Three-component one-pot synthesis of pyrimidinone derivatives in fluorous media: Ytterbium bis(perfluorooctanesulfonyl)imide complex catalyzed biginelli-type reaction

Article abstract of DOI:10.1002/jhet.241

(Chemical Equation Presented) The condensation of aromatic aldehyde, cyclopentanone, and urea or thiourea in the presence of Ytterbium bis(perfluorooctanesulfonyl)imide complex in perfluorodecalin was used to synthesize a variety of benzylidene heterobicyclic pyrimidinones in excellent yields.

Full text of DOI:10.1002/jhet.241

1430
Three-Component One-Pot Synthesis of Pyrimidinone Derivatives
in Fluorous Media: Ytterbium Bis(perfluorooctanesulfonyl)imide
Complex Catalyzed Biginelli-Type Reaction
Vol 46
Mei Hong and Chun Cai*
College of Chemical Engineering, Nanjing University of Science & Technology, Nanjing 210094,
People’s Republic of China
*E-mail: c.cai@mail.njust.edu.cn
Received May 4, 2009
DOI 10.1002/jhet.241
Published online 6 November 2009 in Wiley InterScience (www.interscience.wiley.com).
The condensation of aromatic aldehyde, cyclopentanone, and urea or thiourea in the presence of Yt-
terbium bis(perfluorooctanesulfonyl)imide complex in perfluorodecalin was used to synthesize a variety
of benzylidene heterobicyclic pyrimidinones in excellent yields.
J. Heterocyclic Chem., 46, 1430 (2009).
INTRODUCTION
ponent condensation with aromatic aldehyde, cyclopen-
tanone, and urea or thiourea as starting materials. Each
of the aforementioned methods has its own merits, while
some of these methods are plagued with the limitation
of poor yields, difficult workup, effluent pollution, and
unrecyclability of catalysts.
Multicomponent reactions (MCRs) are powerful tools
in modern medicinal chemistry, enabling straightforward
access to large libraries of structurally related, drug-like
compounds and thereby facilitating the generation of
precursor candidates compounds. Hence, combined with
the use of combinatorial chemistry and high throughput
parallel synthesis, such reactions have constituted an
increasingly valuable approach to drug discovery efforts
in recent years [1,2].
Metal complexes with bis(perfluorooctanesulfonyl)-
imide ligands are active and recyclable catalysts in the
fluorous immobilized phase for Baeyer-Villiger oxida-
tion [11], Diels-Alder reaction [12], esterification [13],
and Friedel-Crafts acylation [14]. A key factor to ac-
complish the catalytic processes was ascribed to the use
of long-enough perfluorinated—N(SO2C8F17)2, whose
structural characteristic can coordinate with a variety of
metal cations to obtain the desired Lewis acid catalysts
with appropriate catalytic activity, and the selective
immobilization in the fluorous. Herein, this letter
attempts to describe the catalytic activity of rare earth
Over the past decade, pyrimidinone derivatives have
attracted strong interest because of their useful biologi-
cal activities, pharmaceutical, and therapeutic properties,
such as antiviral, antitumor, antibacterial, and anti-
inflammatory activities [3–6]. Classical Biginelli reac-
tions involve one-pot condensations of an aldehyde, a,b-
ketoester, and urea under strongly acidic conditions. In
recent decades, the Biginelli reaction was extended the
scope [7]. Especially, some fused pyrimidinones carry-
ing an arylidene moiety exit not only the broad-spec-
trum antitumor activity but also a distinctive pattern of
selectivity toward individual cell line such as that of
leukemia. Thus, synthesis of these heterocycles is of
much current importance for both organic synthesis and
medicinal chemistry. Conventional methods for synthe-
sis of this type of pyrimidinones involve condensation
of a, a0-bis(substituted benzylidene)cycloalkanones with
urea or thiourea using strong Bronsted acid [8] or base
[9] as catalysts. Recently Pan and coworkers [7b] and
Xu and coworkers [10] described efficiently alternative
synthesis of these fused pyrimidinones by a three-com-
(III)
bis-(perfluorooctanesulfonyl)imide
complexes
RE[N(SO2AC8F17)2]3, (RE(NPf2)3) in the one-pot syn-
thesis of pyri-midinone from aromatic aldehyde, cyclo-
pentanone, and urea or thiourea (Scheme 1), the so-
called Biginelli-type three-component reaction.
RESULTS AND DISCUSSION
At first, we began to study the catalytic activities of a
series of rare earth bis(perfluorooctanesulfonyl)imide
complexes to optimize the reaction condition of benzal-
dehyde, cyclopentanone, and urea (Scheme 2), which
was chosen as a model reaction. The results are
C
V
2009 HeteroCorporation

November 2009 Three-Component One-Pot Synthesis of Pyrimidinone Derivatives in Fluorous
Media: Ytterbium Bis(perfluorooctanesulfonyl)imide Complex Catalyzed Biginelli-Type Reaction
1431
Scheme 1
Table 1
RE(NPf2)3-catalyzed one-pot synthesis of benzylidene heterobicyclic
pyrimidinones.a
Entry
Catalyst
Yieldb (%)
1
2
3
Y(NPf2)3
La(NPf2)3
Ce(NPf2)3
Nd(NPf2)3
Sm(NPf2)3
Eu(NPf2)3
Tb(NPf2)3
Dy(NPf2)3
Er(NPf2)3
Yb(NPf2)3
73
64
83
68
71
72
77
79
85
91
4
5
summarized in Table 1. It was obviously that rare earth
bis(perfluorooctanesulfonyl)imide complexes catalyzed
the Bigineli-type reaction efficiently and Yb(NPf2)3
showed the best catalytic activity among these
complexes.
6
7
8
9
10
By using Yb(NPf2)3 as catalyst, we examined the
effect of the amount of the catalyst on the model reac-
tion mentioned earlier. When the amount of Yb(NPf2)3
was increased from 0.4 to 1.2 mol%, the yield was
increased until to a maximum and then gradually
decreased, and the highest yield was obtained at 1
mol% catalyst loading (Table 2, Entries 1–5).
a Reaction conditions: benzaldehyde (0.212 g, 2 mmol), cyclopenta-
none (0.168 g, 2 mmol), urea (0.146 g, 2.4 mmol), C10F18 (2 mL),
RE(NPf2)3 (0.02 mmol), 90ꢀC, 2.5 h.
b Isolated yield.
dehyde, cyclopentanone, and urea under the conditions
as mentioned earlier were run for five consecutive
cycles, respectively, furnishing the corresponding pyri-
midinones with 91%, 89%, 88%, 87%, and 87% isolated
yields.
Based on the earlier optimized results, with 1 mol%
Yb(NPf2)3 as catalyst, we also investigated the effect of
the reaction temperature ranging from 80 to 100ꢀC, and
the best results were obtained at 90ꢀC (Table 2, Entries
4, 6 and 7). Meanwhile, further studies showed that the
molar ratio of benzaldehyde, cyclopentanone, and urea
at 1:1:1.2 was preferred.
The mechanism for formation of benzylidene hetero-
bicyclic pyrimidinones products is assumed to take place
via coordination of Yb(NPf2)3 with an aldehyde, which
then activates the attack of keto compound in its enol
form and subsequent removal of OH group gives enone.
Similar reaction further proceeds on this enone to give
bis-benzylidene derivatives. The next are the Michael
addition of urea, elimination of water, and cyclization to
form pyrimidione.
Under the optimized conditions, the reactions of dif-
ferent aldehydes with cyclopentanone and urea or thiou-
rea were examined. As listed in Table 3, aromatic alde-
hydes carrying different functional groups, such as
methyl, methoxy, chloro, bromo, and nitro, were sub-
jected to the reactions, and in all cases, the desired
products were obtained in high yields (81–93%). All
reactions were clean and free from any by-products. It
is important to note that aldehydes with electron-with-
drawing group were more reactive, and the reactions
with cyclopentanone and urea were faster. The reason
may be that the carbonyl carbon in aldehydes containing
electron-withdrawing group are more electrophilic. Thio-
urea exhibited behavior similar to that urea.
In conclusion, we report a one-pot synthesis of fused
pyrimidinone by Yb(NPf2)3-catalyzed Biginelli-type
reaction of aromatic aldehyde, cyclopentanone, and urea
or thiourea in fluorous media. The easy workup proce-
dure, recyclable catalyst, short reaction times, and very
good yields are the main advantages of this method.
Table 2
Reaction of benzaldehyde, cyclopentanone, and urea in the presence of
Yb(Npf2)3 under different reaction conditions.a
The possibility of recycling Yb(NPf2)3 catalyst for the
synthesis of 1a was also investigated. When the reaction
was finished, the reaction mixture was cooled to room
temperature. The fluorous phase containing catalysts
was separated from reaction mixture by decantation and
reused for the next cycle. The condensations of benzal-
Amount
of Yb(NPf2)3 (mol%)
Temperature
(ꢀC)
Yieldb
(%)
Entry
1
2
3
4
5
6
7
0.4
0.6
0.8
1.0
1.2
1.0
1.0
90
90
90
90
90
80
100
42
67
83
91
89
68
85
Scheme 2
a Reaction conditions: benzaldehyde (0.212 g, 2 mmol), cyclopentanone
(0.168 g, 2 mmol), urea (0.146 g, 2.4 mmol), C10F18 (2 mL), 2.5 h.
b Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1432
M. Hong and C. Cai
Vol 46
Table 3
Typical procedure for the preparation of 7-benzylidene-
4-phenyl-3,4,6,7-tetrahydro-1H- cyclopenta[d] pyrimidin-
2(5H)-one. A mixture of benzaldehyde (0.212 g, 2 mmol),
cyclopentanone (0.168 g, 2 mmol), urea (0.146 g, 2.4 mmol),
and Yb(NPf2)3 (0.062 g, 0.02mmol) in perfluo-rodecalin
(C10F18, cis and trans-mixture, 2mL) was well stirred at 90ꢀC
for appropriate time. After the reaction was completed, the
system was cooled to room temperature. Then, the perfluorode-
calin on the bottom was separated for the next cycle. Water
was added to the reaction mixture, and the pure product was
obtained by filtration followed by washing with acetone, ethyl
acetate, and alcohol. Selected data: 7-benzylidene-4-phenyl-
3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one, pale
Synthesis of benzylidene heterobicyclic pyrimidinones in the presence
a
of Yb(Npf2)3 in C10F18.
Entry
Ar
X
Time (h) Product Yieldb (%)
1
2
3
Ph
O
O
O
O
O
O
O
O
S
2
3
3
3
2
2
2
2
6
6
5
1a
1b
1c
1d
1e
1f
1g
1h
1i
91
93
81
85
89
84
83
92
94
86
92
4-CH3C6H4
2-CH3C6H4
4-OCH3C6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-NO2C6H4
Ph
4
5
6
7
8
1
yellow solid; mp 236–239ꢀC; H NMR (500 MHz, DMSO): d
9
10
11
4-CH3C6H4
4-ClC6H4
S
1j
1k
¼ 1.97–2.01 (m, 1H), 2.49 (m, 1H), 2.71–2.82 (m, 2H), 5.15
13
S
(s, 1H), 6.63 (s, 1H), 7.21–7.38 (m, 11H), 8.78 (s, 1H).
C
NMR: d ¼ 29.5, 29.8, 58.7, 117.8, 119.6, 127.2, 127.4, 128.6,
129.0, 129.5, 129.6, 137.1, 138.8, 140.3, 144.3, 154.4 ppm.
MS (EI) m/z 303 [MþH]þ.
a Reaction conditions: aldehyde (2 mmol), cyclopentanone (2 mmol),
thiourea or urea (2.4 mmol), C10F18(2 mL), 90ꢀC.
b Isolated yield.
EXPERIMENTAL
REFERENCES AND NOTES
Chemicals used were obtained from commercial suppliers
1
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HNEt3. Finally, through acidic ion exchange resin column,
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50% yield. Anal. Calcd. for (C8F17SO2)2NH: C,19.57; N: 1.43
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet