Design, synthesis and conformational analysis of turn inducer cyclopropane scaffolds: microwave assisted amidation of unactivated esters on catalytic solid support to obtain γ-turn mimic scaffolds

Article abstract of DOI:10.1016/j.tet.2008.10.058

Novel constrained 1-aroyl-cyclopropane-2,3-cis-dicarboxylic acid bis-[(2-hydroxy-ethyl)-amides] (17a-e) with varied torsional angles have been synthesized in high yield from unactivated esters of 1-aroyl-2,3-cis-diethoxycarbonylcyclopropanes (15a-e) on a catalytic solid support with reduced reaction times by using the monomode-microwave irradiation; 15a-e were obtained by diastereoselective ethoxycarbonylmethylene transfer from a sulfur ylide to ethyl β-aroylacrylates (10a-e). Torsional angles and interatomic distance measurements on the energy minimized structures of the obtained molecules (17a-e, DFT, B3LYP/6-31G^* level) have established these molecules as valuable γ-turn mimic scaffolds.

Full text of DOI:10.1016/j.tet.2008.10.058

Tetrahedron 65 (2009) 240–246
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Design, synthesis and conformational analysis of turn inducer cyclopropane
scaffolds: microwave assisted amidation of unactivated esters on catalytic
solid support to obtain g-turn mimic scaffolds
,
Surinderjit Singh Bhella a, Munusamy Elango b, Mohan Paul S. Ishar a
*
a Bio-organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
b Chemical Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 August 2008
Received in revised form 18 October 2008
Accepted 21 October 2008
Available online 25 October 2008
Novel constrained 1-aroyl-cyclopropane-2,3-cis-dicarboxylic acid bis-[(2-hydroxy-ethyl)-amides] (17a–e)
with varied torsional angles have been synthesized in high yield from unactivated esters of 1-aroyl-2,3-
cis-diethoxycarbonylcyclopropanes (15a–e) on a catalytic solid support with reduced reaction times by
using the monomode-microwave irradiation; 15a–e were obtained by diastereoselective ethoxy-
carbonylmethylene transfer from a sulfur ylide to ethyl
and interatomic distance measurements on the energy minimized structures of the obtained molecules
(17a–e, DFT, B3LYP/6-31G level) have established these molecules as valuable -turn mimic scaffolds.
Ó 2008 Elsevier Ltd. All rights reserved.
b-aroylacrylates (10a–e). Torsional angles
Keywords:
*
g
b-Aroylacrylates
Sulfur ylide
Cyclopropane
Amidation
Microwave irradiation
Constrained scaffolds
DFT analysis
g-Turn mimics
1. Introduction
H
R2
H
R2
H
H
O
H
R2
O
O
O
O
H
N
O
O
H
H
N
H
N
H
N
H
N
Cyclopropane derivatives are interesting structural scaffolds,
which have attracted considerable attention as rigid replacement
for a dipeptide array and have been employed as dipeptide mimic
to obtain biologically active oligopeptides.1 Martin et al.2 based on
molecular modeling studies suggested that substituted cyclopro-
panes serve as novel, rigid replacements of peptide (1). The cis-
relationship of substituents on cyclopropane (2) is envisioned to
induce a turn and the alternative trans-arrangement of the back-
bone substituents on cyclopropane (3) is shown to locally stabilize
O
N
H
O
R3
R1
R1
R3
R1
R3
HN
3
1
2
Ph
Ph
Ph
O
O
N
O
H
H
O
N
H
O
N
H
H
O
HN
H
HN
H
N
O
N
H
NH
OH
H
NH
O
NH
OMe
a
b-strand conformation. Structural and computational inves-
A γ-turn characterisitc of
Cyclic Enkephalin alogue
tigations have revealed that a turn motif is a structural element in
the biologically active conformation of enkephalins (4) for opioid
receptors,3 and the analogues of enkephalins, such as 5, have been
enekephalin analogues
4
containing a γ-turn mimic
5
6
synthesized having g
-turn motif as a structural element.4 Conse-
Recently, the microwave assisted amide bond formation has
attracted considerable attention. In several cases, the microwave
irradiation has been a successful alternative to the conventional
high temperatures for direct condensation of amines to carboxylic
acids without prior activation.6 The microwave irradiation may be
run with or without a catalyst.7 Different kinds of catalysts such as
K-10 montmorillonite, imidazole, zeolite-HY, polyphosphoric acid,
p-toluenesulfonic acids, TaCl5–silica gel, KF–alumina and silica gel
quently, cis-substituted cyclopropanes have been synthesized and
utilized to develop enkephalin analogue (6).5
* Corresponding author. Tel.: þ91 183 2258802x3321; fax: þ91 183 2258820.
E-mail address: mpsishar@yahoo.com (M.P.S. Ishar).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.058

S.S. Bhella et al. / Tetrahedron 65 (2009) 240–246
241
O
O
O
O
2
O
O
D.C.M.
CH3
C2H5OH
SeO
PH P CH C OC2H5
H +
+
1
2
3
Stirring at
Room
H2O
OC2H5
R
R
R
(90-93%)
9
7
(78-83%)
Temp.
10
8
Et3N
O
O
(H3C)2S
Br
O
Dry THF
Et3N
Br-CH-CO Et
C
(H3C)2S
(CH3)2
S
+
CO2Et
2
CO2Et
+
C
H
H2
0 °c
Dry THF
11
12
13
0 °c to room
temp.
14
O
O
H
1
2
O
O
N
CH2
H2C
H
H
2
3
H
1
H
H2
C
Catalytic
R
OC2H5
O
OH
NH2
Solid Support
H
O
3
+
HO
C
H
(a) R = H
HN
H2
Microwave
irradiation
R
CH2
H2C
(b) R = CH3
C2H5O
16
(c) R = OCH3
(d) R = Br
OH
17
(89-91%)
15
(e) R = NO2
Scheme 1.
have been employed.8 The transformation of the aromatic esters to
the amide by reacting with amines under microwave irradiation
has also been reported over the neutral alumina.8h
Herein, we report the design, synthesis and DFT analysis of the
turn inducercyclopropane scaffolds, i.e.,1-aroyl-2,3-cis-dicarboxylic
acid bis-[(2-hydroxy-ethyl)-amide], as useful precursors to en-
kephalin mimicking ligands for opioid receptor. The amides were
derived from the 1-aroyl-2,3-cis-diethoxycarbonylcyclopropanes by
amidation of the ethoxycarbonyl functions employing focused
monomode-microwave irradiation of reactants on solid support.
attended with high yields as compared to the reported 1,2,3-tri-
substituted cyclopropane syntheses.10
Structures of compounds 15a–e were established by detailed
spectroscopic analysis. For instance, 15a in its 1H NMR spectrum
revealed a 1H triplet at
d
d
3.75 (J¼5.6 Hz, C1–H) and a 2H doublet at
2.71 (J¼5.6 Hz, C2–H and C3–H). In the 13C NMR spectrum of 15a
the resonances of the C2,3 appeared at
d 30.0 and of C1 at d 28.9.
The obtained 1H and 13C NMR spectral data clearly indicated
a cis-arrangement at C2 and C3 between ester functions and the
observed coupling constant value of C2–H/C3–H with C1–H was
characteristic of a trans-arrangement.11 The structures of com-
pounds 15a–e were also corroborated by the IR and mass (ESI)
spectroscopic data.
2. Result and discussion
Mechanistically, the diastereoselective formation of 1-aroyl-2,3-
cis-diethoxycarbonylcyclopropanes (15a–e) can be rationalized in
terms of attack of sulfur ylide on the aroyl-substituted carbon of
acrylates leading to intermediate A, wherein the ester of the ylide
and aroyl moiety is placed trans to each other, and there is complete
retention of the configurations of the acrylates giving rise to the
most stable trans product with respect to the benzoyl moiety and
cis product with respect to the ethoxycarbonyl moiety of the ac-
rylate (10, Scheme 2). The retention of the configuration in case of
similar additions to acrylates during the formation of cyclopro-
panes is precedented.11
The conversion of ester functionalities of 1-aroyl-2,3-diethoxy-
carbonylcyclopropanes (15a–e) into amides (17a–e) with the pri-
mary amine (16) was investigated under microwave irradiation
using a focused monomode-microwave reactor (CEM-Discover).
Different types of solid supports viz. silica gel G, neutral alumina
and montmorillonite KSF were used to convert esters (15a–e)
into amides (17a–e); the results are summarized in Scheme 1 and
Table 1.
The p-substituted acetophenones (7a–e) were converted to
p-substituted phenylglyoxals (8a–e) by oxidation with SeO2 in
ethanol–water mixture (Scheme 1).9a Conversions of the p-
substituted phenylglyoxals (8a–e) into the ethyl b-aroylacrylates
(10a–e) was achieved by their Wittig reaction with ethoxy-
carbonylmethyledine-triphenylphosphorane (9) in dry dichloro-
methane at room temperature (Scheme 1). After column
chromatographic purification, the ethyl
b-aroylacrylates (10a–e)
were isolated in high yields and characterized spectroscopically.
Diastereoselective ethoxycarbonylmethylene transfer from
a sulfur ylide (14) to ethyl
b
-aroylacrylates (10a–e)9b afforded
3-aroyl-2,3-cis-diethoxycarbonylcyclopropanes (15a–e); the sulfur
ylide (14) was generated in situ from dimethyl-ethoxy-
carbonlymethyl-oxosulfonium bromide (13)9 in the presence of
triethylamine under nitrogen environment, in dry tetrahydrofuran
(Scheme 1). The cyclopropanes (15a–e) were obtained in high
yields (89–90%) after column chromatographic purification. The
present approach involving sulfur ylides is less cumbersome and is
O
O
H
O
H
R
O
OCH2CH3
_
R
OEt
R
OCH2CH3
H
H
S
O
H
CO2Et
H
10
O
O
H3C
H3C
EtO
15
O
CO2Et
H3C
S
O
A
H3C
14
Scheme 2.

242
S.S. Bhella et al. / Tetrahedron 65 (2009) 240–246
Table 1
Yieldsa of amides (17a–e) with different solid supports under monomode-micro-
wave irradiation
Entry
Silica gel Gb
Neutral aluminac
Montmorillonite KSFc
(tR¼8 min)
(tR¼5 min)
(tR¼3 min)
17a
17b
17c
17d
17e
32% (114 mg)
35% (124 mg)
30% (105 mg)
35% (121 mg)
32% (113 mg)
75% (267 mg)
75% (266 mg)
73% (257 mg)
75% (259 mg)
75% (265 mg)
96% (342 mg)
97% (344 mg)
95% (334 mg)
96% (332 mg)
96% (340 mg)
tR¼reaction time.
a
Yield refers to isolated pure product.
Power 250 W, temp 198 ꢂC.
Power 150 W, temp 121 ꢂC.
b
c
In the case of the montmorillonite KSF, almost optimal conver-
sion of ester to the amide bond was observed. This conversion of
the ester to the amide bond under focused monomode-microwave
irradiation required very short reaction time and is also cost ef-
fective as compared to the reported conventional method involving
use of metal alkoxides in conjunction with the additives such as
1-hydroxy-7-azabenzotriazole (HOAT).12
Figure 1. Optimized geometrical structures of 17a–e calculated at the B3LYP/6-31G*
The products 17a–e were characterized by rigorous spectro-
scopic analysis. The conversion of the ester functionalities of 15a–e
to the amide bonds (17a–e) was clearly reflected in the IR spectral
data. For instance, in the case of 17d, a sharp band appeared at
1649 cmꢀ1 in the IR spectrum due to the amide carbonyl groups
and erstwhile ester carbonyl band observed in the IR spectrum of
15d disappeared; another sharp band appeared at 1670 cmꢀ1 due
to the carbonyl group of aroyl moiety. The N–H and O–H stretchings
appeared in the range 3423–3314 cmꢀ1 as multiple bands. In the 1H
NMR spectrum of 17d the resonance for the two NHs was observed
level.
2.1. The density functional theory (DFT) analysis
Since, the cyclopropane ring in 17a–e exhibits a certain ‘un-
saturated character’, which results in restriction of the torsion an-
gles about the Ca–C]O bond to small values, due to conjugation of
the carbonyl group with the ring, resulting in marked restriction of
the conformational space to torsional angles between 0ꢂ and ꢃ90ꢂ,
thereby, leading to observed turn conformation.13 For conforma-
tional studies, various dihedral angles for 17a–e were measured by
DFT analysis (Table 2). All the data were taken from the completely
as a broad signal at
appeared at 2.59 (both were suppressed on deuterium exchange).
A multiplet (4H) of two OH linked methylenes (2ꢁCH2) appeared at
3.70–3.56 and protons of two NH linked methylenes (2ꢁCH2–NH)
d 7.86, and the broad resonance of the two OHs
d
optimized structure of the respective molecules at B3LYP/6-31G
level of calculation (Fig. 1).
*
d
appeared as two multiplets (2H each) at
d 3.48–3.31 and d 3.30–
In the case of 17a, the dihedral angle involving C(25)–C(22)–
C(23)–C(26) is ꢀ8.4ꢂ, which is in the synperiplanar range corre-
sponding to the cis-arrangement of amide chains attached at the C2
and C3 carbons of the cyclopropane ring and hence the turn motif,
whereas the dihedral angles between C(25)–C(22)–C(24)–C(2) and
C(26)–C(23)–C(24)–C(2) were 136.5ꢂ and –130.9ꢂ, respectively,
corresponding to the anti or trans conformation (Fig. 2).14 The
reported theoretical and computational calculations14b on the
minimum energy conformations on polypeptides have revealed
that H-bonding (hydrogen bonding) exists between the N–H/
O]C of the backbone peptide bonds if the distance between N–H/
O]C is 1.8–2.9 Å. These H-bonding patterns are responsible for
stabilizing the turn conformations in the peptide chains.14b For
17a–e, the N–H/O]C distance of the two adjacent amide function
is 1.919, 1.893, 1.901, 1.910 and 1.920 Å, respectively, as calculated
from completely optimized structure of the respective molecules at
B3LYP/6-31G* level (Fig. 1 and Table 2); this range of distances is
characteristic for the H-bonding between the C]O/H–N of (i) and
(iþ2) residues of the two adjacent amide chains attached at the C2
and C3 carbons of the cyclopropane ring in 17a–e to form the
3.22. These changes in the 1H NMR spectrum, i.e., appearance of
new resonance and disappearance of the resonances of the erst-
while ethyl moiety of 15d clearly established the structure of amide
17d. The protons of the cyclopropane moiety in 17d appeared as
a triplet at
d
3.79 (J¼5.4 Hz, C1–H) and as a doublet (2H) at
d 2.67
(J¼5.4 Hz, C2–H and C3–H). In the 13C NMR spectrum of 17d the
resonance of ketone carbonyl carbon showed up at
d
195.4 and the
32.1
28.0. The obtained 1H and 13C NMR spectral features of
amide carbonyls appeared at
and C1 at
d 167.7. The C2,3 were located at d
d
the cyclopropane moiety again indicated the retention of cis-ar-
rangement of the amide chains. The formation of 17a–e was also
corroborated by the mass spectroscopy; the mass (ESI) spectrum of
17d revealed the (MþNa)þ peak at 421.0. Attempts to develop the
crystal for X-ray crystallographic structure determination have not
succeeded as yet.
Table 2
Important dihedral angles, hydrogen bond angles and hydrogen bond lengths
calculated at B3LYP/6-31G* level for compounds 17a–e
seven-membered ring or a
angle distribution qualifies these compounds (17a–e) as peptide
mimics, which requires the restriction of the angles (phi), (psi)
and (omega), which determine the 3D structure of the peptide
g-turn (Fig. 3). The obtained restricted
Atoms
17a
17b
17c
17d
17e
4
j
C(25)–C(22)–C(23)–C(26)
(dihedral angles)
C(25)–C(22)–C(24)–C(2)
(dihedral angles)
C(26)–C(23)–C(24)–C(2)
(dihedral angles)
C]O/H–N
ꢀ8.4ꢂ
ꢀ8.0ꢂ
ꢀ8.2ꢂ
ꢀ8.6ꢂ
ꢀ9.2ꢂ
u
backbone,15 as well as the
c (chi) torsional angles that define the
ꢀ136.5ꢂ
130.9ꢂ
134.5ꢂ
130.4ꢂ
151.2ꢂ
1.893 Å
135.6ꢂ
130.6ꢂ
150.9ꢂ
1.901 Å
136.0ꢂ
130.3ꢂ
149.6ꢂ
1.910 Å
137.5ꢂ
129.7ꢂ
148.8ꢂ
1.920 Å
position of the side chain functional groups.15d
149.2ꢂ
3. Conclusions
(H-bond angles)
N–H/O]C
1.919 Å
The direct transformation of diastereoselectively synthesized
unactivated ester functionalities of 15a–e into amides (17a–e) over
(H-bonding lengths)

S.S. Bhella et al. / Tetrahedron 65 (2009) 240–246
243
pellets. Mass spectra, ESI method, were recorded on Bruker Dal-
tonics Esquire 300 mass spectrometers. The CEM-Discover Focused
Monomode-Microwave apparatus (2450 MHz, 300w) was used for
microwave irradiation. CHN analysis was performed on thermo-
electron CHN analyser EA1112 at Department of Chemistry, Guru
Nanak Dev University, Amritsar. All melting points are uncorrected
and measured in open glass capillaries on a Veego MP-D digital
melting point apparatus. The molecules have been optimized at the
B3LYP/6-31G level. All of them were found to be minimum on the
*
potential energy surface with zero imaginary frequency.
4.2. General procedure for the synthesis of p-substituted
phenylglyoxals (8a–e) from p-substituted acetophenones
(7a–e)
In 500 ml round bottom flask were added SeO2 (18 g), ethanol
(100 ml) and water (4 ml), and fitted it with condenser. The mixture
was heated to 50–55 ꢂC and stirred until the solid dissolved. It was
followed by addition of p-substituted acetophenones (7a–e, 1.0 mol
equiv), respectively, and refluxing of the mixture with stirring was
continued. The colour of the solution becomes orange, which in-
stantlychanged toredand then todeep red within half an hour. After
about 2 h the solution becomes clear and little further precipitation
of selenium was observed. The solution was further refluxed for 6 h
and the completion of the reaction was monitored by TLC. The hot
solution was decanted from the precipitated selenium and filtered
through a fluted filter paper. Solvent from filtrate was removed
under vacuum and the residual p-substituted phenylglyoxal (8) was
distilled under reduced pressure and collected the fraction boiling at
95–97 ꢂC. The yields of pure p-substituted phenylglyoxals (8, a yel-
low liquid) were obtained in 78–83% yields.
Figure 2. Diagrammatic representation of 17a showing N–H/O]C distance and
dihedral angles.
montmorillonite KSF under microwave irradiation is potentially
a valuable process for their incorporation into polypeptides. The
present approach involving sulfur ylides is less cumbersome and is
attended with high yields as compared to the reported 1,2,3-tri-
substituted cyclopropane syntheses.10 The DFT analysis of 17a–e
has revealed that the cyclopropane ring with cis-arrangement of
the amide chains attached to the cyclopropane ring induces
a
g
-turn conformation while projecting the amino acid side chains
4.2.1. Phenylglyoxal (8a)
in orientations approximating selected angles, which could serve
as valuable precursors to peptidomimetics of enkephalin ligands
for opioid receptors as well as other polypeptides possessing such
c
Yellow oil; yield 82%; Rf (CHCl3) 0.35; 1H NMR (CDCl3, 200 MHz):
d
9.8 (s, 1H, O]C–H), 8.12 (dd, 2H, J¼8.5 and 1.4 Hz, arom. Hs), 7.59–
7.47 (m, 3H, arom. Hs); 13C NMR (CDCl3, 50 MHz):
d
190.2 (C]O),
g
-turn motifs.16a These cyclopropane scaffolds (17a–e) can be
187.3 (C]O), 136.7 (q), 135.7 (CH), 134.5 (CH), 129.9 (2CH), 129.2
(2CH); Mass (ESI): 157.0 (MþNa)þ.
exploited as photo-switch through the cis–trans photo-isomer-
ization;16b it is anticipated that the trans-arrangement shall lead to
an extended conformation of peptide chains.
4.2.2. p-Tolyl-phenylglyoxal (8b)
Yellow oil; yield 79%; Rf (CHCl3) 0.35; 1H NMR (CDCl3, 200 MHz):
4. Experimental
d
9.8 (s, 1H, O]C–H), 7.96 (d, 2H, J¼7.6 Hz, arom. Hs), 7.17 (d, 2H,
J¼7.4 Hz, arom. Hs), 2.39 (S, 3H, CH3); 13C NMR (CDCl3, 50 MHz):
4.1. General information
d
190.4 (C]O), 186.9 (C]O), 143.6 (C), 133.5 (q), 129.7 (2CH), 129.5
(2CH), 20.9 (CH3); Mass (ESI): 171.1 (MþNa)þ.
Starting materials and reagents were purchased from commer-
cial suppliers and used after further purification (crystallization/
distillation). Bruker AC-200FT (200 MHz) and JEOL AL-300FT
(300 MHz) spectrometers were used to record 1H and 13C (50 and
4.2.3. p-Methoxy-phenylglyoxal (8c)
Yellow oil; yield 83%; Rf (CHCl3) 0.36; 1H NMR (CDCl3, 200 MHz):
d
9.7 (s, 1H, O]C–H), 7.98 (d, 2H, J¼8.5 Hz, arom. Hs), 6.97 (d, 2H,
75 MHz) NMR spectra. Chemical shifts (d) are reported as downfield
J¼8.5 Hz, arom. Hs), 3.78 (s, 3H, OCH3); 13C NMR (CDCl3, 50 MHz):
displacements from TMS that is used as internal standard and
coupling constants (J) are reported in hertz. IR spectra were
recorded with Shimadzu DR-2001 FT-IR spectrophotometer on KBr
d
190.3 (C]O), 187.1 (C]O), 167.8 (C), 130.9 (2CH), 129.2 (q), 114.6
(2CH), 56.0 (CH3); Mass (ESI): 187.0 (MþNa)þ.
4.2.4. p-Bromo-phenylglyoxal (8d)
Yellow oil; yield 78%; Rf (CHCl3) 0.34; 1H NMR (CDCl3, 200 MHz):
Residue 2
(i + 1)
O
d
9.8 (s, 1H, O]C–H), 7.95 (d, 2H, J¼8.7 Hz, arom. Hs), 7.62 (d, 2H,
Residue 3
H
J¼8.6 Hz, arom. Hs); 13C NMR (CDCl3, 50 MHz):
d 190.2 (C]O),187.0
(C]O), 135.7 (q), 132.1 (2CH), 131.9 (2CH), 128.7 (C); Mass (ESI):
(i + 2)
ψ
χ2
R
O
N
H
235.0 (MþNa)þ.
χ3
H
ψ
ω
CH2
H2C
1 H
O
χ
φ
OH
4.2.5. p-Nitro-phenylglyoxal (8e)
ψ
ω
Yellow oil; yield 82%; Rf 0.35 (CHCl3); 1H NMR (CDCl3,
Residue 1
HN
CH2
H2C
(i)
φ
200 MHz):
d
9.6 (s, 1H, O]C–H), 8.38 (d, 2H, J¼8.6 Hz, arom. Hs),
7.99 (d, 2H, J¼8.5 Hz, arom. Hs); 13C NMR (CDCl3, 50 MHz):
d
190.5
OH
(C]O), 187.3 (C]O), 154.2 (C), 142.8 (q), 130.6 (2CH), 124.1 (2CH);
Mass (ESI): 202.0 (MþNa)þ.
Figure 3. Showing
g-turn and different torsional angles in compounds 17a–e.

244
S.S. Bhella et al. / Tetrahedron 65 (2009) 240–246
4.3. General procedure for the synthesis of ethyl
50 MHz): d 193.5 (C]O), 165.0 (C]O), 155.8 (C), 141.6 (q), 135.6
b
-aroylacrylates (10a–e) from p-substituted
(CH), 132.6 (CH), 131.2 (2CH), 124.6 (2CH), 60.3 (CH2), 13.8 (CH3);
Mass (ESI): 272.2 (MþNa)þ. (Found: C, 57.90; H, 4.41; N, 5.57.
C12H11NO5 requires: C, 57.83; H, 4.45; N, 5.62%.)
phenylglyoxals (8a–e)
The solution of ethoxycarbonyl-methyledinetriphenylphosphor-
ane (2 g, 9) in dry dichloromethane (DCM, 10 ml) was taken in the
round bottom flask fitted with guard tube, and a solution of 1 equiv
p-substituted phenylglyoxal (8) in DCM (5 mL) was added to it. The
mixture was stirred for 4 h at room temperature. After the completion
of reaction, which was monitored by TLC, the solvent was removed
under reduced pressure and the contents stirred with hexane, and
filtered. The filtrate was concentrated under vacuum and the obtained
product mixtures were subsequently resolved by column chroma-
tography: column packed in hexane (20 g, 60–120 mesh), eluted with
4.4. General procedure for the synthesis of 1-aroyl-2,3-cis-
diethoxycarbonylcyclopropanes (15a–e) from
b-aroylacrylates (10a–e)
To ice cold solutions of dimethyl-ethoxycarbonlymethyl-oxo-
sulfonium bromide (13, 2.00 g) in a mixture of dry THF (5 ml) and dry
triethylamine (10 ml), stirred in three necked round bottomed flasks
under nitrogen environment for 10 min, were added, drop wise
through a dropping funnel, solution of b-acrylates (10a–e, 0.5 equiv),
hexane only to obtain the ethyl
b
-aroylacrylates (10) in good yields.
in dry THF (2 ml) over a period of 25 min; the contents were stirred for
extended time and allowed to attain ambient temperature. Further
contents were stirred till the completion of reaction (8 h). After the
completion of reaction, monitored by TLC, the contents were parti-
tioned between dichloromethane and water. The aqueous layer was
further extracted with 2ꢁ20 ml of dichloromethane. The combined
dichloromethane extracts were dried over anhydrous sodium sulfate,
suspension was filtered and contents were distilled under reduced
pressure. Subsequently, mixture was resolved by column chroma-
tography, column packed in hexane (20 g, 60–120 mesh), eluted with
hexane/ethylacetate (90:10).
4.3.1. Ethyl
Light yellow oil; yield 4.2 g, 91%; Rf (CHCl3) 0.52; IR (CHCl3):
1723, 1672, 1301, 1270, 1174 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
8.14
b-aroylacrylate (10a)
d
(dd, 2H, J¼8.3 and 1.5 Hz, arom. Hs), 7.91 (d, 1H, J¼15.5 Hz, olefinic
CH), 7.66–7.47 (m, 3H, arom. Hs), 6.88 (d, 1H, J¼15.5 Hz, olefinic
CH), 4.30 (q, 2H, J¼7.1 Hz, CH2), 1.35 (t, 3H, J¼7.1 Hz, CH3); 13C NMR
(CDCl3, 50 MHz): d 193.2 (C]O), 164.8 (C]O), 136.2 (q), 135.7 (CH),
133.3 (CH), 132.5 (CH), 128.9 (2CH), 128.4 (2CH), 60.8 (CH2), 13.7
(CH3); Mass (ESI): 227.4 (MþNa)þ. (Found: C, 70.65; H, 5.96.
C12H12O3 requires: C, 70.57; H, 5.92%.)
4.4.1. 1-Benzoylcyclopropane-2,3-dicarboxylic acid diethyl ester
(15a)
4.3.2. p-Tolyl-ethyl-
Light yellow oil; yield 4.3 g, 90%; Rf (CHCl3) 0.52; IR (CHCl3):
1725, 1673, 1307, 1267, 1172 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
7.92
b-aroylacrylate (10b)
White crystalline solid (hexane/chloroform, 2:1), mp 43–45 ꢂC;
d
yield (2.4 g, 90%); Rf (CHCl3) 0.39; IR (CHCl3): 1735,1670,1207 cmꢀ1
;
(d, 2H, J¼7.8 Hz, arom. Hs), 7.86 (d, 1H, J¼15.5 Hz, olefinic CH), 7.28
(d, 2H, J¼7.2 Hz, arom. Hs), 6.86 (d, 1H, J¼15.5 Hz, olefinic CH), 4.29
(q, 2H, J¼7.0 Hz, CH2), 2.41 (s, 3H, CH3), 1.34 (t, 3H, J¼7.1 Hz, CH3);
1H NMR (CDCl3, 200 MHz):
d
8.19 (dd, 2H, J¼8.5 and 1.6 Hz, arom.
Hs), 7.63–7.49 (m, 3H, arom. Hs), 4.21 (q, 4H, J¼7.1 Hz, 2CH2), 3.75 (t,
1H, J¼5.6 Hz, C1 H), 2.71 (d, 2H, J¼5.6 Hz, C2,3 Hs), 1.31 (t, 6H,
13C NMR (CDCl3, 50 MHz):
d
193.4 (C]O), 164.6 (C]O), 143.6 (C),
J¼7.1 Hz, 2CH3); 13C NMR (CDCl3, 50 MHz):
d 194.5 (C]O), 167.7
135.8 (CH), 134.1 (q), 132.6 (CH), 129.0 (2CH), 128.5 (2CH), 61.1
(CH2), 20.9 (CH3), 13.8 (CH3); Mass (ESI): 241.1 (MþNa)þ. (Found: C,
71.59; H, 6.41. C13H14O3 requires: C, 71.54; H, 6.47%.)
(2C]O), 136.4 (q), 133.6 (CH), 128.6 (2CH), 128.5 (2CH), 61.3 (CH2),
30.0 (2C), 28.9 (C), 14.1 (2CH3); Mass (ESI): 313.6 (MþNa)þ. (Found:
C, 66.24; H, 6.28. C16H18O5 requires: C, 66.19; H, 6.25%.)
4.3.3. p-Methoxy-ethyl-
Light yellow oil; yield 4.6 g, 93%; Rf (CHCl3) 0.50; IR (CHCl3):
1723,1670,1303,1271,1174 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
8.12
b
-aroylacrylate (10c)
4.4.2. 1-(4-Methyl-benzoyl)-cyclopropane-2,3-dicarboxylic acid
diethyl ester (15b)
d
White oil; yield (2.3 g, 90%); Rf (CHCl3) 0.36; IR (CHCl3): 1728,
(d, 2H, J¼8.8 Hz, arom. Hs), 7.96 (d, 1H, J¼15.3 Hz, olefinic CH), 6.94
(d, 2H, J¼8.8 Hz, arom. Hs), 6.83 (d, 1H, J¼15.4 Hz, olefinic CH), 4.27
(q, 2H, J¼7.1 Hz, CH2), 3.87 (s, 3H, OCH3), 1.35 (t, 3H, J¼7.1 Hz, CH3);
1672, 1217, 1180 cmꢀ1 1H NMR (CDCl3, 200 MHz):
; d 7.99 (d, 2H,
J¼8.2 Hz, arom. Hs), 7.31 (d, 2H, J¼7.8 Hz, arom. Hs), 4.20 (q, 4H,
J¼7.2 Hz, 2CH2), 3.75 (t, 1H, J¼5.6 Hz, C1 H), 2.71 (d, 2H, J¼5.6 Hz,
C2,3 Hs), 2.44 (S, 3H, CH3), 1.29 (t, 6H, J¼7.1 Hz, 2CH3); 13C NMR
13C NMR (CDCl3, 50 MHz):
d 193.3 (C]O), 168.4 (C), 164.2 (C]O),
135.8 (CH),132.6 (CH),131.2 (2CH),129.0 (q),114.3 (2CH), 60.7 (CH2),
56.1 (CH3),13.8 (CH3); Mass (ESI): 257.3 (MþNa)þ. (Found: C, 66.70;
H, 6.07. C13H14O4 requires: C, 66.66; H, 6.02%.)
(CDCl3, 50 MHz): d 194.2 (C]O), 167.9 (2C]O), 144.6 (C), 133.8 (q),
129.2 (2CH), 128.6 (2CH), 61.1 (2CH2), 29.8 (2C), 28.7 (C), 21.4 (CH3),
13.9 (2CH3); Mass (ESI): 327.0 (MþNa)þ. (Found: C, 67.12; H, 6.67.
C17H20O5 requires: C, 67.09; H, 6.62%.)
4.3.4. p-Bromo-ethyl-
Light yellow oil; yield 5.1 g, 91%; Rf (CHCl3) 0.49; IR (CHCl3):
1731, 1674, 1301, 1269, 1172 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
8.00
b-aroylacrylate (10d)
4.4.3. 1-(4-Methoxybenzoyl)cyclopropane-2,3-dicarboxylic acid
diethyl ester (15c)
d
(d, 2H, J¼8.8 Hz, arom. Hs), 7.93 (d, 1H, J¼15.3 Hz, olefinic CH), 7.64
(d, 2H, J¼8.4 Hz, arom. Hs), 6.87 (d, 1H, J¼15.3 Hz, olefinic CH), 4.30
(q, 2H, J¼7.1 Hz, CH2), 1.35 (t, 3H, J¼7.1 Hz, CH3); 13C NMR (CDCl3,
White oil; yield 2.2 g, 91%; Rf (CHCl3) 0.37; IR (CHCl3): 1732,
1671, 1205, 1176 cmꢀ1 1H NMR (CDCl3, 200 MHz):
; d 8.04 (d, 2H,
J¼8.8 Hz, arom. Hs), 6.94 (d, 2H, J¼8.8 Hz, arom. Hs), 4.16 (q, 4H,
J¼7.1 Hz, 2CH2), 3.87 (s, 3H, OCH3), 3.65 (t, 1H, J¼5.6 Hz, C1 H), 2.64
(d, 2H, J¼5.6 Hz, C2,3 Hs), 1.27 (t, 6H, J¼7.1 Hz, 2CH3); 13C NMR
50 MHz):
d 193.3 (C]O), 164.8 (C]O), 136.1 (q), 135.6 (CH), 132.6
(CH), 132.3 (2CH), 131.7 (2CH), 128.9 (C), 59.8 (CH2), 13.7 (CH3);
Mass (ESI): 306.8 (MþNa)þ. (Found: C, 50.95; H, 3.88. C12H11BrO3
requires C, 50.91; H, 3.92%.)
(CDCl3, 50 MHz):
d 193.2 (C]O), 168.2 (C), 164.1 (2C]O), 130.9
(2CH), 129.4 (q), 113.9 (2CH), 61.4 (CH2), 55.5 (CH3), 29.8 (2C), 28.8
(C), 14.1 (2CH3); Mass (ESI): 343.3 (MþNa)þ. (Found: C, 63.78; H,
6.32. C17H20O6 requires: C, 63.74; H, 6.29%.)
4.3.5. p-Nitro-ethyl-
Light yellow oil; yield 4.8 g, 92%; Rf (CHCl3) 0.50; IR (CHCl3):
1730, 1674, 1302, 1271, 1174 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
8.13
b-aroylacrylate (10e)
d
4.4.4. 1-(4-Bromo-benzoyl)-cyclopropane-2,3-dicarboxylic acid
diethyl ester (15d)
(d, 2H, J¼8.6 Hz, arom. Hs), 7.95 (d, 1H, J¼15.5 Hz, olefinic CH), 7.74
(d, 2H, J¼8.5 Hz, arom. Hs), 6.85 (d, 1H, J¼15.5 Hz, olefinic CH), 4.29
(q, 2H, J¼7.1 Hz, CH2), 1.35 (t, 3H, J¼7.1 Hz, CH3); 13C NMR (CDCl3,
White oil; yield 2.0 g, 90%; Rf (CHCl3) 0.37; IR (KBr): 1731, 1681,
1205,1178 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
d
8.07 (d, 2H, J¼8.6 Hz,

S.S. Bhella et al. / Tetrahedron 65 (2009) 240–246
245
arom. Hs), 7.03 (d, 2H, J¼8.7 Hz, arom. Hs), 4.18 (q, 4H, J¼7.2 Hz,
4.5.2. 1-(4-Methyl-benzoyl)-cyclopropane-2,3-dicarboxylic
acid bis-[(2-hydroxy-ethyl)-amide] (17b)
2CH2), 3.75 (t, 1H, J¼5.6 Hz, C1 H), 2.71 (d, 2H, J¼5.6 Hz, C2,3 Hs),
1.30 (t, 6H, J¼7.1 Hz, 2CH3); 13C NMR (CDCl3, 50 MHz):
d
194.0
White solid (hexane/chloroform/methanol, 4:2:1), mp 89–
(C]O), 167.8 (2C]O), 135.0 (q), 132.0 (2CH), 129.9 (2CH), 129.1 (C),
61.6 (2CH2), 30.1 (2C), 28.9 (C), 14.0 (2CH3); Mass (ESI): 391.4
(MþNa)þ. (Found: C, 52.07; H, 4.60. C16H17BrO5 requires: C, 52.05;
H, 4.64%.)
93 ꢂC; Rf (CH3OH) 0.16; IR (KBr): 3419, 3353, 1672, 1660, 1556,
1307, 1184 cmꢀ1 1H NMR (DMSO-d6, 300 MHz):
; d 8.11 (d, 2H,
J¼7.5 Hz, arom. Hs), 7.96 (br s, 2H, NHs), 7.61 (d, 2H, J¼7.2 Hz,
arom. Hs), 3.85 (t, 1H, J¼5.4 Hz, C1 H), 3.65–3.56 (m, 4H, 2CH2–
OH), 3.41–3.38 (m, 2H, CH2–NH), 3.36–3.30 (m, 2H, CH2–NH), 2.66
4.4.5. 1-(4-Nitro-benzoyl)-cyclopropane-2,3-dicarboxylic acid
diethyl ester (15e)
(d, 2H, J¼5.4 Hz, C2,3 Hs), 2.60 (br s, 2H, OHs), 1.97 (s, 3H, CH3); 13
C
NMR (DMSO, 75 MHz):
d 195.9 (C]O), 167.8 (2C]O), 136.1 (C),
White oil; yield 2.2 g, 89%; Rf (CHCl3) 0.35; IR (KBr): 1732, 1668,
133.0 (q), 128.1 (2CH), 128.0 (2CH), 60.1 (2CH2), 42.0 (2CH2), 31.9
(2C), 29.0 (C), 28.0 (CH3); Mass (ESI): 357.0 (MþNa)þ. (Found: C,
61.11; H, 6.60; N, 8.36. C17H22N2O5 requires: C, 61.07; H, 6.63; N,
8.38%.)
1234,1188 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
d
8.05 (d, 2H, J¼8.2 Hz,
arom. Hs), 7.22 (d, 2H, J¼8.5 Hz, arom. Hs), 4.20 (q, 4H, J¼7.1 Hz,
2CH2), 3.75 (t, 1H, J¼5.6 Hz, C1 H), 2.71 (d, 2H, J¼5.6 Hz, C2,3 Hs),
1.29 (t, 6H, J¼7.1 Hz, 2CH3); 13C NMR (CDCl3, 50 MHz):
d 194.3
(C]O), 165.7 (2C]O), 152.8 (C), 136.5 (q), 133.5 (2CH), 129.7 (2CH),
61.0 (2CH2), 29.9 (2C), 28.7 (C), 14.1 (2CH3); Mass (ESI): 358.3
(MþNa)þ. (Found: C, 57.35; H, 5.08; N, 4.21. C16H17NO7 requires: C,
57.31; H, 5.11; N, 4.18%.)
4.5.3. 1-(4-Methoxybenzoyl)-cyclopropane-2,3-dicarboxylic acid
bis-[(2-hydroxy-ethyl)-amide] (17c)
White solid (hexane/chloroform/methanol, 4:2:1), mp 154–
157 ꢂC; Rf (CH3OH) 0.16; IR (KBr): 3431, 3359, 1664, 1650, 1556,
1255, 1186 cmꢀ1 1H NMR (DMSO-d6, 300 MHz):
; d 8.00 (d, 2H,
4.5. General procedure for the synthesis of amide adducts
(17a–e) from 1-aroyl-2,3-cis-diethoxycarbonylcyclopropanes
(15a–e) under monomode-microwave irradiation
J¼8.1 Hz, arom. Hs), 7.92 (br s, 2H, NHs), 7.29 (d, 2H, J¼7.8 Hz,
arom. Hs), 3.88 (s, 3H, OCH3) 3.81 (t, 1H, J¼5.4 Hz, C1 H), 3.74–3.57
(m, 4H, 2CH2–OH), 3.46–3.38 (m, 2H, CH2–NH), 3.29–3.18 (m, 2H,
CH2–NH), 2.79 (br s, 2H, OHs), 2.64 (d, 2H, J¼5.5 Hz, C2,3 Hs); 13C
In a 250 ml round bottom flask, the trisubstituted cyclopropane
adducts (300 mg, 15a–e) and ethanolamine (16, 2.5 mol equiv)
were dissolved in dichloromethane. To this solution different cat-
alyst (1.00 g, silica gel G/neutral alumina/montmorillonite KSF) was
added and the solvent was removed under vacuum to absorb the
contents on the catalyst. The obtained powder was exposed to the
microwave irradiation using the focused monomode-microwave
(CEM-Discover) reactor. The round bottom flask containing powder
of contents fitted with condenser was placed in the cavity of the
microwave reactor. The mouth of the cavity was covered with the
cavity lid. Then it was exposed to the microwave irradiation. In
the case of catalyst silica gel, microwave irradiation was done for 3–
8 min (1–3 min for running time and 2–5 min for holding time) by
using 150–180 W power at 123–165 ꢂC. For the catalyst neutral
alumina, the microwave irradiation was done for 5 min (2 min for
running time and 3 min for holding time) by using 150 W power at
123 ꢂC. In the case of montmorillonite KSF, the microwave irradi-
ation was done for 3 min (1 min for running time and 2 min for
holding time) by using 150 W power at 121 ꢂC. In each case, the
adsorbed material was then extracted with 3ꢁ30 ml methanol and
dried over anhydrous sodium sulfate (Na2SO4). The solvent was
then distilled off under reduced pressure. The products were iso-
lated by flash column chromatographic separation, column packed
in chloroform (230–400 mesh, 10 g), eluted with Chloroform/
methanol (60:40). The products were obtained in 30–35% and 73–
75% yield, in the case of the catalyst silica gel G and neutral alumina,
respectively, and in excellent yields (91–94%) for the catalyst
montmorillonite KSF.
NMR (DMSO, 75 MHz): d 195.3 (C]O), 167.8 (2C]O), 143.8 (C),
133.6 (q), 128.7 (2CH), 128.1 (2CH), 60.1 (2CH2), 42.0 (2CH2), 31.8
(2C), 27.8 (C), 21.0 (CH3); Mass (ESI): 373.1 (MþNa)þ. (Found: C,
58.33; H, 6.36; N, 8.19. C17H22N2O6 requires: C, 58.28; H, 6.33; N,
8.23%.)
4.5.4. 1-(4-Bromo-benzoyl)-cyclopropane-2,3-dicarboxylic acid
bis-[(2-hydroxy-ethyl)-amide] (17d)
White solid (hexane/chloroform/methanol, 4:2:1), mp 154–
157 ꢂC; Rf (CH3OH) 0.16; IR (KBr): 3423, 3314, 1670, 1649, 1557,
1232, 1181 cmꢀ1 1H NMR (DMSO-d6, 300 MHz):
; d 8.00 (d, 2H,
J¼8.7 Hz, arom. Hs), 7.86 (br s, 2H, NHs), 7.64 (d, 2H, J¼8.4 Hz,
arom. Hs), 3.79 (t, 1H, J¼5.4 Hz, C1 H), 3.70–3.56 (m, 4H,
2CH2–OH), 3.48–3.31 (m, 2H, CH2–NH), 3.30–3.22 (m, 2H, CH2–
NH), 2.67 (d, 2H, J¼5.4 Hz, C2,3 Hs), 2.59 (br s, 2H, OHs); 13C
NMR (DMSO, 75 MHz):
d 195.4 (C]O), 167.7 (2C]O), 135.0 (q),
131.4 (2CH), 129.7 (2CH), 129.1 (C), 60.2 (2CH2), 42.1 (2CH2),
32.1 (2C), 28.0 (C); Mass (ESI): 421.0 (MþNa)þ. (Found: C,
48.10; H, 4.85; N, 7.06. C16H19BrN2O5 requires: C 48.13, H 4.80,
N 7.02%.)
4.5.5. 1-(4-Nitro-benzoyl)-cyclopropane-2,3-dicarboxylic acid
bis-[(2-hydroxy-ethyl)-amide] (17e)
White solid (hexane/chloroform/methanol, 4:2:1), mp 152–
154 ꢂC; Rf (CH3OH) 0.16; IR (KBr): 3437, 3349, 1668, 1650, 1558,
1255, 1184 cmꢀ1 1H NMR (DMSO-d6, 300 MHz):
; d 8.01 (2H, d,
J¼8.6 Hz, arom. Hs), 7.94 (2H, br s, NHs), 7.63 (2H, d, J¼8.3 Hz, arom.
Hs), 3.81 (1H, t, J¼5.4 Hz, C1 H), 3.73–3.57 (4H, m, 2CH2–OH), 3.48–
3.33 (2H, m, CH2–NH), 3.29–3.21 (2H, m, CH2–NH), 2.65 (2H, d,
J¼5.7 Hz, C2,3 Hs), 2.60 (br s, 2H, OHs); 13C NMR (DMSO, 75 MHz):
4.5.1. 1-Benzoyl-cyclopropane-2,3-dicarboxylic acid
bis-[(2-hydroxy-ethyl)-amide] (17a)
d
195.3 (C]O), 167.8 (2C]O), 151.9 (C), 136.3 (q), 129.5 (2CH), 127.6
White solid (hexane/chloroform/methanol, 4:2:1), mp 81–
83 ꢂC; Rf (CH3OH) 0.16; IR (KBr): 3334, 3309, 1674, 1647, 1558,
(2CH), 60.3 (2CH2), 42.1 (2CH2), 32.0 (2C), 28.1 (C); Mass (ESI): 358.1
(MþNa)þ. (Found: C, 52.54; H, 5.30; N, 11.46. C16H19N3O7 requires:
C, 52.60; H, 5.24; N, 11.50%.)
1215 cmꢀ1
;
1H NMR (DMSO-d6, 300 MHz):
d
8.11 (dd, 2H, J¼8.25
and 1.5 Hz, arom. Hs), 7.78 (br s, 2H, NHs), 7.64–7.38 (m, 3H, arom,
Hs), 3.86 (t, 1H, J¼5.4 Hz, C1 H), 3.72–3.58 (m, 4H, 2CH2–OH), 3.49–
3.41 (m, 2H, CH2–NH), 3.34–3.26 (m, 2H, CH2–NH), 2.68 (d, 2H,
J¼5.4, C2,3 Hs), 2.59 (br s, 2H, OHs); 13C NMR (DMSO, 75 MHz):
Acknowledgements
Use of 300 MHz NMR facilities provided by the Department of
Science and Technology, Government of India, at Department of
Chemistry, Guru Nanak Dev University, Amritsar, and focused
monomode-microwave reactor (CEM-Discover) at IHBT, Palampur,
are gratefully acknowledged.
d
195.8 (C]O), 167.9 (2C]O), 136.0 (q), 133.0 (CH), 128.1 (2CH),
128.0 (CH), 60.2 (2CH2), 42.0 (2CH2), 32.0 (2C), 29.0 (C); Mass (ESI):
343.0 (MþNa)þ. (Found: C, 59.93; H, 6.32; N, 8.79. C16H20N2O5 re-
quires: C, 59.99; H, 6.29; N, 8.74%.)

246
S.S. Bhella et al. / Tetrahedron 65 (2009) 240–246
S.; Dutta, M. P.; Boruah, A.; Prajapati, D.; Sandhu, J. S. Indian J. Chem., Sect. B 1998,
Supplementary data
37, 725; (e) Hajipour, A. R.; Ghasemi, M. Indian J. Chem., Sect. B 2001, 40, 504; (f)
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quez, H.; Plutin, A.; Rodriguez, Y.; Perez, E.; Loupy, A. Synth. Commun. 2000, 30,
1067; (h) Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40, 6177.
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Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; ELBS Longman: Singa-
pore, 1991; p 955; (b) Johnson, A. W.; Amel, R. T. J. Org. Chem. 1969, 34, 1240 and
the references cited therein.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.10.058.
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