Highly efficient asymmetric three-component vinylogous mannich reaction catalyzed by a chiral Scandium(III)N,N'-dioxide complex

Article abstract of DOI:10.1002/adsc.200900877

The asymmetric three-component vinylogous Mannich reaction of an acyclic silyl dienol ester, an aldehyde and 2-aminophenol was accomplished using a chiral N,N'-dioxide-scandium(III) complex as the catalyst. A variety of aldehydes were found to be suitable substrates for the reaction and the desired δ-amino-α,β-unsaturated esters were obtained in 90-99% yields with good to excellent enantioselectivities (up to > 99% ee) and complete regioselectivities. Moreover, the simple experimental procedures were air-tolerant and convenient. The present catalytic process provides the potential for large-scale syntheses of the chiral δamino-α,β- unsaturated esters.

Full text of DOI:10.1002/adsc.200900877

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DOI: 10.1002/adsc.200900877
Highly Efficient Asymmetric Three-Component Vinylogous
Mannich Reaction Catalyzed by a Chiral Scandium(III)-
G
N,N’-Dioxide Complex
Qi Zhang,a Yonghai Hui,a Xin Zhou,a Lili Lin,a Xiaohua Liu,a,*
and Xiaoming Fenga,*
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: December 18, 2009; Published online: April 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900877.
Abstract: The asymmetric three-component vinylo-
gous Mannich reaction of an acyclic silyl dienol
ester, an aldehyde and 2-aminophenol was accom-
of the reaction using chiral binol-based phosphoric
acids.[4] Subsequently, a copper(I)-Fesulphos complex
was developed by Carreteroꢀs group to catalyze the
vinylogous Mannich reaction.[5] In spite of the two
mentioned works as well as the merit of in situ forma-
tion of the imine, searching for an efficient asymmet-
ric catalyst system for the three-component AVM re-
action of acyclic silyl dienolates, which has scarcely
been investigated, is still challenging and interesting.
plished using a chiral N,N’-dioxide-scandiumACTHNUGTRNEUNG(III)
complex as the catalyst. A variety of aldehydes
were found to be suitable substrates for the reaction
and the desired d-amino-a,b-unsaturated esters
were obtained in 90–99% yields with good to excel-
lent enantioselectivities (up to >99% ee) and com-
plete regioselectivities. Moreover, the simple exper-
imental procedures were air-tolerant and conven-
ient. The present catalytic process provides the po-
tential for large-scale syntheses of the chiral d-
amino-a,b-unsaturated esters.
In our previous studies, N,N’-dioxide-ScACTHNUGTRENUNG(OTf)3 com-
plexes have proven to be excellent catalysts for many
asymmetric reactions of N-(2-hydroxyphenyl)imine.[6,7]
It was considered that the chiral scandiumACHTNUTRGNE(UNG III) com-
plex coordinated with N-(2-hydroxyphenyl)imine in a
bidentate manner and exhibited excellent activation
and asymmetric inducing abilities.[8] Such a reaction
pattern provided an ideal platform for the develop-
ment of a catalytic AVM reaction of acyclic silyl
dienol ethers employing the strategy of preparing the
imine in situ. Enlightened by these, we describe
herein the highly enantioselective three-component
vinylogous Mannich reaction of an acyclic silyl dienol
Keywords: asymmetric catalysis; multicomponent
reaction; scandium; silyl dienolates; vinylogous
Mannich reaction
The vinylogous Mannich reaction is one of the most ether, aldehydes and 2-aminophenol using chiral
powerful methods for the synthesis of highly function- N,N’-dioxide-Sc
alized d-amino-a,b-unsaturated carbonyl compounds, tions.
ACHTUNGERTN(NUNG OTf)3 complex under mild condi-
which are versatile intermediates in the synthesis of
alkaloids and other related natural products.[1] In the dioxide-Sc
past decade, considerable effort has been devoted to- (OTf)3 (2:1) complex could promote the three-com-
wards the development of asymmetric vinylogous ponent reaction smoothly. Only racemic product was
Mannich (AVM) reactions.[2–5] However, compared obtained using L1-Sc
(OTf)3 (1:1) complex, while L1-
with the well established methodologies for the addi- Sc(OTf)3 (2:1) complex provided the d-amino-a,b-un-
Preliminary investigation revealed that both N,N’-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tion of imines with cyclic siloxyfurans,[3] the AVM re- saturated ester 4a with 28% ee (Table 1, entry 2 vs. 1).
action of acyclic silyl dienolates was rarely investigat- The distinct performance on the enantioselectivity of
ed. To the best of our knowledge, only two catalytic such two chiral Sc(III) complex might be ascribed to
systems were successfully applied in such a reaction. their different structures.[6a,d] Intensive studies on the
Schneider and co-workers reported the first example chiral ligands showed that both the enantioselectivity
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Adv. Synth. Catal. 2010, 352, 976 – 980

Highly Efficient Asymmetric Three-Component Vinylogous Mannich Reaction
Table 1. Optimization of the three-component vinylogous Mannich reaction of benzaldehyde 1a, amines 2 and acyclic silyl
dienol ester 3.[a]
Entry
Ligand
Solvent
Amine
Product
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
L1
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
THF
THF
THF
THF
THF
THF
CH2Cl2
Toluene
Et2O
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
5
65
63
77
99
87
94
34
99
97
98
98
99
99
82
87
23
0
28
63
71
40
11
45
49
56
75
59
82
77
63
30
0
ACHTUNGTNER(NUNG i-Pr)2O
PhOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
6
7
8
[a]
Unless otherwise noted, reactions were carried out with N,N’-dioxide (10 mol%), Sc
(0.1 mmol) and 3 (0.3 mmol) in the indicated solvent (0.3 mL) at 08C for 12 h.
Isolated yield.
Determined by HPLC using chiral OD-H column.
The molar ratio of N,N’-dioxide L1 to ScACTHNURTGNENG(U OTf)3 was 1:1.
ACHTUNGRTEN(NUNG OTf)3 (5 mol%), 1a (0.1 mmol), 2
[b]
[c]
[d]
and reactivity of the reaction were dependent on the L2 and l-proline-derived L1, giving the desired
chiral backbone of N,N’-dioxide ligands (Figure 1 and adduct with 99% yield and 71% ee (Table 1, entry 4
Table 1, entries 2–4). l-Ramipril acid-derived N,N’-di- vs. 2 and 3). Furthermore, decreasing the steric hin-
oxide L3 was superior to (S)-pipecolic acid-derived drance of the amide moiety had a detrimental influ-
ence on the enantioselectivity. Compared with L3
containing bulky 2,6-diisopropyl-substituted aniline
groups, the employment of ligands with smaller
groups such as 2,6-dimethylphenyl L4 and phenyl L5
species led to lower enantiomeric excesses (Table 1,
entry 4 vs. 5 and 6).
To further improve the enantioseletivity of the re-
action, solvents of the reaction were intensely investi-
gated. The vinylogous Mannich reaction usually pro-
ceeded with better enantioselectivities in ethers
(Table 1, entries 4 and 7–12). To our delight, the enan-
tioselectivity was increased to 82% ee when the reac-
Figure 1. N,N’-Dioxide ligands evaluated in this study.
tion was performed in t-BuOMe (Table 1, entry 12).
Adv. Synth. Catal. 2010, 352, 976 – 980
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Qi Zhang et al.
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Table 2. Substrate scope of the asymmetric three-component vinylogous Mannich reaction.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
99
98
99
94
92
94
91
90
99
98
99
99
94
99
90
97
82
83
80
82
82
92
90
90
84
92
81
88
82
91
>99
84
2-MeC6H4
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
3,4-Cl2C6H3
4-FC6H4
4-BrC6H4
3-CF3C6H4
4-CF3C6H4
3-NO2C6H4
4-NO2C6H4
4-CNC6H4
2-naphthy
9
10
11
12
13
14
15
16
[a]
Unless otherwise noted, reactions were carried out with N,N’-dioxide L3 (10 mol%), Sc
(0.1 mmol) and 3 (0.3 mmol) in t-BuOMe (0.3 mL) at 08C for 12 h.
Isolated yield.
ACHTUNGRTEN(NUNG OTf)3 (5 mol%), 1 (0.1 mmol), 2a
[b]
[c]
Determined by HPLC using commercial chiral columns.
Further investigation on the imine source disclosed (Table 2, entries 2 and 3). Notably, aromatic alde-
that the electronic effect on the phenyl ring of the hydes with electron-withdrawing groups at different
amine had a slight influence on the enantioselectivity positions reacted smoothly with the acyclic silyl
(Table 1, entries 12–14). However, the o-anisidine 2d, dienol ether 3 and were well tolerated in terms of the
which had a strong steric effect compared with the 2a, enantioselectivities and reactivities (Table 2, en-
afforded the corresponding products with poor ee tries 4–15). Particularly, this process was rather effi-
values, and only a racemic adduct was obtained using cient for p-cyanobenzaldehyde and afforded the de-
p-anisidine 2e as the amine (Table 1, entries 15 and sired adduct 4o with >99% ee in 90% yield (Table 2,
16). These phenomena demonstrated that a bidentate entry 15). This N,N’-dioxide-Sc
imine formed in situ was crucial for the N,N’-dioxide- also be applied to multisubstituted aldehydes, which
Sc(OTf)3 complex-catalyzed reaction. Extensive were rarely mentioned previously, and up to 90% ee
ACHTUNGRTEN(NNUG OTf)3 catalyst could
ACHTUNGTRENNUNG
screening showed that this three-component vinylo- values were observed (Table 2, entries 7 and 8). In ad-
gous Mannich reaction was well performed using dition, the condensed aromatic aldehyde was proved
5 mol% N,N’-dioxide-ScACTHUNTGRNEUNG(III) complex in t-BuOMe at to be a good substrate in this process (Table 2,
08C for 12 h with complete d-regioselectivity.
entry 16).
With the optimized conditions in hand, the sub-
To demonstrate the practicality of the present ap-
strate scope of the AVM reaction was explored. A proach, a gram-scale synthesis of the chiral d-amino-
series of aldehydes was investigated and the corre- a,b-unsaturated esters was performed under the opti-
sponding d-amino-a,b-unsaturated esters 4 were ob- mized conditions. As shown in Scheme 1, upon treat-
tained in high yields with good to excellent enantio- ment of 10 mmol of starting materials, the vinylogous
meric excesses and complete regioselectivities.[9] As Mannich product 4o was produced without any loss of
shown in Table 2, the Mannich reactions with the the reactivity and enantioselectivity.[10]
electron-donating substituted aromatic aldehydes pro-
In summary, we have developed the highly enantio-
vided the corresponding products 4b and 4c with selective three-component vinylogous Mannich reac-
good ee values of 83% and 80%, respectively tion of aldehydes, 2-aminophenol and an acyclic
978
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Adv. Synth. Catal. 2010, 352, 976 – 980

Highly Efficient Asymmetric Three-Component Vinylogous Mannich Reaction
Scheme 1. Gram-scale version of the three-component AVM reaction.
dienol ester using a chiral N,N’-dioxide-Sc
N
[3] For catalytic AVM reactions of cyclic siloxyfurans, see:
a) S. F. Martin, O. D. Lopez, Tetrahedron Lett. 1999, 40,
8949; b) E. L. Carswell, M. L. Snapper, A. H. Hoveyda,
Angew. Chem. 2006, 118, 7388; Angew. Chem. Int. Ed.
2006, 45, 7230; c) L. C. Wieland, E. M. Vieira, M. L.
Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131,
570; d) H. Mandai, K. Mandai, M. L. Snapper, A. H.
Hoveyda, J. Am. Chem. Soc. 2008, 130, 17961; e) T.
Akiyama, Y. Honma, J. Itoh, K. Fuchibe, Adv. Synth.
Catal. 2008, 350, 399; f) Z. L. Yuan, J. J. Jiang, M. Shi,
Tetrahedron 2009, 65, 6001; g) H. P. Deng, Y. Wei, M.
Shi, Adv. Synth. Catal. 2009, 351, 2897; h) G. Casiraghi,
F. Zanardi, L. Battistini, G. Rassu, Synlett 2009, 1525.
[4] a) M. Sickert, C. Schneider, Angew. Chem. 2008, 120,
3687; Angew. Chem. Int. Ed. 2008, 47, 3631; b) D. S.
Giera, M. Sickert, C. Schneider, Org. Lett. 2008, 10,
4259.
plex as the catalyst. Various aldehydes could be con-
verted to highly functionalized d-amino-a,b-unsatu-
rated carboxylic esters in high yields with good to ex-
cellent enantioselectivities and complete regioselectiv-
ities. Moreover, the present catalytic process provided
a potential for the large-scale synthesis of the chiral
d-amino-a,b-unsaturated esters. Further studies of the
reaction mechanism are in progress.
Experimental Section
Typical Procedure for the Three-Component AVM
Reaction
The N,N’-dioxide L3 (0.01 mmol), ScACTHNUTRGENUN(G OTf)3 (0.005 mmol),
[5] A. S. Gonzꢂlez, R. G. Arrayꢂs, M. R. Rivero, J. C. Car-
retero, Org. Lett. 2008, 10, 4335.
[6] For examples of enantioselective reactions catalyzed by
aldehyde 1 (0.1 mmol) and amine 2 (0.1 mmol) were stirred
in 0.3 mL t-BuOMe at 308C for 0.5 h. Subsequently, silyl
dienol ether 3 (0.3 mmol) was added under 08C. The reac-
tion mixture was stirred for further 12 h. The mixture was
direct purified by column chromatography on silica gel
(ethyl acetate/petroleum ether=1/5–1/3).
N,N’-dioxide-ScACHTNUTRGNE(NUG OTf)3 complexes, see: a) D. J. Shang,
J. G. Xin, Y. L. Liu, X. Zhou, X. H. Liu, X. M. Feng, J.
Org. Chem. 2008, 73, 630; b) X. Li, X. H. Liu, Y. Z. Fu,
L. J. Wang, L. Zhou, X. M. Feng, Chem. Eur. J. 2008,
14, 4796; c) X. Zhou, D. J. Shang, Q. Zhang, L. L. Lin,
X. H. Liu, X. M. Feng, Org. Lett. 2009, 11, 1401;
d) Y. L. Liu, D. J. Shang, X. Zhou, X. H. Liu, X. M.
Feng, Chem. Eur. J. 2009, 15, 2055; e) M. Kokubo, C.
Ogawa, S. Kobayashi, Angew. Chem. 2008, 120, 7015;
Angew. Chem. Int. Ed. 2008, 47, 6909.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (Nos. 20732003 and 20872097), PCSIRT (No.
IRT0846) and the Major State Basic Research and Develop-
ment Program (No. 2010CB833302) for financial support.
We also thank Sichuan University Analytical & Testing
Center for NMR analysis and the State Key Laboratory of
Biotherapy for HR-MS analysis.
[7] For selected examples of asymmetric reactions cata-
lyzed by chiral scandium complexes based on other
chiral ligands, see: a) S. Kobayashi, M. Araki, I. Ha-
chiya, J. Org. Chem. 1994, 59, 3758; b) S. Ishikawa, T.
Hamada, K. Manabe, S. Kobayashi, J. Am. Chem. Soc.
2004, 126, 12236; c) E. Mai, C. Schneider, Chem. Eur. J.
2007, 13, 2729; d) A. Nojiri, N. Kumagai, M. Shibasaki,
J. Am. Chem. Soc. 2008, 130, 5630, and references cited
therein.
[8] For some selected reports in which the chiral scandium
complexes chelated with bidentate substrates, see: a) D.
Yang, M. Yang, N. Y. Zhu, Org. Lett. 2003, 5, 3749;
b) D. A. Evans, J. Wu, J. Am. Chem. Soc. 2005, 127,
8006; c) D. A. Evans, Y. Aye, J. Am. Chem. Soc. 2006,
128, 11034; d) D. A. Evans, K. R. Fandrick, H. J. Song,
K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007, 129,
10029, and references cited therein.
References
[1] For reviews on the synthetic applications of vinylogous
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[2] For direct catalytic AVM reactions, see: a) T. Y. Liu,
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[9] Aliphatic aldehydes were also investigated. The reac-
tion of cyclohexanecarbaldehyde sluggishly proceeded
to give the corresponding products with 23% ee in 25%
Adv. Synth. Catal. 2010, 352, 976 – 980
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Qi Zhang et al.
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yield. Isobutyraldehyde and pivalaldehyde only provid-
ed the racemic products in 21% and 56% yields, re-
spectively. The distinct performance of the aromatic
and aliphatic aldimines suggested that a p–p interac-
tion might exist between the aromatic aldimine and the
aromatic ring of the catalyst, which played a crucial
role in the asymmetric inducing of the reaction.
[10] A scaled-up reaction of benzaldehyde was also per-
formed which is thirty-fold larger (3 mmol) than the
model reaction (0.1 mmol) and the vinylogous Mannich
product 4a was produced with 80% ee and in 96%
yield.
980
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 976 – 980