p (23)
Reflux
Reflux
–
–
a Yields of pure, isolated product with correct analytical and spectral data.
b Structure established on the basis of X-ray crystallographic study.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Figure 2. (a) ORTEP diagram for 4b23,30 (b) crystal packing diagram with intermolecular interactions for 4b.23,30
Figure 3. ORTEP diagram for 4e.24,30
2.2 C–3 Functionalization of trans-3-phenyl/benzylthio-4-
(thiophenyl)pyrazolyl-β-lactams (4e-i)
phenylthio-4-(thiophenyl)pyrazolyl-β-lactams 6a,d,e were treated
with aromatic nucleophiles (Table 3, entries 6-9) in the presence
of catalytic amount of Stannic chloride (SnCl4) acting as a Lewis
acid in dry methylene chloride at 0 to -5 °C under nitrogen
atmosphere to deliver C–3 monosubstituted products 7a-d (Table
3, entries 6-9) in all cases. The structures of 7a-d were certified
by FT-IR, NMR (1H and 13C), mass spectrometry (ESI-MS) and
elemental analysis (CHN). The spatial relationship of the C4–H
and the new substituent at C–3 in 7a-d was tentatively assigned
cis keeping in view the single crystal X-ray crystallographic
analysis of cis-1-phenyl-3-(prop-2ʹ-ynyloxy)-3-benzylthio-4-(5ʹ-
chloro-3ʹ-methyl-1ʹ-phenyl-1H-pyrazol-4ʹ-yl)azetidin-2-one.27
After successfully synthesizing a series of novel cis-3-aryl-4-
(thiophenyl)pyrazolyl-β-lactams 7a-d, an attempt was made to
introduce an alkoxy nucleophile propargyloxy (Table 3, entry 10)
at C–3 position of representative β-lactam, cis-1-(4ʹ-methoxy
phenyl)-3-chloro-3-benzylthio-4-[1ʹ-phenyl-3ʹ-(thiophen-2ʹʹ-yl)-
1H-pyrazol-4ʹ-yl]azetidin-2-one 6e. Therefore, the reaction was
performed by treating 6e with propargyl alcohol in the presence
of catalytic amount of ZnCl2 as a Lewis acid in refluxing
chloroform (Scheme 3) and the product was identified as cis-1-
The C–3 functionalization of trans-3-phenyl/benzylthio-4-
(thiophenyl)pyrazolyl-β-lactams 4e-i was performed (Scheme 3),
where the stereospecific α-chlorination of β-lactams 4e-i was
achieved using N-chlorosuccinimide (NCS) as mild chlorinating
agent in chloroform at room temperature to furnish cis-3-chloro-
3-phenyl/benzylthio-4-(thiophenyl)pyrazolyl-β-lactams
6a-e
(Table 3, entries 1-5). The structures of chloro-β-lactams 6a-e
were certified by FT-IR, NMR (1H and 13C) and elemental
analysis (CHN). The stereochemistry of 3-chloro-3-phenyl/
benzylthio-4-(thiophenyl)pyrazolyl-β-lactams 6a-e was assigned
cis with respect to C–4 proton on the basis of comparison of their
1H and 13C NMR data to that of cis-3-chloro-3-phenylthio-β-
lactams, whose stereochemistry has already been established by
single crystal X-ray crystallographic analysis.27 cis-3-Chloro-3-
phenyl/benzylthio-4-(thiophenyl)pyrazolyl-β-lactams 6a-e act as
the most appropriate electrophilic β-lactam carbocation
equivalents
for
Friedel-Crafts
alkylation
of
active
aromatic/aliphatic substrates in the presence of a Lewis acid to
furnish C3-functionalized β-lactams.28 Therefore, cis-3-chloro-3-

5
S
ACCEPTED MANUSCRIPT
N
N
NuH
R1S
Nu, SnCl4, CH2Cl2
0 to -5 oC
N
S
S
O
R
N
N
7a-d
N
H H
N
Cl H
R1S
R1S
cis-β-Lactams
NCS, CHCl3
r.t.
N
N
S
O
R
O
R
N
4e-i
6a-e
O H
N
R1S
trans-β-Lactams
cis-β-Lactams
O
Nu =
o
N
ZnCl2-SiO2, MS (4A)
CHCl3, Reflux
O
R
7e
R1 = -C6H5, -CH2C6H5
cis-β-Lactam
,
,
,
Cl
OCH3
CH3
R =
OCH3
,
,
OCH3
O
,
OCH3 H3CO
Nu =
Scheme 3. Synthesis of cis-3-chloro-3-phenyl/benzylthio-4-(thiophenyl)pyrazolyl-β-lactams 6a-e and cis-3-alkyloxy/aryl-4-(thiophenyl)pyrazolyl-β-lactams
7a-e.
Table 3
Synthesis of cis-3-chloro-3-phenyl/benzylthio-4-(thiophenyl)pyrazolyl-β-lactams 6a-ea and cis-3-alkyloxy/aryl-4-(thiophenyl)pyrazolyl-β-lactams 7a-e.
Entry
1
Substrate
R1
R
Nu
–
Product
Yielda (%)
72
4e
-C6H5
OCH3
CH3
Cl
6a
2
3
4
5
6
4f
-C6H5
–
–
–
–
6b
6c
6d
6e
7a
67
64
58
54
72
4g
4h
4i
-C6H5
-C6H5
-CH2C6H5
-C6H5
OCH3
OCH3
6a
OCH3
7
8
6a
6a
-C6H5
-C6H5
OCH3
OCH3
7b
7c
68
64
H3CO
OCH3
OCH3
OCH3
9
6d
6e
-C6H5
7d
7e
65
66
10
-CH2C6H5
OCH3
O
a Yield of pure, isolated product with correct analytical and spectral data.
(4ʹ-methoxyphenyl)-3-(prop-2ʹ-ynyloxy)-3-benzylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
A plausible mechanism for the transformation of cis-3-chloro-
3-phenyl/benzylthio-4-(thiophenyl)pyrazolyl-β-lactams 6a-e into
C–3 functionalized 4-(thiophenyl)pyrazolyl-β-lactams 7a-e has
been outlined in Scheme 4.27 The speculation of the spectroscopic
results27,28 and investigation of literature28 suggested that the
reaction involves the formation of carbocation intermediate at C–
3. Therefore, the first step of the mechanism involves the
generation of carbocation intermediate E, which stabilized by
resonance with lone pair of adjacent sulfur to yield another
intermediate F. Subsequent approach of incoming nucleophile to
this carbocation from relatively less hindered side i.e. the side of
hydrogen at C–4, results in the formation of cis-β-lactams 7 via
SN1 mechanism.
7e
(Table 3, entry 10). The spatial juxtaposition of the C–4 proton
and the new substituent at C–3 was tentatively assigned cis
keeping in view the single crystal X-ray crystallographic analysis
of cis-3-monosubstituted-3-benzyllthio-β-lactams.29 Its structure
was confirmed on the basis of spectral (FT-IR, 1D and 2D NMR)
and elemental data (CHN).
For most cases, the present protocol describes the formation
of C–3 monosubstituted β-lactams 7a-e from cis-3-chloro-3-
phenyl/benzylthio-4-(thiophenyl)pyrazolyl-β-lactams, which is
contrasting to our earlier literature reports,27 where the C–3
functionalization cis-3-chloro-3-phenylthio-β-lactams affords the
disubstituted β-lactams. The favorable formation of
monosubstituted product 7a-e can be accounted due to the
presence of bulky (thiophenyl)pyrazolyl group at C–4 position of
β-lactams.

6
Tetrahedron
ACCEPTED MANUSCRIPT
3. Conclusion
S
In conclusion, novel 4-(thiophenyl)pyrazolyl-β-lactams have
N
H
N
N
been successfully synthesized and fully characterized using
different spectroscopic techniques. Gratifyingly, the present
protocol offers the trans selectivity in almost all cases, except a
few where poor cis selectivity was also achieved. The presence of
(thiophenyl)pyrazolyl substituent is the deciding factor for high
trans as well as poor cis stereoselection. Additionally, a
successful attempt has been pursued towards the synthesis of
novel C–3 functionalized 3-phenyl/benzylthio-4-pyrazolyl-β-
lactams via C–3 carbocation equivalent strategy. Both alkyloxy/
aryl nucleophilic substrates react favorably with α-chloro-β-
lactam to give C–3 monosubstituted 3-phenyl/benzylthio-4-
(thiophenyl)pyrazolyl-β-lactams. Also, the stereospecific
reductive desulfurization was performed, for representative
analogues, to assure the stereochemical outcome of the
monosubstituted C–3 functionalized β-lactams. The synthesized
β-lactams have been submitted for molecular docking studies and
studies towards in vitro evaluation for potential biological
activities are ongoing in the laboratory.
S
R1
S
O
R
N
E
N
Cl H
R1S
Lewis acid
N
O
R
S
6
N
cis-β-Lactams
N
H
N
S
R1
O
R
F
S
Nu
N
NuH
N
R1S
O
N
R
7
cis-β-Lactams
4. Experimental
Scheme 4. Plausible reaction pathway for the formation of C–3
functionalized 4-(thiophenyl)pyrazolyl-β-lactams 7.
4.1. General
Melting points were determined in an open capillary on
melting point apparatus (Perfit GSI-MP-3). Fourier transform
infrared spectra were recorded on a Thermo scientific Nicolet
The cis stereochemistry of monosubstituted β-lactams 7a-e
was also established on the basis of their stereospecific
desulfurization with Raney-nickel.27 The representative
iS50 (FT-IR) spectrophotometer (υ
max in cm–1). 1H (300 and 400
MHz), 13C (75 and 100 MHz) NMR spectra were recorded on
JEOL AL 300 (300 MHz) and BRUKER AVANCE II (400
analogues
cis-3-monosubstituted-3-phenylthio-4-(thiophenyl)
pyrazolyl-β-lactams 7a,b were subjected to the Raney-nickel
desulfurization in absolute ethanol to afford cis-β-lactams 8a,b
(Scheme 5, Table 4).
MHz) spectrometer. Chemical shifts are given in ppm relative
1
to Me4Si as an internal standard (
δ
= 0 ppm) for H NMR and
CDCl3 (
δ
= 77.0 ppm) for 13C NMR spectra. The mass spectra
(ESI-MS) were obtained using Water’s Q-TOF Micromass
(YB361) spectrometer. The elemental analyses (CHN) were
recorded on Flash 2000 Organic elemental analyzer. Column
chromatography was performed using Merck Silica Gel (60–
S
S
N
N
NuH
N
H
H
N
N
R1S
Nu
Raney-Ni, Ethanol
Reflux
120 mesh) using EtOAc–n-hexane as an eluant system.
N
O
R
O
R
Analytical thin-layer chromatography (TLC) was performed on
precoated silica gel F254 aluminium plates with visualization
under UV light.
8a,b
7a,b
cis-β-Lactams
cis-β-Lactams
The syntheses and reactions of β-lactams were carried out
under dry and deoxygenated nitrogen atmosphere. Starting
R1
R
Nu
a
b
-C6H5
OCH3
OCH3
CH3
materials
1 and 2 were prepared following the methods
described in literature.21 Phosphorus oxychloride (Merck),
sodium acetate (Qualigen), triethylamine (Qualigen), phenyl
-C6H5
H3CO
OCH3
hydrazine hydrochloride (Hi-media),
N-chlorosuccinimide
Scheme 5. Synthesis of cis-3-aryl-(thiophenyl)pyrazolyl-β-lactams 8a,b.
Table 4
(Fisher Scientific), Nickel on silica-alumina (Avra Synthesis)
and all other commercially available compounds/reagents/
solvents were of reagent grade quality and used without any
Synthesis of cis-3-aryl-(thiophenyl)pyrazolyl-β-lactams 8a,b.
further purification.
N,N-Dimethylformamide was dried and
Yielda (%)
distilled over alumina. Chloroform and methylene chloride
were dried and distilled over anhydrous calcium chloride
(CaCl2) and phosphorus pentoxide (P2O5) while tetrahydrofuran
and toluene were distilled under N2 from sodium-benzophenone
immediately before use. The theoretical calculations were
performed by using Gaussian 03 package and a GaussView
application was utilized to present molecular geometry (MG)
and frontier molecular orbital (FMO).
Entry
Substrate 7
Product 8
1
2
7a
7b
8a
8b
96
94
a Yield of pure, isolated product with correct analytical and spectral data.
Their structural elucidation was carried out by spectroscopy
1
(FT-IR, H and 13C NMR) and elemental analysis (CHN). The
stereochemistry of reduced products 8a,b was found to be cis as
established from the coupling constant value (J = 5.6 Hz) of C–3
and C–4 protons, that corresponds to cis isomer (J > 3.0 Hz). The
formation of cis isomers 8a,b gives an idea that addition of
hydrogen takes place stereospecifically from the side opposite to
the adsorbed sulfide moiety.29
Single crystals of 4b and 4e suitable for X-ray diffraction
studies, were grown from methylene chloride–n-hexane (3:1).
The intensity data were collected at 295 K on a KAPPA APEX
II diffractometer and Supernova Rigaku Oxford Diffraction by
using θ–2θ scanning mode with graphite monochromatized Mo
Kα radiation. The data were collected for Lorentz and
polarization effects but not for absorption. The structures were
solved by direct methods using SIR97 and refined by full

7
matrix least-square refinement techniques on F2 using
127.5, 127.3, 126.8, 126.7, 126.6, 126.0, 119.3, 118.8,
ACCEPTED MANUSCRIPT
SHELXTL and Olex2.30 Details of the crystallographic data and
supplementary publication CCDC numbers are provided in
references 23 and 24. Crystallographic data (excluding structure
factors) of compounds 4b23 and 4e24 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:
65.4; FT-IR: 1610 (C=N) cm-1; empirical formula:
C21H17N3S; anal. calcd: C, 73.44; H, 4.99; N, 12.23; found:
C, 73.41; H, 4.95; N, 12.19.
4.3. General procedure for the synthesis of (4a-q) and (5n,p)
To a well stirred solution of Schiff’s bases 3a-d (10.00
mmol) and triethylamine (30.00 mmol) in dry toluene (35
mL), was added a solution of 2-substituted ethanoic acid or
ethanoyl chloride (15.00 mmol) in dry toluene (15 mL) in
dropwise fashion, at refluxing and under nitrogen
atmosphere. The progress of the reaction was monitored by
TLC. After the completion of reaction, the solvent was
evaporated under vacuum and the residue was extracted with
methylene chloride. The organic layer was washed
successively with water (3 x 25 mL), 1N HCl (3 x 25 mL),
5% NaHCO3 (3 x 25 mL) and brine (3 x 25 mL) and dried
over anhydrous Na2SO4. The solvent was evaporated under
vacuum and crude product was purified by silica gel column
(internet.)
+44
1223/336
033:
E-mail:
deposit@ccdc.cam.ac.uk].
4.2. General procedure for the synthesis of (3a-d)
A solution of aromatic amines (10.00 mmol) and
2
(10.00
mmol) in dry methylene chloride (15 mL) containing
preactivated molecular sieves (4 ) was stirred at room
temperature. The progress of the reaction was monitored
periodically by TLC. After the completion of reaction, the
resulting mixture was filtered to separate off the molecular
sieves and solvent was removed under vacuum to yield
crude product that was purified through recrystallization
chromatography using 5% ethyl acetate : n-hexane as eluant
to furnish trans-β-lactams 4a-q. However, the synthesis of
5n,p was carried out by performing the same reaction in dry
from a mixture of methylene chloride and
Schiff’s bases 3a-d
n-hexane to afford
.
methylene chloride, instead of toluene, at 0
4a-q and 5n,p were further purified by recrystallization
from a mixture of methylene chloride and -hexane.
°C. The products
4.2.1. N-[(1ʹ-Phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl)
methylene]-4-methoxybenzenamine (3a)
n
Yellow crystalline solid; (3.05 g, 8.49 mmol) yield: 85%;
1
mp 98–100 °C; Rf (15% EtOAc–
(300 MHz, CDCl3) 8.56 (s, 1H, –N=C
C5ʹ– ), 7.76–6.78 (m, 12H, Ar–
), 3.74 (s, 3H, OCH3); 13
NMR (75 MHz, CDCl3) 157.7, 149.4, 146.9, 144.4, 138.6,
n-hexane) 0.63; H NMR
4.3.1. trans-1-(4ʹ-Methoxyphenyl)-3-chloro-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4a)
δ
H–), 8.50 (s, 1H,
H
H
C
Yellow solid; (4.01 g, 9.20 mmol) yield: 94%; mp 105–
δ
1
107 °C; Rf (15% EtOAc–
MHz, CDCl3)
Ar– ), 5.24 (d,
1H, C4–H), 3.67 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
159.8, 156.8, 145.8, 139.1, 133.9, 129.4, 127.9, 127.1,
126.4, 126.3, 119.1, 119.0, 115.6, 114.5, 63.2, 58.0, 55.4;
FT-IR: 1748 (C=O) empirical formula:
cm-1;
n
-hexane) 0.53; H NMR (300
134.0, 128.9, 127.5, 127.2, 126.8, 126.6, 126.0, 121.7,
119.6, 118.5, 114.3, 54.8; FT-IR: 1593 (C=N) cm-1;
empirical formula: C21H17N3OS; anal. calcd: C, 70.17; H,
4.77; N, 11.69; found: C, 70.12; H, 4.73; N, 11.62.
δ
J
7.70 (s, 1H, C5ʹ–H), 7.56–6.72 (m, 12H,
= 1.5 Hz, 1H, C3–H), 4.68 (d, = 1.5 Hz,
H
J
δ
4.2.2. N-[(1ʹ-Phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl)
methylene]-4-methylbenzenamine (3b)
C23H18ClN3O2S; anal. calcd: C, 63.37; H, 4.16; N, 9.64;
found: C, 63.34; H, 4.14; N, 9.61.
Yellow crystalline solid; (2.81 g, 8.19 mmol) yield: 82%;
1
mp 110–112 °C; Rf (15% EtOAc–
(300 MHz, CDCl3) 8.61 (s, 1H, –N=C
13H, Ar–
), 2.29 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
151.5, 132.4, 130.0, 129.7, 129.6, 129.6, 129.5, 128.6,
n-hexane) 0.62; H NMR
δ
H–), 7.75–7.15 (m,
4.3.2. trans-1-(4ʹ-Methylphenyl)-3-chloro-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4b)
H
δ
White crystalline solid; (3.82 g, 9.10 mmol) yield: 91%;
128.0, 127.8, 127.7, 127.6, 127.6, 127.5, 127.4, 127.2,
119.6, 119.6, 119.4, 21.0; FT-IR: 1592 (C=N) cm-1;
empirical formula: C21H17N3S; anal. calcd: C, 73.44; H,
4.99; N, 12.23; found: C, 73.40; H, 4.95; N, 12.20.
1
mp 115–117 °C; Rf (15% EtOAc–
(400 MHz, CDCl3) 7.69 (s, 1H, C5ʹ–
12H, Ar– ), 5.25 (d, = 1.4 Hz, 1H, C3–
Hz, 1H, C4–
), 2.20 (s, 3H, CH3) ); 13C NMR (100 MHz,
CDCl3) 160.1, 145.8, 139.1, 134.8, 134.0, 133.8, 129.8,
n-hexane) 0.50; H NMR
δ
H
), 7.55–7.00 (m,
H
J
H
), 4.67 (d, = 1.5
J
H
δ
4.2.3. N-[(1ʹ-Phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl)
methylene]-4-chlorobenzenamine (3c)
129.4, 127.9, 127.1, 126.4, 126.4, 126.3, 119.1, 117.5,
115.7, 63.1, 57.9, 20.9; FT-IR: 1760 (C=O) cm-1; empirical
formula: C23H18ClN3OS; anal. calcd: C, 65.78; H, 4.32; N,
10.01; found: C, 65.75; H, 4.30; N, 9.98.
Yellow crystalline solid; (3.16 g, 8.69 mmol) yield: 87%;
1
mp 58–60 °C; Rf (15% EtOAc–
(300 MHz, CDCl3) 8.40 (s, 1H, –N=C
13H, Ar–
); 13C NMR (75 MHz, CDCl3)
n
-hexane) 0.81; H NMR
δ
H
–), 7.80–6.99 (m,
149.5, 118.1,
H
δ
4.3.3. trans-1-(4ʹ-Chlorophenyl)-3-chloro-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4c)
104.3, 97.9, 95.2, 95.0, 94.6, 94.1, 93.4, 93.3, 93.1, 92.7,
87.6, 85.2, 85.0, 81.7; FT-IR: 1593 (C=N) cm-1; empirical
formula: C20H14ClN3S; anal. calcd: C, 66.02; H, 3.88; N,
11.55; found: C, 66.00; H, 3.83; N, 11.51.
White solid; (4.10 g, 9.31 mmol) yield: 93%; mp 130–
1
132 °C; Rf (15% EtOAc–
MHz, CDCl3) 7.71 (s, 1H, C5ʹ–
Ar– ), 5.24 (d, = 1.6 Hz, 1H, C3–
1H, C4–
); 13C NMR (100 MHz, CDCl3)
n
-hexane) 0.75; H NMR (400
δ
J
H
), 7.54–7.07 (m, 12H,
), 4.68 (d, = 1.7 Hz,
159.3, 144.7,
H
H
J
4.2.4. N-[(1ʹ-Phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl)
methylene](phenyl)methanamine (3d)
H
δ
138.0, 133.7, 132.7, 129.2, 128.5, 128.4, 126.9, 126.2,
125.6, 125.3, 125.2, 118.1, 117.7, 114.1, 62.2, 57.0; FT-IR:
1743 (C=O) cm-1; empirical formula: C22H15Cl2N3OS; anal.
calcd: C, 60.01; H, 3.43; N, 9.54; found: C, 59.98; H, 3.40;
N, 9.52.
Yellow semi-solid; (3.43 g, 9.99 mmol) yield: 79%; Rf
(15% EtOAc–
8.41 (s, 1H, –N=C
13H, Ar–
), 4.62 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3)
153.4, 146.7, 139.1, 134.4, 129.1, 128.3, 128.1, 127.8,
n δ
-hexane) 0.53; 1H NMR (300 MHz, CDCl3)
H
–), 8.26 (s, 1H, C5ʹ–H), 7.57–6.94 (m,
H
δ

8
Tetrahedron
ACCEPTED MANUSCRIPT
4.3.4. trans-3-Chloro-1-benzyl-4-[1ʹ-phenyl-3ʹ-(thiophen-
126.2 (CAr), 126.2 (CAr), 119.0 (CAr), 62.0 (Ct), 53.7 (Ct),
2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4d)
44.6 (Cs); FT-IR: 1755 (C=O) cm-1; empirical formula:
C29H23N3OS2; anal. calcd: C, 70.56; H, 4.70; N, 8.51; found:
C, 70.53; H, 4.68; N, 8.47.
White solid; (3.74 g, 8.91 mmol) yield: 89%; mp 133–
1
135 °C; Rf (15% EtOAc–
MHz, CDCl3)
n
-hexane) 0.37; H NMR (300
7.64–6.98 (m, 14H, Ar– ), 4.70-4.58 (m,
and C4– ), 4.11 (d, = 15 Hz, 1H, CH2);
163.5, 146.2, 139.1, 134.7,
δ
H
3H, CH2, C3–
H
H
J
4.3.9. trans-1-(4ʹ-Methoxyphenyl)-3-benzylthio-4-[1ʹ-phenyl
-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4i)
Brown viscous oil; (4.76 g, 9.09 mmol) yield: 91%; Rf
13C NMR (75 MHz, CDCl3)
δ
133.7, 129.4, 128.9, 128.3, 128.1, 127.6, 127.1, 126.5,
126.4, 126.2, 118.9, 115.7, 63.4, 57.7, 45.3; FT-IR: 1770
(C=O) cm-1; empirical formula: C23H18ClN3OS; anal. calcd:
C, 65.78; H, 4.32; N, 10.01; found: C, 65.75; H, 4.30; N,
9.98.
(15% EtOAc–
7.62 (s, 1H, C5ʹ–
2.1 Hz, 1H, C3–
2H, CH2), 3.55 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
162.5, 156.1, 145.5, 139.0, 137.2, 134.0, 130.0, 129.2,
n
-hexane) 0.16; 1H NMR (400 MHz, CDCl3)
δ
H
), 7.47–6.63 (m, 17H, Ar–
H
), 4.74 (d,
J
=
H
), 3.94 (d, = 2.2 Hz, 1H, C4–
J
H
), 3.80 (s,
δ
4.3.5. trans-1-(4ʹ-Methoxyphenyl)-3-phenylthio-4-[1ʹ-phenyl
-3ʹ-(thioph-en-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4e)
128.8, 128.3, 127.6, 127.2, 126.7, 126.3, 126.0, 125.9,
118.7, 118.5, 117.0, 114.2, 58.9, 55.2, 54.8, 35.0; FT-IR:
1760 (C=O) cm-1; empirical formula: C30H25N3O2S2; anal.
calcd: C, 68.81; H, 4.81; N, 8.02; found: C, 68.78; H, 4.78;
N, 7.98.
Transparent crystalline solid; (4.68 g, 9.18 mmol) yield:
1
92%; mp 165–167 °C; Rf (15% EtOAc–
NMR (400 MHz, CDCl3) 7.73 (s, 1H, C5ʹ–
(m, 17H, Ar– ), 5.02 (d, = 2.1 Hz, 1H, C3–
= 2.2 Hz, 1H, C4–
), 3.64 (s, 3H, OCH3); 13C NMR (100
MHz, CDCl3) 162.8, 156.4, 145.9, 139.3, 134.1, 133.1,
n-hexane) 0.31; H
δ
H), 7.56–6.66
H
J
H), 4.28 (d,
J
H
4.3.10. trans-1-(4ʹ-Chlorophenyl)-3-benzylthio-4-[1ʹ-phenyl-
3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]aze-tidin-2-one (4j)
Yellow viscous oil; (4.27 g, 8.09 mmol) yield: 81%; Rf
δ
131.2, 130.0, 129.5, 129.3, 128.5, 127.8, 127.1, 126.6,
126.4, 126.2, 119.1, 118.7, 117.2, 114.4, 61.7, 55.4, 54.6;
FT-IR: 1726 (C=O) cm-1; empirical formula: C29H23N3O2S2;
anal. calcd: C, 68.34; H, 4.55; N, 8.25; found: C, 68.30; H,
4.51; N, 8.21; m/z (ESI-MS) 510.40 [M+H]+.
(15% EtOAc–
8.74 (s, 1H, C5ʹ–
2.4 Hz, 1H, C3–
2H, CH2); 13C NMR (75 MHz, CDCl3)
n
-hexane) 0.30; 1H NMR (300 MHz, CDCl3)
δ
=
H
), 8.48–7.05 (m, 17H, Ar–
), 4.02 (d, = 2.1 Hz, 1H, C4–
166.0, 157.0,
H
), 4.78 (d,
J
H
J
H), 3.88 (s,
δ
156.8, 129.9, 129.8, 129.5, 127.6, 127.1, 122.4, 122.1,
122.0, 119.3, 114.8, 114.5, 114.2, 67.6, 55.5, 39.7; FT-IR:
1723 (C=O) cm-1; empirical formula: C29H22ClN3OS2; anal.
calcd: C, 65.96; H, 4.20; N, 7.96; found: C, 65.94; H, 4.15;
N, 7.93.
4.3.6. trans-1-(4ʹ-Methylphenyl)-3-phenylthio-4-[1ʹ-phenyl-
3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4f)
Brown oil; (4.44 g, 8.99 mmol) yield: 90%; Rf (15%
1
EtOAc–
(s, 1H, C5ʹ–
Hz, 1H, C3–
H3); 13C NMR (100 MHz, CDCl3)
n
-hexane) 0.46; H NMR (400 MHz, CDCl3)
δ
7.72
= 2.2
), 2.16 (s, 3H,
δ 162.3, 145.1, 138.5,
H
), 7.56–6.92 (m, 17H, Ar–
H), 5.03 (d, J
H
), 4.27 (d, = 2.2 Hz, 1H, C4–H
J
4.3.11.
trans-1-(4ʹ-Methoxyphenyl)-3-benzylseleno-4-[1ʹ-
C
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
133.4, 133.4, 133.3, 132.2, 128.9, 128.9, 128.7, 127.6,
127.0, 126.2, 125.8, 125.6, 125.3, 119.2, 118.3, 116.5,
116.4, 60.9, 53.7, 20.14; FT-IR: 1747 (C=O) cm-1; empirical
formula: C29H23N3OS2; anal. calcd: C, 70.56; H, 4.70; N,
8.51; found: C, 70.52; H, 4.67; N, 8.48.
(4k)
Brown oil; (5.02 g, 8.80 mmol) yield: 88%; Rf (15%
EtOAc–
(s, 1H, C5ʹ–
Hz, 1H, C3–
H2), 3.73 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
n
-hexane) 0.36; 1H NMR (400 MHz, CDCl3)
δ
7.69
), 7.60–6.77 (m, 17H, Ar– = 2.0
), 4.06 (d, = 2.1 Hz, 1H, C4–H), 3.94 (s, 2H,
H
H), 4.85 (d, J
H
J
C
δ
4.3.7. trans-1-(4ʹ-Chlorophenyl)-3-phenylthio-4-[1ʹ-phenyl-
3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4g)
162.6, 156.3, 145.7, 139.2, 137.2, 134.1, 130.1, 129.4,
129.0, 128.6, 127.7, 127.3, 126.9, 126.4, 126.1, 126.0,
118.9, 118.7, 117.2, 114.3, 59.0, 55.4, 54.9, 35.2; DEPT-135
Brown oil; (4.47 g, 8.70 mmol) yield: 87%; Rf (15%
1
NMR (100 MHz, CDCl3)
δ 129.4 (CAr), 129.1 (CAr), 128.6
EtOAc–
(s, 1H, C5ʹ–
Hz, 1H, C3–
(100 MHz, CDCl3)
n
-hexane) 0.61; H NMR (300 MHz, CDCl3)
δ
8.07
= 1.3
); 13C NMR
162.8, 156.4, 145.9, 139.2, 134.1,
(CAr), 127.8 (CAr), 127.4 (CAr), 126.9 (CAr), 126.5 (CAr),
126.2 (CAr), 126.0 (CAr), 119.0 (CAr), 118.7 (CAr), 114.4
(CAr), 59.1 (Cp), 55.4 (Ct), 55.0 (Ct), 35.3 (Cs); FT-IR: 1756
(C=O) cm-1; empirical formula: C30H25N3O2SSe; anal. calcd:
C, 63.15; H, 4.42; N, 7.36; found: C, 63.13; H, 4.38; N,
7.32.
H
), 7.67–7.15 (m, 17H, Ar–
H), 5.62 (d, J
H
), 4.91 (d, = 1.3 Hz, 1H, C4–H
J
δ
133.0, 131.2, 129.9, 129.5, 129.2, 128.4, 127.8, 127.0,
126.6, 126.4, 126.2, 119.1, 118.7, 117.1, 114.4, 55.4, 55.6;
FT-IR:
1755
(C=O)
cm-1;
empirical
formula:
C28H20ClN3OS2; anal. calcd: C, 65.42; H, 3.92; N, 8.17;
found: C, 65.40; H, 3.90; N, 8.16.
4.3.12.
trans-1-(4ʹ-Chlorophenyl)-3-benzylseleno-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(4l)
4.3.8. trans-1-Benzyl-3-phenylthio-4-[1ʹ-phenyl-3ʹ-(thiophen
-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4h)
Yellow viscous oil; (4.47 g, 7.77 mmol) yield: 78%; Rf
Yellow solid; (4.39 g, 8.89 mmol) yield: 89%; mp 130–
(15% EtOAc–
7.59–7.13 (m, 18H, Ar–
1H, C3– ), 4.09 (d, = 2.3 Hz, 1H, C4–
H2); 13C NMR (100 MHz, CDCl3)
163.3, 145.7, 139.1,
137.1, 135.1, 133.9, 129.5, 129.4, 129.3, 129.0, 128.9,
128.6, 127.7, 127.5, 127.1, 126.5, 126.3, 125.8, 119.0,
118.5, 116.7, 59.2, 55.1, 35.3; DEPT-135 NMR (100 MHz,
n δ
-hexane) 0.43; 1H NMR (400 MHz, CDCl3)
1
132 °C; Rf (15% EtOAc–
MHz, CDCl3) 7.45 (s, 1H, C5ʹ–
Ar– ), 4.64 (d, = 15.1 Mz, 1H, CH2), 4.60 (d,
1H, C3– ), 4.25 (d, = 2.0 Hz, 1H, C4– ), 3.91 (d,
15.0 Hz, 1H, CH2); 13C NMR (100 MHz, CDCl3)
165.8,
n
-hexane) 0.39; H NMR (400
H
and C5ʹ–
H
), 4.84 (d,
J = 2.2 Hz,
H
J
H
), 3.96 (s, 2H,
δ
J
H
), 7.44–6.74 (m, 18H,
= 2.2 Hz,
C
δ
H
J
H
J
H
J =
δ
146.4, 139.3, 134.7, 134.3, 130.4, 129.5, 129.3, 128.7,
128.1, 127.6, 127.5, 127.0, 126.4, 126.2, 126.2, 119.0,
116.8, 62.0, 53.7, 44.6; DEPT-135 NMR (100 MHz, CDCl3)
134.3 (CAr), 129.5 (CAr), 129.3 (CAr), 128.7 (CAr), 128.1
(CAr), 127.6 (CAr), 127.5 (CAr), 127.0 (CAr), 126.4 (CAr),
CDCl3)
δ 129.5 (CAr), 129.3 (CAr), 129.0 (CAr), 128.6 (CAr),
127.8 (CAr), 127.5 (CAr), 127.1 (CAr), 126.5 (CAr), 126.3
(CAr), 125.9 (CAr), 119.0 (CAr), 118.5 (CAr), 77.2 (CAr), 59.2
(Ct), 55.1 (Ct), 35.3 (Cs); FT-IR: 1740 (C=O) cm-1; empirical
δ

9
formula: C29H22ClN3OSSe; anal. calcd: C, 60.58; H, 3.86; N,
7.31; found: C, 60.15; H, 3.80; N, 7.28.
127.9, 127.8, 127.2, 126.9, 126.1, 119.6, 119.0, 117.6,
ACCEPTED MANUSCRIPT
116.9, 91.1, 58.2, 54.9, 20.9; FT-IR: 1747 (C=O) cm-1;
empirical formula: C24H21N3O2S; anal. calcd: C, 69.37; H,
5.09; N, 10.11; found: C, 69.34; H, 5.04; N, 10.08.
4.3.13. trans-1-(4ʹ-Methoxyphenyl)-3-phenoxy-4-[1ʹ-phenyl-
3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4m)
White solid; (4.54 g, 9.20 mmol) yield: 92%; mp 120–
4.3.18. cis-1-(4ʹ-Methoxyphenyl)-3-acetoxy-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (5n)
Brown oil; (1.15 g, 2.50 mmol) yield: 25%; Rf (15%
1
122 °C; Rf (15% EtOAc–
MHz, CDCl3) 7.83 (s, 1H, C5ʹ–
Ar– ), 5.29 (d, = 0.6 Hz, 1H, C3–
1H, C4–
), 3.59 (s, 3H, OCH3); 13C NMR (100 MHz,
CDCl3) 162.0, 157.0, 156.5, 145.8, 139.1, 134.0, 129.8,
n
-hexane) 0.38; H NMR (400
δ
J
H
H
), 7.56–6.67 (m, 17H,
), 5.13 (d, = 0.9 Hz,
H
J
EtOAc–
7.76–6.78 (m, 13H, Ar–
4.60 (d,
n
-hexane) 0.36; 1H NMR (300 MHz, CDCl3)
δ
),
H
δ
H
), 5.30 (d,
J
= 4.8 Hz, 1H, C3–
H
J
= 4.8 Hz, 1H, C4–
H
), 3.60 (s, 3H, OCH3), 2.12 (s,
129.6, 129.4, 127.7, 126.9, 126.5, 126.2, 122.4, 118.9,
118.9, 116.1, 115.9, 115.7, 114.4, 87.7, 55.7, 55.3; FT-IR:
1727 (C=O) cm-1; empirical formula: C29H23N3O3S; anal.
calcd: C, 70.57; H, 4.70; N, 8.51; found: C, 70.54; H, 4.67;
N, 8.49.
3H, CH3COO); FT-IR: 1746 (C=O) cm-1; empirical formula:
C25H21N3O4S; anal. calcd: C, 65.34; H, 4.61; N, 9.14; found:
C, 65.28; H, 4.56; N, 9.06.
4.3.19. cis-1-(4ʹ-Methoxyphenyl)-3-methoxy-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (5p)
Brown oil; (0.99 g, 2.29 mmol) yield: 23%; Rf (15%
4.3.14. trans-1-(4ʹ-Methoxyphenyl)-3-acetoxy-4-[1ʹ-phenyl-
3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4n)
EtOAc–
7.84–6.71 (m, 13H, Ar–
4.83 (d,
n
-hexane) 0.47; 1H NMR (400 MHz, CDCl3)
δ
),
White solid; (4.08 g, 8.88 mmol) yield: 89%; mp 105–
H
), 5.46 (d,
J
= 4.6 Hz, 1H, C3–
H
1
107 °C; Rf (15% EtOAc–
n
-hexane) 0.47; H NMR (400
J
= 4.6 Hz, 1H, C4–
H), 3.68 (s, 3H, OCH3), 3.29 (s,
MHz, CDCl3)
Ar ), 5.68 (d,
1H, C4–
NMR (100 MHz, CDCl3)
δ
J
7.84 (s, 1H, C5ʹ–
= 1.8 Hz, 1H, C3–
H
H
), 7.66–6.80 (m, 12H,
), 5.30 (d, = 1.6 Hz,
3H, C3–OCH3); FT-IR: 1748 (C=O) cm-1; empirical
formula: C24H21N3O3S; anal. calcd: C, 66.80; H, 4.91; N,
9.74; found: C, 66.71; H, 4.85; N, 9.65.
H
J
H
), 3.74 (s, 3H, OCH3), 2.21 (s, 3H, CH3COO); 13
C
δ
169.3, 161.1, 156.7, 145.8,
139.3, 134.1, 129.8, 129.4, 127.6, 127.1, 126.5, 126.3,
126.1, 119.1, 119.0, 116.1, 114.5, 82.0, 55.4, 55.2, 20.5; FT-
IR: 1746 (C=O) cm-1; empirical formula: C25H21N3O4S; anal.
calcd: C, 65.34; H, 4.61; N, 9.14; found: C, 65.30; H, 4.58;
N, 9.10.
4.4. General procedure for the synthesis of (6a-e)
To a well stirred solution of 4e-i (10.00 mmol) in 40 mL of
dry carbon tetrachloride, at room temperature, was added
NCS (12.00 mmol). The reaction mixture was allowed to stir
till completion. The progress of the reaction was monitored
by TLC. Disappearance of spot corresponding to starting
reactant and appearance of a new spot with Rf value higher
than starting β-lactam on TLC indicated the complete
conversion. On completion, reaction mixture was filtered,
solvent was evaporated under vacuum and the crude product
was purified by silica gel column chromatography using
4.3.15. trans-1-(4ʹ-Methylphenyl)-3-acetoxy-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4o)
Yellow solid; (3.14 g, 7.08 mmol) yield: 71%; mp 65–67
1
°C; Rf (15% EtOAc–
n
-hexane) 0.22; H NMR (300 MHz,
CDCl3)
5.59 (d,
H
δ
J
7.79 (s, 1H, C5ʹ–
= 1.8 Hz, 1H, C3–
H
H
), 7.55–6.94 (m, 12H, Ar–
H),
), 5.23 (d, = 1.8 Hz, 1H, C4–
J
), 2.15 (s, 3H, CH3), 2.09 (s, 3H, CH3COO); 13C NMR (75
10% ethyl acetate :
from a mixture of methylene chloride and
6a-e
n
-hexane as eluant and recrystallized
n-hexane to yield
MHz, CDCl3)
δ 169.2, 161.5, 145.5, 139.0, 134.4, 133.8,
.
130.6, 129.5, 129.2, 128.2, 127.4, 126.8, 126.6, 126.5,
126.1, 125.9, 118.9, 117.4, 115.9, 81.7, 54.8, 20.6, 20.2; FT-
IR: 1725 (C=O) cm-1; empirical formula: C25H21N3O3S; anal.
calcd: C, 67.70; H, 4.77; N, 9.47; found: C, 67.67; H, 4.74;
N, 9.44.
4.4.1. cis-1-(4ʹ-Methoxyphenyl)-3-chloro-3-phenylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(6a)
Shiny white solid; (3.92 g, 7.21 mmol) yield: 72%; mp
1
95–97 °C; Rf (15% EtOAc–
MHz, CDCl3) 7.79–6.81 (m, 18H, Ar–
), 3.75 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
n
-hexane) 0.33; H NMR (400
4.3.16. trans-1-(4ʹ-Methoxyphenyl)-3-methoxy-4-[1ʹ-phenyl-
3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4p)
δ
H), 5.66 (s, 1H, C4–
White solid; (3.62 g, 8.39 mmol) yield: 84%; mp 97–100
H
δ
1
°C; Rf (15% EtOAc–
n
-hexane) 0.52; H NMR (400 MHz,
160.1, 156.9, 147.0, 139.2, 135.4, 133.8, 129.5, 129.2,
128.8, 128.4, 128.1, 127.8, 127.2, 127.2, 126.6, 126.4,
119.3, 119.2, 119.1, 114.6, 112.6, 80.3, 64.2, 55.4; FT-IR:
1762 (C=O) cm-1; empirical formula: C29H22ClN3O2S2; anal.
calcd: C, 64.02; H, 4.08; N, 7.72; found: C, 63.95; H, 4.00;
N, 7.69; MS (ESI): m/z (ESI-MS) 566.06 [M+Na]+.
CDCl3)
5.15 (d,
H
δ
J
7.64 (s, 1H, C5ʹ–
= 1.3 Hz, 1H, C3–
H
H
), 7.54–6.70 (m, 12H, Ar–
H),
), 4.46 (d, = 1.5 Hz, 1H, C4–
J
), 3.64 (s, 3H, OCH3), 3.52 (s, 3H, C3–OCH3); 13C NMR
(100 MHz, CDCl3)
δ 163.6, 156.4, 145.5, 139.2, 134.4,
130.0, 129.4, 127.9, 126.9, 126.2, 126.1, 119.0, 118.9,
116.7, 114.4, 91.0, 58.2, 55.4, 55.0; FT-IR: 1736 (C=O) cm-
1; empirical formula: C24H21N3O3S; anal. calcd: C, 66.80; H,
4.91; N, 9.74; found: C, 66.78; H, 4.89; N, 9.71.
4.4.2. cis-1-(4ʹ-Methylphenyl)-3-chloro-3-phenylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(6b)
4.3.17. trans-1-(4ʹ-Methylphenyl)-3-methoxy-4-[1ʹ-phenyl-3ʹ
-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (4q)
Yellow solid; (3.51 g, 6.65 mmol) yield: 67%; mp 80–82
1
°C; Rf (15% EtOAc–
CDCl3) 7.85–6.86 (m, 18H, Ar–
2.20 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
n
-hexane) 0.67; H NMR (300 MHz,
Brown oil; (3.03 g, 7.29 mmol) yield: 73%; Rf (15%
δ
H
), 5.60 (s,1H, C4–
H),
1
EtOAc–
(s, 1H, C5ʹ–
Hz, 1H, C3–
OCH3), 2.16 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
164.0, 145.5, 139.3, 134.2, 129.7, 129.6, 129.4, 128.6,
n
-hexane) 0.50; H NMR (400 MHz, CDCl3)
δ
8.36
= 1.5
), 3.51 (s, 3H,
δ
160.4,
H
), 7.81–6.96 (m, 12H, Ar–
H), 5.15 (d, J
156.0, 146.9, 139.2, 135.5, 135.5, 129.8, 129.4, 128.8,
128.3, 127.8, 127.1, 126.6, 126.4, 126.4, 119.9, 119.2,
117.8, 117.8, 64.0, 61.4, 29.7; FT-IR: 1765 (C=O) cm-1;
H
), 4.44 (d, = 1.6 Hz, 1H, C4–
J
H
δ

10
Tetrahedron
empirical formula: C29H22ClN3OS2; anal. calcd: C, 65.96;
MHz, CDCl )
δ
7.93–6.65 (m, 22H, Ar–
H
), 5.64 (s, 1H, C4–
), 3.74 (s, 3H, OCH3), 3.73 (s, 3H, OCH3); 13C NMR (100
MHz, CDCl3) 165.3, 159.1, 156.4, 139.4, 134.9, 134.1,
ACCEPTED MANUSCRIPT
3
H, 4.20; N, 7.96; found: C, 65.92; H, 4.16; N, 7.94.
H
δ
130.2, 129.4, 129.3, 129.1, 128.9, 128.8, 128.3, 128.3,
128.0, 127.5, 127.1, 127.0, 126.7, 119.2, 118.9, 114.6,
114.5, 113.7, 113.5, 70.3, 60.5, 55.4, 55.2; DEPT-135 NMR
4.4.3. cis-1-(4ʹ-Chlorophenyl)-3-chloro-3-phenylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(6c)
(100 MHz, CDCl3)
δ 134.9 (CAr), 134.7 (CAr), 129.4 (CAr),
Yellow solid; (3.51 g, 6.40 mmol) yield: 64%; mp 145–
1
129.1 (CAr), 129.0 (CAr), 128.8 (CAr), 128.3 (CAr), 128.3
(CAr), 128.0 (CAr), 127.5 (CAr), 127.0 (CAr), 126.7 (CAr),
126.4 (CAr), 119.2 (CAr), 119.2 (CAr), 118.9 (CAr), 114.5
(CAr), 113.7 (CAr), 113.5 (CAr), 60.5 (Ct), 55.4 (Cp), 55.2
(Cp); FT-IR: 1739 (C=O) cm-1; empirical formula:
C36H29N3O3S2; anal. calcd: C, 70.22; H, 4.75; N, 6.82;
found: C, 70.18; H, 4.71; N, 6.78; m/z (ESI-MS) 638.21
[M+Na]+.
147 °C; Rf (15% EtOAc–
MHz, CDCl3) 7.69–7.11 (m, 18H, Ar–
); NMR (100 MHz, CDCl3) 163.3, 137.2, 135.6, 134.4,
n
-hexane) 0.75; H NMR (400
δ
H ), 5.68 (s,1H, C4–
H
δ
134.3, 130.1, 129.7, 129.5, 129.5, 129.5, 129.4, 129.3,
129.2, 128.9, 128.1, 127.8, 127.6, 121.4, 121.2, 119.3,
119.1, 112.2, 80.3, 62.9; FT-IR: 1770 (C=O) cm-1; empirical
formula: C28H19Cl2N3OS2; anal. calcd: C, 61.31; H, 3.49; N,
7.66; found: C, 61.26; H, 3.45; N, 7.60.
4.5.2. cis-1-(4ʹ-Methoxyphenyl)-3-(2ʹ,5ʹ-dimethoxyphenyl)-3-
phenylthio-4-[1ʹ-phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-
yl]azetidin-2-one (7b)
4.4.4. cis-1-Benzyl-3-chloro-3-phenylthio-4-[1ʹ-phenyl-3ʹ-
(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one (6d)
Yellow solid; (3.04 g, 5.76 mmol) yield: 58%; mp 83–85
1
Yellow semi-solid; (0.44 g, 0.68 mmol) yield: 68%; Rf
°C; Rf (15% EtOAc–
n
-hexane) 0.36; H NMR (300 MHz,
(15% EtOAc–
7.72–6.60 (m, 21H, Ar–
OCH3), 3.43 (s, 3H, OCH3), 3.14 (s, 3H, OCH3); 13C NMR
(100 MHz, CDCl3) 191.7, 165.6, 152.7, 150.8, 139.6,
n δ
-hexane) 0.46; 1H NMR (400 MHz, CDCl3)
CDCl3)
4.57 (d,
C
δ
J
7.79–6.78 (m, 19H, Ar–
= 14.7 Hz, 1H, CH2), 4.25 (d,
H2); 13C NMR (100 MHz, CDCl3)
δ 164.0, 147.2, 135.1,
H
), 4.97 (s,1H, C4–
H),
H
), 5.84 (s, 1H, C4–H), 3.64 (s, 3H,
J
= 15.0 Hz, 1H,
δ
135.1, 134.7, 133.6, 129.3, 129.1, 129.0, 128.8, 128.4,
128.2, 127.6, 127.1, 126.5, 126.2, 125.6, 124.4, 124.0,
119.0, 113.1, 81.1, 64.2, 45.2; FT-IR: 1769 (C=O) cm-1;
empirical formula: C29H22ClN3OS2; anal. calcd: C, 65.96; H,
4.20; N, 7.96; found: C, 65.90; H, 4.16; N, 7.92.
136.4, 135.3, 130.9, 130.6, 130.5, 129.7, 129.5, 128.8,
128.6, 128.1, 127.6, 126.9, 125.8, 125.7, 119.3, 118.8,
115.4, 114.3, 111.6, 68.2, 67.3, 59.2, 55.8, 55.4; FT-IR:
1742 (C=O) cm-1; empirical formula: C37H31N3O4S2; anal.
calcd: C, 68.81; H, 4.84; N, 6.51; found: C, 68.77; H, 4.80;
N, 6.47.
4.4.5. cis-1-(4ʹ-Methoxyphenyl)-3-chloro-3-benzylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(6e)
4.5.3. cis-1-(4ʹ-Methoxyphenyl)-3-(2ʹ-methoxynaphthalen-1ʹ-
yl)-3-phenylthio-4-[1ʹ-phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-
pyrazol-4ʹ-yl]azetidin-2-one (7c)
White solid; (3.02 g, 5.41 mmol) yield: 54%; mp 80–82
1
°C; Rf (15% EtOAc–
n
-hexane) 0.69; H NMR (300 MHz,
Yellow solid; (0.42 g, 0.63 mmol) yield: 64%; mp 70–73
CDCl3)
4.31 (d,
C
δ
J
7.68–6.70 (m, 18H, Ar–
= 11.4 Hz, 1H, CH2), 4.04 (d,
H
), 5.59 (s, 1H, C4–
H),
1
°
C; Rf (15% EtOAc–
CDCl3) 7.91–6.45 (m, 24H, Ar–
3.74 (s, 3H, OCH3), 3.57 (s, 3H, OCH3); 13C NMR (100
MHz, CDCl3) 156.2, 154.0, 147.1, 133.5, 130.8, 129.7,
n
-hexane) 0.16; H NMR (300 MHz,
J
= 11.7 Hz, 1H,
H2), 3.63 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
δ
δ
H ), 4.03 (s, 1H, C4–H),
161.7, 147.1, 138.4, 129.7, 129.5, 129.5, 129.4, 128.8,
128.7, 128.5, 128.2, 128.1, 127.8, 127.7, 127.3, 127.0,
125.7, 124.5, 124.0, 119.7, 119.3, 119.2, 119.1, 114.6, 77.2,
68.2, 31.9, 25.2; FT-IR: 1766 (C=O) cm-1; empirical
formula: C30H24ClN3O2S2; anal. calcd: C, 64.56; H, 4.33; N,
7.53; found: C, 64.51; H, 4.29; N, 7.49.
δ
129.6, 129.2, 128.2, 128.1, 127.8, 127.7, 127.6, 125.9,
125.8, 125.6, 125.4, 124.7, 124.5, 124.3, 121.3, 121.0,
120.9, 119.6, 119.0, 118.9, 118.8, 114.4, 114.0, 113.4,
105.4, 68.5, 63.7, 56.9, 55.4; FT-IR: 1719 (C=O) cm-1;
empirical formula: C40H31N3O3S2; anal. calcd: C, 72.16; H,
4.69; N, 6.31; found: C, 72.12; H, 4.64; N, 6.27.
4.5. General procedure for the synthesis of (7a-d)
To a well stirred solution of 6a,d,e (1.00 mmol) and anisole
(1.10 mmol) in dry methylene chloride (10 mL) at 0 °C was
4.5.4. cis-1-Benzyl-3-(4ʹ-methoxyphenyl)-3-phenylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(7d)
added SnCl4 (1.20 mmol) rapidly under nitrogen
atmosphere. The resulting solution was stirred for 1 h at the
same temperature. The progress of the reaction was checked
by TLC, which showed the appearance of a new spot
different than starting substrate. The reaction mixture was
quenched with water, extracted with methylene chloride (4 x
10 mL), dried over anhydrous Na2SO4. The crude product,
after solvent evaporation in vacuo, was purified by silica gel
Pale yellow solid; (0.39 g, 0.70 mmol) yield: 65%; mp
1
75–77
MHz, CDCl3)
C4– ), 4.27 (d,
13C NMR (100 MHz, CDCl3)
°
C; Rf (15% EtOAc–
7.73–6.61 (m, 23H, Ar–
= 14.8 Hz, 2H, CH2), 3.72 (s, 3H, OCH3);
168.4, 165.8, 158.8, 136.1,
n
-hexane) 0.43; H NMR (400
δ
H ), 5.12 (s, 1H,
H
J
δ
135.3, 134.8, 134.6, 134.2, 132.9, 130.6, 129.5, 129.4,
129.2, 129.0, 128.9, 128.9, 128.7, 127.6, 127.4, 126.9,
126.8, 126.6, 126.4, 126.2, 125.7, 119.1, 113.4, 70.9, 60.3,
55.1, 44.6; FT-IR: 1772 (C=O) cm-1; empirical formula:
C36H29N3O2S2; anal. calcd: C, 72.09; H, 4.87; N, 7.01;
found: C, 72.01; H, 4.84; N, 6.97.
column chromatography using 5% ethyl acetate :
as eluant to furnish 7a-d, which was recrystallized from a
mixture of methylene chloride and -hexane.
n-hexane
n
4.5.1.
cis-1,3-Bis(4ʹ-methoxyphenyl)-3-phenylthio-4-[1ʹ-
phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(7a)
4.5.5.
cis-1-(4ʹ-Methoxyphenyl)-3-benzylthio-3-(prop-2ʹ-
ynyloxy)-4-[1ʹ-phenyl-3ʹ-(thiophen-2ʹʹ-yl)-1H-pyrazol-4ʹ-yl]
azetidin-2-one (7e)
Light yellow solid; (0.44 g, 0.72 mmol) yield: 72%; mp
110–112 °C; Rf (15% EtOAc–n
-hexane) 0.44; 1H NMR (400

11
A mixture of silica gel (1.50 g, 100-200 mesh), anhydrous
4.6.2. cis-1-(4ʹ-Methoxyphenyl)-3-(2ʹ,5ʹ-dimethoxyphenyl)-4-
[1ʹ-phenyl-3ʹ-(thiophen-2-yl)-1H-pyrazol-4ʹ-yl]azetidin-2-one
(8b)
ACCEPTED MANUSCRIPT
ZnCl2 (0.30 mmol, 30 mol%), propargyl alcohol (4.50
mmol), molecular sieves (4 , 3.00 g) in dry chloroform (30
mL) under dry and inert conditions was allowed to stir for
25-30 min, followed by addition of 6e (1.00 mmol) in 20
mL of dry chloroform. The reaction mixture was refluxed
for about 2 h with constant stirring. The progress of the
reaction was monitored by TLC. Disappearance of spot
corresponding to 6e was considered as completion of
reaction. The reaction mixture was filtered, washed
successively with water (3 x 10 mL) and brine (3 x 10 mL).
Finally, the organic layer was separated and dried over
anhydrous Na2SO4. The solvent was removed under vacuum
and the crude product was purified by silica gel column
Off-white semi-solid; (0.51 g, 0.95 mmol) yield: 94%; Rf
(20% EtOAc–n-hexane) 0.39; H NMR (400 MHz, CDCl3) δ
1
7.36–6.63 (m, 16H, ArH), 5.39 (d, J = 5.6 Hz, 1H, C3–H), 5.12
(d, J = 5.6 Hz, 1H, C4–H), 3.71 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3), 3.59 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ
163.9, 156.4, 153.3, 129.4, 129.4, 127.4, 126.4, 126.2, 118.9,
118.8, 118.8, 118.8, 118.8, 114.4, 113.6, 109.5, 72.9, 55.5, 54.1,
32.0; FT-IR: 1739 (C=O) cm-1; empirical formula: C31H27N3O4S;
anal. calcd: C, 69.25; H, 5.06; N, 7.82; found: C, 69.21; H, 5.02;
N, 7.79.
chromatography using 5% ethyl acetate : n-hexane as eluant.
Solvent evaporation furnished 7e as pale yellow solid, which
Acknowledgments
was recrystallized using a mixture of methylene chloride and
AB gratefully acknowledges the financial support for this
work from Department of Science and Technology (DST), New
Delhi, Government of India, Project No. SR/FT/CS-037/2010
dated 28-10-2010, FIST II/PURSE II grant (DST) and UGC-
CAS, Panjab University, Chandigarh. PS gratefully indebted to
Council of Scientific and Industrial Research (CSIR), New Delhi,
Government of India for the award of Senior Research
Fellowship (SRF), File No: 09/135(0677)-2012 EMR-I dated 15-
12-2012.
n-hexane.
Yellow solid; (0.38 g, 0.66 mmol) yield: 66%; mp 63–65
1
°
C; Rf (15% EtOAc–
n
-hexane) 0.69; H NMR (400 MHz,
7.85–6.79 (m, 18H, Ar– ), 5.61 (s, 1H, C4– ),
= 1.7 Hz, 2H, CH2O), 3.97 (d, = 12.0 Hz, 1H,
= 12.0 Hz, 1H, CH2S),
); 13C NMR (100 MHz, CDCl3)
161.4, 156.7, 139.3, 136.5, 134.1, 129.5, 129.4, 128.9,
CDCl3)
4.54 (q,
C
2.46 (t, = 2.4 Hz, 1H, ≡C
δ
δ
J
H
H
J
H2S), 3.73 (s, 3H, OCH3), 3.65 (d,
J
J
H
128.8, 128.5, 127.9, 127.2, 127.0, 126.5, 126.3, 119.3,
119.2, 114.5, 113.4, 99.3, 79.0, 61.1, 55.4, 54.5, 32.3;
Supplementary data
DEPT-135 NMR (100 MHz, CDCl3)
δ 129.4 (CAr), 128.9
1
Supplementary data [copies of H NMR spectra of β-lactams
(CAr), 128.8 (CAr), 128.5 (CAr), 127.9 (CAr), 127.2 (CAr),
127.0 (CAr), 126.5 (CAr), 126.3 (CAr), 119.3 (CAr), 119.2
(CAr), 114.5 (CAr), 61.1 (Ct), 55.4 (Cp), 54.5 (Cs), 32.3 (Cs);
FT-IR: 1747 (C=O) cm-1; empirical formula: C33H27N3O3S2;
anal. calcd: C, 68.61; H, 4.71; N, 7.27; found: C, 68.57; H,
4.66; N, 7.21; m/z (ESI-MS) 600.18 [M+Na]+.
4a-q, 5n,p, 6a-e, 7a-e and 8a,b, 13C NMR spectra of β-lactams
4a-q, 6a-e, 7a-e and 8a,b, DEPT–135, COSY and HSQC spectra
of β-lactams 4h-l and 7a,e and ESI-MS of β-lactams 4e, 6a and
7a,e] and the details of computational work associated with this
article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tet.2018.
4.6. General procedure for the synthesis of (8a,b)
References and notes
To a suspension of Raney-nickel (1.10 mmol, 100%
activated) in absolute ethanol (10 mL) was added cis-β-
lactams 7a,b (1.00 mmol). The suspension was refluxed and
the progress of reaction was monitored by TLC.
Disappearance of spot corresponding to starting β-lactam
and the appearance of a new spot with Rf value lower than
that of starting β-lactam indicated the completion of
reaction. The suspension was filtered and the solvent was
evaporated under vacuum, extracted with methylene
chloride (3 x 20 mL) and then dried over anhydrous Na2SO4.
After evaporation of solvent under vacuum, the crude
product was purified by silica gel column chromatography
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ACCEPTED MANUSCRIPT
Highlights
Title: Stereoselective synthesis and characterization of novel trans-4-
(thiophenyl)pyrazolyl-β-lactams and their C–3 functionalization
Preety Saini, S. S. Bari, Subash C. Sahoo, Sadhika Khullar, Sanjay K. Mandal, Aman
Bhalla*
•
•
•
•
Simple and efficient stereoselective synthesis of conformationally restricted trans-
(thiophenyl)pyrazolyl-β-lactams.
C–3 Functionalization and reductive desulphurization to access monosubstituted
/disubtituted β-lactams.
Structural elucidation and stereochemistry establishment of 4b and 4e by single crystal
X-ray crystallographic studies.
Exploration of steric bulk in the target β-lactams in relevance to mechanistic aspects.