Cyclodextrins (CDs) are macrocyclic oligosaccharides pos-
sessing hydrophobic cavities that bind substrates selectively via
noncovalent interactions.11 Native ꢀ-CD has been employed
as a catalyst for thiol12 and aza-Michael addition13 in water
medium with poor chiral induction. Chemical modification of
cyclodextrins is expected to improve the enantioselectivity in
asymmetric catalysis,14a and in chiral NMR analysis.14b Per-
amino-CDs are homogeneous CD derivatives modified by
persubstitution at the primary face with amino pendant groups,
which display combined hydrophobic and electrostatic bindings
of guest molecules relative to native CDs. They are employed
as biomimetic catalysts for Kemp elimination,15a depro-
tonation,15b and chiral recognition.15c Amino catalysts are also
receiving greater attention in asymmetric Michael addition.16
In our group, per-6-amino-ꢀ-cyclodextrin (per-6-ABCD, 1) is
used extensively as a supramolecular chiral host and a base
catalyst for Cu-catalyzed N-arylation,17a for Michael addition
of nitromethane and thiols to chalcones,17b and for the synthesis
of pyranopyrazole derivatives under solvent-free conditions at
room temperature.17c A novel, colorimetric, and ratiometric
sensor is also developed for transition-metal cations Fe3+ and
Ru3+ in water,17d using per-6-ABCD as a supramolecular host
and p-nitrophenol as a spectroscopic probe. In the present work,
we have successfully employed per-6-ABCD (1) as a chiral
base and a host for addition of nitromethane (3)/nitroethane (5)
to substituted aldehydes in ACN/water (1:1 v/v) medium at -20
°C with <99% ee. It is also interesting to note that the promoter
can be recovered and reused several times.
Table 1. Enantioselective Henry Reaction of 2b with 3 under
Various Reaction Conditionsa
temp
(°C)
yieldc
(%)
entry
medium
ratio of 1:2b
% eed
1
2
3
4
5
6
7
8
9
water (ꢀ-CD)
water (ꢀ-CD)
water
methanol
DMF
ACN
methanol/water
DMF/water
ACN/water
1:1e
1:1f
1:1
1:1
1:1
1:1
1:1
1:1
1:1
rt
rt (4 °C)
78 (76) 1.2 (1.3)
rt
99
99
99
99
99
99
99
65
28
34
60
56
60
88
rt
rt
rt
rt
rt
rt
-5, -10,
99, 99, 89, 92,
10 ACN/water
1:1
1:1g
-15, -20 99, 99 94, 99
11 ACN/water
12 ACN/water
13 ACN/water
14 ACN/water
15 ACN/water
16 ACN/water
-20
-20
-20
-20
-20
-20
96
88
90
98
99
99
22
62
71
90
99
99
0.25:1
0.50:1
0.75:1
1:1
2:1
a All reactions were carried out on a 0.1 mmol scale with 0.1 mmol of
per-6-ABCD, 0.1 mmol of aldehyde, and 0.1 mmol of nitromethane in ACN/
H2O (1:1 v/v) mixture at -20 °C for 7 h, unless otherwise noted. b Mole
ratio. c Isolated yield. d Determined by HPLC analysis. e Mole ratio of
ꢀ-CD/aldehyde. f Mole ratio of ꢀ-CD/aldehyde and triethylamine as the
external base. g Mole ratio of mono-6-ABCD/aldehyde.
The potential of per-6-ABCD (1) is optimized in an
enantioselective Henry reaction using p-nitrobenzaldehyde
(2b) and nitromethane (3) as test substrates, and the results
are discussed in Table 1. When carried out in native
ꢀ-cyclodextrin in water, there is no reaction (entry 1). When
triethylamine is employed as an external base along with
native ꢀ-CD, though good conversion is observed, the
enantiomeric excess is very poor at room temperature (ee
of 1.2%) and 4 °C (ee of 1.3%) (entry 2). On the other hand,
per-6-ABCD (1) effectively promotes Henry reaction with
quantitative yield but with only 65% enantioselectivity in
7 h at room temperature (entry 3).
Influence of other experimental parameters such as solvent,
temperature, and amount of per-6-ABCD (1) are also
optimized. Among the different solvents screened, ACN
shows quantitative yield and moderate enantiomeric excess
when compared to other solvents such as water, methanol,
and DMF (entries 3-6). Among the mixture of solvents,
complete conversion and good enantiomeric excess are
achieved in ACN/water at room temperature (entries 7-9).
The effect of temperature on enantioselectivity in the
Henry reaction promoted by per-6-ABCD (1) is also studied
(entries 9 and 10). At -20 °C, high yield and excellent
enantiomeric excess (up to 99%) (entry 10) are obtained.
The absolute configuration of the predominant enantiomer
was assigned as R by comparison with literature data.5-10,19
When mono-6-ABCD18 was used instead of per-6-ABCD
(1) at optimized conditions, although a good yield was
realized, the ee was poor (entry 11). The reaction was also
studied with different molar ratios of host and guest. Though
very good conversions were observed, the ee was excellent
only when the H/G ratio was g1 (entries 12-16).
(9) (a) Wang, J.-L.; Li, X.; Xie, H.-Y.; Liu, B.-K.; Lin, X.-F. J. Bio-
technol. 2010, 145, 240. (b) Ingalsbe, M. L.; St. Denis, J. D.; Gleason,
J. L.; Savage, G. P.; Priefer, R. Synthesis 2010, 1, 98.
(10) (a) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann,
C. Chem.sEur. J. 2009, 15, 12764. (b) Noole, A.; Lippur, K.; Metsala, A.;
Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313.
(11) (a) Takahashi, K. Chem. ReV. 1998, 98, 2013. (b) Sakuraba, H.;
Maekawa, H. J. Inclusion Phenom. Macrocyclic Chem. 2006, 54, 41. (c)
Bhosale, S. V.; Bhosale, S. V. Mini-ReV. Org. Chem. 2007, 4, 231.
(12) (a) Harano, K.; Kiyonaga, H.; Hissano, T. Tetrahedron Lett. 1991,
32, 7557. (b) Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Chem. Commun.
2005, 669.
(13) Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, K. R. Tetra-
hedron Lett. 2006, 47, 2125.
(14) (a) Tang, W.; Tang, J.; Ng, S. C.; Chan, H. S. O. J. Inclusion
Phenom. Macrocyclic Chem. 2006, 56, 287. (b) Dignam, C. F.; Randall,
L. A.; Blacken, R. D.; Cunningham, P. R.; Lester, S.-K. G.; Brown, M. J.;
French, S. C.; Aniagyei, S. E.; Wenzel, T. J. Tetrahedron: Asymmetry 2006,
17, 1199.
(15) (a) McCracken, P. G.; Ferguson, C. G.; Vizitiu, D.; Walkinshaw,
C. S.; Wang, Y.; Thatcher, G. R. J. J. Chem. Soc., Perkin Trans. 2 1999,
911. (b) Kitae, T.; Nakayama, T.; Kano, K. J. Chem. Soc., Perkin Trans. 2
1998, 207. (c) Meo, P. L.; D’Anna, F.; Gruttadauria, M.; Riela, S.; Noto,
R. Tetrahedron 2009, 65, 10413.
This per-6-ABCD (1)-promoted Henry reaction is also
successfully extended to different substituted aliphatic, aromatic,
cyclic, and heterocyclic aldehydes. As depicted in Table 2, this
reaction works very well for a wide range of para-substituted
aldehydes with very good to excellent isolated yields and also
with very high enantiomeric excess. When substituents are
(16) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
(b) Groger, H.; Willken, J. Angew. Chem., Int. Ed. 2001, 40, 529.
(17) (a) Suresh, P.; Pitchumani, K. J. Org. Chem. 2008, 73, 9121. (b)
Suresh, P.; Pitchumani, K. Tetrahedron: Asymmetry 2008, 19, 2037. (c)
Kanagaraj, K.; Pitchumani, K. Tetrahedron Lett. 2010, 51, 3312. (d) Suresh,
P.; Azath, I. A.; Pitchumani, K. Sens. Actuators B 2010, 146, 273.
Org. Lett., Vol. 12, No. 18, 2010
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