Diastereoselective synthesis of polysubstituted cyclopentanols and cyclopentenes containing stereogenic centers via domino Michael/cyclization reaction

Article abstract of DOI:10.1016/j.tet.2015.07.022

A highly efficient domino Michael/cyclization reaction was developed for the synthesis of cyclopentanols and cyclopentenes with four and three stereogenic centers that were generated in one-pot reaction conditions with high diastereoselectivity. The reactions proceeded through a one-pot three-component reaction of β-nitrostyrenes, malononitrile and phenacyl bromide derivatives in basic media at room temperature.

Full text of DOI:10.1016/j.tet.2015.07.022

Accepted Manuscript
Diastereoselective Synthesis of Polysubstituted Cyclopentanols and Cyclopentenes
Containing Stereogenic Centers via Domino Michael/Cyclization Reaction
S. Ahadi, Z. Naghdiani, S. Balalaie, F. Rominger
PII:
S0040-4020(15)01059-5
10.1016/j.tet.2015.07.022
TET 26967
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 April 2015
Revised Date: 21 June 2015
Accepted Date: 6 July 2015
Please cite this article as: Ahadi S, Naghdiani Z, Balalaie S, Rominger F, Diastereoselective Synthesis
of Polysubstituted Cyclopentanols and Cyclopentenes Containing Stereogenic Centers via Domino
Michael/Cyclization Reaction, Tetrahedron (2015), doi: 10.1016/j.tet.2015.07.022.
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ACCEPTED MANUSCRIPT
Diastereoselective Synthesis of Polysubstituted Cyclopentanols and
Cyclopentenes Containing Stereogenic Centers via Domino Michael/Cyclization
Reaction
a
a
*a,b
c
S. Ahadi , Z. Naghdiani , S. Balalaie and F. Rominger
a
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416,
Tehran, Iran, E-mail: balalaie@kntu.ac.ir
b
Medical Biology Research center, Kermanshah University of Medical Sciences, Kermanshah, Iran
c
Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120
Heidelberg, Germany
Abstract
A highly efficient domino Michael/cyclization reaction was developed for the synthesis of
cyclopentanols and cyclopentenes with four and three stereogenic centers that were generated in
one-pot reaction conditions with high diastereoselectivity. The reactions proceeded through a one-
pot three-component reaction of β-nitrostyrenes, malononitrile and phenacyl bromide derivatives in
basic media at room temperature.
Keywords: Domino Micheal/Cyclization, Cyclopentanol, Cyclopentene, diastereoselective, β-
Nitrostyrene
Dedicated to Dr. Mehri Seyed Hashtroudi (my wife) for all of her accompaniment
1

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1. Introduction
The formation of carbon-carbon bonds is one of the important subjects in organic synthesis, and
1
designing novel approaches to access this goal is the aim of organic synthesis researchers. A
domino reaction which includes the constitution of numerous carbon-carbon bonds and stereogenic
centers in one-pot is a very significant and attractive approach due to high bond-forming efficiency
2
3
and access complex molecules. Polysubstituted cyclopentanes are widespread in natural products,
and have demonstrated extended biological activities such as treatment of viral infections including
4
hepatitis and HIV, treatment of autoimmune diseases like multiple sclerosis, rheumatoid arthritis
5
6
and asthma and inhibitor of both influenza A and B. The structures of some bioactive compounds
which contain the cyclopentane moiety are shown in Fig 1.
Figure 1. The structures of some cyclopentane frameworks with biological activity
The synthesis of five-membered rings with multi-stereogenic centers in regio-, diastereo-, and
enantioselective reaction conditions has been an important target for both academic and industrial
researchers. There are several approaches for the synthesis of five-membered rings with multi-
7
stereogenic centers. These approaches can be classified in two categories: a) ring-closing reaction
8
and b) using of cyclopentadiene as starting material.
A domino Henry-Michael-cyclization reaction is a convenient routefor the preparation of five
9
membered ring with multi-stereogenic centers (Scheme 1). Therefore, the development of these
reactions for the synthesis of functionalized cyclopentanes has always been of great interest.
2

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Scheme 1. Sequential Henry Michael reaction to access cyclopentanes
Considering the above background in the context of a Henry-Michael sequence, and in continuation
1
0
of using β-nitrostyrene in designing multicomponent reactions, we envisioned an approach to
access functionalized cyclopentane derivatives through a three-component reaction of phenacyl
bromide 1, malononitrile 2 and β-nitrostyrene 3 based on Michael/cyclization.
Scheme 2. Three-component reaction of phenacyl bromide 1a-b, malononitrile 2 and β-nitrostyrene
3a-h to form cyclopentanol 4a-i
At the beginning, the β-nitrostyrene 3 was prepared through the Henry reaction of nitromethane and
1
1
benzaldehyde derivatives in the presence of sodium hydroxide.
The three-component reaction of 4-bromophenacyl bromide 1a, malononitrile 2, and β-nitrostyrene
a in the presence of sodium hydroxide (1M) was selected as a model reaction for the screening of
3
suitable reaction conditions. The reaction was carried out in ethanol at ambient temperature. The
product 4a was formed as a precipitate and separation was very simple (Scheme 3).
3

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Scheme 3. The model reaction to access cyclopentanol 4a through three-component reaction
The solvent and base played a very important role in creating the desired product. The model
reaction was carried out in various solvents, such as DMF, H O, CH Cl , EtOH and CH CN in the
2
2
2
3
presence of 1M NaOH as base. In water, an oily product was formed and the isolation of product
was not possible and the yield of the desired product was low (25%). Only a trace of the desired
product was observed in DMF and CH Cl . Since the homogenicity of the reaction mixture played
2
2
an important role in the progress of the reaction, in the case of dichloromethane, tetra-
butylammonium bromide was used as phase transfer catalyst (Table 1, entry 2). In CH CN, the
3
yield of product was 50% (Table 1, entry 1). After that the reaction was carried out in ethanol in the
presence of other bases, such as potassium carbonate, cesium carbonate, piperidine, triethylamine,
and diisopropylethylamine DIPEA (Table 1, entry 7) and 1M NaOH. Meanwhile, tetra-
butylammonium hydroxide (TBAH 20% in isopropyl alcohol) was used as the base in the model
reaction at room temperature, although the desired product was formed (Yield= 50%), but the work-
up of the reaction mixture was very difficult (Table 1, entry 8). The model reaction was investigated
at room temperature. Meanwhile, the reaction mixture was heated at 50 °C, 60 °C and also at reflux
conditions. However, heating led to a mixture of products. The best result was obtained with 1 M
NaOH in ethanol giving 87% yield of product with high diastereoselectivity (Table 1, entry 4). The
results are compiled in table 1.
Table 1. Condition screening for the three-component reaction of 4-bromo phenacyl bromide,
malononitrile and β-nitrostyrene as model reaction to form 4a
Entry
solvent
CH CN
CH Cl
Base
Yield (%)
1
2
3
4
5
6
3
NaOH
NaOH
NaOH
NaOH
50
trace
64
2
2
H O
2
EtOH
EtOH
EtOH
87
K
2
CO
52
3
Cs
2
CO
57
3
4

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7
8
9
EtOH
EtOH
EtOH
EtOH
piperidine
NEt
trace
trace
40
3
DIPEA
TBAH
1
0
50
1
In the H NMR spectrum, product 4a showed four doublet peaks at δ 2.82, 3.13, 4.88 and 5.99
1
3
ppm for the geminal CH, CH-Ar and CH-NO respectively. The C NMR data shows that there is a
2
signal in 164.0 ppm which confirms the presence of the carbonyl functional group. As a result, we
proposed that the nitrile group was hydrolyzed to amide group in the alkaline reaction conditions.
Based on these data, the structure of product 4a was confirmed and it was formed through the basic
hydrolysis of the nitrile group. The desired product was formed through domino
Michael/Cyclization. The structure of 4a was clarified using X-ray crystallographic data. The X-ray
crystallographic data could confirm the structure and also diastereoselectivity of reaction (Fig. 2).
Figure 2. ORTEP structure of 4a
The relation between the chemical shifts and also the observed coupling constants is shown in Fig
3.
Figure 3. Structure of compound 4a by displaying the chemical shifts and the coupling constant
5

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Having established the optimum reaction conditions and in order to extend the chemical library,
we investigated the reaction of various β-nitrostyrenes 3a-h, malononitrile 2 and different phenacyl
bromides 1a,b in the optimal reaction conditions. The results are summarized in table 2. It was
observed that most of the reactions are completed within 24 h at room temperature and in all cases,
leading to the formation of the desired cyclopentanols in good yields with high diastereoselectivity.
Table 2. Synthesis of functionalized cyclopentanols 4a-i through three-component reaction of
phenacyl bromides, malononitrile and β-nitrostyrenes
Despite the success of our procedure with phenacyl bromide 1a and 4-bromo phenacyl bromide
1b, we were surprised that the three-component reaction of 4-methoxy phenacyl bromide 1c,
malononitrile 2, and β-nitrostyrenes 3a,e,f,i in the same reaction conditions led to functionalized
cyclopentanes 5a-d instead of cyclopentanols with three stereogenic centers in excellent yields
(table 3). The structure of the products was confirmed using spectroscopic data and also X-ray
6

ACCEPTED MANUSCRIPT
crystallographic data. The ORTEP structure of 5a shows the water elimination and formation of
cyclopentene moiety (Fig 4).
Figure 4. ORTEP structure of 5a
Table 3. Synthesis of functionalized cyclopentene derivatives 5a-d through three-component
reaction
1
1
1
H- H COSY 2D-NMR was used for determination of the structure of the products. The 2D H
NMR spectra of the compounds 4b and 5c are provided in the supporting information.
There are some exchangeable hydrogens in the structure of products 4a-i and also 5a-d.
Investigation of H/D exchange for compound 4h showed that a peak at δ= 8.78 ppm was removed
which is related to the amidic hydrogen.
7

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The X-ray crystallographic data of compounds 4a and 5a shows that there is intermolecular
hydrogen bonding through amidic functional groups as donor and acceptor. The comprehensive
hydrogen bond situation is shown in Fig 4.
After having these results for 4-methoxy phenacyl bromide 1c and formation of cyclopentene
skeleton 5a-d, the mixture of reaction 4-bromo phenacyl bromide 1a, malononitrile 2, and β-
nitrostyrene 3a was heated to access the desired cyclopentene derivatives, but the reaction gave a
mixture of products that was not suitable for purification.
Based on the previous results, we proposed that the reaction could proceed through domino
Michael/cyclization reaction and the following mechanism could be proposed for the observed
diastereoselectivity of the reaction. Besides, β-nitrostryrene is a common starting material used in
different stereoselective reactions due to its structure and in some cases in the presence of chiral
1
2
catalysts.
The possible mechanism of these conversions is shown in Scheme 4. This conversion involves
the initial reaction of phenacyl bromide derivatives with malononitrile as active methylene
compounds to form 6 and after proton abstraction, addition of the desired carbanion 7 to β-
nitrostryrene as Michael acceptor led to 8. The subsequent cyclization of intermediate 8 followed by
the nucleophilic addition to the carbonyl moiety led to two products 9, and 10. In the case of using
phenacyl bromide or 4-bromo-phenacyl bromide product 4 was obtained. On the other hand using
4-methoxy phenacyl bromide led to 5. One of the nitrile groups can hydrolyze in basic media and
convert to amide 4a-i. In the case of 4-methoxy bromide, the final product is cyclopentene ring 5a-
d.
8

ACCEPTED MANUSCRIPT
Scheme 4. Proposed mechanism for the synthesis of functionalized cyclopentanols 4a-i and
cyclopentenes 5a-d
It seems that the existence of the 4-methoxy substituent in the structure of phenacyl bromide 1c has
an essential role in the elimination reaction and reacted as accelerator in the formation of the double
bond and elimination of water to form the desired cyclopentene moiety 5. The formation of the
double bond in the cyclopentene ring could be expressed based on the stability of the formed double
bond in the structure of product (Scheme 5). There are two possibilities (Paths a, b) for the water
elimination in the structure of cyclopentanols. In path A, the double bond leads to steric hindrance
between aryl and nitro groups. However in path B, the strong conjugation between the double bond
9

ACCEPTED MANUSCRIPT
the aryl group and, has an essential role in the stability of product. Moreover, there is no steric
hindrance.
Scheme 5. Two plausible paths for the water elimination and synthesis of 5a-d
a
With this idea in mind and for expanding the reaction, alkyl cyanoacetate was used instead of
malononitrile and three-component reaction of phenacyl bromide, methyl or ethyl cyanoacetate and
β-nitrostyrene was investigated. In this case, the sole product was formed through the reaction of
phenacyl bromide and alkyl cyanoacetate.
Meanwhile, domino four-component reaction of benzaldehyde, nitromethane, malononitrile and
phenacyl bromide in the presence of 1M NaOH was investigated to access cyclopentanol
derivatives. However, the reaction showed that a mixture of products were formed and separation of
the desired product was not possible.
In conclusion, we have developed a highly efficient domino Michael/cyclization reaction to access
diastereoselective functionalized cyclopentanol and cyclopentene derivatives with four and three
stereogenic centers, respectively. These reactions have some advantages such as: high efficiency,
high bond-forming efficiency, practical simplicity of the method, easy work-up, mild reaction
conditions, and high diastereoselectivity for the synthesis of functionalized cyclopentanols 4a-i and
cyclopentenes 5a-d. Future work in our laboratory is in progress to find a suitable basic
organocatalyst to access enantioselective products.
Experimental Section:
Commercially available materials were used without further purification. Melting points were
determined on an Electrothermal 9100 apparatus. IR spectra were obtained on an ABB FT-IR
1
0

ACCEPTED MANUSCRIPT
1
13
FTLA 2000 spectrometer. H NMR and C NMR spectra were run on Bruker DRX-300 AVANCE
1
13
spectrometers at 300 MHz for H NMR, 75 MHz for C NMR. DMSO-d and CDCl was used as
6
3
solvent. High resolution mass spectra were recorded on Mass-ESI-POS (Apex Qe-FT- ICR
instrument) spectrometer. The scanning electron microscope (Hitachi 4160, Japan) was used for
getting the scanning electron micrographs.
General procedure for synthesis of 4 and 5:
In a flask, a mixture of phenacyl bromide (1 mmol), malononitrile (72.6 mg, 1.1 mmol) in EtOH (3
mL) was prepared and NaOH (1M= 0.04 g in 1 mL water ) was added dropwise and the solution
was stirred at ambient temperature for 1h. The progress of the reaction was monitored using TLC
(Eluent:n-hexane: EtOAc 2:1 ).Then, β-nitrostyrene (1.0 mmol) was added and the mixture was
stirred for 24h at room temperature. Finally, the precipitated product was filtered and washed with
methanol to afford the pure product 4a-i or 5a-d.
(±) 4-(4-Bromophenyl)-1-cyano-4-hydroxy-3-nitro-2-phenylcyclopentane-1-carboxamide (4a):
-1
Cream powder; yield: 314 mg (73%); Mp 218-220 ˚C. IR (KBr) (νmax/ cm ): 3462, 3372, 2243,
1
1
694, 1553, 1381. H NMR (300 MHz, DMSO-d ): δ = 2.82 (d, 1H, CH , J= 15.1 Hz), 3.13 (d, 1H,
6
2
CH , J = 15.1 Hz), 4.88 (d, 1H, CH-Ph, J = 12.0 Hz), 5.99 (d, 1H, CH-NO , J = 12.0 Hz), 6.97 (s,
2
2
1H, OH), 7.28 (s, 1H, NH), 7.33-7.39 (m, 5H, H-Ar), 7.54 (s, 1H, NH), 7.62 (d, 2H, H-Ar, J = 8.5
1
3
Hz), 7.68 (d, 2H, H-Ar, J = 8.5 Hz). C NMR (75 MHz, DMSO-d ): δ = 47.4, 50.6, 53.7, 80.4, 92.8,
6
79
1
21.0, 128.0, 128.3, 128.6, 130.9, 133.1, 141.8, 168.0. HR-MS (ESI) Calc. for C H N O Br
19 15 3 3
+
[
(M-OH)+H] : 412.0291; found: 412.0291.
3
Crystallography data of 4a: colourless crystal (plate), dimensions 0.210 x 0.170 x 0.020 mm ,
crystal system monoclinic, space group P2 /n, Z=4, a=7.3723(7) Å, b=6.2733(5) Å, c=38.704(3) Å,
1
3
3
alpha=90 deg, beta=90.184(3) deg, gamma=90 deg, V=1790.0(3) Å , rho=1.597 g/cm , T=200(2)
K, Thetamax= 24.415 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg omega-scans with CCD
area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 2.90and
a completeness of 98.4% to a resolution of 0.86 Å, 8904 reflections measured, 2918 unique
(R(int)=0.0355), 2335 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization
effects, an empirical absorption correction was applied using SADABS based on the Laue
symmetry of the
-1
2
reciprocal space, mu=2.33mm , T =0.84, T =0.97, structure refined against F with a Full-
min
max
matrix least-squares algorithm using the SHELXL (Version 2014-3) software, 256 parameters
refined, hydrogen atoms were treated using appropriate riding models, except those at hetero atoms
(N7 and O3), which were refined isotropically, goodness of fit 1.16 for observed reflections, final
2
residual values R1(F)=0.036, wR(F )=0.087 for observed reflections, residual electron density -0.41
1
1

ACCEPTED MANUSCRIPT
-3
to 0.43 eÅ . CCDC 1030884 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(±) 2-(4-Bromophenyl)-1-cyano-4-hydroxy-3-nitro-4-phenylcyclopentane-1-carboxamide (4b):
-1
Cream powder; yield: 243 mg (60%); Mp 129-131 ˚C. IR (KBr) (νmax/ cm ): 3295, 3013, 2906,
1
2
250, 1706, 1611, 1558, 1356. H NMR (300 MHz, DMSO- d ): δ = 2.81 (d, 1H, CH , J = 15.0
6
2
Hz), 3.07 (d, 1H, CH , J = 15.0 Hz), 3.71 (s, 3H, CH ), 4.79 (d, 1H, CH-Ph, J = 12.0 Hz), 5.87 (d,
2
3
1
7
H, CH-NO , J = 12.0 Hz), 6.88 (1H, s, OH), 6.92 (d, 2H, H-Ar, J = 6.5 Hz), 7.13 (brs, 1H, NH),
2
.28 (d, 2H, H-Ar, J = 8.4 Hz), 7.45 (bs, 1H, NH), 7.58 (d, 2H, H-Ar, J = 8.5 Hz), 7.64 (d, 2H, H-
1
3
Ar, J = 8.6 Hz). C NMR (75 MHz, DMSO- d ): δ = 47.5, 50.3, 53.2, 55.1, 80.3, 93.1, 114.0,
6
120.9, 121.0, 124.6, 128.1, 129.3, 130.9, 141.8, 159.1, 168.2.
(±) 4-(4-Bromophenyl)-1-cyano-4-hydroxy-3-nitro-2-(4-nitrophenyl)cyclopentane-1-
-1
carboxamide (4c): Cream powder; yield: 389 mg (82%); Mp 139-141 ˚C. IR (KBr) (νmax/ cm ):
1
3
283, 3087, 3015, 2967, 1717, 1555, 1348. H NMR (300 MHz, DMSO- d ): δ = 3.35(1H, OH,
6
overlap with solvent signal), 3.42 (d, 1H, CH , J = 11.2 Hz), 3.52 (d, 1H, CH , J = 11.2 Hz), 5.14
2
2
(
d, 1H, CH-Ph, J = 5.1 Hz), 6.42 (d, 1H, CH-NO , J = 5.1 Hz), 7.55-7.83 (m, 6H, H-Ar), 7.96-7.99
2
(d, 1H, H-Ar, J = 7.6 Hz), 8.28-8.31 (d, 1H, H-Ar, J = 8.3 Hz), 8.43 (s, 1H, NH), 8.82 (s, 1H, NH).
1
3
C NMR (75 MHz, DMSO- d ): δ= 43.6, 48.4, 52.4, 89.1, 90.1, 114.8, 123.6, 123.9, 128.4, 129.8,
6
130.1, 130.2, 131.1, 131.6, 132.1, 135.1, 135.6, 147.8, 158.1. HR-MS (ESI) Calc. for
7
5
9
+
81
5
C H N NaO Br [(M-H O)+Na] : 478.99627; found: 478.99615, Calc. for C H N NaO Br
19
13
4
2
19 13
4
+
[
(M-H O)+Na] : 480.9942; found: 480.9941.
2
(±) 1-Cyano-4-hydroxy-3-nitro-2,4-diphenylcyclopentane-1-carboxamide (4d): Cream powder;
-1
yield: 305 mg (87%); Mp 139-141 ˚C. IR (KBr) (νmax/ cm ): 3304, 3118, 2248, 1702, 1559, 1370.
1
H NMR (300 MHz, DMSO-d ): δ = 3.36 (bs, 2H, OH and CH , overlap with solvent signal), 3.56
6
2
(
d, 1H, CH , J = 11.2 Hz), 4.80 (d, 1H, CH-Ph, J = 5.3 Hz), 6.16 (d, 1H, CH-NO , J = 5.3 Hz),
2
2
1
3
7
.42-7.50 (m, 9H, H-Ar and NH), 7.66-7.75 (m, 2H, H-Ar), 8.66 (s, 1H, NH). C NMR (75 MHz,
DMSO-d ): δ = 44.0, 48.4, 53.6, 90.2, 90.5, 115.3, 127.9, 128.1, 128.5, 128.6, 128.8, 129.0, 130.2,
6
+
1
3
30.9, 133.0, 158.7. HR-MS (ESI) Calc. for C H N NaO [(M-H O)+Na] : 356.1005; found:
19
15
3
3
2
56.1005.
(±) 1-Cyano-4-hydroxy-3-nitro-4-phenyl-2-(p-tolyl) cyclo peantane-1-carboxamide (4e): Cream
-1
powder; yield: 335 mg (92%); Mp 170 ˚C. IR (KBr) (νmax/ cm ): 3332, 3034, 2986, 2249, 1703,
1
1
562, 1352. H NMR (300 MHz, DMSO- d ): δ = 2.32 (s, 3H, CH ), 3.35 (d, 1H, CH , J = 11.1
6
3
2
Hz), 3.37 (1H, OH, overlap with solvent signal ), 3.56 (d, 1H, CH , J = 11.1 Hz), 4.74 (d, 1H, CH-
2
Ph, J = 4.8 Hz), 6.11 (d, 1H, CH-NO , J = 4.3 Hz), 7.24 (d, 2H, H-Ar, J = 7.2 Hz), 7.44 (d, 2H, H-
2
1
2

ACCEPTED MANUSCRIPT
1
3
Ar, 7.4 Hz), 7.48 (m, 3H, H-Ar), 7.67 (m, 2H, H-Ar), 8.64 (s, 1H, NH). C NMR (75 MHz, DMSO-
d6): δ = 20.7, 43.9, 48.5, 53.5, 90.3, 90.6, 115.3, 127.4, 128.1, 128.6, 129.1, 129.2, 129.6, 129.9,
+
1
30.2, 130.9, 138.2, 138.4, 158.8. HR-MS (ESI) Calc. for C H N O [(M-H O)+H] : 348.1343;
20
18
3
3
2
found: 348.1342.
(±) 2-(4-Chlorophenyl)-1-cyano-4-hydroxy-3-nitro-4-phenylcyclopentane-1-carboxamide (4f):
-1
Cream powder; yield: 319 mg (83%); Mp 145 ˚C. IR (KBr) (νmax/ cm ): 3487, 3319, 3034, 2911,
1
2
247, 1704, 1559, 1366. H NMR (300 MHz, DMSO- d ): δ = 3.38 (d, 1H, CH , J = 11.1 Hz), 3.40
6
2
(
1H, OH, overlap with solvent signal ), 3.54 (d, 1H, CH , J = 11.1 Hz), 4.90 (d, 1H, CH-Ph, J = 4.5
2
Hz), 6.17 (bs, 1H, CH-NO ), 7.48-7.53 (m, 8H, H-Ar and NH), 7.63-7.70 (m, 2H, H-Ar), 8.67 (s,
2
1
3
1
H, NH). C NMR (75 MHz, DMSO-d ): δ = 43.8, 48.4, 52.7, 89.9, 90.6, 115.1, 127.5, 128.1,
6
1
28.5, 129.0, 130.2, 130.7, 130.8, 131.9, 133.8, 158.6. HR-MS (ESI) Calc. for Calc. for C H N
3
1
9
14
3
5
+
Na O Cl [(M-H O)+Na] :. 390.0616; found: 390.0615.
3
2
(±)
4-(4-Bromophenyl)-1-cyano-4-hydroxy-2-(4-methoxyphenyl)-3-nitrocyclopentane-1-
-1
carboxamide (4g): Cream powder; yield: 339 mg (79%); Mp 149-151 ˚C. IR (KBr) (νmax/ cm ):
1
3
455, 3312, 3030, 2982, 2243, 1705, 1560, 1355. H NMR (300 MHz, DMSO-d ): δ = 3.35(1H,
6
OH, overlap with solvent signal), 3.37 (d, 1H, CH , J = 11.2 Hz), 3.53 (d, 1H, CH , J = 11.2 Hz),
2
2
4
.86 (d, 1H, CH-Ph, J = 4.98 Hz), 6.19 (d, 1H, CH-NO , J = 4.94 Hz), 7.46-7.48 (m, 6H, H-Ar and
2
1
3
NH), 7.65-7.67 (m, 4H, H-Ar), 8.67 (s, 1H, NH). C NMR (75 MHz, DMSO-d ): δ= 43.8, 48.3,
6
52.8, 89.7, 90.6, 115.1, 122.4, 127.5, 128.6, 130.2, 130.8, 131.0, 131.4, 132.4, 158.6. HR-MS (ESI)
7
4
9
+
Calc. for Calc. for C H N NaO
Br [M+Na] : 452.021685; found: 452.02164, Calc. for
1
9
16
3
8
4
1
+
C H N NaO Br [M+Na] : 454.0197; found: 454.0195.
19
16
3
(±) 1-Cyano-4-hydroxy-3-nitro-2-(3-nitrophenyl)-4-phenylcyclopentane-1-carboxamide (4h):
-1
Cream powder; yield: 249 mg (82%); Mp 149-151 ˚C. IR (KBr) (νmax/ cm ): 3310, 3077, 3019,
1
2
939, 2252, 1699, 1576, 1351. H NMR (300 MHz, DMSO- d ): δ = 3.36 (1H, OH, overlap with
6
solvent signal), 3.43 (d, 1H, CH , J = 11.2 Hz), 3.55 (d, 1H, CH , J = 11.2 Hz), 5.13 (d, 1H, CH-Ph,
2
2
J = 5.1 Hz), 6.38 (d, 1H, CH-NO , J = 5.1 Hz), 7.49-7.50 (m, 4H, H-Ar), 7.68-7.71 (m, 2H, H-Ar),
2
7.71 (t, 1H, H-Ar, J = 7.9 Hz), 7.97 (d, 1H, H-Ar, J = 7.6 Hz), 8.29 (d, 1H, H-Ar, J = 8.1 Hz), 8.44
1
3
(
s, 1H, NH), 8.78 (s, 1H, NH). C NMR (75 MHz, DMSO- d ): δ= 43.7, 48.4, 52.4, 89.4, 90.8,
6
114.9, 123.6, 123.9, 127.5, 128.6, 130.1, 130.3, 130.7, 135.1, 135.6, 147.8, 158.4. HR-MS (ESI)
+
Calc. for C H N NaO [(M-H O)+Na] :. 401.0858; found: 401.0856.
1
9
14
4
5
2
(±) 1-Cyano-2-(4-fluorophenyl)-4-hydroxy-3-nitro-4-phenylcyclopentane-1-carboxamide (4i):
-1
White powder; yield: 357 mg (87%); Mp 169-171 ˚C. IR (KBr) (νmax/ cm ): 3325, 3077, 3039,
251, 1703, 1562, 1350. 1H NMR (300 MHz, DMSO-d6): δ = 3.36 (d, 1H, CH , J = 11.2 Hz), 3.37
2
2
(
1H, OH, overlap with solvent signal), 3.54 (d, 1H, CH , J = 11.2 Hz), 4.86 (d, 1H, CHPh, J = 5.1
2
1
3

ACCEPTED MANUSCRIPT
Hz), 6.19 (d, 1H, CH-NO , J = 5.1 Hz), 7.29 (t, 2H, H-Ar, J = 8.54 Hz), 7.37-7.49 (m, 3H, H-Ar
2
1
3
and NH), 7.56-7.60 (m, 3H, H-Ar), 7.63-7.69 (m, 2H, H-Ar), 8.68 (s, 1H, NH). C NMR (75 MHz,
DMSO-d ): δ= 43.8, 48.5, 52.7, 89.9, 90.6, 115.2, 127.4, 128.6, 128.9, 129.0, 129.2, 129.3, 130.2,
6
+
1
30.8, 130.9, 131.1, 158.7. HR-MS (ESI) Calc. for C H FN O [(M-H O)+H] : 352.1093; found:
19
15
3
3
2
352.1092.
(±)
1-Cyano-3-(4-methoxyphenyl)-4-nitro-5-phenylcyclopent-2-ene-1-carboxamide
(5a):
-1
Cream powder; yield: 326 mg (90%); Mp 147-149 ˚C. IR (KBr) (νmax/ cm ): 3560, 3424, 3231,
1
1
694, 1610, 1515, 1367. H NMR (300 MHz, DMSO- d ): δ = 3.76 (s, 3H, OCH ), 4.64 (d, 1H,
6
3
CH-Ph, J= 5.3 Hz), 6.79 (s, 1H, =CH), 6.85 (d, 1H, CH-NO , J = 5.3 Hz), 6.98 (d, 2H, H-Ar, J =
2
8.2 Hz), 7.32-7.38 (m, 5H, H-Ar), 7.47 (s, 1H, NH), 7.54 (s, 1H, NH), 7.59 (d, 2H, H-Ar, J = 8.2
13
Hz). C NMR (75 MHz, DMSO- d ): δ= 55.4, 57.9, 58.7, 94.2, 114.2, 118.8, 123.7, 127.2, 128.1,
6
+
128.4, 134.1, 143.2, 160.2, 164.8. HR-MS (ESI) Calc. for Calc. for C H N NaO [M+Na]
20 17 3 4
386.1112; found: 386.1112.
Crystallography data of 5a: colourless crystal (polyhedron), dimensions 0.160 x 0.160 x 0.140
3
mm , crystal system monoclinic, space group C2/c, Z=8, a=25.9760(10) Å, b=8.4856(3) Å,
3
c=18.9145(7) Å, alpha=90 deg, beta=121.3568(8) deg, gamma=90 deg, V=3560.2(2) Å , rho=1.356
3
g/cm , T=200(2) K, Thetamax= 25.073 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg
omega-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean
redundancy of 3.33and a completeness of 99.5% to a resolution of 0.84 Å, 10816 reflections
measured, 3148 unique (R(int)=0.0220), 2786 observed (I > 2σ(I)), intensities were corrected for
Lorentz and polarization effects, an empirical absorption correction was applied using SADABS
-1
based on the Laue symmetry of the reciprocal space, mu=0.10mm , Tmin=0.90, Tmax=0.96, structure
2
refined against F with a Full-matrix least-squares algorithm using the SHELXL (Version 2014-3)
software, 253 parameters refined, hydrogen atoms were treated using appropriate riding models,
except those of the aminde group, which were refined isotropically, goodness of fit 1.12 for
2
observed reflections, final residual values R1(F)=0.040, wR(F )=0.108 for observed reflections,
-3
residual electron density -0.21 to 0.46 eÅ . CCDC 1030883 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(±) 1-Cyano-3-(4-methoxyphenyl)-4-nitro-5-(p-tolyl)cyclopent-2-ene-1-carboxamide (5b):
-1
Yellow powder; yield: 312 mg (83%); Mp 186-190 ˚C. IR (KBr) (νmax/ cm ): 3313, 3024, 2978,
1
2
248, 1704, 1559, 1367. H NMR (300 MHz, DMSO- d ): δ = 2.26 (s, 3H, CH ),3.77 (s, 3H,
6
3
OCH ), 4.58 (d, 1H, CH-Ph, J = 5.3 Hz), 6.77 (s, 1H, =CH), 6.79 (d, 1H, CH-NO , J = 5.3 Hz),
3
2
6.98 (d, 2H, H-Ar, J = 8.2 Hz), 7.14 (d, 2H, H-Ar, J = 7.6 Hz), 7.27 (2H, d, H-Ar, J = 7.6 Hz), 7.44
1
4

ACCEPTED MANUSCRIPT
1
3
(
1H, s, NH), 7.54 (1H, s, NH), 7.58 (d, 2H, H-Ar, J = 8.3 Hz),. C NMR (75 MHz, DMSO- d ): δ=
6
5
1
5.3, 57.8, 58.6, 94.3, 114.2, 118.9, 123.8, 127.3, 128.0, 128.3, 129.0, 131.1, 137.8, 143.2, 160.2,
+
64.8. HR-MS (ESI) Calc. for Calc. for C H N NaO [M+Na] : 400.1267; found: 400.1267.
2
1
19
3
4
(±) 5-(4-Chlorophenyl)-1-cyano-3-(4-methoxyphenyl)-4-nitro cyclopent-2-ene-1-carboxamide
-1
(
5c): Light yellow powder; yield: 269 mg (68%); Mp 213-215 ˚C. IR (KBr) (νmax/ cm ): 3496,
1
3
382, 2237, 1714, 1598, 1550, 1359. H NMR (300 MHz, DMSO- d ): δ = 3.78 (s, 3H, OCH ), 4.74
6
3
(
d, 1H, CH-Ph, J = 4.9 Hz), 6.80 (s, 1H, =CH), 6.81 (d, 1H, CH-NO , J = 4.9 Hz), 7.00 (d, 2H, H-
2
Ar, J = 8.4 Hz), 7.40-7.42 (m, 4H, H-Ar), 7.52 (brs, 1H, NH), 7.55-7.63 (m, 2H, H-Ar), 7.63 (brs,
1
3
:
1
1
H, NH). C NMR (75 MHz, DMSO- d ) δ= 53.3, 56.7, 58.5, 94.1, 114.3, 118.6, 123.7, 127.4,
6
3
4
5
28.1, 128.3, 130.5, 133.3, 133.5, 143.1, 160.3, 164.8. HR-MS (ESI) Calc. for C H N NaO Cl
2
0
16
3
+
37
+
[
M+Na] : 420.07222; found: 420.07215, Calc. for C H N NaO Cl [M+Na] : 422.0692; found:
20 16 3 4
422.0692.
(±) 1-Cyano-3-(4-methoxyphenyl)-4-nitro-5-(4-(trifluoromethyl) phenyl)cyclopent-2-ene-1-
carbox amide (5d): Light yellow powder; yield: 241 mg (56%); Mp 218-220 ˚C. IR (KBr) (νmax
/
-1
1
cm ): 3506, 3393, 3010, 2924, 2238, 1716, 1552, 1366. H NMR (300 MHz, DMSO- d ): δ = 3.76
6
(
s, 3H, OCH ), 4.83 (brs, 1H, CH-Ph), 6.83 (s, 1H, =CH), 6.89 (brs, 1H, CH-NO ), 6.97 (d, 2H, H-
3
2
1
3
Ar, J = 7.5 Hz), 7.59-7.62 (m, 5H, H-Ar and NH), 7.71 (d, 2H, H-Ar, J = 7.5 Hz). C NMR (75
MHz, DMSO- d ): δ= 55.4, 56.7, 58.5, 93.9, 114.2, 118.5, 122.2, 123.6, 125.1, 125.8, 127.3, 128.2,
6
1
28.6, 129.0, 129.5, 130.6, 139.2, 143.1, 160.2, 164.6. HR-MS (ESI) Calc. for C H F N O [ (M-
21 15 3 3 3
+
H O)+H] 413.2666, found, 413.2666.
2
Acknowledgements
We gratefully acknowledge Iran National Science Foundation (INSF) for their financial support.
Supporting Information
1
13
1
1
Copies of H NMR, C NMR, HRMS spectra for compounds 4a-i and 5a-d and H- H-COSY 2D
NMR 4h and 5c; X-ray crystal data for compound 4a, and 5b
References:
1
. Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem. 2007, 119, 3806.
b) Li, H.; Loh, T-P. J. Am. Chem. Soc. 2008, 130, 7194.
. Guo, H.-C.; Ma, J.-A. Angew. Chem. Int. Ed. 2006, 45, 354. (b) Enders, D.; Grondal, C.; Huttl,
M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570.
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(
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3
Hüttl, M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem. Int. Ed. 2007, 46, 467. (c)
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2004, 43, 1272. (d) Marigo, M.;
1
5

ACCEPTED MANUSCRIPT
Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475. (e) Hayashi, Y.;
Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem. Int. Ed. 2007, 46, 4922. (f) Cao, C.-L.; Sun, X.-
L.; Kang, Y.-B.; Tang, Y. Org. Lett. 2007, 9, 4151.
4. (a) Singh, R.; Vince, R. Chem. Rev. 2012, 112, 4642. (b) Velasco, J.; Ariza, X.; Badia, L.; Bartra,
M.; Berenguer, R.; Farras, J.; Gallardo, J.; Garcia, J.; Gasanz, Y. J. Org. Chem. 2013, 78, 5482. (c)
Verma, V. A.; Rossman, R.; Bennett, F.; Chen, L.; Gavalas, S.; Girijavallabhan,V.; Huang, Y.;
Kim, S. H.; Kosinski, A.; Pinto, P.; Rizvi, R.; Shankar, B.; Tong, L.; Velazquez, F.; Venkatraman,
S.; Kozlowski, J.; MacCoss, M.; Kwong, C. D.; Bansal, N.; Kezar, H. S.; Reynolds, R. C.; Maddry,
J. A.; Ananthan, S.; Secrist, J. A.; Li, C.; Chase, R.; Curry, S.; Huang, H. C.; Tong, X. F.; Njoroge,
G.; .Arasappan, A. Bioorg. Med. Chem. Lett. 2012, 22, 6967. (d) Raboisson, P.; de Kock, H.;
Rosenquist, A.; Nilsson, M.; Salvador-Oden, L.; Lin, T. I.; Roue, N.; Ivanov, V.; Wähling, H.;
Wickström, K.; Hamelink, E.; Edlund, M.; Vrang, L.; Vendeville, S.; de Vreken, W. V.; McGowan,
D.; Tahri, A.; Hu, L.; Boutton, C.; Lenz, O.; Delouvroy, F.; Pille, G.; Surleraux, D.; Wigerinck, P.;
Samuelsson, B.; Simmen, K. Bioorg. Med. Chem. Lett. 2008, 18, 4853.
5
6
. Heasley, B. Current Org. Chem. 2014, 18, 641.
. Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.; Lin, T. -L.; Hutchison, T. L.; Babu, Y. S.;
Bantia, S.; Elliott, A. J.; Montgomery, J. A. J. Med. Chem. 2001, 44, 4379.
. (a) Pellissier, H. Tetrahedron 2007, 63, 3235. (b) Jenkins, A. D.; Herath, A.; Song, M.;
7
Montgomery, J. J. Am. Chem. Soc. 2011, 133, 14460. (c) Zhao, G-L.; Ibrahem, I.; Dziedzic, P.;
Sun, J.; Bonneau, C.; Cordova, A. Chem. Eur. J. 2008, 14, 10007.
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. Boutureira, O.; Matheu, M. I.; Diaz, Y.; Castillon, S. Chem Soc. Rev. 2013, 42, 5056.
. (a) Tan, B.; Chua, P. J.; Zeng, X.; Lu, M.; Zhong, G. Org. Lett. 2008, 10, 3489. (b) Hong, B-C.;
Dange, N. S.; Hsu, C-S.; Liao, J-H.; Lee, G-H. Org. Lett. 2011, 13, 1338. (c) Hong, B.-C.; Nimji, R.
Y.; Lin, C.-W.; Liao, J.-H. Org. Lett. 2011, 13, 1278. (d) Hong, B.-C.; Chen, P.-Y.; Kotame, P.; Lu,
P.-Y.; Lee, G.-H.; Liao, J.-H. Chem. Commun. 2012, 48, 7790.
10. (a) Ghabraie, E.; Bararjanian, M.; Balalaie, S.; Rominger, F.; Bijanzadeh, H. R. Helv. Chim.
Acta 2011, 94, 1440. b) Ghabraie, E.; Balalaie, S.; Bararjanian, M.; Rominger, F.; Bijanzadeh, H. R.
Tetrahedron 2011, 67, 5415. (c) Ghabraie, E.; Moghimi, H.; Balalaie, S.; Bararjanian, M.;
Bijanzadeh, H. R. J. Iran Chem. Soc. 2013, 10, 725.
1
1. Gilman, H. Ed. Organic Synthesis Coll. Vol. I 1941, 413-414, Wiley &Sons, New York.
2. (a) Liu, Y.; Wang, H.; Wan, J. Asian J. Org. Chem. 2013, 2, 374-386. (b) Nair, V.; Mathai, S.;
1
Varma, R. L. J. Org. Chem. 2004, 69, 1413. (c) Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed. Engl.
005, 44, 1602-1634. (d) Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E.; Zangrando, E.
J. Heterocycl. Chem. 2010, 7, 664 (e) rajesh, S. M.; Perumal, S.; Menendez, J. C.; Yageeswari, P.;
2
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Sriram, D. Med. Chem. Commun. 2011, 2, 626-630. (f) Qin, L.; Zhou, J.; Liu, S.; Yang, L.; Wu, X.;
Hu, W. RSC Adv. 2013, 3, 20065-20070. (g) Mancebo-Aracil, J.; Najera, C.; Sansano, J. M. Chem.
Commun. 2013, 49, 11218-11220
1
7

ACCEPTED MANUSCRIPT
Graphical Abstract
Diastereoselective Synthesis of Polysubstituted Cyclopentanols and Cyclopentenes Containing
Stereogenic Centers via Domino Michael/Cyclization Reaction
Somayeh Ahadi, Zeinab Naghdiani, Saeed Balalaie* and Frank Rominger
1
8

S
A
u
C
p
C
p
E
o
P
r
T
t
E
i
D
ngMAIn
N
f
U
o
S
r
C
mation
RI
P
T
Diastereoselective Synthesis of Polysubstituted Cyclopentanoles and Cyclopentenes
Contained Stereogenic Centers via Domino Micheal-Cyclization Reaction
a
a
*a,b
c
Somayeh Ahadi , Zeinab Naghdiani , Saeed Balalaie and Frank Rominger
a
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
Medical Biology Research center, Kermanshah University of Medical Sciences, Kermanshah, Iran
b
c
Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Email:balalaie@yahoo.com and balalaie@kntu.ac.ir
Table of Contents:
General methods
S1
S2
Synthesis of β-nitro styrene derivatives, products 4a-i and 5a-d
General procedure for synthesis of 4 and 5
S2-S7
1
13
Copies of H NMR, C NMR and Mass spectra 4a
S8-S10
S11-S13
S14-S16
S17-S19
S20-S22
S23-S25
S26-S28
S29-S31
S32-S34
S35-S37
S38-S40
S41-S43
S44-S46
S47
1
13
Copies of H NMR, C NMR and Mass spectra 4b
1
13
Copies of H NMR, C NMR and Mass spectra 4c
1
13
Copies of H NMR, C NMR and Mass spectra 4d
1
13
Copies of H NMR, C NMR and Mass spectra 4e
1
13
Copies of H NMR, C NMR and Mass spectra 4f
1
13
Copies of H NMR, C NMR and Mass spectra 4g
1
13
Copies of H NMR, C NMR and Mass spectra 4h
1
13
Copies of H NMR, C NMR and Mass spectra 4i
1
13
Copies of H NMR, C NMR and Mass spectra 5a
1
13
Copies of H NMR, C NMR and Mass spectra 5b
1
13
Copies of H NMR, C NMR and Mass spectra 5c
1
13
Copies of H NMR, C NMR and Mass spectra 5d
1
Copies of H NMR in D O 5h
2
1
13
Copies of H NMR and C NMR ethyl 2-cyano-4-oxo-4-phenylbutanoate
S48-S49
S50-S51
S52-S57
S58-S61
1
1
Copies of H- H-COSY 2D 4b and 5c
X-ray crystallographic data 4a
X-ray crystallographic data 5a
S1

ACCEPTED MANUSCRIPT
General information
High resolution mass spectra were recorded on Mass-ESI-POS and Mass-ESI-NEG (FT-ICR)
spectrometer.
Synthesis of β-nitro styrene derivatives 3 a-g:
The β-nitro styrene derivatives were synthesized based on the reported method. (Organic
Synthesis Coll. Vol. I 1941, 413-414)
General procedure for synthesis of 4 and 5
A mixture of phenacyl bromide (1 mmol), malononitrile (72.6 mg, 1.1 mmol) in EtOH (3 mL)
was added dropwise NaOH (1M) and the solution was stirring at ambient temperature for 1h.
The progress of the reaction was monitored using TLC (Eluent:n-hexane: EtOAc 2:1 ).Then, β-
nitro styrene (1.0 mmol) was added and allowed the mixture to be for 24h at room temperature.
Then, the precipitated product was filtered and washed with methanol to afford the pure product
4
a-i or 5a-d.
S2

4
-(4-Bromophenyl)-1-cyano-4-hydroxy-3-nitro-2-phenylcyclopentane-1-carboxamide (4a)
ACCEPTED MANUSCRIPT
-1
1
Cream powder; yield: 314 mg (73%); Mp 218-220 ˚C. IR (KBr) (νmax/ cm ): 3462, 3372, 1694, 1553, 1381. H
NMR (300 MHz, DMSO-d ): δ= 2.82 (d, 1H, CH , J = 15.1 Hz), 3.13 (d, 1H, CH , J = 15.1 Hz), 4.88 (d, 1H, CH-
6
2
2
Ph, J = 12 Hz), 5.99 (d, 1H, CH-NO , J = 12 Hz), 6.97 (s, 1H, OH), 7.28 (s, 1H, NH), 7.33-7.39 (m, 5H, H-Ar), 7.54
2
13
(
s, 1H, NH), 7.62 (d, 2H, H-Ar, J = 8.5 Hz), 7.68 (d, 2H, H-Ar, J = 8.5 Hz). C NMR (75 MHz, DMSO-d ): δ = 47.4,
6
7
9
5
0.6, 53.7, 80.4, 92.8, 121.0, 128.0, 128.1, 128.3, 128.7, 131.0, 133.1, 141.9, 168.1. HR-MS (ESI) Calc. for C H N O
19 15 3 3
+
Br [(M-OH)+H] : 412.0291; found: 412.0291.
2-(4-Bromophenyl)-1-cyano-4-hydroxy-3-nitro-4-phenylcyclopentane-1-carboxamide (4b)
-1
Cream powder; yield: 243 mg (60%); Mp 129-131 ˚C. IR (KBr) (νmax/ cm ): 3295, 3013, 2906, 2250, 1706, 1611,
1
1
3
2
=
558, 1356. H NMR (300 MHz, DMSO-d ): δ = 2.81 (d, 1H, CH , J = 15.0 Hz), 3.07 (d, 1H, CH , J = 15.0 Hz),
6
2
2
.71 (s, 3H, CH ), 4.79 (d, 1H, CH-Ph, J = 12.0 Hz), 5.87 (d, 1H, CH-NO , J = 12.0 Hz), 6.88 (1H, s, OH), 6.92 (d,
3
2
H, H-Ar, J = 6.5 Hz), 7.13 (brs, 1H, NH), 7.28 (d, 2H, H-Ar, J = 8.4 Hz), 7.45 (brs, 1H, NH), 7.58 (d, 2H, H-Ar, J
13
8.5 Hz), 7.64 (d, 2H, H-Ar, J = 8.6 Hz). C NMR (75 MHz, DMSO- d ): δ = 47.5, 50.3, 53.2, 55.1, 80.3, 93.1, 114.1,
6
1
20.9, 121.0, 124.7, 128.1, 129.3, 130.9, 141.9, 159.2, 168.2.
4
-(4-Bromophenyl)-1-cyano-4-hydroxy-3-nitro-2-(4-nitrophenyl) cyclopentane-1-carboxamide (4c):
-1
Cream powder; yield: 389 mg (82%); Mp 139-141 ˚C. IR (KBr) (νmax/ cm ): 3283, 3087, 3015, 2967, 1717, 1555,
1
1
348. H NMR (300 MHz, DMSO-d ): δ = 3.35(1H, OH, overlap with solvent signal), 3.42 (d, 1H, CH , J = 11.2
6
2
Hz), 3.52 (d, 1H, CH , J = 11.2 Hz), 5.14 (d, 1H, CH-Ph, J = 5.1 Hz), 6.42 (d, 1H, CH-NO , J = 5.1 Hz), 7.55-7.83
2
2
(
m, 6H, H-Ar), 7.96-7.99 (d, 1H, H-Ar, J = 7.6 Hz), 8.28-8.31 (d, 1H, H-Ar, J = 8.3 Hz), 8.43 (s, 1H, NH), 8.82 (s,
1
3
1
1
H, NH). C NMR (75 MHz, DMSO- d ): δ= 43.6, 48.4, 52.4, 89.2, 90.2, 114.8, 123.6, 123.9, 129.8, 130.1, 130.2, 131.7,
6
79
+
35.1, 135.6, 147.8, 158.2. HR-MS (ESI) Calc. for C H N NaO Br [(M-H O)+Na] : 478.99627; found: 478.99615,
19
13
4
5
2
81
+
Calc. for C H N NaO Br[(M-H O)+Na] : 480.9942; found: 480.9941.
19
13
4
5
2
S3

1
-Cyano-4-hydroxy-3-nitro-2,4-diphenylcyclopentane-1-car boxamide (4d):
ACCEPTED MANUSCRIPT
-1
Cream powder; yield: 305 mg (87%); Mp 139-141 ˚C. IR (KBr) (νmax/ cm ): 3304, 3118, 2248, 1702, 1559, 1370.
1
H NMR (300 MHz, DMSO-d ): δ = 3.36 (brs, 2H, OH and CH , overlap with solvent signal), 3.56 (d, 1H, CH , J =
6
2
2
1
7
1
1.2 Hz), 4.80 (d, 1H, CH-Ph, J = 5.3 Hz), 6.16 (d, 1H, CH-NO , J = 5.3 Hz), 7.42-7.50 (m, 9H, H-Ar and NH),
2
13
.66-7.75 (m, 2H, H-Ar), 8.66 (s, 1H, NH). C NMR (75 MHz, DMSO-d ): δ = 44.0, 48.4, 53.6, 90.2, 90.5, 115.3,
6
27.9, 128.1, 128.5, 128.6, 128.8, 129.0, 130.2, 130.9, 133.0, 158.7. HR-MS (ESI) Calc. for C H N NaO [(M-
19
15
3
3
+
H O)+Na] : 356.1005; found: 356.1005.
2
1
-Cyano-4-hydroxy-3-nitro-4-phenyl-2-(p-tolyl) cyclo peantane-1-carboxamide (4e):
-1
Cream powder; yield: 335 mg (92%); Mp 170 ˚C. IR (KBr) (νmax/ cm ): 3332, 3034, 2986, 2249, 1703, 1562, 1352.
1
H NMR (300 MHz, DMSO- d ): δ = 2.32 (s, 3H, CH ), 3.35 (d, 1H, CH , J = 11.1 Hz), 3.37 (1H, OH, overlap with
6
3
2
solvent signal ), 3.56 (d, 1H, CH , J = 11.1 Hz), 4.74 (d, 1H, CH-Ph, J = 4.8 Hz), 6.11 (d, 1H, CH-NO , J = 4.3 Hz),
2
2
7
.24 (d, 2H, H-Ar, J = 7.2 Hz), 7.44 (d, 2H, H-Ar, 7.4 Hz), 7.48 (m, 3H, H-Ar), 7.67 (m, 2H, H-Ar), 8.64 (s, 1H,
13
NH). C NMR (75 MHz, DMSO-d ): δ = 20.7, 43.9, 48.5, 53.5, 90.3, 90.6, 115.3, 127.4, 128.1, 128.6, 129.1, 129.2,
6
+
1
3
29.6, 129.9, 130.2, 130.9, 138.2, 138.4, 158.8. HR-MS (ESI) Calc. for C H N O [(M-H O)+H] : 348.1343; found:
20
18
3
3
2
48.1342.
2
-(4-Chlorophenyl)-1-cyano-4-hydroxy-3-nitro-4-phenyl cyclopentane-1-carboxamide (4f):
H H
CONH2
HO
CN
H
Cl
O N
H
2
-1
Cream powder; yield: 319 mg (83%); Mp 145 ˚C. IR (KBr) (νmax/ cm ): 3487, 3319, 3034, 2911, 2247, 1704, 1559,
1
1
366. H NMR (300 MHz, DMSO- d ): δ = 3.38 (d, 1H, CH , J = 11.1 Hz), 3.40 (1H, OH, overlap with solvent
6
2
signal ), 3.54 (d, 1H, CH , J = 11.1 Hz), 4.90 (d, 1H, CH-Ph, J = 4.5 Hz), 6.17 (brs, 1H, CH-NO ), 7.48-7.53 (m,
2
2
1
3
8
8
H, H-Ar and NH), 7.63-7.70 (m, 2H, H-Ar), 8.67 (s, 1H, NH). C NMR (75 MHz, DMSO-d ): δ = 43.9, 48.5, 52.8,
6
9.9, 90.7, 115.1, 127.5, 128.5, 130.3, 130.7, 130.8, 131.9, 133.8, 158.6. HR-MS (ESI) Calc. for Calc. for C H N Na
19
14
3
35
+
O3 Cl [(M-H O)+Na] :. 390.0616; found: 390.0615.
2
4
-(4-Bromophenyl)-1-cyano-4-hydroxy-2-(4-methoxyphenyl)-3-nitrocyclopentane-1-carboxamide (4g):
S4

ACCEPTED MANUSCRIPT
-1
Cream powder; yield: 339 mg (79%); Mp 149-151 ˚C. IR (KBr) (νmax/ cm ): 3455, 3312, 3030, 2982, 2243, 1705,
1
1
1
7
4
560, 1355. H NMR (300 MHz, DMSO-d ): δ = 3.35(1H, OH, overlap with solvent signal), 3.37 (d, 1H, CH , J =
6
2
1.2 Hz), 3.53 (d, 1H, CH , J = 11.2 Hz), 4.86 (d, 1H, CH-Ph, J = 4.98 Hz), 6.19 (d, 1H, CH-NO , J = 4.94 Hz),
2
2
13
.46-7.48 (m, 6H, H-Ar and NH), 7.65-7.67 (m, 4H, H-Ar), 8.67 (s, 1H, NH). C NMR (75 MHz, DMSO-d ): δ=
6
3.8, 48.3, 52.8, 89.7, 90.6, 115.1, 122.4, 127.5, 128.6, 130.2, 130.9, 131.0, 131.4, 132.4, 158.6. HR-MS (ESI) Calc. for
79
+
81
+
Calc. for C H N NaO Br [M+Na] : 452.021685; found: 452.02164, Calc. for C H N NaO Br [M+Na] : 454.0197;
19
16
3
4
19 16
3
4
found: 454.0195.
1-Cyano-4-hydroxy-3-nitro-2-(3-nitrophenyl)-4-phenyl cyclopentane-1-carboxamide (4h):
-1
Cream powder; yield: 249 mg (82%); Mp 149-151 ˚C. IR (KBr) (νmax/ cm ): 3310, 3077, 3019, 2939, 2252, 1699,
1
1
1
7
576, 1351. H NMR (300 MHz, DMSO- d ): δ = 3.36 (1H, OH, overlap with solvent signal), 3.43 (d, 1H, CH , J =
6
2
1.2 Hz), 3.55 (d, 1H, CH , J = 11.2 Hz), 5.13 (d, 1H, CH-Ph, J = 5.1 Hz), 6.38 (d, 1H, CH-NO , J = 5.1 Hz), 7.49-
2
2
.50 (m, 4H, H-Ar), 7.68-7.71 (m, 2H, H-Ar), 7.71 (t, 1H, H-Ar, J = 7.9 Hz), 7.97 (d, 1H, H-Ar, J = 7.6 Hz), 8.29
13
(
d, 1H, H-Ar, J = 8.1 Hz), 8.44 (s, 1H, NH), 8.78 (s, 1H, NH). C NMR (75 MHz, DMSO- d ): δ= 43.7, 48.4, 52.4,
6
8
9.4, 90.8, 114.9, 123.7, 123.9, 127.6, 128.6, 130.1, 130.3, 130.8, 135.2, 135.6, 147.8, 158.5. HR-MS (ESI) Calc. for
+
C H N NaO [(M-H O)+Na] :. 401.0858; found: 401.0856.
19
14
4
5
2
1-Cyano-2-(4-fluorophenyl)-4-hydroxy-3-nitro-4-phenylcyclopentane-1-carboxamide (4i):
-1
White powder; yield: 357 mg (97%); Mp 169-171 ˚C. IR (KBr) (νmax/ cm ): 3325, 3077, 3039, 2251, 1703, 1562,
350. 1H NMR (300 MHz, DMSO-d6): δ = 3.36 (d, 1H, CH , J= 11.2 Hz), 3.37 (1H, OH, overlap with solvent
1
2
signal), 3.54 (d, 1H, CH , J = 11.2 Hz), 4.86 (d, 1H, CHPh, J = 5.1 Hz), 6.19 (d, 1H, CH-NO , J = 5.1 Hz), 7.29 (t,
2
2
2
H, H-Ar, J = 8.54 Hz), 7.37-7.49 (m, 3H, H-Ar and NH), 7.56-7.60 (m, 3H, H-Ar), 7.63-7.69 (m, 2H, H-Ar), 8.68
13
(
s, 1H, NH). C NMR (75 MHz, DMSO-d ): δ= 43.8, 48.5, 52.7, 89.9, 90.6, 115.2, 115.6, 127.5, 128.6, 130.2, 130.9,
6
+
1
31.0, 131.1, 158.7, 164.0. HR-MS (ESI) Calc. for C H FN O [(M-H O)+H] : 352.1093; found: 352.1092.
19
15
3
3
2
1
-cyano-3-(4-methoxyphenyl)-4-nitro-5-phenylcyclopent-2-ene-1-carboxamide (5a):
S5

ACCEPTED MANUSCRIPT
-
1
Cream powder; yield: 326 mg (90%); Mp 147-149 ˚C. IR (KBr) (νmax/ cm ): 3560, 3424, 3231, 1694,
1
1
610, 1515, 1367. H NMR (300 MHz, DMSO- d ): δ = 3.76 (s, 3H, OCH ), 4.64 (d, 1H, CH-Ph, J = 5.3
6
3
Hz), 6.79 (s, 1H, =CH), 6.85 (d, 1H, CH-NO , J = 5.3 Hz), 6.98 (d, 2H, H-Ar, J = 8.2 Hz), 7.32-7.38 (m,
2
1
3
5
H, H-Ar), 7.47 (s, 1H, NH), 7.54 (s, 1H, NH), 7.59 (d, 2H, H-Ar, J = 8.2 Hz). C NMR (75 MHz, DMSO-
d6): δ= 55.4, 57.9, 58.7, 94.2, 114.2, 118.8, 123.7, 127.2, 128.1, 128.4, 134.1, 143.2, 160.2, 164.8. HR-MS
+
(
ESI) Calc. for Calc. for C H N NaO [M+Na] : 386.1112; found: 386.1112.
20
17
3
4
1
-Cyano-3-(4-methoxyphenyl)-4-nitro-5-(p-tolyl) cyclopent-2-ene-1-carboxamide (5b):
-1
Yellow powder; yield: 312 mg (83%); Mp 186-190 ˚C. IR (KBr) (νmax/ cm ): 3313, 3024, 2978, 2248, 1704, 1559,
1
1
6
367. H NMR (300 MHz, DMSO- d ): δ = 2.26 (s, 3H, CH ),3.77 (s, 3H, OCH ), 4.58 (d, 1H, CH-Ph, J = 5.3 Hz),
6
3
3
.77 (s, 1H, =CH), 6.79 (d, 1H, CH-NO , J = 5.3 Hz), 6.98 (d, 2H, H-Ar, J = 8.2 Hz), 7.14 (d, 2H, H-Ar, J = 7.6
2
13
Hz), 7.27 (2H, d, H-Ar, J = 7.6 Hz), 7.44 (1H, s, NH), 7.54 (1H, s, NH), 7.58 (d, 2H, H-Ar, J = 8.3 Hz). C NMR
(
75 MHz, DMSO- d ): δ= 20.7, 55.4, 57.8, 58.7, 94.3, 114.3, 118.9, 123.8, 127.3, 128.1, 128.4, 129.0, 131.1, 137.9, 143.2,
6
+
1
60.2, 164.8. HR-MS (ESI) Calc. for Calc. for C H N NaO [M+Na] : 400.1267; found: 400.1267.
21
19
3
4
5-(4-Chlorophenyl)-1-cyano-3-(4-methoxyphenyl)-4-nitrocyclopent-2-ene-1-carboxamide (5c):
-
1
Light yellow powder; yield: 269 mg (68%); Mp 213-215 ˚C. IR (KBr) (νmax/ cm ): 3496, 3382, 2237, 1714, 1598,
1
1
550, 1359. H NMR (300 MHz, DMSO-d ): δ = 3.78 (s, 3H, OCH ), 4.74 (d, 1H, CH-Ph, J= 4.9 Hz), 6.80 (s, 1H,
6
3
=
CH), 6.81 (d, 1H, CH-NO , J = 4.9 Hz), 7.00 (d, 2H, H-Ar, J = 8.4 Hz), 7.40-7.42 (m, 4H, H-Ar), 7.52 (brs, 1H,
2
13
:
NH), 7.55-7.63 (m, 2H, H-Ar), 7.63 (brs, 1H, NH). C NMR (75 MHz, DMSO- d ) δ= 55.3, 56.7, 58.5, 94.1, 114.3,
6
3
5
1
18.7, 123.8, 127.4, 128.1, 128.4, 130.5, 133.3, 133.5, 143.2, 160.3, 164.8. HR-MS (ESI) Calc. for C H N NaO Cl
20 16 3 4
+
37
+
[
M+Na] : 420.07222; found: 420.07215, Calc. for C H N NaO Cl [M+Na] : 422.0692; found: 422.0692.
20 16 3 4
1
-Cyano-3-(4-methoxyphenyl)-4-nitro-5-(4-(trifluoromethyl)phenyl)cyclopent-2-ene-1-carboxamide (5d):
S6

-
1
Light yellow powder; yield: 241 mg (56%); Mp 218-220 ˚C. IR (KBr) (ν / cm ): 3506, 3393, 3010, 2924, 2238,
max
ACCEPTED MANUSCRIPT
1
1
716, 1552, 1366. H NMR (300 MHz, DMSO- d ): δ = 3.76 (s, 3H, OCH ), 4.83 (brs, 1H, CH-Ph), 6.83 (s, 1H,
6
3
=
CH), 6.89 (brs, 1H, CH-NO ), 6.97 (d, 2H, H-Ar, J = 7.5 Hz), 7.59-7.62 (m, 5H, H-Ar and NH), 7.71 (d, 2H, H-Ar,
2
13
J = 7.5 Hz). C NMR (75 MHz, DMSO- d ): δ= 55.4, 56.7, 58.5, 93.9, 114.2, 118.5, 122.2, 123.6, 125.2, 125.3, 125.8,
6
+
1
4
27.3, 128.3, 128.6, 129.1, 129.5, 130.7, 139.2, 143.2, 160.3, 164.7. HR-MS (ESI) Calc. for C H F N O3[ (M-H O)+H]
21
15
3
3
2
13.2666, found, 413.2666.
S7

ACCEPTED MANUSCRIPT
1
H NMR (300 MHz, DMSO-d ) 4a
6
S8

ACCEPTED MANUSCRIPT
1
3
C NMR (75 MHz, DMSO-d ) 4a
6
S9

ACCEPTED MANUSCRIPT
HRMS-ESI of 4a
S10

ACCEPTED MANUSCRIPT
1
H NMR (300 MHz, DMSO-d ) 4b
6
S11