Published on Web 03/24/2006
Organocatalytic Direct Michael Reaction of Ketones and Aldehydes with
β-Nitrostyrene in Brine
Nobuyuki Mase,† Kaori Watanabe,† Hidemi Yoda,† Kunihiko Takabe,*,† Fujie Tanaka,‡ and
Carlos F. Barbas III‡
Department of Molecular Science, Faculty of Engineering, Shizuoka UniVersity, 3-5-1 Johoku,
Hamamatsu 432-8561, Japan, and The Skaggs Institute for Chemical Biology and the Departments of Chemistry
and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received January 17, 2006; E-mail: tcktaka@ipc.shizuoka.ac.jp
In 1954, Gilbert Stork showed that enamines could be used in
the alkylation and acylation of aldehydes and ketones,1 and in the
years since then, enamines have been intensively studied in organic
synthesis.2 Recently, small chiral amines have become attractive
and powerful catalysts for C-C bond forming reactions.3 The
reaction, in general, is carried out by stirring a carbonyl compound
1, an amine 2, and an electrophile in conventional organic solvents,
such as DMSO, DMF, or CHCl3, in a one-pot operation (eq 1).
Removal of water is not required for the formation of enamine
intermediates that proceed to directly react with an electrophile.
While the one-pot procedure is convenient, toxic, flammable, and
volatile, organic solvent is often required in these reactions.
In our recent studies, we reported that a designed, small organic
molecule with appropriate hydrophobic groups catalyzes enantioselective, direct aldol reactions in water (eq 2).4 Our artificial
organocatalyst mimicked aldolase antibodies that act on hydrophobic organic reactants in water. Aggregation of the organocatalyst
and the reactants reduces contact with bulk water as the reaction
proceeds. Consequently, the outcome of the aldol reaction was
similar to that performed in organic solvents. To further develop
our catalyst system, we evaluated enamine-based, organocatalytic
direct asymmetric Michael reactions5 of ketones and aldehydes with
β-nitrostyrenes in bulk water and/or brine without using any organic
cosolvent. We found that yields in brine, including seawater, the
most readily available aqueous media in the world, were superior
to those in water.
Michael reactions of cyclohexanone (5a) with β-nitrostyrene (6a)
were performed in water, as shown in Table 1. L-Proline (8)
catalyzes the Michael reaction in DMSO in good yield;5 however,
our first attempt in water gave no product (Table 1, entries 1 and
2). Low conversions and yields were also observed using L-prolinol
(9) (entry 3). Diamine catalyst 10a improved the reactivity as well
as the enantioselectivity, but resulted in low yield (entries 4 and
5). Diamine catalyst 10b, bearing a hydrophobic alkyl group with
TFA, was the best catalyst of those tested in the asymmetric aldol
reaction in water;4 here, it gave Michael product 7a in moderate
†
‡
Shizuoka University.
The Scripps Research Institute.
4966
9
J. AM. CHEM. SOC. 2006, 128, 4966-4967
Table 1. Catalyst Screening in the Direct Asymmetric Michael
Reaction of Cyclohexanone (5a) with β-Nitrostyrene (6a)a
entry
catalyst
solvent
conv. (%)
yield (%)b
syn:antic
ee (%)d
1e
8
8
9
10a
10a/TFA
10a/TFA
10b
10b
10b/TFA
10b/TFA
10b/TFA
10b/TFA
10b/TFA
DMSO
H2O
H2O
H2O
H2O
brine
H2O
brine
DMSO
H2O
brine
seawater
brine
94
0 (88)f
2 (5)f
16
13
49
9 (19)f
19
76 (20)f
54
93
89
79
>95:<5
23
0
58
>99
83
>99
51
31
79
>99
>99
>99
>99
82:18
92:8
94:6
91:9
95:5
92:8
95:5
95:5
95:5
96:4
96:4
61
82
84
85
91
89
89
89
89
91
91
2
3
4
5
6
7
8
9
10
11
12
13g
a Conditions: amine catalyst (0.05 mmol), additive (if used, 0.05 mmol),
5a (1.0 mmol), and 6a (0.5 mmol) in water and/or brine (0.5 mL) at 25 °C
for 24 h with vigorous stirring. b Isolated yield. c Determined by 1H NMR
of the crude product. d Determined by chiral-phase HPLC analysis for synproduct. e See ref 5. f Recovered yield of 6a is shown in parentheses. g Donor
5a (0.5 mmol, 1.0 equiv) was used.
yield (entry 10). Despite high conversion in water, we could not
obtain the Michael product in good yield because a powdery and
insoluble solid side product was formed.
When 6a and 10a (0.1 equiv) were stirred in water and a small
amount of toluene in the absence of 5a, a quantitative amount of
polymerization products of 6a was obtained as a solid. Other studies
have indicated that amine catalysts behave as initiators of polymerization.6 We hypothesized that, if the anion intermediate derived
from the addition of the amine catalyst to 6a could be stabilized,
polymerization should be inhibited and the chemical yield should
be improved. We found that the best results were obtained when
brine was used as a solvent. Brine provided excellent yield and a
high level of diastereo- and enantioselection (entry 11). Yield and
enantioselectivity were essentially the same in seawater taken
directly from the Pacific Ocean (entry 12). In these electrolyterich aqueous solutions, the anion intermediate is readily complexed
by metal cations, and this ionic complexation presumably reduces
polymer propagation responsible for the side product.
Addition of TFA to the reaction in brine improved chemical
yields by acceleration of enamine formation (entry 8 vs 11).7 The
diamine 10b5h bearing dodecyl alkyl chains is a more suitable
catalyst for the Michael reaction in brine than is the diamine 10a
10.1021/ja060338e CCC: $33.50 © 2006 American Chemical Society
COMMUNICATIONS
Table 2. Diamine 10b/TFA-Catalyzed Michael Reactions of 5a
with Various β-Nitrostyrene 6 in Brinea
entry
Ar
1
2
3
4
5
Ph
4-MeOC6H4
2-furyl
2-naphthyl
3-NO2C6H4
product
7a
7b
7c
7d
7e
time (h)
yield (%)b
syn:antic
ee (%)d
12
20
24
48
96
93
98
94
99
57
95:5
96:4
96:4
98:2
74:26
89
83
86
97
83
a Conditions: amine catalyst 10b (0.05 mmol), TFA (0.05 mmol), 5a
(1.0 mmol), and 6a (0.5 mmol) in brine (0.5 mL) at 25 °C with vigorous
stirring. b Isolated yield. c Determined by 1H NMR of the crude product.
d Determined by chiral-phase HPLC analysis for syn-product.
Table 3. Diamine 10b/TFA-Catalyzed Michael Reactions of
Various Ketones and Aldehydes 5 with 6a in Brinea
entry
1
2
3f
4g
5
6
7
8
R1
R2
-(CH2)4-(CH2)3-CH2CH2SCH2Me
H
H
H
H
Me
H
Me
H
Me
R3
H
H
H
H
Et
Me
Et
Pr
product
7a
7f
7g
7h
7i
7j
7k
7l
time (h)
yield
(%)b
12
96
96
24
24
30
72
96
93
75
67
87
99
76
74
97
syn:antic
95:5
77:23
97:3
65:35
59:41
61:39
ee
(%)d,e
89
80
87
32
38
76
74
64
a
Conditions: amine catalyst 10b (0.05 mmol), TFA (0.05 mmol), 5
(1.0 mmol), and 6a (0.5 mmol) in brine (0.5 mL) at 25 °C with vigorous
stirring. b Isolated yield. c Determined by 1H NMR of the crude product.
d Determined by chiral-phase HPLC analysis for syn-product. e (2S)-synIsomers were obtained as a major product in entries 1-4, and (2R)-synisomers were obtained in entries 5-8. f Toluene (100 µL) was added.
g Donor (10 equiv) was used.
in terms of chemical yield (entries 6 and 11). The reaction rate in
brine is also faster than that in DMSO (entry 9 vs 11). Generally,
an excess amount of a ketone donor (10-20 equiv) is employed in
conventional organic solvents;5 however, here, an equal amount of
5a was sufficient to complete the Michael reaction in brine in 79%
yield with 91% ee (entry 13).
We propose that brine improves the chemical yield and stereoselectivity compared to reaction in organic solvent or water through
the following mechanism:8,9 A liquid organic donor 5 assembles
in brine due to hydrophobic interactions. Diamine 10b/TFA catalyst
with its hydrophobic tails and the acceptor 6 dissolve in the liquid
organic phase. Aggregation of the organic molecules excludes water
from the organic phase and drives the equilibrium toward enamine
formation. This is further facilitated by a salting-out effect. Michael
reactions occur quickly in this highly concentrated organic phase
through a transition state similar to that observed in organic solvents.
Catalyst 10b/TFA was chosen for the further study of asymmetric
Michael reactions with various nitroalkene acceptors (Table 2). The
reaction appears quite general with respect to the nature of the
aromatic Michael acceptors. Generally, excellent yields and high
stereoselectivities, ranging from 83 to 97% ee, were observed.
Next we probed the scope of the reaction with a variety of
ketones and aldehydes (Table 3). Cyclic ketones were suitable as
Michael donors, providing high diastereoselectivity as well as
enantioselectivity (entries 1-3). Addition of a small amount of
toluene (100 µL) was sufficient to facilitate the Michael reaction
of the thiopyran 5g with 6a, although both substrates are solid and
insoluble in water (entry 3). Michael products 7j-l bearing an allcarbon quaternary stereocenter5f were obtained with enantioselectivities similar to or slightly lower than those obtained in reactions
with DMSO solvent (entries 6-8). These experiments indicate that
our catalyst system in brine should be broadly applicable to the
synthesis of γ-nitro carbonyl compounds.
To study a multigram-scale synthesis, TFA (0.1 equiv) and 10b
(0.1 equiv) were stirred with 6a (10 mmol, 1.51 g) and 5a (1.2
equiv) in brine (10 mL) at 25 °C. Solid Michael product 7a
gradually formed. The mixture was stirred for 24 h, and the brine
was removed to give the crude product (99% conversion, syn:anti
) 97:3, 89% ee) that was then purified by recrystallization from
ethyl acetate to afford 7a (1.80 g, 73%, syn-isomer, >99% ee). No
extraction, washing, nor chromatography were needed to obtain
the product with excellent purity; therefore, this procedure may
afford great advantage to pharmaceutical and industrial processes.
The major product 7a generated from the 10b/TFA-catalyzed
reaction had (1′R,2S) absolute stereochemistry.5 The absolute
stereochemical results can be explained by related transition state
models previously discussed for diamine 10a/acid-catalyzed Michael
reactions in organic solvent.5f,g
In summary, we have developed a catalytic direct asymmetric
Michael reaction that can be performed in brine without addition
of organic solvents. The diamine 10b/TFA bifunctional catalyst
system demonstrated excellent reactivity, diastereoselectivity, and
enantioselectivity in brine. Further studies focusing on the full scope
of this catalyst in aqueous media and related systems are currently
under investigation and will be reported in due course.
Acknowledgment. This study was supported in part by a Grantin-Aid (No. 16550032) from Scientific Research from the Japan
Society for the Promotion of Science and The Skaggs Institute for
Chemical Biology.
Supporting Information Available: Experimental procedures and
HPLC data. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.
(2) Rappoport, Z. The Chemistry of Enamines; Wiley-VCH: Weinheim,
Germany, 1994.
(3) (a) Acc. Chem. Res. 2004, 37 (8), special issue on organocatalysis. (b)
Dalko, P. I.; Moisan, L. Angew Chem., Int. Ed. 2004, 43, 5138.
(4) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas,
C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
(5) Enamine-based Michael reaction of carbonyl compounds with β-nitrostyrenes in organic solvent. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C.
F., III. J. Am. Chem. Soc. 2001, 123, 5260. (b) Betancort, J. M.; Sakthivel,
K.; Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42,
4441. (c) Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737.
(d) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (e) Enders, D.;
Seki, A. Synlett 2002, 26. (f) Mase, N.; Thayumanavan, R.; Tanaka, F.;
Barbas, C. F., III. Org. Lett. 2004, 6, 2527. (g) Ishii, T.; Fujioka, S.;
Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558. (h)
Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas,
C. F., III. Synthesis 2004, 1509. (i) Cobb, A. J. A.; Longbottom, D. A.;
Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808. (j) Wang, W.;
Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (k) Hayashi, Y.;
Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212.
(l) Terakado, D.; Takano, M.; Oriyama, T. Chem. Lett. 2005, 34, 962.
(m) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460. (n) Kotrusz, P.;
Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem. 2004, 1577.
(6) Carter, M. E.; Nash, J. L., Jr.; Drueke, J. W., Jr.; Schwietert, J. W.; Butler,
G. B. J. Polym. Sci., Polym. Chem. Ed. 1978, 16, 937 and references
therein.
(7) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369.
(8) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; WileyVCH: Weinheim, Germany, 1997.
(9) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159. (b) Mase, N.; Ohno, T.;
Morimoto, H.; Nitta, F.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2005,
46, 3213.
JA060338E
J. AM. CHEM. SOC.
9
VOL. 128, NO. 15, 2006 4967
Supporting Information
Organocatalytic direct Michael reaction of ketones and aldehydes with β-nitrostyrene in brine
Nobuyuki Mase,† Kaori Watanabe,† Hidemi Yoda,† Kunihiko Takabe,*,†
Fujie Tanaka,‡ Carlos F. Barbas III‡
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561,
Japan and The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
tcktaka@ipc.shizuoka.ac.jp
† Shizuoka University, ‡The Scripps Research Institute
General. Chemicals and solvents were either purchased from commercial suppliers or purified by standard techniques.
For thin-layer chromatography (TLC), silica gel plates (Merck 60 F254) were used and compounds were visualized by
irradiation with UV light and/or by treatment with a solution of phosphomolybdic acid in ethanol followed by heating.
Flash column chromatography was performed using KANTO silica gel 60N (particle size 63-210 μm). 1H NMR and 13C
NMR spectra were recorded on JEOL JNM-AL spectrometer at ambient temperature. Chemical shifts are given in δ
relative to tetramethylsilane (TMS), the coupling constants J are given in Hz. The spectra were recorded in CDCl3 as
solvent at ambient temperature. TMS served as internal standard (δ = 0 ppm) for 1H NMR and CDCl3 was used as internal
standard (δ = 77.0) for 13C NMR. Infrared spectra were recorded on a SHIMADZU FTIR-8200A spectrometer. Mass
spectra were recorded on a SHIMADZU GCMS-QP5050 spectrometer. HPLC was carried out using a SHIMADZU
LC-10AD intelligent pump, SPD-10A UV detector, and C-R8A integrator. All Michael reactions were carried out under
an atmosphere of air in a closed system.
Organic substrates cyclohexanone (5a, 108-94-1), cyclopentanone (5f, 120-92-3), tetrahydrothiopyran-4-one (5g,
1072-72-6), acetone (5h, 67-64-1), n-butyraldehyde (5i, 123-72-8), isobutylaldehyde (5j, 78-84-2), 2-methylbutyraldehyde
(5k, 96-17-3), 2-methylvaleraldehyde (5l, 123-15-9), trans-β-nitrostyrene (6a, 5153-67-3), L-proline (8, 147-85-3),
L-prolinol (9, 23356-96-9), and (S)-1-(2-pyrrolidinylmethyl)pyrrolidine (10a, 51207-66-0) were obtained from commercial
sources and were used without any purification. Michael acceptors, such as (E)-1-methoxy-4-(2-nitrovinyl)benzene (6b,
5576-97-6), (E)-2-(2-nitrovinyl)furan (6c, 32782-45-9), (E)-2-(2-nitrovinyl)naphthalene (6d, 37629-37-1), and
(E)-1-nitro-3-(2-nitrovinyl)benzene (6e, 34441-47-9) were prepared by the methods previously described.1 Catalyst 10b
was prepared by the methods previously described.2 Michael adducts 7 are all known compounds. Seawater was taken
from Pacific Ocean at Nakatajima Dune in Hamamatsu city and used without any purification.
A representative procedure for the Michael reaction using the diamine/acid bifunctional catalyst in brine was the following
procedure for the reaction of cyclohexanone (5a) with trans-β-nitrostyrene (6a) in brine using the diamine 10b/TFA
bifunctional catalyst: To a mixture of diamine 10b (19.0 mg, 0.05 mmol) in brine (0.5 mL) trifluoroacetic acid (3.9 μL,
0.05 mmol) was added at 25 °C under air in a closed system. The reaction mixture was stirred for 3 min, then
cyclohexanone (5a, 104 μL, 1.0 mmol) and trans-β-nitrostyrene (6a, 75.3 mg, 0.5 mmol) were added. The reaction
mixture was stirred for 24 h. Brine was removed by decantation. If extraction was needed, brine phase was extracted
with ethyl acetate (3 x 1 mL) and organic extracts were dried over Na2SO4. Diastereoselectivity and conversion were
determined by 1H NMR analysis of the crude Michael product after short column chromatography purification (SiO2, 1 g) to
remove the catalyst. Purification by flash column chromatography (silica gel, hexane/AcOEt) gave the Michael product 7a
as a colorless solid. The enantiomeric excess (ee) of 7a was determined by chiral HPLC analysis.
References
1.
Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5 (14), 2559-2561.
2.
(a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III Synthesis 2004, (9), 1509-1521.
(b) Betancort, J. M.; Barbas, C. F., III Org. Lett. 2001, 3 (23), 3737-3740. (c) Asami, M. Bull. Chem. Soc. Jpn.
1990, 63 (3), 721-727.
S1
1
No.
7a
structure
CAS No.
O
NO2
H NMR (CDCl3, -CHAr, δ)a
HPLCb
Flow rate
(mL/min)
syn (min)
anti (min)
80:20
0.5
19.981 (2R, 1’S)
28.557 (2S, 1’R)
-
AD-H
80:20
0.5
18.467 (2R, 1’S)
22.583 (2S, 1’R)
20.333
23.408
4.18
AD-H
95:5
0.5
30.300 (2S, 1’R)
37.617 (2R, 1’S)
22.183
36.150
3.95
4.18
AS-H
50:50
0.7
8.779 (2R, 1’S)
14.907 (2S, 1’R)
12.066
12.381
3.95
4.22
AD-H
90:10
0.5
42.650 (2R, 1’S)
51.667 (2S, 1’R)
48.350
62.883
column Eluentc
syn
anti
(S,S)-84025-87-6
(R,R)-154568-74-8
(S,R)-84025-83-2
(R,S)-84025-84-3
relative-(S,S)-51262-17-0
relative-(R,S)-51262-18-1
racemic-4591-64-4
3.78
4.02
AS-H
(S,R)-233257-09-5
relative-(S,S)-99391-23-8
relative-(R,S)-67861-09-0
racemic-342819-96-9
3.71
3.91
(S,S)-256338-66-6
3.97
(S,R)-748788-76-3
(S,R)-83976-47-0
OMe
7b
O
NO2
O
7c
7d
O
NO2
O
NO2
NO2
7e
O
NO2
S2
O
7f
NO2
O
7g
NO2
(R,R)-359876-15-6
(S,R)-359876-14-5
(R,S)-475294-96-3
relative-(S,S)-97954-71-7
relative-(R,S)-67861-25-0
racemic-4591-65-5
3.70
3.83
AS-H
80:20
0.5
21.858 (2R, 1’S)
30.525 (2S, 1’R)
19.575
23.492
(S,S)-360062-52-8
3.98
4.15
AS-H
50:50
0.5
16.918 (2R, 1’S)
20.760 (2S, 1’R)
-
AS-H
80:20
0.5
S
7h
O
NO2
(S)-475589-23-2
(R)-361204-86-6
chiral-(+)-142232-08-4
chiral-(-)-122348-55-4
racemic-1574-86-3
4.00
1
No.
structure
CAS No.
O
7i
NO2
H
O
7j
NO2
H
O
7k
H
NO2
(S,R)-475294-88-3
(R,S)-384354-59-0
relative-(R,S)-697745-79-2
racemic-802552-10-9
H NMR (CDCl3, -CHO, δ)a
(R,R)-748807-19-4
HPLCb
Flow rate
(mL/min)
syn (min)
anti (min)
99:1
1.0
23.733 (2R, 3R)
28.233 (2S, 3S)
25.567
27.017
AS-H
90:10
0.5
AD-H
97:3
0.5
syn
anti
column Eluentc
9.69
9.46
AD-H
(R)-748807-16-1
racemic-93086-29-4
9.54
9.52
9.51
S3
27.561 (R)
36.247 (S)
22.500 (S)
23.467 (R)
23.600 (2R, 3R)
26.133 (2S, 3S)
25.358
27.142
O
7l
H
NO2
(R,R)-748807-20-7
9.52
9.51
a
OD-H
Diastereoselectivities were determined by peak integration of -CHAr for 7a-7h and of -CHO for 7i-7l.
eluent.
S4
95:5
b
λ = 254 nm.
1.0
c
27.850 (2R, 3R)
40.942 (2S, 3S)
21.650
43.517
Hexane and 2-propanol were used as an