Antinociceptive pyrimidine derivatives: Aqueous multicomponent microwave assisted synthesis

Article abstract of DOI:10.1016/j.tetlet.2013.04.099

Pyrimidines and their oxo-derivatives are well researched due to their anti-inflammatory, analgesic, antimicrobial, antiviral, and interferon inducing activities. New pyrimidine derivatives are therefore frequently synthesized to build up small molecule libraries for the discovery of drug candidates. Synthesis of 2,6-diaryl-4-(3H)-pyrimidinones and 2,6-diaryl-4-aminopyrimidines is traditionally a 2-day laboratory effort carried out in two steps, always using ethanol as solvent, and triethylamine as base. In this Letter, we advance a one-step alternative synthetic method with a 40 min reaction time using a microwave reactor in an aqueous media with potassium carbonate as base. The average yields were also somewhat improved. This new method thus emerges as more eco-friendly, not only because it does not employ triethylamine as base, but also due to a much reduced usage of organic solvents, leading to less harmful residues. Using this method, we synthesized twenty pyrimidine derivatives with antinociceptive activities in satisfactory chemical yields.

Full text of DOI:10.1016/j.tetlet.2013.04.099

Tetrahedron Letters 54 (2013) 3462–3465
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Antinociceptive pyrimidine derivatives: aqueous multicomponent
microwave assisted synthesis
Augusto L. Xavier a, Alfredo M. Simas a, Emerson P. da S. Falcão b, Janaína V. dos Anjos a,
⇑
a Departamento de Química Fundamental, Universidade Federal de Pernambuco, 50740-560 Recife, PE, Brazil
b Núcleo de Nutrição, Universidade Federal de Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrimidines and their oxo-derivatives are well researched due to their anti-inflammatory, analgesic, anti-
microbial, antiviral, and interferon inducing activities. New pyrimidine derivatives are therefore fre-
quently synthesized to build up small molecule libraries for the discovery of drug candidates.
Received 8 April 2013
Accepted 22 April 2013
Available online 3 May 2013
Synthesis of 2,6-diaryl-4-(3H)-pyrimidinones and 2,6-diaryl-4-aminopyrimidines is traditionally
a
2-day laboratory effort carried out in two steps, always using ethanol as solvent, and triethylamine as
base. In this Letter, we advance a one-step alternative synthetic method with a 40 min reaction time
using a microwave reactor in an aqueous media with potassium carbonate as base. The average yields
were also somewhat improved. This new method thus emerges as more eco-friendly, not only because
it does not employ triethylamine as base, but also due to a much reduced usage of organic solvents, lead-
ing to less harmful residues. Using this method, we synthesized twenty pyrimidine derivatives with
antinociceptive activities in satisfactory chemical yields.
Keywords:
Multicomponent reactions
Heterocycles
Antinociceptive activity
Microwave
Synthetic methods
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
one sole product.1,2,9–11,16 Faster synthetic routes are thus desir-
able to prepare such bio-active heterocycles.
Pyrimidines and their oxo derivatives are six-membered het-
erocycles of importance to medicinal chemistry due to their biolog-
ical activities. They are closely related to nucleic acids, since they
are very much alike in structure to the pyrimidine bases.1 Perhaps,
because of this structural similarity, compounds with such hetero-
cycles in their molecular structure were reported as antitumor,2,3
interferon inducer,4 antiviral,5 anti-hipertensive,6 hypoglycemic,7
anticonvulsant,8 antinociceptive,9,10 and anti-inflammatory11
agents.
Risperidone (I), bropirimine (II), and 5-fluorouracil (III) are
three successful examples of therapeutical tools that contain the
pyrimidinone nucleus in their structures (Fig. 1). Risperidone is
an atypical second-generation antipsychotic drug used in the treat-
ment of schizophrenia, and bipolar and behavior disorders.12 Other
examples are bropirimine and 5-fluorouracil, which are both anti-
cancer agents.13,14
Microwave radiation has been used since the 1980’s as an alter-
native manner to accelerate endothermic organic reactions.20
Microwave radiation can be focused in the reaction medium and
efficiently transfer energy directly to the reacting species, super-
heating them in a much faster manner, when compared to regular
convection heating,20 thereby facilitating the desired chemical
transformations. As a result, many organic reactions have been
performed using microwave energy, like cycloadditions,21 addi-
tions to carbonyl group,22 electrophylic substitutions,23 and het-
erocycle synthesis.24
Multicomponent reactions (MCRs) are one-pot reactions that
begin with three or more reagents that are mixed together, but
react in sequence. In general, these reactions are driven by an
irreversible step that precedes equilibrium in favor of the final
product.25 The use of microwave energy could accelerate this type
of reaction since the conductive heating could improve the rate
determining step for the overall process. Having this in mind,
Matloobi and Kappe, for example, used microwave irradiation to
perform the synthesis of several 2-amino-4-arylpyrimidine deriva-
tives through a Biginelli multicomponent approach.26
Pyrimidine or pyrimidinone scaffolds can be prepared in differ-
ent ways.1 Usually, a Michael adduct and an uronium-containing
molecule (guanidine,15 amidines,16 urea,17 thiourea, and their
derivatives18,19) are condensed in the presence of an organic base
to prepare the heterocyclic nucleus. In general, this process may
take about two days of laboratory work for the preparation of
Our research group has been involved in synthesizing and test-
ing the biological activities of pyrimidines and their oxo deriva-
tives.10,11,16 Some of the products we designed and prepared
presented relevant antinociceptive activities.10 However, the
methodology employed for the synthesis of such products is quite
laborious and requires two or more steps to finish the whole
⇑
Corresponding author. Tel.: +55 81 2126 7411; fax: +55 81 2126 8440.
E-mail address: janaina.anjos@ufpe.br (J.V. dos Anjos).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.099

A. L. Xavier et al. / Tetrahedron Letters 54 (2013) 3462–3465
3463
O
N
O
O
O
N
Br
F
F
NH
NH
N
N
N
NH2
N
H
O
II
I
III
Figure 1. Some examples of drugs containing the pyrimidine scaffold.
O
Accordingly, in this Letter we report our development of a new,
multicomponent, and eco-friendly methodology route for the syn-
thesis of 4-amino-2,6-diaryl-pyrimidine-5-carbonitrile and 6-oxo-
CN
O
NC
Ar
NH
. HCl
NH2
NH
+
+
K2CO3
Ar
H
Ph
COOEt
2,4-diaryl-1,6-dihydro-pyrimidine-5-carbonitrile
derivatives.
Water
MW
N
Ph
4a-j
Some of these derivatives have shown significant analgesic activity
5
6
7a-j
100°C, 40 min
in mice.10
20-51%
Scheme 1. Three-component reaction of aromatic aldehydes, ethyl cyanoacetate,
and benzamidine.
Results and discussion
In our synthetic approach, aromatic aldehydes (4a–j) were
allowed to react with ethyl cyanoacetate (5) and benzamidine
hydrochloride (6), in the presence of potassium carbonate as base.
The reaction was performed in water, under microwave irradiation
and led to the pyrimidinones 7a–j in moderate yields (Scheme 1,
Table 1).28,29
The reaction conditions using microwave irradiation were opti-
mized with benzaldehyde. Under microwave irradiation, the reac-
tion took place in about 40 min.
In order to be able to compare the methods, we also performed
the same reaction without microwave irradiation, using the same
solvent (water) and the same quantities for the reagents and benz-
aldehyde, in reflux. For 6-oxo-2,4-diphenyl-1,6-dihydro-pyrimi-
dine-5-carbonitrile (7a), the yield was only 18%, 8 h after the
beginning of the reaction.
Table 1
Microwave assisted multicomponent reaction for the
synthesis of 6-oxo-2,4-diaryl-1,6-dihydro-pyrimidine-5-
carbonitriles (7a–j)
Compound
Ar
Yield (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
Ph
42
47
33
49
46
45
41
20
43
51
m-Tolyl
p-Tolyl
p-ClPh
p-BrPh
p-FPh
p-OCH3Ph
m-NO2Ph
p-NO2Ph
3,4-diClPh
7j
In both cases, there are, possibly, two subsequent reactions
occurring in order to arrive at the heterocycle scaffold: the first
one is the Knoevenagel reaction,30 where an aromatic aldehyde
reacts with ethyl cyanoacetate, a so called ‘methylene active’ com-
pound because of its easily deprotonable central methylene group,
to form Michael’s intermediate. Once formed, the Knoevenagel ad-
duct can react with benzamidine. Michael’s adduct can then be at-
tacked by the lone electron pair of a nitrogen atom in the uronium
portion. There is then a sequence of additions with a subsequent
ring closure to form the corresponding heterocycle. However, the
last step in this mechanistic explanation for the pyrimidinone scaf-
fold formation is quite intriguing. According to Mendonça et al.,16
synthetic process.16 Indeed, synthesis of 2,6-diaryl-4-(3H)-pyri-
midinones and 2,6-diaryl-4-aminopyrimidines is traditionally a
two-day effort carried out in two steps always using ethanol as sol-
vent and triethylamine as base: in the first, one obtains the alicy-
clic derivative from aromatic aldehydes and a methylene-active
compound, and, in the second, a condensation of this alicyclic
derivative with an uronium donor is performed, followed by an
intramolecular cyclization.
Thus, the development of multicomponent methods for the pro-
duction of these bioactive heterocycles will speed up the synthetic
part of the discovery process for new pyrimidinic drugs.27
NH2
NH
Ph
Ph
Ph
CN
O
CN
H2N
Ph
NH
HN
Ph1
NH
Ph
H
Ph
COOEt
COOEt
NC
EtO
NC
EtO
O
OH
Ph
Ph
Ph
Ph
- HOEt
HN
Ph
NH
OEt
- H2
HN
Ph
N
N
NH
N
NH
O
O
Ph
O
Ph
O
CN
CN
CN
CN
Scheme 2. Mechanism of formation of pyrimidinone derivatives.

3464
A. L. Xavier et al. / Tetrahedron Letters 54 (2013) 3462–3465
NH
Ph
NH
Ph
O
NH
Ph
OH NH
O
N
CN
-H2O
H2N
H
Ph
Ph
N
Ph
N
H
Ph
Ph
H2
COOEt
Ph
Ph
Ph
Ph
-H2
N
NH
N
NH
OEt
N
NH
N
NH
COOEt
Ph
O
Ph
Ph
O
Ph
O
CN
CN
CN
CN
Scheme 3. Another mechanistic explanation for the formation of 2,6-diaryl-4-(3H)-pyrimidinones.
some compounds that contain the pyrimidinone scaffold may
NH2
interfere with the acute inflammatory response induced by acetic
acid, inhibiting or modulating the migration or production of
chemical mediators in the inflammatory site.11,31,32
CN
O
NH
NC
Ar
N
. HCl
NH2
+
+
K2CO3
Ar
H
Ph
CN
Water
MW
100°C, 40 min
N
Ph
4a-j
8
6
9a-j
Conclusions
22-70%
In short, we advanced in this article
a multicomponent
Scheme 4. Synthesis of 2,6-diaryl-4-aminopyrimidines via multicomponent
approach employing microwave energy and water as solvent to
synthesize pyrimidines and their oxo-derivatives. This environ-
mentally friendlier protocol furnishes products with higher chem-
ical yields, employs potassium carbonate as base instead of
triethylamine, and is performed in 40 min, showing to be much
faster than the usual 2 day route. We exemplified this synthetic
methodology by preparing 20 different 2,6-diaryl-4-(3H)-pyrimid-
inones and 2,6-diaryl-4-aminopyrimidines with antinociceptive
activities, in satisfactory chemical yields.
reaction.
atmospheric oxygen is responsible for this oxidation and loss of a
H2 molecule, leading to the heterocycle (Scheme 2).
Another mechanism which can also explain the formation of the
title compounds is the formation of an imine derivative which
takes place as a first step. This intermediate can be produced by
the reaction between the aldehyde and the amidine. Then, a subse-
quent reaction of this imine derivative with ethyl cyanoacetate
forms the desired heterocycle. Once again, in a process analogous
to the pyrimidinone ring formation, oxygen can perform the oxida-
tion of the dihydro derivative to a pyrimidine nucleus in the last
step (Scheme 3).
In order to expand this reaction profile to similar scaffolds, we
tested the protocol changing the ‘‘methylene active’’ compound
and thus, building the pyrimidine nucleus (9a–j). To achieve this
goal, the aromatic aldehydes reacted with malononitrile (8) and
benzamidine under the same reaction conditions (Scheme 4, Table
2).28,29
Acknowledgments
Our thanks are due to the Brazilian agencies CNPq and FACEPE
(PRONEX-0788-1.06/08, PRONEX-0981-1.06/08, PPP/APQ-1225-
1.06/10) for the financial support. One of us, A.L.X., is grateful to
CAPES for a graduate research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04
.099.
Some of the pyrimidinone derivatives described herein (7a, 7d,
and 7g) had their antinociceptive activity evaluated in mice
through acetic acid induced stimuli.10 It was reported that, at the
dose of 50 mg/kg, pyrimidinone 7a showed 85% of analgesia, thus
more potent than indomethacin (76% of activity, in comparison
to non-treated animals), the reference drug. It is suggested that
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carbonate dissolved in 10 mL of distilled water. This mixture was stirred at
room temperature until the neutralization of the benzamidine salt. To the clear
basic solution, 0.94 mmol of the corresponding aromatic aldehyde (1.0 equiv)
and 1.88 mmol (2.0 equiv) of ethyl cyanoacetate (for the synthesis of 7a–j) or
malononitrile (for the synthesis of 9a–j) were added. The mixture was placed
in a microwave reactor under the following conditions: temperature 100 °C
and 300 W of initial power for 40 min. After this time, the consumption of the
starting aldehyde was verified by TLC (hexane/ethyl acetate, 7:3 v/v). The
reaction was allowed to cool to room temperature and poured onto ice. The
formed precipitate was then vacuum filtered, washed with distilled water
(50 mL), and recrystallized from ethanol to provide the pure pyrimidinones or
pyrimidines.
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dihydro-pyrimidine-5-carbonitrile (7a): Colorless solid, yield: 42%; Rf: 0,43
(AcOEt); mp: above 300 °C. 1H NMR (DMSO-d6, 400 MHz) d (ppm): 7.59–7.68
(m, 6H, Harom); 8.04 (2H, d, J 8.0 Hz, Harom); 8.25 (2H, d, J 8.0 Hz); 13.73 (br s,
1H, NH). 13C NMR (DMSO-d6, 100 MHz) d (ppm): 95.6; 115.8;128.6; 128.7;
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28. General procedure for the multicomponent synthesis of 6-oxo-2,4-diaryl-1,6-
dihydro-pyrimidine-5-carbonitriles (7a–j) and 4-amino-2,6-diaryl-pyrimidine-5-
carbonitriles (9a–j): To a sealed vessel appropriated for reactions in microwave
reactors (capacity: 35 mL), were added 1.13 mmol (176 mg, 1.2 equiv) of
benzamidine hydrochloride and 1.88 mmol (249 mg, 2.0 equiv) of potassium
128.8; 131.3; 131.7; 133.1; 135.5; 159.0; 161.8; 168.6. I.R (KBr pellets) mmax
cmÀ1: 2923 (
C–H); 2201 ( C„N); 1552 ( C@O); 1488 ( C@N). ESI-HRMS m/z:
274.0975 (calcd for
17H12N3O [M+H+]: 274.0975). 4-Amino-2,6-diphenyl-
/
m
m
m
m
C
pyrimidine-5-carbonitrile (9a): Colorless solid, yield: 56%; Rf: 0.60 (hexanes/
AcOEt, 1:1 v/v); mp: 210–211 °C. 1H NMR (DMSO-d6, 400 MHz) d (ppm): 7.51–
7.60 (m, 6H, Harom); 7.97–7.99 (m, 4H, Harom, NH2); 8.41 (2H, dd, J 8.0 Hz, J
1.8 Hz, Harom). 13C NMR (DMSO-d6, 100 MHz) d (ppm): 84.4; 116.4; 128.4;
128.5; 128.6; 130.9; 131.5; 136.5; 136.6; 164.0; 164.6; 168.1. I.R (KBr pellets)
m
max/cmÀ1: 3480 (
m
N–H); 3345 (
mN–H); 2217 (mC„N); 1635 (mC@N); 1541 (mC@N).
ESI-HRMS m/z: 273.1134 (calcd for C17H13N4 [M+H+]: 273.1140).
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