A highly syn-selective nitroaldol reaction catalyzed by Cu II-bisimidazoline

Article abstract of DOI:10.1002/chem.201000650

(Chemical Equation Presented) Catalyzing Henry: Chiral bisimidazoline 1-Cu(OTf)₂, in the presence of N-methylmorpholine as a base, was discovered to efficiently catalyze the nitroaldol reaction in a highly syn- and enantioselective manner for a broad range of aldehydes, including aromatic, heteroaromatic, α,β-unsaturated, and aliphatic aldehydes (see scheme).

Full text of DOI:10.1002/chem.201000650

COMMUNICATION
DOI: 10.1002/chem.201000650
A Highly syn-Selective Nitroaldol Reaction Catalyzed by CuII–Bisimidazoline
Liang Cheng, Jiaxing Dong, Jingsong You, Ge Gao,* and Jingbo Lan*[a]
The nitroaldol (Henry) reaction is a valuable and atom-
system.[12] Problems still remain in these limited examples:
low reaction temperatures, long reaction times, a narrow
range of aldehydes, and in particular, low syn selectivity for
aromatic aldehydes.[13,14] Therefore, a more efficient catalyst
for highly syn-selective nitroaldol reaction is of great signifi-
cance. We herein report a highly syn-selective nitroaldol re-
action of nitroethane with both aromatic and aliphatic alde-
hydes catalyzed by a CuII–bisimidazoline system.
À
economic C C bond-formation reaction between a nitroal-
kane and a carbonyl compound to furnish a 1,2-nitro alcohol
that is over 100 years old.[1] Since Shibasaki et al. first used
this reaction in a catalytic enantioselective manner,[2] much
effort has been devoted to this area because facile reduction
of the enantioenriched 1,2-nitro alcohols readily provides
chiral 1,2-amino alcohols, which are ubiquitous segments in
natural products, pharmaceuticals, synthetic intermediates,
and chiral ligands.[3] A highly enantioselective nitroaldol re-
action using nitromethane as a nucleophile has been ach-
ieved by metal catalysis,[4] organocatalysis,[5] and biocataly-
sis.[6] However, highly diastereo- and enantioselective nitro-
aldol reactions that use nitroethane and other nitroalkanes
to simultaneously form two stereocenters still remain chal-
lenging and less explored. In 1995, the Shibasaki group re-
ported the first syn selective[7,8] and enantioselective nitroal-
dol reaction,[9] catalyzed by their modified heterobimetallic
catalyst[2] with 6,6’-disubstituted 1,1’-binaphthol (BINOL) in
place of BINOL. Nitroethane added to hydrocinnamalde-
hyde at À208C for 75 h to afford 4-nitro-1-phenylpentan-3-
ol in 70% yield with a syn/anti diastereoselectivity of 89:11
and 93% enantiomeric excess (ee) of the syn product. Very
few substrates have been used to date. Only sporadic and
tentative examples were reported until recently.[10] Nagasa-
wa et al. disclosed that their guanidinium–thiourea molecule
is a highly syn-selective organocatalyst for the nitroaldol re-
action of nitroalkanes with aliphatic aldehydes.[11] Arai et al.
obtained improved syn selectivity for the reaction of a-
branched-aliphatic aldehydes by modifying their CuII–dia-
We previously reported a highly enantioselective nitroal-
dol reaction between various aldehydes and nitromethane,
catalyzed by our rationally designed chiral bisimidazoline
catalyst 1.[4j] To probe deeper into the potential of this cata-
lyst, we decided to further investigate the nitroaldol reaction
by using nitroethane as a nucleophile. Under the optimal
conditions we used for the reaction of nitromethane
(10 mol% ligand 1, CuACTHNUTRGNEUNG(OTf)2 (Tf=trifluoromethanesulfon-
yl),[15] and Et3N in ethanol), the reaction of nitroethane with
benzaldehyde proceeded smoothly. After 24 h at room tem-
perature, the desired nitroaldol adduct was obtained in 80%
yield with a syn/anti diastereoselectivity of 1.5:1, and the ee
value of the syn product was 78% (Table 1, entry 1). After
preliminary screening of the reaction solvent, dioxane gave
a promising syn/anti selectivity of 2.6:1, and the ee value was
86% (Table 1, entry 6). Different bases were then tested.
Both the more bulky secondary amine, diisopropylamine,
and tertiary amine, diisopropylethylamine, showed much im-
proved reactivity, but the stereoselectivity only increased
slightly with the bulkiness of the base (Table 1, entries 6–8).
The inorganic base potassium carbonate gave very low
enantioselectivity, while a moderate diastereoselectivity was
observed (Table 1, entry 9). Azacycloalkanes exhibited very
mine catalyst[4m] to
a
CuI–sulfonyldiamine–pyridine
[a] L. Cheng, J. Dong, Prof. Dr. J. You, Prof. Dr. G. Gao, Prof. Dr. J. Lan
Key Laboratory of Green Chemistry and Technology of Ministry of
Education College of Chemistry
and State Key Laboratory of Biotherapy
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P.R. China)
Fax : (+86)28-85412203
E-mail: gg2b@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000650.
Chem. Eur. J. 2010, 16, 6761 – 6765
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6761

Table 1. Condition screening for the diastereoselective nitroaldol reac-
tion of nitroethane with benzaldehyde catalyzed by 1–Cu
Table 2. Nitroaldol reaction of nitroethane with different aldehydes cata-
lyzed by 1–Cu
(OTf)2.[a]
N
ACHTUNGTRENNUNG
Solvent Yield [%][b] d.r. (syn/anti)[c] ee [%] (syn)[c]
R
Yield [%][b]
d.r. (syn/anti)[c]
ee [%] (syn)[d]
Base
1
2
3
4
5
6
7
8
Ph
92
87
95
72
90
93
75
90
64
58
73
80
82
90
82
86
87
90
75
75
91
77
80
65
92
88
60
98
90
70
92
90
8.3:1
2.9:1
2.7:1
7.7:1
9.1:1
7.2:1
6.7:1
4.4:1
7.7:1
7.2:1
8.4:1
5.6:1
6.3:1
4.3:1
5.0:1
2.5:1
7.7:1
8.3:1
9.1:1
16.7:1
50:1
12.5:1
25:1
50:1
50:1
14.3:1
17:1
33.3:1
50:1
50:1
8.3:1
50:1
97
97
91
98
96
94
96
91
98
96
94
93
95
91
91
96
97
90
92
96
93
96
95
96
98
92
97
98
99
99
97
92
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
EtOH
toluene 80
CH2Cl2 72
80
1.5:1
1.6:1
1.7:1
1.7:1
1.9:1
2.6:1
2.8:1
3.5:1
2.1:1
4.3:1
3.5:1
4.9:1
3.0:1
6.1:1
8.1:1
78
59
56
72
74
86
88
92
9
87
91
94
92
95
97
2-MeO-Ph
2-NO2-Ph
3-Me-Ph
3-MeO-Ph
3-F-Ph
3-Cl-Ph
3-NO2-Ph
4-Me-Ph
THF
87
EtNO2 82
dioxane 72
dioxane 92
dioxane 90
dioxane 93
iPr2NH
iPr2NEt
K2CO3
pyrrolidine dioxane 48
piperidine dioxane 93
morpholine dioxane 87
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30[e]
31[f]
32[f]
4-MeO-Ph
4-F-Ph
4-Cl-Ph
10
11
12
13
14
4-Br-Ph
NMP
NMM
dioxane 95
dioxane 92
dioxane 92
4-NO2-Ph
4-CN-Ph
1-naphthyl
2-naphthyl
2-furyl
2-thiophenyl
(E)-PhCH=CH
PhCH2CH2
15[d] NMM
[a] Reaction conditions: benzaldehyde (0.25 mmol), nitroethane
(10 equiv), solvent (0.2 mL), 1–Cu(OTf)2 (10 mol%), base (10 mol%);
the local RT was (10Æ2)8C when the experiment was conducted. [b] Iso-
lated yield. [c] Determined by chiral HPLC analysis. [d] The reaction was
carried out at 08C.
AHCTUNGTRENNUNG
CH
CH
CH
(CH2)2
CTHUNGTRENNUNG
interesting results (Table 1, entries 10–12): When pyrrolidine
was employed, the diastereoselectivity was improved to
4.3:1, but the yield was only 48%. Piperidine exhibited good
reactivity and enantioselectivity of the syn product, but the
diastereoselectivity was only 3.5:1. Morpholine, which has
an oxygen atom in place of 4-methylene of the piperidine
ring gave a nice yield of 87% and a good diastereoselectiv-
ity of 4.9:1 with the syn product dominating with 94% ee.
N-Methylmorpholine (NMM)[16] further improved the yield
to 92% and the diastereoselectivity to 6.1:1 while methylat-
ed piperidine (NMP) almost did not affect the result
(Table 1, entries 13 and 14).[17] Lowering the reaction tem-
perature to 08C had no effect on the reactivity, but slightly
increased the diastereoselectivity to 8.1:1 and the enantiose-
lectivity to 97% (Table 1, entry 15). The absolute configura-
tion of the main diastereomer was determined to be R,R by
comparing with HPLC data in the literature (see the Sup-
porting Information). For comparison, the bisoxazoline ana-
logue 2 was tested under the optimal conditions. It exhibited
almost no diastereoselectivity and low enantioselectivity
(40% yield, 1.1:1 of syn/anti, and 39% ee syn). This compar-
ison clearly suggested that the subtle structural change sig-
nificantly affects the selectivity of the catalyst.
U
N
N
cyclopropyl
cyclopentyl
cyclohexyl
A
Ph
PhCH2CH2
[a] Reaction conditions: aldehyde (0.25 mmol), nitroethane (10 equiv),
dioxane (0.2 mL), 1–CuACTHNUTRGNE(UNG OTf)2 (10 mol%), NMM (10 mol%). [b] Isolated
yield. [c] Determined by 1H NMR spectroscopy analysis of the crude re-
action mixture. [d] Determined by chiral HPLC analysis. [e] Catalyst
loading: 2.5 mol%; reaction time: 48 h. [f] The reaction was performed
under an air atmosphere.
with predominately the syn diastereomer and an excellent
ee value. For aromatic aldehydes, the electronic nature of
the substituent on the phenyl ring has limited effect on the
diastereoselectivity, regardless of whether it is electron-with-
drawing or -donating. However, the location of the substitu-
ent has a significant effect on the diastereoselectivity: ortho-
Substituted benzaldehydes exhibited much lower diastereo-
selectivity than meta- and para-substituted ones. For in-
stance, while the reaction with 2-methoxybenzaldehyde af-
forded the adduct with a syn/anti diastereoselectivity of
2.9:1, the reactions with 3-methoxybenzaldehyde and 4-me-
thoxybenzaldehyde gave 9.1:1 and 7.2:1, respectively
(Table 2, entries 2, 5, and 10). More interestingly, the reac-
tion of 2-methylbenzaldehyde did not proceed at all. The
significant lower diastereoselectivity for 1-naphthylaldehyde
relative to 2-naphthylaldehyde could also be attributed to
this ortho-position effect (Table 2, entries 16 and 17). It was
With the optimal conditions in hand (Table 1, entry 15),
the scope of substrates was investigated by performing the
nitroaldol reaction of nitroethane (10 equiv) with aldehydes
in the presence of 1–CuACTHNUTRGNE(NUG OTf)2 (10 mol%) as the catalyst
and NMM (10 mol%) as the base in dioxane at 08C. The re-
sults are summarized in Table 2. For a variety of aromatic,
heteroaromatic, a,b-unsaturated, and aliphatic aldehydes,
the reaction proceeded cleanly within 24 h to afford the de-
sired nitroaldol adduct as the single product in good yield
6762
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6761 – 6765

syn-Selective Nitroaldol Reaction
COMMUNICATION
delightful that heteroaromatic aldehydes also showed good
reactivity and stereoselectivity (Table 2, entries 18 and 19).
The addition to aliphatic aldehydes worked much better
than to aromatic aldehydes in terms of diastereoselectivity.
The reaction of hydrocinnamaldehyde afforded the desired
product in 91% yield with a syn/anti diastereoselectivity of
50:1 and 93% ee of the syn product. A compromised diaste-
reoselectivity of 16.7:1 was obtained for trans-cinnamalde-
hyde, which could probably be attributed to the conjugation
of the aldehyde group with the aromatic phenyl group
(Table 2, entries 20 and 21). For linear aliphatic aldehydes,
the diastereoselectivity increased significantly when the
alkyl carbon chain lengthened (Table 2, entries 22–24). a-
Branched aliphatic aldehydes exhibited much improved dia-
stereoselectivity than linear aldehydes, whereas b-branched
aldehydes showed no impact at all (Table 2, entries 25 and
26). For cycloalkyl aldehydes, the diastereoselectivity largely
increased when the cycloalkyl group became bigger, in ac-
cordance with the trend of linear aldehydes (Table 2, en-
tries 27–29). It was noteworthy that although the diastereo-
selectivity obtained for aromatic aldehydes was lower than
aliphatic aldehydes, the enantioselectivity was excellent in
all cases.[18] For certain aldehydes, such as isobutyraldehyde,
both the diastereo- and enantioselectivity remained unal-
tered even with 2.5 mol% of catalyst loading, although the
reaction was much slower (Table 2, entry 30). Moreover, our
catalytic system was inert to air. The reaction carried out
under an air atmosphere gave the same results as that car-
ried out under the controlled conditions (Table 2, entries 31
and 32).
Figure 1. The X-ray crystallographic structure of 1–CuACTHUNRGTNEUNG(OTf)2–pyridine.
Thermal ellipsoids are shown at the 30% probability level.
A single crystal of the complex 1–CuACTHNUTRGNEUNG(OTf)2 was serendipi-
tously obtained from a solvent mixture of dichloromethane
and toluene in the presence of pyridine (1 equiv)
(Figure 1).[19] X-ray crystallographic analysis clearly revealed
that the complex 1–CuACHTUNTRGNEUNG(OTf)2 adopts an octahedral geome-
try around the copper center. The four nitrogen atoms from
the imidazoline moieties, the pyridinyl spacer, and pyridine
occupy the four equatorial positions of the octahedron, and
two oxygen atoms from OTf anions occupy the two zeniths.
The two isopropyl groups stand out of the imidazoline plane
up and down, respectively, which forms a chiral environment
around the copper center for chiral induction. Note that the
two methyl groups of the isopropyl moiety both point away
from the copper center, indicating a proper and tight space
around the copper center.[20]
Scheme 1. The proposed transition states of the nitroaldol reaction cata-
lyzed by 1–CuACTHUNRGTNEUNG(OTf)2.
The nice diastereoselectivity for heteroaromatic aldehydes
was further demonstrated by the reaction of thiophene-2-
carbaldehyde with nitropropane (Scheme 2). Under the op-
timal conditions, the targeted 2-nitro-1-(thiophen-2-yl)bu-
tan-1-ol was obtained in 57% yield with 92% ee of the syn
diastereomer dominating (syn/anti=11.1:1).
Based on the single-crystal structure, we propose two pos-
sible transition states to interpret the stereoselectivity of the
In summary, we have demonstrated that the chiral bisimi-
dazoline ligand 1, together with CuACTHNUTRGNENUG(OTf)2 in the presence of
nitroaldol reaction catalyzed by 1–Cu
G
N-methylmorpholine, is a highly syn-selective nitroaldol re-
the nitroaldol reaction, the aldehyde takes the position of
pyridine in the crystal structure. Nitroethane can only ap-
proach to the copper center from one side and one oxygen
atom of the nitro group replaces one OTf anion to coordi-
nate with copper. Because of the repulsion between the
methyl group of nitroethane and the isopropyl group of the
catalyst in transition-state II (TS-II), which will lead to the
anti product, transition-state I (TS-I) is most favored and re-
sults in syn product.
action catalytic system. X-ray analysis of a single crystal of
1–CuACTHNURGTEN(UGN OTf)2–pyridine clearly showed the chiral environment
around the copper center, which helped us to understand
the syn selectivity of the nitroaldol reaction catalyzed by 1–
CuACTHUNTRGENNG(U OTf)2. The ease of making ligand 1 from the readily
available natural amino acid,[4j] the simpleness of the reac-
tion procedure and the generally high syn selectivity and ex-
cellent enantioselectivity for a broad range of aldehydes, in-
cluding aromatic, heteroaromatic, a,b-unsaturated, and ali-
Chem. Eur. J. 2010, 16, 6761 – 6765
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6763

G. Gao, J. Lan et al.
[4] Rare-earth metals, see reference [2] and the following: a) J. M. Saꢁ,
F. Tur, J. Gonzꢁlez, M. Vega, Tetrahedron: Asymmetry 2006, 17, 99–
106; b) reaction of trifluoromethyl ketones: F. Tur, J. M. Saꢁ, Org.
Lett. 2007, 9, 5079–5082; zinc: c) B. M. Trost, V. S. C. Yeh, Angew.
Chem. 2002, 114, 889–891; Angew. Chem. Int. Ed. 2002, 41, 861–
863; d) C. Palomo, M. Oiarbide, A. Laso, Angew. Chem. 2005, 117,
3949–3952; Angew. Chem. Int. Ed. 2005, 44, 3881–3884; e) S. Liu,
C. Wolf, Org. Lett. 2008, 10, 1831–1834; f) A. Bulut, A. Aslan, ꢂ.
Dogan, J. Org. Chem. 2008, 73, 7373–7375; copper(II): g) reaction
of a-ketoesters: C. Christensen, K. Juhl, R. G. Hazell, K. A. Jørgen-
sen, J. Org. Chem. 2002, 67, 4875–4881; h) D. A. Evans, D. Seidel,
M. Rueping, H. W. Lam, J. T. Shaw, C. W. Downey, J. Am. Chem.
Soc. 2003, 125, 12692–12693; i) S. K. Ginotra, V. K. Singh, Org.
Biomol. Chem. 2007, 5, 3932–3937; j) K. Ma, J. You, Chem. Eur. J.
2007, 13, 1863–1871; k) H. Maheswaran, K. L. Prasanth, G. G.
Krishna, K. Ravikumar, B. Sridhar, M. L. Kantam, Chem. Commun.
2006, 4066–4068; l) T. Arai, M. Watanabe, A. Fujiwara, N. Yokoya-
ma, A. Yanagisawa, Angew. Chem. 2006, 118, 6124–6127; Angew.
Chem. Int. Ed. 2006, 45, 5978–5981; m) T. Arai, M. Watanabe, A.
Yanagisawa, Org. Lett. 2007, 9, 3595–3597; n) M. Bandini, F. Picci-
nelli, S. Tommasi, A. Umani-Ronchi, C. Ventrici, Chem. Commun.
2007, 616–618; copper(I): o) Y. Xiong, F. Wang, X. Huang, Y. Wen,
X. Feng, Chem. Eur. J. 2007, 13, 829–833; p) B. Qin, X. Xiao, X.
Liu, J. Huang, Y. Wen, X. Feng, J. Org. Chem. 2007, 72, 9323–9328;
cobalt(II): q) Y. Kogami, T. Nakajima, T. Ashizawa, S. Kezuka, T.
Ikeno, T. Yamada, Chem. Lett. 2004, 33, 614–615; r) Y. Kogami, T.
Nakajima, T. Ikeno, T. Yamada, Synthesis 2004, 1947–1950; magne-
sium: s) B. M. Choudary, K. V. S. Ranganath, U. Pal, M. L. Kantam,
B. Sreedhar, J. Am. Chem. Soc. 2005, 127, 13167–13171; chromium
(III): t) R. Kowalczyk, P. Kwiatkowski, J. Skarz˙ewski, J. Jurczak, J.
Org. Chem. 2009, 74, 753–756.
[5] For selected examples, see: a) Y. Sohtome, Y. Hashimoto, K. Naga-
sawa, Adv. Synth. Catal. 2005, 347, 1643–1648; b) T. Marcelli,
R. N. S. Van der Haas, J. H. Van Maarseveen, H. Hiemstra, Angew.
Chem. 2006, 118, 943–945; Angew. Chem. Int. Ed. 2006, 45, 929–
931; c) reaction of a-ketoesters: H. Li, B. Wang, L. Deng, J. Am.
Chem. Soc. 2006, 128, 732–733; d) reaction of a-ketophosphonates:
T. Mandal, S. Samanta, C. Zhao, Org. Lett. 2007, 9, 943–945.
[6] The first biocatalytic asymmetric Henry reaction was reported, but
it is highly substrate dependent, see: a) T. Purkarthofer, K. Gruber,
M. Gruber-Khadjawi, K. Waich, W. Skranc, D. Mink, H. Griengl,
Angew. Chem. 2006, 118, 3532–3535; Angew. Chem. Int. Ed. 2006,
45, 3454–3456; b) M. Gruber-Khadjawi, T. Purkarthofer, W. Skranc,
H. Griengl, Adv. Synth. Catal. 2007, 349, 1445–1450. The addition
of nitroethane to benzaldehyde gave 9:1 anti-selectivity.
Scheme 2. Nitroaldol reaction of nitropropane with thiophene-2-carbalde-
hyde catalyzed by 1–Cu(OTf)2.
ACHTUNGTRENNUNG
phatic aldehydes, make our catalytic system very applicable.
Although the results for aromatic aldehydes are not as good
as those obtained for aliphatic aldehydes, to the best of our
knowledge, they are the best ever achieved. Efforts are still
underway to improve the diastereoselectivity for the nitroal-
dol reaction of aromatic aldehydes.
Experimental Section
General procedure for the catalytic asymmetric nitroaldol reaction: Cu-
ACHTUNGTRENNUNG(OTf)2 (9.05 mg, 0.025 mmol), ligand (11.9 mg, 0.026 mmol), and dioxane
(0.2 mL) were added to a Schlenk tube fitted with a magnetic stirring bar
under nitrogen. The mixture was allowed to stir for 2 h and then cooled
to 08C. An aldehyde (0.25 mmol) was added, followed by the addition of
a
freshly distilled nitroethane (2.5 mmol) and N-methylmorpholine
(2.74 mL, 0.025 mmol). The reaction mixture was stirred for 24 h at 08C.
After removal of volatile compounds in vacuo and the catalyst by filter-
ing through a plug of silica gel, the filtrate was concentrated and the resi-
due was analyzed by 1H NMR spectroscopy to determine the diastereo-
meric ratio. Then the residue was purified by column chromatography on
silica gel to afford the corresponding 1,2-nitro alcohol. The enantiomeric
excess was finally determined by HPLC analysis on a chiral AD-H or
AS-H column.
Acknowledgements
This work was supported by grants from the National Natural Science
Foundation of China (nos. 20972102 and 20902063) and PCSIRT (No.
IRT0846). We also thank the Centre of Testing and Analysis, Sichuan
University, for NMR spectroscopy measurements.
[7] The anti-selective Henry reaction was first achieved by using silyl ni-
tronates as the donors, see: a) T. Ooi, K. Doda, K. Maruoka, J. Am.
Chem. Soc. 2003, 125, 2054–2055; b) T. Risgaard, K. V. Gothelf,
K. A. Jørgensen, Org. Biomol. Chem. 2003, 1, 153–156.
[8] The direct anti-selective Henry reaction was reported recently, see:
a) D. Uraguchi, S. Sakaki, T. Ooi, J. Am. Chem. Soc. 2007, 129,
12392–12393; b) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga,
M. Shibasaki, Angew. Chem. 2008, 120, 3274–3277; Angew. Chem.
Int. Ed. 2008, 47, 3230–3233; c) T. Nitabaru, A. Nojiri, M. Kobaya-
shi, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 13860–
13869; d) T. Nitabaru, N. Kumagai, M. Shibasaki, Tetrahedron Lett.
2008, 49, 272–276; e) G. Blay, L. R. Domingo, V. Hernꢁndez-Olmos,
J. R. Pedro, Chem. Eur. J. 2008, 14, 4725–4730; f) S. Selvakumar, D.
Sivasankaran, V. K. Singh, Org. Biomol. Chem. 2009, 7, 3156–3162;
and also see reference [6].
[9] a) H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shiba-
saki, J. Org. Chem. 1995, 60, 7388–7389; b) T. Arai, Y. M. A.
Yamada, N. Yamamoto, H. Sasai, M. Shibasaki, Chem. Eur. J. 1996,
2, 1368–1372.
[10] a) A. V. Davis, M. Driffield, D. K. Smith, Org. Lett. 2001, 3, 3075–
3078; b) A. Toussaint, A. Pfaltz, Eur. J. Org. Chem. 2008, 4591–
4597; c) H. Y. Kim, K. Oh, Org. Lett. 2009, 11, 5682–5685; and also
see reference [4e] and [4m].
Keywords: aldehydes
bisimidazoline · copper · nitroaldol reaction
·
asymmetric
catalysis
·
[1] L. Henry, C. R. Hebd, Sꢀances Acad. Sci. 1895, 120, 1265–1267.
[2] H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J. Am. Chem.
Soc. 1992, 114, 4418–4420.
[3] For reviews on the catalytic asymmetric Henry reaction, see: a) M.
Shibasaki, H. Grçger in Comprehensive Asymmetric Catalysis,
Vol. III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, pp. 1075–1090; b) M. Shibasaki, H. Grçger, M. Kanai
in Comprehensive Asymmetric Catalysis, Supplement 1 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 2004,
pp. 131–133; c) C. Palomo, M. Oiarbide, A. Mielgo, Angew. Chem.
2004, 116, 5558–5560; Angew. Chem. Int. Ed. 2004, 43, 5442–5444;
d) J. Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetrahedron:
Asymmetry 2006, 17, 3315–3326; e) C. Palomo, M. Oiarbide, A.
Laso, Eur. J. Org. Chem. 2007, 2561–2574.
6764
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6761 – 6765

syn-Selective Nitroaldol Reaction
COMMUNICATION
[11] a) Y. Sohtome, Y. Hashimoto, K. Nagasawa, Eur. J. Org. Chem.
2006, 2894–2897; b) Y. Sohtome, N. Takemura, K. Takada, R.
Takagi, T. Iguchi, K. Nagasawa, Chem. Asian J. 2007, 2, 1150–1160.
[12] T. Arai, R. Takashita, Y. Endo, M. Watanabe, A. Yanagisawa, J.
Org. Chem. 2008, 73, 4903–4906.
[13] For syn-selective nitroaldol reaction for aromatic aldehydes, see ref-
erences [4e], [10b], and [10c].
[14] High anti-selectivity for aliphatic aldehydes is still a challenge.
[17] NMM and NMP are known bases to avoid racemization in the mix
anhydride method of peptide synthesis, see: a) G. W. Anderson, J. E.
Zimmerman, F. M. Callahan, J. Am. Chem. Soc. 1967, 89, 5012–
5017; b) F. M. F. Chen, R. Steinauer, N. L. Benoiton, J. Org. Chem.
1983, 48, 2939–2941.
[18] In our case, the enantiomeric excesses of the minor anti-adducts
were low (7–81% ee). These results indicate that the eventual epi-
merization of the syn adduct to the anti adduct remains at a lower
level.
[19] CCDC-764747 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[20] When the more bulkyl tert-butyl group took the place of the isopro-
pyl group in the catalyst, the diastereo- and enantioselectivity drop-
ped dramatically.
[15] Other Lewis acids, such as [Cu
Mg(OTf)2, and Sc(OTf)3, gave low stereoselectivity, except [Cu-
(ClO4)2]·6H2O, which showed comparable reactivity and stereoselec-
tivity with Cu(OTf)2.
ACHTUGNTRNEU(GNN acac)2], [CuACHTUNRTEGG(NNUN OAc)2]·H2O, ZnCAHTNUGTNER(NUGN OTf)2,
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[16] NMM was previously reported to show less reactivity and enantiose-
lectivity than Et3N in the nitroaldol reaction of pyruvate with nitro-
methane, see reference [4g]. It was also inferior to Et3N in the reac-
tion of benzaldehyde with nitromethane in our catalytic system:
63% yield and 89% ee in EtOH; 77% yield and 90% ee in dioxane.
Received: March 14, 2010
Published online: May 12, 2010
Chem. Eur. J. 2010, 16, 6761 – 6765
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6765