A practical metal-free route to 1,2,4,5-tetrasubstituted imidazoles derivatives from the annulation of amidines and β-keto esters

Article abstract of DOI:10.1016/j.tetlet.2017.01.052

A new practical carbon-nitrogen bond formation reaction of amidines with ethyl acetoacetate to synthesize imidazoles via oxidative cyclization in the presence of bromide. The reactions were occured under mild and metal-free conditions.

Full text of DOI:10.1016/j.tetlet.2017.01.052

Accepted Manuscript
A Practical Metal-free Route to 1,2,4,5-Tetrasubstituted Imidazoles Derivatives
from the Annulation of Amidines and β-Keto esters
Xueguo Zhang, Ping Wu, Yajie Fu, Fangdong Zhang, Baohua Chen
PII:
S0040-4039(17)30074-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.052
TETL 48555
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 December 2016
14 January 2017
17 January 2017
Please cite this article as: Zhang, X., Wu, P., Fu, Y., Zhang, F., Chen, B., A Practical Metal-free Route to 1,2,4,5-
Tetrasubstituted Imidazoles Derivatives from the Annulation of Amidines and β-Keto esters, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.052
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A Practical Metal-free Route to 1,2,4,5-Tetrasubstituted
Imidazoles Derivatives from the Annulation of Amidines and
β-Keto esters
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Xueguo Zhang,a Ping Wu,a Yajie Fu,a Fangdong Zhang,a and Baohua Chena*

1
Tetrahedron Letters
A Practical Metal-free Route to 1,2,4,5-Tetrasubstituted Imidazoles
Derivatives from the Annulation of Amidines and β-Keto esters
Xueguo Zhang,a Ping Wu,a Yajie Fu,a Fangdong Zhang,a and Baohua Chena*
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, Lanzhou 730000, People’s Republic of China
ARTICLE INFO
ABSTRACT
A new practical carbon−nitrogen bond formation reaction of amidines with ethyl acetoacetate to
synthesize imidazoles via oxidative cyclization in the presence of bromide. The reactions were
occured under mild and metal-free conditions.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Amidines
Highly substituted imidazoles synthesis
C-N bond formation
Green chemistry
Introduction
Recently, construction of C-N bond1 plays a more and more
important role in heterocyclic field2. Metal plays a key role in
the synthesis of heterocyclic ring, but meanwhile it has also
brought us a bad influence. For example, metal pollution for
underground water. This will make the metal-free catalyzed or
transition-metal catalyzed3 "green" synthesis of heterocyclic
applications become increasingly popular.
Imidazoles are important fine chemical raw materials.
Possessing obvious biological and pharmacological activity,
they are mainly used in medicine4 and pesticide5, such as
anticancer6, antibacterial7, antifungal8, antiviral9, antiparasitic10
and antagonistic histamine receptor11. Especially as anticancer
drugs, its research is increasingly active and rapidly developed.
However, there are still some problems to be solved in the
synthesis of imidazole, such as low yield, expensive catalysts
and pollution. Those problems seriously troubled the
development and application of imidazole, so a simple and
efficient synthesis of "green" imidazole12 is still the goal
pursuit by many scientific workers.
Scheme 1. Synthesis of imidazoles derivatives.
Results and discussions
In the past few years, our group reported copper-catalyzed
synthesis of 1,2,4,5-Tetrasubstituted imidazoles13 and zinc-
catalyzed synthesis of multi-substituted imidazoles14 (Scheme
1). Recently, Huo group reported the CBr4 mediated oxidative
C−N bond formation through the reactions of 2-
aminopyridines or 2-aminopyrimidines with β-keto esters or
1,3-diones15. It was found that CBr4 has an excellent
performance in the synthesis of imidazoles, the yield is
favorable and the pollution caused by metal is also avoided.
Encouraged by the above reports, herein we put the CBr4
applied in the synthesis of imidazole in the reaction of
amidines and esters or ketones.
Table 1. Optimization of Reaction Conditions.a

2
Table 2 . Reactions of 2b with amidines 1.a
Yield
[%]b
trace
35
Entry
[Hal]
Loading
Solvent
T (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
NCS
NIS
NIS
2 equiv
2 equiv
3 equiv
2 equiv
1 equiv
2 equiv
2 equiv
1 equiv
1.5 equiv
2 equiv
3 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
MeOH
CH2Cl2
DMSO
MeCN
MeCN
MeCN
MeCN
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
45
43
55
75
nd
72
80
90
CuBr2
NBS
NBS
TBAI
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
Subs
Pro-
duct
Yield
Entry
Ar1
Ar2
trate
1a
1b
1c
(%)b
90
1
2
phenyl
4-CF3C6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-NH2C6H4
4-N(CH3)2C6H4
2-ClC6H4
3-ClC6H4
phenyl
phenyl
phenyl
3ab
3bb
3cb
3db
3eb
3fb
88
75c
80d
25
76
86
84
80
77
0
3
phenyl
4
phenyl
1d
1e
9
trace
43
trace
30
46
5
phenyl
6
phenyl
1f
7
phenyl
1g
1h
3gb
3hb
3ib
40
60
100
8
phenyl
65
74
88
92
90
87
78
72
75
91
70
9
phenyl
1i
1j
aReaction conditions: 1a (0.6 mmol), 2b (0.2 mmol), halide, solvent (1.5
b
10
11
12
13
14
15
16
17
phenyl
3jb
mL), at 80 °C in an oil bath for 5 h, unless otherwise specified. Isolated
yields. cReacting for 3 h. dReacting for 10 h.
1k
1l
3kb
3lb
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-MeC6H4
naphthyl
phenyl
Initially, we used N-phenylbenzimidamide 1a and ethyl
acetoacetate 2b as the model substrates to find the optimal
conditions. Fortunately, the desired product 3ab was obtained
in 72% yield in the presence of CBr4 (1 equiv) in acetonitrile
(MeCN) at 80 °C for 5 h (Table 1, Entry 8 ). Subsequently, we
tried some other halogens. It indicated that CuBr2, N-
iodosuccinimide (NIS) and N-bromosuccinimide (NBS) were
weaker than CBr4, while N-chlorosuccinimide (NCS) or
tetrabutylammonium iodide (TBAI) had little target product
formation (Table 1, Entries 1 - 7). When the loading of CBr4
was added from 1 equiv to 1.5 or 2 equiv, the yield of the
target product was remarkably increased, and when the loading
was increased from 2 equiv to 3 equiv, the yield did not change
obviously (Table 1, Entries 9 - 11). Moreover, we screened the
solvents and found that when toluene, methanol (MeOH) ,
dichloro (CH2Cl2) or dimethylsulfoxide (DMSO) used as the
solvents, the yield was not as high as acetonitrile (Table 1,
Entries 14 - 17). In addition, we also had been systematically
researched on the temperature and reaction time, which
revealed that the reaction performed at 80 °C gave the highest
yield of the imidazole product, and a dramatic decrease in
yield was observed when the reaction temperature was
changed (Table 1, Entries 18 - 21). Both increasing and
decreasing the reaction time resulted in lower yields (Table 1,
Entries 12 - 13 ). Eventually, the best conditions of the reaction
was obtained by using CBr4 (2 equiv) as the oxidant in
acetonitrile at 80 °C for 5 h.
phenyl
1m
1n
1o
1p
1q
3mb
3nb
3ob
3pb
3qb
phenyl
phenyl
phenyl
phenyl
3-Me, 4-
MeC6H3
18
phenyl
73
1r
3rb
19
20
21
4-MeOC6H4
4-BrC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
61
84
79
1s
1t
3sb
3tb
3ub
4-MeC6H4
1u
22
3-Br, 4-MeC6H3
4-MeC6H4
78
1v
3vb
aReaction conditions: 1 (0.6 mmol), 2b (0.2 mmol), CBr4, MeCN (1.5 mL),
at 80 °C in an oil bath for 5 h. bIsolated yields.
Table 3 . Reactions of 1a with β-Keto esters/1,3-diones 2.a
With the optimized conditions in hand, we turned to
investigate the reactivity of amidines 1 and ethyl acetoacetate
2b, (Table 2). To our satisfaction, good to excellent yields of
product 3 from a series of amidines and ethyl acetoacetate
were obtained ranging 61% to 92%, with the exception of 1g,
which may be due to the -NH2 group participated in
condensation with ketones (Table 2, Entries 7 and 8).
Obviously, lower yields were obtained when Ar1 or Ar2
substituted with electron-donating groups than electron-
withdrawing ones at the para-position on benzene ring, but 1b
was an exception (Table 2, Entries 2-6, 10-14, and 18-19).
Furthermore, we studied the effect of steric hindrance on this
reaction. When the position of the substituent was changed, the
yield of the target product was correspondingly dramatically
reduced, which indicated that the steric hindrance was
noticeable (Table 2, Entries 3, 8, 9, 13 and 15). Finally, when
electron and steric hindrances coexisted, electronic effects
predominate over steric effects (Table 2, Entries 20 and 21 ).
aReaction conditions: 1 (0.6 mmol), 2b (0.2 mmol), CBr4, MeCN (1.5 mL),
at 80 °C in an oil bath for 5 h.

3
In addition, we also replaced the 2b. The yield was good to
excellent, ranging from 57% to 85%. When the Ar1 group is
ethyl, the reaction yield is significantly lower than that of Ar1
group is phenyl. It was presumed to be due to the large effect
of ethyl propionylacetate Ar1 group steric hindrance, (table 3,
3ac and 3af). When Ar2 changed, the effect on the reaction
was small (table 3, 3ad and 3ae). Even though 2b changed to
1,3-diones, the yield of the reaction is still very good, (table 3,
3ag and 3ah).
to form intermediate B, while off the Br-. Next, B underwent
one-step intramolecular nucleophilic addition to produce
intermediate C. Then the next step of proton transfer would be
carried out to produce product D. After D went through
dehydration and dehydrogenation was the target product 3ab.A
reacted with isomer 1a' of N-phenylbenzimidamide 1a to form
intermediate B, while off the Br-. Next, B underwent one-step
intramolecular nucleophilic addition to produce intermediate C.
Then the next step of electron transfer would be carried out to
produce
product
D.
At
last,
3ab
In order to further understand the mechanism of the reaction,
can be obtained by deprotonation of D.
we had done some control experiments.
2
Equiv
tetramethylpiperidin-1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-
methylphenol (BHT) were added into the standard reaction
respectively as a radical scavenger. As outlined in Scheme 2.
Fortunately, we could got 3ab in good yields. This indicating
that this reaction should not be a free radical process.When 1a
reacted with intermediate A without CBr4, we can also got 3ab.
This provides further evidence for the feasibility of our
proposed mechanism.
In summary, we have developed a new practical strategy
C−N bond formation reaction of amidines with ethyl
acetoacetate to synthesize imidazoles via oxidative cyclization
in the presence of CBr4. This raw materials and oxidizing
agents are economical for industrially and good yields in
relatively mild conditions of the reaction. It is expected that
this method will assist in synthesis of imidazoles in the
subsequent.
Scheme 2 . Control Experiments.
Procedures
Procedure 3ab: The reactions were carried out in a sealed test
tube. 1a (0.6 mmol), 2b (0.2 mmol), CBr4 (2 equiv), and
MeCN (1.5 mL) were added to the tube with magnetic stirring
bar. The mixture was stirred at 80 oC for 5 h. When the
reaction was completed (detected by TLC), the mixture was
cooled to room temperature. The product 3ab was purified by
column chromatography on silica gel (petroleum ether/EtOAc
= 5:1).
Acknowledgments
Based on the results of our previous work and the literature
that we could consult16, we have made a proper prediction of
the reaction mechanism. As outlined in Scheme 3, we took 1a
and 2b as examples. Firstly, the isomer product 2b' of ethyl
acetoacetate 2b forms ethyl 2-bromo-3-oxopropanoate A under
the oxidant CBr4, accompanied by the release of HCBr3.
Then A reacted with isomer 1a' of N-phenylbenzimidamide 1a
We are sincerely grateful for sponsorship of this project by
the National Natural Science Foundation of China (Nos.
21372102).
References and notes
1
2
a) Bloch, R. Chem. Rev. 1998, 98, 1407; b) Friestad, G. K.; Mathies, A.
K. Tetrahedron 2007, 63, 2541; c) Xie, J.; Jiang, H.; Cheng, Y.; Zhu, C.
Chem. Commun. 2012, 48, 979; d) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541; e) Sakamoto, M.; Shimizu, I.; Yamamoto, A.
Bull. Chem. Soc. Jpn. 1996, 69, 1065.
a) Field, L. D.; Messerle, B. A.; Vuong, K. Q.; Turner, P. Organomet.
2005, 24, 4241; b) Burling, S.; Field, L. D.; Li, H. L.; Messerle, B. A.;
Turner, P. Eur. J. Inorg. Chem. 2003, 2003, 3179; c) Wang, Y.; Robinson,
G. H. Inorg. Chem. 2014, 53, 11815; d) Field, L. D.; Messerle, B. A.;
Vuong, K. Q.; Turner, P. Organomet. 2005, 24, 4241; e) Díez-González,
S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612; f) Herrmann,
W. A. Angew. Chem. Int. Ed. 2002, 41, 1290; g) Enders, D.; Niemeier,
O.; Henseler, A. Chem. Rev. 2007, 107, 5606.
3
a) Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1698; b) Ackermann, L.
Chem. Rev. 2011, 111, 1315; c) Li, G. Y. Angew. Chem. 2001, 113, 1561;
d) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780; e)
Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola, N.; List, B. Angew.
Chem. 2005, 117, 110; f) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.;
Williams, V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161;
Scheme 3 . Proposed Mechanism.

4
g) Karimi, B.; Biglari, A.; Clark, J. H.; Budarin, V. Angew. Chem. Int. Ed.
2007, 46, 7210.
Chem. 1995, 38, 266; c) Stark, H.; Hüls, A.; Ligneau, X.; Purand, K.;
Pertz, H.; Arrang, J. M.; Schwartz, J. C.; Schunack, W. Arch. Pharm.
1998, 331, 211.
4
a) Gottlieb, J. A.; Baker, L. H.; Quagliana, J. M.; Luce, J. K.; Whitecar,
J. P.; Sinkovics, J. G.; Rivkin, S. E.; Brownlee, R.; Frei, E. Cancer 1972,
30, 1632; b) Tai, H.-H.; Yuan, B. Biochem. Biophys. Res. Commun.
1978, 80, 236; c) Costanza, M. E.; Nathanson, L.; Lenhard, R.; Wolter,
J.; Colsky, J.; Oberfield, R. A.; Schilling, A. Cancer 1972, 30, 1457; d)
Goldman, R. L.; Jones, S. E.; Heusinkveld, R. S. Cancer 1977, 39, 1955.
a) Pence, R. J. J. Econ. Entomol. 1963, 56, 1; b) Pilling, E.;
Bromleychallenor, K.; Walker, C.; Jepson, P. Pestic. Biochem. Physiol.
1995, 51, 1.
12 a) Heravi, M. M.; Derikvand, F.; Bamoharram, F. F. J. Mol. Catal. A:
Chem. 2007, 263, 112; b) Davoodnia, A.; Heravi, M. M.; Safavi-Rad, Z.;
Tavakoli-Hoseini, N. Synth. Commun.® 2010, 40, 2588; c) Sharma, S.
D.; Hazarika, P.; Konwar, D. Tetrahedron Lett. 2008, 49, 2216; d)
Sharma, G.; Jyothi, Y.; Lakshmi, P. S. Synth. Commun. 2006, 36, 2991.
13 Wu, P.; Qu, J.; Li, Y.; Guo, X.; Tang, D.; Meng, X.; Yan, R.; Chen, B.
Adv. Synth. Catal. 2015, 357, 3868.
14 Qu, J.; Wu, P.; Tang, D.; Meng, X.; Chen, Y.; Guo, S.; Chen, B. New J.
Chem. 2015, 39, 4235.
15 Huo, C.; Tang, J.; Xie, H.; Wang, Y.; Dong, J. Org. Lett. 2016, 18, 1016.
16 a) Tang, D.; Wang, J.; Wu, P.; Guo, X.; Li, J.-H.; Yang, S.; Chen, B.-H.
RSC Adv. 2016, 6, 12514; b) Liu, X.; Wang, D.; Chen, Y.; Tang, D.;
Chen, B. Adv. Synth. Catal.2013, 355, 2798.
5
6
7
Liu, J.; Lee, H.; Huesca, M.; Young, A.; Allen, C. Cancer Chemother.
Pharmacol. 2006, 58, 306.
a) Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.; Ursini,
A. Bioorg. Med. Chem. Lett. 1999, 9, 1023; b) Heerding, D. A.; Chan,
G.; DeWolf, W. E.; Fosberry, A. P.; Janson, C. A.; Jaworski, D. D.;
McManus, E.; Miller, W. H.; Moore, T. D.; Payne, D. J. Bioorg. Med.
Chem. Lett. 2001, 11, 2061; c) Bossche, H. V.; Lauwers, W.; Willemsens,
G.; Marichal, P.; Cornelissen, F.; Cools, W. Pestic. Sci. 1984, 15, 188.
a) Bossche, H. V.; Lauwers, W.; Willemsens, G.; Marichal, P.;
Cornelissen, F.; Cools, W. Pestic. Sci. 1984, 15, 188; b) Rodrigues, A.;
Gibson, G.; Ioannides, C.; Parke, D. Biochem. Pharmacol. 1987, 36,
4277.
a) Sharma, D.; Narasimhan, B.; Kumar, P.; Judge, V.; Narang, R.; De
Clercq, E.; Balzarini, J. Eur. J. Med. Chem. 2009, 44, 2347; b)
Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S.
Heterocycles 1998, 9, 1887; c) Starčević, K.; Kralj, M.; Ester, K.; Sabol,
I.; Grce, M.; Pavelić, K.; Karminski-Zamola, G. Bioorg. Medi. Chem.
2007, 15, 4419; d) Chien, T.-C.; Saluja, S. S.; Drach, J. C.; Townsend, L.
B. J. Med. Chem. 2004, 47, 5743.
8
9
Supplementary Material
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process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
10 a) Soeiro, M. N.; De Souza, E.; Stephens, C. E.; Boykin, D. Expert Opin.
Inv. Drug. 2005, 14, 957; b) Athri, P.; Wenzler, T.; Ruiz, P.; Brun, R.;
Boykin, D. W.; Tidwell, R.; Wilson, W. D. Bioorg. Medi. Chem. 2006,
14, 3144.
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11 a) Ash, A.; Schild, H. Br. J. Pharmacol. Chemother. 1966, 27, 427; b)
Vollinga, R. C.; Menge, W. M.; Leurs, R.; Timmerman, H. J. Med.
Highlights
Presents a new practical way to synthesize imidazoles with the
pollution caused by metal is also avoided.
The reactions were occured under mild and metal-free conditions.
The reaction has a good tolerance of different groups to obtain our
desired product.