Unexpected reactions of push-pull N-heterocyclic carbene derived from N-(4-methoxyphenyl)-N-(4-nitrophenyl)-imidazolium chloride

Article abstract of DOI:10.1055/s-0029-1217813

A new precursor of N-heterocyclic carbene bearing push-pull substituents has been synthesized by the quaternization of 1-(4-methoxyphenyl)-imidazole. Unexpected reactions between the carbene generated in situ and aromatic aldehydes or acrylates were observed resulting in the formation of imidazole derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217813

LETTER
2305
Unexpected Reactions of Push–Pull N-Heterocyclic Carbene Derived from
N-(4-Methoxyphenyl)-N-(4-nitrophenyl)-imidazolium Chloride
Unexpected
R
ea
h
ctions of Pu
i
sh–Pul
-
l
N-Hete
Q
rocyclic Carbene iang Zhu,a Ming-Yue Jiang,b Jin-Hong Lin,a Cheng-Pan Zhang,a Xiao-Chun Hang,a Chang-Ge Zheng,b
Qing-Yun Chen,a Ji-Chang Xiao*a
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: jchxiao@mail.sioc.ac.cn
School of Chemical and Material Engineering, Southern Yantze University, 1800 Lihu Road, Wuxi 214122, P. R. of China
b
Received 5 May 2009
imidazoles usually resulted in the formation of unsym-
metrically N,N¢-disubstituted imidazolium salts. How-
ever, the direct quaternization of N-aryl substituted
imidazoles with other aryl halides are difficult or even im-
possible.13 We and others have recently described the syn-
thesis of several imidazolium-based ionic salts with
donor–acceptor substituents and investigated their appli-
cations as second-order nonlinear materials.14 These re-
sults prompted us to extend our research to the possible
applications of the imidazolium salts bearing push–pull
substituents as NHC precursors.
Abstract: A new precursor of N-heterocyclic carbene bearing
push–pull substituents has been synthesized by the quaternization
of 1-(4-methoxyphenyl)-imidazole. Unexpected reactions between
the carbene generated in situ and aromatic aldehydes or acrylates
were observed resulting in the formation of imidazole derivatives.
Key words: N-heterocyclic carbenes, nucleophilic addition, aro-
matic substitution, rearrangements
Significant achievements have been made during the past
decades in the area of N-heterocyclic carbenes (NHC) for
the important roles they played in coordination chemistry
and organocatalysis.1 Compared with traditional phos-
phine ligands and metallic catalysts, NHC are often more
economical and environmentally friendly. They have
been widely used in olefin metathesis (second-generation
Grubbs metathesis catalyst),2 Heck reaction,3 benzoin
condensation,4 Stetter reaction,5 transesterification,6 and
other reactions.7 Besides, NHC also participate as nucleo-
philic reactants towards a variety of electrophilic species
leading to novel molecular frameworks.8 Very recently,
Nair and Ma have reported the application of NHC in mul-
ticomponent reactions.9 It could be expected that the ex-
ploration of the structure and chemical reactivity of NHC
will definitely have fascinating prospects. Substituents on
the N-atoms of NHC have strong influence on their prop-
erties. Since the isolation of the first stable NHC by
Arduengo,10 it is recognized that the steric shielding of the
carbene carbon by means of the sterically demanding ad-
amantyl groups is an important factor affecting the stabil-
ity of NHC. Much attention has been paid on the steric
factors of the substituents thereafter.11 Interestingly, NHC
with different electron-donating or -withdrawing substitu-
ents on the nitrogen atoms have not been much studied.
For simplicity, the methoxy and the nitro group were cho-
sen as a push–pull combination of substituents on N-hete-
reocyclic carbene to be synthesized. The imidazolium salt
was prepared according to our previous work.14 Coupling
reaction of imidazole and 1-bromo-4-methoxybenzene
afforded the N-arylated product 1-(4-methoxyphenyl)-
imidazole. Subsequent quaternization with aryl halides
presented challenges in terms of chemical reactivity,
which is different from the quaternization with 1-chloro-
2,4-dinitrobenzene. Higher temperature and prolonged
reaction time were required for the quaternization to occur
(Scheme 1). The corresponding imidazolium salt 1 was
obtained in 18% yield after heating at 160 °C for 48 hours.
Ar1
N
Ar1
N
H
N
Ar2Cl
CuI, L-proline
Ar1Br
Cl–
+
xylene
160 °C
48 h
K2CO3, DMSO
N
N
Ar2
N
1
Ar1 = 4-MeOC6H4, Ar2 = 4-O2NC6H4
Scheme 1 Synthesis of NHC precursor 1
NHC are most frequently prepared via deprotonation of With the imidazolium salt 1 in hand, we then explored its
the corresponding azolium salts which can be readily syn- application as a NHC precursor in organic synthesis. It is
thesized.1f For example, symmetrically N,N¢-disubstituted well known that the condensation of benzaldehyde to ben-
imidazolium salts can be easily obtained from the multi- zoin can be catalyzed by most NHC.4 The benzoin con-
component condensation of primary amines, glyoxal and densation was therefore investigated using the NHC with
formaldehyde,12 while the quaternization of N-substituted donor–acceptor substituents generated in situ from 1. A
mixture of 1, K3PO4, and 3,4-dichlorobenzaldehyde in
dried ethyl acetate was stirred at room temperature for 8
SYNLETT 2009, No. 14, pp 2305–2308
Advanced online publication: 07.08.2009
DOI: 10.1055/s-0029-1217813; Art ID: W06709ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9
hours. After usual workup, to our surprise, no expected
benzoin product could be detected. Only one unknown
compound was isolated.

2306
Z.-Q. Zhu et al.
LETTER
The mass spectrum and 1H NMR of the unknown product carbonyl carbon to give the intermediate B. The presence
suggested the formation of an adduct between the NHC of nitro group in B might hamper its further rearrange-
and 3,4-dichlorobenzaldehyde. Its structure was then con- ment to a Breslow intermediate.16 Thus no benzoin prod-
sidered to be 2a¢ or 2a¢¢ (Scheme 2). However, no charac- uct was observed. The intermediate B then undergoes an
teristic absorption peak of hydroxyl or carbonyl group intramolecular nucleophilic attack to give the cyclized in-
was observed in its IR spectrum. Fortunately, single crys- termediate C, which rearranged subsequently to afford
tals of the unknown compound suitable for X-ray crystal- imidazole derivatives 2a–d. The formation of 2a–d could
lography were obtained. Then the structure was also be regarded as an intramolecular nucleophilic aro-
unambiguously assigned to be p-nitrophenyl group mi- matic substitution of B, which might be resulted from the
grated product (see Supporting Information).15 The NHC electronically push–pull effect of the substituents, show-
here did not act as a catalyst, but instead, act as a reactant ing its large difference in chemical reactivity from the oth-
in the reaction.
er common NHC.
Ar
Ar1
N
Ar1
Ar1
N
Ar1
N
Ar1
N
Ar
Ar
N
Ar
Ar
O
H
base
O
1
N
Ar2
N
Ar2
O
N
Ar2
N
OH
N
OH
A
2a'
Breslow
2a''
intermediate
Ar1 = 4-MeOC6H4, Ar2 = 4-O2NC6H4
NO2
N
Ar1 = 4-MeOC6H4
Ar2 = 4-O2NC6H4
B
O
O
Scheme 2 Possible product from the reaction of 1 with 3,4-dichlor-
obenzaldehyde
O
Ar
H
Ar1
N
Similar results were also obtained when other aromatic al-
dehydes with electron-withdrawing or -donating group on
the phenyl ring were used as substrates. The yields were
not significantly changed while varying the substituents
on the aromatic aldehydes, indicating good functional-
group tolerance of the reaction (Table 1).
O
Ar1
Ar
Ar
Ar
Ar
O
N
N
OH
not observed
O
Ar2
N
2a–i
A plausible mechanism for this unexpected reaction is
proposed as outlined in Scheme 3. The nucleophilic NHC
A generated from 1 in the presence of base attacked the
N
C
O
O
Scheme 3 Proposed mechanism
Table 1 Reaction of NHC Precursor 1 with Aromatic Aldehydes
Considerable interest has been attracted in using NHC as
nucleophilic reagents.8 Enders et al. found that reaction of
NHC 1,3,4-triphenyl-4,5-dihydro-l,2,4-triazol-5-ylidene
with a,b-unsaturated carbonyl compound ethyl maleate
produced methylenetriazoline rather than cyclopropane
derivatives.8a To gain more insight into the reactivity of
the NHC bearing push–pull substituents, we explored its
reaction with a,b-unsaturated carbonyl compounds.
Ar1
N
Ar1
N
Ar
O
K3PO4
Cl–
ArCHO
+
EtOAc
r.t., 8 h
Ar2
N
Ar2
N
2a–i
Ar1 = 4-MeOC6H4, Ar2 = 4-O2NC6H4
Entry
Ar
Product
2a
Yield (%)a
Under the same conditions as described above, the reac-
tion of the NHC generated in situ from 1 with methacry-
late proceeded smoothly to deliver the product 3a in 79%
yield (Table 2), which was fully characterized by spectro-
scopic analysis, ESI-HRMS, and IR. The structure of 3a
was further confirmed by single-crystal X-ray diffraction
analysis (see Supporting Information).15 The reaction was
found to be applicable to a variety of other acrylates, giv-
ing the corresponding products 3b–d in good yields. It can
be seen that the reaction is very sensitive to the steric hin-
drance of the a,b-unsaturated carbonyl compounds. The
presence of b-methyl group of the acrylates decreased the
yield of 3d remarkably (entry 4). Nevertheless, 89% yield
of 3d can be obtained by increasing the reaction time and
temperature (entry 5).
1
2
3
4
5
6
7
8
9
3,4-Cl2C6H3
4-MeC6H4
Ph
81
69
78
73
83
79
75
68
72
2b
2c
3-O2NC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
3,5-(OMe)2C6H3
2d
2e
2f
2g
2h
2i
a Isolated yields.
Synlett 2009, No. 14, 2305–2308 © Thieme Stuttgart · New York

LETTER
Unexpected Reactions of Push–Pull N-Heterocyclic Carbene
2307
Table 2 Reaction of NHC Precursor 1 with Acrylates
lium salts have important effects on the reactivity of the
resulting NHC and changed the subsequent reaction path-
way, demonstrating much difference from the commonly
used NHC. It can be expected that the reactions presented
here will provide useful clues to the development of new
NHC. Further work is currently underway on the synthe-
sis and reaction of NHC bearing new combinations of
push–pull substituents.
Ar1
N
Ar1
N
O
O
K3PO4
Cl–
+
OR2
OR2
EtOAc
r.t., 8 h
N
Ar2
N
R1
Ar2 R1
3a–d
Ar1 = 4-MeOC6H4, Ar2 = 4-O2NC6H4
Entry
R1
H
R2
Product
Yield (%)a
1
2
3
4
5
Me
Et
3a
3b
3c
3d
3d
79
82
58
11
89b
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
H
H
t-Bu
Me
Me
Acknowledgment
Me
Me
We thank the Chinese Academy of Sciences (Hundreds of Talents
Program) and the National Natural Science Foundation (20772147)
for financial support.
a Isolated yields.
b At 65 °C for 13 h.
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reaction (Scheme 4). The NHC A formed first by the
deprotonation of 1. Conjugated addition of carbene A to
acrylate afforded the zwitterion D. Subsequent intramo-
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R1
Ar1
R1
OR2
Ar1
N
N
OR2
base
O
1
O–
N
N
Ar2
A
D
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N
–O
O
Ar1 = 4-MeOC6H4
Ar2 = 4-O2NC6H4
Ar1
N
Ar1
O
N
N
R1
OR2
N
OR2
Ar2 R1
3a–d
O
N
E
–O
O
Scheme 4 Proposed mechanism
In conclusion, we have synthesized a novel N,N¢-diaryl-
substituted imidazolium salt bearing push–pull substitu-
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reactions with aromatic aldehydes or acrylates gave rise to
imidazole derivatives. Possible mechanisms are proposed
involving an intramolecular nucleophilic aromatic substi-
tution. The presence of push–pull substituents in imidazo-
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LETTER
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Synlett 2009, No. 14, 2305–2308 © Thieme Stuttgart · New York