Enantioselective nitroaldol reaction catalyzed by sterically modified salen-chromium complexes

Article abstract of DOI:10.1021/jo802107b

A group of modified (salen)Cr(III)Cl complexes with bulky benzylic substituents in the 3,3'-position of the salicylidene moiety have been successfully applied for the asymmetric nitroaldol reaction. The readily accessible complex bearing 3-phenylpent-3-yl groups (2 mol %) leads to β-nitro alcohols in up to 92% yield and 94% ee.

Full text of DOI:10.1021/jo802107b

Enantioselective Nitroaldol Reaction Catalyzed by Sterically
Modified Salen-Chromium Complexes
Rafał Kowalczyk,† Piotr Kwiatkowski,‡ Jacek Skarz˙ewski,*,† and Janusz Jurczak*,‡,§
Department of Organic Chemistry, Faculty of Chemistry, Wrocław UniVersity of Technology,
50-370 Wrocław, Poland, Institute of Organic Chemistry, Polish Academy of Sciences,
01-224 Warsaw, Poland, and Department of Chemistry, UniVersity of Warsaw, 02-093 Warsaw, Poland
jurczak@icho.edu.pl; jacek.skarzewski@pwr.wroc.pl
ReceiVed September 26, 2008
A group of modified (salen)Cr(III)Cl complexes with bulky benzylic substituents in the 3,3′-position of
the salicylidene moiety have been successfully applied for the asymmetric nitroaldol reaction. The readily
accessible complex bearing 3-phenylpent-3-yl groups (2 mol %) leads to ꢀ-nitro alcohols in up to 92%
yield and 94% ee.
Introduction
complexes based on lanthanum(III), zinc, cobalt(II), and cop-
per(II) are widely exemplified. In spite of significant advances
in this area, many of the reported catalytic systems required
long reaction time, use of expensive catalyst or its high loading,
and the need of dry solvents and molecular sieves.
The asymmetric nitroaldol (Henry) reaction provides direct
access to chiral ꢀ-nitro alcohols, which are synthetic precursors
of bioactive compounds.1 Moreover, the nitro group opens the
way for further modifications by reduction, Nef reaction, as well
as displacement by the carbon, sulfur, and azide nucleophiles.
Thus, the Henry reaction provides access to a large set of useful
bifunctional compounds, particularly unusual amino alcohols
with the stereogenic carbinol center not accessible by reduction
of amino acids. When imine is applied, sequential aza-Henry
reaction and reduction afford chiral diamines.2 This powerful
tool for creating at least one stereogenic center is therefore
applicable to the synthesis of chiral ligands, pharmaceuticals,
and natural compounds.
(3) For reviews on the asymmetric nitroaldol reactions, see: (a) Palomo, C.;
Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442–5444. (b)
Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006,
17, 3315–3326. (c) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007,
2561–2574. For some latest examples of the asymmetric nitroaldol reaction, see:
(d) Ma, K.; You, J. Chem.sEur. J. 2007, 13, 1863–1871. (e) Xiong, Y.; Wang,
F.; Huang, X.; Wen, Y.; Feng, X. Chem.sEur. J. 2007, 13, 829–833. (f) Bandini,
M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem. Commun.
2007, 616–618. (g) Bandini, M.; Benaglia, M.; Sinisi, R.; Tommasi, S.; Umani-
Ronchi, A. Org. Lett. 2007, 9, 2151–2153. (h) Arai, T.; Watanabe, M.;
Yanagisawa, A. Org. Lett. 2007, 9, 3595–3597. (i) Ginotra, S. K.; Singh, V. K.
Org. Biomol. Chem. 2007, 5, 3932–3937. (j) Qin, B.; Xiao, X.; Liu, X.; Huang,
J.; Wen, Y.; Feng, X. J. Org. Chem. 2007, 72, 9323–9328. (k) Liu, X. G.; Jiang,
J. J.; Shi, M. Tetrahedron: Asymmetry 2007, 18, 2773–2781. (l) Sohtome, Y.;
Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.; Nagasawa, K. Chem. Asian
J. 2007, 2, 1150–1160. (m) Arai, T.; Yokoyama, N.; Yanagisawa, A. Chem.sEur.
J. 2008, 14, 2052–2059. (n) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R. Org.
Biomol. Chem. 2008, 6, 468–476. (o) Blay, G.; Domingo, L. R.; Hernandez-
Olmos, V.; Pedro, J. R. Chem.sEur. J. 2008, 14, 4725–4730. (p) Arai, T.;
Yokoyama, N. Angew. Chem., Int. Ed. 2008, 47, 4989–4992. (q) Liu, S.; Wolf,
C. Org. Lett. 2008, 10, 1831–1834. (r) Arai, T.; Takashita, R.; Endo, Y.;
Watanabe, M.; Yanagisawa, A. J. Org. Chem. 2008, 73, 4903–4906. (s) Lai,
G.; Wang, S.; Wang, Z. Tetrahedron: Asymmetry 2008, 19, 1813–1819. (t) Bulut,
A.; Aslan, A.; Dogan, O. J. Org. Chem. 2008, 73, 7373–7375.
Bearing in mind its value, the asymmetric nitroaldol reactions
have received increased attention from researchers, and numer-
ous catalytic systems have been drawn up.3 Among them, metal
† Faculty of Chemistry.
‡ Polish Academy of Sciences.
§ University of Warsaw.
(1) (a) Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (b) Trost, B. M.; Yeh,
V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621–2623. (c) Dodda, R.;
Goldman, J. J.; Mandal, T.; Zhao, C.-G.; Broker, G. A.; Tiekink, E. R. T. AdV.
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10.1021/jo802107b CCC: $40.75
Published on Web 12/08/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 753–756 753

Kowalczyk et al.
C2-Symmetric metallosalen complexes proved to be useful
catalysts for a wide range of reactions.4 Moreover, usually salen
ligands are easy to prepare5 and their complexes with various
metals have a benchtop stability. It is noteworthy that steric
and electronic properties of salen complexes can be varied easily
by simple modifications of salicylidene unit. Variations at the
positions 3,3′ in close proximity to the metal center have been
studied extensively,6 also in our group.7 It was proven that
increasing of steric hindrance of substituents occupying the ortho
position to the phenolic oxygen in salen ligand exerts a beneficial
effect on enantioselectivity in various reactions. Enhancement
in the effectiveness of branched ligands was rationalized to be
of steric-based distortion of a nearly planar, flat salen framework.
Metallosalens were applied in various aldol-type reactions;8
however, there are only a few successful examples for nitroaldol
reaction, utilizing cobalt(II)8a and heterobimetallic Pd/La8b salen
complexes. The first method with a classical cobalt complex8a
requires long reaction time, and its applicability is limited mainly
to halogenated aromatic aldehydes and nitromethane. In addition,
reaction with benzaldehyde provided the respective nitro alcohol
with low yield and moderate enantioselectivity (36% and 62%
ee). Therefore, we decided to investigate this reaction with other
metallosalen complexes, and we have recently found the
commercially available, salen-chromium(III)9 complex 1a
(Figure 1) to be a useful catalyst for the asymmetric Henry
reaction.10 The respective nitroaldols were achieved with
moderate to good yields and enantioselectivities (up to 76%
FIGURE 1. Salen-chromium(III) complexes 1a-h.
SCHEME 1. General Synthesis of the Sterically Modified
Catalysts
(4) For reviews on metallosalen complexes in asymmetric catalysis, see: (a)
Canali, L.; Sherrington, D. C. Chem. Soc. ReV. 1999, 28, 85–93. (b) Atwood,
D. A.; Harvey, M. J. Chem. ReV. 2001, 101, 37–52. (c) Katsuki, T. AdV. Synth.
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Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem. 2004, 6, 123–152. (g)
Cozzi, P. G. Chem. Soc. ReV. 2004, 33, 410–422. (h) McGarrigle, E. M.;
Gilheany, D. G. Chem. ReV. 2005, 105, 1563–1602. (i) Achard, T. R. J.;
Clutterbuck, L. A.; North, M. Synlett 2005, 1828–1847. (j) Baleiza˜o, C.; Garcia,
H. Chem. ReV. 2006, 106, 3987–4043. (k) Gupta, K. C.; Sutar, A. K. Coord.
Chem. ReV. 2008, 252, 1420–1450.
ee). In continuation of these studies, we attempted to optimize
the salen-chromium(III) system via modifications of the ligand
based on introduction of a more sterically demanding surround
of the metal (Figure 1).7
Results and Discussion
(5) (a) Farrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp,
C. M. J. Org. Chem. 1994, 59, 1939–1942. (b) Larrow, J. F.; Jacobsen, E. N.
Org. Synth. 1997, 75, 1–11.
Applying the concept of steric modifications of salen com-
plexes to nitroaldol reaction, several modified ligands were
prepared in an easy manner from readily accessible and
inexpensive materials (Scheme 1). Bulky subsitituents were
introduced in the ortho-position via the acid-catalyzed alkylation
of 4-tert-butyl- and 4-methylphenol by corresponding alkenes,
leading to 2,4-disubstituted phenols 2c-h. Salicylic aldehydes
of type 3 were prepared from phenols 2 according to the
Casiraghi11 procedure and finally condensed with (1R,2R)-1,2-
diaminocyclohexane tartrate to afford the crystalline salen
ligands 4 (Scheme 1).5 Chromium complexes 1a-h were
prepared using CrCl2 according to the Jacobsen procedure.12
(6) (a) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron
Lett. 1990, 31, 7345–7348. (b) Jacobsen, E. N.; Gu¨ler, M. L.; Zhang, W. J. Am.
Chem. Soc. 1991, 113, 6703–6704. (c) Hosoya, N.; Irie, R.; Katsuki, T. Synlett
1993, 261–264. (d) Sasaki, T.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T.
Tetrahedron 1994, 50, 11827–11838. (e) Pospisil, P. J.; Carsten, D. H.; Jacobsen,
E. N. Chem.sEur. J. 1996, 2, 974–980. (f) Ito, Y. N.; Katsuki, T. Bull. Chem.
Soc. Jpn. 1999, 72, 603–619. (g) Pietikainen, P. Tetrahedron 2000, 56, 417–
424. (h) O’Mahony, C. P.; McGarrigle, E. M.; Renehan, M. F.; Rayan, K. M.;
Kerrigan, N. J.; Bousquet, C.; Gilheany, D. G. Org. Lett. 2001, 3, 3435–3438.
(i) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 5950–
5951. (j) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702–2704. (k) Nicewicz,
D. A.; Yates, C. M.; Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 2652–
2655. (l) Hutson, G. E.; Dave, A. H.; Rawal, V. H. Org. Lett. 2007, 9, 3869–
3872.
(7) (a) Kwiatkowski, P.; Chaładaj, W.; Jurczak, J. Synlett 2005, 2301–2304.
(b) Kwiatkowski, P.; Chaładaj, W.; Jurczak, J. Tetrahedron 2006, 62, 5116–
5125. (c) Chaładaj, W.; Kwiatkowski, P.; Jurczak, J. Synlett 2006, 3263–3266.
(d) Chaladaj, W.; Kwiatkowski, P.; Majer, J.; Jurczak, J. Tetrahedron Lett. 2007,
48, 2405–2408. (e) Chaladaj, W.; Kwiatkowski, P.; Jurczak, J. Tetrahedron Lett.
2008, 49, 6810–6811.
(8) For aldol-type reactions catalyzed by metallosalens, see: (a) Kogami, Y.;
Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis 2004, 1947–1950. (b) Handa, S.;
Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2008, 47, 3230–3233. (c) Mascarenhas, C. M.; Miller, S. P.; White, P. S.;
Morken, J. P. Angew. Chem., Int. Ed. 2001, 40, 601–603. (d) Evans, D. A.;
Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40,
1884–1888. (e) Shimada, Y.; Matsuoka, Y.; Irie, R.; Katsuki, T. Synlett 2004,
5, 7–60. (f) Chen, D.; Timmons, C.; Liu, J.; Headley, A.; Li, G. Eur. J. Org.
Chem. 2004, 3330–3335. (g) Chen, D.; Guo, L.; Kotti, S. R. S. S.; Li, G.
Tetrahedron: Asymmetry 2005, 16, 1757–1762. (h) Chen, Z.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 130, 2170–2171. (i) Wang,
S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Org. Lett. 2007, 9, 3615–3618. (j)
Kull, T.; Peters, R. Angew. Chem., Int. Ed. 2008, 47, 5461–5464.
(9) For some recent examples of asymmetric reactions catalyzed by salen-
chromium complexes, see: (a) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2005, 127, 62–63. (b) Shimada, Y.; Katsuki, T. Chem. Lett. 2005, 34, 786–787.
(c) Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128, 4940–4941. (d)
Berkessel, A.; Vogl, N. Eur. J. Org. Chem. 2006, 5029–5036. (e) Berkessel, A.;
Erturk, E. AdV. Synth. Catal. 2006, 348, 2619–2625. (f) Doyle, A. G.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2007, 46, 3701–3705. (g) Kwon, H. Y.; Park,
C. M.; Lee, S. B.; Youn, J.-H.; Kang, S. H. Chem.sEur. J. 2008, 14, 1023–
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A.; Mellah, M.; Guillot, R.; Schulz, E. Eur. J. Org. Chem. 2008, 2118–2129.
(10) Kowalczyk, R.; Sidorowicz, Ł.; Skarzewski, J. Tetrahedron: Asymmetry
2007, 18, 2581–2586.
(11) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. J. Chem.
Soc., Perkin Trans. 1 1980, 1862–1865.
754 J. Org. Chem. Vol. 74, No. 2, 2009

EnantioselectiVe Nitroaldol Reaction
TABLE 1. Screening of the Catalyst in the Nitroaldol Reactiona
TABLE 2. Optimization of Reaction Conditions for the Complex
1ha
entry
T (°C)
nitromethane (equiv) yieldb (%) eec (%)
1
2
-78
74 (2 mL)
74 (2 mL)
10
10
1.0
2.0
18
62
51
58
72
77
48
93
87
82
93
93
-78 (0.5 h) -20
-78 (0.5 h) -20
-78 (0.5 h) -20
-78 (0.5 h) -20
-78 (0.5 h) -20
3
catalyst
4d
5
entry
no.
R1
R2
R3
yieldb (%)
eec (%)
6e
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Me
H
Me
-(CH2)4-
Me
Me
-(CH2)4-
Et
Me
H
36
16
70
55
65
77
78
62
57 (S)
19 (R)
76 (S)
70 (S)
90 (S)
79 (S)
89 (S)
93 (S)
a Reactions were carried out using 2 mol % of catalyst 1h, 0.5 mmol
of benzaldehyde, and 0.5 mmol of DIPEA in 2.0 mL of CH2Cl2.
b Yields of isolated product 5a by column chromatography on silica gel.
c ee were determined by HPLC on chiral stationary phase (OD-H).
d (Salen)Cr(III)BF4 was used. e The reaction was performed in 1.0 mL
of CH2Cl2.
i-Pr
Me
Ph
Ph
Ph
Ph
1g
1h
t-Bu
t-Bu
a Reactions were performed on 0.5 mmol of benzaldehyde, 0.5 mmol
of DIPEA, and 2.0 mL of nitromethane in 2.0 mL of CH2Cl2 applying 2
mol % of the respective (1R,2R)-salen-chromium(III) complex initially
at -78 °C (0.5 h) and then at -20 °C (20 h). b Yields of isolated
product by column chromatography on silica gel. c ee were determined
by HPLC on chiral stationary phase (OD-H).
TABLE 3. Scope of Aldehydes in the Henry Reaction with
Nitromethane Catalyzed by 1ha
product
For the initial study, we employed the reaction of benzalde-
hyde with nitromethane in the presence of diisopropylethylamine
(DIPEA) and 2 mol % of chromium complexes of type 1 (Figure
1, Table 1). The classical Jacobsen complex 1a catalyzes
the trial reaction with a moderate enantioselectivity (entry 1,
Table 1); however, use of the complex 1b with smaller methyl
groups at the 3,3′-positions instead of tert-butyl resulted in
dropping of both the yield and enantioselectivity (entry 2).
Additionally, the direction of asymmetric induction was re-
versed. Simple expansion of bulkiness of the substituents by
replacement of tert-butyl group in Jacobsen catalyst with 2,3-
dimethylbut-2-yl (complex 1c, entry 3) led to a substantial
increase of the yield and enantioselectivity from 57 to 76% ee.
A steady increase of ee’s was noted as a result of further
modifications of the substituent at 3,3′ position of salicylidene
unit. Interestingly, introduction of the branched benzylic sub-
stituents had a beneficial effect on stereoselectivity as well as
activity (entries 5-8) in each case compared to the classical
salen-chromium 1a10 and cobalt(II)8a complexes. A simple
replacement of one methyl in the 3,3′-tert-butyl groups in 1a
with phenyl (catalyst 1e) resulted in a significant increase of
enantioselectivity to 90% (entry 5). Bulky groups at the 5,5′-
positions also have a beneficial effect on the selectivity in this
reaction; the use of the corresponding complex with methyl
instead of 5,5′-tert-butyl groups, 1f, gave the product 5a with
lower enantioselectivity (79% ee, entry 6). Until now, the best
result was obtained for the catalyst 1h bearing a sterically
demanding 3-phenylpent-3-yl group in the 3,3′-positions (93%
ee, entry 8).
entry
no.
R
yieldb (%) eec (%) and configurationd
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
77
82
76
68
65
74
84
81
92
51
56
25
54
38
61
93 (S)
94 (S)
85 (S)
85 (S)
80 (S)
84 (S)
83 (S)
75 (S)
91 (S)
70 (S)
86 (R)
80 (S)
81 (S)
90 (S)
83 (S)
pPh-C6H4
pCl-C6H4
pBr-C6H4
pCN-C6H4
mCl-C6H4
oF-C6H4
oMeO-C6H4
2-naphthyl
1-naphthyl
2-furyl
9
10
11
12
13e
14
15e
5j
5k
5l
PhCHdCH
PhCHdCH
5l
5m cyclohexyl
5m cyclohexyl
a Reactions were performed using 2 mol % of catalyst 1h, 1.0 mmol
of aldehyde, 1.0 mmol of DIPEA, and 2.0 mmol of nitromethane in 1.0
mL of CH2Cl2 initially at -78 °C (0.5 h) and then at -20 °C (20 h).
b Yields of isolated product by column chromatography on silica gel.
c ee were determined by HPLC on chiral stationary phases (OD-H,
AD-H). d Absolute configuration assigned by measurement of optical
rotation and comparison with the literature data. e Reactions were
performed 0.5 h at -78 °C and then 20 h at -4 °C.
The reaction works well for aromatic aldehydes with enanti-
oselectivities usually over 80% up to 94% ee (entries 1-11). The
highest enantiomeric excesses (over 90%) were observed for
benzaldehyde, p-biphenylcarbaldehyde, and 2-naphthaldehyde (en-
tries 1, 2, and 9). Benzaldehydes bearing an electron-withdrawing
group (Cl, Br, CN) at the para (entries 3, 4 and 5) and meta (entry
6) positions gave the respective nitro alcohols with slightly
diminished ee (80-86%). Interestingly, for the aromatic aldehydes
with substituents at the ortho position, e.g., 2-methoxybenzaldehyde
and 1-naphthaldehyde, the ee was below 80% (entries 8 and 10),
with the exception for small substituents, e.g., fluorine (83% ee,
entry 7). This implies that the geometry of the substrate has a
detrimental effect on the enantioselectivity.
Heteroaromatic (furfural, entry 11), R,ꢀ-unsaturated (cinna-
maldehyde, entry 12), and aliphatic aldehydes (cyclohexylcar-
baldehyde, entry 14) were also possible partners in the nitroaldol
reaction affording the respective nitroalcohols in up to 90% ee.
Low conversions of some substrates were overcame by increas-
ing the reaction temperature with slight or no lowering of the
ee (entries 13 and 15).
After screening of the most efficient ligand structure, we
studied effects of temperature and concentration on enantiose-
lectivity in the nitroaldol reaction with benzaldehyde catalyzed
by complex 1h (Table 2).
Our efforts revealed that increasing concentration and the
reaction temperature from -78 to -20 °C led to the product in
77% yield and 93% ee (entry 6). Application of the more acidic
chromium complex with ligand 4h and the less coordinating
counterion BF4- gave the product with a lower enantioselectivity
(entry 4).
In order to evaluate the scope of the nitroaldol reaction
catalyzed by complex 1h, we applied the optimized procedure
to various aldehydes (Table 3).
(12) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am.
Chem. Soc. 1995, 117, 5897–5898.
J. Org. Chem. Vol. 74, No. 2, 2009 755

Kowalczyk et al.
Precursors of Catalyst 1h. 4-tert-Butyl-2-(3-phenylpent-3-
yl)phenol (2h). To stirred solution of p-tert-butylphenol (6.0 g,
40.0 mmol) and 3-phenylpent-2-ene (9.76 g, 60 mmol, 1.5 equiv)
in 20 mL of CH2Cl2 was added methanosulfonic or sulfuric acid
(2 mL) dropwise at 0 °C. The resulting solution was stirred
overnight at room temperature. Then water (30 mL) and CH2Cl2
(30 mL) were added, and the organic phase was separated, washed
with saturated NaHCO3, dried with MgSO4, and concentrated. The
resulting crude reaction mixture was dissolved in a minimum
volume of hot EtOH and crystallized giving the product with 52%
yield as a colorless crystals: mp ) 120-122 °C; IR (film) ν 3504,
2965, 2950, 2877, 1494, 1209, 824, 764, 704 cm-1; 1H NMR (200
MHz, CDCl3) δ 7.43 (d, J)2.4 Hz, 1H), 7.38-7.19 (m, 5H), 7.16
(dd, J ) 8.4, 2.4 Hz, 1H), 6.65 (d, J ) 8.4 Hz, 1H), 3.81 (bs, 1H),
2.30-1.95 (m, 4H), 1.35 (s, 9H), 0.60 (t, J ) 7.3 Hz, 6H); 13C
NMR (50 MHz, CDCl3) δ 151.5, 146.4, 142.3, 132.1, 128.9, 127.4,
126.9, 125.2, 124.3, 117.0, 48.4, 34.3, 31.7, 27.4, 8.3; HRMS calcd
for C21H28ONa (ESI, [M + Na]+) 319.2032, found 319.2040.
5-tert-Butyl-2-hydroxy-3-(3-phenylpent-3-yl)benzaldehyde (3h). Pre-
pared according to the Casiraghi procedure:11 yield 70%, light yellow
crystals; mp ) 96-97 °C, crystallized from MeOH; IR (KBr) ν 3059,
Salen-chromium complexes with (1R,2R) configuration led
to formation of nitroalcohols 5 with (S)-configuration ((R) in
the case of furfural), as a consequence of nitronate approach at
the Re face of the aldehyde. This direction of asymmetric
induction is in a good agreement with the results observed in
other reactions of aldehydes catalyzed by salen-chromium
complexes and the proposed stereochemical model.7b
Conclusion
We have shown that the easily accessible (salen)Cr(III)Cl
complex 1h with bulky substituents at the 3,3′-positions
catalyzes the asymmetric nitroaldol reaction with enantioselec-
tivities usually over 80% up to 94% ee, significantly higher than
the classical Jacobsen complex. Although a dozen protocols have
been reported to provide nitro alcohols of type 5 with ees
reaching 90%,3d-j,m,o,q-t we believe that application of modified
salen-chromium complexes demonstrates a promising alterna-
tive approach to these products. Moreover, the advantage of
our catalytic system is low loading of 1h (2 mol %), relatively
short reaction time, and mild conditions, with no need for
anhydrous solvents or an inert atmosphere.
1
2961, 2875, 1644, 1611, 1446, 1259, 1210, 761, 698, 545 cm-1; H
NMR (400 MHz, CDCl3) δ 11.17 (d, J ) 0.6 Hz, 1H), 9.79 (s, 1H),
7.77 (d, J ) 2.4 Hz, 1H), 7.37 (d, J ) 2.4 Hz, 1H), 7.24-7.20 (m,
2H), 7.14-7.12 (m, 3H), 2.41 (dt, J ) 7.3 Hz, 2H), 2.04 (dt, J ) 7.3
Hz, 2H), 1.38 (s, 9H), 0.60 (t, J ) 7.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 196.9, 158.4, 147.7, 141.1, 135.1, 133.9, 127.8, 127.4, 126.9,
125.1, 119.9, 48.7, 34.2, 31.3, 26.9, 8.5; HRMS calcd for C22H28O2Na
(ESI [M + Na]+) 347.1982, found 347.1998.
Experimental Section
General Procedure for Catalyst Screening in the Nitroaldol
Reaction of Benzaldehyde with Nitromethane (Table 1).
Salen-chromium(III) complex 1a-h (0.01 mmol, 2 mol%) was
placed in a 10 mL reaction vessel and dissolved in dichloromethane
(0.5 mL). After the complex was cooled to -78 °C (acetone-dry
ice bath), benzaldehyde (53 mg, 51 µL, 0.5 mmol, 1.0 equiv) in
CH2Cl2 (0.5 mL) followed by nitromethane (2.0 mL) and solution
of DIPEA (86 µL, 1.0 equiv) in CH2Cl2 (1.0 mL) were added at 5
min intervals. The resulting solution was stirred for 0.5 h at -78
°C, then put into the freezer (-20 °C) for 20 h, and finally diluted
with n-hexane (5 mL). Purification by flash chromatography on
silica gel (gradient n-hexane/AcOEt 9:1-7:3, v/v) afforded the
desired nitro alcohol 5a.
(1R,2R)-N,N′-Bis[5-tert-butyl-3-(3-phenylpent-3-yl)salicylidene]-
1,2-cyclohexanediamine (4h). Prepared according tothe Jacobsen
procedure.5 A round-bottom, 150 mL flask was charged with (1R,2R)-
cyclohexanediamine L-tartrate salt (2.65 g, 10 mmol, 1.0 equiv), K2CO3
(3.1 g, 22 mmol), and water (12 mL). The resulted mixture was stirred
for 10 min followed by addition of ethanol (96%, 50 mL) and heated
to 60-70 °C for 0.5 h. The temperature was maintained, and aldehyde
3h (6.82 g, 21 mmol) was added in one portion. The mixture was
vigorously stirred and refluxed for 3 h. Ligand 4h oiled out from the
reaction mixture. The mixture was concentrated to ca. 1/4 of its initial
volume, dissolved in CH2Cl2 (75 mL), and washed with water (2 ×
50 mL). The organic phase was dried and concentrated to give a yellow
solid which was dissolved in 25 mL of hot ethanol. The resulting
solution was cooled to ambient temperature, and 10 mL of 50%
aqueous ethanol was added to produce yellow precipitate that was
collected with 81% yield: yellow crystals; mp ) 92-94 °C; [R]D)
+325.6 (c 0.53, CHCl3); IR (KBr) ν· 2963, 2875, 1628 (νCdN), 1597,
1445, 1263, 699 cm-1; 1H NMR (500 MHz, CDCl3) δ 13.10 (s, 2H),
7.98 (s, 2H), 7.43 (d, J ) 2.4 Hz, 2H), 7.08-7.20 (m, 10H), 6.89 (d,
J ) 2.4 Hz, 2H), 3.02-3.07 (m, 2H), 2.28-2.44 (m, 4H), 1.98-2.07
(m, 4H), 1.70-1.80 (m, 4H), 1.49-1.59 (m, 2H), 1.29-1.32 (m, 2H),
(S)-1-Phenyl-2-nitroethanol (5a):13 77% yield; [R]22D ) +41.7
(c 0.28, CH2Cl2), 93% ee by HPLC analysis (Chiracel OD-H
column, 1.0 mL/min, n-hexane/i-PrOH 90:10, λ ) 206 nm), (R)-
1
isomer tR ) 13.33 min and (S)-isomer tR )16.19 min; HNMR
(CDCl3, 500 MHz) δ 7.35-7.41 (m, 5H), 5.46 (dd, J ) 9.6, 2.9
Hz, 1H), 4.61 (dd, J )13.4, 9.6 Hz, 1H), 4.52 (dd, J )13.4, 3.0
Hz, 1H), 2.82 (bs, 1H); 13CNMR (CDCl3, 125 MHz) δ 138.1, 129.0,
128.9, 125.9, 81.2, 71.0.
General Procedure for the Optimized Nitroaldol Reaction
Catalyzed by Complex 1h (Table 3). Complex 1h(8.2 mg, 0.02
mmol, 2 mol %) was dissolved in dichloromethane (0.5 mL) in a 5
mL reaction vessel stoppered with a rubber septum. The resulted brown
solution was cooled to -78 °C, and a solution of the respective
aldehyde (1.0 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) was added via
syringe. After 5 min, nitromethane (100 µL, 2.0 mmol, 2.0 equiv)
followed by DIPEA (172 µL, 1.0 mmol, 1.0 equiv) were infused. The
reaction mixture was stirred 0.5 h at -78 °C and then left at -20 °C
in the refrigerator for 20 h. Dilution by n-hexane and purification by
flash chromatography on silica gel (gradient n-hexane/AcOEt 9:1-7:
3, v/v) afforded the desired products 5a-m. Ee’s were determined by
HPLC on chiral columns (Chiralcel OD-H or Chiralpak AD-H).
Catalyst 1h. Prepared according to the Jacobsen procedure.12
(1R,2R)-1h: [R]D ) -1420.0 (c 0.01 CHCl3); IR (KBr) ν 3429,
2961, 1622 (νCdN), 1533, 1437, 1258, 700, 546 cm-1; HRMS calcd
for C50H64N2O2Cr (ESI [M - Cl]+) 776.4373, found 776.4392.
Anal. Calcd for C50H64N2O2CrCl: C, 73.91; H, 7.94; N, 3.45; Cl,
4.36. Found: C, 73.76; H, 8.10; N, 3.17; Cl, 4.35.
1.28 (s, 18H), 0.57 (t, J ) 7.3 Hz, 6H), 0.51 (t, J ) 7.3 Hz, 6H); 13
C
NMR (125 MHz, CDCl3) δ 165.6, 157.5, 148.6, 139.2, 133.2, 129.2,
127.2, 127.0, 125.9, 124.7, 117.6, 72.3, 49.0, 34.0, 32.9, 31.4, 28.1,
27.2, 24.2; HRMS calcd for C50H66N2O2Na (ESI [M + Na]+)
749.5022, found 749.5021. Anal. Calcd for C50H66N2O2: C, 82.60; H,
9.15; N, 3.85. Found: C, 82.55; H, 9.23; N, 3.83.
Acknowledgment. Financial support from the Ministry of
Science and Higher Education (Grant PBZ-KBN-118/T09/16)
and from the Foundation for Polish Science (individually for
R.K. and P.K.) is gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures, analytical data for (salen)Cr(III)Cl complexes 1 and their
precursors (2-4), as well as reprints of NMR spectra for
nitroaldol products 5a-m. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, W. H.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693.
JO802107B
756 J. Org. Chem. Vol. 74, No. 2, 2009