Dipolar cycloadditions of imidazoline 3-oxides with N-arylmaleimides. Synthesis and diethylamine induced ring-opening of exo and endo hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-diones

Article abstract of DOI:10.1016/j.tet.2005.11.038

1,4-Diarylimidazoline 3-oxides react with N-arylmaleimides in benzene to give predominantly the corresponding endo adducts. Chiral imidazoline 3-oxides react diastereospecifically (cis configuration of the tetrahydroimidazo ring) and diastereoselectively to give cis-endo adducts. The effects of substituents on the aromatic ring of the maleimide was investigated. The presence of electron-withdrawing or releasing groups have minor effect on the total yields but more pronounced is the effect on the ratio of exo and endo diastereomers. The adducts undergo an interesting and unprecedented ring-opening in the presence of secondary amines to give deoxygenated 3-imidazoline 3-oxides instead of the expected double cis elimination products. Tertiary amines did not induce any reaction.

Full text of DOI:10.1016/j.tet.2005.11.038

Tetrahedron 62 (2006) 1351–1359
Dipolar cycloadditions of imidazoline 3-oxides with
N-arylmaleimides. Synthesis and diethylamine induced
ring-opening of exo and endo
hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-diones
*
Necdet Cos¸kun, Habibe Mert and Nevin Arıkan
˘
¨ ¨
Department of Chemistry, Uludag University, 16059 Gorukle Bursa, Turkey
Received 13 August 2005; revised 31 October 2005; accepted 17 November 2005
Available online 9 December 2005
Abstract—1,4-Diarylimidazoline 3-oxides react with N-arylmaleimides in benzene to give predominantly the corresponding endo adducts.
Chiral imidazoline 3-oxides react diastereospecifically (cis configuration of the tetrahydroimidazo ring) and diastereoselectively to give
cis–endo adducts. The effects of substituents on the aromatic ring of the maleimide was investigated. The presence of electron-withdrawing
or releasing groups have minor effect on the total yields but more pronounced is the effect on the ratio of exo and endo diastereomers. The
adducts undergo an interesting and unprecedented ring-opening in the presence of secondary amines to give deoxygenated 3-imidazoline
3-oxides instead of the expected double cis elimination products. Tertiary amines did not induce any reaction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
subject them to ring-opening in the presence of secondary
and tertiary amines.8 The latter reaction would serve as an
important entry into the synthesis of chiral 3-hydroxypyrro-
lidines, which have attracted attention after the discovery
of the glycosidase inhibitor activity of the natural product
nojirimycin.9 The retrosynthetic plan related to the synthesis
of chiral pyrrolidin-3-ols is depicted in Scheme 1. (S)-
Nitrone would give the exo and endo adducts; the
ring-opening of the exo adduct would give (S)-pyrrolidin-
2,5-diones while endo would give (R), and the reduction of
both would give the corresponding chiral pyrrolidin-3-ols.
The reverse will be true if we start from (R)-nitrone.
Nitrones are well-known 1,3-dipoles in thermal cyclo-
addition reactions with multiple bond systems to provide
various heterocyclic five membered ring systems.1 The
cycloadducts of di- and triarylimidazoline 3-oxides2 with a
variety of dipolarophiles3 give bicyclic compounds with
potentially interesting biological activity.4 On the other
hand, they are source of new heterocyclic compounds via
interesting ring-opening reactions.5 In our previous work,
the 1,3-dipolar cycloadditions of imidazoline 3-oxides was
shown to proceed regio- and diastereoselectively and
interesting reactions of these adducts under a variety
of conditions especially the double cis elimination they
undergo in the presence of dialkylamines was reported.3d–e,5
exo Adducts of N-methyl and N-phenylmaleimides with
chiral 1-benzyl-4-phenyl-2-imidazoline 3-oxide were
reported recently.6 As a continuation of our interest in the
synthesis of imidazoisoxazolidines with potential anticancer
activity and in the stereochemistry of dipolar cycloadditions
of 1,4-diaryl and 1,2,4-triarylimidazoline 3-oxides with
different dipolarophiles, we planned to react a series of
N-arylmaleimides with imidazoline 3-oxides7 1 and to
For the most widely studied nitrone, C-phenyl-N-methylni-
trone, the frontier orbital energies indicate HOMO control
for electron-deficient dipolarophiles.10 Our observations on
the cycloadditions of compounds 1 with electron deficient
dipolarophiles corroborate the conclusion that the process
is HOMO controlled. In this investigation we were
also interested in the effect of substituents on the N-aryl
group of the maleimide on the reaction yield and the
exo–endo selectivity of the cycloaddition reaction with
cyclic nitrones 1. The problem of endo–exo selectivity in
1,3-dipolar cycloadditions is far from definitively assessed
and the endo–exo selectivity of the cycloaddition of
3,4-dihydroisoquinoline 2-oxide with different types of
dipolarophiles was reported.11a The exo–endo selectivity
of 1,3-dipolar cycloaddition of C,N-diphenylnitrone to
Keywords: Cyclic nitrone; 1,3-Dipolar cycloaddition; 3-Imidazoline
3-oxides; sec-Amine induced ring-opening; 3-Imidazoline.
Corresponding author. Tel.: C90 44292561308; fax: C90 4428022;
e-mail: coskun@uludag.edu.tr
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.038

1352
N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
O
O
Ar
O
H
Ar
O
Ar
H
R N
R1
Ph
N
N
N
N
O
HO
H
Ph
O
HO
HO
H
H
R N
R1
(S)-pyrrolidin-3-ol
exo
N
O
O
Ar
H
Ar
O
H
Ph
N
H
Ar
N
N
N
R N
R1
(S)-Nitrone
O
O
HO
(R)-pyrrolidin-3-ol
H
H
H
endo
Scheme 1. Retrosynthetic analysis for the asymmetric synthesis of pyrrolidin-3-ols.
tert-butyl vinyl ether in the presence of chiral Ti(IV) species
was recently reported.11
The cycloaddition nearly completes within 10 h in the cases
where C-2 of the nitrone is unsubstituted, while in the cases
of C-2 aryl substituted nitrones 1c–e the reaction time was
five times longer to achieve the same yields due to the steric
hindrance of the aryl groups. The exo–endo ratio is
approximately the same in the cycloaddition of nitrones
1a–d with N-phenylmaleimide. The ratio is close to 1:1 in
the case of 1e (C-2 substituent is 3-nitrophenyl group) the
steric hindrance of which probably does not support the
formation of the transition state leading to the endo adduct.
To understand the role of the substituents on the N-aryl
group of 2 it is useful to compare the exo–endo ratio of
cycloadditions with 1a,f–i (Table 2). It is seen that the
electron-donating groups favor the formation of endo
adducts, while electron-withdrawing groups do not. Beside
the steric effects contributing to the exo–endo ratio,
secondary orbital interactions between the aryl rings at
N-2 and N-5 and may be between N-5 and the carbonyls at
the pyrrolidine ring are probably also responsible for the
stabilization of the transition state leading to endo adduct.
The effect of substituents on the total yields of adducts 3 and
4 are of the same magnitude independent of their nature.
This means electron-donating groups somewhat increase the
LUMO energy of the electron deficient maleimide and thus
decelerate the exo adduct formation. Computations of the
HOMO and LUMO energies for maleimides 2 confirmed
this. On the other hand, computation of the HOMO and
LUMO energies for nitrone 1a and comparison with the
corresponding HOMO and LUMO energies of maleimides 2
clearly revealed that the cycloaddition should be a HOMO
controlled process. The same electron-donating substituent
probably raises the energy of N-2 phenyls HOMO to give a
better p interaction between the N-5 aryl. Conversely,
electron-withdrawing groups decrease the LUMO energy of
the electron deficient maleimide thus accelerating the exo
We report herein the synthesis and ring-opening reactions of
a new class of compounds, namely hexahydro-7-oxa-2,5,6a-
triaza-cyclopenta[a]pentalene-1,3-diones. The reaction of
nitrones 1a–i with N-arylmaleimides 2 in benzene and
toluene was shown to proceed selectively to give the endo
adducts as major products. The exo–endo ratio increases
when electron-donating groups are present on the N-2 aryl,
and decreases when the groups are electron-withdrawing.
The reaction of adducts 3 and 4 separately or their mixture
with diethylamine led to a so far unobserved interesting
ring-opening to give di- and triaryl-3-imidazolines 5 instead
of the expected double cis elimination products. The
mechanism of this reaction is also briefly discussed.
2. Results and discussions
To elucidate the solvent effect on the rate and product ratio
of the dipolar cycloaddition, nitrone 1a was refluxed in
different solvents in the presence of 4 equiv of N-phenyl-
maleimide (Scheme 2 and Table 1). The reaction was
observed to proceed much faster in solvents such as
benzene, acetonitrile and toluene. The reaction proceeds
with higher endo selectivity in toluene while the cyclo-
addition in dichloromethane, THF and acetonitrile was
unselective. The reaction is too slow in DCM, 39% yield
was achieved after 48 h reflux.
At first we decided to develop the model reaction starting
with racemic nitrones 1. Compounds 1a–i were reacted with
maleimides 2 in benzene to give adducts 3 and 4 in high
total yields (Scheme 2 and Table 2).
O
Ar
N
Ph
R N
Ph
Ph
O
N
O
O
3
ii
i
R1
+
N
N
N
N
R
O
Ar
R
Ph
N
R1
R1
R N
O
5
N
1
O
R1
4
Scheme 2. Reagents and reaction conditions; (i) 4 equiv N-arylmaleimide 2; benzene, reflux; (ii) Diethylamine, reflux, 23 h.

N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
1353
Table 1. Solvent effect on the 1,3-dipolar cycloaddition of 1a with
N-phenylmaleimide
The exo stereochemistry of adducts 3a–b,f–i was confirmed
by NOESY1D experiments performed on compound 3a
(Fig. 1) as follows:
Solvent
Reaction
time (h)
Total yield
(%)
Yield (%)
3a
4a
Irradiation of proton at C-7a enhanced the signal of 3aH
(1%). Irradiation of the doublet of 6Ha enhanced the signals
of 6Hb (12.72%) and ortho protons of N-tolyl group
(6.66%). The irradiation of 6Hb enhances the signal of 6Ha
(13.62%) and the ortho protons’ signals of N-tolyl (3.92%)
and 3b-phenyl (2.93%). Irradiation of 4Hb, enhanced
the signals of 4Ha, and the ortho protons of both phenyls
at N-5 and C-3b by 19.0, 6.81, and 9.13%, respectively.
The irradiation of 3aH enhances the signals of 7aH (3.3%),
4Ha (3.09%) and ortho protons of 3b-phenyl by 0.5%.
Irradiation of 4Ha enhances the signals of 4Hb (18.7%), 3aH
(6.17%), 7a (1%), and ortho protons of N-tolyl group. 7aH
was irradiated to give enhancement for 3aH (1.75%) and
the ortho protons of N-phenyl group at 7.04 ppm (4.0%).
Benzene
Toluene
THF
DCM
Acetonitrile
10
10
10
48a
10
100
80
56
39
86
35
24
23
19
45
65
57
33
20
41
a The yield of the reaction for 10 h reaction time is 12% and the ratio of exo
and endo isomers is 1:2.
adduct formation but lower the p interaction between the
N-5 aryl.
Some characteristic assignments for adducts 3 and 4 based
on extensive 1D and 2D NMR experiments are given in
Table 3.
Table 2. Synthesis of hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-diones 3a–i and 4a–i
Entry
R
R1
Ar
Total yield
Yield (%) of
exo–endoa
3
4
a
b
c
d
e
f
g
h
i
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
H
Ph
Ph
Ph
Ph
100b
100b
90c
35
38
33
32
33
24
35
36
28
65
62
57
60
41
69
50
52
60
1:1.86
1:1.63
1:1.73
1:1.87
1:1.24
1:2.88
1:1.43
1:1.44
1:2.14
H
4-MeOC6H4
4-MeOC6H4
3-NO2C6H4
H
H
H
H
92c
Ph
74c
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
93b
85b
88b
88b
a The ratio of the isolated adducts.
b Reaction time 10 h.
c Reaction time 51 h.
Table 3. Characteristic 1H NMR spectroscopic data for exo and endo adducts 3 and 4
exo
endo
3aH
4Ha
4Hb
6Ha
6Hb
7aH
3a
4Ha
4Hb
6Ha
6Hb
7aH
3a
3b
3c
3d
3e
3f
3g
3h
3i
3.98
3.98
3.92
3.92
3.92
3.96
4.02
3.97
3.95
3.80
3.79
3.96
3.96
3.96
3.79
3.81
3.79
3.78
4.17
4.12
4.61
4.61
4.70
4.16
4.19
4.16
4.15
4.79
4.76
4.53
4.53
5.81
5.76
5.85
5.17
5.17
5.17
5.19
5.21
5.15
5.21
5.16
5.14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4.02
4.01
4.04
4.04
4.06
4.01
4.05
4.01
4.01
3.11
3.05
4.77
4.71
4.69
3.10
3.08
3.08
3.10
4.60
4.56
3.87
3.85
3.95
4.58
4.62
4.59
4.59
4.49
4.44
4.66
4.63
5.64
5.63
5.76
5.15
5.15
5.16
5.17
5.22
5.15
5.19
5.15
5.14
4.78
4.79
4.78
4.78
4.52
4.49
4.47
4.48
4.49
4.65
4.54
4.52
4.52
4.59
4.63
4.65
3.98
4.17
O
3.8
H
Hb
Ha
N
N
3a
1
4
7
O
O
N
5.17
H
6
Ha
4.79
Hb
4.53
Figure 1. Some selected chemical shifts assignments for 3a and its energy minimised 3D model (total energy 99.4078 kcal/mol).

1354
N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
4.02
O
4.60
3.11
H
N
Hb
Ha
3a
1
4
7
N
O
N
O
H
5.15
6
Ha
Hb
4.66
4.49
Figure 2. Some selected chemical shifts assignments for 4a and its energy minimised 3D model (total energy 99.0050 kcal/mol).
7.59
4.04
3.87
O
4.77
H
Hb
Ha
N
3a
1
4
N
6
7
O
O
N
H
5.16
Ha
5.64
6.39
7.13
O
Figure 3. Some selected chemical shifts for cis–endo adduct 4c and its energy minimised 3D model (total energy 27.2092 kcal/mol).12
Finally, the ortho protons of 3b-phenyl were irradiated to
give enhancements for the signals of 4Hb (2.11%) and 6Hb
(0.5%). The energy minimised conformations of com-
pounds 3a, 4a and 4c (see Figs. 1–3) are supporting the
observed correlations by NOESY1D experiments. On the
other hand, the total energy of 3a was by 0.4028 kcal/mol
higher than that of 4a.
4Ha enhanced the signals of 4Hb (27.8%) and the signals
of N- and C-3b-phenyls’ ortho protons by 10.0 and 2.71%,
respectively. The irradiation of C-6H enhanced the
signals of C-6 phenyls and N-5 phenyls ortho protons.
This unequivocally proves the cis–endo configuration of
compounds 4c–e.
According to the developed procedure isolated, compounds
3 and 4 or their mixture were refluxed in diethylamine in
order to prepare the racemic mixtures of pyrrolidin-3-ols as
in Scheme 1, however, this treatment led to the formation of
new 3-imidazolines 5a–e (Scheme 2 and Table 4). The
compounds were easily characterized by elemental analyses
and spectral methods. The characteristic IR frequencies for
C]N appears at ca.1630 cmK1. The methylenes at C-2 and
C-5 in the cases of 5a–b appear as two proton triplets as a
results of long range coupling between them. The long range
The NOESY1D experiment results for endo adduct 4a are as
follows: irradiation of 6Ha enhanced the signals of 6Hb
(17.2%), the ortho protons of N-tolyl group (3.07%) and
4Ha (0.66%). The irradiation of 4Ha enhanced the signals of
4Hb (19.18%), ortho protons of N-tolyl and 3b-phenyl by
1.69 and 0.9%, respectively. Irradiation of 3aH enhanced
the signals of 7aH and 3b-phenyls ortho protons by 3.3 and
2.66%, respectively. Irradiation of 4Hb enhances the signal
of 4Ha by 17.71% and the ortho protons of N-tolyl and
3b-phenyl by 7.30 and 2.59%. Irradiation of ortho protons
of 3b-phenyl enhances the signals of 4Hb and 3aH by 1.5
and 1%, respectively.
Table 4. Synthesis of 3-imidazolines 5a–e
Starting
material
Product
Yield (%)
Mp (8C)
To prove the cis orientation of the phenyls at C-3b and C-6
we have irradiated the corresponding protons at the
imidazolidine and isoxazolidine rings of 4c as follows: the
proton at C-3a was irradiated to give enhancements for
the C-3b-phenyls’ ortho protons (3.61%) and for the 7aH
(3.98%). 4Hb was irradiated to give enhancements for 4Ha
(27.0%) and the ortho protons of the phenyls at C-3b, N-5
and C-6 by 2.84, 2.58 and 4.13%, respectively. Irradiation of
3aC4a
3bC4b
4c
5a
5b
5c
5c
5d
5e
5e
90
100a
92
98
88
117–119
129–130
176–178
176–178
152–153
182–184
182–184
3c
3dC4d
3e
4e
92
92
a The reaction time was 23 h for all entries except for entry 2 where the
reaction time is 39 h.

N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
1355
Ar
NH
O
O
A
Ar
NH
O
O
Ph
N
Ar
O
Ar
Ph
N
N
O
Et2NH
R
N
N
N
N
R
N
+
R
O
H
H
N
N
O
R1
HO
R1
R1
3 + 4
5
Scheme 3. Proposed mechanism for the conversion of adducts 3 and 4 into 5.
coupling is observed between the protons at C-2 and the AB
system at C-5 in the cases of 5c–d.
Compounds 3a,c and 4a,c were refluxed in triethylamine for
48 h but no conversion was observed, the starting materials
were recovered unchanged.
The probable mechanism for the ring-opening of com-
pounds 3 and 4 in diethylamine is depicted in Scheme 3. The
nucleophilic attack of diethylamine leads to intermediate A
(isolated in the case of 4b), which probably undergo
diethylamine assisted synchronous ring-opening to give
imidazolines 5 and the corresponding oxaloacetic acid
amides. The isolated and characterized A (5-(4-methoxy-
phenyl)-3a-phenyl-hexahydroimidazo[1,5-b]isoxazole-
2,3-dicarboxylic acid 2-diethylamide 3-phenylamide 4b0,
was isolated from the reaction of 3b and 4b in diethylamine
for 23 h) was refluxed in diethylamine for 23 h to give
imidazoline 5b in 92% yield.
3. Conclusions
In conclusion, we studied the reaction of imidazoline
3-oxides 1 with of N-arylmaleimides 2. The reactions of
nitrones 1a–b,f–i with N-arylmaleimides 2 in benzene give
predominantly the corresponding endo adducts 4a–b,f–i.
Chiral imidazoline 3-oxides 1c–e react diastereospecifically
with respect to the cis configuration in the tetrahydro-
imidazo ring and diastereoselectively to give cis–endo
adducts 4c–e.The effect of substituents on the phenyl ring of
the maleimide was investigated. The presence of electron-
withdrawing or releasing groups have minor effects on the
total yields but the effect on the ratio of exo and endo
diastereomers is more pronounced. The exo–endo ratio
increases when electron-donating groups are present on the
N-2 aryl, and decreases when the groups are electron-
withdrawing. Adducts 3 and 4 undergo an interesting ring-
opening in the presence of secondary amines to give the
deoxygenated 3-imidazoline 3-oxides 5 instead of the
expected double cis elimination products. This reaction
will serve as a convenient method for the synthesis of
otherwise inaccessible 3-imidazolines. Tertiary amines did
not induce any reaction.
To prove the structure of 5-(4-methoxyphenyl)-3a-phenyl-
hexahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylic acid
2-diethylamide 3-phenylamide 4b0 we have performed
NOESY1D experiments as follows: irradiation of C-4Hb
proton led to enhancement of the signals of C-4Ha
(18.05%), p-anisyl (3.58%) and C-3b phenyls (4.27%)
ortho protons. While the irradiation of C-4Ha enhances the
signals of C-4Hb (16.34%), N-p-anisyl (7.20%) and C-3b
phenyls ortho protons (1.3%). Irradiation of C-3H enhanced
the signals of C-2H (4.09%), C-3b phenyls ortho protons
(2%) and the amide proton at 8.89 ppm. The latter
correlation was indicative for the determination of the
right regioisomer. Thus, all these experiments allowed us to
assign the configuration shown in Figure 4.
4. Experimental
4.1. General
3.79
172.4(calcd 174.4)
Melting points were recorded on an Electrothermal Digital
melting point apparatus. Infrared spectra were recorded on
a Mattson 1000 FTIR. 1D and 2D NMR experiments
were performed on a Varian Mercury Plus 400 MHz
spectrometer. Visualisation was effected with UV light.
Imidazoline 3-oxides 1a–e were prepared according to the
method we have recently reported.7 The elemental analyses
were performed on a EuroEA 3000 CHNS analyser. The
total energies of compounds 3a, 4a, 4c, cis–exo 3c and the
FMO energy calculations for maleimides 2 and nitrone 1a
were performed using CS MOPAC Pro in ChemOffice 6.
8.89
168.6(calcd 168.0)
3.15
4.12
Ph
NH
O
O
H
Hb
Ha
N
Ph
O
N
N
O
H
Hb
Ha
3.95
4.95
4.72
Figure 4. Some characteristic chemical shifts for intermediate bisamide 4b0.
4.1.1. 1,2-Bis-(4-methoxyphenyl)-4-phenyl-2,5-dihydro-
1H-imidazole 3-oxide 1d. Yield, 2.0 g, 23%; white needles;
1
mp 200–201.5 8C; IR (KBr) nC]N 1610 cmK1; H NMR d
exo Adduct 3a was shown to give nucleophilic addition
product faster than endo adduct 4a. The reaction times for
the disappearance of the corresponding adducts (TLC
controls) were 1.5 and 6 h, respectively.
3.73 (3H, s), 3.80 (3H, s), 4.81 (1H, dd, JZ14.0, 3.2 Hz),
5.14 (1H, dd, JZ14.0, 5.6 Hz), 6.10 (1H, dd, JZ5.6,
3.2 Hz), 6.57 (2H, d, JZ8.8 Hz), 6.82 (2H, d, JZ8.8 Hz),

1356
N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
6.94 (2H, d, JZ8.4 Hz), 7.45–7.49 (3H, m), 7.56 (2H, d,
JZ8.4 Hz), 8.34 (2H, dd, JZ7.6, 3.6 Hz). 13C NMR d 53.4;
55.6; 55.9; 90.0; 113.9; 114.6; 115.3; 127.2; 128.9; 129.0;
129.6; 131.1; 134.5; 136.9; 138.8; 153.0; 161.2. Anal. Calcd
for C23H22N2O3 (374.43) C, 73.78; H, 5.92; N, 7.48; found
C, 73.75; H, 5.90; N, 7.45.
4.2.2. exo-5-(4-Methoxyphenyl)-2,3b-diphenyl-hexa-
hydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-
dione 3b. Yield 0.020 g, 38%; white needles; mp
120–121 8C; IR (KBr) nC]O 1716 cmK1
;
1H NMR
(400 MHz, CDCl3): d 3.74 (3H, s), 3.79 (1H, d,
JZ8.4 Hz), 3.98 (1H, d, JZ7.2 Hz), 4.12 (1H,
d, JZ8.8 Hz), 4.53 (1H, d, JZ11.2 Hz), 4.76 (1H, d,
JZ11.2 Hz), 5.17 (1H, d, JZ7.2 Hz), 6.46 (2H, d,
JZ8.8 Hz), 6.83 (2H, d, JZ9.2 Hz), 6.99 (2H, d, JZ
7.6 Hz), 7.30–7.40 (6H, m), 7.56 (2H, d, JZ7.2 Hz). 13C
NMR (100 MHz, CDCl3): d 56.1; 56.9; 57.2; 71.5; 77.3;
80.8; 113.3; 115.4; 126.2; 126.5; 129.0; 129.1; 129.2; 129.4;
131.3; 136.1; 140.5; 152.3; 171.2; 174.1. Anal. Calcd for
C26H23N3O4 (441.48) C, 70.73; H, 5.25; N, 9.52; found C,
70.80; H, 5.40; N, 9.42.
4.1.2. 1-(4-Methoxyphenyl)-2-(3-nitrophenyl)-4-phenyl-
2,5-dihydro-1H-imidazole 3-oxide 1e. Yield 2.38 g, 26%;
yellow needles; mp 190–191 8C; nC]N 1610 cmK1 1H
;
NMR (400 MHz, CDCl3): d 3.80 (3H, s), 4.86 (1H, dd,
JZ14.0, 3.2 Hz), 5.26 (1H, dd, JZ14.0, 5.6 Hz), 6.25 (1H,
dd, JZ5.6, 3.2 Hz), 6.55 (2H, d, JZ9.2 Hz), 6.84 (2H, d,
JZ9.2 Hz), 7.48–7.52 (3H, m), 7.65 (1H, t, JZ7.6 Hz),
8.06 (1H, d, JZ8.0 Hz), 8.29–8.33 (3H, m), 8.51 (1H, t,
JZ2.0 Hz). 13C NMR (100 MHz, CDCl3): d 53.9; 55.9;
89.1; 114.2; 115.5; 123.2; 123.4; 126.9; 127.2; 129.1; 130.1;
131.7; 134.9; 135.6; 138.3; 138.5; 148.0; 153.7. Anal. Calcd
for C22H19N3O4 (389.40) C, 67.86; H, 4.92; N, 10.79; found
C, 67.83; H, 4.90; N, 10.75.
4.2.3. exo-6-(4-Methoxyphenyl)-2,3b-diphenyl-5-p-tolyl-
hexahydro-7-oxa-2,5,6a-triaza cyclopenta[a]pentalene-
1,3-dione 3c. Yield 0.021 g, 33%; white needles; mp
167–168 8C; IR (KBr) nC]O 1712 cmK1
;
1H NMR
(400 MHz, CDCl3): d 2.23 (3H, s), 3.70 (3H, s), 3.92 (1H,
d, JZ7.6 Hz), 3.96 (1H, d, JZ9.2 Hz), 4.61 (1H, d, JZ
9.2 Hz), 5.17 (1H, d, JZ7.6 Hz), 5.81 (1H, s), 6.43 (2H, d,
JZ8.8 Hz), 6.58 (2H, d, JZ8.4 Hz), 6.89–7.18 (10H, m),
7.18–7.51 (4H, m). 13C NMR (100 MHz, CDCl3): d 20.5;
55.5; 57.5; 57.7; 77.0; 79.7; 85.5; 113.4; 113.5; 126.1;
127.0; 127.4; 128.2; 128.6; 128.9; 129.1; 129.3; 129.9;
130.2; 131.3; 135.3; 144.0; 159.5; 171.1; 174.1. Anal. Calcd
for C33H29N3O4 (531.60) C, 74.56; H, 5.50; N, 7.90; found
C, 74.60; H, 5.60; N, 7.78.
The maleimides used were prepared according to a method
known in the literature.13a Maleimide 2g was prepared
according to a modified literature procedure:13b to a mixture
of 4-nitroaniline (5.1 mmol, 0.772 g) and maleic anhydride
(6.04 mmol, 0.592 g) PPA (7 g) was added and the mixture
stirred for 15 h at 80 8C on a water bath. The mixture was
poured into cold water and the product precipitated was
filtered and dried in a vacuum oven. Yield 0.598 g, 54%;
yellow amorphous solid; mp 163–164 8C; IR (KBr) nC]O
1
1724 cmK1; H NMR (400 MHz, CDCl3): d 6.93 (2H, s),
7.68 (2H, d, JZ9.6 Hz), 8.34 (2H, d, JZ9.6 Hz). 13C NMR
(100 MHz, CDCl3): d 124.7; 125.7; 134.9; 137.3; 146.4;
168.8.
4.2.4. exo-5,6-Bis-(4-methoxyphenyl)-2,3b-diphenyl-
hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-
1,3-dione 3d. Yield 0.021 g, 32%; white needles; mp
165–166 8C; IR (KBr) nC]O 1712 cmK1
;
1H NMR
(400 MHz, CDCl3): d 3.70 (3H, s), 3.72 (3H, s), 3.92–3.96
(2H, two overlapping d, JZ7.6, 8.8 Hz), 4.61 (1H, d,
JZ8.8 Hz), 5.19 (1H, d, JZ7.6 Hz), 5.76 (1H, s), 6.46
(2H, d, JZ8.4 Hz), 6.58 (2H, d, JZ8.0 Hz), 6.78 (2H,
d, JZ8.4 Hz), 6.95–6.99 (3H, m), 7.08–7.14 (3H, m),
7.21–7.25 (2H, m), 7.30–7.35 (4H, m). 13C NMR
(100 MHz, CDCl3): d 55.5; 55.9; 57.6; 57.8; 77.0; 79.7;
85.4; 113.5; 114.4; 115.1; 126.1; 127.0; 127.4; 128.3; 128.7;
128.9; 129.1; 129.3; 129.6; 135.3; 144.7; 152.6; 159.5;
171.1; 174.1. Anal. Calcd for C33H29N3O5 (547.60) C,
72.38; H, 5.34; N, 7.67; found C, 72.32; H, 5.40; N, 7.60.
4.2. Synthesis of hexahydro-7-oxa-2,5,6a-triaza-cyclo-
penta[a]pentalene-1,3-diones 3a–i and 4a–i. General
procedure
To a solution of imidazoline 3-oxide 1 (0.12 mmol) in
benzene (10 mL) maleimide (0.48 mmol) was added and
the reaction mixture stirred for the specified time. The
solvent was evaporated and the mixture was separated by
column chromatography using silica gel as an adsorbent
and petroleum ether ethyl acetate as a solvent mixture.
The compounds were recrystallized from ether or
ethanol.
4.2.5. exo-5-(4-Methoxyphenyl)-6-(3-nitrophenyl)-2,3b-
diphenyl-hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]-
pentalene-1,3-dione 3e. Yield 0.022 g, 33%; yellow
4.2.1. exo-2,3b-Diphenyl-5-p-tolyl-hexahydro-7-oxa-
2,5,6a-triaza-cyclopenta[a]pentalene-1,3-dione 3a. Yield
0.018 g, 35%; white needles; mp 177–178 8C; IR (KBr)
nC]O 1713 cmK1; 1H NMR (400 MHz, CDCl3): d 2.24 (3H,
s), 3.80 (1H, d, JZ8.8 Hz), 3.98 (1H, d, JZ7.6 Hz), 4.17
(1H, d, JZ8.8 Hz), 4.53 (1H, d, JZ11.2 Hz), 4.79 (1H, d,
JZ11.2 Hz), 5.17 (1H, d, JZ7.6 Hz), 6.42 (2H, d,
JZ8.0 Hz), 7.00–7.05 (4H, m), 7.31–7.40 (6H, m), 7.57
(2H, d, JZ7.2 Hz). 13C NMR (100 MHz, CDCl3): d 20.5;
56.7; 56.8; 71.0; 80.7; 112.3; 126.2; 126.6; 126.9; 129.0;
129.2; 129.3; 129.4; 130.1; 131.3; 136.0; 143.6; 171.2;
174.1. Anal. Calcd for C26H23N3O3 (425.48) C, 73.39; H,
5.45; N, 9.88; found C, 73.34; H, 5.40; N, 9.95.
1
needles; mp 173–174 8C; IR (KBr) nC]O 1715 cmK1; H
NMR (400 MHz, CDCl3): d 3.73 (3H, s), 3.92 (1H, d,
JZ7.1 Hz), 3.96 (1H, d, JZ8.8 Hz), 4.70 (1H, d,
JZ8.8 Hz), 5.21 (1H, d, JZ7.1 Hz), 5.85 (1H, s), 6.44
(2H, d, JZ8.8 Hz), 6.80 (2H, d, JZ8.8 Hz), 7.01–7.09 (5H,
m), 7.18–7.38 (6H, m), 7.52 (1H, d, JZ7.6 Hz), 7.79 (1H,
s), 7.96 (1H, d, JZ7.6 Hz). 13C NMR (100 MHz, CDCl3): d
55.9; 57.2; 57.4; 77.1; 80.0; 85.3; 114.5; 115.3; 122.9;
123.2; 125.9; 126.9; 128.5; 129.0; 129.2; 129.3; 129.4;
131.2; 134.1; 134.3; 140.0; 140.2; 148.2; 153.1; 170.8;
173.8. Anal. Calcd for C32H26N4O6 (562.57) C, 68.32; H,
4.66; N, 9.96; found C, 68.30; H, 4.60; N, 9.98.

N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
1357
4.2.6. exo-2-(4-Methoxyphenyl)-3b-phenyl-5-p-tolyl-
hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-
1,3-dione 3f. Yield 0.013 g, 24%; white needles; mp
4.2.10. endo-2,3b-Diphenyl-5-p-tolyl-hexahydro-7-oxa-
2,5,6a-triaza-cyclopenta[a]pentalene-1,3-dione 4a. Yield
0.033 g, 65%; white needles; mp 185–186 8C; IR (KBr)
nC]O 1709 cmK1; 1H NMR (400 MHz, CDCl3): d 2.28 (3H,
s), 3.11 (1H, d, JZ10.1 Hz), 4.02 (1H, d, JZ8.6 Hz), 4.49
(1H, d, JZ9.4 Hz), 4.60 (1H, d, JZ10.1 Hz), 4.66 (1H, d,
JZ9.4 Hz), 5.15 (1H, d, JZ8.6 Hz), 6.52 (2H, d, JZ
8.6 Hz), 6.88 (2H, d, JZ7.0 Hz), 7.08 (2H, d, JZ8.6 Hz),
7.19–7.25 (3H, m), 7.35 (1H, t, JZ7.4 Hz), 7.44 (2H, t, JZ
7.4 Hz), 7.66 (2H, d, JZ7.4 Hz). 13C NMR (100 MHz,
CDCl3): d 20.7; 54.2; 59.8; 75.3; 80.6; 80.9; 115.0; 125.8;
126.5; 128.4; 128.9; 129.2; 129.3; 129.8; 130.2; 131.4;
141.5; 142.9; 173.0; 174.1. Anal. Calcd for C26H23N3O3
(425.48) C, 73.39; H, 5.45; N, 9.88; found C, 73.40; H, 5.33;
N, 10.05.
187–188 8C; IR (KBr) nC]O 1716 cmK1
;
1H NMR
(400 MHz, CDCl3): d 2.23 (3H, s), 3.78 (3H, s), 3.79 (1H,
d, JZ8.6 Hz), 3.96 (1H, d, JZ7.4 Hz), 4.16 (1H, d,
JZ8.6 Hz), 4.52 (1H, d, JZ10.9 Hz), 4.78 (1H, d, JZ
10.9 Hz), 5.15 (1H, d, JZ7.4 Hz), 6.41 (2H, d, JZ8.2 Hz),
6.87–6.94 (4H, m), 7.03 (2H, d, JZ8.2 Hz), 7.31 (1H, t,
JZ7.2 Hz), 7.37 (2H, t, JZ7.2 Hz), 7.55 (2H, t, JZ7.2 Hz).
13C NMR (100 MHz, CDCl3): d 20.5; 55.7; 56.7; 56.8; 71.0;
77.2; 80.7; 112.3; 114.7; 123.8; 126.5; 126.8; 127.4; 129.2;
129.3; 130.1; 136.0; 143.6; 159.8; 171.5; 174.4. Anal. Calcd
for C27H25N3O4 (455.51) C, 71.19; H, 5.53; N, 9.22; found
C, 71.21; H, 5.50; N, 9.27.
4.2.11. endo-5-(4-Methoxyphenyl)-2,3b-diphenyl-hexa-
hydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-
dione 4b. Yield 0.033 g, 62%; white needles; mp
4.2.7. exo-2-(4-Nitrophenyl)-3b-phenyl-5-p-tolyl-hexa-
hydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-
dione 3g. Yield 0.020 g, 35%; yellow needles; mp 175 8C;
IR (KBr) nC]O 1728 cmK1; 1H NMR (400 MHz, CDCl3): d
2.24 (3H, s), 3.81 (1H, d, JZ8.8 Hz), 4.02 (1H, d,
JZ7.2 Hz), 4.19 (1H, d, JZ8.8 Hz), 4.54 (1H, d,
JZ10.8 Hz), 4.79 (1H, d, JZ10.8 Hz), 5.21 (1H, d, JZ
7.2 Hz), 6.40 (2H, d, JZ8.4 Hz), 7.04 (2H, d, JZ8.4 Hz),
7.24–7.26 (3H, m), 7.35–7.41 (2H, m), 7.54 (2H, d, JZ
8.0 Hz), 8.23 (2H, d, JZ9.2 Hz). 13C NMR (100 MHz,
CDCl3): d 20.5; 56.8; 56.9; 71.0; 77.2; 80.8; 112.4; 124.6;
126.4; 126.6; 127.1; 129.3; 129.5; 130.2; 135.8; 136.6;
143.5; 147.3; 170.5; 173.4. Anal. Calcd for C26H22N4O5
(470.48) C, 66.37; H, 4.71; N, 11.91; found C, 66.40; H,
4.76; N, 11.90.
182–183 8C; IR (KBr) nC]O 1712 cmK1
;
1H NMR
(400 MHz, CDCl3): d 3.05 (1H, d, JZ10.4 Hz), 3.75 (3H,
s), 4.01 (1H, d, JZ8 Hz), 4.44 (1H, d, JZ9.6 Hz), 4.56 (1H,
d, JZ10.0 Hz), 4.63 (1H, d, JZ9.6 Hz), 5.15 (1H, d, JZ
8.0 Hz), 6.57 (2H, d, JZ8.5 Hz), 6.81 (2H, d, JZ8.5 Hz),
6.90 (2H, d, JZ7.4 Hz), 7.2–7.25 (3H, m), 7.34 (1H, t, JZ
7.41 Hz), 7.43 (2H, t, JZ7.4 Hz), 7.66 (2H, d, JZ7.4 Hz).
13C NMR (100 MHz, CDCl3): d 54.8; 55.9; 59.8; 75.9; 80.8;
81.0; 115.2; 116.3; 125.8; 126.6; 128.4; 128.9; 129.2; 129.3;
131.4; 139.3; 141.58; 154.1; 173.0; 174.3. Anal. Calcd for
C26H23N3O4 (441.48) C, 70.73; H, 5.25; N, 9.52; found C,
70.85; H, 5.33; N, 9.48.
4.2.12. endo-6-(4-Methoxyphenyl)-2,3b-diphenyl-5-p-
tolyl-hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]penta-
lene-1,3-dione 4c. Yield 0.036 g, 57%; white needles; mp
4.2.8. exo-2-(4-Chlorophenyl)-3b-phenyl-5-p-tolyl-hexa-
hydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-
dione 3h. Yield 0.020 g, 36%; white needles; mp
189–191 8C; IR (KBr) nC]O 1720 cmK1
;
1H NMR
186–187 8C; IR (KBr) nC]O 1720 cmK1
;
1H NMR
(400 MHz, CDCl3): d 2.22 (3H, s), 3.74 (3H, s), 3.87 (1H,
d, JZ10.0 Hz), 4.04 (1H, d, JZ8.4 Hz), 4.77 (1H, d, JZ
10.0 Hz), 5.16 (1H, d, JZ8.4 Hz), 5.64 (1H, s), 6.38 (2H, d,
JZ8.6 Hz), 6.76 (2H, d, JZ8.6 Hz), 6.80 (2H, d, JZ
7.4 Hz), 6.93 (2H, d, JZ8.2 Hz), 7.12 (2H, d, JZ8.6 Hz),
7.19–7.32 (4H, m), 7.37 (2H, t, JZ7.4 Hz), 7.60 (2H, d, JZ
7.4 Hz). 13C NMR (100 MHz, CDCl3): d 20.5; 52.7; 55.4;
59.4; 79.9; 80.3; 84.6; 114.2; 114.3; 126.0; 126.3; 127.9;
128.3; 128.7; 128.8; 129.0; 129.2; 129.9; 131.2; 131.5;
141.3; 141.6; 159.6; 172.9; 174.0. Anal. Calcd for
C33H29N3O4 (531.60) C, 74.56; H, 5.50; N, 7.90; found C,
74.45; H, 5.63; N, 7.85.
(400 MHz, CDCl3): d 2.24 (3H, s), 3.79 (1H, d, JZ
8.4 Hz), 3.97 (1H, d, JZ7.6 Hz), 4.16 (1H, d, JZ8.4 Hz),
4.52 (1H, d, JZ11.2 Hz), 4.78 (1H, d, JZ11.2 Hz), 5.16
(1H, d, JZ7.6 Hz), 6.41 (2H, d, JZ8.6 Hz), 6.95–6.98 (2H,
m), 7.04 (2H, d, JZ8.6 Hz), 7.31–7.40 (5H, m), 7.54 (2H, d,
JZ8.6 Hz). 13C NMR (100 MHz, CDCl3): d 20.5; 56.7;
56.8; 71.0; 77.2; 80.7; 112.3; 126.5; 127.0; 127.4; 129.2;
129.3; 129.6; 129.7; 130.1; 134.8; 135.9; 143.6; 171.0;
173.8. Anal. Calcd for C26H22ClN3O3 (459.92) C, 67.90; H,
4.82; N, 9.14; found C, 68.05; H, 4.96; N, 9.27.
4.2.9. exo-3b-Phenyl-2,5-di-p-tolyl-hexahydro-7-oxa-
2,5,6a-triaza-cyclopenta[a]pentalene-1,3-dione 3i. Yield
0.015 g, 28%; white needles; mp 194–195 8C; IR (KBr)
nC]O 1716 cmK1; 1H NMR (400 MHz, CDCl3): d 2.23 (3H,
s), 2.30 (3H, s), 3.78 (1H, d, JZ8.19 Hz), 3.95 (1H, d, JZ
7.4 Hz), 4.15 (1H, d, JZ8.19 Hz), 4.52 (1H, d, JZ10.9 Hz),
4.78 (1H, d, JZ10.9 Hz), 5.14 (1H, d, JZ7.4 Hz), 6.41
(2H, d, JZ8.0 Hz), 6.88 (2H, d, JZ8.0 Hz), 7.03 (2H, d,
JZ8.0 Hz), 7.17 (2H, d, JZ8.0 Hz), 7.30–7.37 (3H,
m), 7.55 (2H, d, JZ7.6 Hz). 13C NMR (100 MHz,
CDCl3): d 20.5; 21.4; 55.7; 56.8; 71.0; 77.0; 80.7; 112.3;
126.0; 126.6; 126.8; 128.6; 129.1; 129.2; 130.0; 130.1;
136.0; 139.1; 143.6; 173.3; 174.2. Anal. Calcd for
C27H25N3O3 (439.51) C, 73.78; H, 5.73; N, 9.56; found C,
73.75; H, 5.70; N, 9.50.
4.2.13. endo-5,6-Bis-(4-methoxyphenyl)-2,3b-diphenyl-
hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-
1,3-dione 4d. Yield 0.039 g, 60%; white needles; mp
159–160 8C; IR (KBr) nC]O 1716 cmK1
;
1H NMR
(400 MHz, CDCl3): d 3.70 (3H, s), 3.73 (3H, s), 3.85 (1H,
d, JZ10.0 Hz), 4.04 (1H, d, JZ8.4 Hz), 4.71 (1H, d,
JZ10.0 Hz), 5.17 (1H, d, JZ8.4 Hz), 5.63 (1H, s), 6.41
(2H, d, JZ9.0 Hz), 6.69 (2H, d, JZ9.0 Hz), 6.74 (2H, d,
JZ8.6 Hz), 6.85–6.87 (2H, m), 7.09 (2H, d, JZ8.6 Hz),
7.21–7.33 (4H, m), 7.38 (2H, t, JZ7.8 Hz), 7.60 (2H, d,
JZ7.8 Hz). 13C NMR (100 MHz, CDCl3): d 53.0; 55.4;
55.9; 59.4; 79.9; 80.4; 85.0; 114.1; 115.0; 115.6; 126.0;
126.2; 128.3; 128.8; 128.8; 129.1; 129.2; 131.2; 131.4;
137.7; 141.7; 152.9; 159.5; 172.9; 174.1. Anal. Calcd for

1358
N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
C33H29N3O5 (547.60) C, 72.38; H, 5.34; N, 7.67; found C,
72.35; H, 5.53; N, 7.51.
54.2; 59.8; 75.3; 80.6; 81.0; 115.0; 125.8; 127.8; 128.4;
129.4; 129.4; 129.8; 130.0; 130.3; 134.7; 141.4; 142.8;
172.8; 174.0. Anal. Calcd for C26H22ClN3O3 (459.92) C,
67.90; H, 4.82; N, 9.14; found C, 68.00; H, 4.80; N, 9.22.
4.2.14. endo-5-(4-Methoxyphenyl)-6-(3-nitrophenyl)-
2,3b-diphenyl-hexahydro-7-oxa-2,5,6a-triaza-cyclopenta-
[a]pentalene-1,3-dione 4e. Yield 0.028 g, 41%; yellow
4.2.18. endo-3b-Phenyl-2,5-di-p-tolyl-hexahydro-7-oxa-
2,5,6a-triaza-cyclopenta[a]pentalene-1,3-dione 4i. Yield
0.032 g, 60%; white needles; mp 178–179 8C; IR (KBr)
needles; mp 119–120 8C; IR (KBr) nC]O 1714; 1724 cmK1
;
1H NMR (400 MHz, CDCl3): d 3.70 (3H, s), 3.95 (1H, d, JZ
10.0 Hz), 4.06 (1H, d, JZ8.0 Hz), 4.69 (1H, d, JZ10.0 Hz),
5.22 (1H, d, JZ8.0 Hz), 5.76 (1H, s), 6.41 (2H, d, JZ8.8 Hz),
6.71 (2H, d, JZ9.2 Hz), 6.90 (2H, d, JZ8.8 Hz), 7.25–7.57
(10H, m), 8.05–8.08 (2H, m). 13C NMR (100 MHz, CDCl3): d
53.1; 55.9; 59.5; 80.0; 80.3; 84.5; 115.2; 115.7; 122.7; 123.5;
125.8; 126.1; 126.3; 129.0; 129.2; 129.3; 129.4; 131.1; 133.7;
134.4; 140.8; 141.5; 148.6; 153.4; 172.7; 173.6. Anal. Calcd
for C32H26N4O6 (562.57) C, 68.32; H, 4.66; N, 9.96; found C,
68.43; H, 4.59; N, 9.90.
nC]O 1706 cmK1 1H NMR (400 MHz, CDCl3): d 2.28
;
(3H, s), 2.29 (3H, s), 3.10 (1H, d, JZ10.0 Hz), 4.01 (1H, d,
JZ8.4 Hz), 4.49 (1H, d, JZ9.2 Hz), 4.59 (1H, d,
JZ10.0 Hz), 4.65 (1H, d, JZ9.2 Hz), 5.14 (1H, d, JZ
8.4 Hz), 6.52 (2H, d, JZ8.0 Hz), 6.76 (2H, d, JZ8.0 Hz),
7.02 (2H, d, JZ8.0 Hz), 7.06 (2H, d, JZ8.0 Hz), 7.35 (1H,
t, JZ7.6 Hz), 7.43 (2H, t, JZ7.2 Hz), 7.66 (2H, d,
JZ7.2 Hz). 13C NMR (100 MHz, CDCl3): d 20.5; 21.1;
54.0; 59.5; 75.0; 80.4; 80.6; 114.8; 125.6; 126.1; 128.1;
128.5; 129.0; 129.5; 129.6; 130.0; 138.8; 141.4; 142.8;
172.9; 174.0. Anal. Calcd for C27H25N3O3 (439.51) C,
73.78; H, 5.73; N, 9.56; found C, 73.70; H, 5.70; N, 9.50.
4.2.15. endo-2-(4-Methoxyphenyl)-3b-phenyl-5-p-tolyl-
hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-
1,3-dione 4f. Yield 0.038 g, 69%; white needles; mp
187–187.4 8C; IR (KBr) nC]O 1705 cmK1
;
1H NMR
4.2.19. 5-(4-Methoxyphenyl)-3a-phenyl-hexahydro-
imidazo[1,5-b]isoxazole-2,3-dicarboxylic acid 2-diethyl-
amide 3-phenylamide 4b0. Yield 0.023 g, 18%; white
needles; mp 166–167 8C; IR (KBr) nNH 3445 cmK1; nC]O
1691 and 1620 cmK1; 1H NMR (400 MHz, CDCl3): d 0.92
(6H, t, JZ7.6 Hz), 2.58 (4H, q, JZ7.6 Hz), 3.17 (1H, d,
JZ10.0 Hz), 3.70 (3H, s), 3.79 (1H, d, JZ7.2 Hz), 3.95
(1H, d, JZ10.8 Hz), 4.12 (1H, d, JZ10.0 Hz), 4.72 (1H, d,
JZ7.2 Hz), 4.95 (1H, d, JZ10.8 Hz), 6.50 (2H, d,
JZ8.6 Hz), 6.70 (2H, d, JZ8.6 Hz), 6.94 (1H, t, JZ
7.0 Hz), 7.09 (2H, t, JZ7.0 Hz), 7.21–7.35 (6H, m), 7.59
(2H, d, JZ7.8 Hz), 8.90 (1H, s). 13C NMR (100 MHz,
CDCl3): d 11.3; 42.2; 55.8; 58.3; 66.7; 72.7; 79.4; 80.5;
115.0; 116.0; 120.1; 124.1; 125.9; 127.7; 128.7; 129.0;
138.2; 140.5; 144.7; 153.2; 168.6; 172.4. Anal. Calcd for
C30H34N4O4 (514.62) C, 70.02; H, 6.66; N, 10.89; found C,
70.10; H, 6.60; N, 10.85.
(400 MHz, CDCl3): d 2.27 (3H, s), 3.10 (1H, d, JZ
10.0 Hz), 3.75 (3H, s), 4.01 (1H, d, JZ8.4 Hz), 4.49 (1H, d,
JZ9.6 Hz), 4.58 (1H, d, JZ10.0 Hz), 4.65 (1H, d,
JZ9.6 Hz), 5.15 (1H, d, JZ8.4 Hz), 6.51 (2H, d, JZ
8.2 Hz), 6.71 (2H, d, JZ8.9 Hz), 6.8 (2H, d, JZ8.9 Hz),
7.05 (2H, d, JZ8.2 Hz), 7.34 (1H, t, JZ7.02 Hz), 7.43 (2H,
t, JZ7.4 Hz), 7.66 (2H, d, JZ7.4 Hz). 13C NMR (100 MHz,
CDCl3): d 20.7; 54.2; 55.7; 59.7; 75.3; 80.5; 80.8; 114.5;
115.0; 123.9; 125.8; 127.8; 128.3; 129.3; 129.7; 130.2;
141.6; 143.0; 159.7; 173.2; 174.3. Anal. Calcd for
C27H25N3O4 (455.51) C, 71.19; H, 5.53; N, 9.22; found C,
71.09; H, 5.70; N, 9.25.
4.2.16. endo-2-(4-Nitrophenyl)-3b-phenyl-5-p-tolyl-hexa-
hydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-
dione 4g. Yield 0.028 g, 50%; yellow needles; mp
176–177 8C; IR (KBr) nC]O 1716 cmK1
;
1H NMR
(400 MHz, CDCl3): d 2.29 (3H, s), 3.08 (1H, d, JZ
10.0 Hz), 4.05 (1H, d, JZ8.0 Hz), 4.47 (1H, d, JZ9.6 Hz),
4.59 (1H, d, JZ9.6 Hz), 4.62 (1H, d, JZ10.0 Hz), 5.19 (1H,
d, JZ8.0 Hz), 6.50 (2H, d, JZ8.2 Hz), 7.05 (2H, d, JZ
8.2 Hz), 7.14 (2H, d, JZ9.0 Hz), 7.36 (1H, t, JZ7.4 Hz),
7.43 (2H, t, JZ7.4 Hz), 7.65 (2H, d, JZ7.4 Hz), 7.54 (2H,
d, JZ9.0 Hz). 13C NMR (100 MHz, CDCl3): d 20.7; 54.2;
59.9; 75.4; 80.7; 81.4; 115.1; 124.4; 125.8; 127.1; 128.6;
129.4; 130.4; 130.5; 136.8; 141.0; 142.6; 147.2; 172.3;
173.5. Anal. Calcd for C26H22N4O5 (470.48) C, 66.37; H,
4.71; N, 11.91; found C, 66.30; H, 4.65; N, 11.85.
4.3. Base catalysed ring-opening of compounds 3 and 4.
Synthesis of 2,5-dihydro-1H-imidazole 5a–e. General
procedure
Method A. Compound 3 or 4 (0.25 mmol) were refluxed in
diethylamine (5 mL) for 23 h. The solvent was evaporated
and the product was purified by preparative TLC using
petroleum ether ethyl acetate as eluent (2:1). The products
were recrystallized from ethanol or ether. Method B. The
mixture of adducts 3 and 4 from the cycloaddition of
nitrones 1 (0.25 mmol) with maleimides (1 mmol) 2 was
dissolved in diethylamine (5 mL) and refluxed for 23 h. The
solvent was evaporated and the isolation of the product 5 is
as in Method A.
4.2.17. endo-2-(4-Chlorophenyl)-3b-phenyl-5-p-tolyl-
hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-
1,3-dione 4h. Yield 0.029 g, 52%; white needles; mp
158–160 8C; IR (KBr) nC]O 1712 cmK1
;
1H NMR
4.3.1. 4-Phenyl-1-p-tolyl-2,5-dihydro-1H-imidazole 5a.
Method B; yield 0.053 g, 90%; white needles; mp
(400 MHz, CDCl3): d 2.28 (3H, s), 3.08 (1H, d,
JZ10.0 Hz), 4.01 (1H, d, JZ8.0 Hz), 4.48 (1H, d, JZ
9.6 Hz), 4.59 (1H, d, JZ10.0 Hz), 4.63 (1H, d, JZ9.6 Hz),
5.15 (1H, d, JZ8.0 Hz), 6.50 (2H, d, JZ8.4 Hz), 6.83 (2H,
d, JZ9.2 Hz), 7.05 (2H, d, JZ8.4 Hz), 7.17 (2H, d,
JZ9.2 Hz), 7.31–7.38 (1H, m), 7.42–7.46 (2H, m),
7.64–7.67 (2H, m). 13C NMR (100 MHz, CDCl3): d 20.7;
117–119 8C; IR (KBr) nC]N 1631 cmK1
;
1H NMR
(400 MHz, CDCl3): d 2.28 (3H, s), 4.57 (2H, t, JZ5.2 Hz),
5.43 (2H, t, JZ5.2 Hz), 6.52 (2H, d, JZ8.4 Hz), 7.11 (2H, d,
JZ8.4 Hz), 7.38–7.53 (3H, m), 7.82–7.89 (2H, m). 13C NMR
(100 MHz, CDCl3): d 20.6; 55.3; 79.0; 112.2; 121.5; 127.6;
129.0; 130.3; 131.6; 136.0; 143.4; 169.3. Anal. Calcd for

N. Cos¸kun et al. / Tetrahedron 62 (2006) 1351–1359
1359
C16H16N2 (236.31) C, 81.32; H, 6.82; N, 11.85; found C,
81.30; H, 6.85; N, 11.90.
was evaporated and the starting material was recovered
unchanged.
4.3.2. 1-(4-Methoxyphenyl)-4-phenyl-2,5-dihydro-1H-
imidazole 5b. Method B; yield 0.063 g, 100%; white
Acknowledgements
1
needles; mp 129–130 8C; IR (KBr) nC]N 1631 cmK1; H
NMR (400 MHz, CDCl3): d 3.78 (3H, s), 4.55 (2H, t,
JZ5.2 Hz), 5.41 (2H, t, JZ5.2 Hz), 6.56 (2H, d,
JZ9.2 Hz), 6.91 (2H, d, JZ8.4 Hz), 7.45–7.51 (3H, m),
7.87 (2H, d, JZ8.0 Hz). 13C NMR (100 MHz, CDCl3): d
55.7; 56.1; 79.4; 113.0; 115.5; 127.6; 129.0; 131.7; 132.5;
140.4; 152.0; 169.7. Anal. Calcd for C16H16N2O (252.31) C,
76.16; H, 6.39; N, 11.10; found C, 76.20; H, 6.30; N, 11.05.
˘
Uludag University Research Fund and Turkish State
Planning Organization (DPT) are gratefully acknowledged
for the financial support (Project No 2001-2)
References and notes
4.3.3. 2-(4-Methoxyphenyl)-4-phenyl-1-p-tolyl-2,5-
dihydro-1H-imidazole 5c. Method B; yield 0.080 g, 93%;
1. (a) Black, D. St. C.; Crozier, R. F.; Davis, V. C. Synthesis
1975, 205–221. (b) Padwa, A. Angew. Chem., Int. Ed. Engl.
1976, 15, 123–180. (c) Oppolzer, W. Angew. Chem., Int. Ed.
Engl. 1977, 16, 10–23. (d) Dell, C. P. J. Chem. Soc., Perkin
Trans. 1 1998, 3873–3905.
white needles; mp 176–178 8C; IR (KBr) nC]N 1623 cmK1
;
1H NMR (400 MHz, CDCl3): d 2.23 (3H, s), 3.79 (3H, s),
4.72 (1H, dd, JZ15.2, 3.6 Hz), 4.99 (1H, dd, JZ15.2,
6.0 Hz), 6.45 (1H, dd, JZ6.0, 3.6 Hz), 6.51(2H, d, JZ
8.8 Hz), 6.89 (2H, d, JZ8.6 Hz), 7.02 (2H, d, JZ8.8 Hz),
7.39–7.48 (5H, m), 7.88 (2H, d, JZ7.8 Hz). 13C NMR
(100 MHz, CDCl3): d 20.5; 55.5; 57.5; 91.6; 113.0; 114.5;
126.6; 127.9; 128.3; 128.9; 130.0; 131.6; 132.4; 133.1;
143.3; 159.7; 166.8. Anal. Calcd for C23H22N2O (342.43) C,
80.67; H, 6.48; N, 8.18; found C, 80.60; H, 6.40; N, 8.20.
2. Cos¸kun, N.; Su¨mengen, D. Synth. Commun. 1993, 23,
1699–1706.
3. (a) Cos¸kun, N. Tetrahedron Lett. 1997, 38, 2299–2302.
(b) Cos¸kun, N. Tetrahedron 1997, 53, 13873–13882.
(c) Cos¸kun, N.; Ay, M. Heterocycles 1998, 48, 537–544. (d)
¨
Cos¸kun, N.; Tat, F. T.; Gu¨ven, O. O.; Ulku¨, D.; Arıcı, C.
¨
¨
Tetrahedron Lett. 2000, 41, 5407–5409. (e) Cos¸kun, N.;
¨ ¨
Tat, F. T.; Gu¨ven, O. O. Tetrahedron 2001, 57, 3413–3417. (f)
4.3.4. 1,2-Bis-(4-methoxyphenyl)-4-phenyl-2,5-dihydro-
1H-imidazole 5d. Method B; yield 0.079 g, 88%; white
¨
¨
Cos¸kun, N.; Tat, F. T.; Gu¨ven, O. O. Tetrahedron: Asymmetry
2001, 12, 1463–1467.
1
needles; mp 152–153 8C; IR (KBr) nC]N 1623 cmK1; H
NMR (400 MHz, CDCl3): d 3.73 (3H, s), 3.79 (3H, s), 4.69
(1H, dd, JZ14.8, 4.0 Hz), 4.99 (1H, dd, JZ14.4, 6.0 Hz),
6.40 (1H, dd, JZ6.0, 4.0 Hz), 6.55 (2H, d, JZ9.2 Hz), 6.81
(2H, d, JZ9.2 Hz), 6.9 (2H, d, JZ8.8 Hz), 7.4–7.5 (5H, m),
7.87–7.89 (2H, m). 13C NMR (100 MHz, CDCl3): d 55.5;
56.0; 57.9; 91.9; 113.8; 114.5; 115.2; 127.9; 128.3; 128.9;
131.5; 132.4; 133.2; 140.2; 152.0; 159.6; 166.9. Anal. Calcd
for C23H22N2O2(358.43) C, 77.07; H, 6.19; N, 7.82; found
C, 77.09; H, 6.10; N, 7.87.
4. A series of tetrahydroimidazo compounds were tested for their
anticancer activity and found to be quite active at 10K5 molar
concentrations.
5. (a) Cos¸kun, N. Turk. J. Chem. 2001, 25, 267–272. (b) Cos¸kun,
N.; Tat, F. T. Phosphorus Sulfur2003, 178, 881–886. (c) Cos¸kun,
N.; Tat, F. T. Turk. J. Chem. 2004, 28, 1–7.
6. Jones, R. C. F.; Martin, J. N.; Smith, P. Synlett 2000, 7,
967–970.
7. (a) Cos¸kun, N.; Asutay, O. Chim. Acta Turc. 1997, 25,
69–72. (b) Cos¸kun, N.; Asutay, O. Chim. Acta Turc. 1999,
27, 17–23.
4.3.5. 1-(4-Methoxyphenyl)-2-(3-nitrophenyl)-4-phenyl-
2,5-dihydro-1H-imidazole 5e. Method A (from 3e) yield
0.086 g, 92%; Method A (from 4e) yield 0.086 g, 92%; yellow
8. Although the mentioned cis elimination was unsuccessful in
the cases of tetrahydroimidazoisoxazolidines prepared from
different alkene type of dipolarophiles3c,f we were encour-
aged from the fact that carbon 3a is in a position to a
carbonyl.
1
needles; mp 182–184 8C; IR (KBr) nC]N 1623 cmK1; H
NMR (400 MHz, CDCl3): d 3.74 (3H, s), 4.74 (1H, dd, JZ
14.8, 4.0 Hz), 5.08 (1H, dd, JZ14.8, 5.6 Hz), 6.49–6.54
(coincident 2H, d, JZ9.0 Hz, 1H, dd, JZ5.6, 4.0 Hz), 6.83
(2H, d, JZ9.0 Hz), 7.44–7.57 (4H, m), 7.86–7.88 (3H, m),
8.16–8.19 (1H, m), 8.37 (1H, t, JZ2.0 Hz). 13C NMR
(100 MHz, CDCl3): d 55.6; 58.5; 91.5; 114.1; 115.4; 122.44;
123.5; 127.9; 129.1; 130.1; 131.9; 132.0; 133.5; 139.7; 143.5;
149.0; 152.7; 168.4. Anal. Calcd for C22H19N3O3 (373.40) C,
70.76; H, 5.13; N, 11.25; found C, 70.80; H, 5.10; N, 11.14.
9. Bols, M. Acc. Chem. Res. 1998, 31, 1–8.
10. Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301–7315.
11. (a) Burdisso, M.; Gamba, A.; Gandolfi, R.; Oberti, R.
Tetrahedron 1988, 44, 3735–3748. (b) Bayon, P.; March, P.;
Espinosa, M.; Figueredo, M.; Font, J. Tetrahedron: Asymmetry
2000, 11, 1757–1765.
12. The total energy of cis–exo 3c was calculated to be
25.9129 kcal/mol.
4.4. The treatment of compounds 3 and 4 with
triethylamine
13. (a) Zentz, F.; Valla, A.; Guillou, R. L.; Labia, R.; Mathot, A. G.;
Sirot, D. Il Farmaco 2002, 57, 421–426. (b) Mederski,
W. W. K. R.; Baumgarth, M.; Germann, M.; Kux, D.;
Weitzel, T. Tetrahedron Lett. 2003, 44, 2133–2136.
Compound 3 or 4 (0.25 mmol) was dissolved in triethyl-
amine (5 mL) and the mixture refluxed for 48 h. The solvent