Versatility of the Biginelli reaction: Synthesis of new biphenyl dihydropyrimidin-2-thiones using different ketones as building blocks

Article abstract of DOI:10.1016/j.tetlet.2018.06.006

A multi-component synthesis of biphenyl dihydropyrimidin-2-thiones from 1-phenylthiourea, aldehydes and ketones or di-ketones has been demonstrated. The reaction proceeded well for aldehydes with electron donor or acceptor substituents under mild conditions.

Full text of DOI:10.1016/j.tetlet.2018.06.006

Accepted Manuscript
Versatility of the Biginelli Reaction: synthesis of new biphenyl dihydropyrimi-
din-2-thiones using different ketones as building blocks
Itamar Gonçalves, Leonardo Davi, Liliana Rockenbach, Gustavo Machado das
Neves, Luciano Porto Kagami, Rômulo Faria Santos Canto, Fabrício Figueiró,
Ana Maria Oliveira Batastini, Vera Lucia Eifler-Lima
PII:
S0040-4039(18)30735-4
https://doi.org/10.1016/j.tetlet.2018.06.006
TETL 50044
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 May 2018
30 May 2018
2 June 2018
Please cite this article as: Gonçalves, I., Davi, L., Rockenbach, L., das Neves, G.M., Kagami, L.P., Canto, R.F.S.,
Figueiró, F., Batastini, A.M.O., Eifler-Lima, V.L., Versatility of the Biginelli Reaction: synthesis of new biphenyl
dihydropyrimidin-2-thiones using different ketones as building blocks, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.06.006
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Versatility of the Biginelli Reaction:
synthesis of new biphenyl dihydropyrimidin-
2-thiones using different ketones as building
blocks.
Leave this area blank for abstract info.
Itamar Gonçalvesa, Leonardo Davia, Liliana Rockenbacha, Gustavo Machado das Nevesa, Luciano Porto
Kagamia, Rômulo Faria Santos Cantoc, Fabrício Figueirób, Ana Maria Oliveira Batastinib, Vera Lucia Eifler-
Limaa*

1
Tetrahedron Letters
Versatility of the Biginelli Reaction: synthesis of new biphenyl dihydropyrimidin-2-
thiones using different ketones as building blocks
Itamar Gonçalvesa, Leonardo Davia, Liliana Rockenbacha, Gustavo Machado das Nevesa, Luciano Porto
Kagamia, Rômulo Faria Santos Cantoc, Fabrício Figueirób, Ana Maria Oliveira Batastinib, Vera Lucia
Eifler-Limaa*
a Laboratório de Síntese Orgânica Medicinal (LaSOM), Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul. Avenida Ipiranga, 2752, Porto
Alegre / RS, Brazil.
b Laboratório 22, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul. Rua Ramiro Barcelos, 2600, Porto Alegre / RS, Brazil.
c Laboratório de Química Medicinal de Compostos de Selênio (QMCSe), Programa de Pós-Graduação em Ciências da Saúde,, Universidade Federal de
Ciências da Saúde de Porto Alegre, Rua Sarmento Leite, 245 - Centro Histórico, Porto Alegre / RS, Brazil
* Corresponding author: veraeifler@ufrgs.br
ARTICLE INFO
ABSTRACT
Article history:
Abstract: A multi-component synthesis of biphenyl dihydropyrimidin-2-thiones from 1-
phenylthiourea, aldehydes and ketones or di-ketones has been demonstrated. The reaction
proceeded well for aldehydes with electron donor or acceptor substituents under mild conditions.
2009 Elsevier Ltd. All rights reserved.
Received: 06.05.2018
Received in revised form 29.05.2018
Accepted
Available online
Keywords:
Biginelli reaction
Structural diversity
multicomponent reaction
undergo hydrolysis to carboxylic acids and inactivation by in
vivo metabolism 10. Recent in silico ADMET prediction indicated
1. Introduction
Biginelli
reaction
involves
the
acid-catalyzed
the hydrolysis of the ester group of DHPMs as reactions of
multicomponent synthesis of 3,4-dihydropyrimidin-2(1H)-
ones(thiones) (DHPMs), employing easily accessible starting
materials, such as aldehydes, urea or analogue and compounds
with methylene active hydrogens. Thus, this reaction is a
powerful tool for the fast and easy generation of libraries with
great structural diversity 1, 2. However, the structural diversity of
N-1 aryl substituted DHPMs has been poorly explored. In fact,
only a few investigations have reported direct N1 alkylation of
DHPMs 3, 4, and the arylation in the N1 position has not been
reported at all. The literature relates that the reactions to obtain
N1-substituted DHPMs using substituted thio(ureas)5 have only
been performed with ethyl acetoacetate as a methylene active
metabolism catalyzed by CYP enzymes 11
.
2. Results and discussion
In a previous study, a focused library of two sets of N1-
aryl substituted DHPMs was synthesized, using eleven different
substituted phenylthiourea, ethyl acetoacetate and two aromatic
aldehydes 12. In continuation of the projects of our group, with
the aim of obtaining structural diversity in DHPM scaffolds,
chemical diversity in the library was achieved by using the
versatility of the Biginelli reaction through exploration of
variations at the C-5 position of the biphenyl dihydropyrimidin-
2-thione core, using ketones as building blocks instead of a β-
ketoester. Thus, using four different ketones 1-4 and three
aldehydes 6-8 in the Biginelli reaction, with 1-phenylthiourea 5,
under mild conditions, it was possible to create a small focused
library of 12 DHPMs 9-20 with a good chemical and structural
variety and purity. For this purpose, di-ketones (2,4-pentanedione
1 and 1,3-cyclohexanodione 2) and simple ketones were chosen
as building blocks (cyclohexanone 3 and 3,4-dihydro-1(2H)
naphthalenone 4).
hydrogen compound 6, 7
As the pharmacologic effect of these molecules has been
extensively investigated in the last few years, it is very important
.
8
to obtain structural diversity in DHPMs . This heterocycle class
is defined as a privileged structure, a term that refers to scaffolds
with versatility for interacting with different biological targets,
giving rise to important pharmacological effects 9. In this context,
the synthesis of N1-substituted DHPMs with a replacement of the
ester moiety by ketones is
a very useful strategy for
pharmacological in vivo investigation, as the ester group may

2
Tetrahedron
Table 1 - Synthesis of biphenyl dihydropyrimidin-2-thiones by
the Biginelli reaction using four different ketones (1-4) and
three aldehydes (6-8) with 1-phenylthiourea (5)a
Methylene
active
Aldehyde
Product
Yield
56%
61%
76%
81%
67%
69%
65%
58%
52%
Figure 1 - The methylene active compound (A), 1-phenylthiourea (B),
and aldehyde (C) building blocks used in the Biginelli reaction
To access the designed library, chlorotrimethylisane (TMSCl)
was used as the promoting agent in DMF at room temperature.
The isolated yield values are listed in Table 1. The structure of
the N1-substituted new biphenyl dihydropyrimidin-2-thiones
1
were characterized using H NMR, 13C NMR and HRMS. These
data may be accessed in supporting information.
When other ketones such as 21 and 22 were employed in the
Biginelli reaction promoted by TMSCl under the same
conditions, the formation of a large amount of impurities were
detected. Thus, the use of propanone 21 and methyl phenyl
ketone 22 did not allow for the isolation of the products 23 and
Scheme 1
24,
as
sho
wn
in
Sche
me
1.
Scheme 2

3
ketone carbonyl presence at 199 ppm 13C NMR. The HRMS
Table 1 – Continued
spectrum of this compound also allowed for confirmation of its
structure (electronic supporting information, Figure S40). A
similar trend was also found in the preparation of 18 and 19,
while in their preparation, through thin layer chromatography,
like 27, the formation of the non-cyclized intermediary was
observed after 72 hours. This finding may be associated with the
lower flexibility of the cyclohexanone ring when fused to the
aromatic ring in the starting material (3,4-dihydro-1(2H)-
naphthalenone 4). In order to solve the problem, the reactional
time was extended to 14 days for the compound 18-20 and the
yields were significantly improved.
42%
49%
65%
Based on this finding and on the literature reports 6, 13, two
plausible mechanisms involving the formation of the
intermediate 27 are depicted for the compound 20 in Scheme 3.
The first possibility (up part) starts with aldol reaction promoted
by TMSCl between 3-nitrobenzaldehyde 8 and the ketone 4,
yielding the Michael adduct 26. This compound undergoes the
Michael addition with 1-phenhylthiourea 5 and the intermediary
27 is formed. In the last step, its cyclization occurs by attack of
the amino group to the ketone carbonyl, thereby yielding the
product 20. Another approach is described in the lower part of
Scheme 3, and starts with imine 28 formation by the reaction
between phenylthiourea 5 and 3-nitrobenzaldehyde 8. This imine
is attacked by the ketone 4, leading to the intermediary 27. In a
similar way to the last proposed mechanism (Scheme 3, upper
part), this route is finalized with cyclization of 27, leading to
formation of the product 20.
a
Reaction conditions: ketone or di-ketone (1 mmol), aromatic
aldehyde (1 mmol), phenylthiourea (1 mmol) in DMF (~ 1.0 mL)
and TMSCl (6 mmol) at room temperature.
Furthermore, the current investigation also aimed at
obtaining the compound 25, by use of 2 equivalents of
benzaldehyde 6. The reaction in urea, 2 equivalents of aromatic
aldehyde and a cycloalkanone has previously been reported as a
strategy for accessing DHPMs with structures like compound 25,
without substitution at N1 13, 14. However, under our employed
reaction conditions, only compound 12 was obtained.
3. Conclusions
Notably, when 3,4-dihydro-1(2H)-naphthalenone 4 and 3-
nitrobenzaldehyde 8 were used as reagent, after 72 hours under
stirring and room temperature, a mixture of the product 20 with
intermediary 27 was isolated through acetonitrile recrystallization
In summary, it has been demonstrated that new structural
diversity may be reached through multicomponent DHPM
synthesis with the use of ketones or diketones and 1-
phenylthiourea. Thus, this is the first report in the literature
describing these series of compounds produced by the Biginelli
reaction. In addition, this synthesis will be useful in preparing
various analogs of DHPMs with specific substitution patterns,
which may provide a route to the synthesis of potentially
1
(Scheme 3). The NMR H and 13C spectrum of the intermediary
27 are shown in Figures S37 and S38, in electronic supporting
information; it’s structure was confirmed by: (i) the multiplicity
of benzylic hydrogen in 1H NMR, (ii) the presence of a CH signal
at 50 ppm, corresponding to the α carbonyl carbon; and (iii) the
Scheme 3

4
Tetrahedron
biologically active heterocycles.
5
Goncalves, I. L.; de Azambuja, G. O.; Kawano, D. F.;
Eifler-Lima, V. L. Mini Rev Org Chem, 2018, 15, 28.
Ryabukhin, S. V.; Plaskon, A. S.; Ostapchuk, E. N.;
Volochnyuk, D. M.; Tolmachev, A. A. Synth, 2007, 417.
Ostapchuk, E. N.; Plaskon, A. S.; Grygorenko, O. O.;
Conflicts of interest
There are no conflicts to declare.
6
Acknowledgements
7
Tolmachev, A. A.; Ryabukhin, S. V. J Heterocyclic Chem, 2013, 50,
1299.
The authors are thankful to CNPq/MCT, INCT-if (Instituto
Nacional de Ciência e Tecnologia para Inovação Farmacêutica),
FINEP, IQ-UFRGS. The authors are grateful to CNPq and
CAPES for their scholarship.
8
de Fátima, Â.; Braga, T. C.; Neto, L. d. S.; Terra, B. S.;
Oliveira, B. G. F.; da Silva, D. L.; Modolo, L. V. J Adv Res, 2015, 6,
363.
9
Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr Opin
A. Supplementary data
Chem Biol, 2010, 14, 347.
10 Testa, B.; Kramer, S. D. Chem Biodivers, 2007, 4, 2031.
11 Hassan, S. F.; Rashid, U.; Ansari, F. L.; Ul-Haq, Z. J Mol
Graph Model, 2013, 45, 202.
12 Gonçalves, I.; Rockenbach, L.; das Neves, G.; Göethel, G.;
Soares do Nascimento, F.; Porto Kagami, L.; Figueiró, F.; Oliveira
de Azambuja, G.; de Fraga Dias, A.; Amaro, A.; de Souza, L.; da
Rocha Pitta, I.; Avila, D.; Kawano, D.; Garcia, S.C; Battastini, A. M.
O.; Eifler-Lima, V. L. MedChemComm, 2018, xx, xxx. DOI:
10.1039/C8MD00095F
Supplementary data associated with this article can be
found,
in_the_online_version,_at_https://doi.org/xx.xxxx/j.tetlet.xxxx.x
x.xxx.
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5
Highlights
▪
Biphenyl dihydropyrimidin-2-thiones were
synthesized via Biginelli reaction;
▪ The synthesis was performed using simple
ketones and di-ketones as starting materials;
▪ Products could be obtained in high yield and
purity after easy work-up (filtration and
recrystallization);