Practical multi-component synthesis of di-or tri-aryl (heteraryl) substituted 2-(pyridin-2-yl)imidazoles from simple building blocks

Article abstract of DOI:10.1021/cc100079b

A convenient and highly efficient multicomponent protocol has been developed for the synthesis of various poly-substituted 2-(pyridin-2-yl) imidazoles from 2-cyanopyridine, corresponding aromatic aldehydes, and NH ₄OAc/primary amine. Notably, tri-substituted 2-(pyridin-2-yl) imidazoles were highly yielded when aromatic primary amines were used as substrates, but both di-and tri-substituted 2-(pyridin-2-yl)imidazoles were obtained in one pot when some aliphatic primary amines were used as substrates.

Full text of DOI:10.1021/cc100079b

J. Comb. Chem. 2010, 12, 829–835
829
Practical Multi-Component Synthesis of Di- or Tri-Aryl (Heteraryl)
Substituted 2-(Pyridin-2-yl)imidazoles from Simple Building Blocks
Xiao-Jin Wu, Ran Jiang, Xiao-Ping Xu, Xiao-Ming Su, Wei-Hong Lu, and
Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu ProVince, College of Chemistry, Chemical Engineering
and Materials Science, Soochow UniVersity, Suzhou 215123, China
ReceiVed May 12, 2010
A convenient and highly efficient multicomponent protocol has been developed for the synthesis of various
poly-substituted 2-(pyridin-2-yl)imidazoles from 2-cyanopyridine, corresponding aromatic aldehydes, and
NH4OAc/primary amine. Notably, tri-substituted 2-(pyridin-2-yl)imidazoles were highly yielded when
aromatic primary amines were used as substrates, but both di- and tri-substituted 2-(pyridin-2-yl)imidazoles
were obtained in one pot when some aliphatic primary amines were used as substrates.
Introduction
be successfully synthesized from 2-cyanopyridine, corre-
sponding aromatic aldehydes and NH4OAc/primary amine
in the solvent of acetic acid at 170 °C. Compared with Tu
et al.’s work, not only more di-substituted 2-(pyridin-2-
yl)imidazoles but also a variety of tri-substituted 2-(pyridin-
2-yl)imidazoles could be efficiently synthesized in our
protocol. Moreover, while some aliphatic primary amines
were used as substrates, both di- and tri-substituted 2-(py-
ridin-2-yl)imidazoles were generated in one pot. Herein, we
report these results.
Imidazoles with the heterocyclic substituent in 2-position,
which are found in many natural products and drug cores,
have exhibited extensive applications in organic synthesis.1
2-(Pyridin-2-yl)imidazoles are one of the key intermediates
in the syntheses of pharmacologically active compounds,
such as I and II (Scheme 1).2 Moreover, 2-(pyridin-2-
yl)imidazoles have also been used as excellent ligands in
transition-metal-catalyzed coupling reactions.3 Because of
the extensive applicability of 2-(pyridin-2-yl)imidazoles,
several strategies for the synthesis of the 2-(pyridin-2-
yl)imidazole derivatives have been developed.4 Although
these methodologies have achieved remarkable success, the
potential limitations including the demand of substrates
which are not readily or commercially available and inef-
ficiency of the transformations restrain the wider utilization.
Therefore, to develop a concise and practical synthetic
protocol for the preparation of 2-(pyridin-2-yl)imidazole
derivatives is still currently an area of considerable interest.
Recently, Tu et al. have developed a concise and efficient
four-component approach to di-substituted 2-(pyridin-2-
yl)imidazoles under the solvent-free and microwave-irradia-
tion conditions.4l Compared with the traditional synthetic
routes for imidazoles using complicated substrates such as
1,2-diketone, amino-acetaldehyde, or R-ketomonoxime,5 they
utilized more simple and readily available starting materials
to construct a series of di-substituted 2-(pyridin-2-yl)imida-
zoles in good to excellent yields. As our continuing
endeavors in developing novel multicomponent reactions to
synthesize valuable heterocyclic compounds,6 we made a
systematic and deeper discussion to the novel approach based
on the work of Tu et al. and explored a versatile, highly
efficient multicomponent reaction to synthesize di- or tri-
substituted 2-(pyridin-2-yl)imidazoles. As shown in Scheme
2, various poly-substituted 2-(pyridin-2-yl)imidazoles could
Results and Discussion
Our initial attempts to explore the feasibility of the
proposed process focused on heating the 0.5:1:5 mixtures
of 2-cyanopyridine, 4-chlorobenzaldehyde, and NH4OAc in
the solvent of HOAc at 170 °C. Satisfyingly, the process
Scheme 1. Pharmacologically Active 2-Pyridiny-Substituted
Imidazoles
Scheme 2. Novel Strategy to Synthesize Poly-Substituted
2-(Pyridin-2-yl)imidazoles
* To whom correspondence should be addressed. E-mail: chemjsj@
suda.edu.cn.
10.1021/cc100079b  2010 American Chemical Society
Published on Web 09/08/2010

830 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Wu et al.
Table 2. Substrate Scope for the Synthesis of 4, 5-Disubstitued
2-(pyridin-2-yl)imidazolesa
Figure 1. Crystal Structure of 4d.
Table 1. Optimization of Reaction Conditionsa
entry
substrate 1:2d:3
temperature (°C)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
0.5:1:5
1:1:5
1.5:1:5
2:1:5
2.5:1:5
3:1:5
2.5:1:3
2.5:1:1
2.5:1:5
2.5:1:5
2.5:1:5
2.5:1:5
170
170
170
170
170
170
170
170
150
130
170
170
10
10
10
10
10
10
10
10
10
10
6
52
62
70
79
93
89
77
74
77
69
87
74
9
10
11
12
4
a Reactions run in 3.0 mL of HOAc with 1.0 mmol
4-chlorobenzaldehyde. b Isolated yield, calculated based on the amount
of aldehyde.
was successfully accomplished and generated di-substituted
2-(pyridin-2-yl)imidazole 4d in 52% yield. The definite
structure of the final product was confirmed by the X-ray
crystal structure (Figure 1).7
Subsequently, optimization of the reaction conditions was
undertaken to increase the yield by employing various molar
ratios of substrates at different temperatures for several hours.
The results are summarized in Table 1. The yield was
increased up to 93% under the optimized conditions with a
molar ratio of 2.5:1:5 for 2-cyanopyridine/4-chlorobenzal-
dehyde/NH4OAc in 3.0 mL solvent of HOAc at 170 °C for
10 h (entry 5).
According to the optimized conditions, we continued to
examine 2-cyanopyridine, NH4OAc, and a wide variety of
aromatic aldehydes to establish the scope of the strategy.
As shown in Table 2, aromatic adehydes bearing either
electron-withdrawing or electron-donating groups perform
equally well in the reactions (entries 1-6). However,
aliphatic aldehydes (propionaldehyde) have no reaction
activity in the novel method (entry 17). To study the steric
influence of the approach, we also tested several aromatic
aldehydes with substituent in different positions. To our
delight, 3-substituted aromatic aldehydes were also very
a Reaction conditions: 1 (2.5 mmol), 2 (1.0 mmol), 3 (5.0 mmol), 3.0
mL of HOAc at 170 °C for 10 h. b Isolated yield, calculated based on
the amount of aldehydes. c These products have been reported in
reference 4l.
reactive (entries 7-9). However, aromatic aldehydes with
electron-withdrawing groups at ortho-position just provided
modest yields of the corresponding 2-(pyridin-2-yl)imida-
zoles (entries 10, 11). We supposed that it was contributed
to the strong steric and electron-withdrawing influence.
Notably, the activity of 1-naphthaldehyde was much worse
than 2-naphthaldehyde in this transformation (entries 12, 13).
In addition, several heteroaromatic aldehydes also delivered
the corresponding 2-(pyridin-2-yl)imidazoles in satisfactory
yields (entries 14-16). All these examples illustrated the
excellent generality of this approach for a wide variety of
aromatic aldehydes.

Poly-Substituted 2-(Pyridin-2-yl)imidazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 831
Table 3. Substrate Scope Study for the Synthesis of
Scheme 3
1,4,5-Trisubstituted 2-(pyridin-2-yl)imidazolesa
substrate
entry
R1
R2
product
yieldb (%)
1
2
3
4
5
6
7
8
4-OCH3 (2a)
4-OCH3 (2a)
4-OCH3 (2a)
4-OCH3 (2a)
4-OCH3 (2a)
4-Cl (2d)
4-Cl (2d)
4-Cl (2d)
4-Cl (2d)
4-Cl (2d)
4-OCH3 (5a)
4-CH3 (5b)
4-H (5c)
4-Cl (5d)
3-Cl (5e)
4-OCH3 (5f)
4-CH3 (5g)
4-H (5h)
6a
6b
6c
6d
6e
6f
6g
6h
6i
92
89
83
87
82
97
95
85
92
90
90
9
10
11
4-Cl (5i)
4-Br (5j)
3-Cl (5k)
6j
6k
4-Cl (2d)
either electron-deficient or electron-rich groups could be
subjected successfully to this protocol. Moreover, the strategy
is highly efficient to the sterically hindered systems as well.
Furthermore, 3- or 4-cyanopyridine were used as substrates
to extend the generality of this approach to synthesize 3- or
4-(pyrid-2-yl)imidazoles. As shown in Scheme 3, no product
was obtained from either reaction as shown in the eqs 1 and
2 in Scheme 3. Additionally, the reaction also did not occur
when benzonitrile was taken as substrate (Scheme 3, eq. 3).
All these results indicated that 2-position cyanopyridine
played a key role in the reaction. We thought that it might
be due to the special electron influence of the 2-substituted
pyridine. To confirm our assumption, 2-cyanoquinoline, the
analogue of 2-cyanopyridine, was selected as the substrate
to realize the transformation. As expected, the similar product
4r was obtained in 94% yield (Scheme 3, eq. 4). Conse-
quently, all these results lead us to pay attention to the insight
into the mechanism of the reaction.
a Reaction conditions: 1 (2.5 mmol), 2 (1.0 mmol), 5 (5.0 mmol), 3.0
mL of HOAc at 170 °C for 10 h. b Isolated yield, calculated based on
the amount of aldehyde.
Though a mechanism had been proposed by Tu el al.,4l it
was demonstrated in the basic reaction condition. We thought
that the mechanism was not suitable to our acidic reaction
condition; we needed to explore a more reasonable mecha-
nism. According to the literature,6 two common mechanistic
hypotheses might be possible: One path involved the
cyclocondensation of 1, 2-diketone or R-hydroxyketone,
2-cyanoarene, and NH4OAc. To explore the possibility, our
initial attempt was taken by employing benzil or benzoin as
substrate, but none of the reactions occurred (Scheme 4).
Subsequently, we attempted to explore another possibility
for the involvement of the cyclocondensation of amidine A
and benzaldehyde. Unfortunately, no product was observed.
Either, the amidine A could not be synthesized from
2-cyanopyridine and NH4OAc in the acid condition (Scheme
4). All these results indicated that our approach could not
be achieved on this mechanism.
Figure 2. Crystal Structure of 6c.
So far, the novel approach was found highly efficient for
the syntheses of di-substituted 2-(pyridin-2-yl)imidazoles.
Next, we were interested in the formation of tri-substituted
2-(pyridin-2-yl)imidazoles using this strategy. Although
intensive efforts have been made to form highly substituted
imidazoles, to our best knowledge, only a handful of general
methods exist for the construction of tetra-substituted imi-
dazoles.8 Herein, we try our approach to construct tri-
substituted 2-(pyridin-2-yl)imidazoles using the multicom-
ponent condensation simply by changing NH4OAc to primary
amine. First, the same reaction conditions were applied for
the synthesis of the product 6c via the condensation of
2-cyanopyridine, 4-methoxybenzaldehyde, and aniline. To
our pleasure, the 1,4,5-trisubstituted 2-(pyridin-2-yl)imidazole
6c was obtained in a high yield (83%, Table 3, entry 3).
The definite structure of 6c was confirmed by the X-ray
crystal structure (Figure 2).9 Subsequently, the substrate
scope of the reaction was evaluated using a variety of
structurally diverse aldehydes and primary aromatic amines
(Table 3). Both aromatic aldehydes and primary amines with
Fortunately, while 1-phenylethanamine 5l served as sub-
strate, the unexpected products gave us some clue to the
mechanism. In this reaction, no 4,5-bis(4-chlorophenyl)-2-
(pyridin-2-yl)-1-benzyl-imidazole was obtained, as expected.
However, some unexpected products were observed (Scheme
5): one confirmed product, which was characterized by the

832 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Wu et al.
Scheme 4
Figure 3. Crystal Structure of 6l.
next step, which might be the key step, involved the
intramolecular nucleophilic attack to finally construct the
imidazole core. We consider that this step may be the result
of the special electron influence of the 2-substituted pyridine,
which has been confirmed in some reported researches.12
This hypothesis is also supported by the fact that only
2-substituted pyridine and its analogue can achieve the
transformation (Scheme 4).
According to our proposed mechanism, the structure of
quaternary ammonium cation may emerge in the transforma-
tion. Considering the thermalytic cleavage mechanism of
quaternary ammonium, we predicted that di- or tri-substituted
2-(pyridin-2-yl)imidazoles might be synthesized in a one-
pot manner using our protocol. Therefore, we selected butan-
1-amine 5m (aliphatic amine) as the ammonia source to
achieve our prediction. As expected, both products (6m and
4d) were obtained (Table 4, entry 1). The structure of tri-
substituted 2-(pyridin-2-yl)imidazole 6m was also confirmed
by the X-ray crystal structure (Figure 4).13 The possible
synthetic route was also shown in Scheme 7. Furthermore,
the same situation also happened in the syntheses of 6n and
4d with cyclohexylamine 5n as a substrate (Table 4, entry
X-ray crystal structure (Figure 3),10 was an unexpected tri-
substituted 2-(pyridin-2-yl)imidazole 6l. Other products were
the di-substituted 2-(pyridin-2-yl)imidazole 4d and styrene.
According to the literature,11 we thought that they were
formed from the route as shown in Scheme 5. To confirm
our assumption, we chose imine as a substrate to achieve
the reaction. However, no product was formed and the
phenomenon of the cleavage of imine was observed. The
known cleavage products were well observed in the TLC.
This result also supported our hypothetic synthetic route to
the product 6l.
On the basis of all above observations and the literature,
the mechanism is thought to include the following steps
(Scheme 6). First, the imine was obtained from aromatic
aldehyde and amine. Second the swift nucleophilic attack
occurred between imine, 2-cyanopyridine, and another
molecule of aromatic aldehyde in the acidic condition. The
Scheme 5. Routes to the Synthesis of 6l and 4d

Poly-Substituted 2-(Pyridin-2-yl)imidazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 833
Scheme 6. Possible Mechanism for the Formation of poly-Substituted 2-(Pyridin-2-yl)imidazole
Table 4. Substrate Scope Study for the Synthesis of Both Di-
and Tri-substituted 2-(pyridin-2-yl)imidazolesa
substrates, both di- and tri-substituted 2-(pyridin-2-yl)imi-
dazoles could be synthesized in one pot.
Experimental Section
General Experimental Methods. All reagents were
purchased form Aldrich or Alfa. Analytical thin-layer chro-
matography was performed using glass plates precoated with
200-400 mesh silica gel impregnated with a fluorescent
indicator (254 nm). Melting points were recorded on an
electrothermal digital melting point apparatus. IR spectra
were recorded on a Varian FT-1000 spectrophotometer using
KBr optics. NMR spectra were recorded in CDCl3 on a
Varian Inova-400 NMR spectrometer (300 MHz for 1H NMR
and 100 or 75 MHz for13C NMR) with TMS as an internal
reference. High resolution mass spectra were obtained using
Microma GCT-TOF instrument. X-ray diffraction data were
recorded on a Rigaku Mercury CCD area detector with
graphite monochromated MoKR radiation.
entry
R3
yieldb (%)
yieldb (%)
1
2
R3 ) n-Bu (5m)
69 (6m)
31 (6n)
28 (4d)
62 (4d)
R3 ) CyHex (5n)
a Reaction conditions: 1 (2.5 mmol), 2d (1.0 mmol), 5 (5.0 mmol),
3.0 mL of HOAc at 170 °C for 10 h. b Isolated yield, calculated based
on the amount of aldehyde.
Typical Experimental Procedure for the Synthesis of
2,4,5-Trisubstituted Imidazole (4a). 2-Cyanopyridine (260
mg, 2.5 mmol), 4-methoxy-benzaldehyde (136 mg, 1.0
mmol), and NH4OAc (385 mg, 5.0 mmol) were combined
and heated in 3 mL of acetic acid at 170 °C for 10 h in
a Teflon-lined stainless steel autoclave(25 mL of the
volume). After that, the mixture was added to by the
freshly prepared saturated solution of NaHCO3, brought
pH to 7, and extracted with ethyl acetate; then the organic
phase was dried by anhydrous MgSO4, filtered and
evaporated under vacuum. The residue was purified by
Figure 4. Crystal Structures of 6m.
2). Moreover, in the presence of benzyl amine 5o as a
substrate, only tri-substituted 2-(pyridin-2-yl)imidazole 6o
was obtained in 92% yield, without observing the formation
of 4d (Scheme 8). We thought that this was due to the
absence of the active ꢀ-hydrogen in the structure of benzyl
amine 5o to accomplish the thermalytic cleavage.
flash column chromatography (Vethyl acetate/Vpetroleum ether
)
Therefore, all these results of aliphatic amine substrates
demonstrated that the synthetic processes of both di- and
tri-substituted 2-(pyridin-2-yl)imidazoles could be achieved
in one-pot using this approach. Moreover, these results also
supported our hypothetic mechanism to some extent.
1:8) to afford the pure product (164 mg). Mp: 189-191
°C (lit.mp:190-191 °C).4m IR(KBr) ν: 3412, 3060, 2948,
1612, 1597, 1568, 1516, 1458, 1422 cm-1. 1H NMR (300
MHz, CDCl3): δ ) 3.82 (s, 6H, 2OCH3), 6.85-6.89 (m,
4H, ArH), 7.18 (t, J ) 6.2 Hz, 1H, ArH), 7.37 (d, J )
8.4 Hz, 2H, ArH), 7.60 (d, J ) 8.4 Hz, 2H, ArH), 7.76 (t,
J ) 7.8 Hz, 1H, ArH), 8.27 (d, J ) 8.0 Hz, 1H, ArH),
8.44 (d, J ) 4.2 Hz, 1H, ArH), 10.82 (s, 1H, NH) ppm.
13C NMR (100 MHz, CDCl3): δ ) 149.06, 148.86, 145.35,
137.50, 129.66, 129.39, 123.32, 120.45, 114.56, 114.22,
55.70 ppm. HRMS M+: calcd for C22H19N3O2: 357.1477,
found: 357.1478.
Conclusion
In summary, we have developed a novel and highly
efficient method for the synthesis of various di- or tri-aryl
(heteraryl) substituted 2-(pyridin-2-yl)imidazoles from simple
and readily available starting materials. Moreover, while
aliphatic primary amines with beta-hydrogen were used as

834 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Scheme 7. Approach to Synthesis of 4d and 6m
Wu et al.
Scheme 8. Approach to Synthesis of 6o
Science & Technology Innovation Cultivation Program of
Soochow University.
Supporting Information Available. Characterization data
including Mp, IR, MS, 1H and 13C NMR spectra for
compounds 4a-4r, 6a-6o. This material is available free of
charge via the Internet at http://pubs.acs.org.
Typical Experimental Procedure for the Synthesis of
1,2,4,5-Tetrasubstituted Imidazole (6a). 2-Cyanopyridine
(260 mg, 2.5 mmol), 4-methoxy-benzaldehyde (136 mg, 1.0
mmol), and 4-methoxyaniline (616 mg, 5.0 mmol) were
combined and heated in 3 mL of acetic acid at 170 °C for
10 h in a Teflon-lined stainless steel autoclave (25 mL of
the volume). After that the mixture was added to by the
freshly prepared saturated solution of NaHCO3, brought pH
to 7, and extracted with ethyl acetate; then the organic phase
was dried by anhydrous MgSO4, filtered and evaporated
under vacuum. The residue was purified by flash column
chromatography (Vethyl acetate/Vpetroleum ether ) 1:8) to afford the
pure product (213 mg). Mp: 197-198 °C. IR(KBr) ν: 2956,
References and Notes
(1) (a) Manley, P. J.; Balitza, A. E.; Bilodeau, M. T.; Coll, K. E.;
Hartman, G. D.; McFall, R. C.; Rickert, K. W.; Rodman,
L. D.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2003, 13,
1673–1677. (b) Ring, D. B.; Johnson, K. W.; Henriksen, E. J.;
Nuss, J. M.; Goff, D.; Kinnick, T. R.; Ma, S. T.; Reeder, J. W.;
Samuels, I.; Slabiak, T.; Wagman, A. S.; Hammond, M.-E. W.;
Harrison, S. D. Diabetes 2003, 52, 588–595. (c) Caron, S.;
Do, N. M.; McDermott, R. E.; Bahmanyar, S. Org. Process
Res. DeV. 2006, 10, 257–261. (d) Murray, M.; Wilkinson, C. F.
Chem. Biol. Interact. 1984, 50, 267–275.
(2) (a) Vaher, B.; Bonnaud, B.; Funes, F.; Jubault, N.; Koek, W.;
Assie, M.-B.; Cosi, C. J. Med. Chem. 1998, 41, 5070–5083.
(b) Mano, T.; Stevens, R. W.; Ando, K.; Okumura, Y.;
Sakakibara, M.; Okumura, T.; Tamura, T.; Miyamoto, K.
Bioorg. Med. Chem. 2003, 11, 3879–3887.
1
2833, 1615, 1587, 1515, 1488, 1383 cm-1. H NMR (300
MHz, CDCl3): δ ) 3.77-3.78 (m, 9H, 3OCH3), 6.72-6.81
(m, 6H, ArH), 6.98-7.13 (m, 5H, ArH), 7,54 (d, J ) 8.4
Hz, 2H, ArH), 7.63 (t, J ) 7.4 Hz, 1H, ArH), 7.80 (d, J )
(3) (a) Akiharu, S.; Hiroyuki, K.; Tadashi, N. Chem. Lett. 1999,
49–51. (b) Wang, R.; Xiao, J. C.; Twamley, B.; Shreeve, J. M.
Org. Biomol. Chem. 2007, 5, 671–678. (c) Dupont, J.; de
Souza, R. F.; Suarez, P. A. Z. Chem. ReV. 2002, 102, 3667–
3692.
7.8 Hz, 1H, ArH), 8.38 (d, J ) 3.0 Hz, 1H, ArH) ppm. 13
C
NMR (75 MHz, CDCl3): δ ) 159.58, 159.18, 158.80, 150.30,
149.35, 145.91, 138.48, 136.50, 132.84, 131.55, 131.01,
129.80, 128.94, 127.71, 124.23, 123.31, 122.85, 114.27,
114.08, 113.96, 55.74, 55.60, 55.55 ppm. HRMS M+: calcd
for C29H25N3O3: 463.1896, found: 463.1899.
(4) (a) McManus, J. M.; Herbst, R. M. J. Org. Chem. 1959, 24,
1042–1044. (b) Irving, H.; Weber, O. J. Chem. Soc. 1959,
2296–2298. (c) Voss, M. E.; Beer, C. M.; Mitchell, S. A.;
Blomgren, P. A.; Zhichkin, P. E. Tetrahedron. 2008, 64, 645–
651. (d) Torelli, S.; Delahaye, S.; Hauser, A.; Bernardinelli,
G.; Piguet, C. Chem.sEur. J. 2004, 10 (4), 3503–3516. (e)
Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis.
2005, 1, 47–56. (f) Chattopadhyay, S. K.; Mitra, K.; Biswas,
S.; Lucas, C. R.; Adhikary, B. J. Chem. Res., Synop. 2003, 9,
562–563. (g) Dubey, P. K.; Kumar, C. R.; Reddy, V. P. Indian
J. Chem., Sect B. 2003, 42 (9), 2115–2118. (h) Romanenko,
I. V.; Sheinkman, A. K.; Baranov, S. N.; Poltavets, V. N.;
Klyuev, N. A. Chem. Heterocycl. Compd. 1980, 16 (12),
1261–1267. (i) Sharghi, H.; Asemani, O.; Tabaei, S. M. H.
J. Heterocycl. Chem. 2008, 45 (5), 1293–1298. (j) Salehi, P.;
Dabiri, M.; Zolfigol, M. A.; Otokesh, S.; Baghbanzadeh, M.
Tetrahedron Lett. 2006, 47 (15), 2557–2560. (k) Matsushita,
H.; Lee, S. H.; Joung, M.; Clapham, B.; Janda, K. D.
Acknowledgment. The work was partially supported by
the National Natural Science Foundation of China (No.
20672079, 20910102041), Natural Science Foundation of
Jiangsu Province (No. BK 2006048), Nature Science of
Jiangsu Province for Higher Education (No. 05KJB150116),
Nature Science Key Basic Research of Jiangsu Province for
Higher Education (No.06KJ A15007), the Specialized Re-
search Fund for the Doctoral Program of Higher Education
(No. 20060285001), Key Laboratory of Organic Synthesis
of Jiangsu Province (No. JSK 008), and Key Project in

Poly-Substituted 2-(Pyridin-2-yl)imidazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 835
Tetrahedron Lett. 2004, 45 (2), 313–316. (l) Jiang, B.; Wang,
X.; Shi, F.; Tu, S. J.; Ai, T.; Ballew, A.; Li, G. J. Org. Chem.
2009, 24, 9486–9489. (m) Seko, N.; Yoshino, K.; Yokota,
K.; Tsukamoto, G. Chem. Pharm. Bull. 1991, 39, 651–657.
(n) Kori, S.; Narisawa, S. Asahi Garasu Kenkyu Hokoku 1962,
12, 55–70.
(8) (a) Balalaie, S.; Arabanian, A. Green Chem. 2000, 2, 274–
276. (b) Karimi, A. R.; Alimohammadi, Z.; Azizian, J.;
Mohammadi, A. A.; Mohammadizadeh, M. R. Catal. Com-
mun. 2006, 7, 728–732. (c) Sadeghi, B.; Mirjalili, B. B. F.;
Hashemi, M. M. Tetrahedron Lett. 2008, 49, 2575–2577.
(9) Crystallographic data for the crystal structure of 6c has been
deposited at the Cambridge Crystallographic Data Centre as
supplementary publication with No. CCDC 749497. Copies
of this information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, U.
(5) (a) van Leusen, D.; van Leusen, A. M. Org. React. 2001, 57,
417–666. (b) Radziszewski, B. Chem. Ber. 1882, 15, 1493–
1496. (c) App, J F. R.; Robinson, H. H. Chem. Ber. 1882,
15, 1268–1270. (d) Valentina, Z.; Giuseppe, C.; Marco, F.;
Chiara, G.; Mirko, R. J. Org. Chem. 2007, 72, 4551–4553.
(e) Usyatinsky, A. Y.; Khemelnitsky, Y. L. Tetrahedron Lett.
2000, 41, 5031–5034. (f) Wolkenberg, S. E.; Wisnoski, D. D.;
Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org.
Lett. 2004, 6, 1453–1456. (g) Sparks, R. B.; Combs, A. P.
Org. Lett. 2004, 6, 2473–2478. (h) Oskooie, H. A.; Alimo-
hamma di, Z.; Heravi, M. M. Heteroatom Chem. 2006, 17,
699–702. (i) Siddiqui, S. A.; Narkhede, U. C.; Palimkar, S. S.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2005,
61, 3539–3546. (j) Wang, J.; Mason, R.; Derveer, D. V.; Feng,
K.; Bu, X. R. J. Org. Chem. 2003, 68, 5415–5418. (k) Sarshar,
S.; Siev, D.; Mjalli, M. M. Tetrahedron Lett. 1996, 37, 835–
838. (l) Domling, A. Chem. ReV. 2006, 106, 17–89. (m)
Domling, A.; Ugi, I. Angew, Chem, Int, Ed. 2000, 39, 3168–
3210. (n) Khalili, B.; Tondro, T.; Hashemi, M. M. Tetrahe-
dron. 2009, 65, 6882–6887.
(6) (a) Zhu, S. L.; Ji, S. J.; Su, X. M.; Liu, Y. Tetrahedron Lett.
2008, 49, 1777–1781. (b) Zhu, S. L.; Ji, S. J.; Liu, Y.
Tetrahedron Lett. 2008, 49, 2578–2582. (c) Zhu, S. L.; Ji,
S. J.; Zhang, Y. Tetrahedron. 2007, 63, 9365–9372. (d) Sun,
C.; Ji, S. J.; Liu, Y. Tetrahedron Lett. 2007, 48, 8987–8989.
(e) Zhao, K.; Xu, X. P.; Zhu, S. L.; Shi, D. Q.; Zhang, Y.; Ji,
S. J. Synthesis 2009, 2697–2708. (f) Wu, X. J.; Xu, X. P.;
Su, X. M.; Ji, S. J. Eur. J. Org. Chem. 2009, 29, 4963–4970.
(7) Crystallographic data for the crystal structure of 4d has
been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication with No. CCDC
749496. Copies of this information may be obtained free
of charge from The Director, CCDC, 12 Union Road,
K (E-mail: linstead@ccdc.cam.ac.uk or deposit@ccdc.cam.ac.uk;
fax: +44 01223 336033). Structural parameters for 6c: data
collection: Rigaku Mercury CCD area detector; crystal size:
0.70 × 0.37 × 0.27 mm3; C28H23N3O2, Mr ) 433.49,
Monoclinic, space group P21/c, a ) 21.8446(15) Å, b )
11.8324(6) Å, c ) 19.3978 (13) Å, R ) 90°, ꢀ )114.9330(10)°,
γ ) 90°, V ) 4546.5(5) Å3, Z ) 8, Dcalcd ) 1.267 mg /cm-3
R[I > 2σ(I)] ) 0.0643, wR[I > 2σ(I)] ) 0.1606.
,
(10) Crystallographic data for the crystal structure of 6l has been
deposited at the Cambridge Crystallographic Data Centre
as supplementary publication with No. CCDC 749494.
Copies of this information may be obtained free of charge
from The Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, U.K. (E-mail: linstead@ccdc.cam.ac.uk or
deposit@ccdc.cam.ac.uk; fax: +44 01223 336033). Structural
parameters for 6l: data collection: Rigaku Mercury CCD area
detector; crystal size: 0.45 × 0.22 × 0.20 mm3; C27H18N3Cl3,
j
Mr ) 490.79, Triclinic, space group P1, a ) 9.6681(6) Å, b
) 10.5590(8) Å, c ) 12.4197(10) Å, R ) 78.349(8)°, ꢀ )
75.715(8) °, γ ) 71.087(7)°, V ) 1152.00(15) Å3, Z ) 2,
Dcalcd ) 1.415 mg /cm-3, R[I > 2σ(I)] ) 0.0472, wR[I > 2σ(I)]
) 0.1106.
(11) Ohta, S.; Okamoto, M. Synthesis 1982, 756–758.
(12) Klappa, J. J.; Rich, A. E.; McNeill, K. Org. Lett. 2002, 4,
435–437.
(13) Crystallographic data for the crystal structure of 6m has
been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication with No. CCDC
749495. Copies of this information may be obtained free
of charge from The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, U.K. (E-mail: linstead@ccdc.cam.ac.uk
or deposit@ccdc.cam.ac.uk; fax: +44 01223 336033). Structural
parameters for 6m: data collection: Rigaku Mercury CCD area
detector; crystal size: 0.30 × 0.20 × 0.20 mm3; C24H21N3Cl2,
Cambridge, CB2 1EZ, U.K. (E-mail: linstead@ccdc.cam.ac.uk
or deposit@ccdc.cam.ac.uk; fax: +44 01223 336033). Structural
parameters for 4d: data collection: Rigaku Mercury CCD area
detector; crystal size: 0.40 × 0.20 × 0.18 mm3; C20H13N3Cl2,
j
Mr ) 421.33, Triclinic, space group P1, a ) 9.4780(11) Å, b
) 9.9982(12) Å, c ) 11.3848(13) Å, R ) 94.844(5)°, ꢀ )
90.128(4)°, γ ) 91.815(4)°, V ) 1074.5(2) Å3, Z ) 2, Dcalcd
) 1.302 mg/cm-3, R[I > 2σ(I)] ) 0.0599, wR[I > 2σ(I)] )
0.1480.
j
Mr ) 366.23, Triclinic, space group P1, a ) 11.2229(13) Å,
b ) 12.0539(13) Å, c ) 13.1038 (14) Å, R ) 86.733(8)°, ꢀ
) 86.017(7)°, γ ) 77.070(7)°, V ) 1722.0(4) Å3, Z ) 4,
Dcalcd ) 1.413 mg/cm-3, R[I > 2σ(I)] ) 0.0865, wR[I > 2σ(I)]
) 0. 2024.
CC100079B