Polymer-supported ionic-liquid-catalyzed synthesis of 1,2,3,4-tetrahydro-2- oxopyrimidine-5-carboxylates via Biginelli reaction

Article abstract of DOI:10.1002/hlca.200590093

The Biginelli reaction between an aromatic aldehyde, ethyl acetoacetate. and urea - catalyzed by polymer-supported, re-usable, room-temperature ionic liquids (RTIL) such as 1b - was shown to efficiently proceed in glacial AcOH at 100° to afford the corres

Full text of DOI:10.1002/hlca.200590093

9
86
Helvetica Chimica Acta ± Vol. 88 (2005)
Polymer-Supported Ionic-Liquid-Catalyzed Synthesis of 1,2,3,4-Tetrahydro-
-oxopyrimidine-5-carboxylates via Biginelli Reaction
2
a
a
b
by Zong-Ting Wang* ), Shu-Chao Wang ), and Li-Wen Xu )
a) Department of Applications Chemistry, University of Petroleum (East China), Dongying, Shandong,
257062, P. R. China (e-mail: ztiwang@hdpu.edu.cn)
b) State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou, Gansu, 730000, P. R. China
The Biginelli reaction between an aromatic aldehyde, ethyl acetoacetate, and urea ± catalyzed by polymer-
supported, re-usable, room-temperature ionic liquids (RTIL) such as 1b ± was shown to efficiently proceed in
glacial AcOH at 1008 to afford the corresponding pyrimidine-5-carboxylates 3 in yields up to 99% within 2 h
(
Table 2). The catalyst(s) could be reused at least five times, basically without loss of activity, which makes this
transformation not only straight-forward, but also considerably less expensive compared to methods involving
classical RTIL catalysts.
Introduction. ± Recently, the classical Biginelli reaction [1] has found great interest
because partly hydrated pyrimidinones have shown pharmacological activities. These
compounds may act as antihypertensives, calcium channel blockers, a-1a antagonists
[
2], and neuropeptide Y (NPY) antagonists [3]. Furthermore, several marine alkaloids
with interesting biological activities containing the dihydropyrimidine-5-carboxylate
skeleton were isolated recently [4].
The main drawback of the Biginelli reaction is the low yield for extended reaction
times in the case of substituted aromatic and aliphatic aldehydes [5]. So, the
development of alternative synthetic methodologies is of great importance. This has led
to the development of several new synthetic strategies involving combinations of Lewis
acids [6], e.g., BF ´ OEt , KSF, PPE (ˆ polyphosphate ester), B(OH) , onium salts,
3
2
3
and (transition) metal salts [7] such as InCl , LiBr, LaCl ´ 7 H O, CeCl ´ 7 H O,
3
3
2
3
2
Mn(OAc) ´ 2 H O, Cu(OTf) (Tf ˆ F CSO ), or FeCl ´ 6 H O.
3
2
2
3
2
3
2
Room-temperature ionic liquids (RTIL) have attracted much interest among
organic chemists. Typically, RTIL used for organic reactions are Lewis acids that can
catalyze acid/base reactions. Some RTIL-catalyzed Biginelli reactions have been
reported [8], e.g., with 1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate
(
BMimBF ) or the corresponding hexafluorophosphate (BMImPF ). Unfortunately,
4
6
these and other compounds are generally very expensive and difficult to remove from
the products. Thus, we immobilized the catalyst on Merrifield resin to obtain
polystyrene ± methylimidazolium (PsMim)-based, re-usable ionic liquids of type 1
[
9]. These compounds were found to efficiently catalyze Biginelli reactions, giving rise
to very good yields in short reaction times.
In this paper, we describe the application of catalysts 1 for the synthesis of a variety
of substituted tetrahydropyrimidine-5-carboxylates 3.
ꢀ
2005Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta ± Vol. 88 (2005)
987
Results and Discussion. ± To optimize the conditions for the RTIL-catalyzed
Biginelli reaction, we investigated the condensation between benzaldehyde (2a), ethyl
acetoacetate (ˆethyl 3-oxobutanoate), and urea, which gave rise to ethyl 1,2,3,4-
tetrahydro-6-methyl-2-oxo-4-phenylpyrimidine-5-carboxylate (3a; Table 1). First, we
determined the efficiency of the two polymer-supported catalysts Ps-MimBF (1a) and
4
PsMimPF (1b) as a function of solvent. Both were found to readily catalyze the
6
reaction. However, PsMimBF produced more insoluble byproducts in EtOH and
4
CHCl compared to PsMimPF . Also, the solvent (and temperature) remarkably
3
6
affected the yield, glacial AcOH being better than MeCN or EtOH, with isolated yields
of 3a of 98%, 85%, and 71%, respectively (Table 1). Thereby, the same catalyst (1b)
could be used at least five times without significant loss in activity (Entry 6), and no
precipitation was observed during reaction, which is a prerequisite for high yields.
Table 1. Polymer-Supported,Ionic-Liquid-Catalyzed Biginelli Reaction with Benzaldhyde. Conditions: catalyst,
3.5mol-%; aldehyde and ethyl acetoacetate, 10 mmol each; urea, 15mmol.
Entry
Catalyst
Solvent
T
Time
3a [%]a)
Turnoverb)
±
1
2
3
4
5
6
7
None
None
None
PsMImPF
PsMImPF
PsMImPF
PsMImBF
EtOH
MeCN
AcOH
EtOH
MeCN
AcOH
MeCN
788
4 h
4 h
2 h
4 h
4 h
2 h
4 h
13
25±
70
828
1008
788
788
1008
828
±
20
6
6
6
71
8524
c
98 )
28
24
d
4
84 )
a) Isolated yield after recrystallization. b) Ratio of product (equiv.) rel. to catalyst. c) When the same catalyst
was used five times, the yields were 98, 97, 94, 90, and 91%, resp., with basically constant turnovers of 28 to 26.
d
)
3
Most by-products were insoluble in EtOH or CHCl .
Encouraged by the above results, other substrates, i.e., several aromatic and
aliphatic aldehydes 2, were reacted under optimized conditions in the presence of
PsMImPF (1b) in AcOH at 1008 for 2 h (Table 2).
6
Aromatic aldehydes with electron-donating groups R (2a, g) favored the Biginelli
condensation under these conditions (ꢀ 98% yield). In contrast, aromatic aldehydes

9
88
Helvetica Chimica Acta ± Vol. 88 (2005)
with electron-withdrawing substituents (2b ± f) gave rise to somewhat lower, but still
good yields (74 ± 91%). Steric effects due to ortho-substituents negatively affected the
reactivity of the substrates (Entry 2 vs. 3 in Table 2). The low yield of 3h was most-
likely due to protonation of the 4-Me N group of 2h, thus becoming an electron-
2
‡
withdrawing 4-Me NH group. Finally, the aliphatic aldehyde 2i (butanal) was not
2
suited for this kind of transformation under the conditions applied (Entry 9).
Table 2. Polymer-Supported,Ionic-Liquid-Catalyzed Synthesis of Compounds 3 with PsMImPF 6 (1b).
Conditions: catalyst, 3.5mol-%; aldehyde and ethyl acetoacetate, 10 mmol each; urea, 15mmol.
Entry
No.
R
3a ± i [%]a)
M.p. [8]
Turnover
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Ph
2-Cl-C
4-Cl-C
2,4-Cl
4-NO
2-MeO-C
4-Me-C
4-Me
Pr
98
80
91
74
88
87
99
53
23
200 ± 202
215± 217
212 ± 213
248 ± 250
207 ± 209
201 ± 202
171 ± 173
230 ± 232
152 ± 153
28
23
26
21
25
25
28
15
7
6
H
H
4
4
6
2
-C
6 3
H
2
-C
6
H
4
6
H
4
6
H
4
2 6 4
N-C H
a) Isolated yield after recrystallization.
Conclusions. ± The use of recoverable, polymer-supported room-temperature ionic
liquids (RTIL) as catalysts provides a simple and effective method for the Biginelli
reaction performed with aromatic aldehydes. The problem of separating expensive
RTIL from the products, especially problematic for large-scale preparations, can be
readily circumvented with the catalyst PsMImPF (1b).
6
Experimental Part
General. All solvents and reagents were used without purification. Thin-layer chromatography (TLC) was
performed on silica-gel H 60 plates; visualization by UV and exposure to I . Melting points (m.p.) were
2
measured on a Rapido PHMK 79/2523 instrument (VEB Wagetechnik) and are uncorrected. IR Spectra were
1
recorded on an FT-IR apparatus. H-NMR Spectra were recorded at 400 MHz and referenced to internal
solvent signal. GC/MS were recorded on Agilent 6890N/5793N/HP-5. All products (3) were fully characterized,
and their anal. data were compared with those given in the literature. For m.p., see Table 2.
Catalyst Preparation. To a flask containing polystyrene-based chloromethyl resin (5.0 g; 200 ± 400 mesh,
3
(
.5mmol Cl/g) was added DMF (15ml), and the resin was stirred for 2 h. Then, 1-methyl 1- H-imidazole
20 mmol) was added, and the mixture was heated at 808 for 24 h. The resin was filtered under reduced pressure,
washed with anh. EtOH, and stirred for 12 h in EtOH at 808. Then, the beads were filtered off and dried in vacuo
to afford yellowish PsMImCl resin, which was subjected to ion exchange with 20 weight-% NaBF or NH PF in
4
4
6

Helvetica Chimica Acta ± Vol. 88 (2005)
989
H
(
2
O for 24 h. The beads were then filtered, washed neutral with H
1a) or PsMImPF (1b), resp.
General Procedure for the PsMImPF
10 mmol), ethyl acetoacetate (1.30 g, 10 mmol), urea (0.91 g, 15mmol), and PsMImPF
) in glacial AcOH (40 ml) was heated at 1008 for 2 h in a single-neck flask. Then, the hot soln. was filtered
2 4
O, and dried in vacuo to afford PsMImBF
6
6
Catalyzed Preparation of Compounds 3. A soln. of the aldehyde
(1b; 100 mg, 3.5mol-
(
%
6
through a sintered funnel to remove the catalyst for re-use. The filtrate was cooled to r.t., and then poured onto
crushed ice (40 g). Stirring was continued for several minutes, and the solid product was filtered through another
sintered funnel. The crude product was purified by recrystallization (EtOH).
This work was financially supported in part by the State Natural Science Foundation (29933050 and
2
0373082) of China.
REFERENCES
1] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360; C. O. Cape, Tetrahedron 1993, 49, 6937.
[
[2] K. S. Atawal, G. C. Rovnyak, B. C. O. Reilly, J. Schwartz, J. Org. Chem. 1989, 54, 5898; C. O. Kappe,
W. M. F. Fabian, M. A. Semones, Tetrahedron 1997, 53, 2803.
[
3] K. S. Atwal, G. C. Rovnyak, S. D. Kimball, D. M. Floyd, S. Moreland, B. N. Swanson, J. Z. Gougoutas, J.
Schwartz, K. M. Smillie, M. F. Malley, J. Med. Chem. 1990, 33, 2629; G. G. Rovnyak, S. D. Kimball, B.
Beyer, G. Cucinotta, J. D. DiMarco, J. Z. Gougoutas, A. Hedberg, M. F. Mally, J. P. McCarthy, R. Zhang, S.
Moreland, J. Med. Chem. 1995, 38, 119.
[
[
[
4] B. B. Snider, Z. Shi, J. Org. Chem. 1993, 58, 3828.
5] J. Barluenga, M. Tomas, A. Ballesteros, L. A. Lopez, Tetrahedron Lett. 1989, 30, 4573.
6] E. H. Hu, D. R. Sidler, U. H. Dolling, J. Org. Chem. 1998, 63, 3454; F. Bigi, B. Frullanti, R. Maggi, G.
Sartori, Tetrahedron Lett. 1999, 40, 3465; C. O. Kappe, S. F. Falsone, Synlett 1998, 718; S. J. Tu, F. Feng, C. B.
Miao, H. Jiang, Y. J. Feng, D. Q. Shi, X. S. Wang, Tetrahedron Lett. 2003, 44, 6153; K. R. Reddy, C. V.
Reddy, M. Mahesh, P. V. K. Raju, V. V. N. Reddy, Tetrahedron Lett. 2003, 44, 8173.
[
7] B. C. Ranu, A. Harja, U. Jano, J. Org. Chem. 2000, 65, 6270; P. B. Partha, G. Sunil, P. Dipak, S. S. Jagir,
Chem. Lett. 2002, 10, 1038; G. Sabitha, G. S. K. K. Reddy, C. S. Reddy, J. S. Yadav, Synlett 2003, 858; J. Lu,
Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron Lett. 2000, 41, 9075; D. S. Bose, F. Liyakat, M. H. Babu, J.
Org. Chem. 2003, 68, 587; K. A. Kumar, M. Kasthuraiah, C. S. Reddy, C. D. Reddy, Tetrahedron Lett. 2001,
42, 7873; A. S. Paraskar, G. K. Dewkar, A. Sudalai, Tetrahedron Lett. 2003, 44, 3305; J. Lu, H. R. Ma,
Synlett 2000, 63.
[
[
8] J. J. Peng, Y. Q. Deng, Tetrahedron lett. 2001, 42, 5917.
9] A. Dondoni, A. Massi, Tetrahedron Lett. 2001, 42, 7975; P. Salehi, M. Dabiri, M. A. Zolfigol, M. A. B. Fard,
Tetrahedron Lett. 2003, 44, 2889 ± 2891.
Received January 26,2005