Synthesis of novel N-sulfonyl monocyclic β-lactams as potential antibacterial agents

Article abstract of DOI:10.3390/11010049

New cis monocyclic β-lactams were synthesized by [2+2] Staudinger cycloaddition reactions of the imine (3,4-dimethoxybenzylidene)-(4- methoxyphenyl)amine and ketenes derived from different acyl chlorides and Et₃N. These monocyclic β-lactams wer

Full text of DOI:10.3390/11010049

Molecules 2006, 11, 49-58
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Novel N-Sulfonyl Monocyclic β-Lactams as
Potential Antibacterial Agents
Aliasghar Jarrahpour * and Maaroof Zarei
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran. Tel.: (+98) 711
2284822; Fax: (+98) 711 2280926;
* Author to whom correspondence should be addressed; e-mail: jarrah@chem.susc.ac.ir or
aliasghar6683@yahoo.com
Received: 9 March 2005 / in revised form: 12 December 2005 / Accepted: 14 December 2005
Published: 31 January 2006
Abstract— New cis monocyclic β-lactams were synthesized by [2+2] Staudinger
cycloaddition reactions of the imine (3,4-dimethoxybenzylidene)-(4-methoxyphenyl)-
amine and ketenes derived from different acyl chlorides and Et3N. These monocyclic
β-lactams were then cleaved by ceric ammonium nitrate (CAN) to give NH-monocyclic
β-lactams, which in turn were converted to N-sulfonyl monocyclic β-lactams by
treatment with four different sulfonyl chlorides in the presence of Et3N and 4,4-dimethyl-
aminopyridine (DMAP).
Keywords: 2-Azetidinones, N-Sulfonyl β-lactams, Ketene, Imine, CAN, DMAP
Introduction
Even more than 70 years after the discovery of penicillin, β-lactam antibiotics remain as one of the
most important contributions of science to Humanity [1]. The β-lactam skeleton is the common
structural element of the widely used penicillins, cephalosporins, thienamycine, nocardicins,
aztreonam and carumonam [2]. The first member of this class of compounds was synthesized by
Staudinger in 1907 [3], but until the discovery of penicillin by Fleming in 1929, the importance of
β-lactams as antibiotics was not recognized [4]. Widespread use of β-lactam antibiotics exerts selective
pressure on bacteria and permits the proliferation of resistant organisms [5]. A comparison of current
antibiograms with those from previous decades shows an alarming increase in bacterial resistance to

Molecules 2006, 11
50
β-lactam antibiotics [6]. Consequently, because of the growing resistance of bacteria towards β-lactam
antibiotics and the need for medicines with a more specific antibacterial activity several synthetic and
semi-synthetic β-lactam antibiotics have been developed by the pharmaceutical industry [7]. An
interesting group of β-lactams are the monocyclic β-lactams, which are molecules that do not contain
another ring fused to the β-lactam one. In the late 1970s and early 1980s, the first classes of
monocyclic β-lactams antibacterial agents were isolated from natural sources [8]. The discovery of the
nocardicins, 1, and monobactams, 2, demonstrated for the first time that β-lactams do not require a
conformationally constrained bicyclic structure to have antibacterial properties [9], suggesting that the
biological activity was strictly correlated to the presence of a suitably functionalized 2-azetidinone ring
[10]. In addition to the monobactams and nocardicins, some other monocyclic β-lactams such as
compounds 3 [11], 4 [12], and 5 [13] have also shown good antibacterial activity. Cyclic sulfonamides
have been shown to be highly useful heterocycles in medicinal chemistry [13]. The sulfonamido group,
in addition to its antibacterial activity, shows potent anti-HIV and latent leishmanicidal activities [15].
Numerous articles can be found through out the literature describing the preparation and use of N-
sulfonyl β-lactams as intermediates in synthesis [16]. About 600 N-sulfonyl β-lactams have been
examined for biological properties [17]. Turos and coworkers [18] synthesized the N-sulfonyl
monocyclic β-lactams 6 and have tested them against some bacteria. Recently, it has been reported that
monocyclic β-lactams have novel biological activities such as cytomegalovirus protease inhibitors
[19], thrombin and tryptase inhibitors [20], cholesterol absorption inhibitors [21], human leukocyte
elastease (HLE) inhibitors [22], porcine pancereatic elastease (PPE) inhibitors [23] and anticancer
activities [24]. Besides their biological activities, the importance of β-lactams as synthetic
intermediates has been widely recognized in organic synthesis [25] for example in the semisynthesis of
Taxol [26].
Ph
RCOHN
O
RCOHN
O
PhthN
O
CH2OAc
OAc
OH
O
N
HO2C
1
N
N
-
SO3
OAc
OAc
2
3
R1
Ph
Cl
Cl
R
MeO
PhthN
O
N
CO2Et
Ph
N
O
N
O
SO2Me
R2
5
4
6
The β-lactam moiety is accessible by several synthetic methods and the topic has been reviewed
several times [27]. Stereoselection at positions 3 and 4 of the 2-azetidinone ring is obviously of utmost
importance with the perspective of its participation in biologically or pharmacologically-active
molecules [28]. The most popular method for the preparation of the β-lactam ring involves the
classical ketene-imine (Staudinger) reaction [29] that leads to β-lactams with cis selectivity [30]. In
this paper, we describe the synthesis of some new monocyclic β-lactams bearing different sulfonyl
groups at their N1-positions.

Molecules 2006, 11
51
Results and Discussion
Aldimine 7 was prepared in quantitative yield by condensation of p-methoxyaniline and
3,4-dimethoxybenzaldehyde in refluxing ethanol. The formation of the Schiff base 7 was readily
established from its spectral data. Treatment of 7 with ketenes derived from the acyl chlorides 3-nitro-
phthaloylglycyl chloride (8), 3-nitrophthaloylalaninyl chloride (9) and phenoxyacetyl chloride in the
presence of triethylamine afforded cis-2-azetidinones 10-12 (Scheme 1). The presence of these new
compounds was confirmed by t.l.c. monitoring. The IR spectra showed the β-lactam carbonyl at
1755.0-1786.6 cm-1. The indicated cis stereochemistry for these monocyclic β-lactams was deduced
from analysis of their 1H-NMR spectra. The coupling constant of H-3 and H-4 is J= 5.2-5.3 Hz for β-
lactam 10 and J= 5.6-5.8 Hz for β-lactam 12, which are indicative of their cis stereochemistry. In
addition, 13C-NMR spectroscopic data of β-lactams 10-12 definitely showed the lactam CO (C2) signal
at 161.8-166.8 ppm, whereas C-3 resonated at around 63.2-70.2 ppm and C-4 at 59.8-63.8 ppm.
Scheme 1
OMe
OMe
OMe
OMe
R2
H
R1
R1R2CHCOCl
MeO
N
CH2Cl2, Et3N
-10oC to r.t.
N
O
PMP
7
10-12
(NH4)2Ce(NO3)6
CH3CN, H2O
-10oc
OMe
H
OMe
OMe
R2
H
R2
R3SO2Cl, Et3N
R1
R1
OMe
N
N
H
DMAP, CH2Cl2
-10oc to r.t.
O
O
O
S
O
R3
16-27
13-15
Monocyclic β-lactams 10-12 were then converted to N-unsubstituted β-lactams 13-15 by reaction
with ceric ammonium nitrate (CAN) at –10oC. In this reaction, the quinone released was removed by
forming the corresponding bisulfite adduct, which can be washed out with water after workup with
aqueous NaHSO3solution [31]. The IR spectra of the N-unsubstituted β-lactams 13-15 exhibited the
characteristic NH absorption at 3290.3-3380.0 cm-1 and the 2-azetidinone carbonyl at 1762.5-1785.0
cm–1. Furthermore, the 1H-NMR spectra showed the NH peaks at 6.55-6.60 ppm and H-4 as a doublet
of doublet peak at 5.04 ppm for 13, 4.77 ppm for 15 and a doublet peak at 4.6 ppm for 14, that
confirmed the NH-β-lactam structures for 13-15. N-Sulfonyl monocyclic β-lactams 16-27 were
obtained by reaction of N-unsubstituted β-lactams 13-15 with methanesulfonyl chloride, benzene-
sulfonyl chloride, p-tolouenesulfonyl chloride and 2-naphthalenesulfonyl chloride, respectively, in the
presence of 4,4-dimethylaminopyridine (DMAP) and Et3N (see Table 1). The IR spectra showed the β-
lactam carbonyls at 1766.4-1788.1 cm-1, S=O absorptions (strong peaks) at 1328.5-1336.2 cm-1 and the

Molecules 2006, 11
52
disappearance of the NH peaks. Other spectroscopic and analytical data were consistent with the
indicated structures of the N-sulfonyl moncyclic β-lactams 16-27.
Conclusions
In summary, new cis-monocyclic β-lactams 10-12 bearing N1-p-methoxyphenyl (PMP) groups
were obtained with high stereoselectivity using classical Staudinger methodology. These β-lactams
were oxidatively cleaved to NH-β-lactams 13-15 by reaction with ceric ammonium nitrate. A novel
series of monocyclic β-lactams containing sulfonamidos groups at N1 were then synthesized from the
NH-β-lactams 13-15 and the appropriate sulfonyl chlorides. The coexistence of a β-lactam ring and a
sulfonamido group may make these valuable compounds for study of antimicrobial activities.
Table 1. Monocyclic β-lactams
Compound
R1
R2
H
Me
H
H
Me
H
H
H
H
H
R3
-
-
-
-
-
-
Me
Ph
Yield%
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3-NO2Phth
3-NO2Phth
PhO
3-NO2Phth
3-NO2Phth
PhO
3-NO2Phth
3-NO2Phth
3-NO2Phth
3-NO2Phth
3-NO2Phth
3-NO2Phth
3-NO2Phth
3-NO2Phth
PhO
58
97
79
88
83
78
85
88
73
79
76
83
82
83
86
74
4-MeAr
2-naphthalene
Me
Me
Me
Me
Ph
4-MeAr
Me 2-naphthalene
H
H
H
H
Me
Ph
PhO
PhO
PhO
4-MeAr
2-naphthalene
72
Acknowledgments
The authors thank the Shiraz University Research Council for financial support (Grant No. 83-GR-
SC-31).
Experimental
General
All required chemicals were purchased from the Merck and Fluka chemical companies.
Dichloromethane and triethylamine were dried by distillation over CaH2 and then stored over 4Å

Molecules 2006, 11
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1
molecular sieves. IR spectra were run on a Shimadzu FT-IR 8300 spectrophotometer. H-NMR and
13C-NMR spectra were recorded in CDCl3 (compounds 7, 10-15) or DMSO-d6 (compounds 16-27)
1
using a Bruker Avance DPX instrument (operating at 250 MHz for H and 62.9 MHz for 13C).
Chemical shifts were reported in ppm (δ) downfield from TMS. All of the coupling constants (J) are in
Hertz. The mass spectra were recorded on a Shimadzu GC-MS QP 1000 EX instrument. Melting
points were determined in open capillaries with a Buchi 510 melting point apparatus and are not
corrected. Thin-layer chromatography (t.l.c.) was carried out on silica gel 254 analytical sheets
obtained from Fluka. Column chromatography was performed on Merck Kieselgel (230-270 mesh).
Synthesis of (3,4-dimethoxybenzylidene)-(4-methoxyphenyl)amine (7):
A mixture of p-methoxyaniline (5.00 g, 40.71 mmol) and 3,4-dimethoxybenzaldehyde (6.80 g,
40.71 mmol) was refluxed in ethanol for 4 hours. After cooling the solution the precipitate formed was
filtered off and washed with ethanol to give pure Schiff base 7 as a yellow solid (10.46 g, 95%). m.p.
o
1
128-130 C; IR (KBr, cm-1) 1620.1 (C=N); H-NMR δ 3.85, 4.01, 4.02 (3 OMe, 3 s, 9H), 6.87-7.72
(ArH, m, 7H), 8.40 (HC=N, s, 1H); 13C-NMR δ 64.59, 65.11 (OMe), 117.90-160.88 (aromatic
carbons), 167.15 (C=N); MS (m/e) 272, 271 (M+), 257, 256, 240, 154, 134, 115, 77.
Synthesis of 3-nitrophthaloylglycyl chloride (8):
3-Nitrophthaloylglycine was prepared by a reported method [32]. 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 hours, the excess of thionyl chloride was removed by distillation and the residue was
crystallized from light petroleum to give acyl chloride 8 as a light yellow crystalline solid (10.65 g, 93
o
%). It was stable for long periods when stored in a dessicator over CaCl2; m.p. 116-118 C; IR (KBr,
cm-1) 1735, 1775 (phthalimido, CO), 1805 (COCl).
Synthesis of 3-nitrophthaloylalaninyl chloride (9):
3-Nitrophthaloylalanine was prepared by a reported method [32]. 3-Nitrophthaloylalanyl chloride
o
(9) was prepared by the same method as compound 8. Yield 90 %; m.p. 108-110 C; IR (KBr, cm-1)
1740, 1785 (phthalimido, CO), 1810 (COCl).
General procedure for synthesis of monocyclic β-lactams 10-12:
A solution of the corresponding acyl chloride (1.50 mmol) in dry CH2Cl2 (10 mL) was slowly
added to a solution of (3,4-dimethoxybenzylidene)-(4-methoxyphenyl) amine (7, 1.00 mmol) and
o
triethylamine (3.00 mmol) in CH2Cl2 (15 mL) at –10 C. The reaction mixture was then allowed to
warm to room temperature, stirred overnight and then it was washed with saturated sodium
bicarbonate solution (20 mL), 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.

Molecules 2006, 11
54
2-[2-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)-4-oxoazetidin-3-yl]-4-nitroisoindole-1,3-dione (10).
β-Lactam 10 was obtained as a light brown solid from Schiff base 7 and acyl chloride 8. Yield 60 %
o
(eluent hexane/EtOAc 5:5); m.p. 198-200 C; IR (KBr, cm-1) 1735.0, 1770.0 (phth. CO), 1778.0 (CO
1
β-lactam); H-NMR δ 3.65, 3.74, 3.78 (3 OMe, 3 s, 9H), 5.33 (H-4, d, 1H, J=5.2), 5.53 (H-3, d, 1H,
J=5.3), 6.64-8.01 (ArH, m, 10H); 13C-NMR δ 55.80, 56.10, 56.39 (OMe), 61.16 (C-4), 63.29 (C-3),
109.12-156.96 (aromatic carbons), 161.20 (CO), 163.52 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)-3-methyl-4-oxo-azetidin-3-yl]-4-nitroiso indole-1,3-
dione (11). β-Lactam 11 was obtained as a light brown solid from Schiff base 7 and acyl chloride 9.
o
Yield 58 % (eluent hexane/EtOAc 4:6); m.p. 181-183 C; IR (KBr, cm-1) 1735.0, 1775.7 (phth. CO),
1
1786.6 (CO β-lactam); H-NMR δ 1.82 (Me, s, 3H), 3.73, 3.75, 3.82 (3 OMe, 3 s, 9H), 5.69 (H-4, s,
1H), 6.74-8.07 (ArH, m, 10H); 13C-NMR δ 20.41 (Me), 56.51, 56.81, 61.85 (OMe), 63.84 (C-4), 70.20
(C-3), 113.81-157.45 (aromatic carbons), 166.01 (CO), 166.82 (CO, β-lactam).
4-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)-3-phenoxy-2-azetidinone (12). β-Lactam 12 was
obtained as a light yellow solid from Schiff base 7 and phenoxyacetyl chloride. Yield 97 %; m.p. 158-
160 oC; IR (KBr, cm-1) 1755.0 (CO, β-lactam); 1H-NMR δ 3.62, 3.72, 3.76 (3 OMe, 3 s, 9H), 5.44 (H-
13
4, d, 1H, J=5.8), 5.71 (H-3, d, 1H, J=5.6), 6.68-7.37 (ArH, m, 12H); C-NMR δ 54.36, 54.72, 55.09
(OMe), 59.85 (C-4), 66.50 (C-3), 113.65-156.25 (aromatic carbons), 161.87(CO, β-lactam).
General procedure for synthesis of N-unsubstituted β-lactams 13-15:
A solution of (NH4)2Ce(NO3)6 (CAN).(3.00 mmol) in water (15 mL) was added dropwise to a
o
solution of each of the β-lactams 10-12 (1.00 mmol) in CH3CN (25mL) at –10 C. The mixture was
stirred at this temperature for 45 minutes, 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 successively with 10 % NaHSO3 (2×30 mL), NaHCO3 (20 mL), brine (20 mL) and then dried
over sodium sulfate. After filtration and evaporation of the solvent in vacuo, the crude product was
purified by recrystalization from 4:6 hexane-EtOAc to afford the products 13-15, respectively.
2-[2-(3,4-Dimethoxyphenyl)-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-dione (13). β-Lactam 13 was
o
prepared by deprotection of β-lactam 10. Brown solid (79 %); m.p. 117-119 C; IR (KBr, cm-1)
1
1735.0, 1770.2 (phth., CO), 1785.0 (CO, β-lactam), 3380.5 (NH); H-NMR δ 3.61, 3.75 (2 OMe, 2 s,
6H), 5.04 (H-4, dd, 1H, J=12.2, 3.5), 5.53 (H-3, d, 1H, J=5.5), 6.55 (NH, br s, 1H), 6.97-8.63 (ArH, m,
6H); 13C-NMR δ 55.44, 55.85 (OMe), 60.81 (C-4), 63.16 (C-3), 110.08-150.07 (aromatic carbons),
163.36 (CO), 164.49 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-3-methyl-4-oxoazeti- din-3-yl]-4-nitroisoindole-1,3-dione (14). β-Lactam
14 was prepared by deprotection of β-lactam 11. Brown solid (88 %); m.p. 113-115 oC; IR (KBr, cm-1)
1
1735.0, 1775.0 (phth., CO), 1790.0 (CO, β-lactam), 3310.0 (NH); H-NMR δ 1.63 (Me, s, 3H), 3.22,
3.83 (2 OMe, 2 s, 6H), 4.69 (H-4, d, 1H, J=7.3), 6.57 (NH, br s, 1H), 7.23-8.63 (ArH, m, 6H);

Molecules 2006, 11
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13C-NMR δ 16.51 (Me), 49.72, 50.02 (OMe), 64.52 (C-4), 69.88 (C-3), 117.20-164.45 (aromatic
carbons), 167.05 (CO), 171.85 (CO, β-lactam).
4-(3,4-Dimethoxyphenyl)-3-phenoxy-2-azetidinone (15). β-Lactam 15 was prepared by deprotection of
1
β-lactam 12. Red oil (83 %); IR (neat, cm-1) 1762.5 (CO, β-lactam), 3290.3 (NH); H-NMR δ 3.67,
3.79 (2 OMe, 2 s, 6H), 4.77 (H-4, dd, 1H, J=13.5, 5.2), 5.27 (H-3, d, 1H, J=8.2), 6.60 (NH, br s, 1H),
6.67-7.88 (ArH, m, 8H); 13C-NMR δ 56.80, 60.80 (OMe), 81.68 (C-4), 82.95 (C-3), 111.25-157.16
(aromatic carbons), 167.81 (CO, β-lactam).
Typical procedure for synthesis of N-sulfonyl-β-lactams 16-27:
To a solution of N-unsubstituted β-lactams 13-15 (1.00 mmol), separately, in dry CH2Cl2 (10 mL)
cooled to –10 oC was added triethylamine (1.5 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (0.1
mmol). A solution of corresponding sulfonyl chloride (1.5 mmol) in dry CH2Cl2 (5 mL) was slowly
added to the resulting mixture. After stirring at –10 oC for one hour, 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 in reduced pressure to give the N-sulfonyl β-
lactams 16-27.
2-[2-(3,4-Dimethoxyphenyl)-1-methanesulfonyl-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-dione (16).
β-Lactam 16 was obtained by reaction of β-lactam 13 and methanesulfonyl chloride as a red oil (78
%); IR (neat, cm-1) 1331.7 (S=O), 1735.0, 1776.2 (phth., CO), 1785.0 (CO, β-lactam); 1H-NMR δ 3.54
(SO2Me, s, 3H), 4.48, 4.55 (2 OMe, 2 s, 6H), 5.14 (H-4, d, 1H, J=5.5), 5.60 (H-3, d, 1H, J=5.0), 6.88-
8.13 (ArH, m, 6H); 13C-NMR δ 31.82 (Me), 56.03, 59.12 (OMe), 60.26 (C-4), 61.65 (C-3), 106.92-
151.61 (aromatic carbons), 161.81(CO), 164.73 (CO, β-lactam).
2-[1-Benzenesulfonyl-2-(3,4-dimethoxyphenyl)-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-dione (17). β-
Lactam 17 was obtained by reaction of β-lactam 13 and benzenesulfonyl chloride as a red oil (85 %);
IR (neat, cm-1) 1331.7 (S=O), 1735.0, 1776.2 (phth., CO), 1785 (CO, β-lactam); 1H-NMR δ 3.77, 3.78
(2 OMe, 2 s, 6H), 5.39 (H-4, d, 1H, J=5.2), 5.48 (H-3, d, 1H, J=5.6), 6.87-8.10 (ArH, m, 11H);
13C-NMR δ 55.13, 55.89 (OMe), 59.91 (C-4), 61.59 (C-3), 107.88-152.72 (aromatic carbons),
161.47(CO), 164.71 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-4-oxo-1-(toluene-4-sulfonyl)-azetidin-3-yl]-4-nitroisoindole-1,3-dione
(18) β-Lactam 18 was obtained by reaction of β-lactam 13 and 4-toluenesulfonyl chloride as a red oil
(88 %); IR (neat, cm-1) 1330.9 (S=O), 1737.5, 1777.3 (phth., CO), 1787.2 (CO, β-lactam); 1H-NMR δ
2.16 (MePh, s, 3H), 3.21, 3.37 (2 OMe, 2 s, 6H), 5.02 (H-4, d, 1H, J=5.1), 5.48(H-3, d, 1H, J=5.0),
6.48-8.08 (ArH, m, 10H); 13C-NMR δ 23.20 (MePh), 46.47, 52.56 (OMe), 56.22 (C-4), 60.09 (C-3),
108.04-156.12 (aromatic carbons), 161.85 (CO), 164.75 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-1-(naphthalene-2-sulfonyl)-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-di-
one (19). β-Lactam 19 was obtained by reaction of β-lactam 13 and naphthalene-2-sulfonyl chloride as
a red oil (73 %); IR (neat, cm-1) 1336.2 (S=O), 1741.2, 1775.6 (phth., CO), 1784.9 (CO, β-lactam);

Molecules 2006, 11
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1H- NMR δ 3.04, 3.22 (2 OMe, 2 s, 6H), 5.05 (H-4, d, 1H, J=5.5), 5.67 (H-3, d, 1H, J=5.8), 6.55-8.05
(ArH, m, 13H); 13C-NMR δ 53.45, 55.68 (OMe), 56.55 (C-4), 61.67 (C-3), 106.12-156.47 (aromatic
carbons), 161.65 (CO), 164.77 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-1-methanesulfonyl-3-methyl-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-di-
one (20). β-Lactam 20 was obtained by reaction of β-lactam 14 and methanesulfonyl chloride as a red
oil (79 %); IR (neat, cm-1) 1331.9 (S=O), 1736.9, 1777.0 (phth., CO), 1788.1 (CO, β-lactam); 1H-NMR
δ 1.49 (Me, s, 3H), 2.63 (SO2Me, s, 3H), 3.52, 3.68 (2 OMe, 2 s, 6H), 5.22( H-4, s, 1H), 6.76-8.11
(ArH, m, 6H); 13C-NMR δ 19.16 (Me), 32.46 (SO2Me), 59.66, 59.97 (OMe), 69.80 (C-4), 70.39 (C-3),
112.57-163.70 (aromatic carbons), 166.76 (CO), 168.14 (CO, β-lactam).
2-[1-Benzenesulfonyl-2-(3,4-dimethoxyphenyl)-3-methyl-4-oxo-azetidin-3-yl]-4-nitroisoindole1,3-di-
one (21). β-Lactam 21 was obtained as a red oil (76 %) by reaction of β-lactam 14 and benzene-
sulfonyl chloride. IR (neat, cm-1) 1329.2 (S=O), 1739.1, 1778.1 (phth., CO), 1786.3 (CO, β-lactam);
1H-NMR 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 δ 20.74 (Me), 55.97, 58.15 (OMe), 67.64 (C-4), 73.33 (C-3), 114.99-165.27 (aromatic
carbons), 167.51 (CO), 171.35 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-3-methyl-4-oxo-1-(toluene-4-sulfonyl)-azetidin-3-yl]-4-nitroisoindole-1,3-
dione (22). β-Lactam 22 was obtained by reaction of β-lactam 14 and 4-toluenesulfonyl chloride as a
red oil (83 %). IR (neat, cm-1) 1335.1 (S=O), 1740.0, 1777.0 (phth., CO), 1788.1 (CO, β-lactam);
1H-NMR δ 1.58 (Me, s, 3H), 2.36 (MePh, s, 3H), 3.48, 3.55 (2 OMe, 2 s, 6H), 5.70 (H-4, s, 1H), 6.88-
13
8.16 (ArH, m, 10H); C-NMR δ 18.98 (Me), 20.48 (MePh), 55.18, 55.86 (OMe), 60.57 (C-4), 70.03
(C-3), 108.14-152.97 (aromatic carbons), 161.22 (CO), 165.85 (CO, β-lactam).
2-[2-(3,4-Dimethoxyphenyl)-3-methyl-1-(naphthalene-2-sulfonyl)-4-oxo-azetidin-3-yl]-4-nitro-iso-
indole-1,3-dione (23). β-Lactam 23 was obtained by reaction of β-lactam 14 and naphthalene-2-
sulfonyl chloride as a red oil (82 %). IR (neat, cm-1) 1333.1 (S=O), 1738.4, 1776.9 (phth., CO), 1787.1
(CO, β-lactam); 1H-NMR δ 2.15 (Me, s, 3H), 3.06, 3.19 (2 OMe, 2 s, 6H), 5.62 (H-4, s, 1H), 6.74-8.75
(ArH, m, 13H); 13C-NMR δ 30.55 (Me), 56.13, 56.88 (OMe), 57.35 (C-4), 60.42 (C-3), 107.32-156.60
(aromatic carbons), 165.32 (CO), 167.66 (CO, β-lactam).
4-(3,4-Dimethoxyphenyl)-1-methanesulfonyl-3-phenoxy-azetidin-2-one (24). β-Lactam 24 was
obtained by reaction of β-lactam 15 and methanesulfonyl chloride as a red oil (83 %). IR (neat, cm-1):
1
1332.2 (S=O), 1766.4 (CO, β-lactam); H-NMR δ 2.15 (SO2Me, s, 3H), 3.83, 3.98 (2 OMe, 2 s, 6H),
5.35 (H-4, d, 1H, J=5.8), 5.60 (H-3, d, 1H, J=4.1), 6.72-7.87 (ArH, m, 8H); 13C-NMR δ 26.83
(SO2Me), 59.62, 59.87 (OMe), 81.32 (C-4), 82.52 (C-3), 107.14-163.31 (aromatic carbons), 165.83
(CO, β-lactam).
1-Benzenesulfonyl-4-(3,4-dimethoxyphenyl)-3-phenoxy-azetidin-2-one (25). β-lactam 25 was obtained
by reaction of β-lactam 15 and benzenesulfonyl chloride as a red oil (86 %); IR (neat, cm-1): 1328.5
(S=O), 1772.0 (CO, β-lactam); 1H-NMR δ 3.60, 3.69 (2 OMe, 2 s, 6H), 5.17 (H-4, d, 1H, J=6.5), 5.46

Molecules 2006, 11
57
(H-3, d, 1H, J=4.8), 6.55-7.75 (ArH, m, 13H); 13C-NMR δ 59.30, 60.21 (OMe), 78.49 (C-4), 82.43 (C-
3), 108.15-156.75 (aromatic carbons), 157.52 (CO, β-lactam).
4-(3,4-Dimethoxyphenyl)-3-phenoxy-1-(toluene-4-sulfonyl)-azetidin-2-one (26). β-Lactam 26 was
obtained by reaction of β-lactam 15 and 4-toluenesulfonyl chloride as a red oil (74 %); IR (neat, cm-1)
1
1329.8 (S=O), 1769.3 (CO, β-lactam); H-NMR δ 2.14 (MePh, s, 3H), 3.68, 3.80 (2 OMe, 2 s, 6H),
5.74 (H-4, d, 1H, J=6.0), 5.90 (H-3, d, 1H, J=5.5), 6.62-7.65 (ArH, m, 12H); 13C-NMR δ 22.06
(MePh), 56.10, 56.72 (OMe), 61.43 (C-4), 61.65 (C-3), 108.24-157.77 (aromatic carbons), 165.06
(CO, β-lactam).
4-(3,4-Dimethoxyphenyl)-1-(naphthalene-2-sulfonyl)-3-phenoxy-azetidin-2-one (27). β-Lactam 27 was
obtained by reaction of β-lactam 15 and naphthalene-2-sulfonyl chloride as a red oil (72 %); IR (neat,
cm-1) 1332.1 (S=O), 1770.1 (CO, β-lactam); 1H-NMR δ 3.29, 3.64 (2 OMe, 2 s, 6H), 5.18 (H-4, d, 1H,
J=5.0), 5.85 (H-3, d, 1H, J=5.6), 6.85-8.65 (ArH, m, 15H); 13C-NMR δ 55.89, 57.06 (OMe), 65.60 (C-
4), 68.11 (C-3), 118.34-158.84 (aromatic carbons), 166.79 (CO, β-lactam).
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