DMAP-Catalyzed C—N Bond Formation for Diverse Synthesis of Imidazo[1,2-a]pyrimidine and Pyrimido[1,2-a]benzimidazole Derivatives

Article abstract of DOI:10.1002/cjoc.202000214

A DMAP (2-dimethylaminopyridine)-catalyzed condensation reactions for the successful direct construction of pyrimido[1,2-a]benzimidazole or imidazo[1,2-a]pyrimidine has been developed. The method utilizes readily available α-bromocinnamaldehydes with 2-am

Full text of DOI:10.1002/cjoc.202000214

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: DMAP-Catalyzed C-N Bond Formation for the Diverse Synthesis of
Imidazo[1,2-a]pyrimidine and Pyrimido[1,2-a]benzimidazole Derivatives
Authors: Le-Le Shang, Yun Feng, Xing-Lian Gao, Zi-Ren Chen, Yu Xia, Wei-Wei Jin
and Chen-Jiang Liu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000214.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000214.
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Chinese Journal
of Chemistry
DMAP, C-N Bond, Fused Heterocyclic, Pyrimido[1,2-a]benzimidazoles,
Imidazo[1,2-a]pyrimidines,
Report
CJC
中
国 化 学 - An International Journal
DMAP-Catalyzed C-N Bond Formation for the Diverse Synthesis of
Imidazo[1,2-a]pyrimidine and Pyrimido[1,2-a]benzimidazole Derivatives
Le-Le Shang, Yun Feng, Xing-Lian Gao, Zi-Ren Chen, Yu Xia, Wei-Wei Jin and Chen-Jiang Liu*
The Key Laboratory of Oil and Gas Fine Chemicals, Ministry of Education & Xinjiang Uygur Autonomous Region, Urumqi Key Laboratory of Green Catalysis
and Synthesis Technology, School of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, P. R. China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion
A DMAP-catalyzed condensation reactions for the successful direct construction of
pyrimido[1,2-a]benzimidazole or imidazo[1,2-a]pyrimidine has been developed. The method utilizes readily available α-bromocinnamaldehydes with
2-aminobenzimidazole or 2-aminoimidazole as starting materials in the presence of 2-DMAP/TBHP. In the process, two C-N bonds were successfully
constructed to synthesize target compounds. The current method features wide substrate scope, product diversification, and metal-free conditions.
imidazo[1,2-a]pyrimidine compounds, and a series of eminent
Background and Originality Content
Nitrogen-containing fused heterocyclic compounds are
important organic compounds. They are core structural fragments
approaches have been developed.[9] In 2019, Chai searched a
highly efficient one-pot method for the synthesis of fused
pyrimido[1,2-a]benzimidazoles from 2-aminobenzoimidazole,
in various of natural products, pharmaceutical molecules, and
functional Among them, the
materials.[1]
pyrimido[1,2-a]benzimidazole and imidazo[1,2-a]pyrimidine
skeleton are related to the pharmacological activity of related
drugs. For example, anticancer activity drugs, anxiolytic drugs,
anti-inflammatory activity drugs, the HCV inhibitor and the PET
tracer in imaging of Tau Pathologies.[2-7] More generally,
pyrimido[1,2-a]benzimidazole derivatives also behave as
antimicrobial agent drugs.[8] Moreover, the imidazo[1,2 ‑
a]pyrimidine motif has shown biological activities (Figure 1).
benzaldehyde and propiolic acid. (Scheme 1a).[10] Next, the
Scheme 1. Synthetic Approaches to Pyrimido[1,2-a]benzimidazole Scaffolds
from Benzimidazole Precursors
work:
Privious
a)
H
N
NH2
N
N
N
CuI
K2CO
mol%)
eq.)
N
N
(10
3 (1.2
N
N
CH2OH
Ph
DMSO, 110 o 12 h
C,
Ph
Ph
N
H
COOH
18F
Ph
N
N
b)
O
N
N
N
N
N
R1
Activating
Agent
N
18F]-T808
N
N
[
EtO
H
PET
for
agent
imaging
MeCN/MeTHF
(1:1)
0-70 o 3 h
Ph
O
N
O
Ph
N
R2
visualization of tau
N
plaques
S
Ar
OCH
CN
H2N
3(H)
3(H)
C,
N
N
N
N
Ph
N
O
R
C)
N
N
O
OCH
NHC
K2HPO
o
mol%)
(10
N
O
N
N
eq.)
4 (1.5
and
anticancer
analgesic
/anti-inflammatory activities
R
H
R1
NH2
NH
N
N
N
anticancer activity
N
H
rt
4A MS, acetone,
Br
R1
work:
This
N
TBHP
OH
O
eq.)
mol%)
N
(1.4
O
N
N
N
2-DMAP
(20
R1
NH2
R2
N
N
R2
R
R1
120 o 4 h
C,
N
O
1,4-Dioxane,
N
N
H
X
N
X
R
NH
N
=
X
Br, Cl
O
N
N
N
antiinflammatory activity
HCV Inhibitor
N
O
Gosselin group also reported that activation of the acrylamide
N
with POCl3 combined with the use of different N-phosphorylation
Fasiplon
anxiolytic drugs
of aminoimidazole products providing
a
string of
pyrimido[1,2-a]benzimidazole derivatives (Scheme 1b).[11] In 2020,
Wang proposed NHC-catalyzed [3+3] cyclization reaction, the raw
materials of which were 2-aminobenzimidazole and
α-bromoenals (Scheme 1c).[12] Although these protocols have
some great advantages, they still have some limitations. For
Figure 1. Typical Pyrimido[1,2-a]benzimidazole and
Imidazo[1,2-a]pyrimidine scaffolds.
As a result, Many people have put a great number of effort in
preparing
pyrimido[1,2-a]benzimidazole
and
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through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000214
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Shang et al.
Report
example, severe conditions, narrow substrate range, toxic metal
salt catalysts, which may restrict their wide applications in natural
product synthesis. Therefore, the development of a simple, direct,
and mild reaction system for the generation of
pyrimido[1,2-a]benzimidazole and imidazo[1,2-a]pyrimidine
skeleton is still highly desirable. DMAP is a commonly used
organic base, but it also can be used as a catalyst or promoter for
organic reactions. [13-14] Therefore, we propose a new method, the
new method utilizes readily available α-bromocinnamaldehyde,
2-aminobenzimidazole and 2-aminoimidazole as starting
materials in the presence of 2-DMAP/TBHP. The method features
wide substrate scope, product diversification, and metal-free
conditions.
9
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
2-DMAP
TBHP
H2O2
toluene
120
120
120
120
130
110
120
120
120
120
120
35
26
37
18
58
56
58
57
40
57
10
10
11
12
13
14
15c
16d
17e
18f
19
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
K2S2O8
m-CPBA
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
-
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), base (20 mol%),
b
c
oxidant (1.4 eq.), solvent (2.0 mL), under air, 4 h. Isolated yields.
2-DMAP (10 mol %), d 2-DMAP (30 mol %). e TBHP (1.0 eq.), f TBHP (2.0
eq.).
Results and Discussion
The reaction of α-bromocinnamaldehyde (1a) and
o
2-aminobenzimidazole (2a) at 120 C in the presence of 4-DMAP
and TBHP in 1,4-dioxane gave the target product 3a in 46% yield
(Table 1, entry 1). Subsequently, other bases such as Et3N, Cs2CO3,
t-BuONa, and 2-DMAP were examined (Table 1, entries 1-5), and
2-DMAP showed the best result to obtain the product 3a in 83%
yield (Table 1, entry 5). Besides, various oxidants and solvents
were screened (Table 1, entries 6-12). Further exploration of
TBHP and 1,4-dioxane were shown to be an ideal oxidant and
medium (Table 1, entry 5, 83% yield). Increasing the temperature
to 130 oC did not afford a good yield (Table 1, entry 13). The yield
declined when the temperature was decreased to 110 oC (Table 1,
entry 14). Further optimization of using 2-DMAP as the base
showed that the reaction efficiency was obviously affected by the
amount of base catalyst. The yields of 3a were obtained in 58%
and 57% when the catalyst loading was reduced to 10 mol% or
increased to 30 mol% (Table 1, entries 15 and 16). The amounts of
TBHP did not affect the reaction efficiency, however the yield of
the reaction decreased when the amount of catalyst was reduced
(Table 1,entries 17-18). In addition, blank experiments showed
that the oxidant played an indispensable role in the cyclization
process (Table 1, entry 19). Therefore, the reaction conditions of
entry 5 proved to be optimal.
Under the first-rank conditions, the scope of this
α-bromocinnamaldehyde and 2-aminobenzimidazole was
explored (Scheme 2). The structure of products 3a and 3l were
further proved by X-ray crystallography. Generally, a string of
electron-rich (Me, MeO, N(CH3)2) and electron-absorbing (F, Cl, Br,
CF3, NO2) substituted α-bromocinnamaldehydes 1 were good
substrates and produced target products (3a-3n) with moderate
to good yields (26-83%). The aliphatic derivatives (1o) and
heteroaryl derivatives (1p) also reacted smoothly with
2-aminobenzimidazole (2a) to give the corresponding products in
moderate yields. Notably, α-chlorocinnamaldehyde (1q) also
reacted smoothly with 2-aminobenzimidazole (2a) to afford the
target product in 18% yield. The scope of 2-aminobenzimidazole
was further studied. The electron-withdrawing groups (F, CF3)
substituted 2-aminobenzimidazoles 2 can also obtain the target
products in moderate yields (3r-3s). Surprisingly, the phenyl
substituted α-bromocinnamaldehydes
1 can also smoothly
reacted with 2-aminobenzimidazole 2a and produced the target
products in moderate yields (3t-3u).
Scheme 2 Substrate Scope a
N
Table 1 Screen of Reaction Conditions a
TBHP
eq.)
mol%)
N
(1.4
(20
O
N
R1
2-DMAP
N
R2
NH2
R2
R1
N
120 o 4 h
X
R4
N
H
N
1,4-dioxane
(2 mL),
C,
O
X
N
conditions
=
X
Br, Cl
N
NH2
H
=
R1
Ph
H,
R4
N
Br
Br
1
2
3
H
1a
2a
3a
Yieldb
(%)
Entry
Base
Oxidant
Solvent
T (oC)
1
2
3
4
5
6
7
8
4-DMAP
Et3N
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
EtOAc
120
120
120
120
120
120
120
120
46
52
10
36
83
32
48
44
Cs2CO3
t-BuONa
2-DMAP
2-DMAP
2-DMAP
2-DMAP
THF
DCE
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
Br
Br
OCH3
OCH3
N
Y
Cl
,
=
=
=
CCDC: 1984213
3b: Y
3c: Y
3d: Y
CH3 53%
,
OCH3 56%
3a:
3e: 75%
83%
=
=
5c:
Z
=
=
%
,74
5a:
X
X
Br, 60%
Cl, 49%
N(CH3)2
5d: Z Cl, 60%
,
5b:
5e:
90%
81%
N
26%
N(CH3)2
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
Br
Br
Br
Cl
Cl
Y
=
Y
CF3
74%
F3C
Br
,
=
Br 46%
,
3f: Y
3g:
F
57%
Y
3j:
3h:
3i:
39%
54%
,
,
=
=
Y
Cl 50%
3k: Y NO2 33%
=
5h: Z
CF3, 67%
5f: 64%
31%
5j:
,
5g:
=
5i: Z NO2
70%
N
N
N
N
N
N
N
N
N
N
N
N
Br
Br
Br
NO2
O
CF3
37%
F3C
3l:
3m:
3n:
36%
45%
N
CCDC: 1984211
5k:
Trace
N
N
N
N
N
F3C
a Reaction conditions: 1 (0.3 mmol), 4a (0.6 mmol), 2-DMAP (20 mol%), TBHP
N
N
N
N
N
N
(1.4 eq.), 1,4-dioxane (2.0 mL), under air, 4 h.
Cl
Br
Br
O
Br
In order to test the practicability of this method, we
conducted gram scale reaction. Our catalytic reaction could also
be performed on gram scale with the desired product 3a in good
yield (Scheme 4a). We also conducted a gram scale reaction of 5a
in Scheme 4b. No significant reduction in yield was observed
under gram-scale conditions. Due to the compatibility of bromine
in the reaction, this leaves a modification site, so we then
connected 3-bromo-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine
3a and phenylboronic acid together through the Suzuki-Miyaura
reaction, producing a new compound which has potential new
bioactivity (Scheme 4c).
3o: 22%
14%
3r:
19%
18%
3q:
3p:
N
N
F
N
N
N
N
Br
Br
Y
3t: Y
3u: Y
=
=
CH3, 64%
3s:
45%
F
46%
,
a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), 2-DMAP (20 mol%),
TBHP (1.4 eq.), 1,4-dioxane (2 mL), under air, 4 h.
Scheme 4 Gram-Scale Reaction and Derivatization Reaction
a)
Interestingly, the reaction of α-bromocinnamaldehydes (1)
with 2-aminoimidazole (4a) was conducted to form a set of
imidazo[1,2-a]pyrimidine derivatives (5) (Scheme 3). Under
optimal conditions, a series of α-bromocinnamaldehydes with
electron-withdrawing (Cl, Br, CF3, NO2) or electron-rich (MeO,
N(CH3)2) groups attached to the phenyl ring were all fitting for this
transformation, and the corresponding imidazo[1,2-a]pyrimidine
compounds were generated in good yields (5a－5i). Satisfactory
result was obtained for the phenyl substituted products 5j. It is
also regrettable that when the phenyl ring of reactant 1a was
replaced by a heteroaromatic ring, only a trace amount of
product is detected.
TBHP
eq.)
(1.4
2-DMAP
N
N
O
N
mol%)
(20
N
NH2
H
N
H
120 o 4 h
C,
Br
Br
1,4-Dioxane
(32 mL),
mmol)
mmol)
1a
2a
3a
(1.0405 g),
9.6
66%
(
yield
(4.8
b)
TBHP
eq.)
(1.4
N
N
O
2-DMAP
mol%)
(20
N
N
NH2
H
N
H
120 o 4 h
C,
Br
1,4-Dioxane
(24 mL),
Scheme 3 Substrate Scope a
mmol)
mmol)
1a
4a
5a
51%
yield
(3.6
(7.2
(0.3618 g),
N
TBHP
eq.)
(1.4
(20
N
O
c)
N
R1
R3
2-DMAP
mol%)
N
NH2
R1
Ph P
mol%)
(10
3
R5
N
H
o
N
N
120
4 h
C,
1,4-dioxane
X
(2 mL),
N
N
K2CO
eq.)
3 (2.0
=
X
Br, Cl
mol%)
N
N
Pd(OAc)2 (10
B(OH)2
=
R1
Ph
R5
H,
Br
THF
MeOH
70 o 15 h
C,
(1mL),
(1mL),
1
4a
5
3a
6
7
46%
(0.2mmol)
(0.4mmol)
yield
We conducted control experiments to gain
a
deeper
Chin. J. Chem. 2019, 37, XXX－XXX
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Shang et al.
Report
understanding of the reaction mechanism (Scheme 5). Under the
action of radical inhibitors, the efficiency of the model reaction
was not completely except with TEMPO, indicating that an ionic
process maybe involved in this reaction (Scheme 5a). The radical
scavengers TEMPO and BHT were engaged in this reaction, but
the reactions were not significantly inhibited when 2.0 equiv of
TEMPO or BHT was used. When 2.0 equiv of 1,4-benzoquinone
was added to the reaction mixture, 3a was detected in 23% yield
(Scheme 5b). The outcome further suggested that this reaction
was not a radical process. In order to test the electronic effect of
1 on the reaction, we conducted a competition experiment and
found that the electron-donating group was beneficial to the
reaction (Scheme 5c).[15]
H2N
R
X
O
N
H
N
2-DMAP
R1
N
N
R
R1
N
-H
R2
2O
X
R2
1
2
H
A
=
X
Br, Cl
X
N
R
X
H
R
-2H+
R1
N
N
R1
N
TBHP
R2
N
R2
H
N
3
B
Scheme 5 Mechanistic Studies
Radical
trapping experiments
a)
According to the results of control experiments and literature
report, a plausible reaction mechanism was proposed in Scheme
6.[16,17] First of all, the imine intermediate A is formed by the
condensation of 1 and 2 in the presence of 2-DMAP which is
converted into intermediate B through a rapid intramolecular
cyclization reaction. Finally, the corresponding product
pyrimido[1,2-a]benzimidazole 3 is conveniently obtained by
aromatization to emit a molecule of H2O in the presence of TBHP
(Scheme 6).
TBHP
N
N
O
N
N
2-DMAP
N
NH2
H
120 o 4 h
C,
Br
1,4-dioxane,
Br
H
1a
2a
3a
Radical scavengers
(eq.)
Entry
Yield of 3a (%)
1
2
3
TEMPO (2.0)
Trace
58%
64%
BHT (2.0)
Conclusions
1,1-diphenylethylene (2.0)
trapping experiments
In conclusion, we described a mild and environmentally
Radical
b)
friendly
reaction
system
for
or
the
synthesis
of
TBHP
pyrimido[1,2-a]benzimidazole
imidazo[1,2-a]pyrimidine
N
N
O
N
2-DMAP
derivatives through the DMAP-catalyzed condensation of
α-bromocinnamaldehyde compounds with 2-aminobenzimidazole
or 2-aminoimidazole compounds. The process constructed two
new C-N bonds. It was an useful supplement to enrich and
develop the synthetic methods of pyrimido[1,2-a]benzimidazole
and imidazo[1,2-a]pyrimidine compounds.
N
NH2
H
120 o 4 h
C,
N
H
1,4-dioxane,
Br
1a
4a
5a
Radical scavengers
(eq.)
Entry
Yield of 5a (%)
Experimental
1
2
3
TEMPO (2.0)
56%
58%
23%
BHT (2.0)
Unless otherwise stated, all reagents and solvents were
purchased from commercial suppliers and used without further
1,4-benzoquinone (2.0)
1
purification. H NMR and 13C NMR spectra were recorded at 400
experiment
c) Competition
N
N
MHz NMR spectrometer using CDCl3 as solvent and TMS as an
internal standard.
N
N
O
H
O
N
N
mmol)
2a
(0.6
Standard conditions
Br
Br
H
Br
Br
Br
=
3b 3j 1:1.2
H3C
/
Supporting Information
H3C
Br
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
mmol)
mmol)
(0.3
:
:
3j
35%
1b
1j
3b
39%
(0.3
Scheme 6 A proposed mechanism
Acknowledgement
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21961037, 21702175 and 21572195).
References
[1] (a) Butler, M. S. The Role of Natural Product Chemistry in Drug
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Discovery. J. Nat. Prod. 2004, 67, 2141-2149; (b) Enguehard-Gueiffier,
Cherkasov, R. A.; Fomum, Z. T.; Doepp, D. Heterocycles of Biological
C.; Gueiffier, A. Recent Progress in the Pharmacology of
Imidazo[1,2-a]pyridines. Mini-Rev. Med. Chem. 2007, 7, 888-899; (c)
Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Yang, Q.-Q.; Liu, X.-P.; Li, Y.; Deng,
Q.-H.; Chen, J.-R.; Xiao, W.-J. Highly Enantioselective Friedel-Crafts
Alkylation/N-Hemiacetalization Cascade Reaction with Indoles.
Angew. Chem. Int. Ed. 2013, 52, 3350-3254.
Importance: Part 8. Formation of Pyrimido[1,2-a]benzimidazoles and
Oxazolo[3,2-a]benzimidazoles
by
Conjugate
Addition
of
2-Aminobenzimidazoles to 4-Hydroxy-2-alkynenitriles. Arkivoc. 2004,
i, 130-137; (c) Kiselyov, A. S.; Smith, L. Novel One Pot Synthesis of
Polysubstituted Pyrazolo[1,5-a]-and Imidazo[1,2-a]pyrimidines.
Tetrahedron Lett. 2006, 47, 2611-2614; (d) Zhang, Z.; Qiu, L.; Xue, D.;
[2] Zhang, W.; Arteaga, J.; Cashion, D. K.; Chen, G.; Gangadharmath, U.;
Gomez, L. F.; Kasi, D.; Lam, C.; Liang, Q.; Liu, C.; Mocharla, V. P.; Mu,
F.; Sinha, A.; Szardenings, A. K.; Wang, E.; Walsh, J. C.; Xia, C.; Yu, C.;
Zhao, T.; Kolb, H. C. A Highly Selective and Specific PET Tracer for
Imaging of Tau Pathologies. J. Alzheimers Dis. 2012, 31, 601-612.
[3] El-Shekeil, A.; Obeid, A. O.; Al-Aghbari, S. Anticancer Activity Studies
of Some Cyclic Benzimidazole Derivatives. Eur. J. Chem. 2012, 3,
356-358.
[4] (a) Seth, P. P.; Miyaji, A.; Jefferson, E. A.; Sannes-Lowery, K. A.;
Osgood, S. A.; Propp, S. S.; Ranken, R.; Massire, C.; Sampath, R.;
Ecker, D. J.; Swayze, E. E.; Griffey, R. H. SAR by MS: Discovery of a
New Class of RNA-Binding Small Molecules for the Hepatitis C Virus:
Internal Ribosome Entry Site IIA Subdomain. J. Med. Chem. 2005, 48,
7099-7102; (b) Parsons, J.; Castaldi, M. P.; Dutta, S.; Dibrov, S. M.;
Wyles, D. L.; Hermann, T. Conformational Inhibition of the Hepatitis
C Virus Internal Ribosome Entry Site RNA. Nat. Chem. Biol. 2009, 5,
823-825; (c) Kojima, T.; Mochizuki, M.; Takai, T.; Hoashi, Y.;
Morimoto, S.; Seto, M.; Nakamura, M.; Kobayashi, K.; Sako, Y.;
Tanaka, M.; Kanzaki, N.; Kosugi, Y.; Yano, T.; Aso, K. Discovery of
1,2,3,4-Tetrahydropyrimido[1,2-a]benzimidazoles as Novel Class of
Corticotropin Releasing Factor 1 Receptor Antagonists. Bioorg. Med.
Chem. 2018, 26, 2229-2250.
Wu,
J.;
Xu,
F.
Concise
Synthesis
of
2,3-Diarylpyrimido[1,2-a]benzimidazole Based on Isoflavones. J.
Comb. Chem. 2010, 12, 225-230; (e) Majumder, S.; Odom, A. L.
Titanium Catalyzed One-pot Multicomponent Coupling Reactions for
Direct Access to Substituted Pyrimidines. Tetrahedron 2010, 66,
3152-3158; (f) Herath, A.; Dahl, R.; Cosford, N. D. P. Fully Automated
Continuous Flow Synthesis of Highly Functionalized Imidazo[1,2-a]
Heterocycles. Org. Lett. 2010, 12, 412-415; (g) Chen, C.; Yellol, G. S.;
Lin, P.; Sun, C. Base-Catalyzed Povarov Reaction: An Unusual [1,3]
Sigmatropic Rearrangement to Dihydropyrimidobenzimidazoles. Org.
Lett. 2011, 135, 5120-5123; (h) Povalyakhina, M. A.; Antonov, A. S.;
Dyablo, O.; Ozeryanskii, V. V. A.; Pozharskii, A. F. H-Bond-Assisted
Intramolecular Nucleophilic Displacement of the 1-NMe2 Group in
1,8-Bis(dimethylamino)naphthalenes as a Route to Multinuclear
Heterocyclic Compounds and Strained Naphthalene Derivatives. J.
Org. Chem. 2011, 76, 7157-7166; (i) Saleh, T. S.; Eldebss, T. M.;
Albishri, H. M. Ultrasound Assisted One-pot, Three-components
Synthesis
of
Pyrimido[1,2-a]benzimidazoles
and
Pyrazolo[3,4-b]pyridines: A New Access via Phenylsulfone Synthon.
Ultrason. Sonochem. 2012, 19, 49-55; (j) Shang, E.; Zhang, J.; Bai, J.;
Wang, Z.; Li, X.; Zhu, B.; Lei, X. Syntheses of
[1,2,4]Triazolo[1,5-a]benzazoles
Enabled
by
the
[5] Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. 2-(O
xadiazoly1)-and 2-(Thiazolyl)imidazo[1,2-a]pyrimidines as Agonists
and Inverse Agonists at Benzodiazepine Receptors. J. Med. Chem.
1991, 34, 2060-2067.
[6] Bharate, S. B.; Mahajan, T. R.; Gole, Y. R.; Nambiar, M.; Matan, T. T.;
Kulkarni-Almeida, A.; Balachandran, S.; Junjappa, H.; Balakrishnan, A.;
Transition-metal-free Oxidative N-N Bond Formation. Chem.
Commun. 2016, 52, 7028-7031; (k) Li, C.; Zhang, W.-T.; Wang, X.-S.
CuI-Catalyzed C-N Bond Formation and Cleavage for the Synthesis of
Benzimidazo[1,2-a]quinazoline Derivatives. J. Org. Chem. 2014, 79,
5847-5851; (l) Mehranpour, A. M.; Zahiri, M. Synthesis and
Characterization of New Benzimidazole Derivatives Using
Vishwakarma,
R.
A.
Synthesis
and
Evaluation
of
2-Substituted
1,3-Bis(dimethylamino)-trimethinium
Salts.
Pyrazolo[3,4-b]pyridines and Its Structural Analogues as TNF-alpha
and IL-6 Inhibitors. Bioorg. Med. Chem. 2008, 16, 7167-7176.
Tetrahedron Lett. 2014, 55, 3969-3971; (m) Kumar, A.; Kumar, M.;
Maurya, S.; Khanna, R. S. Regioselective Synthesis of Fused
[7] (a) Shaaban, M. R.; Saleh, T. S.; Mayhoub, A. S.; Farag, A. M. Single
Step Synthesis of New Fused Pyrimidine Derivatives and Their
Evaluation as Potent Aurora-A kinase Inhibitors. Eur. J. Med. Chem.
2011, 46, 3690-3695; (b) Shaaban, M. R.; Saleh, T. S.; Mayhoub, A. S.;
Mansour, A.; Farag, A. M. Synthesis and Analgesic/Anti-inflammatory
Evaluation of Fused Heterocyclic Ring Systems Incorporating
Phenylsulfonyl moiety. Bioorg. Med. Chem. 2008, 16, 6344-6352.
[8] (a) Abdelhamid, A. O.; Abdelall, E. K. A.; Abdel-Riheem, N. A. Ahmed,
S. A. Synthesis and Antimicrobial Activity of Some New
Imidazo[1,2-a]pyrimidines
Formation/6-Endo-Dig Cycloisomerization. J. Org. Chem. 2014, 79,
6905-6912; (n) Liu, Y.; Xia, G.; Luo, C.; Sun, J.; Ye, B.; Yuan, Y.; Wang,
via
Intramolecular
C-N
Bond
H.
One-step
Synthesis
of
Alkyl
under
2-Chloropyrimido[1,2-a]benzimidazole-3-carboxylates
Catalyst-free: Combined Experimental and Computational Studies.
Tetrahedron Lett. 2015, 56, 5071-5075; (o) Shinde, V. V.; Jeong, Y. T.
Molybdate Sulfuric Acid (MSA): an Efficient Solid Acid Catalyst for the
Synthesis
of
Diversely
Functionalized
Fused
5-Arylazothiazole,
Pyrazolo[1,5-a]Pyrimidine,
Imidazo[1,2-a]pyrimidines under Solvent-free Conditions. New J.
Chem. 2015, 39, 4977-4986; (p) Kumar, P.; Singh, A. K.; Bahadur, V.;
Len, C.; Richards, N. G. J.; Parmar, V. S.; Vander Eycken, E. V.; Singh, B.
K. Microwave-Assisted, Metal-Free, Base-Mediated C-N Bond
Formation/Cleavage: Synthesis of Benzimidazo[1,2-a]quinazoline
Derivatives. ACS Sustain. Chem. Eng. 2016, 4, 2206-2210; (q) Rao, C.;
Mai, S.; Song, Q. Cu-Catalyzed Synthesis of 3-Formyl
Imidazo[1,2-a]pyridines and Imidazo[1,2-a]pyrimidines by Employing
Ethyl Tertiary Amines as Carbon Sources. Org. Lett. 2017, 19,
[1,2,4]Triazolo[4,3-a]Pyrimidine, and Pyrimido[1,2-a]Benzimidazole
Derivatives Containing the Thiazole Moiety. Phosphorus Sulfur Silicon
Relat. Elem. 2010, 185, 709-718; (b) Farghaly, T. A.; Abdallah, M. A.;
Aziz, M. R. Synthesis and Antimicrobial Activity of Some New
1,3,4-Thiadiazole derivatives. Molecules 2012, 17, 14625-14636.
[9] (a) Tseng, S. S.; Epstein, J. W.; Brabander, H. J.; Francisco, G. A Simple
Regioselective Synthesis of Pyrimido [1,2-a]Benzimidazoles. J.
Heterocycl. Chem. 1987, 24, 837-843; (b) Wahe, H. Asobo, P.;
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Shang et al.
Report
4726-4729; (r) Foley, C.; Shaw, A.; Hulme, C. Oxidative Deaminations
W. A.; O'Shea, P. D.; Zhang, H.; Gosselin, F. Phosphoramidates as
Steering Elements for Highly Selective Access to Complementary
Imidazo[1,2-a]pyrimidine Isomers. Org. Lett. 2019, 21, 9527-9531.
[12] Xie, Y.; Li, L.; Sun, S.; Wu, Z.; Lang, M.; Jiang, D.; Wang, J.
and Deisatinylations of Ugi-Azide and Ugi-3CR Products: A Two-Step
MCR-Oxidation Protocol toward Functionalized α-Ketoamides and
α-Ketotetrazoles. Org. Lett. 2017, 19, 2238-2241; (s) Ho, S.; Dao, P.;
Cho,
C.
Microwave-Assisted
Synthesis
of
Enantioselective
NHC-Catalyzed
[3+3]
Annulation
of
Benzo[4,5]imidazo[1,2-a]pyrimidines from β-Bromo-α,β-unsaturated
Aldehydes and 2-Aminobenzimidazoles. Synlett 2017, 28, 1811-1815;
(t) Halskov, K. S.; Witten, M. R.; Hoang, G. L.; Mercado, B. Q.; Ellman,
J. A. Rhodium(III)-Catalyzed Imidoyl C-H Activation for Annulations to
Azolopyrimidines. Org. Lett. 2018, 20, 2464-2467; (u) Guo, X.; Hu, J.;
Zhang, M.; Wang, L. Palladium-Catalyzed C(sp2)−H Activation for the
Formation of C-N Bonds: Rapid Access to Benzimidazoquinazolines.
Asian J. Org. Chem. 2019, 8, 417-421; (v) Ye, Z.; Li, Y.; Xu, K.; Chen, N.;
Zhang, F. Cascade pi-Extended Decarboxylative Annulation Involving
Cyclic Diaryliodonium Salts: Site-Selective Synthesis of
Phenanthridines and Benzocarbazoles via a Traceless Directing
Group Strategy. Org. Lett. 2019, 21, 9869-9873; (w) Liu, P.; Yang, M.;
Gong, Y.; Yu, Y.; Zhao, Y.-L. Copper-Catalyzed Cascade Cyclization
Reaction of Enamines and Electron-Deficient Terminal Alkynes:
Synthesis of Polysubstituted Pyrido[1,2-a]indoles. Org. Lett. 2020, 22,
36-40; (x) Hu, Y.; Wang, T.; Liu, Y.; Nie, R.; Yang, N.; Wang, Q.; Li,
G.-B.; Wu, Y. Practical Synthesis of Benzimidazo[1,2-a]quinolines via
Rh(III)-Catalyzed C-H Activation Cascade Reaction from Imidamides
and Anthranils. Org. Lett. 2020, 22, 501-504; (y) Raji Reddy, C.;
Subbarao, M.; Sathish, P.; Kolgave, D. H.; Donthiri, R. R. One-Pot
Alpha-Bromoenals with 2-Aminobenzimidazoles. Org. Lett. 2020, 22,
391-394.
[13] Lu, L.-Q.; Cao, Y.-J.; Liu, X.-P.; An, J.; Yao, C.-J.; Ming, Z.-H.; Xiao, W.-J.
A New Entry to Cascade Organocatalysis: Reactions of Stable Sulfur
Ylides and Nitroolefins Sequentially Catalyzed by Thiourea and DMAP.
J. Am. Chem. Soc. 2008, 130, 6946－6948.
[14] Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Development of Cascade Reactions
for the Concise Construction of Diverse Heterocyclic Architectures.
Acc. Chem. Res. 2012, 45, 1278－1293.
[15] Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. Synthesis and Reactions of
3-(Bromomethyl)-1-carbethoxy-4-iodoindole: The Preparation of
3,4-DifferentiallySubstituted Indoles. J. Org. Chem. 1994, 59,
7164-7168.
[16] Reddy, M. V.; Reddy, G. C. S.; Lien, N. T. K.; Kim, D. W.; Jeong, Y. T. An
Efficient and Green Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidines
Using Highly Active and Stable Poly Acrylic Acid-supported Layered
Double Hydroxides. Tetrahedron 2017, 73, 1317-1323.
[17] Fang, S.; Niu, X.; Yang, B.; Li, Y.; Si, X.; Feng, L.; Ma, C. One-Pot
Synthesis of Benzo[4,5]imidazo[1,2-a]quinazoline Derivatives via
Facile Transition-Metal-Free Tandem Process. ACS Comb. Sci. 2014,
16, 328-332.
Assembly
of
3-Hydroxycarbazoles
via
Uninterrupted
Propargylation/Hydroxylative Benzannulation Reactions. Org. Lett.
2020, 22, 689-693; (z) Dao, P. D. Q.; Lim, H.-J.; C. Cho, S. Transition
Metal-free Construction of Trinuclear N-F used Hybrid Scaffolds by
Double Nucleophilic Aromatic Substitution under Microwave
Irradiation. Green Chem. 2019, 21, 6590-6593.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
[10] Wu, J.; Luo, H.; Wang, T.; Sun, H.; Zhang, Q.; Chai, Y. Diverse
Synthesis
of
Pyrimido[1,2-a]benzimidazoles
and
Manuscript revised: XXXX, 2019
Imidazo[2,1-b]benzothiazoles via CuI-Catalyzed Decarboxylic
Multicomponent Reactions of Heterocyclic Azoles, Aldehydes and
Alkynecarboxylic Acids. Tetrahedron 2019, 75, 1052-1063.
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
[11] White, N. A.; Clagg, K.; Sirois, L. E.; Mack, K. A.; Al-Sayah, M. A.; Nack,
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
DMAP-Catalyzed C−N Bond Formation for the
Diverse Synthesis of Imidazo[1,2-a]pyrimidine
and Pyrimido[1,2-a]benzimidazole Derivatives
TBHP
eq.)
mol%)
N
(1.4
O
N
N
2-DMAP
(20
R1
NH2
R2
N
R2
R
R1
Br, Cl
120 o 4 h
C,
N
H
1,4-Dioxane,
X
X
R
=
X
A
DMAP-catalyzed condensation reactions for the successful direct construction of
pyrimido[1,2-a]benzimidazole or imidazo[1,2-a]pyrimidine has been developed. The current
method features wide substrate scope, product diversification, and metal-free conditions.
Le-Le Shang, Yun Feng, Xing-Lian Gao, Zi-Ren
Chen, Yu Xia, Wei-Wei Jin and Chen-Jiang Liu*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.