I2/TBPB mediated oxidative reaction of aryl acetaldehydes with amidines: Synthesis of 1,2,5-triaryl-1H-imidazoles

Article abstract of DOI:10.1039/c7ra01966a

A direct method for the synthesis of 1,2,5-triaryl-1H-imidazoles was achieved easily from cyclization of aryl acetaldehydes with amidines catalyzed by I₂. Various substitued groups can be employed, and this reaction proceeds smoothly in moderate to good yields.

Full text of DOI:10.1039/c7ra01966a

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I2/TBPB mediated oxidative reaction of aryl
acetaldehydes with amidines: synthesis of 1,2,5-
Cite this: RSC Adv., 2017, 7, 24594
triaryl-1H-imidazoles†
a
Jing Wang,
Fang-Dong Zhang,a Dong Tang,b Ping Wu,a Xue-Guo Zhanga
a
*
and Bao-Hua Chen
Received 18th February 2017
Accepted 24th April 2017
A direct method for the synthesis of 1,2,5-triaryl-1H-imidazoles was achieved easily from cyclization of aryl
acetaldehydes with amidines catalyzed by I2. Various substitued groups can be employed, and this reaction
proceeds smoothly in moderate to good yields.
DOI: 10.1039/c7ra01966a
rsc.li/rsc-advances
imidazoles by employing amidines and aldehydes14/nitro-
olens15/ketones.16 We herein report a more environment-
Introduction
friendly and efficient methodology to construct 1,2,5-triaryl-
1H-imidazoles17 which uses I2/TBPB mediated oxidative formal
[3 + 2] cycloaddition of aryl acetaldehydes with amidines
Scheme 1.18
As one of the most valuable types of N-heterocyclic compound,
imidazoles have been found in numerous natural products1 and
functional materials.2 They also have good biological activities,
such as antitumor,3 antimicrobial,4 antihypertensive5 and
protein kinase inhibitory activities.6 In addition, they can also
act as organocatalysts,7 ionic liquids,8 and precursors of N-
heterocyclic carbenes.9
Results and discussion
Due to their indisputable importance and great application
prospects, more and more researchers are dedicating effort to
constructing imidazoles. As for tri-substituted imidazoles,
a number of methods have been developed. The existing
synthetic methodologies have mostly focused on 1,2,4-triarylated
imidazoles10 and 2,4,5-triarylated imidazoles.11 The most common
route for producing 1,2,4-triarylated imidazoles is combining
amidines with terminal alkynes and nitroolens with ketones.
Besides, most of the reported methods for obtaining 2,4,5-triary-
lated imidazoles involve the condensation of 1,2-diketones and
aldehydes with amines or ammonia. However, until now only
a few methods have been developed for making 1,2,5-triarylated
imidazoles.12 Therefore, it is a big challenge for organic chemists
to nd an efficient and simple way to construct 1,2,5-triarylated
imidazoles.
To elucidate the optimal reaction conditions, we initially
studied the reaction of N-phenylbenzimidamide 1a (0.20 mmol)
Our group is dedicated to the efficient synthesis of 1,2,4-
triarylated imidazoles by employing amidines and alkynes via
metal-catalyzed oxidative processes.13 In recent years, our group
has been interested in the synthesis of 1,2,4-triarylated
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University Gansu, Key
Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu
Province, Lanzhou 730000, People's Republic of China. E-mail: chbh@lzu.edu.cn;
Fax: +86-931-891-2582
bDepartment of Chemistry, Lishui University, Lishui 323000, People's Republic of
China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra01966a
Scheme 1 Synthesis of imidazole from amidine.
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Table 1 Optimization of the reaction conditionsa
Entry
Catalyst (mol%)
Oxidant (equiv.)
Solvent (mL)
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
I2(20)
I2(20)
I2(20)
I2(20)
I2(20)
I2(20)
I2(20)
KI(20)
TBAI(20)
NIS(20)
PIDA(20)
I2(20)
I2(20)
I2(20)
I2(20)
I2(20)
I2(20)
—
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
100
100
100
100
100
100
100
100
100
100
100
80
110
100
100
100
100
40
78
93
38
42
12
41
69
54
65
31
66
68
42
50
88
85
TBHP(1)
TBPB(1)
DTBP(1)
H2O2(1)
K2S2O8(1)
O2
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
TBPB(1)
9
10
11
12
13
14
15
16
17
DMSO
Toluene
DCB
a
Reaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), catalyst (20 mol%), oxidant (1 eq), solvent (2 mL), in air for 5 h; TBHP ¼ tert-butyl
hydroperoxide (70% in water); TBPB ¼ tert-butyl peroxybenzoate; DTBP ¼ di-tert-butyl peroxide; TBAI ¼ tetrabutylammonium iodide; NIS ¼
niodosuccinimide; PIDA ¼ iodosobenzene diacetate. b Isolated yield.
with phenylacetaldehyde 2a (0.24 mmol) in the presence of I2 ring could also be applied to this strategy, even with a relatively
ꢀ
(20 mol%) in dioxane at 100 C in air for 5 h. As expected, the low yield (Table 2, entry 5).
desired product 1,2,5-triphenyl-1H-imidazole 3aa was obtained
We next examined the substrate scope of this reaction using
in 40% yield (Table 1, entry 1). In order to improve the yield of R2-substituted arylamidines. Electron-rich-substituted arylami-
3aa, we further screened different oxidants, such as TBHP, dines such as 4-OMe, 4-Me, 2-Me, 3,4-diMe were easily con-
TBPB, DTBP, H2O2, K2S2O8 and O2 for this reaction in the verted into the corresponding products in excellent yields
presence of iodine (Table 1, entries 2–7). Among them, TBPB (Table 2, entries 6–9). Moreover, the substrate with ethyl at the
was found to be the most optimal oxidant for the trans- ortho-position afforded the corresponding product 3ka in 86%
formation. Next, the reaction proceeded less efficiently in other yield (Table 3, entry 10). Electron-decient arylamidines bearing
iodine-containing catalysts such as KI, TBAI, NIS, and PIDA halide (4-F, 4-Cl) groups reacted under the standard conditions
(Table 1, entries 8–11). Then, the reaction did not give a supe- to afford the desired products in moderate yields (Table 2,
ꢀ
rior result with variations in temperature (80, 110 C, Table 1, entries 11–12).
entries 12–13). Furthermore, different solvents such as DMF,
In addition, bifunctional amidines were also studied, and
DMSO, toluene and DCB were failed to improve the yield (Table were well compatible in this transformation in 72–92% yields
1, entries 14–17). Aer several experimental iterations, the (Table 2, entries 13–17).
optimal reaction conditions emerged with N-phenyl-
To further study the scope and generality of the present
benzimidamide 1a (0.20 mmol) with phenylacetaldehyde 2a protocol, various aryl acetaldehyde 2 were studied for the
(0.24 mmol) in the presence of I2 (20 mol%) and TBPB (1 eq.) cycloaddition reactions with N-phenylbenzimidamide 1a under
ꢀ
in dioxane (2 mL) at 100 C in air for 5 h (Table 1, entry 3)
the optimized reaction conditions (Table 3). Substrates bearing
With the optimized conditions in hand, we proceeded to electron-donating groups (4-OMe, 4-Me, 3-Me, 2-Me, 3,4-diMe
examine the substrate scope (Table 2). First, we studied the R1- and 2-Et) at the aromatic ring produced the corresponding
substituted arylamidines.
A variety of 1,2,5-trisubstituted products in moderate yields (Table 3, entries 1–6). The presence
imidazoles could be obtained by employing various arylami- of electron-withdrawing substituents (2-F, 4-F) reduced the
dines (1) and phenylacetaldehyde (2a) giving 44–85% yields efficiency of the reaction, as the corresponding products could
(Table 2, entries 1–5). Generally, electron donating groups be isolated in slightly lower yields (Table 3, entries 7–8).
substituents (4-Me, 4-MeO) as well as some electron with-
Based on the results and the literature reports,19 a plausible
drawing groups (4-CF3, 2-Cl) provided moderate yields (Table 2, mechanism was proposed as shown in Scheme 2. Initially, the
entries 1–4). In addition, the substrate N-p with the pyridine intermediate A is produced by the condensation reaction of N-
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Table 2 Reactions of amidines 1 with phenylacetaldehyde 2aa
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4
4-Me C6H4
4-CF3 C6H4
2-Cl C6H4
2-Pyridyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
81
85
78
79
44
95
92
90
91
86
86
89
92
91
78
76
72
Scheme 2 Plausible reaction pathway.
Phenyl
4-MeO C6H4
4-Me C6H4
2-Me C6H4
3,4-diMe C6H3
2-Et C6H4
4-F C6H4
4-Cl C6H4
4-Me C6H4
4-Me C6H4
4-Me C6H4
4-Me C6H4
4-Me C6H4
with a catalytic cycle of Iꢁ being oxidized to I2 by TBPB. Then,
a subsequent oxidation of C to give the desired product 3aa.
9
10
11
12
13
14
15
16
17
Phenyl
Phenyl
Conclusion
4-MeO C6H4
4-Me C6H4
(3-Br,4-Me)C6H3
4-Cl C6H4
4-Br C6H4
In conclusion, we have successfully described a practical and
efficient strategy for one-pot synthesis of 1,2,5-triaryl-1H-imid-
azoles which uses I2/TBPB mediated oxidative formal [3 + 2]
cycloaddition of aryl acetaldehydes with amidines. The reaction
is carried out smoothly and the corresponding products are
formed in good to excellent yields with excellent regioselectivity.
Importantly, operational simplicity, inexpensive catalysts, an
excellent functional groups tolerance to the desired compounds
from easily available starting materials. And further studies
with respect to the details on the subject remain in progress.
a
Reaction conditions: 1 (0.20 mmol), 2a (0.24 mmol), I2 (20 mol%),
TBPB(1 eq.), dioxane (2 mL), 100 ꢀC in air for 5 h, unless otherwise
stated. b Isolated yields.
Table 3 Reactions of N-phenylbenzimidamide 1a with aryl acetalde-
hydes 2a
Acknowledgements
We are grateful to the project sponsored by the National Science
Foundation of P. R. China (No. 21372102 and 21403256).
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