Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles, aldehydes and alkynecarboxylic acids

Article abstract of DOI:10.1016/j.tet.2019.01.009

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomp

Full text of DOI:10.1016/j.tet.2019.01.009

Accepted Manuscript
Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles
via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,
aldehydes and alkynecarboxylic acids
Jiarong Wu, Huan Luo, Tao Wang, Huaming Sun, Qi Zhang, Yonghai Chai
PII:
S0040-4020(19)30024-9
https://doi.org/10.1016/j.tet.2019.01.009
TET 30061
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 October 2018
Revised Date: 24 December 2018
Accepted Date: 7 January 2019
Please cite this article as: Wu J, Luo H, Wang T, Sun H, Zhang Q, Chai Y, Diverse synthesis of
pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic
multicomponent reactions of heterocyclic azoles, aldehydes and alkynecarboxylic acids, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.01.009.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Diverse
a]benzimidazoles
b]benzothiazoles
synthesis
of
and
via
pyrimido[1,2-
imidazo[2,1-
CuI-catalyzed
Leave this area blank for abstract info.
decarboxylic multicomponent reactions of
heterocyclic azoles, aldehydes and
alkynecarboxylic acids
Jiarong Wua, † , Huan Luoa, † , Tao Wanga , Huaming Suna , Qi Zhanga, and Yonghai Chaib,
aSchool of Chemistry and Chemical Engineering, Shaanxi Normal University
bKey Laboratory of Applied Surface and Colloid Chemistry, MOE, Shaanxi Normal University
N
N
R
X
R1 = R2 = H
NH2
R = aryl
N
N
R
N
+
path a
R
CHO
R2 = H
X = NR2
N
+
N
R1
COOH
6-endo-dig
R
cyclization
R1
10 mol% CuI
K2CO3
(1.2 equiv)
NR2
R2 = alkyl
N
N
R
X
NH
R1
N
S
b
N
path b
X = S
a
R
N
R1
5-exo-dig cyclization
R
R1
high atom-, step- and pot-efficiency
diverse synthesis
assemblying pyrimidoimidazole scaffold and its C-3
position functionalization in one pot
forming 3 or 4 new bonds in single operation

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Diverse
synthesis
of
pyrimido[1,2-a]benzimidazoles
and
imidazo[2,1-
b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of
heterocyclic azoles, aldehydes and alkynecarboxylic acids
Jiarong Wua,† , Huan Luoa,† , Tao Wanga , Huaming Suna , Qi Zhanga, and Yonghai Chaib,
aSchool of Chemistry and Chemical Engineering, Shaanxi Normal University, No. 199 South Chang’an Road, Xi’an 710062, P. R. of China
bKey Laboratory of Applied Surface and Colloid Chemistry, MOE, Shaanxi Normal University, No. 199 South Chang’an Road, Xi’an 710062, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted
pyrimido[1,2-a]benzimidazoles,
2,4,10-trisubstituted
2,10-dihydropyrimido[1,2-
Received in revised form
Accepted
Available online
a]benzimidazoles and 2,3-disubstituted imidazo[2,1-b]benzothiazoles via multicomponent
reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling
alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K2CO3, the
pyrimido[1,2-a]benzimidazole or imidazo[2,1-b]benzothiazole scaffold could be rapidly
constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary
mechanistic study suggested that the formation of 2,3- disubstituted pyrimido[1,2-
a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position
functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A3
coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.
Keywords:
diverse synthesis
decarboxylic multicomponent reactions
pyrimido[1,2-a]benzimidazoles
imidazo[2,1-b]benzothiazoles
alkynecarboxylic acids
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Fused heterocyclic compounds are key structural scaffolds in
a broad variety of natural products, drug molecules, and
functional
materials.
Among
them,
pyrimido[1,2-
a]benzimidazoles and imidazo[2,1-b]benzothiazoles have been
related to an extensive range of pharmacological activities, such
as anti-asthmatic,1 antitumor,2 antibacterial,3 etc,4 and thus play a
significant role in drug discovery. In addition, due to their
interesting photophysical properties, such kinds of compounds
have also been widely employed in other technological fields, for
instance, as bipolar host materials in organic light-emitting
diodes5 (Fig. 1).
As a consequence, great efforts have been devoted to the
construction of pyrimido[1,2-a]benzimidazole and imidazo[2,1-
b]benzothiazole frameworks, and a number of elegant methods6-
Fig. 1. Representative drug candidates and functional molecules
containing pyrimido[1,2-a]benzimidazole or imidazo[2,1-
b]benzothiazole moiety.
10
have been established. Among them, employing the A3-
coupling-based
multicomponent reactions (MCRs) of
heterocyclic azoles, aldehydes and alkynes to assemble these two
kinds of structural cores has attracted considerable attention
owing to the expeditious formation of heterocyclic systems and
———
the highly pot-, step- and atom-economic manner of this
MCRs.7,10 However, the A3-coupling-based multicomponent
protocol still suffers from some limitations. For example, low-
Corresponding author. +86-29-81530782; fax: +86-29-81530783; e-mail: qiqizhang@snnu.edu.cn (Q. Zhang)
Corresponding author. Tel.: +86-29-81530783; fax: +86-29-81530783; e-mail: ychai@snnu.edu.cn (Y. Chai)
† Contributes equally to this work

2
Tetrahedron
molecular-weight alkynes, such as gaseous acetylene, are not
the assembly of the pyrimido[1,2-a]benzimidazole scaffold and
ACCEPTED MANUSCRIPT
compatible in this one-pot procedure. Alkynecarboxylic acids, a
kind of commercially available, easily storable and handling
compounds, are appealing surrogates for alkynes, especially
those in gaseous state at room temperature. With or without
transition-metal catalysts, alkynecarboxylic acids can undergo
decarboxylation, followed by various cascade reactions, such as
coupling reactions, acylation, etc., to afford 1,3-diynes, 1,4-
enynes and other useful compounds.11
its C-3 position functionalization in a cascade process hasn’t
been reported yet.
Results and discussion
Initially, 2-aminobenzoimidazole (1a), benzaldehyde (2a
and propiolic acid (3a) were chosen as the model substrates
to optimize the reaction conditions (Table 1). In the presence
of 10 mol% CuI in DMSO at 110 C, the MCR happened
)
o
X
and delivered a 6-endo-dig product, 2-phenylimidazo[1,2-
+
R CHO
R1
COOH
+
NH2
a]benzopyrimidine 4aa, in 32% yield (Entry 1). When 1.2
N
X = NR2, 1
S, 1'
equiv. of K2CO3 was introduced into the reaction system, the
yield of 4aa was decreased to 16%. Interestingly, another
product, 3-benzyl-2-phenylimidazo[1,2-a]benzopyrimidine
10 mol%
CuI
Decarboxylation
and
K2CO3
(1.2 equiv)
A
3 coupling
5aa, which was installed an additional benzyl group in the
C3-position comparing with 4aa, was obtained in 32% yield
(Entry 2). The structure of 5aa was firmly confirmed by
NMR, MS as well as X-ray analysis (see the Supplementary
Information, Fig. S1). We then adjusted the ratio of the three
reactants and found that with the increase of the amount of
X
N
HN
b
R
a
Cu
R1
B
When X = NR2:
When X = S:
aldehyde 1a
, 5aa became to the major product while the
path a
path b
5-exo-dig
yield of 4aa was further degraded (65% vs 7%, 5aa vs 4aa
,
6-endo-dig
cyclization
Entry 3). The following investigation of the catalyst,
including different Pd(II), Au(III), Ag(I), Fe(III), Cu(I),
Cu(II) salts, showed that the low-cost and non-toxic CuI was
the most effective catalyst for the formation of 5aa (Entries
3-13). Other commonly used inorganic bases were also
examined, and the best result was achieved when K2CO3
was utilized as the reaction additive (Entries 3, 14 and 15).
Reaction in other solvents didn’t lead to any improvement in
the yields (Entries 16-18). It is noted that in all cases, no 5-
cyclization
NR2
N
NR2
S
N
N
N
N
R
N
R
R
R1
R1
C
R1
Cu
2,10-dihydropyrimido
[1,2-a]benzimidazoles
R1,R2 = H, R = Ar:
Nucleophilic Adn
R
2 = H:
aromatization
RCHO
+
Oxidation
followed by
dehydration
exo-dig
]benzoimidazole, was observed at all. Thus, the optimal
conditions were finalized with (2.1 equiv), (1.2
product,
3-benzyl-2-methylimidazo[1,2-
N
S
N
N
a
N
N
1,
2
3
N
2
2
2
2
N
N
4
R1
Ar
R
equiv), CuI (10 mol%) and K2CO3 (1.2 equiv) in DMSO at
4
3
3
3
R
110 oC for 12 h.
3
4
R1
Ar
2,3-disubstituted-
pyrimido[1,2-a]benzimidazoles
Table 1 Optimization of the reaction conditionsa,b
2,4-disubstituted-
imidazo[2,1-b]
benzothiazoles
Scheme 1. Our work: diverse synthesis of pyrimido[1,2-
a]benzimidazoles
and
imidazo[2,1-b]benzothiazoles
via
decarboxylic MCRs.
In view of the significance of fused heterocyclic compounds
and the convenience of using alkynecarboxylic acids as alkyne
sources, we were interested in developing
straightforward approach to the diverse synthesis of
pyrimido[1,2-a]benzimidazoles and imidazo[2,1-
a facile and
Entry Ratio of Cat.
Add.
Solv.
Results
b]benzothiazoles via the decarboxylic MCRs of heterocyclic
azoles, aldehydes and alkynecarboxylic acids. Herein, we’d like
to report some interesting results of our investigation (Scheme 1).
In the presence of a catalytic amount of CuI and K2CO3, a
propargylamine intermediate B could be in situ generated
through decarboxylation and A3 coupling. Using different types
of heterocyclic azoles (1 or 1’) as the reacting substance, B could
undergo 6-endo-dig cyclization (X = NR2, 1) or 5-exo-dig
cyclization (X = S, 1’) to form the pyrimido[1,2-a]benzimidazole
skeleton or the imidazo[2,1-b]benzothiazole skeleton,
respectively. More interestingly, when propargylic acid, aromatic
aldehyde and 2-aminobenzoimidazole (R1 = R2 = H, R = Ar)
were employed in the MCRs as substrates, the cyclized
intermediate C could further occur nucleophilic addition with the
other molecular aldehyde, followed by dehydration, to lead to
2,3-disubstituted pyrimido[1,2-a]benzimidazoles, in which four
new chemical bonds were formed in a single operation without
isolating the intermediates or changing the reaction conditions.
To the best of our knowledge, one-pot methods for completing
1a/2a/3a (10 mol%) (1.2 equiv) (110 oC)
4aa 5aa
1
1: 1.1: 1.2 CuI
1: 1.1: 1.2 CuI
1: 2.1: 1.2 CuI
1: 2.1: 1.2 PdCl2
1: 2.1: 1.2 AuCl3
-
DMSO 32% 0
2
K2CO3
K2CO3
K2CO3
K2CO3
DMSO 16% 32%
DMSO 7% 65%
3
4
DMSO
0
0
5
DMSO 15% 12%
DMSO Trace 0
6
1: 2.1: 1.2 Fe(OTf)3 K2CO3
7
1: 2.1: 1.2 AgOTf
1: 2.1: 1.2 CuCl
1: 2.1: 1.2 CuBr
1: 2.1: 1.2 CuCl2
1: 2.1: 1.2 CuBr2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO Trace 0
8
DMSO 10% 12%
DMSO 8% 18%
9
10
11
DMSO 4%
0
DMSO 14% 20%

3
11
12
13
1: 2.1: 1.2 Cu(OTf)2 K2CO3
1: 2.1: 1.2 Cu(acac)2 K2CO3
DMSO 12% 18%
ACCEPTED MANUSCRIPT
N
N
N
DMSO 8% 36%
N
N
N
N
N
N
Br
1: 2.1: 1.2 CuI/
Cu(OTf)2
K2CO3
DMSO 12% 32%
Br
5af
, 70%
5ad
5ae, 38%
, 70%
14
15
16
17
18
1: 2.1: 1.2 CuI
1: 2.1: 1.2 CuI
1: 2.1: 1.2 CuI
1: 2.1: 1.2 CuI
1: 2.1: 1.2 CuI
K2HPO4
CsCO3
K2CO3
K2CO3
K2CO3
DMSO 17% 12%
DMSO 20% 38%
N
N
N
DMF
18% 30%
Cl
N
N
N
N
N
N
Cl
Cl
CH3CN 13% Trace
PhCH3 Trace Trace
Cl
Cl
5ai
5ag
5ah
, 40%
, 68%
, 71%
a All reactions were carried out with 1a (1 mmol), 2a, 3a, catalysbt
Cl
o
and additive in Solvents at 110 C for 12 h in a sealed tube.
N
N
N
Isolated yields.
N
N
N
N
N
N
With the optimal conditions in hand, we first investigated the
substrate scope of this new MCR using different aldehydes (2)
and substituted 2-aminobenzoimidazoles (1), and the results are
illustrated in Scheme 2. To our delight, the MCR of 1a, 3a with a
variety of aromatic aldehydes performed smoothly, providing the
corresponding 2,3-disubstituted pyrimido[1,2-a]benzimidazoles
in moderate yields (Scheme 2, 5aa-5ak). Generally, the
aldehydes with substituents in ortho position of the phenyl ring
resulted in relatively lower yields (5ea and 5ia, 38-40%) than
those with substituents in para and/or meta positions (5ac, 5ad,
5ag, 5ah and 5ak, 56-70%), indicating that the steric hindrance
from the ortho-substituent on the phenyl ring has a big impact on
this transformation. However, the electronic effect was found not
to influence the cascade process too much. Most of the electron-
deficient and electron-rich aromatic aldehydes were well
tolerated under the optimal condition and furnished the desired
products 5 in similar yields (5aa, 5ab, 5ac, 5af, 5ag and 5aj, 65-
71%). Polycyclic aromatic and heteroaromatic aldehydes were
also compatible with this procedure and the corresponding
products were attained in practical yields (5al and 5am, 67-70%).
Unfortunately, when using pentanal 2n as aldehyde component,
the starting material 1a disappeared but no anticipated 2,3-
dialkylpyrimido[1,2-a]benzimidazole was detected, which
reveals that aliphatic aldehydes are not suitable substrates for the
direct formation of 5 (5an). 2-Aminobenzoimidazoles bearing
different substituents on the phenyl ring were also employed in
the reaction system. It was found that imidazole substrates with
electron-donating group were more efficient than those with
electron-withdrawing group (5ba, 67% vs 5ca, 40%). This is
probably because the former [Y = electron-donating group, such
as OMe (1b)] has higher reactivity towards the proposed
condensation reaction of 2-amino azoles with aldehydes.
NC
S
CN
S
5al
5aj
, 70%
, 67%
N
5ak
, 56%
Y
N
N
N
N
N
N
N
N
5an
, n.d.
5am
, 67%
5ba
, 67%
, 40%
Y: OMe,
5ca
Br,
Scheme 2. Synthesis of 2,3-disubstituted pyrimido[1,2-
a]benzimidazoles 5 from 3a, different aldehydes 2 and 1. Unless
otherwise noted, all reactions were carried out with 1 (1 mmol), 2
(2.1 equiv), 3a (1.2 equiv), CuI (10 mol%) and K2CO3 (1.2
equiv) in DMSO at 110 oC for 12 h in a sealed tube.
Next, we focused on the substrate scope in terms of different
alkynecarboxylic acids (Scheme 3, 4ab-4af). Surprisingly, no
matter if alkyl substituted (3b, 3c) or aryl substituted propiolic
acid (3d) was employed in the MCR, under the above standard
conditions,
only
2,4-disubstituted
imidazo[1,2-
a]benzopyrimidine 4 (which doesn’t bear any substituent in C-3
position) was obtained with no compound 5 formed (4aba-4ada).
After further optimizing the reaction conditions, the yield of 4
could be enhanced slightly (4abb-4adb, from 14-70% to 43-74%).
Moreover, 3-arylpropiolic acids, regardless of the electronic
nature of the substituents on the aryl ring, led to better outcomes
compared to 3-alkylpropiolic acids substrates (4adb-4afb, 65-74%
vs 4abb-4acb, 43-60%). The MCRs of 1a, 3-substituted propiolic
acid 3a with other aldehydes could also occur to give the C3-
positional unfunctionalized 4 as the only pyrimidoimidazole
products in moderate yields (Scheme 3, 4bd-4kd), which is
consistent with our previous observation from 4ab-4af. The
aldehyde component was proved to have little effect on the
formation of compound 4. Various aromatic, heteroaromatic,
polycyclic aromatic as well as aliphatic aldehydes were all well
tolerated for this one-pot transformation. Interestingly, when 3H-
imidazo[4,5-b]pyridin-2-ylamine 1d was used as the substrate,
the MCR of 1d, benzaldehyde 2a and phenylpropiolic acid 3d
also occurred and delivered the pyrido imidazo[1,2-a]pyrimidine
product 7 in 42% yield with regio-specificity. The structure of 7
is determined by NMR, HRMS and X-ray analysis (See the
Supporting Information, Scheme S1 and Figure S3). The
changed chemoselectivity (from 5 to 4) probably attributes to the
increased steric hindrance of C-4 position in imidazo[1,2-
a]benzopyrimidines.

4
Tetrahedron
propiolic acid component didn’t affect the reaction pathway and
ACCEPTED MANUSCRIPT
only imidazo[2,1-b]benzothiazole scaffold was constructed as a
result (6b-6e). That is to say, the cascade cyclization in the MCR
mainly relies on the heterocyclic azole component, especially the
heteroatom in 1-position.
N
N
N
N
N
N
N
N
N
Cl
OMe
MeO
4af, 65%b
4bd, 67%b
4ae, 68%b
N
N
N
N
N
N
N
N
N
OMe
4dd, 72%b
Cl
4ed, 65%b
4cd,72%b
OMe
N
N
N
N
N
N
N
N
N
NC
Cl
4gd, 76%b
Scheme
a]benzimidazoles 4’ and imidazo[2,1-b]benzothiazoles 6 from
different heterocyclic azinesazoles, aldehydes and
4.
Synthesis
of
2,10-dihydropyrimido[1,2-
4fd, 62%b
4hd, 70%b
Cl
N
N
N
alkynecarboxylic acids. Unless otherwise noted, all reactions
were carried out with 1 (1 mmol), 2 (1.1 equiv), 3 (1.2 equiv),
CuI (10 mol%) and K2CO3 (1.2 equiv) in DMSO at 110 oC for 12
h in a sealed tube.
N
N
N
N
N
N
S
4jd, 70%b
4kd, 60%b
4ie, 63%b
To gain some insight into the reaction mechanism,
a the ratio of 1a/2/3 = 1:2.1:1.2
b the ratio of 1a/2/3 = 1:1.1:1.2
especially the formation pathway for compound
5, we
carried out a series of experiments (see the Supporting
Information for details). In the presence of CuI (10 mol%)
and K2CO3 (1.2 equiv) in DMSO at 110 oC, 2-
Scheme 3. Synthesis of 2,4-disubstituted pyrimido[1,2-
a]benzimidazoles 4 from 1a, different propiolic acids 3 and
aldehydes 2. All reactions were carried out with 1a (1 mmol), 2
(2.1 or 1.1equiv), 3a (1.2 equiv), CuI (10 mol%) and K2CO3 (1.2
equiv) in DMSO at 110 oC for 12 h in a sealed tube.
phenylimidazo[1,2-
with benzylaldehyde 2a to install the substituent in C-3
position, implying that the novel product isn’t formed
from compound [Eq. (1)]. Deuterium reagents, C6H5CDO
2a-D) and D2O, were then introduced into the reaction
system to figure out the source of the benzylic protons in
a]benzopyrimidine 4aa couldn’t react
5
4
(
The scope of this MCR was further elaborated with different
types of heterocyclic azoles. As shown in Scheme 4, by treatment
of CuI (10 mol%) and K2CO3 (1.2 equiv) in DMSO at 110 oC, 1-
alkyl-2-aminobenzoimidazole (X = NR, 1), benzaldehyde (2a)
and 3-aryl propiolic acid (3) could react and delivered 2,10-
dihydropyrimido[1,2-a]benzimidazoles 4’ in good yields via a
cascade process of decarboxylation, A3 coupling and subsequent
6-endo-dig cyclization (4’a-4’d). It was found that the MCR is
independent of either the N1-positional alkyl group in 2-
aminobenzoimidazole (4’a, 4’b) or the substituent in the aryl ring
of propiolic acid (4’c, 4’d). However, to our surprise, when 2-
aminobenzothiazole (X = S, 1’) was used as the reactant, under
5.
Under the standard conditions, the MCR of C6H5CDO, 1a
and 3a offered the non-deuterated 5aa in 11% proportion
and the monodeuterated product 5aa-D in 89% proportion
1
(calculated by H NMR), with no dideuterated product 5aa
-
D2 observed [Eq. (2)]. When 10 equiv. of D2O was also
brought into the reaction system12, the benzylic
monodeuterated 5aa-3-1’-D was obtained in 47%
proportion, along with 53% of the benzylic dideuterated
5aa-3-1’-D2 (calculated by 1H NMR) [Eq. (3)]. Furthermore,
under the same conditions, the benzylic H/D exchange of
5aa didn’t happen [Eq. (4)]. The outcomes of these three
experiments suggest that one of the benzylic protons of
the
same
conditions,
3-benzyl-2-phenylimidazo[2,1-
b]benzothiazole 6a, a product involved a 5-exo-dig cyclization
instead of a 6-endo-dig mode, was isolated as the major product
in 68% yield (6a). Moreover, changing the aldehye or 3-aryl
product
5 may come from the aldehyde and the other from

5
X
N
H2O
the proton source generated during the reaction, such as
H2O.
ACCEPTED MANUSXCRIPT
O
N
NH2
+
R
R
H
N
A
1
1'
2
or
Based on the above preliminary experimental results and
[Cu]
previous literature reports7,11e,13-14, a plausible mechanism of this
one-pot MCR was proposed in Scheme 5. Initially, the
condensation of azole and aldehyde furnishes the imine A,
together with 1 equiv of water. Imine A then undergoes
nucleophilic addition with alkynyl copper, which is generated
through the decarboxylation of alkynecarboxylic acid, to yield
the propargylamine B. When the heteroatom in 1-position is
sulfur (X = S), B experiences a 5-exo-dig cyclization, followed
by aromatization, to produce the imidazo[2,1-b]benzothiazole 6
(Path a); when the heteroatom is nitrogen (X = N), a 6-endo-dig
cyclization takes place to form the intermediate C (Path b),
which can be converted into the dihydropyrimido[1,2-
CO2H
CO2
S
H
N
S
N
X
Path b
X = S, 1'
5-exo-dig
Rcyclization
Naromatization
R
N
R
N
N
b
B
Cu
a
R1
R1
6
X = NR2, 1
6-endo-dig
R1
N
Path a
cyclization
NR2
N
NR2
N
Path c
R2 = H
oxidation
N
N
H+-Cu+
N
N
exchange
R
R
R
C
R1
a]benzimidazole 4’ via Cu/H exchange (R2
=
alkyl) or
R1
Cu
R1
R2 = alkyl, 4'
4
Path d
R1 = H
R =Ar
RCHO
2
pyrimido[1,2-a]benzimidazole
4 via Cu/H and subsequent
oxidation7 (R2 = H) (Path c). For propiolic acid and aromatic
aldehyde substrates, C can further attack on the second molecular
aldehyde, giving the addition intermediate D (Path d). D may
predominantly go through Path e to form the final product 5.
Base
H
N
H
N
H
N
Path f
shift
H
N
N
N
Ar
1. H+-Cu+
exchange,
N
N
Ar
N
R
D
G
H
Concretely, intermediate
E
was first generated with the
H
2. -OH
OCu
1. H+-Cu+
exchange,
H
participation of lone pair electrons in N-3; then, the base, which
is indispensable for the formation of 5 (Table 1, 1 and 3), extracts
the proton in C-2 position and simultaneously, the benzylic
carbon obtains a proton from water (or H-Base+), yielding the
intermediate F; F undergoes aromatization to afford the final 2,3-
disubstituted pyrimido[1,2-a]benzimidazole 5. Another pathway,
Path f, involved an intermolecular hydride transfer (G to H), was
ruled out by the control experiment [Eq. (3)] in which no
dideuterated product 5aa-D2 was observed. In addition, for
propiolic acid, the generation of the propargylamine B may
undergo an alternative pathway proposed by Lee and coworkers
(see the Supporting Information for details).11e
Ar
Path e
Ar
H
2. -OH
Ar
H
Base
H
N
N
N
N
N
N
N
H
N
N
Ar
Ar
Ar
5
E
F
H
H2O
or H-B+
H
Ar
Ar
Ar
Scheme 5. Control experiments and proposed mechanism
Conclusion
In summary, we have developed a facile and economic
protocol for assembling pyrimido[1,2-a]benzimidazole and
imidazo[2,1-b]benzothiazole
scaffolds
via
decarboxylic
multicomponent reactions of heteroclyclic azoles, aldehydes and
alkynecarboxylic acids. By the treatment with a catalytic amount
of CuI and K2CO3, biologically potent 2,3-, 2,4-disubstituted
pyrimido[1,2-a]benzimidazoles,
2,4,10-trisubstituted
2,10-
dihydropyrimido[1,2-a]benzimidazoles and 2,3-disubstituted
imidazo[2,1-b]benzothiazoles were obtained diversely in
moderate to good yields. The mechanistic study indicated that a
novel cascade process including a decarboxylation, A3 coupling,
6-endo-dig cyclization, nucleophilic addition and dehydration is
involved in the direct formation of 2,3-disubstituted
pyrimido[1,2-a]benzimidazoles. Notable features of this new
approach include readily available starting materials, easily
storable and handling alkyne sources, common and inexpensive
catalysts, convenient operations, and no need for isolating the
reaction intermediates. The reaction should therefore have
widespread applications in the rapid construction of various
pyrimidoimidazole and imidazothiazole derivatives which has
bright prospect in medicine, materials and other important fields.
Experimental section
General
1H NMR and 13C NMR spectra were recorded in CDCl3 or
DMSO-d6 on a Bruker Avance 400 or 600 instrument. Chemical
shifts (δ) are referenced to internal TMS, DMSO-d6 or CDCl3.
High-resolution mass spectra were recorded on a Bruker Impact
mass spectrometer. Melting points were determined by using a
Stuart Scientific SMP10 instrument and are uncorrected. IR
spectra were recorded in the ATR mode on a Nicolet 6700 FT-IR

6
Tetrahedron
ACCEPTED MANUSCRIPT
Thermo Scientific spectrometer; only the more significant
(165.8 mg, 1.2 mmol), gave 5ac (243.3 mg, 67%) as a yellow
o 1
peaks are reported. All reagents and solvents were obtained
commercially and used as received without further purification.
Reactions were monitored by TLC on glass-backed plates coated
with a 0.2 mm thickness of silica gel 60 F254; chromatograms
were visualized by UV radiation (254 nm) or by staining with
phosphomolybdic acid, 2,4-dinitrophenylhydrazine and KMnO4.
Flash column chromatography was performed on 300–400 mesh
silica gel.
solid after chromatography; mp 152−154 C; H NMR (400
MHz, CDCl3): δ = 8.34 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d,
J = 8.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.41-7.32 (m, 4H), 7.28
(d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 4.06 (s, 2H), 2.39 (s,
3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 166.1,
150.1, 145.0, 138.6, 138.5, 138.2, 138.1, 132.6, 130.2, 129.6
(2C), 128.7, 128.1, 127.6,126.7, 126.1, 125.9, 125.8, 121.5,
120.5, 119.0, 110.6, 36.5, 21.4, 21.3; IR (KBr): v = 3019, 1734,
1601, 1506, 1483, 1443, 1421, 1335, 1260, 790, 728 cm-1; HR-
MS (ESI): m/z = 364.1820, calcd for [C25H21N3 +H]+: 364.1814.
4.2.1 General Procedure for the Synthesis of 2,3-Disubstituted
Pyrimido[1, 2-a]benzimidazoles (5aa-5ma)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), the aldehyde
(2.1 mmol, 2.1 equiv.), the alkyne carboxylic acid (1.2 mmol, 1.2
equiv.), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (1.2 mmol,
1.2 equiv.), and DMSO (4 mL) were placed in a 10 mL reaction
tube. The reaction mixture was tightly sealed and heated at 110
°C for 12 h. After cooling, the mixture was poured into CH2Cl2
(30 mL), washed with water (2×10 mL), saturated aqueous
NH4Cl (3×10 mL) and brine (2×10 mL), and then dried with
Na2SO4 and passed through a celite pad. Evaporation of the
solvent under reduced pressure provided the crude product,
which was purified by column chromatography on silica gel with
4.2.5
3-(4-Methylbenzyl)-2-(4-methylphenyl)pyrimido[1,2-
a]benzimidazole (5ad)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 4-
methylbenzaldehyde (0.26 mL, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ad (254.2 mg, 70%) as a yellow
solid after chromatography; mp 170−172 oC; 1H NMR (400 MHz,
CDCl3): δ = 8.27 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J =
8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H),
7.28 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.6
Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 4.03 (s, 2H), 2.39 (s, 3H), 2.32
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.6, 150.1, 144.8,
139.6, 136.4, 135.4, 135.4, 132.7, 129.5, 128.9 (2C), 128.7, 126.6,
126.0, 121.3, 120.2, 119.0, 110.6, 36.0, 21.3, 21.0; IR (KBr): v =
3014, 1708, 1628, 1598, 1511, 1478, 1445, 1305, 1259, 1029,
756, 730 cm-1; HR-MS (ESI): m/z = 364.1821, calcd for
[C25H21N3+H]+: 364.1814.
petroleum ether:ethyl acetate (V:V
=
3:1−1:1) or
methylbenzene: ethyl acetate (V:V = 6:1−2:1) as the eluent to
afford the final product.
4.2.2 3-Benzyl-2-phenylpyrimido[1,2-a]benzimidazole (5aa
)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.21 mL, 2.1 mmol), propiolic acid (74.2 ꢀL, 1.2 mmol), CuI
(19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg, 1.2 mmol),
4.2.6
3-(2-Methylbenzyl)-2-(2-methylphenyl)pyrimido[1,2-
gave 5aa (217.8 mg, 65%) as
a
yellow solid after
a]benzimidazole (5ae)
o
1
chromatography; mp 228−230 C; H NMR (400 MHz, CDCl3):
δ = 8.35 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz,
1H), 7.61 (d, J = 5.6 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.46-7.44
(m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.32 – 7.22 (m, 3H), 7.06 (d, J
= 7.2 Hz, 2H), 4.11 (s, 2H); 13C NMR (100 MHz, CDCl3): δ =
165.7, 150.2, 145.0, 138.4, 138.3, 132.8, 129.5, 128.8, 128.8,
128.8, 128.2, 127.8, 126.8, 126.1, 121.6, 120.4, 118.8, 110.7,
36.5; IR (KBr): v = 3059, 3021, 1630, 1603, 1513, 1484, 1446,
1419, 762, 736, 714, 698 cm-1; HR-MS (ESI): m/z = 336.1504,
calcd. for [C23H16N3+H]+: 336.1501.
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
methylbenzaldehyde (0.26 mL, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ae (138.0 mg, 38%) as a yellow
solid after chromatography; mp 158−160 °C; 1H NMR (400
MHz, CDCl3): δ = 8.09 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.71 (d,
J = 8.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.37-7.34 (m, 2H), 7.33
(s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.23-7.16
(m, 3H), 7.05 (d, J = 7.2 Hz, 1H), 3.76 (s, 2H), 2.21 (s, 3H), 2.07
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.1, 145.0, 144.8,
137.7, 136.3, 135.6, 135.4, 131.5, 130.8, 130.6, 130.0, 129.0,
127.7, 127.4, 126.8, 126.5, 126.2, 125.8, 121.6, 120.6, 119.3,
110.5, 33.8, 19.5, 19.3; IR (KBr): v = 3013, 1710, 1605, 1513,
1485, 1443, 1310, 1254, 1029, 759, 730 cm-1; HR-MS (ESI): m/z
= 364.1824, calcd for [C25H21N3+H]+: 364.1814.
4.2.3
3-(3-Methoxybenzyl)-2-(3-methoxyphenyl)pyrimido[1,2-
a]benzimidazole (5ab)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
methoxybenzaldehyde (0.25 mL, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ab (280.5 mg, 71%) as a yellow
4.2.7
3-(3-Bromobenzyl)-2-(3-bromophenyl)pyrimido[1,2-
1
semi-solid after chromatography; H NMR (400 MHz, CDCl3): δ
a]benzimidazole (5af)
= 8.41 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H),
7.50 (t, J = 7.6 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.18-7.11 (m, 2H),
7.09 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H),
6.60 (d, J = 7.6 Hz, 1H), 6.53 (s, 1H), 4.02 (s, 2H), 3.72 (s, 3H),
3.69 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.4, 159.8,
159.3, 149.8, 144.7, 140.1, 139.3, 132.9, 129.6, 129.1, 126.5,
126.0, 121.4, 120.9 (2C), 120.1, 118.3, 115.6, 114.4, 113.8,
111.9, 110.7, 55.1, 55.0, 36.3; HR-MS (ESI): m/z = 396.1710,
calcd for [C25H21N3O2+H]+: 396.1712.
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
bromobenzaldehyde (0.25 mL, 2.1 mmol,), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5af (343.6 mg, 70%) as a yellow
1
solid after chromatography; mp 164−166 °C; H NMR (400
MHz, CDCl3): δ = 8.44 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.81 (d,
J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.45 – 7.35
(m, 3H), 7.29 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.93
(d, J = 7.6 Hz, 1H), 4.04 (s, 2H); 13C NMR (100 MHz, CDCl3): δ
= 163.8, 149.6, 145.0, 140.4, 139.8, 133.0, 132.5, 131.7, 131.6,
130.3, 130.1, 129.8, 127.3, 127.2, 126.6, 126.5, 122.9, 122.4,
122.0, 120.5, 117.7, 110.9, 36.1; IR (KBr): v = 3057, 1734, 1600,
1567, 1510, 1474, 1445, 1421, 1253, 1218, 1050, 794, 758, 731,
4.2.4
3-(3-Methylbenzyl)-2-(3-methylphenyl)-pyrimido[1,2-
a]benzimidazole (5ac)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
methylbenzaldehyde (0.26 mL, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3

7
698 cm-1; HR-MS (ESI): m/z
[C23H15Br2N3+H]+: 491.9711.
=
491.9714, calcd for
7.55 – 7.48 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.6
ACCEPTED MANUSCRIPT
Hz, 1H), 7.27 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 4.12 (s, 2H); 13C
NMR (100 MHz, CDCl3): δ = 162.7, 149.4, 145.0, 139.5, 139.2,
133.4, 133.0, 133.0, 132.8, 132.1, 132.1, 130.9, 129.8, 129.5,
126.9, 126.5, 122.5, 120.7, 118.2, 117.9, 116.8, 113.1, 112.8,
111.0, 36.1; IR (KBr): v = 3040, 2222, 1727, 1516, 1481, 1447,
1261, 1159, 1052, 797, 727, 689 cm-1; HR-MS (ESI): m/z =
386.1416, calcd for C25H15N3+H]+: 386.1406.
4.2.8
3-(3-Chlorobenzyl)-2-(3-chlorophenyl)pyrimido[1,2-
a]benzimidazole (5ag)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
chlorobenzaldehyde (0.25 mL, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ag (274.0 mg, 68%) as a yellow
solid after chromatography; mp 175−177 °C; 1H NMR (400
MHz, CDCl3): δ = 8.43 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.81 (d,
J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.55-7.51 (m, 1H), 7.45
– 7.38 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.22-7.20 (m, 2H), 7.00
(s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.05 (s, 2H); 13C NMR (100
MHz, CDCl3): δ = 163.9, 149.6, 144.9, 140.1, 139.6, 134.6,
134.3, 133.0, 130.0, 129.6 (2C), 128.8, 128.8, 127.1, 126.8,
126.7, 126.5, 126.4, 122.0, 120.5, 117.7, 110.9, 36.1; IR (KBr): v
= 3055, 1741, 1565, 1513, 1476, 1448, 1253, 1213, 933, 788, 738
4.2.12
3-(3,4-Dimethylbenzyl)-2-(3,4-dimethylphenyl)
pyrimido[1,2-a]benzimidazole (5ak)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3, 4-
dimethylbenzaldehyde (0.28 mL, 2.1 mmol,), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ak (219.1 mg, 56%) as a yellow
solid after chromatography; mp 166-168 °C; 1H NMR (400 MHz,
CDCl3): δ = 8.30 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.75 (d, J =
8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J =
8.0 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H),
7.09 (d, J = 8.4 Hz, 1H), 6.86-6.84 (m, 2H), 4.06 (s, 2H), 2.34 (s,
3H), 2.31 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 165.8, 150.1, 144.8, 138.2, 136.9, 136.4,
135.9, 135.7, 134.8, 132.6, 130.2, 130.0, 129.9, 129.2, 126.6,
126.2, 126.1, 125.8, 121.2, 120.0, 119.1, 110.6, 36.0, 19.6, 19.6,
19.5, 19.2; IR (KBr): v = 3047, 1726, 1509, 1478, 1446, 1303,
1261, 996, 741, 577, 538, 500, 458, 419 cm-1; HR-MS (ESI): m/z
= 392.2128, calcd for [C27H25N3+H]+: 392.2127.
cm-1; HR-MS (ESI): m/z
[C23H15Cl2N3+H]+: 404.0721.
=
404.0723, calcd for
4.2.9
3-(4-Chlorobenzyl)-2-(4-chlorophenyl)pyrimido[1,2-
a]benzimidazole (5ah)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 4-
chlorobenzaldehyde (295.2 mg, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ah (286.1 mg, 71%) as a yellow
1
solid after chromatography; mp 188−190 °C; H NMR (400
4.2.13 2-(Thiophen-2-yl)-3-(thiophen-2-ylmethyl)pyrimido[1,2-
MHz, CDCl3): δ = 8.37 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.78 (d,
J = 8.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz,
2H), 7.42 –7.36 (m, 3H), 7.28 – 7.25 (m, 2H), 6.97 (d, J = 8.0
Hz, 2H), 4.06 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 164.3,
149.8, 145.0, 136.7, 136.5, 136.0, 133.0, 132.9, 130.2, 130.0,
129.1, 128.6, 126.6, 126.5, 122.0, 120.6, 117.9, 110.7, 35.9; IR
(KBr): v = 3060, 1731, 1683, 1512, 1485, 1442, 1421, 1254,
1090, 1012, 835, 735, 541 cm-1; HR-MS (ESI): m/z = 404.0729,
calcd for [C23H15Cl2N3+H]+: 404.0721.
a]benzimidazole (5al)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
thiophenecarboxaldehyde (0.20 mL, 2.1 mmol), propiolic acid
(74.2ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5al 242.9 mg, 70%) as a yellow solid
1
after chromatography; mp 202−204 °C; H NMR (400 MHz,
CDCl3): δ = 8.41 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.73 (d, J =
8.0 Hz, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 4.0 Hz, 1H),
7.53 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 5.2
Hz, 1H), 7.13 – 7.09 (m, 1H), 7.04 – 7.00 (m, 1H), 6.89-6.88 (m,
1H), 4.55 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 156.8,
149.7, 145.4, 142.6, 140.5, 133.1, 131.4, 130.2, 128.2, 127.5,
126.8, 126.5, 126.4, 125.2, 121.7, 120.3, 116.5, 110.5, 31.7; IR
(KBr): v = 3048, 1715, 1494, 1425, 1257, 1211, 963, 910 cm-1;
HR-MS (ESI): m/z = 348.0637, calcd for C19H13N3 S2+H]+:
348.0629.
4.2.10
3-(2-Chlorobenzyl)-2-(2-chlorophenyl)pyrimido[1,2-
a]benzimidazole (5ai)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
chlorobenzaldehyde (0.25 mL, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5ai (161.2 mg, 40%) as a yellow
1
solid after chromatography; mp 187−189 °C; H NMR (400
MHz, CDCl3): δ = 8.29 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.76 (d,
J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 8.0 Hz,
1H), 7.40 –7.37 (m, 1H), 7.38 – 7.35 (m, 1H), 7.33 – 7.32 (m,
1H), 7.31 – 7.30 (m, 2H), 7.22 – 7.13 (m, 2H), 7.01 (d, J = 7.2
Hz, 1H), 4.02 (s,1H) , 3.97 (s, 1H); 13C NMR (100 MHz, CDCl3):
δ = 164.1, 149.7, 144.8, 137.2, 135.4, 134.2, 132.1, 131.9, 131.2,
130.4, 130.3, 130.0, 129.8, 129.5, 128.6, 127.1, 127.0, 126.2,
121.8, 120.5, 118.4, 110.7, 33.6; IR (KBr) v = 3055, 1752, 1628,
1602, 1515, 1475, 1439, 1306, 1262, 1031, 741 cm-1; HR-MS
(ESI): m/z = 404.0722, calcd for [C23H15Cl2N3+H]+: 404.0721.
4.2.14 2-(Naphthalen-2-yl)-3-(naphthalne-2-ylmethyl)pyrimido
[1,2-a]benzimidazole (5am)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
naphthaldehyde (327.9 mg, 2.1 mmol), propiolic acid (74.2 ꢀL,
1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8
mg, 1.2 mmol), gave 5am (291.5 mg, 67%) as a yellow solid
1
after recrystallization; mp 252–254 °C; H NMR (400 MHz,
CDCl3): δ = 8.44 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 4.8 Hz, 1H),
7.90 (t, J = 9.2 Hz, 2H), 7.85 – 7.82 (m, 1H), 7.79 (d, J = 8.4 Hz,
3H), 7.71 – 7.67 (m, 1H), 7.57-7.46 (m, 7H), 7.34 (t, J = 7.6 Hz,
1H), 7.21 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ = 165.6, 136.0, 135.6, 133.7, 133.5, 133.1, 132.8,
132.4, 129.0, 128.8, 128.7, 128.1, 127.72, 127.70, 127.6, 127.5,
127.2, 126.9, 126.6, 126.5, 126.3, 126.2, 126.0, 121.7, 120.6,
118.7, 110.7, 36.9；IR (KBr): v = 3296, 3053, 1727, 1602, 1510,
1443, 1261, 952, 894, 818, 738 cm-1; HR-MS (ESI): m/z =
436.1822, calcd for [C31H21N3+H]+: 436.1814.
4.2.11
3-(3-Cyanobenzyl)-2-(3-cyanophenyl)pyrimido[1,2-
a]benzimidazole (5aj)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
cyanobenzaldehyde (275.3 mg, 2.1 mmol), propiolic acid (74.2
ꢀL, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 5aj (258.0 mg, 67%) as a yellow
1
solid after chromatography; mp 198−200 °C; H NMR (400
MHz, CDCl3): δ = 8.49 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.79 (d,
J = 8.0 Hz, 1H), 7.74 – 7.67 (m, 3H), 7.59 (t, J = 7.6 Hz, 1H),
4.2.15
a]benzimidazole (5ba)
3-Benzyl-8-methoxy-2-phenylpyrimido[1,2-

8
Tetrahedron
ACCEPTED MANUSCRIPT
2-Amino-8-methoxybenzimidazole (163.1 mg, 1.0 mmol),
benzaldehyde (0.11 mL, 1.1 mmol), propiolic acid (74.2 ꢀL, 1.2
mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg,
1.2 mmol), gave 5ba (252.1 mg, 67%) as a yellow solid after
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), 2-butynoic acid (100.8 mg, 1.2 mmol), CuI
(19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg, 1.2 mmol),
chromatography; mp 198−200 C;1H NMR (400 MHz, CDCl3) δ
o
gave 4ab (111.4 mg, 43%) as
a
yellow solid after
8.32 (s, 1H), 7.62 (d, J = 3.2 Hz, 3H), 7.46 (s, 3H), 7.32 –
7.23(m, 4H), 7.06 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H),
4.11 (s, 2H), 3.93 (s, 3H). 13C NMR (100 MHz, CDCl3) δ164.4,
160.4, 159.1, 136.8, 132.6, 131.2, 129.4, 129.4, 128.9, 128.9,
128.9, 128.3, 127.7, 126.90, 112.9, 111.1, 103.8, 55.8, 36.5; IR
(KBr): v = 3053, 2994, 2831, 1607, 1545, 1526, 1513, 1477,
1442, 1422, 1251, 1203, 1157, 1105, 953, 815, 795, 695 cm-1;
HR-MS (ESI): m/z = 366.1606, calcd for [C24H19N3O+H]+:
366.1604.
1
chromatography; mp 168–170 °C; H NMR (400 MHz, CDCl3):
δ = 8.24 – 8.21 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4
Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.51 – 7.47 (m, 3H), 7.30 (t, J
= 7.6 Hz, 1H), 7.11 (s, 1H), 3.04 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 160.9, 152.0, 147.9, 145.5, 136.6, 131.1, 128.8,
128.0, 127.7, 125.8, 121.5, 120.2, 114.5, 104.4, 21.0; IR (KBr): v
= 3052, 2921, 1733, 1621, 1598, 1527, 1437, 1309, 1231, 1021,
758, 736, 691, 545 cm-1; HR-MS (ESI): m/z = 260.1191, calcd
for [C17H13N3+H]+: 260.1188.
4.2.16 3-Benzyl-8-bromo-2-phenylpyrimido[1,2-a]benzimidazole
(5ca)
4.3.4 4-Amyl-2-phenylpyrimido[1,2-a]benzimidazole (4ac)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), 2-octynoic acid (0.17 mL, 1.2 mmol), CuI
(19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg, 1.2 mmol),
2-Amino-8-bromobenzimidazole (210.9 mg, 1.0 mmol),
benzaldehyde (0.11 mL, 1.1 mmol), propiolic acid (74.2 ꢀL, 1.2
mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg,
1.2 mmol), gave 5ca (165.2 mg, 40%) as a yellow solid after
gave 4ac (179.6 mg, 57%) as
a
yellow solid after
1
o
chromatography; mp 140−142 °C; H NMR (400 MHz, CDCl3):
δ = 8.23 – 8.21 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4
Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.50 – 7.46 (m, 3H), 7.30 (t, J
= 7.6 Hz, 1H), 7.08 (s, 1H), 3.27 (t, J = 7.6 Hz, 2H), 1.97 – 1.85
(m, 2H), 1.63 – 1.51 (m, 2H), 1.50 – 1.42 (m, 2H), 0.97 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 160.8, 152.2,
152.0, 145.5, 136.7, 131.0, 128.8, 127.7, 127.4, 125.7, 121.5,
120.2, 114.7, 102.8, 33.2, 31.4, 25.8, 22.4, 13.9; IR (KBr): v =
3055, 2922, 1738, 1627, 1601, 1575, 1532, 1493, 1441, 1350,
1308, 1233, 1024, 760, 738, 689, 545 cm-1; HR-MS (ESI): m/z =
316.1823, calcd for [C21H21N3+H]+: 316.1814.
chromatography; mp 202−204 C;1H NMR (400 MHz, CDCl3) δ
8.19 (s, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.55 (d, J =
6.4 Hz, 3H), 7.48-7.37 (m, 3H), 7.29 – 7.21 (m, 3H), 7.00 (d, J =
6.0 Hz, 2H), 4.04 (s, 2H). 13C NMR (100MHz, CDCl3) δ 166.4,
150.3, 143.7, 138.0, 132.5, 129.8, 129.6, 129.0, 128.9, 128.8,
128.4, 127.1, 121.8, 119.8, 114.4, 113.7, 109.4, 100.0, 36.6; IR
(KBr): v = 3048, 2899, 1633, 1508, 1453, 1332, 1217, 1185,
1138, 1093, 945, 797, 696 cm-1; HR-MS (ESI): m/z = 414.0606,
calcd for [C23H16BrN3+H]+: 414.0599.
4.3.1 General Procedure for the Synthesis of 2,4-Disubstituted
Pyrimido[1,2-a]benzimidazoles
(4aa-4ld)
and
2,4,10-
4.3.5 2,4-Diphenylpyrimido[1,2-a]benzimidazole (4ad)7a
Trisubstituted 2,10-Dihydropyrimido[1,2-a]benzimidazoles (4’a-
4’d)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), phenylpropiolic acid (175.3 mg, 1.2
mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg,
1.2 mmol), gave 4ad (237.5 mg, 74%) as a yellow solid after
2-Aminobenzimidazole or 1-alkyl-2-aminobenzimidazole (1.0
mmol), the aldehyde (1.1 mmol, 1.1 equiv.), the alkyne
carboxylic acid (1.2 mmol, 1.2 equiv.), CuI (19.8 mg, 0.1 mmol,
10 mol%), K2CO3 (1.2 mmol, 1.2 equiv.), and DMSO (4 mL)
were placed in a 10 mL reaction tube. The reaction mixture was
tightly sealed and heated at 110 °C for 12 h. After cooling, the
mixture was poured into CH2Cl2 (30 mL), washed with water
(2×10 mL), saturated aqueous NH4Cl (3×10 mL) and brine (2×10
mL), and then dried with Na2SO4 and passed through a celite pad.
Evaporation of the solvent under reduced pressure provided the
crude product, which was purified by column chromatography on
silica gel with petroleum ether:ethyl acetate (V:V = 3:1−1:1,
containing 1% NEt3) as the eluent to afford the final product.
1
chromatography; mp 198−200 °C; H NMR (400 MHz, CDCl3):
δ = 8.32 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 7.69 (m, 5H), 7.59 –
7.51 (m, 3H), 7.46 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.03 (t, J =
7.8 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ = 161.1, 152.1, 149.3, 145.5, 136.7, 132.6, 131.3,
131.0, 129.4, 128.9, 128.4, 127.8, 127.4, 125.9, 121.1, 120.2,
114.5, 105.3; IR (KBr): v = 3057, 1623, 1592, 1530, 1484, 1444,
1394, 1357, 1304, 762, 734, 698 cm-1; HR-MS (ESI): m/z =
322.1337, calcd for [C22H15N3+H]+: 322.1344.
4.3.6
4-(4-Methoxyphenyl)-2-phenylpyrimido[1,2-
a]benzimidazole (4ae)6j
4.3.2 2-Phenylpyrimido[1,2-a]benzimidazole (4aa)15
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), 4-methoxyphenylpropiolic acid (211.2 mg,
1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8
mg, 1.2 mmol), gave 4ae (238.7 mg, 68%) as a yellow solid after
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), propiolic acid (74.2 ꢀL, 1.2 mmol), CuI
(19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg, 1.2 mmol),
gave 4aa (39.2 mg, 16%) as a yellow solid after chromatography;
mp 205–207 °C; 1H NMR (400 MHz, CDCl3): δ = 8.76 (d, J =
7.2 Hz, 1H), 8.30 – 8.24 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.86
(d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.56 – 7.51 (m, 3H),
7.41 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 161.6,
151.0, 145.0, 136.6, 133.0, 131.4, 129.0, 127.8, 127.0, 126.3,
121.9, 120.4, 110.4, 103.9; IR (KBr): v = 3046, 1699, 1593,
1526, 1487, 1445, 1305, 1267, 1210, 1031, 969, 772, 741, 705
cm-1; HR-MS (ESI): m/z = 246.1032, calcd for [C16H11N3+H]+:
246.1031.
1
chromatography; mp 217−219 °C; H NMR (400 MHz, CDCl3):
δ = 8.29 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.8 Hz,
2H), 7.55 – 7.48 (m, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.22 (s, 1H),
7.16 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 8.4
Hz, 1H), 3.97 (s, 3H); 13C NMR (150 MHz, CDCl3): δ = 161.7,
161.0, 152.3, 149.4, 145.5, 136.7, 131.2, 129.9, 128.9, 127.8,
127.6, 125.8, 124.8, 121.0, 120.1, 114.7, 114.7, 105.4, 55.6; IR
(KBr): v = 3017, 1619, 1597, 1533, 1484, 1449, 1306, 1217,
1085, 1015, 839, 822, 760, 738, 686 cm-1; HR-MS (ESI): m/z =
352.1452, calcd for [C23H17N3O+H]+] 352.1450.
4.3.3 4-Methyl-2-phenylpyrimido[1,2-a]benzimidazole (4ab)16

9
4.3.7
4-(4-Chlorophenyl)-2-phenylpyrimido[1,2-a]
129.4, 129.4, 127.7, 126.2, 125.3, 122.8, 120.6, 120.1, 114.2,
ACCEPTED MANUSCRIPT
benzimidazole (4af)6j
111.6, 56.7; IR (KBr): v = 3057, 2938, 2838, 2476, 1597, 1515,
1476, 1444, 1351, 1289, 1255, 1163, 1111, 1018, 749, 701 cm-1;
HR-MS (ESI): m/z = 352.1446, calcd for [C23H17N3O+H]+:
352.1450.
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), 4-chlorophenylpropiolic acid (216.0 mg,
1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8
mg, 1.2 mmol), gave 4af (230.8 mg, 65%) as a yellow solid after
chromatography; mp 231−233 °C; 1H NMR (400 MHz, CDCl3):
δ = 8.26 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.8 Hz,
2H), 7.61 (d, J = 8.4 Hz, 2H), 7.52 – 7.47 (m, 3H), 7.44 (t, J =
7.6 Hz, 1H), 7.20 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.73 (d, J =
8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 160.8, 148.0,
145.5, 145.5, 137.3, 136.4, 133.6, 131.3, 130.9, 129.8, 129.7,
128.8, 127.7, 125.9, 121.3, 120.3, 114.3, 105.3; IR (KBr): v =
3043, 1672, 1641, 1610, 1594, 1537, 1515, 1495, 1444, 13006,
1284, 1258, 1177, 1025, 831, 763, 737, 687; HR-MS (ESI): m/z
= 356.0951, calcd for [C22H14ClN3+H]+: 356.0955.
4.3.11
2-(4-Chlorophenyl)-4-phenylpyrimido[1,2-
a]benzimidazole (4ed)7a
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 4-
chlorobenzaldehyde (154.6 mg, 1.1 mmol), phenylpropiolic acid
(175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4ed (230.8 mg, 65%) as a
1
yellow solid after chromatography; mp 197−199 °C; H NMR
(600 MHz, CDCl3): δ = 8.22 (m, 2H), 7.93 (d, J = 8.2 Hz, 1H),
7.73 (m, 1H), 7.70 – 7.62 (m, 4H), 7.45 (m, 3H), 7.20 (s, 1H),
7.03 (t, J = 7.8 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H); 13C NMR (150
MHz, CDCl3): δ = 159.7, 151.8, 149.6, 145.3, 137.6, 135.0,
132.3, 131.1, 129.4, 129.2, 129.0, 128.3, 127.3, 126.1, 121.3,
120.2, 114.5, 104.9; IR (KBr): v = 3075, 3049, 3029, 2919, 2849,
1625, 1592, 1532, 1483, 1446, 1397, 1304, 1218, 1092, 820, 767
cm-1; HR-MS (ESI): m/z = 356.0948, calcd for [C22H14ClN3+H]+:
356.0955.
4.3.8
2-(4-Methoxyphenyl)-4-phenylpyrimido[1,2-
a]benzimidazole (4bd)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 4-
methoxybenzaldehyde (0.13 mL, 1.1 mmol), phenylpropiolic
acid (175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4bd (235.2 mg, 67%) as a
4.3.12
a]benzimidazole (4fd)
2-(3-Chlorophenyl)-4-phenylpyrimido[1,2-
1
yellow solid after chromatography; mp 194−196 °C; H NMR
(400 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.0
Hz, 1H), 7.68-7.28 (m, 5H), 7.37 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H),
6.95 (m, 3H), 6.60 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ = 162.3, 160.5, 152.2, 148.9, 145.3, 132.6,
130.9, 129.4, 129.2, 129.0, 128.3, 127.4, 125.6, 120.8, 119.8,
114.3, 114.2, 104.8, 55.3; IR (KBr): v = 3071, 3043, 1595, 1528,
1483, 1442, 1303, 1215, 1042, 760, 738, 706 cm-1; HR-MS
(ESI): m/z = 352.1452, calcd for [C23H17N3O+H]+: 352.1450.
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
chlorobenzaldehyde (0.12 mL, 1.1 mmol), phenylpropiolic acid
(175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4fd (220.1 mg, 62%) as a
1
yellow solid after chromatography; mp 196−198 °C; H NMR
(400 MHz, CDCl3): δ = 8.31 (m, 1H), 8.19 (m, 1H), 7.99 (d, J =
8.2 Hz, 1H), 7.70 (m , 5H), 7.54 – 7.43 (m, 3H), 7.24 (s, 1H),
7.05 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ = 159.4, 149.7, 145.6, 138.4, 135.1, 132.4,
131.2, 131.1, 130.1, 129.9, 129.4, 128.4, 128.3, 127.9, 126.1,
125.8, 121.4, 120.3, 114.6, 105.0; IR (KBr): v = 3064, 1623,
1590, 1528, 1486, 1443,1391, 1303, 1216, 1085, 766, 741, 703
cm-1; HR-MS (ESI): m/z = 356.0954, calcd for [C22H14ClN3+H]+:
356.0955.
4.3.9
2-(3-Methoxyphenyl)-4-phenylpyrimido[1,2-
a]benzimidazole (4cd)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
methoxybenzaldehyde (0.13 mL, 1.1 mmol), phenylpropiolic
acid (175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4cd (252.8 mg, 72%) as a
yellow solid after chromatography; mp 214−216 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.99 (br s, 1H), 7.94 (d, J = 8.4 Hz, 1H),
7.78 – 7.72 (m, 2H), 7.71-7.69 (m, 1H), 7.67 (br s, 1H), 7.66 (br
s, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.25 (s,
1H), 7.08 (dd, J = 10.4, 2.4 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H),
6.68 (d, J = 8.4 Hz, 1H),3.92 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 160.9, 160.2, 152.1, 149.2, 145.4, 138.0, 132.6,
131.1, 129.8, 129.4, 128.4, 127.4, 125.9, 121.2, 120.2, 120.1,
118.2, 114.5, 112.1, 105.4, 55.6; IR (KBr): v = 3054, 3020, 1625,
1593, 1526, 1483, 1448, 1261, 1209, 1171, 1036, 874, 797, 767,
734, 702 cm-1; HR-MS (ESI): m/z = 352.1444, calcd for
[C23H17N3O+H]+: 352.1450.
4.3.13
2-(2-Chlorophenyl)-4-phenylpyrimido[1,
2-
a]benzimidazole (4gd)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
chlorobenzaldehyde (0.12 mL, 1.1 mmol), phenylpropiolic acid
(175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4gd (269.8 mg, 76%) as a
1
yellow solid after chromatography; mp 194−196 °C; H NMR
(400 MHz, CDCl3): δ = 8.00 (d, J = 8.0 Hz, 1H), 7.96 (dd, J =
6.4, 2.8 Hz, 1H), 7.71 – 7.67 (m, 1H), 7.65 (m, 4H), 7.53 – 7.46
(m, 2H), 7.43 (m, 2H), 7.25 (s, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.76
(d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 161.5,
151.8, 151.8, 148.2, 145.3, 137.1, 132.3, 132.2, 132.0, 131.0,
131.0, 130.3, 129.3, 128.3, 127.2, 125.9, 121.3, 120.4, 114.7,
109.6; IR (KBr): v = 3071, 3043, 1595, 1528, 1483, 1442, 1303,
1215, 1042, 760, 738, 706 cm-1; HR-MS (ESI): m/z = 356.0951,
calcd for [C22H14ClN3+H]+: 356.0955.
4.3.10
2-(2-Methoxyphenyl)-4-phenylpyrimido[1,2-
a]benzimidazole (4dd)7b
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
methoxybenzaldehyde (0.13 mL, 1.1 mmol), phenylpropiolic
acid (175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4dd (252.8 mg, 72%) as a
yellow solid after chromatography; mp 160−162 °C; 1H NMR
(400 MHz, CDCl3): δ = 8.02 (d, J = 7.6 Hz, 1H), 7.95 (d, J =
8.4Hz, 1H), 7.70 -7.69 (m, 3H), 7.64 -7.63 (m, 2H), 7.55 (t, J =
7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.11
(d, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.47 (d, J = 8.4 Hz,
1H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 156.7,
155.7, 149.0, 145.6, 136.2, 134.9, 133.6, 132.0, 130.5, 129.5,
4.3.14
3-(4-Phenybenzo[4,5]imidazo[1,2-a]pyrimidin-
2yl)benzonitrile (4hd)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 3-
Cyanobenzaldehyde (144.2 mg, 1.1 mmol), Phenylpropiolic acid
(175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4hd (242.3 mg, 70%) as a
1
yellow solid after chromatography; mp = 154−156 °C; H NMR
(400 MHz, CDCl3): δ = 8.55 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H),

10
Tetrahedron
ACCEPTED MANUSCRIPT
7.78 (d, J = 7.6 Hz, 1H), 7.76 – 7.61 (m, 6H), 7.47 (t, J = 7.6
1-Isopropyl-2-aminobenzimidazole (175.1 mg, 1.0 mmol),
Hz, 1H), 7.22 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 8.4
Hz, 1H); 13C NMR (150 MHz, CDCl3): δ = 158.3, 151.5, 150.2,
145.6, 137.8, 134.1, 132.2, 131.8, 131.3, 131.2, 129.8, 129.5,
128.3, 127.3, 126.3, 121.7, 120.4, 118.2, 114.7, 113.3, 104.6; IR
(KBr): v = 3066, 2227, 1624, 1588, 1527, 1484, 1444, 1389,
1304, 767, 740, 703 cm-1; HR-MS (ESI): m/z = 347.1291, calcd
for [C23H14N4+H]+: 347.1297.
benzaldehyde (0.11 mL, 1.1 mmol), phenylpropiolic acid (175.3
mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 4’a (262.9 mg, 72%) as a red solid
after chromatography; mp 70−72 °C; 1H NMR (400 MHz,
CDCl3): δ = 7.86 (d, J = 7.6 Hz, 2H), 7.39 (m, 2H), 7.33 (q, J =
7.6 Hz, 4H), 7.25 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.99 (t, J =
7.8 Hz, 1H), 6.84 (t, J = 7.8 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H),
6.16 (d, J = 3.6 Hz, 1H), 5.37 (d, J = 3.6 Hz, 1H), 5.17 (m, 1H),
1.64 (dd, J = 11.2, 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ =
149.2, 142.7, 142.1, 139.5, 130.4, 130.2, 128.9, 128.0, 127.9,
127.6, 126.6, 125.7, 121.3, 120.3, 108.9, 108.6, 97.2, 59.4, 45.2,
20.3, 20.1; IR (KBr): v = 3059, 2976, 2930, 1616, 1582, 1483,
1344, 738, 700 cm-1; HR-MS (ESI): m/z = 388.1789, calcd for
[C25H23N3+Na]+: 388.1790.
4.3.15 2-Thienyl-4-phenylpyrimido[1,2-a]benzimidazole (4id)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-thenaldehyde
(0.10 mL, 1.1 mmol), phenylpropiolic acid (175.3 mg, 1.2
mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg,
1.2 mmol), gave 4id (206.1 mg, 63%) as a yellow solid after
chromatography; mp 210−212 °C; 1H NMR (400 MHz, CDCl3):
δ = 7.92 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 3.7 Hz, 1H), 7.74 – 7.61
(m, 5H), 7.59 (d, J = 5.0 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.17
(t, J = 4.4 Hz, 1H), 7.09 (s, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.62 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 156.2, 149.1,
145.5, 143.0, 132.4, 131.6, 131.1, 129.4, 128.7, 128.4 (2C),
127.7, 125.8, 121.1, 120.1, 114.3, 114.2, 104.6; IR (KBr): v =
3063, 1621, 1594, 1519, 1485, 1421, 1301, 1257, 1206, 762, 735,
4.3.19
a]benzimidazole (4’b)
10-Butyl-2,4-diphenyl-2,10-dihydropyrimido[1,2-
1-Butyl-2-aminobenzimidazole (189.1 mg, 1.0 mmol),
benzaldehyde (0.11 mL, 1.1 mmol), phenylpropiolic acid (175.3
mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3
(165.8 mg, 1.2 mmol), gave 4’b (314.7 mg, 83%) as a red solid
after chromatography; mp 53−55 °C; 1H NMR (400 MHz,
CDCl3): δ = 7.79 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.25 (q, J =
7.6 Hz, 4H), 7.17 (m, 2H), 6.97 – 6.88 (m, 2H), 6.77 (t, J = 7.2
Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 6.08 (d, J = 3.6 Hz, 1H), 5.29
(d, J = 3.2 Hz, 1H), 4.03 (t, J = 7.2 Hz, 2H), 1.86 – 1.74 (m, 2H),
1.41 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 149.7, 142.6, 142.2, 139.5, 131.8, 129.9, 128.9,
128.0, 127.9, 127.6, 126.7, 125.7, 121.5, 120.5, 108.8, 106.9,
97.3, 59.4, 41.1, 30.2, 20.2, 13.8; IR (KBr): v = 3046, 2954,
2923, 2856, 1633, 1602, 1527, 1487, 1452, 1375, 1260, 1096,
1014, 811, 767, 738, 703 cm-1; HR-MS (ESI): m/z = 402.1939,
calcd for [C26H25N3+Na]+) 402.1946.
703 cm-1; HR-MS (ESI): m/z
[C20H13N3S+H]+: 328.0908.
=
328.0900, calcd for
4.3.16 2-Naphthyl-4-phenylpyrimido[1,2-a]benzimidazole (4jd)
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), 2-
naphthaldehyde (171.8 mg, 1.1 mmol), phenylpropiolic acid
(175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4jd (259.7 mg, 70%) as a
yellow solid after chromatography; mp 184−186 °C; 1H NMR
(600 MHz, DMSO-d6): δ = 8.71 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H),
8.08 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 7.9
Hz, 1H), 7.73 (m, 1H), 7.62 (m, 2H), 7.48 (m, 1H), 7.25 – 7.23
(m, 2H), 7.20( m, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 6.6
Hz, 1H), 6.08 (s, 1H), 5.37 (d, J = 6.5 Hz, 1H); 13C NMR (150
MHz, DMSO-d6): δ = 169.2, 142.7, 140.6, 136.3, 134.6, 133.04,
133.01, 132.5, 129.5, 129.3, 129.1, 128.5, 128.4, 128.2, 127.6,
126.9, 125.7, 123.6, 123.4, 122.3, 119.6, 110.0, 64.3, 60.3; IR
(KBr): v = 3112, 3057, 3028, 1642, 1561, 1502, 1457, 1418,
1060, 835, 735, 701, 469 cm-1; HR-MS (ESI): m/z = 372.1499,
calcd for [C26H17N3+H]+: 372.1501.
4.3.20
10-Butyl-4-(4-chlorophenyl)-2-phenyl-2,10-
dihydropyrimido[1,2-a]benzimidazole (4’c)
1-Butyl-2-aminobenzimidazole (189.1 mg, 1.0 mmol),
benzaldehyde (0.11 mL, 1.1 mmol), 4-chlorophenylpropiolic acid
(216.7 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4’c (351.2 mg, 85%) as a red
liquid after chromatography; 1H NMR (400 MHz, CDCl3): δ =
7.85 (d, J = 7.2 Hz, 2H), 7.37 – 7.22 (m, 7H), 7.06 – 6.97 (m,
2H), 6.87 (t, J = 7.4 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.14 (d, J
= 3.6 Hz, 1H), 5.32 (d, J = 3.6 Hz, 1H), 4.10 (t, J = 7.2 Hz, 2H),
1.91 – 1.82 (m, 2H), 1.51-1.45 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ = 149.6, 142.6, 141.4, 139.3,
133.7, 131.7, 129.6, 129.0, 127.99, 127.96, 127.7, 125.6, 121.8,
120.6, 108.7, 107.1, 96.7, 58.7, 41.2, 30.2, 20.1, 13.8; IR (KBr):
v = 3062, 2908, 2870, 1727, 1683, 1622, 1545, 1480, 1347, 1079,
913, 726, 690 cm-1; HR-MS (ESI): m/z = 414.1735, calcd for
[C26H24ClN3+H]+: 414.1737.
4.3.17
(4kd)
2-Citronellyl-4-phenylpyrimido[1,2-a]benzimidazole
2-Aminobenzimidazole (133.5 mg, 1.0 mmol), citronellal
(0.20 mL, 1.1 mmol), phenylpropiolic acid (175.3 mg, 1.2
mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg,
1.2 mmol), gave 4kd (221.5 mg, 60%) as a yellow solid after
1
chromatography; mp 75-77 °C; H NMR (400 MHz, CDCl3): δ
= 7.94 (d, J = 8.4 Hz, 1H), 7.72 – 7.55 (m, 5H), 7.42 (t, J = 7.6
Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.61
(s, 1H), 5.10 (t, J = 6.8 Hz, 1H), 2.96 (dd, J = 13.6, 6.0 Hz, 1H),
2.71 (dd, J = 13.6, 8.4 Hz, 1H), 2.28 – 2.16 (m, 1H), 2.13-1.99
(m, 2H), 1.67 (s, 3H), 1.60 (s, 3H), 1.53 – 1.44 (m, 1H), 1.38 –
1.23 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 168.4, 151.8, 148.3, 144.7, 132.2, 131.3, 130.8,
129.2, 128.2, 127.2, 125.5, 124.3, 120.7, 119.9, 114.3, 108.9,
46.2, 36.9, 32.6, 25.5, 25.4, 19.5, 17.6; IR (KBr): v = 3056, 2961,
2907, 2851, 1628, 1593, 1526, 1484, 1449, 1304, 1287, 760, 738,
4.3.21
10-Butyl-4-(4-methoxyphenyl)-2-phenyl-2,10-
dihydropyrimido[1,2-a]benzimidazole (4’d)
1-Butyl-2-aminobenzimidazole (189.1 mg, 1.0 mmol),
benzaldehyde (0.11 mL, 1.1 mmol), 4-methoxyphenylpropiolic
acid (211.2 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 4’d (356.0 mg, 87%) as a red
1
liquid after chromatography; H NMR (400 MHz, CDCl3): δ =
700 cm-1; HR-MS (ESI): m/z
[C25H27N3+H]+: 370.2283.
= 370.2288, calcd for
7.87 (d, J = 8.4 Hz, 2H), 7.35-7.31 (m, 4H), 7.26 (d, J = 7.2 Hz,
1H), 7.02-6.95 (m, 2H), 6.86-6.82 (m, 3H), 6.62 (d, J = 7.6 Hz,
1H), 6.11 (d, J = 3.6 Hz, 1H), 5.35 (d, J = 3.6 Hz, 1H), 4.10 (t, J
= 7.2 Hz, 2H), 3.74 (s, 3H), 1.91 – 1.82 (m, 2H), 1.51-1.45 (m,
2H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ =
4.3.18
10-Isopropyl-2,4-diphenyl-2,10-dihydropyrimido[1,2-
a]benzimidazole (4’a)

11
159.3, 149.6, 142.1, 139.5, 135.0, 131.7, 129.9, 128.0, 127.9,
127.5, 125.6, 121.5, 120.5, 114.1, 108.9, 106.9, 97.6, 58.7, 55.2,
41.2, 30.2, 20.1, 13.8; IR (KBr): v = 2962, 2917, 1618, 1511,
1483, 1240, 1173, 1028, 728, 697 cm-1; HR-MS (ESI): m/z =
410.2232, calcd for [C27H27N3O+H]+: 410.2232.
2835, 1605, 1578, 1499, 1459, 1424, 1367, 1246, 1224, 1050,
ACCEPTED MANUSCRIPT
1028, 867, 779, 739, 721, 696 cm-1; HR-MS (ESI): m/z =
371.1222, calcd for [C23H18N2OS+H]+: 371.1218.
4.4.5
(6d)
3-Benzyl-2-(thiophen-2-yl)imidazo[2,1-b]benzothiazole
4.4.1 General Procedure for the Synthesis of Imidazo[2,1-
b]thiazoles (6a-6e)
2-Benzothiazolamine (150.2 mg, 1.0 mmol), 2-thenaldehyde
(0.19 mL, 2.1 mmol,), propiolic acid (74.2 ꢀL, 1.2 mmol), CuI
(19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg, 1.2 mmol),
gave 6d (211.1 mg, 61%) as a red liquid after chromatography;
1H NMR (400 MHz, CDCl3): δ = 7.56 – 7.51 (m, 1H), 7.35 –
7.31 (m, 1H), 7.29 – 7.24 (m, 2H), 7.20 (m, 5H), 7.15 – 7.10 (m,
2H), 6.97 (dd, J = 4.8 , 3.6Hz, 1H), 4.59 (s, 2H); 13C NMR (100
MHz, CDCl3): δ = 147.1, 139.9, 137.1, 136.9, 132.5, 130.1,
128.9, 127.5, 127.4, 126.8, 125.9, 124.6, 124.2, 124.0, 123.2,
121.1, 112.8, 30.7; IR (KBr): v = 3016, 2946, 1641, 1525, 1486,
847, 774, 952, 740, 574, 482 cm-1; HR-MS (ESI): m/z =
347.0675; calcd for [C20H14N2S2+H]+: 347.0677.
2-Benzothiazolamine (150.2 mg, 1.0 mmol), the aldehyde (1.1
mmol, 1.1 equiv.), the alkyne carboxylic acid (1.2 mmol, 1.2
equiv.), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (1.2 mmol,
1.2 equiv.), and DMSO (4 mL) were placed in a 10 mL reaction
tube. The reaction mixture was tightly sealed and heated at 110
°C for 12 h. After cooling, the mixture was poured into CH2Cl2
(30 mL), washed with water (2×10 mL), saturated aqueous
NH4Cl (3×10 mL) and brine (2×10 mL), and then dried with
Na2SO4 and passed through a celite pad. Evaporation of the
solvent under reduced pressure provided the crude product,
which was purified by column chromatography on silica gel with
petroleum ether:ethyl acetate (V:V = 20:1−2:1) as the eluent to
afford the final product.
4.4.6 3-(4-Methoxybenzyl)-2-phenylimidazo[2,1-b]benzothiazole
(6e)
2-Benzothiazolamine (150.2 mg, 1.0 mmol), benzaldehyde
(0.1mL, 1.1 mmol), 4-methoxyphenylpropiolic acid (211.2 mg,
1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8
mg, 1.2 mmol), gave 6d (199.8 mg, 54%) as a red liquid after
chromatography; 1H NMR (400 MHz, CDCl3): δ = 7.67 (m, 3H),
7.38 (m, 3H), 7.31 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 6.0 Hz, 2H),
7.18 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H),
3.78 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 158.5, 147.1,
145.4, 134.4, 133.0, 130.4, 129.5, 128.6, 128.6, 127.4, 127.3,
126.0, 124.3, 124.2, 122.0, 114.6, 113.3, 55.2, 30.1; IR (KBr): v
= 3056, 2998, 2240, 2201, 1668, 1591, 1501, 1416, 1299, 1253,
1214, 1163, 1019, 914, 833 cm-1; HR-MS (ESI): m/z = 371.1213,
calcd for [C23H18N2OS+H]+: 371.1218.
4.4.2 3-Benzyl-2-phenyimidazo[2,1-b]benzothiazole (6a)
2-Benzothiazolamine (150.2 mg, 1.0 mmol), benzaldehyde
(0.11 mL, 1.1 mmol), phenylpropiolic acid (175.3 mg, 1.2
mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%), K2CO3 (165.8 mg,
1.2 mmol), gave 6a (231.2 mg, 68%) as a red solid after
1
chromatography; mp 126–128 °C; H NMR (400 MHz, CDCl3):
δ 7.70 – 7.64 (m, 3H), 7.41 – 7.37 (m, 2H), 7.35 – 7.30 (m, 3H),
7.31– 7.25 (m, 4H), 7.21 – 7.16 (m, 2H), 4.64 (s, 2H); 13C NMR
(100 MHz): δ = 147.1, 145.4, 137.6, 134.2, 132.7, 130.2, 129.1,
128.5, 127.5, 127.3, 127.3, 126.8, 125.8, 124.2, 124.0, 121.4,
113.0, 30.7; IR (KBr): v = 3083, 2923, 2371, 2338, 1544, 1493,
1459, 1065, 1000, 911 cm-1; HR-MS (ESI): m/z = 341.1110,
calcd for [C22H16N2S+H]+: 341.1112.
Acknowledgments
4.4.3 3-Benzyl-2-(3-chlorophenyl)imidazo[2,1-b]benzothiazole
(6b)
This work was supported by the National Natural Science
Foundation of China (21471093, 21302119) and the Fundamental
Research Funds for the Central Universities (GK201701002).
2-Benzothiazolamine
(150.2
mg,
1.0
mmol),
3-
chlorobenzaldehyde (0.12 mL, 1.1 mmol), phenylpropiolic acid
(175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 6b (209.5 mg, 56%) as a red
solid after chromatography; mp 137–139 °C; 1H NMR (400
MHz, CDCl3): δ = 7.34 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.49 (m,
1H), 7.35 – 7.28 (m, 3H), 7.26 – 7.19 (m, 5H), 7.1 – 7.13 (m,
2H), 4.57 (s, 2H). 13C NMR (100 MHz, CDCl3): δ = 147.3, 144.0,
137.2, 136.0, 134.5, 132.6, 130.3, 129.7, 129.1, 127.5, 127.5,
127.2, 127.0 126.0, 125.1, 124.4, 124.1, 122.1, 113.1, 30.7. IR
(KBr): v = 3061, 2956, 2787, 1771, 1732, 1701, 1560, 1541,
1506, 1487, 989, 941, 909, 874, 839, 817, 779, 740, 611, 570,
533, 504 cm-1; HR-MS (ESI): m/z = 375.0722, calcd for
[C22H15ClN2S+H]+: 375.0723.
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(6c)
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(150.2
mg,
1.0
mmol),
3-
methoxybenzaldehyde (0.13 mL, 1.1 mmol), phenylpropiolic
acid (175.3 mg, 1.2 mmol), CuI (19.8 mg, 0.1 mmol, 10 mol%),
K2CO3 (165.8 mg, 1.2 mmol), gave 6c (214.6 mg, 58%) as a red
1
liquid after chromatography; H NMR (400 MHz, CDCl3): δ =
7.58 (d, J = 8.4 Hz, 1H), 7.34 – 7.21 (m, 8H), 7.16-7.11 (m, 2H),
6.84 (d, J = 7.2 Hz, 2H), 4.59 (s, 2H), 3.72 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ = 159.7, 147.0, 145.3, 137.5, 135.5, 132.7,
130.2, 129.4, 129.0, 127.5, 126.8, 125.8, 124.2, 124.0, 121.6,
119.6, 113.6, 113.0, 112.3, 55.0, 30.8; IR (KBr): v = 3065, 3025,

12
Tetrahedron
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