Asymmetrie nitroaldol reaction with a chiral copper complex derived from D-tartaric acid

Article abstract of DOI:10.1139/V08-012

A novel catalytic enantioselective Henry reaction has been developed using a tetradentate copper complex derived, from. D-tartaric acid, to give β-nitroalkanols in moderate to high enantioselectivities.

Full text of DOI:10.1139/V08-012

261
Asymmetric nitroaldol reaction with a chiral
copper complex derived from D-tartaric acid
Changsheng Gan
Abstract: A novel catalytic enantioselective Henry reaction has been developed using a tetradentate copper complex
derived from D-tartaric acid to give β-nitroalkanols in moderate to high enantioselectivities.
Key words: Henry reaction, D-tartaric acid, enantioselective, β-nitroalkanols.
Résumé : On a développé le champ d’application de la nouvelle réaction catalytique énantiosélective d’Henry en utili-
sant le complexe tétradentate de cuivre de l’acide D-tartrique pour préparer des β-nitroalcanols avec des énantiosélectivi-
tés allant de modérées à élevées.
Mots-clés : réaction d’Henry, acide D-tartrique, énantiosélective, β-nitroalcanols.
[Traduit par la Rédaction] Gan
263
Introduction
Scheme 1. The synthetic route of complex 1.
The nitroaldol reaction (or Henry reaction) constitutes an
important class of C–C bond-forming reactions that provide
straightforward access to important synthetic intermediates
from readily accessible nitroalkanes and carbonyl com-
pounds (1). Because of its significance in organic synthesis,
considerable efforts have been devoted to the development
of catalytic asymmetric nitroaldol reactions (2). Several effi-
cient catalysts have been developed, such as BINOL by
Shibasaki (3), bis(oxazoline) by Evans and Jørgensen (4),
cinchona alkaloid by Deng (5), dinuclear zinc complex by
Trost (6), amino alcohol (7), thiourea (8), and Schiff base
catalysts (9). Because D-tartaric acid is available very
cheaply from natural chiral sources, it has been widely stud-
ied in asymmetric catalysis, and different catalysts have been
developed for a series of asymmetric reactions (10). We have
been studying it for some time. In this article, we report a
novel enantioselective Henry reaction catalyzed by a C2-
symmetric tetradentate catalyst 1 derived from D-tartaric
acid, which is similar in structure to the salen derivative
(11).
Scheme 1 summarizes the synthesis of complex 1 from D-
tartaric acid. (4S, 5S)-(–)-Diethyl 2, 3-O-isopropylidene-D-
tartarate (2) was prepared from D-(–)-tartaric acid using a re-
ported procedure (12, 13). Dropping 25% ammonia into 2 in
the presence of ammonium chloride in an ice-salt bath, then
stirring overnight, gave diamide 3 in 85% yield. Reduction
of the diamide moiety of 3 to diamine 4 with LiAlH4 in
refluxing ether for 18 h, followed by condensation with cor-
responding salicylaldehyde, provided chiral ligand 5.
Finally, mixing 5 and Cu(OAc)2CH2O in methanol followed
by the addition of excess sodium hydroxide produced the
tetradentate copper complex 1.
Received 18 October 2007. Accepted 13 January 2008.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 19 February 2008.
C. Gan.1 Engineering Research Center of Bio-process of
Ministry of Education, Hefei University of Technology,
Hefei, Anhui 230009, P.R. China.
1Contact (e-mail: gancs@mail.ustc.edu.cn).
2Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca) or may be purchased
from the Depository of Unpublished Data, Document
Delivery, CISTI, National Research Council Canada, Ottawa,
ON K1A 0R6, Canada. DUD 3715. For more information on
obtaining material refer to cisti-icist.nrc-
Results and discussions2
The complex
1 was added to a mixture of 4-
nitrobenzaldehyde and nitromethane (Scheme 2). The results
are shown in Table 1. Entries 1 and 2 show that the
tetradentate complex 1b, with a bulky tert-butyl substituent,
cnrc.gc.ca/irm/unpub_e.shtml.
Can. J. Chem. 86: 261–263 (2008)
doi:10.1139/V08-012
© 2008 NRC Canada

262
Can. J. Chem. Vol. 86, 2008
Table 1. Studies on the asymmetric nitroaldol reactions with chiral copper complexes.
Entry
Cat.
Solvent
CH3NO2
Time (h)
Yielda (%)
Eeb (%)
1
2
3
1a
1b
1b
Tol
Tol
CH2Cl2
2.5 mmol
2.5 mmol
2.5 mmol
80
80
80
38
39
42
12
63
34
4
1b
CH3CN
2.5 mmol
80
36
23
5
6
7
8
9c
10d
11e
12f
13g
1b
1b
1b
1b
1b
1b
1b
1b
1b
THF
Tol
Tol
EtOH
Tol
Tol
Tol
Tol
Tol
0.5 mL
0.5 mL
1 mL
80
80
60
60
72
72
72
24
48
75
67
77
79
68
66
65
95
98
52
68
44
26
69
59
72
11
25
1 mL
0.5 mL
0.5 mL
1 mL
0.5 mL
0.5 mL
Note: All reactions were performed with 0.5 mmol 4-nitrobenzaldehyde, nitromethane, and 10 mol% of cata-
lyst 1 in 2 mL solvent at room temperature unless otherwise specified.
aIsolated yield.
bDetermined by chiral HPLC using an OD-H column.
c20 mol% of catalyst 1b was used.
d100 mg 4A molecular sieve was added to the reaction mixture.
e4 mL toluene and 1 mL nitromethane were used.
f20 mol% Et3N was added to the reaction mixture.
gThe reaction was carried out at –20 °C in the presence of 20 mol% Et3N.
Scheme 2. Asymmetric nitroaldol reaction of 4-nitrobenzaldehyde
and nitromethane.
Table 2. Studies on the asymmetric nitroaldol reactions of
nitromethane with various aldehydes.
Entry
1
R
Product Time (h) Yield (%)a Ee (%)b
4-NO2Ph
4-ClPh
1-naphthyl 6c
6a
6b
72
65
72
2
3
4
5
6
7
8
9
72
72
72
84
72
72
72
72
64
66
61
40
79
71
60
59
58
80
48
52
84
70
57
45c
Ph
6d
6e
6f
6g
6h
6i
4-MeOPh
2-ClPh
2-MeOPh
4-MePh
PhCH2
catalyzed the reaction much better than 1a. Then different
solvents were screened. Toluene proved the best, followed
by THF, whereas EtOH, CH2Cl2, and CH3CN gave only
poor enantioselectivities (entries 2–5, 8). Increasing the
amount of CH3NO2 to 0.5 mL promoted both the yield and
the enantioselectivity (entry 6), but when 1 mL of CH3NO2
was used, the enantioselectivity was significantly decreased
(entry 7). Neither increasing the amount of catalyst nor add-
ing a molecular sieve to the reaction mixture was effective
in improving the enantioselectivity (entries 9 and 10). But
diluting the catalyst concentration by doubling the amount
of solvent and nitromethane did further improve the enantio-
selectivity without significant loss of yield (entry 11). Con-
ducting the reaction under lower temperature was then
examined. However, very low enantioselectivity was ob-
tained (entry 13). The absolute configuration of the product
in Table 1 was determined as S by comparing the HPLC elu-
tion order of the enantiomers and the optical rotations re-
ported in the literature (4a).
10
11
i-Pr
i-Bu
6j
6k
72
72
56
60
57
61
Note: All reactions were performed on a 0.5 mmol scale with 10 mol%
of complex 1b using 1 mL nitromethane in 4 mL toluene. Reactions were
run at room temperature for the indicated time.
aIsolated yields.
bEnantiomeric excess was determined by HPLC using a Chiracel OD-H
or OJ-H column.
cThe absolute configuration was not determined.
chlorobenzaldehyde (entry 2), 4-methoxybenzaldehyde
(entry 5), and 4-methylbenzaldehyde (entry 8). 2-Chloro-
benzaldehyde (entry 6) was shown to produce the highest
enantioselectivity among all the substrates examined. When
it came to the sterically less-encumbered benzaldehyde
(entry 4), the ee value diminished to 48%. As far as aliphatic
aldehydes were concerned, the enantioselectivities were only
moderate (entries 9–11). The absolute configurations of the
products in Table 2 were assigned as S based on the data re-
ported in the literature (4, 9, 14), except for 6i, whose con-
figuration was not determined.
With the optimized reaction conditions, the complex 1b
was used to catalyze the addition of nitromethane to a
variety of aldehydes (Scheme 3). The results are summa-
rized in Table 2. Moderate enantioselectivities were obtained
for the para-substituted aromatic aldehydes, such as 4-
© 2008 NRC Canada

Gan
263
Scheme 3. Asymmetric nitroaldol reactions of nitromethane with
various aldehydes.
(b) C. Christensen, K. Juhl, R.G. Hazell, and K.A. Jørgensen.
J. Org. Chem. 67, 4875 (2002); (c) C. Christensen, K. Juhl,
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Conclusions
7. (a) C. Palomo, M. Oiarbide, and A. Laso. Angew. Chem. Int.
Ed. 44, 3881 (2005); (b) Y.-W. Zhong, P. Tian, and G.-Q. Lin.
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Angew. Chem. Int. Ed. 45, 929 (2006); (b) Y. Sohtome, Y.
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17, 2046 (2006).
In summary, we have developed a novel and facile
enantioselective nitroaldol reaction. It is the first reported
use of tartaric acid derivatives in the catalytic enantioselec-
tive Henry reaction. Moderate to high enantioselectivities
were obtained for the ortho-substituted aromatic aldehydes.
This reaction works quite well at room temperature, avoid-
ing the use of low temperature. Since the catalyst is very sta-
ble in the air, airproof conditions in N2 or Ar are also
unnecessary. Considering that the chiral catalyst can be
readily prepared from naturally abundant tartaric acid, this
method provides a practical and convenient way to prepare
optically active nitroalkanols. Further study is currently in
progress to improve the yield and enantiomeric excess and
to elucidate the reaction mechanism.
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© 2008 NRC Canada