Novel synthesis of 3-pyrrole substituted β-lactams via microwave-induced bismuth nitrate-catalyzed reaction

Article abstract of DOI:10.1016/j.tet.2012.06.009

Highly stereoselective synthesis of 3-pyrrole substituted β-lactams is accomplished. The first step involves the synthesis of 3-phthalimido substituted β-lactams following Staudinger cycloaddition reaction of acid chloride equivalent with imines. Synthesi

Full text of DOI:10.1016/j.tet.2012.06.009

Tetrahedron 68 (2012) 10686e10695
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Novel synthesis of 3-pyrrole substituted b-lactams via
microwave-induced bismuth nitrate-catalyzed reaction
y
*
Debasish Bandyopadhyay, Jessica Cruz , Bimal K. Banik
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly stereoselective synthesis of 3-pyrrole substituted b-lactams is accomplished. The first step in-
Received 16 February 2012
Received in revised form 30 May 2012
Accepted 4 June 2012
volves the synthesis of 3-phthalimido substituted b-lactams following Staudinger cycloaddition reaction
of acid chloride equivalent with imines. Synthesis of 3-amino
of phthalimido group with ethylenediamine. These 3-amino
b
-lactams is achieved via the deprotection
b
-lactams are converted to a new series of
Available online 12 June 2012
N-substituted pyrroles at room temperature as well as using microwave-induced bismuth nitrate-
catalyzed reaction with an excellent yield. Exclusive formation of trans pyrrole-substituted -lactams
is observed with N-chrysenyl system. The method is equally efficient for the synthesis of racemic as well
as optically pure 3-pyrrole substituted -lactams.
b
Keywords:
b-Lactam
b
Microwave
Ó 2012 Elsevier Ltd. All rights reserved.
Bismuth nitrate
Polyaromatic
Pyrrole
Optical purity
1. Introduction
substituted
b
-lactams is further strengthened because pyrroles are
found to be the fundamental structural motifs in various classes of
natural and biologically important molecules,6 such as porphyrins,
bile pigments, coenzymes, and alkaloids. This moiety is also pres-
ent7 in several synthetic pharmaceuticals as well as electrically
conducting polymers. However, despite huge applications, syn-
Synthesis of
b
-lactams as biologically active compounds is very
crucial. The use of
b-lactams as antibiotics is experimentally proved
by several thousands of papers and patents.1 In contrast, we2 and
others3 have reported limited research on anticancer
b
b
-lactams till
-lactams is
now. The most important method for the preparation
thesis of 3-pyrrole substituted
atically. Very recently, Tidwell et al. has described8 a fascinating
synthetic method of 3-pyrrole substituted -lactams through
Staudinger cycloaddition reaction. We present herein an expedi-
tious synthetic method of 3-pyrrole-substituted -lactams using
b-lactams is not explored system-
Staudinger cycloaddition reaction.4 This reaction requires an imine,
a tertiary base, and acid chloride (or equivalent). It is known that
b
the stereochemistry of
b-lactams varies depending on the sub-
stituents present in the imine, and acid chloride, and the conditions
of the reactions. In contrast to the existing literature, we have
disclosed that the reaction of polyaromatic imines with acid chlo-
b
bismuth nitrate pentahydrate-catalyzed modified PaaleKnorr re-
action under microwave irradiation in the absence of any solvent.
ride in the presence of triethylamine produced trans-
describe herein stereocontrolled synthesis of a few novel 3-pyrrole
substituted -lactams (both racemic and optically pure). Some of
these -lactams have a chrysenyl group at the nitrogen-1 of the
b
-lactams. We
Optically active 3-pyrrole substituted b-lactams have also been
successfully prepared using this newly developed method.
b
b
2. Results and discussion
four-membered lactam ring.
In our earlier studies on anticancer drug development program,
we have discovered5 that the basicity of the compounds plays an
important role in the determining their potency against a number
of cancer cell lines. Our concept on the synthesis of 3-pyrrole-
During the course of investigation on pyrroles, we envision that
3-prrole substituted
b-lactams can be easily synthesized if we use
3-amino -lactams and 2,5-dimethoxytetrahydrofuran as the star-
b
ing materials and react them in the presence of an acidic catalyst
following ClausoneKass (modified PaaleKnorr) method. The 3-
amino b-lactams could be easily derived from 3-phtalimido b-lac-
tams, which could be made through Staudinger cycloaddition re-
action of imines and acid chloride (equivalent). On this basis, the
retro-synthetic approach is described as follows.
* Corresponding author. Tel.: þ1 956 6658741; fax: þ1 956 3845006; e-mail
addresses: banik@utpa.edu, banik@panam.edu, bkbanik04@yahoo.com (B.K. Banik).
y
Undergraduate research participant.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.009

D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
10687
2.1. Synthesis of 3-phthalimido
b
-lactams
greatly. The electron withdrawal properties of monocyclic aromatic
groups at the N-site of the imine are not sufficient to have a com-
plete isomerization of the enolate and therefore, a mixture of cis-
and trans-isomers is formed.
At the beginning of the approach, cycloaddition of imine with
phthalimidoacetic acid (acid chloride equivalent) in presence of
triethylamine was performed (Scheme 1).
Reaction of N-phenyl and p-methoxyphenyl 1 with phthalimi-
doacetic acid in the presence of triethylamine and N-methylpyr-
idinium iodide was performed at 0 ꢀC-room temperature and
2.2. Preparation of 3-amino b-lactams
Having an attractive route for the synthesis of phthalimido-
substituted -lactams of diverse structures, our attention was
a mixture of (ꢁ)-cis and (ꢁ)-trans
polyaromatic imine 1 derived from 6-chrysenyl amine produced
exclusively (ꢁ)-trans -lactam. High temperature reaction also gave
b
-lactams was isolated. However,
b
turned to deprotect the phthalimido group. Deprotection of
phthalimido group was investigated with hydrazine hydrate.
However, the yields of the products were not satisfactory. In con-
b
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. The formation
of mixture of isomeric products 2a, 3a, and 2b, 3b with their cor-
responding imines had cast doubt about the analysis of the product
distributions of earlier studies. For example, while our current
studies confirmed the formation of two isomeric cis and trans
products, previous studies on the same reaction reported1eeg the
formation of trans isomer only with imines that have monocyclic
aromatic groups at the C- and N-terminus. The formation of cis
isomer was observed with activated phthalimidoacetic acid and N-
alkyl imine. Conjugated imine also produced the cis isomer. It ap-
pears that the electron withdrawing aromatic groups at the C- and
N-terminus of the imine is responsible for the formation of the
trans isomer. The effect of electron withdrawing properties is highly
significant when chrysene group is present at the N-terminus of the
imine. The formation of trans isomer in case of N-chrysenyl imines
and N-diaryl imines can be rationalized through an isomerization of
the enolate as described2b,c earlier. Polyaromatic group (in this
example, chrysene) at the nitrogen stabilizes the iminium ion
trast, reaction of 3-phthalimido
room temperature produced the corresponding 3-amino
in good yield. The stereochemistry of -lactams remains unchanged
b
-lactams with ethylenediamine at
b
-lactams
b
during this conversation. No cleavage of the
observed under this condition (Scheme 2).
b-lactam rings was
2.3. Preparation of 3-pyrrole-substituted b-lactams under
microwave irradiation in the absence of solvents
We have been engaged in the microwave-induced reactions for
many years. Using microwave irradiation technique we have suc-
cessfully developed several new organic methodologies, which
include stereoselective synthesis of b
-lactams,9 synthesis of pyr-
roles,10 aza-Michael addition,11 and synthesis of quinoxalines.12
Parallel to this study, we have demonstrated the catalytic activity
of trivalent bismuth nitrate pentahydrate in a number of reactions.
These experiments have resulted in various methods that include
nitration of aromatic systems,13 Michael reaction,14 protection of
carbonyl compounds,15 deprotection of oximes, and hydrazones,16
Scheme 1. Synthesis of 3-phthalimido substituted b-lactams.

10688
D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
Scheme 2. Synthesis of 3-amino substituted b-lactams.
PaaleKnorr synthesis of pyrroles,17 hydrolysis of amide,18 electro-
Table 1
Microwave-assisted synthesis of 3-pyrrole substituted b-lactam from 1 mmol of
philic substitution of indoles,19 synthesis of
a-amino-
(ꢁ)-trans 3-amino-1-(chrysen-6-yl)-4-phenylazetidin-2-one with 1.2 mmol of 2,5-
dimethoxytetrahydrofuran using bismuth-salts as catalyst (10 mol %) under sol-
ventless condition (5 min): catalyst optimization
phosphonates,20 and Biginelli condensation.21 During the course of
studies on bismuth nitrate-catalyzed reactions and microwave-
induced methods, it has been conceived that 3-pyrrole
Entry
Bi-salt (10 mol %)
Yield (%)a
substituted
b-lactams can be easily prepared if we react 3-amino
1
2
3
4
5
6
7
BiCl3
Bi(OTf)3
BiI3
Bi5O(OH)9(NO3)3
BiBr3
Bi(NO3)3.5H2O
No catalyst
61
54
43
31
41
83
24
b-lactams with 2,5-dimethoxytetrahydrofuran. Our success in the
bismuth nitrate-induced reaction has revealed that this reagent
acts as a Lewis acid. Moreover, it has been discovered that this re-
agent is compatible in the presence of chemically sensitive func-
tional groups and rings (amino group and four-membered cyclic
amide).
Because of their interesting biological properties various
methods for the synthesis of substituted pyrroles are described in
the literature. We have identified an expeditious synthetic method
a
Isolated yield.
Table 2
Microwave-assisted synthesis of 3-pyrrole substituted
(ꢁ)-trans 3-amino-1-(chrysen-6-yl)-4-phenylazetidin-2-one with 1.2 mmol of 2,5-
dimethoxytetrahydrofuran using bismuth nitrate pentahydrate as catalyst under
solventless condition (5 min): optimization of the amount of the catalyst
for the preparation of pyrroles fused with
b-lactams by reacting 3-
b
-lactam from 1 mmol of
amino -lactams with 2,5-dimethoxytetrahydrofuran in the pres-
b
ence of catalytic amounts (5 mol %) of bismuth nitrate at room
temperature. It has also been discovered that the reaction gives
products with extreme rapidity under microwave irradiation. The
presence of small amounts of catalyst (5 mol %) is necessary for the
success of the reaction. Our initial work started with screening of
catalyst loading to obtain optimal reaction conditions for the syn-
Entry
Bi (NO3)3$5H2O (mol %)
Yield (%)a
1
2
3
4
5
6
7
8
30
25
20
15
10
5
57
51
62
68
83
89
56
37
thesis of 3-pyrrole substituted b-lactams. First of all, a number of
bismuth salts, e.g., bismuth chloride, bismuth triflate, bismuth
subnitrate, bismuth bromide bismuth iodide, and bismuth nitrate
pentahydrate have been screened using 1 mmol of (ꢁ)-trans 3-
2
1
amino-1-(chrysen-6-yl)-4-phenylazetidin-2-one
(5c)
with
a
Isolated yield.
1.2 mmol of 2,5-dimethoxytetrahydrofuran as a model reaction
under automated CEM microwave irradiation (300 Watts, 50 ꢀC,
20e45 psi, 5 min). The results are shown in Table 1.
From these conditions, it was proved that bismuth nitrate penta-
hydrate is the best catalyst for this reaction (Entry 8, Table 3).
Considering the above observations we carried out a series of re-
Bismuth nitrate pentahydrate was found to be the best catalyst
under this condition (Entry 6, Table 1). Without using any catalyst
(only microwave irradiation) 24% yield of the product was isolated
in 5 min (Entry 7, Table 1). The same reaction was used to optimize
the amount of the catalyst (Table 2). The results show that 5 mol %
bismuth nitrate pentahydrate was required to complete the re-
action within 5 min (Entry 6, Table 2). The reaction was then per-
formed in various solvents as well as in neat condition under an
identical microwave power using bismuth nitrate pentahydrate
(5 mol %) as the catalyst to identify the best condition (Table 3).
action using 3-amino
b-lactams (1 mmol) with 2,5-
dimethoxytetrahydrofuran (1.2 mmol) in presence of bismuth ni-
trate pentahydrate (5 mol %) under microwave irradiation (Table 4).
Bismuth nitrate pentahydrate, a solid salt is commercially
available from a number of companies, very economical, and much
less toxic than other Lewis acids. It is very convenient to conduct
the reaction with bismuth nitrate because of its stability in the
presence of moisture and oxygen.

D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
10689
Table 3
nitrate-catalyzed pyrrole formation reaction of 3-amino
as described herein is very simple and can be used with remarkable
success.
b
-lactams
Microwave-assisted synthesis of 3-pyrrole substituted b-lactam from 1 mmol of
(ꢁ)-trans 3-amino-1-(chrysen-6-yl)-4-phenylazetidin-2-one with 1.2 mmol of 2,5-
dimethoxytetrahydrofuran using bismuth nitrate pentahydrate as catalyst
(5 mol %) for 5 min: solvent optimization
A plausible mechanistic pathway for the synthesis of 3-pyrrole
substituted
b-lactams from 3-amino b-lactams is suggested
Entry
Solvent (1 mL)
Yield (%)a
(Scheme 4). The methoxy groups in 2,5-dimethoxytetrahydrofuran
can undergo a deprotection reaction under mild acidic conditions
and this process can be highly facilitated by microwave irradiation.
The intermediate can easily form the reactive dialdehyde 8 (Scheme
1
2
3
4
5
6
7
8
Water
THF
67
76
65
47
69
53
70
89
Ethanol
Toluene
Methanol
Dichloromethane
DMSO
4). The reactive dialdehyde 8 on reaction with 3-amino
can lead to the corresponding 3-pyrrole substituted -lactams fol-
lowing nucleophilic addition and subsequent dehydration-
b-lactams
b
a
Neat
aromatization route. This reaction suggests the capability of bis-
muth nitrate to serve as a Lewis activator. 1H NMR spectroscopy has
been used to strengthen the proposed mechanism. Upon irradiating
aCDCl3 solutionof 2,5-dimethoxytetrahydrofuran for5 min,1H NMR
has been taken. A downfield signal due to the eCHO group is ob-
served. The intensity of the eCHO group becomes more pre-
dominant in the 1H NMR when 2,5-dimethoxytetrahydrofuran was
irradiated in CDCl3 in the presence of catalytic amounts of bismuth
nitrate. This suggests the formation of 8 in the reaction media in the
presence of bismuth nitrate under microwave irradiation. Deme-
thylation should take place in 2,5-dimethoxytetrahydrofuran be-
cause electrophilic reagent bismuth nitrate should attack 2,5-
dimethoxytetrahydrofuran. The success of this reaction could be
explained because of the release of nitric acid in the medium.
However, reaction of a few substrates with catalytic amounts of
nitric acid produced products with very low yields. Experiments
were conducted with nitric acid that could be obtained from the
decomposition of 5 mol % of bismuth nitrate pentahydrate. Two
reactions described in Scheme 3 (4a and 4b) were performed with
a
Isolated yield.
Table 4
Bismuth nitrate-induced synthesis of 3-pyrrole substituted
substituted -lactams under solventless condition
b
-lactams from 3-amino
b
Entry Substrate Product Condition A
Condition B MWI
(50 ꢀC, 300 Watts)
(3-amino (3-pyrrole stirring at
b
-lactam)
b
-lactam) room temperature
Time (h) Yield (%)a Time (min) Yield (%)a
1
2
3
4
5
6
7
8
4a
4b
5a
5b
5c
5d
5e
5f
6a
6b
7a
7b
7c
7d
7e
7f
12
12
12
12
24
24
24
24
24
12
12
64
67
62
72
43
46
59
52
55
70
77
2
2
2
2
5
5
5
5
5
5
5
93
88
96
95
89
91
88
90
89
92
94
9
10
11
5g
10a
10b
7g
11a
11b
16.2
m
L of concentrated nitric acid (24 mg of bismuth nitrate pen-
a
Isolated yield.
tahydrate can liberate16.2
m
L of concentrated nitric acid). However,
results were disappointing since the yields of the products could not
be increased. Low yields (10e20%) of the products were observed
(not isolated). An increase of the amount of nitric acid was not
helpful to increase the yield of the products. Although every attempt
was made to use a precise amount of nitric acid and to obtain good
The 3-amino b-lactam, 2,5-dimethoxytetrahydrofuran and bis-
muth nitrate (catalytic amounts) were mixed and stirred at room
temperature. Upon extraction of the reaction mixture 80e90% yield
of the products were obtained. In another method, the mixture was
irradiated in an automated CEM microwave oven at 50 ꢀC for 5 min
using a power level of 300 Watts and 20e45 psi pressure in the
absence of solvent.22,23 The reaction proceeded equally well irre-
yield of 3-pyrrole substituted b-lactams (10 mgegram scale), how-
ever, the yields of the products could not be increased. Moreover,
catalytic amounts of hydrochloric acid and sulfuric acid also failed to
yield the desired products in satisfactory yields. In contrast, 3-
spective of the nature of substituent present in the b-lactam ring
pyrrole substituted b-lactams was prepared very easily in excel-
without any change of stereochemistry. The trans stereochemistry
of the compound (7g) was further confirmed by X-ray crystallo-
graphic analysis24 (Fig. 1, for description, see Ref. 24). The bismuth
lent yield with non-corrosive and crystalline bismuth nitrate pen-
tahydrate. No special precaution was needed because bismuth
nitrate is stable in the presence of air and moisture. The reaction was
extremely fast. This method described herein can be classified under
PaaleKnorr25 or ClausoneKass26 reaction. PaaleKnorr prepared
pyrroles by reacting a 1,4-dicarbonyl compound and an amine in the
presence of acid/activator. ClausoneKass synthesized pyrrole by
reacting 2,4-deimethoxytetrahydrofuran and an amine in the pres-
ence of acid/activator. However, ClausoneKass and our current
study had confirmed that a reactive 1,4-dicarbonyl compound is
really formed as an intermediate.
Finally, we have tested the efficacy of our procedure for the
synthesis of optically active
-lactams (9) were synthesized from optically pure 2,2-dimethyl-
1,3-dioxolane-4-carboxaldehyde following a published method
from our laboratory.27 The 3-phthalimido substituted
-lactams
were deprotected by ethylenediamine as described above. The
corresponding 3-amino substituted -lactams (10) produced 3-
pyrrole substituted -lactams (11) upon treatment with 2,5-
b-lactams. 3-Phthalimido substituted
b
b
b
b
diemthoxytetrahydrofuran in the presence of catalytic amounts of
bismuth nitrate pentahydrate at room temperature as well as under
microwave-induced procedure (Scheme 5). Synthetic method for
Fig. 1. X-ray crystallographic (ORTEP) structure of (7g).
the preparation of optically active 3-pyrrole-substituted b-lactams,

10690
D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
Scheme 3. Synthesis of 3-pyrrole substituted b-lactams.
Scheme 4. Plausible mechanism for the synthesis of 3-pyrrole substituted b-lactams.
Scheme 5. Synthesis of 3-pyrrole substituted optically pure b-lactams.

D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
10691
following this strategy, is not known despite huge development in
this area since 1945. Because of the mild conditions of the experi-
ments, it is gratifying to note that no deprotection of the acid-
sensitive ketal group to diol and subsequent oxidation, rearrange-
ment, and lactonization was occurred in the synthesis of pyrroles
(11) (Scheme 5).
d
5.79 (d, J¼5.32 Hz, 1H), 5.53 (d, J¼5.32 Hz, 1H), 7.07e7.85 (m,
14H); 13C NMR (150 MHz, CDCl3)
d
59.90, 61.11, 117.35, 120.74,
123.44, 123.82, 127.17, 128.47, 129.12, 131.69, 134.24, 134.60, 137.11,
139.51, 161.95, 166.80. Anal. calcd for C23H16N2O3: C, 74.99; H, 4.38;
N, 7.60. Found: C, 74.87; H, 4.31; N, 7.54.
4.2.2. (ꢁ)-cis-1-(4-Methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl
isoindoline-1,3-dione (2b). Yellow solid (64%); mp 157 ꢀC; IR (KBr)
3. Conclusions
3255, 2905, 1759, 1720, 1511, 1452, 1299, 1116, 951, 718, 529 cmꢂ1
;
In conclusion, a new synthetic strategy for the synthesis of novel
3-pyrrole substituted
forms is described. The procedure is equally effective with
1H NMR (600 MHz, CDCl3)
d
3.79 (s, 3H), 5.46 (d, J¼5.58 Hz, 1H),
b
-lactams in racemic and optically active
-lac-
5.67 (d, J¼5.52 Hz, 1H), 6.85e7.91 (m, 13H); 13C NMR (150 MHz,
b
CDCl3) d 55.47, 58.94, 61.41, 114.16, 118.67, 123.73, 126.24, 128.39,
tams that have different types of aromatic systems at the nitrogen
and various substituents at C-4 of the ring. The extreme rapidity
with excellent yield of the final step can be rationalized as a syn-
ergistic effect of the Lewis acid catalyst (bismuth nitrate) and mi-
crowave irradiation. In view of our earlier publications, this method
may find future applications on anticancer therapeutics.
129.14, 131.02, 131.76, 134.21, 134.57, 156.89, 160.11, 166.85. Anal.
calcd for C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.31; H,
4.53; N, 6.94.
4.2.3. (ꢁ)-trans-1,4-Diphenyl-2-oxo-4-phenylazetidin-3-yl isoindo-
line-1,3-dione (3a). Reddish brown solid (33%); mp 200 ꢀC; IR (KBr)
2955, 1763, 1712, 1599, 1385, 1084, 879, 711 cmꢂ1 1H NMR
;
4. Experimental section
4.1. General
(600 MHz, CDCl3)
d
5.28 (d, J¼2.70 Hz, 1H), 5.39 (d, J¼2.70 Hz, 1H),
7.11e7.92 (m, 14H); 13C NMR (150 MHz, CDCl3)
d
61.23, 62.77, 117.63,
123.67, 124.50, 126.15, 129.14, 129.42, 131.85, 131.85, 134.45, 134.49,
135.83, 137.15, 162.04, 167.24. Anal. calcd for C23H16N2O3: C, 74.99;
H, 4.38; N, 7.60. Found: C, 74.90; H, 4.28; N, 7.51.
Melting points were determined in a Fisher Scientific electro-
chemical Mel-Temp* manual melting point apparatus (Model 1001)
equipped with a 300 ꢀC thermometer. FTIR spectra were registered
on a Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. 1H
NMR (600 MHz) and 13C NMR (150 MHz) spectra were obtained at
room temperature with Bruker superconducting UltrashieldÔ Plus
600 MHz NMR spectrometer with central field 14.09 T, coil in-
ductance 89.1 H, and magnetic energy 1127.2 kJ using CDCl3 as
solvent. Elemental analyses (C, H, N) were conducted using the
PerkineElmer 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 #
248592-500 G, Batch # MKBC6772) purchased from SigmaeAldrich
Corporation was used. All other chemicals were purchased from
SigmaeAldrich Corporation (analytical grade). Throughout the
project solvents were purchased from FishereScientific. Deionized
water was used for the preparation of all aqueous solutions.
4.2.4. (ꢁ)-trans-1-(4-Methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl
isoindoline-1,3-dione (3b). Brownish yellow solid (31%); mp 168 ꢀC;
IR (KBr) 3048, 2833, 1755, 1660, 1466, 1389, 1244, 1029, 826,
699 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 3.75 (s, 3H), 5.28 (d,
J¼2.59 Hz,1H), 5.35 (d, J¼2.58 Hz,1H), 6.81e7.77 (m,13H); 13C NMR
(150 MHz, CDCl3) d 55.50, 60.90, 62.78, 114.41, 119.13, 123.82, 127.21,
128.47, 129.40, 131.19, 132.26, 134.34, 135.92, 156.54, 160.27, 166.93.
Anal. calcd for C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.27; H, 4.47; N, 6.98.
4.2.5. (ꢁ)-trans-1-(Chrysen-6-yl)-2-oxo-4-phenylazetidin-3-yl iso-
indoline-1,3-dione (3c). Yellow solid (76%); mp 272 ꢀC; IR (KBr)
3246, 1765, 1716, 1597, 1451, 1388, 1095, 973, 753 cmꢂ1 1H NMR
;
(600 MHz, CDCl3)
d
5.60 (d, J¼2.34 Hz, 1H), 5.89 (d, J¼2.22 Hz, 1H),
7.27e7.94 (m, 17H), 8.49 (d, J¼8.16 Hz, 1H), 8.63 (d, J¼8.34 Hz, 1H),
8.71 (d, J¼8.28 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 61.16, 62.72,
4.2. General procedure for the synthesis of 3-phthalimido
lactam via the Staudinger reaction
b
-
121.71, 122.59, 122.98, 123.91, 124.62, 126.71,126.96, 127.06, 127.25,
127.35, 127.85, 128.68, 129.15, 129.17, 129.81, 130.74, 131.10, 131.30,
131.82, 134.65, 135.65, 163.88, 167.07. Anal. calcd for C35H22N2O3: C,
81.07; H, 4.28; N, 5.40. Found: C, 81.00; H, 4.22; N, 5.32.
A representative experimental procedure is described as follow.
A solution consisting of phthalimidoacetic acid (N-phthaloylgly-
cine) (1.5 mmol) in anhydrous dichloromethane (10 mL) was added
4.2.6. (ꢁ)-trans-1-(Chrysen-6-yl)-2-(4-methoxyphenyl)-4-
oxoazetidin-3-yl isoindoline-1,3-dione (3d). Yellow solid (69%); mp
133 ꢀC; IR (KBr) 3459, 2960, 2860, 2356, 1727, 1666, 1600, 1580,
2-chloro-1-methylpyridinium
iodide
(Mukaiyama
reagent,
3 mmol) and triethylamine (6 mmol) at ice-cold temperature. This
mixture was stirred for 2 h. Imine (1 mmol) in dry dichloromethane
(10 mL) was then added drop wise to this mixture at 0 ꢀC. The re-
action mixture was then stirred overnight at room temperature and
monitored by TLC. After completion of the reaction, the reaction
mixture was washed with saturated sodium bicarbonate solution
(10 mL), brine (10 mL) and deionized water successively. The or-
ganic layer was dried with anhydrous sodium sulfate and evapo-
rated to obtain the crude product. Column chromatography over
silica gel was performed using ethyl acetate/hexanes mixtures to
1463, 1382, 1287, 1123, 1072, 1039, 957, 744 cmꢂ1 1H NMR
;
(600 MHz, CDCl3)
J¼2.28 Hz, 1H), 6.57 (d, J¼9.12 Hz, 2H), 7.00 (d, J¼8.52 Hz, 2H),
7.31e8.19 (m, 15H); 13C NMR (150 MHz, CDCl3)
55.60, 68.16, 68.17,
105.94, 114.33, 114.65, 120.72, 120.79, 123.47, 123.69, 123.90, 126.66,
126.81,128.09,128.40,128.59,128.82,128.90,130.89,131.86,132.00,
132.47, 133.79, 133.95, 134.45, 134.63, 138.26, 139.55, 163.19, 167.76.
Anal. calcd for C36H24N2O4: C, 78.82; H, 4.41; N, 5.11. Found: C,
78.75; H, 4.36; N, 5.02.
d
3.54 (s, 3H), 5.68 (d, J¼2.46 Hz, 1H), 5.91 (d,
d
isolate the 3-phthalimido b-lactam in pure form. The cis:trans ratio
was 2:1 for monoaromatic imines (Ar1]phenyl, PMP; Scheme 1)
but for N-chrysenyl imines trans isomers were obtained
stereoselectively.
4.2.7. (ꢁ)-trans-1-(Chrysen-6-yl)-2-oxo-4-(thiophen-2-yl)azetidin-
3-yl isoindoline-1,3-dione (3e). Brown solid (82%); mp 163 ꢀC; IR
(KBr) 2958, 2927, 2854, 1772, 1718, 1593, 1465, 1394, 1287, 1217,
1120, 1073, 1034, 962, 823, 713 cmꢂ1 1H NMR (600 MHz, CDCl3)
;
4.2.1. (ꢁ)-cis-1,4-Diphenyl-2-oxo-4-phenylazetidin-3-yl isoindoline-
1,3-dione (2a). Yellow solid (61%); mp 181 ꢀC; IR (KBr) 3012, 1759,
d
5.81 (d, J¼2.70 Hz, 1H), 6.19 (d, J¼2.64 Hz, 1H), 6.90 (dd, J¼3.72 Hz
and 1.26 Hz, 1H), 7.16 (d, J¼3.48 Hz, 1H), 7.28 (d, J¼4.86 Hz, 1H),
7.62e8.00 (m, 15H); 13C NMR (150 MHz, CDCl3)
59.50, 62.13,
1716, 1623, 1503, 1104, 966, 748 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d

10692
D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
118.15, 120.92, 123.09, 123.48, 123.70, 123.91, 123.97, 124.44, 126.71,
126.89, 126.93, 127.20, 127.40, 127.55, 127.79, 128.09, 128.22, 128.33,
128.60, 130.25, 130.46, 131.49, 131.81, 132.19, 134.49, 134.70, 139.06,
163.72, 167.05. Anal. calcd for C33H20N2O3S: C, 75.56; H, 3.84; N,
5.34. Found: C, 75.48; H, 3.81; N, 5.25.
TLC. After completion of the reaction (15 mine1 h) the ethanol
was removed by rotavapor and the crude mass was dissolved in
ethyl acetate (25 mL). The solution was washed with brine and
water successively (10 mL each), and dried over anhydrous so-
dium sulfate. The pure products were obtained via column
chromatography over silica gel using ethyl acetateehexanes as
the eluent.
4.2.8. (ꢁ)-trans-1-(Chrysen-6-yl)-2-oxo-4-(pyridin-2-yl)azetidin-3-
yl isoindoline-1,3-dione (3f). Yellow solid (73%); mp 224 ꢀC; IR (KBr)
1767, 1716, 1618, 1440, 1393, 1107, 1075, 910,753, 713 cmꢂ1; 1H NMR
4.3.1. (ꢁ)-cis-3-Amino-1,4-diphenylazetidin-2-one
(4a). Brown
(600 MHz, CDCl3)
d
6.01 (d, J¼1.98 Hz, 1H), 6.04 (d, J¼1.98 Hz, 1H),
solid (88%); mp 152 ꢀC; IR (KBr) 3292, 1751, 1647, 1535, 1455,
7.19e8.79 (m, 19H); 13C NMR (150 MHz, CDCl3)
d
59.78, 64.07,
1306, 754 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
4.52 (d, J¼5.48 Hz,
117.98, 120.88, 122.55, 123.15, 123.41, 123.70, 123.87, 123.94, 124.57,
126.69, 126.89, 127.18, 127.39, 127.63, 127.98, 128.05, 128.27, 128.55,
130.22, 131.10, 131.45, 131.90, 132.15, 134.45, 134.59, 137.04, 150.49,
155.00, 164.23, 167.18. Anal. calcd for C34H21N3O3: C, 78.60; H, 4.07;
N, 8.09. Found: C, 78.48; H, 3.99; N, 8.02.
1H), 5.29 (d, J¼5.48 Hz, 1H), 6.91 (s, 2H), 7.30e7.46 (m, 10H); 13C
NMR (150 MHz, CDCl3)
d
61.76, 64.55, 117.42, 124.14,
125.85,127.64, 128.20, 129.08, 130.42, 135.77, 168.06. Anal. calcd
for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.53; H,
5.81; N, 11.67.
4.2.9. (ꢁ)-trans-1-(Chrysen-6-yl)-2-(ferrocenyl)-4-oxoazetidin-3-yl
isoindoline-1,3-dione (3g). Brown solid (77%); mp 158 ꢀC; IR (KBr)
3060, 2919, 1774, 1720, 1656, 1583, 1466, 1381, 1302, 1107, 946, 876,
4.3.2. (ꢁ)-cis-3-Amino-1-(4-methoxyphenyl)-4-phenylazetidin-2-
one (4b). Light yellow solid (79%); mp 137 ꢀC; IR (KBr) 3364, 2824,
1732, 1515, 1493, 1395, 1297, 1178, 1106, 832, 748, 603 cmꢂ1 1H
;
763, 715 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
3.89 (s, 5H), 4.10 (m,
NMR (600 MHz, CDCl3)
d
3.75 (s, 3H), 4.60 (d, J¼5.46 Hz, 1H), 5.23
1H), 4.14 (m, 1H), 4.24 (m, 1H), 4.31 (m, 1H), 5.69 (d, J¼1.98 Hz, 1H),
(d, J¼5.46 Hz, 1H), 6.80 (s, 2H), 7.23e7.41 (m, 9H); 13C NMR
5.98 (d, J¼1.86 Hz, 1H), 7.65e8.89 (m, 15H); 13C NMR (150 MHz,
(150 MHz, CDCl3) d 55.45, 62.15, 66.68,114.37,118.68,125.91,127.03,
CDCl3)
d
65.72, 68.57, 68.67, 69.03, 69.43, 70.84, 82.63, 110.28,
128.56, 130.95, 134.41, 156.18, 167.37. Anal. calcd for C16H16N2O2: C,
71.62; H, 6.01; N, 10.44. Found: C, 71.49; H, 5.93; N, 10.36.
117.97, 119.82, 120.92, 123.00, 123.81, 123.93, 126.82, 127.01, 127.11,
127.47, 127.82, 127.99, 128.13, 128.69, 130.63, 131.54, 132.28, 164.27,
168.49. Anal. calcd for C39H26FeN2O3: C, 74.77; H, 4.18; N, 4.47.
Found: C, 74.68; H, 4.10; N, 4.36.
4.3.3. (ꢁ)-trans-3-Amino-1,4-diphenylazetidin-2-one (5a). Yellow
solid (83%); mp 146 ꢀC; IR (KBr) 3095, 1755, 1597, 1501, 1383, 1138,
The optically pure 3-phthalimido
b-lactams (9a and 9b) were
691 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
4.02 (d, J¼2.10 Hz, 1H), 4.66
synthesized following a reported procedure from our laboratory.27
The physical and spectral data are of the compounds 9a and 9b are
as follows:
(d, J¼1.86 Hz, 1H), 6.87 (s, 2H), 7.34e7.49 (m, 10H); 13C NMR
(150 MHz, CDCl3)
d 66.57, 69.89, 117.51, 124.32, 126.29,127.99,
128.71, 129.63, 131.90, 136.25, 169.42. Anal. calcd for C15H14N2O: C,
75.61; H, 5.92; N, 11.76. Found: C, 75.55; H, 5.86; N, 11.62.
4.2.10. 2-((2R,3R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-oxo-1-
phenylazetidin-3-yl)isoindoline-1,3-dione (9a). Yellowish brown
crystalline solid (69%); mp 84 ꢀC; IR (KBr) 3357, 2980, 1766, 1717,
1601,1500,1382,1207,1065, 876, 717, 682 cmꢂ1; 1H NMR (600 MHz,
4.3.4. (ꢁ)-trans-3-Amino-1-(4-methoxyphenyl)-4-phenylazetidin-2-
one (5b). Yellow solid (81%); mp 122 ꢀC; IR (KBr) 3280, 1725, 1453,
1395, 1246, 1106, 914, 823, 698, 522 cmꢂ1 1H NMR (600 MHz,
;
CDCl3)
d
1.41 (s, 3H), 1.51 (s, 3H), 3.47 (dd, J¼7.62, 1.68 Hz, 1H), 3.68
CDCl3)
d
3.73 (s, 3H), 4.04 (d, J¼2.10 Hz, 1H), 4.64 (d, J¼2.04 Hz, 1H),
(dd, J¼7.50, 1.92 Hz, 1H), 4.44 (m, 2H), 5.48 (d, J¼5.64 Hz, 1H),
6.78 (s, 2H), 7.21e7.39 (m, 9H); 13C NMR (150 MHz, CDCl3)
d
55.41,
7.07e7.32 (m, 5H), 7.74e7.86 (m, 4H); 13C NMR (150 MHz, CDCl3)
63.78, 69.91, 114.12, 118.72, 125.76, 127.00, 128.14, 130.73, 136.95,
156.04, 167.10. Anal. calcd for C16H16N2O2: C, 71.62; H, 6.01; N,
10.44. Found: C, 71.65; H, 6.10; N, 10.39.
d
25.29, 26.43, 54.37, 62.76, 65.94, 75.27, 110.19, 115.21, 118.27,
124.15, 124.74, 128.80, 134.93, 137.65, 161.24, 167.02. Anal. calcd for
C22H20N2O5: C, 67.34; H, 5.14; N, 7.14. Found: C, 67.21; H, 5.06; N,
7.10.
4.3.5. (ꢁ)-trans-3-Amino-1-(chrysen-6-yl)-4-phenylazetidin-2-one
(5c). Yellow solid (87%); mp 132 ꢀC; IR (KBr) 3381, 1741, 1707, 1647,
4.2.11. 2-((2R,3R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-(4-
methoxyphenyl)-4-oxoazetidin-3-yl)isoindoline-1,3-dione (9b). Pale
yellow crystalline solid (72%); mp 160 ꢀC; IR (KBr) 3491, 2986, 1754,
1593, 1541, 1439, 1393, 1309, 837, 756 cmꢂ1 1H NMR (600 MHz,
;
CDCl3)
d
4.37 (d, J¼1.61 Hz, 1H), 5.27 (d, J¼1.59 Hz, 1H), 7.21e7.95
(m, 13H), 8.37e8.75 (m, 5H); 13C NMR (150 MHz, CDCl3)
d
68.13,
1717, 1512, 1383, 1244, 1069, 835, 711 cmꢂ1
;
1H NMR (600 MHz,
68.44, 114.38, 120.90, 122.82, 123.51, 124.63, 126.25, 126.62, 126.75,
126.76, 127.01, 127.31, 127.46, 127.55, 128.60, 128.63, 129.02, 130.01,
131.49, 131.52, 132.20, 136.84, 169.40. Anal. calcd for C27H20N2O: C,
83.48; H, 5.19; N, 7.21. Found: C, 83.45; H, 5.14; N, 7.16.
CDCl3)
d
1.42 (s, 3H), 1.50 (s, 3H), 3.46 (dd, J¼7.62, 1.62 Hz, 1H), 3.68
(dd, J¼7.53, 1.62 Hz, 1H), 3.74 (s, 3H), 4.38 (dd, J¼7.23, 3.06 Hz, 1H),
4.44 (, 1H), 5.46 (d, J¼5.70 Hz, 1H), 6.83 (d, J¼9.12 Hz, 2H), 7.66 (d,
J¼9.12 Hz, 2H), 7.73 (m, 2H), 7.84 (m, 2H); 13C NMR (150 MHz,
CDCl3)
d
25.05, 26.59, 54.42, 55.51, 62.86, 65.93, 75.88, 110.16,
4.3.6. (ꢁ)-trans-3-Amino-1-(chrysen-6-yl)-4-(4-methoxyphenyl)
azetidin-2-one (5d). Yellow solid (86%); mp 128 ꢀC; IR (KBr) 32, 491,
741,1594,1512,1438,1394,1305,1246,1174,1022, 817, 755 cmꢂ1; 1H
NMR (600 MHz, CDCl3)
J¼1.42 Hz, 1H), 6.76 (d, J¼8.52 Hz, 2H), 7.34 (d, J¼8.52 Hz, 2H),
7.57e8.71 (m, 13H); 13C NMR (150 MHz, CDCl3)
55.19, 67.90, 68.37,
114.41, 114.56, 120.87, 122.83, 123.47, 124.59, 126.57, 126.70, 127.07,
127.22, 128.56, 128.68, 130.00, 131.41, 131.43, 132.17, 159.82, 169.54.
Anal. calcd for C28H22N2O2: C, 80.36; H, 5.30; N, 6.69. Found: C,
80.31; H, 5.23; N, 6.62.
114.07, 119.78, 124.11, 131.15, 131.33, 134.90, 156.68, 160.69, 167.06.
Anal. calcd for C23H22N2O6: C, 65.39; H, 5.25; N, 6.63. Found: C,
65.31; H, 5.18; N, 6.59.
d
3.65 (s, 1H), 4.34 (d, J¼1.42 Hz,1H), 5.19 (d,
4.3. General procedure for the synthesis of 3-amino
from 3-phthalimido -lactam
b-lactam
d
b
A representative experimental procedure is described as fol-
low. A solution consisting of 3-phthalimido -lactam (1 mmol) in
b
anhydrous ethyl alcohol (5 mL) was added ethylenediamine
(2 mmol) at room temperature. This mixture was stirred at room
temperature and the progress of the reaction was monitored by
4.3.7. (ꢁ)-trans-3-Amino-1-(chrysen-6-yl)-4-(thiophen-2-yl)azeti-
din-2-one (5e). Yellow solid (89%); mp 184 ꢀC; IR (KBr) 1740, 1594,

D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
10693
1438, 1395, 1118, 817, 755 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
4.54
dried over anhydrous sodium sulfate and the solvent was re-
moved under reduced pressure. The crude mass was purified
through a small silica gel column using ethyl acetate/hexanes as
eluent.
(d, J¼2.16 Hz, 1H), 5.49 (d, J¼2.04 Hz, 1H), 6.85 (dd, J¼3.66 Hz and
1.20 Hz, 1H), 7.11 (d, J¼3.42, 1H), 7.16 (d, J¼4.92 Hz, 1H), 7.63e8.75
(m, 13H); 13C NMR (150 MHz, CDCl3)
d 64.51, 69.45, 109.79, 110.10,
115.77, 120.91, 122.89, 123.51, 124.40, 125.88, 126.65, 126.66, 126.81,
126.83, 127.19, 127.32, 127.42, 127.61, 127.68, 128.62, 131.46, 132.21,
140.39, 168.98. Anal. calcd for C25H18N2OS: C, 76.12; H, 4.60; N, 7.10.
Found: C, 76.01; H, 4.53; N, 7.02.
4.4.1. (ꢁ)-cis-1,4-Diphenyl-3-(1H-pyrrol-1-yl)azetidin-2-one
(6a). White solid (93%); mp 158 ꢀC; IR (KBr) 3247, 2913, 1759, 1516,
1450, 1291, 1115, 712 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 5.43 (d,
J¼5.41 Hz, 1H), 5.74 (d, J¼5.40 Hz, 1H), 5.87 (t, J¼2.04 Hz, 2H), 6.47
4.3.8. (ꢁ)-trans-3-Amino-1-(chrysen-6-yl)-4-(pyridin-2-yl)azetidin-
2-one (5f). Light yellow solid (80%); mp 154 ꢀC; IR (KBr) 3366,
(t, J¼2.04, 2H), 7.14e7.42 (m, 10H); 13C NMR (150 MHz, CDCl3)
d
62.12, 68.43, 109.08, 117.90, 120.44, 125.05, 126.77, 128.60, 129.59,
1742, 1591, 1513, 1437, 1395, 1309, 860, 816, 755 cmꢂ1
;
1H NMR
132.67, 137.84, 162.03. Anal. calcd for C19H17N2O: C, 79.14; H, 5.59;
N, 9.72. Found: C, 79.01; H, 5.52; N, 9.63.
(600 MHz, CDCl3)
d
4.60 (d, J¼1.92 Hz, 1H), 5.40 (d, J¼1.92 Hz, 1H),
7.10e8.76 (m, 17H); 13C NMR (150 MHz, CDCl3)
d
67.21, 68.86,
115.03, 120.84, 121.14, 122.98, 123.37, 123.45, 124.65, 124.79,
125.12, 125.77, 126.66, 126.78, 126.81, 127.14, 127.32, 127.55,
128.32, 128.55, 131.99, 132.17, 137.00, 150.05, 156.34, 169.33. Anal.
calcd for C26H19N3O: C, 80.18; H, 4.92; N, 10.79. Found: C, 80.11; H,
4.83; N, 10.75.
4.4.2. (ꢁ)-trans-1,4-Diphenyl-3-(1H-pyrrol-1-yl)azetidin-2-one
(7a). White solid (96%); mp 155 ꢀC; IR (KBr) 3128, 2945, 2914, 1750,
1593, 1493, 1447, 1375, 1317, 1222, 1133, 1084, 961, 896, 728,
705 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
4.97 (d, J¼1.92 Hz, 1H), 5.12
(d, J¼2.04 Hz, 1H), 6.26 (t, J¼1.98 Hz, 2H), 6.77 (t, J¼1.92 Hz, 2H),
7.09e7.42 (m, 10H); 13C NMR (150 MHz, CDCl3)
65.36, 73.25,
d
4.3.9. (ꢁ)-trans-3-Amino-1-(chrysen-6-yl)-4-(ferrocenyl)azetidin-2-
one (5g). Yellow solid (79%); mp 205 ꢀC; IR (KBr) 3077, 1740, 1593,
110.08, 117.68, 119.58, 124.78, 125.89, 126.01, 129.14, 129.48, 135.68,
136.78, 161.93. Anal. calcd for C19H17N2O: C, 79.14; H, 5.59; N, 9.72.
Found: C, 79.08; H, 5.56; N, 9.65.
1513, 1439, 1393, 1315, 1243, 1104, 818, 796 cmꢂ1 1H NMR
;
(600 MHz, CDCl3)
1H), 4.28 (m, 1H), 4.46 (d, J¼1.86 Hz, 1H), 5.00 (d, J¼1.86 Hz, 1H),
7.56e8.79 (m, 13H); 13C NMR (150 MHz, CDCl3)
65.69, 65.99,
66.85, 68.50, 68.68, 69.03, 69.20, 69.57, 83.73, 116.63, 120.98,
122.98, 123.61, 124.37, 126.69, 126.80, 126.88, 17.31, 127.61, 127.71,
127.82, 128.67, 130.19, 131.34, 131.49, 132.28, 170.00. Anal. calcd for
C31H24FeN2O: C, 75.01; H, 4.87; N, 5.64. Found: C, 74.89; H, 4.76; N,
5.52.
d 4.08 (s, 5H), 4.14 (m, 1H), 4.16 (m, 1H), 4.25 (m,
4.4.3. (ꢁ)-cis-1-(4-Methoxyphenyl)-4-phenyl-3-(1H-pyrrol-1-yl)
azetidin-2-one (6b). White crystalline solid (88%); mp 162 ꢀC; IR
(KBr) 3060, 2966,1742, 1510,1488, 1388, 1297, 1242,1172,1092, 808,
d
725, 692 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 3.77 (s, 3H), 5.39 (d,
J¼5.28 Hz, 1H), 5.76 (d, J¼5.34 Hz, 1H), 5.88 (t, J¼2.04 Hz, 2H), 6.47
(t, J¼1.98 Hz, 2H), 6.83 (d, J¼9.0 Hz, 2H), 7.11e7.27 (m, 5H), 7.36 (d,
J¼9.0 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d 55.48, 62.02, 68.23,
109.04, 114.48, 118.79, 120.17, 126.65, 128.31, 128.53, 130.69, 132.55,
156.66, 161.07. Anal. calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.31; H, 5.63; N, 8.72.
4.3.10. (3R,4R)-3-Amino-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-
phenylazetidin-2-one (10a). White amorphous solid (70%); mp
177 ꢀC; IR (KBr) 3276, 2982, 1757, 1645, 1539, 1372, 1304, 1259, 1212,
1154, 1065, 752, 692 cmꢂ1; 1H NMR (600 MHz, DMSO)
d
1.26 (s, 3H),
4.4.4. (ꢁ)-trans-1-(4-Methoxyphenyl)-4-phenyl-3-(1H-pyrrol-1-yl)
azetidin-2-one (7b). White crystalline solid (95%); mp 145 ꢀC; IR
(KBr) 3126, 2958, 2931, 1757, 1728, 1514, 1463, 1450, 1382, 1321,
1.47 (s, 3H), 3.63 (m, 1H), 3.79 (m, 1H), 3.92 (t, J¼5.80 Hz, 1H), 4.23
(m, 1H), 4.43 (dd, J¼5.64, 2.40 Hz, 1H), 7.36e7.65 (m, 5H); 13C NMR
(150 MHz, DMSO)
d
24.95, 26.40, 60.01, 62.94, 65.19, 76.30, 108.98,
1288, 1258, 1135, 1091, 1069, 1036, 827, 740, 727 cmꢂ1 1H NMR
;
117.65, 127.68, 128.67, 129.33, 138.05, 167.06. Anal. calcd for
C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.01; H, 6.88; N,
10.65.
(600 MHz, CDCl3)
d
3.74 (s, 3H), 4.93 (d, J¼2.04 Hz, 1H), 5.10 (d,
J¼2.04 Hz, 1H), 6.25 (t, J¼2.16 Hz, 2H), 6.76 (t, J¼2.10 Hz, 2H), 6.80
(d, J¼2.16 Hz, 1H), 6.81 (d, J¼2.22 Hz, 1H), 7.28e7.40 (m, 7H); 13C
NMR (150 MHz, CDCl3)
d 55.45, 65.44, 73.24, 110.00, 114.47,
4.3.11. (3R,4R)-3-Amino-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-
(4-methoxyphenyl)azetidin-2-one (10b). White crystalline solid
(78%); mp 149 ꢀC; IR (KBr) 3273, 2972, 1736, 1642, 1514, 1377, 1299,
119.02, 119.56, 125.95, 129.10, 129.44, 130.87, 135.74, 156.65,
161.29. Anal. calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.36; H, 5.59; N, 8.74.
1252, 1050 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 1.27 (s, 3H), 1.36 (s,
3H), 3.72 (s, 3H), 3.73 (m, 1H), 3.78 (dd, J¼7.14, 2.04 Hz, 1H), 4.13 (t,
4.4.5. (þ)-trans-1-(Chrysen-6-yl)-4-phenyl-3-(1H-pyrrol-1-yl)azeti-
din-2-one (7c). White solid (89%); mp 124 ꢀC; IR (KBr) 2919, 2353,
2323,1762,1707,1593,1488,1455,1438,1387,1346,1314,1092,1070,
J¼5.82 Hz, 1H), 4.23e4.29 (m, 2H), 6.78 (d, J¼9.06 Hz, 2H), 7.47 (d,
J¼9.06 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d 25.17, 26.49, 55.46,
60.60, 61.24, 66.91, 76.56, 109.73, 114.14, 119.96, 131.34, 156.43,
168.43. Anal. calcd for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found:
C, 61.47; H, 6.81; N, 9.46.
817 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
5.44 (d, J¼2.02Hz,1H), 5.54 (d,
J¼2.02 Hz, 1H), 6.35 (t, J¼2.08 Hz, 2H), 6.96 (t, J¼2.12 Hz, 2H),
7.27e7.98 (m, 11H), 8.41e8.81 (m, 11H); 13C NMR (150 MHz, CDCl3)
d
67.51, 7191, 110.25, 115.53, 119.74, 120.87, 122.85, 123.72, 124.30,
4.4. General procedure for the synthesis of 3-pyrrole
126.33, 126.79, 126.92, 127.03, 127.46, 127.50, 127.72, 127.92, 128.67,
129.21, 129.35, 130.01, 130.89, 131.61, 132.24, 135.71, 163.46. Anal.
calcd for C31H22N2O: C, 84.91; H, 5.06; N, 6.39. Found: C, 84.77; H,
4.97; N, 6.31.
substituted
b-lactam from 3-amino substituted
b-lactam
The substrate (3-amino substituted
b
-lactam, 1.0 mmol), 2,5-
dimethoxytetrahydrofuran (1.2 mmol), and bismuth nitrate
pentahydrate (24 mg, 5 mol %) were mixed together in a micro-
wave 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 re-
action (Table 4) diethyl ether (10 mL) was added to the reaction
mixture and the organic layer was washed with saturated so-
dium bicarbonate solution, brine, and water successively. It was
4.4.6. (ꢁ)-trans-1-(Chrysen-6-yl)-4-(4-methoxyphenyl)-3-(1H-pyr-
rol-1-yl)azetidin-2-one (7d). Light yellow solid (91%); mp 160 ꢀC; IR
(KBr) 3099, 2990, 2357, 1755, 1603, 1509, 1478, 1439, 1232, 1173,
1142, 1095, 1017, 958, 821, 743 cmꢂ1 1H NMR (600 MHz, CDCl3)
;
d
3.71 (s, 3H), 5.35 (d, J¼2.22 Hz, 1H), 5.41 (d, J¼2.16 Hz, 1H), 6.27 (t,
J¼2.10 Hz, 2H), 6.74 (d, J¼8.64 Hz, 2H), 6.88 (t, J¼2.10 Hz, 2H), 7.31
(d, J¼8.58 Hz, 2H), 7.63e8.82 (m, 11H); 13C NMR (150 MHz, CDCl3)

10694
D. Bandyopadhyay et al. / Tetrahedron 68 (2012) 10686e10695
d
55.27, 67.35, 71.99, 110.17, 114.75, 115.77, 119.74, 120.87, 122.88,
calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C, 66.49;
123.71, 124.27, 126.77, 126.91, 127.00, 127.01, 127.45, 127.48, 127.69,
127.77, 127.88, 128.66, 130.03, 130.81, 131.59, 132.24, 160.28, 163.63.
Anal. calcd for C32H24N2O2: C, 82.03; H, 5.16; N, 5.98. Found: C,
81.96; H, 5.11; N, 5.90.
H, 6.36; N, 8.04.
Acknowledgements
We gratefully acknowledge the funding support from Kleberg
Foundation of Texas and NCI (NIH/NCI-P20, Grant# 5P20CA13
8022-02).
4.4.7. (ꢁ)-trans-1-(Chrysen-6-yl)-3-(1H-pyrrol-1-yl)-4-(thiophen-
2-yl)azetidin-2-one (7e). Yellow solid (88%); mp 150 ꢀC; IR (KBr)
1762, 1593, 1487, 1438, 1389, 1371, 816 cmꢂ1 1H NMR (600 MHz,
;
CDCl3)
d
5.58 (d, J¼2.04 Hz, 1H), 5.76 (d, J¼1.98 Hz, 1H), 6.36 (t,
Supplementary data
J¼1.92 Hz, 2H), 6.88 (dd, J¼3.78 Hz, 1.08 Hz, 1H), 6.98 (t, J¼2.04 Hz,
2H), 7.11 (d, J¼3.36 Hz, 1H), 7.23 (d, J¼4.98 Hz, 1H), 7.61e8.79 (m,
IR, 1H and 13C NMR spectra of compounds 7aeg, 6b and 11b can
be found online. Supplementary data related to this article can be
found online at http://dx.doi.org/10.1016/j.tet.2012.06.009.
11H); 13C NMR (150 MHz, CDCl3)
d 63.87, 72.90, 110.28, 110.36,
116.99, 119.74, 119.83, 120.85, 122.91, 123.73, 124.02, 126.56, 126.81,
126.99, 127.08, 127.29, 127.32, 127.42, 127.50, 128.01, 128.12, 128.66,
130.08, 130.19, 131.56, 132.22, 138.95, 163.22. Anal. calcd for
C29H20N2OS: C, 78.35; H, 4.53; N, 6.30. Found: C, 78.21; H, 4.45; N,
6.24.
References and notes
1. (a) Banik, B. K.; Banik, I.; Becker, F. F. Top. Heterocycl. Chem. 2010, 22, 349e373;
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Manhas, M. S.; Banik, B. K.; Srirajan, V. In The Amide Linkage: Selected Structural
Aspects in Chemistry, Biochemistry, and Material Science; Greenberg, A., Brene-
man, C. M., Liebman, J. F., Eds.; Wiley-Interscience: New York, NY, 2000;
4.4.8. (ꢁ)-trans-1-(Chrysen-6-yl)-4-(pyridin-2-yl)-3-(1H-pyrrol-1-
yl)azetidin-2-one (7f). White solid (90%); mp 224 ꢀC; IR (KBr)
3057, 1756, 1591, 1488, 1471, 1437, 1393, 1318, 1141, 1095, 1070,
Chapter 7 (
b
-Lactams: Cyclic Amides of Distinction), pp 157e214; (d) Georg, G.
-Lactams; Georg, G. I., Ed.; VCH:
I.; Ravikumar, V. T. In The Organic Chemistry of
b
816, 761 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
5.56 (d, J¼1.68 Hz,
New York, NY, 1992; (e) Manhas, M. S.; Amin, S. G.; Ram, B.; Bose, A. K. Synthesis
1976, 10, 689e690; (f) Bose, A. K.; Chiang, Y. H.; Manhas, M. S. Tetrahedron Lett.
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1H), 5.88 (d, J¼1.68 Hz, 1H), 6.35 (t, J¼1.92 Hz, 2H), 7.02 (t,
J¼1.95 Hz, 2H), 7.16e8.78 (m, 15H); 13C NMR (150 MHz, CDCl3)
d
68.18, 70.19, 110.10, 117.45, 119.98, 120.82, 122.63, 123.91, 124.10,
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126.96, 127.03, 127.45, 127.51, 127.88, 128.02, 128.62, 130.10,
130.76, 131.49, 132.18, 136. 94, 150.54, 154.62, 163.99. Anal. calcd
for C30H21N3O: C, 81.98; H, 4.82; N, 9.56. Found: C, 81.89; H, 4.76;
N, 9.49.
4.4.9. (ꢁ)-trans-1-(Chrysen-6-yl)-4-(ferrocenyl)-3-(1H-pyrrol-1-yl)
azetidin-2-one (7g). Orange crystalline solid (89%); mp 208 ꢀC; IR
(KBr) 2360, 1754, 1593, 1490, 1439, 1381, 1314, 1105, 819, 756,
727 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 3.82 (s, 5H), 4.02 (m, 1H),
4.07 (m, 1H), 4.16 (m, 1H), 4.24 (m, 1H), 5.29 (d, J¼2.28 Hz, 1H), 5.43
(d, J¼2.28 Hz, 1H), 6.32 (t, J¼2.10 Hz, 2H), 6.98 (d, J¼2.28 Hz, 2H),
7.48e8.76 (m, 11H); 13C NMR (150 MHz, CDCl3)
d 65.72, 68.58,
68.68, 69.03, 69.43, 70.84, 82.63, 110.28, 117.96, 119.83, 120.92,
123.00, 123.81, 123.93, 126.82, 127.01, 127.10, 127.47, 127.82, 127.99,
128.13, 128.69, 130.15, 130.64, 131.54, 132.28, 164.27. Anal. calcd for
C35H26FeN2O: C, 76.93; H, 4.80; N, 5.13. Found: C, 76.81; H, 4.69; N,
5.06.
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4.4.10. (3R,4R)-4-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-phenyl-3-
(1H-pyrrol-1-yl)azetidin-2-one (11a). Pale yellow crystalline solid
(92%); mp 131 ꢀC; IR (KBr) 2918, 1766, 1593, 1570, 1370, 1204, 1095,
822, 730, 691 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d 1.17 (s, 3H), 1.40 (s,
3H), 2.88 (t, J¼7.02 Hz, 1H), 3.26 (m, 1H), 4.05 (dd, J¼11.01, 8.16 Hz,
1H), 4.29 (m, 1H), 5.44 (d, J¼5.58 Hz, 1H), 6.16 (s, 2H), 6.62 (s, 2H),
7.09 (t, J¼7.38 Hz, 1H), 7.29 (t, J¼7.80 Hz, 2H), 7.73 (d, J¼8.22 Hz,
2H); 13C NMR (150 MHz, CDCl3)
d 25.12, 26.52, 62.91, 64.82, 65.76,
77.21, 109.81, 110.55, 118.78, 120.69, 124.99, 128.98, 137.55, 162.19.
Anal. calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C,
69.11; H, 6.40; N, 8.90.
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4.4.11. (3R,4R)-4-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-(4-
methoxyphenyl)-3-(1H-pyrrol-1-yl)azetidin-2-one
crystalline solid (94%); mp 142 ꢀC; IR (KBr) 3122, 2986, 1738,
1514, 1385, 1237, 832, 736 cmꢂ1; 1H NMR (600 MHz, CDCl3)
1.18
(11b). White
d
(s, 3H), 1.39 (s, 3H), 2.87 (dd, J¼7.74, 3.24 Hz, 1H), 3.26 (t,
J¼8.22 Hz, 1H), 3.74 (s, 3H), 4.03 (dd, J¼11.37, 7.32 Hz, 1H), 4.23
(dd, J¼7.08, 3.12 Hz, 1H), 5.41 (d, J¼5.52 Hz, 1H), 6.16 (s, 2H), 6.61
(s, 2H), 6.82 (d, J¼8.88 Hz, 2H), 7.67 (d, J¼8.88 Hz, 2H); 13C NMR
(150 MHz, CDCl3)
d 25.15, 26.54, 55.50, 63.04, 64.85, 65.78, 77.20,
109.78, 110.49, 114.09, 119.81, 120.68, 131.02, 156.84, 161.61. Anal.

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24. X-ray crystallographic data were recorded with an automatic single crystal X-
ray diffractometer consists of a 3 kw X-ray generator, Saturn 724 CCD detector,
AFC12K goniometer, and X-stream 2000 (for nitrogen generation). The com-
pound crystallizes in the P-1 space group with only one molecule in the
asymmetric unit, situated on a general position. All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were located in a difference Fourier
map and were refined with Uiso(H)¼1.2Ueq(C). The compound (25 mg) was
dissolved into approximately 10 mL of methylene chloride. Orange crystals,
suitable for X-ray diffraction, were obtained through slow evaporation of sol-
vent. An X-ray quality platelet crystal (crystal system: triclinic) was selected for
structural analysis. Crystallographic data for trans-1-(chrysen-6-yl)-4-(ferro-
cenyl)-3-(1H-pyrrol-1-yl)azetidin-2-one have been deposited as DBTX-331(1)
with Cambridge Crystallographic Data Centre as CCDC 866026. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 IEZ, UK (fax: þ441,223,336,033 or e-mail: deposit@ccdc.cam.ac.
uk).
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