Rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates to pyrrolo[1,2-e]imidazol-6-ols, precursors of 2,5-dihydro-1H-pyrrole derivatives

Article abstract of DOI:10.1016/j.tet.2008.11.019

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD rearrange in the presence of methoxide to give cis-3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olates 3 with 100% de. The acidic

Full text of DOI:10.1016/j.tet.2008.11.019

Tetrahedron 65 (2009) 648–658
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates to
pyrrolo[1,2-e]imidazol-6-ols, precursors of 2,5-dihydro-1H-pyrrole derivatives
*
Necdet Cos¸kun , Meliha Çetin
Uludag˘ University, Department of Chemistry, 16059 Bursa, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD rearrange in the presence of
methoxide to give cis-3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo-2,3,5,7a-tetrahydro-1H-pyr-
rolo[1,2-e]imidazol-6-olates 3 with 100% de. The acidic hydrolysis of 3 led to kinetically controlled
formation of methyl 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-((arylamino)methyl)-2,5-dihydro-1H-pyr-
role-3-carboxylates 6a–e. The intramolecular transformylations of the latter to the corresponding
(E)- and (Z)-methyl 4-hydroxy-2-((N-(aryl)formamido)methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-
Received 3 September 2008
Received in revised form 21 October 2008
Accepted 6 November 2008
Available online 12 November 2008
Keywords:
pyrrole-3-carboxylates 7a–e were shown to be substituent dependent (correlate with
acterized by Hammett type equations. The effect of temperature was investigated and the
determined for the same reaction series at 50, 60 and 70 ꢀC. The amide diastereomeric ratio [(E)-7]/
s
) and char-
constants
Dipolar cycloaddition
Cyclic nitrones
4-Isoxazolines
Pyrrole derivative
Rearrangement
Iminium salts
NHCs
r
[(Z)-7] is substituent dependent and can be described by the equation log[(E)]/[(Z)]x¼ꢁrsIþlog[(E)]/
[(Z)]x¼H
.
Ó 2008 Elsevier Ltd. All rights reserved.
LFERs
1. Introduction
2. Results and discussion
The synthetic utility of the 1,3-dipolar cycloaddition reaction is
evident from the number and the scope of targets that can be
prepared by this chemistry. The nitrones are the most useful
through their ability to generate nitrogen- and oxygen-based
functionalities from the cycloaddition reactions.1 The cycloadducts
of di- and triarylimidazolin-3-oxides2 with variety of dipolaro-
philes3 are bicyclic compounds with potentially interesting bi-
ological activities. On the other hand, they are source of new
heterocyclic compounds via interesting ring-opening reactions.4
Previously, we reported the synthesis of stable adducts of 3-imid-
azolin-3-oxides with dimethyl acetylenedicarboxylate (DMAD)3d,e
and alkyl 3-phenylpropiolates.3f Thermally- and base-induced ring-
opening reactions of these adducts were demonstrated.
Recently, we have reported the reaction of acyclic nitrones8 with
DMAD in benzene at room temperature to produce 4-isoxazolines
in good yields. These latter were shown to undergo substituent
dependent rearrangement to the corresponding oxazolines, which
fragment to an aldehyde and extremely reactive iminocarbene.9 We
have also reported the treatment of 4-isoxazolines with methoxide
in methanol at room temperature to produce highly functionalized
diastereomeric mixtures of 1-(methoxy(aryl)methyl)-4-(methoxy-
carbonyl)-2-oxo-5-aryl-2,5-dihydro-1H-pyrrol-3-ols,9 which can
be further elaborated to give some biologically active pyrrole10
analogues of (ꢁ)-codonopsinine and (ꢁ)-codonopsine alkaloids.11
The latter are attractive for both synthetic and medicinal chemists
due to the challenging penta-substituted pyrrolidine nucleus, and
their varied biological activities as antibiotics and as antihyper-
tensive agents without any effects on the central nervous system.12
As part of an ongoing program in our laboratory for the synthesis
of NHC based catalysts useful in C–C coupling reactions such as Heck,
Suzuki, etc. we aimed to prepare imidazolinium salts 4 (Scheme 1)
and treat them with bases to asses their ability to give NHCs 5.
The treatment of imidazolin-3-oxides13 1 with DMAD will pro-
duce compounds 2, heating the latter at reflux in methanol in the
presence of methoxide would give enolates 3 as we have recently
reported for acyclic nitrone DMAD adducts. The treatment of
There is still a large interest in 4-isoxazolines1a,5,6 due to their bi-
ological activities7a and as a source of interesting rearrangements.7b,c
* Corresponding author. Tel.: þ90224 2941725.
E-mail address: coskun@uludag.edu.tr (N. Cos¸kun).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.019

N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
649
CO2Me
CO2Me
Ph
Ph
N
CO2Me
OH
Ph
N
Ar
N
O
O
Ar
N
OH
Ar
N
N
O
O
O
5a-e
4a-e
3a-e
CO2Me
Ph
N
Ph
Ar
1a-e
Scheme 1. Retrosynthetic analysis of NHCs 5.
N
CO2Me
Ar
N
N
O
O
2a-e
enolates 3 with acids was expected to produce imidazolinium salts
4, which upon basification would provide NHCs 5.
NOESY1D experiments revealed that the MeO group at C3 is on
the same side as the aromatic ring at C7a. The energy minimized
model of 3c and some characteristic NOE correlations are given in
Figure 2. The irradiation of the methoxy group led to enhancements
of the signals of C3–H and C1–Ha by 0.5 and 0.6%, respectively. C1–
Ha was irradiated and the signal for the o-protons of the C7a-aro-
matic ring and C1–Hb were enhanced by 10 and 9%, respectively.
Irradiation of the o-protons of the C7a–Ph enhanced the signal of
C3–OMe by 1.4%. Thus we concluded that the methoxy group at C3
and the phenyl at C7a are cis oriented.
Here we report on the methoxide-induced diastereoselec-
tive rearrangement of isoxazolines 2a–e (Schemes 1 and 2) into
3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo-2,3,5,7a-tetra-
hydro-1H-pyrrolo[1,2-e]imidazol-6-olates 3a–e and their conversion
to the corresponding methyl 1-formyl-4-hydroxy-5-oxo-2-phenyl-
2-((arylamino)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylates
6a–e. The effect of substituents on the transformylation of 6a–e to
the corresponding amides (E)- and (Z)-methyl 4-hydroxy-2-((N-
(aryl)formamido)methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-
carboxylates 7a–e as well as the effect of substituents on the
(E)- and (Z)-7 ratio is reported.
2.2. Probable mechanism for the rearrangement of
isoxazolines 2 to pyrroloimidazoles 3
A methoxide-induced intramolecular elimination of 2 gives
resonance stabilized imine enolates A and B (Scheme 3). This, or
most probably its protonated form C, reacts with methoxide to give
the diastereomer D, the cyclization of which produces enolate 3.
The preferred cis product formation can be rationalized by as-
suming that the addition of the methoxide to the C]N bond from
the side where the phenyl group is located (path a) is accompanied
by synchronous protonation from the opposite side, thus the
transition state leading to D should be much more stable than the
one leading to the trans product D0 (path b).
2.1. Synthesis and structural elucidation of compounds 3a–e
Heating isoxazolines 2a–e in methanol at reflux in the presence
of a three fold excess of sodium methoxide produced the corre-
sponding cis enolates 3a–e with 100% de. The treatment of
cis-dimethyl 3a,5,6-triaryl-3a,4,5,6-tetrahydroimidazo[1,5-b]isox-
azole-2,3-dicarboxylates with methoxide produced the corre-
sponding mixture of Michael adducts dimethyl 2-methoxy-3a,5,
6-triaryl-hexahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates.3e
Enolates 3 have carbonyl stretching frequencies at 1727 and
1679 cmꢁ1. Characteristic AB system parts in the 1H NMR spectra of
2.3. Synthesis and structural elucidation of compounds 6
the compounds in DMSO-d6 at
d
3.08 (1H, d, J¼9.4 Hz) and
4.70 ppm (1H, d, J¼9.4 Hz) are assigned to C1–H2. The one proton
singlet at 5.57 ppm corresponds to the C3–H proton. The three
proton singlets at 3.12 and 3.41 ppm are assigned to the ether and
ester methoxy groups, respectively. All other peaks are in agree-
ment with the proposed structures. Characteristic chemical shifts
assignments based on 1D and 2D NMR experiments for compound
3c are given in Figure 1.
The reaction of compounds 3 with CF3CO2H led to the forma-
tion of a white solid upon pouring the reaction mixtures in ice
water.14 The elemental analyses and spectral data revealed that
the compounds are the corresponding 6a–e hydrates instead of
the expected 4a–e. The compounds have broad bands corre-
sponding to nOH at ca. 3470 and a broad highly structured band
characteristic for ammonium salts at 2955–2492 cmꢁ1 in their IR
CO2Me
Ph
CO2Me
Ph
CO2Me
OH
Ph
Ar
N
CO2Me
H3O
MeO
Ar
N
O
N
Ar NH
O
N
2 N
O
O
O
O
2a-e
3a-e
6a-e
O
H
CO2Me
OH
CO2Me
OH
Ph
Ph
N
H
N
Ar
O
N
Ar
DMSO
CDCl3
+
(E)-7a-e
N
H
H
O
O
(E)-7a-e
(Z)-7a-e
Scheme 2. 1–7a, Ar¼Ph; 1–7b, Ar¼4-MeC6H4; 1–7c, Ar¼4-MeOC6H4; 1–7d, Ar¼4-ClC6H4; 1–7e, Ar¼4-BrC6H4.

650
N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
spectra. nC]O at 1760, 1710, 1691 and nC]C at 1646 cmꢁ1 are in
agreement with the proposed structure. The characteristic 1H and
13C NMR assignments based on gCOSY, gHMQC and gHMBC ex-
periments are given for 6c in Figure 1. The signals for the enolic
protons and the aromatic amine NH are seen in the cases of 6d,e
while in the case of 6a–c they are seen under one broad singlet
together with the water resonances at ca. 3.70 ppm. However
when the spectra are repeated with addition of an equimolar
amount of Et3N an ABX spectral pattern for the NHCH2 appeared
with the following characteristics: ca. 4.20 ppm (1H, dd, J¼13.2 Hz,
6.4 Hz), 4.33 ppm (1H, dd, J¼13.2 Hz, 5.2 Hz), 4.84 ppm (1H, t,
J¼6.4 Hz, 5.2 Hz). The triplet of NH at ca. 4.84 ppm disappeared
upon treatment with D2O.
Compound 6c was heated in methanol at reflux in the presence
of 2 equiv of methoxide. The solvent was evaporated and the
residue was triturated with ether to give 4-(methoxycarbonyl)-5-
((4-methoxyphenylamino)methyl)-2-oxo-5-phenyl-2,5-dihydro-
1H-pyrrol-3-olate. The 1H NMR spectrum of the crude mixture
indicated that the main compound is the corresponding deformy-
lation product, which have characteristic ABX pattern 3.44 (1H, dd,
JAB¼12.0 Hz, JAx¼4.0 Hz), 3.97 (1H, dd, JAB¼12.0 Hz, JBx¼7.6 Hz),
4.49 (1H, dd, JBx¼7.6 Hz, JAx¼4.0 Hz). The D2O exchange experi-
ments revealed that the protons at 4.49 and 8.76 ppm corre-
sponding to the ArNH and the pyrrolidin-5-one NH, respectively are
readily exchangeable. 13C NMR data also revealed the absence of the
carbon signal corresponding to N–CHO. It was surprising that the
mixture contained 3c (ca. 7%), which implies that under these re-
action conditions the deformylation process is accompanied by
the competing cyclization to 4, which then undergo nucleophilic
addition of methoxide.
NOE
O
N
H
O
NOE
N
O
O-
O
O
Figure 2. Characteristic NOE correlations shown on the energy minimized molecular
model of cis-enolate 3c.
unexpected case of N-acyliminium salt hydrolysis since the prod-
ucts of such hydrolyzes lead to the corresponding amide and the
carbonyl derivative.
2.4. Substituent effect on the transformylation of 6 to 7
To elucidate the effect of substituents on the transformylation of
6 to (E)- and (Z)-7 and on the product ratios we performed a series
of experiments for 6a–e each 3.75ꢂ10ꢁ2 M in DMSO-d6 at 20 ꢀC and
followed the reactions by 1H NMR spectroscopy after a week. The
relative amounts of the diastereomers and the starting 6 were
measured by integration of the corresponding formyl hydrogen
peaks in their 1H NMR spectra. The concentrations (%) determined
after a week and the corresponding log K are given in Table 1. The
data clearly reveal that the nature of the substituent on the N-aromatic
ring determines the ratio of the products. Electron-donating groups
accelerate while electron-withdrawing groups decelerate the re-
actions. The reaction susceptibility constants of (E)- and (Z)-7 are
too close to each other.
The probable mechanism for the formation of 4 and their
hydrolyzes to 6 is shown in Scheme 4.
The log of both ratios [(E)-7]/[6] (KE) and [(Z)-7]/[6] (KZ) corre-
The treatment of enolates 3 with acids led to the protonation of
the enolate oxygen as well as demethoxylation at C3 to give com-
pounds 4. The hydrolysis of the latter through 40 and 400 produces
protonated 6. The most characteristic peak for compounds 6 in
DMSO-d6, the formyl hydrogen at ca. 8.91 ppm, gradually disap-
pears while singlets at ca. 8.10, 8.23, 9.07, 9.32 and 11.11 ppm ap-
pear. The latter four singlets disappear upon treatment with D2O.
NMR analyses of the formed two products revealed that they are
the corresponding amides15 (E)- and (Z)-7. Characteristic assign-
ments for the (E)- and (Z)-7c and NOE based correlations are given
in Figure 3. Irradiation of the signal at 8.19 ppm led to the en-
hancement of the N–Ar ortho proton signal while the irradiation
of the singlet at 8.16 ppm enhanced the signal of one of the N–CH2
as well as the signal of the pyrrolinone NH. These data were used
to assign (E)- geometry for the first and (Z)- for the second
diastereomer.
late with the Hammett
K defined as [(E)-7][(Z)-7]/[6], with the same constants produced
s constants (Fig. 4). The correlation of log K,
equation log(K)x¼ꢁ6.38 þlog(K)H. The value of the reaction con-
s
stant clearly implies that there is a high charge separation in the
rate limiting step of the transformylation reaction. Attempts to
correlate the (E)/(Z) ratios with substituent constants did not pro-
duce an acceptable linearity.
2.5. Probable mechanism for the transformylation of 6 to 7
The probable mechanism for the formation of (E)- and (Z)-7 is
depicted in Scheme 5. As the Hammett correlations imply, the
transformylation reaction rate limiting step should be the nucleo-
philic attack of the amine nitrogen to the N-formyl group. The at-
tack to the upward orientated carbonyl will produce imidazolidine
A while the downward orientated will produce the other di-
astereomer A0. Proton migration from the ammonium nitrogen to
the pyrrolinone carbonyl will produce intermediates B and B0. The
It is clear that the hydrolyzes of compounds 4 are chemo-
selective, kinetically controlled processes. This in fact is an
66.8
167.0
67.6
162.7
3.37; 49.6
4.67;3,03;57.5
3.54; 51.8
4.41;4.25;45.0
Ha
CO2Me
Ph
N
Ha
CO2Me
OH
Hb
106.5
173.5
Ph
N
Hb
NH
117.7
152.1
O
N
O
O
O
O
Hc
O
3.09;
52.2
O
165.4
167.3
5.50;
95.8
8.91;158.5
Figure 1. Comparison of the characteristic NMR data of 3c and 6c in DMSO-d6.

N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
651
O
Ph
O
Ph
O
CO2Me
O
Ph
N
-MeOH
CO2Me
Ar
N
CO2Me
Ar
N
CO2Me
Ar
N
N
N
N
O
O
O
H
MeO-
H
B
A
2
O
Ph
CO2Me
Ph
O
Ar
O
O
-MeOH
-MeOH
N
CO2Me
Ar
N
O
Ph
O
O
NH
a
O
O
Me
O
CO2Me
Me
3
Ar
a
N
MeOH
D
N
H
O
Ph
CO2Me
Ph
N
O
MeO-
b
Ar
N
O
O
C
CO2Me
b
Ar
N
X
NH
O
O
Me
O
Me
3'
D'
Scheme 3. Probable mechanism for the rearrangement of isoxazolines 2 into 3.
deprotonation and tautomerization of the latter will give the cor-
responding (E)- and (Z)-7.
under vacuum. The spectra of the latter compounds in CDCl3
(5.6ꢂ10ꢁ3 M) revealed that they are (E)-7a–e confirmed by NOE-
SY1D experiments.18 The spectra of the same compounds dissolved
in DMSO-d6 (5.6ꢂ10ꢁ3 M) revealed that they easily convert to the
corresponding amide isomers (E)- and (Z)-7. The isomer ratios
measured at 25 ꢀC were in linear correlation with sI constants with
2.6. Temperature effect on the transformylation of 6 to 7
To elucidate the temperature effect on the susceptibility of
a
r
¼ꢁ0.24 (Table 4 and Fig. 7). This implies that the N-aromatic ring
transformylation reaction of 6 to 7 we have determined the
r
constants at 50, 60 and 70 ꢀC. The reaction series equilibrated for 8
days in DMSO-d6 at 20 ꢀC then were heated at 50 ꢀC for 1 h. The
contents of the corresponding (E)-, (Z)-7 and 6 were determined
in compounds 7 is not coplanar with the amide functional group
thus it cannot exert its full electronic effect (otherwise the corre-
lations would be better with
s
or sþ constants).
The geometry of the stereoisomer (E)-7 is suitable for the for-
mation of intramolecular hydrogen bond between the carbonyl
oxygen and the pyrroline NH moiety (see Fig. 3). This is probably
the main reason for the predomination of the latter in polar sol-
vents in the cases where substituents with ꢁsI are present on the
N-aromatic ring.
and the log KE, log KZ and log K plotted versus the Hammett
s
constants. The same was repeated for the reaction series at 60 and
70 ꢀC. The plots were linear in all cases (Table 2, Fig. 5). The E/Z
ratios remained nearly constant at all reaction temperatures. It was
observed that the increase of the temperature decreased the ab-
solute values of the reaction constants.
The heating of the same reaction series again at 50 ꢀC for 14 h
revealed that the reaction is not reversible but the values obtained
3. Conclusions
again are in linear correlation with the Hammett
(Table 3, Fig. 6).
s constants
Thus we disclose for the first time a new diastereoselective
rearrangement of isoxazolines 2 in the presence of a base to give
3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo-2,3,5,7a-tetra-
hydro-1H-pyrrolo[1,2-e]imidazol-6-olates 3. Compounds 3 were
demonstrated to be useful precursors in the synthesis of pyrrole
derivatives as 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-((arylami-
no)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylates 6a–e or their
transformylated analogues. Compounds 7 preferred (E)-configura-
tion in relatively less polar solvents as CDCl3 while in more polar
solvents as DMSO-d6 they exist as an equilibrium mixture.
The comparison of the
that they decrease as the temperature is increased. The comparison
of the reaction constants
at 50 ꢀC for 1 h and 14 h revealed that its
r
constants at 20–70 ꢀC clearly indicates
r
absolute value is also decreasing as the reaction time is increased.
2.7. Solvent effect on the (E)-, (Z)-7 equilibria
The extraction of the products with CHCl3 from the reactions of
6 in DMSO-d6 produced yellowish oils, which solidify on drying
CO2Me
CO2Me
OH
Ph
N
CO2Me
Ph
Ph
N
2H+
-MeOH
H2O
Ar
N
O
O
Ar
N
Ar
N
OH
N
O
O
O
O
H
H
4a-e
4'a-e
3a-e
CO2Me
OH
Ph
N
CO2Me
OH
Ph
CO2Me
OH
Ph
N
H
H
Ar
N
Ar NH
O
2 N
Ar
N
O
O
H
O
O
O
H
4"a-e
6a-e
Scheme 4. Ring opening of compounds 4 to methyl 2-arylaminomethyl-1-formyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylates 6.

652
N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
8.16
162.6,
162.7
63.8,
64.0
4.75;4.7
47.7,
52.7
4.84;4.36
163.9
H
O
NOE, 3.5%
3.29
CO2Me
CO2Me
Ph
N
Ph
HN
H
3.19
CO2Me
OH
N
O
Ph
NOE, 2.4%
NOE, 1%
O
N
H
OH
OH
O
N
11.11
11.39
HN
H
O
O
155.3,
155.5
O
O
O
112.4,
112.8
165.7,
166.1
157.6,
(Z)-7c
9.07
8.19
(E)-7c
(E,Z)-7c
9.32
158.0
Figure 3. Characteristic assignments for pyrroles (E)- and (Z)-7c. The enolic hydrogens chemical shifts are from the 1H NMR of 7b.
Although the species 4 were not isolated as stable products this
does not restrict the possibility for their in situ formation from 6 or
7 in acidic anhydrous media. The investigations in this respect are
underway. For the first time the conversion of 6 to 7 was charac-
terized by a Hammett equation log(K)x¼rsþlog(K)H. The ratios of
amide isomers in equilibrium are controlled by the inductive effect
of the substituents on the N-aromatic ring.
bis(4-aryl)imidazolidin-4-yl)(phenyl)methanones 10d,e (Scheme 6).
The probable mechanism for their formation is discussed below.
4.2.2. 1,4-Diphenyl-2,5-dihydro-1H-imidazole 3-oxide 1a
Yield 1.90 g, 40%. Colourless powder, mp 206–207.5 ꢀC; lit2b mp
186–187 ꢀC. IR (KBr) nC]N–O 1587, nC]N–O 1229 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6):
d
4.81 (2H, t, J¼4.0 Hz), 5.31 (2H, t, J¼4.0 Hz),
6.71 (2H, d, J¼8.0 Hz), 7.78 (1H, t, J¼7.6 Hz), 7.27 (2H, t, J¼8.0 Hz),
7.51–7.53 (3H, m), 8.37–8.40 (2H, m). 13C NMR (100 MHz, DMSO-
4. Experimental
4.1. General
d6): d 53.1 (C5), 78.1 (C2), 112.5 (N–Ar-o), 118.2 (N–Ar-p), 127.0 (C4–
Ph-o),127.8 (C4),129.0 (C4–Ph-m), 129.7 (N–Ar-m),131.0 (C4–Ph-p),
136.2 (C4–Ph-ipso), 145.1 (N–Ar-ipso).
Anal. Calcd for C15H14N2O (238.28) C, 75.61; H, 5.92; N, 11.76.
Found C, 75.55; H, 5.93; N, 11.80.
The solvents and the reagents used in the syntheses of
compounds 1–3,6–7 were Merck (MeOH, CHCl3, petroleum ether
40–60 ꢀC, EtOH, benzene and the aromatic amines), Aldrich
(Formaldehyde, DMAD, CF3CO2H) or Fluka (Phenacyl bromide and
(NH2OH)2H2SO4) quality.
Melting points were recorded on an Electrothermal Digital
melting point apparatus. Infrared spectra were recorded on
a Thermo-Nicolet 6700 FTIR. 1D and 2D NMR experiments were
performed on a Varian Mercury Plus 400 MHz spectrometer. The
compounds prepared were dried in a vacuum oven at room tem-
perature. Nitrones 1a–f were prepared according to the previously
reported methods.2 The elemental analyses were performed on
a EuroEA 3000 CHNS analyzer.
4.2.3. 4-Phenyl-1-p-tolyl-2,5-dihydro-1H-imidazole 3-oxide 1b
Yield 2.27 g, 45%. Colourless crystals, mp 223–224 ꢀC; lit2b mp
223–224 ꢀC. IR (KBr) nC]N–O 1581, nC]N–O 1236 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6):
t, J¼4.0 Hz), 6.62 (2H, d, J¼8.0 Hz), 7.02 (2H, d, J¼8.4 Hz), 7.50–7.53
(3H, m), 8.36–8.38 (2H, m). 13C NMR (100 MHz, DMSO-d6):
20.5
d
2.21 (3H, s), 4.77 (2H, t, J¼4.0 Hz), 5.27 (2H,
d
(Me), 53.3 (C5), 78.4 (C2), 112.7 (N–Ar-o), 126.9 (N–Ar-p), 127.0 (C4–
Ph-o), 127.8 (C4), 129.0 (C4–Ph-m), 130.1 (N–Ar-m), 131.0 (C4–Ph-p),
136.3 (C4–Ph-ipso), 143.1 (N–Ar-ipso).
Anal. Calcd for C16H16N2O (252.31) C, 76.16; H, 6.39; N, 11.10.
Found C, 75.94; H, 6.36; N, 11.36.
4.2. Synthesis of 4-phenyl-1-aryl-2,5-dihydro-1H-imidazole
3-oxides 1a–e
4.2.1. General procedure
To a solution of aniline derivative (40 mmol) in ethanol (80 mL)
phenacyl bromide oxime (20 mmol, 4.28 g) was added and the mix-
turestirredatroomtemperaturefor25 min. Formaldehyde(40 mmol,
3.2 mL, 37%) was added to the reaction mixture and stirred for further
3 h. The precipitated product was filtered and recrystallized from
ethanol. In the cases of p-chloro- and bromoanilines a second product
precipitates together with the imidazoline 3-oxide. The latter were
separated by column chromatography and characterized to be (1,3-
Table 1
Linear free energy relationships in the transformylation of 6 to (E)-7 and (Z)-7 at
20 ꢀC17
Ar
E-7a
Z-7a
6a
log KE
log KZ
log Kb
s
Ph
28.5
45
51.5
6
23
48.5
22
3
88.5
91
ꢁ0.23
0.31
1.24
ꢁ0.32
0.18
1.18
1.13
1.84
2.89
0
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
33.5
45.5
5.5
ꢁ0.14
ꢁ0.28
0.24
0.26
ꢁ1.17
ꢁ1.21
ꢁ0.43
4.5
4.5
ꢁ1.31
ꢁ1.31
ꢁ0.65
a
Content of the compound (%) after a week at 20 ꢀC.
The ratios were defined as follows KE¼[(E)-7]/[6], KZ¼[(Z)-7]/[6], K¼[(E)-7][(Z)-
b
Figure 4. Plot of log KE, log KZ and log K versus s.
7]/[6].

N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
653
CO2Me
OH
CO2Me
Ph
N
Ph
CO2Me
OH
CO2Me
Ph
N
Ph
N
H
N
H
N
H
N
H
Ar NH2
O
Ar
OH
Ar
Ar
OH
+
N
HO
O
O
O
H
O
O
H
OH
A
A'
6
CO2Me
OH
CO2Me
OH
CO2Me
CO2Me
OH
Ph
N
Ph
Ph
N
Ph
N
Ar
H
Ar
Ar
N
Ar
N
N
N
H
OH
+
N
OH
+
HO
O
H
HO
H
O
H
H
O
OH
O
H
H
(E)-7.H+
(Z)-7.H+
B
B'
deprotonation
tautomerization
+
(Z)-7
(E)-7
Scheme 5. Probable mechanism for the transformylation of methyl 2-arylaminomethyl-1-formyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylates 6a–e.
4.2.4. 1-(4-Methoxyphenyl)-4-phenyl-2,5-dihydro-1H-imidazole
3-oxide 1c
4.2.6. 1-(4-Bromophenyl)-4-phenyl-2,5-dihydro-1H-imidazole
3-oxide 1e
Yield 2.41 g, 45%. Colourless crystals, mp 189–190 ꢀC; lit2b mp
Yield 1.14 g, 16%. Colourless crystals from ethanol, mp 236–
237 ꢀC; IR (KBr) nC]N–O 1598, nC]N–O 1245 cmꢁ1 1H NMR
(400 MHz, DMSO-d6):
4.80 (2H, t, J¼4.0 Hz), 5.31 (2H, t, J¼4.0 Hz),
6.67 (2H, d, J¼9.2 Hz), 7.42 (2H, d, J¼8.8 Hz), 7.51–7.53 (3H, m),
8.36–8.38 (2H, m). 13C NMR (100 MHz, DMSO-d6):
53.2 (C5), 77.9
189–190 ꢀC. IR (KBr) nC]N–O 1588, nC]N–O 1225 cmꢁ1
;
1H NMR
;
(400 MHz, DMSO-d6):
t, J¼4.0 Hz), 6.68 (2H, d, J¼9.2 Hz), 6.89 (2H, d, J¼8.8 Hz), 7.49–7.53
(3H, m), 8.36–8.38 (2H, m). 13C NMR (100 MHz, DMSO-d6):
53.7
d
3.68 (3H, s), 4.75 (2H, t, J¼4.0 Hz), 5.25 (2H,
d
d
d
(C5), 55.8 (MeO), 78.8 (C2), 113.7 (N–Ar), 115.3 (N–Ar), 126.9 (C4–
Ph), 127.8 (C4), 129.0 (C4–Ph), 130.9 (C4–Ph), 136.3 (C4–Ph-ipso),
139.7 (N–Ar-ipso), 152.6 (N–Ar-p).
(C2), 109.5 (N–Ar-p), 114.6 (N–Ar-o), 126.9 (C4–Ph), 127.7 (C4), 129.1
(C4–Ph), 131.0 (C4–Ph), 132.2 (N–Ar-m), 136.1 (C4Ph-ipso), 144.2
(N–Ar-ipso).
Anal. Calcd for C16H16N2O2 (268.31) C, 71.62; H, 6.01; N, 10.44.
Found C, 71.78; H, 5.87; N, 10.06.
Anal. Calcd for C15H13BrN2O (317.18) C, 56.80; H, 4.13; N, 8.83.
Found C, 56.45; H, 4.18; N, 8.81.
4.2.5. 1-(4-Chlorophenyl)-4-phenyl-2,5-dihydro-1H-imidazole
3-oxide 1d
4.3. Spectral data for (1,3-bis(4-aryl)imidazolidin-4-
yl)(phenyl)methanones 10d,e
Yield 0.54 g, 10%. Colourless crystals, mp 231–232 ꢀC; IR (KBr)
nC]N–O 1595, nC]N–O 1235 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
4.3.1. (1,3-Bis(4-chlorophenyl)imidazolidin-4-
yl)(phenyl)methanone 10d
d
4.81 (2H, t, J¼4.0 Hz), 5.31 (2H, t, J¼4.0 Hz), 6.72 (2H, d, J¼9.2 Hz),
7.31 (2H, d, J¼8.8 Hz), 7.51–7.54 (3H, m), 8.36–8.38 (2H, m). 13C
Yield 0.397 g, 5%. Mp 175–176 ꢀC. IR (KBr) nC]O, 1693 cmꢁ1
;
1H
NMR (100 MHz, DMSO-d6):
d 53.3 (C5), 78.0 (C2), 114.1 (N–Ar-o),
NMR (400 MHz, DMSO-d6):
d
3.69 (1H, dd, J¼10.0, 1.6 Hz), 3.94 (1H,
126.0 (N–Ar-p), 126.9 (C4–Ph), 127.7 (C4), 129.1 (C4–Ph), 129.4 (N–
Ar-m), 131.0 (C4–Ph), 136.1 (C4–Ph-ipso), 143.9 (N-Ar-ipso).
Anal. Calcd for C15H13ClN2O (272.73) C, 66.06; H, 4.80; N, 10.27.
Found C, 65.64; H, 4.71; N, 9.88.
dd, J¼10.0, 8.4 Hz), 4.70 (1H, d, J¼3.6 Hz), 4.88 (1H, d, J¼3.6 Hz), 6.03
(1H, dd, J¼8.4, 1.6 Hz), 6.63 (2H, d, J¼8.8 Hz), 6.73 (2H, d, J¼8.8 Hz),
7.21 (2H, d, J¼8.0 Hz), 7.22 (2H, d, J¼8.8 Hz), 7.59 (2H, t, J¼7.2 Hz),
7.72 (1H, t, J¼7.2 Hz), 8.09 (2H, d, J¼7.8 Hz). 13C NMR (100 MHz,
Table 2
Linear free energy relationships in the transformylation of 6 to (E)-7 and (Z)-7 in DMSO-d6 at different temperatures
Ar
E-7a
Z-7a
6a
log KE
log KZ
log Kb
(E)/(Z)
50 ꢀC-1 h
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
Content (%)
34
50
54
8
27
37
46
8
39
13
ꢁ0.06
ꢁ0.16
1.37
2.15
1.24
1.34
1.13
1.09
1.00
0.59
0.45
84
86
ꢁ1.02
ꢁ1.09
ꢁ1.02
ꢁ1.09
ꢁ0.12
ꢁ0.24
7
7
60 ꢀC-1 h
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
Content (%)
36
51
54
11
8
29
40
46
11
8
35
9
0.012
0.75
ꢁ0.08
1.48
2.36
1.26
1.35
1.18
1.00
1.00
0.65
78
84
ꢁ0.85
ꢁ1.02
ꢁ0.85
ꢁ1.02
0.19
ꢁ0.12
70 ꢀC-1 h
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
Content (%)
42
52
52
14
14
34
41
48
15
14
24
7
0.24
0.87
0.15
0.77
1.77
2.48
1.24
1.28
1.15
1.00
1.00
71
72
ꢁ0.71
ꢁ0.71
ꢁ0.66
ꢁ0.71
0.47
0.44
a
Content of the compound (%) after 1 h heating at the corresponding temperature.
The ratios defined as in the legend of Table 1.
b

654
N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
Figure 6. Plot of log K, log KE and log KZ versus
50 ꢀC.
s for the reaction series after 14 h at
Figure 5. Plot of log K versus
s at different temperatures.
DMSO-d6): d 50.5 (C5), 61.4 (C4), 66.6 (C2),114.3,114.6 (N1–Ar-o and
DMAD was 1:1.5 instead of 1:4 as was before. To a solution of 1
(2 mmol) in benzene (13 mL) DMAD (3 mmol, 0.431 g, 99%) was
added and the reaction mixture heated at reflux for 3 h; 2a,e are
new compounds and the spectral and elemental analyses results
are given below. The other adducts are previously reported nev-
ertheless we report their 1H and 13C NMR spectra recorded in
DMSO-d6. The previous reports included mainly their 1H NMR
spectra in CDCl3. The conversions were monitored by 1H NMR and
were quantitative. The yields reported are based on the isolated
crystals after crystallizations from ethanol.
N3–Ar-o), 121.3, 121.6 (N1–Ar-p and N3–Ar-p), 129.0 (Bz-o), 129.1,
129.2 (N1–Ar-m and N3–Ar-m),129.5 (Bz-m),134.5 (2C; Bz-p and Bz-
ipso), 144.1 (N1–Ar-ipso), 145.0 (N3–Ar-ipso), 198.0 (C]O).
Anal. Calcd for C22H18Cl2N2O (397.3) C, 66.51; H, 4.57; N, 7.05.
Found C, 66.61; H, 4.48; N, 7.14.
4.3.2. (1,3-Bis(4-bromophenyl)imidazolidin-4-yl)(phenyl)
methanone 10e
Yield 0.778 g, 8%. Mp 174–175 ꢀC. IR (KBr) nC]O 1685 cmꢁ1
;
1H
NMR (400 MHz, DMSO-d6):
d
3.69 (1H, dd, J¼10 Hz, 1.2 Hz), 3.94
(1H, t, J¼9.2 Hz), 4.69 (1H, d, J¼3.6 Hz), 4.86 (1H, d, J¼3.6 Hz),
6.03 (1H, d, J¼9.2, 1.2 Hz), 6.59 (2H, d, J¼9.2 Hz), 6.68 (2H, d,
J¼9.2 Hz), 7.32 (2H, d, J¼9.2 Hz), 7.33 (2H, d, J¼9.2 Hz), 7.59 (2H, t,
J¼8.0 Hz), 7.72 (1H, t, J¼7.2 Hz), 8.09 (2H, d, J¼7.2 Hz). 13C NMR
4.4.2. Dimethyl 3a,5-diphenyl-3a,4,5,6-tetrahydroimidazo[1,5-
b]isoxazole-2,3-dicarboxylate 2a
Yield 0.684 g, 90%. Yellow crystals, mp 138.5–139.5 ꢀC. IR (KBr)
nC]O 1754, 1712; nC]C 1657 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
(100 MHz, DMSO-d6):
d 50.4 (C5), 61.3 (C4), 66.5 (C2), 108.8, 109.2
d
3.42 (1H, d, J¼10.4 Hz), 3.57 (3H, s), 3.82 (3H, s), 4.19 (1H, d,
(N1–Ar-p and N3–Ar-p), 114.9, 115.1 (N1–Ar-o and N3–Ar-o), 129.0
(Bz-o), 129.6 (Bz-m), 132.0, 132.1 (N1–Ar-m and N3–Ar-m), 134.5
(Bz-p), 134.6 (Bz-ipso), 144.5, 145.3 (N1–Ar-ipso and N3–Ar-ipso),
198.0 (C]O).
Anal. Calcd for C22H18Br2N2O (486.2) C, 54.35; H, 3.73; N, 5.76.
Found C, 54.55; H, 3.93; N, 6.00.
J¼11.2 Hz), 4.56 (1H, d, J¼10.4 Hz), 5.25 (1H, d, J¼11.2 Hz), 6.83 (1H,
t, J¼7.2 Hz), 6.92 (2H, d, J¼8.0 Hz), 7.24 (2H, t, J¼8.0 Hz), 7.33 (1H, t,
J¼7.2 Hz), 7.40 (2H, t, J¼7.2 Hz), 7.52 (2H, d, J¼7.2 Hz). 13C NMR
(100 MHz, DMSO-d6):
d 52.4, 54.0, 56.6, 75.9, 82.5, 110.4, 115.9,
119.9, 127.3, 128.5, 128.8, 129.6, 141.1, 146.6, 152.5, 159.3, 162.2.
Anal. Calcd for C21H20N2O5 (380.39) C, 66.31; H, 5.30; N, 7.36.
Found C, 66.26; H, 5.36; N, 7.26.
4.4. Synthesis of 2,5-dihydro-1H-imidazole 3-oxide DMAD
adducts 2a–e
4.4.3. Dimethyl 3a-phenyl-5-p-tolyl-3a,4,5,6-tetrahydro
imidazo[1,5-b]isoxazole-2,3-dicarboxylate 2b
4.4.1. General procedure
Yield 0.733 g, 93%. Colourless crystals, mp 139–140 ꢀC, lit3d–e mp
The adducts were prepared according to the procedure, which
134.8 ꢀC. IR (KBr) nC]O 1754, 1711; nC]C 1658 cmꢁ1 1H NMR
;
we have recently reported.3d–e The ratio of the starting nitrone
(400 MHz, DMSO-d6):
d
2.20 (3H, s), 3.36 (1H, d, J¼10.4 Hz), 3.57
Table 3
Linear free energy relationships in the transformylation of 6 to (E)-7 and (Z)-7 in
DMSO-d6 after 14 h at 50 ꢀ
C
Table 4
Substituent dependence of [(E)-7]/[(Z)-7] in DMSO-d6 at 25 ꢀ
C
Ar
E-7a
Z-7a
6a
log KE
log KZ
log Kb
(E)/(Z)
50 ꢀC-14 h
Content (%)
Ar
E-7
Z-7
[(E)-7]/[(Z)-7]a
log[(E)-7]/[(Z)-7]
sI
Ph
52
56
54
28
26
41
42
46
28
25
7
2
0
44
49
0.87
1.45
0.77
1.32
2.48
3.07
1.27
1.33
1.17
1
Ph
56.5
57.6
53.7
50.5
50.4
43.5
42.4
46.3
49.5
49.6
1.30
1.36
1.16
1.02
1.02
0.11
0.13
0.06
0.01
0.01
0
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
ꢁ0.05
0.27
0.46
0.44
ꢁ0.20
ꢁ0.28
ꢁ0.20
ꢁ0.29
1.25
1.12
1.04
a
a
Content of the compound (%) after 14 h heating at 50 ꢀC.
The ratios defined as in the legend of Tables 1 and 2.
The values are averages of three measurements for each mixture, STDEV are ca.
b
0.01.

N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
655
(400 MHz, DMSO-d6):
d
3.45 (1H, d, J¼10.4 Hz), 3.57 (3H, s), 3.82
(3H, s), 4.22 (1H, d, J¼11.6 Hz), 4.55 (1H, d, J¼10.4 Hz), 5.25 (1H, d,
J¼11.6 Hz), 6.94 (2H, d, J¼8.8 Hz), 7.26 (2H, d, J¼8.8 Hz), 7.33 (1H, t,
J¼7.2 Hz), 7.40 (2H, t, J¼6.8 Hz), 7.52 (2H, d, J¼9.2 Hz). 13C NMR
(100 MHz, DMSO-d6): d 52.3, 54.0, 57.5, 76.9, 82.6, 110.4,115.0,117.4,
127.3, 128.4, 128.8, 140.5, 141.2, 152.5, 153.6, 159.3, 162.2.
Anal. Calcd for C21H19ClN2O5 (414.84) C, 60.80; H, 4.62; N, 6.75.
Found C, 61.2; H, 4.62; N, 6.76.
4.4.6. Dimethyl 5-(4-bromophenyl)-3a-phenyl-3a,4,5,6-tetra
hydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate 2e
Yield 0.817 g, 89%. Colourless crystals, mp 149–150 ꢀC. IR (KBr)
nC]O 1754, 1711; nC]C 1658 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d
3.45 (1H, d, J¼10.8 Hz), 3.57 (3H, s), 3.82 (3H, s), 4.21 (1H, d,
J¼11.6 Hz), 4.55 (1H, d, J¼10.8 Hz), 5.41 (1H, d, J¼11.6 Hz), 6.90 (2H,
d, J¼8.8 Hz), 7.31–7.42 (5H, m), 7.51 (2H, d, J¼7.6 Hz). 13C NMR
(100 MHz, DMSO-d6): d 52.4, 54.1, 56.5, 76.6, 82.5, 110.4, 111.2, 118.0,
127.3, 128.6, 128.8, 132.1, 140.9, 145.9, 152.4, 159.2, 162.1.
Anal. Calcd for C21H19BrN2O5 (459.30) C, 54.92; H, 4.17; N, 6.10.
Found C, 55.33; H, 4.15; N, 6.15.
Figure 7. Plot of log[(E)]/[(Z)]x versus sI at 25 ꢀC.
4.5. Synthesis of 3-methoxy-7-(methoxycarbonyl)-2,7a-
diaryl-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-
6-olates 3a–e
(3H, s), 3.82 (3H, s), 4.11 (1H, d, J¼11.6 Hz), 4.53 (1H, d, J¼10.4 Hz),
5.19 (1H, d, J¼11.6 Hz), 6.82 (2H, d, J¼8.4 Hz), 7.05 (2H, d,
J¼8.4 Hz), 7.32 (1H, t, J¼7.6 Hz), 7.40 (2H, t, J¼7.6 Hz), 7.52 (2H, d,
4.5.1. General procedure
J¼7.6 Hz). 13C NMR (100 MHz, DMSO-d6):
d 20.6, 52.4, 54.0, 57.0,
76.3, 82.5, 110.5, 116.1, 127.3, 128.5, 128.7, 128.8, 130.0, 141.2, 144.4,
152.5, 159.3, 162.2.
To a solution of sodium methoxide in methanol (5 mL, 1.5 mmol
Na, 0.035 g) at reflux, 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-
2,3-dicarboxylate 2 (0.5 mmol) was added and the mixture stirred
for an hour, except 1a where the reaction time is 3 h. The white
precipitate was filtered and dried under vacuum.
Anal. Calcd for C22H22N2O5 (394.42) C, 66.99; H, 5.62; N, 7.10.
Found C, 66.98; H, 5.60; N, 7.22.
4.5.2. (cis)-3-Methoxy-7-(methoxycarbonyl)-5-oxo-2,7a-diphenyl-
2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olate 3a
4.4.4. Dimethyl 5-(4-methoxyphenyl)-3a-phenyl-3a,4,5,6-tetra
hydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate 2c
Yield 0.125 g, 62%. White powder, mp 282–283 ꢀC. IR (KBr) nC]O
Yield 0.681 g, 83%. Colourless crystals, mp 118–119 ꢀC, lit3d–e mp
1727, 1676 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
; d 3.10 (1H, d,
116 ꢀC. IR (KBr) nC]O 1753, 1711; nC]C 1656 cmꢁ1
;
1H NMR
J¼9.6 Hz), 3.12 (3H, s), 3.38 (3H, s), 4.72 (1H, d, J¼9.6 Hz), 5.59 (1H,
(400 MHz, DMSO-d6):
d
3.30 (1H, d, J¼10.4 Hz), 3.37 (3H, s), 3.68
s), 6.74–6.78 (3H, m), 7.13 (1H, t, J¼7.2 Hz), 7.19–7.24 (4H, m), 7.50
(3H, s), 3.83 (3H, s), 4.06 (1H, d, J¼11.6 Hz), 4.49 (1H, d, J¼10.4 Hz),
5.17 (1H, d, J¼11.6 Hz), 6.83 (2H, d, J¼9.6 Hz), 6.89 (2H, d, J¼9.6 Hz),
7.32 (1H, t, J¼7.2 Hz), 7.40 (2H, t, J¼7.2 Hz), 7.51 (2H, d, J¼7.2 Hz). 13C
(2H, d, J¼7.6 Hz). 13C NMR (100 MHz, DMSO-d6):
d 49.5, 52.3, 57.1,
66.8, 95.1, 106.4, 110.0, 113.4, 118.9, 126.6, 127.7, 129.5, 143.9, 145.8,
165.3, 166.8, 173.4.
NMR (100 MHz, DMSO-d6):
d 52.3 (C3–CO2Me), 54.0 (C2–CO2Me),
Anal. Calcd for C21H19N2NaO5 (402.38) C, 62.68; H, 4.76; N, 6.96.
Found C, 62.55; H, 4.70; N, 6.85.
55.7 (MeO), 57.5 (C4), 76.9 (C6), 82.6 (C3a), 110.4 (C3), 115.0 (N–Ar-
o), 117.4 (N–Ar-m), 127.3 (C3a–Ph), 128.4 (C3a–Ph), 128.8 (C3a–Ph),
140.5 (C3a–Ph-ipso), 141.2 (N–Ar-ipso), 152.5 (N–Ar-p), 153.6 (C2),
159.3 (C3–CO2Me), 162.2 (C2–CO2Me).
Anal. Calcd for C22H22N2O6 (410.42) C, 64.38; H, 5.40; N, 6.83.
Found C, 64.53; H, 5.53; N, 6.90.
4.5.3. (cis)-3-Methoxy-7-(methoxycarbonyl)-5-oxo-7a-phenyl-2-
p-tolyl-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olate 3b
Yield 0.164 g, 79%. White powder, mp 287–289 ꢀC. IR (KBr) nC]O
1727, 1676 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d 2.18 (3H, s), 3.05
(1H, d, J¼9.6 Hz), 3.10 (3H, s), 3.38 (3H, s), 4.69 (1H, d, J¼9.6 Hz),
5.34 (1H, s), 6.66 (2H, d, J¼8.0 Hz), 7.02 (2H, d, J¼8.0 Hz), 7.13 (1H, t,
J¼7.2 Hz), 7.22 (2H, t, J¼7.2 Hz), 7.50 (2H, d, J¼7.2 Hz). 13C NMR
4.4.5. Dimethyl 5-(4-chlorophenyl)-3a-phenyl-3a,4,5,6-tetra
hydroimidazo[1,5-b]isoxazole-2,3-dicarboxylate 2d
Yield 0.704 g, 85%. Colourless crystals, mp 134–135 ꢀC, lit3d–e mp
135.5 ꢀC. IR (KBr) nC]O 1754, 1721; nC]C 1659 cmꢁ1
;
1H NMR
(100 MHz, DMSO-d6): d 20.5, 49.5, 52.2, 63.5, 66.8, 95.4,106.5,113.4,
126.6, 127.5, 127.7, 129.9, 143.7, 144.0, 152.4, 165.4, 165.6, 173.5.
Anal. Calcd for C22H21N2O5Na (416.41) C, 63.46; H, 5.08; N, 6.72.
Found C, 63.40; H, 5.06; N, 7.00.
Ph
H
Ar
Ph
H
N
NH N OH
Ar
Br
Br
N
H2C=O
-NH2OH.HBr
Ar
N
Ar
Ar
N
N
OH
4.5.4. (cis)-3-Methoxy-7-(methoxycarbonyl)-2-(4-methoxy
phenyl)-5-oxo-7a-phenyl-2,3,5,7a-tetrahydro-1H-pyrrolo
[1,2-e]imidazol-6-olate 3c
H
A
B
C
.HBr
Yield 0.166 g, 77%. White powder, mp 287–288 ꢀC. IR (KBr) nC]O
Ph
Ar
Ph
Ar
Ph
OH
N
O
1727, 1676 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
; d 3.03 (1H, d,
-H
N
Ar
O
J¼9.2 Hz), 3.09 (3H, s), 3.37 (3H, s), 3.66 (3H, s), 4.67 (1H, d,
J¼9.2 Hz), 5.50 (1H, s), 6.72 (2H, d, J¼9.2 Hz), 6.82 (2H, d, J¼9.2 Hz),
7.13 (1H, t, J¼7.2 Hz), 7.22 (2H, t, J¼7.6 Hz), 7.50 (2H, d, J¼7.2 Hz). 13C
Ar
N
N
N
N
Ar
Ar
D
1'a-e
E
NMR (100 MHz, DMSO-d6):
d 49.6 (7-CO2Me), 52.2 (C3–OMe), 55.7
Scheme 6. Probable mechanism for the formation of compounds 10a–e.
(N–Ar–OMe), 57.5 (NCH2), 66.8 (C7a), 95.8 (C3), 106.5 (C7), 114.5

656
N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
(N–Ar), 115.0 (N–Ar), 126.6 (C7a–Ph), 126.7 (C7a–Ph), 127.7 (C7a–
Ph), 140.2 (C7a–Ph-ipso), 143.8 (N–Ar-ipso), 152.9 (N–Ar-p), 165.4
(NCO), 167.0 (C7–CO2Me), 173.5 (C6).
Anal. Calcd for C22H21N2O6Na (432.41) C, 61.11; H, 4.89; N, 6.48.
Found C, 60.95; H, 4.64; N, 6.74.
6ꢂ10ꢁ3 M DMSO-d6):
d 2.10 (3H, s), 3.54 (3H, s), 3.71 (5H, br s),
4.27 (1H, d, J¼13.6 Hz), 4.43 (1H, d, J¼13.6 Hz), 6.44 (2H, d,
J¼8.8 Hz), 6.82 (2H, d, J¼8.8 Hz), 7.24 (1H, t, J¼6.8 Hz), 7.30 (2H, t,
J¼7.2 Hz), 7.35 (2H, d, J¼7.2 Hz), 8.91 (1H, s). 13C NMR (100 MHz,
3.75ꢂ10ꢁ2 M DMSO-d6):
d 20.5 (N–Ar–Me), 44.1 (N–CH2), 51.7
(CO2Me), 67.6 (C2), 113.0 (N–Ar-o), 115.8 (q, J1 ¼288.1 Hz), 117.6
CF
4.5.5. (cis)-2-(4-Chlorophenyl)-3-methoxy-7-(methoxycarbonyl)-
5-oxo-7a-phenyl-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-
olate 3d
(C3), 124.9 (N–Ar-p), 126.5 (C2–Ph-o), 128.0 (C2–Ph-p), 128.6 (C2–
Ph-m), 129.7 (N–Ar-m), 138.0 (C2–Ph-ipso), 147.0 (N–Ar-ipso), 152.1
(C4), 158.8 (q, J2 ¼37.4 Hz), 158.8 (N–CHO), 162.8 (C3–CO2Me),
CF
Yield 0.146 g, 67%. White powder, mp 286–287 ꢀC. IR (KBr) nC]O
167.3 (C5).
1727, 1676 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6):
d
3.11 (1H, d,
Anal. Calcd for 6b$CF3CO2H$H2O, C23H23F3N2O8: (512.43) C,
53.91; H, 4.52; N, 5.47. Found C, 53.95; H, 4.42; N, 5.38.
J¼9.2 Hz), 3.11 (3H, s), 3.38 (3H, s), 4.72 (1H, d, J¼9.2 Hz), 5.60 (1H,
s), 6.77 (2H, d, J¼9.2 Hz), 7.13 (1H, t, J¼7.6 Hz), 7.20–7.24 (4H, m),
7.49 (2H, d, J¼7.2 Hz). 13C NMR (100 MHz, DMSO-d6):
d
49.5, 52.4,
4.6.4. Methyl 1-formyl-4-hydroxy-2-((4-methoxyphenylamino)
methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate 6c
Yieldþ0.067 g, 85%. White powder, mp 110–111 ꢀC. IR (KBr) nOH
3472; nNH2 2955–2492 medium, broad highly structured band;
57.2, 66.8, 94.9, 106.4, 115.1, 118.5, 122.6, 126.6, 127.7, 129.2, 143.8,
144.6, 165.3, 166.7, 173.4.
Anal. Calcd for C21H18ClN2NaO5 (436.83) C, 57.74; H, 4.15; N, 6.41.
Found C, 57.60; H, 4.10; N, 6.37.
nC]O 1760, 1710, 1691; nC]C 1646 cmꢁ1
.
1H NMR (400 MHz,
6ꢂ10ꢁ3 M DMSO-d6 solution):
d 3.54 (3H, s), 3.61 (3H, s), 3.78 (5H,
4.5.6. (cis)-2-(4-Bromophenyl)-3-methoxy-7-(methoxycarbonyl)-
5-oxo-7a-phenyl-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-
olate 3e
br s), 4.26 (1H, d, J¼13.6 Hz), 4.41 (1H, d, J¼13.6 Hz), 6.51 (2H, d,
J¼8.8 Hz), 6.65 (2H, d, J¼8.8 Hz), 7.24 (1H, t, J¼6.8 Hz), 7.30 (2H, t,
J¼7.2 Hz), 7.34 (2H, d, J¼7.2 Hz), 8.91 (1H, s). 13C NMR (100 MHz,
Yield 0.168 g, 70%. White powder, mp 295–296 ꢀC. IR (KBr)
3.75ꢂ10ꢁ2 M DMSO-d6):
d 45.0 (N–CH2), 51.8 (CO2Me), 55.7 (N–Ar–
nC]O 1727, 1676 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
3.10 (1H, d,
OMe), 67.6 (C2), 114.5 (N–Ar-o), 114.9 (N–Ar-m), 115.7 (q,
J¼9.6 Hz), 3.11 (3H, s), 3.37 (3H, s), 4.71 (1H, d, J¼9.6 Hz), 5.59 (1H,
s), 6.72 (2H, d, J¼9.2 Hz), 7.13 (1H, t, J¼7.2 Hz), 7.22 (2H, t,
J¼7.6 Hz), 7.34 (2H, d, J¼9.2 Hz), 7.49 (2H, d, J¼7.2 Hz). 13C NMR
J1 ¼289.1 Hz), 117.7 (C3), 126.5 (C2–Ph-o), 128.0 (C2–Ph-p), 128.6
CF
(C2–Ph-m), 138.0 (C2–Ph-ipso), 143.0 (N–Ar-ipso), 151.5 (N–Ar-p),
152.1 (C4), 158.8 (q, J2 ¼37.4 Hz), 158.9 (N–CHO), 162.7 (C3–
CF
(100 MHz, DMSO-d6):
d
49.6, 52.4, 57.2, 66.8, 94.8, 106.4, 110.3,
CO2Me), 167.3 (C5).
115.6, 126.6 (C7a–Ph, 2C), 127.7, 132.0, 143.8, 145.0, 165.3, 166.7,
173.4.
Anal. Calcd for 6c$CF3CO2H$H2O, C23H23F3N2O9 (528.43) C,
52.28; H, 4.39; N, 5.30. Found C, 52.06; H, 4.25; N, 5.25.
Anal. Calcd for C21H18BrN2NaO5 (481.28) C, 52.41; H, 3.77; N,
5.82. Found C, 52.37; H, 3.65; N, 5.86.
4.6.5. Methyl 2-((4-chlorophenylamino)methyl)-1-formyl-4-
hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate 6d
Yieldþ0.051 g, 63%. White powder, mp 101–102 ꢀC. IR (KBr) nOH
3452; nNH2 2955–2492 medium, broad highly structured band;
4.6. Synthesis of 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-
((arylamino)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylate
trifloroacetates 6a–e
nC]O 1768, 1710, 1691; nC]C 1652 cmꢁ1
.
1H NMR (400 MHz,
6ꢂ10ꢁ3 M DMSO-d6):
d 3.54 (3H, s), 3.80 (3H, br s), 4.29 (1H, d,
4.6.1. General procedure
J¼13.6 Hz), 4.47 (1H, d, J¼13.6 Hz), 5.87 (1H, br s), 6.53 (2H,
d, J¼8.8 Hz), 7.03 (2H, d, J¼8.8 Hz), 7.24 (1H, t, J¼6.8 Hz), 7.30 (2H, t,
J¼7.2 Hz), 7.36 (2H, d, J¼7.2 Hz), 8.91 (1H, s), 11.86 (1H, br s). 13C
Compound 3 (0.15 mmol) was dissolved in CF3CO2H (0.5 mL)
and stirred for 5 min. The solution was dropped into ice water
(2.5 mL). The white solid precipitated was filtered and dried under
vacuum.
NMR (100 MHz, 3.75ꢂ10ꢁ2 M DMSO-d6):
d 43.7 (N–CH2), 51.8
(CO2Me), 67.5 (C2), 114.1 (N–Ar-o), 115.8 (q, J1 ¼288.1 Hz), 117.4
CF
(C3), 119.6 (N–Ar-p), 126.5 (C2–Ph-o), 128.1 (C2–Ph-p), 128.6 (C2–
Ph-m), 129.0 (N–Ar-m), 137.9 (C2–Ph-ipso), 148.3 (N–Ar-ipso), 152.2
4.6.2. Methyl 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-((phenyl
amino)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylate 6a
(C4), 158.8 (q, J2 ¼37.4 Hz), 158.9 (N–CHO), 162.8 (C3–CO2Me),
CF
Yield 0.038 g, 51%. White powder, mp 94–95 ꢀC. IR (KBr) nOH
3466; nþNH2 2955–2492 medium, broad highly structured
167.2 (C5).
Anal. Calcd for 6d$CF3CO2H$H2O, C22H20ClF3N2O8 (532.85) C,
49.59; H, 3.78; N, 5.26. Found C, 50.00; H, 3.77; N, 5.43.
band; nC]O 1762, 1710, 1692, 1653 cmꢁ1 1H NMR (400 MHz,
.
6.25ꢂ10ꢁ3 M DMSO-d6):
d 3.54 (3H, s), 3.96 (5H, br s), 4.30 (1H,
d, J¼13.6 Hz), 4.48 (1H, d, J¼13.6 Hz), 6.48 (1H, t, J¼7.6 Hz), 6.53
(2H, d, J¼7.6 Hz), 7.00 (2H, t, J¼7.6 Hz), 7.24 (1H, t, J¼7.2 Hz),
7.30 (2H, t, J¼7.6 Hz), 7.36 (2H, d, J¼7.6 Hz), 8.91 (1H, s). 13C
NMR (100 MHz, 3.75ꢂ10ꢁ2 M DMSO-d6): 43.8 (N–CH2), 51.8
4.6.6. Methyl 2-((4-bromophenylamino)methyl)-1-formyl-4-
hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate 6e
Yieldþ0.052 g, 74%. White powder, mp 96–97 ꢀC. IR (KBr) nOH
3460; nNH2 2955–2492 medium, broad highly structured band;
(CO2Me), 67.6 (C2), 112.9 (N–Ar-o), 115.7 (q, J1 ¼288.3 Hz), 116.5
nC]O 1767, 1712, 1691; nC]C 1652 cmꢁ1
.
1H NMR (400 MHz,
CF
(N–Ar-p), 117.6 (C3), 126.5 (C2–Ph-o), 128.0 (C2–Ph-p), 128.6 (C2–
Ph-m), 129.3 (N–Ar-m), 138.0 (C2–Ph-ipso), 149.4 (N–Ar-ipso),
6ꢂ10ꢁ3 M DMSO-d6):
d 3.54 (3H, s), 3.65 (3H, br s), 4.29 (1H, d,
J¼13.6 Hz), 4.47 (1H, d, J¼13.6 Hz), 5.91 (1H, br s), 6.49 (2H,
d, J¼8.8 Hz), 7.14 (2H, d, J¼8.8 Hz), 7.24 (1H, t, J¼6.8 Hz), 7.30 (2H, t,
J¼7.2 Hz), 7.35 (2H, d, J¼7.2 Hz), 8.91 (1H, s), 11.84 (1H, br s). 13C
152.2 (C4), 158.8 (q, J2 ¼37.4 Hz), 158.9 (N–CHO), 162.8 (C3–
CF
CO2Me), 167.3 (C5).
Anal. Calcd for 6a$CF3CO2H$H2O C22H21F3N2O8 (498.41) C,
53.02; H, 4.25; N, 5.62. Found C, 52.66; H, 3.99; N, 5.58.
NMR (100 MHz, 3.75ꢂ10ꢁ2 M DMSO-d6):
d 43.6 (N–CH2), 51.8
(CO2Me), 67.5 (C2), 107.0 (N–Ar-p), 114.7 (N–Ar-o), 115.8 (q,
J1 ¼288.1 Hz), 117.4 (C3), 126.5 (C2–Ph-o), 128.1 (C2–Ph-p), 128.6
CF
4.6.3. Methyl 2-((p-toluidino)methyl)-1-formyl-4-hydroxy-5-oxo-
2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate 6b
(C2–Ph-m), 131.8 (N–Ar-m), 137.9 (C2–Ph-ipso), 148.6 (N–Ar-ipso),
152.2 (C4), 158.8 (q, J2 ¼37.4 Hz), 158.9 (N–CHO), 162.8 (C3–
CF
Yieldþ0.055 g, 72%. White powder, mp 112–113 ꢀC. IR (KBr) nOH
CO2Me), 167.2 (C5).
3460; nNH2 2955–2492 medium, broad highly structured band;
Anal. Calcd for 6e$CF3CO2H$H2O, C22H20BrF3N2O8 (577.3) C,
45.77; H, 3.49; N, 4.85. Found C, 45.46; H, 3.40; N, 4.94.
nC]O 1759, 1712, 1691; nC]C 1652 cmꢁ1 1H NMR (400 MHz,
.

N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
657
4.7. Synthesis of methyl 4-hydroxy-5-oxo-2-phenyl-2-
((N-arylformamido)methyl)-2,5-dihydro-1H-pyrrole-3-
carboxylates 7a–e
under vacuum to give yellow oil, which solidifies on standing in
a vacuum oven.
Compound 7c; yield 0.072 g, 91%. The spectral characteristics of
the product were identical with those of obtained according to
procedure A.
4.7.1. General procedure A
Solutions (DMSO-d6, 0.8 mL) of compounds 6 (0.03 mmol) in
NMR tubes were heated at 80 ꢀC on a water bath for 5, 2.5,1, 14,14 h
for 6a–e, respectively. The reaction mixtures were poured into ice
water (5 mL) and extracted with CHCl3 (2ꢂ5 mL). The combined
extracts were washed with water (2ꢂ10 mL). The organic phase
was dried over anhydrous Na2SO4, filtered and the organic solvent
evaporated under vacuum. The residue was dried under vacuum
and triturated with ether.
4.7.6. Procedure C
A solution of 6 (0.25 mmol) in acetonitrile (2.5 mL) was heated
at reflux for 4 h. The solvent was evaporated under vacuum and the
residue treated with ether. The formed yellow powder was filtered
and dried.
4.7.7. (E,Z)-Methyl 4-hydroxy-2-((N-(4-methoxyphenyl)
formamido)methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-
pyrrole-3-carboxylates (E,Z)-7c
4.7.2. (E)-Methyl 4-hydroxy-5-oxo-2-phenyl-2-((N-phenyl
formamido)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylate 7a
Yield 0.0092 g, 91%. Yellow powder, mp 189–190 ꢀC. IR (KBr) nOH
3423; nNH 3199; nC]O 1723, 1694, 1674; nC]C 1625 cmꢁ1. 1H NMR
The following NMR data are for the (E,Z)-mixture formed in
DMSO-d6 at 20 ꢀC after 7 days.
1H NMR (400 MHz, DMSO-d6):
d 3.19 (3H, s, CO2Me), 3.29
(400 MHz, CDCl3):
d
3.51 (3H, s), 4.70 (1H, d, J¼13.6 Hz), 5.00 (1H, d,
(3H, s, CO2Me), 3.72 (3H, s, OMe), 3.73 (3H, s, OMe), 4.36 (1H,
d, J¼14.8 Hz), 4.7 (1H, d, J¼13.6 Hz), 4.75 (1H, d, J¼13.6 Hz),
4.84 (1H, d, J¼14.8 Hz), 6.82–6.99 (8H, m), 7.22–7.35 (10H, m),
8.16 (1H, s, N–CHO), 8.19 (1H, s, N–CHO), 9.07 (1H, s, –NH–
CO–), 9.32 (1H, s, –NH–CO–). 13C NMR (100 MHz, DMSO-d6):
J¼13.6 Hz), 6.53 (1H, s, D2O exch.), 7.04 (2H, d, J¼8.8 Hz), 7.25–7.40
(8H, m), 8.34 (1H, s).
13C NMR (100 MHz, CDCl3):
d 47.9 (N–CH2), 51.8 (CO2Me), 64.6
(C7a), 114.3 (C3), 124.6 (N–Ar), 125.9 (C7a–Ph), 127.2 (N–Ar), 128.5
(C7a–Ph),128.5 (N–Ar),129.7 (N–Ar),137.4 (C7a–Ph-ipso),140.8 (N–
Ar-ipso), 158.1 (C4), 164.1 (C3–CO2Me), 164.3 (N–CHO), 165.0 (C5).
Anal. Calcd for C20H18N2O5 (366.37) C, 65.57; H, 4.95; N, 7.65.
Found C, 65.30; H, 4.90; N, 7.55.
d
47.7 (N–CH2), 50.8, 50.9 (CO2Me), 52.7 (N–CH2), 55.7, 55.8
(N–Ar–OMe), 63.8, 64.0 (C2), 112.4, 112.8 (C–3), 113.8, 114.6 (N–
Ar-o), 115.7 (q, J1 ¼286.8 Hz), 126.5, 126.7, 127.9, 128.1, 128.5,
CF
128.7 (C5–Ph), 132.4, 134.6 (N–Ar-ipso), 139.8, 140.0 (C2–Ph-
ipso), 155.3, 155.5 (C4), 157.6, 158.0 (N–Ar-p), 158.8 (q,
4.7.3. (E)-Methyl 4-hydroxy-5-oxo-2-phenyl-2-((N-p-tolylform
amido)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylate 7b
J2 ¼38.2 Hz), 162.6, 162.8 (C3–CO2Me), 163.9 (N–CHO), 165.7,
CF
166.1 (C5).
Yield 0.011 g, 97%. Yellowish powder, mp 176–177 ꢀC. IR
(KBr) nOH 3447; nNH 3180; nC]O 1719, 1699, 1672; nC]C
4.7.8. (E)-Methyl 4-hydroxy-2-((N-(4-chlorophenyl)formamido)
methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylates 7d
Yield 0.011 g, 92%. White powder, mp 174–175 ꢀC. IR (KBr)
1632 cmꢁ1 1H NMR (400 MHz, CDCl3):
. d 2.34 (3H, s), 3.52 (3H,
s), 4.66 (1H, d, J¼14.0 Hz), 4.97 (1H, d, J¼14.0 Hz), 6.49 (1H, s,
D2O exch.), 6.91 (2H, d, J¼8.0 Hz), 7.17 (2H, d, J¼8.0 Hz), 7.31–
7.40 (5H, m), 8.29 (1H, s), 8.94 (1H, br s, D2O exch.). 13C NMR
nOH 3423; nNH 3246; nC]O 1716, 1694, 1674; nC]C 1634 cmꢁ1 1H
.
NMR (400 MHz, CDCl3):
d
3.56 (3H, s), 4.68 (1H, d, J¼14.0 Hz),
(100 MHz, CDCl3):
d
20.9 (N–ArMe), 48.0 (N–CH2), 51.7 (CO2Me),
4.96 (1H, d, J¼14.0 Hz), 6.54 (1H, s, D2O exch.), 6.98 (2H, d,
64.5 (C7a), 114.5 (C3), 124.6 (N–Ar), 125.9 (C7a–Ph), 128.6 (N–
Ar), 128.8 (C7a–Ph), 130.2 (Ar), 137.4 (N–Ar-ipso), 137.5 (C7a–
Ph-ipso), 138.2 (N–Ar-ipso), 158.1 (C4), 164.1 (C3–CO2Me), 164.3
(N–CHO), 165.0 (C5).
Anal. Calcd for C21H20N2O5 (380.39) C, 66.31; H, 5.30; N, 7.36.
Found C, 66.45; H, 5.18; N, 7.18.
J¼8.8 Hz), 7.32–7.37 (7H, m), 8.30 (1H, s), 8.94 (1H, br s, D2O
exch.). 13C NMR (100 MHz, CDCl3):
d 48.0 (N–CH2), 51.9 (CO2Me),
64.6 (C7a), 114.3 (C3), 125.8 (C7a–Ph), 125.9 (C7a–Ph), 128.7 (N–
Ar), 128.9 (C7a–Ph), 129.8 (N–Ar), 133.1 (N–Ar), 137.2 (C7a–Ph-ipso),
139.4 (N–Ar-ipso), 157.8 (C4), 163.7 (C3–CO2Me), 164.2 (N–CHO),
164.6 (C5).
Anal. Calcd for C20H17ClN2O5 (400.81) C, 59.93; H, 4.28; N, 6.99.
Found C, 59.99; H, 4.38; N, 6.85.
4.7.4. (E)-Methyl 4-hydroxy-2-((N-(4-methoxyphenyl)formamido)
methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylates 7c
Yield 0.012 g, 99%. Yellowish powder, mp 124–125 ꢀC. IR (KBr)
4.7.9. (E)-Methyl 2-((N-(4-bromophenyl)formamido)methyl)-4-
hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate 7e
Yield 0.012 g, 91%. Yellow powder, mp 174–175 ꢀC. IR (KBr)
nOH 3447; nNH 3214; nC]O 1718, 1699, 1663 cmꢁ1 1H NMR
.
(400 MHz, CDCl3):
d 3.54 (3H, s, CO2Me), 3.81 (3H, s, OMe), 4.61
(1H, d, J¼14.4 Hz, C1–Ha), 4.96 (1H, d, J¼14.4 Hz, C1–Ha), 6.57
(1H, s, OH), 6.88 (2H, d, J¼9.2 Hz), 6.95 (2H, d, J¼9.2 Hz), 7.30–
7.39 (5H, m), 8.26 (1H, s, C3–H), 9 (1H, br s). 13C NMR (100 MHz,
nOH 3423; nNH 3246; nC]O 1716, 1694, 1674; nC]C 1634 cmꢁ1 1H
.
NMR (400 MHz, CDCl3):
d
3.56 (3H, s), 4.68 (1H, d, J¼13.6 Hz),
4.96 (1H, d, J¼13.6 Hz), 6.57 (1H, s, D2O exch.), 6.92 (2H, d,
J¼8.8 Hz), 7.32–7.39 (5H, m), 7.51 (2H, d, J¼8.8 Hz), 8.30 (1H, s),
CDCl3):
d 48.4 (N–CH2), 51.8 (CO2Me), 55.6 (N–Ar–OMe), 64.6
(C7a), 114.6 (N–Ar-o), 115.5 (N–Ar-m), 115.5 (C3), 125.9 (C7a–Ph),
126.3 (C7a–Ph), 128.8 (C7a–Ph), 132.6 (N–Ar-ipso), 137.5 (C7a–
Ph-ipso), 158.1 (N–Ar-p), 158.6 (C4), 164.1 (C3–CO2Me), 164.3 (N–
CHO), 165.0 (C5).
Anal. Calcd for C21H20N2O6 (396.39) C, 63.63; H, 5.09; N, 7.07.
Found C, 63.55; H, 4.98; N, 7.26.
8.94 (1H, br s, D2O exch.). 13C NMR (100 MHz, CDCl3):
d 48.0 (N–
CH2), 51.9 (CO2Me), 64.6 (C7a), 114.3 (C3), 120.8 (N–Ar), 125.9
(C7a–Ph), 126.2 (C7a–Ph), 128.7 (N–Ar), 128.8 (C7a–Ph), 132.8
(N–Ar), 137.2 (C7a–Ph-ipso), 139.9 (N–Ar-ipso), 157.7 (C4), 163.6
(C3–CO2Me), 164.4 (N–CHO), 164.7 (C5).
Anal. Calcd for C20H17BrN2O5 (445.26) C, 53.95; H, 3.85; N, 6.29.
Found C, 53.85; H, 3.90; N, 6.32.
4.7.5. Procedure B
A solution of 6 (0.20 mmol) in methanol (5 mL) and H2O
(2.5 mL) was refluxed for 15 min. The solvent was evaporated under
vacuum and the residue dissolved in chloroform (15 mL). The or-
ganic phase was washed with water (2ꢂ15 mL), separated, dried
over anhydrous Na2SO4 and filtered. The solvent was evaporated
Acknowledgements
_
Turkish Scientific and Technological Research Council (TUBITAK)
is gratefully acknowledged for the financial support (Project No.
107T840).

658
N. Cos¸kun, M. Çetin / Tetrahedron 65 (2009) 648–658
11. (a) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin. 1969, 5,
References and notes
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3873–3905; (e) Martin, J. N.; Jones, R. C. F. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products. In Nitrones.
The Chemistry of Heterocyclic Compounds; United Kingdom: Chichester, 2002;
Vol. 59, pp 1–81.
2. (a) Cos¸kun, N.; Su¨mengen, D. Synth. Commun. 1993, 23, 1699–1706; (b) Cos¸kun,
N.; Asutay, O. Chim. Acta Turc. 1997, 25, 69–72; (c) Cos¸kun, N.; Asutay, O. Chim.
Acta Turc. 1999, 27, 17–23.
13. Nitrones 1a–f were prepared according to the previously reported methods.2 In
the cases of p-chloro- and bromoanilines the corresponding (1,3-bis(4-aryl)-
imidazolidin-4-yl)(phenyl)methanones 10d,e were isolated. The probable
mechanism for their formation is discussed below. (Scheme 6): the methyl-
enimminium salt A probably in equilibrium with N-bromomethylenaniline B
reacts with anilinoacetophenone oxime to give intermediate C. The latter un-
derwent condensation with formaldehyde and hydrolyze to imminium salts D
and E the intramolecular Mannich reaction of which produce compounds 10a–e.
14. Attempts to isolate compounds 4 according to a procedure involving their
formation in ether solution failed. The products in the filtrate after separation
of ether insoluble CF3CO2Na were shown to be identical with those prepared
according to the main procedure.
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) Cos¸kun, N.; Yılmaz, B. Synth. Commun. 2004, 34, 1617–1623; (g)
¨
¨
15. The amide16 group is one of the most important functional groups in chemistry.
Its planarity and relatively high barrier to rotation about the C–N bond are
important factors in determining the conformations of peptides and related
compounds.
¨
¨
Cos¸kun, N.; Tat, F. T.; Gu¨ ven, O. O Tetrahedron: Asymmetry 2001, 12, 1463–1467;
(h) Cos¸kun, N.; Tunçman, S. Tetrahedron 2006, 62, 1345–1350.
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Sulfur 2003, 178, 881–886; (c) Cos¸kun, N.; Tat, F. T. Turk. J. Chem. 2004, 28, 1–7.
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17. Solutions (DMSO-d6, 0.8 mL) of compounds 6 (0.03 mmol) in NMR tubes were
heated at 80 ꢀC on a water bath and the reaction times determined by 1H NMR
spectroscopy as 5, 2.5, 1, 14, 14 h for 6a–e, respectively. As expected the loga-
rithms of the average rates of the reactions are in linear correlation with the
Hammett
s
constants,
r
¼ꢁ2.09 and R2¼0.99.
18. The NOESY1D experiments in CDCl3 solution confirmed the stereochemistry of
the (E)-7. Irradiation of the singlet at 8.26 led to the enhancement of the N–Ar
ortho protons (0.8%), while the irradiation of N–Ar ortho protons enhanced the
C3–H by 2.26%. The same irradiation enhanced also the C1–Ha (upward) by 2.
31% C1–Hb by 1%. The irradiation of the latter proton signal enhanced the N–
Ar ortho protons signal, C1–Hb (downward) and the C7a–Ph ortho protons by
5.48, 19.8 and 4.26%, respectively. The irradiation of C1–Hb enhanced the
signals of C1–Ha, N–Ar ortho and C7a–Ph ortho by 17, 4.65 and 2.93%,
respectively.
8. Cos¸kun, N.; Parlar, A. Synth. Commun. 2005, 35, 2445–2451.
9. Cos¸kun, N.; Oztu¨rk, A. Tetrahedron 2006, 62, 12057–12063.
¨
10. (a) Mesnard, F.; Girard, S.; Fliniaux, O.; Bhogal, R. K.; Gillet, F.; Lebreton, J.;
Fliniaux, M. A.; Robins, R. J. Plant Sci. 2001, 161, 1011–1018; (b) Sunagawa, M.;
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Tetrahedron 2000, 56, 7705–7713.