Stereoselective synthesis of trans-3-functionalized-4-pyrazolo[5,1-b]thiazole-3-carboxylate substituted β-lactams: Potential synthons for diverse biologically active agents

Article abstract of DOI:10.1080/00397911.2020.1788599

An efficient protocol for the stereoselective synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate tethered β-lactam conjugates 8a–j from novel pyrazolo [5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f is reported here. The reaction between various ketene precursors and novel Schiff’s bases 6a–f afforded exclusive formation of trans-β-lactams 8a–j. The substrate scope of this approach was investigated extensively by varying different groups (R, Z). All the novel compounds were characterized using various spectroscopic techniques, such as FT-IR, ¹H NMR, ¹³C NMR, elemental analysis, ¹³C NMR (DEPT-135), and mass spectrometry in representative cases. Single crystal X-ray crystallographic study of trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a has confirmed the molecular structure and the stereochemical outcome. To the best of our knowledge, the synthesis of such types of Schiff’s bases and β-lactam conjugates has not been reported so far.

Full text of DOI:10.1080/00397911.2020.1788599

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Stereoselective synthesis of trans-3-
functionalized-4-pyrazolo[5,1-b]thiazole-3-
carboxylate substituted β-lactams: Potential
synthons for diverse biologically active agents
Shiwani Berry , Shamsher S. Bari , Pooja Yadav , Ankita Garg , Sadhika
Khullar , Sanjay K. Mandal & Aman Bhalla
To cite this article: Shiwani Berry , Shamsher S. Bari , Pooja Yadav , Ankita Garg ,
Sadhika Khullar , Sanjay K. Mandal & Aman Bhalla (2020): Stereoselective synthesis
of trans-3-functionalized-4-pyrazolo[5,1-b]thiazole-3-carboxylate substituted β-lactams:
Potential synthons for diverse biologically active agents, Synthetic Communications, DOI:
10.1080/00397911.2020.1788599
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https://doi.org/10.1080/00397911.2020.1788599
Stereoselective synthesis of trans-3-functionalized-4-
pyrazolo[5,1-b]thiazole-3-carboxylate substituted b-lactams:
Potential synthons for diverse biologically active agents
Shiwani Berrya, Shamsher S. Baria, Pooja Yadava, Ankita Garga, Sadhika Khullarb,
Sanjay K. Mandalc, and Aman Bhallaa
aDepartment of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh,
b
India; Department of Chemistry, Dr. B. R. Ambedkar National Institute of Technology, Jalandhar,
c
Punjab, India; Department of Chemical Sciences, Indian Institute of Science Education and Research
Mohali, S.A.S. Nagar, Punjab, India
ABSTRACT
ARTICLE HISTORY
Received 6 May 2020
An efficient protocol for the stereoselective synthesis of pyrazolo[5,1-
b]thiazole-3-carboxylate tethered b-lactam conjugates 8a–j from
novel pyrazolo [5,1-b]thiazole-3-carboxylate substituted Schiff’s bases
6a–f is reported here. The reaction between various ketene precur-
sors and novel Schiff’s bases 6a–f afforded exclusive formation of
trans-b-lactams 8a–j. The substrate scope of this approach was inves-
tigated extensively by varying different groups (R, Z). All the novel
compounds were characterized using various spectroscopic techni-
ques, such as FT-IR, 1H NMR, 13C NMR, elemental analysis, 13C NMR
(DEPT-135), and mass spectrometry in representative cases. Single
crystal X-ray crystallographic study of trans-ethyl 7-(1-(4-methoxy-
phenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyra-
zolo[5,1-b]thiazole-3-carboxylate 8a has confirmed the molecular
structure and the stereochemical outcome. To the best of our know-
ledge, the synthesis of such types of Schiff’s bases and b-lactam con-
jugates has not been reported so far.
KEYWORDS
Cycloaddition; pyrazolo[51-
b]thiazole-3-carboxylate;
single crystal X-ray;
stereoselective;
trans-b-Lactams
GRAPHICAL ABSTRACT
CONTACT Aman Bhalla
amanbhalla@pu.ac.in
Department of Chemistry & Centre of Advanced Studies in
Chemistry, Panjab University, Chandigarh, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
S. BERRY ET AL.
Introduction
The nitrogen and sulfur heterocyclic compounds have their own importance in organic
derivatives. Especially, five-membered heterocycles are present in numerous bioactive
compounds, including antioxidants, cyclooxygenase inhibitors, GPCR antagonists, kinase
inhibitors, dopamine transporter inhibitors, and phosphatase inhibitors.[1] The fusion of
two different heterocycles can result in a novel scaffold, which have attracted consider-
able attention of various researchers. In particular, thiazole heterocyclic structural units
condensed to pyrazole derivatives are an important source of bioactive molecules. This
new category of heterocyclic compounds, [5]-fused pyrazolo-thiazole systems, have been
studied for their diverse pharmacological applications including corticotropin-releasing
factor 1 (CRF1) receptor antagonists I,[2] hematopoietic protein tyrosine phosphate
(HePTP) inhibitor II,[3] cyclin-dependent kinase (CDK) inhibitor III (Fig. 1),[4] antibac-
terial agents,[5–7] antiproliferative,[8] antiviral[9], and anticancer agents.[10,11] Moreover,
pyrazolothiazole substituted with carboxylate moiety IV has also been reported as
potent as anti-inflammatory agent (Fig. 1).[12]
The search for novel b-lactam antibiotics with reduced toxicity profile is a relevant
field of pharmaceutical research. Among various heterocycles, synthesis of pyrazole and
thiazole substituted b-lactams is being explored constantly. Several b-lactam analogs
comprising pyrazole and thiazole show diverse bioactivity. Penem V (Fig. 1) containing
Figure 1. Some representative structures of bioactive pyrazolothiazoles and b-lactams in relevance to
target compound synthesis.

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3
O
O
O
O
O
Br
NH
NH2NH2.H2O
CH3
Ethanol
O
O
N
N
O
C2H5O
N
110 o
C
CH3
CH3
1
2
3
DMF/POCl3
Reflux
O
O
N
O
SCH3
O
N
CS2/KOH/DMSO
CH3I
Cl
S
N
N
CHO CH3
CHO CH3
4
5
Scheme 1. Synthesis of pyrazolo[5,1-b]thiazole aldehyde 5.
dihydropyrazolo[1,5-c][1,3]thiazole moiety have been reported as effective b-lactamase
inhibitors[13–15] and CTX-M inhibitors[16] whereas pyrazolo-substituted 6-fluorobenzo-
thiazole b-lactam VI (Fig. 1) showed best antidiabetic activity.[17] Furthermore, b-lactam
bearing alkenyl-carboxylate group VII has also been reported as a synthon for the prep-
aration of diversely functionalized spiropyrrolidine/pyrrolizidine[18] grafted b-lactam
analogs (Fig. 1).
In view of the synthetic and pharmaceutical applications of b-lactams, a broad range
of mono-, bi-, and spirocyclic b-lactams with diverse substitution patterns, such as with
aliphatic/aromatic and heterocyclic varied b-lactams, their C3/C4 functionalization has
been developed in our laboratory.[19–25] In this article, we are describing the design
and synthesis of novel pyrazolo[5,1-b]thiazole-3-carboxylate anchored Schiff’s bases and
3-halo/oxo/seleno/thio-b-lactams having pyrazole, thiazole and b-lactam heterocycles
along with ester linkage in single system as a novel core structure which will be the ver-
satile synthons for diverse heterocyclic molecules as well as potential bioactive agents,
such as antibacterial/anti-inflammatory agents.
Results and discussion
In the first step, for the synthesis of 3-methylpyrazolone 2, ethyl acetoacetate 1 was con-
densed with hydrazine hydrate in ethanol which further underwent N-alkylation reac-
tion to afford pyrazolone-acetate 3 on treatment with ethyl bromoacetate at 110 ꢀC.
Pyrazolone-acetate 3 was formylated via Vilsmeier–Haack reaction by reacting the mix-
ture of pyrazolone-acetate 3 and N, N-dimethylformamide (DMF) with phosphorus oxy-
chloride (POCl3) to provide pyrazolone-acetate substituted aldehyde 4. Thereafter,
aldehyde 4 was treated with carbon disulfide and potassium hydroxide in DMSO fol-
lowed by the addition of iodomethane to furnish bicyclic product, i.e., fused pyra-
zolo[5,1-b]thiazole aldehyde 5 (Scheme 1).[26]
The synthesis of novel pyrazolo[5,1-b]thiazole-3-carboxylate substituted Schiff’s bases
6a–f was achieved by stirring appropriate primary amines with the aldehyde 5 using
molecular sieves (4 Å) in dry dichloromethane (Scheme 2, Table 1). The structure of

4
S. BERRY ET AL.
O
N
H3CS
O
O
H3CS
O
S
N
CH2Cl
2 (dry)
S
N
RNH2
N
H
CH3
MS (4Å), Stirring, r.t.
OHC
CH3
N
R
5
6a-f
Scheme 2. Synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f.
Table 1. Synthesis of Schiff’s bases 6a–f.
S. No.
R
Product 6
Yielda (%)
m.p. (ꢀC)
1
2
3
4
5
6
–C6H4OCH3(p)
–C6H5
–CH2C6H5
–C6H4Cl(p)
–C6H4F(p)
–C6H4CH3(p)
6a
6b
6c
6d
6e
6f
85
89
76
84
79
81
155–157
105–107
143–145
182–184
132–134
134–135
aYields of pure isolated product with correct analytical and spectral data.
O
N
O
H3CS
H3CS
O
O
POCl3, Et3N
or
Z
S
S
N
Et3N
N
N
H H
O
OH/Cl
Z
H
Toluene, Reflux
CH3
CH3
N
N
7
O
R
R
6a-f
8a-j
Scheme 3. Synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate-b-lactams 8a–j.
pyrazolo[5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f were confirmed on
the basis of spectroscopic techniques, namely, FT-IR, NMR (1H, 13C), and CHN elem-
ental analysis.
The synthesis of novel trans-4-pyrazolo[5,1-b]thiazole-3-carboxylate substituted b-lac-
tams 8a–j has been achieved via Staudinger cycloaddition reaction between the ketene
generated from 2-substituted ethanoic acids or acid chloride 7 and pyrazolo[5,1-b]thia-
zole-3-carboxylate substituted Schiff’s bases 6a-f (Scheme 3, Table 2). Initially, 2-phe-
noxyacetic acid 7 was treated with Schiff’s base 6a in the presence of POCl3 and
triethylamine (Et3N) under nitrogen atmosphere in refluxing toluene. The reaction pro-
gress was monitored by thin-layer chromatography (TLC). Solvent was evaporated
under vacuum after the completion of the reaction and crude product was purified by
silica gel column chromatography using 10% ethyl acetate: hexanes as eluant. The prod-
uct was identified as trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-

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5
Table 2. trans-4-Pyrazolo[5,1-b]thiazole-3-carboxylate substituted b-lactams 8a–j.
S. No.
R
Z
trans-b-Lactams 8
Yielda (%)
Mp (ꢀC)
1
2
3
4.
5
6
7
8
–C6H4OCH3(p)
–C6H5
–CH2C6H5
–C6H4Cl(p)
–C6H4F(p)
–C6H4OCH3(p)
–C6H4OCH3(p)
–C6H4CH3(p)
–C6H4CH3(p)
–C6H4CH3(p)
–C6H5O
–C6H5O
–C6H5O
–C6H5O
–C6H5O
–CH3COO
–C6H5Se
–C6H5S
–Br
8a
8b
8c
8d
8e
8f
8g
8h
8i
76
80
69
67
62
71
63
74
68
72
164–165
209–210
109–110
195–196
185–186
115–116
150–151
Semisolid
164–165
218–219
9
10
–Cl
8j
aYields quoted for isolated products characterized by FT-IR, NMR (1H, 13C).
6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a (Scheme 3, Table 2,
1
entry 1) on the basis of various spectroscopic techniques viz., FT-IR, H NMR, 13C
NMR, elemental analysis, DEPT-135 13C NMR in representative cases (8a–c and 8f),
and ESI-MS in representative cases (8a and 8f). Further, the reaction was done success-
fully with 2-phenoxyacetic acid 7 and Schiff’s bases 6b–e to furnish trans-b-lactams
8b–e (Table 2, entries 2–5). Similar results were obtained when Schiff’s bases 6a–f
treated with other substituted ethanoic acids/acid chloride, such as phenylselenoacetic
acid, phenylthioacetic acid, bromoacetic acid, chloroacetic acid, and acetoxyacetyl chlor-
ide, which resulted in exclusive formation of trans-b-lactams 8f–j and the results are
summarized in Table 2.
All these newly synthesized novel monocyclic trans-4-pyrazolo[5,1-b]thiazole-3-carb-
oxylate substituted b-lactams 8 were purified by silica gel column chromatography using
10% ethyl acetate: hexanes as eluant and their structure characterization was accom-
plished on the basis of various spectroscopic techniques, namely, FT-IR, NMR (1H,
13C), 13C NMR (DEPT-135), and ESI-MS (in representative cases) along with elemental
analysis. Stability toward moisture and air was observed by all of the analyzed products.
They are soluble in haloalkanes and many other polar solvents such as acetone, N,N-
DMF, and ethyl acetate.
The strong absorption bands recorded in the range of 1730–1764 cmꢁ1 and
1672–1715 cmꢁ1 confirms the presence of carbonyl group (>C ¼ O) of b-lactam ring
and ester group. The spatial juxtaposition of the C3–H and C4–H was assigned trans in
products 8a–j on the basis of coupling constant (J) value of C3–H and C4–H which
was found to be in the range of 0.8–2.4 Hz.[27,28] 13C NMR spectra of 8a–j displayed
resonance for b-lactam amide carbonyl carbon in the range of d 158.08–160.84 ppm.
Data of trans-4-pyrazolo[5,1-b]thiazole-3-carboxylate-b-lactams 8a–j recorded by CHNS
elemental analysis also supported the structures of the synthesized compounds.
In addition, 13C NMR (DEPT-135) spectroscopic studies (distortionless enhancement
of polarization transfer using a 135-degree decoupler pulse) of 8a, 8b, 8c, and 8f have
been performed to explain the pulse sequence produces by methyl (CH3) and methene
(CH2), and methyne (CH) carbons. 13C NMR (DEPT-135) spectrum of trans-ethyl 7-(1-
(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-
b]thiazole-3-carboxylate 8a displayed resonance at d 62.2 ppm with negative amplitude
confirming the presence of methylene group (-OCH2CH3). The resonances at d 12.9,
14.3, 17.7 ppm and 55.4, 85.7 ppm with positive amplitude are also due to three methyl

6
S. BERRY ET AL.
Figure 2. ORTEP view with atom numbering scheme of trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-
phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a.
(–CH3) and two methine (C4–H, C3–H) carbon atoms, respectively. In 13C NMR
(DEPT-135) of 8b and 8f, resonances at d 62.2 and 62.1 ppm, respectively, with negative
amplitude confirmed the presence of one methylene group. The 13C NMR (DEPT-135)
of 8c clearly indicates the presence of two methylene groups resonating at d 45.0 and
62.3 ppm with reverse amplitude. All the 13C NMR (DEPT-135) spectra are given in the
supporting information.
Electrospray-ionization mass spectrometry (ESI-MS) analysis has been determined for
the representative compounds 8a and 8f. The ESI-MS spectra of trans-ethyl 7-(1-(4-
methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-
b]thiazole-3-carboxylate ([C26H25N3O5S2]þ) 8a showed peaks at m/e 546.2 (65) and m/e
524.2 (33) for [M þ Na]þ and [M þ H]þ fragments which correspond to
[C26H25N3O5S2Na]þ and [C26H26N3O5S2]þ, respectively. In the ESI-MS spectrum of
trans-ethyl 7-(3-acetoxy-1-(4-methoxyphenyl)-4-oxo-azetidin-2-yl)-6-methyl-2-(methyl-
thio)pyrazolo[5,1-b]thiazole-3-carboxylate 8f, one peak was observed at m/e 512.1 (86)
for [M þ Na]þ ion. In addition to this, spectra also displayed peak at m/e 490.2 (67) for
[M þ H]þ corresponding to [C22H24N3O6S2]þ fragment which further confirms the for-
mation of target compound. The ESI-MS spectra are listed in the supporting
information.

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7
H
O
Z
Z
O
P
Z
H
O
P
Cl
Cl Cl
Cl
Cl
O
OH
O
A
O
Cl
Et3N
H
O
Z
Et3NH+Cl-
P Cl
+
+
HO
Cl
C
O
(In case of
(In case of
ethanoic acids)
acid chlorides)
O
O
H3CS
O
N
O
H3CS
O
H3CS
O
S
N
N
S
N
Path A
S
Z
H
N
N
H H
CH3
+
C
Z
H
H
C
O
CH3
N
C
CH3
Z
k1
H
R
N
R
N
exo-attack
direct ring-closure
O
R
O
E-imine
B
cis - -lactams
C
Path B isomerization
'
k2
k2
O
N
H3CS
O
H3CS
O
k3
S
S
H
C
O
conrotatory ring closure
(electrocyclization)
N
H H
N
H
Z
Z
CH3
N
R
N
CH3
O
O
R
trans - -Lactams
D
8
Scheme 4. Plausible reaction pathway for the synthesis of trans-4-pyrazolo[5,1-b]thiazole-3-carboxyl-
ate-b-lactams 8.
The formation of a sterically congested b-lactam system appended with pyrazolo[5,1-
b]thiazole-3-carboxylate moiety having trans-stereochemistry at C–3 and C–4 of the four-
membered ring 8 was unequivocally confirmed by X-ray structural analysis of trans-ethyl
7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-methylthio)pyrazolo[5,
1-b]thiazole-3-carboxylate 8a (Fig. 2).[29] It was crystallized from dichloromethane: hexane
(1:3) as a colorless crystalline solid suitable for single crystal X-ray diffraction. A perspective
view of the molecular structure with atom numbering has been given in Figure 2.
The crystallographic data and structural refinement for the compound 8a, the signifi-
cant bond lengths, bond angles, and torsion angles are listed in supporting information.
All these cycloaddition reactions were found to be highly stereoselective as exclusive
formation of trans-b-lactams 8a–j was observed. The plausible reaction mechanism for
the formation of trans-4-pyrazolo[5,1-b]thiazole-3-carboxylate-b-lactams 8a–j has been
depicted in Scheme 4.
Initially, POCl3 reacts with the 2-substituted ethanoic acid and results in the in situ
generation of an active ester intermediate A which further in the presence of Et3N
affords corresponding ketene B that serves as a basic intermediate for ketene-imine
cycloaddition reaction. Thereafter, nucleophilic attack of lone pair of imine nitrogen to
carbonyl carbon of ketene B from the side of hydrogen (less hindered side) furnishes
zwitterionic intermediate C. This zwitterionic intermediate C upon direct conrotatory
electrocyclic ring closure (k1) should yield thermodynamically less stable cis-b-lactams
by following Path A (k1 > k2), which is highly unfavorable, due to steric factors

8
S. BERRY ET AL.
Figure 3. Synthetic utility of synthesized pyrazolo[5,1-b]thiazole-3-carboxylate anchored b-lactam con-
jugates 8a–j.
associated with bulky group at C-4. As the formation of non-activated ketene dimin-
ished the tendency for direct ring closure, therefore, in our case zwitterionic intermedi-
ate C undergoes an imine isomerization (k2) by following Path B (k2 > k1) to provide
sterically less congested and more-stable zwitterionic intermediate D, leading to the
thermodynamically favorable trans-b-lactams 8 exclusively via conrotatory cyclization
(isomerization-ring closure).[30]
Conclusion
In conclusion, a higher stereoselective synthesis of series of pyrazolo[5,1-b]thiazole-3-
carboxylate tethered Schiff’s bases 6a–f and b-lactam conjugates 8a–j has been achieved.
The structures and stereochemistry of all the novel compounds were established on the
1
basis of various spectroscopic techniques, such as FT-IR, H NMR, 13C NMR, 13C NMR
(DEPT-135), mass spectrometry (ESI-MS) in representative cases, and elemental ana-
lysis. The X-ray crystallographic analysis of compound 8a allowed the stereochemistry
at C-3 of trans-b-lactams 8a–j. In addition, efforts are in progress to synthesize corre-
sponding C-3 functionalized b-lactams. These trans-4-pyrazolo[5,1-b]thiazole-3-carb-
oxylate derivatized b-lactams would also serve as synthons for variety of potential
alcohol, acid, hydrazide, and peptide substituted b-lactams via modification of ester
linkage in accordance with literature reports (Fig. 3).[31–34] The synthesis and further
investigations are underway in this regard in our laboratory. Moreover biological poten-
tial of [5]-fused pyrazolo-thiazole systems are found promising antibacterial agents
against Escherichia coli and Bacillus polymyxa. Additionally, novel Schiff’s bases and
b-lactam conjugates have been submitted for molecular modeling studies which will be
followed by in-vitro screening against of best fit molecules for potential biological activ-
ities and will be reported in near future.
Experimental
All solvents used were of LR grade. The solvents were distilled and dried prior to use
by standard methods[35]. All the reactions were carried out under dry and deoxygenated

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SYNTHETIC COMMUNICATIONSV
9
1
nitrogen atmosphere. H and 13C NMR spectra were recorded on JEOL AL 300 MHz
and BRUKER AVANCE II 400 MHz spectrometer in CDCl3 using TMS as an internal
1
1
standard (400 MHz, H, 100 MHz, 13C, 300 MHz, H, 75 MHz, and 13C). The following
abbreviations are used to indicate the multiplicity in NMR spectra: s – singlet, d –
doublet, t – triplet, q – quartet, m – multiplet. Coupling constants (J) are quoted in
hertz. Infrared spectra were recorded using Thermo scientific Nicolet iS50 (FT-IR) spec-
trophotometer (tmax in cmꢁ1). Melting points were determined in an open capillary on
melting point apparatus Perfit GSI-MP-3. Elemental analysis for C, H, and N atom was
performed with Flash 2000 Organic elemental analyzer. The mass spectra (ESI-MS)
were obtained using a Waters Q-TOF Micromass (YB361) spectrometer (permissible %
error ¼ 5–10 ppm). All the reactions were monitored by thin-layer chromatography
(TLC) using precoated silica 60 F254, 0.25 mm aluminum plates (Merck, Kenilworth,
NJ) with visualization under UV light. Separation and purification of compounds were
done by column chromatography performed on activated silica gel (Qualigen
Chemicals, 60–120 mesh) using 10% ethyl acetate: hexanes as an eluant system.
Preparation of trans-3-functionalized-4-pyrazolo[5,1-b]thiazole-3-carboxylate substi-
tuted b-lactams was carried out under dry and deoxygenated nitrogen atmosphere.
Phosphorus oxychloride (Merck), Et3N (Qualigen), and all other commercially available
compounds/reagents/solvents were of reagent grade quality and used without any fur-
ther purification. Dichloromethane was dried and distilled over anhydrous calcium
chloride (CaCl2) and phosphorus pentoxide (P2O5) respectively. Toluene was distilled
under N2 from sodium-benzophenone immediately before use.
General procedure for the synthesis of pyrazolo[5,1-b]thiazole aldehyde 5
Pyrazolo[5,1-b]thiazole aldehyde 5 was prepared by using reported procedure described
in the cited reference.[26]
Representative procedure for the synthesis of Schiff’s bases 6a–f
Solution of aromatic amine (1 mmol) and pyrazolo[5,1-b]thiazole aldehyde 5 (1 mmol)
in the presence of molecular sieves (4 Å) in dry dichloromethane (15 mL) was stirred at
room temperature. Progress of the reaction was monitored by TLC. After the comple-
tion, reaction mixture was filtered and solvent was evaporated to yield crude product
which was purified by recrystallization from a mixture of dichloromethane and hexane.
Ethyl 7-((4-methoxyphenylimino)methyl)-6-methyl-2-(methylthio)pyrazolo[5,1-
b]thiazole-3-carboxylate (6a)
1
White fluffy solid (0.32 g, 85%). m.p. 155–157 ꢀC. FT-IR: ꢀ (cmꢁ1) 1608 (N ¼ CH). H
NMR (300 MHz, CDCl3): d 1.38 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 2.51 (s, 3H, SCH3), 2.56
(s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.44 (q, J ¼ 6.9 Hz, 2H, CH2CH3), 6.79–7.11 (m, 4H,
ArH), 8.36 (s, 1H, –N ¼ CH). 13C NMR (75 MHz, CDCl3): d 12.6, 14.3, 17.4, 55.3, 61.9,
96.1, 111.6, 114.2, 120.1, 121.9, 137.2, 143.7, 145.2, 148.1, 152.9, 157.8, and 158.1. Anal.

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S. BERRY ET AL.
calcd. for C18H19N3O3S2 (389.49): C, 55.51; H, 4.92; N, 10.79; S, 16.47; found: C, 55.44;
H, 4.86; N, 10.63; S, 16.35.
Representative procedure for the synthesis of pyrazolo[5,1-b]thiazole-3-
carboxylate substituted b-lactams 8a-j
To a solution of Schiff’s base (6) (1 mmol), 2-substituted ethanoic acid/acetoxyacetyl
chloride (7) (1 mmol), and Et3N (3 mmol) in 50 mL dry toluene, was added drop wise,
under nitrogen atmosphere, at reflux temperature, a solution of phosphorus oxychlor-
ide, POCl3 (1.5 mmol) in 20 mL of dry toluene with constant stirring. The reactants
were refluxed for 3–4 h. Progress of the reaction was monitored by TLC. After the com-
pletion, the contents were washed successively with 1 N HCl (30 mL), water (3 ꢂ 30 mL),
5% NaHCO3 (30 mL), and brine (30 mL). The organic layer was separated and dried
over anhydrous sodium sulfate. The solvent was removed under vacuum and the crude
product was purified by column chromatography using silica gel eluting with 10% ethyl
acetate: hexanes and subsequently, products, so obtained, were identified using spectro-
scopic studies.
trans-Ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-
(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate (8a)
Light yellow solid (1.04 g, 76%). m.p. 164–165 ꢀC. FT-IR: ꢀ (cmꢁ1): 1753 (C¼O, b-lac-
tam), 1686 (C¼O, ester). 1H NMR (400 MHz, CDCl3): d 1.44 (t, J ¼ 7.2 Hz, 3H,
CH2CH3), 2.45 (s, 3H, SCH3), 2.51 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.48 (q, J ¼ 7.2 Hz,
2H, CH2CH3), 4.98 (d, J ¼ 1.6 Hz, 1H, C4-H), 5.25 (d, J ¼ 1.6 Hz, 1H, C3-H), 6.77–7.28
(m, 9H, ArH). 13C NMR (100 MHz, CDCl3): d 12.9, 14.3, 17.7, 55.4, 56.0, 62.2, 85.7,
105.7, 114.5, 115.1, 118.4, 120.5, 122.5, 129.8, 130.3, 135.3, 141.9, 151.3, 156.8, 158.1,
161.4. 13C NMR (DEPT-135, CDCl3) d: 12.9 (þ), 14.3 (þ), 17.7 (þ), 55.4 (þ), 56.0 (þ),
62.2 (2), 85.7 (þ), 114.5 (þ), 115.1 (þ), 118.4 (þ), 122.5 (þ), 129.8 (þ), 161.3 (þ).
ESI-MS: Found: m/z 524.25. Calcd for C26H26N3O5S: (M þ H)þ 524.62. Anal. calcd. for
C26H25N3O5S2 (523.62): C, 59.64; H, 4.81; N, 8.02; S, 12.25; found: C, 59.52; H, 4.74; N,
7.90; S, 12.16.
Methods and materials of all the synthesized compounds, general experimental proce-
dures, their spectroscopic data (6a–f and 8a–j), X-Ray Single Crystal data for compound
1
8a, copies of H NMR and 13C NMR (6a–f and 8a–j), DEPT-135 13C NMR (8a–c and
8f) and ESI-MS spectra of (8a and 8f) have been included in the supplementary data.
Supplementary data associated with this article can be found via the supplementary con-
tent section of this article’s web page.
Funding
AB gratefully acknowledges the financial support for this work from the 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 (DST) and UGC-CAS, Panjab University, Chandigarh. SB and PY
acknowledges the financial support from University Grant Commission (UGC), New Delhi vide
Award No. 201112-RGNF-ST-HIM-9284 and 58/(OBC) (CSIR-UGC NET 2016), respectively.

R
SYNTHETIC COMMUNICATIONSV
11
ORCID
Aman Bhalla
http://orcid.org/0000-0003-4081-4116
References
[1] Muller, G. Drug Discov. Today 2003, 8, 681–691. DOI: 10.1016/S1359-6446(03)02781-8.
[2] Takahashi, Y.; Hashizume, M.; Shin, K.; Terauchi, T.; Takeda, K.; Hibi, S.; Tai, K. M.;
Fujisawa, M.; Shikata, K.; Taguchi, R.; et al. J. Med. Chem. 2012, 55, 8450–8463. DOI: 10.
1021/jm300864p.
[3] Mustelin, T.; Tauts, L.; Cosford, N. D. P.; Sergienko, E. Methods for treating leukemia
and myelodysplastic syndrome, and methods for identifying agents for treating same. U.
S. Patent 20090105240. 2009.
[4] Bounaud, P. Y.; Hopkins, S.; Jefferson, E.; Wilson, M.; Wong, M.; Kanouni, M.
Pyrazolothiazole protein kinase modulators. Patent WO2007059341. 2007.
[5] Cherkupally, S. R.; Desari, C. R.; Vookanti, Y.; Adki, N. Org. Commun. 2010, 3, 57–69.
[6] Dangi, R. R.; Hussain, N.; Joshi, A.; Premawat, G.; Talesara, G. L. Ind. J. Chem. 2011,
50B, 1165–1172.
[7] Satbhaiya, S.; Chourasia, O. P. Chem. Sci. Trans. 2015, 4, 819–827.
[8] Madni, M.; Hameed, S.; Ahmed, M. N.; Tahir, M. N.; Al-Masoudi, N. A.; Pannecouque,
C. Med. Chem. Res. 2017, 26, 2653–2665. DOI: 10.1007/s00044-017-1963-1.
[9] el-Sabbagh, O. I.; Baraka, M. M.; Ibrahim, S. M.; Pannecouque, C.; Andrei, G.; Snoeck, R.;
Balzarini, J.; Rashad, A. A. Eur. J. Med. Chem. 2009, 44, 3746–3753. DOI: 10.1016/j.
ejmech.2009.03.038.
[10] Salman, A. S.; Mahmoud, N. A.; Mohamed, M. A.; Abdel-Aziem, A.; Elsisi, D. M. Am. J.
Org. Chem. 2016, 6, 39–53.
[11] Kamel, M. M. Acta Chim. Slov. 2015, 62, 136–151 DOI: 10.17344/acsi.2014.828.
[12] Yuvaraj, S.; Mendon, M.; Almeida, A.; Dhiman, M.; Girish, M. Med. Chem. Res. 2014, 23,
2667–2675. DOI: 10.1007/s00044-013-0825-8.
[13] Bethel, C. R.; Distler, A. M.; Ruszczycky, M. W.; Carey, M. P.; Carey, P. R.; Hujer, A. M.;
Taracila, M.; Helfand, M. S.; Thomson, J. M.; Kalp, M.; et al. Antimicrob. Agents
Chemother. 2008, 52, 3135–3143. DOI: 10.1128/AAC.01677-07.
[14] Thomson, J. M.; Distler, A. M.; Bonomo, R. A. Biochemistry 2007, 46, 11361–11368. DOI:
10.1021/bi700792a.
[15] Weiss, W. J.; Petersen, P. J.; Murphy, T. M.; Tardio, L.; Yang, Y.; Bradford, P. A.;
Venkatesan, A. M.; Abe, T.; Isoda, T.; Mihira, A.; et al. Antimicrob. Agents Chemother.
2004, 48, 4589–4596. DOI: 10.1128/AAC.48.12.4589-4596.2004.
[16] Bethel, C. R.; Taracila, M.; Shyr, T.; Thomson, J. M.; Distler, A. M.; Hujer, K. M.; Hujer,
A. M.; Endimiani, A.; Papp-Wallace, K.; Bonnet, R.; Bonomo, R. A. Antimicrob. Agents
Chemother. 2011, 55, 3465–3475. DOI: 10.1128/AAC.00089-11.
[17] Reddy, D. V. S.; Namratha, R. Der Pharm. Chem. 2013, 5, 235–240.
[18] Arumugam, N.; Periyasami, G.; Raghunathan, R.; Kamalraj, S.; Muthumary, J. Eur. J. Med.
Chem. 2011, 46, 600–607. DOI: 10.1016/j.ejmech.2010.11.039.
[19] Bhalla, A.; Bari, S. S.; Bhalla, J.; Khullar, S.; Mandal, S. Tetrahedron Lett. 2016, 57,
2822–2828. DOI: 10.1016/j.tetlet.2016.05.047.
[20] Bhalla, A.; Bari, S. S.; Vats, S.; Bhalla, J.; Sharma, K.; Narula, D. Tetrahedron Lett. 2016,
57, 4763–4766. DOI: 10.1016/j.tetlet.2016.09.043.
[21] Bhalla, A.; Modi, G.; Bari, S. S.; Kumari, A.; Berry, S.; Hundal, G. Tetrahedron. Lett. 2017,
58, 1160–1165. DOI: 10.1016/j.tetlet.2017.02.011.
[22] Berry, S.; Bari, S. S.; Banik, B. K.; Bhalla, A. Synth. Commun. 2017, 47, 2239–2246. DOI:
10.1080/00397911.2017.1371759.
[23] Bhalla, J.; Bari, S. S.; Rathee, A.; Kumar, A.; Bhalla, A. J. Heterocyclic Chem. 2017, 54,
2297–2306. DOI: 10.1002/jhet.2817.

12
S. BERRY ET AL.
[24] Bhalla, A.; Nagpal, Y.; Berry, S.; Narula, D.; Bari, S. S.; Bhasin, K. K.; Kumar, K. R. Inorg.
Chim. Acta 2018, 477, 172–182. DOI: 10.1016/j.ica.2018.03.028.
[25] Kumari, A.; Bari, S. S.; Modi, G.; Berry, S.; Khullar, S.; Mandal, S. K.; Bhalla, A.
Tetrahedron 2018, 74, 4400–4408. DOI: 10.1016/j.tet.2018.07.008.
[26] Wang, Z.; Ren, J.; Li, Z. Synth. Commun. 2000, 30, 763–769. DOI: 10.1080/
00397910008087378.
[27] Bari, S. S.; Reshma, A.; Bhalla , Hundal, G. Tetrahedron 2009, 65, 10060–10068. DOI: 10.
1016/j.tet.2009.09.086.
[28] Aleksandar, R. T.; Vnya, B. K.; Ranko, P. B.; Niolay, G. V. Tetrahedron 2006, 62,
10339–10347.
[29] X-ray crystal structure deposition number CCDC 1911174.
[30] Bhalla, A.; Venugopalan, P.; Bari, S. S. Tetrahedron 2006, 62, 8291–8302. DOI: 10.1016/j.
tet.2006.06.062.
[31] Mukarram, S.; Bandgar, B. P.; Shaikh, R. U.; Ganapure, S. D.; Chavan, H. V. Med. Chem.
Res. 2017, 26, 262–273. DOI: 10.1007/s00044-016-1744-2.
[32] Muralikrishna, S.; Raveendrareddy, P.; Ravindranath, L. K.; Harikrishna, S.; Raju, P. A. G.
J. Chem. Pharm. Res. 2013, 5, 280–288.
[33] da Costa, J. C. S.; Pais, K. C.; Fernandes, E. L.; de Oliveira, P. S. M.; Mendonca, J. S.; de
Souza, M. V. N.; Peralta, M. A.; Vasconcelos, T. R. A. ARKIVOC 2006, 128–133.
[34] Couty, F.; Evano, G.; Rabasso, N. Tetrahedron 2003, 14, 2407–2412. DOI: 10.1016/S0957-
4166(03)00493-2.
[35] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s text book of prac-
tical organic chemistry. In Vogel’s Text Book of Practical Organic Chemistry. 5th ed. 1989,
1–1540. Raddick, J. A., Bunger, W. B., “Organic solvents” in “Techniques of chemistry”,
3rd ed., Vol. II; Wiley Interscience: New York, 1970, 1–1344