Practical synthesis of 4H-pyrido[1, 2-a]pyrimidin-4-ones using ethylene glycol as a promoting solvent

Article abstract of DOI:10.1016/j.tetlet.2020.152269

A simple and useful protocol leading to different 4H-pyrido[1, 2-a] pyrimidin-4-ones have been established by cyclization of various 2-amino pyridines with β-oxo ester or alkynoate. The use of ethylene glycol was demonstrated to facilitate this condensati

Full text of DOI:10.1016/j.tetlet.2020.152269

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Practical synthesis of 4 H-pyrido[1, 2-a]pyrimidin-4-ones using ethylene gly‐
col as a promoting solvent
Mustafa Hussain, Jianhui Liu
PII:
DOI:
Reference:
S0040-4039(20)30736-X
https://doi.org/10.1016/j.tetlet.2020.152269
TETL 152269
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 May 2020
29 June 2020
17 July 2020
Please cite this article as: Hussain, M., Liu, J., Practical synthesis of 4 H-pyrido[1, 2-a]pyrimidin-4-ones using
ethylene glycol as a promoting solvent, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152269
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Practical synthesis of 4 H-Pyrido[1, 2-a]pyrimidin-4-ones
using ethylene glycol as a promoting solvent
Mustafa Hussain, [a] Jianhui Liu * [a] [b]
Leave this area blank for abstract info.
O
O
N
OEt
N
N
NH2
O
100-120 oC
EG
N
N
O
Ph
O
OEt

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Practical synthesis of 4 H-pyrido[1, 2-a]pyrimidin-4-ones using ethylene glycol as a
promoting solvent
Mustafa Hussain, [a] Jianhui Liu * [a] [b]
a State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, PR China
b School of Petroleum and Chemical Engineering, Dalian University of Technology, Panjin Campus, Panjin, Liaoning Province 124221, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and useful protocol leading to different 4H-pyrido[1, 2-a] pyrimidin-4-ones have been
established by cyclization of various 2-amino pyridines with -oxo ester or alkynoate. The use of
ethylene glycol was demonstrated to facilitate this condensation. This reaction proceeds by
nontoxic, cheap, environment friendliness and biodegradable solvent at the normal green
atmospheric condition in the absence of catalyst.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Ethylene glycol
PPO
–oxo esters
Green synthesis
Cyclization
1. Introduction
Green synthesis has a large importance in current synthetic
chemistry due to the environmental, health and societal concerns.
It has many diverse scope in different sectors like
pharmaceutical, industry, and academia due to their facile, clean,
efficient and non-polluting synthetic procedures that reduce the
use of organic toxic solvents and reagents.1 Except for a few
solvents such as water, ethanol, glycerol, and ionic liquids
ethylene glycol (EG) is considered to be a most important green
solvent which has high boiling point, low viscosity, high specific
energy and easily miscible with many other organic solvents.2
These unique properties made it highly applicable in industry
such as automobile, fine chemical, plastics, and textiles.3 It also
plays important roles in nano chemistry such as reducing agent
or ligand. 4
R
N
O
N
O
N
F
N
N
F
pirenperone
(tranquilizer)
N
N
N
O
CH3
N
O
NK
N
O
R=H, Risperidone
R=OH,Paliperidone
(antipsychotic drugs)
N
Pemirolast
(Antiasthmatic agent)
O
N
O
N
O
N
N
O
O
N
S
O
O
N
O
N
O
lusaperidone
(anti-depressant )
SSR69071
(human leukocyte elastase inhabitor)
Figure 1. Selected biologically and medicinally active molecules with pyrido
[1, 2-a] pyrimidin-4-ones.
Of many heterocyclic compounds related to some natural
products, drugs and other bio-medicinal materials5, compounds
containing pyrimidine cores have been considered to be
important and attracted many attention due to their high
biological activity, similarity in structure with purines bases, as
well as the building block of DNA and RNA.6 The skeletal
structure of 4H-pyrido[1, 2-a]pyrimidin-4-ones (PPO) is the
common part for many drugs such as pirenperone (tranquilizer
agent), pemirolast (antiasthmatic agent), SSR69071 (human
leukocytes inhastase inhibitors), risperidone and paliperidone
Due to their wide range of biological activities, different
methods to prepare the 2-substituted 4H-pyrido[1,2-a]pyrimidin-
4-ones were recorded in the literature. The most commonly used
one remains the condensation of 2-aminopyridines and -oxo
esters. Different catalysts, such as, AgSO3CF3, Al3PW12O40, and
BiCl3 are required in this process.8, 7c However in some cases for
this transformation, the temperature needed is very high at about
150-200 °C.9 While many new methods at lower temperature
have been developed, using strong corrosive acidic reagent like
H2SO4, POCl2, and polyphosphoric acid is unavoidable.10
Catalyst-free synthesis with low to moderate yield by refluxing in
(oral antipsychotic drugs) and lusaperidone (anti-depressant)
(Fig.1).5b, 7

2
Tetrahedron
ethanol using 2-aminopyridines with various activated
reduction from 6 to 4 hour did not affect the yield (Table 1
entries 12 and 14). But a further decrease to 2 h resulted in a
significant drop of the yield to 55 % (Table 1 entries 14 and 15).
Finally, increased concentration is a favorable effect for the yield.
Decreasing the EG amount from 3.5 to 1.5 mL can increase the
yield from 78% to 85% (Table 1 entries 14, 15 and 16).
alkynoates and alkoxyvinyl tri-chloromethyl ketones has been
reported.11 Solid-phase synthesis of different PPO derivatives
have also been done at 90 °C but longer reaction time was
needed in an aprotic solvent mixed with acetic acid.12 An
efficient method for the synthesis of novel PPO via
Cu(OAc)2·H2O catalyzed domino synthesis from 1,4-enediones
and 2-aminoheterocycles was reported by Wu et al. to give good
to moderate yields after heating at 80 oC for 6 hours.13 Pd-
catalyzed carbonylative cycloamidation of ketoimines for the
construction of PPO has been disclosed by Zeng et al.14
However, all above reported methods usually suffered from
many drawbacks, such as narrow functional group
compatibilities, harsh reaction conditions, a large amount of
additives, complicated materials, and highly hazardous
chemicals. Therefore, it is still a challenge to synthesize various
substituted 4H-pyrido[1,2-a] pyrimidin-4-ones using readily
available and inexpensive starting materials through a simple
procedure. Herein we describe an efficient synthesis of EG
promoted intermolecular cyclization of 2-aminopyridines with -
oxo ester or alkynoate to afford 2-substituted 4H-pyrido [1,2-a]
pyrimidin-4-ones.
Table 1. Optimization of reaction conditions a
N
NH2
+
O
O
EG
N
N
OEt
80-120 oC
O
2
3a
Yield %b
1a
S.No Catalyst
Solvent
Toluene
Toluene
Toluene
Toluene
EG
Temp (oC) Time (h)
1
ZnCl2
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
6
6
6
6
6
6
6
6
6
6
6
6
6
4
2
4
4
4
15
30
30
65
50
55
65
78
0
2
Ag2CO3
3
AgOAc
4
CuBr
5
ZnCl2
6
Ag2CO3
EG
7
AgOAc
EG
8
CuBr
EG
9
CuBr
EtOH
DMSO
MeOH
H2O
10
11
12
13
14
15
16
17
18
CuBr
0
2. Result and Discussion
-
-
-
-
-
-
-
-
58
67
15
78
55
80
85
85
Initially, our investigation started with the one-pot cyclization
reaction of 2-aminopyridine (1a) with ethyl acetoacetate (2),
which were performed using different catalysts in toluene at 100
oC for 6 hours. When ZnCl2 was used, target 3a was formed in
15% yield (Table 1, entry 1). An improved yield (30%) was
obtained when Ag2CO3 and AgOAc was added respectively
(Table 1, entries 2-3). A better yield to 65% was observed when
using CuBr (Table 1, entry 4). Next, the solvent was changed to
EG with much improved yields using the same series of catalysts,
affording 3a in yields of 50%, 55%, 65% and 78% for ZnCl2,
Ag2CO3, AgOAc and CuBr (Table 1, entries 4-8). As observed,
-
EG
EG
EGc
EGc
100
120
EGc
a Reaction conditions: 1a (1 mmol), 2 (1 mmol), catalysts (5 mol%, 0.1mmol),
and solvent (3.5 ml), b Isolated yield, c EG (1.5 ml).
The solvent of EG promotes the reaction in the absence of any
catalyst and provides a high yield as compared to other solvents
due to it acidic activity, high boiling point and hygroscopic liquid
with low viscosity (Table 1, entries 14-18).
According to the above results, we then investigated the scope
and limitation from various substrates for the synthesis of 4H-
pyrido[1,2-a]pyrimidin-4-ones using various 2-aminopyridines
and ethyl acetoacetate (2) and ethyl 3-phenylpropionate (4), as
shown in Table 2. Initially, we treated ethyl acetoacetate with 2-
the reactivity was in the order CuBr > AgOAc ≥ Ag2CO3 > ZnCl2
for the catalysts and EG > toluene for the solvent. CuBr was the
most effective catalyst compared with other catalysts due to its
unique Lewis acid property and its solubility in EG solvent
making this catalyst more favorable to derive above reaction
condition (Table 1, entry 8). No reactions occurred in either
EtOH or DMSO with the above mentioned four catalysts (Table
1 entries 9 and 10). Then, when we performed the reaction in the
absence of catalysts in MeOH and H2O at temperature of 100 oC,
the yields of desire product were 58 and 67% respectively (Table
1, entries 11 and 12). In the absence of solvent and catalyst, only
15% of desired product was obtained (Table 1 entry 13). The
temperature effect was also observed. When we performed the
reaction in the absence of catalysts in EG at temperature of 80 oC
and 100 oC, the yields of desire product increased respectively to
80% and 85% (Table 1, entries 16 and 17). Higher temperature to
120oC afforded the same yield of 85% compared with 100oC
(Table 1, entry 18). This showed that the reaction strongly
depended on solvents and temperature. The best result with a
yield of 85% was obtained at a temperature of 100 oC with EG as
the solvent and promoting medium (Table 1, entry 17). Other
factors were also considered by reducing the reaction time. The
aminopyridine,
2-amino-5-fluoropyridine,
2-amino-5-
bromopyridine, 2-amino-4-chloropyridine, 2-amino-4-methyl
pyridine, and 2-aminothiazole. All products were obtained in
good to excellent yield with different electronic environment of
the pyridines (Table 2, 3a-3g). 2-Aminopyridines with both
electron donating and electron withdrawing group tolerated the
reaction and helped in cyclization (90-88%) (Table 2, 3a-3g).
Unfortunately, the reaction of ethyl acetoacetate with 2-
aminopyrimidine failed due to the inductive effect of the
additional N-atom on the pyrimidine ring, which reduces the
nucleophilicity of the NH2 group. Since the -oxo esters are
not a strong electrophile, it would be difficult to react with
pyrimidine which is not nucleophilic enough. Further work is
still needed for the activation of the -oxo esters.

3
intramolecular proton transfer takes place to give neutral
Besides ethyl acetoacetate, we also tried the possibilities to
employ ethyl 3-phenylpropionate as the substrate to react with 2-
amino substituted heterocycles (Table 2, 5a-5j).Indeed, the
reaction was well performed, and all the products were obtained
in good yields, whereas the reactions using ethyl acetoacetate
took longer time for completion. It is important to mention that
the 2-amino-5-nitropyridine and 2-aminopyrimidine easily
cyclized with alkynoates moiety due to its higher electrophilicity
compared to -oxo esters, where we did not get the desire
product (Table 2, 5h-5i).
intermediate II. Then the cyclization occurs after the low laying
energy π electrons attacks the carbonyl carbon of the ester group
to form III. On further proton transfer via IV and elimination, the
desired 4H-pyrido [1,2-a] pyrimidin-4-one is formed. This
analysis is based on the above results and the previous reports in
which, A. R. Katritzky et al. have clearly demonstrated the
hemiaminal formation followed by the extrusion of ethanol, and
the final water elimination gives pyrimidinone type products.15
OH
O
H
Table 2. Scope of the reaction. a, b
H2
N
H
proton
transfer
O
OC2H5
N
OC2H5
Ph
C
O
O
N
Ph
O
N
Ph
O
OC2H5
N
V
OEt
VI
NH2
N
2
N
H
H
N
N
Ph
Ph
N
Ph
O
3a
NH2
-
H
EG,4h
100 0C
N
N
O
N
O
N
1a
N
OC2H5
O
VII
O
N
Ph
OEt
Scheme 2. Proposed mechanism of reaction aminopyridine with
alkynes.
O
5a
4
The proposed mechanism for the reaction of 2-aminopyridine
and ethyl 3-phenylpropionate is proposed in scheme 2 by the help
of previous literatures, where W. Zhang et al have clearly
demonstrated the formation of enamine intermediate followed by
the cyclization.16 Initially, EG combines the carbonyl oxygen and
the β-carbon of the triple bond is activated by conjugation which
become more favorable for the attack of amine to form
intermediate V. After proton transfer to the triple bond to give
VI, the low-lying energy π bonding electrons attacks the carbonyl
groups of the ester after the lone pair nitrogen electrons
delocalized to the ring to form intermediate VII. The desired
molecule is finally formed after losing a proton.
N
N
O
N
N
N
N
N
N
Cl
Br
F
O
O
O
3c 87%
3a 89%
3b 84%
3d 88%
N
O
N
N
N
S
N
N
N
I
N
O
O
O
3e 90%
3f 85%
3g 88%
5a 90%
N
N
N
N
N
N
O
N
F
N
Cl
Br
I
O
O
O
5e 92%
5b 82%
5c 83%
5d 86%
N
N
N
N
N
N
N
N
N
O2N
O
O
O
O
5i 78%
3. Conclusion
5g 88%
5f 89%
5h 85%
In conclusion, we have developed an efficient methodology
for the one-pot green synthesis of 4H-pyrido[1, 2-a]pyrimidin-4-
ones from 2-aminopyridines and ethyl acetoacetate/ethyl 3-
phenylpropionate. We also demonstrate the effectiveness of by
EG as promoting solvent, by which no catalysts are required for
this condensation. This methodology can be applied to a wide
range of β-oxo esters, alkynoates, and 2-aminopyridine reagent.
Different 4H-pyrido[1, 2-a]pyrimidin-4- ones derivatives were
obtained which may have high biological activities and a broad
range of application in the pharmaceutical industry. This catalyst-
free protocol has several features such as environmental
friendliness, easy operation, nontoxic solvents, and economical
methodology.
N
N
S
O
5j 88%
a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), 4 (1.0 mmol) and EG
(1.5 ml) at 100 oC for 4 h. b Percentage Isolated yields.
O
H
O
O
H
O
O
OH
H
O
H
N
H
N
O
O
H+ transfer
N
H
-EtOH
H
N
N
N
O
O
II
I
H
N
N
OH2
H
N
OH
H+ transfer
-H2O
-EG
N
4. Acknowledgments
N
N
O
H
O
H
O
O
O
This work was supported by the National Key Research and
Development Program of China (2016YFA0602900) and the
National Natural Science Foundation of China.
IV
III
Scheme 1. Proposed mechanism of reaction aminopyridine with
-ketoesters.
The possible reaction mechanism is proposed in scheme 1.
Initially, acidic proton of EG activates the carbonyl group of
ketone moiety, making the carbonyl carbon more favorable to be
attacked by amine and formed intermediate I. Next the
5. Reference
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4
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5
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Practical synthesis of 4 H-Pyrido[1, 2-a]pyrimidin-4-ones
using ethylene glycol as a promoting solvent
Mustafa Hussain, [a] Jianhui Liu * [a] [b]
Leave this area blank for abstract info.
O
O
N
OEt
N
N
NH2
O
100-120 oC
EG
N
N
O
Ph
O
OEt
Highlights





Green synthesis has many diverse scopes in
pharmaceutical, industry and academia
Ethylene glycol is considered to be a most important
green solvent
The cyclization of various 2-amino pyridines with -
oxo ester lead to Pyrido[1,2-a] pyrimidin-4-ones
The use of ethylene glycol was demonstrated to
facilitate this condensation
The skeletal structure of pyrido [1, 2-a] pyrimidin-4-
ones is the common part for many drugs