Highly enantioselective Michael addition of pyrazolin-5-ones catalyzed by chiral metal/N,N′-dioxide complexes: Metal-directed switch in enantioselectivity

Article abstract of DOI:10.1002/anie.201008256

Make the switch: The first example of a switch in enantioselectivity in the asymmetric Michael addition of pyrazolin-5-ones to 4-oxo-4-arylbutenoates that is controlled by the metal center of the catalyst is reported. By using the same N,N′-dioxide ligand

Full text of DOI:10.1002/anie.201008256

Communications
DOI: 10.1002/anie.201008256
Asymmetric Synthesis
Highly Enantioselective Michael Addition of Pyrazolin-5-ones
Catalyzed by Chiral Metal/N,N’-Dioxide Complexes: Metal-Directed
Switch in Enantioselectivity**
Zhen Wang, Zhigang Yang, Donghui Chen, Xiaohua Liu, Lili Lin, and Xiaoming Feng*
Control of the absolute configuration of newly created
stereocenters is of special interest and is still a challenging
problem in asymmetric catalysis.[1] Generally, a switch in
enantioselectivity is most obviously achieved through the use
of enantiomeric ligands. However, the two enantiomers of a
chiral ligand are not always readily available or economically
feasible to synthesize. Alternatively, the enantioselectivity
can also be switched when using the same metal in the
presence of ligands that are from the same chiral source but
contain modified subunits.[2] The development of new and
effective catalytic asymmetric methods to induce a switch in
the preferred enantioselectivity of a reaction when using the
same chiral ligand is an interesting and demanding challenge.
In fact, several metal-based systems, in which the metal and
reaction conditions (solvent, pressure, and additive) were
tuned, have been developed for this enantiodivergent syn-
thesis.[3] In these systems the unique characteristics of the
metal ions, such as the atomic radius and their electronic
properties, altered their coordination pattern even with the
same chiral ligand. This behavior suggests the existence of
different transition states that lead to the switch in enantio-
selectivity. Pyrazolone derivatives, an important class of five-
membered-ring lactams, have exhibited a variety of applica-
tions as pharmaceutical candidates and biologically important
structural components.[4] The development of asymmetric
methods to access pyrazolone enantiomers with the construc-
tion of contiguous quaternary and tertiary stereocenters is
therefore of considerable interest.[5] To date, there is only one
example of the organocatalytic diastereo- and enantioselec-
tive Michael addition of 4-substituted-pyrazolin-5-ones to
nitroolefins.[4l] We report herein a highly enantioselective
Michael addition of 4-substititued-5-pyrazolones to 1,4-dicar-
bonyl but-2-enes,[6] using the same ligand with either Sc(OTf)3
or Y(OTf)3 to switch the enantioselectivity.[7]
We initially investigated the reaction of 4-benzyl-5-
pyrazolone (1a) with ethyl (E)-4-oxo-4-phenylbutenoate
(2a) in EtOH at 308C catalyzed by scandium(III)/N,N’-
dioxide complexes, which contain ligands that are derived
from (S)-pipecolic acid (Table 1, entries 1–5). The reaction
proceeded smoothly to afford the desired adducts with
2.3:1 d.r. and 75% ee (Table 1, entry 1). The N,N’-dioxides
that contained a methyl group at the ortho position on the
aniline ring exhibited a positive effect on both the diastereo-
selectivity and enantioselectivity (Table 1, entries 1–3). The
yield could be improved to 95% by adding molecular sieves
(4 ꢀ; 10 mg). The role of the molecular sieves might be to
promote the enolation of pyrazolone and accelerate the
Table 1: Optimization of the Michael addition of 4-benzyl-5-pyrazolone
(1a) to ethyl (E)-4-oxo-4-phenylbutenoate (2a) using metal/N,N’-dioxide
complexes.[a]
Entry Metal
L
Solvent Yield [%][b]
d.r.[c]
2.3:1
3.2:1
4.3:1
4.6:1
4.5:1
>49:1 ꢀ65
>49:1 ꢀ66
>49:1 ꢀ81
>49:1 ꢀ96
>49:1 ꢀ95
>49:1 ꢀ90
>49:1 ꢀ95
>49:1 ꢀ93
>49:1 ꢀ93
>49:1 ꢀ94
>49:1 ꢀ96
ee [%][c,d]
1
Sc(OTf)3
L1 EtOH
L2 EtOH
L3 EtOH
L3 EtOH
L3 EtOH
L3 EtOH
L3 THF
L3 MeCN
L3 CH2Cl2
L3 CH2Cl2
L3 CH2Cl2
85
79
80
95
80
88
86
70
95
73
93
94
92
94
86
86
75
83
86
86
86
2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
La(OTf)3
3
4[e]
5[e,f]
6[g]
7[g]
8[g]
9[g]
10[f,g]
11[g]
12[g]
13[g]
14[g]
15[g]
16[g]
[*] Z. Wang, Z. G. Yang, D. H. Chen, Dr. X. H. Liu, Dr. L. L. Lin,
Prof. Dr. X. M. Feng
Sm(OTf)3 L3 CH2Cl2
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Gd(OTf)3
Dy(OTf)3
Er(OTf)3
Yb(OTf)3
L3 CH2Cl2
L3 CH2Cl2
L3 CH2Cl2
L3 CH2Cl2
[**] We acknowledge the National Natural Science Foundation of China
(Nos. 20732003 and 21021001), the PCSIRT (No. IRT0846), and the
National Basic Research Program of China (973 Program: No.
2011CB808600) for financial support. We also thank the Sichuan
University Analytical & Testing Center for NMR analysis.
[a] Reaction conditions: ligand (5.5 mol%), metal (5 mol%), 1a
(0.12 mmol), 2a (0.1 mmol), solvent (0.4 mL), 308C, 24 h. [b] Yield of
the isolated product. [c] Determined by HPLC on a chiral stationary
phase. [d] The ee value of the opposite configuration is defined as minus.
[e] 10 mg of molecular sieves (4 ꢀ) were added. [f] 2 mol% catalyst
loading was used. [g] The reaction was carried out in 0.3 mL of solvent at
08C for 30 h. Bn=benzyl, Tf=trifluoromethanesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008256.
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Angew. Chem. Int. Ed. 2011, 50, 4928 –4932

Table 2: Sc(OTf)3-catalyzed enantioselective Michael addition of
4-substituted pyrazolones 1 to 4-oxo-4-arylbutenoates 2.[a]
reaction rate. Notably, the catalyst loading could be lowered
to 2 mol% without an appreciable drop in reactivity and
enantioselectivity (Table 1, entry 5). The optimal reaction
conditions were 5 mol% of Sc(OTf)3/L3 and 10 mg of
molecular sieves at 308C in EtOH.
To investigate the scope of orthogonal enantioselectivity
in the catalytic asymmetric Michael addition, we next
explored the effect of the metal center. Pleasingly, the
yttrium(III)/L3 system gave the opposite configuration of
the product 3a with excellent diastereoselectivity and mod-
erate enantioselectivity (Table 1, entry 6). A screen of sol-
vents (Table 1, entries 7–9) indicated that the same diaste-
reoselectivity and higher enantioselectivity could be obtained
in CH2Cl2 (Table 1, entry 9). Furthermore, when the catalyst
loading was lowered to 2 mol%, good results could still be
obtained (Table 1, entry 10). Although similar results were
obtained using many other rare-earth-metal salts (Table 1,
entries 11–16), the optimal reaction conditions were estab-
lished using 5 mol% of Y(OTf)3/L3 at 08C to obtain the
enantiomer.
Entry
R1
R2
R3
Yield [%][b]
d.r.[c]
4.6:1
ee [%][c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1e
1 f
1h
1i
Ph
Ph
Et
95 (3a)
83 (3c)
91 (3e)
85 (3 f)
95 (3g)
96 (3h)
85 (3i)
83 (3j)
89 (3k)
95 (3m)
97 (3n)
91 (3o)
97 (3p)
95 (3r)
95 (3s)
97 (3v)
92 (3w)
86
90
92
94
93
93
92
92
90[d]
90
91
95
90
95
95
93
86
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
9:1
6.7:1
6.1:1
7.3:1
4.5:1
5.7:1
13.3:1
10.1:1
3:1
8.1:1
9:1
4.9:1
6.1:1
19:1
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-ClC6H4
3,4-Cl2C6H3
2-thienyl
2-naphthyl
Ph
9
10
11
12
13
14
15
16
17
Under the optimized reaction conditions, we examined
the scope of the scandium(III)-catalyzed Michael addition of
4-substituted
pyrazolones
to
4-oxo-4-arylbutenoates
Ph
Ph
Ph
Ph
(Table 2). The more sterically hindered isopropyl 4-oxo-4-
arylbutenoate exhibited better enantioselectivity than ethyl 4-
oxo-4-arylbutenoate (compare Table 2, entries 1 and 2), and
the reaction proceeded well for many differently substituted
alkyl 4-oxo-4-arylbutenoates and 4-substituted pyrazolones,
independent of the electron-donating or electron-withdraw-
ing character of the substituents (up to 95% ee, 19:1 d.r.).
Moreover, heteroaromatic and fused-ring substrates were
also applicable, and gave the desired products with good
results (Table 2, entries 10, 11, and 15).
19:1
13.3:1
Ph
[a] Reaction conditions: L3 (5.5 mol%), Sc(OTf)3 (5 mol%), molecular
sieves (4 ꢀ, 10 mg), 1 (0.12 mmol), 2 (0.1 mmol), EtOH (0.4 mL), 308C,
24 h. [b] Yield of the isolated product. [c] Determined by HPLC on a chiral
stationary phase. [d] The absolute configuration was determined to be
2R,4’R by comparison of the HPLC and optical rotation values (Table 3,
entry 11).
We then investigated the Michael addition of 4-substi-
tuted pyrazolones and alkyl 4-oxo-4-arylbutenoates in the
presence of 5 mol% of Y(OTf)3/L3 (Table 3) and the
corresponding enantiomers were obtained with excellent
diastereoselectivity and enantioselectivity (up to 98% ee,
> 49:1 d.r.). The ester groups of the alkyl 4-oxo-4-arylbute-
noates exhibited little effect on the enantioselectivity but they
did influence the reactivity of the substrates (Table 3,
entries 1–4). The enantioselectivity of the reaction was not
sensitive to either the steric or the electronic properties of the
substituents on the phenyl ring (Table 3, entries 5–12), and
the corresponding products were isolated in good yields and
excellent enantiomeric excess. In addition, heteroaromatic
and fused-ring substrates also reacted well with pyrazolones
to deliver the desired products with excellent results (Table 3,
entries 13 and 14). Similar to the Sc(OTf)3 system, pyrazo-
lones with different alkyl substituents were also competent
substrates, thus providing the Michael addition products with
up to 95% yield, greater than 49:1 d.r. and up to 98% ee
(Table 3, entries 15–21). The absolute configuration of 3k was
determined to be 2S,4’S by single-crystal X-ray analysis (see
Figure 1a).[8]
Scheme 1. The gram-scale synthesis of 3a that demonstrates the
switch in enantioselectivity. M.S.=molecular sieves.
desired product without loss of reactivity and enantioselec-
tivity.
To gain insight into the reaction mechanism, we inves-
tigated the relationship between the ee value of ligand L3 and
the product 3a. Poor nonlinear effects were observed for both
catalytic systems,[9] thus suggesting that minor oligomeric
aggregates of Sc(OTf)3/L3 and Y(OTf)3/L3 might exist in the
reaction system (see the Supporting Information). The effects
of the solvent showed that using ethanol lowered the
enantioselectivity in the yttrium(III)-catalyzed reaction, how-
ever, in the scandium(III)-catalyzed reaction it not only
To test the synthetic potential of the present approach, a
gram-scale synthesis of the chiral pyrazolones was performed
(Scheme 1). The reaction of 4 mmol of starting materials,
under the optimized reaction conditions, produced the
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Communications
Table 3: Y(OTf)3-catalyzed enantioselective Michael addition of 4-sub-
stituted pyrazolones 1 to alkyl 4-oxo-4-arylbutenoates 2.[a]
Entry
R1
R2
R3
Yield [%][b]
ee [%][c]
1[d]
2[d]
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1 f
Ph
Ph
Ph
Ph
Et
95 (3a)
93 (3b)
87 (3c)
82 (3d)
80 (3e)
84 (3 f)
91 (3g)
95 (3h)
75 (3i)
91 (3j)
89 (3k)
83 (3l)
82 (3m)
91 (3n)
90 (3o)
84 (3p)
94 (3q)
82 (3r)
87 (3s)
89 (3t)
93 (3u)
96
90
98
97
97
98
97
98
91
97
96[f]
94
95
97
98
97
90
95
96
92
83
Me
iPr
Bn
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Et
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-ClC6H4
3,4-Cl2C6H3
2-ClC6H4
2-thienyl
2-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9[e]
10
11
12
13
14
15
16
17[d]
18
19
20
21[d]
Figure 1. a) X-ray structure of 3k. Thermal ellipsoids shown at 30%
probability (H atoms omitted for clarity). b) Survey of the effect of
ethanol as an additive in the Sc(OTf)3/L3 system.
iPr
iPr
iPr
Et
1g
1h
lone could hydrogen bond to the coordinated alcohol (see the
Supporting Information). In contrast, the larger ionic radius
of yttrium(III) could allow the coordination of the two
reactants to the metal center.[12,13] The unique characteristics
of the metal ion, such as the radius and electronic properties,
altered the activation pattern and this change created the
enantioswitch to give both enantiomers, even in the presence
of the same ligand.
[a] Reactions conditions: L3 (5.5 mol%), Y(OTf)3 (5 mol%),
1
(0.12 mmol), 2 (0.1 mmol), CH2Cl2 (0.3 mL), 08C, 48 h. [b] Yield of the
isolated product. Generally, >49:1 d.r. was observed. [c] Determined by
HPLC on a chiral stationary phase. [d] Reaction time was 30 h. [e] 10 mg
of molecular sieves (4 ꢀ) were added and the reaction time was 72 h.
[f] The absolute configuration was determined to be 2S,4’S by single-
crystal X-ray analysis.
In summary, we have successfully developed a highly
enantioselective Michael addition of 4-substituted pyrazo-
lones and 4-oxo-4-arylbutenoates, to give a range of 4-
substititued-5-pyrazolone derivatives. By using the ligand L3,
both enantiomers of the product were obtained in good to
excellent enantioselectivities and diastereoselectivities; the
respective enantiomers were obtained by changing the metal
center. Furthermore, excellent ee values and yields can also
be obtained in gram-scale reactions, thus showing the
potential value of the catalyst system. This method constitutes
the first report of a Sc(OTf)3/Y(OTf)3-promoted switch in
enantioselectivity in the asymmetric Michael addition of 4-
substititued-5-pyrazolones to 1,4-dicarbonyl but-2-enes and
thereby expands the class of reactions amenable to asym-
metric catalysis by rare-earth metals. Further investigations
into the full reaction scope and mechanism of this catalytic
system are still in progress.
accelerated the reaction dramatically but also improved the
enantioselectivity (Table 1, entries 4–6). Other alcohols also
promoted the scandium(III)-catalyzed reaction in satisfactory
rates with improved enantioselectivity.[10] Notably, the steric
hindrance of the alcohol affected the outcome greatly and
bulkier alcohols exhibited lowered enhancement in both the
yield (MeOH > EtOH > iPrOH > tBuOH) and the enantio-
selectivity (MeOH > EtOH < iPrOH > tBuOH). Investiga-
tions into the use of EtOH as an additive in CH2Cl2 showed
that the enantioselectivity increased with the addition of
EtOH. When 5 equivalents of EtOH were added, the reaction
was accelerated and the enantioselectivity improved from
12% ee to 73% ee (Figure 1b); thus suggesting that the
alcohol would plausibly coordinate to the scandium center to
participate in the activation of the nucleophile.
Although a detailed mechanistic explanation requires
further studies, one interpretation is that the pronounced
difference in the ionic radii between scandium(III) and
yttrium(III) leads to solvent effects which could be respon-
sible for the switch in enantioselectivity. Scandium(III) has a
smaller ionic radius than yttrium(III) (0.754 ꢀ versus
0.93 ꢀ),[11] therefore the alcohol, rather than the sterically
hindered pyrazolones, would be expected to coordinate to
scandium(III) and the nitrogen atom of the enolized pyrazo-
Experimental Section
Typical experimental procedure for the Michael addition of 4-
substititued-5-pyrazolones to 1,4-dicarbonyl but-2-enes: L3 (3.1 mg,
0.0055 mmol), scandium triflate (2.5 mg, 0.005 mmol), 1a (31.7 mg,
0.12 mmol), and molecular sieves (4 ꢀ, 10 mg) were stirred in EtOH
(0.3 mL) under nitrogen at 308C for 30 min and then 2a (20.4 mg,
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Angew. Chem. Int. Ed. 2011, 50, 4928 –4932

0.10 mmol in 0.1 mL EtOH) was added. The reaction mixture was
stirred at 308C for 24 h. Then the reaction mixture was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate =
9:1!5:1) to afford the desired product 3a in 95% yield with 86% ee
and 4.6:1 d.r.
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Received: December 30, 2010
Revised: February 24, 2011
Published online: April 14, 2011
Keywords: asymmetric synthesis · homogeneous catalysis ·
.
Michael addition · nitrogen heterocycles · rare-earth metals
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25% yield, 70:30 d.r., 12 and 72% ee for the respective
diastereomers; CH3OH: 99% yield, 81:19 d.r., 80 and 63% ee
for the respective diastereomers; C2H5OH: 90% yield,
82:18 d.r., 86 and 90% ee for the respective diastereomers;
iPrOH: 80% yield, 80:20 d.r., 67 and 77% ee for the respective
diastereomers; tBuOH: 60% yield, 75:25 d.r., 60 and 73% ee for
the respective diastereomers (see the Supporting Information).
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Angew. Chem. Int. Ed. 2011, 50, 4928 –4932
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www.angewandte.org
4931

Communications
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substrate (see the Supporting Information).
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4932 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4928 –4932