A green, chemoselective, and practical approach toward N-(2-azetidinonyl) 2,5-disubstituted pyrroles

Article abstract of DOI:10.1039/c3ra42266f

Pyrrole and 2-azetidinone are two essential heterocyclic scaffolds, which are being broadly used in medicinal chemistry and drug discovery field. A green and practical method to synthesize novel N-(2-azetidinonyl) 2,5-disubstituted pyrroles, which are com

Full text of DOI:10.1039/c3ra42266f

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A green, chemoselective, and practical approach toward Nꢀ
(2ꢀazetidinonyl) 2,5ꢀdisubstituted pyrroles
Debasish Bandyopadhyay, Elvira Rhodes†, and Bimal K. Banik*
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive,
Edinburg, Texas 78539, USA
*Corresponding author; Phone: +1(956)6658741, Fax: +1(956)3845006, Eꢀmail: banik@utpa.edu
†Undergraduate research participant
Abstract
Pyrrole and 2ꢀazetidinone are two essential heterocyclic scaffolds are being broadly used in
medicinal chemistry and drug discovery field. A green and practical method to synthesize novel
Nꢀ(2ꢀazetidinonyl) 2,5ꢀdisubstituted pyrroles, which comprise of both pyrrole and 2ꢀazetidinone
moieties, has been developed. The classical PaalꢀKnorr reaction is one of the simplest and most
economical methods for the synthesis of biologically important and pharmacologically useful
pyrrole derivatives. The present procedure for the synthesis of Nꢀ(2ꢀazetidinonyl) 2,5ꢀ
disubstituted pyrroles (1,2,5ꢀtrisubstituted pyrroles) has been accomplished by reacting 3ꢀamino
βꢀlactams and 2,5ꢀhexanedione in the presence of bismuth nitrate pentahydrate as an ecofriendly
catalyst using microwave irradiation under solvent free condition. A comparison has also been
made between the efficiency of microwaveꢀassisted condition and the classical method (stirring
at room temperature). The present method is equally effective for Nꢀpolyaromatic substituted βꢀ
lactams and optically pure βꢀlactams with chemically sensitive functionalities. The structure and
stereochemistry of the products have been confirmed by extensive spectroscopic and Xꢀray
crystallographic analyses. The present procedure of synthesizing Nꢀ(2ꢀazetidinonyl) 2,5ꢀ

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disubstituted pyrroles may find application in the development of potent pharmacologically
active molecules.
Keywords
1,2,5ꢀTrisubstituted pyrroles; 2ꢀAzetidinone; Green synthesis; Solventless reaction; PaalꢀKnorr
reaction; Optically pure βꢀlactam; Microwave; Bismuth nitrate.
Running title
Green synthesis of 1,2,5ꢀtrisubstituted pyrroles

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Introduction
Nitrogen heterocycles are pervasive in drug development research, among which pyrrole and 2ꢀ
azetidinone (βꢀlactam) are two most important pharmacophores, often found in synthetic and
natural drugs.1They possess a central place among various classes of pharmacophores due to
their diverse and interesting medicinal properties. However, more than 70 years of extensive and
sometimes unnecessary, use of βꢀlactams has enabled bacteria to develop a broad range of
resistance mechanisms. The development of multidrug resistance has reduced the effectiveness
of βꢀlactams as antimicrobial drugs.2 The main reason of βꢀlactam resistance is the production of
βꢀlactamase; consequently, the development of βꢀlactamase inhibitors has been one of the main
strategies in drug development. Nonetheless, the versatility of the βꢀlactam core structure,
combined with the innovation of medicinal chemists, has repeatedly led to the development of
new generations of βꢀlactam antibiotics that are capable of overcoming the problems caused by
mounting bacterial resistance. Other than antiꢀinfective properties βꢀlactam derivatives have also
demonstrated a wide range pharmacological activity which includes antidiabetic, antiꢀ
inflammatory, antiparkinsonian, antiꢀHIV as well as anticancer.1ꢀ6
On the other hand, pyrroleꢀderived alkaloids along with lamellarins are a large family of marine
alkaloids with novel structures and promising bioactivities.7 A variety of naturally occurring 3,4ꢀ
or 2,5ꢀ diꢀ or 1,2,5ꢀtrisubstituted pyrroles have been isolated from ascidians, mollusks, sponges
and cucumbers. Many of these highly complex pyrroles have been found to exhibit
bioactivity.8,9The pharmacological activity of 1ꢀ(2ꢀhydroxyꢀ3ꢀdimethylaminopropyl)ꢀ2,5ꢀ
dimethylpyrrole was also reported.10 Based upon these encouraging results, the synthesis of
novel Nꢀ(2ꢀazetidinonyl)ꢀ2,5ꢀdisubstituted pyrroles was undertaken. We report herein the green
synthesis of a variety of 1,2,5ꢀtrisubstituted pyrroles having 2ꢀazetidinone scaffold on pyrrole

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nitrogen. These structurally unique molecules may reveal potential application in future drug
discovery research.
Results and discussion
The continuing drive for practically simple and efficient organic transformations has resulted in
the development of many novel concepts and methodologies. Of particular importance is the
field of environmentally benign reactions. Over the past decade, protection of the environment
and waste prevention has been increasingly emphasized by researchers from both academia and
industry.11 For this reason the elimination or reduction of volatile solvents in organic synthesis is
an important goal. These types of processes can contribute significantly in green chemistry. In
this context development of solventꢀfree synthetic methods or the replacement of hazardous
solvents with environmentally benign solvents has become an important and popular research
topic in recent years.12,13
Our laboratory has been performing the microwaveꢀinduced reactions for many years. We have
successfully developed several new reaction methodologies using microwave irradiation
technique. Some recent examples include stereoselective synthesis of βꢀlactams,14ꢀ16 synthesis of
pyrroles,17ꢀ20 azaꢀMichael addition,21 and synthesis of quinoxalines22. On the other hand organoꢀ
bismuth chemistry23ꢀ26 is considered as a promising field of research in synthetic organic
chemistry. Bismuth nitrate pentahydrate, a solid salt is commercially available from a number of
companies around the world, very economical and nontoxic compared to other Lewis acids. We
have demonstrated the catalytic activity of trivalent bismuth nitrate pentahydrate in a number of
examples. These investigations resulted in various novel methods that include nitration of
aromatic systems,27ꢀ29 Michael reaction,30 protection of carbonyl compounds,31 deprotection of
oximes and hydrazones,32 PaalꢀKnorr synthesis of pyrroles,33 hydrolysis of amide,34 electrophilic

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substitution of indoles,35,36 synthesis of αꢀaminophosphonates,37 and Hantzsch 1,4ꢀ
dihydropyridines38. Our success in the bismuth nitrateꢀinduced reaction has revealed that this
reagent acts as a Lewis acid type of activator. It has been conceived by our group that Nꢀ(2ꢀ
azetidinonyl) 2,5ꢀdimethyl pyrroles can be easily prepared using bismuth nitrate as the catalyst.
Moreover, it has been found that this reagent is compatible in the presence of acidꢀsensitive
functionalities like primary amine and fourꢀmembered cyclic amide (βꢀlactam moiety). This idea
has been extended in this paper to react 2,5ꢀhexanedione with 3ꢀamino substituted 2ꢀazetidinones
in the presence of catalytic amount of bismuth nitrate under solventꢀfree condition.
In another note, the anticancer activity of the marketed drugs often results in a number of
undesired side effects as well as multidrug resistance (MDR). Therefore, it has become essential
to develop new anticancer agents with less side effects, minimum toxicity, superior
pharmacological properties, and improved overall activity against diverse classes of tumors. As a
part of our ongoing research, we have been engaged for the synthesis of new anticancer agents
with special emphasis on βꢀlactam anticancer for the past several years.39ꢀ45 We have also
developed new methodologies for the synthesis of anticancer pyrroles.33,39 During the course of
investigation on PaalꢀKnorr synthesis of pyrroles, we envisage that 1,2,5ꢀtrisubstituted pyrroles,
where position 1 (nitrogen) is substituted by βꢀlactam moiety can be synthesized by reacting 3ꢀ
amino βꢀlactams and 2, 5ꢀhexanedione as the staring materials in the presence of an acidic
catalyst following PaalꢀKnorr method.46,47The 3ꢀamino βꢀlactams are easily prepared from 3ꢀ
phthalimido βꢀlactams which are synthesized through Staudinger cycloaddition48 reaction of
imines and acid chloride (equivalent) following Scheme 1.

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Scheme 1. Synthesis of 3ꢀamino 2ꢀazetidinones
Reaction of C,Nꢀdiaryl imines 1 with Nꢀphthaloylglycine in the presence of triethylamine and 2ꢀ
chloroꢀNꢀmethylpyridinium iodide was performed at 0°C―room temperature and a mixture of
(+)ꢀcis and (+)ꢀtrans βꢀlactams was isolated. However, polyaromatic imines 1 derived from 6ꢀ
chrysenyl amine produced exclusively (+)ꢀtrans βꢀlactams. High temperature reaction also gave
an identical result in comparable yield. The reaction proceeded well with diverse imines that
have different types of aromatic groups (Scheme 1) in good to excellent yield of the products. At
the beginning of our approach, to synthesize Nꢀ(2ꢀazetidinonyl) 2,5ꢀdimethyl pyrroles from 3ꢀ
amino substituted βꢀlactams the reaction between (+)ꢀtransꢀ3ꢀaminoꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone
(3a) with 1.1 mmol of 2,5ꢀhexanedione was used as a model study. Our initial study started with
screening of catalyst loading to obtain optimal reaction conditions for the synthesis of Nꢀ(2ꢀ
azetidinonyl) 2,5ꢀdisubstituted pyrroles. A number of bismuth salts e.g. bismuth chloride,
bismuth bromide bismuth iodide, bismuth triflate, bismuth subnitrate, and bismuth nitrate
pentahydrate were screened using 1 mmol of 3a with 1.1 mmol of 2,5ꢀhexanedione as the
substrates under automated CEM microwave irradiation (260 Watts, 80 °C, 20–45 psi, 1 minute).
The results are shown in Table 1. It has also been discovered that the reaction gives products
with extreme rapidity under microwave irradiation.

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Table 1. Microwaveꢀassisted (260 Watts, 80 °C, 20–45 psi) synthesis of Nꢀ(2ꢀazetidinonyl) 2,5ꢀdisubstituted pyrrole
from 1 mmol of (+)ꢀtransꢀ3ꢀaminoꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone with 1.1 mmol of 2,5ꢀhexanedione using bismuthꢀ
salts as catalyst (10 mol%) under solventless condition (1 minute): catalyst optimization
.
Entry Biꢀsalt (10 mol %) Yield (%)a
1
2
3
4
5
6
7
BiCl3
BiBr3
BiI3
56
51
40
57
Bi(OTf)3
Bi5O(OH)9(NO3)3 36
Bi(NO3)3.5H2O
No catalyst
91
16
aisolated yield
Bismuth nitrate pentahydrate was found to be the best catalyst among other bismuth salts under
this condition (Entry 6, Table 1). Without using any catalyst (only microwave irradiation) 16%
yield of the product was isolated after five minutes irradiation (Entry 7, Table 1). The same
probe was used to optimize the amount of the catalyst bismuth nitrate pentahydrate (Table 2).
The results show that 5 mol% bismuth nitrate pentahydrate was required to complete the reaction
within a minute (Entry 6, Table 2).
Table 2. Microwaveꢀassisted (260 Watts, 80 °C, 20–45 psi) synthesis of Nꢀ(2ꢀazetidinonyl) 2,5ꢀdisubstituted pyrrole
from 1 mmol of (+)ꢀtransꢀ3ꢀaminoꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone with 1.1 mmol of 2,5ꢀhexanedione using bismuth
nitrate pentahydrate as catalyst under solventless condition (1 minute): optimization of the amount of the catalyst.
Entry Bi (NO3)3.5H2O (mol %) Yield (%)a
1
2
3
4
5
6
7
8
30
25
20
15
10
5
73
71
83
87
91
96
63
39
2
1
aisolated yield
It is very convenient to conduct the reaction with bismuth nitrate because of its stability in the
presence of moisture and oxygen. The presence of small amounts of catalyst (5 mol%) is
necessary for the success of the reaction. The reaction was then performed in various solvents as

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well as in neat condition under an identical microwave power using bismuth nitrate pentahydrate
(5 mol%) as the catalyst to identify the best solvent/condition (Table 3). From these studies, it
was confirmed that bismuth nitrate pentahydrate is the best catalyst, among all other Lewis acids
investigated for this reaction, under neat condition (Entry 8, Table 3).
Table 3. Microwaveꢀassisted (260 Watts, 80 °C, 20–45 psi) synthesis of Nꢀ(2ꢀazetidinonyl) 2,5ꢀdisubstituted pyrrole
from 1 mmol of (+)ꢀtransꢀ3ꢀaminoꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone with 1.1 mmol of 2,5ꢀhexanedione using bismuth
nitrate pentahydrate as catalyst (5 mol%) for 1 minute: solvent optimization.
Entry Solvent (1 mL)
Yield (%)a
1
2
3
4
5
6
7
8
Toluene
Dichloromethane 27
Tetrahydrofuran
Methanol
Ethanol
32
78
80
77
Dimethylsulfoxide 72
Water
Neat
81
96
aisolated yield
After determining the optimized condition we carried out a series of reaction (Scheme 2) using
3ꢀamino βꢀlactams (1 mmol) with 2,5ꢀhexanedione (1.1 mmol) in the presence of bismuth nitrate
pentahydrate (5 mol%) under microwave irradiation (260 Watts, 80 °C, 20–45 psi). The 3ꢀamino
substituted βꢀlactams were synthesized following the procedure developed in our laboratory.49,50
Scheme 2. Stereoselective synthesis of Nꢀ(2ꢀazetidinoyl)ꢀ2,5ꢀdimethyl pyrroles

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The reaction proceeded equally well irrespective of the nature of substituent present in the βꢀ
lactam ring without any change of stereochemistry. A series of diversely C,Nꢀdisubstituted 3ꢀ
amino βꢀlactams yielded the corresponding Nꢀ(2ꢀazetidinoyl)ꢀ2,5ꢀdimethyl pyrroles following
Scheme 2. Upon extraction of the reaction mixture excellent yield of the corresponding pyrroles
were obtained (Table 4). The model reaction was also conducted following classical condition,
stirring a mixture of (+)ꢀtransꢀ3ꢀaminoꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone (1 mmol), 2,5ꢀhexanedione
(1.1 mmol) and bismuth nitrate (5 mol%) at room temperature, under solventless condition. The
reaction yielded only 48% corresponding pyrrole even after 36 hours. Next, the model reaction
was conducted following the same classical condition in presence of 0.5 mL water which yields
the corresponding pyrrole in 61% yield after 16 hours. The same set of reactions (Table 4) were
performed under classical condition by stirring a mixture of 3ꢀamino βꢀlactam (1 mmol), 2,5ꢀ
hexanedione (1.1 mmol) and bismuth nitrate (5 mol%) at room temperature in water (0.5 mL)
and the results are summarized in Table 4.
Table 4. Bismuth nitrateꢀinduced synthesis of Nꢀ(2ꢀazetidinonyl) 2,5ꢀdimethyl pyrroles from 3ꢀamino substituted βꢀ
lactams under solventless condition
Entry Substrate
(3ꢀamino
Product
[Nꢀ(2ꢀ
azetidinonyl)ꢀ temperature
2,5ꢀdimethyl
Condition A
Stirring at room
Condition B
MWI (260 Watts,
80 °C, 20–45 psi)
βꢀlactam)
pyrrole]
Time (h)
Yield
(%)a
58
61
66
59
49
52
57
47
44
67
64
Time (min) Yield
(%)a
1
16
16
16
16
24
24
24
24
24
16
16
1
1
1
1
5
5
4
3
5
1
1
90
96
98
92
91
87
94
88
87
89
94
3a
3a′
3b
3b′
3c
4a
4a′
4b
4b′
4c
2b
3
4b
5
6
7
3d
3e
4d
4e
8
3f
4f
9
10
11
3g
5a
5b
4g
6a
6b
aisolated yield; bcis stereochemistry

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The formation of a mixture of isomeric products in case of monoaryl imines had cast doubt about
the analysis of the product distributions of earlier studies.51,52The present study confirmed the
formation of two isomeric cis and trans products. Previous studies on the same reaction reported
the formation of trans isomer only with imines that have monoaromatic groups at the Cꢀ and Nꢀ
terminus. It appears that the electron withdrawing aromatic groups at the Cꢀ and Nꢀterminus of
the imine is responsible for the formation of the trans isomer. The effect of electron withdrawing
property is highly significant when chrysenyl group is present at the Nꢀterminus of the imine. In
case of Nꢀchrysenyl imines only the trans isomer was isolated as the sole product. The formation
of trans isomer in case of Nꢀchrysenyl imines and Nꢀmonoaryl imines can be rationalized
through an isomerization of the enolate as described earlier.42ꢀ44 Polyaromatic group (in this
example, chrysenyl) on the nitrogen stabilizes the iminium ion greatly. The electron withdrawing
property of monocyclic aromatic groups at the Nꢀsite of the imine is not sufficient to have a
complete isomerization of the enolate and therefore, a mixture of cisꢀ and transꢀisomers is
formed. The stereochemistries of the corresponding cis and trans Nꢀ(2ꢀazetidinonyl) 2,5ꢀ
dimethyl pyrroles (4b and 4b′ ) have been confirmed by Xꢀray crystallographic analysis (Figures
1 and 2).53,54

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Figure 1. Xꢀray crystallographic (ORTEP) structure of (4b). Thermal ellipsoids are shown with
50% probability.
Figure 2. Xꢀray crystallographic (ORTEP) structure of (4b′ ). Thermal ellipsoids are shown with
50% probability.
As mentioned earlier, the trans Nꢀ(2ꢀazetidinonyl) 2,5ꢀdimethyl pyrrole was isolated as the sole
product for Nꢀchrysenyl imine 1, retaining the stereochemistry of the corresponding phthalimido
βꢀlactams. No change in stereochemistry was observed in this reaction. The trans

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stereochemistry of one the polyaromatic imine derived trans Nꢀ(2ꢀazetidinonyl) 2,5ꢀdimethyl
pyrrole (4e) has been confirmed by Xꢀray crystallographic analysis (Figure 3).55 The sulfur atom
of the thiophenyl moiety (S1AꢀB) and the carbon atom (C25AꢀB) are disordered. Both the sulfur
atom and the carbon atom occupy 50% of the time flipping back and forth from each position.
Probably because of extremely high rate of flipping the subsequent flippomers are not visible
individually in NMR time scale and only one set of values was observed.56 This observation is
highly interesting because this is the first example of a molecule, having βꢀlactam core, exists in
flippomer forms.
Figure 3. Xꢀray crystallographic (ORTEP) structure of (4e) acetone solvate. Thermal ellipsoids
are shown with 50% probability.
The mechanism of the reaction has not been studied in detail. A plausible mechanistic pathway
involves the nucleophilic attack of the electron pair on nitrogen attached to Cꢀ3 of the 2ꢀ
azetidinone ring system to one of the carbonyl groups of 2,5ꢀhexanedione under the influence of
bismuth nitrate pentahydrate. The process is highly accelerated under microwave irradiation. A
second nucleophilic attack to the other carbonyl group and subsequent dehydrationꢀaromatization

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yields Nꢀ(2ꢀazetidinonyl) 2,5ꢀdimethyl pyrrole as the sole product (Scheme 3). This reaction
suggests the capability of bismuth nitrate to serve as a Lewis activator.
Bi (III)
Bi (III)
OH
CH3
O
O
MWI (260 Watts,
80ºC, 20-45 psi)
O
CH3
CH3
CH3
H H
H H
HN
Ar2
Ar1
H2N
Ar2
Ar1
N
N
O
O
(+)-cis or (+)-trans
OH
CH3
HO
H H
N
- 2 H2O
N
Ar2
Ar1
H3C
N
N
O
H
(+)-cis or (+)-trans
H
O
Ar2
Ar1
Scheme 3. Plausible mechanism for the synthesis of Nꢀ(2ꢀazetidinonyl) 2,5ꢀdimethyl pyrroles.
The effectiveness of our newly developed methodology was further tested for the synthesis of
optically pure Nꢀ(2ꢀazetidinoyl)ꢀ2,5ꢀdimethyl pyrroles. To achieved this goal, 3ꢀPhthalimido
substituted 2ꢀazetidinones were synthesized from optically pure 2,2ꢀdimethylꢀ1,3ꢀdioxolaneꢀ4ꢀ
carboxaldehyde following a published method.57 The 3ꢀphthalimido substituted βꢀlactams were
deprotected by ethylene diamine as reported from our laboratory.50 The corresponding 3ꢀamino
substituted βꢀlactams (5) produced 3ꢀpyrrole substituted βꢀlactams (6) upon treatment with 2,5ꢀ
hexanedione in the presence of 5 mol% of bismuth nitrate pentahydrate at room temperature as
well as under microwaveꢀinduced procedure (Scheme 4) as discussed herein. Synthetic method
for the preparation of optically pure Nꢀ(2ꢀazetidinoyl)ꢀ2,5ꢀdimethyl pyrroles is still unknown
despite gigantic development in this field in the past several decades. Because of the mild
conditions of the experiments, it is gratifying to note that no deprotection of the acidꢀsensitive

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ketal group to diol and subsequent oxidation, rearrangement and lactonization was occurred in
the synthesis of pyrroles (6) (Scheme 4). The bismuth nitrateꢀcatalyzed pyrrole formation
reaction of 3ꢀamino βꢀlactams as described herein is very simple and can be used with
remarkable success.
Scheme 4. Synthesis of optically pure Nꢀ(2ꢀazetidinoyl)ꢀ2,5ꢀdimethyl pyrroles
Conclusion
Among the wide variety of heterocycles, which have been explored for developing
pharmaceutical significant molecules, 2ꢀazetidinones and pyrroles are noteworthy. The
discovery, development and identification of pharmacologically active compounds have gained
immense importance at present era. Because of the interest of β–lactams and pyrroles in organic
and medicinal chemistry, research in this field continues in producing new appealing progresses.
The discovery and development of commercially viable orally active βꢀlactam antibiotics and
inhibitors of Class A and C βꢀlactamases remain as significant challenges for medicinal chemists.
The production, under environmentally benign conditions, of efficient and more costꢀeffective
medicines is one of most exciting dreams of the industrial medicinal chemistry. The present
economical method satisfies most of the principles of green chemistry and the unique structures
of the Nꢀ(2ꢀazetidinoyl)ꢀ2,5ꢀdimethyl pyrroles reported in this paper may provide important new
leads for the discovery of drugs for many dreadful diseases with novel mechanisms of action.

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Experimental
General
Melting points were determined in a Fisher Scientific electrochemical MelꢀTemp* manual
melting point apparatus (Model 1001) equipped with a 300°C thermometer. FTꢀIR spectra were
recorded on a Bruker Alpha modular PlatinumꢀATR FTꢀIR spectrometer with OPUS software,
1
using the samples directly (neat) without making pallets. HꢀNMR (600 MHz) and 13CꢀNMR
(150 MHz) spectra were obtained at room temperature with Bruker superconducting
UltrashieldTM Plus 600 MHz NMR spectrometer with central field 14.09 Tesla, coil inductance
89.1 Henry and magnetic energy 1127.2 kJ using CDCl3 as solvent. Elemental analyses (C, H, N)
were conducted using the PerkinꢀElmer 2400 series II elemental analyzer, their results were
found to be in good agreement (± 0.2%) with the calculated values for C, H, N. Bismuth nitrate
pentahydrate (reagent grade) 98% (Cat # 248592ꢀ500G, Batch # MKBC6772) purchased from
SigmaꢀAldrich Corporation was used. All other chemicals were purchased from SigmaꢀAldrich
Corporation (analytical grade). Throughout the project solvents were purchased from Fisherꢀ
Scientific. Deionized water was used for the preparation of all aqueous solutions.
General procedure for the synthesis of Nꢀ(2ꢀazetidinonyl)ꢀ2,5ꢀdimethyl pyrrole from 3ꢀamino
substituted βꢀlactam.
The substrate (3ꢀamino substituted βꢀlactam, 1.0 mmol), 2,5ꢀhexanedione (1.1 mmol) and
bismuth nitrate pentahydrate (5 mol%, 24 mg) were mixed together in a microwave vial with a
magnetic stir bar. The mixture was irradiated in an automated microwave (CEM Corporation)
and the progress of the reaction was monitored by TLC. After completion of the reaction (Table
4) dichloromethane (7 mL) was added to the reaction mixture and the organic layer was washed
with saturated sodium bicarbonate solution, brine and water successively. It was dried over
anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude mass
was purified through a small silica gel column using ethyl acetate/hexanes as eluent. The spectral
and analytical data are as follow:
(+)ꢀTransꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone (4a): Yellowish crystals
(90%, 284 mg, dichloromethane/hexanes); mp 149–150 °C; IR (neat) 2966 ( Ar CH), 1751
(lactam CO), 1598 and 1499 (Ar C=C), 1370 (CH3), 1228 (C―N), 768 and 745 (monoꢀ
substituted benzene) cmꢀ1; 1HꢀNMR (600 MHz, CDCl3) δ 2.13 (6H, s, pyrroyl C(2,5) CH3), 5.07
(1H, d, J = 2.34 Hz, C(4)H), 5.19 (1H, d, J = 2.46 Hz, C(3)H), 5.84 (2H, s, pyrroyl C(3,4)H),

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7.13–7.44 (10H, m, phenyl H); 13CꢀNMR (150 MHz, CDCl3) δ 12.98, 64.02, 70.15, 107.48,
117.50, 124.70, 125.72, 128.60, 129.00, 129.36, 129.41, 135.99, 137.04, 163.63. Anal. Calcd for
C21H20N2O: C, C, 79.72; H, 6.37; N, 8.85. Found: C, 79.87; H, 6.29; N, 8.88.
(+)ꢀTransꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀphenylazetidinꢀ2ꢀone (4b):
white crystals (98%, 339 mg, dichloromethane/hexanes); mp 164–165 °C; IR (neat) 2926 ( Ar
CH), 1759 (lactam CO), 1548 and 1508 (Ar C=C), 1381 (CH3), 1292, 1239 (C―N), 838 (paraꢀ
substituted benzene) cmꢀ1; 1HꢀNMR (600 MHz, CDCl3) δ 2.02 (6H, s, pyrroyl C(2,5) CH3), 3.67
(3H, s, OCH3), 4.91 (1H, d, J = 2.10 Hz, C(4)H), 5.05 (1H, d, J = 2.28 Hz, C(3)H), 5.72 (2H, s,
pyrroyl C(3,4)H), 6.74 (2H, d, J = 6.84 Hz, C(2,6) pꢀmethoxyphenyl H), 7.18–7.31 (7H, m,
C(3,5) pꢀmethoxyphenyl and phenyl H); 13CꢀNMR (150 MHz, CDCl3) δ 12.96, 55.47, 64.11,
70.12, 107.41, 114.55, 118.85, 125.77, 128.59, 128.96, 129.42, 130.52, 136.05, 156.63, 162.98.
Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.22; H, 6.37; N, 8.02.
(+)ꢀTransꢀ1ꢀ(chrysenꢀ6ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀphenylazetidinꢀ2ꢀone
(4c):
yellow crystals (91%, 424 mg, dichloromethane/diethyl ether/hexanes); mp 111–113 °C; IR
(neat) 2959 ( Ar CH), 1767 (lactam CO), 1593 (Ar C=C), 1386 (CH3), 1303, 1239 (C―N), 820,
1
756, 699 (metaꢀsubstituted benzene) cmꢀ1; HꢀNMR (600 MHz, CDCl3) δ 2.19 (6H, s, pyrroyl
C(2,5) CH3), 5.37 (1H, d, J = 2.58 Hz, C(4)H), 5.60 (1H, d, J = 2.58 Hz, C(3)H), 5.81 (2H, s,
pyrroyl C(3,4)H), 7.15–7.26 (5H, m, phenyl H), 7.54–7.62 (2H, m, chrysenyl H), 7.70–7.71 (2H,
m, chrysenyl H), 7.88–7.90 (2H, m, chrysenyl H), 8.40–8.42 (1H, m, chrysenyl H), 8.43 (1H, s,
chrysenyl C(5)H), 8.48 (1H, d, J = 8.34 Hz, chrysenyl H), 8.57 (1H, d, J = 9.12 Hz, chrysenyl
H), 8.72–8.74 (1H, m, chrysenyl H); 13CꢀNMR (150 MHz, CDCl3) δ 13.31, 65.70, 68.43, 107.65,
114.02, 120.92, 122.81, 123.67, 124.55, 125.97, 126.79, 126.84, 126.90, 126.95, 127.54, 127.56,
127.76, 128.66, 128.71, 128.99, 129.30, 129.99, 131.41, 131.68, 132.28, 135.85, 164.95. Anal.
Calcd for C33H26N2O: C, 84.95; H, 5.62; N, 6.00. Found: C, 84.83; H, 5.51; N, 5.93.
(+)ꢀTransꢀ1ꢀ(chrysenꢀ6ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)azetidinꢀ2ꢀone
(4d): yellowish red amorphous solid (87%, 431 mg, dichloromethane/diethyl ether/hexanes); mp
142 °C; IR (neat) 2951 ( Ar CH), 1758 (lactam CO), 1611, 1592, 1516, (Ar C=C), 1388 (CH3),
1301, 1244, 1173 (C―N), 822 (paraꢀsubstituted benzene), 754 (metaꢀsubstituted benzene) cmꢀ1;
1HꢀNMR (600 MHz, CDCl3) δ 2.20 (6H, s, pyrroyl C(2,5) CH3), 3.59 (3H, s, OCH3), 5.36 (1H,
d, J = 2.64 Hz, C(4)H), 5.54 (1H, d, J = 2.64 Hz, C(3)H), 5.80 (2H, s, pyrroyl C(3,4)H), 6.70
(2H, d, J = 8.88 Hz, paraꢀmethoxyphenyl C(2,6)H), 7.28 (2H, d, J = 8.82 Hz, paraꢀ

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methoxyphenyl C(3,5)H), 7.55–7.90 (6H, m, chrysenyl H), 8.38–8.40 (1H, m, chrysenyl H), 8.42
(1H, s, chrysenyl C(5) H), 8.49 (1H, d, J = 8.28 Hz, chrysenyl H), 8.56 (1H, d, J = 9.06 Hz,
chrysenyl H), 8.71–8.73 (1H, m, chrysenyl H); 13CꢀNMR (150 MHz, CDCl3) δ 13.32, 55.19,
65.55, 68.47, 107.54, 114.29, 114.70, 120.92, 122.83, 123.66, 124.49, 126.77, 126.89, 126.90,
127.42, 127.48, 127.55, 127.58, 127.72, 128.66, 128.70, 160.07, 165.09. Anal. Calcd for
C34H28N2O2: C, 82.23; H, 5.68; N, 5.64. Found: C, 82.07; H, 5.62; N, 5.56.
(+)ꢀTransꢀ1ꢀ(chrysenꢀ6ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀ(thiophenꢀ2ꢀyl)azetidinꢀ2ꢀone
(4e): Light yellow (almost colorless) crystal (94%, 443 mg, dichloromethane/diethyl
ether/hexanes); mp 231 °C; IR (neat) 3102, 2970 ( Ar CH), 1765 (lactam CO), 1510, 1588 (Ar
1
C=C), 1388 (CH3), 1301, 1237 (C―N), 822, 757, 701 (metaꢀsubstituted benzene) cmꢀ1; Hꢀ
NMR (600 MHz, CDCl3) δ 2.26 (6H, s, pyrroyl C(2,5) CH3), 5.56 (1H, d, J = 2.52 Hz, C(4)H),
5.82 (2H, s, pyrroyl C(3,4)H), 5.84 (1H, d, J = 2.52 Hz, C(3)H), 6.77 (1H, dd, J = 4.98 Hz and
3.60 Hz, thiophenyl C(3)H), 7.04 (1H, dd, J = 4.50 Hz and 0.84 Hz, thiophenyl C(4)H), 7.11
(1H, dd, J = 5.94 Hz and 0.96 Hz, thiophenyl C(5)H), 7.57–7.92 (4H, m, chrysenyl H), 8.29–
8.30 (2H, m, chrysenyl H), 8.47 (1H, s, chrysenyl C(5) H), 8.52–8.73 (4H, m, chrysenyl H); 13Cꢀ
NMR (150 MHz, CDCl3) δ 13.32, 62.19, 69.31, 107.73, 115.36, 120.92, 122.84, 123.65, 124.31,
126.36, 126.82, 126.97, 126.98, 127.11, 127.29, 127.42, 127.53, 127.82, 127.96, 128.71, 128.73,
130.06, 130.73, 131.62, 132.27, 139.06, 164.73. Anal. Calcd for C31H24N2OS: C, 78.78; H, 5.12;
N, 5.93. Found: C, 78.89; H, 5.02; N, 5.87.
(+)ꢀTransꢀ1ꢀ(chrysenꢀ6ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀ(ferrocenyl)azetidinꢀ2ꢀone (4f):
Orange crystal (88%, 505 mg, dichloromethane/diethyl ether); mp 244–246 °C; IR (neat) 2953,
2926 ( Ar CH), 1728 (lactam CO), 1597, 1574 (Ar C=C), 1381 (CH3), 1273 (C―N), 822, 738,
699 (metaꢀsubstituted benzene) cmꢀ1; 1HꢀNMR (600 MHz, CDCl3) δ 2.39 (6H, s, pyrroyl C(2,5)
CH3), 3.68 (5H, s, ferrocenyl C(1′, 2′, 3′, 4′, 5′)H, 3.99 (1H, m, ferrocenyl H), 4.01 (1H, m,
ferrocenyl H), 4.06 (1H, m, ferrocenyl H), 4.08 (1H, m, ferrocenyl H), 5.38 (1H, d, J = 2.58 Hz,
C(4)H), 5.49 (1H, d, J = 2.58 Hz, C(3)H), 5.84 (2H, s, pyrroyl C(3,4)H), 7.58–7.96 (6H, m,
chrysenyl H), 8.22 (1H, m, chrysenyl H), 8.57 (1H, s, chrysenyl H), 8.59–8.78 (3H, m, chrysenyl
H); 13CꢀNMR (150 MHz, CDCl3) δ 13.50, 63.52, 65.97, 66.95, 67.04, 68.67, 68.71, 68.76, 68.88,
83.62, 107.77, 116.61, 120.99, 122.81, 123.79, 124.27, 126.87, 127.05, 127.09, 127.53, 127.57,
127.88, 127.98, 128.08, 128.56, 128.80, 130.09, 131.25, 131.63, 132.35, 165.56. Anal. Calcd for
C37H30FeN2O: C, 77.35; H, 5.26; N, 4.88. Found: C, 78.23; H, 5.17; N, 4.79.

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(+)ꢀTransꢀ1ꢀ(chrysenꢀ6ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀ(furanꢀ2ꢀyl)azetidinꢀ2ꢀone (4g):
Yellow crystal (87%, 396 mg, dichloromethane/diethyl ether/hexanes); mp 135–137 °C; IR:
2912 ( Ar CH), 1753 (lactam CO), 1581, 1560 (Ar C=C), 1377 (CH3), 1310 (C―N),, 782 (metaꢀ
substituted benzene) cmꢀ1; 1HꢀNMR δ (ppm): 1HꢀNMR (600 MHz, CDCl3) δ 2.30 (6H, s, pyrroyl
C(2,5) CH3), 5.47 (1H, d, J = 2.46 Hz, C(4)H), 5.65 (1H, d, J = 2.46 Hz, C(3)H), 5.91 (2H, s,
13
pyrroyl C(3,4)H), 6.77 (2H, m, furyl H), 7.35–8.59 (12H, m, ArꢀH); CꢀNMR δ (ppm): 13.45,
65.63, 68.55, 107.65, 114.41, 114.77, 122.98, 123.77, 124.56, 126.86,127.00, 127.55, 127.81,
128.78, 129.07, 129.38, 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.
(+)ꢀCisꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone
(4a′):
Deep
brown
amorphous solid (96%, 303 mg, dichloromethane/hexanes); mp 136–137 °C; IR (neat) 2958 (
Ar CH), 1720 (lactam CO), 1603 and 1460 (Ar C=C), 1384 (CH3), 1278 (C―N), 742 and 697
1
(monoꢀsubstituted benzene) cmꢀ1; HꢀNMR (600 MHz, CDCl3) δ 2.09 (6H, s, pyrroyl C(2,5)
CH3), 5.21 (1H, d, J = 5.49 Hz, C(4)H), 5.32 (1H, d, J = 5.49 Hz, C(3)H), 7.03 (2H, m, pyrroyl
C(3,4)H), 7.27–7.81 (10H, m, phenyl H); 13CꢀNMR (150 MHz, CDCl3) δ 14.12, 61.27, 68.18,
107.99, 117.65, 124.52, 125.95, 126.16, 128.81, 129.03, 129.14, 129.17, 135.84, 137.16, 162.05.
Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 79.69; H, 6.31; N, 8.89.
(+)ꢀCisꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀphenylazetidinꢀ2ꢀone
(4b′):
white crystals (92%, 318 mg, dichloromethane/hexanes); mp 147–148 °C; IR (neat) 2922 ( Ar
CH), 1739 (lactam CO), 1546 and 1512 (Ar C=C), 1396 (CH3), 1239 and 1173 (C―N), 819
1
(paraꢀsubstituted benzene) cmꢀ1; Hꢀ NMR (600 MHz, CDCl3) δ 2.11 (6H, br s, pyrroyl C(2,5)
CH3), 3.72 (3H, s, OCH3), 5.34 (1H, d, J = 5.58 Hz, C(4)H), 5.67 (1H, d, J = 5.58 Hz, C(3)H),
6.80 (2H, d, J = 9.06 Hz, C(2,6) pꢀmethoxyphenyl H), 6.95 (2H, d, J = 7.02 Hz, pyrroyl
C(3,4)H), 7.09–7.37 (7H, m, C(3,5) pꢀmethoxyphenyl and phenyl H); 13CꢀNMR (150 MHz,
CDCl3) δ 13.64, 55.54, 61.43, 64.83, 107.04, 114.54, 118.59, 126.57, 128.09, 128.28, 131.40,
132.66, 136.46, 156.64, 162.37. Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found:
C, 76.31; H, 6.33; N, 8.00.
(3R,4R)ꢀ4ꢀ((S)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolanꢀ4ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀ
phenylazetidinꢀ2ꢀone (6a): Yellow amorphous solid (89%, 302 mg, dichloromethane/hexanes);
mp 122–124 °C; IR (neat) 2958, 2930 ( Ar CH), 1759 (lactam CO), 1602 and 1495 (Ar C=C),
1
1370 (CH3), 1291, 1212 (C―N), 712 and 699 (monoꢀsubstituted benzene) cmꢀ1; HꢀNMR (600

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MHz, CDCl3) δ 1.39 (3H, s, dioxolane CH3), 1.39 (3H, s, dioxolane CH3), 2.12 (3H, s, pyrroyl
CH3), 2.31 (3H, s, pyrroyl CH3), 2.91 (1H, dd, J = 7.53 Hz and 2.46 Hz, dioxolane C(5)H), 3.16
(1H, dd, J = 8.30 Hz and 0.54 Hz, dioxolane C(5)H), 4.30 (1H, dd, J = 5.70 Hz and 3.12 Hz,
C(4)H), 5.42 (1H, d, J = 5.70 Hz, C(3)H), 5.74 (1H, ddd, J = 14.46 Hz, 3.33Hz and 0.60 Hz,
dioxolane C(4)H), 7.09–7.74 (7H, m, Ar H); 13CꢀNMR (150 MHz, CDCl3) δ 14.05, 14.39, 25.54,
26.57, 62.95, 65.78, 68.18, 76.34, 107.77, 109.15, 118.22, 124.86, 130.88, 132.48, 137.82,
163.15. Anal. Calcd for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23. Found: C, 70.48; H, 6.99; N,
8.16.
(3R,4R)ꢀ4ꢀ((S)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolanꢀ4ꢀyl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀ(4ꢀ
methoxyphenyl)azetidinꢀ2ꢀone (6b): Pale yellow amorphous solid (94%, 347 mg,
dichloromethane/hexanes); mp 130–132 °C; IR (neat) 2967 ( Ar CH), 1753 (lactam CO), 1572
and 1516 (Ar C=C), 1398 (CH3), 1291, 1254 (C―N), 832 (paraꢀsubstituted benzene) cmꢀ1; 1Hꢀ
NMR (600 MHz, CDCl3) δ 1.26 (3H, s, dioxolane CH3), 1.35 (3H, s, dioxolane CH3), 2.18 (3H,
s, pyrroyl CH3), 2.38 (3H, s, pyrroyl CH3), 2.98 (1H, dd, J = 7.71 Hz and 2.46 Hz, dioxolane
C(5)H), 3.23 (1H, t, J = 8.58 Hz, dioxolane C(5)H), 3.81 (3H, s, OCH3), 3.86 (1H, dd, J = 8.34
Hz and 2.40 Hz, C(4)H), 5.49 (1H, d, J = 5.58 Hz, C(3)H), 5.77 (2H, s, pyrroyl H), 5.84 (1H, dd,
J = 14.79 Hz, 2.82 Hz, dioxolane C(4)H), 6.90 (2H, d, J = 9.06 Hz, C(2,6) pꢀmethoxyphenyl H),
7.85 (2H, d, J = 8.92 Hz, C(3,5) pꢀmethoxyphenyl H); 13CꢀNMR (150 MHz, CDCl3) δ 14.03,
14.31, 25.55, 26.55, 55.47, 63.05, 65.75, 68.13, 76.30, 105.81, 107.67, 114.09, 119.63, 123.41,
134.18, 156.72, 162.57. Anal. Calcd for C21H26N2O4: C, 68.09; H, 7.07; N, 7.56. Found: C,
67.96; H, 7.00; N, 7.47.
Acknowledgement
We gratefully acknowledge the funding support from Kleberg Foundation of Texas.
Supplementary data
1
13
The Hꢀ, CꢀNMR and IR spectra of the compounds 4(aꢀf), 4(a′, b′) and 6(a, b) can be found
online.
Notes and references
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33. S. Rivera, D. Bandyopadhyay and B. K. Banik, Tetrahedron Lett. 2009, 50, 5445–5448.
34. D. Bandyopadhyay, R. S. Fonseca and B. K. Banik, Heterocycl. Lett. 2011, 1 (special issue,
July): 75–77.
35. L. Iglesias, C. Aguilar, D. Bandyopadhyay and B. K. Banik, Synth. Commun. 2010, 40,
3678–3682.
36. S. Rivera, D. Bandyopadhyay and B. K. Banik, Heterocycl. Lett. 2011, 1 (special issue, July):
43–46.
37. A. Banik, S. Bhatta, D. Bandyopadhyay and B. K. Banik, Molecules 2010, 15, 8205–8213.
38. D. Bandyopadhyay, S. Maldonado and B. K. Banik, Molecules 2012, 17, 2643–2662.
39. D. Bandyopadhyay, S. Mukherjee, J. C. Granados, J. D. Short and B. K. Banik, Eur. J. Med.
Chem. 2012, 50, 209–215.
40. B. K. Banik and F. F. Becker, Bioorg. Med. Chem. 2001, 9, 593–605.
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2000, 8, 2693–2699.
46. C. Paal, Chem. Ber. 1885, 18, 367–371.
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48. H. Staudinger, Liebigs Ann. 1907, 356, 51–123.

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49. D. Bandyopadhyay, M. Xavier and B. K. Banik, Heterocycl. Commun. 2009, 15, 229–232.
50. G. Rivera, D. Bandyopadhyay, S. Jaggi, R. C. Gonzales and B. K. Banik, Heterocycl.
Commun. 2009, 15, 323–325.
51. M. S. Manhas, S. G. Amin, B. Ram and A. K. Bose, Synthesis 1976, 10, 689–690.
52. A. K. Bose, Y. H. Chiang and M. S. Manhas, Tetrahedron Lett. 1972, 40, 4091–4094.
53. All reflection intensities were measured at 110(2) K using a KM4/Xcalibur (detector:
Sapphire3) with enhance graphiteꢀmonochromated Mo Kα radiation (λ = 0.71073 Å) under
the program CrysAlisPro (Version 1.171.36.20, Agilent Technologies, 2012). The program
CrysAlisPro (Version 1.171.36.20, Agilent Technologies, 2012) was used to refine the cell
dimensions. Data reduction was done using the program CrysAlisPro (Version 1.171.36.20,
Agilent Technologies, 2012). The structure was solved with the program SHELXSꢀ97
(Sheldrick, 2008) and was refined on F2 with SHELXLꢀ97 (Sheldrick, 2008). Analytical
numeric absorption corrections based on a multifaceted crystal model were applied using
CrysAlisPro (Version 1.171.36.20, Agilent Technologies, 2012). The temperature of the data
collection was controlled using the system Cryojet (manufactured by Oxford Instruments).
The H atoms were placed at calculated positions using the instruction AFIX 13, AFIX 43 or
AFIX 137 with isotropic displacement parameters having values 1.2 or 1.5 times Ueq of the
attached C atoms. Fw = 346.42, colorless lath, 0.34 × 0.14 × 0.08 mm3, orthorhombic, Pbcn
(no. 60), a = 31.2908(12), b = 9.2585(3), c = 12.6610(5) Å, V = 3668.0(2) Å3, Z = 8, Dx =
1.255 g cm−3,
ꢀ
= 0.081 mm−1, abs. corr. range: 0.990−0.998. 8916 Reflections were
max = 0.57 Å−1. 2867 Reflections were unique (Rint =
measured up to a resolution of (sin θ/λ)
0.0505), of which 2068 were observed [I > 2
σ(I)]. 238 Parameters were refined. R1/wR2 [I >
2
σ(I)]: 0.0434/0.0870. R1/wR2 [all refl.]: 0.0730/0.0960. S = 1.015. Residual electron density

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found between –0.18 and 0.17 e Å−3. Crystallographic data for (+)ꢀCisꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀ
pyrrolꢀ1ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀphenylazetidinꢀ2ꢀone have been deposited as DBTXꢀ
312 (Cis) with the Cambridge Crystallographic Data Centre as CCDC 932934. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 IEZ, UK (fax: +44 1223 336033 or eꢀmail: deposit@ccdc.cam.ac.uk).
54. All reflection intensities were measured at 100(2) K using a SuperNova diffractometer
(equipped with Atlas detector) with Cu Kα radiation (mirror optics, λ = 1.54178 Å) under the
program CrysAlisPro (Version 1.171.36.24 Agilent Technologies, 2012). The program
CrysAlisPro (Version 1.171.36.24 Agilent Technologies, 2012) was used to refine the cell
dimensions. Data reduction was done using the program CrysAlisPro (Version 1.171.36.24
Agilent Technologies, 2012). The structure was solved with the program SHELXSꢀ97
(Sheldrick, 2008) and was refined on F2 with SHELXLꢀ97 (Sheldrick, 2008). Analytical
numeric absorption corrections based on a multifaceted crystal model were applied using
CrysAlisPro (Version 1.171.36.24 Agilent Technologies, 2012). The temperature of the data
collection was controlled using the system Cryojet (manufactured by Oxford Instruments).
The H atoms were placed at calculated positions using the instructions AFIX 13, AFIX 43 or
AFIX 137 with isotropic displacement parameters having values 1.2 or 1.5 times Ueq of the
attached C atoms. Fw = 346.42, very thin colorless lath, 0.49 × 0.17 × 0.03 mm3, monoclinic,
P21/n (no. 14), a = 9.5368(2), b = 11.2841(3), c = 16.5037(5) Å,
1775.90(8) Å3, Z = 4, Dx = 1.296 g cm−3, = 0.664 mm−1, abs. corr. range: 0.830−0.981.
= 0.59 Å−1. 3194
β = 90.689(2)°, V =
ꢀ
18253 Reflections were measured up to a resolution of (sin
θ/λ)
max
Reflections were unique (Rint = 0.0284), of which 3004 were observed [I > 2
σ(I)]. 238
Parameters were refined. R1/wR2 [I > 2 (I)]: 0.0392/0.0941. R1/wR2 [all refl.]:
σ

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0.0415/0.0957. S = 1.067. Residual electron density found between −0.20 and 0.21 e Å−3.
Crystallographic data for (+)ꢀTransꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ
phenylazetidinꢀ2ꢀone (4a) have been deposited as DBTXꢀ312 (Trans) with the Cambridge
Crystallographic Data Centre as CCDC 932935. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (fax: +44 1223
336033 or eꢀmail: deposit@ccdc.cam.ac.uk).
55. Xꢀray crystallographic data were recorded with an automatic single crystal Xꢀray
diffractometer consists of a 3kw Xꢀray generator, Saturn 724 CCD detector, AFC12K
goniometer, and Xꢀstream 2000 (for nitrogen generation). The compound crystallizes in the
P21/n space group with only one molecule in the asymmetric unit, situated on a general
position. All nonꢀhydrogen atoms were refined anisotropically. Hydrogen atoms were placed
on calculated positions and were refined with Uiso(H) = 1.2ꢀ1.5Ueq (C). The title compound
(20 mg) was added to 10 mL of acetone then methylene chloride was added drop wise until
the compound dissolved. Suitable Xꢀray quality crystals were formed from slow evaporation
of the solvent. An Xꢀray quality colorless platelet crystal (crystal system: monoclinic) was
selected for structural analysis. In regards to the thiophene ring, there is only one sulfur atom
but this sulfur atom flips back and forth between two positions hence there is one sulfur atom
located 50% of the time at each position. Crystallographic data for (+) Trans-Nꢀ(chrysenꢀ6ꢀ
yl)ꢀ3ꢀ(2,5ꢀdimethylꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀ(thiophenꢀ2ꢀyl)azetidinꢀ2ꢀone acetone solvate have
been deposited as tcdptaa with the Cambridge Crystallographic Data Centre as CCDC
933213. Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 IEZ, UK (fax: +44 1223 336033 or eꢀmail:
deposit@ccdc.cam.ac.uk).

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56. A. Banerji, D. Bandyopadhyay, P. Sengupta, B. Basak, T. Prangé and A. Neuman,
Tetrahedron Lett. 2006, 47, 3827–3830.
57. A. K. Bose, B. K. Banik, C. Mathur, D. R. Wagle and M. S. Manhas, Tetrahedron 2000, 56,
5603–5619.

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A green, chemoselective, and practical approach toward N-(2-azetidinonyl) 2,5-disubstituted pyrroles
Debasish Bandyopadhyay, Elvira Rhodes, and Bimal K. Banik
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, Texas
78539, USA
A rapid, easy and ecofriendly high yielding method for the synthesis of N-(2-azetidinonyl) 2,5-disubstituted
pyrroles is described.