N,N′-Dioxide-nickel(II) complex catalyzed asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2011.04.089

A direct asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-ketoesters could be efficiently catalyzed by an N,N′-dioxide-nickel(II) complex. A series of chiral warfarin derivatives were obtained in excellent yields (up to 99%) with high enantioselectivities (up to 90% ee) under mild conditions within shorter reaction time.

Full text of DOI:10.1016/j.tetlet.2011.04.089

Tetrahedron Letters 52 (2011) 3433–3436
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Tetrahedron Letters
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N,N0-Dioxide–nickel(II) complex catalyzed asymmetric Michael addition
of cyclic 1,3-dicarbonyl compounds to b,c-unsaturated
a-ketoesters
⇑
⇑
Zhenhua Dong, Juhua Feng, Weidi Cao, Xiaohua Liu, Lili Lin , Xiaoming Feng
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds to b,c-unsaturated a-ketoest-
ers could be efficiently catalyzed by an N,N0-dioxide–nickel(II) complex. A series of chiral warfarin deriv-
atives were obtained in excellent yields (up to 99%) with high enantioselectivities (up to 90% ee) under
mild conditions within shorter reaction time.
Received 5 March 2011
Revised 10 April 2011
Accepted 22 April 2011
Available online 4 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
b,c-Unsaturated a-ketoester
Michael addition
Warfarin
Nickel
Coumarin derivatives are probably one of the most common skel-
etons found in natural products.1 Due to their extensive array of bio-
logical activities and pharmacological properties, the synthesis of
this kind of compounds has been long-standing challenge in organic
chemistry. Among the coumarin family members, 4-hydroxycoum-
arin core, such as warfarin, bromadiolone and phenproocoumon are
especially important.2 Warfarin has been used as an anticoagulant
for more than half a century. Since different pharmacological effects
of two enantiomers, the synthesis of chiral warfarin and analogues
are of great interest.3
reported an N,N0-dioxide–copper(II) complex catalyzed Michael
addition of cyclic diketones to b,c-unsaturated a-ketoester produc-
ing a chromene derivative. On the other hand, chiral N,N0-dioxide
metal complexes have shown powerful catalytic capability in var-
ious reactions with a tunable electronic and steric chiral scaf-
folds.8,9 Herein, we describe
a
readily available chiral N,N0-
dioxide–nickel(II) complex for the enantioselective synthesis of
warfarin derivatives via a direct Michael addition of cyclic 1,3-
dicarbonyl compounds to b,c-unsaturated a-ketoester. Excellent
yields and high enantioselectivities were obtained for a wide range
Several methodologies have been made for the synthesis of di-
of substrates using 5 mol % catalyst loading.
versely structured chiral warfarin.4 Among them, the asymmetric
At the outset of this study, N,N0-dioxide L1 derived from (S)-pro-
line was coordinated with various metal salts and used to catalyze
Michael addition of 4-hydroxycoumarin to a,b-unsaturated system
has become a very attractive methodology in recent years, since
the direct Michael reaction of 4-hydroxycoumarin 2a and b,
c-unsat-
chiral warfarin can be obtained simply and quickly via such
urated -ketoester 1a in CH2Cl2 at room temperature. As shown in
a
method.5 Compared with
a
,b-unsaturated ketone which can
conduce chiral warfarin directly, the reaction using b, -unsatu-
rated -ketoester as Michael accepter was also significant which
can be obtained as a warfarin analogue.6,7 Initially, Jørgensen and
co-workers developed bisoxazoline–copper(II) complex
catalyzed Michael addition of cyclic 1,3-dicarbonyl compound to
Table 1, the rare-metal complexes promoted the reaction smoothly
in 12 h, but the enantioselectivities were very poor (Table 1, entries
1–3). Considering the excellent ability of N,N0-dioxide-copper
system for the asymmetry Michael addition of cyclic diketones to
c
a
a
b,c-unsaturated a-ketoester, we test various transition metal
complexes including Cu(II), Fe(II), Co(II) and Ni(II) (Table 1, entries
4–7). To our delight, the Ni(acac)2–L1 complex could promote the
reaction very quickly. Excellent yield and promising enantioselec-
tivity could be obtained in 10 min (99% yield, 29% ee; Table 1, entry
7). To improve the enantioselectivity, various N,N0-dioxide ligands
with different chiral backbone moieties and amines were investi-
gated (Fig. 1). It was found that the chiral backbone moiety of the
N,N0-dioxides had a significant effect on the enantioselectivity
(Table 1, entries 7–9). (S)-Pipecolic acid derived N,N0-dioxide L3
b,c-unsaturated a-ketoester which can be obtained as a warfarin
analogue.7a Last year, Xu group,7b Zhao group,7c and Wang group7d
reported organocatalyst squaramides and thioureas catalyzed
enantioselective Michael reaction of 4-hydroxycoumarin and b,c-
unsaturated
a-ketoester, respectively. Recently, our group
⇑
Corresponding authors. Fax: +86 28 8541 8249.
E-mail address: xmfeng@scu.edu.cn (X. Feng).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.089

3434
Z. Dong et al. / Tetrahedron Letters 52 (2011) 3433–3436
Table 1
Table 2
Screening of ligands and metals for the Michael reactiona
Optimization of the reaction conditionsa
OH
OH
COOMe
COOMe
OH
O
OH
O
O
O
O
L5 / Ni(acac)2 (1:1, 5-10 mol%)
L / Metal (1:1,10 mol%)
Ph
O
Ph
O
+
+
Ph
COOMe
Ph
COOMe
CH2Cl2, rt
solvent, temperature
O
O
O
O
O
2a
1a
4a
2a
1a
4a
Yieldb (%)
eec (%)
Entry
Solvent
Time
Yieldb (%)
eec (%)
Entry
Ligand
Metal
Time
1
2
3
4
5
6
THF
PhCH3
Et2O
MeOH
CHCl3
Cl2CHCHCl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
3 h
3 h
3 h
3 h
30 min
30 min
20 min
40 min
40 min
4 h
96
95
97
96
96
99
99
99
99
99
17
29
13
3
45
71
73
79
83
89
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
Sc(OTf)3
La(OTf)3
Yb(OTf)3
Cu(OTf)2
Fe(acac)2
Co(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
12 h
12 h
12 h
12 h
12 h
12 h
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
63
81
86
95
78
81
99
99
99
99
99
99
99
99
99
0
0
9
17
0
10
29
17
55
59
70 (S)d
43
69
35
5
7
8d
9d,e
10d,e,f
9
10
11
12
13
14
15
a
Unless otherwise noted, the reactions were performed with 2a (0.10 mmol), 1a
(0.11 mmol), N,N0-dioxide (0.01 mmol), metal (0.01 mmol) in 1 mL solvent at room
temperature for required time.
b
Yield of isolated product.
Determined by HPLC analysis.
5 mol % catalyst loading was used.
10 mg 4 Å MS was added.
c
a
d
Unless otherwise noted, the reactions were performed with 2a (0.10 mmol), 1a
(0.11 mmol), N,N0-dioxide (0.01 mmol), metal (0.01 mmol) in 1 mL CH2Cl2 at room
temperature for required time.
e
f
Reaction was carried out at 0 °C.
b
Yield of isolated product.
c
Determined by HPLC analysis.
The absolute configuration was determined by comparing with literature.7c
d
vealed that except chlorinated alkanes, other solvents all had
greatly deleterious effects on the activity and enantioselectivity
(Table 2, entries 1–4). Minor improvement of the enantioselectivity
was obtained when CH2Cl2 was changed to ClCH2CH2Cl (Table 2,
entry 7). Up to 79% ee value was attained when the catalyst loading
was decreased to 5 mol % with a little extension of reaction time
(Table 2, entry 8). When 10 mg 4 Å MS was used, the enantioselec-
tivity was increased to 83% ee (Table 2, entry 9). Decreasing the
reaction temperature to 0 °C improved the ee value to 89% with a
longer reaction time (4 h, 99% yield; Table 2, entry 10). Further-
more, this reaction could tolerate air and moisture. It was unneces-
sary to prepare the catalyst beforehand, herein the experimental
procedure could become very simple.
N
N
O
N
O
N
O
O
O
O
O
O
N
N
N
N
H
H
H
H
Ar
Ar
Ar
Ar
L1 : Ar = 2,6-iPr2C6H3
L2 : Ar = 2,6-iPr2C6H3
Under the optimal reaction conditions, the asymmetric Michael
addition of various cyclic 1,3-dicarbonyl compounds to a series of
b,c-unsaturated a-ketoesters were examined. As shown in Table 3,
L3: Ar = 2,6-iPr2C6H3
L4: Ar = 2,6-Me2C6H3
L5: Ar = 2,6-Et2C6H3
L6: Ar = 2-MeC6H4
L7: Ar = 2-tBuC6H4
L8: Ar = 2-ClC6H4
L9: Ar = Ph
O
O
N
O
N
O
for nearly all of the substrates, this reaction could proceed quickly
to afford warfarin analogues in nearly complete yields with high
enantioselectivities. Neither the steric hindrance nor the electronic
nature of the aromatic ring (R1) had any obvious effect on the
enantioselectivities (87–90% ee value; Table 3, entries 1–12). It is
worth noting that the substrates with condensed-ring, heteroaro-
matic and cinnamyl group performed well, giving the correspond-
ing products in excellent yields and high enantioselectivities
N
N
H
Ar
Ar
H
Figure 1. N,N0-Dioxide ligands evaluated for this reaction.
(Table 3, entries 13–15). Moreover, a-keto ester 1p with ethyl sub-
strate also gave excellent yield and high enantioselectivity (Table 3,
entry 16). 4-Hydroxycoumarin 2b, containing 6-methyl group, also
afforded excellent yield and high enantioselectivity (Table 3, entry
17). To our delight, the catalyst system could be extended to the
was superior to both L1 (derived from (S)-proline) and L2 (derived
from (S)-ramipril acid) with excellent yield and moderate ee value
(Table 1, entry 9). In addition, the amide moiety of the N,N0-dioxide
played an important role on the enantioselectivity. Ligands with a
bulkier electron-donating group at the ortho position of the aniline
gave higher enantioselectivity (Table 1, entries 10–13 vs entry 14).
The best result was obtained with 99% yield and 70% ee value when
the ligand L5, having an appropriate ethyl group at the ortho position
of the aniline, was used (Table 1, entry 11).
Michael addition of 4-hydroxy-6-methyl-2-pyrone 3 to the b,
unsaturated -ketoester 1a. Pyranone analogue could be obtained
with excellent yield and good enantioselectivity (Scheme 1).
c-
a
To explain the reaction process, a possible transition state was
proposed based on the absolute configuration of the product
(Fig. 2). We speculated that N,N0-dioxide L5 and b,
c-unsaturated
The effect of solvent, additive, reaction temperature, and cata-
lyst loading were also investigated. The screening of solvent re-
a-ketoester 1a coordinated with Ni(acac)2 to form a complex. Then

Z. Dong et al. / Tetrahedron Letters 52 (2011) 3433–3436
3435
Table 3
Substrate scope for catalytic asymmetric Michael additiona
O
O
H
OH
COOR2
OH
OH
O
O
O
L5 / Ni(acac)2 (1:1, 5 mol%)
R1
O
X
+
X
N
R1
COOR2
4 Å MS, ClCH2CH2Cl, 0 o
C
MeO
O
O
O
O
O
Ni
O
O
4a-4q
HN
2
1
O
NH
2a: X = H
2b: X = 6-CH3
4a-p: X = H
4q: X = 6-CH3
1a-o: R2 = Me
1p: R2 = Et
N
Figure 2. The proposed transition state.
Entry
2
1
Time (h)
Yieldb (%)
eec (%)
X
R1, R2
1
H
H
H
H
H
Ph, Me (1a)
4
4
4
4
4
99
99
99
99
99
89 (S)d
89
89 (S)
87
Acknowledgments
2
3
4
5
3-MeC6H4, Me (1b)
4-MeC6H4, Me (1c)
3-MeOC6H4, Me (1d)
4-MeOC6H4, Me (1e)
We thank the National Natural Science Foundation of China
(Nos. 20732003 and 21021001), PCSIRT (No. IRT0846), and the Na-
tional Basic Research Program of China (973 Program: No.
2011CB808600) for financial support, and Sichuan University Ana-
lytical & Testing Centre for NMR analyses.
88
O
, Me (1f)
6
H
5
98
89
O
7
8
9
H
H
H
H
H
H
H
H
H
H
4-PhC6H4, Me (1g)
3-ClC6H4, Me (1h)
4-ClC6H4, Me (1i)
3-BrC6H4, Me (1j)
4-BrC6H4, Me (1k)
4-FC6H4, Me (1l)
2-Naphthyl, Me (1m)
2-Thienyl, Me (1n)
PhCH@CH, Me (1o)
Ph, Et (1p)
4
10
4
5
4
4
4
6
10
9
98
78
99
89
99
99
97
98
96
98
98
87
89
Supplementary data
87 (S)
87
89 (S)
90 (S)
89
87
89
85 (S)
87
10
11
12
13
14
15
16
17
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.089.
References and notes
6-CH3
Ph, Me (1a)
4
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a
Unless otherwise noted, the reactions were performed with 2 (0.10 mmol), 1
(0.11 mmol), N,N0-dioxide L5 (0.005 mmol), Ni(acac)2 (0.005 mmol), 4 Å MS 10 mg
in 1 mL ClCH2CH2Cl at 0 °C for required time.
b
Yield of isolated product.
c
ˇ
Determined by HPLC analysis.
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In summary, we have developed a highly enantioselective
Michael addition of cyclic 1,3-dicarbonyl compound to b,
rated
The reaction performed well for a range of substituted b,
rated
c
-unsatu-
a
-ketoester catalyzed by N,N0-dioxide–Ni(acac)2 complex.
c-unsatu-
a
-ketoester and cyclic 1,3-dicarbonyl compounds, giving the
desired warfarin analogues in excellent yields (up to 99%) with high
enantioselectivities (up to 90% ee). Based on experimental results, a
possible transition state has been proposed. Further application of
the methodology is ongoing.
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OH
COOMe
OH
O
O
L5 / Ni(acac)2 (1:1, 5 mol%)
4 Å MS, ClCH2CH2Cl, 0 oC
Ph
+
Ph
COOMe
O
O
O
O
1a
4r, 95% yield, 81% ee
3
Scheme 1. 4-Hydroxy-6-methyl-2-pyrone was used as nucleophilic reagent.

3436
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