Synthesis of new N-sulfonyl monocyclic β-lactams and the investigation of their antibacterial activities

Article abstract of DOI:10.1080/10426500902773161

New monocyclic β-lactams 4-6 were synthesized by a ketene-imine [2+2] cycloaddition reaction. The prepared monocyclic -lactams 4-6 were cleaved by ceric ammonium nitrate (CAN) to give NH β- lactams 7-9. The NH -β- lactams were converted to N-sulfonyl -lactams 10-21 by treatment with four different sulfonyl chlorides in the presence of Et₃N and 4-N,N-dimethylaminopyridine (DMAP). Some of these monocyclic β-lactams were active against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa.

Full text of DOI:10.1080/10426500902773161

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis of New N-Sulfonyl Monocyclic
β-Lactams and the Investigation of Their
Antibacterial Activities
Aliasghar Jarrahpour a , Mohammad Motamedifar b , Maaroof Zarei a
& Mostafa Mimouni c
a Department of Chemistry, College of Sciences , Shiraz University ,
Shiraz, Iran
b Department of Bacteriology and Virology, Shiraz Medical School ,
Shiraz University Medical Science , Shiraz, Iran
c Laboratoire Chimie des Matériaux , Université Mohammed
Premier , Oujda, Morocco
Published online: 03 Feb 2010.
To cite this article: Aliasghar Jarrahpour , Mohammad Motamedifar , Maaroof Zarei & Mostafa
Mimouni (2010) Synthesis of New N-Sulfonyl Monocyclic β-Lactams and the Investigation of Their
Antibacterial Activities, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:2, 287-297
To link to this article: http://dx.doi.org/10.1080/10426500902773161
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Phosphorus, Sulfur, and Silicon, 185:287–297, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902773161
SYNTHESIS OF NEW N-SULFONYL MONOCYCLIC
β-LACTAMS AND THE INVESTIGATION OF THEIR
ANTIBACTERIAL ACTIVITIES
Aliasghar Jarrahpour,1 Mohammad Motamedifar,2
Maaroof Zarei,1 and Mostafa Mimouni3
1Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran
2Department of Bacteriology and Virology, Shiraz Medical School, Shiraz
University Medical Science, Shiraz, Iran
3Laboratoire Chimie des Mate´riaux, Universite´ Mohammed Premier,
Oujda, Morocco
New monocyclic β-lactams 4–6 were synthesized by a ketene-imine [2+2] cycloaddition
reaction. The prepared monocyclic β-lactams 4–6 were cleaved by ceric ammonium nitrate
(CAN) to give NH-β-lactams 7–9. The NH-β-lactams were converted to N-sulfonyl β-lactams
10–21 by treatment with four different sulfonyl chlorides in the presence of Et3N and 4-N,N-
dimethylaminopyridine (DMAP). Some of these monocyclic β-lactams were active against
Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antibacterial activity; 2-azetidinones; imines; ketenes; Staudinger reaction;
N-sulfonyl β-lactams
INTRODUCTION
The class of compounds known as β-lactam antibiotics has served an important and
highly successful role in medicine and in pharmaceutical industry.1 Miracle drugs such as
penicillins and cephalosporins have improved the health and life expectancy of humans since
their discovery in the early part of the 20th century.2 However the widespread use of these
agents has resulted in an ever increasing number of antibiotic-resistant bacterial strains, and
the need for β-lactams with greater potency and broader range has become increasingly
important.3 Following the initial introduction of penicillin during World War II, a variety of
classes of β-lactam antibiotics were sequentially identified, including the penams, cephems,
clavulanates, monobactams, carbapenems, and trinems.4,5 In the mid 1970s, a new class
of β-lactam antibiotics characterized by a single monocyclic structure, called monocyclic
Received 16 September 2008; accepted 20 January 2009.
The authors thank the Shiraz University Research Council for financial support (Grant No. 87-GR-SC-23).
Address correspondence to Aliasghar Jarrahpour, Department of Chemistry, College of Sciences, Shiraz
University, Shiraz 71454, Iran. E-mail: jarrah@susc.ac.ir or aliasghar6683@yahoo.com
287

288
A. JARRAHPOUR ET AL.
β-lactams, was introduced.6 These are molecules that do not contain a ring fused to the
β-lactam ring.7 Some monocyclic β-lactams containing the phthalimido group have shown
good antibacterial activity.8,9 Recently scientists have found that monocyclic β-lactams are
also as inhibitors of cytomegalovirus protease,10,11 inhibitors of thrombin and tryptase,12,13
cholesterol absorption,14,15 human leukocyte elastase (HLE),16,17 porcine pancreatic elastase
(PPE),18 and cysteine protease,19,20 and are used as anticancer agents.21,22 In addition to
their diverse current uses as pharmaceuticals, β-lactams are of interest as synthetic building
blocks23,24 and in the semisynthesis of Taxol.25 Selective bond cleavage of the strained
β-lactam ring coupled with further interesting synthetic transformations renders these
fascinating molecules powerful synthetic building blocks.26,27 In addition, the existence of
the methoxy group on the molecules enhances the various biological activities.28
One group of monocyclic β-lactams is the N-sulfonyl monocyclic β-lactams.29,30
Recently, N-sulfonyl β-lactams have been shown to be highly useful compounds for medic-
inal chemistry.31 Numerous articles can be found throughout the literature describing the
preparation and use of N-sulfonyl β-lactams (N-SO2R-β-lactams) as intermediates in the
synthesis of other target molecules.32 About 600 N-sulfonyl-β-lactams have been examined
for biological properties.33 Konaklieva et al. have synthesized the N-sulfonyl-β-lactams and
have tested them against some bacteria.34 It appears that the nature of the substituents has
many crucial roles to play in bioactivity (bioavailability and bioselectivity).
As a consequence, a large number of chemical methods for the production of β-
lactams have been developed, and the topic has been documented and reviewed several
times.35–37 Ketene–imine cycloaddition (Staudinger reaction) has provided useful and eco-
nomical entries to β-lactams, mainly due to the ready availability of both Schiff bases
and ketenes.38–40 The Staudinger reaction was the first method by which a 2-azetidinone
was synthesized.41 Ketene–imine cycloaddition is one of the most effective methods that
allows us to obtain selectively cis-β-lactams.42–44 Generally, acid chlorides are used as
precursors of ketene in the Staudinger reaction.45–47 p-Methoxyphenyl group (PMP) has
been used extensively as an N-protecting group in β-lactam chemistry. The N-PMP-β-
lactams were oxidatively cleaved with ceric ammonium nitrate (CAN) into N-unsubstituted
β-lactams.48–50
In this article, we describe the synthesis and antibacterial activities of some new
monocyclic β-lactams bearing various sulfonyl groups at position N1.
RESULTS AND DISCUSSION
2,3-Dimethoxybenzaldehyde was condensed with p-anisidine to give, after
recrystallization from cold methanol, the Schiff base, (2,3-dimethoxybenzylidene)-
(4-methoxyphenyl)amine 1 as a yellow solid. 3-Nitrophthaloylglycyl chloride 2 and
3-nitrophthaloyl alaninyl chloride 3 were prepared from 3-nitrophthalic anhydride and
amino acids glycine and alanine, respectively, in two steps. Monocyclic β-lactams
4–6 were obtained by the [2+2] cycloaddition of imine 1 with ketenes derived from
acyl chlorides 2, 3, and phenoxyacetyl chloride in the presence of triethylamine in dry
dichloromethane at −10◦C, respectively. The 1H NMR spectra of 4 and 6 showed doublets
for H-3 and H-4 with coupling constants of J = 4.5–5.5 Hz, which confirmed the cis
stereochemistry for these monocyclic β-lactams. The IR spectra definitely showed the
characteristic absorption of carbonyl β-lactam at 1743–1785 cm−1 and the 13C NMR
spectra exhibited carbonyl function (β-lactam ring) at 163.3–166.5 ppm for β-lactams

NEW N-SULFONYL MONOCYCLIC β-LACTAMS
289
4–6. These monocyclic β-lactams were then transformed to N-unsubstituted monocyclic
β-lactams 7–9 by treatment with ceric ammonium nitrate (NH4)2Ce(NO3)6 called CAN),
at −10◦C, in a short reaction time and with good yields.
Then the crude products were purified by recrystallization from (hexane:EtOAc, 4:6).
The deprotection of the PMP group from these monocyclic β-lactams was confirmed by
1
the presence of NH absorption at 3301–3422 cm−1 in their IR spectra. Of course, H
NMR spectra showed the NH at 6.33–6.73 ppm for compounds 7–9. Treatment of N-
unsubstituted monocyclic β-lactams 7–9 with methanesulfonyl chloride, benzenesulfonyl
chloride, p-toluenesulfonyl chloride, and 2-naphthalenesulfonyl chloride in the presence of
triethylamine and 4-N,N-dimethylaminopyridine (DMAP) gave the N-sulfonyl β-lactams
10–21 (Scheme 1, Table I).
The formation of N-SO2R β-lactams 10–21 was conveniently established from their
spectral data. The IR spectra showed the 2-azetidinone carbonyls at 1765–1788 cm−1, S O
absorptions at 1326–1355 cm−1 and the NH peaks have been eliminated. TLC monitoring
O
O
O
O
2
2
R
1
R
1
CH2Cl2, Et3N
+
R
R
N
Cl
N
O
O
4-5
O
1
O
4: (R1, R2) = (3-NO2PhthN, H)
5: (R1, R2) = (3-NO2PhthN, CH3)
6: (R1, R2) = (PhO, H)
(NH4)2Ce(NO3)6
CH3CN, H2O
7: (R1, R2) = (3-NO2PhthN, H)
8: (R1, R2) = (3-NO2PhthN, CH3)
9: (R1, R2) = (PhO, H)
O
O
O
R3SO2Cl, CH2Cl2
Et3N, DMAP
2
2
R
R
1
1
R
R
O
N
O
O
N
O
S
O
H
3
R
10-21
NO2
7-9
3-NO2PhthN :
O
N
O
10: (R1, R2, R3) = (3-NO2PhthN, H, CH3)
11: (R1, R2, R3) = (3-NO2PhthN, H, C6H5)
12: (R1, R2, R3) = (3-NO2PhthN, H, 4-CH3-C6H4)
13: (R1, R2, R3) = (3-NO2PhthN, H, 2-naphtalene)
14: (R1, R2, R3) = (3-NO2PhthN, CH3, CH3)
15: (R1, R2, R3) = (3-NO2PhthN, CH3, C6H5)
16: (R1, R2, R3) = (3-NO2PhthN, CH3, 4-CH3-C6H4)
17: (R1, R2, R3) = (3-NO2PhthN, CH3, 2-naphtalene)
18: (R1, R2, R3) = (C6H5O, H, CH3)
19: (R1, R2, R3) = (C6H5O, H, C6H5)
20: (R1, R2, R3) = (C6H5O, H, 4-CH3-C6H4)
21: (R1, R2, R3) = (C6H5O, H, 2-naphtalene)
Scheme 1 Synthesis of N-sulfonyl β-lactams 10–21.

290
A. JARRAHPOUR ET AL.
Table I Monocyclic β-lactams 4–21
Compounds
R1
R2
R3
Isolated Yield %
4
5
6
7
8
3-NO2PhthN
3-NO2PhthN
PhO
3-NO2PhthN
3-NO2PhthN
PhO
3-NO2PhthN
3-NO2PhthN
3-NO2PhthN
3-NO2PhthN
3-NO2PhthN
3-NO2PhthN
3-NO2PhthN
3-NO2PhthN
PhO
H
Me
H
H
Me
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
—
—
—
—
—
—
Me
57
52
90
87
85
90
78
80
85
72
82
80
75
68
88
83
84
81
9
10
11
12
13
14
15
16
17
18
19
20
21
Ph
4-MeAr
2-Naphthalene
Me
Ph
4-MeAr
2-Naphthalene
Me
PhO
PhO
PhO
Ph
4-MeAr
2-Naphthalene
in all of the above reactions confirmed the presence of the new compound. All new product
structures have been confirmed by elemental analyses and mass spectra (molecular ion).
ANTIMICROBIAL ACTIVITY AND RESULTS
All the synthesized compounds were screened for antimicrobial activity against one
Gram-positive, methicillin-resistant strain (Staphylococcus aureus), one Gram-negative
(Pseudomonas aeruginosa), one capsulated Gram-negative (Kelebsiella pneumonia), and a
Gram-positive spore forming (Bacillus subtilis) bacteria using the reported method.51 (See
Supplemental Materials and Table II, available online.)
CONCLUSION AND PERSPECTIVES
A series of new N-sulfonyl β-lactams monocyclic Gram-positive and Gram-
negative inhibitors was prepared. Improvement in bacteria-based inhibitor potency
was observed in comparison to previously disclosed bicyclic β-lactams carrying the
“amino(phenyl)acetyl]amino tail” at lactam C-6 of penicillin, for example. Antibacterial
activity for several of the C2-substituted inhibitors was examined, with a N-sulfonyl
β-lactams analog achieving good balance in protein-shifted MIC studies. This first series
described here leads us to prepare some analogues containing combined pharmacophores
sites able to inhibit HIV-integrase and bacteria.53 The inclusion of a P atom instead of S
will increase the tolerance of the future series.
EXPERIMENTAL
All needed chemicals were purchased from Merck and Fluka chemical companies.
Dichloromethane and triethylamine were dried by distillation over CaH2 and then stored

NEW N-SULFONYL MONOCYCLIC β-LACTAMS
291
over molecular sieve 4Å. IR spectra were run on a Shimadzu FT-IR 8300 spectrophotometer.
1H NMR and 13C NMR spectra were recorded in DMSO-d6 and CDCl3 using a Bruker
Avance DPX instrument (1H NMR 250 MHz, 13C NMR 62.9 MHz). Chemical shifts were
reported in ppm (δ) downfield from TMS. The mass spectra were recorded on a Shimadzu
GC-MS QP 1000 EX instrument. Elemental analyses were run on a Thermo Finnigan Flash
EA-1112 series. Melting points were determined in open capillaries with Buchi 510 melting
point apparatus and are not corrected. Thin-layer chromatography was carried out on silica
gel 254 analytical sheets obtained from Fluka. Column chromatography was carried out on
silica gel 60 Merck (230–270 mesh).
((2,3-Dimethoxybenzylidene)-(4-methoxyphenyl)amine (1)
A mixture of p-anisidine (5.00 g, 40.71 mmol) and 2,3-dimethoxy benzaldehyde
(6.80 g, 40.71 mmol) was refluxed in ethanol for 5 h. Then the solvent was evaporated
under reduced pressure. The crude product was recrystallized from cold methanol to give
pure Schiff base 1 as a yellow solid (8.82 g, 80%). mp 66–68◦C. IR (KBr) (cm−1): 1618
(C N). 1H NMR (CDCl3): δ 3.62, 3.70, 3.85 (3 OMe, 3 s, 9H), 6.54–7.74 (ArH, m, 7H),
8.85 (HC N, s, 1H). 13C NMR (CDCl3) δ 64.4, 64.8 (OMe), 122.8, 123.7, 127.8, 131.4,
133.3, 139.2, 154.4, 158.9, 161.9, 163.1 (aromatic carbons), 167.4 (C N). MS (m/z,%):
271 (M+, 11), 256 (8), 241 (14), 149 (29), 134 (15), 128 (6), 123 (100), 121 (36), 92 (19),
77 (30). Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 71.07; H, 6.44;
N, 5.12.
3-Nitrophthaloylglycyl Chloride (2)
3-Nitrophthaloylglycinewaspreparedbyareportedmethod.52 3-Nitrophthaloylglycyl
chloride was obtained by heating 3-nitrophthaloyl glycine (10.0 g, 39.9 mmol) and thionyl
chloride (20 mL, 275 mmol) for 2 h. Then the excess of thionyl chloride was removed by
distillation, and it was crystallized from light petroleum to give acyl chloride 2 as a light
yellow crystal (9.98 g, 93%). It was stable for long periods in a desiccator over CaCl2. mp
116–118◦C. IR (KBr) (cm−1): 1735, 1775 (phthalimido, CO), 1805 (COCl).
3-Nitrophthaloylalaninyl Chloride (3)
3-Nitrophthaloylalaninewaspreparedbyareportedmethod.52 3-Nitrophthaloylalanyl
chloride 3 was prepared by the same method as compound 2. Yield 90%. mp 108–110◦C.
IR (KBr) (cm−1): 1740, 1785 (phthalimido, CO), 1810 (COCl).
General Procedure for Synthesis of Monocyclic β-Lactams (4–6)
A solution of the corresponding acyl chloride (1.50 mmol) in dry CH2Cl2 (10 mL)
was slowly added to a solution of (2,3-dimethoxybenzylidene)-(4-methoxyphenyl) amine
1 (1.00 mmol) and triethylamine (3.00 mmol) in CH2Cl2 (15 mL) at −10◦C. The reaction
mixture was then allowed to warm to room temperature and stirred overnight. Then it
was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried
(Na2SO4), and the solvent was evaporated to give the crude product, which was then purified
by column chromatography over silica gel.

292
A. JARRAHPOUR ET AL.
2-[2-(2,3-Dimethoxyphenyl)-1-(4-methoxyphen-yl)-4-oxo-azetidin-3-yl]-
4-nitroiso-indole-1,3-dione (4). β-Lactam 4 was obtained from Schiff base 1 and acyl
chloride 2. Yield 57% (eluent hexane/EtOAc 6:4). mp 186–188◦C. IR (KBr) (cm−1): 1730,
1
1775 (phth. CO), 1785 (CO, β-lactam). H NMR (CDCl3): δ 3.71, 3.87, 4.52 (3 OMe, 3
s, 9H), 5.28 (H-4, d, 1H, J = 4.5 Hz), 5.78 (H-3, d, 1H, J = 5.5 Hz), 6.76–8.03 (ArH,
m, 10H). 13C NMR (CDCl3): δ 53.9, 55.8, 56.1 (OMe), 58.8 (C-4), 61.2 (C-3), 113.5,
114.7, 118.9, 119.3, 120.9, 123.3, 125.7, 127.7, 131.2, 133.6, 136.2, 147.2, 152.3, 156.8
(aromatic carbons), 161.6 (CO), 164.5 (CO, β-lactam). MS (m/z,%): 503 (M+, 32), 486
(17), 354 (63), 311 (12), 271 (6), 162 (27), 149 (51), 134 (18), 123 (100), 108 (36), 91
(13), 75 (38). Anal. Calcd for C26H21N3O8: C, 62.03; H, 4.20; N, 8.35. Found: C, 62.18;
H, 4.27; N, 8.43.
2-[2-(2,3-Dimethoxyphenyl)-1-(4-methoxyphen-yl)-3-meth-yl-4-oxo-azeti
din-3-yl]-4-nitroisoindole-1,3-dione (5). β-Lactam 5 was obtained from Schiff base
1 and acyl chloride 3. Yield 52% (eluent hexane/EtOAc 1:1). mp 178–180◦C. IR (KBr)
(cm−1): 1740, 1778 (phth. CO), 1785 (CO, β-lactam). 1H NMR (CDCl3): 1.81 (Me, s, 3H),
3.71, 3.80, 3.88 (3 OMe, 3 s, 9H), 5.68 (H-4, s, 1H), 6.69–8.12 (ArH, m, 10H). 13C NMR
(CDCl3): 20.4 (Me), 56.5, 56.8, 61.8 (OMe), 63.5 (C-4), 71.5 (C-3), 113.8, 114.3, 115.4,
119.8, 120.7, 124.7, 127.6, 129.6, 131.9, 134.5, 137.0, 146.1, 148.2, 157.4 (aromatic
carbons), 166.1 (CO), 166.5 (CO, β-lactam). MS (m/z,%): 517 (M+, 15), 500 (10), 368
(13), 351 (17), 294 (25), 271 (22), 193 (8), 165 (7), 149 (25), 123 (100), 108 (22), 91 (11),
75 (18). Anal. Calcd for C27H23N3O8: C, 62.67; H, 4.48; N, 8.12. Found: C, 62.59; H,
4.55; N, 8.09.
4-(2,3-Dimethoxyphenyl)-1-(4-methoxyphenyl)-3-phenoxy-2-azetidinone
(6). β-Lactam 6 was obtained from Schiff base 1 and phenoxyacetyl chloride. Yield 90%
1
(eluent hexane/EtOAc 7:3). mp 148–150◦C. IR (KBr) (cm−1): 1743 (CO β-lactam). H
NMR (CDCl3): δ 3.71, 3.81, 3.85 (3 OMe, 3 s, 9H), 5.52 (H-4, d, 1H, J = 5 Hz), 5.78
(H-3, d, 1H, J = 5.1 Hz), 6.77–7.28 (ArH, m, 12H). 13C NMR (CDCl3): δ 55.8, 56.1, 56.5
(OMe), 78.0 (C-4), 81.8 (C-3), 113.1, 114.8, 116.5, 119.2, 120.6, 122.6, 124.2, 126.8,
129.8, 130.9, 148.0, 152.7,156.8, 157.7 (aromatic carbons), 163.3 (CO, β-lactam). MS
(m/z,%): 405 (M+, 34), 374 (10), 312 (12), 256 (100), 241 (8), 213 (16), 163 (15), 148
(38), 134 (19), 123 (65), 108 (23), 77 (55). Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72;
N, 3.45. Found: C, 70.96; H, 5.68; N, 3.52.
General Procedure for Synthesis of N-Unsubstituted (NH)-β-Lactams
(7–9)
A solution of (NH4)2Ce(NO3)6 (CAN) (3.00 mmol) in water (15 mL) was added
dropwise to a solution of each of β-lactams 4–6 (1.00 mmol) in CH3CN (25 mL) at –10◦C.
The mixture was stirred at this temperature for 45 min. Then, water (30 mL) was added, and
the mixture was extracted with EtOAc (3 × 20 mL) and washed with a saturated solution
of NaHCO3 (40 mL). The aqueous layer of NaHCO3 was extracted again with EtOAc
(15 mL), and all organic layers were combined and washed with 10% NaHSO3 (2 × 30
mL), NaHCO3 (20 mL), and brine (20 mL), and dried over sodium sulfate. After filtration
and evaporation of the solvent in vacuo, the crude product was purified by recrystallization
from hexane:EtOAc, 4:6 to afford the products.
2-[2-(2,3-Dimethoxyphenyl)-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-
dione (7). (87%). mp 106–108◦C. IR (KBr) (cm−1): 1736, 1778 (phth, CO), 1790 (CO,
1
β-lactam), 3422 (NH). H NMR (CDCl3): δ 3.52, 3.62 (2 OMe, 2 s, 6H), 5.20 (H-4, dd,

NEW N-SULFONYL MONOCYCLIC β-LACTAMS
293
1H, J = 10.0, 5.0 Hz), 5.61 (H-3, d, 1H, J = 5.2 Hz), 6.61 (NH, brs, 1H), 6.89–8.07 (ArH,
m, 6H). 13C NMR (CDCl3): δ 58.5, 59.3 (OMe), 59.7 (C-4), 61.0 (C-3), 111.9, 116.8,
118.9, 122.7, 126.7, 129.9, 134.6, 143.8, 151.3, 160.2 (aromatic carbons), 163.2 (CO),
164.2 (CO, β-lactam). MS (m/z,%): 397 (M+, 16), 354 (11), 298 (16), 237 (8), 205 (39),
192 (15), 166 (30), 148 (25), 119 (11), 103 (36), 91 (13), 75 (100), 43 (50). Anal. Calcd
for C19H15N3O7: C, 57.43; H, 3.81; N, 10.58. Found: C, 57.57; H, 3.87; N, 10.51.
2-[2-(2,3-Dimethoxyphenyl)-3-methyl-4-oxo-azetidin-3-yl]-4-nitroisoin
dole-1,3-dione (8). (85%). mp 124–126◦C. IR (KBr) (cm−1): 1730, 1770 (Phth, CO),
1
1785 (CO, β-lactam), 3410.1 (NH). H NMR (CDCl3): δ 1.92 (Me, s, 3H), 3.57, 3.72 (2
OMe, 2 s, 6H), 5.11 (H-4, d, 1H, J = 4.5 Hz), 6.33 (NH, brs, 1H), 6.66–7.99 (ArH, m,
6H). 13C NMR (CDCl3): δ 20.6 (Me), 57.2, 60.3 (OMe), 62.2 (C-4), 73.8 (C-3), 114.1,
117.3, 120.5, 125.3, 130.4, 137.4, 146.3, 153.4, 163.4, 166.2 (aromatic carbons), 169.5
(CO), 171.2 (CO, β-lactam). MS (m/z,%): 411 (M+, 17), 368 (13), 351 (13), 321 (7), 246
(17), 219 (32), 177 (46), 166 (33), 148 (45), 133 (12), 103 (46), 75 (100), 55 (30). Anal.
Calcd for C20H17N3O7: C, 58.39; H, 4.17; N, 10.21. Found: C, 58.43; H, 4.30; N, 10.29.
4-(2,3-Dimethoxyphenyl)-3-phenoxy-2-azetidin-one (9). (90%). mp 116–
1
118◦C. IR (neat)(cm−1): 1761 (CO, β-lactam), 3301 (NH). H NMR (CDCl3): δ 3.71,
3.79 (2 OMe, 2 s, 6H), 5.14 (H-4, dd, 1H, J = 8.3, 4.3 Hz), 5.29 (H-3, d, 1H, J = 4.6
Hz), 6.73 (NH, br s, 1H), 6.85–7.83 (ArH, m, 8H). 13C NMR (CDCl3): δ 57.1, 61.1 (OMe),
82.0 (C-4), 83.6 (C-3), 112.8, 113.6, 116.4, 122.8, 124.3, 129.7, 138.4, 147.6, 152.5, 157.6
(aromatic carbons), 168.1 (CO, β-lactam). MS (m/z,%): 299 (M+, 28), 268 (14), 256 (32),
238 (9), 206 (7), 165 (23), 134 (12), 105 (20), 93 (37), 77 (100), 43 (21). Anal. Calcd for
C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.16; H, 5.79; N, 4.60.
Typical Procedure for Synthesis of N-Sulfonyl-β-lactams (10–21)
To a solution of N-unsubstituted-β-lactams 7–9 (1.00 mmol), separately, in dry
CH2Cl2 (10 mL) cooled to −10◦C, triethylamine (1.5 mmol) and 4-N,N-dimethylamino-
pyridine (DMAP) (0.1 mmol) were added. A solution of the corresponding sulfonyl chloride
(1.5 mmol) in dry CH2Cl2 (5 mL) was slowly added to the resulting mixture. After stirring
at −10◦C for 1 h, the reaction mixture was allowed to warm to room temperature and stirred
overnight. The mixture was washed with brine (10 mL) and dried over sodium sulfate. The
solvent was evaporated at reduced pressure, and the crude products were purified by column
chromatography over silica gel (hexane:EtOAc, 2:8) to give the N-sulfonyl-β-lactams as
oil.
2-[2(2,3-Dimethoxyphenyl)-1-methanesulfonyl-4-oxo-azetidin-3-yl]-4-
nitroisoindole-1,3-dione (10). (78%). β-Lactam 10 was obtained by the reaction of
β-lactam 7 and methanesulfonyl chloride. IR (neat) (cm−1): 1330 (S O), 1735, 1775
(phth., CO), 1785 (CO, β-lactam). 1H NMR (DMSO): δ 3.44 (SO2Me, s, 3H), 4.48, 4.50
(2 OMe, 2 s, 6H), 5.04 (H-4, d, 1H, J = 4.5 Hz), 5.60 (H-3, d, 1H, J = 5.5 Hz), 6.81–8.23
(ArH, m, 6H). 13C NMR (DMSO): δ 31.8 (SO2Me), 56.0, 59.1 (OMe), 60.3 (C-4), 61.6
(C-3), 106.9, 113.5, 118.5, 124.6, 127.9, 129.4, 132.6, 137.1, 144.7, 151.6 (aromatic
carbons), 161.8 (CO), 164.7 (CO, β-lactam). MS (m/z,%): 475 (M+, 22), 444 (11), 353
(33), 314 (9), 284 (6), 243 (13), 166 (44), 121 (48), 94 (53), 75 (100), 51 (67). Anal. Calcd
for C20H17N3O9S: C, 50.53; H, 3.60; N, 8.84. Found: C, 50.61; H, 3.72; N, 8.76.
2-[1-Benzenesulfonyl-2-(2,3-dimethoxyphenyl)-4-oxoazetidin-3-yl]-4-
nitroisoindole-1,3-dione (11). (80%). β-Lactam 11 was obtained by the reaction of
β-lactam 7 and benzenesulfonyl chloride. IR (neat) (cm−1): 1350 (S O), 1738, 1778

294
A. JARRAHPOUR ET AL.
(phth., CO), 1788 (CO, β-lactam). 1H NMR (DMSO): δ 3.67, 3.77 (2 OMe, 2 s, 6H),
5.37 (H-4, d, 1H, J = 5.5 Hz), 5.59 (H-3, d, 1H, J = 5.5 Hz), 6.77–8.12 (ArH, m, 11H).
13C NMR (DMSO): δ 54.1, 55.8 (OMe), 59.6 (C-4), 60.6 (C-3), 106.9, 114.1, 120.9,
123.6, 125.8, 128.2, 129.9, 133.1, 134.5, 136.8, 138.9, 144.8, 147.4, 152.3 (aromatic
carbons), 161.4 (CO), 164.0 (CO, β-lactam). MS (m/z,%): 537 (M+, 28), 506 (37), 476
(15), 396 (10), 354 (32), 305 (24), 215 (11), 158 (31), 141 (18), 121 (25), 77 (100), 75
(39). Anal. Calcd for C25H19N3O9S: C, 55.86; H, 3.56; N, 7.82. Found: C, 55.93; H, 3.64;
N, 7.78.
2-[2-(2,3-Dimethoxyphenyl)-4-oxo-1-(toluene-4-sulfon-yl)-azetidin-3-yl]-
4-nitroiso-indole-1,3-dione (12). (85%). β-Lactam 12 was obtained by the reaction
of β-lactam 7 and 4-toluenesulfonyl chloride. IR (neat) (cm−1): 1346 (S O), 1743, 1775
(phth, CO), 1780 (CO, β-lactam).1H NMR (DMSO): δ 2.06 (Me, s, 3H), 3.01, 3.07
(2 OMe, 2 s, 6H), 5.12 (H-4, d, 1H, J = 6.1 Hz), 5.58 (H-3, d, 1H, J = 6.5 Hz), 6.37–8.15
(ArH, m, 10H). 13C NMR (DMSO): δ 21.2 (Me), 45.5, 52.3 (OMe), 55.2 (C-4), 60.9 (C-3),
107.0, 110.5, 113.1, 117.6, 119.0, 122.4, 125.9, 127.3, 129.6, 133.7, 142.2, 147.6, 151.4,
156.3 (aromatic carbons), 161.9 (CO), 164.7 (CO, β-lactam). MS (m/z,%): 551 (M+, 19),
536 (13), 490 (8), 354 (26), 229 (18), 197 (28), 149 (33), 137 (41), 121 (100), 91 (44), 75
(65), 41 (37). Anal. Calcd for C26H21N3O9S: C, 56.62; H, 3.84; N, 7.62. Found: C, 56.72;
H, 3.96; N, 7.64.
2-[2-(2,3-Dimethoxyphenyl)-1-(naphthalene-2-sulfonyl)-4-oxo-azetidin-
3-yl]-4-nitro-isoindole-1,3-dione (13). (72%). β-Lactam 13 was obtained by the
reaction of β-lactam 7 and naphthalene-2-sulfonyl chloride. IR (neat) (cm−1): 1355 (S O),
1740, 1775 (phth, CO), 1785 (CO, β-lactam). 1H NMR (DMSO): δ 3.04, 3.12 (2 OMe, 2
s, 6H), 5.15 (H-4, d, 1H, J = 5.5 Hz), 5.75 (H-3, d, 1H, J = 4.8 Hz), 6.45–8.15 (ArH, m,
13H). 13C NMR (DMSO): δ 53.1, 55.8 (OMe), 56.5 (C-4), 60.7 (C-3), 107.1, 109.2, 113.5,
120.2, 122.3, 122.9, 123.7, 124.3, 126.7, 127.7, 128.8, 129.0, 129.4, 132.9, 137.2, 139.9,
142.6, 145.6, 147.4, 150.8, 151.6, 157.0 (aromatic carbons), 161.8 (CO), 164.7 (CO,
β-lactam). MS (m/z,%): 587 (M+, 31), 526 (7), 460 (22), 355 (17), 233 (15), 207 (31), 191
(19), 149 (27), 143 (14), 127 (100), 103 (15), 75 (98). Anal. Calcd for C29H21N3O9S: C,
59.28; H, 3.60; N, 7.15. Found: C, 59.21; H, 3.65; N, 7.12.
2-[2-(2,3-Dimethoxyphenyl)-1-methanesulfonyl-3-methyl-4-oxoazetidin-
3-yl]-4-nitroisoindole-1,3-dione (14). (82%). β-Lactam 14 was obtained by the
reaction of β-lactam 8 and methanesulfonyl chloride. IR (neat) (cm−1): 1333 (S O),
1730, 1773 (Phth, CO), 1783 (CO, β-lactam). 1H NMR (DMSO): δ 1.69 (Me, s, 3H), 2.69
(SO2Me, s, 3H), 3.62, 3.76 (2 OMe, 2 s, 6H), 5.11 (H-4, s, 1H), 6.56–8.01 (ArH, m, 6H).
13C NMR (DMSO): δ 18.2 (Me), 36.5 (Me), 58.7, 59.3 (OMe), 69.8 (C-4), 71.4 (C-3),
111.6, 117.5, 118.0, 122.2, 125.8, 127.4, 132.5, 135.0, 143.8, 150.9, 160.9, 163.7 (aromatic
carbons), 166.7 (CO), 168.2 (CO, β-lactam). MS (m/z,%): 489 (M+, 23), 458(18), 428(9),
368(29), 298(14), 246(37), 243(17), 165(12), 121(52), 94(23), 75(100), 43(35). Anal.
Calcd for C21H19N3O9S: C, 51.53; H, 3.91; N, 8.59; found: C, 51.46; H, 4.02; N, 8.63.
2-[1-Benzenesulfonyl-2-(2,3-dimethoxyphenyl)-3-methyl-4-oxo-azetidin-
3-yl]-4-nitroisoindole-1,3-dione (15). (80%). β-Lactam 15 was obtained by the
reaction of β-lactam 8 and benzenesulfonyl chloride. IR (neat) (cm−1): 1338.0 (S O),
1740, 1772 (phth, CO), 1787 (CO, β-lactam). 1H NMR (DMSO): δ 1.72 (Me, s, 3H), 3.73,
3.80 (2 OMe, 2 s, 6H), 5.19 (H-4, s, 1H), 6.58–8.03 (ArH, m, 11H). 13C NMR (DMSO):
δ 20.7 (Me), 56.0, 58.2 (OMe), 67.6 (C-4), 73.3 (C-3), 115.0, 120.9, 125.9, 128.3, 129.5,
130.7, 131.3, 132.2, 137.1, 138.4, 143.5, 147.3, 154.2, 162.8, 165.3 (aromatic carbons),
167.5 (CO), 171.3 (CO, β-lactam). MS (m/z,%): 551 (M+, 30), 536 (16), 490 (15), 368

NEW N-SULFONYL MONOCYCLIC β-LACTAMS
295
(22), 305 (27), 246 (14), 182 (7), 177 (35), 143 (14), 141 (28), 77 (100), 75 (47). Anal.
Calcd for C26H21N3O9S: C, 56.62; H, 3.84; N, 7.62. Found: C, 56.70; H, 3.94; N, 7.55.
2-[2-(2,3-Dimethoxyphenyl)-3-methyl-4-oxo-1-(toluene-4-sulfonyl)-azeti
din-3-yl]-4-nitroisoindole-1,3-dione (16). (75%). β-Lactam 16 was obtained by the
reaction of β-lactam 8 and 4-toluenesulfonyl chloride. IR (neat) (cm−1): 1329 (S O),
1737, 1770 (phth., CO), 1782 (CO, β-lactam). 1H NMR (DMSO): δ 1.78 (Me, s, 3H), 2.46
(MePh, s, 3H), 3.57, 3.66 (2 OMe, 2 s, 6H), 5.71 (H-4, s, 1H), 6.84–8.19 (ArH, m, 10H).
13C NMR (DMSO): δ 18.0 (Me), 21.5 (MePh), 55.2, 56.0 (OMe), 60.5 (C-4), 70.7 (C-3),
107.1, 118.7, 123.4, 125.9, 126.2, 128.2, 129.2, 130.7, 133.9, 137.2, 144.7, 146.3, 149.6,
152.0 (aromatic carbons), 161.2 (CO), 165.8 (CO, β-lactam). MS (m/z,%): 565 (M+, 25),
550 (33), 534 (19), 410 (20), 368 (27), 319 (18), 246 (28), 197 (12), 155 (8), 91 (24), 75
(100), 43 (31). Anal. Calcd for C27H23N3O9S: C, 57.34; H, 4.10; N, 7.43. Found: C, 57.38;
H, 4.18; N, 7.49.
2-[2-(2,3-Dimethoxyphenyl)-3-methyl-1-(naphthalene-2-sulfonyl)-4-oxo-
azetidin-3-yl]-4-nitroisoindole-1,3-dione (17). (68%). β-Lactam 17 was obtained
by the reaction of β-lactam 8 and naphthalene-2-sulfonyl chloride. IR (neat) (cm−1): 1336
1
(S O), 1740, 1776 (phth, CO), 1785 (CO, β-lactam). H NMR (DMSO): δ 2.05 (Me, s,
3H), 3.00, 3.10 (2 OMe, 2 s, 6H), 5.72 (H-4, s, 1H), 6.85–8.70 (ArH, m, 13H). 13C NMR
(DMSO): δ 31.0 (Me), 55.2, 56.0 (OMe), 56.3 (C-4), 60.4 (C-3), 107.1, 109.5, 119.2,
122.7, 124.2, 124.4, 126.7, 127.7, 128.3, 128.8, 129.9, 130.7, 133.6, 137.3, 141.1, 145.9,
147.8, 149.6, 150.4, 152.7, 156.7 (aromatic carbons), 162.8 (CO), 165.7 (CO, β-lactam).
MS (m/z,%): 601 (M+, 18), 586 (8), 570 (27), 410 (26), 335 (24), 246 (36), 219 (33), 191
(14), 127 (100), 75 (82). Anal. Calcd for C30H23N3O9S: C, 59.90; H, 3.85; N, 6.98. Found:
C, 59.97; H, 3.93; N, 7.05.
4-(2,3-Dimethoxyphenyl)-1-methanesulfonyl-3-phenoxy-azetidin-2-one
(18). (88%). β-Lactam 18 was obtained by the reaction of β-lactam 9 and methanesulfonyl
chloride. IR (neat) (cm−1): 1326 (S O), 1768 (CO, β-lactam). 1H NMR (DMSO): δ 2.05
(Me, s, 3H), 3.73, 3.78 (2 OMe, 2 s, 6H), 5.33 (H-4, d, 1H, J = 4.8 Hz), 5.68 (H-3, d, 1H,
J = 5.0 Hz), 6.82–7.67 (ArH, m, 8H). 13C NMR (DMSO): δ 29.8 (Me), 59.4, 59.7 (OMe),
80.1 (C-4), 82.0 (C-3), 106.1, 11.7, 114.8, 121.6, 128.6, 138.2, 143.5, 151.1, 155.8, 156.3
(aromatic carbons), 165.8 (CO, β-lactam). MS (m/z,%): 377 (M+, 38), 346 (13), 316
(6), 298 (13), 256 (63), 243 (18), 120 (11), 93 (75), 77 (100), 43 (29). Anal. Calcd for
C18H19NO6S: C, 57.28; H, 5.07; N, 3.71. Found: C, 57.19; H, 5.21; N, 3.73.
1-Benzenesulfonyl-4-(2,3-dimethoxyphenyl)-3-phenoxy-azetidin-2-one
(19). (83%). β-Lactam 19 was obtained by the reaction of β-lactam 9 and benzenesulfonyl
chloride. IR (neat) (cm−1): 1330 (S O), 1765 (CO, β-lactam). 1H NMR (DMSO): δ 3.63,
3.71 (2 OMe, 2 s, 6H), 5.37 (H-4, d, 1H, J = 5.5 Hz), 5.56 (H-3, d, 1H, J = 5.8 Hz),
6.61–7.70 (ArH, m, 13H). 13C NMR (DMSO): δ 59.5, 61.2 (OMe), 78.2 (C-4), 82.1 (C-3),
107.0, 113.6, 116.4, 123.1, 126.5, 127.9, 128.8, 130.2, 134.7, 139.1, 143.7, 148.2, 152.5,
157.0 (aromatic carbons), 167.3 (CO, β-lactam). MS (m/z,%): 439 (M+, 16), 408 (19),
346 (10), 305 (9), 298 (22), 256 (58), 182 (21), 134 (15), 93 (69), 77 (100), 75 (37). Anal.
Calcd for C23H21NO6S: C, 62.86; H, 4.82; N, 3.19. Found: C, 62.92; H, 5.01; N, 3.16.
4-(2,3-Dimethoxyphenyl)-3-phenoxy-1-(toluene-4-sulfonyl)-azetidin-2-
one (20). (84%). β-Lactam 20 was obtained by the reaction of β-lactam 9 and 4-toluene
sulfonyl chloride. IR (neat) (cm−1): 1327 (S O), 1772 (CO, β-lactam). 1H NMR (DMSO):
δ 2.04 (Me, s, 3H), 3.75, 3.82 (2 OMe, 2 s, 6H), 5.70 (H-4, d, 1H, J = 6.3 Hz), 5.95 (H-3,
d, 1H, J = 7.5 Hz), 6.82–7.68 (ArH, m, 12H). 13C NMR (DMSO): δ 22.3 (Me), 56.0, 56.9
(OMe), 61.4 (C-4), 61.8 (C-3), 108.0, 114.5, 116.6, 123.1, 126.7, 128.3, 130.6, 132.0,

296
A. JARRAHPOUR ET AL.
135.9, 140.1, 146.7, 151.7, 153.0, 157.3 (aromatic carbons), 165.1 (CO, β-lactam). MS
(m/z,%): 453 (M+, 23), 438 (15), 422 (26), 319 (16), 256 (68), 229 (7), 197 (19), 134 (7),
121 (100), 93 (43), 91 (29), 77 (79). Anal. Calcd for C24H23NO6S: C, 63.56; H, 5.11; N,
3.09. Found: C, 63.48; H, 5.19; N, 3.05.
4-(2,3-Dimethoxyphenyl)-1-(naphthalene-2-sulfonyl)-3-phenoxy-azetidin-
2-one (21). (81%). β-Lactam 21 was obtained by the reaction of β-lactam 9 and
naphthalene-2-sulfonyl chloride. IR (neat) (cm−1): 1329 (S O), 1769 (CO, β-lactam).
1H NMR (DMSO): δ 3.19, 3.55 (2 OMe, 2 s, 6H), 5.08 (H-4, d, 1H, J = 4.8 Hz), 5.75
(H-3, d, 1H, J = 5.2 Hz), 6.71–8.73 (ArH, m, 15H). 13C NMR (DMSO): δ 56.1, 57.8
OMe), 65.6 (C-4), 68.0 (C-3), 116.3, 117.7, 119.4, 123.0, 124.9, 126.1, 127.7, 128.0,
128.6, 129.1, 129.5, 131.2, 133.2, 136.4, 140.5, 143.3, 148.1, 150.6, 151.5, 156.3, 158.9
(aromatic carbons), 166.8 (CO, β-lactam). MS (m/z,%): 489 (M+, 35), 458 (22), 396 (14),
355 (41), 256 (37), 233 (10), 191 (13), 134 (29), 127 (100), 93 (75), 77 (54). Anal. Calcd
for C27H23NO6S: C, 66.24; H, 4.74; N, 2.86. Found: C, 66.17; H, 4.91; N, 2.89.
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