Highly enantioselective water-compatible organocatalyst for Michael reaction of ketones to nitroolefins

Article abstract of DOI:10.1021/ol070082x

(Chemical Equation Presented) A chiral diamine was found to catalyze enantioselective addition of ketones to nitroolefins in aqueous/saline/organic media. The products were obtained with excellent diastereoselectivities (syn/anti = 99:1) and enantioselect

Full text of DOI:10.1021/ol070082x

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1117-1119
Highly Enantioselective
Water-Compatible Organocatalyst for
Michael Reaction of Ketones to
Nitroolefins
Vishnumaya and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, India-208 016
Vinodks@iitk.ac.in
Received January 11, 2007
ABSTRACT
A chiral diamine was found to catalyze enantioselective addition of ketones to nitroolefins in aqueous/saline/organic media. The products
were obtained with excellent diastereoselectivities (syn/anti
a mild acid.
) 99:1) and enantioselectivities up to 99%. The reaction could be facilitated using
Enantioselective reactions catalyzed by small organic mol-
ecules (asymmetric organocatalysis)1 have attracted attention
from a large number of organic chemists working in the area
of asymmetric synthesis. This is mainly due to environmental
concern where use of metals in organic reactions could be
avoided. It would be a win-win situation from a green
chemistry perspective if the above reaction could be carried
out in aqueous media.2 In our recent study, we reported a
new organocatalyst for enantioselective direct aldol reaction.3
While the work in the area with respect to environmentally
clean and friendly conditions is still in progress, we got
interested in the organocatalytic direct asymmetric Michael
reaction of ketones with commonly used acceptors such as
â-nitrostyrene for which some excellent papers have appeared
using chiral amines as catalysts.4 The reaction is supposed
to proceed via an enamine intermediate.1c Although most of
the reports deal with reactions in organic solvents, there are
only two papers where aqueous medium has been used for
the Michael reaction.4b,c
To the best of our knowledge, there is no universal catalyst
which gives high enantioselectivity for this reaction, both
in the presence of water and also in a wide range of organic
solvents.5 In this paper, we disclose such a catalyst which is
compatible with water as well as with various conventional
organic solvents providing high enantioselectivity and di-
astereoselectivity.
(1) (a) For a special issue on asymmetric organocatalysis, see: Acc.
Chem. Res. 2004, 37, 487. (b) Review: Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138. (c) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719. (d) Berkessel, A.; Groger, H. Asymmetric Organocatalysis:
From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005.
(2) For reviews on organic reactions in aqueous media, see: (a) Brogan,
A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45,
8100. (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (c) Li, C.-J.
Chem. ReV. 2005, 105, 3095. (d) Lindstrom, U. M. Chem. ReV. 2002, 102,
2751. (e) Li, C.-J.; Chan, T.-H. Organic Reaction in Aqueous Media; Wiley-
VCH: Weinheim, Germany, 1997.
The diamine 1 (Scheme 1), having substituted nonpolar
dibenzylic type groups in the tertiary amine part, was
conceptualized based on an intuition that the binaphthyl
group would enhance the hydrophobic hydration when the
reaction is done in aqueous medium and should also work
(3) Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006,
8, 4097.
10.1021/ol070082x CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/23/2007

observed that, by changing the chirality of the binaphthyl
part as in 1b, the results were equally good with enantio-
selectivity of 94% (entry 2). It appears that chirality of the
binaphthyl group is not playing much of a role because 88%
ee was obtained for the same reaction by using 1c, a
diastereomeric mixture of 1a and 1b (1:1) (entry 3).
Scheme 1. Synthesis of Chiral Ligands
The diamine 1a was taken as the catalyst of choice and
evaluated for the same reaction in different solvents with or
without TFA (Table 2). Initially, the reaction was done by
Table 2. Screening of Solventsa
in organic medium due to the aromatic nature of the
binaphthyl part. The coupling of L-proline with a chiral (SS
or RR) amine A6 under usual conditions gave an amide which
was converted into the final diamine 1a and 1b, respectively,
in two steps as described in Scheme 1. The preliminary
experiments were conducted by taking cyclohexanone as a
donor and â-nitrostyrene as an acceptor using 10 mol % of
the diamine 1 and TFA in brine (Table 1). The diamine
time
(h)
yield
(%)
eec (%)
syn
entry
solvent
DMSO
DMF
CH3CN
CHCl3
DCM
EtOH
MeOH
IPA
THF
toluene
water
brine
water
brine
THF/water
THF/brine
DMSO/water
DMSO/brine
syn/antib
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
16
18
15
18
18
20
20
15
15
35
12
16
10
10
16
10
17
12
77
65
87
48
80
77
77
90
94
40
90
95
95
98
91
92
88
88
94:6
94:6
98:2
97:3
98:2
96:4
95:5
98:2
97:3
94:6
94:6
94:6
97:3
94:6
95:5
98:2
98:2
95:5
62
85
90
91
92
88
89
92
90
66
90d
91d
90
96
92
86
91
92
Table 1. Catalytic Screening of Ligandsa
time
(h)
yield
(%)
eec (%)
syn
entry
catalyst
syn/antib
1
2
3
1a
1b
1c
10
10
12
98
96
85
94:6
97:3
95:5
96
94
88
a 10 mol % of 1 and TFA used. b Diastereoselectivities were determined
by 1H NMR analysis of the products. c The ee’s were determined by HPLC
using a Chiralpak AS-H column.
a 10 mol % of 1a and TFA used unless stated otherwise. b Diastereo-
1
selectivities were determined by H NMR analysis of the products. c The
ee’s were determined by HPLC using a Chiralpak AS-H column. d Reactions
were carried out in the absence of TFA.
(S,SS)-1a gave the best result: 98% yield and 96% ee (entry
1) for the syn diastereomer (dr ) 94:6). Interestingly, it was
using 10 mol % of 1a and TFA in a variety of organic
solvents (entries 1-10). The most polar aprotic solvent, such
as DMSO, and nonpolar aprotic solvent, such as toluene,
gave poor enantioselectivity: 62 and 66% ee, respectively
(entries 1 and 10). MeCN, CHCl3, and CH2Cl2 gave excellent
diastereoselectivity (syn/anti ) 98:2) and high enantio-
selectivity (90-92% ee). Protic solvents such as MeOH,
EtOH, and i-PrOH gave similar results (entries 6-8). When
the medium was changed from organic to aqueous, the
enantioselectivity remained in the same range. For example,
when the Michael reaction was done in water, the enantio-
selectivity was 90% and TFA did not have any role to play
on the results (entries 11 and 13). However, in brine, the
enantioselectivity could be increased from 91 to 96% using
TFA (entries 12 and 14). A combination of organic solvent
and water also gave high enantioselectivities in the reaction
(entries 15-18).
(4) (a) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460. (b) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 4966. (c) Zu, L.; Wang, J.; Li, H.; Wang, W. Org.
Lett. 2006, 8, 3077. (d) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006,
128, 9624. (e) Zhu, M.-K.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-
Z. Tetrahedron: Asymmetry 2006, 17, 491. (f) Luo, S.; Mi, X.; Zhang, L.;
Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093. (g)
Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.;
Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (h) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (i)
Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (j)
Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.;
Huthmacher, K. Eur. J. Org. Chem. 2005, 4995. (k) Hayashi, Y.; Gotoh,
T.; Hayasji, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (l)
Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
(m) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
(n) Wang, J.; Li, H.; Duan, W.-H.; Zu, L.-S.; Wang, W. Org. Lett. 2005,
7, 4713. (o) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
126, 9906. (p) Ishii, T.; Fiujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am.
Chem. Soc. 2004, 126, 9558. (q) Cobb, A. J. A.; Longbottom, D. A.; Shaw,
D. M.; Ley, S. V. Chem. Commun. 2004, 1808. (r) Mase, N.; Thayumana-
van, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527. (s) Kotrusz,
P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem. 2004, 1577.
(t) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559.
(u) Tian, S.; Ran, H.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900. (v)
Enders, D.; Seki, A. Synlett 2002, 26. (w) List, B.; Pojarliev, P.; Martin,
H. J. Org. Lett. 2001, 3, 2423.
(5) For a catalyst that works both in isopropanol and water, see ref 4c.
(6) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820.
1118
Org. Lett., Vol. 9, No. 6, 2007

by the binaphthyl group in the reaction.7 This helps solubilize
the organic donor and acceptor molecule in a small volume.
There are several unanswered questions about an appropriate
transition state model for this reaction, but the absolute
stereochemical outcome can be explained by a model based
on the literature.4b,p,8
For the enantioselective Michael reaction with cyclohex-
anone, several substituted â-nitrostyrenes were evaluated
under the best condition, and the results are summarized in
Table 4. In most of the cases, we got high diastereoselectivity
(>95%) and enantioselectivity (90-99% ee) for the syn
adduct. The reaction was also facile as can be depicted by
the reaction time and chemical yield in almost all of the
substrates (Table 4).
Table 3. Screening of Protonic Acidsa
yield
eec (%)
syn
entry
acid
(%)
syn/antib
1
2
3
4
5
6
7
8
9
TFA
p-TSA
CSA
AcOH
DNBSA
98
67
75
85
90
85
87
80
89
94:6
94:6
98:2
97:3
98:2
95:5
94:6
98:2
97:3
96
92
91
92
93
92
92
92
93
C6H5COOH
p-NO2C6H4COOH
p-OMeC6H4COOH
n-butyric acid
The Michael reaction was evaluated with other ketones
as well (Table 5). In most of the cases, we got high
enantioselectivity and diastereoselectivity.
a 10 mol % of 1a and an acid was used. b Diastereoselectivities were
determined by 1H NMR analysis of the products. c The ee’s were determined
by HPLC using a Chiralpak AS-H column.
Table 5. Screening of Different Ketones with â-Nitrostyrenesa
Since we had 96% enantioselectivity in doing the Michael
reaction in brine by using 10 mol % of TFA, other acids
were also evaluated with the hope to improve the enantio-
selectivity. Unfortunately, the results were unaffected (Table
3).
time yield
eec (%)
syn
entry
ketone
acetone
cyclopentanone
-CH2SCH2-
-CH2OCH2-
(h)
(%)
syn/antib
High yield and enantioselectivity in aqueous/brine medium
can be explained by the hydrophobic environment created
1
2
3
4
5
06
20
18
16
20
89
78
92
95
90
-
16
77:23
96:4
93:7
96:4
75
92d
93
89d
Table 4. Screening of Different Nitroolefins with
Cyclohexanonea
6
20
88
95:5
88d
a 10 mol % of 1a and TFA used. b Diastereoselectivities were determined
by 1H NMR analysis of the products. c The ee’s were determined by HPLC
using chiral columns. d 100 µL of THF was added for solid carbonyls.
time yield
(h)
eec (%)
syn
entry
R
(%) syn/antib
1
2
3
4
5
6
7
8
9
Ph
10
19
12
22
12
7
98
75
78
75
85
75
70
92
80
91
90
95
90
80
75
86
78
70
71
88
94:6
94:6
98:2
94:6
95:5
95:5
94:6
99:1
97:3
94:6
94:6
94:6
97:3
99:1
96:4
98:2
98:2
95:5
95:5
95:5
96
94
96
95
96
90
90
99
86
98
93
92d
88d
97
96
90
95
97
82d
87
In summary, we have developed a highly efficient water-
compatible diamine organocatalyst, which has been success-
fully applied to the asymmetric Michael reaction of ketones
with both aryl and alkyl nitroolefins. The added advantage
of the catalyst is that it gives high enantioselectivities in
organic solvents as well. This broadens the scope of the
reaction. Further investigation on the application of this
organocatalyst in asymmetric catalysis is still in progress.
4-Cl-C6H4
2-Cl-C6H4
3-F-C6H4
4-F-C6H4
2-NO2-C6H4
4-Br-C6H4
18
7
3,4-methylenedioxy-C6H3
4-iPr-C6H4
30
12
18
13
18
18
18
20
8
10 2-Cl-6-F-C6H3
11 2,3-DiF-C6H3
12 2-MeO-C6H4
13 4-MeO-C6H4
14 2-furyl
Acknowledgment. V.K.S. thanks DST, India, for a
Ramanna fellowship. V. thanks CSIR for a senior research
fellowship.
15 2-thienyl
16 2-naphthyl
17 4-CN-C6H4
18 3-Me-C6H4
19 4-CF3O-C6H4
20 cyclohexyl
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
18
24
30
OL070082X
a 10 mol % of 1a and TFA used. b Diastereoselectivities were determined
by 1H NMR analysis of the products. c The ee’s were determined by HPLC
using chiral columns. d 20 mol % of catalyst used.
(7) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315.
(8) Seebach, D.; Golinski, J. HelV. Chim. Acta 1981, 64, 1413.
Org. Lett., Vol. 9, No. 6, 2007
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