Highly enantioselective one-pot, three-component mannich-type reaction catalyzed by an N,N'-dioxide-scandium(III) complex

Article abstract of DOI:10.1002/chem.200900392

A novel N,N'-dioxide scandium (III) triflate (2:1) complex was used in the highly enantioselective asymmetric one-pot, three-component Mannich type reaction of ketene silyl acetal. The complex facilitated the asymmetric synthesis of biologically interesti

Full text of DOI:10.1002/chem.200900392

DOI: 10.1002/chem.200900392
Highly Enantioselective One-Pot, Three-Component Mannich-type Reaction
Catalyzed by an N,N’-Dioxide–ScandiumACTHNUTRGENU(GN III) Complex
Shikui Chen, Zongrui Hou, Yin Zhu, Jing Wang, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*[a]
Optically active b-amino esters are important precursors
for the preparation of natural products, pharmaceutical
agents, and mimics of protein structural motifs.[1] The cata-
lytic asymmetric Mannich reaction is one of the most power-
ful and direct methods to obtain such chiral building
blocks.[2] Since 1997 when Kobayashiꢀs group reported the
first example of Mannich-type reaction of aldimines using a
BINOL-derived ZrIV complex (BINOL=2,2’-binaphthol),[3]
a couple of efficient catalysts, such as Wulffꢀs VAPOL-ZrIV
complex (VAPOL=vaulted 3,3’-biphenanthrol)[4] and
Akiyamaꢀs TADDOL-[5a] and BINOL-based phosphoric
tivities (up to 98% ee) were obtained for a series of sub-
strates with 5 mol% of catalyst.
At the beginning of our research, l-proline-derived N,N’-
dioxide L1 scandiumACTHNUTRGNEUNG(III) triflate complexes were examined
in the asymmetric three-component Mannich-type reaction
acids
(TADDOL=a,a’-(dimethyl-1,3-dioxolane-4,5-diyl)-
bis(diphenylmethanol)),[5b–d] have been developed. The first
example of catalytic asymmetric Mannich-type reaction of
simple ketoimines was published by Shibasakiꢀs group using
a CuI complex with P ligands.[6] Subsequently, Hoveydaꢀs
group disclosed an efficient diastereo- and enantioselective
Ag-catalyzed method for the vinylogous Mannich reaction
of a-ketoimine esters.[7] Nevertheless, the catalytic asymmet-
ric Mannich-type reaction of aldimines with ketene silyl ace-
tals in a one-pot, three-component method has scarcely
been reported. The one-pot, multicomponent reaction has
many advantages such as the simplified operation, mild re-
action conditions, high atom economy, and environmental
friendliness.[8] On the other hand, our previous studies
showed that N,N’-dioxides and their complexes were useful
for many asymmetric reactions.[9,10] Herein, we reported the
between benzaldehyde (1a), 2-aminophenol (2), and ketene
silyl acetal (3; Table 1, entries 1 and 2).[12] As expected, this
sort of N,N’-dioxide–scandium complex could promote the
reaction with the promising results (Table 1, entries 1 and
2), and increasing the L1/ScACHTNUTRGNENG(U OTf)3 molar ratio from 1:1 to
2:1, the enantioselectivity was significantly enhanced
(Table 1, entry 2 vs. 1). The effect of the structure of N,N’-
dioxide ligands was then examined (Table 1, entries 3–7).
The N,N’-dioxide L3, based on l-ramipril acid, was superior
to l-proline-derived N,N’-dioxide L1 and (S)-pipecolic acid-
based L2 (Table 1, entry 4 vs. 2 and 3). Furthermore, the
enantioselectivity was greatly dependent on the steric hin-
drance of amide moiety of the ligand. N,N’-Dioxide L3,
which contains bulky 2,6-diisopropyl-substituted aniline
groups, displayed the best results (38% yield, and 89% ee,
Table 1, entry 4). In contrast, while simple aniline derivative
L4 was employed, a racemic product was obtained (Table 1,
entry 5). Although increasing the steric hindrance on the
mono-ortho-position of aniline could enhance the enantiose-
lectivity (Table 1, entries 5–7), it was not as good as N,N’-di-
oxide L3 (Table 1, entry 4 vs. 5–7).
use of a novel N,N’-dioxide scandiumACHTUNTRGNEUNG(III) triflate (2:1) com-
plex in the asymmetric one-pot, three-component Mannich-
type reaction of ketene silyl acetal. Excellent enantioselec-
[a] S. Chen, Z. Hou, Y. Zhu, J. Wang, Dr. L. Lin, Dr. X. Liu,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
Fax : (+86)28-8541-8249
To further improve the reactivity and enantioselectivity,
other reaction conditions such as solvent, additive, and reac-
tion temperature were examined (Table 1, entries 8–12).[12,13]
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900392.
5884
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Chem. Eur. J. 2009, 15, 5884 – 5887

COMMUNICATION
Table 1. Optimization of the Mannich-type reaction of benzaldehyde 1a,
2-aminophenol 2, and ketene silyl acetal 3.[a]
Table 2. Substrate scope for the asymmetric Mannich-type reaction.[a]
Entry
R
Product
t [h]
Yield [%][b]
ee [%][c]
1
2
3
Ph (1a)
4-Me-Ph (1b)
2-Me-Ph (1c)
4a
4b
4c
72
136
136
72
68
65
93 (R)[d]
90
86
Entry
L
Additive[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
L1[e]
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
–
–
–
–
–
–
–
–
53
48
42
38
27
31
40
48
50
53
65
72
43
70
83
89
0
15
79
93
78
92
91
93
4
4d
136
65
82
5
6
7
8
9
4-CF3-Ph (1e)
4-Br-Ph (1 f)
4-F-Ph (1g)
4-Cl-Ph (1h)
3,4-Cl2-Ph (1i)
4-Ph-Ph (1j)
2-naphthyl (1k)
4e
4 f
4g
4h
4i
120
120
120
96
136
96
60
58
55
65
58
82
68
98
95
93
97
94
93
92
6
7
8[f]
9[f]
10[f]
11[f]
12[f,g]
tBuOH
2-adamantanol
1-adamantanol
1-adamantanol
10
11
4j
4k
120
[a] Unless otherwise noted, reactions were carried out with aldehyde 1
(0.1 mmol), 2-aminophenol (2; 0.1 mmol), ketene silyl acetal (3;
0.2 mmol), N,N’-dioxide L3 (0.01 mmol), ScACTHNUTRGENUN(G OTf)3 (0.005 mmol), 1-ada-
[a] Unless otherwise noted, reactions were carried out with N,N’-dioxide
(10 mol%), Sc(OTf)3 (5 mol%), benzaldehyde (1a; 0.1 mmol), 2-amino-
ACHTUNGTRENNUNG
phenol (2; 1 equiv), ketene silyl acetal (3; 2 equiv), 4 ꢂ MS (7.5 mg), and
THF (0.5 mL) under N2 atmosphere at 238C for 72 h. [b] One equivalent
of additive was used. [c] Isolated yield. [d] Determined by HPLC analysis
(see the Supporting Information). [e] The molar ratio of N,N’-dioxide L1
mantanol (0.1 mmol), 4 ꢂ MS (7.5 mg), and CHCl3 (0.5 mL) under N2 at-
mosphere at 408C. [b] One equivalent of additive was used. [c] Isolated
yield. [d] Absolute configuration was assigned after converting the prod-
uct 4a to known compound 7.[11]
to ScACHTUNGTRENUNG(OTf)3 was 1:1. [f] CHCl3 was used as the solvent. [g] The reaction
was carried out at 408C.
When chloroform was used as the solvent, both the reactivi-
ty and enantioselectivity were improved (48% yield, and
93% ee, Table 1, entry 8). The addition of one equivalent of
secondary or tertiary alcohols evidently enhanced the reac-
tivity (Table 1, entries 9–11). Especially, when 1-adamanta-
nol was employed, the isolated yield was increased to 65%
(Table 1, entry 11). Moreover, increasing the reaction tem-
perature to 408C led to the desired adduct 4a with 72%
yield and 93% ee (Table 1, entry 12).[14]
Scheme 1. Scaled-up version of the Mannich-type reaction.
conditions, the desired product was produced without loss of
enantioselectivity.
Under optimized conditions, the scope of this three-com-
ponent reaction with different aldehydes was investigated.
Various aldehydes worked well in this reaction, delivering
the corresponding products in excellent ee values with mod-
erate to good yields (Table 2).[15] Neither the electronic
properties nor the steric hindrance of the substituent at the
aromatic ring had any apparent effect on the enantioselec-
tivity (Table 2, entries 1–10). For electron-donating aromatic
aldehydes, a range of 82–90% ee was obtained (Table 2, en-
tries 2–4). Notably, this method was rather efficient for aro-
matic aldehydes bearing electron-withdrawing groups at the
para-position, which provided adducts in excellent enantio-
selectivities (93–98% ee, Table 2, entries 5–9). The con-
densed aromatic aldehyde (2-naphthaldehyde) was also
found to be suitable substrate, giving the corresponding
product 4k in 68% yield with 92% ee (Table 2, entry 11).
To test the synthetic potential of the present approach, a
large-scale synthesis of the chiral N-substituent b-amino
esters was performed. As shown in Scheme 1, by treatment
of 2 mmol of starting materials under the optimal reaction
The absolute configuration of 4a was determined after
converting to known compound 7 (Scheme 2). Methylation
of 4a gave product 5,[4a] followed by hydroxylation and
esterification to afford the adduct 7, thereby assigning the
absolute configuration of 4a to be R by comparing the opti-
cal rotation of 7 with that given in the literature.[11] Further-
more, the N-substituent of the product 4a could also be
easily removed,[4a] affording b-amino ester 6 in 65% yield.
In summary, we have presented a highly enantioselective
one-pot, three-component Mannich-type reaction of alde-
hydes, 2-aminophenol, and ketene silyl acetal by using
5 mol% of the C2-symmetric, N,N’-dioxide L3 scandiumACHTUNGTRENNUNG(III)
triflate (2:1) complex, which facilitated the asymmetric syn-
thesis of biologically interesting b-amino esters. Various al-
dehydes could be converted to N-substituted b-amino esters
with excellent enantioselectivities (up to 98% ee) and mod-
erate to good yields under mild conditions. Further investi-
gation on the mechanism of this catalytic system is currently
underway.[16]
Chem. Eur. J. 2009, 15, 5884 – 5887
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5885

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Scheme 2. Conversion to b-amino ester 6 and known compound 7 for assignment of the absolute configuration
of 4a.
Experimental Section
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General experimental procedure: Under N2 atmosphere, benzaldehyde
(1a; 10.2 mL, 0.1 mmol) was added through a syringe to the dry tube con-
taining a suspension of 2-aminophenol (2; 10.9 mg, 0.1 mmol), N,N’-di-
ACHTUNGTRENNUNGoxide L3 (7.0 mg, 0.01 mmol), ScCAHTUNGTRNE(NUGN OTf)3 (2.5 mg, 0.005 mmol), 1-adaman-
tanol (15.2 mg, 0.1 mmol), 4 ꢂ MS (7.5 mg) in CHCl3 (0.5 mL). After the
mixture was heated to 408C, ketene silyl acetal (3; 41.0 mL, 0.2 mmol)
was added; the resulting solution was stirred at this temperature for a
period of time indicated in Table 2. After cooling, the reaction was
quenched with aqueous NaCl, extracted with AcOEt, and the combined
organic layer was dried over Na2SO4. Filtration, evaporation, and purifi-
cation by silica gel column chromatography (AcOEt:PET=1:8–1:6) gave
the product 4a in 72% yield (22.5 mg) with 93% ee.
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Acknowledgements
We appreciate the National Natural Science Foundation of China (Nos.
20732003 and 20872097) and the Ministry of Education, P. R. China (No.
20070610019) for financial support. We also thank Sichuan University
Analytical & Testing Center for NMR analysis and the State Key Labo-
ratory of Biotherapy for HRMS analysis.
Keywords: amino esters
enantioselectivity Mannich-type reaction
reactions · scandium
·
asymmetric catalysis
·
·
·
one-pot
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Asymmetric Catalysis
COMMUNICATION
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enantioselectivities: iso-butyraldehyde (72% yield, 65% ee), n-hexa-
nal (65% yield, 67% ee).
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[12] For details see the Supporting Imformation.
[13] Other ketene silyl acetals such as the methyl isobutyrate and methyl
acetate derivatives were also investigated. However, poor enantiose-
lectivities were obtained (less than 35% ee).
[14] Further increase in the reaction temperature to 808C resulted in a
dramatic decrease in the enantioselectivity (33% ee).
[16] To understand the structure of the catalyst, we tried to obtain a
single crystal of L3–Sc
structure of L1–Sc(OTf)3 (1:1) complex was determined by X-ray
crystallography. CCDC 704000 contains the supplementary crystallo-
graphic data for the L1–Sc(OTf)3 (1:1) complex. These data can be
ACHTUNGRTENN(UNG OTf)3 (2:1) complex but failed. However, the
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif
[15] Aliphatic aldehydes were also investigated. The reaction proceeded
smoothly to give the corresponding products with only moderate
Received: February 12, 2009
Published online: May 6, 2009
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