Enantioselective Henry reaction catalyzed by trianglamine-Cu(OAc)2 complex under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2008.02.113

Chiral trianglamine-Cu(OAc)₂ complex was found to be an efficient catalyst for enantioselective Henry reaction between nitromethane and various aldehydes to provide β-hydroxynitoroalkanes with high enantiomeric excesses under solvent-free condi

Full text of DOI:10.1016/j.tetlet.2008.02.113

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2533–2536
Enantioselective Henry reaction catalyzed by trianglamine–Cu(OAc)2
complex under solvent-free conditions
Koichi Tanaka *, Satoshi Hachiken
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering & High-Tech Research Centre,
Kansai University, Suita, Osaka 564-8680, Japan
Received 25 January 2008; revised 15 February 2008; accepted 21 February 2008
Available online 4 March 2008
Abstract
Chiral trianglamine–Cu(OAc)2 complex was found to be an efficient catalyst for enantioselective Henry reaction between nitrometh-
ane and various aldehydes to provide b-hydroxynitoroalkanes with high enantiomeric excesses under solvent-free conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
The Henry (nitroaldol) reaction is one of the versatile
C–C bond forming reaction in organic synthesis for the
formation of b-hydroxynitroalkanes.1 Optically active
b-hydroxynitroalkanes are useful intermediates in the syn-
thesis of several pharmacologically important compounds,
such as chloroamphenicol, ephedrine, propranolol, and
sphingosine.2 Recently, much attention has been paid for
the development of catalytic asymmetric Henry reactions.
For example, metal complexes with chiral ligands, such
as BINOL–metal complex,3 Zn amino alcohol complex,4
Co salen complex,5 and some Cu chiral amine complexes6
have been developed. However, these catalysts still have
some limitations such as moisture or air sensitivity, need
for bases and low temperature, low enantioselectivity,
and difficult preparation of the catalysts. As a part of our
research on chiral recognition study of optically active tri-
anglamines,7 we explored the potential application of their
Cu(OAc)2 complexes for enantioselective Henry reaction
between nitromethane and aromatic and aliphatic alde-
hydes under solvent-free conditions.
NaBH4 reduction of the intermediate trianglimines.8 Equi-
molar amounts of trianglamines (1–4) and Cu(OAc)2 were
stirred at room temperature in CH2Cl2, furnishing the
desired chiral Cu complexes as pale green solids.9 The
enantiomeric nature of (S,S,S,S,S,S)-(+)- and (R,R,R,
R,R,R)-(À)-1 and their complex with Cu(OAc)2 were
demonstrated by the CD spectra, which showed almost
the mirror images of each other (Fig. 1).
A series of chiral trianglamines (1–4) were prepared by
treating enantiomerically pure (S,S)-1,2-cyclohexanedi-
amine with the corresponding dialdehydes followed by
*
Fig. 1. CD spectra of (a) (+)-1, (b) (À)-1, (c) (+)-1–Cu(OAc)2 complex,
and (d) (À)-1–Cu(OAc)2 complex in EtOH.
Corresponding author.
E-mail address: ktanaka@ipcku.kansai-u.ac.jp (K. Tanaka).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.113

2534
K. Tanaka, S. Hachiken / Tetrahedron Letters 49 (2008) 2533–2536
NH HN
NH HN
NH
NH
HN
HN
NH
NH
HN
HN
(S,S,S,S,S,S)-(+)-1
(S,S,S,S,S,S)-(+)-2
NH HN
NH HN
NH
HN
HN
NH
NH
HN
HN
NH
(S,S,S,S,S,S)-(+)-4
(S,S,S,S,S,S)-(+)-3
The complex of (S,S,S,S,S,S)-(+)-1 with Cu(OAc)2 was
evaluated as a catalyst (3 mol %) by using benzaldehyde
(5a) and 10 equiv of nitromethane in an open air without
using any solvents (Table 1). From the results of Table 1,
best result in both enantioselectivity and reactivity was
obtained when the reaction was carried out at 0 °C for
48 h using a catalyst loading of 3 mol %.10 We next explore
the effectiveness of the size of the various ligands (1–4) for
the catalyst.
Table 2
Enantioselective Henry reaction of MeNO2 and aromatic aldehydes under
solvent-free conditions
.
L
Cu(OAc)2
(3 mol %)
OH
NO2
Ar CHO
+
MeNO2
Ar
C,48 h
0 °
(R)-6
5
solvent-free
a: Ar = Ph
b: Ar = 2-NO2C6H4 d: Ar = 4-ClC6H4
c: Ar = 4-NO2C6H4 e: Ar = 4-MeOC6H4
Ligands 1 and 2 (Table 2, entries 1 and 2) gave good
chemical yield and high enantioselectivity (82–86% ee),
while both yield and enantioselectivity decreased using lar-
ger ligands in size 3 and 4 (Table 2, entries 3 and 4).
Entry
Ar
L
Conv.a (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
96
91
90
87
93
97
97
95
86
88
79
75
82
67
77
74
65
57
69
48
78
62
40
15
48
75
84
82
65
66
74
75
48
39
53
45
52
55
56
38
82
86
79
58
56
74
72
63
62
77
39
16
73
87
63
46
84
79
83
75
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Table 1
Optimization of reaction conditions for the enantioselective Henry
reaction of 5a and MeNO2 using 3 mol % of (+)-1–Cu(OAc)2
OH
10
11
12
13
14
15
16
17
18
19
20
a
.
(+)-1 Cu(OAc)2
NO2
(3 mol %)
CHO
+ MeNO2
48 h
solvent-free
(R)-6a
5a
Entry
Temp (°C)
Conv.a (%)
Yielda (%)
eeb (%)
1
2
3
4
a
25
10
0
À10
93
97
96
86
54
76
78
49
42
73
82
85
Determined by GC and 1H NMR.
Determined by chiral HPLC.
Determined by GC and 1H NMR.
Determined by chiral HPLC.
b
b

K. Tanaka, S. Hachiken / Tetrahedron Letters 49 (2008) 2533–2536
2535
To explore the generality of this method, we examined
wide variety of aromatic aldehydes listed in Table 1 under
the optimal conditions in the presence of Cu(OAc)2 com-
plex with chiral ligands (1–4). In all the cases, the reactions
proceeded smoothly to give the desired products. The pres-
ence of either electron-withdrawing (entries 5–16) or elec-
tron-donating (entries 17–20) substitution at the para- or
ortho-positions of the aromatic ring of the aldehydes was
well tolerated and furnished the corresponding nitroaldol
products in moderate to good yields with high enantiose-
lectivities (Table 2).
21, 25, and 29). For example, the reaction of 1-octanal pro-
vided the corresponding nitroaldol (8b) in 74% yield with
93% ee. Pivaldehyde was also applicable in the Henry reac-
tion, providing the corresponding nitroaldol (8f) with 90%
ee in 88% yield (entry 21).
It is noteworthy that the products were obtained in the
(R)-form in all the reactions examined in Tables 1–3, show-
ing the nucleophilic addition of nitromethane at the si-face
of the aldehyde. The mechanistic details of the reaction are
still under investigation.
In conclusion, the Cu(OAc)2 complex with chiral tri-
anglamine was found to be efficient for the catalytic enan-
tioselective Henry reaction under solvent-free conditions. It
showed broad substrate applicability, good product yield,
and high enantioselectivity under the mild and solvent-free
conditions. Further studies using this catalytic system in
environmentally friendly asymmetric transformation are
underway.
More interestingly, aliphatic (cyclic, linear, and
branched) aldehydes were smoothly converted to nitroald-
ols in good yields with excellent enantioselectivity (83–93%
ee) especially using ligand 1 (Table 3, entries 1, 5, 9, 13, 17,
Table 3
Enantioselective Henry reaction of MeNO2 and aliphatic aldehydes under
solvent-free conditions
.
L
Cu(OAc)2
(3 mol %)
OH
Acknowledgments
NO2
R CHO
+
MeNO2
R
0 °C, 48 h
solvent-free
d: R = n-C5H11
e: R = n-C4H9
f: R = t-C4H9
This work was supported by ‘High-Tech Research Cen-
ter’ Project for Private Universities: matching fund subsidy
from MEXT (Ministry of Education, Culture, Sports, Sci-
ence and Technology), 2005–2009.
(R)-8
7
a: R = Cyclohexyl
b: R = n-C7H15
c: R = n-C6H13
g: R = i-C3H7
h: R = C2H5
i: R = CH3
Entry
R
L
Conv.a (%)
Yielda (%)
eeb (%)
References and notes
1
2
3
4
5
6
7
8
9
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
n-C7H15
n-C7H15
n-C7H15
n-C7H15
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C4H9
n-C4H9
n-C4H9
n-C4H9
t-C4H9
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
(+)-1
(+)-2
(+)-3
(+)-4
57
75
60
53
95
97
89
90
97
85
97
89
57
63
25
36
74
22
49
68
60
34
17
35
73
82
32
46
88
48
46
61
88
12
7
92
81
80
71
93
80
89
80
91
83
83
75
88
78
82
70
89
83
83
73
90
93
88
76
83
81
81
63
84
79
78
66
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Ikeno, T.; Yamada, T. Synthesis 2004, 12, 1947.
t-C4H9
t-C4H9
t-C4H9
i-C3H7
i-C3H7
i-C3H7
i-C3H7
C2H5
13
67
56
49
43
83
72
12
43
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C2H5
C2H5
C2H5
Determined by GC and 1H NMR.
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Not determined.
b
c

2536
K. Tanaka, S. Hachiken / Tetrahedron Letters 49 (2008) 2533–2536
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9. Synthesis of trianglamine–Cu(OAc)2 complex: Cu(OAc)2–H2O
(0.03 g, 0.15 mmol) was added to a solution of ligand 1 (0.1 g,
0.15 mmol) in CH2Cl2 (40 ml) and the mixture stirred for 4 h. Then,
the solvent was evaporated under reduced pressure. The crude
product obtained was washed with dry Et2O (40 ml), and the pale blue
solid was collected by filtration and dried under vacuum. 0.074 g (60%
10. Representative enantioselective Henry reaction (Table 2, entry 1): A
mixture of nitromethane (0.57 g, 9.4 mmol), (+)-1–Cu(OAc)2 complex
(0.023 g, 0.028 mmol), and benzaldehyde (0.1 g, 0.94 mmol) was
stirred at 0 °C for 48 h. Then, the volatiles were removed under
reduced pressure and the residue chromatographed on a short silica
gel to give nitoalkanol (R)-6a6f (0.13 g, 78% yield) in 82% ee. The
optical purity was determined by HPLC (Chiralcel OD, Detection:
UV 254 nm; eluent: n-hexane–2-propanol = 90:10, flow rate: 1.0 ml/
min; tR = 14.0 min; tS = 16.9 min).