An enantioselective Biginelli reaction catalyzed by a simple chiral secondary amine and achiral Bronsted acid by a dual-activation route

Article abstract of DOI:10.1002/chem.200701581

An enantioselective Biginelli reaction that proceeds by a dual-activation route has been developed by using a combined catalyst of a readily available trans-4-hydroxyproline-derived secondary amine and a Bronsted acid. Aromatic, heteroaromatic, and fusedr

Full text of DOI:10.1002/chem.200701581

FULL PAPER
DOI: 10.1002/chem.200701581
An Enantioselective Biginelli Reaction Catalyzed by a Simple Chiral
Secondary Amine and Achiral Brønsted Acid by a Dual-Activation Route
Junguo Xin,[a] Lu Chang,[a] Zongrui Hou,[a] Deju Shang,[a] Xiaohua Liu,[a] and
Xiaoming Feng*[a, b]
Abstract: An enantioselective Biginelli
reaction that proceeds by a dual-activa-
tion route has been developed by using
a combined catalyst of a readily avail-
reaction. The corresponding dihydro-
pyrimidines were obtained in moder-
ate-to-good yields with up to 98% ee
under mild conditions. Based on the
experimental results and the observed
absolute configurations of the products,
a plausible transition state has been
proposed to explain the origin of the
activation and the asymmetric induc-
tion.
able
trans-4-hydroxyproline-derived
Keywords: asymmetric catalysis
·
secondary amine and a Brønsted acid.
Aromatic, heteroaromatic, and fused-
ring aldehydes were found to be suita-
ble substrates for this multicomponent
Biginelli reaction · dual activation ·
multicomponent reactions · pyrimi-
dines · reaction mechanisms
Introduction
ated salen–ytterbium complex.[7] The other catalytic system
was Gong and co-workerꢀs BINOL-derived phosphoric acid,
which was the first organocatalyst used in this multicompo-
nent reaction.[4h,8] Although great success has been achieved
in previous work, the design and synthesis of new catalysts
remains an interesting challenge. Herein we report an orga-
nocatalytic asymmetric Biginelli reaction that involves the
use of a simple chiral secondary amine and a Brønsted acid
as a combined catalyst, a reaction that proceeds by a dual-
activation route. The reactions afforded various DHPMs
with good-to-excellent enantioselectivities, particularly those
reactions involving aldehydes bearing electron-donating
groups.
Chiral secondary amines have undoubtedly been the most
successful catalysts in enamine-type reactions, and a number
of asymmetric reactions catalyzed by chiral secondary
amines have been reported.[9,10] In the light of these success-
es and with knowledge of the mechanism of the Biginelli re-
action,[4a] we assumed that the combination of a secondary
amine and a Brønsted acid could promote the asymmetric
Biginelli reaction through a dual-activation pathway.[11,12] As
shown in Scheme 1, N-acylimine 5 activated by a Brønsted
acid would be attacked by chiral enamine 6 generated from
amine 8 and 1,3-keto ester 3 to provide enantioenriched
product 4 via the intermediate 9.
In recent years, optically active dihydropyrimidine (DHPM)
derivatives have attracted considerable attention because of
their important pharmacological and biological propertie-
s[1a–d] as well as their use in analytical chemistry.[1e] The Bigi-
nelli reaction,[2] one of the most useful multicomponent re-
actions,[3] allows straightforward access to multifunctional-
ized 3,4-dihydropyrimidin-2(1H)-ones and related com-
pounds.[4] Besides chemical resolution and auxiliary-assisted
asymmetric synthesis,[5] only a few examples of the enantio-
selective synthesis of these heterocyclic compounds have
been reported.[6] Despite the importance of preparing chiral
dihydropyrimidines, to the best of our knowledge, just two
chiral catalyst systems catalyze this reaction efficiently. The
breakthrough in the catalytic asymmetric Biginelli reaction
was realized by Zhu and co-workers with a chiral hydrogen-
[a] J. Xin, L. Chang, Z. Hou, D. Shang, Dr. X. Liu, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology (Sichuan Univer-
sity)
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[b] Prof. Dr. X. Feng
State Key Laboratory of Oral Diseases, Sichuan University
Chengdu 610041 (China)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 3177 –3181
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3177

TFA. As shown in Table 1, both the amine and the amide
moieties were important for the enantioselectivity of the re-
Scheme 1. Possible catalytic cycle of the dual-activation mechanism.
Results and Discussion
Initially, the catalytic asymmetric Biginelli reaction of ben-
zaldehyde, urea, and ethyl acetoacetate was carried out with
l-proline-derived amine 8a and trifluoroacetic acid (TFA)
at room temperature in THF. The reaction proceeded to
give DHPM 4aa in a yield of 32% with 9% ee (Table 1,
action (Table 1, entries 1–10). Compared with l-proline and
other amino acid derivatives, chiral amines derived from
trans-4-hydroxyproline exhibited superior catalytic proper-
ties (Table 1, entries 1–3). With this backbone, bulkier
amide-substituted amines gave higher enantioselectivities
(Table 1, entries 4–10). In the presence of an amine with an
adamantyl group (8j) and TFA, the reaction delivered 4aa
in a yield of 23% with 51% ee (Table 1, entry 10). When
the hydroxy group on the pyrrole ring of 8j was methylated,
a low ee of 4aa was observed, which further established the
importance of the hydroxy group in the reaction (Table 1,
entry 10 vs. 11). The amidic proton did not exert a signifi-
cant influence on the enantioselectivity of the reaction
(Table 1, entry 4 vs. 8). Therefore, on the basis of the results
obtained from the reactions with amines 8a–k, trans-4-hy-
droxyproline derivative 8j was evidently the best choice for
the present reaction system in terms of both enantioselectiv-
ity and reactivity. Furthermore, increasing the catalyst load-
ing from 10 to 20 mol% did not affect the yield, but resulted
in a lower ee (Table 1, entry 12). In contrast, the enantiose-
lectivity (up to 71% ee) was greatly improved when the cat-
alyst loading was decreased to 5 mol% (Table 1, entry 13).
Various acids combined with 8j were then employed to
catalyze the reaction (Table 2). Compared with TFA and
other sulfonic acids, 4-methylbenzenesulfonic acid (7b) pro-
vided the best results (Table 2, entries 1–4). Further experi-
ments revealed that, under the same experimental condi-
tions, the enantioselectivity of the reaction could be further
improved to 81% by using 3,5-dinitrobenzoic acid, although
the yield of 4aa was poor (Table 2, entry 5). To our delight,
screening of differently substituted benzoic acids indicated
that 2-chloro-4-nitrobenzoic acid (7g) was favorable in
terms of reactivity, and the enantioselectivity was main-
tained as well (Table 2, entries 5 and 7). The optimized re-
sults shown in Table 2 clearly demonstrate the advantage of
electron-withdrawing-substituted benzoic acids over sulfonic
Table 1. Asymmetric Biginelli reaction catalyzed by the combined cata-
lyst of a secondary amine and TFA.[a]
Entry
Amine
Loading
[mol%]
Yield
[%][b]
ee
A
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
8a
8b
8c
8d
8e
8 f
8g
8h
8i
10
10
10
10
10
10
10
10
10
10
10
20
5
32
trace
trace
29
37
17
20
22
25
23
9
<3
<3
39
13
32
36
36
23
51
9
8j
8k
8j
25
23
22
30
71
8j
[a] Reagents and conditions: After stirring a solution of amine 8 and
TFA in THF (0.5 mL) at room temperature for 30 min, 2 (0.25 mmol), 1a
(0.25 mmol), 3a (0.25 mmol), and THF (0.5 mL) were added sequentially.
[b] Yield of isolated product. [c] Determined by HPLC analysis (Chiral-
cel OD-H).
entry 1). Although the enantioselectivity was low, this result
encouraged us to further optimize the catalyst scaffold. The
efficacy of a series of chiral secondary amines derived from
various amino acids 8a–k was evaluated in the presence of
3178
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3177 –3181

An Enantioselective Biginelli Reaction
Table 2. Investigation of Brønsted acids.[a]
FULL PAPER
Table 3. Optimization of conditions for the asymmetric Biginelli reac-
tion.
Entry[b]
Acid
Yield
[%][c]
ee
[%][d]
Entry
Solvent
Method[a]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
TFA (7a)
p-TSA (7b)
D-CSA (7c)
p-NH2-benzenesulfonic acid (7d)
3,5-dinitrobenzoic acid (7e)
2-nitrobenzoic acid (7 f)
2-chloro-4-nitrobenzoic acid (7g)
4-methoxybenzoic acid (7h)
22
26
13
15
8
11
22
n.r.
71
76
66
71
81
80
81
–
1
2
3
4
5
6
7
8
9
THF
THF
DMSO
2-propanol
anisole
A
B
B
B
B
B
B
B
B
22
27
trace
trace
14
26
trace
25
81
85
n.d.
n.d.
63
80
90
82
88
CH2Cl2
1,4-dioxane
CH2Cl2/THF (2:8)
1,4-dioxane/THF (2:8)
[a] Reagents and conditions: After stirring a solution of 8j (5 mol%) and
acid (5 mol%) in THF (0.5 mL) at room temperature for 30 min, 2
(0.25 mmol), 1a (0.25 mmol), 3a (0.25 mmol), and THF (0.5 mL) were
added sequentially. [b] p-TSA=4-methylbenzenesulfonic acid; d-CSA=
d-camphorsulfonic acid. n.r.=no reaction. [c] Yield of isolated product.
[d] Determined by HPLC analysis (Chiralcel OD-H).
28
[a] Method A: After stirring
a
solution of 8j (5 mol%) and 7g
(0.25 mmol), 1a
(5 mol%) in THF (0.5 mL) at 258C for 30 min,
2
(0.25 mmol), 3a (0.25 mmol), and THF (0.5 mL) were added sequentially.
Method B: After stirring a solution of 1a (0.25 mmol), 2 (0.25 mmol),
and 7g (5 mol%) in solvent (1.0 mL) at 258C for 30 min, 8j (5 mol%)
and 3a (0.25 mmol) were added sequentially. [b] Yield of isolated prod-
uct. [c] Determined by HPLC analysis (Chiralcel OD-H). n.d.=not de-
termined.
acids and TFA in the control of enantioselectivity which
probably results from the substituted benzoic acids in this
reaction system having an appropriate acidity. Moreover,
the acidity of the benzoic acids, adjusted by different sub-
stituents, could further affect the reaction yield (Table 2, en-
tries 5–7). The fact that the reaction with 4-methoxybenzoic
acid did not yield any of the corresponding product some-
what supported this hypothesis (Table 2, entry 8).
Table 4. Screening additives for the reaction.[a]
Optimization of other reaction parameters with the com-
bined catalyst of 7g and 8j led to further improvement in
enantioselectivity. Slightly better results were achieved by
adjusting the experimental procedure; compound 4aa was
obtained in a yield of 27% with an 85% ee (Table 3, entry 1
vs. 2). In addition, solvent effects were studied. The use of
polar solvents such as DMSO and 2-propanol almost pre-
vented the reaction (Table 3, entries 3 and 4). In anisole and
CH2Cl2, the reaction proceeded without any improvement in
terms of both enantioselectivity and yield (Table 3, entries 5
and 6). Interestingly, the reaction in 1,4-dioxane gave the
best ee (up to 90%), but the yield dropped dramatically
(Table 3, entry 7). Therefore, mixed solvents were screened
and revealed that the best results were obtained in 1,4-diox-
ane/THF (2:8, v/v) as compared with neat solvents or anoth-
er mixed solvent (Table 2, entries 8 and 9).
Entry
Additive
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
p-TSA
49
12
43
37
38
43
34
45
60
60
89
83
83
83
85
85
86
80
1-adamantanamine
1-adamantyl-NH2·p-TSA
piperidine·p-TSA
Et3N·p-TSA
tBuNH2·p-TSA
tBuNH2·HCl
8
tBuNH2·TFA
tBuNH2·TFA
9[d]
[a] Reagents and conditions: After stirring a solution of 1a (0.25 mmol),
2 (0.25 mmol), 7g (5 mol%), and additive (5 mol%) in solvent (1.0 mL)
at 258C for 30 min, 8j (5 mol%) and 3a (0.25 mmol) were added sequen-
tially. [b] Yield of isolated product. [c] Determined by HPLC analysis
(Chiralcel OD-H). [d] The reaction was carried out with a reaction time
of 60 h and a 1a/2/3a ratio of 1:1.2:2.
To further improve the reactivity and enantioselectivity,
the effect of additives was investigated. Although a signifi-
cantly decreased ee was obtained by adding p-TSA, the
yield was improved significantly (Table 4, entry 1). In con-
trast, addition of 1-adamantanamine favored the enantiose-
lectivity but the yield was dramatically reduced (Table 4,
entry 2). Inspired by these results, the effect of organic
amine salts as additives was surveyed. To our delight, the
combination of p-TSA and 1-adamantanamine indeed im-
proved the yield of the reaction, although a little loss of
enantioselectivity was observed (Table 4, entry 3). Similar
results were obtained when other p-TSA salts, including pri-
mary, secondary, and tertiary amines, were investigated
(Table 4, entries 4–6). Fortunately, after further screening
the acidic component of the tBuNH2 salt, it was found that
employment of tBuNH2·TFA gave superior results in terms
of reactivity and enantioselectivity (45% yield, 86% ee,
Table 4, entry 8). The yield could be improved to 60% by
prolonging the reaction time and increasing the amount of
urea and 1,3-keto ester, albeit with 80% ee (Table 4,
entry 9). Accordingly, extensive screening has shown that
the optimized catalytic reaction conditions are 0.25 mmol al-
dehyde, 1.2 equiv urea, 2.0 equiv 1,3-keto ester, 5 mol% 7g,
Chem. Eur. J. 2008, 14, 3177 –3181
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3179

X. Feng et al.
5 mol% 8j, and 5 mol% tBuNH2·TFA in 1.0 mL 1,4-diox-
ane/THF (2:8, v/v) at 258C.
With the optimized conditions, the substrate scope of the
reaction was probed (Table 5). The corresponding DHPM
derivatives were obtained in moderate-to-good yields with
up to 98% ee. As shown in Table 5, both the electronic and
To determine the absolute configurations of the products,
the CD spectra of 4aa–4 fa, 4ab, 4cb, and 4jb–4cc were
measured in EtOH (see the Supporting Information). These
compounds all exhibited a similar Cotton effect in their CD
spectra. It can be deduced, therefore, that these compounds
possess the same R configuration as (À)-4aa.[7]
The involvement of both a Brønsted acid and a secondary
amine in this multicomponent reaction was quite crucial as
neither 7g nor 8j alone could catalyze the formation of
DHPM efficiently.[14] The achiral acid 7g might not only
favor the formation of the N-acylimine 5 and the enamine
intermediate 6 in Scheme 1, but may also serve to activate
the N-acylimine 5 and participate in the asymmetric induc-
tion of the reaction. Based on the observed absolute config-
urations of the products and the discussion above, we have
proposed a possible transition state that requires dual acti-
vation in the asymmetric-induction step (Figure 1).[15] In this
Table 5. Scope of the organocatalytic enantioselective Biginelli reactio-
n.[a]
Entry
Ar
R
4
t [d]
Yield
[%][b]
ee
[%][c]
1
C6H5 (1a)
Et
Et
Et
Et
Et
Et
Et
Et
iPr
iPr
iPr
iPr
iPr
Me
Me
4aa
4ba
4ca
4da
4ea
4 fa
4ga
4ha
4ab
4cb
4ib
2.5
4
5.5
5.5
6
3.5
6.5
3
3
6.5
5
4.5
6.5
6.5
5.5
60
46
73
56
68
54
60
34
61
60
62
46
57
50
62
80 (R)[d]
77 (R)
98 (R)
71 (R)
98 (R)
73 (R)[d]
97
2[e]
3[f]
4
3-ClC6H4 (1b)
3-MeC6H4 (1c)
4-MeC6H4 (1d)
3-MeOC6H4 (1e)
3-HOC6H4 (1 f)
1-naphthyl (1g)
2-thiophene (1h)
C6H5 (1a)
3-MeC6H4 (1c)
2-naphthyl (1i)
piperonal (1j)
4-BrC6H4 (1k)
3-MeOC6H4 (1e)
3-MeC6H4 (1c)
5[f]
6
7[f]
8[f]
9
70
77 (R)
83 (R)
72
80 (R)
75 (R)
97 (R)
71 (R)
10[f]
11[f]
12[f]
13[e]
14[f]
15
4jb
4kb
4ec
4cc
[a] Reagents and conditions: After stirring a solution of 7g (5 mol%),
tBuNH2·TFA (5 mol%), 1 (0.25 mmol), and 2 (0.3 mmol) in 1,4-dioxane/
THF (2:8, v/v, 1.0 mL) at 258C for 30 min, 8j (5 mol%) and 3 (0.5 mmol)
were added sequentially. [b] Yield of isolated product. [c] Determined by
HPLC analysis (Chiralcel OD-H or AD-H). The absolute configurations
were assigned by comparing the Cotton effect of the CD spectra with
that of 4aa. [d] The absolute configuration was determined by compari-
son of the optical rotation with the literature.[7] [e] tBuNH2·TFA was not
used and the amount of 7g and 8j was 2.5 mol%. [f] The amount of 7g,
8j, and tBuNH2·TFA used was 10 mol%.
Figure 1. Proposed transition state in the asymmetric Biginelli condensa-
tion reaction.
transition state (TS-1), one face of the enamine was effi-
ciently shielded by the steric hindrance of the bulky ada-
mantyl amide moiety, whereas the other face was available
to attack the imine. Favorable hydrogen-bonding interac-
tions between the pyrrolic hydroxy group and the ureic car-
bonyl, and the nitrogen atom of the pyrrole, the proton of
the Brønsted acid, and the N-acylimine moiety positioned
the Brønsted acid activated imine moiety under the enam-
ine, which allowed the enamine double bond to approach
the Re face of the imine via a stable six-membered-ring
transition state. Through this approach, the reaction resulted
in the product with R configuration. We considered that for
the strong interaction between the Brønsted acid and the ni-
trogen atom of pyrrole, a stronger acid was unfavorable for
the formation of this hydrogen-bridged transition state. On
the other hand, a weaker acid could not efficiently activate
N-acylimine 5. Hence, a Brønsted acid of suitable acidity is
essential for this organocatalytic multicomponent reaction.
In TS-2, when the Si face of the N-acylimine was directed
towards the enamine an unstable eight-membered-ring tran-
sition state compared with TS-1 was formed. In addition, un-
activated N-acylimine might exhibit lower activity. There-
fore, the generation of the S product was not favored.
steric effects of the aromatic ring have a significant influ-
ence on the enantioselectivity. In most cases, aromatic alde-
hydes with electron-donating groups at the meta position
(Table 5, entries 3, 5, 10, and 14) afforded excellent enantio-
selectivities (83–98% ee).[13] In contrast, p-methylbenzalde-
hyde (1d) gave a moderate ee (Table 5, entry 4). Excellent
enantioselectivity was obtained when fused-ring 1-naphtha-
lenecarbaldehyde (1g) was employed (Table 5, entry 7). The
reactions were also applied to hydroxy-substituted benzalde-
hyde 1 f and heteroaromatic aldehyde 1h; enantioselectivi-
ties of 73 and 70%, respectively, were obtained, (Table 5,
entries 6 and 8). For aromatic aldehydes bearing electron-
withdrawing groups, moderate enantioselectivities were ach-
ieved by using 2.5 mol% catalyst in the absence of additive
(Table 5, entries 2 and 13). Isopropyl (3b) and methyl 3-oxo-
butanoate (3c) gave similar results to 1,3-keto ester 3a
(Table 5, entries 9–15).
3180
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3177 –3181

An Enantioselective Biginelli Reaction
FULL PAPER
Acc. Chem. Res. 2000, 33, 879; d) D. S. Bose, L. Fatima, H. B. Mer-
eyala, J. Org. Chem. 2003, 68, 587; e) B. Gerardo, K. Eihab, J.
Comb. Chem. 2004, 6, 596; f) M. J. Lusch, J. A. Tallarico, Org. Lett.
2004, 6, 3237; g) J. Mabry, B. Ganem, Tetrahedron Lett. 2006, 47, 55;
h) L. Z. Gong, X. H. Chen, X. Y. Xu, Chem. Eur. J. 2007, 13, 8920.
[5] a) A. Dondoni, A. Massi, S. Sabbatini, V. Bertolasi, J. Org. Chem.
2002, 67, 6979; b) A. Dondoni, A. Massi, S. Sabbatini, Tetrahedron
Lett. 2002, 43, 5913; c) B. Schnell, W. Krenn, K. Faber, C. O. Kappe,
J. Chem. Soc., Perkin Trans. 1, 2000, 4382; d) B. Schnell, U. T.
Strauss, P. Verdino, K. Faber, C. O. Kappe, Tetrahedron: Asymmetry
2000, 11, 1449.
Conclusion
In summary, we have developed an enantioselective multi-
component Biginelli reaction catalyzed by a trans-4-hydrox-
yproline-derived secondary amine and a Brønsted acid as
the combined catalyst with an organic amino salt as additive,
a reaction that proceeds through a dual-activation route.
The reaction occurs with good-to-excellent ee values (up to
98%). Attractive features of the method include the ease of
catalyst preparation, mild reaction conditions, and a broad
substrate generality. A plausible transition state has been
proposed to explain the origin of the activation and the
asymmetric induction. Further studies focused on the design
of more efficient catalysts for the enantioselective Biginelli
reaction are underway.
[6] a) A. Dondoni, A. Massi, Acc. Chem. Res. 2006, 39, 451; b) O.
ˇ
ˇ
Munoz-Munniz, E. Juaristi, ARKIVOC 2003, xi, 16; c) A. Dondoni,
A. Massi, S. Sabbatini, V. Bertolasi, J. Org. Chem. 2002, 67, 6979;
d) S. Lou, B. M. Taoka, A. Ting, S. E. Schaus, J. Am. Chem. Soc.
2005, 127, 11256.
[7] Y. J. Huang, F. Y. Yang, C. J. Zhu, J. Am. Chem. Soc. 2005, 127,
16386.
[8] X. H. Chen, X. Y. Xu, H. Liu, L. F. Cun, L. Z. Gong, J. Am. Chem.
Soc. 2006, 128, 14802.
[9] For reviews, see: a) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248; Angew. Chem. Int. Ed. 2004, 43, 5138; b) D. Enders, C. Gron-
dal, M. R. M. Hüttl, Angew. Chem. 2007, 119, 1590; Angew. Chem.
Int. Ed. 2007, 46, 1570; c) B. List, Chem. Commun. 2006, 819; d) G.
Guillena, D. J. Ramón, Tetrahedron: Asymmetry, 2006, 17, 1465.
[10] For examples, see: a) A. B. Northrup, D. W. C. MacMillan, J. Am.
Chem. Soc. 2002, 124, 2458; b) M. P. Brochu, S. P. Brown, D. W. C.
MacMillan, J. Am. Chem. Soc. 2004, 126, 4108; c) M. K. Zhu, L. F.
Cun, A. Q. Mi, Y. Z. Jiang, L. Z. Gong, Tetrahedron: Asymmetry
2006, 17, 491; d) Z. Tang, F. Jiang, X. Cui, L. Z. Gong, A. Q. Mi,
Y. Z. Jiang, Y. D. Wu, Proc. Natl. Acad. Sci. USA 2004. 16, 5755;
e) B. List, J. Am. Chem. Soc. 2000, 122, 9336; f) B. List, P. Pojarliev,
W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124, 827; g) K.
Juhl, K. A. Jørgensen, Angew. Chem. 2003, 115, 1536; Angew.
Chem. Int. Ed. 2003, 42, 1498; h) N. S. Chowdari, D. B. Ramachary,
C. F. Barbas III, Org. Lett. 2003, 5, 1685; i) H. SundØn, I. Ibrahem,
L. Eriksson, A. Córdova, Angew. Chem. 2005, 117, 4955; Angew.
Chem. Int. Ed. 2005, 44, 4877; j) W. Wang, J. Wang, H. Li, Org. Lett.
2004, 6, 2817; k) N. S. Chowdari, M. Ahmad, K. Albertshofer, F.
Tanka, C. F. Barbas III, Org. Lett. 2006, 8, 2839; l) W. Zhuang, S.
Saaby, K. A. Jørgensen, Angew. Chem. 2004, 116, 4576; Angew.
Chem. Int. Ed. 2004, 43, 4476; m) C. Palomo, S. Vera, A. Mielgo, E.
Gómez-Bengoa, Angew. Chem. 2006, 118, 6130; Angew. Chem. Int.
Ed. 2006, 45, 5984; n) K. Frisch, A. Landa, S. Saaby, K. A. Jørgen-
sen, Angew. Chem. 2005, 117, 6212; Angew. Chem. Int. Ed. 2005, 44,
6058; o) W. Wang, H. Li, J. Wang, Org. Lett. 2005, 7, 1637; p) W.
Wang, J. Wang, H. Li, Angew. Chem. 2005, 117, 1393; Angew. Chem.
Int. Ed. 2005, 44, 1369.
Experimental Section
Typical procedure for the organocatalytic asymmetric Biginelli reaction:
After stirring
a solution of 7g (2.6 mg, 5 mol%, 0.0125 mmol),
tBuNH2·TFA (2.4 mg, 5 mol%, 0.0125 mmol), benzaldehyde 1a (25.0 mL,
0.25 mmol), and 2 (18.0 mg, 0.3 mmol, 1.2 equiv) in 1,4-dioxane/THF
(2:8, v/v, 1.0 mL) at 258C for 30 min, 8j (3.3 mg, 5 mol%, 0.0125 mmol)
and 3a (63.0 mL, 0.5 mmol, 2.0 equiv) were added sequentially. The reac-
tion mixture was stirred at 258C for 2.5 days. Then, the crude product
was purified by preparative TLC (petroleum ether/ethyl acetate, 2:3) to
afford 4aa (40 mg, 60% yield) as a white solid with 80% ee; [a]3D0 =À30.5
(c=0.2 in MeOH) {lit.:[7] 90% ee; [a]2D0 =À58 (c=0.5 in MeOH)}; m.p.
199–2028C; 1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.93 (s, 1H),
7.33–7.28 (m, 5H), 5.65 (m, 1H), 5.41–5.40 (d, J=2.9 Hz, 1H), 4.10–4.03
(m, 2H), 2.35 (s, 3H), 1.18–1.14 ppm (t, J=11.4 Hz, 3H); HPLC (Chiral-
pak OD-H column, hexane/2-propanol 85:15, 1.0 mLminÀ1): tR (minor)=
7.860, tR (major)=9.634 min.
Acknowledgement
We thank the National Natural Science Foundation of China (No.
20732003) for financial support. We also thank the Sichuan University
Analytic & Testing Centre for CD spectra and NMR analysis and the
State Key Laboratory of Biotherapy for HRMS analysis.
[11] For a review, see: J. A. Ma, D. Cahard, Angew. Chem. 2004, 116,
4666; Angew. Chem. Int. Ed. 2004, 43, 4566, and references therein.
[12] a) F. X. Chen, X. M. Feng, B. Qin, G. L. Zhang, Y. Z. Jiang, Org.
Lett. 2003, 5, 949; b) F. X. Chen, X. M. Feng, B. Qin, G. L. Zhang,
Y. Z. Jiang, Synlett 2003, 4, 558; c) F. X. Chen, B. Qin, X. M. Feng,
G. L. Zhang, Y. Z. Jiang, Tetrahedron 2004, 60, 10449; d) F. X. Chen,
H. Zhou, X. H. Liu, B. Qin, X. M. Feng, G. L. Zhang, Y. Z. Jiang,
Chem. Eur. J. 2004, 10, 4790; e) F. X. Chen, X. M. Feng, Curr. Org.
Synth., 2006, 3, 77.
[1] For examples, see: a) G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cu-
cinotta, J. D. DiMarco, J. Gougoutas, A. Hedberg, M. Malley, J. P.
McCarthy, R. Zhang, S. Moreland, J. Med. Chem. 1995, 38, 119;
b) T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L.
Schreiber, T. J. Mitchison, Science 1999, 286, 971; c) C. O. Kappe,
Eur. J. Med. Chem. 2000, 35, 1043; d) C. O. Kappe, QSAR Comb.
Sci. 2003, 22, 630; e) K. Lewandowski, P. Murer, F. Svec, J. M. J. FrØ-
chet, J. Comb. Chem. 1999, 1, 105.
[13] This phenomenon is very similar to Gong and co-workerꢀs BINOL-
derived phosphoric acid system, see ref. [8].
[2] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
[3] For reviews, see: a) G. Guillena, D. J. Ramón, M. Yus, Tetrahedron:
Asymmetry 2007, 18, 693; b) D. J. Ramón, M. Yus, Angew. Chem.
2005, 117, 1628; Angew. Chem. Int. Ed. 2005, 44, 1602; c) C. O.
Kappe in Multicomponent Reactions (Eds.: J. Zhu, H. BienaymØ),
Wiley-VCH, Weinheim, 2005, p.95; d) M. D. Burke, S. L. Schreiber,
Angew. Chem. 2004, 116, 48; Angew. Chem. Int. Ed. 2004, 43, 46;
e) N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199.
[14] The sole application of 7g afforded trace amounts of 4aa, whereas
in the absence of 7g, amine 8j did not catalyze the reaction.
[15] For a previous report on the catalytic model involving trans-4-hy-
droxyprolinamide, see ref. [10m].
Received: October 7, 2007
Revised: December 12, 2007
Published online: February 1, 2008
[4] a) C. O. Kappe, J. Org. Chem. 1997, 62, 7201; b) E. H. Hu, D. R.
Sidler, U. H. Dolling, J. Org. Chem. 1998, 63, 3454; c) C. O. Kappe,
Chem. Eur. J. 2008, 14, 3177 –3181
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3181