Synthesis of trisubstituted imidazoles via a convergent reaction network from methyl ketones and benzoins

Article abstract of DOI:10.1016/j.tet.2013.11.080

A novel method for constructing trisubstituted imidazoles has been created using simple and readily available aromatic ketones, benzoins, and ammonium acetate as starting materials. The new synthetic strategy utilized a convergent integration of two self-labor domino sequences, providing a typical example for logical self-organization synthesis.

Full text of DOI:10.1016/j.tet.2013.11.080

Tetrahedron 70 (2014) 239e244
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of trisubstituted imidazoles via a convergent reaction
network from methyl ketones and benzoins
,b,
Wei-Jian Xue a, Hong-Zheng Li a, Fang-Fang Gao a, Anxin Wu a
*
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR
China
b Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2013
Received in revised form 14 November 2013
Accepted 22 November 2013
Available online 27 November 2013
A novel method for constructing trisubstituted imidazoles has been created using simple and readily
available aromatic ketones, benzoins, and ammonium acetate as starting materials. The new synthetic
strategy utilized a convergent integration of two self-labor domino sequences, providing a typical ex-
ample for logical self-organization synthesis.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Reaction network
Imidazole
Convergent
Domino reaction
1. Introduction
Retrosynthetic analysis, which searches a set of reactions for
synthesizing complex molecule by multistep chemical synthesis,
was devised by Corey in the mid 1960s (Scheme 1A).1 Based on the
same strategy, we attempt to find a set of compatible reactions,
which can be integrated in one-pot to construct the desired product
by self-sequence synthesis to achieve from artificial stepwise syn-
thesis to self-organization logical synthesis (Scheme 1B). In view of
this idea, we have been focusing on convergent integration of
multipath reaction sequences, such as, self-sorting domino re-
action,2 a focusing domino reaction,3 and a self-labor domino re-
action.4 This is because convergent synthesis was one of the most
efficient methods in the construction of complex molecules.5 To
further verify the versatility of this strategy, an additional novel
convergent self-labor reaction network for the construction of tri-
substituted imidazoles from three simple and readily available
starting substrates has been reported in this work.
Scheme 1. Self-sequence synthesis strategy.
starting materials into amides,11 imines,12 nitriles,13 amino acids,14
isocyanides,15 and other precursors.16 Despite some recent interest,
the direct cyclization of acyclic precursors has not yet been fully
explored.17
Retrosynthetically (Scheme 2), the synthesis of imidazole
derivatives could be constructed from two different easily
available starting substrates, methyl ketones and benzoins, based
Imidazoles are an important class of five-member heterocycles,
which can be found in drug cores,6 natural products,7 important
ligands,8 ionic liquids,9 etc.10 Due to the significance of imidazoles,
various methods have been developed for the construction of im-
idazole derivatives. These methods can be classified by their
on
reactions.
a convergent integration of two parallel linear domino
In the previous literature, phenacyl iodine could be obtained by
iodination of acetophenone.18 In addition, benzoins could be oxi-
dized to benzils under basic conditions catalyzed by iodine.19
Phenacyl bromine could react with benzaldehyde to afford imid-
azoles in the presence of phenylamine and ammonium acetate.17c
* Corresponding author. Tel./fax: þ86 (0)27 6786 7773; e-mail address: chwuax@
mail.ccnu.edu.cn (A. Wu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.080

240
W.-J. Xue et al. / Tetrahedron 70 (2014) 239e244
Table 1 (continued)
Entry
I2
Catalyst
(0.5 equiv)
Base
(1.0 equiv)
Solvent
Temp
(ꢀC)
Yieldb
(%)
(equiv)
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3.0
4.0
5.0
CuCl
CuCl2
Cu(OAc)2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
80
80
80
80
80
80
80
20
40
60
80
80
80
80
36
24
25
42
53
43
21
34
12
23
45
60
70
71
71
10
11
12
13
14
15
16
17
18
19
20
Cs2CO3
K2CO3
DBU
Scheme 2. Retrosynthetic analysis.
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Moreover, benzyl could react with formaldehyde to afford imid-
azole in the presence of phenylamine and ammonium chloride.20 In
this study, we therefore tried to integrate two self-labor domino
sequences in one-pot, which could merge the previous funda-
mental reactions (Scheme 3AeD) together to directly construct
imidazole derivatives (Scheme 3E).
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), NH4OAc (5 mmol) in 3 mL
solvent for 4 h.
b
Isolated yields.
a promotion in the dose of I2. After several experimental optimi-
zations, it was found that 1a (0.5 mmol) could react with 2a
(0.5 mmol) and NH4OAc (5 mmol) in the presence of I2 (1.5 mmol)
and Cs2CO3 (0.5 mmol) in CH3CN at 80 ꢀC to afford the desired
product in 70% yield (Table 1, entry 18).
A wide range of aryl methyl ketones was investigated under
the optimal conditions. As shown in Scheme 4, the substituted
aryl methyl ketones performed smoothly with benzoin 1a to af-
ford the desired products in moderate to good yields (50e88%).
The electron-donating groups attached to the phenyl rings of aryl
methyl ketones, such as 4-Me, 4-OMe, 4-OEt, 3-OMe, and 3,4,5-
(OMe)3, exhibited good reactivity (Scheme 4, 3bef). However, the
electron withdrawing groups, such as F, Cl, Br, and NO2, decreased
the reactivity (Scheme 4, 3gej and 3m). In addition, 2-naphthyl
methyl ketone and 2-acetylphenanthren reacted with benzoin
1a to obtain satisfying results (80% and 74% yields). Encouraged by
the results, the heteroaryl methyl ketones were then examined
under the optimal conditions. To our delight, the substrates with
heterocycle, such as furanyl (2k), thiophenyl (2l), and benzofuryl
(2o), obtained the corresponding products in moderate yields
(63e72%).
Scheme 3. Integration of two parallel linear domino reactions.
2. Results and discussion
The reaction conditions were initially optimized from benzoin
(1a) and aryl methyl ketones (2a). As shown in Table 1, various
catalysts, bases, solvents, and temperatures were examined. To our
delight, the reaction of 1a performed smoothly with 2a to produce
a 42% yield in the presence of I2 (0.5 mmol) at 80 ꢀC in CH3CN
without any catalyst. A series of bases were then screened for the
reaction, such as Cs2CO3, K2CO3, DBU, and Na2CO3 (Table 1, entries
10e13). Pleasingly, the reaction was achieved in moderate yields
with Cs2CO3. To our surprise, good yields were also obtained with
Table 1
Optimization of the reaction conditionsa
Entry
I2
Catalyst
(0.5 equiv)
Base
(1.0 equiv)
Solvent
Temp
(ꢀC)
Yieldb
(%)
(equiv)
1
2
3
4
5
1.0
1.0
1.0
1.0
1.0
CuI
CuI
CuI
CuI
CuI
H2O
MeOH
EtOH
t-Bu-OH
CH3CN
80
60
78
80
80
12
15
16
33
39
Scheme 4. Scope of aryl methyl ketones.

W.-J. Xue et al. / Tetrahedron 70 (2014) 239e244
241
Different benzoins were then examined to further expand the
scope of the substrates. As shown in Scheme 5, the benzoin with
electron-donating groups could afford the desired product in good
yield. Moreover, the target molecular could be obtained in mod-
erate yield when heteroaryl benzoin was used as substrate. This
implied that the electronic effect has a great influence on the re-
action. Furthermore, the structure of 3a was also confirmed by X-
ray crystallography.21
Based on the aforementioned experiments, it can be supposed
that this reaction would be a novel self-labor reaction network. The
possible mechanism for this reaction is illustrated with the exam-
ple from benzoin (1a), acetophenone (2a), and ammonium acetate
(as shown in Scheme 7). Firstly, a-iodo ketone 2aa could be ob-
tained by iodination of acetophenone (2a). Then, benzil (1aa) could
be generated by oxidation of benzoin (1a) catalyzed by I2. Sub-
sequently, intermediate (1ab) could be formed as a product after
the addition of ammonium acetate to benzil (1aa). Next, A or its
enolizational isomer B could be obtained from 2aa and 1ab. When
B underwent intramolecular nucleophilic reaction, C was obtained.
Finally, C underwent dehydration reaction to afford the final
product 3a.
Scheme 5. Scope of benzoins.
Scheme 7. Plausible mechanism of the present reaction.
To gain some insight into the mechanism of the reaction process,
the following experiments were performed (Scheme 6). The target
molecule was obtained from benzyl and acetophenone in 64% yield.
3. Conclusion
In conclusion, this study has developed a novel method for the
synthesis of polysubstituted imidazoles from methyl ketones and
benzoins based on a convergent reaction network. This trans-
formation is not only an efficient example to prove the versatile of
the strategy but also a tool to discover novel reaction. Further
studies on the applications of this reaction will be reported in due
course.
The reaction of
a-iodo ketone (0.5 mmol) and benzoin 1a
(0.5 mmol) with I2 (1.5 mmol) and Cs2CO3 (0.5 mmol) were refluxed
for 4.0 h in MeCN and the directed product was obtained in 72%
yield. Then the mixture of a-iodo ketone (0.5 mmol) and benzil
(0.5 mmol) with I2 (1.5 mmol) and Cs2CO3 (0.5 mmol) was refluxed
for 4.0 h in MeCN and the directed product was obtained in 70%
yield. However, regardless of whether benzoin or benzil was used
as substrate, the products could not be obtained when aryl methyl
ketone 2a was substituted with 2-aminoacetophenone hydrochlo-
4. Experimental
4.1. General
ride. This result clearly confirmed
a-iodo ketone and benzil as
important intermediates in this reaction. In addition, 2-
aminoacetophenone evidently could not participate in the re-
action. Finally, GCeMS and 1H NMR were used to detect the pro-
posed intermediates for this reaction (Supplementary data). These
also verified the significance of a-iodo ketone and benzil as im-
portant intermediates.
All substrates and reagents were commercially available and
used without further purification. TLC analysis was performed us-
ing pre-coated glass plates. Flash column chromatography was
performed on silica gel (200e300 mesh). IR spectra were recorded
as KBr pellets with absorption in cmꢁ1. 1H spectra were recorded in
CDCl3 on 600 MHz NMR spectrometers and resonances (d) are
given in parts per million (ppm) relative to tetramethylsilane. 13C
spectra were recorded in CDCl3 on 100 MHz NMR spectrometers
and resonances (d) are given in parts per million (ppm). HRMS were
obtained on an apex-Ultra MS spectrometer. MS was recorded us-
ing EI (70 eV). Melting points were determined using an electro-
thermal capillary melting point apparatus and not corrected. The X-
ray crystal-structure determinations were obtained on a Bruker
SMART APEX CCD system.
4.2. General procedure for synthesis of 3 (3a as an example)
A mixture of 1a (106.0 mg, 0.5 mmol), acetophenone 2a
(60.0 mg, 0.5 mmol), NH4OAc (385.0 mg, 5.0 mmol), Cs2CO3
(163.0 mg, 0.5 mmol) and iodine (381.0 mg, 1.5 mmol) in CH3CN
(3 mL) was stirred at 80 ꢀC for 4 h. After disappearance of the re-
actant (monitored by TLC), and added 50 mL water to the mixture,
then extracted with EtOAc three times (3ꢂ50 mL). The extract was
washed with 10% Na2S2O3 solution (w/w), dried over anhydrous
Na2SO4, and evaporation. The residue was purified by column
Scheme 6. Control experiments.

242
W.-J. Xue et al. / Tetrahedron 70 (2014) 239e244
chromatography on silica gel (petroleum ether/EtOAc¼10:1) to
yield the desired product 3a as a yellow solid.
NMR (100 MHz, CDCl3) d (ppm) 180.0, 152.6, 144.3, 143.0, 140.4,
134.1, 131.6, 130.5, 129.7, 128.8, 128.3, 127.6, 127.5, 109.0, 60.9, 56.1;
HRMS (ESI): m/z [MþH]þ calcd for C25H23N2O4: 415.16523; found:
415.16486.
4.3. Characterization data
4.3.7. (4,5-Diphenyl-1H-imidazol-2-yl)(4-fluorophenyl)methanone
(3g). Yield 65%, 111.2 mg; light yellow solid; mp 219.5e222.8 ꢀC; IR
4.3.1. (4,5-Diphenyl-1H-imidazol-2-yl)(phenyl)methanone
(3a).22 Yield 71%, 115.0 mg; light yellow solid; mp 204.1e207.2 ꢀC;
IR (KBr): 3256, 3240, 1628, 1599, 1498, 1453, 1439, 1302, 1285, 907,
(KBr): 3286, 1641, 1623, 1598, 1452, 1442, 1234, 1157, 911, 673 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
(ppm) 11.86 (s, 1H), 8.69 (t, J¼6.6 Hz,
727 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d
(ppm) 11.33 (s, 1H), 8.67 (d,
J¼7.2 Hz, 2H), 7.62 (t, J¼7.8 Hz, 4H), 7.51 (t, J¼7.8 Hz, 3H), 7.37 (s,
6H); 13C NMR (100 MHz, CDCl3)
(ppm) 181.7, 144.2, 140.7, 135.6,
2H), 7.60 (s, 4H), 7.36 (s, 6H), 7.14 (t, J¼7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d (ppm) 180.0, 167.4, 164.8, 144.0, 134.3, 134.2,
d
131.9, 128.7, 128.2, 115.5, 115.3, 109.7; HRMS (ESI): m/z [MþH]þ
134.1, 133.3, 131.5, 129.8, 128.9, 128.8, 128.5, 128.4, 128.2, 127.9,
127.5; HRMS (ESI): m/z [MþH]þ calcd for C22H17N2O: 325.13354;
found: 325.13326.
calcd for C22H16FN2O: 343.12412; found: 343.12378.
4.3.8. (4-Chlorophenyl)(4,5-diphenyl-1H-imidazol-2-yl)methanone
(3h).22 Yield 62%, 110.9 mg; light yellow solid; mp 207.6e210.9 ꢀC;
IR (KBr): 3257, 1620, 1585, 1451, 1441, 1302, 1229, 1091, 906, 766,
4.3.2. (4,5-Diphenyl-1H-imidazol-2-yl)(p-tolyl)methanone
(3b). Yield 73%,123.4 mg; light yellow solid; mp 235.3e238.1 ꢀC; IR
(KBr): 3053, 1640, 1606, 1460, 1441, 1416, 1308, 1242, 1174, 910, 765,
696 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d (ppm) 11.48 (s, 1H), 8.63 (d,
J¼8.4 Hz, 2H), 7.66 (d, J¼6.0 Hz, 2H), 7.53 (d, J¼6.0 Hz, 2H), 7.46 (d,
696 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d (ppm) 11.75 (s, 1H), 8.55 (d,
J¼7.8 Hz, 2H), 7.41 (d, J¼7.2 Hz, 3H), 7.34 (d, J¼6.6 Hz, 2H), 7.31 (d,
J¼7.2 Hz, 2H), 7.67 (d, J¼6.6 Hz, 2H), 7.54 (d, J¼5.4 Hz, 2H), 7.38 (s,
J¼6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d (ppm) 180.0, 143.9,
3H), 7.32 (d, J¼6.6 Hz, 2H), 7.28 (d, J¼6.6 Hz, 3H), 2.44 (s, 3H); 13C
140.8, 140.0, 133.9, 132.9, 131.9, 129.7, 129.0, 128.6, 128.4, 127.9,
127.7; HRMS (ESI): m/z [MþH]þ calcd for C22H16ClN2O: 359.09457;
found: 359.09424.
NMR (100 MHz, CDCl3)
d (ppm) 181.2, 144.4, 144.3, 133.1, 131.6,
129.0, 128.8, 128.6, 128.1, 21.8; HRMS (ESI): m/z [MþH]þ calcd for
C
23H19N2O: 339.14919; found: 339.14890.
4.3.9. (4-Bromophenyl)(4,5-diphenyl-1H-imidazol-2-yl)methanone
(3i). Yield 64%, 128.7 mg; light yellow solid; mp 228.5e231.8 ꢀC;
IR (KBr): 3268, 1625, 1584, 1452, 1442, 1425, 1237, 1214, 1070,
4.3.3. (4,5-Diphenyl-1H-imidazol-2-yl)(4-methoxyphenyl)meth-
anone (3c).22 Yield 85%; 150.5 mg light yellow solid; mp
192.3e195.8 ꢀC; IR (KBr): 3058, 1622, 1602, 1571, 1459, 1442, 1411,
1101, 906, 767, 695 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d (ppm)
1314, 1260, 1248, 1164, 910, 778, 698 cmꢁ1 1H NMR (600 MHz,
;
11.70 (s, 1H), 8.51 (d, J¼8.4 Hz, 2H), 7.65 (d, J¼7.2 Hz, 2H), 7.62 (d,
CDCl3):
d
(ppm) 11.56 (s,1H), 8.73 (d, J¼9.0 Hz, 2H), 7.68 (s, 2H), 7.54
J¼7.2 Hz, 2H), 7.53 (d, J¼7.2 Hz, 2H), 7.44e7.38(m, 3H), 7.35e7.29
(s, 2H), 7.39e7.29 (m, 6H), 6.98 (d, J¼9.0 Hz, 2H), 3.90 (s, 3H); 13C
(m, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm) 180.0, 143.9, 134.3,
NMR (100 MHz, CDCl3)
d (ppm) 180.0, 163.9, 144.5, 140.3, 134.2,
133.8, 132.9, 131.6, 129.7, 129.0, 128.9, 128.5, 127.9, 127.7; HRMS
(ESI): m/z [MþH]þ calcd for C22H16BrN2O: 403.04405; found:
403.04366.
133.9,131.4, 129.9,128.9,128.6,128.5, 128.3,127.9, 127.4, 113.6, 55.5;
HRMS (ESI): m/z [MþH]þ calcd for C23H19N2O2: 355.14410; found:
355.14376.
4.3.10. (3,4-Dichlorophenyl)(4,5-diphenyl-1H-imidazol-2-yl)methano
ne (3j). Yield 50%, 98.0 mg; light yellow solid; mp 203.9e207.3 ꢀC; IR
(KBr): 3262, 1623, 1578, 1452, 1441, 1288, 1256, 1216, 1131, 940, 778,
4.3.4. (4,5-Diphenyl-1H-imidazol-2-yl)(4-ethoxyphenyl)methanone
(3d). Yield 84%, 154.6 mg; light yellow solid; mp 205.3e208.9 ꢀC;
IR (KBr): 3251, 1616, 1599, 1564, 1461, 1450, 1260, 1237, 1181, 1168,
695 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d (ppm) 11.53 (s, 1H), 8.71 (s,
908, 808, 696 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d (ppm) 11.88 (s,
1H), 8.60 (d, J¼8.4 Hz, 1H), 7.65 (d, J¼6.6 Hz, 2H), 7.56 (d, J¼8.4 Hz,
1H), 8.67 (d, J¼8.4 Hz, 2H), 7.68 (d, J¼6.6 Hz, 2H), 7.54 (d, J¼6.0 Hz,
1H), 7.52 (d, J¼6.6 Hz, 2H), 7.41 (d, J¼7.8 Hz, 3H), 7.34e7.31(m, 3H);
2H), 7.37e7.27 (m, 6H), 6.94 (d, J¼8.4 Hz, 2H), 4.14e4.10 (m, 2H),
13C NMR (100 MHz, CDCl3)
d (ppm) 178.8, 143.6, 141.1, 138.0, 135.1,
1.45 (t, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm) 180.0,
133.6,133.0,130.7, 130.4, 129.4, 129.3, 129.1, 128.5, 128.4, 127.9; HRMS
(ESI): m/z [MþH]þ calcd for C22H15Cl2N2O: 393.05559; found:
393.05562.
163.4, 144.5, 133.9, 128.8, 128.5, 128.4, 128.3, 127.9, 127.8, 114.0, 63.7,
14.7; HRMS (ESI): m/z [MþH]þ calcd for C24H21N2O2: 369.15975;
found: 369.15937.
4.3.11. (4,5-Diphenyl-1H-imidazol-2-yl)(furan-2-yl)methanone
(3k). Yield 63%, 98.9 mg; light yellow solid; mp 252.7e255.2 ꢀC; IR
(KBr): 3177, 1619, 1557, 1468, 1443, 1426, 1253, 1216, 1011, 884, 768,
4.3.5. (4,5-Diphenyl-1H-imidazol-2-yl)(3-methoxyphenyl)meth-
anone (3e). Yield 78%, 138.1 mg; light yellow solid; mp
169.4e172.8 ꢀC; IR (KBr): 3054, 1651, 1603, 1578, 1498, 1484, 1441,
695 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d (ppm) 10.86 (s, 1H), 8.55 (d,
1418, 1258, 1226, 1054, 969, 764, 696 cmꢁ1 1H NMR (600 MHz,
;
J¼8.4 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J¼7.2 Hz, 2H), 7.60 (s, 2H), 7.49 (s,
CDCl3):
(d, J¼6.0 Hz, 2H), 7.53 (s, 2H), 7.41e7.29 (m, 7H), 7.16 (d, J¼7.8 Hz,
1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
(ppm) 181.3, 159.3,
d
(ppm) 11.48 (s, 1H), 8.31 (d, J¼6.6 Hz,1H), 8.23 (s, 1H), 7.67
3H), 7.43e7.40 (m, 3H), 6.75 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 168.9, 150.3, 148.0, 143.0, 140.5, 134.0, 129.6, 129.0, 128.9,
d
128.4, 128.1, 127.9, 127.6, 124.3, 112.8; HRMS (ESI): m/z [MþH]þ
144.2, 140.6, 136.8, 134.0, 131.8, 129.7, 129.3, 128.9, 128.4, 127.9,
127.5, 124.3, 120.2, 115.4, 55.4; HRMS (ESI): m/z [MþH]þ calcd for
C23H19N2O2: 355.14410; found: 355.14378.
calcd for C20H15N2O2: 315.11280; found: 315.11255.
4.3.12. (4,5-Diphenyl-1H-imidazol-2-yl)(thiophen-2-yl)methanone
(3l). Yield 64%, 105.6 mg; light yellow solid; mp 242.2e245.9 ꢀC; IR
(KBr): 3259, 1600, 1509, 1453, 1442, 1425, 1240, 1206, 1180, 820, 766,
4.3.6. (4,5-Diphenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)
methanone (3f). Yield 88%, 182.2 mg; light yellow solid; mp
176.2e179.9 ꢀC; IR (KBr): 3243, 1622, 1581, 1506, 1494, 1453, 1438,
691 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d
(ppm) 11.33 (s, 1H), 9.36 (s,
1H), 7.93 (s, 1H), 7.68 (d, J¼6.6 Hz, 2H), 7.54 (s, 2H), 7.40 (s, 3H),
7.34e7.28 (m, 4H); 13C NMR (100 MHz, CDCl3)
(ppm) 175.1, 144.1,
139.2, 137.6, 134.1, 129.8, 129.0, 128.9, 128.7, 128.4, 128.3, 127.9, 127.6,
1415, 1339, 1240, 1219, 1132, 996, 719 cmꢁ1 1H NMR (600 MHz,
;
d
CDCl3):
d
(ppm) 11.80 (s, 1H), 8.14 (s, 2H), 7.67 (d, J¼7.2 Hz, 2H), 7.54
(d, J¼6.6 Hz, 2H), 7.38e7.29 (m, 6H), 3.97 (s, 3H), 3.92 (s, 6H); 13C

W.-J. Xue et al. / Tetrahedron 70 (2014) 239e244
243
125.4; HRMS (ESI): m/z [MþH]þ calcd for C20H15N2OS: 331.08996;
J¼7.8 Hz, 2H), 7.46 (d, J¼5.4 Hz, 1H), 7.42e7.38 (m, 2H), 7.32 (d,
J¼4.2 Hz, 1H), 7.15 (t, J¼4.8 Hz, 1H), 7.04 (t, J¼4.8 Hz, 1H); 13C NMR
found: 331.08973.
(100 MHz, CDCl3)
d (ppm) 181.1, 143.9, 136.3, 135.4, 133.5, 131.4,
4.3.13. (4,5-Diphenyl-1H-imidazol-2-yl)(4-nitrophenyl)methanone
(3m). Yield 50%, 92.3 mg; red solid; mp 251.2e254.7 ꢀC; IR (KBr):
3278, 1628, 1594, 1517, 1452, 1442, 1349, 1319, 1230, 912, 849,
129.7, 128.5, 128.4, 127.8, 127.6, 127.3, 125.7, 125.6, 124.4; HRMS
(ESI): m/z [MþH]þ calcd for C18H13N2OS2: 337.04638; found:
337.04611.
768, 698 cmꢁ1 1H NMR (600 MHz, CDCl3):
; d (ppm) 11.11 (s, 1H),
8.85 (d, J¼7.8 Hz, 2H), 8.35 (d, J¼8.4 Hz, 2H), 7.67 (d, J¼7.2 Hz,
Acknowledgements
2H), 7.54 (d, J¼6.6 Hz, 2H), 7.45 (d, J¼6.6 Hz, 2H), 7.38e7.34 (m,
4H); 13C NMR (100 MHz, CDCl3)
d (ppm) 179.3, 150.3, 143.5, 140.4,
We thank the National Natural Science Foundation of China
(Grants 21032001 and 21272085). We also thank Dr. Xianggao
Meng for his help with X-ray diffraction analysis and Dr. Chuanqi
Zhou, Hebei University, for analytical support.
132.3, 129.1, 128.9, 128.6, 128.5, 128.3, 127.9, 127.8, 125.2, 123.3;
HRMS (ESI): m/z [MþH]þ calcd for C22H16N3O3: 370.11862;
found: 370.11835.
4.3.14. (4,5-Diphenyl-1H-imidazol-2-yl)(naphthalen-2-yl)meth-
anone (3n). Yield 80%, 149.6 mg; light yellow solid; mp
215.3e218.9 ꢀC; IR (KBr): 3245, 1635, 1612, 1591, 1451, 1442, 1416,
Supplementary data
Evidence in support of the hypothetic mechanism, and 1H and
13C NMR spectra and X-ray crystal data for 3a. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2013.11.080.
1250, 1219, 963, 829, 763, 708 cmꢁ1 1H NMR (600 MHz, CDCl3):
;
d
(ppm) 11.34 (s, 1H), 9.52 (s, 1H), 8.53 (d, J¼8.4 Hz, 1H), 8.07 (d,
J¼8.4 Hz, 1H), 7.94e7.89 (m, 2H), 7.73 (d, J¼7.2 Hz, 2H), 7.62 (d,
J¼6.6 Hz, 1H), 7.58e7.56 (m, 3H), 7.42e7.31 (m, 6H); 13C NMR
(100 MHz, CDCl3)
d (ppm) 181.3, 144.4, 140.7, 135.8, 134.4, 134.1,
References and notes
132.9, 132.5, 131.7, 130.3, 129.8, 129.0, 128.9, 128.7, 128.4, 128.0,
127.7, 127.6, 126.4, 126.2; HRMS (ESI): m/z [MþH]þ calcd for
1. Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis; Wiley: New York, NY,
1989.
C
26H19N2O: 375.14919; found: 375.14883.
2. Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan, Y. J. Org. Lett. 2006, 8, 2245.
3. Gao, M.; Yang, Y.; Wu, Y. D.; Deng, C.; Shu, W. M.; Zhang, D. X.; Cao, L. P.; She, N.
F.; Wu, A. X. Org. Lett. 2010, 12, 4026.
4. Xue, W. J.; Li, Q.; Zhu, Y. P.; Wang, J. G.; Wu, A. X. Chem. Commun. 2012, 3485.
5. Wang, Y.; Zhang, W. X.; Wang, Z. T.; Xi, Z. F. Angew. Chem. 2011, 123, 8272;
Angew. Chem., Int. Ed. 2011, 50, 8122.
4.3.15. Benzofuran-2-yl(4,5-diphenyl-1H-imidazol-2-yl)methanone
(3o). Yield 72%, 131.1 mg; light yellow solid; mp 257.3e260.9 ꢀC; IR
(KBr): 3278, 1625, 1547, 1513, 1513, 1463, 1451, 1442, 1326, 1259, 1228,
1185, 956, 768, 695 cmꢁ1; 1H NMR (600 MHz, CDCl3):
d (ppm) 11.09
6. (a) Carini, D. J.; Duncia, J. V.; Johnson, A. L.; Chiu, A. T.; Price, W. A.; Wong, P. C.;
Timmermans, P. J. Med. Chem. 1990, 33, 1330; (b) Lee, J. C.; Laydon, J. T.;
McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; McNully, D.; Blumenthal, M.; Heys,
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Med. Chem. 1998, 41, 4744.
(s, 1H), 8.89 (s, 1H), 7.82 (s, 1H), 7.71 (s, 2H), 7.66 (d, J¼6.6 Hz, 1H),
7.56e7.52 (m, 3H), 7.42e7.35 (m, 7H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 170.4, 156.2, 150.4, 143.2, 140.8, 133.9, 131.7, 129.5, 129.1,
128.7, 128.5, 128.1, 128.0, 127.8, 127.6, 124.0, 120.2, 112.5; HRMS (ESI):
7. (a) Jin, Z. Nat. Prod. Rep. 2009, 26, 382; (b) Jin, Z. Nat. Prod. Rep. 2006, 23, 464; (c)
Jin, Z. Nat. Prod. Rep. 2005, 22, 196.
m/z [MþH]þ calcd for C24H17N2O2: 365.12845; found: 365.12802.
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10580; (b) Kuwano, R.; Kameyama, N.; Ikeda, R. J. Am. Chem. Soc. 2011, 133,
7312; (c) Ueda, S.; Su, M.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 700; (d)
Laroche, C.; Li, J.; Freyer, M.; Kerwin, W. S. M. J. Org. Chem. 2008, 73, 6462; (e)
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R. D. Org. Lett. 2004, 6, 843; (b) Zhong, Y. L.; Lee, J.; Reamer, R. A.; Askin, D. Org.
Lett. 2004, 6, 929; (c) Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2, 323.
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Angew. Chem. 2011, 123, 6682; Angew. Chem., Int. Ed. 2011, 50, 6552; (b) Siamaki,
A. R.; Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128, 6050; (c) Piccionello, A. P.;
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4.3.16. (4,5-Diphenyl-1H-imidazol-2-yl)(phenanthren-2-yl)meth-
anone (3p). Yield 74%, 156.9 mg; light yellow solid; mp
269.6e273.8 ꢀC; IR (KBr): 3240, 1627, 1607, 1584, 1568, 1462, 1449,
1425, 1234, 1218, 972, 848, 766, 698 cmꢁ1 1H NMR (600 MHz,
;
CDCl3):
d
(ppm) 11.14 (s, 1H), 9.44 (s, 1H), 8.87 (d, J¼9.0 Hz, 1H), 8.78
(d, J¼8.4 Hz, 1H), 8.75 (d, J¼8.4 Hz, 1H), 7.94e7.90 (m, 2H), 7.81 (d,
J¼8.4 Hz, 1H), 7.75 (d, J¼7.8 Hz, 2H), 7.72e7.66 (m, 2H), 7.57 (s, 2H),
7.43 (s, 2H), 7.39e7.32 (m, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm)
180.9,144.5,140.7,134.1,133.7,133.5,133.3,131.5,129.8,129.1,129.0,
128.7, 128.4, 128.3, 128.0, 127.8, 127.6, 127.5, 126.9, 123.5, 122.8;
HRMS (ESI): m/z [MþH]þ calcd for C30H21N2O: 425.16484; found:
425.16437.
13. (a) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E. Angew. Chem. 2009, 121,
3162; Angew. Chem., Int. Ed. 2009, 48, 3116; (b) Shen, H.; Xie, Z. J. Am. Chem. Soc.
2010, 132, 11473; (c) Jiang, B.; Wang, X.; Shi, F.; Tu, S. J.; Ai, T.; Ballew, A.; Li, G. J.
Org. Chem. 2009, 74, 9486; (d) Horneff, T.; Chuprakov, S.; Chernyak, N.; Ge-
vorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972.
4.3.17. (4,5-Bis(4-methoxyphenyl)-1H-imidazol-2-yl)(phenyl)methan
one (3q).22 Yield 84%, 161.3 mg; light yellow solid; mp
185.4e188.9 ꢀC; IR (KBr): 3320, 1607, 1591, 1566, 1526, 1488, 1462,
1434,1298,1249,1228,1178, 904, 838, 693 cmꢁ1; 1H NMR (600 MHz,
14. (a) Attanasi, O. A.; Caselli, E.; Davoli, P.; Favi, G.; Mantellini, F.; Ori, C.; Prati, F.
Org. Lett. 2009, 11, 2840; (b) Petit, S.; Fruit, C.; Bischoff, L. Org. Lett. 2010, 12,
4928.
ꢀ
15. (a) Bienayme, H.; Bouzid, K. Angew. Chem. 1998, 110, 2349; Angew. Chem., Int. Ed.
1998, 37, 2234; (b) Lygin, A. V.; de Meijere, A. Angew. Chem. 2010, 122, 9280;
Angew. Chem., Int. Ed. 2010, 49, 9094; (c) Kanazawa, C.; Kamijo, S.; Yamamoto, Y.
J. Am. Chem. Soc. 2006, 128, 10662.
CDCl3):
d
(ppm) 11.61 (s, 1H), 8.62 (d, J¼7.8 Hz, 2H), 7.60 (t, J¼7.2 Hz,
2H), 7.54e7.48 (m, 5H), 6.88 (d, J¼8.4 Hz, 4H), 3.82 (s, 6H); 13C NMR
16. For selected examples, see: (a) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.;
Looper, R. E. Angew. Chem. 2011, 123, 710; Angew. Chem., Int. Ed. 2011, 50, 684;
(b) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem. 2011,
123, 5796; Angew. Chem., Int. Ed. 2011, 50, 5678; (c) Smith, M. R.; Blake, A. J.;
Hayes, C. J.; Stevens, M. F. G.; Moody, C. J. J. Org. Chem. 2009, 74, 9372; (d) Nie, Y.
B.; Wang, L.; Ding, M. W. J. Org. Chem. 2012, 77, 696; (e) Zaman, S.; Mitsuru, K.;
Abell, A. D. Org. Lett. 2005, 7, 609; (f) Attanasi, O. A.; Davoli, P.; Favi, G.; Fili-
ppone, P.; Forni, A.; Moscatelli, G.; Prati, F. Org. Lett. 2007, 9, 3461.
17. (a) Huang, H. W.; Ji, X. C.; Wu, W. Q.; Jiang, H. F. Adv. Synth. Catal. 2013, 355, 170;
(b) Thomas, P. J.; Axtell, A. T.; Klosin, J.; Peng, W.; Rand, C. L.; Clark, T. P.; Landis, C. R.;
Abboud, K. A. Org. Lett. 2007, 9, 2665; (c) Adib, M.; Ansari, S.; Feizi, S.; Damavandi, J.
A.; Mirzaei, P. Synlett 2009, 3263.
(100 MHz, CDCl3)
d (ppm) 181.4, 143.8, 135.8, 133.2, 131.4, 129.4,
128.2, 114.1, 112.3, 55.3; HRMS (ESI): m/z [MþH]þ calcd for
C24H21N2O3: 385.15467; found: 385.15426.
4.3.18. (4,5-Di(thiophen-2-yl)-1H-imidazol-2-yl)(phenyl)methanone
(3r). Yield 62%, 104.2 mg; light yellow solid; mp 172.1e175.9 ꢀC;
IR (KBr): 3232, 1627, 1594, 1571, 1469, 1453, 1401, 1341, 1244, 1209,
1180, 901, 847, 696 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
(ppm)
10.86 (s, 1H), 8.68 (d, J¼7.2 Hz, 2H), 7.63 (t, J¼7.2 Hz, 1H), 7.53 (t,

244
W.-J. Xue et al. / Tetrahedron 70 (2014) 239e244
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2661.
21. The details of the crystal data (3a) have been deposited with Cambridge
Crystallographic Data Centre as Supplementary Publication, CCDC 949845.
_
ꢁ
22. (a) Kayagil, I.; Demirayak, S¸ . Turk. J. Chem. 2011, 35, 13; (b) Dora, E. K.; Dash, B.;
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