Ring-expansion reaction of cyclopropane: A novel process for synthesis of bicyclic dicarboximides from cyclopropanedicarboximides and carbon nucleophile

Article abstract of DOI:10.1080/00397910802031378

The ring-expansion reaction of cyclopropane with carbon nucleophile was studied. The novel process for synthesis of bicyclic dicarboximides from cyclopropanedicarboximides with malononitrile or ethyl cyanoacetate was described. Copyright Taylor & Francis

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Ring-Expansion Reaction
of Cyclopropane: A Novel
Process for Synthesis of
Bicyclic Dicarboximides from
Cyclopropanedicarboximides
and Carbon Nucleophile
Zhongjiao Ren a , Weiguo Cao a b , Yeying Lu a , Yun
Wang a & Sihui Wang a
a Department of Chemistry, Shanghai University,
Shanghai, China
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai, China
Version of record first published: 18 Aug 2008.
To cite this article: Zhongjiao Ren , Weiguo Cao , Yeying Lu , Yun Wang & Sihui Wang
(2008): Ring-Expansion Reaction of Cyclopropane: A Novel Process for Synthesis of
Bicyclic Dicarboximides from Cyclopropanedicarboximides and Carbon Nucleophile,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:13, 2215-2226
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Synthetic Communications1, 38: 2215–2226, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802031378
Ring-Expansion Reaction of Cyclopropane:
A Novel Process for Synthesis of
Bicyclic Dicarboximides from
Cyclopropanedicarboximides and
Carbon Nucleophile
Zhongjiao Ren,1 Weiguo Cao,1,2 Yeying Lu,1 Yun Wang,1
and Sihui Wang1
1Department of Chemistry, Shanghai University, Shanghai, China
2State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Abstract: The ring-expansion reaction of cyclopropane with carbon nucleophile
was studied. The novel process for synthesis of bicyclic dicarboximides from
cyclopropanedicarboximides with malononitrile or ethyl cyanoacetate was
described.
Keywords: Bicyclic lactam; Cyclopropyl lactam; Malononitrile; Ring-expansion
reaction
There has been increasing interest in cyclopropyl lactam, because it is
an important structural unit in both natural and synthetic organic
compounds.[1] However, up to now, less attention has been paid to the
synthetic potential of the cyclopropyl lactam.
The ring-expansion reaction of cyclopropane bearing electron-
withdrawing groups with nucleophiles is a methodology that has been
widely applied in organic synthesis.[2] We have engaged in the ring-expansion
reaction of cyclopropane with nitrogen nucleophile and reported the syn-
thesis of 5-aryl-3-phenylpyrazole from cyclopropane with hydrazine,[3]
lactam, and pyridone from cyclopropane with amine.[4] A survey of the
Received January 18, 2008
Address correspondence to Zhongjiao Ren, Department of Chemistry, Shanghai
University, Shanghai 200444, China. E-mail: renrui198229@hotmail.com
2215

2216
Z. Ren et al.
Scheme 1. Preparation of cyclopropanedicarboximindes 4.
literature revealed that ring-expansion reaction of cyclopropane with
carbon nucleophile was rarely reported.
The formation of a carbon–carbon bond is the essence of organic
chemistry. Therefore, we turned our attention to exploring the synthetic
utility of the ring-expansion reaction of cyclopropyl lactam with the
carbon nucleophile. Here we report a novel process for synthesis of
bicyclic dicarboximides from cyclopropanedicarboximides with malono-
nitrile or ethyl cyanoacetate in the presence of K2CO3 (Scheme 2).
We began by preparing cyclopropyl lactam. We have reported the
approach for synthesis of cyclopropane derivatives with olefin and tri-
phenylarsonium salt.[5] According to our reported approach, the syn-
thesis of cyclopropyl lactam is outlined in Scheme 1. The ammonolysis
of NCCH2CO2CH2CH3 1 with primary aliphatic amine provided amide
2, and subsequent Knoevenagel condensation of aldehyde with amide
gave olefin 3. The cyclopropanedicarboximides 4 were obtained via cyclo-
propanation reaction of olefins with triphenylarsonium salt. The results
of preparing cyclopropanedicarboximides are shown in Table 1.
Scheme 2. Synthesis of bicyclic dicarboximides 6.

Cyclopropane Ring Expansion
2217
Table 1. Synthesis of cyclopropanedicarboximides from
olefins and triphenylarsonium salt
Entry
Ar
R
Yielda (4) (%)
1
2
3
4
5
6
7
4-ClC6H4
4-BrC6H4
4-CH3OC6H4
4-CH3C6H4
C6H5
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclopentyl
cyclopentyl
a 68
b 62
c 60
d 50
e 63
f 78
g 75
4-CH3OC6H4
4-CH3C6H4
aIsolated yield.
The results of Table 1 relate to Scheme 1.
It should be emphasized that the expected cyclopropanedi-
carboximide 4 was not obtained when the amines were n-propylamine,
iso-propylamine, and n-butylamine.
The structures of compounds 4a–g were confirmed by 1H NMR, MS,
IR, elemental analysis, and X-ray crystallographic analyses Fig. 1). The
trans configurations of the compounds 4a–g were also supported by
comparison of the coupling constant of two protons situated at adjacent
carbon atoms in the cyclopropane ring. It has been reported that the
cyclopropyl protons with a cis relationship have larger coupling constants
(ꢀ7–10Hz), whereas those with a trans relationship have smaller coupling
constants ( ꢀ 3–7Hz).[6] The coupling constants of cyclopropanes 4a–g
were 4.2–4.7 Hz.
The most general means of generating carbon nucleophiles involve
removal of a proton from an active methylene compound by a base. First,
we tested some inorganic bases such as NaOH, K2CO3, and NaHCO3. In
Figure 1. X-ray crystal structure of compound 4a.

2218
Z. Ren et al.
the model experiment, the mixture of cyclopropanedicarboximide 4a (1
equiv), malononitrile 5 (1 equiv), and base (3 equiv) in dimethoxyethane
(DME) was stirred at room temperature. The completion of the reaction
was determined by thin-layer chromatography (TLC). When NaOH was
employed as base, unidentified complex mixtures were obtained. No reac-
tion occurred in the presence of NaHCO3. The bicyclic dicarboximide 6a
was obtained in 70% yield when K2CO3 used a base. Then we examined
the reaction temperature. When temperature raised, the reaction solution
became a deep color and a complex mixture appeared. At 80ꢁC, no
desired compound 6a was afforded (Table 2, entries 13). At 40ꢁC, the
compound 6a was given in 56% yield (Table 2, entry 12). It is obvious
that the high reaction temperatures do not favor reaction.
To investigate the scope of this reaction, a variety of cyclopropane-
dicarboximides and active methylene compounds were examined. The
results are shown in Table 2. The reaction of cyclopropanedicarboximide
4 with malononitrile proceeded smoothly to give corresponding bicyclic
dicarboximides (6a–g) in 60–82% yields under the optimized condition
(Table 2, entries 1–7). The desired bicyclic lactams were afforded from
cyclopropanedicarboximide 4 and ethyl cyanoacetate, but the their yields
were lower (Table 2, entries 8, 9). No reaction was observed when the
acetylacetone and ethyl acetoacetate were employed as carbon nucleo-
philes in the presence of K2CO3 (Table 2, entries 10, 11). These results
suggested that no significant concentration of carbanion of ethyl cyanoa-
cetate was produced, and the deprotonation of acetylacetone and ethyl
acetoacetate was difficult in the presence of weakly basic K2CO3.
Table 2. Synthesis of bicyclic dicarboximides 6a–i
Entry
Ar
R
Y
X
Temp.ꢁC Yielda of 6 (%)
1
2
4-ClC6H4
4-BrC6H4
4-CH3OC6H4 Cyclohexyl
Cyclohexyl
Cyclohexyl
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
80
6a 70
6b 60
6c 71
6d 76
6e 80
6f 82
6g 80
6h 50
6i 43
0
3
4
4-CH3C6H4
C6H5
Cyclohexyl
Cyclohexyl
5
6
4-CH3OC6H4 Cyclopentyl
4-CH3C6H4 Cyclopentyl
4-ClC6H4 Cyclohexyl
4-CH3OC6H4 Cyclohexyl
7
8
9
10
11
12
13
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Cyclohexyl COCH3 COCH3
Cyclohexyl COCH3 CO2Et
Cyclohexyl
Cyclohexyl
0
CN
CN
CN
CN
6a 56
6a 0
aIsolated yield.
The results of Table 2 relate to Scheme 2.

Cyclopropane Ring Expansion
2219
The structures of compounds 6a–i were confirmed by 1H NMR, MS,
IR, and elemental analysis. The trans configuration of the compound 6
was assigned by nuclear overhauser effect (NOE) experiment. Interest-
ingly, this ring-expansion reaction is highly stereoselective. In all cases,
the trans configuration compound 6 is obtained as sole product, and
no cis isomer is observed.
A plausible mechanism for the formation of product 6 is shown in
Scheme 3. First, the carbanion A is generated by the deprotonation of active
methylene compound with K2CO3 used a base and subsequent the ring-
expansion reaction of cyclopropane with A occurs to give carbanion B, which
is stabilized by cyano and amide groups. The three possible conformers (C, D,
and E) may be given from B, which could lead to a trans or cis isomer. It is
obvious that the ring-closure reaction could not take place through confor-
mers D and E. So the conformation C controls reaction pathway to generate
trans configuration product 6. Next, the bicyclic intermediate F is formed via
the nucleophilic attack of the carbanion C to cyano group followed by the
protonation of the intermediate F to provide imine G. Then the product H
is afforded through the rearrangement of the imine G.
In conclusion, the ring-expansion reaction of cyclopropane with
carbon nucleophile was studied and the novel process for synthesis of
bicyclic dicarboximides from cyclopropanedicarboximides with malono-
nitrile or ethyl cyanoacetate was achieved.
Scheme 3. Proposed mechanism for the formation of 6.

2220
Z. Ren et al.
Figure 2. NOE spectrum of compound 6f.
EXPERIMENTAL
All reagents and solvents were obtained from commercial sources and
used without purification. All melting points were uncorrected. Melting
points were determined on WRS-1 digital melting-point apparatus made
by Shanghai Physical Instrument Factory (SPOIF), China. IR spectra
1
were measured in KBr on a PE-580B spectrometer. H NMR spectra
were recorded at a Bruker AM-300, using CDCl3 as solvent and TMS
as internal reference. Mass spectra were obtained on the Agilent
5973 N spectrometer. Elemental analyses were measured on the
Elemental Vario EL III. X-ray crystal data sets were collected with a Bru-
ker Smart Apex2 CCD.
General Procedure
Method A for Preparing 5,6-trans-dihydro-6-aryl-3-cyclics-
2,4-dioxo-3aza-bicyclo[3,1,0]hexan-1-carbonitrile 4a–g
A mixture of methoxycarbonylmethyltriphenylarsonium bromide (0.505 g,
1.1 mmol), arylidenecyanoactamides 3 (1 mmol), K2CO3 (0.165g, 1.2 mmol),
and a trace of water was stirred at room temperature in dimethoxyethane

Cyclopropane Ring Expansion
2221
(5 mL) for several hours. The completion of the reaction was determined
by TLC. The solid suspended in DME was filtered off, and the solvent
was removed off under reduced pressure at room temperature. The residue
was purified by a silica-gel chromatographic column with petroleum
ether–ethyl acetate (v:v 3:1) as eluant, and the crude product 4 was
obtained. The crude product 4 was washed by a small amount of 95%
ethanol and recrystallized by 95% ethanol.
Method B for Preparing 6,6a-trans-Dihydro-6-aryl-4-amino-2-
cycloalkyl-1,3-dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6a-g)
and 4,4a-trans-Dihydro-4-aryl-6-amino-6a-cyano-2-cyclohexyl-1,3-
dioxo-cyclopentene-5[c]pyrrole-,5-dicarboxylic Acid Ethyl Ester 6h–i
A
mixture of 5,6-trans-dihydrogen-6-aryl-3-cyclics-2,4-dioxo-3aza-
bicyclo[3,1,0]hexan-1-carbonitrile 4 (1 mmol), malononitrile or ethyl cya-
noacetate (0.66 g or 0.113 g, 1 mmol), and K2CO3 (0.414 g, 3 mmol ) was
stirred at room temperature in 5 mL of DME for several hours. The com-
pletion of the reaction was determined by TLC. The solid suspended in
DME was filtered off, and the solvent was removed off under reduced
pressure at room temperature. The residue was purified by a silica-gel chro-
matographic column with petroleum ether–ethyl acetate (v:v 3:1) as eluant,
and the crude product 6 was obtained. The crude product 6 was washed by
a small amount of 95% ethanol and recrystallized by 95% ethanol.
Data
5,6-trans-Dihydro-3aza-3-cyclohexyl-2,4-dioxo-6-(4-chlorophenyl)
bicyclo[3,1,0]hexan-1-carbonitrile (4a)
ꢁ
1
White solid, mp 191–192 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.18–1.38 (m, 3H), 1.58–1.70 (m, 3H), 1.84–1.88 (m, 2H), 2.00–2.13
(m, 2H), 3.09 (d, J ¼ 4.4 Hz, 1H), 3.43 (d, J ¼ 4.4 Hz, 1H), 3.82–3.93
(m, 1H), 7.22 (d, J ¼ 8.5 Hz, 2H), 7.42 (d, J ¼ 8.5 Hz, 2H); IR (KBr)
2249, 1710, 1599 cmꢂ1; MS (EI, 70 eV) m=z (%): 330 (Mþ þ 2, 1), 329
(Mþ þ 1, 2), 328 (Mþ , 3), 301 (100), 219 (78), 207 (65), 203 (47), 190
(64), 140 (43) 55 (47), 41 (40). Anal. calcd. for C18H17ClN2O2: C, 65.75;
H, 5.21; N, 8.52. Found: C, 65.92; H, 5.43; N, 8.30.
5,6-trans-Dihydro-3aza-3-cyclohexyl-2,4-dioxo-6-(4-bromophenyl)
bicyclo[3,1,0]hexan-1-carbonitrile (4b)
ꢁ
1
White solid, mp 186–187 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.19–1.38 (m, 3H), 1.56–1.70 (m, 3H), 1.84–1.88 (m, 2H), 2.00–2.13

2222
Z. Ren et al.
(m, 2H), 3.07 (d, J ¼ 4.7 Hz, 1H), 3.42 (d, J ¼ 4.7 Hz, 1H), 3.73–3.92
(m, 1H), 7.16 (d, J ¼ 8.5 Hz, 2H), 7.58 (d, J ¼ 8.5 Hz, 2H); IR (KBr)
2248, 1710, 1594 cmꢂ1; MS (EI, 70 eV) m=z (%): 249 (55), 247 (58), 168
(100), 140 (83), 67 (30), 55 (77), 43 (38), 41 (72). Anal. calcd. for
C18H17BrN2O2: C, 57.92; H, 4.59; N, 7.51. Found: C, 58.04; H, 4.60;
N, 7.40.
5,6-trans-Dihydro-3aza-3-cyclohexyl-2,4-dioxo-6-(4-methoxyphenyl)
bicyclo[3,1,0]hexan-1-carbonitrile (4c)
White solid, mp 174–175ꢁC (95% ethanol); 1H NMR (CDCl3, 300MHz) d
1.22–1.33 (m, 3H), 1.59–1.65 (m, 3H), 1.83–1.87 (m, 2H), 2.05–2.09 (m, 2H),
3.09 (d, J ¼ 4.2 Hz, 1H), 3.42 (d, J ¼ 4.2 Hz, 1H), 3.83 (s, 3H), 3.84–3.89
(m, 1H), 6.93 (d, J ¼ 8.4 Hz, 2H), 7.18 (d, J ¼ 8.4 Hz, 2H); IR (KBr)
2049, 1710, 1609 cmꢂ1; MS (EI, 70 eV) m=z (%): 324 (Mþ , 6), 200 (15),
199 (100), 184 (6), 171 (8), 156 (17), 128 (14), 41 (6). Anal. calcd.
for C19H20N2O3 C, 70.35; H, 6.21; N, 8.64. Found: C, 70.31; H, 6.28;
N, 8.37.
5,6-trans-Dihydro-3aza-3-cyclohexyl-2,4-dioxo-6-(4-methylphenyl)
bicyclo[3,1,0]hexan-1-carbonitrile (4d)
ꢁ
1
White solid, mp 161–162 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.18–1.37 (m, 3H), 1.59–1.69 (m, 3H), 1.83–1.87 (m, 2H), 2.00–2.12
(m, 2H), 2.36 (s, 3H), 3.08 (d, J ¼ 4.4 Hz, 1H), 3.43 (d, J ¼ 4.4 Hz, 1H),
3.82–3.93 (m, 1H), 7.14 (d, J ¼ 8.2 Hz, 2H), 7.25 (d, J ¼ 8.2 Hz, 2H);
IR (KBr) 2249, 1712, 1616 cmꢂ1; MS (EI, 70 eV) m=z (%): 308 (Mþ , 1),
184 (15), 183 (100), 182 (7), 155 (6), 154 (9), 140 (14), 128 (4), 127 (5). Anal.
calcd. for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.99;
H, 6.69; N, 9.01.
5,6-trans-Dihydro-3aza-3-cyclohexyl-2,4-dioxo-6-phenyl-bicyclo[3,1,0]-
hexan-1-carbonitrile (4e)
ꢁ
1
White solid, mp 197–198 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.17–1.34 (m, 3H), 1.60–1.70 (m, 3H), 1.84–1.88 (m, 2H), 2.00–2.09
(m, 2H), 3.12 (d, J ¼ 4.2 Hz, 1H), 3.47 (d, J ¼ 4.2 Hz, 1H), 3.84–3.92
(m, 1H), 7.25–7.29 (m, 3H), 7.40–7.45 (m, 2H); IR (KBr) 2251, 1705,
1500 cmꢂ1; MS (EI, 70 eV) m=z (%): 170 (14), 169 (100), 141 (12), 140
(15), 115 (4), 114 (8), 55 (5), 41 (4). Anal. calcd. for C18H18N2O2:
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.66; H, 6.28; N, 9.28.

Cyclopropane Ring Expansion
2223
5,6-trans-Dihydro-3aza-3-cyclopentyl-2,4-dioxo-6-(4-methoxyphenyl)
bicyclo[3,1,0]hexan -1-carbonitrile (4f)
ꢁ
1
White solid, mp 130–131 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.55–1.60 (m, 3H), 1.83–1.92 (m, 5H), 3.12 (d, J ¼ 4.7 Hz, 1H), 3.42
(d, J ¼ 4.7 Hz, 1H), 3.82 (s, 3H), 4.35–4.41 (m, 1H), 6.93 (d, J ¼ 8.6 Hz,
Hz, 2H), 7.19 (d, J ¼ 8.6 Hz, 2H); IR (KBr) 2246, 1707, 1611 cmꢂ1; MS
(EI, 70 eV) m=z (%): 310 (Mþ , 5), 200 (15), 199 (100), 184 (9), 171 (2),
156 (30), 128 (25), 67 (9), 41 (16). Anal. calcd. for C18H18N2O3:
C, 69.66; H, 5.85; N, 9.03. Found: C, 69.54; H, 5.88; N, 8.96.
5,6-trans-Dihydro-3aza-3-cyclopentyl-2,4-dioxo-6-(4-methylphenyl)
bicyclo[3,1,0]hexan-1-carbonitrile (4 g)
ꢁ
1
White solid, mp 168–169 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.53–1.61 (m, 3H), 1.83–1.92 (m, 5H), 2.37 (s, 3H), 3.12 (d, J ¼ 4.4 Hz,
1H), 3.44 (d, J ¼ 4.4 Hz, 1H), 4.36–4.41 (m, 1H), 7.14 (d, J ¼ 8.2 Hz,
2H), 7.25 (d, J ¼ 8.2 Hz, 2H); IR (KBr) 2244, 1707, 1518 cmꢂ1; MS
(EI, 70 eV) m=z (%): 294 (Mþ , 1), 184 (15), 183 (100), 155 (7), 154
(14), 140 (21), 128 (9), 127 (8), 41 (11). Anal. calcd. for C18H18N2O2:
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.52; H, 6.38; N, 9.40.
6,6a-trans-Dihydro-4-amino-6-(4-chloro-phenyl)-2-cyclohexyl-1,3-
dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6a)
ꢁ
1
White solid, mp 296–297 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.09–1.19 (m, 3H), 1.21–1.61 (m, 4H), 1.87–1.99 (m, 3H), 3.73–3.84 (m,
1H), 3.92 (d, J ¼ 10.4 Hz, 1H), 4.69 (d, J ¼ 10.4 Hz, 1H), 5.19 (br, s, 2H),
7.00 (d, J ¼ 8.3 Hz, 2H), 7.31 (d, J ¼ 8.3 Hz, 2H); IR (KBr) 3387, 3218,
2204, 1785, 1708, 1663 cmꢂ1; MS (EI, 70 eV) m=z (%): 396 (Mþ þ 2, 9),
395 (Mþ þ 1, 9), 394 (Mþ , 26), 359 (17), 284 (19), 243 (35), 242 (27), 241
(100), 206 (47), 55 (19). Anal. calcd. for C21H19ClN4O2: C, 63.88; H, 4.85;
N, 14.19. Found: C, 63.94; H, 4.71; N, 13.89.
6,6a-trans-Dihydro-4-amino-6-(4-bromo-phenyl)-2-cyclohexyl-1,3-
dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6b)
White solid, mp 316–317ꢁC (95% ethanol); 1H NMR (CDCl3, 300 MHz) d
1.10–1.22 (m 3H), 1.49–1.65 (m, 4H), 1.78–1.95 (m, 3H), 3.73–3.80
(m, 1H), 3.93 (d, J ¼ 10.4 Hz, 1H), 4.60 (d, J ¼ 10.4 Hz, 1H), 5.19 (br, s,
2H), 6.94 (d, J ¼ 8.2 Hz, 2H), 7.48 (d, J ¼ 8.2 Hz, 2H); IR (KBr) 3387,

2224
Z. Ren et al.
3218, 2204, 1784, 1708, 1663 cmꢂ1; MS (EI, 70 eV) m=z (%): 440 (Mþ þ 2,
7), 439 (Mþ þ 1, 2), 438 (Mþ , 7), 287 (66), 286 (26), 285 (65), 206 (68), 179
(27), 83 (52), 55 (100), 41 (60). Anal. calcd. for C21H19BrlN4O2: C, 57.41;
H, 4.36; N, 12.75. Found: C, 57.38; H, 4.46; N, 12.35.
6,6a-trans-Dihydro-4-amino-2-cyclohexyl-6-(4-methoxy-phenyl)-1,3-
dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6c)
ꢁ
1
White solid, mp 327–328 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.13–1.25 (m, 3H), 1.47–1.63 (m, 4H), 1.76–1.91 (m, 3H), 3.73–3.84
(m, 4H), 3.90 (d, J ¼ 10.4 Hz, 1H), 4.69 (d, J ¼ 10.4 Hz, 1H), 5.15
(br, s, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 6.97 (d, J ¼ 8.6 Hz, 2H); IR (KBr)
3394, 3218, 2208, 1782, 1707, 1665 cmꢂ1; MS (EI, 70 eV) m=z (%): 391
(Mþ þ 1, 6), 390 (Mþ , 25), 238 (21), 237 (100), 236 (24), 222 (20), 108
(16), 55 (47), 41 (31). Anal. calcd. for C22H22N4O3: C, 67.68; H, 5.68;
N, 14.35. Found: C, 67.55; H, 5.44; N, 14.68.
6,6a-trans-Dihydro-4-amino-2-cyclohexyl-6-(4-methyl-phenyl)-1,3-
dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6d)
ꢁ
1
White solid, mp 279–280 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.09–1.24 (m, 3H), 1.47–1.63 (m, 4H), 1.80–1.96 (m, 3H), 2.33 (s, 3H),
3.73–3.81 (m, 1H), 3.91 (d, J ¼ 10.5 Hz, 1H), 4.67 (d, J ¼ 10.5 Hz, 1H),
5.15 (br, s, 2H), 6.93 (d, J ¼ 8.0 Hz, 2H), 7.14 (d, J ¼ 8.0 Hz, 2H); IR
(KBr) 3391, 3219, 2204, 1785, 1708, 1663 cmꢂ1; MS (EI, 70 eV) m=z
(%): 375 (Mþ þ 1, 4), 374 (Mþ , 17), 222 (21), 221 (100), 220 (19), 206
(21), 83 (9), 55 (28), 42 (18). Anal. calcd. for C22H22N4O2: C, 70.57; H,
5.92; N, 14.96. Found: C, 70.89; H, 5.92; N, 14.69.
6,6a-trans-Dihydro-4-amino-2-cyclohexyl-6-(phenyl)-1,3-dioxo-
cyclopentene-4[c]pyrrole-3a, 5-dicarbonitrile (6e)
ꢁ
1
White solid, mp 252–253 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.03–1.25 (m, 3H), 1.42–1.85 (m, 4H), 1.85–1.98 (m, 3H), 3.70–3.81
(m, 1H), 3.92 (d, J ¼ 10.5 Hz, 1H), 4.70 (d, J ¼ 10.5 Hz, 1H), 5.23
(br, s, 2H), 7.05–7.7 (m, 2H), 7.33–7.38 (m, 3H); IR (KBr) 3397, 3219,
2203, 1786, 1712, 1661 cmꢂ1; MS (EI, 70 eV) m=z (%): 361 (Mþ þ 1, 3),
360 (Mþ , 13), 250 (10), 208 (22), 207 (100), 206 (21), 83 (9), 55 (26),
41 (16). Anal. calcd. for C21H20N4O2: C, 69.98; H, 5.59; N, 15.55. Found:
C, 70.11; H, 5.48; N, 15.54.

Cyclopropane Ring Expansion
2225
6,6a-trans-Dihydro-4-amino-2-cyclopentyl-6-(4-methoxy-phenyl)-1,3-
dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6f)
ꢁ
1
White solid, mp 235–236 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.52–1.66 (m, 3H), 1.67–1.81 (m, 5H), 3.80 (s, 3H), 3.93 (d, J ¼ 10.4 Hz,
1H), 4.24–4.27 (m, 1H), 4.67 (d, J ¼ 10.4 Hz, 1H), 5.17 (br, s, 2H), 6.86
(d, J ¼ 8.8 Hz, 2H), 6.96 (d, J ¼ 8.8 Hz, 2H); IR (KBr) 3388, 3219,
2208, 1783, 1709, 1665 cmꢂ1; MS (EI, 70 eV) m=z (%): 377 (Mþ þ 1, 9),
376 (Mþ , 33), 237 (95), 236 (28), 91 (30), 57 (25), 43 (37), 41 (54), 40
(100). Anal. calcd. for C21H20N4O3: C, 67.01; H, 5.36; N, 14.88. Found:
C, 67.27; H, 5.45; N, 14.73.
6,6a-trans-Dihydro-4-amino-2-cyclohexyl-6-(4-methyl-phenyl)-1,3-
dioxo-cyclopentene-4[c]pyrrole-3a,5-dicarbonitrile (6g)
ꢁ
1
White solid, mp 249–250 C (95% ethanol); H NMR (CDCl3, 300 MHz)
d 1.50–1.65 (m, 3H), 1.67–1.84 (m, 5H), 2.33 (s, 3H), 3.93 (d, J ¼ 10.4 Hz,
1H), 4.20–4.26 (m, 1H), 4.66 (d, J ¼ 10.4 Hz, 1H), 5.20 (br, s, 2H), 6.92
(d, J ¼ 8.2 Hz, 2H), 7.14 (d, J ¼ 8.2 Hz, 2H); IR (KBr) 3390, 3218,
2208, 1786, 1712, 1664 cmꢂ1; MS (EI, 70 eV) m=z (%): 361 (Mþ þ 1, 6),
360 (Mþ , 24), 345 (12), 275 (15), 222 (19), 221 (100), 220 (19), 206
(22), 41 (20). Anal. calcd. for C21H20N4O2: C, 69.98; H, 5.59; N, 15.55.
Found: C, 69.90; H, 5.40; N, 15.74.
4,4a-trans-Dihydro-6-amino-4-(4-chloro-phenyl)-6a-cyano-2-
cyclohexyl-1,3-dioxo-cyclopentene-5[c]pyrrole-,5-dicarboxylic acid
ethyl ester (6h)
White solid, mp 193–194ꢁC (95% ethanol); 1H NMR (CDCl3, 300 MHz) d
0.92 (tr, J ¼ 7.1 Hz, 3H), 1.13–1.24 (m, 3H), 1.41–1.62 (m, 4H),
1.76–1.81 (m, 3H), 3.74–3.81 (m, 1H), 3.94 (d, J ¼ 10.7 Hz, 1H), 4.00 (d,
J ¼ 10.7Hz, 1H), 4.69 (q, J ¼ 7.1 Hz, 2H), 6.10 (br, s, 2H), 7.22 (br, s,
4H); IR (KBr) 3472, 3319, 2248, 1786, 1709, 1676cmꢂ1; MS (EI, 70 eV)
m=z (%): 443 (Mþ þ 2, 4), 442 (Mþ þ 1, 3), 441 (Mþ , 11), 290 (33), 288
(92), 217 (36), 216 (30), 215 (100), 55 (56), 41 (46). Anal. calcd. for
C23H24ClN3O4: C, 62.51; H, 5.47; N, 9.51. Found: C, 62.56; H, 5.14; N, 9.30.
4,4a-trans-Dihydro-6-amino-6a-cyano-4-(4-methoxy-phenyl)-2-cyclohexyl-
1,3-dioxo-cyclopentene-5[c]pyrrole-,5-dicarboxylic acid ethyl ester (6i)
White solid, mp 188–189ꢁC (95% ethanol); 1H NMR (CDCl3, 300 MHz) d
0.92 (tr, J ¼ 7.1 Hz, 3H), 1.12–1.25 (m, 3H), 1.42–1.61 (m, 4H), 1.73–1.79

2226
Z. Ren et al.
(m, 3H), 3.67–3.73 (m, 1H), 3.76 (s, 3H), 3.89 (d, J ¼ 10.7 Hz, 1H), 3.96
(q,J ¼ 7.1 Hz, 2H), 4.67 (d, J ¼ 10.7 Hz, 1H), 6.08 (br, s, 2H), 6.08 (br, s,
4H); IR (KBr) 3446, 3335, 2254, 1785, 1709, 1676 cmꢂ1; MS (EI, 70 eV)
m=z (%): 438 (Mþ þ 1, 7), 437 (Mþ , 23), 284 (54), 239 (41), 238 (41),
237 (32), 212 (25), 211 (100), 55 (57). Anal. calcd. for C24H27N3O5:
C, 65.89; H, 6.22; N, 9.60. Found: C, 65.83; H, 5.85; N, 9.38.
ACKNOWLEDGMENT
Thanks are due to the National Natural Science Foundation of China
and Natural Science Foundation of Shanghai for financial support
(Nos. 20472047 and 04ZR 14060).
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