An efficient and environmentally friendly procedure for synthesis of pyrimidinone derivatives by use of a Biginelli-type reaction

Article abstract of DOI:10.1007/s00706-010-0357-6

A Biginelli-type three-component reaction involving cyclopentanone, aromatic aldehyde, and urea or thiourea for preparation of pyrimidinone derivatives under neat conditions is described. This condensation reaction can also take place smoothly in the pres

Full text of DOI:10.1007/s00706-010-0357-6

Monatsh Chem (2010) 141:1005–1008
DOI 10.1007/s00706-010-0357-6
ORIGINAL PAPER
An efficient and environmentally friendly procedure for synthesis
of pyrimidinone derivatives by use of a Biginelli-type reaction
•
Min Lei Lei Ma Lihong Hu
•
Received: 28 February 2010 / Accepted: 13 June 2010 / Published online: 1 July 2010
Ó Springer-Verlag 2010
Abstract
A
Biginelli-type three-component reaction
catalysts [8–15]. Pan et al. [16] reported an efficient
alternative for synthesis of fused pyrimidinones by a
three-component condensation with aromatic aldehyde,
cyclopentanone, and urea or thiourea. However, the use of
stoichiometric amounts of TMSCl as additional reagent and
mixed DMF/CH3CN as reaction solvent seemed to be nec-
essary to obtain satisfactory results. Furthermore, TMSCl
is toxic, corrosive, and environmental unfriendly. More
recently, Zhang described the three-component condensa-
tion of aromatic aldehyde, cyclopentanone, and urea or
thiourea in the presence of YbCl3 [17]. For conservation of
the environment combined with economic aspects, the
application of metal ion-free, environmentally safe, and
convenient reagents in synthetic and medicinal chemistry is
in demand [18–20].
involving cyclopentanone, aromatic aldehyde, and urea or
thiourea for preparation of pyrimidinone derivatives under
neat conditions is described. This condensation reaction
can also take place smoothly in the presence of vitamin B1
in EtOH at 80 °C in good yield. The procedure is simple,
high-yielding, time-saving, and environment friendly.
Keywords Multicomponent reactions Á Aldehyde Á
Organocatalyst Á Green chemistry
Introduction
Multicomponent reactions (MCRs), by virtue of their
convergence, productivity, facile execution, and generally
high yield of products, have attracted much attention [1–4].
The century-old Biginelli reaction as a classical multi-
component reaction has gained much importance in
organic synthesis, partly because of the diverse types of
physiological activity associated with the dihydropyrimid-
inones produced by this reaction [5–7].
Thus, the development of a simple, efficient, and envi-
ronmentally friendly method for the Biginelli-type reaction
is needed. Herein, we wish to report a novel and efficient
procedure for synthesis of pyrimidinone derivatives via the
three-component condensation of aromatic aldehyde,
cyclopentanone, and urea or thiourea under neat conditions
(Scheme 1) or in the presence of vitamin B1 as an organ-
ocatalyst in EtOH (Scheme 2).
The classical Biginelli reaction is a simple one-pot
cyclocondensation of b-dicarbonyl compounds with alde-
hydes and urea or thiourea in the presence of various
Results and discussion
M. Lei Á L. Ma (&)
School of Pharmacy, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237,
People’s Republic of China
Initially, we studied the Biginelli-type reaction of benzal-
dehyde (1a, 5 mmol), cyclopentanone (2, 5 mmol), and
urea (3a, 6 mmol) under solvent-free conditions at 140 °C.
To our delight, reaction was complete in 10 min, giving
the desired product 4a in 92% yield. Encouraged by the
result, a series of aldehydes were selected to undergo the
condensation under solvent-free conditions at 140 °C
(Table 1).
e-mail: malei@ecust.edu.cn
L. Hu (&)
Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203,
People’s Republic of China
e-mail: simmhulh@mail.shcnc.ac.cn
123

1006
M. Lei et al.
Scheme 1
Ar
O
X
Neat
NH
+
+
2 Ar CHO
H2N
NH2
140 oC
N
H
X
Ar
1
2
3
4
R1
Scheme 2
R2
R3
O
Vitamin B1
3 mol%
O
R1
2
CHO
+
+
NH
H2N
NH2
EtOH
R2
R3
N
H
O
1i-1k
2
3a
R1
R3
4i-4k
R2
: R1 = OH, R2 = CH3O, R3 = H
: R1 = Cl, R2 = H, R3 = Cl
i
j
k
: R1 = OBz, R2 = R3 = H
However, several side reactions were observed when
Table 1 Synthesis of Biginelli-type product 4
aromatic aldehydes bearing the –OH were used as a start-
ing material and the desired product could not be isolated
(Table 1, entry 9). In addition, very low yields of the target
products were obtained when using 1j and 1k as substrates
because the reaction mixture could not be efficiently stirred
(Table 1, entries 10 and 11). Hence, we turned our atten-
tion towards the synthesis of pyrimidinone derivatives
4i–4k by condensation of cyclopentanone (2), urea (3a),
and aromatic aldehydes 1i–1k.
Entry Ar
X Time
(min)
Product Yield
(%)a
Ref.
1
2
3
4
5
6
7
8
9
C6H5 (1a)
O 10
O 15
O 25
O 15
O 15
O 10
O 15
O 15
4a
4b
4c
4d
4e
4f
92
95
85
86
86
90
90
88
[16]
[16]
[16]
[16]
[17]
[16]
[16]
[17]
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
3-NO2C6H4 (1d)
4-NO2C6H4 (1e)
4-ClC6H4 (1f)
4-FC6H4 (1g)
4g
4h
4i
As shown in Table 2, the mixture of 4-hydroxy-3-meth-
oxybenzaldehyde (1i), cyclopentanone (2), and urea (3a) was
chosen as the model reaction under different reaction condi-
tions. First, we changed the reaction temperature from 20 to
140 °C (Table 2, entries 1–4), because, unfortunately, no
desired product 4i was observed when the mixture was stirred
at 20 °C for 10 h (Table 2, entry 1). In addition, several side
reactions were observed, as indicated by TLC, when the
three-component condensation reaction took place at
80–140 °C under solvent-free conditions (Table 2, entries
2–5). We also carried out the condensation reaction at 80 °C
in various solvents (Table 2, entries 5–10), for example
MeOH, EtOH, THF, DMF, CH3CN, and DMSO. Unfortu-
nately, only trace amounts of the target product were observed
when the mixture was stirred at 80 °C in these solvents.
In our previous study, we found that several multi-com-
ponent reactions proceeded smoothly in the presence of
vitamin B1 as catalyst [21]. Therefore, we carried out the
reaction in EtOH at 80 °C, taking a 1:1:1.2 mol ratio of
4-hydroxy-3-methoxybenzaldehyde (1i), cyclopentanone (2),
and urea(3a) in thepresence of3 mol% vitamin B1 for 3 h. To
our delight, the desired product 4i was obtained in 86% yield
(Scheme 2). We changed the amount of vitamin B1 from 1 to
10 mol%, and found use of 3 mol% was optimum to ensure
4-CNC6H4 (1h)
b
3-MeO-4-OHC6H3 O 20
(1i)
–
10
11
12
13
14
15
16
2,4-Cl2C6H3 (1j)
4-BzOC6H4 (1k)
C6H5 (1a)
O 20
O 20
4j
20
25
82
84
80
82
86
4k
4l
S
S
S
S
S
60
60
60
60
60
[16]
[17]
[16]
[16]
[16]
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-NO2C6H4 (1d)
4-ClC6H4 (1f)
4m
4n
4o
4p
Conditions: aromatic aldehyde (1, 5 mmol), cyclopentanone (2,
5 mmol), and urea (3a) or thiourea (3b) (6 mmol), 140 °C
a
Isolated yield
b
Several side reactions were observed and the desired product could
not be isolated
As shown in Table 1, aromatic aldehydes bearing
functional groups (for example –H, –CH3, –OCH3, –Cl, –F,
–NO2, and –CN) react smoothly to give the corresponding
products in good yields (80–95%). We also found that this
condensation reaction was complete within 60 min, much
quicker than reported methods (3–10 h) [16, 17].
123

Synthesis of pyrimidinone derivatives through a Biginelli-type reaction
1007
spectra were recorded on a Varian 400 MHz spectrometer
at 400 and 100 MHz, with TMS as an internal standard.
Chemical shifts (d) are given in ppm relative to TMS,
coupling constants (J) in Hz. Melting points were deter-
mined with an X-4 apparatus and are corrected. Mass
spectra were measured with a Thermo Finnigan LCQ-
Advantage. Elemental analyses (C, H, N, S) were per-
formed on a Fisons EA 1110 CHNS elemental analyzer;
results agreed favorably with calculated values.
Table 2 Synthesis of Biginelli-type product 4i under various
conditions
Entry Solvent Catalyst (mol%) Temp. (°C) Time (h) Yield (%)a
1
None
None
None
None
MeOH
EtOH
THF
0
0
0
0
0
0
0
0
20
80
10
1
NRb
c
2
–
c
3
120
140
80
0.3
0.3
3
–
c
4
–
5
Trace
Trace
Trace
Trace
Trace
Trace
45
6
80
3
7
80
3
General procedure for synthesis of compounds 4a–4h
and 4l–4p
8
DMF
80
3
9
CH3CN 0
DMSO
80
3
10
11
12
13
14
0
80
3
An aldehyde (1a–1h, 5 mmol), cyclopentanone (2,
5 mmol), and urea (3a) or thiourea (3b) (3.6 mmol) were
mixed in a round-bottomed flask. The mixture was stirred
at 140 °C for the time needed to complete the reaction
(monitored by TLC). After cooling to room temperature,
the reaction was quenched with 20 cm3 H2O and stirred for
10 min. The pure product 4 was isolated by filtration,
followed by washing with EtOAc.
EtOH Vitamin B1 (1)
EtOH Vitamin B1 (3)
EtOH Vitamin B1 (5)
80
3
80
3
86
80
3
86
EtOH Vitamin B1 (10) 80
3
85
Conditions: 4-hydroxy-3-methoxybenzaldehyde (1i, 5 mmol), cyclo-
pentanone (2, 5 mmol), and urea (3a, 6 mmol), solvent-free or solvent
3 cm3
a
Isolated yield
b
No reactions were observed
General procedure for the synthesis of compounds
4i–4k
c
Several side reactions were observed and the desired product could
not be isolated
A mixture of aldehyde (1i–1k, 5 mmol), cyclopentanone (2,
5 mmol), urea (3a, 3.6 mmol), and vitamin B1 (0.15 mmol)
in 3 cm3 ethanol was heated to 80 °C, with stirring, for 3 h to
complete the reaction (monitored by TLC). After cooling to
room temperature, the reaction was quenched with 20 cm3
H2O and stirred for 10 min. The pure product was isolated
by filtration, followed by washing with EtOAc.
high reaction efficiency (Table 2, entries 11–14). Then, we
carried out the three-component condensation reaction using
aromatic aldehydes 1i–1k in the presence of 3 mol% vitamin
B1 in EtOH for 3 h and obtained the desired products 4i–4k in
86, 83, and 90% yield, respectively (Scheme 2).
In conclusion, this method is a new and simple modifi-
cation of the Biginelli-type reaction of aromatic aldehyde,
cyclopentanone, and urea or thiourea. The three-component
condensation reaction can proceed under solvent-free con-
ditions at 140 °C without any catalysts in excellent yields
(80–95%). In addition, the condensation reaction can also
take place smoothly in the presence of 3 mol% vitamin B1 in
EtOH at 80 °C in good yields (83–90%). It is important to
note that the reaction can proceed smoothly in good yield by
employing a catalytic amount of vitamin B1 as the catalyst
when using an aldehyde carrying a hydroxy group as the
starting material, which normally gives an extremely poor
yield under catalyst-free conditions. This one-pot synthesis
of hydropyrimidinone derivatives is therefore simple, high
yielding, time saving, and environmentally friendly. It is an
useful addition to existing methods.
1,3,4,5,6,7-Hexahydro-7-(4-hydroxy-3-methoxybenzylidene)-
4-(4-hydroxy-3-methoxyphenyl)-2H-cyclopenta[d]pyrimidin-
2-one (4i, C22H22N2O5)
Yellow solid, yield 86%; m.p.: 241–244 °C; 1H NMR
(400 MHz, DMSO-d6): d = 9.03 (brs, 1H), 8.93 (brs, 1H),
8.60 (brs, 1H), 7.04 (s, 1H), 6.88 (s, 1H), 6.81 (d,
J = 2 Hz, 1H), 6.75–6.78 (m, 3H), 6.67 (dd, J1 = 2.0 Hz,
J2 = 8.4 Hz, 1H), 6.52 (brs, 1H), 5.04 (brs, 1H), 3.78 (s,
3H), 3.76 (s, 3H), 2.77–2.85 (m, 2H), 2.32–2.41 (m, 1H),
2.02–2.11 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 153.7, 148.0, 147.9, 146.4, 145.7, 136.5, 136.3, 134.9,
129.9, 121.6, 119.4, 117.6, 117.2, 116.1, 115.9, 112.3,
111.3, 57.6, 56.1, 55.9, 28.9, 28.7 ppm; MS (ESI): m/z =
417 ([M ? Na]?).
7-(2,4-Dichlorobenzylidene)-4-(2,4-dichlorophenyl)-
1,3,4,5,6,7-hexahydro-2H-cyclopenta[d]pyrimidin-2-one
(4j, C20H14Cl4N2O)
Experimental
White solid, yield 83%; m.p.: 251-254 °C; 1H NMR
(400 MHz, DMSO-d6): d = 9.19 (brs, 1H), 7.33–7.68
(m, 6H), 7.25 (s, 1H), 6.74 (brs, 1H), 5.6 (s, 1H), 2.62–2.83
Reagents and all solvents were analytically pure grade and
1
were used without further purification. H and 13C NMR
123

1008
M. Lei et al.
(m, 2H), 2.37–2.46 (m, 1H), 1.91–2.04 (m, 1H) ppm;
13C NMR (100 MHz, DMSO-d6): d = 153.6, 142.6, 139.8,
136.9, 134.9, 133.7, 133.3, 132.3, 131.7, 131.1, 130.6, 129.3,
129.2, 128.8, 128.4, 127.6, 113.0, 54.5, 28.4, 28.3 ppm; MS
(EI): m/z = 442, 440, 438 (M?).
References
1. Ugi I, Domling A, Werner B (2000) J Heterocycl Chem 37:647
2. Shanthi G, Perumal PT (2009) Tetrahedron Lett 50:3959
3. Shirakawa S, Kobayashi S (2006) Org Lett 8:4939
4. Bagley MC, Lubinu MC (2006) Synthesis 8:1283
5. Heravi MM, Baghernejad B, Oskooie HA (2009) Tetrahedron
Lett 50:767
6. Huang X, Zhang T (2009) Tetrahedron Lett 50:208
7. Cui S, Wang J, Wang Y (2008) Org Lett 10:1267
8. Lu J, Ma H (2000) Synlett p 63
9. Reddy CV, Mahesh M, Raju PVK, Babu TR, Reddy VVN (2002)
Tetrahedron Lett 43:2657
10. Ramalinga K, Vijayalakshmi P, Kaimal TNB (2001) Synlett 6,
p 863
7-[4-(Benzyloxy)benzylidene]-4-[4-(benzyloxy)phenyl]-
1,3,4,5,6,7-hexahydro-2H-cyclopenta[d]pyrimidin-2-one
(4k, C34H30N2O3)
Yellow solid, yield 90%; m.p.: 201–204 °C; 1H NMR
(400 MHz, DMSO-d6): d = 8.68 (brs, 1H), 6.95–7.45 (m,
19H), 6.56 (s, 1H), 5.03–5.13 (m, 5H), 2.67–2.78 (m, 2H),
1.95–2.04 (m, 1H), 1.78–1.90 (m, 1H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 165.2, 158.2, 153.7, 143.1,
143.0, 137.6, 137.4, 136.2, 136.1, 131.1, 131.0, 129.6,
128.9, 128.8, 128.3, 128.2, 128.1, 118.1, 116.6, 115.4,
115.3, 69.7, 69.6, 57.3, 28.7, 28.8 ppm; MS (ESI): m/z = 537
([M ? Na]?).
11. Lu J, Bai Y, Wang Z, Yang B, Ma H (2000) Tetrahedron Lett
41:9075
12. De SK, Gibbs RA (2005) Synthesis 1748
13. Ranu BC, Hazra A, Jana U (2000) J Org Chem 65:6270
14. Su W, Li J, Zheng Z, Shen Y (2005) Tetrahedron Lett 46:6037
15. Peng J, Deng Y (2001) Tetrahedron Lett 42:5917
16. Zhu Y, Huang S, Pan Y (2005) Eur J Org Chem 2354
17. Zhang H, Zhou Z, Yao Z, Xu F, Shen Q (2009) Tetrahedron Lett
50:1622
18. Kantevari S, Vuppalapati SVN, Nagarapu L (2007) Catal Com-
mun 8:1857
19. Chen W, Lu J (2005) Synlett 1337
Acknowledgments This work was supported by the Chinese
National Science and Technology Major Project ‘‘Key New Drug
Creation and Manufacturing Program’’ (grants 2009ZX09301-001,
2009ZX09102), the Chinese National High-Tech R&D Program
(grants 2007AA02Z147), the National Natural Science Foundation of
China (grants 90713046, 30772638, 30925040), and the CAS Foun-
dation (grant KSCX2-YW-R-179).
20. Azizi N, Torkiyan L, Saidi MR (2006) Org Lett 8:2079
21. Lei M, Ma L, Hu L (2009) Tetrahedron Lett 50:6393
123