New ytterbium complex-catalyzed multieomponent reactions for synthesis of dihydropyrimidines: [4 + 2] cycloaddition vs. Biginelli type reaction

Article abstract of DOI:10.1246/cl.2009.56

A new sehiff base ytterbium complex was synthesized and used as catalyst for a three-component, one-pot reaction involving 1,3-keto ester with urea or thiourea and aldehyde. The reactions resulted in the formation of two different dihydropyrimidines, the

Full text of DOI:10.1246/cl.2009.56

56
Chemistry Letters Vol.38, No.1 (2009)
New Ytterbium Complex-catalyzed Multicomponent Reactions for Synthesis
of Dihydropyrimidines: [4 þ 2] Cycloaddition vs. Biginelli Type Reaction
Jie Zhu, Mingjie Zhang,ꢀ Bo Liu, and Xiaojuan Li
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China
(Received October 14, 2008; CL-080985; E-mail: zhujie@tju.edu.cn)
A new schiff base ytterbium complex was synthesized and
Ar
Ar
RO2C
Me
X
RO2C
Me
Me
used as catalyst for a three-component, one-pot reaction involv-
ing 1,3-keto ester with urea or thiourea and aldehyde. The reac-
tions resulted in the formation of two different dihydropyrimi-
dines, the Biginelli type 3,4-dihydropyrimidin-2-(1H)-ones and
non-Biginelli type. A new mechanism based on [4 þ 2] cycload-
dition was proposed which serves as a reasonable explanation for
the two different products.
Yb(pic)3· L
NH
NH
+
+
ArCHO
N
+
H2N
NH2
O
THF, RT
N
H
X
RO2C
N
H
X
N
O
a
b
HO
HO
OH
OH
L=
RO2C
Me
CHO
Y
Yb(pic)3·L
+
HO
+
H2N
NH2
O
THF, RT
RO2C
Me
NH
Multicomponent reactions (MCRs) have received increasing
interest in organic and medicinal chemistry1 during the past two
decades mainly owing to the high demands of drug discovery.2
The venerable Biginelli reaction, one-pot cyclocondensation of
aldehyde, ꢀ-keto ester, and urea or thiourea, is a classical way
to produce multifunctionalized 3,4-dihydropyrimidin-2(1H)-
ones (DHPMs).3 DHPMs show a wide scope of important phar-
macological properties and make up a large family of medicinal-
ly relevant compounds. The present attention on Biginelli type
DHPMs is mainly due to their close structural relationship to
the pharmacologically important as calcium channel modulators
of the nifedipine type, and several marine natural products con-
taining the dihydropyrimidine-5-carboxylate core exhibit anti-
cancer properties.4,5
Pharmacological studies concerning the absolute configura-
tion have demonstrated individual enantiomers perform oppos-
ing biological activities in most cases.4 Nevertheless, only a
few examples of asymmetric synthesis of this heterocyclic target
have been reported.6,7 Although the reaction was described over
a century ago, and more and more attention are focused on
Biginelli DHPMs, the mechanism of the classical three-compo-
nent Biginelli condensation has not been elucidated with cer-
tainty and remains controversial.8 The first so-called ‘‘ureido-
crotonate mechanism’’ was proposed by Folkers and Johnson9
in 1933. They suggested that the primary bimolecular condensa-
tion product N,N0-benzylidenebisurea is the first intermediate in
this reaction. 40 years later in 1973, the ‘‘carbenium ion mecha-
nism,’’ proposed by Sweet and Fissekis,10 suggested that an acid-
catalyzed aldol condensation is the first and limiting step of the
Biginelli reaction. The widely accepted mechanism proposed by
Kappe11 is the ‘‘N-acyliminium ion intermediate’’ path, which is
a confirmation of Folkers and Johnson’s. According to this
mechanism, only a single product can be obtained. Herein, we
proposed a new mechanism for the Biginelli reaction via
[4 þ 2] cycloaddition,12 which serves as a reasonable explana-
tion for the observation of two different dihydropyrimidine prod-
ucts during our experiment.
O
1. Y=O, R=Et
2. Y=S, R=Et
3. Y=S, R=t-Bu 17a
15a
16a
N
H
Y
Scheme 1. The reaction resulted in different products.
The Biginelli condensation of ethyl acetoacetate, benzaldehyde,
and urea was catalyzed by ytterbium picrate [Yb(pic)3] with the
ligand (Scheme 1, Table 1, Entry 1). The result was not satisfac-
tory for the reaction showing high conversion but the yield of ex-
pected product 1a is very low (37%). After screening the reac-
tion mixture carefully, we surprisingly found a new product 1b
yield in 54% which is also a dihydropyrimidine and is different
in the methyl and ester group positions from the expected one.
The differences are demonstrated by 1H NMR characterizations.
Because this intriguing finding, we proceeded to examine
the scope of this side product with various substituted aromatic
aldehydes, two 1,3-keto esters, and urea/thiourea.13 Two differ-
ent dihydropyrimidine products were found for most substrates
(Table 1, Entries 1–14), and for salicylaldehyde (Table 1, Entries
15–17), because of the Biginelli type precursors were much easi-
er to conduct intramolecular etherification, three sole diazatricy-
clic products were produced. The X-ray diffraction analysis of
compound 4a, 7a, 11a, and 16a were then performed to confirm
that the molecular structures are indeed as shown in Supporting
Information.15
The non-Biginelli products could not be obtained according
to the mechanism of Kappe’s.11 Thus, we proposed a new mech-
anism based on a [4 þ 2] cycloaddition (Scheme 2). Condensa-
tion of urea and benzaldehyde affords imine, which is then
enolized to form a diene, 1-benzylideneisourea. The Yb(pic)3ꢁL
complex is assumed to contribute to the stabilization of diene
intermediate. This is the key step which is different from the
N-acyliminium intermediate. Subsequent cycloaddition with the
enol generates the ꢀ-carbonyl compound and then gives the
corresponding dihydropyrimidine 1a and 1b after elimination
of a water molecule.
Methyl acrylate, instead of 1,3-keto ester, serving as a di-
enophile, was added to the mixture of benzaldehyde, urea and
the ytterbium catalyst to validate the existence of diene inter-
mediate. After 24 h stirring, two new compounds were observed
(Scheme 3). The formation of A and B demonstrated generation
At the beginning, we focused on the asymmetric synthesis of
DHPMs via the Biginelli reaction. A new BINOL-salen type
chiral ligand was developed from the corresponding amine and
BINOL-derived aldehyde in alcohol under ambient atmosphere.
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.1 (2009)
57
Table 1. Dihydropyrimidines
Yb(pic)3ꢁLa
synthesis
catalyzed
by
tion of diene intermediate, 1-benzylideneisourea was proven
indirectly and the structures of 4a, 7a, 11a, and 16a were deter-
mined by single X-ray diffraction analysis.14 Further work is
undergoing to investigate the precise and specific role of
Yb(pic)3ꢁL and improve selectivity of two DHPMs.
Yieldb Yieldb
Entry
Ar
Y
R
a/%
b/%
1
2
3
4
5
6
7
8
C6H5
C6H5
O
O
O
O
O
O
O
S
Et
t-Bu
Et
t-Bu
Et
t-Bu
t-Bu
Et
t-Bu
Et
37
54
31
40
29
62
46
45
52
39
51
47
46
48
69
59
82
54
38
21
49
52
27
45
43
44
26
37
46
45
42
0
References and Notes
1
p-CH3-C6H4
p-CH3-C6H4
p-OH-C6H4
p-OH-C6H4
o-Cl-C6H4
C6H5
For reviews, see: J. Zhu, in Multicomponent Reactions, ed.
´
by H. Bienayme, Wiley-VCH, Weinheim, Germany, 2005;
D. J. Ramon, M. Yus, Angew. Chem., Int. Ed. 2005, 44,
´
1602; M. D. Burke, S. L. Schreiber, Angew. Chem., Int.
Ed. 2004, 43, 46.
2
3
4
M. Plunkett, J. A. Ellman, Sci. Am. 1997, 276; S. L.
Schreiber, Science 2000, 287, 1964.
P. G. Biginelli, Chim. Ital. 1893, 23, 360; C. O. Kappe, Acc.
Chem. Res. 2000, 33, 879.
Dihydropyrimidine calcium channel modulators: K. S.
Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S.
Moreland, A. Hedberg, B. C. O’Reilly, J. Med. Chem.
1991, 34, 806; C. O. Kappe, Eur. J. Med. Chem. 2000, 35,
1043; C. O. Kappe, QSAR Comb. Sci. 2003, 22, 630.
L. Heys, C. G. Moore, P. Murphy, Chem. Soc. Rev. 2000, 29,
9
C6H5
S
10
11
12
13
14
15
16
17
p-CH3-C6H4
p-OH-C6H4
p-OH-C6H4
o-Cl-C6H4
p-Cl-C6H4
o-OH-C6H4
o-OH-C6H4
o-OH-C6H4
S
S
S
S
S
O
S
Et
t-Bu
t-Bu
Et
Et
Et
t-Bu
0
0
5
S
´
57; J. Barluenga, M. Tomas, V. Rubio, V. J. Gotor, J. Chem.
aAll reactions were carried out at room temperature with
10 mol % catalyst. Isolated yields.
b
Soc., Chem. Commun. 1979, 675; Z. D. Aron, L. E.
Overman, Chem. Commun. 2004, 253.
ˇ
ˇ
6
7
O. Munoz-Muniz, E. Juaristi, Arkivoc 2003, xi, 16.
Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127,
16386; X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun, L.-Z. Gong,
J. Am. Chem. Soc. 2006, 128, 14802; L.-Z. Gong, X.-H.
Chen, X.-Y. Xu, Chem.—Eur. J. 2007, 13, 8920.
O
C
O
O
cat.
H
H
C
H
cat.
C
Ar
N
N
Ar
N
NH
H2N
NH2
ArCHO
+
H
Diene
Imine
Ar
Ar
Ar
8
9
C. O. Kappe, Tetrahedron 1993, 49, 6937.
K. Folkers, T. B. Johnson, J. Am. Chem. Soc. 1933, 55, 3784.
10 F. Sweet, J. D. Fissekis, J. Am. Chem. Soc. 1973, 95, 8741.
11 C. O. Kappe, J. Org. Chem. 1997, 62, 7201.
12 Y. Zhu, S. Huang, J. Wan, L. Yan, Y. Pan, A. Wu, Org. Lett.
2006, 8, 2599; I. Matsuda, S. Yamamoto, Y. Ishii, J. Chem.
HO
HO
NH
N
NH
H
RO2C
N
H
O
RO2C
N
H
OH
RO2C
RO2C
N
H
O
O
C
CH3
R
C
1'
1
O
OH
Dienophile
Ar
Ar
Ar
RO2C
HO
RO2C
HO
N
NH
NH
´
Soc., Perkin Trans. 1 1976, 1523; J. Barluenga, M. Tomas,
A. Ballesteros, L. A. Lopez, Synthesis 1989, 228.
N
H
OH
N
H
O
N
H
O
´
2'
2
13 General procedure for the catalytic Biginelli reaction: In a
10-mL Schlenk flask, a solution of 2 mL of THF, Yb(pic)3
(0.05 mmol) and ligand (0.05 mmol) was stirred at room tem-
perature. After 10 min, ꢀ-keto ester compound (0.5 mmol),
aldehyde (0.5 mmol), and urea or thiourea (0.5 mmol) were
introduced. After approximately 60 h, 5 mL of water was
added, and the product was extracted with ethyl acetate
(5 mL ꢂ 3). After the organic layer was dried (anhydrous
Na2SO4) and evaporated, the residue was purified by column
chromatography (petroleum ether (60–90 ꢃC)/ethyl acetate,
6:1–4:1) to afford the corresponding product.
Scheme 2. The proposed mechanism.
CHO
O
O
+
Yb(pic) ·L
3
+
H CO C
3
2
+
H N
NH
2
2
NH
NH
THF, RT
O
H CO C
N
H
O
N
O
3
2
H
A, 42%
B, 37%
Scheme 3. The indirect evidence.
of the diene, and then went through [4 þ 2] cycloaddition with
methyl acrylate. This is an indirect evidence for the existence
of diene intermediate, and thus it is a reasonable assumption that
the Biginelli reaction also proceeds via this path. Besides that,
methyl acrylate is demonstrated to be a potential substrate for
the Biginelli reaction.
In conclusion, we developed a new method for synthesis
of two kinds of dihydropyrimidine (Biginelli type and non-
Biginelli type), and a new mechanism for the Biginelli reaction
based on [4 þ 2] cycloaddition was proposed, which serves as
a good explanation for the observed two products. The forma-
14 Crystallographic data reported in this manuscript have been
deposited with Cambridge Crystallographic data centre as
supplementary publication no. CCDC 685708 4a, 685709
7a. Copies of the data can be obtained, free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic data centre, 12, Union Road,
Cambridge, CB2 1EZ, UK; fax: +44-1223-336033; or
e-mail: deposit@ccdc.cam.ac.uk).
15 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Published on the web (Advance View) December 6, 2008; doi:10.1246/cl.2009.56