Efficient synthesis of pyrimidinone derivatives by ytterbium chloride catalyzed Biginelli-type reaction under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.01.103

An efficient and clean method was developed for the one-pot synthesis of pyrimidinones by ytterbium chloride catalyzed Biginelli-type reaction of aromatic aldehyde, cyclopentanone, and urea or thiourea under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2009.01.103

Tetrahedron Letters 50 (2009) 1622–1624
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of pyrimidinone derivatives by ytterbium chloride catalyzed
Biginelli-type reaction under solvent-free conditions
*
*
Huihui Zhang, Zhuqing Zhou, Zhigang Yao, Fan Xu , Qi Shen
Key Laboratory of Organic Synthesis, College of Chemistry and Chemical Engineering, Soochow University, Suzhou 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and clean method was developed for the one-pot synthesis of pyrimidinones by ytterbium
chloride catalyzed Biginelli-type reaction of aromatic aldehyde, cyclopentanone, and urea or thiourea
under solvent-free conditions.
Received 8 October 2008
Revised 16 January 2009
Accepted 20 January 2009
Available online 23 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidinone
Ytterbium chloride
Biginelli-type reaction
Catalysis
Pyrimidinone skeleton exists in many natural or synthetic bio-
logically active materials, and its derivatives are applied in various
pharmaceutical and biochemical fields.1,2 It is of great interest that
specifically functionalized pyrimidinone may possess specific bio-
logical properties. For example, it was recently found that some
fused pyrimidinones 2 carrying an arylidene moiety (Scheme 1)
are potential antitumor agents based on sufficient antitumor
screening data.3 Some of these analogues also showed, besides
the broad-spectrum antitumor activity, a distinctive pattern of
selectivity toward individual cell line such as that of leukemia.
These findings make it highly necessary to develop efficient meth-
ods for the synthesis of this type of pyrimidinones. According to
the previous literature, these arylidene heterobicyclic pyrimidi-
gard to the development of green chemistry. In this area, notable
progress has been made in the applications of lanthanide reagents
as catalysts in organic synthesis in recent years.8 Lanthanides are
nontoxic and relatively abundant in nature, and the success in
developing many useful reactions efficiently catalyzed by lantha-
nide compounds is attributed to the unique features of lanthanide
centers such as the high electrophilicity, variable metal ion radius,
and tunable coordination patterns. Our interest in this area has led
us to explore the lanthanide compounds effective in the synthesis
of a series of biologically active materials including a-amino phos-
phonates, quinolines, and pyrimidines.9 Herein, this letter at-
tempts to describe the catalytic activity of lanthanide chloride
(LnCl3) in the one-pot synthesis of pyrimidinone from aromatic
aldehyde, cyclopentanone, and urea or thiourea, the so-called Bigi-
nelli-type three-component reaction.
nones were typically synthesized by the reaction of a,
a0-bis(arylid-
ene)cycloalkanones with urea or thiourea (Scheme 1). In most
cases, strong Bronsted acid4 such as HCl, or base3,5 such as sodium
alkoxide and potassium hydroxide was a necessary requirement
for the smooth reaction. More recently, Pan6 described an efficient
alternative for the synthesis of these fused pyrimidinones by a
three-component condensation with aromatic aldehyde,
cyclopentanone, and urea or thiourea as starting materials, which
was supposed to be a Biginelli-type reaction. However, the use of
stoichiometric amounts of TMSCl as additional reagent and mixed
DMF/CH3CN as reaction solvent appeared to be necessary to obtain
satisfactory results.
Previous work has demonstrated that samarium diiodide (SmI2)
can effectively catalyze the classical Biginelli reaction of aldehydes,
Ar
O
X
Y
NH
+
Ar
Ar
H2N
NH2
N
H
X
Y
Ar
Metal-catalyzed reactions7 are recognized as attractive and
environmentally benign methods in synthetic chemistry with re-
1
2
X = O, S
Y = -CH2-, -CH2CH2-, -N(CH3)-CH2-
* Corresponding authors. Tel.: +86 512 65880331; fax: +86 512 65880305.
E-mail addresses: xufan@suda.edu.cn (F. Xu), qshen@suda.edu.cn (Q. Shen).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.103

H. Zhang et al. / Tetrahedron Letters 50 (2009) 1622–1624
1623
Table 2
urea, and b-dicarbonyl compounds affording pyrimidinones in
moderate to excellent yields.9c However, we failed to achieve the
Biginelli-type three-component condensation of aldehyde, cycloal-
kanone, and urea with SmI2 as catalyst, and none of the expected
arylidene heterobicyclic pyrimidinone was detected. Surprisingly,
when the reaction was conducted in the presence of catalytic
amount of ytterbium chloride (YbCl3), a readily available and eco-
nomical lanthanide Lewis acid, a satisfying result was obtained.
This encouraged us to examine the catalytic activity of a series of
lanthanide chlorides in the condensation of benzaldehyde, cyclo-
pentanone with urea, as a model reaction, at 90 °C under sol-
vent-free condition. As shown in Table 1, all the lanthanide
chlorides screened were effective in catalyzing the reaction, and
the influence of central metal on the activity was observed. The ac-
tive sequence is Yb > Er ꢀ Y ꢀ Gd ꢀ Sm > Nd ꢀ La, which is in con-
trast to the order of their ionic radius. YbCl3 was then chosen as a
representative lanthanide source for the investigation on catalyst
loading. When the loading of YbCl3 was increased from 1 mol %
to 10 mol % (entries 7–10), the yield of pyrimidinone first increased
until to a maximum and then gradually decreased, and the highest
yield was obtained at 3 mol % of catalyst loading (entry 8). The
analysis of the crude product indicated that overused catalyst
may lead to undesired side reactions.
To our delight, this Lewis acid-catalyzed reaction was carried
out under a mild, simple, and clean condition. First, no solvent is
required during the reaction stage, which not only avoids the use
of auxiliary reagents that may be toxic or flammable, but also sim-
plifies the follow-up operation, and the purifications of the prod-
ucts are performed simply by filtration and washing. Second, the
reaction works well while being exposed to air, so the steps of dry-
ing and protection, which is usually essential for most of the reac-
tions that lanthanide compounds participate in, are eliminated.
Thus, this procedure provides an efficient, convenient, and envi-
ronmentally friendly protocol for the synthesis of pyrimidinones.
Further optimization of the reaction conditions was attempted.
The results are summarized in Table 2. The influence of tempera-
ture was examined for the model reaction first. Raising the reaction
temperature from 60 °C to 90 °C (entries 1–3) led to an increase in
yield from 43% to 79%, while the temperature over 100 °C (entries
4–5) resulted in a decrease in yield. Then the effect of reaction time
on yield (entries 3 and 6–9) was investigated and the highest yield
was obtained after 3 h. The results showed that lower temperature
and shorter reaction time may result in incomplete reaction while
Effects of temperature, time, and ratio of substrates on the synthetic reaction of 6a
Entry
Temp. (°C)
Time (h)
3a:4:5a
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
60
80
90
100
120
90
90
90
90
90
3
3
3
3
3
2
6
10
3
3
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
2:1:1.2
2:1:2.4
2:1:3.6
2:2:1.2
2:3:1.2
43
68
79
79
74
65
69
62
43
55
70
71
78
90
90
90
3
3
3
overheating and excessively prolonged time lead to complicated
side reactions.
It is worth mentioning that although the product 6a is actually
condensed by benzaldehyde, cyclopentanone, and urea at a 2:1:1
ratio, the reaction at this ratio of substrate gave the yield lower
than that obtained at a 1:1:1.2 ratio (entries 3 and 9). This means
that excessively used cyclopentanone and urea played important
roles in promoting the conversion of benzaldehyde to the product.
Corresponding contrastive reactions were performed and the re-
sults indicated that whichever of the cyclopentanone or urea was
used at double the equivalent, respectively, the yields were appre-
ciably improved (entries 10 and 12). Further excessive cyclopenta-
none or urea still affected the yield in the positive direction
(entries 11 and 13), but the results obtained in all these attempts
could not reach that in the case cyclopentanone and urea were
used at the double equivalent at the same time. The reason for this
is not yet clear.
Table 3
YbCl3-catalyzed one-pot synthesis of pyrimidinone 6a
Ar
O
X
NH
3 mol% YbCl3
90 ºC, neat
+
+
ArCHO
H2N
NH2
N
H
X
X = O, S
Ar
Product
3
5
4
6
Entry
Ar
Ph
X
Time (h)
Yield (%)
Table 1
LnCl3 catalyzed one-pot synthesis of pyrimidinone 6aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
3
5
5
5
5
5
5
4
3
3
3
3
3
3
5
5
5
6a
6b
6c
6d
6e
6f
6g
6h
6i
79
81
70
51
69
71
60
74
75
71
55
91
61
64
90
89
1-naphthyl
p-CH3Ph
o-CH3Ph
p-CH3OPh
m-CH3OPh
o-CH3OPh
p-BrPh
p-ClPh
m-ClPh
o-ClPh
p-FPh
m-FPh
o-FPh
p-CNPh
p-NO2Ph
m-NO2Ph
Ph
p-ClPh
p-FPh
Ph
O
O
NH
cat. LnCl3
90 C, 3 h, neat
Ph
+
+
PhCHO
H2N
NH2
º
N
H
O
6j
6k
6l
3a
4
5a
6a
Entry
Catalyst
Loading (mol %)
Yield (%)
6m
6n
6o
6p
6q
6r
6s
6t
1
2
3
4
5
6
7
8
9
LaCl3
NdCl3
SmCl3
GdCl3
YCl3
ErCl3
YbCl3
YbCl3
YbCl3
YbCl3
3
3
3
3
3
3
1
3
5
62
62
71
71
72
72
52
79
71
63
50
10
10
8
90 (74)b
82
S
S
S
92
59
p-CH3Ph
12
6u
a
Typical reaction conditions: aldehyde/cyclopentanone/urea or thio-
10
10
urea = 1:1:1.2, 3 mol % YbCl3 relative to aldehyde, 90 °C.
a
b
Typical reaction conditions: aldehyde/cyclopentanone/urea = 1:1:1.2, 90 °C, 3 h.
The reaction was run for 3 h.

1624
H. Zhang et al. / Tetrahedron Letters 50 (2009) 1622–1624
[Yb]
[Yb]
[Yb]
H
H
O
O
O
HC
O
O
O
H2O
YbCl3
CH
Ph
Ph
PhCHO
Ph
+
PhCHO
[Yb]
O
[Yb]
H2O
Ph
Ph
Ph
Ph
Ph
A
NH
NH2
NH
CO(NH2)2
O
O
N
H
O
H2N
O
O
H2N
Ph
Ph
Ph
H
[Yb]
[Yb]
B
Scheme 2.
Inorder toexaminethescopeandgeneralityof thisprocedure, we
extended the methodology to different aromatic aldehydes. The re-
sults are presented in Table 3. All the reactions, consisting of those
involving ortho-, meta-, and para-substituted benzaldehydes, pro-
ceeded smoothly and afforded the corresponding benzylidene hete-
robicyclic pyrimidinones in moderate to high yields. Electronic
effects can be observed. The electron-donating group(EDG)-substi-
tuted benzaldehydes (para-substituted, entries 3 and 5) required
prolonged reaction time to give the yields close to those of weaker
Acknowledgments
The authors thank the National Natural Science Foundation of
China (20872106, 20632040), State Key Laboratory of Organome-
tallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences for financial support.
Supplementary data
electron-withdrawing group(EWG)-substituted ones (entries
8
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.103.
and 9), while stronger EWG-substituted ones (entries 12, 15, and
16) gave evidently increasing yields. ortho-Substituted benzalde-
hydes (entries 4, 7, 11, and 14), whether the substituent is EDG or
EWG, afforded the corresponding pyrimidinones in relatively lower
yields, indicating an obvious steric effect. Thiourea exhibited behav-
ior similar to that of urea.
References and notes
1. Atwal, K. S.; Rovnyak, G. C.; O0Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
5898–5907.
2. Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron 1997, 53, 2803–2816.
3. El-Subbagh, H. I.; Abu-Zaid, S. M.; Mahran, M. A.; Badria, F. A.; Al-Obaid, A. M. J.
Med. Chem. 2000, 43, 2915–2921.
4. (a) Lorand, T.; Deli, J.; Szabo, D.; Foeldesi, A.; Zschunke, A. Pharmazie 1985, 40,
536–539; (b) Elgemeie, G. E. H.; Attia, A. M. E.; Alkabai, S. S. Nucleos. Nucleot.
Nucl. 2000, 19, 723–734.
5. (a) Hammam, A. E. G.; Sharaf, M. A.; El-Hafez, N. A. A. Indian J. Chem., Sect. B
2001, 40, 213–221; (b) Al-Omran, F.; Al-Awadi, N. J. Chem. Res. 1995, 10, 2201–
2220; (c) Al-Omar, M. A.; Youssef, K. M.; El-Sherbeny, M. A.; Awadalla, S. A. A.;
El-Subbagh, H. I. Arch. Pharm. (Weinheim Ger.) 2005, 338, 175–180; (d) Ali, M. I.;
Hammam, A. E. G.; Youssef, N. M. J. Chem. Eng. Data 1981, 26, 214–215.
6. Zhu, Y.; Huang, S.; Pan, Y. Eur. J. Org. Chem. 2005, 2354–2367.
7. D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095–1108.
8. (a) Collin, J.; Giuseppone, N.; Van de Weghe, P. Coord. Chem. Rev. 1998, 178–180,
117–144; (b) Molander, G. A.; Romero, J. A. C. Chem. Rev. 2002, 102, 2161–2185;
(c) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2209; (d) Inanaga,
J.; Furuno, H.; Hayano, T. Chem. Rev. 2002, 102, 2211–2225; (e) Kobayashi, S.;
Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem. Rev. 2002, 102, 2227–2302; (f)
Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673–686; (g) Shibasaki, M.;
Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269–279.
The mechanism of the Biginelli reaction established by Kappe10
proposed that the key step in this cyclocondensation process
should involve the formation of an N-acyliminium ion intermedi-
ate or a Lewis acid stabilized imine intermediate from the aldehyde
and urea precursors under acid-catalyzed conditions. However, the
byproduct isolated from the crude product of our model reaction,
which was detected as
a,
a0-dibenzylidene cyclopentanone A and
should be produced from benzaldehyde and cyclopentanone, sug-
gests another hypothesis. The first step of the present reaction is
probably a Lewis acid-catalyzed cross-aldol condensation of alde-
hyde with ketone to produce A, which is similar to the Yb(OTf)3-
catalyzed same reaction described by Wang.11 Then the Michael
addition of urea to A leads to ureide B, which subsequently elimi-
nates water and cyclizes to form pyrimidinone (Scheme 2).
In conclusion, we describe here an efficient method for the syn-
thesis of fused pyrimidinone by YbCl3-catalyzed Biginelli-type
reaction of aromatic aldehyde, cyclopentanone, and urea or thio-
urea under solvent-free conditions. The reaction presented here
has several advantages: it is clean, one-pot, and can be handled
easily. These environmentally friendly features make the catalytic
procedure a practically and environmentally acceptable method
for the synthesis of pyrimidinones.
9. (a) Xu, F.; Luo, Y.; Deng, M.; Shen, Q. Eur. J. Org. Chem. 2003, 4728–4730; (b)
Zhou, Z.; Xu, F.; Han, X.; Zhou, J.; Shen, Q. Eur. J. Org. Chem. 2007, 5265–5269;
(c) Han, X.; Xu, F.; Luo, Y.; Shen, Q. Eur. J. Org. Chem. 2005, 1500–1503.
10. (a) Kappe, C. O. J. Org. Chem. 1997, 62, 7201–7204; (b) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879–888.
11. Wang, L.; Sheng, J.; Tian, H.; Han, J.; Fan, Z.; Qian, C. Synthesis 2004, 18, 3060–
3064.