Thermal rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates. Synthesis of 3H-imidazol-1-ium ylides and their silver derivatives

Article abstract of DOI:10.1016/j.tet.2010.01.037

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD undergo rearrangement to 3,4-dihydro-2H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 3, which spontaneously undergo elimination to give 3H-imidazol-1-ium-1-(1,2-bis-me

Full text of DOI:10.1016/j.tet.2010.01.037

Tetrahedron 66 (2010) 2053–2060
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Thermal rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-
dicarboxylates. Synthesis of 3H-imidazol-1-ium ylides and their silver derivatives
*
Necdet Cos¸kun , Meliha Çetin
Uludag˘ University, Department of Chemistry, Gorukle-Bursa, 16059-Bursa, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2009
Received in revised form 1 December 2009
Accepted 11 January 2010
Available online 18 January 2010
Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD undergo rearrangement to
3,4-dihydro-2H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 3, which spontaneously
undergo elimination to give 3H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides)
5 or
1H-imidazoles 6 when heated in toluene at reflux. The presence of the aromatic ring at C-6 decelerated the
conversion and enhanced the yield of 5. Solvents more polar than toluene (e.g., DMSO) provided quanti-
tative conversion of 2 into 6 in mild conditions, while in less polar solvents such as CCl4, the reaction rate
was lowered and the yield of 5 enhanced. C-2 unsubstituted ylides 5 were treated with Ag2O or AgNO3 in
the presence of Et3N at room temperature to give C-2 metallated derivatives 9 in excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Dipolar cycloaddition
Cyclic nitrones
4-Isoxazolines
Ylides
Rearrangement
NHCs
Ag(I) metallated imidazolium ylides
1. Introduction
cycloaddition with alkyne dipolarophiles and the cycloadducts were
shown to convert into the corresponding ene-1,1-diamines.5 There is
The cycloadducts of di- and triarylimidazoline 3-oxides1 with
a variety of dipolarophiles2 are bicyclic compounds with potentially
interesting biological activities. They are also a source of new het-
erocyclic compounds via interesting ring-opening reactions.3 Pre-
viously we reported the synthesis of stable adducts of 3-imidazoline
3-oxides with dimethyl acetylenedicarboxylate (DMAD)2d,e and alkyl
3-phenylpropiolates.2f Isoxazolines 2 undergo diastereoselective
rearrangement into 3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-
oxo-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olates in the
presence of methoxide in methanol. The latter were converted to
highly functionalized pyrrole derivatives.2i The synthesis and rear-
rangements of the alkyne adducts of some nitrones have been
reviewed.4 4,5-Dihydroimidazole N-oxides undergo 1,3-dipolar
still a large interest for 4-isoxazolines due to their biological
activities6a and asa sourceof interesting rearrangements.6b,c Inrecent
reports from our laboratory we described the utility of isoxazolo[3,2-
a]isoquinolines as precursors for the synthesis of stable azomethine
ylides7a while the adducts of acyclic nitrones were shown to undergo
a cascade reaction to form reactive iminocarbenes.7b The reactions of
2-alkynylbenzaldoximes, DMAD and bromine was reported to afford
the unexpected isoquinoline based azomethine ylides in good to ex-
cellent yields.7c
To assess the scope of these rearrangements for the synthesis of
cyclic azomethine ylides 3, or isoazomethine ylides 30 we de-
veloped the retrosynthetic analysis depicted in Scheme 1. The
treatment of imidazoline 3-oxides 1 with DMAD will produce
Ph
Ph
O
Ph
O
O
O
O
O
Ph
O
O
O
R
N
Ph
R2
N
O
R
N
R
N
R
N
O
N
N
N
R1
R N
R1
O
R2
R1
N
R1
R2
O
R1
R2
O
O
O
O
1
3'
3
3"
2
Scheme 1. Retrosynthetic analysis of cyclic ylides 3 and iminocarbenes 3.
compounds 2, the heating of which in toluene at reflux would give
stable ylides 3. In case that the corresponding ylides are prone to
further rearrangements the formation of iminocarbenes 30 is
* Corresponding author. Tel.: þ90224 2941725.
E-mail address: coskun@uludag.edu.tr (N. Cos¸kun).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.037

2054
N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
O
Ph
Ph
Ph
N O
R1
OMe
R2
O
O
O
O
O
Ph
R
N
R
N
DMAD
N
O
N
OMe
R2
OMe
OH
R
N
N
R1
R1
N
R1
O
R
O
-
O
3
2
1
7
R2
O
Ph
Ph
Ph
O
O
R
R1
N
R
N
R
N
R1
Ph
N
N
O
N
OMe
R2
OMe
R2
OMe
R2
R
N
R1
H
H
N
O
H O
enol-4
-H2
O
R1
OMe
R2
O
O
-
O
O
ketone-4
6
5
Scheme 2. Synthesis and probable mechanism for the formation of ylides 3 and their elimination reactions to imidazolium ylides 5 or to imidazoles 6.
expected as we have recently reported for acyclic nitrone DMAD
adducts.7b
authentic samples in the cases of known imidazoles. The IR and NMR
spectroscopic characteristics of ylides 5 are similar to the ylides
obtained from the rearrangements of 3,4-dihydroisoquinolin-2-ox-
ide DMAD adducts.7a All compounds have 3-proton singlets ca. 3.33
Here we report on the rearrangement of isoxazolines 2 and
solvent dependent competing elimination reactions of the rear-
rangement products to the corresponding 3H-imidazol-1-ium
ylides 5 and 1H-imidazoles 6 (Scheme 2). The reaction of C-2
unsubstituted ylides 5 with Ag(I) in the presence of Et3N at room
temperature provides C-2 metallated derivatives 9 precursors of
useful coupling reaction catalysts.
Table 2
Solvent effect on the rearrangements of compounds 2
Starting material Solvent
RT (h) and T (ꢀC) Producta Yield (%) Mp (ꢀC) 6
5
6
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2b
2b
2c
2i
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CCl4
0.5, 77
0.5, 77
0.5, 77
0.5, 77
0.5, 77
0.5, 77
24, rt
24, rt
24, rt
24, rt
24, rt
0
0
0
0
0
0
0
0
0
0
0
54
54
50
0
0
0
100
100
100
100
100
100
72
80
77
82
81
46
46
50
100
100
100
100
100
93–94
2. Results and discussion
132–133
103–104
139–140
151–152
128–130
Nitrones 1 were heated at reflux in toluene in the presence of
equimolar amounts of DMAD to give the corresponding imidazolium
ylides 5 and imidazoles2d,e,3a 6 (Schemes 2 and 3). The formed ylides
5 (Table 1) and imidazoles 6 (Table 2) were characterized by ana-
lytical methods and spectroscopy as well as comparison with
O
Ph
Ph
40, 77
React. Cond.
Table 2
O
Ph
O
Degassed CCl4 40, 77
CCl4
R
N
O
O
R
N
N
O
40, 77
20, 77
20, 77
20, 77
20, 77
20, 77
N
OMe
OMe
R
N
+
R1
DMSO
DMSO
DMSO
DMSO
DMSO
110
144
122–123
121–122
158–159
N
R1
O
2j
2k
2l
R1
O
6
5
2
0
0
2m
Scheme 3. Synthesis of ylides 5 and 1H-imidazoles 6.
a
The yields were determined by 1H NMR.
Table 1
Synthesis of 3H-imidazol-1-ium ylides 5a–n
1–6
R
R1
R2
RTa
Yieldb
Mp (ꢀC)
a
b
c
d
e
f
C6H5
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
(ꢁ)-O-Menthyl
(ꢁ)-O-Menthyl
OMe
OMe
OMe
OMe
OMe
13
10
7
5
5
11
10
4
23
16
19
6
14
15
14
22c
25d
40
40
19
15
14
48
49
52
38
60
57
273–274
289–291
302–303
292–293
305–306
255–257
242–245
253–255
149–150
117–118
140–142
155–156
222–223
128–130
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
3,4(MeO)2C6H3
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
ge
h
i
j
k
l
Ph
Ph
4-MeOC6H4
4-ClC6H4
3-NO2C6H4
m
n
3,4(MeO)2C6H3
OMe
a
The reaction times in hours for the reaction in toluene at reflux temperatures.
The isolated yields of 5 from the reaction in toluene (%).
The yield remained the same when the reaction was performed passing air through the reaction mixture.
The yields of 5 were 25 and 22% when the reaction was performed under nitrogen atmosphere and the solvent was degassed, respectively.
Compounds 5g,h were prepared from the corresponding 2g,h (unseparable diastereomeric mixtures of 2-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 3-methyl 3a-phenyl-
b
c
d
e
5-aryl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates).

N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
2055
and 3.70 ppm in their 1H NMR spectra corresponding to the ester
methoxy groups. The doublets at ca. 8.49 and 9.77 ppm (J¼2.0 Hz)
belong to the imidazolium ring protons at C4-H and C2-H, re-
spectively in the spectra of 2-unsubstituted ylides 5 recorded in
DMSO-d6. In the 13C spectra, the carbonyls of the ester functional
groups have signals at ca. 165.0 and 168.7 ppm, while the ketone
carbonyl resonates at ca.173.7. The ylide carbons’ peaks appear at ca.
95 ppm in the 13C NMR spectra of compounds 5.
The formation of adducts 2 and their further conversions was
monitored by TLC and 1H NMR. The probable mechanism for the
formation of ylides 5 and imidazoles 6 is depicted in Scheme 2.
Ylides 3 formed as we have discussed previously7a,b probably
isomerize to 2-hydroxy-3-(2,3-dihydroimidazol-1-yl)maleates 4.
Compounds 5 were assumed to be products from the de-
hydrogenation (most probably proceeding as synchronous 1,5-
elimination as shown in Scheme 2) of enol-4 while the keto-4 isomer
undergoes 1,2-elimination to give 6 and dimethyloxaloacetate.
Performing the reaction under nitrogen and in degassed toluene did
not affect the yield (See the legend of Table 1). Performing the re-
action passing air through the mixture in the case of 4c also did not
lead to new product distribution. The latter facts confirm that oxy-
gen has no effect on the mechanism of the reaction and support the
proposed non-radical eliminations. Other possibilities such as dis-
proportionation8 of 3 or reduction of unsaturated reagents and
products in the reaction were also considered, however no adequate
structures in the crude reaction mixtures were detected.
solution and the imidazole ylide ratio was 1:0.6. The reaction in
degassed CCl4 under nitrogen atmosphere proceeded with the
same rate and product ratio. The reaction rate in the CCl4 was 80
times lower than in DMSO, and the rate limiting step in the cascade
was the ring-opening reaction of 2. To separate the ylide 5b from
the corresponding imidazole we dissolved the mixture of 5/6b in
36% HCl at room temperature and stirred for several minutes then
the mixture was diluted with water. The formed imidazole hy-
drochloride was separated by filtration and the filtrate was basified
with ammonia and extracted with CHCl3. The extract contained 1-
methoxycarbonylmethyl-3,5-diphenyl-3H-imidazol-1-ium 7b the
structure of which was confirmed by spectroscopy.9 The chemo-
selective imidazole formations ensured by the polar solvent can be
rationalized by assuming that the transition state of ketone-4
conversion to 6 probably involves much more charge separation
than the case of enol-4 to 5. The apolar solvents probably stabilize
better the transition state of enol-4 to 5 than polar solvents. Cer-
tainly the formation of compounds 4, by a cascade reaction in-
volving initial homolysis of the corresponding C–C bond in adducts
2, is not excluded.
In fact, ylides 5 are isomeric structures with 8, which we were
planning to use as ligands for catalyst of Heck, Suzuki etc. coupling
reactions. To convert compounds 5 to NHCs 8 we treated them with
an excess of Et3N in CH2Cl2 at room temperature for several hours,
however no change was detected. The treatment of ylide 5b with
Ag2O in CH2Cl2 at room temperature in the dark for 22 h also did
not lead to any change of the starting 5b. However, addition of an
excess of Et3N to the latter mixture and stirring for 2 h induced
a metallation of 5b at C-2 carbon to give compound 9b quantita-
tively. Compounds 9a–f were prepared (Scheme 4, Table 3) by the
use of AgNO3 as a metal source. The first structurally characterized
silver–NHC complex was made by using a free carbene and a silver
salt,10 however, generally silver bases were reacted with imidazo-
lium salts formed in situ. The silver salts reported so far in the
formation of Ag(I)–NHC complexes are silver acetate,11 Ag2O12 and
Ag2CO3.13 Silver N-heterocyclic carbene complexes have played an
important role in the development of other metal-carbene systems.
Transmetalation reactions using silver carbenes have been reported
for a wide variety of transition metals.14
To understand the mechanism of the eliminations outlined in
Scheme 2 we heated adducts 2 in solvents more and less polar than
toluene. The reaction of adducts 2 in DMSO-d6 at 77 ꢀC proceeded
quantitatively to the corresponding imidazoles (Scheme 3, Table 2)
and dimethyloxaloacetate. The conversions of 2a–e to 6a–e in
DMSO-d6 at room temperature after 24 h were 72, 80, 77, 82, 81%,
respectively. In the cases of chlorosubstituted adduct 2d, an in-
termediate was detected whose 1H NMR characteristics are in
agreement with structures 4. The compound has the following
resonances in DMSO-d6,
d 3.29 (3H, s), 3.40 (3H, s), 4.67 (2H, d,
J¼6.0 Hz, C2-H), 6.11 (1H, t, J¼6.0 Hz, C4-H), 6.68 (2H, d, J¼8.8 Hz,
N2-Ar-o), 7.08 (2H, d, J¼8.8 Hz, N2-Ar-m), 7.55 (2H, t, J¼8.0 Hz, C5-
Ar-m), 8.05 (2H, d, J¼8.0 Hz, C5-Ar-o). Some characteristic peaks for
1. Et3N
2. Ag(I)
Ph
Ph
H
Ph
R
N
R
N
R
N
N
O
CO2Me
CO2Me
N
O
CO2Me
CO2Me
N
O
CO2Me
CO2Me
-H
NAg
Et3
H
imidazolium ylide 5
N-heterocyclic carbene (NHC) 8
NHC-Ag(I) complex 9
Scheme 4. Metallation of ylides 5a–f.
Table 3
Synthesis of 3H-imidazol-1-ium ylides Ag(I) derivatives 9a–f
Entry
R
Yielda (%)
Mpb (ꢀC)
Entry
R
Yielda (%)
Mpb (ꢀC)
a
b
c
C6H5
4-MeC6H4
4-MeOC6H4
91
99c
87
268–269
282–283
285–286
d
e
f
4-ClC6H4
4-BrC6H4
3,4(MeO)2C6H3
97
98
98
287–288
286–288
258–260
a
The yields of 9a–f from the reactions of 5a–f with AgNO3 in CH2Cl2 at room temperature for 2 h.
The decomposition temperatures of the compounds, which first loss Et3N as revealed by their TGA data.
The yield from the reaction with Ag2O is the same.
b
c
dimethyloxaloacetate are as follows;
d
3.38–3.90 (6H, 10 peaks,
The IR spectra of compounds 9 have stretches at ca. 1729 and
1679 cmꢁ1 corresponding to the carbonyl groups. A comparison
with the frequencies of the same groups in the starting 5 (Table 4,
columns 7, 13) reveal that, except in the cases 9a,b where nC]O(1)
increases while nC]O(2) decreases by ca. 15 cmꢁ1, there are no sig-
nificant changes in the carbonyl frequencies.
MeO groups of oxaloacetate tautomers), 4.67, 4.69, 4.99, 5.17, 5.81
(1H, 5 peaks), 9.42, 11.21 (1H, 2 br s). The reaction in the less polar
CCl4 at 77 ꢀC proceeded with increased yield of 5 (Table 2). The
conversion rate of 2b when 0.083 M solution was heated at reflux in
CCl4 was nearly half the rate of the reaction performed with 0.17 M

2056
N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
Table 4
Comparison of the characteristic chemical shifts and C]O stretching of ylides 5 and their Ag(I)-complexes 9
5
9
C2(H)
C4(H)
C]Oa
C]O(1)
C]O(2)
nC]O
C2b
C4(H)b
C]O
C]O(1)
C]O(2)
nC]O
a
b
c
d
e
f
138.9
9.91
138.7
9.84
138.5
9.77
137.5
9.90
137.5
9.90
138.5
9.81
118.2
8.59
118.2
8.54
118.5
8.49
118.3
8.58
118.3
8.58
118.2
8.54
172.8
164.8
3.38
164.8
3.38
164.7
3.38
164.7
3.29
164.7
3.38
164.8
3.33
168.6
3.63
168.7
3.63
168.4
3.62
168.6
3.63
168.6
3.63
168.6
3.63
1736;
1659
1742;
1663
1726;
1663
1740;
1659
1740;
1657
1732;
1667
118.7
7.99
118.7
7.94
118.9
7.90
118.6
8.01
118.6
8.01
119.1
7.93
174.1
166.3
3.27
166.3
3.26
166.3
3.25
166.3
3.25
166.3
3.25
166.3
3.26
169.5
3.60
169.5
3.59
169.5
3.60
169.6
3.60
169.6
3.60
169.6
3.59
1728;
1671
1729;
1679
1728;
1663
1736;
1650
1732;
1655
1732;
1667
174.5
172.9
173.6
173.5
173.6
184.3
183.9
184.8
184.8
174.1
174.1
174.1
174.1
174.1
a
C]O; C]O(1) and C]O(2) are the ketone and ester carbonyls at C1 and C2 of the ethanide carbons, respectively.
The C2(Ag) carbons are not observed in the 13C NMR spectra, however in the case of 9b–e it was deduced from their g-HMBC spectra.
b
The comparison of the NMR data for 5a–f and 9a–f reveals also
Table 5
Thermal analysis data for complexes 9a–f
that the electronic density changes around the ylide carbon are
very small (Table 4, a comparison of the characteristic NMR data for
5b and 9b is given in Fig. 1), which implies that the ketone carbonyl
oxygen in 9 is slightly interacting with the metal centre. The ele-
mental analysis data and the 1H NMR data (400 MHz, DMSO-d6)
reveal the presence of 1 mol of Et3N coordinated to the metal
centre. The peaks corresponding to C2-H in 5 are absent in 9 and
the peaks of C4-H at ca. 8.53 ppm are up fielded by 0.60 ppm due to
substitution of C2-H for the less electronegative Ag (Table 4, col-
umns 3,9). The hydrolysis of 9b in DMSO-d6 at room temperature
provided the starting 5b, while the reaction with D2O in DMSO-d6
allowed us to prepare C-2-deuterated 5b. The resonance for the
C2-H was absent, while the C4-H signal was shifted up-field by ca.
0.15 ppm.
Complex
TG
DTG
Peak temperature (ꢀC)
Theoreticala
Observeda
9a
9b
9c
9d
9e
9f
17.2b
16.8
16.4
16.3
15.1
15.6
45.2c
16.5b
14.3
13.0
14.1
15.7
15.4
48.0c
106.3b
117.6
115.5
133.2
128.8
104.2
262.1c
279.6; 291.5
291.3
287.3; 289.7
292.6; 302.7
256.9
39.0
40.6
40.9
44.8
43.3
40.2
37.6
38.8
40.6
40.6
a
wt. loss (%).
The loss of Et3N.
The loss of the corresponding 1,3-diarylimidazole.
b
c
3. Conclusions
The thermal rearrangements of 1,2,4-triaryl- and 1,4-diaryl-
2,5-dihydro-1H-imidazole 3-oxide 1 DMAD adducts 2 lead to 3,4-
dihydro-2H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-
ethanides) 3, which spontaneously undergo competing 1,5- and
1,2-eliminations to give 3H-imidazol-1-ium-1-(1,2-bis-methox-
ycarbonyl-2-oxo-ethanides) 5 or 1H-imidazole 6 when heated in
toluene at reflux. Adducts 2 was shown to convert quantitatively to
imidazoles 6 in polar solvent such as DMSO. For the first time ylides
5 were metallated at C-2 with Ag(I). The latter compounds will be
used as precursors in the preparation of Pd–NHC complexes.
7.70;
137.5
123.1
7.94;
8.53;
118.2
118.7
7.54; 128.4
3.43; 50.3
7.49; 128.1
3.26; 49.8
N 98.1CO2Me
166.4
95.1CO2Me
N
N
N
O
9.83;
138.7
164.8
Et3NAg
3.59; 51.2
CO2Me
168.6
3.63; 51.6
O
CO2Me
169.5
7.77;
121.5
1.01; 12.7
2.55; 48.0
174.1
174.5
9b
5b
Figure 1. Comparison of the characteristic chemical shifts of ylide 5b and its metal-
lated analog 9b.15
4. Experimental
4.1. General
The solvents and the reagents used in the syntheses were pur-
chased from Merck (MeOH, CHCl3, CH2Cl2, petroleum ether 40–
60 ꢀC, EtOH, benzene and the aromatic amines, Et3N and Ag2O),
Aldrich (formaldehyde, DMAD and AgNO3), Fluka (phenacyl bro-
mide and (NH2OH)2H2SO4). 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
The thermal behaviour of complexes 9 were studied by thermal
gravimetry (TG) and differential thermal gravimetry (DTG) in
a dynamic N2 atmosphere. The thermal decompositions of 9 occur
in multiple steps (Scheme 5, Table 5). The compounds first lose Et3N
to give intermediate A then lose the corresponding 1,3-diary-
limidazole derivative to give structures B. The final product
detected is corresponding to Ag2O.
Ph
Ph
CO2Me
R
N
-imidazole
R
N
-Et3N
N
O
CO2Me
N
O
CO2Me
Ag
Ag2O
O
CO2Me
Et3NAg
Ag
CO2Me
CO2Me
A
B
Scheme 5. Thermal decomposition pattern of compounds 9.

N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
2057
spectrometer. Thermogravimetric (TG) and differential thermog-
4.4. Synthesis of 3H-imidazol-1-ium ylides 5a–n
ravimetric (DTG) curves were obtained using a SII Exstar TG/DTA
6200 analyser in the range 25–100 ꢀC in platinum crucibles under
nitrogen at a heating rate of 10 ꢀC minꢁ1 using alumina as refer-
ence. The elemental analyses were performed on a EuroEA 3000
CHNS analyser. The compounds prepared were dried in a vacuum
oven at room temperature. Nitrones 1a–l were prepared according
to the previously reported methods.1,2i
4.4.1. General procedure. DMAD (1 mmol, 0.145 g, 98%) was added
to a solution of imidazoline 3-oxide 1 (1 mmol) in toluene (25 mL)
and the reaction mixture heated at reflux for the specified time. In
the cases of 5a–f the precipitated products were filtered and dried
in a vacuum oven. In the other cases the solvent was evaporated
and the reaction mixture was extracted with petroleum ether
(3ꢂ15 mL) heating at reflux. The residue was dissolved in hot THF–
petroleum ether (25 mL, 1:4) and left to crystallize. The amorphous
solid was filtered and dried under vacuum to give compounds 5.
The petroleum ether extracts were combined and the solvent
evaporated. The residue contained mainly the corresponding
imidazoles.
4.2. Synthesis of 4-phenyl-1-aryl-2,5-dihydro-1H-imidazole
3-oxides 1
4.2.1. 1-(3,4-Dimethoxyphenyl)-4-phenyl-2,5-dihydro-1H-imidazole
3-oxide 1f. Yield 0.320 g, 9%. Colourless powder, mp 183–184 ꢀC. IR
(KBr) nC]N–O 1579, nC]N–O 1245 cmꢁ1
;
1H NMR (400 MHz, DMSO-
4.4.2. 3,5-Diphenyl-3H-imidazol-1-ium-1-(1,2-bis-methox-
d6):
d
3.65 (3H, s), 3.78 (3H, s), 4.75 (2H, t, J¼4.0), 5.26 (2H, t, J¼4.0),
ycarbonyl-2-oxoethanide) 5a. Gold coloured powder, mp 273–
6.17 (1H, dd, J¼8.4; 2.8), 6.39 (1H, d, J¼2.8), 6.86 (1H, d, J¼8.4), 7.49–
274 ꢀC. IR (KBr) nC]O 1736 and 1659 cmꢁ1 1H NMR (400 MHz,
;
7.52 (3H, m), 8.36–8.38 (2H, m). 13C NMR (100 MHz, DMSO-d6):
DMSO-d6): d 3.33 (3H, s), 3.63 (3H, s), 7.46–7.58 (6H, m), 7.65 (2H, t,
d
53.6; 56.1; 56.8; 78.8; 98.8; 103.7; 114.5; 126.9; 127.8; 129.0;
J¼7.6), 7.89 (2H, d, J¼7.6), 8.59 (1H, d, J¼1.6), 9.91 (1H, d, J¼1.6). 13C
131.0; 136.4; 140.4; 142.1; 150.5. Anal. Calcd for C17H18N2O3
(298.34): C, 68.44; H, 6.08; N, 9.39. Found: C, 68.50; H, 5.90; N, 9.49.
NMR (100 MHz, DMSO-d6): d 50.3; 51.6; 118.2; 121.7; 126.7; 128.4;
129.1; 129.4; 130.1; 130.7; 135.0; 137.5; 138.9; 164.8; 168.6; 172.8.
Anal. Calcd for C21H18N2O5 (378.4): C, 66.66; H, 4.79; N, 7.40. Found:
C, 66.45; H, 4.55; N, 7.15.
4.3. Synthesis of (R)- and (S)-2-((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl) 3-methyl 3a-phenyl-5-aryl-3a,4,5,6-
tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates 2g,h
4.4.3. 5-Phenyl-3-p-tolyl-3H-imidazol-1-ium-1-(1,2-bis-methoxy-
carbonyl-2-oxoethanide) 5b. White powder, mp 289–291 ꢀC. IR
(KBr) nC]O 1742 and 1663 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 2.47
Compounds 2b,c were reacted with the Reformatsky reagent
prepared from (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bro-
moacetate according to the transesterification procedure we have
recently reported.2h
(3H, s), 3.45 (3H, s), 3.86 (3H, s), 7.39–7.47 (8H, m), 7.55–7.57 (2H,
m), 8.44 (1H, d, J¼2.0). 13C NMR (100 MHz, CDCl3):
d 21.2; 50.5;
52.0; 95.1; 116.7; 121.8; 125.7; 128.4; 128.8; 130.2; 131.2; 132.4;
136.4; 139.4; 141; 165.0; 168.7; 173.7. 1H NMR (400 MHz, DMSO-
d6): d 2.38 (3H, s), 3.33 (3H, s), 3.63 (3H, s), 7.44–7.47 (5H, m), 7.53–
4.3.1. (R)- and (S)-2-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl)
3-methyl 3a-phenyl-5-p-tolyl-3a,4,5,6-tetrahydroimidazo[1,5-b]iso-
xazole-2,3-dicarboxylate 2g. Yield 0.830 g, 80%. Yellowish oil. IR
(neat) nC]O 1753, 1711, nC]C 1656 cmꢁ1; 1H NMR (400 MHz, CDCl3):
7.55 (2H, m), 7.77 (2H, d, J¼8.4), 8.54 (1H, d, J¼2.0), 9.84 (1H, d,
J¼2.0). 13C NMR (100 MHz, DMSO-d6):
d 21.0; 50.3; 51.6; 93.9;
118.2; 121.5; 126.7; 128.4; 129.1; 130.1; 131.1; 132.7; 137.5; 138.7;
139.9; 164.8; 168.7; 174.5. Anal. Calcd for C22H20N2O5 (392.4): C,
67.34; H, 5.14; N, 7.14. Found: C, 66.98; H, 5.17; N, 7.00.
d
ppm 0.78–2.07 (18H, m), 2.28 (3H, s), 3.43 (0.5H, d, J¼10.0); 3.44
(0.5H, d, J¼10.0), 3.62 (3H, s), 4.23 (0.5H, d, J¼10.8), 4.24 (0.5H, d,
J¼10.8), 4.66 (0.5H, d, J¼10.0), 4.68 (0.5H, d, J¼10.0), 4.88 (1H, dt,
J¼11.2, 4.8), 5.04 (0.5H, d, J¼10.8), 5.05 (0.5H, d, J¼10.8), 6.71 (2H, d,
J¼8.4), 7.09 (2H, d, J¼8.4), 7.28–7.32 (1H, m), 7.36–7.40 (2H, m),
4.4.4. 3-(4-Methoxyphenyl)-5-phenyl-3H-imidazol-1-ium-1-(1,2-
bis-methoxycarbonyl-2-oxoethanide) 5c. Cream coloured powder,
mp 302–303 ꢀC. IR (KBr) nC]O 1726 and 1663 cmꢁ1 1H NMR
;
7.60–7.63 (2H, m). 13C NMR (100 MHz, CDCl3):
d
ppm 16.1; 16.2;
(400 MHz, DMSO-d6):
(2H, d, J¼8.4), 7.45–7.53 (5H, m), 7.80 (2H, d, J¼8.4), 8.49 (1H, s),
9.77 (1H, s). 13C NMR (100 MHz, DMSO-d6):
50.4; 51.7; 56.2; 94.3;
d 3.33 (3H, s), 3.62 (3H, s), 3.83 (3H, s), 7.17
16.3; 20.4; 20.6; 20.7; 21.0; 22.0; 22.2; 23.1; 23.2; 23.5; 25.8; 25.9;
26.1; 29.7; 31.4; 31.6; 34.0; 34.1; 34.5; 40.3; 45.0; 46.6; 50.1; 51.6;
57.1; 57.2; 71.5; 76.0; 76.1; 82.3; 82.4; 109.3; 109.4; 115.1; 115.2;
121.3; 124.9; 126.9; 128.0; 128.3; 129.0; 129.8; 141.0; 143.9; 144.0;
152.7; 152.9; 158.4; 158.5; 162.6. Anal. Calcd for C31H38N2O5
(518.64): C, 71.79; H, 7.38; N, 5.40. Found: C, 71.50; H, 7.22; N, 5.24.
d
115.7; 118.5; 123.2; 126.7; 128.1; 128.4; 129.1; 130.1; 137.3; 138.5;
160.3; 164.7; 168.4; 172.9. Anal. Calcd for C22H20N2O6 (408.4): C,
64.70; H, 4.94; N, 6.86. Found: C, 64.60; H, 5.12; N, 6.75.
4.4.5. 3-(4-Chlorophenyl)-5-phenyl-3H-imidazol-1-ium-1-(1,2-bis-
methoxycarbonyl-2-oxoethanide) 5d. Cream coloured powder, mp
292–293 ꢀC. IR (KBr) nC]O 1740 and 1659 cmꢁ1; 1H NMR (400 MHz,
4.3.2. (R)- and (S)-2-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl) 3-
methyl 5-(4-methoxyphenyl)-3a-phenyl-3a,4,5,6-tetrahydroimidazo
[1,5-b]isoxazole-2,3-dicarboxylate 2h. Yield 0.802 g, 75%. Yellowish
DMSO-d6): d 3.29 (3H, s), 3.63 (3H, s), 7.47–7.53 (5H, m), 7.74 (2H, d,
oil. IR (neat) nC]O 1753, 1711, nC]C 1656 cmꢁ1
;
1H NMR (400 MHz,
J¼8.0), 7.94 (2H, d, J¼8.0), 8.58 (1H, d, J¼2.0), 9.90 (1H, d, J¼2.0). 13C
CDCl3):
d
ppm 0.78–2.07 (18H, m), 3.40 (0.5H, d, J¼10.0); 3.39 (0.5H,
NMR (100 MHz, DMSO-d6): d 50.3; 51.6; 118.3; 123.5; 126.6; 128.4;
d, J¼10.0), 3.77 (3H, s), 3.622 (1.5H, s); 3.619 (1.5H, s), 4.18 (0.5H, d,
J¼10.8), 4.19 (0.5H, d, J¼10.8), 4.63 (0.5H, d, J¼10.0), 4.64 (0.5H, d,
J¼10.0), 4.89 (1H, dt, J¼11.0, 4.4), 5.01 (0.5H, d, J¼10.8), 5.02 (0.5H,
d, J¼10.8), 6.75–6.77 (2H, m), 6.84–6.87 (2H, m), 7.28–7.32 (1H, m),
7.36–7.40 (2H, m), 7.60–7.63 (2H, m). 13C NMR (100 MHz, CDCl3):
129.2; 130.2; 130.6; 133.9; 134.5; 137.5; 139.1; 164.7; 168.6; 173.6.
Anal. Calcd for C21H17ClN2O5 (412.8): C, 61.10; H, 4.15; N, 6.79.
Found: C, 60.75; H, 4.04; N, 6.62.
4.4.6. 3-(4-Bromophenyl)-5-phenyl-3H-imidazol-1-ium-1-(1,2-bis-
methoxycarbonyl-2-oxoethanide) 5e. Cream coloured powder, mp
305–306 ꢀC. IR (KBr) nC]O 1740 and 1657 cmꢁ1; 1H NMR (400 MHz,
d
ppm 16.0; 16.1; 16.3; 20.6; 20.7; 21.0; 22.0; 22.2; 23.1; 23.3; 23.5;
25.8; 26.1; 29.7; 31.4; 31.6; 34.0; 34.5; 40.3; 45.0; 46.6; 50.1; 51.8;
55.6; 57.7; 71.5; 82.4; 82.5; 109.2; 109.4; 114.8; 116.5; 116.6; 123.2;
125.0; 127.0; 128.0; 128.3; 140.3; 141.1; 152.7; 152.9; 153.5; 158.4;
158.5; 162.6. Anal. Calcd for C31H38N2O6 (534.64): C, 69.64; H, 7.16;
N, 5.24. Found: C, 69.35; H, 7.00; N, 5.00.
DMSO-d6):
d 3.33 (3H, s), 3.63 (3H, s), 7.46–7.48 (3H, m), 7.52–7.55
(2H, m), 7.87 (4H, s), 8.58 (1H, d, J¼2.0), 9.90 (1H, d, J¼2.0). 13C NMR
(100 MHz, DMSO-d6): d 50.3; 51.6; 118.3; 123.0; 123.8; 126.5; 128.4;
129.2; 130.2; 133.6; 134.3; 137.5; 139.0; 164.7; 168.6; 173.5. Anal.

2058
N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
Calcd for C21H17BrN2O5 (457.3): C, 55.16; H, 3.75; N, 6.13. Found: C,
55.19; H, 3.50; N, 5.95.
168.6; 174.6. Anal. Calcd for C29H26N2O6 (498.53): C, 69.87; H, 5.26;
N, 5.62. Found: C, 69.75; H, 5.33; N, 5.54.
4.4.7. 3-(3,4-Dimethoxyphenyl)-5-phenyl-3H-imidazol-1-ium-1-
4.4.13. 2-(4-Chlorophenyl)-5-phenyl-3-p-tolyl-3H-imidazol-1-ium-
1-(1,2-bis-methoxycarbonyl-2-oxoethanide) 5l. Cream coloured
powder, mp 155–156 ꢀC. IR (KBr) nC]O 1738 and 1682 cmꢁ1; 1H NMR
(1,2-bis-methoxycarbonyl-2-oxoethanide) 5f. Cream coloured pow-
der, mp 255–257 ꢀC. IR (KBr) nC]O 1732 and 1667 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6):
d
3.33 (3H, s), 3.63 (3H, s), 3.82 (3H, s), 3.87
(400 MHz, CDCl3):
7.29–7.32 (2H, m), 7.37–7.39 (3H, m), 7.42–7.46 (3H, m), 7.57–7.59 (2H,
m). 13C NMR (100 MHz, CDCl3):
21.2; 50.8; 51.9; 95.5; 119.5; 120.6;
125.4; 125.6; 128.8; 129.1; 129.2; 130.2; 130.7; 131.5; 132.7; 138.3;
138.7; 140.7; 146.5; 165.0; 167.8; 173.3. Anal. Calcd for C28H23ClN2O5
(502.95): C, 66.87; H, 4.61; N, 5.57. Found: C, 66.75; H, 4.73; N, 5.32.
d 2.37 (3H, s), 3.39 (3H, s), 3.71 (3H, s), 7.22 (4H, s),
(3H, s), 7.17 (1H, d, J¼8.4), 7.41 (1H, d, J¼2.4), 7.43 (1H, d, J¼2.8),
7.46–7.49 (3H, m), 7.54–7.60 (2H, m), 8.54 (1H, d, J¼2.0), 9.81 (1H,
d
d, J¼2.0). 13C NMR (100 MHz, DMSO-d6):
d
50.3; 51.6; 56.3; 51.6;
105.7; 112.5; 113.3; 118.2; 126.7; 128.1; 128.4; 129.1; 130.1; 137.3;
138.5; 149.8; 150.0; 164.8; 168.6; 173.6. Anal. Calcd for
C23H22N2O7 (438.4): C, 63.01; H, 5.06; N, 6.39. Found: C, 63.08; H,
5.06; N, 6.09.
4.4.14. 2-(3-Nitrophenyl)-5-phenyl-3-p-tolyl-3H-imidazol-1-ium-1-
(1,2-bis-methoxycarbonyl-2-oxoethanide) 5m. Cream coloured
4.4.8. 5-Phenyl-3-p-tolyl-3H-imidazol-1-ium-1-[(1-methoxy-
powder, mp 222–223 ꢀC. IR (KBr) nC]O 1732 and 1662 cmꢁ1 1H
;
carbonyl)-2-menthyloxycarbonyl]-2-oxoethanide 5g. White powder,
NMR (400 MHz, CDCl3): d 2.33 (3H, s), 3.34 (3H, s), 3.64 (3H, s),
mp 242–245 ꢀC. IR (KBr) nC]O 1728 and 1665 cmꢁ1
;
1H NMR
7.15–7.21 (4H, m), 7.38–7.42 (4H, m), 7.54–7.60 (3H, m), 7.93 (1H, d,
(400 MHz, CDCl3):
4.76–4.85 (1H, m), 7.38–7.41 (8H, m), 7.57–7.99 (2H, m), 8.41 (1H, s).
13C NMR (100 MHz, CDCl3):
16.5; 20.9; 21.2; 22.1; 23.6; 25.8; 31.4;
d
0.82–2.32 (18H, m), 2.46 (3H, s), 3.48 (3H, s),
J¼8.0), 8.09 (1H, s), 8.26 (1H, d, J¼8.8). 13C NMR (100 MHz, CDCl3):
d
21.2; 50.7; 51.8; 95.5; 110.0; 119.5; 123.9; 125.3; 125.4; 126.5;
d
128.9; 129.0; 130.3; 130.4; 131.0; 132.2; 136.3; 139.3; 141.4; 145.0;
147.8; 165.0; 168.2; 174.4. Anal. Calcd for C28H23N3O7 (513.5): C,
65.49; H, 4.51; N, 8.18. Found: C, 65.28; H, 4.70; N, 7.95.
34.3; 40.4; 47.0; 50.4; 74.8; 94.9; 116.7; 121.9; 125.8; 128.5; 128.7;
130.0; 131.1; 132.4; 136.6; 139.3; 140.9; 159.7; 167.8; 173.9. Anal.
Calcd for C31H36N2O5 (516.63): C, 72.07; H, 7.02; N, 5.42. Found: C,
72.00; H, 6.90; N, 5.68.
4.4.15. 2-(3,4-Dimethoxyphenyl)-5-phenyl-3-p-tolyl-3H-imidazol-1-
ium-1-(1,2-bis-methoxycarbonyl-2-oxoethanide) 5n. Cream col-
4.4.9. 5-Phenyl-3-p-methoxyphenyl-3H-imidazol-1-ium-1-[(1-me-
oured powder, mp 128–130 ꢀC. IR (KBr) nC]O 1732 and 1687 cmꢁ1
;
thoxycarbonyl)-2-menthyloxycarbonyl]-2-oxoethanide
powder, mp 253–255 ꢀC. IR (KBr) nC]O 1729 and 1665 cmꢁ1
NMR (400 MHz, CDCl3): 0.82–2.28 (18H, m), 3.48 (3H, s), 3.90 (3H,
s), 4.76–4.85 (1H, m), 7.07 (2H, d, J¼8.8), 7.41–7.47 (6H, m), 7.57–
7.59 (2H, m), 8.36 (1H, s). 13C NMR (100 MHz, CDCl3):
16.5; 20.9;
5h. White
1H NMR (400 MHz, CDCl3):
3.86 (3H, s), 3.88 (3H, s), 6.74–6.76 (2H, m), 7.19–7.28 (5H, m), 7.46–
7.48 (4H, m), 7.61–7.63 (2H, m). 13C NMR (100 MHz, CDCl3):
21.2;
d 2.40 (3H, s), 3.37 (3H, s), 3.75 (3H, s),
;
1H
d
d
50.5; 51.7; 55.8; 56.1; 95.4; 110.7; 112.8; 114.2; 118.6; 123.5; 125.2;
126.1; 128.7; 129.0; 130.0; 130.5; 133.3; 138.8; 140.3; 147.9; 149.1;
151.6; 165.2; 168.6; 174.2. Anal. Calcd for C30H28N2O7 (528.55): C,
68.17; H, 5.34; N, 5.30. Found: C, 68.00; H, 5.30; N, 5.35.
d
22.1; 23.6; 25.9; 31.4; 34.3; 40.4; 47.0; 50.4; 55.8; 74.9; 115.6; 117.0;
123.7; 125.8; 127.8; 128.4; 128.7; 130.0; 136.6; 139.1; 155.5; 160.9;
167.8; 173.9. Anal. Calcd for C31H36N2O6 (532.63): C, 69.90; H, 6.81;
N, 5.26. Found: C, 69.60; H, 6.66; N, 5.40.
4.5. Synthesis of 1H-imidazoles 6
4.4.10. 3-(4-Methoxyphenyl)-2,5-diphenyl-3H-imidazol-1-ium-1-
(1,2-bis-methoxycarbonyl-2-oxoethanide) 5i. Brown powder, mp
149–150 ꢀC. IR (KBr) nC]O 1736 and 1674 cmꢁ1; 1H NMR (400 MHz,
4.5.1. General procedure. Imidazoline 3-oxide 1 (1 mmol) was
reacted with DMAD (1.5 mmol) in benzene (7 mL) for 1 h heating
at reflux. The solvent was evaporated and the residue dissolved in
DMSO (5 mL). The mixture was heated at 77 ꢀC for 0.5 h in the
cases of 1a–f and 20 h in the cases of 1i–m. The mixture was
poured into crushed ice (8 g) and the precipitated product filtered,
washed several times with water and dried in a vacuum oven. The
yields are quantitative.
CDCl3):
7.24 (2H, d, J¼8.8), 7.35–7.39 (5H, m), 7.44–7.47 (4H, m), 7.61–7.63
(2H, m). 13C NMR (100 MHz, CDCl3):
50.5; 51.7; 55.6; 95.6; 115.0;
d
3.37 (3H, s), 3.72 (3H, s), 3.82 (3H, s), 6.90 (2H, d, J¼8.8),
d
119.0; 122.4; 125.9; 126.8; 128.2; 128.72; 128.73; 129.0; 130.05;
130.09; 131.7; 138.7; 147.8; 160.4; 165.2; 168.5; 174.5. Anal. Calcd
for C28H24N2O6 (484.5): C, 69.41; H, 4.99; N, 5.78. Found: C, 69.10;
H, 5.05; N, 5.65.
4.5.2. 1,4-Diphenyl-1H-imidazole 6a. Recrystallized from ether–
hexane (1:2). Yellowish crystals, mp 93–94 ꢀC. Lit3a mp 93–94.2 ꢀC.
4.4.11. 3-(p-Tolyl)-2,5-diphenyl-3H-imidazol-1-ium-1-(1,2-bis-me-
1H NMR (400 MHz, DMSO-d6):
d 7.23–7.27 (1H, m), 7.37–7.42 (3H,
thoxycarbonyl-2-oxoethanide) 5j. Yellow powder, mp 117–118 ꢀC. IR
m), 7.55 (2H, t, J¼8.0), 7.73 (2H, d, J¼7.6), 7.87 (2H, d, J¼6.8), 8.30
(KBr) nC]O 1736 ad 1679 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 2.38
(1H, d, J¼1.2), 8.35 (1H, d, J¼1.2). 13C NMR (100 MHz, DMSO-d6):
(3H, s), 3.36 (3H, s), 3.72 (3H, s), 7.16–7.22 (4H, m), 7.35–7.38 (4H,
d 114.5; 120.6; 124.9; 127.2; 127.4; 129.0; 130.4; 134.4; 136.4; 137.3;
m), 7.43–7.47 (5H, m), 7.61–7.63 (2H, m). 13C NMR (100 MHz,
142.3. Anal. Calcd for C15H12N2 (220.27): C, 81.79; H, 5.49; N, 12.72.
Found: C, 81.65; H, 5.45; N, 12.65.
CDCl3):
d 21.2; 50.5; 51.8; 95.0; 113.9; 118.8; 122.3; 125.2; 125.9;
128.72; 128.73; 129.0; 130.1; 130.5; 131.8; 133.0; 138.8; 140.4;
147.8; 165.2; 168.5; 174.5. Anal. Calcd for C28H24N2O5 (468.5): C,
71.78; H, 5.16; N, 5.98. Found: C, 71.50; H, 5.30; N, 5.71.
4.5.3. 4-Phenyl-1-p-tolyl-1H-imidazole 6b. Recrystallized from
ether. White crystals, mp 132–133 ꢀC. Lit3a mp 134–135 ꢀC. 1H NMR
(400 MHz, DMSO-d6):
d
2.36 (3H, s), 7.24 (1H, t, J¼7.6), 7.34–7.42
4.4.12. 3-(p-Tolyl)-2-(4-methoxyphenyl)-5-phenyl-3H-imidazol-1-
(4H, m), 7.61 (2H, t, J¼8.4), 7.87 (2H, d, J¼8.0), 8.25 (1H, d, J¼1.2),
ium-1-(1,2-bis-methoxycarbonyl-2-oxoethanide) 5k. Cream col-
8.30 (1H, d, J¼1.2). 13C NMR (100 MHz, DMSO-d6):
d 20.9; 114.5;
oured powder, mp 140–142 ꢀC. IR (KBr) nC]O 1740 and 1679 cmꢁ1
;
120.5; 124.9; 127.1; 129.0; 130.7; 134.5; 134.9; 136.3; 136.8; 142.1.
Anal. Calcd for C16H14N2 (234.30): C, 82.02; H, 6.02; N, 11.96. Found:
C, 81.95; H, 6.03; N, 11.90.
1H NMR (400 MHz, CDCl3):
d 2.32 (3H, s), 3.30 (3H, s), 3.68 (3H, s),
3.73 (3H, s), 6.79 (2H, d, J¼8.8), 7.10–7.19 (6H, m), 7.30 (2H, d, J¼9.2),
7.38–7.39 (2H, m), 7.53–7.56 (2H, m). 13C NMR (100 MHz, CDCl3):
d
21.2; 50.5; 51.8; 55.3; 95.1; 114.1; 114.3; 118.6; 125.2; 128.7; 129.0;
4.5.4. 1-(4-Methoxyphenyl)-4-phenyl-1H-imidazole 6c. Recrystallized
130.0; 130.6; 131.8; 133.2; 138.7; 140.3; 147.9; 162.0; 165.0; 165.2;
from ether–hexane (1:2). White crystals, mp 103–104 ꢀC. Lit3a mp

N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
2059
100–101 ꢀC. 1H NMR (400 MHz, DMSO-d6):
d
3.79 (3H, s), 7.08 (2H,
7.41–7.47 (4H, m), 7.78–7.81 (1H, m), 7.89 (2H, d, J¼8.0; 1.2),
8.11–8.13 (1H, m), 8.35 (1H, t, J¼2.0). 13C NMR (100 MHz, CDCl3):
d, J¼9.2), 7.22 (1H, t, J¼7.6), 7.37 (2H, t, J¼7.6), 7.61 (2H, t, J¼9.2),
7.84 (2H, d, J¼8.8), 8.17 (1H, d, J¼1.2), 8.2 (1H, d, J¼1.2). 13C NMR
d
21.2; 119.6; 122.9; 123.4; 125.0; 125.7; 127.3; 128.7; 129.2; 130.5;
(100 MHz, DMSO-d6):
d
55.9; 114.9; 115.4; 122.3; 124.9; 127.0;
132.0; 133.4; 134.1; 135.3; 139.2; 142.1; 144.4; 148.1. Anal. Calcd for
C22H17N3O2 (355.39): C, 74.35; H, 4.77; N, 11.73. Found: C, 74.00; H,
4.82; N, 11.82.
129.0; 130.6; 134.6; 136.4; 142.0; 158.5. Anal. Calcd for C16H14N2O
(250.30): C, 76.78; H, 5.64; N, 11.19. Found: C, 76.70; H, 5.58; N,
11.10.
4.6. Synthesis of C2-metallated 3H-imidazol-1-ium ylides 9
4.5.5. 1-(4-Chlorophenyl)-4-phenyl-1H-imidazole 6d. Recrystallized
from ethanol. White crystals, mp 139–140 ꢀC. IR (KBr) nC]N 1597
4.6.1. General procedure. To a solution of 5a–f (0.15 mmol) in
CH2Cl2 (25 mL), AgNO3 (0.173 mmol, 0.029 g) or Ag2O (0.08 mmol,
0.019 g) and Et3N (10.8 mmol, 1.095 g, 1.5 mL, 0.73 kg/L) were
added successively and the reaction mixture stirred for 3 h in the
dark. The reaction mixture was washed with water (25 mL) and the
organic phase separated and dried over Na2SO4. The solvent was
evaporated and the residual solid was dried under vacuum in the
dark.
and nC]C 1552 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
; d 7.24 (1H, t,
J¼7.2), 7.39 (2H, t, J¼7.6), 7.61 (2H, J¼8.4), 7.77 (2H, d, J¼8.4), 7.84
(2H, d, J¼7.6), 8.32 (1H, s), 8.37 (1H, s). 13C NMR (100 MHz, DMSO-
d6):
d 114.4; 122.2; 124.9; 127.2; 129.0; 130.2; 131.5; 134.3; 136.1;
136.5; 142.5. Anal. Calcd for C15H11ClN2 (254.71): C, 70.73; H, 4.35;
N, 11.00. Found: C, 70.65; H, 4.30; N, 11.03.
4.5.6. 1-(4-Bromophenyl)-4-phenyl-1H-imidazole 6e. Recrystallized
from ethanol. Orange crystals, mp 151–152 ꢀC. IR (KBr) nC]N 1597
4.6.2. 5a Ag(I) complex, 9a. Brown powder, mp 268–269 ꢀC. IR
and nC]C 1552 cmꢁ1; NMR (400 MHz, DMSO-d6):
d
7.26 (1H, t,
(KBr) nC]O 1728 and 1671 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
J¼7.2), 7.41 (2H, t, J¼8.0), 7.71–7.77 (4H, m), 7.86 (2H, dd, J¼8.0, 1.2),
d
0.99 (9H, t, J¼7.2), 2.50 (6H, q, J¼7.2), 3.27 (3H, s), 3.60 (3H, s),
8.33 (1H, d, J¼1.2), 8.39 (1H, d, J¼1.2). 13C NMR (100 MHz, DMSO-
7.34–7.39 (3H, m), 7.44 (1H, t, J¼6.8), 7.49–7.55 (4H, m), 7.82 (2H, d,
d6):
d
114.4; 119.7; 122.5; 125.0; 127.3; 129.0; 133.2; 134.3; 136.4;
J¼6.8), 7.99 (1H, s). 13C NMR (100 MHz, DMSO-d6):
d 12.5; 47.4;
136.5; 142.5. Anal. Calcd for C15H11BrN2 (299.17): C, 60.22; H, 3.71;
N, 9.36. Found: C, 60.15; H, 3.69; N, 9.30.
49.8; 51.2; (Ylide C not observed) 118.7; 123.3; 128.1; 128.4; 128.7;
128.8; 129.1; 130.2; 138.0; 140.0; 166.3; 169.5; 174.1. Anal. Calcd for
C27H32AgN3O5 (586.43): C, 55.30; H, 5.50; N, 7.17. Found: C, 55.00;
H, 5.55; N, 7.07.
4.5.7. 1-(3,4-Dimethoxyphenyl)-4-phenyl-1H-imidazole 6f. Recry-
stallized from DMSO–water. Cream coloured powder, mp 128–
130 ꢀC. IR (KBr) nC]N 1601 and nC]C 1552 cmꢁ1; 1H NMR (400 MHz,
4.6.3. 5b Ag(I) complex, 9b. Brown powder, mp 282–283 ꢀC. IR
DMSO-d6):
d
3.94 (3H, s), 3.96 (3H, s), 6.93–7.00 (3H, m), 7.28 (1H, t,
(KBr) nC]O 1729 and 1679 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
J¼7.6), 7.41 (2H, t, J¼7.6), 7.50 (1H, d, J¼1.2), 7.84 (2H, d, J¼7.6), 7.85
d
1.01 (9H, t, J¼7.2), 2.33 (3H, s), 2.53 (6H, q, J¼7.2), 3.26 (3H, s), 3.59
(1H, d, J¼1.2). 13C NMR (100 MHz, DMSO-d6):
d
56.2 (2C); 106.0;
(3H, s), 7.31–7.39 (5H, m), 7.49 (2H, dd, J¼8.0; 2.0 Hz), 7.70 (2H, d,
111.6; 114.0; 114.5; 124.9; 127.1; 128.7; 130.7; 133.6; 136.1; 142.7;
148.7; 149.8. Anal. Calcd for C17H16N2O2 (280.32): C, 72.84; H, 5.75;
N, 9.99. Found: C, 72.60; H, 5.65; N, 9.86.
J¼8.4), 7.94 (1H, s). 13C NMR (100 MHz, DMSO-d6):
d 12.8; 21.0;
48.0; 49.8; 51.2; 98.1; 118.7; 121.5; 123.1; 128.1; 128.7; 129.2; 130.6;
137.7 (2C); 137.8; 166.3; 169.5; 174.1; 184.3 (Deduced from the g-
HMBC spectrum). Anal. Calcd for C28H34AgN3O5 (600.50): C, 56.01;
H, 5.71; N, 7.00. Found: C, 55.95; H, 5.52; N, 7.26.
4.5.8. 1-(4-Methoxyphenyl)-2,4-diphenyl-1H-imidazole 6i. Recry-
stallized from hexane. White crystals, mp 110 ꢀC. Lit3a mp 110 ꢀC.
4.6.4. 5c Ag(I) complex, 9c. Brown powder, mp 285–286 ꢀC. IR
4.5.9. 2,4-Diphenyl-1-p-tolyl-1H-imidazole 6j. Recrystallized from
(KBr) nC]O 1728 and 1663 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
hexane. White crystals, mp 144 ꢀC. Lit3a mp 144.5–145 ꢀC.
d
1.01 (9H, t, J¼7.2), 2.58 (6H, q, J¼7.2), 3.25 (3H, s), 3.60 (3H, s), 3.78
(3H, s), 7.07 (2H, d, J¼9.2), 7.34–7.39 (3H, m), 7.48–7.51 (2H, m), 7.73
4.5.10. 2-(4-Methoxyphenyl)-4-phenyl-1-p-tolyl-1H-imidazole
6k. Recrystallized from ethanol–water. White crystals, mp 122–
123 ꢀC. IR (KBr) nC]N 1610 and nC]C 1579 cmꢁ1; 1H NMR (400 MHz,
(2H, d, J¼9.2), 7.90 (1H, s). 13C NMR (100 MHz, DMSO-d6):
d 12.4;
47.5; 49.8; 51.2; 55.9; 98.2; 115.2; 118.9; 124.7; 128.1; 128.7; 129.1;
129.2; 133.3; 137.7; 159.2; 166.3; 169.5; 174.1; 183.9 (Deduced from
the g-HMBC spectrum). Anal. Calcd for C28H34AgN3O6 (616.45): C,
54.55; H, 5.56; N, 6.82. Found: C, 54.45; H, 5.43; N, 7.00.
CDCl3):
d
2.41 (3H, s), 3.79 (3H, s), 6.80 (2H, d, J¼8.0), 7.13–7.28 (4H,
m), 7.39–7.41 (6H, m), 7.82 (2H, d, J¼8.0). 13C NMR (100 MHz,
CDCl3): d 21.2; 55.2; 113.6; 118.3; 122.9; 124.9; 125.6; 126.9; 128.6;
130.1; 130.2; 133.9; 136.1; 138.1; 141.2; 146.9; 159.7. Anal. Calcd for
C23H20N2O (340.42): C, 81.15; H, 5.92; N, 8.23. Found: C, 81.20; H,
5.95; N, 8.30.
4.6.5. 5d Ag(I) complex, 9d. Brown powder, mp 287–288 ꢀC. IR
(KBr) nC]O 1736 and 1650 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d
0.99 (9H, t, J¼6.8), 2.50 (6H, q, J¼6.8), 3.25 (3H, s), 3.60 (3H, s),
7.34–7.39 (3H, m), 7.48–7.51 (2H, m), 7.59 (2H, d, J¼9.2), 7.88 (2H,
4.5.11. 2-(4-Chlorophenyl)-4-phenyl-1-p-tolyl-1H-imidazole
d, J¼9.2), 8.01 (1H, s). 13C NMR (100 MHz, DMSO-d6):
d 12.6; 47.5;
6l. Recrystallized from EtOH–ether. White crystals, mp 121–
49.8; 51.3; (Ylide C not observed) 118.6; 125.0; 128.2; 128.7; 128.8;
129.0; 130.2; 132.7; 138.1; 138.8; 166.3; 169.6; 174.1; 184.8
(Deduced from the g-HMBC spectrum). Anal. Calcd for
C27H31AgClN3O5 (620.87): C, 52.23; H, 5.03; N, 6.77. Found: C,
52.09; H, 5.08; N, 7.01.
122 ꢀC. IR (KBr) nC]N 1605 and nC]C 1575 cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
d
2.42 (3H, s), 7.14 (2H, d, J¼8.0), 7.22–7.29 (5H,
m), 7.39–7.42 (5H, m), 7.87 (2H, d, J¼8.0). 13C NMR (100 MHz,
CDCl3):
d 21.2; 118.9; 125.0; 125.6; 127.1; 128.5; 128.6; 128.9;
130.0; 130.2; 133.7; 134.4; 135.7; 138.5; 141.7; 145.8. Anal. Calcd
for C22H17ClN2 (344.84): C, 76.63; H, 4.97; N, 8.12. Found: C, 76.62;
H, 4.97; N, 8.24.
4.6.6. 5e Ag(I) complex, 9e. Brown powder, mp 286–288 ꢀC. IR
(KBr) nC]O 1732 and 1655 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d
1.00 (9H, t, J¼7.2), 2.53 (6H, q, J¼7.2), 3.25 (3H, s), 3.60 (3H, s),
4.5.12. 2-(3-Nitrophenyl)-4-phenyl-1-p-tolyl-1H-imidazole
6m. Recrystallized from EtOH–ether. Yellow crystals, mp 158–
159 ꢀC. IR (KBr) nC]N 1601 and nC]C 1575 cmꢁ1; 1H NMR (400 MHz,
7.35–7.39 (3H, m), 7.48–7.51 (2H, m), 7.71 (2H, d, J¼8.8), 7.82 (2H, d,
J¼8.8), 8.01 (1H, s). 13C NMR (100 MHz, DMSO-d6):
d 12.5; 47.4;
49.8; 51.3; (Ylide C not observed) 118.6; 121.1; 125.3; 128.2; 128.7;
130.0; 133.1; 138.2; 139.3; 142.8; 166.3; 169.6; 174.1; 184.8
CDCl3):
d
2.43 (3H, s), 7.18 (2H, d, J¼8.4), 7.26–7.32 (3H, m),

2060
N. Cos¸kun, M. Çetin / Tetrahedron 66 (2010) 2053–2060
4. Freeman, J. P. Chem. Rev. 1983, 83, 241–261.
5. Jones, R. C. F.; Martin, J. N.; Smith, P.; Gelbrich, T.; Light, M. E.; Hursthouse, M. B.
Chem. Commun. 2000, 1949–1950.
6. (a) Habeeb, A. G.; Praveen Rao, N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 2921–
2927; (b) Ishikawa, T.; Kudoh, T.; Yoshida, J.; Yasuhara, A.; Manabe, S.; Saito, S.
Org. Lett. 2002, 4, 1907–1910; (c) Chiacchio, U.; Rescifina, A.; Chiacchio, M. A.;
Romeo, G.; Romeo, R. J. Org. Chem. 2003, 68, 3718–3720.
(Deduced from the g-HMBC spectrum). Anal. Calcd for
C27H31AgBrN3O5 (665.32): C, 48.74; H, 4.70; N, 6.32. Found: C,
48.33; H, 4.77; N, 6.50.
4.6.7. 5f Ag(I) complex, 9f. Brown powder, mp 258–260 ꢀC. IR (KBr)
nC]O 1732 and 1667 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
; d 0.99
7. (a) Cos¸kun, N.; Tunçman, S. Tetrahedron 2006, 62, 1345–1350; (b) Cos¸kun, N.;
¨
Oztu¨rk, A. Tetrahedron 2006, 62, 12057–12063; (c) Ding, Q.; Wang, Z.; Wu, J. J.
(9H, t, J¼7.2), 2.50 (6H, q, J¼7.2), 3.26 (3H, s), 3.59 (3H, s), 3.78 (3H,
s), 3.82 (3H, s), 7.06–7.50 (8H, m), 7.93 (1H, s). 13C NMR (100 MHz,
Org. Chem. 2009, 74, 921–924.
8. (a) Venkov, A. P.; Vodenicharov, D. M. Synthesis 1990, 253–255; (b) Cos¸kun, N.;
Tirli, F. T. Synth. Commun. 1997, 27, 1–9; (c) Cos¸kun, N.; Buyukuysal, L. Hetero-
cycles 1998, 48, 53–59; (d) Cos¸kun, N.; Kızılkus¸ak, Y. T. Synth. Commun. 2005, 35,
2435–2443.
DMSO-d6):
d 12.6; 47.4; 49.8; 51.2; 56.2; 56.3; 107.7; 115.2; 119.1;
124.1; 128.1; 128.6; 129.1; 133.5; 137.6; 148.8; 149.6; 166.3; 169.6;
174.1 (Ylide C and C-Ag are not observed). Anal. Calcd for
C29H36AgN3O7 (646.48): C, 53.88; H, 5.61; N, 6.50. Found: C, 54.00;
H, 5.87; N, 6.70.
9. A mixture of 5b and 6b (0.120 g, 1.17:1) was dissolved in concd HCl (0.5 mL,
36%) and stirred for 5 min then water was added (1 mL) and the mixture fil-
tered. The solid separated was the hydrochloride of 6b. The filtrate was basified
with ammonia (1.5 mL, 26%) and extracted with CHCl3 (2ꢂ5 mL). The combined
extracts were dried over Na2SO4 and filtered. The solvent was evaporated un-
der vacuum and the remaining solid washed with warm ether. 1-Methox-
ycarbonylmethyl-5-phenyl-3-p-tolyl-3H-imidazol-1-ium 7b. Yield, 0.056 g, 83%
purity, the impurity is from the starting 5b. Mp 127–128 ꢀC. IR (KBr) nC]O 1738
Acknowledgements
_
Turkish Scientific and Technological Research Council (TUBITAK) is
cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 2.43 (3H, s), 3.73 (3H, s), 5.61 (2H, s), 7.36–
7.45 (4H, m), 7.52–7.58 (4H, m), 7.67 (2H, d, J¼7.2), 11.2 (1H, s). 13C NMR
gratefullyacknowledged for the financial support (Project No 107T840).
(100 MHz, CDCl3):
d 21.1; 48.4; 53.3; 117.4; 121.6; 123.9; 129.5; 129.6; 131.0;
131.1; 131.2; 132.0; 136.4; 140.9; 166.9. 5-Phenyl-3-p-tolyl-3H-imidazol-1-ium
chloride 6b$HCl. Yield, 0.023g. Mp 230–232 ꢀC. 1H NMR (400 MHz, CDCl3):
d
2.
References and notes
38 (3H, s), 7.42–7.52 (5H, m), 7.72 (2H, d, J¼8.4), 7.92 (2H, d, J¼8.4), 8.67 (1H, s),
9.52 (1H, s).
1. (a) Cos¸kun, N.; Su¨mengen, D. Synth. Commun. 1993, 23, 1699–1706; (b) Cos¸kun,
N.; Asutay, O. Chim. Acta Turc. 1997, 25, 69–71; (c) Cos¸kun, N.; Asutay, O. Chim.
Acta Turc. 1999, 27, 17–23.
2. (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)
Cos¸kun, N.; Tat, F. T.; Gu¨ven, O. O. Tetrahedron: Assymetry 2001, 12, 1463–1467;
(h) Cos¸kun, N.; Er, M. Tetrahedron 2003, 59, 3481–3485; (i) Cos¸kun, N.; Çetin, M.
Tetrahedron 2009, 65, 648–658.
3. (a) Cos¸kun, N. Turk. J. Chem. 2001, 25, 267–272; (b) Cos¸kun, N.; Tat, F. T. Phosphorus
Sulfur 2003, 178, 881–886; (c) Cos¸kun, N.; Tat, F. T. Turk. J. Chem. 2004, 28, 1–7.
10. Arduengo, A. J., III; Dias, H. V. R.; Calabrese, J. C.; Davidson, F. Organometallics
1993, 12, 3405–3409.
11. Guerret, O.; Sole´, S.; Gornitzka, H.; Teichert, M.; Trinquier, G.; Bertrand, G. J. Am.
Chem. Soc. 1997, 119, 6668–6669.
12. Wang, H. M. J.; Lin, I. J. B. Organometallics 1998, 17, 972–975.
13. Tulloch, A. A. D.; Danopoulos, A. A.; Winston, S.; Kleinhenz, S.; Eastham, G. J.
Chem. Soc., Dalton Trans. 2000, 4499–4506.
¨
¨
¨
¨
¨
14. For recent reviews on Ag–NHC complexes see. (a) Arnold, P. L. Heteroat. Chem.
2002, 13, 534–539; (b) Garrison, J. C.; Youngs, W. J. Chem. Rev. 2005, 105,
3978–4008.
¨
¨
15. The 1H NMR chemical shifts of the free amine in DMSO-d6 are
6), 2.39 (6H, q, J¼7.6).
d
0.90 (9H, t, J¼7.