Cooperative and enantioselective NbCl5/primary amine catalyzed Biginelli reaction

Article abstract of DOI:10.1002/ejoc.201000894

A series of chiral organocatalysts and Lewis acids have been evaluated in the Lewis acid/organocatalysts-based cooperative catalytic Biginelli reaction, which resulted in the determination of a novel cooperative Lewis acid/primary amine catalyst system, N

Full text of DOI:10.1002/ejoc.201000894

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000894
Cooperative and Enantioselective NbCl5/Primary Amine Catalyzed Biginelli
Reaction
Yong-Feng Cai,[a] Hua-Meng Yang,[a] Li Li,[a] Ke-Zhi Jiang,[a] Guo-Qiao Lai,*[a]
Jian-Xiong Jiang,[a] and Li-Wen Xu*[a]
Keywords: Biginelli reaction / Cooperative catalysis / Lewis acids / Organocatalysis / Asymmetric synthesis
A series of chiral organocatalysts and Lewis acids have been
evaluated in the Lewis acid/organocatalysts-based coopera-
tive catalytic Biginelli reaction, which resulted in the deter-
mination of a novel cooperative Lewis acid/primary amine
catalyst system, NbCl5/QN-NH2. The synergistic effect of
NbCl5 and the quinine-derived primary amine is pronounced
and gave dihydropyrimidiones (DHPMs) in moderate to good
enantioselectivities (up to 84% ee) and good to excellent
yields (up to 99% yield) under mild conditions.
Biginelli reactions have been a long-standing challenge. In
contrast, compounds containing the DHPM moiety have
an inherent stereogenic center, which is very important, and
the influence of the absolute configuration of the chiral cen-
ter on the biological activity has been extensively investi-
gated. In most cases only one enantiomer was found to be
biologically active.[7] Therefore, an efficient method for the
preparation of optically pure DHPMs is highly desirable.
Currently, besides chemical resolution and auxiliary-
assisted asymmetric synthesis,[8] several revolutionary ex-
amples of the enantioselective synthesis of these DHPMs
through asymmetric Biginelli or Mannich reaction have
been reported.[9] The breakthrough in the catalytic asym-
metric Biginelli reaction was realized by Zhu and co-
workers in 2006 with a chiral ytterbium complex with a
hexadenate ligand.[10] Another important improvement was
developed by Gong et al. who established an organocata-
lytic, chiral BINOL-derived phosphoric acid catalyzed Bigi-
nelli reaction.[11] Very recently, bifunctional and combined
organocatalytic systems consisting of chiral secondary/pri-
mary amines and Brønsted acids have been reported to pro-
mote the Biginelli reaction with moderate to good enantio-
selectivities.[12] Despite these elegant examples, it is still de-
sirable to develop novel strategies for this important trans-
formation. As a part of our continued interest in the studies
of combined Lewis acids and organocatalysts for organic
transformations,[13] we assumed that the combination of a
primary amine and Lewis acid could promote the asymmet-
ric Biginelli reaction through a dual-activation pathway.[14]
As shown in Scheme 1, the chiral enamine intermediate 4,
activated by a metal-based Lewis acid, would react with N-
acylimine 6 in situ, generated from aldehyde and urea, to
provide enantioenriched DHPM product 8.
Introduction
The Biginelli reaction, a well-known three-component
one-pot condensation reaction of urea or thiourea, alde-
hyde, and β-oxo ester, was originally described by Pietro
Biginelli over a century ago.[1] This reaction played an im-
portant role in organic and medicinal chemistry, because it
offers a straightforward approach to multifunctional dihy-
dropyrimidiones (DHPMs) and related heterocyclic com-
pounds.[2] It is well recognized that the DHPMs and their
derivatives are pharmaceutically important as calcium
channel blockers, α1-1-a-antagonists, antihypertensive
agents, inhibitors of the fatty acid transporter, and mitotic
kinesin inhibition.[3] These compounds have also been
found to possess antiviral, antitumor, and antibacterial
properties.[4] Furthermore, the biological activity of some
isolated marine natural products and alkaloids has been at-
tributed to the dihydropyrimidinone moiety.[5] Thus, the de-
velopment of new methods for the Biginelli reaction, Bigi-
nelli-like reactions, or the synthesis of DHPMs and its de-
rivatives has received renewed interest. In the last decades,
many improved procedures with new catalysts have been
reported.[6] However, most of the reported methods only
resulted in racemic DHPMs, and the asymmetric catalytic
[a] Key Laboratory of Organosilicon Chemistry and Material
Technology of Ministry of Education, Hangzhou Normal
University,
Hangzhou 310012, P. R. China
Fax: +86-571-28865135
E-mail: liwenxu@hznu.edu.cn
licpxulw@yahoo.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000894.
View this journal online at
wileyonlinelibrary.com
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Eur. J. Org. Chem. 2010, 4986–4990

NbCl5/Primary Amine Catalyzed Biginelli Reaction
Table 1. Screening metal salt based Lewis acids for the asymmetric
Biginelli reaction.
Entry[a]
MXn
% ee[b] Entry
MXn
% ee
Scheme 1. Possible catalytic cycle of the dual-activation mechanism
in the combined metal salt based Lewis acid and primary amine
catalyzed Biginelli reaction.
[c]
1
2
3
4
5
6
InCl3
FeCl3
LiClO4
Mg(ClO4)2
Bi(OTf)3
Cu(OTf)2
–
7
8
9
10
11
12
NbCl5
SbCl3
ZnCl2
41[d]
19[d]
25[d]
[c]
[c]
–
–
[c]
[c]
–
Ni(OAc)2
CeCl3·7H2O
AgF
–
9[d]
2[d]
–
[c]
Results and Discussion
[c]
–
Chiral primary amines and derivatives have proven to be
extraordinarily useful organocatalysts in asymmetric syn-
thesis.[15] Being interested in the effort to enhance the cata-
lytic activities of the simultaneous use of Lewis acid and
[a] The reaction was carried out on a 1 mmol scale at room tem-
perature for 72 h, and the ratio of 1/2/3 was 5:1.2:1. [b] The enanti-
omer excess was determined by HPLC (chiral OD-H). [c] The yield
was poor (Ͻ20%), and therefore the enantiomer excess was not
chiral primary amines, we started to investigate the develop- determined. [d] The conversion was complete, and the yield was
Ͼ95%.
ment of a novel combined catalyst system for the Biginelli
reaction. Our study began with a preliminary screening of
several different commercially available metal salts with best result (Table 2, Entry 8). Encouragingly, we found that
strong Lewis acid activity. By using the Biginelli reaction the combination of QN-NH2 and NbCl5 could promote this
of benzaldehyde, ethyl acetoacetate, and urea, as a model reaction effectively to provide product 8a in 76% yield and
reaction with a quinine-derived primary amine (QN-NH2) 69% ee at room temperature. The absolute configuration of
and metal salts as co-catalyst, the asymmetric transforma- the major enantiomer was determined to be (R) by compar-
tion was performed under solvent-free conditions at room ing the reported data.[11,12] Furthermore, we screened some
temperature. As shown in Table 1, significant variations in representative structurally modified quinine derivatives in
the stereoselectivity (2–41% ee) were observed depending this reaction under the optimal conditions. Surprisingly,
on the nature of the metal salts. The salts of FeIII, NbIII
,
with the same backbone, the primary amine moiety was
SbIII gave promising enantioselectivities (Ͼ10% ee). When proven to be a crucial group in the activation of oxo ester
the salts of InIII, LiI, MgII, ZnII, CeIII, NiII, AgI were used, (Table 2, Entries 9, 10). In the presence of a catalytic
no product or only a trace amount of the Biginelli adduct amount of HCl and TFA, the yield or enantioselectivity is
was detected (Ͻ20% yield). It is worthy to note that QN- poor (Table 2, Entries 11, 12). Therefore, on the basis of the
NH2 only resulted in poor conversion under solvent-free results obtained from the reactions with NbCl5 and organo-
conditions. Therefore, the NbCl5 was found to be the best catalysts screened, QN-NH2 was evidently the best choice
Lewis acid in the primary amine based cooperative catalyst for the present reaction system.
system.
With the optimized conditions, the scope of this reaction
To improve the enantioselectivity based on this strategy, was then investigated by using the cooperative catalyst sys-
dozens of known cinchona alkaloids and derivatives, and tem (NbCl5/QN-NH2). The corresponding DHPMs were
some chiral primary amines derived from (R,R)-1,2-diphen- obtained in good to excellent yields (up to 99%) and mod-
ylethylenediamine (DPEN), were screened as cooperative erate to good enantioselectivities (up to 84% ee) at room
organocatalysts in the NbCl5-catalyzed Biginelli reaction temperature. As shown in Scheme 2, both the electronic and
(see Supporting Information); however, no organocatalyst steric effects of the aromatic ring have a significant influ-
evaluated in this work could replace the cinchona alkaloid ence on the enantioselectivity and conversion. In most
derived primary amine. These results show that both the cases, aromatic aldehydes with electron-donating groups in
quinine-derived primary amine plays a privileged role in the the para position afforded moderate enantioselectivities,
enantiomeric induction. In addition, solvent effects were and halogen-substituted aromatic aldehydes resulted in bet-
evaluated after finding the cooperative Nb/primary amine ter enantioselectivities. For aromatic aldehydes bearing elec-
catalyst system (Table 2, Entries 1–8). In terms of both yield tron-donating groups in the meta position, good enantio-
and enantioselectivity, 1,4-dioxane as the solvent gave the selectivities (84% ee) were achieved. In addition, the cata-
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4987

G.-Q. Lai, L.-W. Xu et al.
SHORT COMMUNICATION
Table 2. Screening of organocatalysts and solvents for the NbCl5-
catalyzed asymmetric Biginelli reaction.[a]
Entry Catalyst
Solvent
t [h]
Yield [%][b] % ee[c]
1
2
3
4
5
6
7
8
9
9
9
EtOH
THF
toluene
DCM
CH3CN
CH3NO2
acetone
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
48
48
48
48
48
48
48
48
48
48
48
48
43
59
56
42
84
73
74
76
40
64
12
41
41
38
54
69
35
3
9
9
Scheme 2. NbCl5/QN-NH2-catalyzed Biginelli reaction.
9
9
9
9
be obtained directly without column chromatography as the
workup was modified: Different from the general pro-
cedure, after the reaction was completed, most of the sol-
vent was removed under reduced pressure. Then the crude
product was precipitated with small amounts of ethanol
and water, and then the product was filtered by suction and
washed twice with cold ethanol to yield a pure product with
high enantiomeric excess. These results show that one
should be very careful in evaluating the catalytic activity
and stereoselectivity of a catalyst in the Biginelli reaction.
For the Biginelly reaction, high enantioselectivities were ob-
served for the DHPMs obtained directly by simple precipi-
tation with the solvent or water; thus, it was revealed that
column chromatography is necessary to determine the en-
antiomeric excess values of the DHPMs accurately.
10a
10b
10c
10d
Ͻ10
Ͻ10
65
10
11
12
36
4
13
[a] The reaction was carried out on a 1 mmol scale in the presence
of 10 mol-% of NbCl5 and 10 mol-% of organocatalyst 10 or 9 at
room temperature, and the ratio of 1/2/3 was 5:1.2:1. [b] Isolated
yields. [c] The enantiomer excess was determined by HPLC (chiral
OD-H).
lytic system required a markedly shorter reaction time
(16 h) compared with previous organocatalytic systems (36–
72 h).[12] Notably, although the enantioselectivities are not
very satisfying, the catalytic system described in this work
was proven to be a novel cooperative strategy, in which the
application of metal complexes or Lewis acids in tuning the
reactivity of reactions promoted by organic molecules
would be a simple, efficient, privileged, and highly enantio-
selective biomimetic catalytic process in asymmetric cataly-
sis.
Conclusions
We have developed a novel strategy for the asymmetric
In the meantime, our efforts to improve the enantiomeric Biginelli reaction by using a combined cooperative catalyst
excess of DHPMs commenced with crystallization. Interest- system of Lewis acid and primary amine. The screening and
ingly, when 8a (65% ee) was used as model substrate, eth- optimization of catalyst structures and metal-based Lewis
anol (EtOH) was found to be an excellent solvent in the acids, including transition metal salts and organocatalysts,
crystallization, and an excellent enantiomeric excess (Ͼ99% resulted in the determination of a novel and effective co-
ee) was obtained easily with one simple operation. Very im- operative catalyst system, NbCl5/QN-NH2, which provi-
portantly, under the same reaction conditions, we also ded the corresponding 3,4-dihydropyrimidine-2(1H)-one
found that an excellent enantiomeric excess (99% ee) could (DHPM) derivatives in good to excellent yields and
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NbCl5/Primary Amine Catalyzed Biginelli Reaction
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out purification. Flash column chromatography was performed on
1
silica (200–300 mesh). H and 13C NMR spectra were recorded at
400 and 100 MHz, respectively with a Bruker Avance 400 MHz
NMR spectromer, and were referenced to the internal solvent sig-
nals. Thin layer chromatography was performed by using silica gel
F254 TLC plates and visualized with ultraviolet light. HPLC was
carried out with a Waters 2695 Millennium system equipped with
a photodiode array detector. EI and CI mass spectra were per-
formed with a Trace DSQ GC/MS spectrometer. Data are reported
in the form of m/z values. The organocatalysts were commercially
available and used directly. The Biginelli reaction products were
known and confirmed by GC–MS and usual spectral methods (1H,
13C NMR). The ESI-MS analysis of the samples was carried out
with an LCQ advantage mass spectrometer (ThermoFisher Com-
pany, USA), equipped with an ESI ion source in the positive ion-
ization mode, with data acquisition using the Xcalibur software
(version 1.4). Organocatalysts were synthesized according to re-
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General Procedure for the Biginelli Reaction: A catalytic amount of
QN-NH2 (10 mol-%) and NbCl5 (10 mol-%) were added to a vial
containing aldehyde (1 mmol), urea (1.2 mmol), and ethyl aceto-
acetate (5 mmol) in 1,4-dioxane (2 mL). After vigorous stirring at
room temperature for the times shown in the tables or schemes, the
reaction mixture was poured into an extraction funnel containing
brine, diluted with distilled water, and EtOAc. The aqueous phase
was extracted with EtOAc. The combined organic phases were
dried with Na2SO4, and the solvent was removed under reduced
pressure. The crude product was purified by silica gel column
chromatography to furnish the desired known DHPMs, which were
confirmed by GC–MS and NMR analysis; the ees of the DHPMs
were determined by chiral-phase HPLC analysis using a chiral col-
umn and the indicated eluent systems (see Supporting Infor-
mation).
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Supporting Information (see footnote on the first page of this arti-
cle): General remarks, spectral data and HPLC diagrams for the
Biginelli adducts.
Acknowledgments
This project was supported by the National Natural Science Foun-
dation of China (grant no. 20973051) and the Zhejiang Provincial
Natural Science Foundation of China (Y4090139).
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Eur. J. Org. Chem. 2010, 4986–4990
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SHORT COMMUNICATION
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Published Online: August 16, 2010
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