Highly enantioselective michael addition of malonate derivatives to enones catalyzed by an N,N'-dioxide-scandium(III) complex

Article abstract of DOI:10.1002/chem.200901157

A highly enantioselective Michael addition of malonate derivatives to chalcone derivatives catalyzed by L-Ramipril acid derived N,N'-dioxide-scandium (III) complex was reported. The experiment included use of L-Ramipril acid derived N,N'-dioxide L1-nickle(II) complex to catalyze the asymmetric Michael addition of diethyl malonate to chalcone in EtOH at 35°C. The results show that 4 A molecular sieves when added as additives result in an improved reactivity and a 95% yield without loss of enantioselectivity. Diisopropyl malonate is found to be an excellent Michael donor than the reaction accomplished in 15hr in 98% yield with 99% ee. The results also show that the electronic nature or the position of the substituents at the aromatic rings of R² or ³ has little influence on the enantioselectivity.

Full text of DOI:10.1002/chem.200901157

COMMUNICATION
DOI: 10.1002/chem.200901157
Highly Enantioselective Michael
N
ddition of Malonate Derivatives to
Donghui Chen, Zhenling Chen, Xiao Xiao, Zhigang Yang, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*[a]
The catalytic asymmetric conjugate addition reaction is
YIII, ScIII salts were investigated, which were known to be
chelated well with dicarbonyl compounds.[8] As summarized
in Table 1, scandium triflate was found to be superior to all
the other metals tested, producing 3a in good yield with
91% ee (Table 1, entries 1–6). Encouraged by the results,
scandium triflate was selected as the central metal for fur-
ther research. Then a series of N,N’-dioxides was synthesized
and combined with scandium triflate to promote the conju-
À
one of the most powerful methods for the carbon carbon
bond formation because various chiral functionalized ad-
ducts can be obtained from numerous Michael acceptors
and donors.[1] Among them, the asymmetric Michael addi-
tion of 1,3-dicarbonyl compounds to enones provides a
simple way for the preparation of synthetically useful 1,5-di-
carbonyl compounds and attracts more and more chemistsꢀ
interests.[2–6] There have been several catalysts developed for
this reaction, such as chiral metal complexes,[3] chiral ammo-
nium salts,[4] chiral amine catalysts[5] and thiourea catalysts,[6]
but only few reports appeared successfully when chalcone
derivatives were used as Michael acceptors.[3k,4e,6b] Despite
excellent enantioselectivity have been achieved by Maruo-
ka,[4e] Wang[6b] and Kobayashi et al.,[3k] developing new and
efficient chiral catalyst systems is still in great need. Recent-
ly, N,N’-dioxide–metal complexes have been successfully ap-
plied to promote many kinds of asymmetric transforma-
tions,[7] herein we wish to report a highly enantioselective
Michael addition of malonate derivatives to chalcone deriv-
atives catalyzed by l-Ramipril acid derived N,N’-dioxide–
Figure 1. Chiral N,N’-dioxide catalysts used in the study.
gate addition reaction (Figure 1). We found that the amide
moiety in the N,N’-dioxide ligands had significant effect on
the enantioselectivity (Table 1, entries 6–9). Unexpectly,
when introducing bulky substitute at the ortho position of
the aromatic ring, the enantioselectivity as well as the yield
decreased remarkably (Table 1, entry 7). When R was re-
placed by aliphatic tert-butyl group, product 3a was ob-
tained in lower yield with slightly decreased enantioselectiv-
ity (Table 1, entries 8 vs 6). Excitingly, when R was benzyl
group, the enantioselectivity rapidly increased up to 99% ee
with moderate yield (Table 1, entry 9). Next, the chiral back-
bone of the N,N’-dioxides was also examined, but no better
results were obtained (Table 1, entries 10–11 vs 9). It should
be noted that when 4 ꢁ molecular sieves was added as addi-
tives, the reactivity was largely improved and 3a could be
obtained in 95% yield without loss of enantioselectivity
(Table 1, entry 12). The catalyst loading could be reduced to
5 mol% while the yield and enantioselectivity were almost
maintained (Table 1, entry 13).
scandiumACHTUNGTRENNUNG(III) complex. A wide range of substrates can be
tolerated, affording the desired products with up to 99%
yield and 99% ee.
Inspired by our previous studies,[7i] we initiated the experi-
ment by using l-Ramipril acid derived N,N’-dioxide L1–
nickel(II) complex to catalyze the asymmetric Michael addi-
tion of diethyl malonate 1a to chalcone 2a in EtOH at
358C. However, only racemic product 3a was obtained.
Then serveral other Lewis acids, such as CuII, ZnII, LaIII,
[a] D. Chen, Z. Chen, X. Xiao, Z. Yang, 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 (P.R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901157.
Chem. Eur. J. 2009, 15, 6807 – 6810
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6807

Table 1. Screen of catalysts in the asymmetric Michael addition of dieth-
yl malonate to chalcone.[a]
Table 2. Scope of malonate derivatives in the asymmetric Michael addi-
tion to chalcone.[a]
R1
t [h]
Product
Yield [%][b]
ee [%][c]
Ligand
Metal
Ni(acac)2
Yield [%][b]
ee [%][c]
1
2
3
4
Et 1a
Me 1b
iPr 1c
tBu 1d
Bn 1e
iPr 1c
iPr 1c
45
70
15
65
70
72
64
3a
3b
3c
3d
3e
3c
3c
93
50
98
90
40
66
72
99 (R)
97 (R)
99
98
97
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L4
L4
G
24
0
–
–
Cu
Zn
U
NR[d]
NR[d]
34
La
A
8 (S)
0
5
Y
A
46
68
4
36
57
52
64
95
6[d]
7[e]
99
97
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
N
91
49
88
99
85
96
99
99
[a] Unless otherwise noted, the reaction was carried out with 2a
(0.1 mmol), 5 mol% L4–ScIII complex (1.2:1) and 4 ꢁ MS (10 mg) in
EtOH (0.5 mL) under nitrogen at 358C for 0.5 h, then the respective mal-
onate 1 (0.12 mmol) was added. [b] Isolated yield. [c] Determined by
HPLC analysis (see Supporting Information). The absolute configuration
was determined by comparison of the optical rotation values in the litera-
9
10
11
12[e]
13[e,f]
93
ture.[3k] [d] 1 mol% L4–ScIII complex (L4/Sc
ACTHNUTRGNEU(NG OTf)3 1.2:1) was used.
[a] Unless otherwise noted, the reactions were performed with 2a
(0.1 mmol), N,N’-dioxide (12 mol%), metal (10 mol%) in EtOH
(0.5 mL) under nitrogen at 358C for 0.5 h, then diethyl malonate
(0.12 mmol) was added. [b] Isolated yield. [c] Determined by HPLC anal-
ysis (Chiralcel AS-H). Unless specified, the absolute configuration was
R, which was determined by comparison with the optical rotation values
in the literature.[3k] [d] No reaction. [e] 4 ꢁ molecular sieves (10 mg) were
added. [f] 6 mol% L4 and 5 mol% scandium triflate were used.
[e] The reaction was performed in water (0.5 mL). No molecular sieves
were used.
afforded the corresponding products 3ac–ah with excellent
enantioselectivities (Table 3, entries 25–30).
Finally, in order to show the synthetic utility of the cata-
lyst system, Michael addition of diisopropyl malonate to
chalcone was expanded to a gram-scale (Scheme 1). As
shown in Scheme 1, the reaction proceeded smoothly in
77% yield with 98% ee using 1 mol% N,N’-dioxide L4–
Having optimized the reaction parameters, an ester group
effect of malonate derivates was investigated for the asym-
metric Michael addition of chalcone. As shown in Table 2,
the ester groups apparently had little or no effect on the
enantioselectivity of the reaction (Table 2, entries 1–5). In-
terestingly, the more sterically hindered malonate derivates
1c and 1d seemed more reactive compared to 1b and 1e.
Diisopropyl malonate turned out to be an outstanding Mi-
chael donor that the reaction accomplished in 15 h in 98%
yield with 99% ee (Table 2, entry 3). Moreover, the catalyst
loading could be further reduced to 1 mol% with good yield
without loss of enantioselectivity (Table 2, entry 6). It is
noteworthy that the reaction proceeded well even in water
in 72% yield with a slightly decreased enantioselectivity
(Table 2, entry 7).
scandiumACTHNUTRGNE(NUG III) complex as catalyst.
In conclusion, we have devoloped a l-Ramipril acid de-
rived N,N’-dioxide–scandium triflate complex for the asym-
metric conjugate addition of malonate to chalcone deriva-
tives. A variety of optical pure ketoesters could be obtained
with high yields and excellent enantioselectivities. The reac-
tion performed well in EtOH, making the process environ-
mentally friendly. The reaction could be amplified to gram
scales in 77% yield with 98% ee under 1 mol% N,N’-diox-
ide L4–scandiumACTHNUTRGNEUNG(III) complex as catalyst, which showed the
potential value of the catalyst system. Further studies of the
mechanism and application of the catalyst system to other
reactions are underway.
Under the optimized conditions, the scope of the conju-
gate addition of diisopropyl malonate to a variety of sub-
strates was tested, and the results were summarized in
Table 3. In all cases, the substrates could give the desired
products in high yields with excellent enantioselectivities. It
is interesting that either the electronic nature or the position
of the substituents at the aromatic ring of R2 or R3 had little
influence on the enantioselectivity (Table 3, entries 1–16,
19–24). Notably, when R2 was unsaturated cinnamyl group
or aliphatic cyclohexyl group, Michael adducts 3u–v could
also be obtained in good yield with 97% and 96% ee, re-
spectively (Table 3, entries 17–18). Remarkably, substrates
bearing heteroaromatic substituentes, either in R2 or R3,
were also suitable acceptors for the conjugate reaction and
Experimental Section
Typical experimental procedure: N,N’-Dioxide L4 (6.7 mg, 0.012 mmol),
scandium triflate (4.9 mg, 0.01 mmol), chalcone (41.7 mg, 0.20 mmol) and
4 ꢁ molecular sieves (20 mg) were stirred in a dry reaction tube in EtOH
(1.0 mL) under nitrogen at 358C for 0.5 h, then diethyl malonate (37 mL,
0.24 mmol) was added. The process was monitored by TLC. After chal-
cone disappeared, the reaction mixture was purified by flash chromatog-
raphy (petroleum ether/ethyl acetate 12:1) on silica gel to afford the de-
sired product.
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Chem. Eur. J. 2009, 15, 6807 – 6810

Highly Enantioselective Michael Addition
COMMUNICATION
Table 3. Substrate scope of enones with diisopropyl malonate.[a]
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R2
R3
t
Product Yield ee
[%][b] [%][c]
[h]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
15 3c
40 3 f
30 3g
90 3h
40 3i
45 3j
90 3k
36 3l
36 3m
36 3n
36 3o
35 3p
40 3q
35 3r
40 3s
35 3t
45 3u
90 3v
35 3w
98 99
96 99
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-NO2C6H4
4-NO2C6H4
93
80
92
93
87
92
97
82
90
95
96
92
60
62
66
96
99
70
81
72
94
94
73
74
92
92
94
81
99
99
97
99
98
99
98
98
97
99
99
99
98
99
97
96
98
96
98
99
99
98
98
96
99
99
99
96
10 3-MeC6H4
11 4-MeC6H4
12 4-FC6H4
13 4-CNC6H4
14 2,4-Cl2C6H3
15 3,4-methylenedioxy-C6H3 Ph
16 2-naphthyl
17
18 cyclohexyl
19 Ph
20 Ph
21 Ph
22 Ph
23 Ph
24 Ph
25 2-furyl
26 2-thienyl
27 2-pridinyl
28 Ph
Ph
Ph
Ph
4-ClC6H4
4-NO2C6H4 45 3x
2-MeOC6H4 20 3y
3-MeOC6H4 35 3z
4-MeOC6H4 20 3aa
2-naphthyl
Ph
Ph
Ph
2-furyl
2-thienyl
2-furyl
À
CH=CHPh
40 3ab
35 3ac
40 3ad
40 3ae
40 3af
40 3ag
45 3ah
29 Ph
30 2-furyl
[a] Unless specified, the reactions were performed with 2 (0.1 mmol), 5
mol% L4–ScIII complex (1.2:1) and 4 ꢁ MS (10 mg) in EtOH (0.5 mL)
under nitrogen at 358C for 0.5 h, then diisopropyl malonate (0.12 mmol)
was added. [b] Isolated yield. [c] Determined by HPLC analysis (see Sup-
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Scheme 1. Asymmetric conjugate addition of diisopropyl malonate to
chalcone on a gram scale.
Acknowledgements
We appreciate the National Natural Science Foundation of China (Nos.
20732003 and 20602025) and the Ministry of Education (No.
20070610019) for financial support, the Sichuan University Analytical &
Testing Centre for NMR analysis, and the State Key Laboratory of Bio-
therapy for HRMS analysis.
À
Keywords: asymmetric synthesis · C C bond formation ·
chalcone · Michael addition · scandium
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Received: May 1, 2009
Published online: June 10, 2009
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