Cu-catalyzed asymmetric Henry reaction promoted by chiral camphor Schiff bases

Article abstract of DOI:10.1016/j.molcata.2016.02.004

Five novel chiral camphor Schiff bases have been synthesized and utilized as ligands in asymmetric Henry reaction between nitromethane and aldehydes. The diastereoisomeric Schiff bases 5a and 5a' were separated successfully and gave completely different a

Full text of DOI:10.1016/j.molcata.2016.02.004

Accepted Manuscript
Title: Cu-catalyzed Asymmetric Henry Reaction Promoted by
Chiral Camphor Schiff Bases
Author: Tangqian Jiao Jingxuan Tu Gaoqiang Li Feng Xu
PII:
S1381-1169(16)30038-3
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.02.004
MOLCAA 9769
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
28-10-2015
30-1-2016
2-2-2016
Please cite this article as: Tangqian Jiao, Jingxuan Tu, Gaoqiang Li,
Feng Xu, Cu-catalyzed Asymmetric Henry Reaction Promoted by Chiral
Camphor Schiff Bases, Journal of Molecular Catalysis A: Chemical
http://dx.doi.org/10.1016/j.molcata.2016.02.004
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Cu-catalyzed Asymmetric Henry Reaction Promoted by Chiral Camphor Schiff
Bases
Tangqian Jiao, Jingxuan Tu, Gaoqiang Li, Feng Xu*
Key Laboratory of Macromolecular Science of Shaanxi Province, School of
Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi
710062, PR China
Highlights

Cu-camphor Schiff base complexes were firstly investigated as catalysts in
asymmetric Henry reaction

The diastereoisomeric Schiff bases 5a and 5a' were successfully isolated and
gave completely converse absolute configuration of catalyzed products when it
used in the Henry reaction as ligand, respectively.

The chiral camphor Schiff base 5a, together with CuCl, showed high efficiency in
catalyzed asymmetric Henry reactions between various aldehydes and
nitromethane.
Abstract
Five novel chiral camphor Schiff bases have been synthesized and utilized as ligands
in asymmetric Henry reaction between nitromethane and aldehydes. The
diastereoisomeric Schiff bases 5a and 5a' were separated successfully and gave
completely different absolute configurations in the reaction. The reactions were
carried out with CuCl-Schiff base 5a complex under mild condition with good yields
and enantioselectivities. This is the first time that camphor-derivated Schiff bases
were used as ligands in asymmetric Henry reaction.
Keywords: Camphor；Schiff base; Henry reaction; Copper complex;
enantioselectivity.
1. Introduction
The Henry (nitroaldol) reaction is an attractive C-C bond-forming reaction in which

a nitroalkane compound is added to an aldehyde or ketone to obtain primarily a
β-nitroalcohol, which may be subsequently converted into synthetically useful
derivatives such as carboxylic acids, aldehydes, α-hydroxy ketones, amino alcohols,
azides, sulphides and other useful compounds by FGT (Functional Group
Transformation)[1]. Significantly, chiral amino alcohols obtained by reduction of
chiral β-nitroalcohols have been found widespread utility as chiral ligands in
asymmetric catalysis, and as an important building block of natural products as well
as pharmaceuticals[2]. Due to the importance of chiral β-nitroalcohols in organic
synthesis, considerable efforts have been focused on the development of catalytic
enantioselective version of the Henry reaction on the basis of the use of coordinating
complexes of transition metals or lanthanides with chiral ligands[3]. In particular,
chiral copper complexes have received particular attention in terms of wide structural
variability of the chiral ligands (bisoxazolines[4], amino alcohols[5], diamines[6],
sulfonamides[7], aminopyridines[8], Schiff bases[9] etc.), low toxicity, low cost,
excellent chelating ability, ease of handling and ready availability. Chiral Schiff bases
and their complexes with transition metals are one of the most studied chiral catalysts
and have been extensively applied in asymmetric synthesis[10]. D-(+)-camphor plays
an important role in the asymmetric synthesis in terms of its low cost, rigid structure
and convenience to transform into synthetically useful derivatives. Chiral camphor
derived Schiff base has already been reported in enantioselective
trimethylsilylcyanation of aldehydes[11]. But the report of chiral camphor derived
Schiff bases used in enantioselective Henry reaction is still rare. We have paid much
attention to modifying the novel chiral frame of camphor and studying their
applications in asymmetric reaction[12]. Therefore, the development of new chiral
camphor Schiff bases and investigation on its activities in Cu-catalyzed
enantioselective Henry reaction are proceeding in our laboratory. The results are
recorded here.
2. Experimental section
2.1 General
All the starting materials and reagents were obtained from commercial sources and

used directly without further purification. The solvents were purified by standard
techniques. The reactions were monitored by thin layer chromatography (TLC). Flash
1
column chromatography was carried out on silica gel (200-400 mesh). H NMR and
13C NMR spectra were recorded on Bruker AVANCE-300 and Bruker AVANCE-400
spectrometers (with TMS as an internal standard). Melting points were recorded on a
melting point apparatus and uncorrected. Optical rotations were measured on a
Rudolph Autopol IV-T polarimeter in the indicated solvent. Enantiomeric excesses
were determined using Shimadzu LC-20AT high performance liquid chromatography
with a chiralcel OD-H column.
2.2 General procedure for the preparation of diastereoisomers 5a and 5a'
Camphor amino ketone 1 (1.53g, 10 mmol) was added to a 50 mL round-bottomed
flask containing 10 mL methanol, then cooled to -15oC. Sodium borohydride (0.95g,
25 mmol) was slowly added portionwise to the flask over 20 minutes. The mixture
was stirred overnight at -15oC, then warmed to room temperature naturally and stirred
for additional 3h, subsequently, removed the methanol under reduced pressure, added
the H2O (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined
organic solution was dried over Na2SO4, filtered and concentrated under vacuum. The
mixed diastereoisomer of amino alcohol 2 was obtained (1.29g, 83%).
The produced diastereoisomeric amino alcohol 2 (0.78g, 5 mmol), the
4-hydroxy-salicylaldehyde 4a (0.69g, 5 mmol) and anhydrous sodium sulfate (1.42g,
10 mmol) were suspended in dry ethanol (35 mL). The mixture was stirred at reflux
for 12h, and then the solvent was evaporated under reduced pressure to obtain crude
product. Diastereoisomer 5a and 5a' were obtained in 74% (1.02g) and 20% (0.28g)
yield by purification the crude product through flash column chromatography on a
silica gel using petroleum ether and ethyl acetate as eluent.
2.2.1 4-(((1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-ylimino)methyl)
benzene-1,3-diol 5a
。
Pale yellow solid, 1.02g, yield: 74%, mp: 220 – 221.8℃, [α]20 =
(c 0.95,
-174.59
D

1
CH2Cl2); H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 9.90 (d, J = 22.4 Hz, 1H),
8.26 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.09 (dd, J = 8.8, 2.0 Hz, 1H), 5.98
(d, J = 2 Hz, 1H), 5.24 – 5.25 (m, 1H), 3.75 – 3.78 (m, 1H), 1.91 – 1.94 (m, 1H), 1.76
– 1.83 (m, 4H), 1.19 – 1.31 (m, 2H), 1.12 (s, 3H), 0.81 (s, 3H). 13C NMR (101 MHz,
DMSO) δ 171.6, 163.0, 162.2, 134.2, 111.2, 105.9, 103.6, 75.6, 71.4, 47.3, 42.4, 40.4,
28.44, 26.6, 19.7, 19.7. HRMS (ESI, M+H+) calcd. for C16H22NO3 276.1594, found
276.1599.
2.2.2 4-(((1S,2S,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-ylimino)methyl)
benzene-1,3-diol 5a'
Pale yellow solid, 0.28 g, yield: 20%, mp: 226.4 – 227.8℃, [α]2D0 =-216o (c 1.0,
CHCl3); 1H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 9.92 (s, 1H), 8.24 (s, 1H), 7.21
(d, J = 8.4 Hz, 1H), 6.24 (dd, J = 8.4, 2.3 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 4.97(d, J
= 5.3Hz, 1H), 4.15 (t, J = 4.9Hz, 1H), 2.25 – 2.31 (m, 2H), 1.75 – 1.90 (m, 1H), 1.69
– 1.71 (m, 1H), 1.42 – 1.49 (m, 2H), 1.08 (d, J = 3.4 Hz, 1H), 1.05 (s, 3H), 0.85 (s,
13
3H). C NMR (101 MHz, DMSO) δ 166.1, 163.9, 162.1, 133.8, 112.1, 106.9, 103.1,
74.8, 73.3, 49.1, 42.9, 40.6, 28.1, 21.9, 20.2, 18.9. HRMS (ESI, M+H+) calcd. for
C16H22NO3 276.1600, found 276.1599.
2.3 General procedure for the preparation of the chiral camphor amino alcohol 2a[12]
Solid CeCl3•7H2O (2.60g, 7 mmol) was added to a solution of the chiral camphor
isocyanate 3 (5.01g, 28 mmol) in 100 mL of dry methanol in 250 mL single-necked
flask at 0℃. The mixture was cooled to -78℃, slowly added solid sodium
borohydride (5.30g, 140 mmol) portionwise over 1h, then continuously stirred at
-78℃ for one more hour. After that, the reaction mixture was warmed to -40℃ and
continuously stirred for 2h, then naturally warmed to 25℃. 6N KOH (50 mL) was
added to the remaining slurry which was obtained by removing the methanol from the
reaction mixture under reduced rotation. The resulting mixture was heated to reflux
for 3h, cooled to room temperature, and extracted with dichloromethane (100mL) for
three times. The combined organic phases were dried over anhydrous sodium sulfate,

filtered, concentrated to obtain a white crude camphor amino alcohol. The optically
pure camphor amino alcohol 2a (2.83g, 65%) was obtained after separating the crude
camphor amino alcohol by column chromatography.
2.4 General procedure for the preparation of the chiral camphor Schiff base ligands
Chiral camphor amino alcohol 2a (0.62g, 4 mmol), the corresponding
salicylaldehyde derivatives 4a-4f (4 mmol) and anhydrous sodium sulfate (1.14g, 8
mmol) were dissolved in dry ethanol (30 mL). The mixture was stirred at reflux for
12h, and then the solvent was evaporated under reduced pressure. The crude product
was purified to obtain the final product by flash column chromatography on a silica
gel using petroleum ether and ethyl acetate as eluent.
2.4.1 4-(((1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-ylimino)methyl)
benzene-1,3-diol 5a
Pale yellow solid, 0.83g, yield: 75%.
2.4.2
(1S,2R,4R)-1-(4-butoxy-2-hydroxybenzylideneamino)-7,7-dimethylbicyclo-
[2.2.1]heptan-2-ol 5b
。
Yellow solid, 1.03 g, yield: 78%, mp: 78 – 79.2℃, [α]20 =
(c 1.0, CH2Cl2),
-197.67
D
1H NMR (400 MHz, CDCl3) δ 14.21 (s, 1H), 7.54 (s, 1H), 6.61 – 6.64 (m, 1H), 5.98 –
6.01 (m, 2H), 5.12 (s, 1H), 3.83 – 3.89 (m, 3H), 1.94 – 1.96 (m, 1H), 1.66 – 1.85 (m,
6H), 1.39 – 1.44 (m, 2H), 1.15 – 1.20 (m, 5H), 0.86 – 0.90 (m, 3H), 0.70 – 0.73 (m,
13
3H). C NMR (101 MHz, CDCl3) δ 174.4, 164.5, 159.8, 133.3, 110.1, 105.1, 102.0,
75.9, 70.4, 66.5, 47.0, 41.9, 38.9, 30.1, 26.5, 25.8, 18.7, 18.5, 18.2, 12.8. HRMS (ESI,
M+H+) calcd. for C20H30NO3 332.2220, found 332.2225.
2.4.3 (1S,2R,4R)-1-(3,5-di-tert-butyl-2-hydroxybenzylideneamino)-7,7-dimethylbicy
clo[2.2.1]heptan-2-ol 5c
。
Yellow solid, 1.28 g, yield: 86%, mp: 149 – 150℃, [α]20 =
(c 0.4, CH2Cl2),
- 51.34
D
1H NMR (400 MHz, CDCl3) δ 13.97 (s, 1H), 8.46 (s, 1H), 7.40 (s, 1H), 7.14 (s, 1H),

3.85 (d, J = 6.0 Hz, 1H), 2.15 (s, 1H), 1.88 – 2.10 (m, 5H), 1.45 (s, 9H), 1.32 (s, 9H),
1.25 – 1.30 (m, 5H), 0.86 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.0, 158.6, 140.0,
137.1, 127.1, 126.2, 118.1, 78.8, 74.8, 48.1, 43.7, 39.8, 35.1, 34.2, 31.5, 29.5, 28.0,
27.1, 20.2, 20.0. HRMS (ESI, M+H+) calcd. for C24H38NO2 372.2897, found
372.2906.
2.4.4
(1S,2R,4R)-1-(5-bromo-2-hydroxybenzylideneamino)-7,7-dimethylbicyclo
[2.2.1]heptan-2-ol 5d
20
。
Yellow solid, 1.12 g, yield: 83%, mp: 101.4 – 105℃, [α] =
(c 0.98,
- 74.56
D
1
CH2Cl2). H NMR (400 MHz, CDCl3) δ 14.22 (s, 1H), 8.27 (s, 1H), 7.34 – 7.38 (m,
2H), 6.81 (d, J = 8.8 Hz, 1H), 3.90 (dd, J = 8.0, 3.6 Hz, 1H), 2.46 (s, 1H), 2.04 – 2.10
(m, 1H), 1.88 – 2.00 (m, 4H), 1.23 – 1.34 (s, 5H), 0.84 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 195.4, 163.0, 139.7, 135.6, 133.8, 120.4, 119.8, 108.7, 78.3, 74.4, 48.4, 43.5,
40.1, 27.7, 27.0, 19.8. HRMS (ESI, M+H+) calcd. for C16H21BrNO2 338.0750, found
338.0755.
2.4.5
(1S,2R,4R)-1-(2-hydroxy-3-methylbenzylideneamino)-7,7-dimethylbicyclo
[2.2.1]heptan-2-ol 5e
20
。
Yellow solid, 0.87g, yield: 80%, mp: 148.8 – 149.6℃, [α] =
(c 1.0,
-55.26
D
1
CH2Cl2). H NMR (400 MHz, CDCl3) δ 14.20 (s, 1H), 8.39 (s, 1H), 7.19 (d, J = 7.2
Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 3.86 (dd, J = 8.0, 3.6 Hz,
1H), 2.38 (s, 1H), 2.28 (s, 3H), 2.03 – 2.08 (m, 1H), 1.87 – 2.00 (m, 4H), 1.23 – 1.33
(s, 5H), 0.85 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.9, 160.7, 133.5, 129.3, 126.5,
118.1, 117.8, 78.7, 74.6, 48.2, 43.6, 40.0, 28.0, 27.1, 20.1, 19.9, 15.6. HRMS (ESI,
M+H+) calcd. for C17H24NO2 274.1802, found 274.1807.
2.5 General procedure for the addition of nitromethane to aldehydes
Under a nitrogen atmosphere, the ligand 5a (13.8 mg, 0.05mmol, 10 mol %) and
CuCl (5.0 mg, 0.05 mmol, 10 mol %) were suspended in anhydrous tert-butanol (2.0
mL). The reaction mixture was stirred for 2h at room temperature, added

nitromethane (0.54 mL, 20 mmol) and continuously stirred for additional 0.5h, then
added the aldehyde (0.5 mmol). The reaction mixture was stirred for a specified
period at room temperature, and then the volatile components were removed under
reduced pressure to obtain the crude product. It was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to obtain the pure
product. The enantiomeric excess of the product was determined by HPLC analysis.
The absolute configurations of the products were assigned by comparison to literature
values.
2.5.1 (R)-1-(4-Nitropheny)-2-nitroethanol 7a[13]
Off-white solid, 95 mg, 90% yield, 84% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 85:15, 1.0 mL/min, 254 nm): tR (major) = 22.4 min, tR (minor) = 27.3 min. 1H
NMR (400 MHz, CDCl3) δ 8.21 – 8.24 (m, 2H), 7.62 – 7.64 (m, 2H), 5.60 – 5.62 (m,
1H), 4.60 –4.62 (m, 2H), 3.72 (s, 1H).
2.5.2 (R)-1-(3-Nitropheny)-2-nitroethanol 7b[14]
Brown solid, 87 mg, 82% yield, 80% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) = 35.3 min, tR (minor) = 39.7 min.1H
NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.13 – 8.16 (m, 1H), 7.70 – 7.72 (m, 1H),
7.52 –7.56 (m, 1H), 5.55 (t, J = 3.6 Hz, 1H), 4.54 – 4.56 (m, 2H), 3.23 (s, 1H).
2.5.3 (R)-1-(2-Nitropheny)-2-nitroethanol 7c[13]
Off-white solid, 85 mg, 80% yield, 68% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) = 20.2 min, tR (minor) = 22.4 min.1H
NMR (400 MHz, CDCl3) δ 8.00 – 8.02 (m, 1H), 7.87 – 7.89 (m, 1H), 7.66 – 7.70 (m,
1H), 7.49 – 7.51 (m, 1H), 5.97 – 5.99 (m, 1H), 4.78 – 4.82 (m, 1H), 4.46 – 4.52 (m,
1H), 3.18 (s, 1H).
2.5.4 (R)-1-(4-Fluorophenyl)-2-nitroethanol 7d[15]
Colorless oil, 67 mg, 72% yield, 73% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) = 15.3 min, tR(minor)= 17.9 min. 1H
NMR (400 MHz, CDCl3) δ 7.30 – 7.34 (m, 2H), 7.00 – 7.04 (m, 2H), 5.37 – 5.40 (m,
1H), 4.40 – 4.52 (m, 2H), 2.85(s, 1H).

2.5.5 (R)-1-(3-Fluorophenyl)-2-nitroethanol 7e[13]
Colorless oil, 75 mg, 81% yield, 76% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 90:10，1.0 mL/min, 254 nm): tR (major) = 31.1 min, tR (minor)=38.2 min. 1H
NMR (400 MHz, CDCl3) δ 7.29 – 7.30 (m, 1H), 7.05 – 7.10 (m, 2H), 6.85 – 6.97 (m,
1H), 5.38 (t, J = 4.4 Hz, 1H), 4.45 – 4.50 (m, 2H), 3.0 (s, 1H).
2.5.6 (R)-1-(4-Bromophenyl)-2-nitroethanol 7f[13]
Colorless oil, 96 mg, 78% yield, 81% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) =19.4 min, tR (minor) = 24.9 min. 1H
NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 5.36 (t,
J = 4.4 Hz, 1H), 4.01 – 4.50 (m, 2H), 2.90 (s, 1H).
2.5.7 (R)-1-(3-Bromophenyl)-2-nitroethanol 7g[13]
Colorless oil, 92 mg, 75% yield, 83% e.e., HPLC(Chiralcel OD-H, n-hexane /
i-PrOH 90:10，1.0 mL/min, 254 nm): tR (major) = 19.8 min, tR (minor) = 25.8 min.1H
NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.42 (s, 1H), 5.36 – 5.39 (m, 1H), 4.45 – 4.50
(m, 1H), 2.87 (s, 1H).
2.5.8 (R)-1-(4-Chlorophenyl)-2-nitroethanol 7h[13]
Colorless oil, 77 mg, 76% yield, 87% e.e., HPLC (Chiralcel OD-H, n-hexane /
1
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) =17.2 min, tR (minor) = 21.1 min. H
NMR (400 MHz, CDCl3) δ 7.36 – 7.39 (m, 4H), 5.44 – 5.46 (m, 1H), 4.48 – 4.60 (m,
2H), 2.68 (s, 1H).
2.5.9 (R)-1-(3-Chlorophenyl)-2-nitroethanol 7i[16]
Colorless oil, 69 mg, 68% yield, 74% e.e., HPLC (Chiralcel OD-H, n-hexane /
1
i-PrOH 90:10，1.0 mL/min, 254nm): tR (major) =18.4 min, tR (minor)= 22.9 min. H
NMR (400 MHz, CDCl3) δ 7.50 – 7.58 (m, 1H), 7.48 – 7.50 (m, 1H), 7.32 (t, J = 7.6
Hz, 1H), 7.15 – 7.18 (m, 1H), 5.71 – 5.73 (m, 1H), 4.59 – 4.62 (m, 1H), 4.34 – 4.38
(m, 1H), 3.03 (s, 1H).
2.5.10 (R)-1-(4-Trifluoromethylphenyl)-2-nitroethanol 7j[17]
Colorless oil, 92 mg, 78% yield, 78% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) =13.4 min, tR (minor) =16.8 min. 1H
NMR (400 MHz, CDCl3) δ 7.59 – 7.61 (m, 2H), 7.47 – 7.49 (m, 2H), 5.47 (t, J = 4.8

Hz, 1H), 4.48 – 4.52 (m, 2H), 3.00 (s, 1H).
2.5.11 (R)-1-(3-Trifluoromethylphenyl)-2-nitroethanol 7k[18]
Colorless oil, 80 mg, 68% yield, 86% e.e., HPLC (Chiralcel OD-H, n-hexane /
1
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) =12.7 min, tR (minor)=14.4 min. H
NMR (400 MHz, CDCl3) δ 7.54 – 7.71 (m, 4H), 5.53 – 5.56 (m, 1H), 4.53 – 4.64 (m,
2H), 2.99 (s, 1H).
2.5.12 (R)-4-(1-hydroxy-2-nitroethyl)benzonitrile 7l[19]
White solid, 79 mg, 82% yield, 81% e.e., HPLC (Chiralcel OD-H, n-hexane /
1
i-PrOH 90:10, 1.0 mL/min, 254 nm): tR (major) = 42.7 min, tR (minor)= 49.5 min. H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 10.8 Hz, 2H), 7.56 (d, J = 10.8 Hz, 2H), 5.55
(t, J = 5.6 Hz, 1H), 4.55 – 4.59 (m, 2H), 3.18 (s, 1H).
2.5.13 (R)-1-Phenyl-2-nitroethanol 7m[13]
Colorless oil, 63 mg, 75% yield, 66% e.e., HPLC (Chiralcel OD-H, n-hexane /
1
i-PrOH 92:8, 0.8 mL/min, 254 nm): tR (major) = 26.5 min, tR (minor) = 32.7 min. H
NMR (400 MHz, CDCl3) δ 7.57 – 7.59 (m, 1H), 7.23 – 7.32 (m, 3H), 5.76 (m, 1H),
4.58 – 4.62 (m, 1H), 4.35 – 4.41 (m, 1H), 2.98 (s, 1H).
2.5.14 (R)-1-(4-Methoxyphenyl)-2-nitroethanol 7n[13]
Colorless oil, 44 mg, 45% yield, 69% e.e., HPLC (Chiralcel OD-H, n-hexane /
1
i-PrOH 90:10, 0.8 mL/min, 254 nm): tR (major)= 30.2 min, tR (minor) = 38.1 min. H
NMR (400 MHz, CDCl3) δ 7.22 – 7.25 (m, 2H), 6.80 – 6.86 (m, 2H), 5.30 – 5.34 (m,
1H), 4.49 – 4.55 (m, 1H), 4.37 – 4.42 (m, 1H), 3.73 (s, 3H), 2.78 (s, 1H).
2.5.15 (R)-1-Nitro-4-phenylbutan-2-ol 7o [15]
Yellow oil, 64 mg, 66% yield, 48% e.e., HPLC (Chiralcel AD-H, n-hexane /
i-PrOH 95:5, 1.0 mL/min, 254nm): tr (major) = 33.5 min, tr (minor) = 40.4 min. 1H
NMR (400 MHz, CDCl3) δ 7.30 – 7.15 (m, 5H), 4.44 – 4.32 (m, 2H), 4.31 (s, 1H),
2.90 – 2.71 (m, 2H), 2.68 (s, 1H), 1.95 – 1.71 (m, 2H).
2.5.16 (R)-1-(4-Nitropheny)-2-nitroethanol (R)-1-Nitrooctan-2-ol 7p[20]
Colorless oil, 19 mg, 22% yield, 43% e.e., HPLC (Chiralcel AD-H, n-hexane /
i-PrOH 95:5, 0.5 mL/min, 254nm): tr (major) = 26.3 min, tr (minor) = 37.7 min. 1H

NMR (400 MHz, CDCl3) δ 4.50 – 4.38 (m,2H), 4.35 (m,1H), 2.42 (br,1H), 1.63 –
1.44 (m,3H), 1.36 (m,7H), 0.91 (t, J = 6.4 Hz,3H).
2.5.17 (R)-4-Methyl-1-nitropentan-2-ol: 7q[20]
Colorless oil, 20 mg, 27% yield, 82% e.e., HPLC (Chiralcel AD-H, n-hexane /
i-PrOH 95:5, 0.5 mL/min, 254nm): tr (major) = 21.7 min, tr (minor) = 31.1 min. 1H
NMR (400 MHz, CDCl3) δ 4.47 – 4.31 (m, 3H), 2.57 (s, 1H), 1.91 – 1.78 (m, 1H),
1.52 (dd, J = 10.0, 4.9 Hz, 1H), 1.26 – 1.20 (m, 1H), 0.97 (t, J = 6.2 Hz, 6H).
2.5.18 (S)-1-(4-Nitropheny)-2-nitroethanol 7a'[13]
Yellow oil, 87 mg, 82% yield, 62% e.e., HPLC (Chiralcel OD-H, n-hexane /
i-PrOH 85:15, 1.0 mL/min, 254nm): tr (minor) = 22.2 min, tr (major) = 26.3 min. 1H
NMR (400 MHz, CDCl3) δ 8.21 – 8.24 (m, 2H), 7.62 – 7.64 (m, 2H), 5.60 – 5.62 (m,
1H), 4.60 –4.62 (m, 2H), 3.72 (s, 1H).
3. Results and discussion
The diastereoisomeric Schiff bases 5a and 5a’ were prepared from
4-hydroxy-salicylaldehyde 4a and diastereoisomers of amino alcohol
(1S,4R)-1-amino-7,7-dimethylbicyclo[2.2.1]heptan-2-ol 2, which were obtained by
reduction of (1S,4R)-1-amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one 1 in 83% yield
(Scheme 1).
Scheme 1. Preparation of diastereoisomer 5a and 5a'
At the beginning, we have not realized the strong effect of the configuration of
2-hydroxyl group in camphor frame on the enantioselective Henry reaction. The
mixture diastereoisomer of amino alcohol was used directly to react with general
aromatic aldehydes to obtain the diastereoisomer Schiff bases, both of the

diastereoisomer of amino alcohol 2 and diastereoisomer Schiff bases cannot be
separated by simple methods. When the mixture of diastereoisomer Schiff bases was
used as ligand to promote the enantioselectivity, no enantioselective results were
observed in catalytic Henry reaction. When the aromatic aldehydes was changed to
4-hydroxy-salicylaldehyde 4a, fortunately, the mixture of diastereoisomer Schiff
bases 5a and 5a’ can be separated by chromatography on silica gel for its different
retention factors. The enantioselective results were produced using either a pair of
diastereoisomer Schiff bases 5a or 5a’ as a ligand in Henry reaction. With this result,
enantiomerically pure amino alcohol (1S,2R,4R)-1-amino-7,7–dimethyl-bicylco[2.2.1]
heptan-2-ol 2a was synthesized by one-pot reaction starting from the chiral camphor
isocyanate 3 (Scheme 2)[21] and converted to diastereoisomerically pure Schiff bases
5a.
Scheme 2. Prepration of enantiomerically pure aminol alcohol 2a
The structures of 5a and 5a’ were confirmed by NMR and HRMS (see supporting
information) as well as the comparison of rotation values with 5a of a determined
configuration synthesized by enantiomerically pure amino alcohol 2a.
After learning the key factor to the enantioselective Henry reaction of chiral
camphor amino alcohol, we established the preparation process of enantiomerically
pure amino alcohol (1S,2R,4R)-1-amino-7,7-dimethylbicylco[2.2.1]heptan-2-ol 2a.
For investigation on the structure effect of chiral camphor Schiff bases, a serial of key
enantiomerically pure amino alcohol Schiff bases 5a-5e were prepared in high yields
from amino alcohol 2a and salicylaldehyde derivatives 4a-4e (Scheme 3).

Scheme 3. Synthesis of chiral camphor Schiff bases 5a-5e
Reaction between 4-nitrobenaldehyde and nitromethane was selected as the model
reaction to evaluate the performance of chiral camphor Schiff bases in the presence of
CuCl in tert-butanol solvent (Table 1). The sequential investigations on the steric and
electronic effects of the chiral camphor Schiff base showed that the chemical
reactivity and enantioselectivity were closely related to the chiral backbone and the
substituents of the Schiff base ligands. The performance of the ligand 5a, with a
hydroxyl group at the 4-position of salicylaldehyde moiety was the best, giving 90%
yield and 84% e.e. value (Table 1, entry 1). While the enantioselectivity was
decreased sharply to 46% e.e. when the hydroxyl group was changed to a more
electron-donating butoxyl group (Table 1, entry 3). The Schiff base 5c with two
hindered tert-butyl substituents only generated 21% e.e. and 75% yield (Table 1, entry
4). Schiff base 5d with a bromo substituent on para position to the hydroxyl of
salicylaldehyde moiety afforded moderate enantioselectivity (Table 1, entry 5). Schiff
base 5e with a methyl group on ortho position to the hydroxyl of salicylaldehyde
moiety generated 66% e.e. value due to the attribution of the steric effect (Table 1,
entry 6). It is notable that Schiff base 5a’ affords the product with a completely
different steric configuration compared to Schiff base 5a (Table 1, entry 2).
Table 1.Screening of the Schiff base ligands and copper salts in the asymmetric
Henry reactiona

a All the reaction were carried out with 0.5 mmol p-nitrobenzaldehyde and 10 mmol nitromethane
in 2 mL tBuOH in the presence of 10 mol% copper salt and 10 mol% ligand at room temperature
for 24 h.
b Isolated yield.
c Determined by HPLC analysis on a chiralcel OD-H column.
d By comparison with the literature data.
e 10 mol% CuCl and 20 mol% 5a were used.
f 5 mol% CuCl and 5 mol% 5a were used.
g 15 mol% CuCl and 15 mol% 5a were used.
Then, the effects of different copper salts were evaluated using Schiff base 5a as a
ligand in 10 mol% catalyst loading with 1:1 ratio of copper salt and ligand. Amongst
them, Cu(OAc)2•H2O generated a high chemical yield but moderate e.e. value, 92%
yield and 66% e.e. (Table 1, entry 7). CuCl2•6H2O showed completely no
performances both in activity and selectivity (Table 1, entry 8). Both Cu(OTf)2 and
CuBr displayed moderate chemical yield and enantioselectivity (Table 1, entries 9-10).
CuCl proved to be the best copper catalyst, affording the corresponding product with
high chemical yield and excellent e.e. value. When the ratio of copper metal to ligand
was changed to 1:2, the chemical yield and e.e. value of the reaction remained almost

unchanged (Table 1, entry 11). Furthermore, when the catalyst loading was reduced to
5 mol% with 1:1 ratio of copper salt and ligand, a distinct decrease in chemical yield
was observed (Table 1, entry 12). No improvement in chemical yield and e.e. value
was observed when the catalyst loading was increased to 15 mol% (Table 1, entry 13).
Thus, 10 mol% of catalyst loading in 1:1 ratio of CuCl/Schiff base 5a was selected as
the most efficient catalyst for the selected model reaction.
Table 2 Screening of the solvents in the asymmetric Henry reactiona
a All the reaction were carried out with 0.5 mmol p-nitrobenzaldehyde and 10 mmol nitromethane
in 2 mL solvent in the presence of 10 mol% CuCl and 10 mol% 5a.
b Isolated yield.
c Determined by HPLC analysis on a chiralcel OD-H column.
The solvent was generally vital for the activity of the catalyst, especially in
asymmetric reaction. A series of solvents (e.g., tert-butanol, ethanol, THF,
iso-propanol, DMF, acetonitrile, dichloromethane, toluene, dioxane, and ethylene
glycol) were examined in the catalytic enantioselective Henry reaction between
4-nitrobenzaldehyde and nitromethane with 10 mol% catalyst loading using CuCl and
Schiff base 5a in 1:1 ratio at room temperature (Table 2). Amongst the screened

solvents, protic solvents, such as tert-butanol, ethanol, and iso-propanol were superior
to aprotic solvents since it might coordinate the copper to enhance the
enantioselectivity[22]. tert-Butanol was clearly optimal for this reaction with 90%
yield and 84% e.e. (Table 1, entry 1).
The reaction temperature plays an important role in determining the reaction rate
and enantioselectivity. The influence of the different temperature on the reaction
results was examined using iso-propanol as a solvent. When the reaction was carried
out at 0oC, the chemical yield decreased sharply with a slightly enhanced
enantioselectivity (Table 2, entry 11). By further decreasing the reaction temperature
to -20oC, 83% e.e. was observed, accompanied by only 51% chemical yield.
Therefore, the combination of tert-butanol and room temperature was clearly the best
choice for current reaction system.
Table 3 Asymmetric Henry reactions between nitromethane and various
aldehydesa

O
10 mol% CuCl
OH
NO2
10 mol% 5a
+
CH3NO2
R
7a-7q
R
H
tBuOH, rt
6
Configd
Yieldb (%)
90
6
Entry
Time (h) Product
eec (%)
84
4-nitrobenzaldehyde
3-nitrobenzaldehyde
2-nitrobenzaldehyde
4-fluorobenzaldehyde
3-fluorobenzaldehyde
4-bromobenzaldehyde
3-bromobenzaldehyde
4-chlorobenzaldehyde
3-chlorobenzaldehyde
7a
7b
7c
7d
7e
7f
R
R
R
R
R
R
R
R
R
R
R
R
R
1
2
3
4
5
6
7
8
9
24
24
36
24
36
36
36
36
36
24
36
36
36
48
80
82
68
80
73
72
76
81
81
78
7g
7h
7i
83
75
87
76
74
68
4-(trifluoromethyl)benzaldehyde
3-(trifluoromethyl)benzaldehyde
4-formylbenzonitrile
7j
10
11
12
13
14
78
78
7k
7l
86
68
81
82
benzaldehyde
7m
7n
66
75
4-methoxybenzaldehyde
R
R
R
R
69
45
3-phenyl propanal
heptanal
7o
7p
15
16
17
48
43
82
66
22
48
48
48
27
7q
3-methylbutanal
a All the reaction were carried out with 0.5 mmol p-nitrobenzaldehyde and 10 mmol nitromethane
in 2 mL tBuOH in the presence of 10 mol% CuCl and 10 mol% 5a.
b Isolated yield.
c Determined by HPLC analysis on a chiralcel OD-H or AD-H column.
d By comparison with the literature data.
With the identification of the optimal reaction condition, the scope of the
asymmetric Henry reaction was investigated by treatment of various aldehydes with
nitromethane in the presence of 10 mol% of CuCl/Schiff base 5a 1:1 complex in
tert-butanol at room temperature. The results are presented in Table 3. It clearly shows
that the electronic properties of the substituent on the phenyl ring of aromatic
aldehydes have a great effect on the chemical yield and enantioselectivity. In general,
the aromatic aldehydes with electron-withdrawing groups generated the
β-nitroalcohols in higher chemical yields and e.e. values compared with aromatic

aldehydes with electron-donating group. The bulky 2-nitrobenzaldehyde also
successfully afforded the product 7c, with 80% chemical yield and 68% e.e. (Table 3,
entry 3). The aldehydes with halogenic substituent afforded adducts with good yields
and enantioselectivities (Table 3, entries 4-9). However, aromatic aldehyde with
electron-donating group provided poor reactivity and stereoselectivity (Table 3, entry
14). When the aromatic aldehydes were changed to aliphatic aldehydes, such as
3-phenyl propanal, heptanal and 3-methylbutanal, the catalytic reaction provided
relative lower chemical yield or enantioselectivity (Table 3, entry 15-17). The steric
configuration of all products is R configuration using Schiff base 5a as the ligand. It is
quite different with Mariusz J. Bosiak reported[11] trimethylsilylcyanation of aldehydes
using Schiff bases ligand prepared from (1R,2S,3R,4S)-3-amino-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-ol and salicylaldehydes, in which the aldehydes with
electron-withdrawing groups shows lower e.e. value and the steric configurations of
all products is disordered.
4. Conclusion
In summary, five novel chiral camphor Schiff bases have been synthesized. The
diastereoisomers 5a and 5a' were separated successfully. The chiral camphor Schiff
base 5a, together with CuCl, showed high efficiency in asymmetric Henry reactions
between nitromethane and various aldehydes, especially for the aromatic aldehydes.
This is the first time that camphor-derivated Schiff bases were used as ligands in
asymmetric Henry reaction. Notably, the absolute configuration of the products in
Henry reaction can be easily regulated with diastereoisomers 5a and 5a'.
β-Nitroaldols with R absolute configuration could be obtained using Schiff base 5a,
β-nitroaldols with S absolute configuration could be obtained with Schiff base 5a’.
Further modification of these ligands as well as applications in asymmetric catalysis is
in progress in our laboratory.
Acknowledgements

We are grateful for the financial support from the National Natural Science
Foundation of China (21172138, 21302117 and 21572123) and Fundamental
Research Funds for the Central Universities (GK201402060 and GK261001106).
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