On water synthesis of the novel 2-oxo-1,2,3,4-tetrahydropyrimidines

Article abstract of DOI:10.1016/j.tet.2020.131790

A simple on water approach for the synthesis of novel tetrahydropyrimidine (THPM) derivatives has been developed under a green and sustainable fashion. For the first time, a deuterated Biginelli's hybrid was synthesized. Novel THPMs are suitable for further derivatization and could be an excellent toolkit for lead-oriented synthesis and/or cross-coupling reactions.

Full text of DOI:10.1016/j.tet.2020.131790

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On water synthesis of the novel 2-oxo-1,2,3,4-tetrahydropyrimidines
,
*
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ꢀ b
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Emilija Milovic , Nenad Jankovic , Goran A. Bogdanovic , Jelena Petronijevic ,
ꢀ a
Nenad Joksimovic
a
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University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovica 12, 34000, Kragujevac, Serbia
University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Science, Jovana Cvijica bb, Kragujevac, 34000, Serbia
"VINCA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia
b
ꢀ
c
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a r t i c l e i n f o
a b s t r a c t
Article history:
A simple on water approach for the synthesis of novel tetrahydropyrimidine (THPM) derivatives has been
developed under a green and sustainable fashion. For the first time, a deuterated Biginelli’s hybrid was
synthesized. Novel THPMs are suitable for further derivatization and could be an excellent toolkit for
lead-oriented synthesis and/or cross-coupling reactions.
Received 10 September 2020
Received in revised form
12 November 2020
Accepted 19 November 2020
Available online xxx
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
On water
Pyrimidines
Biginelli reaction
Isotopic labeling
1. Introduction
different functional groups required for some further synthetic
manipulation. Considering, many different methods and catalysts
The Biginelli reaction is well-known multicomponent reaction
through which is possible to access 2-oxo- and 2-thioxo-1,2,3,4-
have been applied for accessing THPMs [9]. Almost all the THPM
derivatives were synthesized directly via one-pot fashion [10,11].
Although there were six diversity points at the THPM core (N1, C2,
N3, C4, C5, and C6) that could be furthermore functionalized, the
most interesting seemed to be the derivatization of the substituent
at the C6 position (Fig. 1, methyl group). Functionalization
(bromination) of the methyl group from THPM was easily reached
by substitution reaction, giving the 6-bromomethyl and 6-
dibromomethyl THPM derivatives as products [12,13]. Another
way implies catalytic olefination of a methyl group at the C6 using
benzaldehyde under high temperature, hazardous solvents, and
catalysts consumption [13e15].
Therefore, the behavior of THPM core under hydrolytic condi-
tions was very interesting (Fig. 1) [16e20]. Pietro Biginelli noted
that the presence of KOH (in water under reflux) initiated deep
decomposition of the THPM core into benzaldehyde, ammonia, and
potassium carbonate [1]. Lately, Zigeuner showed that the N1-
unsubstituted THPMs were inactive under the hydrolytic condi-
tions (5% KOH, reflux) [19,20]. Also, some data showed that the
THPM can react with excess benzaldehyde and KOH in boiled 70%
EtOH, while the appropriate product was isolated in moderate yield
(<50%). It was also published that the N1-unsubstituted THPMs can
easily undergo to hydrolysis/decarboxylation process giving a
tetrahydropyrimidines-THPMs
[former
name
3,4-
dihydropyrimidine-2(1H)-ones(thiones)]. This reaction was found
by Pietro Biginelli in 1893 [1]. Since then, the synthetic potential of
the mentioned reaction has been ignored, and this discovery has
been put undercover by the scientific community. In the second
half of the 20th century (1980s) a significant exploration of Biginelli
chemistry started after decades of silence and disregarding that
discovery. The principal reason for this action was the discovery in
the terms of great and broad biological potential that Biginelli’s
products possess. From the 1980s until now, over 70 000 Biginelli-
like compounds have been synthesized (source SciFinder). A sig-
nificant number of THPM derivatives have been found to be potent
calcium-channel blockers, antihypertensive agents, adrenergic an-
tagonists, mPGES-1 inhibitors, antimicrobials, anticancer, and an-
tivirals agents [2e4]. They were also used as
a tool for
combinatorial [5] as well as material science [6e8]. From a struc-
tural point of view, the Biginelli reaction is attractive because
substituents attached at THPM core can be readily transformed into
* Corresponding author.
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E-mail address: nenad.jankovic@kg.ac.rs (N. Jankovic).
https://doi.org/10.1016/j.tet.2020.131790
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
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Please cite this article as: E. Milovic, N. Jankovic, G.A. Bogdanovic et al., On water synthesis of the novel 2-oxo-1,2,3,4-tetrahydropyrimidines,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131790

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E. Milovic, N. Jankovic, G.A. Bogdanovic et al.
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Fig. 1. Derivatization of THPM at C6 position.
complicated mixture of the products [17]. Based on the literature
survey, we also found some contradictory data in Dhankar and
Shutalev results [16,18], although both reactions were done under
nearly the same hydrolytic conditions (Fig. 1). Shutalev and Aksinov
performed the reaction to obtain product A (Fig. 1) by boiling two
equivalents of THPMs in 2.5% sodium hydroxide water solution
without loading the aldehyde [18]. Lately, Dhankar performed the
reaction under the same fashion, but with the stronger alkaline
conditions (5% and 10% aq. NaOH), obtaining product B [16]. At the
same time, Kappe discussed the poor reactivity of ester group of
THPMs towards the hydrolysis [21]. So, many available data are
limited and there is a need for further investigations in this area.
Taking into account disagreements between the reported results
and our interest in green [22e25] and Biginelli chemistry [26e29],
we investigated the reactivity towards hydrolysis of such an
important position (methyl at C6) at THPM core in reaction with
different aromatic aldehydes.
bases, the best yields for 3a′ were noted when applied NaOH (84%),
KOH (77%) or K2CO3 (51%) at 70 ꢀC through 4 h reaction time. Other
bases gave lower yields compared to NaOH for the same temper-
ature and reaction time. In the next experiments, we loaded 10 and
20eq. of NaOH to investigate the effects of base excess on the yields.
Achieved results indicated that the excess of sodium hydroxide
does not have an influence on the yield of 3a’. Synthesis of 3a′ in
low concentration of aqueous sodium hydroxide solution (0.75%)
was investigated. Therefore, under this reaction mode yield of 3a′
was significantly lower (42%). The crucial effect on the yield has had
the concentration of applied base and temperature. In further ex-
periments, instead of THPM methyl ester (1a) we explored the
reactions between ethyl (1b), benzyl (1c), and allyl (1d) esters with
2a′ in the presence of 2eq. NaOH. As expected, lower yields were
achieved (75%, 71%, and 81% of 3a′ for applied 1b, 1c, and 1d,
respectively) compared to ones obtained applying methyl ester 1a.
Respecting optimization, the best-yielding reaction condition
was as follows: 1a (5 mmol), 1eq. of 2a’ (5 mmol) and 2eq. of NaOH
(10 mmol, 7.5% aq. solution) via on water at 70 ꢀC through 4 h. To
demonstrate the substrate scope of the method, we applied opti-
mized reaction conditions to the other aromatic aldehydes (Fig. 2)
and THPMs (Fig. 3). After a simple work-up (see ESI), the newly
synthesized products were isolated and characterized (Figs. S1-
S19). The structures and isolated yields of products 3a′-i’ are out-
lined in Fig. 2. Generally, good-to-excellent yields were noted, but
the best yield was realized for 3h’. Also, in the case of utilization
THPMs 1a’’ and 1b’’ in reaction with 2a′, good yields of targeted
products 3a’a’’ and 3a’b’’ were achieved (Fig. 3). Taking into ac-
count that investigated reactions have been done under on water
fashion, it is reasonable to explore the destiny of protons from
water molecules [30]. In order to track the route of protons through
the reaction, the next experiment was carried out using NaOD/D2O
instead of NaOH/H2O. To our delight, deuterated THPM 3a′-d2 was
isolated in good yield (82%), proving the role of protons from water
(Fig. 4). In addition, the same deuteration manner appeared using
NaOH/D2O. Based on NMR spectra, two protons and their appro-
priate carbons peaks disappeared due to deuteration (Figs. S24-
S27). Because of the presence of deuterons in the molecule 3a
′-d2, signals of adjacent protons (benzylic and benzylidene) were
simplified into a singlet. However, we assumed that H/D exchange
2. Results and discussion
Our investigations began with conditions screening. For the
model reaction, we used 1a (1eq.), benzaldehyde (1eq. of 2a′), and
two equivalents of different bases (LiOH, NaOH, KOH, K2CO3, Li2CO3
and Cs2CO3) under on water and solvent-free mode (Table 1).
All the applied modes that included the application of all bases
at room temperature produced product in traces. However, under
higher temperature conditions (70 ꢀC), the best yields were ob-
tained via on water fashion, for all applied bases. Among applied
Table 1
Optimization of the reaction conditions.
Yields of 3a0 (%)
Base
on water
solvent-free
LiOH
47
e
NaOH
KOH
K2CO3
Li2CO3
Cs2CO3
84
77
51
<10
<10
<10
<10
e
e
e
2

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E. Milovic, N. Jankovic, G.A. Bogdanovic et al.
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Fig. 2. General outline for the synthesis of 3a′-i’; reaction conditions as follow: 1 (5 mmol), 1eq. of 2a′-i’ (5 mmol) and 2eq. of NaOH (10 mmol, 7.5% aq. solution) at 70 ꢀC.
Fig. 3. Olefination of different THPMs (1a00, 1b00) with 2a′.
happened between 3a′ and D2O, on the organic-water interface.
Hence, we explored the control reaction by investigating isotopic
labeling properties of protons in 3a′ skeleton under optimized
conditions. However, protons in 3a0 did not display exchangeable
properties, approving that direct conversion of 3a′ into 3a′-d2 in
NaOD/D2O was not possible (Fig. 4).
We proposed that the deuteration most likely took place during
the formation of some stable intermediates which were formed on
the reaction path. Hence the control experiments were performed
in NaOD/D2O, and intermediate III-d was isolated (Figs. 4, S28 and
S29). Also, nondeuterated intermediate III was obtained by using
NaOH/H2O (Figs. S30 and S31). Using system NaOD/D2O in refluxing
CD3OD inseparable mixture of deuterated and nondeuterated
THPM were produced in very low yields [17]. Mentioned facts and
achieved results imply that reaction of THPMs with NaOH needed
to carry out under on water fashion and at the same time in the
absence of organic solvents. Also, the presence of deuterons in the
final product pointed out that the reaction probably involved
interfacial proton transfer from water to intermediate (III-d), and
then to the product (3a′-d2) at the organic-water interface.
Fig. 4. On-D2O synthesis of III-d and 3a′-d2 (top); Proposed mechanism, deuterons are
given in red.
Considering the experimental examinations and the results, we
proposed a followed mechanistic path (Fig. 4). In the first step, 1a
3

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E. Milovic, N. Jankovic, G.A. Bogdanovic et al.
Tetrahedron xxx (xxxx) xxx
underwent hydrolysis to producing I. Then, the intermediate I
underwent the decarboxylation through II, giving intermediate III-
d. Finally, III-d formed carbanion IV, that in reaction with carbonyl
moiety from aldehyde forms V, that gave product 3a′-d2.
3. Materials and methods
3.1. General experimental procedures
Tetrahydropyrimidines 1a-d, 1a00 and 1b00 were synthesized
following our published method [27]. Aromatic aldehydes and so-
dium deuteroxide solution were purchased from Sigma. The
melting points (mp) were determined on a Mel-Temp apparatus
and are uncorrected. The NMR spectra of compounds (Figs. S1-S31)
were performed in DMSO‑d6 on a Varian Gemini 200 MHz NMR
spectrometer (1H at 200 and 13C at 50 MHz). Abbreviations for the
NMR signal that were used are: s ¼ singlet, d ¼ doublet,
dd ¼ doublet of doublet, t ¼ triplet, m ¼ multiplet, and br.
s. ¼ broad singlet. Mass spectrometry was performed by Waters
Micromass Quattro II triple quadrupole mass spectrometer and
MassLynx software for control and data processing. Electrospray
ionization in the positive mode was used. The electrospray capillary
was set at 1.0 kV and the cone at 5 V. The ion source temperature
was set at 140 ꢀC and the flow rates for nitrogen bath and spray
were 500 l/h and 50 l/h, respectively. The collision energy was
10 eV.
Molecular structures of 3a′ and 3e′ are confirmed by single-
crystal X-ray analysis (Fig. 5). Both compounds crystallized in the
triclinic space group Pꢁ1 but only 3a′ incorporates one molecule of
DMSO in the asymmetric unit of the unit cell. Regardless of this
structural difference in crystal state and the fact that DMSO forms a
relatively strong N1eH/O2 hydrogen bond with 3a′ molecule (see
Fig. 5 and Table S2), both compounds exhibit similar conformation
(Fig. S32). Namely all atoms in 3a′ and 3e′ are placed in two planes.
The smaller plane is defined by the C5eC10 phenyl ring while the
rest of the atoms define another plane. These two parts of mole-
cules are interconnected through the C4eC5 bond which is the
longest CeC bond in both crystal structures (See Table S1).
The spatial orientation of the C5eC10 phenyl ring regarding the
six-membered heterocyclic ring is very similar in both compounds
(Fig. S32). Thus the C3eC4eC5eC6 torsion angle is ꢁ84.0(3)
and ꢁ84.5(2)ꢀ in 3a′ and 3e′ respectively. The crystallographic
analysis also confirmed that the C11eC12 bond [1.333(4) and
1.327(3) Å in 3a′ and 3e′ respectively] has a double bond character
in both structures. Corresponding NeC bonds (N1eC1 vs. N2eC1
and N1eC2 vs. N2eC4) in two molecules display some differences
in bond lengths (Table S1) and it can be explained by the influence
of C4 which is only sp3 hybridized atom. Both compounds form
centrosymmetric dimers in the crystal lattice with two molecules
interconnected by two relatively strong NeH/O1 hydrogen bonds
(Table S2). The main difference between the two molecules is that
they use different NeH groups for hydrogen bonding within the
dimers (Fig. S33). The geometrical parameters of all hydrogen
bonds are given in Table S2.
3.2. General procedures for synthesis 3a0-i’, 3a’a00, 3a’b00 and 3a0-d2
In 25 ml round-bottom flask 5 ml 7.5% NaOH water solution
(2eq., 10 mmol, 0.400 g in 5 ml) and temperature raised to 70 ꢀC.
Then, 5 mmol of aromatic aldehyde and 5 mmol of appropriate
THPM were added. The reactants swam on water and the reaction
mixture was stirred for 4 h. Reaction progress was followed by TLC.
Target products fall out as solid, then hot mixture was filtered off,
washed with 50% ethanol, and dried in vacuum. The same pro-
cedures for the synthesis of 3a′-d2 were used, but with the
Fig. 5. Crystal structure and atom-numbering scheme of 3a’ (top) and 3e’ (bottom). Displacement ellipsoids are drawn at the 40% probability level. Hydrogen bonds between
molecule 3a′ and DMSOare shown in light blue dotted lines.
4

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E. Milovic, N. Jankovic, G.A. Bogdanovic et al.
Tetrahedron xxx (xxxx) xxx
exception that instead of NaOH/H2O we applied NaOD/D2O at 70 ꢀC
through 12 h.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131790.
3.3. Synthesis of intermediate III and III-d
In 10 ml round-bottom flask benzaldehyde (1 mmol) and THPM
1a (1 mmol) were added in 2 ml 7.5% NaOH/H2O (for synthesis of
III) or NaOD/D2O (for synthesis of III-d) at 70 ꢀC. To track decar-
boxylation in both reactions, every half hour 1H NMR spectra were
recorded. Then, reactions mixtures after cooling down, were fil-
trated, and washed with 50% ethanol, and dried in vacuum, to give
products III or III-d. the Products were recrystallized from mixture
EtOAc/MeOH (3:1).
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In summary, an elegant, catalyst-free, and green synthesis of
novel tetrahydropyrimidines (THPMs) via on water fashion has
been developed. In the majority of cases, good-to-excellent yields
were achieved. The synthesized compounds possess disubstituted
benzylidene fragments that are exclusively found as E-isomers. This
feature makes the benzylidene decorated THPMs especially inter-
esting for the future application in cross-coupling chemistry. Dur-
ing deuterium labeling experiments, two deuterated compounds
(intermediate and target product) were isolated proving the pres-
ence of the reactive anionic species on the reaction path. From 1893
(the discovery of THPM by Biginelli) to the present, only a few at-
tempts demonstrate the reactivity of THPM core towards hydroly-
sis. Bearing in mind that among the published results have been
disagreements, we believe that the presented results are of great
importance for the future development of Biginelli’s chemistry.
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Declaration of competing interest
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[24] E. Milovic, N. Jankovic, M. Vranes, S. Stefanovic, J. Petronijevic, N. Joksimovic,
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J. Muskinja, Z. Ratkovic, Environ. Chem. Lett. (2020), https://doi.org/10.1007/
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S. Gadzuric, ACS Sustain. Chem. Eng. 7 (2019) 10773e10783.
[26] N. Jankovic, S. Stefanovic, J. Petronijevic, N. Joksimovic, S.B. Novakovic,
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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G.A. Bogdanovic, J. Muskinja, M. Vranes, Z. Ratkovic, Z. Bugarcic, ACS Sustain.
Chem. Eng. 6 (2018) 13358e13366.
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[27] N. Jankovic, Z. Bugarcic, S. Markovic, J. Serb. Chem. Soc. 80 (2015) 1e13.
Acknowledgements
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[29] N. Jankovic, J. Trifunovic, M. Vranes, A. Tot, J. Petronijevic, N. Joksimovic,
The authors are grateful to the Ministry of Education, Science
and Technological Development of the Republic of Serbia for
financial support (451-03-68/2020-14/200378).
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T. Stanojkovic, M. ÐorCic Crnogorac, N. Petrovic, I. Boljevic, I.Z. Matic,
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