One-step synthesis of alkyl 2-chloropyrimido[1,2-a]benzimidazole-3-carboxylates under catalyst-free: Combined experimental and computational studies

Article abstract of DOI:10.1016/j.tetlet.2015.07.050

An efficient method for the preparation of pyrimido[1,2-a]benzimidazole derivatives utilizing squaric acid dichloride has been developed at room temperature without catalyst. This method provided a rapid synthesis of pyrimido[1,2-a]benzimidazole system. T

Full text of DOI:10.1016/j.tetlet.2015.07.050

Tetrahedron Letters 56 (2015) 5071–5075
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step synthesis of alkyl 2-chloropyrimido[1,2-a]benzimidazole-
3-carboxylates under catalyst-free: combined experimental and
computational studies
a,b,
Yang Liu a, Guoming Xia a, Chao Luo a, Jianqi Sun a,b, Benfei Ye a,b, Yanli Yuan b, , Hongming Wang
⇑
⇑
a Institute for Advanced Study, Nanchang University, Nanchang, Jiangxi 330031, China
b School of Chemistry, Nanchang University, Nanchang, Jiangxi 330031, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the preparation of pyrimido[1,2-a]benzimidazole derivatives utilizing squaric
acid dichloride has been developed at room temperature without catalyst. This method provided a rapid
synthesis of pyrimido[1,2-a]benzimidazole system. The result indicates that those expeditious reactions
could be carried out only in the presence of alcohols, affording the corresponding alkyl 2-chloropyrim-
ido[1,2-a]benzimidazole-3-carboxylates. Furthermore, the yield of products seems to be closely relevant
to the steric hindrance of the added alcohols. On the basis of experimental and theoretical analyses, a
plausible mechanism has been proposed and corroborated through DFT calculations for exploring a prac-
tical way to efficiently synthesize those highly versatile substituted homologs.
Received 26 May 2015
Revised 11 July 2015
Accepted 16 July 2015
Available online 21 July 2015
Keywords:
Pyrimido[1,2-a]benzimidazole
Catalyst-free
Squaric acid dichloride
DFT calculation
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
series of electron-deficient reactants like enaminones,15
acetylenic aldehydes,16 tetracyanoethylene,17
a,b-unsaturated
As we all know, fused heterocyclic compounds1 are often of
much greater interest and application than the constituent mono-
cyclic systems2 in the aspect of various chemistry fields including
functional materials,3 molecular recognition4 medicinal chem-
istry,5 and coordination chemistry.6 Among those heterocycles,
the N-based heteroaromatic pyrimido[1,2-a]benzimidazole has
been widely applied7 and functionalized in view of their particular
privileged structures8 and wide spectrum of biological activity.9 In
fact, almost all the reported pyrimido[1,2-a]benzimidazoles,
known as effective pharmacophores possess antibiotic10 and
anti-arrhythmic11 activity, substance p receptor-binding activity,12
as well as promising antineoplastic activity,13 are highly
substituted by various effective groups inherited from the
reaction precursors. For instance, Matthew’s group14 utilized
pyrimido[1,2-a]benzimidazole structure as a central skeleton to
study the treatment of T-cell-mediated autoimmune and
inflammatory disorder and organ transplant, and they found that
those highly modified derivatives exhibited potent inhibition of
lymphocyte specific kinase activity.
ketones/esters,18 etc. Recently, one-pot synthetic approaches
utilizing aromatic aldehydes19 for substituted pyrimido[1,2-a]-
benzimidazoles have also been reported. And also, Pozharskii and
his coworkers20 utilized an aldehyde derivative to react with
2-aminobenzimidazole to synthesize the substance with the
pyrimido[1,2-a]benzimidazole structure. However, these methods
often need a suitable metallic catalyst or longtime refluxing at high
temperature. Therefore, developing
a synthetic method in a
straightforward manner is to be extremely desired for medicinal
chemists.
In this Letter, we provide an efficient method that can be con-
ducted at the room temperature and under metal-free condition.
The synthesis is based on 3,4-dichlorocyclobut-3-ene-1,2-dione
(squaric acid dichloride) for synthesizing a series of novel pyrim-
ido[1,2-a]benzimidazole derivatives. Laboratory findings reveal
that the present system could be rapidly operated only in the pres-
ence of alcohols and the obtained products are assigned to be the
corresponding Cl-substituted carboxylic esters. Interestingly, the
product yields are inversely proportional to the steric hindrance
of the hydroxy group of the added alcohols. To explore the reason
for the phenomena observed, underlying reaction mechanisms
were calculated in detail and compared employing density func-
tional theory (DFT), a method of choice for the cost-effective treat-
ment of large chemical systems with high accuracy.21–23 The B3LYP
Currently, pyrimido[1,2-a]benzimidazole tricyclic systems are
prepared by condensation of 1H-benzimidazol-2-amine with a
⇑
Corresponding authors.
E-mail addresses: yuanyanli@ncu.edu.cn (Y. Yuan), hongmingwang@ncu.edu.cn
(H. Wang).
http://dx.doi.org/10.1016/j.tetlet.2015.07.050
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5072
Y. Liu et al. / Tetrahedron Letters 56 (2015) 5071–5075
R
Cl
Cl
O
O
O
H
O
O
N
O
O
H
N
ROH
rt
N
N
EtOH
rt
N
NH2
+
O
N
NH2
N
N
+
Cl
Cl
N
N
Cl
Cl
Re2
Re1
PRo
Re2
Re1
R=methly, ethyl, propyl, isopropyl,n-butyl,tertiarybutyl, benzyl
Scheme 1. The synthesis of compound PRo.
Scheme 2. The reaction between 1H-benzimidazol-2-amine (Re1) and squaric acid
dichloride (Re2).
Table 1
The reaction of 1H-benzimidazol-2-amine and squaric acid dichloride in various
solvents
Entry
Solvent
R
Timeb
Product
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
MeOH
EtOH
n-PrOH
i-PrOH
n-BuOH
t-BuOH
Phemethylol
CH3CN + EtOHd
THF + EtOHd
DMF + EtOHd
CH3
20
20
20
40
20
60
20
20 + 40
20 + 40
20 + 40
P1
P2
P3
P4
P5
P6
P7
P2
P2
P2
52
46
41
CH2CH3
(CH2)2CH3
CH(CH3)2
(CH2)3CH3
C(CH3)3
PhCH2
CH2CH3
CH2CH3
CH2CH3
Tracea
38
Trace
35
25
26
23
a
b
c
Compared with obtained product by TLC.
Times are in minute.
The isolated yield of spectroscopically pure product.
Figure 1. ORTEP diagram of the product.
d
The reactions were operated in CH3CN, THF or DMF (5 ml) for 20 min followed
by additional EtOH (5 ml) for another 40 min.
method together with the standard 6-311G(d,p) basis were used in
all calculations under the Gaussian 09 program.24
As reported, we firstly attempted to react 1H-benzimidazol-
2-amine with diethyl squarate for synthesizing squaramide
derivatives, but the results, unexpectedly, showed that the reaction
only gave the starting materials even if refluxing for 24 h in EtOH
(determined with TLCs). Several other solvents (DMF, CH3CN, and
DMF) were subsequently tried but the results remained.
Considering the activity, we improved the project by adding a sat-
urated EtOH solution of equivalent 2-aminobenzimidazole into
fresh squaric acid dichloride under vigorous stirring (Scheme 1).
To our great surprise, the reaction mixtures turned into orange-
red immediately accompanied by white smoke as well as heat
release, then a large amount of solid precipitated out after a further
20 min stirring at room temperature. The yellow fluorescent
product was isolated in 46% yield and crystallized by the slow
evaporation method. Surprisingly, the X-ray diffraction analysis
showed that the product was assigned to be the alkyl 2-chloropy-
rimido[1,2-a]benzimidazole-3-carboxylates (PRo) (Fig. 1) instead
of squaramide derivatives. Meanwhile, compound PRo was
characterized by 1H and 13C NMR spectroscopy, FT-IR and elemen-
tal analysis (see Supporting information).
Curiously, the EtOH in the magical system above was replaced
by a series of alcohols and several other common solvents in the
laboratory. As shown in Scheme 2, the reactions could be rapidly
operated in the presence of any tested alcohols and the products
were assigned to be the corresponding alkyl 2-chloropyrim-
ido[1,2-a]benzimidazole-3-carboxylates confirmed by NMR analy-
ses (see Supporting information). On the contrary, the mixtures
turned into jelly-like substance instantly after adding the other
solvents (CH3CN, THF, and DMF) of 1H-benzimidazol-2-amine into
fresh squaric acid dichloride under vigorous stirring.
Unfortunately, we failed to isolate any pure product because of
the extreme instability in the presence of ambient moisture.
Addition with equivalent stilled EtOH, noteworthily, the intract-
able intermediate in mixtures will immediately dissolve and
afforded the corresponding P2 under the same conditions. The
6.2
TS1
4.7
TS2
1.4
0.0
IN2
Re1+Re2
+HCl
-8.3
IN1
Figure 2. The potential energy profile of the process from Re1 to IN2 (energies are
in kcalÁmolÀ1).
yields of the reactions operating in various solvents are summa-
rized in Table 1. It is interesting to find that the yield of products
seems to be closely relevant to the nature of the added alcohols.
As shown below, the yield undergoes an insignificant decrease
from 52% to 35% after addition with primary alcohols. The yields
are nearly trace after addition with the secondary (i-PrOH) or ter-
tiary alcohol (t-BuOH). That is, the yield goes down with the
increase of steric hindrance of alcohol (see Fig. 2).
On the basis of theoretical analyses, there are two possible
mechanisms for the reaction between Re1 and Re2 in EtOH solu-
tion. As shown in Scheme 3, the N(1) atom of Re1 firstly attacks
the carbon atom linked to Cl atom of the electron-deficient four-
membered ring of Re2. This classical Michael addition involves a
low energy barrier of 6.2 kcalÁmolÀ1 and affords the intermediate
IN1 via a transition state TS1 (Fig. 3). After that, compound IN1
eliminates
a
HCl molecule with an energy barrier of
13.0 kcalÁmolÀ1 and forms the intermediate IN2. Additionally, this

Y. Liu et al. / Tetrahedron Letters 56 (2015) 5071–5075
5073
H
H
N
H
N
N(3)HN
O
N(2)O
N
NH
C(1)
+H
-HCl
H
N
N
Cl
NH2
+
O
O
N(N1)
Re1
Cl
Cl
C(2)
O
Cl
Cl
O
Re2
IN1
H
IN2
H
N
N
N
N
N
N
H
OH
NH
-H
N
NH
NH
A
O
O
N
N
O
OH
H
O
H
O
O
Cl
Cl
Cl
Cl
O
INa4
INa2
INa1
INa3
H
N
N
-H2O
-H2O
N
N
OH
O
N
O
NH
O
O
OH
N
N
N
O
O
Cl
Cl
H
H
Cl
INa5
PRo
INa6
H
N
H
N
N
N
N
N
-H
NH
O
N
NH
N
B
O
O
N
N
OH
O
O
H
Cl
Cl
Cl
Cl
OH
OH
INb2
INb3
INb4
INb1
Scheme 3. Overall reaction mechanisms for the reaction between 1H-benzimidazol-2-amine and squaric acid dichloride in EtOH.
7.2
0.0
TSa1
-10.6
INa1
+EtOH
+EtOH
INa2
-64.1
+EtOH
+EtOH
TSa2
-99.6
TSah2
+EtOH
-144.0
-150.2
TSa5
-158.7
TSa3
-155.4
TSa4
INa3
-161.2
INa5
+EtOH
-176.3
TSah5
-186.6
INa4
-196.5
INa6
-197.9
+EtOH
PRo
+H2O
Figure 3. The potential energy profile of route A (energies are in kcalÁmolÀ1).
reaction is an endothermic process with the energy of
1.4 kcalÁmolÀ1. Theoretically, the N atom of secondary amino-
group in IN2 undergoes an intramolecular nucleophilic addition
instantly by attacking the carbon atom linked to the oxygen atom.
There are two possible attacking ways which are defined as route A
and route B, with the corresponding active sites labeled C(1) and
C(2) atoms, respectively.
However, this synergistic step holds a high energy barrier of
79.9 kcalÁmolÀ1 (TSa2) without considering the solvent effect,
which means that this step is not able to occur at the room temper-
ature. Then we introduce the solvent effect of EtOH to assist the
proton transfer. As expected, the energy barrier sharply decreases
to 44.4 kcalÁmolÀ1 (TSah2) which is the rate-determining step in
route A (see Figs. 4 and 5).
In route A, the first step involves a transition state TSa1 with an
energy barrier of 7.2 kcal molÀ1 and affords a fused-heterocycle
INa2, which can easily lose a proton to form INa3 directly without
extra energy. Because of the tensile force, the four-membered ring
of INa3 tends to break to form a loose plane seven-membered ring
in INa4 which accompanies intramolecular proton transfer.
Whereafter, the O atom of EtOH molecule attacks the carbon
atom of carbonyl group bonded with N(2) atom in INa4, which
involves a transition state TSa3 to form INa5 with an energy
barrier of 27.9 kcalÁmolÀ1. Then, compound INa5 encounters an
intramolecular rearrangement to form
a
more stable
six-membered ring intermediate INa6, which will eliminate a

5074
Y. Liu et al. / Tetrahedron Letters 56 (2015) 5071–5075
0.0
INb1
+EtOH
-31.6
-33.2
TSb4
+H2O
-35.0
INb4
+EtOH
+H2O
TSb3
+EtOH
-76.2
TSb2
Figure 4. The optimization structure of transition states TSah2 and TSa2 (bond
lengths are in Å).
+EtOH
-88.0
INb3
+EtOH
-114.9
INb2
+EtOH
-138.9
PRo
+H2O
Figure 7. The potential energy profile of route B (energies are in kcalÁmolÀ1).
INa5
INa6
Figure 5. The optimization structure of intermediates INa5 and INa6 (bond lengths
are in Å).
a series of Cl-substituted pyrimido[1,2-a]benzimidazole carboxylic
esters at the room temperature under metal-free conditions.
Furthermore, the underlying mechanism in the present system is
particularly depicted by means of experimental and DFT theoreti-
cal analyses. Results reveal that the expeditious procedure could
be carried out only in the presence of alcohols with an energy bar-
rier of 44.4 kcalÁmolÀ1. The expansion of the magic system and the
pharmacodynamic screening of these heteroaromatic derivatives
will be reported in the future.
Acknowledgment
TSa5
TSah5
The support of the National Natural Science Foundation of
China (21363014 and 21103082) is gratefully acknowledged.
Figure 6. The optimization structure of transition states TSah5 and TSa5 (bond
lengths are in Å).
Supplementary data
H2O molecule to afford the target product PRo. The energy barrier
for this step is 20.2 kcalÁmolÀ1 (TSa5) which is lack of the solvent
effect and 5.8 kcalÁmolÀ1 (TSah5) assisted in EtOH, respectively
(see Figs. 6 and 7).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
050.
For route B, the proton on the N(3) atom firstly breaks away to
form a more stable intermediate INb2, which is 114.9 kcalÁmolÀ1
lower than INb1. Then N(2) atom attacks the protonated carbonyl
at C(2) atom to afford INb3 via TSb2 with an energy barrier of
38.7 kcalÁmolÀ1. Comparing with route A, this step encounters a
more apparent distortion. After that, in the rate-determining step,
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