Asymmetric conjugate addition of malonates to enones using Perfluorobutanesulfonamide organocatalyst

Article abstract of DOI:10.1246/cl.130575

Perfluorobutanesulfonamide organocatalyst 4 efficiently promotes asymmetric conjugate additions of malonates to α,β-unsaturated ketones to afford the corresponding adducts with excellent enantioselectivities (up to 99% ee).

Full text of DOI:10.1246/cl.130575

doi:10.1246/cl.130575
Published on the web October 5, 2013
1151
Asymmetric Conjugate Addition of Malonates to Enones
Using Perfluorobutanesulfonamide Organocatalyst
Yuji Kamito,1 Akira Masuda,1 Hiroki Yuasa,1 Norihiro Tada,1 Akichika Itoh,1 Yuji Koseki,2 and Tsuyoshi Miura*2
1Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196
2Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392
(Received June 20, 2013; CL-130575; E-mail: tmiura@toyaku.ac.jp)
Perfluorobutanesulfonamide organocatalyst
4
efficiently
efficient conjugate additions of malonates to ¡,¢-unsaturated
ketones using a perfluorobutanesulfonamide organocatalyst 4.
We examined ¢-aminosulfonamide organocatalysts 1-4,
which we previously reported for direct aldol reactions7 and
conjugate additions to vinyl sulfone,8 as shown in Table 1. With
the exception of 1 among these, excellent enantioselectivities
were obtained (Entries 1-4). When using perfluorobutanesulfon-
amide 4, the highest enantioselectivity was obtained. Therefore,
we considered that 4 is the most suitable catalyst for the
conjugate addition of 6a to 5a.
A study of the optimal solvent conditions for the asym-
metric conjugate addition using 4 is shown in Table 2. The
conjugate addition reactions were conducted with 6a and 5a as
test reactants in the presence of a catalytic amount of 4 at room
temperature. Among the reaction solvents examined, cyclohex-
ane was the most suitable (Entries 1-7). Furthermore, we
examined the amount of catalyst loading necessary for optimal
promotes asymmetric conjugate additions of malonates to ¡,¢-
unsaturated ketones to afford the corresponding adducts with
excellent enantioselectivities (up to 99% ee).
The catalytic enantioselective Michael addition of carbon
nucleophiles to ¡,¢-unsaturated carbonyl compounds is one
of the most fundamental and important carbon-carbon bond-
forming methods to synthesize useful chiral building blocks.1,2
In particular, metal-free asymmetric Michael additions using
organocatalysts have been intensively investigated over the past
decade from the perspective of green chemistry.2 Malonates are
good Michael donors in organocatalysis because they can be
easily converted to enolates under mild conditions by the two
electron-withdrawing esters. Moreover, versatile products ob-
tained by the reactions of malonates with ¡,¢-unsaturated
ketones can be readily converted to the corresponding ¤-
ketoesters as useful synthetic building blocks after decarbox-
ylation.3,4 Successful conjugate additions of malonates to ¡,¢-
unsaturated ketones using organocatalysts have been reported;4,5
however, the development of organocatalysts that can catalyze
the Michael addition of malonates to ¡,¢-unsaturated enones
more effectively is desirable. Recently, Du and co-workers
reported the Michael addition of malonates to ¡,¢-unsaturated
enones using p-toluenesulfonamide organocatalyst;6 however,
their method requires 0.2 equiv of catalyst loading and long
reaction times (72 h) to obtain adduct 7aa from dibenzyl
malonate (6a) and (E)-4-phenylbut-3-en-2-one (5a).
On the other hand, we have reported that perfluoroalkane-
sulfonamide organocatalysts such as 1 and 2 (Figure 1), which
are easily prepared from L-phenylalanine, are excellent organo-
catalysts for a direct asymmetric aldol reaction.7 In addition, we
have recently reported the stereoselective construction of all-
carbon quaternary centers by asymmetric conjugate additions of
branched aldehydes to vinyl sulfone using organocatalysts 3 and
4 derived from L-valine.8 To further demonstrate the effective-
ness of perfluoroalkanesulfonamide organocatalysts derived
from L-phenylalanine or L-valine, we attempted additional
applications for other types of asymmetric conjugate additions
using organocatalysts 1-4. Herein, we would like to report the
Table 1. Selection of organocatalysts
CO2Bn
catalyst
(0.1 equiv)
O
BnO2C
CO2Bn
BnO2C
+
Ph
6a
Ph
7aa
O
CH2Cl2, r.t., 24 h
5a
(2.0 equiv)
Entry
Catalyst
Yielda/%
%eeb
1
2
3
4
1
2
3
4
8
43
53
38
49
96
97
98
b
aIsolated yield. Determined by HPLC analysis.
Table 2. Optimization of reaction conditions
CO2Bn
H2N
NHSO2C4F9
O
BnO2C
CO2Bn
4
BnO2C
+
Ph
6a
(2 equiv)
Ph
7aa
O
solvent, r.t.
5a
Entry Solvent
4/equiv Time/h Yielda/% %eeb
1
2
3
4
5
6
7
8
9
MeOH
MeCN
EtOAc
Et2O
CH2Cl2
hexane
cyclohexane
cyclohexane
cyclohexane
b
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.01
24
24
24
24
24
24
24
72
136
64
43
34
74
38
89
96
88
35
76
91
88
98
98
97
98
97
98
Ph
H2N
NHR1
R2HN
NHR1
1: R1 = SO2CF3, R2 = H
2: R1 = H, R2 = SO2CF3
3: R1 = SO2CF3
4: R1 = SO2C4F9
aIsolated yield. Determined by HPLC analysis.
Figure 1. Structure of organocatalysts.
Chem. Lett. 2013, 42, 1151-1153
© 2013 The Chemical Society of Japan
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1152
Table 3. Conjugate additions using organocatalyst 4
H2N
4 (0.1 equiv)
cyclohexane, r.t.
NHSO2C4F9
O
Malonate
Product
7
R
R'
6
(2 equiv)
5
%eeb
98
Entry
1
Enone
Malonate
Time/h
Product
Yielda/%
96
BnO2C
CO2Bn
O
BnO2C
CO2Bn
24
48
6a
6a
O
7aa
5a
5b
BnO2C
CO2Bn
O
BnO2C
CO2Bn
2
3
4
5
6
85
88
91
94
77
98
94
97
99
94
Br
Br
O
7ba
O
BnO2C
CO2Bn
BnO2C
CO2Bn
96
48
6a
6a
O2N
5c
O2N
O
7ca
O
BnO2C
CO2Bn
BnO2C
CO2Bn
Me
5d
5e
Me
O
7da
O
BnO2C
CO2Bn
BnO2C
CO2Bn
120
88
6a
6a
MeO
MeO
O
7ea
BnO2C
CO2Bn
O
BnO2C
CO2Bn
O
7fa
5f
BnO2C
CO2Bn
O
BnO2C
CO2Bn
7
144
14
99
6a
6b
O
5g
7ga
MeO2C
CO2Me
O
MeO2C
CO2Me
8
9
72
94
55
60
34
90
96
99
5a
5a
O
7ab
EtO2C
CO2Et
O
O
EtO2C
CO2Et
6c
O
7ac
iPrO2C
CO2iPr
iPrO2C
CO2iPr
10
144
6d
O
5a
7ad
b
aIsolated yield. Determined by HPLC analysis.
Chem. Lett. 2013, 42, 1151-1153
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1153
conditions. High enantioselectivities were retained, although a
prolonged reaction time and lower yield were observed when the
catalyst loading was lowered to 0.05 and 0.01 equiv (Entries 8
and 9). Therefore, the optimal conditions were determined to be
0.1 equiv of 4 in cyclohexane at room temperature (Entry 7).
With these optimal conditions in hand, the scope and
limitations of the conjugate addition of malonate 6 to ¡,¢-
unsaturated ketones 5 were examined (Table 3).9 We selected
bromo and nitro substituents as representative electron-with-
drawing groups on the benzene ring and methyl and methoxy
substituents as the electron-donating groups. The reactions of
substituted enones 5b-5e with 6a smoothly proceeded to give
the corresponding adducts in high yields with excellent
enantioselectivities (Entries 2-5). Moreover, we examined the
reaction of 6a with enone 5f possessing a naphthalene skeleton;
the corresponding adduct 7fa was obtained with 94% ee
(Entry 6). The reaction of chalcone 5g as an inactive substrate6
provided the addition product 7ga in only 14% yield, although
excellent stereoselectivity was obtained (Entry 7). Other malo-
nates such as dimethyl malonate 6b, diethyl malonate 6c, and
diisopropyl malonate 6d also reacted with 5a to afford the
corresponding adducts (7ab, 7ac, and 7ad, respectively) with
high enantioselectivities (90-99% ee), although the yields were
only low to good (Entries 8-10). The stereochemistry of the
addition products 7 obtained using 4 was determined by
comparing them with the reported chiral-phase HPLC retention
times and optical rotation data.6
We propose that the conjugate addition of malonates to
enones using 4 proceeds via the following mechanism. The
primary amino group of 4 condenses with 5 to generate iminium
intermediates. Then, the acidic protons of the sulfonamide group
successfully interact with the oxygen of 6 to direct the approach
of malonates to the iminium intermediates. This ultimately
affords the corresponding addition products with high stereo-
selectivity. We speculate that the acidity of the N-H groups is
enhanced by the strong electron-withdrawing effect of the
perfluorobutyl group, enabling them to strongly coordinate to the
malonates and stabilize the rigid transition states during the
conjugate addition.
2
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Roca-Lopez, D. Sadaba, I. Delso, R. P. Herrera, T. Tejero, P.
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3
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6
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C. Luo, Y. Jin, D.-M. Du, Org. Biomol. Chem. 2012, 10,
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T. Miura, M. Ina, K. Imai, K. Nakashima, A. Masuda, N.
Tada, N. Imai, A. Itoh, Synlett 2011, 410. d) T. Miura, M.
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8
9
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A typical procedure for the conjugate additions using 4 is as
follows: Dibenzyl malonate (6a, 102 ¯L, 0.410 mmol) was
added to a solution of 5a (30.0 mg, 0.205 mmol) and
organocatalyst 4 (8.1 mg, 0.021 mmol) in 1.0 mL of cyclo-
hexane at room temperature. After stirring at room temper-
ature for 24 h, the reaction mixture was directly purified by
flash column chromatography on silica gel with a 4:1
mixture of hexane and AcOEt to afford the pure 7aa
In conclusion, sulfonamide organocatalyst 4, which is a
simple structure, efficiently catalyzes the conjugate addition of
dibenzyl malonate (6a) to ¡,¢-unsaturated ketones 5 at room
temperature to afford the corresponding addition products 7 in
high yields with excellent enantioselectivities. Furthermore,
application of this catalyst in the synthesis of bioactive
compounds is currently being investigated in our laboratory.
1
(86.7 mg, 96%) as a colorless powder. H NMR (400 MHz,
References and Notes
CDCl3): ¤ 1.95 (s, 3H), 2.88 (d, J = 6.9 Hz, 2H), 3.82 (d,
J = 9.7 Hz, 1H), 4.00 (dt, J = 9.7, 6.9 Hz, 1H), 4.89 (s, 2H),
5.11 (d, J = 12.3 Hz, 1H), 5.15 (d, J = 12.3 Hz, 1H), 7.04-
7.07 (m, 2H), 7.16-7.33 (m, 13H); 13C NMR (100 MHz,
CDCl3): ¤ 30.15, 40.44, 47.05, 57.30, 67.06, 67.24, 127.21,
128.05, 128.11, 128.18, 128.22, 128.36, 128.39, 128.52,
135.01, 135.13, 140.24, 167.33, 167.81, 205.79.
1
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Chem. Lett. 2013, 42, 1151-1153
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/