Remarkable iodine-catalyzed synthesis of novel pyrrole- bearing n-polyaromatic β-lactams

Article abstract of DOI:10.3390/molecules15021082

Because of their interesting biological properties various methods for the synthesis of substituted pyrroles are described in the literature. However, synthesis of pyrroles fused with a β-lactam ring has not been reported. Our group has demonstrated synth

Full text of DOI:10.3390/molecules15021082

Molecules 2010, 15, 1082-1088; doi:10.3390/molecules15021082
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Remarkable Iodine-Catalyzed Synthesis of Novel Pyrrole-
Bearing N-Polyaromatic β-Lactams
Debasish Bandyopadhyay, Gildardo Rivera, Isabel Salinas, Hector Aguilar and Bimal K. Banik *
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive,
Edinburg, TX 78541, USA
* Author to whom correspondence should be addressed; E-Mail: banik@panam.edu;
Tel.: +1-956-380-8741; Fax: +1-956-384-5006.
Received: 22 December 2009; in revised form: 8 February 2010 / Accepted: 20 February 2010 /
Published: 23 February 2010
Abstract: Because of their interesting biological properties various methods for the
synthesis of substituted pyrroles are described in the literature. However, synthesis of
pyrroles fused with a β-lactam ring has not been reported. Our group has demonstrated
synthesis and biological evaluation of various β-lactams as anticancer agents. The
anticancer activities of these compounds have prompted us to study the synthesis of
pyrroles bound to the β-lactams. We have identified an expeditious synthetic method for
the preparation of pyrroles fused with β-lactams by reacting 3-amino β-lactams with
acetonylacetone in the presence of catalytic amounts (5 mol%) of molecular iodine at room
temperature. It has also been discovered that the reaction gives products under domestic
and automated microwave oven irradiation. To our knowledge, there are no other prior
reports that describe the synthesis of pyrrole-substituted β-lactams.
Keywords: iodine; catalysis; β-lactams; pyrroles
1. Introduction
The biological activities of pyrroles have investigated extensively [1,2]. For this reason, diverse
methods for the synthesis of pyrroles are described in the literature [3]. Conjugate addition reactions
have been performed for the preparation of polysubstituted pyrroles [4]. Pyrroles have also been
prepared from transition metal intermediates [5], reductive coupling reactions [6], aza-Wittig reactions

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[7], and other multi-step processes [8,9]. Despite these new developments, the Paal-Knorr [10] reaction
has remained one of the most attractive methods for the synthesis of pyrroles. Clay-induced [11]
reactions and a microwave irradiation method [12] have been used for the synthesis of pyrroles under
Paal-Knorr conditions. Reactions in the presence of silica gel and alumina as solid supports have been
investigated, but the reactions did not proceeded to completion. The use of montmorillonite clay under
identical conditions, however, has produced products in good yield. These methods have extended the
scope of pyrrole synthesis, although synthesis of pyrroles attached to a β-lactam ring has not been
reported. In this paper, we describe a simple and rapid iodine-catalyzed method for the synthesis of
substituted pyrroles bound to several racemic trans-β-lactams.
2. Results and Discussion
Our group has reported the synthesis and biological evaluation as novel anticancer agents of various
β-lactams and polyaromatic compounds [13–17]. It was reported that alteration of the heterocyclic ring
is determining in the biological activity of these compounds. The anticancer activity of these
derivatives had prompted us to undertake an exploratory program in the synthesis of pyrroles bound to
β-lactams with different structures. Our laboratory is engaged in devising synthetic methods which are
practical or ecologically friendly [18–25]. The reaction between 1 and 2 does not proceed at all without
iodine even after 10 minutes of microwave irradiation. The presence of small amounts of iodine (5
mol%) is necessary for the success of the reaction. The same has been studied extensively in our
laboratory in several iodine-catalyzed reactions [26–31].
Scheme 1. Synthesis of 3-pyrrole substituted β-lactams.
H2N
N
O
I2/THF/rt
N
N
or
O
O
I2/THF/MWI
O
1
R
R
3a: R=H
2a: R=H
2b: R=OCH3
3b: R=OCH3
Ar
H2N
Ar
N
I2/THF/rt
1
N
or
N
O
I2/THF/MWI
O
5a: Ar =
5b: Ar =
4a: Ar =
4b: Ar =
O
O
S
4c: Ar =
5c: Ar =
S
In continuation of our studies on iodine-catalyzed reactions [29–31], we have identified an
expeditious synthetic method for the preparation of pyrroles fused with β-lactams starting from 3-

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amino β-lactams and 1,4-diketo compound at room temperature and using microwave-induced
reactions. To our knowledge, there are no other prior reports that describe the iodine-catalyzed
synthesis of pyrrole-substituted β-lactams. Several trans 3-amino β-lactams were used for this study.
The other starting material was commercially available 2,5-hexanedione (Scheme 1).
The diketo compound, the amine and iodine (catalytic amounts) were mixed in ethanol and stirred
overnight at room temperature. Upon extraction of the reaction mixture, 80–90% products were
obtained. In another method, the mixture was irradiated in a CEM microwave oven for 5 min at a
power level of 300 µ power. The reaction mixture was then extracted with dichloromethane. The
reaction proceeded equally well irrespective of the nature of substituent present in the β-lactam ring.
The iodine-catalyzed pyrrole formation reaction of 3-amino β-lactams (±)-2 and (±)-4 as described
herein is very simple and can be used with remarkable success. In view of our earlier publications on
anticancer β-lactams, this method may find future applications.
3. Experimental
3.1. General
Melting points were measured in a Fisher Scientific electrochemical Mel-Temp* manual melting
point apparatus (Model 1001) equipped with a 300°C thermometer. Elemental analysis (C, H, N) were
conducted using the Perkin-Elmer 2400 series II elemental analyzer, their results were found to be in
good agreement (± 0.2%) with the calculated values for C, H, N. FT-IR spectra were registered on a
1
Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. H-NMR (300 MHz) and 13C-NMR
(75.4 MHz) spectra were obtained at room temperature with JEOL Eclipse-300 equipment using TMS
as internal standard and CDCl3 as solvent. Analytical grade chemicals (Sigma-Aldrich incorporation)
were used throughout the project. Deionized water was used for the preparation of all
aqueous solutions.
3.1.1. General procedure for the synthesis of imines
Amine and aldehyde were mixed in equimolar ratio and refluxed in dry toluene using a Dean-Stark
water separator. After completion of the reaction (monitored by TLC), the solvent was removed by
rotavapor and the pure imine was isolated by crystallization from diethyl ether/hexanes. Polyaromatic
amine (6-amino chrysene) took longer time than their monoaromatic analogues.
3.1.2. General procedure for the synthesis of 3-phthalimido β-lactams
In dry dichloromethane (5 mL), phthalimidoacetic acid (1.5 mmol) was mixed with 2-chloro-N-
methylpyridinium iodide (3 mmol) and dry triethylamine (6 mmol) at 0 °C and the mixture was stirred
for two hours. The imine (1 mmol) in dry dichloromethane (5 mL) was added drop wise and stirring
was continued for another two hours at 0 °C to room temperature. After that, the mixture was refluxed
for 14 hours (monitored by TLC) to obtain a single 3-phthalimido-substituted trans β-lactam. The
reaction mixture was washed with saturated aqueous solution of sodium bicarbonate, brine and water
successively. The organic layer was dried over anhydrous sodium sulfate and crystallized from

Molecules 2010, 15
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dichloromethane/hexanes following usual procedure. The overall isolated yield was 76-85% [32]. The
reaction proceeded well with diverse imines that have different types of aromatic groups.
3.1.3. General procedure for the synthesis of 3-amino β-lactams
3-Phthalimido β-lactam (1 mmol) was mixed with ethylenediamine (1.5 mmol) in dry ethanol (3
mL) and stirred at room temperature for 15 minutes (monitored by TLC). After completion of the
reaction, the reaction mixture was washed with brine and water successively. The organic layer was
dried over anhydrous sodium sulfate and the 3-amino β-lactam was isolated in pure form by column
chromatography over neutral alumina (methanolic ethyl acetate) in good yield [33]. The
stereochemistry of β-lactams remains unchanged during this conversation. No cleavage of the β-lactam
rings was observed under this condition.
3.2. General procedure for the synthesis of pyrroles (±)-3 and (±)-5
To a solution of the β-lactam amine (±)2 or (±)4 (1 mmol) and hexane-2,4-dione (1, 1.2 mmol) in
ethanol (1 mL) at room temperature, iodine (5 mol%) was added. The mixture was irradiated using a
CEM DISCOVER Microwave at 300 µ power. Dichloromethane (10 mL) was added to the reaction
mixture and it was then washed successively with 5% NaHCO3 solution (2 mL) and brine (2 mL) and
water (2 mL). The organic layer was dried with sodium sulfate and concentrated. These pyrroles (±) 3
or (±)5 were found to be sufficiently pure (more than 90%) and finally crystallized from
dichloromethane/hexane.
3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1,4-diphenylazetidin-2-one (±)3a. White crystals. Crystallized from
dichloromethane/hexane mixture; Mp: 158 °C; IR: 2915, 1754, 1312, 1108, 780, 612 cm-1; 1H-NMR δ
(ppm): 2.08 (s, 6H, CH3), 5.01 (d, J = 2.46, H-4), 5.13 (d, J = 2.49, H-3), 5.78 (s, 2H, pyrrole), 7.26-
7.50 (m, 10H, Ar-H); 13C-NMR δ (ppm): 13.05 (2C), 64.05, 70.19, 107.51 (2C), 117.55 (2C), 124.76,
125.77 (2C), 128.66, 129.06 (2C), 129.37 (2C), 129.53 (2C), 136.02, 137.08, 163.67. Anal. Calcd for
C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Experimental: C, 79.68; H, 6.31; N, 8.77.
3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (±)3b. Brown crystals.
Crystallized from dichloromethane/hexane mixture; Mp: 149 °C; IR: 2922, 1752, 1297, 1110, 776 cm-1;
1H-NMR δ (ppm): 2.14 (s, 6H, CH3), 3.72 (s, 3H, OCH3), 5.14 (d, J = 2.31, H-4), 5.25 (d, J = 2.31, H-
3), 5.71 (s, 2H, pyrrole), 7.25-7.81(m, 9H, Ar-H); 13C-NMR δ (ppm): 13.09 (2C), 55.52 (OCH3), 64.71,
66.89, 107.90 (2C), 117.87 (2C), 119.71 (2C), 126.04, 127.65 (2C), 128.32 (2C), 128.74 (2C), 132.50,
143.76, 158.43, 166.36. Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Experimental: C,
76.14; H, 6.36; N, 8.02.
1-(Chrysen-6-yl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-4-phenylazetidin-2-one (±)5a. Pale yellow crystals.
Crystallized from dichloromethane/hexane mixture; Mp: 111―113 °C; IR: 2920, 1754, 1302, 1112,
780 cm-1; 1H-NMR δ (ppm): 2.24 (s, 6H, CH3), 5.44 (d, J = 2.19, H-4), 5.67 (d, J = 2.19, H-3), 5.88 (d,
J = 1.11, 2H, pyrrole), 7.24-8.12 (m, 16H, Ar-H); 13C-NMR δ (ppm): 13.41(2C), 65.73, 68.47, 107.71
(2C), 114.07, 122.87, 126.04 (2C), 126.09 (2C), 127.04 (2C), 128.45 (2C), 127.62 (2C), 128.74 (2C),

Molecules 2010, 15
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129.07 (2C), 129.38 (2C), 129.97 (2C), 131.19(2C), 131.98, 132.50, 135.90, 148.50, 165.05. Anal.
Calcd for C33H26N2O: C, 84.95; H, 5.62; N, 6.00. Experimental: C, 84.86; H, 5.59; N, 5.93.
1-(Chrysen-6-yl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(furan-2-yl)azetidin-2-one (±)5b. Yellow crystals.
Crystallized from dichloromethane/hexane mixture; Mp: 135―137 °C; IR: 2912, 1753, 1310, 1110,
782 cm-1; 1H-NMR δ (ppm): 2.30 (s, 6H, CH3), 5.47 (d, J = 2.46, H-4), 5.65 (d, J = 2.46, H-3), 5.91 (s,
2H, pyrrole), 6.77 (m, 2H, furan), 7.35-8.59 (m, 12H, Ar-H); 13C-NMR δ (ppm): 13.45(2C), 65.63,
68.55, 107.65 (2C), 114.41, 114.77 (2C), 122.98, 123.77 (2C), 124.56, 126.86,127.00 (2C), 127.55
(2C), 127.81(2C), 128.78 (2C), 129.07 (2C), 129.38 (2C), 129.97, 135.98, 141.05, 160.14, 165.23.
Anal. Calcd for C31H24N2O2: C, 81.56; H, 5.30; N, 6.14. Experimental: C, 81.58; H, 5.29; N, 6.08.
1-(Chrysen-6-yl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(thiophen-2-yl)azetidin-2-one (±)5c. Yellowish
white crystals. Crystallized from dichloromethane/hexane mixture; Mp: 231―233 °C; IR: 2914, 1755,
1306, 1105, 784 cm-1; 1H-NMR δ (ppm): 2.34 (s, 6H, CH3), 5.34 (d, J = 2.50, H-4), 5.92 (d, J = 2.50,
H-3), 5.90 (s, 2H, pyrrole), 6.85 (m, 1H, thiophene), 7.11-8.66 (m, 13H, Ar-H); 13C-NMR δ (ppm):
13.42(2C), 62.24, 69.35, 107.79 (2C), 115.42, 120.99, 122.91, 123.74, 124.37, 126.45 (2C), 127.05,
127.21 (2C), 127.51, 127.60, 127.89, 128.03 (2C), 128.79 (2C), 129.31, 130.78, 131.34 (2C), 132.33,
139.10, 148.50, 164.83. Anal. Calcd for C31H24N2OS: C, 78.78; H, 5.12; N, 5.93. Experimental: C,
78.71; H, 5.05; N, 5.90.
4. Conclusion
As part of our current research on anticancer β-lactams we have demonstrated an easy preparation
of 3-pyrrole-substituted β-lactams through molecular iodine-catalyzed reactions. This simple method
may find useful applications in drug synthesis. Furthermore, the compounds reported herein will be
tested against a number of cancer cells in vitro.
Acknowledgements
We gratefully acknowledge the funding support from the NIH-SCORE, 2506M008038-37.
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Sample Availability: Samples of the compounds are available from the authors.
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