Asymmetric direct aldol reactions catalyzed by chiral amine macrocycle-metal(ii) complexes under solvent-free conditions

Article abstract of DOI:10.1039/c3nj00361b

Solvent-free asymmetric aldol reactions between cyclohexanone and 4-nitrobenzaldehyde using chiral amine macrocycle-metal(ii) complexes as catalysts in a ball mill afforded the anti-aldol product as the major isomer with up to 93% ee.

Full text of DOI:10.1039/c3nj00361b

NJC
View Article Online
View Journal | View Issue
PAPER
Asymmetric direct aldol reactions catalyzed by
chiral amine macrocycle–metal(II) complexes under
solvent-free conditions†
Cite this: NewJ.Chem., 2013,
37, 2851
Koichi Tanaka,*a Azusa Asakura,a Toshihide Muraoka,a Przemysław Kalickib and
Zofia Urbanczyk-Lipkowskab
Received (in Montpellier, France)
6th April 2013,
Accepted 27th June 2013
Solvent-free asymmetric aldol reactions between cyclohexanone and 4-nitrobenzaldehyde using chiral
amine macrocycle–metal(II) complexes as catalysts in a ball mill afforded the anti-aldol product as the
major isomer with up to 93% ee.
DOI: 10.1039/c3nj00361b
www.rsc.org/njc
Henry reaction.8 75% ee was obtained in the zinc-catalyzed Henry
Introduction
reaction in THF using ligand 6.9 Moreover, the condensation of
Aldol condensation is a key carbon–carbon bond forming
reaction for creating a b-hydroxy carbonyl structural unit found
in many natural products and drugs.1 Several excellent asymmetric
aldol reactions have been developed using organic solvents.2 The
application of solvent-free reaction conditions to perform the aldol
reaction has allowed reduction of the excess use of starting
aldehydes and ketones to perform this reaction more greener.3
However, the aldol reactions under solvent-free conditions have
been studied scarcely to date.4–6 For example, Bolm and co-workers
reported the asymmetric aldol reactions under solvent-free
conditions catalyzed by (S)-proline in a ball mill. The anti-aldol
products were obtained in high ee.4 Najera and co-workers
reported the solvent-free asymmetric aldol reactions catalyzed
by (S)-binam-L-prolinamide with high ee (up to 88%).5 In more
recent work, Juaristi and co-workers reported a similar reaction
using (S)-proline-containing thiodipeptides as catalysts with
high ee (up to 96%).6 Metal complexes with chiral ligands
are widely used as asymmetric catalysts for Henry reactions.
However, the metal complexes with macrocyclic chiral ligands
have been scarcely developed. For example, the trianglamines
1–3 are effective ligands in Cu(OAc)2-catalyzed Henry reactions
of nitromethane with aromatic aldehydes (up to 87% ee) and
aliphatic aldehydes (up to 93% ee) under solvent-free conditions.7
Hexamethyl-substituted macrocycles 5 revealed a lesser degree of
asymmetric induction as compared to ligand 3 in the Cu-catalyzed
a Department of Chemistry and Materials Engineering, Faculty of Chemistry,
Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
E-mail: ktanaka@kansai-u.ac.jp; Fax: +81-06-6339-4026; Tel: +81-06-6368-0861
b Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa, Poland
† Electronic supplementary information (ESI) available: Experimental procedures
for 7–20, and their 1H NMR spectra and Chiral HPLC data. CCDC 894524. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3nj00361b
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 2851--2855 2851

View Article Online
Paper
NJC
nitromethane and aromatic and aliphatic aldehydes in the the reaction resulted in a very low yield (13%) with good
presence of catalytic amounts of copper diacetate and pyrrole enantio- and diastereo-selectivities (Table 1, entry 9).
macrocyclic ligand 7 in ethanol provided products with up to
In order to determine the effect of ball milling on the aldol
95% ee.10 Herein, we report asymmetric aldol reactions under reaction, a comparative study using conventional magnetic
solvent-free conditions using a ball mill, catalyzed by chiral stirring was carried out. For example, conventional magnetic
amine macrocycle(1–4)–metal(II) complexes.
stirring afforded (10R, 2S)-10 (anti–syn = 60 : 40) in only 4% yield
with an enantioselectivity of 63% ee (Table 1, entry 10). Thus,
the solvent-free aldol reaction of 4-nitrobenzaldehyde and
cyclohexanone was faster under ball-milling conditions than
in a solution or neat liquid.
Next, we screened Cu salts for the aldol reaction. By using
CuBr2, (10R, 2S)-10 was obtained in 90% ee, and the use of
Cu(OAc)2 resulted in poor enantioselectivity (63% ee) (Table 2,
runs 1 and 3). The type of metal ion used was also an important
parameter in this reaction. The use of Co ions resulted in the
best ee (93%) (Table 2, entries 10–12), followed by Cu ions
(Table 2, entries 1–3), Zn ions (Table 2, entries 4–6), and Ni ions
(Table 2, entries 7–9).
Under the optimal reaction conditions, the scope of the
reaction was studied varying the ketone and aldehyde (Table 3).
Several cyclic ketones were used as nucleophiles in the reaction
with p-nitrobenzaldehyde. As expected cyclopentanone and
cycloheptanone gave the anti-products (13, 14) as the major
isomers with lower enantioselectivities (Table 3, entries 4 and 5).
Other cyclic ketones such as tetrahydropyran-4-one or tetra-
hydrothiapyran-4-one gave moderate enantioselectivities (Table 3,
entries 6 and 7).
Different aldehydes were used in the reaction with cyclohexanone
giving the expected products. Both the yield and enantioselectivity of
the product decreased in the order of p- > m- > o-nitrobenzaldehyde
(Table 3, entries 1–3). Between p- and o-nitrobenzaldehyde,
more steric crowding at the ortho position may lead to lower
conversion for the ortho variety. In the case of chloro-substituted
benzaldehyde, a similar trend in both activity and stereo-
selectivity was observed (Table 3, entries 8–10). Whereas the
lower electronegativity of the bromo variety compared to the
Results and discussion
A series of chiral amine macrocycles (1–4) were prepared by
treating enantiomerically pure (S,S)-1,2-cyclohexanediamine
with the corresponding dialdehydes followed by reduction of
NaBH4 of the intermediate imine macrocycles.11
The chiral macrocyclic ligand was tested as a chiral catalyst
for the asymmetric aldol reaction of 4-nitrobenzaldehyde
and cyclohexanone in a ball mill. A mixture of (S,S,S,S,S,S)-1
(0.1 mmol), CuCl2 (0.1 mmol), cyclohexanone 8 (2.0 mmol), and
4-nitrobenzaldehyde 9 (1.0 mmol) was milled by a planetary ball
mill for 24 h at 100 rpm and at room temperature. The crude
reaction mixture was purified using column chromatography
(silica gel, hexane–EtOAc = 2 : 1) to afford a mixture of syn- and
anti-aldol reaction products (10R, 2S)-10 (anti–syn = 67 : 33) in
11% yield with an enantioselectivity of 67% ee (Table 1, entry 1).
Initially, we examined the effects of varying catalyst
amounts. Ratios for the ligand/CuCl2 and reaction time are
shown in Table 1, entries 2–5. This analysis revealed that the
best results were obtained when the reaction was carried out
using the ligand (0.2 mmol) and CuCl2 (0.4 mmol) for 48 h,
affording (10R, 2S)-10 (anti–syn = 71 : 29) in 85% yield with an
enantioselectivity of 83% ee (Table 1, entry 5). Next, the effective-
ness of the size of various ligands 1–4 for the catalyst was
explored. Ligands 2 and 4 gave good enantioselectivity (80% ee)
with lower yield and diastereoselectivity (Table 1, entries 6 and 8),
while ligand 3 gave a poor result under the same reaction
conditions (Table 1, entry 7). However, in the MeOH solution
Table 1 Asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone
catalyzed by the chiral amine macrocycle–CuCl2 complex in a ball milla
Table 2 Asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone
catalyzed by the (S,S,S,S,S,S)-1-metal complex in a ball milla
Time
(h)
Ligand
(mmol)
CuCl2
(mmol)
Yield
(%)
Entry
anti–syn
ee (%) Entry
MX2
Yield (%)
anti–syn
ee (%)
1
2
3
4
5
6
7
8
24
24
24
24
48
48
48
48
48
48
48
1 (0.1)
1 (0.1)
1 (0.1)
1 (0.2)
1 (0.2)
2 (0.2)
3 (0.2)
4 (0.2)
1 (0.2)
1 (0.2)
1 (0.2)
0.1
0.2
0.3
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0
11
12
7
45
85
73
43
59
13
4
67 : 33
54 : 46
54 : 46
70 : 30
71 : 29
61 : 39
49 : 51
63 : 37
70 : 30
60 : 40
68 : 32
67
69
45
75
83
80
17
80
79
63
59
1
2
3
4
5
6
7
8
Cu(OAc)2
CuCl2
CuBr2
Zn(OAc)2
ZnCl2
ZnBr2
Ni(OAc)2
NiCl2
NiBr2
Co(OAc)2
CoCl2
CoBr2
63
85
30
44
52
22
14
21
26
63
83
82
53 : 47
71 : 29
75 : 25
67 : 33
72 : 28
38 : 62
51 : 49
50 : 50
54 : 46
53 : 47
73 : 27
71 : 29
63
83
90
79
52
56
60
75
73
63
91
93
9b
10c
11
9
10
11
12
17
a
Reaction conditions: ketone 8 (2.0 mmol), aldehyde 9 (1.0 mmol), rt.
Reaction was carried out in MeOH. Reaction was carried out in neat
b
c
a
Reaction conditions: ketone 8 (2.0 mmol), aldehyde 9 (1.0 mmol),
(S,S,S,S,S,S)-1 (0.2 mmol), MX2(0.4 mmol), rt.
liquid.
c
2852 New J. Chem., 2013, 37, 2851--2855
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
Table 3 Asymmetric aldol reaction of 4-nitrobenzaldehyde with ketone catalyzed
by the (S,S,S,S,S,S)-1-metal complex in a ball milla
chloro one causes a higher enantioselectivity in the case of o- and
m-bromobenzaldehydes (Table 3, entries 11–13). More electron-
rich groups lowered both the reactivity and stereoselectivity
(Table 3, entries 14 and 15). In contrast, acetone afforded a
product with only 20% ee (Table 3, entry 16).
In order to investigate the effect of the ball-milling, both the
reaction of neat-liquid using conventional magnetic stirring
and the reaction in MeOH solution were examined. For example,
while under conventional stirring the reaction between cyclo-
hexanone and 4-nitrobenzaldehyde in the neat-liquid afforded
the aldol product in only 4% yield with 63% ee, ball-milling led
to the same product in 82% yield with 93% ee. Reaction in
CH2Cl2 solution also showed poor reactivity (9% yield) and
lower enantioselectivities (63% ee).
The ligand (S,S,S,S,S,S)-1 could easily be recovered using
column chromatography, and was recycled as a catalyst.
To gain insight into the mechanism within the enantio-
selective aldol reaction of 4-nitrobenzaldehyde and cyclohexa-
none in the presence of a chiral amine macrocycle-(S,S,S,S,S,S)-
1-metal(II) complex, we tried synthesis of complex crystals.
When a 1 : 2 mixture of (S,S,S,S,S,S)-1 and Cu(OAc)2 was dissolved
in MeOH, and the solution was kept at room temperature for
several days, an accidental formation of a 1 : 3 complex between
(S,S,S,S,S,S)-1 and Cu(OAc)2 was observed as a dark green crystal.
X-ray structure of a 1 : 3 complex between (S,S,S,S,S,S)-1 and
Cu(OAc)2 was analysed at 100 K. In the solid state, the
(S,S,S,S,S,S)-1ꢀCu3(CH3CO2)6ꢀ11H2O complex has triangular
capsule-like structure (Fig. 1). The two Cu2+ ions (Cu1, Cu2)
have a distorted square planar N, O coordination sphere involving
close contacts with both oxygen atoms of the acetates, whereas the
Cu3 is coordinated in the apical position with an extra water
molecule O13, displaying more perfect square-pyramidal geometry.
Typically, each acetate group has one short distance to the copper
atom: Cu1 ... O1 1.944(5), Cu1 ... O3 2.012(3), Cu2 ... O5 1.983(4),
Entry
1
Product
Yield (%)
82
anti–syn
ee (%)
93
71 : 29
2
3
4
5
6
72
52
51
42
55
69 : 31
77 : 23
74 : 26
52 : 48
61 : 39
87
86
75
26
69
7
54
14
35
42
12
20
50 : 50
51 : 49
57 : 43
51 : 49
50 : 50
64 : 36
60
22
65
75
88
85
8
9
10
11
12
13
14
15
44
48
69 : 31
50 : 50
75
56
4
54 : 46
—
n.d.
20
16
23
Fig. 1 Ortep diagram showing structure of the 1 : 3 complex between
(S,S,S,S,S,S)-1 and Cu(OAc)2 at 100 K. Thermal ellipsoids are shown at the 30%
probability level; 8 water molecules of crystallization were omitted for clarity.
a
Reaction conditions: ketone (2.0 mmol), aldehyde (1.0 mmol),
(S,S,S,S,S,S)-1 (0.2 mmol), CoBr2 (0.4 mmol), rt.
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 2851--2855 2853

View Article Online
Paper
NJC
Cu2 . . . O7 1.963(4), and Cu3 . . . O9 1.959(4), Cu3 . . . of 93% ee. The diastereoselectivity was determined using
O11 1.953(4) Å. The two out of remaining 10 water molecules 1H NMR of the crude product. The ee was determined by
are located inside of the capsule due to hydrogen bonding with chiral HPLC using a Chiralpak AD-H column (hexane : 2-PrOH
amino groups of the organic ligand [N4 . . . O18 3.080(6) Å, (90 : 10), 1 mL minꢁ1).
N4-H4N 0.91 Å, H4N . . . O18 2.21 Å, angle 1601; N5 . . .
O20 2.998(7) Å, N5-H5N 0.91 Å, H5N . . . O20 2.13 Å, angle
1591]. The remaining 8 water molecules are located in the
crystal around the acetate anions.
The possible solid state host–guest interactions allowing
migration of the substrate molecules into the catalytic sites
located inside of the capsule might be due to their planar
structure and relatively small size. The distance between Cu1
and Cu2 atoms in a wider part of the capsule is 8.864(2) Å. The
only possible coordination places are located in triplicate
inside of this capsule.
X-ray crystal data for the complex
C54 H100 Cu3 N6 O23, M = 1392.02, orthorhombic, space group
P212121, (no. 19), a = 11.6000(2) Å, b = 16.6558(3) Å, c =
35.0297(7) Å, V = 6768.0(2) Å3, Z = 4, dcalc = 1.366 mg Mꢁ3
,
F(000) = 2948, T = 100 K, 36 640 reflections were collected on a
Bruker Apex II diffractometer using MoKa radiation (l =
0.7107 Å), 10 630 unique reflections with I > 2sI (Rint = 0.0587)
were used for structure solution and refinement. Final R1
=
0.0561, wR2 = 0.1530, goodness of fit = 1.162. All hydrogen
atoms were placed in calculated positions and refined as riding
on their parent atoms with Uiso = 1.2Ueq(N, C). Hydrogen atoms
from 11 water molecules could not be found from difference
maps. Absolute configuration of the ligand is known and follows
known configuration of the (S,S)-1,2-cyclohexanediamine substrate;
Flack parameter = 0.261(12). CCDC 894524.†
Conclusions
In summary, a 1 : 2 complex of (S,S,S,S,S,S)-1 with CoBr2 was an
excellent catalyst for the asymmetric aldol reaction between
cyclohexanone and 4-nitrobenzaldehyde under solvent-free
conditions using a planetary ball mill. The anti-aldol adduct
(10R, 2S)-10 was obtained with high enantioselectivity (up to
93% ee), relative to the same reaction in the solution or in neat
liquid with traditional magnetic stirring. Further studies using
this catalytic system in environmentally friendly asymmetric
transformations are underway.
Notes and references
1 Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH, Weinheim,
2004, vol. 1 and 2.
2 For general reviews: (a) H. Groger, E. M. Vogl and
¨
M. Shibasaki, Chem.–Eur. J., 1998, 4, 1137–1141;
(b) S. G. Nelson, Tetrahedron: Asymmetry, 1998, 9, 357–389;
(c) R. Mahrwald, Chem. Rev., 1999, 99, 1095–1120;
(d) T. D. Machajewski and C.-H. Wong, Angew. Chem., Int.
Ed., 2000, 39, 1352–1374; B. Alcaide and P. Almendros, Eur.
J. Org. Chem., 2002, 1595–1601; (e) C. Palomo, M. Oiarbide
Experimental section
General
All reagents were purchased from commercial suppliers.
1H-NMR spectra were recorded on a JEOL JNM-AL 400 spectro-
meter with tetramethylsilane as the internal standard.
The diastereoselectivity of the reaction was determined by
1H-NMR spectroscopy of the crude product. Enantiomeric
excesses were determined by high-performance liquid chromato-
graphy (HPLC) either on a Chiralpak OD or a Chiralpak AD-H
column (Daisel). The absolute configuration of aldol products
was determined by comparison with published HPLC retention
times. Reactions in the ball mill were conducted using a Fritsch
Planetary Micro Mill model ‘‘Pulverisette 7’’. In the planetary
mill grinding bowls rotate around their own axes while also
orbiting around a central axis.
´
and J. M. Garcıa, Chem. Soc. Rev., 2004, 33, 65–74;
( f ) R. Mestres, Green Chem., 2004, 6, 583–603;
´
(g) J. L. Vicario, D. Badıa, L. Carillo, E. Reyes and
J. Etxbarria, Curr. Org. Chem., 2005, 9, 219–235;
(h) B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed.,
´
2006, 45, 7506–7525; (i) G. Guillena, C. Najera and
´
D. J. Ramon, Tetrahedron: Asymmetry, 2007, 18, 2249–2293.
´
3 (a) B. Rodrıguez, T. Rantanen and C. Bolm, Angew. Chem.,
Int. Ed., 2006, 45, 6924–6926; (b) G. Guillena, M. C. Hita,
´
´
C. Najera and S. F. Viozquez, Tetrahedron: Asymmetry, 2007,
´
18, 2300–2304; (c) G. Guillena, M. C. Hita, C. Najera and
´
S. F. Viozquez, J. Org. Chem., 2008, 73, 5933–5943;
Typical procedure for the solvent-free asymmetric aldol
reaction between cyclohexanone and 4-nitrobenzaldehyde
in a ball mill
´
(d) B. Bradshaw, G. Etxebarrıa-Jardi, J. Bonjoch,
S. F. Viozquez, G. Guillen and C. Najera, Adv. Synth. Catal.,
2009, 351, 2482–2490; (e) B. Bradshaw, G. Etxebarria-Jardı
´
´
´
A mixture of (S,S,S,S,S,S)-1 (0.13 g, 0.02 mmol), CoBr2 (0.087 g,
0.04 mmol), cyclohexanone 8 (2.0 mmol) and 4-nitrobenz-
aldehyde 9 (0.151 g, 1.0 mmol) was milled for 24 h at
100 rpm and at room temperature using a planetary ball mill
(Fritsch P-7). The crude reaction mixture was purified using
column chromatography (silica gel, hexane–EtOAc = 2 : 1)
to afford a mixture of syn- and anti-aldol reaction products
(10R, 2S)-10 (anti–syn = 71 : 29) in 82% yield with an enantioselectivity
and J. Bonjoch, J. Am. Chem. Soc., 2010, 132, 5966–5967.
´
4 (a) B. Rodrıguez, T. Rantanen and C. Bolm, Angew. Chem.,
´
Int. Ed., 2006, 45, 6924–6926; (b) B. Rodrıguez,
A. Bruckmann and C. Bolm, Chem.–Eur. J., 2007, 13,
4710–4722; (c) T. Rantanen, I. Schiffers and C. Bolm, Org.
Process. Res. Dev., 2007, 11, 592–597.
´
5 (a) G. Guillena, M. d. C. Hita, C. Najera and S. F. Viozquez,
Tetrahedron: Asymmetry, 2007, 18, 2300–2304; (b) G. Guillena,
c
2854 New J. Chem., 2013, 37, 2851--2855
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
M. d. C. Hita, C. Najera and S. F. Viozquez, J. Org. Chem.,
2008, 73, 5933–5943.
9 J. Gao and A. E. Martell, Org. Biomol. Chem., 2003, 1,
2801–2806.
6 J. G. Hernandez, V. Garcia-Lopez and E. Juaristi, Tetrahedron, 10 A. Gualandi, L. Cerisoli, H. Stoeckli-Evans and D. Savoia,
2012, 68, 92–97. J. Org. Chem., 2011, 76, 3399–3408.
7 K. Tanaka and S. Hachiken, Tetrahedron Lett., 2008, 49, 11 (a) J. Gawronski, H. Kolbon and A. Katrusiak, J. Org.
2533–2536.
Chem., 2000, 65, 5768–5773; (b) M. Kwit, P. Skornet,
H. Kolbon and J. Gawronski, Chirality, 2005, 17,
93–100.
8 D. Savoia, A. Gualandi and H. Stoeckli-Evans, Org. Biomol.
Chem., 2010, 8, 3992–3996.
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 2851--2855 2855