In search of enantioselective catalysts for the Henry reaction: Are two metal centres better than one?

Article abstract of DOI:10.1039/b821995h

Catalysts for the asymmetric Henry reaction involving copper(ii) complexes of the chiral Schiff bases N,N′-(1R,2R)-(-)-1,2-cyclohexylenebis(3- hydroxysalicylideneamine) (H₂1) and N,N′-(1R,2R)-(-)-1,2- cyclohexylenebis(3-ethoxysalicylideneamine)

Full text of DOI:10.1039/b821995h

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PAPER
www.rsc.org/njc | New Journal of Chemistry
In search of enantioselective catalysts for the Henry reaction: are two
metal centres better than one?w
Edwin C. Constable,* Guoqi Zhang, Catherine E. Housecroft,* Markus Neuburger,
Silvia Schaffner and Wolf-D. Woggon
Received (in Montpellier, France) 9th December 2008, Accepted 22nd January 2009
First published as an Advance Article on the web 20th February 2009
DOI: 10.1039/b821995h
Catalysts for the asymmetric Henry reaction involving copper(II) complexes of the chiral
0
Schiff bases N,N -(1R,2R)-(ꢀ)-1,2-cyclohexylenebis(3-hydroxysalicylideneamine) (H 1) and
2
0
N,N -(1R,2R)-(ꢀ)-1,2-cyclohexylenebis(3-ethoxysalicylideneamine) (H 2), and H 3, which is the
2
2
reduced analogue of H 1, have been studied. Whereas [Cu(1)] and [Cu(2)] give poor yields and
2
enantioselectivity, [Cu(3)] produced moderate to high yields and enantioselectivities were optimal
when reactions were carried out in toluene rather than a polar solvent. A significant finding is that
both yield and enantioselectivity are enhanced when a second equivalent of Cu(OAc)
2
is added to
the catalyst. The single-crystal structures of [Cu(3)] and [Cu(1)(H O)] are presented, and the
2
2
host–guest interactions and molecular packing in the latter are compared with those in [Cu(2)(H O)].
1
13
Introduction
chemical shifts for H and C NMR spectra are referenced
to residual solvent peaks with respect to TMS = d 0 ppm.
Infrared spectra were recorded on a Shimadzu FTIR-8400S
spectrophotometer with solid samples on a Golden Gate
diamond ATR accessory. Electronic absorption spectra
were recorded on a Varian-Cary 5000 spectrophotometer.
Electrospray mass spectra were recorded using a Finnigan
MAT LCQ mass spectrometer. HPLC was carried out using
an intelligent pump, detector and integrator on a Hewlett
Packard S1100 instrument using a Chiralcel OD–H column
The Henry (nitroaldol) reaction is an important carbon–carbon
1–3
bond forming reaction in synthetic chemistry. The resultant
b-hydroxy nitro compounds are useful precursors for the syn-
thesis of biologically significant building blocks including chiral
2–6
b-amino alcohols and a-hydroxyl carboxylic acids. Over the
last few years, attention has focused on enantioselective Henry
7–10
reactions,
and among the catalysts employed have been a
23,24
copper(I),
10–22
variety of chiral copper(II),
25
cobalt(II) and
26
chromium(III) complexes. In addition to the selectivity required
of a catalyst, it is advantageous for it to be insensitive to air and
moisture, easy to prepare and inexpensive. It is also desirable to
have mild reaction conditions and no requirement for the
addition of organic bases. Copper(II) catalysts are proving to
be the most successful in the asymmetric Henry reaction, and
enantioselectivities reported to date range from moderate to
3
ꢀ1
(
85 : 15, heptane–isopropanol, 0.8 cm min , 230 nm).
2
8
29
2
27
Ligands H
2
1
and H
2
(Scheme 1) and complex [Cu(2)]
were prepared as previously reported. (1R,2R)-(ꢀ)-1,2-diamino-
cyclohexane and 3-ethoxysalicylaldehyde were used as received
(
Fluka or Sigma-Aldrich).
10–22
high.
We recently described the synthesis and structural
characterization of the copper(II) Schiff base complex
0
Synthesis of H
3
2
[
Cu(2)(H O)] where H
2
2
2 is N,N -(1R,2R)-(ꢀ)-1,2-cyclohexylene-
A solution of (1R,2R)-(ꢀ)-1,2-diaminocyclohexane (0.228 g,
27
bis(3-ethoxysalicylideneamine) (Scheme 1). This chiral com-
plex is formed under mild conditions and in near quantitative
yield. Here we report the facile formation of two related
chiral copper(II) complexes, and the performance of all three
complexes as catalysts in an asymmetric Henry reaction.
3
.00 mmol) in methanol (10 cm ) was added dropwise
2
to a stirring solution of 3-ethoxysalicylaldehyde (0.665 g,
3
4
.00 mmol) in methanol (20 cm ). The mixture was heated
to reflux for 2 h, and then cooled to room temperature. Solid
NaBH (0.38 g, 10 mmol) was added in small portions over a
4
period of 1 h, and the resulting colourless solution was stirred
overnight at room temperature. Solvent was removed under
Experimental
3
reduced pressure, and water (100 cm ) was added. The product
General
3
was extracted with CH
2
Cl
2
(3 ꢁ 60 cm ); the combined organic
Commercially available chemicals were reagent grade and
1
phases were washed with water and brine, and dried over
Na SO . The solution was filtered and evaporated under
13
were used without further purification. H and C NMR
spectra were recorded on a Bruker Avance DPX-400 spectrometer;
2
4
reduced pressure to dryness to give colourless oil which was
purified by column chromatography (SiO , hexane–EtOAc
3 : 1 with 5% MeOH). H 3 was isolated as a white solid
2
Department of Chemistry, University of Basel, Spitalstrasse 51, Basel,
CH 4056, Switzerland. E-mail: catherine.housecroft@unibas.ch;
Fax: +41 61 267 1018; Tel: +41 61 267 1008
w CCDC reference numbers 717570 and 717571. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b821995h
2
1
(
3
0.73 g, 88%). H NMR (400 MHz, CDCl ) d/ppm 6.76 (dd,
A4/6
A5
), 6.70 (t, J = 7.7 Hz, 2H, H ),
A4/6
J = 8.0, 1.6 Hz, 2H, H
6.64 (dd, J = 7.6, 2.0 Hz, 2H, H
), 4.06 (q, J = 7.0 Hz, 4H,
1
064 | New J. Chem., 2009, 33, 1064–1069
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+
98.4 [M + Na ] (base peak, calc. 498.2). Found C 59.16, H
4
1
6
.76, N 5.47; C24
H32CuN
2
O
4
2 2
ꢃ / H O requires C 59.43, H 6.86,
N 5.78%.
Typical procedure for asymmetric Henry reaction
Complex [Cu(3)] (4.76 mg, 0.01 mmol) was dissolved in
3
toluene (0.4 cm ) in a screw-capped vial containing a magnetic
stirrer bar at room temperature. The reaction solution was
stirred for 10 min before Cu(OAc)
2
(1.81 mg, 0.01 mmol) was
added. The deep-green solution was stirred for another 30 min,
3
after which time MeNO (0.13 cm , 1.0 mmol) and 4-nitro-
2
Scheme 1 Structures of ligands and labelling for NMR spectroscopic
assignments for H 3.
2
benzaldehyde (0.2 mmol, 1.0 equiv.) were added sequentially.
The mixture was allowed to stir at room temperature for 60 h.
The volatile components were removed under reduced
pressure and the crude product was purified by column
CH
2
CH
3
a
), 3.99 (d, J = 13.5 Hz, 2H, H ), 3.83 (d, J = 13.5 Hz,
H
a0
B
H, H ), 2.38 (m, 2H, H ), 2.11 (m, 2H, H ), 1.67 (m, 2H,
B
2
B
CH
2
CH
3
B
H ), 1.43 (t, J = 7.0 Hz, 6H, H
), 1.21 (m, 4H, H ).
, 400 MHz) d/ppm 147.1, 146.7, 124.4,
20.9, 119.1, 112.1, 64.5, 60.8, 48.9, 30.7, 24.6, 15.2. ESI-MS
1
3
2
chromatography (SiO , hexane–EtOAc, 3 : 1, v/v) to give the
C NMR (CDCl
3
nitroaldol product 4, isolated as a pale-yellow solid (26 mg,
1
1
6
3
1%). H NMR (400 MHz, CDCl ) d/ppm 8.27 (d, 2H, J =
Ar
.8 Hz, H ), 7.63 (d, 2H, J = 8.4 Hz, H ), 5.61 (m, 1H,
+
(
MeOH) m/z 415.3 [M + H ] (base peak, calc. 415.3),
Ar
8
+
4
1
37.1 [M + Na ] (calc. 437.2). UV/VIS l /nm (1.45 ꢁ
max
ꢀ4 ꢀ3 3 3 ꢀ1 ꢀ1
CHOH
CH
2
H
), 4.61 (dd, 1H, J = 14.0, 8.4 Hz, H ), 4.56 (dd, 1H,
0
mol dm , THF) 236 (e/10 dm mol cm 4.6), 280
1
3.0). FT-IR (solid, cm ): 2936m, 1584m, 1471s, 1393m,
CH
J = 13.6, 4.0 Hz, H ), 3.14 (d, 1H, J = 4.0 Hz, H ). The
2
OH
ꢀ
(
enantiomeric excess was determined by HPLC: minor
1
8
1
279s, 1241s, 1116s, 1073s, 988w, 963w, 948w, 905w, 887m,
39w, 832w, 724s. Found C 68.74, H 8.16, 6.27; C24
enantiomer t
r
2
= 19.0 min, major enantiomer t
0
r
= 23.3 min;
H
34
N
2
O
4
ꢃ
7
7% ee; [a]D + 15.2 (c 0.5, CH OH). The absolute con-
2
0
3
/3H
2
O requires C 68.54, H 8.31, N 6.66%. [a]
Cl ).
D
= ꢀ73.5
figuration of Henry product was assigned as (S) by comparison
3
of its optical rotation with literature values.
(
c = 0.5, CH
2
2
0
Synthesis of [Cu(1)]
An aqueous solution (3 cm ) of Cu(OAc)
was added to a stirring solution of H 1 (35.4 mg, 0.100 mmol)
Crystal structure determinations
3
2
(18.1 mg, 0.100 mmol)
Data were collected on a Bruker-Nonius Kappa CCD instru-
2
3
ment; data reduction, solution and refinement (on F(obs)) used
3
in MeOH (10 cm ) at room temperature. The purple solution
was stirred for 2 h, and then allowed to evaporate slowly at
room temperature. After 2 d, the brown precipitate that had
1
32
the progammes COLLECT,
DENZO/SCALEPACK,
3
SIR92 and CRYSTALS. Structures have been analysed
3
34
3
using Mercury v. 1.4.2. ORTEP figures were drawn using
5
formed was collected by filtration, washed with Et
in vacuo. [Cu(1)] was isolated as a brown crystalline solid
40.2 mg, 0.0967 mmol, 96.7%). ESI-MS (MeOH) m/z 438.4
2
O and dried
3
6
Ortep-3 for Windows.
(
+
+
[
M + Na ] (base peak, calc. 438.1), 853.2 [2M + Na ] (calc.
[Cu(1)(H
2
O)]
ꢀ5
ꢀ3
8
53.1). UV/VIS l /nm (9.47 ꢁ 10 mol dm , THF) 249
max
3 3 ꢀ1 ꢀ1
C H CuN O , M = 433.95, purple plate, monoclinic, space
2
0
22
2
5
(e/10 dm mol cm 24.3), 284 (23.6), 379 (5.75), 566 (0.28).
1
FT-IR (solid, cm ): 3484m, 2937m, 1622s, 1552m, 1447s,
˚
ꢀ
group P2 , a = 7.9835(3), b = 20.8163(7), c = 11.0230(4) A,
1
3
ꢀ3
,
˚
b = 101.777(2)1, U = 1793.3(1) A , Z = 4, D
c
= 1.607 Mg m
) = 1.255 mm , T = 173 K, 12 420 reflections
collected. Refinement of 8548 reflections (506 parameters)
with I 4 3s(I) converged at final R = 0.0235 (R all
1
6
384m, 1345w, 1317s, 1236s, 1090w, 1025m, 868m, 735s,
2
68m. Found C 54.38, H 5.00, 6.36; C20 20CuN O
ꢀ
1
m(Mo-K
a
H
2
O
4
ꢃ3/2H
requires C 54.23, H 5.23, N 6.32%.
1
1
data = 0.0412), wR2 = 0.0262 (wR2 all data = 0.0370),
Synthesis of [Cu(3)]
Rint = 0.033, gof = 1.067, Flack parameter = 0.004(7).
A solution of Cu(OAc) (18.1 mg, 0.100 mmol) in MeOH
2
3
(
5 cm ) was added to a stirring solution of H 3 (41.4 mg,
2
3
.100 mmol) in MeOH (10 cm ) at room temperature. The
[Cu(3)]
0
green solution was stirred for 30 min, and was then evaporated
under reduced pressure to dryness. The solid was washed well
24 2 4
C H32CuN O , M = 476.08, red block, triclinic, space group
˚
P1, a = 8.8481(3), b = 11.8842(4), c = 11.9786(4) A, a =
3
˚
with Et
2
O, and then dried in vacuo. [Cu(3)] was isolated as an
96.919(2), b = 106.430(2), g = 109.055(2)1, U = 1110.04(7) A ,
ꢀ3
ꢀ1
orange–brown powder (46.9 mg, 0.0985 mmol, 98.5%).
Z = 2, D
c
= 1.424 Mg m , m(Mo-K
a
) = 1.017 mm ,
ꢀ
5
ꢀ3
UV/VIS lmax/nm (8.84 ꢁ 10
mol dm , THF) 251
ꢀ1
16.5), 289 (10.6), 342 (1.19), 410
T = 123 K, 13 379 reflections collected. Refinement of 7017
reflections (560 parameters) with I 4 3sI) converged at
final R1 = 0.0452 (R1 all data = 0.1012), wR2 = 0.0470
(wR all data = 0.0877), R = 0.041, gof = 1.175, Flack
3
3
ꢀ1
cm
(
(
e/10 dm mol
1.21), 597 (0.39). FT-IR (solid, cm ): 3196w, 2932m,
ꢀ1
1
1
588w, 1564w, 1469s, 1423w, 1284m, 1233s, 1165w, 1115m,
2
int
077s, 1044s, 925w, 904w, 844m, 737s. ESI-MS (MeOH) m/z
parameter = 0.04(2).
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Results and discussion
Synthesis and structures of catalysts
We recently reported the structure of [Cu(2)(H O)], which
2
exhibits host–guest, hydrogen-bonded recognition of H
2
O in
0
00
0 0 0
27
the O,O ,O ,O -cavity of [Cu(2)]. In addition to structural
2
7
aspects of this class of compound, we were also interested in
testing them as selective asymmetric catalysts. We have there-
fore prepared complexes [Cu(1)] and [Cu(3)], which comprise a
series of chiral copper(II) complexes that vary either in the size
0
00
0 00
of the O,O ,O ,O -cavity or in having an unsaturated or
2
saturated backbone. Ligands H21 and H22 have previously
8
29
been reported. Ligand H 3 (Scheme 1) was prepared by the
2
Fig. 2 Face-to-face stacking of a pair of crystallographically inde-
˚
condensation of (1R,2R)-(ꢀ)-1,2-diaminocyclohexane with
pendent Cu(1)(H O) units in [Cu(1)(H
2
2
O)]; Cu1ꢃ ꢃ ꢃCu2 = 3.6945(4) A.
3
-ethoxysalicylaldehyde, followed by reduction with NaBH ,
4
and was characterized by routine spectroscopic methods. The
reactions of equimolar amounts of Cu(OAc) with enantio-
pure ligands H 1 or H 3 result in the formation of [Cu(1)] or
Cu(3)], respectively, in high yield. The base peak in the
molecules is shown in Fig. 1. Important bond parameters for
both molecules are given in the figure caption. The coordina-
tion sphere around each of atoms Cu(1) and Cu(2) is close to
being square planar; the donor atoms N1, N2, O1 and O3 lie
2
2
2
[
˚
electrospray mass spectrum of each complex corresponded
+
to [M + Na] (m/z 438.1 for [Cu(1)], 498.4 for [Cu(3)]). The
ꢄ0.06 A out of the least squares plane through them, while
˚
around Cu(2), donor atoms N3, N4, O5 and O7 lie ꢄ0.12 A
electronic absorption spectra of a THF solution of each
complex exhibited a low intensity MLCT band (566 nm for
out of the corresponding least squares plane. Each pair of
Cu(1) units in the asymmetric unit assembles in a face-to-face
2
[
Cu(1)], 597 nm for [Cu(3)]), in addition to more intense
arrangement (Fig. 2). Although the distance between pairs of
aryl rings containing atoms C1 and C21, and C20 and C40, is
absorptions at higher energy assigned to ligand p* ’ p
transitions.
˚
E3.6 A, the rings are offset and any p-stacking is therefore
Single crystals of [Cu(1)(H
2
O)] suitable for X-ray diffraction
Cl –MeOH solution
weak. Within the asymmetric unit, the Cu1ꢃ ꢃ ꢃCu2 separation
˚
is 3.6945(4) A. While shorter than that observed in
were grown by slow evaporation of a CH
2
2
2
7
˚
2 2
O)] (3.816(1)A), the interaction in [Cu(1)(H O)]
of [Cu(1)] over a period of 3 days. The complex crystallizes in
the chiral space group P1, and one of the two independent
[Cu(2)(H
must be considered weak. However, the recurrence of this
packing unit in both [Cu(1)(H O)] and [Cu(2)(H O)] indicates
that the weak p-stacking and Cuꢃ ꢃ ꢃCu interactions favourably
reinforce one another. The water molecule in [Cu(1)(H O)] is
hydrogen bonded within the O,O ,O ,O -cavity, in a similar
2
2
2
0
00
0 0 0
2
7
manner to that observed in [Cu(2)(H O)]. However, the
2
molecular packing in the two structures is markedly different,
and can be rationalized in terms of the differences in which the
hydroxy and ethoxy substituents, respectively, in [Cu(1)] and
2
[Cu(2)] interact with the H O molecule (Scheme 2, hydrogen
atoms were located). In addition to being a guest within the
Cu(2) host, the water molecule is hydrogen bonded to a
hydroxy substituent of an adjacent molecule (Fig. 3). The
2
result is that stacks of [Cu(1)(H O)] units are organized in a
herringbone fashion, in contrast to the parallel stacking in
2
7
Cu(2)(H O)] and [Cu(3)] (see below).
[
2
Fig. 1 Molecular structure of one of the crystallographically inde-
2 2
pendent Cu(1)(H O) units in [Cu(1)(H O)] with ellipsoids plotted at
the 50% probability level. Selected bond distances and angles:
Cu1–N1 = 1.934(2), Cu1–N2 = 1.942(2), Cu1–O1 = 1.899(2),
Cu1–O3
N2–C13
=
=
1.900(2), N1–C7
1.479(2), N2–C14
=
1.286(3), N1–C8
˚
= 1.473(3),
=
1.289(2) A; N1–Cu1–N2
=
84.55(8), N1–Cu1–O1
=
94.65(7), O1–Cu1–O3
=
87.05(7),
N2–Cu1–O3 = 93.88(7)1. For the second independent molecule, corres-
ponding parameters are: Cu2–N3 = 1.933(2), Cu2–N4 = 1.945(2),
Cu2–O5 = 1.910(2), Cu2–O7 = 1.898(2), N3–C27 = 1.286(3),
˚
N3–C28 = 1.475(2), N4–C33 = 1.482(3), N4–C34 = 1.279(3) A;
N3–Cu2–N4 = 84.89(8), N3–Cu2–O5 = 94.06(7), O5–Cu2–O7 =
Scheme 2 Comparison of host–guest interactions in [Cu(2)(H
2
O)]
87.75(7), N4–Cu2–O7 = 94.06(7)1.
and [Cu(1)(H O)].
2
1
066 | New J. Chem., 2009, 33, 1064–1069
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i
i
˚
2.904(2) A,
N52H4ꢃ ꢃ ꢃO2
=
2.06, N52ꢃ ꢃ ꢃO2
=
i
N52–H4ꢃ ꢃ ꢃO2 = 1601; symmetry code i = 1 + x, y, z).
The only interactions between stacks are repulsive, close
Hꢃ ꢃ ꢃH contacts.
Catalytic studies
The catalytic activities of the chiral copper(II) complexes
[Cu(1)], [Cu(2)] and [Cu(3)] in the Henry reaction shown in
Scheme 3 were tested both in the absence and presence of
added metal salts. The enantiomeric excess of the product was
determined by HPLC, and the results are presented in Table 1.
All reactions were performed on a 0.20 mmol scale with
5 mol% of catalyst at a 0.5 M concentration using 5 equiv.
of nitromethane in solvents indicated in Table 1. Reactions
(except for one, see Table 1) were carried out at room
temperature over a period of 60 h. The absolute configuration
of the b-hydroxynitroalkane was assigned as (S) by comparison
2
Fig. 3 Packing of molecules in [Cu(1)(H O)] showing hydrogen
bonding interactions; symmetry codes: i = 1 ꢀ x, 1/2 + y, 1 ꢀ z;
ii = ꢀx, ꢀ1/2 + y, 1 ꢀ z.
X-Ray quality crystals of [Cu(3)] were grown over a period
of a week by slow diffusion of Et O into an EtOH solution of
2
the complex. Crystallization without a guest water molecule
3
0
contrasts with the observations for [Cu(1)(H O)] and
2
of the optical rotation with literature data.
[
Cu(2)(H O)]. [Cu(3)] crystallizes in the chiral space group
2
Initial reactions were carried out using copper(II) complexes
P1, and there are two crystallographically independent mole-
cules in the asymmetric unit, one of which is shown in Fig. 4.
The two molecules pack face-to-face, but are significantly
of the Schiff base ligands H 1 and H 2 in ethanol. No or
2
2
negligible enantioselectivity was observed. In an investigation
of the activities of copper(II) complexes of ligands 5 and 6 and
related oligothienyl ligands, as catalysts in asymmetric Henry
offset with respect to one another leading to a longer
˚
20
Cu1ꢃ ꢃ ꢃCu2 separation (4.443(2) A) than in [Cu(1)(H
2
O)].
reactions, Bandini et al. have observed that saturated 6
The coordination environments of Cu1 and Cu2 deviate more
from planarity than in [Cu(1)(H O)], with the sets of donor
atoms being ꢄ0.30 and ꢄ0.18 A out of the least squares plane
through them. The lack of guest molecule in the
O,O ,O ,O -cavity means that the ethoxy groups are less
produces significantly higher ee’s than the unsaturated 5
2
1,22
2
(Scheme 4). Similarly, Blay and co-workers
have shown
˚
that, whereas Cu(OAc) and imine 7 catalyse a Henry reaction
2
a
giving products in high yields but moderate enantio-
selectivities, the use of copper(II) with the saturated ligand 8
leads to an enhancement of the enantioselectivity (Scheme 5).
In accordance with these observations, we have found that,
under the same conditions as the reactions using [Cu(1)] and
[Cu(2)], [Cu(3)] produced both higher yields and enantio-
selectivity (Table 1). We therefore focused our attentions on
0
00
00 0
2
7
constrained than in [Cu(2)(H O)], and, as a result, lie above
2
and below the coordination plane. Molecules of [Cu(3)] pack
in parallel stacks, with the most dominant intermolecular
interactions being NHꢃ ꢃ ꢃO hydrogen bonds (N51H3ꢃ ꢃ ꢃO1 =
˚
2
.11, N51ꢃ ꢃ ꢃO1 = 2.956(2) A, N51–H3ꢃ ꢃ ꢃO1 = 1611;
[Cu(3)]. The effects of solvent were examined, and the highest
ee (48%) was obtained in toluene rather than in a polar
solvent. However, this was at the expense of yield (Table 1).
Structural data for complexes formed between copper(II)
2
2
7
and ligands H
2
1 (see above) and H
2
confirm the ability of
0
00
00 0
the O,O ,O ,O -cavity to host a water molecule. More
relevant to catalytic studies is the fact that this cavity is
able to bind a metal centre, as confirmed structurally in
3
7
[
Cu(2)Gd(O
2
NO)
3
]
and [Cu(1 ꢀ 2H)UCl
3 2
(py) ] (the pendant
2
ꢀ
38
OH groups of ligand 1 are deprotonated). We have there-
fore looked at the effects of adding equimolar amounts (with
respect to the [Cu(3)]) of copper(II), nickel(II), zinc(II) and
palladium(II) acetate to the reaction mixture. The addition of
Zn(OAc) leads to extremely poor yield, but in contrast, the
2
added Cu(OAc) resulted in high yields when the solvent was
2
Fig. 4 Molecular structure of one of the crystallographically inde-
pendent [Cu(3)] complexes with ellipsoids plotted at the 40% proba-
bility level. Selected bond distances and angles: Cu1–N1 = 2.006(6),
Cu1–N2 = 2.014(5), Cu1–O1 = 1.913(5), Cu1–O2 = 1.915(5),
˚
N1–C7 = 1.473(7), N2–C14 = 1.454(8) A; N1–Cu1–N2 = 85.4(2),
N1–Cu1–O1 = 95.1(2), N2–Cu1–O2 = 93.9(2), O1–Cu1–O2 =
Scheme 3 Catalytic asymmetric Henry reaction of 4-nitrobenzaldehyde
91.0(2)1. Bond parameters for the second molecule are similar.
and nitromethane.
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Table 1 Results for the catalytic asymmetric Henry reaction shown in Scheme 3
a
b
Complex
Added metal salt
Solvent
Temperature/K
Yield (%)
ee (%)
[Cu(1)]
[Cu(2)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
[Cu(3)]
None
None
None
None
None
None
None
None
Cu(OAc)
Cu(OAc)
Cu(OAc)
Pd(OAc)
Cu(OAc)
EtOH
EtOH
EtOH
THF
295 K
295 K
295 K
295 K
295 K
295 K
295 K
295 K
295 K
273 K
295 K
295 K
295 K
295 K
295 K
65
52
86
81
80
40
56
41
94
82
92
65
61
5
0
23
25
15
23
9
48
39
44
39
30
77
2 2
CH Cl
MeOH
MeCN
Toluene
EtOH
EtOH
THF
EtOH
Toluene
Toluene
Toluene
2
2
2
2
2
Zn(OAc)
Ni(OAc)
2
o5
Not measured
54
2
45
a
b
Isolated yield after chromatographic purification. Enantiomeric excess was determined by HPLC using a Chiralcel OD–H column.
results complement the recent studies of Shibasaki and
co-workers, who have shown that homo- and heterodimetallic
(
Ni
2
, Cu–Sm) Schiff base complexes are efficient asymmetric
4
0–42
catalysts for Mannich-type reactions.
These authors have
also reported that trimetallic (Gd ) complexes containing
3
chiral ligands designed around a central cyclohexane ring
bearing a pendant phosphine oxide are highly active enantio-
4
3
selective catalysts for ring-opening of meso-aziridines.
20
Conclusions
Scheme 4 Ligands 5 and 6 from the work of Bandini et al.
The single-crystal structures of [Cu(1)(H O)] and [Cu(3)] are
2
presented. In the former, the host–guest interactions and
2
7
2
molecular packing contrast with those in [Cu(2)(H O)], as a
consequence of the differences in which the hydroxy and ethoxy
substituents, respectively, in [Cu(1)] and [Cu(2)] interact with
the H
complexes of the chiral Schiff bases H
the reduced analogue of H 1) as catalysts for an asymmetric
2
O molecule. We have investigated the use of copper(II)
2
1 and H 2, and of H
2
2
3
(
2
21,22
Scheme 5 Ligands 7 and 8 from the work of Blay et al.
Henry reaction. [Cu(1)] and [Cu(2)] give poor yields and
enantioselectivity, but with [Cu(3)], moderate to high yields
and enantioselectivities were observed. The latter are solvent
dependent, being highest in toluene rather than a polar solvent.
Both yield and enantioselectivity are significantly enhanced
either EtOH or THF and the reaction carried out at room
temperature. Moderate ee’s were obtained (Table 1). In EtOH,
an 82% yield and 44% ee were obtained even when the
reaction was run at 273 K. The highest ee was obtained when
2
when a second equivalent of Cu(OAc) is added to the catalyst.
We are currently attempting to establish this role for the metal
ion by performing studies with less coordinating anions.
Ligand modification aimed towards further improvements
of enantioselectivity in the Henry reaction and development of
multimetallic catalysts based on reduced salen ligands are
currently ongoing within our group.
2
the catalyst consisted of [Cu(3)]–Cu(OAc) (1 : 1) and the
solvent was toluene, and the yield was also enhanced with
respect to the reaction catalysed only by [Cu(3)].
Starting from the crystallographically determined structure
of [Cu(3)], we attempted to model a structure in which the
39
0
00
00 0
O,O ,O ,O -cavity of [Cu(3)] binds
a Cu(II) centre.
However, as expected, a severely distorted 4-coordinate
environment is imposed upon the second copper(II) centre.
The effect of the added metal ions is marked although we can
only speculate as to the precise role. Assuming that the added
copper(II) is bound by the catalyst, we propose that acetate
ions are also involved, completing the coordination sphere.
However, efforts to isolate a dimetallic complex from the
reaction mixture have not been successful. Nonetheless, the
observation that the addition of a second copper(II) centre
enhances the performance of the catalyst is significant. These
Acknowledgements
We thank the Swiss National Science Foundation and the
University of Basel for financial support.
Notes and references
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