β-Lactam-synthon-interceded diastereoselective synthesis of functionally enriched thioxo-imidazolidines, imidazolidin-2-ones, piperazine-5,6-diones and 4,5-dihydroimidazoles

Article abstract of DOI:10.1016/j.tet.2012.08.005

The manuscript explicates simple and convenient protocols for the diastereoselective synthesis of functionally decorated thioxo-imidazolidines, imidazolidin-2-ones, piperazine-5,6-diones and 4,5-dihydroimidazoles using β-lactam synthon approach with an ex

Full text of DOI:10.1016/j.tet.2012.08.005

Tetrahedron 68 (2012) 8395e8402
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
b-Lactam-synthon-interceded diastereoselective synthesis of functionally
enriched thioxo-imidazolidines, imidazolidin-2-ones, piperazine-5,6-diones
and 4,5-dihydroimidazoles
*
Vishu Mehra, Pardeep Singh, Vipan Kumar
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2012
Received in revised form 24 July 2012
Accepted 2 August 2012
Available online 7 August 2012
The manuscript explicates simple and convenient protocols for the diastereoselective synthesis of
functionally decorated thioxo-imidazolidines, imidazolidin-2-ones, piperazine-5,6-diones and 4,5-
dihydroimidazoles using
b-lactam synthon approach with an extension towards one-pot synthesis.
Since the developed methodology does not employ either the use of Lewis acid conditions or Pd-
catalyzed customary procedures, the developed route can be easily modulated for the synthesis of
functionalized imidazoles with acid-sensitive functionalities and do not suffer from typical intricacies
associated with conventional methods.
Keywords:
b
-Lactam synthon approach
Ó 2012 Elsevier Ltd. All rights reserved.
Thioxo-imidazolines
4,5-Dihydroimidazoles
Imidazolidine-2-ones
Piperazine-5,6-diones
1. Introduction
reported as potent neurokinin antagonists20 while spiro imidazo-
lidin-2-one has shown ability to protect against the epilepsy.21
Nitrogen containing heterocycles constitute important core
fragments in different natural products and pharmaceutical agents
imparting unique physical and biological properties.1 The chemis-
try of imidazoles, in particular, has attracted more attention re-
cently due to their reactivity and novel biological properties.
Differently substituted imidazoles have been regarded as anti-
helmintic,2 analgesic,3 antibacterial,4 antifungal,5 antiviral,6 anti-
tubercular,7 anticancer8 and COX-2/LOX inhibitors.9 In addition,
many of the substituted diaryl imidazoles are potential inhibitors of
the p38 MAP kinase,10 glucagon11 and CB1 cannabinoid receptor
antagonists12 as well as modulators of P-glycoprotein mediated
multidrug resistance (MDR).13 Fused imidazole derivatives viz.
benzoimidazoles and phenanthroimidazole14 have been used in
fabrication of light emitting devices and dye-sensitized solar cells.15
Recent advances in the areas of green chemistry and organome-
tallic chemistry have extended the utility of imidazoles as ionic
liquids16 and N-heterocyclic carbenes.17 Similarly, imidazolidin-2-
ones have shown potential as HIV protease inhibitor18 with po-
tent activity as 5HT3 antagonists19 implicated in anxiety, emesis
and drug abuse. Di-substituted imidazolidin-2-ones have been
They are also considered as important chiral auxiliaries to induce
stereoselectivity in reactions.22 The structural motif piperazine
diones has also been considered as a privileged scaffold with a va-
riety of therapeutic potential being an important constituent of
antibiotics, synthetic vaccines and in chemotherapy.23 They also
constitute an important class of herbicides mainly as proto-
porphyrinogen-IX oxidase inhibitors with advantage such as high
resistance to soil leaching, slow development of weed resistance24
and low toxicity.
A number of reports have appeared in the literature for the
synthesis of 1,2,4,5-tetrasubstituted imidazoles.25,26 Generally,
their synthesis involved a four-component condensation of a 1,2-
diketone,
a-hydroxyketone or a-ketomonoxime with an aldehyde,
primary amine and ammonium acetate using microwaves,25a het-
25d
25e
eropolyacid,25b BF3$SiO2,25c silica gel/NaHSO4
or HClO4eSiO2
and ionic liquids25f Such imidazoles have also been synthesized
by the cycloaddition reaction of mesoionic 1,3-oxazolium-5-olates
with N-(arylmethylene) benzenesulfonamides,26a hetero-Cope
rearrangement,26b condensation of a 1,2-diketone with an aryl ni-
trile and primary amine under microwave irradiation.26c However,
most of these reactions either require protic or Lewis acid condi-
tions, which are not compatible with acid-sensitive functionalities
or require amino acetal or ketal subunits prepared via several
synthetic steps. The reported protocols for the synthesis of
* Corresponding author. Tel.: þ91 183 2258802x3320; fax: þ91 183 2258819 20;
e-mail address: vipan_org@yahoo.com (V. Kumar).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.005

8396
V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
imidazolidin-2-ones employed palladium catalyzed allylic alkyl-
ation,27 alkene diamination,28 ureidomercuriation29 and rear-
rangement of amino acids using bromine.30 These protocols are
invariably associated with a number of disadvantages ranging from
the isolation of complex mixture of products, alkene isomerization,
preference for (E)-alkene over the (Z)-isomer for the carboamina-
tion along with longer reaction times and incomplete conversions.
Thus, in continuation with our pursuit for the synthesis of novel
heterocyclic compounds with medicinal potential,31 and our recent
epimerization and is suggestive of the fact that the relaxation of
ring strain is the driving force for the described transformation.
R
R
O
N
NH
O
R
O
N
N
H
CH3ONa
CH3OH
PPh3
CS2, CHCl3
OCH3
S
H
C
C
S
N3
N
7
6
1
exposure to the prospective of b-lactam synthon approach for the
R
O
N
synthesis of novel heterocyclic compounds,32 we have recently
reported diastereoselective synthesis of thioxo-imidazolidines en
route to multi-functionalized imidazoles.32d The present manu-
script provides a detailed account on the extension of this protocol
for the synthesis of functionalized imidazolines, imidazolidin-2-
ones and piperazine-5,6-diones.
S
O
H
N
H
OCH3
OCH3
S
NH
H
C
8
R
N
Products
5a R=C6H5
%age yields
68
S
5b R=p-NO2-C6H4 71
5c R=p-F-C6H4
5d R=p-Cl-C6H4
5e R=p-CH3-C6H4
70
74
72
R
NH
N
OCH3
2. Results and discussion
H
H
O
Thus, the treatment of racemic cis-3-azido-azetidin-2-ones 1,
prepared via Staudinger reaction,31a with sodium methoxide in dry
methanol at room temperature resulted in the isolation of equi-
5
Scheme 2. Diastereoselective synthesis of trans-2-thioxo-imidazolidines.
molar diastereomeric mixtures of corresponding b-amino esters 2
The diastereoselectively synthesized 5 was further utilized for
the synthesis of structurally diverse 4,5-dihydroimidazoles in
quantitativeyields via usual synthetic steps as depicted in Scheme 3.
and 3. The diastereomeric mixture of 2 and 3 was utilized as such
for further synthetic endeavours viz. an initial Staudinger reaction
with triphenylphosphine followed by the treatment with carbon
disulfide. This synthetic sequence resulted in the isolation of di-
astereomeric mixture of cis and trans (1-aryl-5-styryl-2-thioxo-
imidazolidin-4-yl)-acetic acid methyl esters 4 and 5 presumably via
intramolecular cyclization of 2-isothiocyanato-3-methylamino-5-
phenyl-pent-4-enoic acid methyl esters (I and II) as shown in
Scheme 1. The careful chromatographic separation of 2-thioxo-
imidazolidines enabled the isolation and characterization of 4 and 5
with the help of spectral data and analytical evidences. The ste-
reochemistry assigned to 4 and 5 was on the basis of coupling
constant J¼9.6 Hz for cis-isomer and J¼5.7 Hz for trans-isomer,
respectively.
S
F
N
N
OCH3
O
12
allyl bromide
K2CO3
F
acetone
CH3
N
S
S
CH3
F
CH3I
K2CO3
acetone
S
F
N
NH
N
C2H5I
K2CO3
acetone
N
N
OCH3
OCH3
OCH3
The diastereoselectivity in the above sequence of reactions has
been achieved by introducing an electrophilic site viz. iso-
thiocyanate prior to amidolysis of b-lactam ring, which would re-
O
O
9
5
O
propargyl bromide
K2CO3
acetone
11
sult in the preference of intramolecular cyclization over
epimerization as observed in Scheme 1. Thus, the treatment of ra-
cemic 3-azido-azetidin-2-one with triphenylphosphine and carbon
disulphide led to the synthesis of 3-isothiocyanato-1-phenyl-4-
styryl-azetidin-2-one 6. This upon amidolysis with sodium meth-
oxide resulted in diastereoselective synthesis of trans-2-thioxo-
imidazolidines 5 via aminoesters 7 as shown in Scheme 2. The
absence of even traces of 4 as well as 3-thiocarbamic acid O-methyl
ester 8 in the 1H NMR of crude reaction mixture ruled out
%age yield
9
80
84
85
79
S
F
10
11
12
N
N
OCH3
O
10
Scheme 3. Synthesis of multi-functionalized 4,5-dihydroimidazoles.
R
R
R
R
O
NH
H
O
R
NH
H
O
NH
H
O
C
NH
H
O
C
H
N
H
CH3ONa
CH3OH
H
H
+
OCH3
OCH3
+
OCH3
S
OCH3
S
1 PPh3
N3
N3
N3
N
N
2 CS2
2
3
1
II
I
Products (%age yields)a
S
S
R
4
5
2a+3a C6H5
37
45
44
47
46
46
R
R
NH
NH
N
N
2b+3b p-NO2-C6H4 36
OCH3
OCH3
+
2c+3c p-F-C6H4
2d+3d p-Cl-C6H4
2e+3e p-CH3-C6H4 35
31
37
H
H
H
H
O
O
aIsolated yields after column chromatography
5
4
Scheme 1. Synthetic sequence for the preparation of 2-thioxo-imidazolidines.

V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
8397
The above-developed protocol has been further extended to-
wards the diastereoselective synthesis of functionalized imidazo-
lidin-2-ones and piperazine-5,6-diones. The synthetic approach
involved an initial amidolysis of racemic cis-3-amino-2-
azetidinones 13, obtained from 1 using Zn/NH4Cl reduction pro-
diastereoselective formation of corresponding trans-imidazolidin-
2-one 16 and piperazine-5,6-diones 18, respectively, without the
isolation of corresponding amino esters 15 and 17. The formation of
diastereomerically pure trans-product, without the formation of
corresponding cis-isomer even in traces as confirmed by 1H NMR of
crude reaction mixture, is a consequence of bringing closer the
latent functionalities involving CeC bond rotation in the amino-
esters as shown in Scheme 6.
tocol,33 to yield the corresponding
a-aminoesters 14 in a diaster-
eoselective manner. The absence of diastereomeric mixture in 13 as
was observed in amidolysis of 1 can thus be attributed to the strong
electron withdrawing nature of azido group, which makes the hy-
drogen at
zation is, however, discouraged by the presence of polar donating
eNH2 group resulting in the isolation of corresponding cis- -ami-
noesters 14 in a highly diastereoselective manner (Scheme 4).
a-position acidic and facilitates enolization. Such enoli-
a
Scheme 4. Diastereoselective synthesis of cis-a-aminoesters via base assisted
amidolysis.
The synthesized cis-a-aminoesters 14 were then reacted with
phenyl chloroformate to yield the corresponding cis-2-phenoxy
carbonyl amino-5-phenyl-3-arylamino-pent-4-enoic acid methyl
esters 15, which upon subsequent refluxing in toluene in the
presence of p-toluene sulfonic acid led to the isolation of 1,4,5-
trisubstituted trans-imidazolidin-2-ones 16. Similar protocol in-
volving an initial treatment of 14 with ethyl oxalylchloride with
subsequent heating in toluene in the presence of p-TsOH led to the
diastereoselective formation of 1,2,3-trisubstituted trans-pipera-
zine-5,6-diones 18 in good to excellent yields. The trans-stereo-
chemistry to these products were assigned on the basis of observed
coupling constant viz. J¼5.4 Hz for 16 and J¼2.1 Hz for 18, re-
spectively (Scheme 5).
Scheme 6. Single-pot synthesis of imidazolidin-2-one and piperazine-5,6-dione.
3. Conclusions
In conclusion, we have urbanized a convenient synthetic pro-
tocol for the diastereoselective synthesis of functionalized thioxo-
imidazolidines, 4,5-dihydroimidazoles, imidazolidin-2-ones and
R
R
R
NH
O
O
NH
H
O
NH
H
O
H
H
piperazine-5,6-diones utilizing b-lactam synthon protocol. The
H
ClCO2C6H5
Dry CHCl3
ClCOCO2C2H5
Dry CHCl3
OCH3
O
OCH3
OCH3
O
H
synthesized precursors with latent functionalities can be easily
utilized for further transformations to biologically and medicinally
important imidazole/piperazine based scaffolds. Since the reaction
does not employ protic or Lewis acid conditions, the strategy can be
easily modulated for the synthesis of imidazoles with acid-sensitive
functionalities. Further, the developed protocol for the synthesis of
imidazolidine-2-ones does not suffer from typical intricacies as-
sociated with conventional methodologies viz. the utilization of
palladium catalyst, alkene isomerization and preference for (E)-
alkene over (Z)-isomer along with incomplete conversions and
longer reaction times.
HN
15
NH2
HN
14
17
C6H5
O
OC2H5
Toluene
120oc
Toluene
120oc
PTSA
PTSA
R
Products
R
R
16a/18a
16b/18b
16c/18c
16d/18d
16e/18e
H
NO2
F
H
N
O
Cl
H3CO
N
H
H
N
O
O
H
CH3
O
16
H3CO
N
H
H
O
18
4. Experimental section
4.1. General
Scheme 5. Diastereoselective synthesis of trans-imidazolidin-2-one and piperazine-
5,6-dione.
Since the above methodology involved an initial formation of a-
aminoesters 15 and 17 having appropriately placed electrophilic
and nucleophilic viz. alkoxy and N-aryl amino groups, it was felt
worthwhile to explore the single pot version of the above synthetic
protocols. This could be achieved by introducing an electrophilic
site viz. carbonylamino and ethoxyoxalyl amino prior to the ami-
Melting points were determined by open capillary using Veego
Precision Digital Melting Point apparatus (MP-D) and are un-
corrected. IR spectra were recorded on a Shimadzu D-8001
spectrophotometer. 1H NMR spectra were recorded in deutero-
chloroform with Jeol 300 (300 MHz) spectrometers using TMS as
internal standard. Chemical shift values are expressed as parts per
million downfield from TMS and J values are in hertz. Splitting
patterns are indicated as s: singlet, d: doublet, t: triplet, m:
multiplet, dd: double doublet, ddd: doublet of a doublet of
dolysis of b-lactam ring. Thus the treatment of racemic 3-amino-2-
azetidinone 13 with phenyl chloroformate/ethyl chloro-oxalyl
chloride led to the synthesis of 19/20, respectively. The amidolytic
cleavage of 19 and 20 using sodium methoxide led to the

8398
V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
0
a doublet, and br: broad peak. 13C NMR spectra were recorded on
Jeol 300 (75 MHz) spectrometers in deuterochloroform using TMS
as internal standard. Mass spectra were recorded on Shimadzu
GCeMS-QP-2000 mass spectrometer. Elemental analyses were
performed on Heraus CHN-O-Rapid Elemental Analyzer. Column
chromatography was performed on a silica gel (60e120 mesh). All
the starting materials as well as the products were racemates.
6.56e6.65 (m, 2H, H7, H7 , 4H, ArH), 7.08e7.15 (m, 4H, aromatic),
7.23e7.34 (m, 10H, aromatic). dC (CDCl3, 75 MHz): 52.8, 52.9, 57.0,
57.1, 63.8, 64.2, 115.2, 115.3, 124.1, 126.0, 126.6, 126.7, 128.1, 128.2,
128.6, 128.7, 128.8, 129.1, 129.2, 129.3, 133.3, 134.0, 135.8, 135.9,
144.2, 144.7, 168.7, 168.8. nmax (KBr)/cmꢁ12100,1750,1582, 1500. m/z
357(Mþ).
4.2.5. 2(SR)-Azido-5-phenyl-3(SR)-p-tolylamino-pent-4-enoic acid
methyl ester (2e) and 2(RS)-azido-5-phenyl-3(SR)-p-tolylamino-
pent-4-enoic acid methyl ester (3e). Yellow oil. dH (CDCl3, 300 MHz):
4.2. Sodium methoxide assisted intermolecular amidolysis of
3-azido-azetidin-2-one
2.21 (s, 3H, CH3), 2.23 (s, 3H, CH3), 3.74 (s, 3H, eOCH3), 3.80 (s, 3H,
0
To a solution of 3-azido-
b
-lactam 1 (1 mmol) in dry methanol
eOCH3), 4.38 (a pair of d, J¼3.3, 3.9 Hz, 2H, H4, H4 ), 4.58e4.63 (m,
0
0
was added a solution of sodium methoxide (0.3 mmol) in dry
methanol. The reaction mixture was allowed to stir at room tem-
perature and the progress was monitored using TLC using a mixture
of (80:20) hexane/ethyl acetate. On completion, the reaction mix-
ture was quenched with water (10 ml) and extracted with chloro-
form (2ꢀ50 ml). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated under reduced pres-
2H, H5, H5 ), 6.09 (a pair of dd, 2H, J¼6.3, 6.9, 15.9, 16.2 Hz, H6, H6 ),
0
6.56e6.68 (m, 6H, H7, H7 , 4ArH), 6.98 (a pair of d, 4H, J¼7.4, 6.3 Hz,
ArH), 7.02e7.34 (m, 10H, H, aromatic). dC (CDCl3, 75 MHz): 20.3,
20.4, 52.8, 52.9, 57.3, 57.4, 64.8, 66.2, 114.4, 114.5, 124.7, 126.5, 126.6,
126.7, 126.8, 127.9, 128.0, 128.2, 128.4, 128.5, 128.6, 129.7, 129.9,
133.0, 133.7, 136.1, 143.2, 168.9, 169.0. nmax (KBr)/
cmꢁ12100,1750,1582, 1500. m/z 337 (Mþ).
sure to yield diastereomeric mixture of
pale yellow viscous liquids.
b-amino esters 2 and 3 as
4.3. Typical procedure for the preparation of diastereomeric
mixture of thioxo-imidazolidines 4 and 5
4.2.1. 2(SR)-Azido-5-phenyl-3(SR)-phenylamino-pent-4-enoic acid
methyl ester (2a) and 2(RS)-azido-5-phenyl-3(SR)-phenylamino-
pent-4-enoic acid methyl ester (3a). Yellow oil. dH (CDCl3,
300 MHz): 3.77 (s, 3H, eOCH3), 3.81 (s, 3H, eOCH3), 4.38 (a pair of
To a stirred solution of b-amino esters 2 and 3 (1 mmol) in dry
chloroform was added a solution of triphenylphosphine (1.2 mmol)
in dry chloroform. On completion of the reaction, carbon disulphide
(5.0 mmol) was added and the solution was allowed to stir for 14 h
and the progress was monitored using TLC. The reaction mixture
was then concentrated under reduced pressure and purified via
column chromatography using (35:65) ethyl acetate/hexane
mixture.
0
0
d, J¼3.6, 3.9 Hz, 2H, H4, H4 ), 4.57 (dd, J¼6.0, 4.3 Hz, 02H, H5, H5 ),
6.09 (a pair of dd, 2H, J¼6.3, 6.9, 15.9, 16.2 Hz, H6, H6 ), 6.55e6.66
0
(m, 6H, H7, H7 , 4H, ArH), 7.07e7.17 (m, 4H, aromatic), 7.21e7.44 (m,
12H, aromatic). dC (CDCl3, 75 MHz): 52.7, 52.8, 56.9, 57.0, 64.9, 66.2,
114.1, 114.2, 118.5, 118.8, 124.6, 126.5, 126.6, 126.7, 127.9, 128.0, 128.2,
128.5, 129.2, 129.5, 133.1, 133.8, 136.1, 145.6, 168.8, 168.9. nmax (KBr)/
cmꢁ1 2100, 1750, 1582, 1500. m/z 323 (Mþ).
4.3.1. 1-Phenyl-5(RS)-styryl-2-thioxo-imidazolidine-4(RS)-carboxylic
acid methyl ester (5a). Yellow oil. Found: C, 71.35; H, 3.94, N, 4.53.
C19H13NO2S requires C, 71.45; H, 4.10; N, 4.39%. dH (CDCl3,
300 MHz): 3.79 (s, 3H, eOCH3), 4.32 (d, J¼5.7 Hz, 1H, H4), 5.07 (dd,
J¼5.7, 8.4 Hz, 1H, H5), 6.12 (dd, J¼8.4, 15.9 Hz, 1H, H6), 6.48 (d,
J¼15.9 Hz, 1H, H7), 7.17e7.39 (m, 10H, aromatic), 7.42 (s, 1H, NH). dC
(CDCl3, 75 MHz): 52.8, 61.3, 67.2, 120.1, 125.6, 127.8, 128.6, 128.9,
129.2, 132.9, 134.6, 136.3, 136.9, 168.8, 183.0. nmax (KBr)/cmꢁ1 1750,
1500, 1210. m/z 319 (Mþ).
4.2.2. 2(SR)-Azido-3(SR)-(4-nitro-phenylamino)-5-phenyl-pent-4-
enoic acid methyl ester (2b) and 2(RS)-azido-3(SR)-(4-nitro-phenyl-
amino)-5-phenyl-pent-4-enoic acid methyl ester (3b). Yellow oil. dH
(CDCl3, 300 MHz): 3.78 (s, 3H, eOCH3), 03.81 (s, 3H, eOCH3), 4.36
(a pair of d, J¼3.6, 3.9 Hz, 2H, H4, H4 ), 4.57e4.61 (m, 2H, H5,
0
0
H5 ),6.09 (a pair of dd, 2H, J¼6.3, 6.9, 15.9, 16.2 Hz, H6, H6 ),
0
6.54e6.65 (m, 6H, H7, H7 , 4ArH), 7.08e7.16 (m, 4H, H, aromatic),
7.25e7.46 (m, 10H, aromatic). dC (CDCl3, 75 MHz): 52.8, 52.9, 57.0,
57.1, 63.8, 64.2, 115.2, 115.3, 124.2, 126.0, 126.6, 126.7, 128.1, 128.2,
128.5, 128.6, 128.7, 129.0, 129.1, 129.3, 133.3, 134.0, 135.8, 135.9,
144.2, 144.7, 168.7, 168.8. nmax (KBr)/cmꢁ12100, 1750, 1582, 1500.
m/z 368 (Mþ).
4.3.2. 1-Phenyl-5(SR)-styryl-2-thioxo-imidazolidine-4(RS)-carbox-
ylic acid methyl ester (4a). White solid. Found: C, 71.37; H, 3.98, N,
4.52. C19H13NO2S requires C, 71.45; H, 4.10; N, 4.39%. Mp
153e154 ꢂC. dH (CDCl3, 300 MHz): 3.69 (s, 3H, eOCH3), 4.88 (d,
J¼9.6 Hz, 1H, H4), 5.14 (dd, J¼9.3, 9.6 Hz, 1H, H5), 6.05 (dd, J¼9.3,
15.6 Hz, 1H, H6), 6.50 (d, J¼15.6 Hz, 1H, H7), 6.93 (s, 1H, NH),
7.23e7.37 (m, 10H, aromatic). dC (CDCl3, 75 MHz): 52.7, 60.2, 67.8,
121.0, 126.7, 128.7,128.8, 129.1, 129.4, 133.1,134.9, 136.5, 137.2,168.4,
182.9. nmax (KBr)/cmꢁ1 1750, 1500, 1210. m/z 319 (Mþ).
4.2.3. 2(SR)-Azido-3(SR)-(4-fluoro-phenylamino)-5-phenyl-pent-4-
enoic acid methyl ester (2c) and 2(RS)-azido-3(SR)-(4-fluoro-phe-
nylamino)-5-phenyl-pent-4-enoic acid methyl ester (3c). Yellow oil.
dH (CDCl3, 300 MHz): 3.79 (s, 3H, eOCH3), 3.81 (s, 3H, eOCH3), 4.18
0
(s, 1H, 0NH), 4.37 (a pair of d, J¼3.6, 3.9 Hz, 2H, H4, H4 ), 4.57 (m, 2H,
0
H5, H5 ), 6.09 (a pair of dd, 2H, J¼6.3, 6.9, 15.9, 16.2 Hz, H6, H6 ),
0
4.3.3. 1-(4-Nitro-phenyl)-5(RS)-styryl-2-thioxo-imidazolidine-4(RS)-
carboxylic acid methyl ester (5b). Yellow oil. Found: C, 59.43; H,
4.35, N, 11.12. C19H17N3O4S requires C, 59.52; H, 4.47; N, 10.96%. dH
(CDCl3, 300 MHz): 3.86 (s, 3H, eOCH3), 4.31 (d, J¼5.7 Hz, 1H, H4),
5.10 (dd, J¼5.7, 8.4 Hz, 1H, H5), 6.17 (dd, J¼8.4, 15.6 Hz, 1H, H6), 6.51
(d, J¼15.6 Hz, 1H, H7), 6.54 (s, 1H, NH), 7.23e7.36 (m, 5H, H, aro-
matic), 7.76 (d, 2H, J¼8.7 Hz, ArH), 8.20 (d, 2H, J¼8.7 Hz, ArH). dC
(CDCl3, 75 MHz): 52.7, 61.3, 67.1, 120.4, 125.3, 127.6, 128.7, 128.6,
129.0, 132.6, 134.7, 136.5, 136.6, 168.7, 182.9. nmax (KBr)/cmꢁ1 1750,
1500, 1210. m/z 384 (Mþ).
6.60e6.67 (m, 2H, , H7, H7 , 4H, ArH), 6.85e6.91 (m, 4H, aromatic),
7.22e7.32 (m, 10H, aromatic). dC (CDCl3, 75 MHz): 52.8, 52.9, 57.2,
57.8, 63.9, 64.3, 115.4, 115.5, 115.6, 115.8, 115.9, 116.1, 124.5, 126.4,
126.6, 126.7, 128.1, 128.2, 128.6, 128.7, 133.2, 134.0, 134.8, 136.0,
141.9,142.4,168.8,168.9. nmax (KBr)/cmꢁ1 2100,1750,1582,1500. m/z
344 (Mþ).
4.2.4. 2(SR)-Azido-3(SR)-(4-chloro-phenylamino)-5-phenyl-pent-4-
enoic acid methyl ester (2d) and 2(RS)-azido-3(SR)-(4-chloro-phe-
nylamino)-5-phenyl-pent-4-enoic acid methyl ester (3d). Yellow oil.
dH (CDCl3, 300 MHz): 3.76 (s, 3H, eOCH3), 3.80 (s, 3H, eOCH3), 4.17
4.3.4. 1-(4-Nitro-phenyl)-5(SR)-styryl-2-thioxo-imidazolidine-4(RS)-
carboxylic acid methyl ester (4b). Yellow solid. Found: C, 62.56; H,
3.24, N, 7.72. C19H12N2O4S requires C, 62.63; H, 3.32; N, 7.69%. Mp
0
(s, 1H, 0NH), 4.38 (a pair of d, J¼3.6, 3.9 Hz, 2H, H4 H4 ), 4.57 (m, 2H,
0
H5, H5 ), 6.08 (a pair of dd, 2H, J¼6.3, 6.9, 15.9, 16.2 Hz, H6, H6 ),

V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
8399
158e160 ꢂC. dH (CDCl3, 300 MHz): 3.71 (s, 3H, eOCH3), 4.89 (d,
J¼9.9 Hz, 1H, H4), 5.31 (dd, J¼9.6, 9.9 Hz, 1H, H5), 6.03 (dd, J¼9.6,
15.9 Hz, 1H, H6), 6.61 (d, J¼15.9 Hz, 1H, H7), 6.86 (s, 1H, NH),
7.24e7.37 (m, 5H, aromatic), 7.74 (d, 2H, J¼9.0 Hz, ArH), 8.21 (d, 2H,
J¼9.0 Hz, ArH). dC (CDCl3, 75 MHz): 52.9, 60.6, 68.4, 121.8, 127.1,
127.4, 128.8, 129.6, 129.9, 135.5, 135.9, 136.7, 137.7, 168.5, 183.0. nmax
(KBr)/cmꢁ1 1751, 1510, 1200. m/z 384 (Mþ).
(CDCl3, 75 MHz): 21.1, 52.6, 60.3, 68.1, 121.5, 126.7, 127.4, 128.6,
129.7, 129.9, 135.2, 135.3, 136.9, 137.6, 168.4, 183.3. nmax (KBr)/cmꢁ1
1751, 1510, 1200. m/z 333 (Mþ).
4.4. Typical procedure for the diastereoselective synthesis of
1,2,4,5-tetrahydroimidazoles
To a stirred solution of 3-azido-b-lactams (1 mmol) in dry
4.3.5. 1-(4-Fluoro-phenyl)-5(RS)-styryl-2-thioxo-imidazolidine-
4(RS)-carboxylic acid methyl ester (5c). Yellow oil. Found: C, 63.87;
H, 4.72, N, 8.04. C19H17FN2O2S requires C, 64.03; H, 4.81; N, 7.86%. dH
(CDCl3, 300 MHz): 3.86 (s, 3H, eOCH3), 4.34 (d, J¼5.7 Hz, 1H, H4),
5.10 (dd, J¼5.7, 8.7 Hz, 1H, H5), 6.17 (dd, J¼8.7, 15.6 Hz, 1H, H6), 6.50
(d, J¼15.6 Hz, 1H, H7), 6.68 (s, 1H, NH), 7.02e7.36 (m, 9H, H, aro-
matic). dC (CDCl3, 75 MHz): 52.8, 60.7, 68.6, 115.4, 115.7, 123.8, 126.1,
126.5, 128.0, 128.9, 133.5, 134.6, 135.7, 168.9, 182.0. nmax (KBr)/cmꢁ1
1750, 1500, 1210 m/z 357 (Mþ).
chloroform was added a solution of triphenylphosphine (1.2 mmol)
in dry chloroform. On completion of the reaction, carbon disulphide
(5.0 mmol) was added and the progress was monitored using TLC
using a mixture of (70:30) hexane/ethyl acetate. The synthesized 3-
isothiocyanato-
raphy with a solution of (5:95) ethyl acetate/hexane. The purified 3-
isothiocyanato- -lactam (1 mmol) was dissolved in dry methanol
b-lactams were purified using column chromatog-
b
and a solution of sodium methoxide (0.3 mmol) was added to it.
The reaction mixture after completion was quenched with water
(10 mmol) and extracted with chloroform (2ꢀ50 ml). The com-
bined organic layers were dried over anhydrous sodium sulfate,
concentrated under reduced pressure and purified via column
chromatography using a solution of (35:65) ethyl acetate/hexane to
yield trans-thioxo-imidazolines 5. To the stirred solution of thioxo-
imidazolines (1.0 mmol) in dry acetone were added K2CO3
(5.0 mmol) and the alkyl halide (1.2 mmol) at room temperature.
On completion of the reaction as monitored by TLC, the reaction
mixture was filtered, washed with water (25 ml) extracted with
dichloromethane (2ꢀ25 ml). The combined organic layer was dried
upon anhydrous sodium sulfate and concentrated under reduced
pressure to form the corresponding 1,2,4,5-tetrahydroimidazoles.
4.3.6. 1-(4-Fluoro-phenyl)-5(SR)-styryl-2-thioxo-imidazolidine-
4(RS)-carboxylic acid methyl ester (4c). White solid. Found: C,
63.93; H, 4.65, N, 8.03. C19H17FN2O2S requires C, 64.03; H, 4.81; N,
7.86%. Mp 156e158 ꢂC. dH (CDCl3, 300 MHz): 3.69 (s, 3H, eOCH3),
4.89 (d, J¼9.9 Hz, 1H, H4), 5.12 (dd, J¼9.3, 9.9 Hz, 1H, H5), 6.07 (dd,
J¼9.3, 15.6 Hz, 1H, H6), 6.48 (d, J¼15.6 Hz, 1H, H7), 6.94 (s, 1H, NH),
7.01e7.37 (m, 9H, H, aromatic). dC (CDCl3, 75 MHz): 50.7, 58.3, 66.2,
113.8, 114.1, 119.3, 124.8, 124.9, 126.8, 127.8, 132.0, 133.1, 135.3, 166.6,
181.3. nmax (KBr)/cmꢁ1 1750, 1500, 1210. m/z 357 (Mþ).
4.3.7. 1-(4-Chloro-phenyl)-5(RS)-styryl-2-thioxo-imidazolidine-
4(RS)-carboxylic acid methyl ester (5d). Yellow oil. Found: C, 61.00;
H, 4.42, N, 7.67. C19H17ClN2O2S requires C, 61.20; H, 4.60; N, 7.51%. dH
(CDCl3, 300 MHz): 3.78 (s, 3H, eOCH3), 4.33 (d, J¼5.7 Hz, 1H, H4),
5.07 (dd, J¼5.7, 8.4 Hz, 1H, H5), 6.10 (dd, J¼8.4, 15.9 Hz, 1H, H6), 6.47
(d, J¼15.9 Hz, 1H, H7), 7.16e7.38 (m, 9H, H, aromatic), 7.42 (s, 1H,
NH). dC (CDCl3, 75 MHz): 53.1, 61.1, 68.7.7, 124.2, 126.7, 128.5, 128.7,
128.9, 129.1, 133.1, 134.9, 136.0, 136.5, 169.3, 182.0. nmax (KBr)/cmꢁ1
1750, 1500, 1210. m/z 373 (Mþ).
4.4.1. 1-(4-Fluoro-phenyl)-2-methylsulfanyl-5(SR)-styryl-4,5-
dihydro-1H-imidazole-4(SR)-carboxylic acid methyl ester (9). Yellow
oil. Found: C, 64.73; H, 5.29, N, 7.44. C20H19FN2O2S requires C, 64.85;
H, 5.17; N, 7.56%. dH (CDCl3, 300 MHz): 2.11 (s, 3H, CH3), 4.92 (t,
J¼9.0, 10.2 Hz, 1H, H5), 5.05 (d, J¼10.5 Hz, 1H, H4), 6.04 (dd, J¼9.0,
15.9 Hz, 1H, H6), 6.45 (d, J¼15.9 Hz, 1H, H7), 6.51 (d, 2H, J¼8.2 Hz,
ArH), 6.82 (d, 2H, J¼8.2 Hz, ArH), 7.16e7.28 (m, 5H, ArH). dC (CDCl3,
75 MHz): 18.9, 53.0, 71.6, 72.4, 117.2, 117.6, 125.3, 128.2, 129.9, 130.1,
130.4, 130.7, 137.6, 137.7, 166.2, 171.5. m/z 370 (Mþ).
4.3.8. 1-(4-Chloro-phenyl)-5(SR)-styryl-2-thioxo-imidazolidine-
4(RS)-carboxylic acid methyl ester (4d). White solid. Found: C,
61.02; H, 4.43, N, 7.65. C19H17ClN2O2S requires C, 61.20; H, 4.60; N,
7.51%. Mp 163e164 ꢂC. dH (CDCl3, 300 MHz): 3.70 (s, 3H, eOCH3),
4.86 (d, J¼9.9 Hz, 1H, H4), 5.14 (dd, J¼9.6, 9.9 Hz, 1H, H5), 6.04 (dd,
J¼9.6, 15.9 Hz, 1H, H6), 6.50 (d, J¼15.9 Hz, 1H, H7), 6.68 (s, 1H, NH),
7.25e7.35 (m, 9H, H, aromatic). dC (CDCl3, 75 MHz): 52.7, 60.2, 67.9,
121.0,126.7,128.7,128.7,128.8,129.1,133.2,135.0,136.5,137.3,168.2,
183.1. nmax (KBr)/cmꢁ1 1750, 1500, 1210. m/z 373 (Mþ).
4.4.2. 1-(4-Fluoro-phenyl)-2-prop-2-ynylsulfanyl-5(SR)-styryl-4,5-
dihydro-1H-imidazole-4(SR)-carboxylic acid methyl ester (10).
Yellow oil. Found: C, 67.50; H, 3.72, N, 7.31. C19H17FN2O2S requires C,
67.68; H, 3.87; N, 7.18%. dH (CDCl3, 300 MHz): 2.24 (t, J¼1.5, 2.7 Hz,
1H, acetylinic), 3.65 (s, 3H, eOCH3), 3.94 (dABq, 2H, J¼1.5, 2.7,
11.2 Hz, CH2), 4.95 (dd, J¼9.0, 10.2 Hz, 1H, H5), 5.05 (d, J¼10.5 Hz,
1H, H4), 6.08 (dd, J¼9.0 Hz, 15.9 Hz, 1H, H6), 6.44 (d, J¼15.9 Hz, 1H,
H7), 7.00 (d, 2H, J¼9.0 Hz, ArH), 7.16e7.28 (m, 7H, H, aromatic). dC
(CDCl3, 75 MHz): 37.0, 53.3, 71.8, 72.9, 73.3, 80.0, 117.5, 117.8, 125.1,
128.1, 129.8, 130.0, 130.1, 130.2, 137.3, 137.4, 166.4, 171.8. m/z 391
(Mþ).
4.3.9. 5(RS)-Styryl-2-thioxo-1-p-tolyl-imidazolidine-4(RS)-carbox-
ylic acid methyl ester (5e). Yellow oil. Found: C, 72.13; H, 3.83, N,
4.62. C19H13NO2S requires C, 72.05; H, 4.53; N, 4.20%. dH (CDCl3,
300 MHz): 2.31(s, 3H, CH3), 3.86 (s, 3H, eOCH3), 4.32 (d, J¼5.7 Hz,
1H, H4), 5.12 (dd, J¼5.7, 8.7 Hz, 1H, H5), 6.19 (dd, J¼8.7, 15.6 Hz, 1H,
H6), 6.50 (d, J¼15.6 Hz, 1H, H7), 6.53 (s, 1H, NH), 7.16 (d, 2H,
J¼8.4 Hz, ArH), 7.22e7.31 (m, 7H, aromatic). dC (CDCl3, 75 MHz):
21.2, 52.8, 60.2, 67.1, 120.3, 125.4, 127.7, 128.8, 128.7, 129.1, 132.7,
134.8, 136.4, 136.7, 168.8, 183.1. nmax (KBr)/cmꢁ1 1750, 1500, 1210 m/
z 333 (Mþ).
4.4.3. 2-Ethylsulfanyl-1-(4-fluoro-phenyl)-5(SR)-styryl-4,5-dihydro-
1H-imidazole-4(SR)-carboxylic acid methyl ester (11). Yellow oil.
Found: C, 65.48; H, 5.60, N, 7.44. C21H21FN2O2S requires C, 65.60; H,
5.51; N, 7.29%. dH (CDCl3, 300 MHz): 1.27 (t, J¼7.2 Hz, 3H, CH3), 3.15
(q, J¼7.2 Hz, 2H, CH2), 4.95 (t, J¼9.0, 10.2 Hz, 1H, H5), 5.02 (d,
J¼10.5 Hz, 1H, H4), 6.07 (dd, J¼9.0, 15.9 Hz, 1H, H6), 6.47 (d,
J¼15.9 Hz, 1H, H7), 6.53 (d, 2H, J¼8.2 Hz, ArH), 6.87 (d, 2H, J¼8.2 Hz,
ArH), 7.12e7.31 (m, 5H, ArH). dC (CDCl3, 75 MHz): 15.9, 19.7, 53.2,
71.8, 72.5, 117.8, 118.3, 125.8, 128.0, 129.9, 130.2, 130.8, 131.2, 137.6,
137.9, 166.5, 171.9. m/z 384 (Mþ).
4.3.10. 5(SR)-Styryl-2-thioxo-1-p-tolyl-imidazolidine-4(RS)-carbox-
ylic acid methyl ester (4e). White solid. Found: C, 71.85; H, 4.38, N,
4.32. C19H13NO2S requires C, 72.05; H, 4.53; N, 4.20%. Mp
160e162 ꢂC. dH (CDCl3, 300 MHz): 2.30 (s, 3H, CH3), 3.69 (s, 3H,
eOCH3), 4.86 (d, J¼9.9 Hz, 1H, H4), 5.10 (dd, J¼9.9, 9.6 Hz, 1H, H5),
6.17 (dd, J¼9.6, 15.9 Hz, 1H, H6), 6.48 (d, J¼15.9 Hz, 1H, H7), 6.57 (s,
1H, NH), 7.15 (d, 2H, J¼8.4 Hz, ArH), 7.23e7.31 (m, 7H, aromatic). dC
4.4.4. 1-(4-Fluoro-phenyl)-2-methylsulfanyl-5-styryl-4,5-dihydro-
1H-imidazole-4-carboxylic acid methyl ester (12). Yellow oil. Found:
C, 65.69; H, 5.29, N, 7.01. C22H22FN2O2S requires C, 66.65; H, 5.34; N,

8400
V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
7.07%. dH (CDCl3, 300 MHz): 4.04(d, J¼1.4 Hz, 2H, eCH2e), 3.64 (s,
3H, eOCH3), 4.93 (d, J¼9.0, 9.6 Hz, 1H, H5), 5.05 (d, J¼9.6 Hz, 1H,
H4), 5.17 (m, 2H, allylic eCH2e), 5.7 (m, 1H, CH), 6.07 (dd, J¼9.0,
15.9 Hz, 1H, H6), 6.45 (d, J¼15.9 Hz, 1H, H7), 7.04 (d, 2H, J¼8.6 Hz,
ArH), 7.16e7.28 (m, 7H, H, aromatic). dC (CDCl3, 75 MHz): 28.2, 53.3,
63.2, 67.9, 115.9, 117.5, 117.8, 125.1, 128.1, 129.8, 130.0, 130.1, 130.2,
132.7, 137.3, 137.4, 166.4, 171.8. m/z 397 (Mþ).
3.68 (s, 3H, eOCH3), 4.31 (q, J¼7.2 Hz, 2H, CH2), 4.66 (dd, J¼4.8,
6.0 Hz, H2), 4.93 (dd, J¼4.8, 7.2 Hz, H1), 6.06 (dd, J¼6.0, 15.9 Hz, H3),
6.62 (d, J¼15.9 Hz, H4), 7.14e7.40 (m, 10H, ArH), 7.82 (d, J¼7.2 Hz,
NH, exchangeable with D2O). dC (CDCl3, 75 MHz): 12.7, 19.7, 56.5,
58.5, 69.2, 112.3, 116.9, 123.3, 126.2, 127.4, 127.7, 128.4, 129.3, 130.1,
133.0, 160.2, 160.3, 183.4. m/z 380 (Mþ).
4.6.3. 2-Oxo-1-phenyl-5(SR)-styryl-imidazolidin-4(RS)-carboxylic
acid methyl ester (16a). White solid. Found: C, 70.66; H, 5.71, N,
8.75. C19H18N2O3 requires C, 70.79; H, 5.63; N, 8.69%. Mp
221e222 ꢂC. Yield: 68%. dH (CDCl3, 300 MHz): 3.68 (s, 3H, eOCH3),
4.95 (dd, J¼5.4, 6.2 Hz, 1H, H3), 5.38 (dd, J¼5.5, 9.0 Hz, 1H, H4), 5.42
(d, J¼8.94 Hz, 1H, NH, exchangeable with D2O), 6.10 (dd, J¼6.1,
16.04 Hz, 1H, H2), 6.72 (d, J¼16.04 Hz, 1H, H1), 7.00e7.24 (m, 6H,
ArH), 7.30e7.65 (m, 4H, ArH). dC (CDCl3, 75 MHz): 52.6, 59.8, 60.4,
117.9,122.1,126.6,128.5,128.7,129.4,134.2,134.5,135.7,138.2,156.7,
163.2. nmax (KBr)/cmꢁ1 1759, 1697. m/z 322 (Mþ).
4.5. Typical procedure for the sodium methoxide assisted
intermolecular amidolysis of 3-amino-azetidin-2-one
To a solution of 3-amino-b-lactam 13 (1 mmol) in dry methanol
was added a solution of sodium methoxide (0.3 mmol) in dry
methanol. The reaction mixture was allowed to stir at room tem-
perature and the progress was monitored using TLC using a mixture
of (60:40) hexane/ethyl acetate. On completion, the reaction mix-
ture was quenched with water (10 ml) and extracted with chloro-
form (2ꢀ50 ml). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated under reduced pres-
4.6.4. 1-(4-Nitro-phenyl)-2-oxo-5(SR)-styryl-imidazolidin-4(RS)-
carboxylic acid methyl ester (16b). White solid. Found: C, 62.02; H,
4.73, N, 11.49. C19H17N3O5 requires C, 62.12; H, 4.66; N, 11.44%. Mp
225e227 ꢂC. Yield: 69%. dH (CDCl3, 300 MHz): 2.34 (s, 3H, eCH3),
3.69 (s, 3H, eOCH3), 4.95 (dd, J¼5.4, 6.3 Hz, 1H, H3), 5.32 (dd, J¼5.2,
9.0 Hz, 1H, H4), 5.41 (d, J¼8.90 Hz, 1H, NH, exchangeable with D2O),
6.17 (dd, J¼6.4, 16.04 Hz, 1H, H2), 6.75 (d, J¼16.08 Hz, 1H, H1),
7.14e7.30 (m, 5H, ArH), 7.90 (d, J¼8.2 Hz, 2H, ArH), 8.17 (d, J¼8.2 Hz,
2H, ArH). dC (CDCl3, 75 MHz): 52.9, 59.9, 60.7, 117.5, 122.4, 126.5,
128.6, 128.8, 129.5, 134.1, 134.7, 135.4, 144.3, 156.1, 163.2. nmax (KBr)/
cmꢁ1 1759, 1697 m/z 367 (Mþ).
sure to yield cis-a-amino ester 14 as pale yellow viscous liquid.
4.5.1. 2(SR)-Amino-5-phenyl-3(RS)-phenylamino-pent-4-enoic acid
methyl ester (14a). Yellow liquid. Found: C, 72.87; H, 6.92, N, 9.52.
C18H20N2O2 requires C, 72.95; H, 6.80; N, 9.45%. Yield: 90%. dH
(CDCl3, 300 MHz): 3.68 (s, 3H, eOCH3), 4.42 (dd, J¼5.4, 9.0 Hz, 1H,
H2), 4.7 (d, J¼5.4 Hz, 1H, H1), 6.15 (dd, J¼9.0, 15.9 Hz, 1H, H3), 6.68
(d, J¼15.9 Hz, 1H, H4), 6.83e7.04 (m, 5H, ArH), 7.14e7.30 (m, 5H,
ArH). dC (CDCl3, 75 MHz): 50.4, 61.0, 61.8, 112.4, 116.5, 123.6, 126.2,
127.3, 127.7, 128.4, 129.5, 134.7, 143.5, 172.0. m/z 296 (Mþ).
4.6. Typical procedure for the diastereoselective synthesis of
imidazolidin-2-one and piperazine-5,6-dione
4.6.5. 1-(4-Fluoro-phenyl)-2-oxo-5(SR)-styryl-imidazolidin-4(RS)-
carboxylic acid methyl ester (16c). White solid. Found: C, 67.10; H,
5.07, N, 8.11. C19H17FN2O3 requires: C, 67.05; H, 5.03; N, 8.23%. Mp
215e216 ꢂC. Yield: 68%. dH (CDCl3, 300 MHz): 3.67 (s, 3H, eOCH3),
4.96 (dd, J¼5.4, 6.1 Hz, 1H, H3), 5.35 (dd, J¼5.4, 9.0 Hz, 1H, H4), 5.40
(d, J¼9.0 Hz, 1H, NH, exchangeable with D2O), 6.14 (dd, J¼6.2,
16.08 Hz, 1H, H2), 6.72 (d, J¼16.04 Hz, 1H, H1), 6.95e7.30 (m, 7H,
aromatic), 7.62 (d, J¼8.2 Hz, 2H, ArH). dC (CDCl3, 75 MHz): 52.9, 60.1,
60.8, 117.4, 122.0, 126.7, 128.6, 128.9, 129.7, 134.3, 134.9, 135.2, 147.7,
156.4, 163.5. nmax (KBr)/cmꢁ1 1759, 1697. m/z 340 (Mþ).
To a stirred solution of cis-a-amino ester (1 mmol) in a dry
chloroform was added phenyl chloroformate/ethyloxalyl chloride
(1 mmol) at 0 ꢂC and the solution was allowed to stir for 2 h. The
progress of reaction was monitored by using TLC and on comple-
tion, the reaction mixture was treated with a saturated solution of
sodium bicarbonate and extracted with chloroform (2ꢀ50 ml). The
combined organic layer was dried over anhydrous sodium sulfate
and concentrated under reduced pressure to yield cis-2-phenoxy
carbonyl amino-5-phenyl-3-arylamino-pent-4-enoic acid methyl
esters 15/cis-2-(ethoxy oxalyl amino)-5-phenyl-3-arylamino-pent-
4-enoic acid methyl esters 17. Compound 15/17 was then refluxed
in toluene in the presence of p-toluene sulfonic acid for 12 h. On
completion, as evidenced by TLC, the reaction mixture was con-
centrated under reduced pressure and purified via column chro-
matography using a mixture of ethyl acetate/hexane (60:40) to
yield the corresponding imidazolidin-2-one 16/piperazine-5,6-
dione 18, respectively.
4.6.6. 1-(4-Chloro-phenyl)-2-oxo-5(SR)-styryl-imidazolidin-4(RS)-
carboxylic acid methyl ester (16d). White solid. Found: C, 63.82; H,
4.78, N, 7.90. C19H17ClN2O3 requires C, 63.96; H, 4.80; N, 7.85%. Mp
224e225 ꢂC. Yield: 72%. dH (CDCl3, 300 MHz): 3.69 (s, 3H, eOCH3),
4.97 (dd, J¼5.1, 6.3 Hz, 1H, H3), 5.38 (dd, J¼5.3, 9.0 Hz, 1H, H4), 5.42
(d, J¼8.96 Hz, 1H, NH, exchangeable with D2O), 6.12 (dd, J¼6.3,
16.04 Hz, 1H, H2), 6.71 (d, J¼16.04 Hz, 1H, H1), 7.14e7.30 (m, 7H,
ArH), 7.58 (d, J¼8.2 Hz, 2H, ArH). dC (CDCl3, 75 MHz): 52.5, 60.3,
60.5, 117.5, 122.5, 126.4, 128.0, 129.1, 129.4, 134.0, 134.6, 135.6, 136.2,
156.1, 163.5. nmax (KBr)/cmꢁ1 1759, 1697. m/z 356 (Mþ).
4.6.1. 2(SR)-Phenoxycarbonylamino-5-phenyl-3(RS)-phenylamino-
pent-4-enoic acid methyl ester (15a). Yellow Liquid. Found: C,
72.03; H, 5.93; N, 6.60. C25H24N2O4 requires C, 72.10; H, 5.81; N,
6.73%. Yield: 82%. dH (CDCl3, 300 MHz): 3.68 (s, 3H, eOCH3), 4.68
(dd, J¼4.8, 6.0 Hz, H2), 4.96 (dd, J¼4.8, 7.2 Hz, H1), 6.02 (dd, J¼6.0,
15.9 Hz, H3), 6.69 (d, J¼15.9 Hz, H4), 6.83e7.04 (m, 5H, ArH),
7.14e7.28 (m, 10H, ArH), 7.87 (d, J¼7.2 Hz, NH, exchangeable with
D2O). dC (CDCl3, 75 MHz): 54.5, 57.9, 69.0, 112.5, 116.9, 123.3, 124.0,
125.7, 126.2, 127.1, 127.3, 128.5, 129.7, 130.0, 131.4, 133.3, 135.7, 160.1,
170.7. m/z 416 (Mþ).
4.6.7. 2-Oxo-5(SR)-styryl-1-p-tolyl-imidazolidin-4(RS)-carboxylic
acid methyl ester (16e). White solid. Found: C, 71.27; H, 6.06, N, 8.37.
C20H20N2O3 requires C, 71.41; H, 5.99; N, 8.33%. Mp 219e220 ꢂC.
Yield: 75%. dH (CDCl3, 300 MHz): 2.31 (s, 3H, eCH3), 3.68 (s, 3H,
eOCH3), 4.93 (dd, J¼5.4, 6.2 Hz, 1H, H3), 5.33 (dd, J¼5.4, 9.0 Hz, 1H,
H4), 5.43 (d, J¼8.92 Hz, 1H, NH, exchangeable with D2O), 6.18 (dd,
J¼6.2, 16.08 Hz, 1H, H2), 6.73 (d, J¼16.04 Hz, 1H, H1), 7.11 (d,
J¼8.28 Hz,2H, ArH), 7.28e7.40(m, 7H,ArH). dC (CDCl3, 75 MHz):20.9,
52.7, 59.9, 60.9, 117.2, 122.3, 126.7, 128.5, 128.7, 129.6, 134.2, 134.9,
135.6, 136.1, 156.2, 163.4. nmax (KBr)/cmꢁ1 1759, 1698. m/z 336 (Mþ).
4.6.2. 2(SR)-(Ethoxyoxalyl
amino)-5-phenyl-3(RS)-phenylamino-
pent-4-enoic acid methyl ester (17a). Yellow Liquid. Found: C,
69.56; H, 6.24, N, 7.39. C22H24N2O4 requires C, 69.46; H, 6.36; N,
7.36%. Yield: 85%. dH (CDCl3, 300 MHz): 1.32 (t, J¼7.2 Hz, 3H, CH3),
4.6.8. 5,6-Dioxo-4-phenyl-3(SR)-styryl-piperazine-2(RS)-carboxylic
acid methyl ester (18a). White solid. Found: C, 68.66; H, 5.11, N, 7.91.
C20H18N2O4 requires C, 68.56; H, 5.18; N, 8.00%. Mp 233e234 ꢂC.

V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
8401
Yield: 68%. dH (CDCl3, 300 MHz): 3.78 (s, 3H, eOCH3), 4.30 (dd,
J¼2.3, 5.0 Hz, 1H, H4), 4.92 (dd, J¼2.3, 6.8 Hz, 1H, H3), 6.34 (dd,
J¼6.8, 15.6 Hz, 1H, H2), 6.52 (d, J¼15.6 Hz,1H, H1), 7.00e7.30 (m, 8H,
aromatic), 7.64 (m, 2H, ArH), 8.10 (d, J¼5.0 Hz, NH, exchangeable
with D2O). dC (CDCl3, 75 MHz): 52.7, 59.7, 60.4, 117.2, 122.5, 126.7,
128.1, 128.9, 129.2, 134.1, 134.4, 135.8, 136.2, 156.0, 163.2, 171.9 nmax
(KBr)/cmꢁ1 1749, 1693, 1681. m/z 350 (Mþ).
styryl-azetidin-3-yl)-carbamic acid phenyl ester 19 and N-(2-oxo-
1-aryl-4-styryl-azetidin-3-yl)-oxalamic acid ethyl ester 20, re-
spectively, purified via column chromatography using a mixture of
(30:70) ethyl acetate/hexane mixture. To a stirred solution of 19 and
20 (1 mmol) in dry methanol was added a solution of sodium
methoxide (0.3 mmol) in dry methanol. The reaction mixture was
allowed to stir at room temperature and the progress was monitored
using TLC. On completion, the reaction mixture was quenched with
water (10 ml) and extracted with chloroform (2ꢀ50 ml). The com-
bined organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure to yield imidazolidin-2-one
16 and piperazine-5,6-dione 18, which were recrystallized using
a mixture of (20:80) chloroform/hexane mixture.
4.6.9. 4-(4-Nitro-phenyl)-5,6-dioxo-3(SR)-styryl-piperazine-2(RS)-
carboxylic acid methyl ester (18b). White solid. Found: C, 60.66; H,
4.20, N, 10.66. C20H17N3O6 requires C, 60.76; H, 4.33; N, 10.63%. Mp
238e239 ꢂC. Yield: 66%. dH (CDCl3, 300 MHz): 3.79 (s, 3H, eOCH3),
4.32 (dd, J¼2.0, 5.1 Hz, 1H, H4), 4.93 (dd, J¼2.0, 6.6 Hz, 1H, H3), 6.35
(dd, J¼6.6,15.9 Hz,1H, H2), 6.50 (d, J¼15.9 Hz,1H, H1), 7.14e7.30 (m,
5H, aromatic), 7.90 (d, J¼8.2 Hz, 2H, ArH), 8.10 (d, J¼5.1 Hz, NH,
exchangeable with D2O), 8.17(d, J¼8.2 Hz, 2H, ArH). dC (CDCl3,
75 MHz): 52.9, 59.8, 60.6, 117.3, 122.6, 126.8, 128.2, 128.8, 129.3,
134.0, 134.6, 135.6, 144.4, 156.1, 163.0, 171.5. nmax (KBr)/cmꢁ1 1749,
1693,1681. m/z 395 (Mþ).
4.7.1. (2-Oxo-1-phenyl-4(RS)-styryl-azetidin-3(SR)-yl)-carbamic
acid phenyl ester (19a). Yellow liquid. Found: C, 74.87; H, 5.41, N,
7.21. C24H20N2O3 requires C, 74.98; H, 5.24; N, 7.29%. Yield: 86%. dH
(CDCl3, 300 MHz): 4.64 (dd, J¼6.0, 4.8 Hz, H2), 4.92 (dd, J¼4.8,
7.2 Hz, H1), 6.08 (dd, J¼6.0, 15.9 Hz, H3), 6.61 (d, J¼15.9 Hz, H4),
7.07e7.31 (m, 15H, ArH), 7.82 (d, J¼7.2 Hz, NH, exchangeable with
D2O). dC (CDCl3, 75 MHz): 57.4, 59.2, 120.3, 121.4, 123.3, 124.1, 125.5,
126.2,127.2,127.7,128.4,128.7,128.9,134.6,140.8, 153.1,157.6,179.9.
m/z 384 (Mþ).
4.6.10. 4-(4-Fluoro-phenyl)-5,6-dioxo-3(SR)-styryl-piperazine-
2(RS)-carboxylic acid methyl ester (18c). White solid. Found: C,
65.13; H, 4.76, N, 7.67. C20H17FN2O4 requires C, 65.21; H, 4.65; N,
7.60%. Mp 234e235 ꢂC. Yield: 67%. dH (CDCl3, 300 MHz): 3.80 (s, 3H,
eOCH3), 4.33 (dd, J¼2.0, 5.1 Hz, 1H, H4), 4.91 (dd, J¼2.0, 6.6 Hz, 1H,
H3), 6.34 (dd, J¼6.6, 15.9 Hz,1H, H2), 6.51 (d, J¼15.9 Hz,1H, H1), 6.95
(d, J¼8.2 Hz, 2H aromatic), 7.14e7.30 (m, 5H, aromatic), 7.62 (d,
J¼8.2 Hz, 2H aromatic), 8.09 (d, J¼5.1 Hz, NH, exchangeable with
D2O). dC (CDCl3, 75 MHz): 52.7, 59.6, 60.4, 117.4, 122.6, 126.7, 128.3,
128.9, 129.3, 134.1, 134.8, 135.6, 136.0, 156.0, 163.2, 172.4. nmax (KBr)/
cmꢁ1 1749, 1693, 1681. m/z 368 (Mþ).
4.7.2. N-(2-Oxo-1-phenyl-4(RS)-styryl-azetidin-3(SR)-yl)-oxalamic
acid ethyl ester (20a). Yellow liquid. Found: C, 69.15; H, 5.58, N,
7.56. C21H20N2O4 requires C, 69.22; H, 5.53; N, 7.69%. Yield: 89%. dH
(CDCl3, 300 MHz): 1.31 (t, J¼7.2 Hz, 3H, CH3), 4.30 (q, J¼7.2 Hz,
CH2), 4.64 (dd, J¼4.8, 6.0 Hz, H2), 4.92 (dd, J¼4.8, 7.2 Hz, H1), 6.08
(dd, J¼6.0, 15.9 Hz, H3), 6.61 (d, J¼15.9 Hz, H4), 7.10e7.24 (m, 6H,
ArH), 7.30e7.32 (m, 4H, ArH), 7.82 (d, J¼7.2 Hz, NH, exchangeable
with D2O). dC (CDCl3, 75 MHz): 12.8, 56.3, 58.5, 59.6, 120.3, 123.6,
124.2, 126.3, 127.4, 127.8, 128.5, 128.7, 134.6, 140.8, 160.2, 160.3,
170.5. m/z 364 (Mþ).
4.6.11. 4-(4-Chloro-phenyl)-5,6-dioxo-3(SR)-styryl-piperazine-
2(RS)-carboxylic acid methyl ester (18d). White solid. Found: C,
62.30; H, 4.57, N, 7.37. C20H17ClN2O4 requires C, 62.42; H, 4.45; N,
7.28%. Mp 243e244 ꢂC. Yield: 71%. dH (CDCl3, 300 MHz): 3.82 (s, 3H,
eOCH3), 4.34 (dd, J¼2.2, 5.2 Hz, 1H, H4), 4.90 (dd, J¼2.2, 6.8 Hz, 1H,
H3), 6.35 (dd, J¼6.8, 15.6 Hz, 1H, H2), 6.50 (d, J¼15.6 Hz, 1H, H1),
7.14e7.30 (m, 7H, ArH), 7.58 (d, J¼8.20 Hz, 2H, ArH), 8.10 (d, J¼5.2 Hz,
NH, exchangeable with D2O). dC (CDCl3, 75 MHz): 52.8, 59.7, 60.4,
117.2,122.5, 126.7,128.4, 128.7,129.4,134.1,134.9, 135.8,136.0, 156.1,
163.5, 172.1. nmax (KBr)/cmꢁ1 1749, 1693, 1681. m/z 384 (Mþ).
Acknowledgements
The financial support from CSIR New Delhi under Scheme No.
01(2407)/10/EMR-II (V.K.) is gratefully acknowledged.
References and notes
1. (a) Kumar, V.; Mahajan, M. P. In Pyrimidines and Imidazoles in Heterocycles in
Natural Product Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Eds.; Wiley-
VCH: Weinheim, 2011; Chapter 14, pp 507e533; (b) Laufer, S. A.; Zimmermann,
W.; Ruff, K. J. J. Med. Chem. 2004, 47, 6311.
4.6.12. 5,6-Dioxo-3(SR)-styryl-4-p-tolyl-piperazine-2(RS)-carboxylic
acid methyl ester (18e). White Solid. Found: C, 69.28; H, 5.66, N,
7.70. C21H20N2O4 requires C, 69.22; H, 5.53; N, 7.69%. Mp
239e240 ꢂC. Yield: 73%. dH (CDCl3, 300 MHz): 2.53 (s, 3H, eCH3),
3.81 (s, 3H, eOCH3), 4.37 (dd, J¼2.1, 5.0 Hz, 1H, H4), 4.91 (dd, J¼2.1,
6.9 Hz, 1H, H3), 6.37 (dd, J¼6.9, 15.9 Hz, 1H, H2), 6.55 (d, J¼15.9 Hz,
1H, H1), 7.12 (d, J¼8.28 Hz, 2H, ArH), 7.23e7.37 (m, 7H, ArH), 8.09 (d,
J¼5.0 Hz, NH, exchangeable with D2O). dC (CDCl3, 75 MHz): 20.7,
52.5, 59.9, 60.6, 117.1, 122.3, 126.5, 128.4, 128.7, 129.6, 134.1, 134.9,
135.6, 136.0, 156.2, 163.8, 172.3. nmax (KBr)/cmꢁ1 1749, 1693,1681. m/
z 364 (Mþ).
2. Dutta, S. Acta Pharm. 2010, 60, 229.
3. Gupta, P.; Hameed, S.; Jain, R. Eur. J. Med. Chem. 2004, 39, 805.
4. Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.; Ursini, A. Bioorg. Med.
Chem. Lett. 1999, 9, 1023.
5. Ellis, G. P.; Epstein, C.; Fitzmaurice, C.; Golberg, L.; Lord, G. H. J. Pharm. Phar-
macol. 1964, 16, 400.
6. Ram, V. J.; Vanden Berghe, D. A.; Vlietinck, A. Justus Liebigs Ann. Chem. 1987, 9,
797.
7. Tanaka, F.; Takeuchi, S.; Tanaka, N.; Yonehara, H.; Umezawa, H.; Sumiki, Y. J.
Antibiot. 1961, 14, 161.
8. Nicolaou, K. C.; Xu, J. Y.; Kim, S.; Pfefferkorn, J.; Ohshima, T.; Vourloumis, D.;
Hosokawa, S. J. Am. Chem. Soc. 1998, 34, 8661.
9. Barta, T. E.; Stealey, M. A.; Collins, P. W.; Weier, R. M. Bioorg. Med. Chem. Lett.
1998, 8, 3443.
10. Murry, J. A. Drug Discov. Dev. 2003, 6, 945.
11. De Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J.
V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Bioorg. Med. Chem.
Lett. 1999, 9, 641.
4.7. Typical procedure for single-pot synthesis of imidazoli-
din-2-one and piperazine-5,6-dione
To a stirred solution of 3-amino-b-lactam (1 mmol) in a dry
12. Eyers, P. A.; Craxton, M.; Morrice, N.; Cohen, P.; Goedert, M. Chem. Biol. 1998, 5,
chloroform was added phenyl chloroformate/ethyloxalyl chloride
(1 mmol) at 0 ꢂC and the solution was allowed to stir for 2 h. The
progress of reaction was monitored by using TLC and on completion,
the reaction mixturewas treated with a saturated solution of sodium
bicarbonate and extracted with chloroform (2ꢀ50 ml). The com-
bined organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to yield (2-oxo-1-phenyl-4-
321.
13. Newman, M. J.; Rodarte, J. C.; Benbatoul, K. D.; Romano, S. J.; Zhang, C.; Krane,
S.; Moran, E. J.; Uyeda, R. T.; Dixon, R.; Guns, E. S.; Mayer, L. D. Cancer Res. 2000,
60, 2964.
14. (a) Fang, Z.; Wang, S.; Zhao, L.; Xu, Z.; Ren, J.; Wang, X. Mater. Lett. 2007, 61,
4803; (b) Ge, Z.; Hayakawa, T.; Ando, S.; Ueda, M.; Akiike, T.; Miyamoto, H.
Chem. Mater. 2008, 20, 2532; (c) Lai, M. Y.; Chen, C. H.; Huang, W. S.; Lin, J. T.;
Ke, T. H.; Chen, L. Y. Angew. Chem., Int. Ed. 2008, 47, 581; (d) Fang, Z.; Wang, S.;

8402
V. Mehra et al. / Tetrahedron 68 (2012) 8395e8402
Zhao, L.; Xu, Z.; Ren, J.; Wang, X. Mater. Chem. Phys. 2008, 107, 305; (e) Chen, C.
H.; Huang, W. S.; Lai, M. Y.; Tsao, W. C.; Lin, J. T.; Wu, Y. H. Adv. Funct. Mater.
2009, 19, 2661.
A. R.; Alimohammadi, Z.; Azizian, J.; Mohammadi, A. A.; Mohammadizadeh, M.
R. Catal. Commun. 2006, 7, 728; (e) Kantevari, S.; Vuppalapati, S. V. N.; Biradar,
D. O.; Nagarapu, L. J. Mol. Catal., A: Chem. 2007, 266, 109; (f) Siddiqui, S. A.;
Narkhede, U. C.; Palimkar, S. S.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Tetra-
hedron 2005, 61, 3539.
15. (a) Shin, R. Y. C.; Kietzke, T.; Sudhakar, S.; Dodabalapur, A.; Chen, Z. K.; Sellinger,
A. Chem. Mater. 2007, 19, 1892; (b) Tsai, M. S.; Hsu, Y. C.; Lin, J. T.; Chen, H. C.;
Hsu, C. P. J. Phys. Chem. C 2007, 111, 18785; (c) Chang, Y. T.; Hsu, S. L.; Chen, G. Y.;
Su, M. H.; Singh, T. A.; Diau, E. W. G. Adv. Funct. Mater. 2008, 18, 2356; (d) Chang,
Y. T.; Hsu, S. L.; Su, M. H.; Wei, K. H. Adv. Funct. Mater. 2009, 21, 2093; (e) Ve-
lusamy, M.; Hsu, C. Y.; Lin, J. T.; Chang, C. W.; Hsu, C. P. Chem. Asian J. 2010, 5, 87.
16. (a) Dupont, J.; DeSouza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667; (b)
Nara, S. J.; Naik, P. U.; Harjani, J. R.; Salunkhe, M. M. Indian J. Chem. 2001, 45B,
2257; (c) Chowdhury, S.; Mohan, R. S.; Scott, J. L. Tetrahedron 2007, 63, 2363.
17. (a) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39;
(b) Arnold, P. L.; Liddle, S. T. Chem. Commun. 2006, 3959; (c) Kuhl, O. Chem. Soc.
Rev. 2007, 36, 592.
18. (a) Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D. G.; Furfine, E. S.;
Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.; Tung, R. D.; Wright, L. L. Bioorg.
Med. Chem. Lett. 2000, 10, 1159; (b) Kazmierski, W. M.; Furfine, E.; Gray-Nunez,
Y.; Spaltenstein, A.; Wright, L. Bioorg. Med. Chem. Lett. 2004, 14, 5685.
19. Heidempergher, F.; Pillan, A.; Pinciroli, V.; Vaghi, F.; Arrigoni, C.; Bolis, G.;
Caccia, C.; Dho, L.; McArthur, R.; Varasi, M. J. Med. Chem. 1997, 40, 3369.
20. (a) Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D. J.; Paliwal, S.; Lin, L.; Gu, D.;
Schwerdt, J. H.; Shah, S.; Reichard, G. A.; Piwinski, J. J.; Duffy, R. A.; Lachowicz, J.
E.; Coffin, V. L.; Liu, F.; Nomeir, A. A.; Morgan, C. A.; Varty, G. B. Bioorg. Med.
Chem. Lett. 2005, 15, 3896; (b) Shue, H.-J.; Chen, X.; Schwerdt, J. H.; Paliwal, S.;
Blythin, D. J.; Lin, L.; Gu, D.; Wang, C.; Reichard, G. A.; Wang, H.; Piwinski, J. J.;
Duffy, R. A.; Lachowicz, J. E.; Coffin, V. L.; Nomeir, A. A.; Morgan, C. A.; Varty, G.
B.; Shih, N. Y. Bioorg. Med. Chem. Lett. 2006, 16, 1065.
26. (a) Consonni, R.; Croce, P. D.; Ferraccioli, R.; Rosa, C. L. J. Chem. Res., Synop. 1991,
188; (b) Lantos, I.; Zhang, W. Y.; Shui, X.; Eggleston, D. S. J. Org. Chem. 1993, 58,
7092; (c) Balalaie, S.; Hashemi, M. M.; Akhbari, M. Tetrahedron Lett. 2003, 44,
1709; (d) Sharma, G. V. M.; Jyothi, Y.; Sree Lakshmi, P. Synth. Commun. 2006, 36,
2991.
27. Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124, 12.
28. (a) Muniz, K.; Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763; (b)
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688; (c) Bar, G. L. J.; Lloyd-
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308.
29. Danishefsky, S.; Taniyama, E.; Webb, R. R., II. Tetrahedron Lett. 1983, 24, 11.
30. (a) Doyle, M. P.; Khou, Q. L.; Raab, C. E.; Roos, G. H. P.; Simonsen, S. H.; Lynch, V.
Inorg. Chem. 1996, 35, 6064; (b) Doyle, M. P.; Colyer, J. T. Tetrahedron: Asymmetry
2003, 14, 3601; (c) Doyle, M. P.; Morgan, J. P.; Fettinger, J. C.; Zavalij, P. Y.; Colyer,
J. T.; Timmons, D. J.; Carducci, M. D. J. Org. Chem. 2005, 70, 5291.
31. (a) Singh, P.; Sachdeva, S.; Raj, R.; Kumar, V.; Mahajan, M. P.; Nasser, S.; Vivas, L.;
Gut, J.; Rosenthal, P. J.; Feng, T. S.; Chibale, K. Bioorg. Med. Chem. Lett. 2011, 21,
4561; (b) Singh, P.; Kaur, S.; Kumar, V.; Bedi, P. M. S.; Mahajan, M. P.; Sehar, I.;
Pal, H. C.; Saxena, A. K. Bioorg. Med. Chem. Lett. 2011, 21, 3017; (c) Singh, P.; Raj,
R.; Kumar, V.; Mahajan, M. P.; Bedi, P. M. S.; Kaur, T.; Saxena, A. K. Eur. J. Med.
Chem. 2012, 47, 594; (d) Singh, P.; Singh, P.; Kumar, M.; Gut, J.; Rosenthal, P. J.;
Kumar, K.; Kumar, V.; Mahajan, M. P.; Bisetty, K. Bioorg. Med. Chem. Lett. 2012,
22, 57; (e) Anand, A.; Singh, P.; Mehra, V.; Amandeep; Kumar, V.; Mahajan, M. P.
ꢀ
Tetrahedron Lett. 2012, 2417; (f) Kumar, K.; Singh, P.; Kremer, L.; Guerardel, Y.;
21. Byrtus, H.; Obniska, J.; Czopek, A.; Kaminski, K.; Pawlowski, M. Bioorg. Med.
Biot, C.; Kumar, V. Dalton Trans. 2012, 41, 5778.
Chem. 2011, 20, 6149.
32. (a) Anand, A.; Bhargava, G.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett. 2010, 51,
2312; (b) Singh, P.; Bhargava, G.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett.
2010, 51, 4272; (c) Raj, R.; Mehra, V.; Singh, P.; Kumar, V.; Bhargava, G.; Ma-
hajan, M. P.; Handa, S.; Slaughter, L. M. Eur. J. Org. Chem. 2011, 14, 2697; (d)
Singh, P.; Mehra, V.; Anand, A.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett. 2011,
52, 5060.
22. Wang, D.; Zhang, B.; He, C.; Wu, P.; Duan, C. Chem. Commun. 2010, 4728.
23. Chai, C. L. L.; Hockless, D. C. R.; Weerasauria, K. D. V. Polyhedron 1997, 16, 1577.
24. Li, B.; Xiang, D.; Hsu, C. T.; Liu, Z. L.; Wu, C.; Yang, H. Z. Molecules 2005, 10, 1119.
25. (a) Balalaie, S.; Arabanian, A. Green Chem. 2002, 2, 274; (b) Heravi, M. M.; De-
rikvand, F.; Bamoharram, F. F. J. Mol. Catal., A: Chem. 2007, 263, 112; (c) Sadeghi,
B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron Lett. 2008, 49, 2575; (d) Karimi,
33. Lin, W.; Zhang, X.; He, Z.; Jin, Y.; Gong, L.; Mi, A. Synth. Commun. 2002, 32, 3279.