Stereoselective synthesis of novel monocyclic trans-3-halogenated-4-pyrazolyl-β-lactams: Potential synthons and promising biologically active agents

Article abstract of DOI:10.1080/00397911.2017.1371759

Stereoselective synthesis of novel monocyclic trans-3-halogenated-4-pyrazolyl-β-lactams 5 is described. The reaction of ketene derived from α-bromo/chloroethanoic acids 4 using POCl₃ and Et₃N with pyrazolyl substituted imines 3a–d in

Full text of DOI:10.1080/00397911.2017.1371759

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Stereoselective synthesis of novel monocyclic
trans-3-halogenated-4-pyrazolyl-β-lactams:
Potential synthons and promising biologically
active agents
Shiwani Berry, Shamsher S. Bari, Bimal K. Banik & Aman Bhalla
To cite this article: Shiwani Berry, Shamsher S. Bari, Bimal K. Banik & Aman Bhalla (2017):
Stereoselective synthesis of novel monocyclic trans-3-halogenated-4-pyrazolyl-β-lactams:
Potential synthons and promising biologically active agents, Synthetic Communications, DOI:
10.1080/00397911.2017.1371759
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1371759
View supplementary material
Accepted author version posted online: 31
Aug 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of Connecticut]
Date: 01 September 2017, At: 20:02

Stereoselective synthesis of novel monocyclic trans-3-
halogenated-4-pyrazolyl-β-lactams: Potential Synthons and
promising biologically active agents
Shiwani Berry
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University,
Chandigarh, India
Shamsher S. Bari
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University,
Chandigarh, India
Bimal K. Banik
Community Health Systems of South Texas, Edinburg, TX, USA
Aman Bhalla
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University,
Chandigarh, India
Address correspondence to Aman Bhalla, Department of Chemistry and Centre of Advanced
Studies in Chemistry, Panjab University, Chandigarh 160014, India. Tele: +91-172-253-
4417/+919872659217. Fax: +91-172-254-5074. E-mail: amanbhalla@pu.ac.in
1

Full experimental details, their spectral data (3a-d and 5a-h) and copies of 1H NMR, 13C NMR
and FT-IR spectra of (3d and 5a-h) have been included in the supplementary data.
Supplementary data associated with this article can be found via the supplementary content
section of this article’s web page.
ABSTRACT
Stereoselective synthesis of novel monocyclic trans-3-halogenated-4-pyrazolyl-β-lactams
5 is described. The reaction of ketene derived from α-bromo/chloro ethanoic acids 4 using POCl3
and Et3N with pyrazolyl substituted imines 3a-d in refluxing toluene resulted exclusive formation
of trans-β-lactams via [2+2] through cycloaddition reaction. The chemical structures of all the
newly synthesized β-lactams were verified on the basis of spectroscopic techniques such as FT-
IR, 1H NMR, 13C NMR and elemental analysis (CHN). The trans configuration of β-lactams 5 was
assigned with respect to position of C3-H and C4-H. The novel β-lactams 5 are potential synthons
for azetidines, aziridines, 3-unsubstituted azetidinones, 3-alkyl-halo-azetidinones and promising
biologically active agents.
GRAPHICAL ABSTRACT
KEYWORDS: cycloaddition, β-lactams, pyrazolyl, stereoselective, trans-3-halogenated-4-
pyrazolyl-β-lactams
2

Introduction
Nitrogen-containing heterocyclic compounds, always drawn the attention of chemist over
the years due to their wide occurrence in natural products, drugs and pharmaceuticals.[1],[2] Among
these, pyrazole and its analogues has been appreciated in medicinal chemistry due to their potency
as EP1 receptor antagonists (I),[3] monoamine oxidase inhibitor,[4a] anti-COX-1 (II)[4b] and
hypoglycaemic agent[5] (Figure 1). Several other substituted pyrazole derivatives have also shown
diverse pharmacological properties including antirheumatoidal,[6] anti-alzheimer,[7] and hormone
oxytocin agonists.[8] Synthesis of various 3-halogenated monocyclic β-lactams[9] and their hetero-
substituted analogues[10] (III-IV) (Figure 1) have been greatly facilitated due to their promising
medicinal properties and attendant rich chemistry.
Furthermore, 3-halo-4-functionalized β-lactams acts as an effective synthon for the
synthesis of many substituted β-lactams.[11a–c] The transformation of 3-halogenated β-lactams (V-
VIII) (Figure 1) into corresponding 1,4-benzothiazepines (via ring expansion),[11d,e]
aziridines[11f]/azetidines[11g] (via ring opening), 3-unsubstituted azetidinones (via
dehalogenation),[12a] and 3-alkyl/hydroxyalkyl-flouro-β-lactams (via aldol and direct
alkylation)[12b] have been well documented. Although different methods have been reported in
literature for the generation of Cα-halogen center using alkylation, reduction and metalation,
however, synthesis involving cycloaddition of imine and haloketene generated in-situ has been
still a facile, efficient and convenient route for the stereocontrolled formation of α-halo-β-
lactams.[13a,b]
Encouraged by above reports and in continuation to our interest towards the synthesis of
monocyclic-β-lactams, bicyclic-β-lactams, spirocyclic-β-lactams and heterocyclic-β-lactams,[14a–
3

c] we further envisaged to incorporate α-halo-β-lactams with sterically constrained pyrazolyl ring
system into single framework.
Results and Discussion
Starting substrate, pyrazole carbaldehyde 2 was prepared via Vilsmeier-Haack reaction of
pyrazolinone 1 which in turn were prepared by the condensation of phenyl hydrazine with ethyl
acetoacetate at reflux temperature (Scheme 1).[15]
The pyrazole substituted Schiff’s bases 3a-d were prepared by stirring equivalent amount
of an appropriate primary amine and pyrazole carbaldehyde 2 using molecular sieves (4Å) in
dichloromethane at room temperature (Scheme 1, Table 1).
Following thin-layer chromatography (TLC), solvent evaporation and crystallization, the
structure of pyrazole substituted Schiff’s bases 3a-d were confirmed on the basis of spectroscopic
techniques viz., FTIR, NMR (1H, 13C) and CHN elemental analysis.
The synthesis of novel trans-3-bromo/chloro-4-pyrazolyl-β-lactams 5a-h has been
achieved via Staudinger cycloaddition reaction between the ketene generated from α-halo ethanoic
acids 4a-b and Schiff’s bases 3a-d. Initially, 2-bromoethanoic acid 4a was treated with Schiff's
base 3a in the presence of phosphorus oxychloride (POCl3) and triethylamine (Et3N) under
nitrogen atmosphere in dry toluene at reflux temperature. Following thin-layer chromatography
(TLC), solvent evaporation and purification by column chromatography, the product was
identified as trans-1-phenyl-3-bromo-4-(5'-chloro-3'-methyl-1'-phenyl-1H-pyrazol-4'-yl)azetidin-
2-one 5a (Scheme 1, Table 2, entry 1) on the basis of various spectroscopic techniques viz. FT-
IR, 1H NMR, 13C NMR and elemental analysis.
4

Further, the reaction was performed by altering R and X substituents (R = C6H5,
C6H4OCH3(p), CH2C6H5, C6H4CH3(p); X = Br/Cl) (Table 2, entries 2-8). The reaction was found
to be highly stereoselective and has resulted in exclusive formation of trans-β-lactams in all the
cases. All these newly synthesized novel monocyclic trans-3-bromo/chloro-4-pyrazolyl β-lactams
5b-h were purified by column chromatography and their structures were fully characterized on the
13
basis of various spectroscopic techniques viz., FT-IR, NMR (1H and C) along with elemental
analysis (CHN).
FT-IR spectra of the target compounds 5a–h, showed strong absorption bands at 1766-
1758 cm-1 for the C=O of β-lactam ring, medium absorption at 1597-1548 cm-1 for C=N group and
a stong absorption recorded in the range of 684-758 cm-1 is for C–Br/C–Cl supported the formation
of β-lactams. The spatial juxtaposition of the C3-H and C4-H was assigned trans for the title
compounds 5a-h on the basis of the coupling constant values (J = 1.5-2.1 Hz; C3-H and C4-H) in
1H NMR spectra.[14] CHN elemental analysis data of all the synthesized molecules 5a–h were also
in full support with their depicted structures.
It is quite noteworthy that the Staudinger [2+2] cycloaddition favours the stereospecific
formation of α-bromo and α-chloro β-lactams in all cases due to steric hindrance of the bulky
pyrazole group in imine moieties i.e. reaction is highly selective towards trans- configuration and
no traces of cis isomer were detected. These facts can be explained according to plausible
mechanism reported for ketene-imine Staudinger reaction[14] depicted in Scheme 2.
Initially, ketene IX is generated by the addition of phosphorus oxychloride and
triethylamine to α-bromo/chloro ethanoic acids 4 in refluxing toluene. Further, zwitterionic
intermediate X formed by nucleophilic attack of imine nitrogen at the carbonyl carbon of the
ketene which isomerises to zwitterionic intermediate XI followed by conrotatory
5

electrocyclization (isomerization-ring closure) afforded trans-3-halogenated-4-pyrazolyl-β-
lactams 5. These 4-pyrazolyl-β-lactams 5a-h, are air- and moisture-stable, soluble in solvents such
as dichloromethane, chloroform, acetone, toluene, ethyl acetate and obtained as stable solids. In
addition, studies have been underway in laboratory for the transformation of these novel 3-
bromo/chloro β-lactams to diversely functionalized molecules such as azetidines, aziridines, 3-
unsubstituted azetidinones, 3-alkyl-halo-azetidinones in relation to recent reports[11] (Figure 2).
Conclusion
In conclusion, stereoselective synthesis of novel 3-bromo/chloro β-lactams bearing
pyrazole ring has been achieved by treatment of α-bromo/α-chloro acetic acids and
heterosubtituted imines using Et3N. The structures and stereochemistry of all the novel compounds
1
13
were established on the basis of various spectroscopic techniques such as FT-IR, H NMR, C
NMR and elemental analysis. These novel trans-3-halogenated-4-pyrazolyl-substituted-β-lactams
have been submitted for molecular modelling studies which will be followed by in-vitro screening
of best fit molecules for potential biological activities. Further, a detailed report elaborating the
results of biological evaluation and synthetic applications of these newly synthesized β-lactams
will be reported in near future.
Experimental
Melting points were determined in an open capillary on melting point apparatus (Perfit
GSI-MP-3) and are uncorrected. IR spectra were recorded by using Thermo scientific Nicolet iS50
(FT-IR) spectrophotometer (υmax in cm–1). 1H and 13C NMR spectra were recorded on JEOL AL
300 MHz and BRUKER AVANCE II 400 MHz spectrometer using TMS as an internal standard.
The elemental analysis (C, H, N) were recorded on Flash 2000 Organic elemental analyzer All the
6

reactions were monitored by thin layer chromatography (TLC) using precoated silica 60 F254,
0.25 mm aluminum plates (Merck) with visualization under UV light. Column chromatography
was performed using Merck Silica Gel (60-120 mesh) using ethyl acetate-hexanes (10:90) as an
eluant system.
Preparation of novel pyrazole linked 3-halogenated-β-lactams was carried out under dry
and deoxygenated nitrogen atmosphere. Phosphorus oxychloride (Merck), triethylamine
(Qualigen), hydrazine hydrate (Qualigen) and all other commercially available
compounds/reagents/solvents were of reagent grade quality and used without any further
purification. Dimethylformamide and dichloromethane were 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 preparation of Schiff base 3a-d
Solution of aromatic amine (1 mmol) and pyrazole carbaldehyde (1 mmol) in the presence
of molecular sieves (4 Å) in dry methylene chloride (15 mL) was stirred at room temperature.
Progress of the reaction was monitored by TLC. After the completion, reaction mixture was
filtered and solvent was evaporated to yield crude product which was purified by recrystallization
from a mixture of methylene chloride and hexane.
N-[(5'-chloro-3'-methyl-1'-phenyl-1H-pyrazol-4'-yl)methylene]-4methyl
benzenamine 3d
Yellow crystalline solid; yield: 80%; mp: 105-107 °C; FT-IR (νmax, cm-1): 1625, 2917; 1H
NMR (300 MHz, CDCl3): δ 2.36 (3H, s, CH3), 2.62 (3H, s, CH3), 7.01-7.57 (9H, m, Ar-H), 8.39
(1H, s, -N=CH-); 13C NMR (100 MHz, CDCl3): δ 13.8, 20.4, 20.9, 21.0, 109.5, 115.5, 115.8, 117.2,
7

118.8, 120.7, 121.1, 125.0, 125.2, 126.5, 128.5, 128.8, 128.9, 129.1, 129.2, 129.3, 129.7, 130.5,
135.4, 137.6, 137.7, 138.3, 150.2, 150.6, 150.9, 152.7, 161.3; Anal. Calcd. for C18H16ClN3: C
69.79, H 5.21, N 11.44%. Found: C 69.52, H 5.08, N 11.31%.
General procedure for synthesis of 3-bromo/chloro-4-pyrazolyl-β-lactams 5a-h
A solution of phosphorus oxychloride (POCl3, 0.69 mmol, 1.5 equiv.) in dry toluene was
added dropwise to a stirred solution of 2-substituted ethanoic acid (0.55 mmol, 1.2 equiv.), Schiff’s
base (0.46 mmol, 1 equiv.) and distilled triethyl amine (1.38 mmol, 3 equiv.) in dry toluene under
nitrogen atmosphere. The reaction mixture was refluxed for 3-4 h. The solvent was evaporated and
crude product was extracted with CH2Cl2. The organic layer was washed with water (3x10 ml),
1N HCl (3x10 ml), 5% NaHCO3 (3x10 ml) and brine (3x10 ml), then dried (Na2SO4) and
concentrated. The crude product was then isolated by column chromatography over Silica gel
using hexane/EtOAc (90:10) as eluent to afford pure products.
trans-1-Phenyl-3-bromo-4-(5'-chloro-3'-methyl-1'-phenyl-1H-pyrazol-4'-yl)-
azetidin-2-one 5a
White solid; yield 75%; mp 118-120 °C; IR (νmax, cm-1): 1760 (C=O); 1H NMR (300 MHz,
CDCl3): δ 2.31 (3H, s, CH3), 4.97 (1H, d, J = 2.1 Hz, C4–H), 5.05 (1H, d, J = 2.1 Hz, C3–H), 7.11-
13
7.52 (10H, m, ArH); C NMR (75 MHz, CDCl3): δ 13.0, 29.8, 48.0, 57.9, 61.4, 117.0, 117.1,
124.8, 125.0, 128.5, 129.1, 129.4, 136.9, 137.7, 148.0, 159.8; Anal. Calcd. for C19H15BrClN3O: C
54.76, H 3.63, N 10.08%. Found: C 54.62, H 3.56, N 9.82%.
Acknowledgements and Funding
8

A.B. 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 (DST) and UGC-CAS, Panjab University,
Chandigarh. S.B. acknowledge the financial support from University Grants Commission (UGC)
vide sanction No. F1-17.1/2011-12/RGNF-ST-HIM-9284/ (SA-III/ web site) dated 06-06-2012.
References
[1] Dasari, B.; Jimmidi, R.; Arya, P. Eur. J. Med. Chem. 2015, 94, 497.
[2] Kaur, K.; Kumar, V.; Sharma, A. K.; Gupta, G. K. Eur. J. Med. Chem. 2014, 77, 121; (b) Singh,
N.; Mishra, B. B.; Bajpai, S.; Singh, R. K.; Tiwari, V. K. Bioorg. Med. Chem. 2014, 22,
18.
[3] Hall, A.; Billinton, A.; Brown, S. H.; Clayton, N. M.; Chowdhury, A.; Giblin, G. M. P.;
Goldsmith, P.; Hayhow, T. G.; Hurst, D. N.; Kilford, I. R. et al. Bioorg. Med. Chem. Lett.
2008, 18, 3392.
[4] (a) Manna, F.; Chimenti, F.; Bolasco, A.; Secci, D.; Bizzarri, B.; Befani, O.; Turini, P.;
Mondovı`, B.; Alcaro, S.; Tafi, A. Bioorg. Med. Chem. Lett. 2002, 12, 3629; (b) Elshemy,
H. A. H.; Abdelall, E. K. A.; Azouz, A. A.; Moawad, A.; Ali, W. A. M.; Safwat, N. M.
Eur. J. Med. Chem. 2017, 127, 10.
[5] Mokhtar, H. M.; El-Khawass, S. M. J. Chin. Chem. Soc. 1988, 35, 57.
[6] Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S; Graneto,
M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M. et al. J. Med. Chem. 1997, 40, 1347.
[7] Narlawar, R.; Pickhardt, M.; Leuchtenberger, S.; Baumann, K.; Krause, S.; Dyrks, T.; Weggen,
S.; Mandelkow, E.; Schmidt, E. Chem. Med. Chem. 2008, 3, 165.
[8] Pitt, G. R. W.; Batt, A. R.; Haigh, R. M.; Penson, A. M.; Robson, P. A.; Rooker, D. P.; Tartar,
A. L.; Trim, J. E.; Yea, C. M.; Roe, M. B. Bioorg. Med. Chem. Lett. 2004, 14, 4585.
[9] (a) Subudhi, B. B.; Ghosh, G. Bull. Chem. Soc. Ethiop. 2012, 26(3), 455; (b) Gawande, S. K.;
Khadsan, R. E. Int. J. Pharm. Sci. Res. 2014, 5(7), 2966; (c) Chavan, A. A.; Pai, N. R.
Molecules 2007, 12, 2467; (d) Desai, P. S.; Naik, P. J. Discovery 2014, 17(47), 7; (e) Azab,
I. H. E.; Rady, E. A. E. Ind. J. Chem. 2014, 53B, 1194.
[10] (a) Chandrashekaraiah, M.; Lingappa, M.; Gowda, V. D. C.; Bhadregowda, D. G. J. Chem.
2014, 2014, 1; (b) Patel, N. B.; Patel, J. C. Arabian J. Chem. 2011, 4, 403; (c) Bhagat, T.
M.; Rathod, S. P.; Swamy, D. K.; Kuberkar, S. V. Int. J. Chem. Tech. Res. 2012, 4, 272;
(d) Muralikrishna, S.; Raveendrareddy, P.; Ravindranath, L. K.; Harikrishna, S.; Raju, P.
A. G. J. Chem. Pharm. Res. 2013, 5(10), 280; (e) Shah, S. H.; Patel, P. S. Res. J. Chem.
Sci. 2012, 2, 62.
[11] (a) Skiles, J. W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277; (b) Firestone, R. A.; Barker,
P. L.; Pisano, J. M.; Ashe, B. M.; Dahlgreen, M. E. Tetrahedron 1990, 46, 2255; (c) Singh,
G. S.; Singh, T.; Lakhan, R. Nat. Acad. Science Lett. 1997, 20, 49; (d) Fodor, L.; Csomos,
P.; Csampai, A.; Sohar, P. Synthesis 2010, 2010, 2943; (e) Csomos, P.; Fodor, L.; Csampai,
A.; Sohar, P. Tetrahedron 2010, 66, 3207; (f) D’hooghe, M.; Mollet, K.; Dekeukeleire, S.;
9

De Kimpe, N. Org. Biomol. Chem. 2010, 8, 607; (g) Driessche, B. V.; Brabandt, W. V.;
D’hooghe, M.; Dejaegher, Y.; De Kimpe, N. Tetrahedron 2006, 62, 6882.
[12] (a) Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.; Piersanti, G. Org. Lett. 2000, 2(8), 1077;
(b) Tarui, A.; Kawashima, N.; Kawakita, T.; Sato, K.; Omote, M.; Ando, A. J. Org. Chem.
2013, 78, 7903.
[13] (a) Bose, A. K.; Spiegelman, G.; Manhas, M. S. Tetrahedron Lett. 1971, 12, 3167; (b) Duran,
F.; Ghosez, L. Tetrahedron Lett. 1970, 11, 245.
[14] (a) Bhalla, A.; Bari, S. S.; Vats, S.; Bhalla, J. Sharma, K.; Narula, D. Tetrahedron Lett. 2016,
57, 4763; (b) Bhalla, A.; Modi, G.; Bari, S. S.; Kumari, A.; Narula, D.; Berry, S.
Tetrahedron: Asymmetry 2017, 28, 307; (c) Bhalla, A.; Modi, G.; Bari, S. S.; Kumari, A.;
Berry, S.; Hundal, G. Tetrahedron Lett. 2017, 58, 1160. (and references cited therein).
[15] Xu, C.-J.; Shi, Y.-Q. J. Chem. Crystallogr. 2011, 41, 1816.
10

Table 1. Synthesis of pyrazolyl substituted Schiff’s bases 3a-d.
Entry
R
Schiff’s base 3
Yielda (%)
1
2
3
4
C6H5
3a
3b
3c
3d
85
82
79
80
C6H4OCH3(p)
CH2C6H5
C6H4CH3(p)
aYield of pure isolated product with correct analytical and spectral data.
11

Table 2. 3-Bromo/chloro-4-pyrazolyl-β-lactams 5a-h.
Entry
X
R
trans-β-Lactams 5
Yielda (%)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Cl
Cl
Cl
Cl
C6H5
5a
5b
5c
5d
5e
5f
75
68
66
72
79
74
69
70
C6H4OCH3(p)
CH2C6H5
C6H4CH3(p)
C6H5
C6H4OCH3(p)
CH2C6H5
C6H4CH3(p)
5g
5h
aYield of pure isolated product after chromatographic purification with correct analytical and spectral data.
12

Figure 1. Structures of biologically active pyrazoles (I-II), α-halo heterosubstituted β-lactams
(III-IV), α-halo β-lactams of synthetic utility (V-VIII) and title compounds 5(a-h).
13

Figure 2. Synthetic utility of 3-bromo/chloro-4-pyrazolyl-β-lactams 5a-h.
14

Scheme 1. Synthesis of pyrazolyl substituted Schiff’s bases 3a-d and 3-bromo/chloro-4-
pyrazolyl-β-lactams 5a-h.
15

Scheme 2. A plausible mechanism for the formation of trans-3-halogenated-4- pyrazolyl-β-
lactams 5.
16