Cu (II)-catalyzed asymmetric Henry reaction with a novel C1-symmetric aminopinane-derived ligand

Article abstract of DOI:10.3390/molecules20046224

A novel C₁-symmetric dinitrogen ligand was synthesized in high yield from commercially available (1R,2R,3R,5S)-(-)-isopinocampheylamine and 1-methyl-2-imidazolecarboxaldehyde. In combination with Cu(OAc)₂·H₂O, this new ligand promote the reaction between nitromethane and aliphatic aldehydes with high yields (up to 97%) and moderate enantioselectivities (up to 67% ee). The reactions with benzaldehyde required prolonged reaction time that resulted in diminished yields, but accompanied with ee-values in the 55%-76% range.

Full text of DOI:10.3390/molecules20046224

Molecules 2015, 20, 6224-6236; doi:10.3390/molecules20046224
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Cu (II)-Catalyzed Asymmetric Henry Reaction with a Novel
C1-Symmetric Aminopinane-Derived Ligand
Liudmila Filippova 1, Yngve Stenstrøm 1,* and Trond Vidar Hansen 1,2
1
Department of Chemistry, Biology and Food Science, Norwegian University of Life Sciences,
P.O. Box 5003, N-1432 Ås, Norway; E-Mail: liudmila.filippova@nmbu.no
2
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068,
Blindern, N-0316 Oslo, Norway; E-Mail: t.v.hansen@farmasi.uio.no
* Author to whom correspondence should be addressed; E-Mail: yngve.stenstrom@nmbu.no;
Tel.: +47-6496-5893; Fax: +47-6496-5901.
Academic Editor: Derek J. McPhee
Received: 19 February 2015 / Accepted: 3 April 2015 / Published: 9 April 2015
Abstract: A novel C1-symmetric dinitrogen ligand was synthesized in high yield from
commercially available (1R,2R,3R,5S)-(−)-isopinocampheylamine and 1-methyl-2-
imidazolecarboxaldehyde. In combination with Cu(OAc)2∙H2O, this new ligand promote the
reaction between nitromethane and aliphatic aldehydes with high yields (up to 97%) and
moderate enantioselectivities (up to 67% ee). The reactions with benzaldehyde required
prolonged reaction time that resulted in diminished yields, but accompanied with ee-values
in the 55%–76% range.
Keywords: asymmetric catalysis; Henry reaction; nitrooaldol; chiral ligand; copper
1. Introduction
The asymmetric Henry (nitroaldol) reaction provides a straightforward entry to enantiomerically
enriched β-nitro alcohols, which are valuable intermediates in the synthesis of natural compounds and
biologically interesting molecules [1,2]. In particular, the nitroaldol products can be reduced into vicinal
amino-alcohols which is a common structural motif found in many pharmaceuticals, such as
(−)-pindolol [3], (−)-arbutamine [4], ritonavir [5], (R)-salmeterol [6], and epinephrine [7]. In addition,

Molecules 2015, 20
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the β-amino alcohol functionality is present in long-chain lipids such as sphingosines [8,9]. Thus, the
development of an efficient asymmetric protocol for this type of reaction is of current interest [10,11].
The first asymmetric procedure for nitroaldol reaction employing a bimetallic Li-La BINOL complex
was reported in 1992 by the Shibasaki group [3]. Since then, extensive collection of organocatalysts [12–15]
and transition metal based catalytic systems, i.e., Zn [4,16], Co [17,18] Cr [19,20], Cu [21–50],
have been developed with variable success. The majority of these metal-based catalysts reported
involved the use of copper complexes with either a bi- or polydentate aza-containing chiral ligand (such
as BOX-type [21–23], diamines [7,24–32], Schiff bases [17,33–35] amino-alcohols [9,36–39],
amino/iminopyridines [40–44], sulfonamides [45,46]). These systems have gained some applications,
but some limitations still exist. For example, multistep synthetic procedures are often necessary for the
preparation of some of the ligands, and obtaining the catalyst in both enantiomeric forms is sometimes
a challenge. Moreover, many of the catalytic systems display poor enantioselectivity together with low
yields of the products when employing aliphatic aldehydes as substrates. Therefore, the development of
easily obtainable, novel ligands, in both enantiomeric forms, is still desired for this class of aldehydes.
In this view, the chiral camphor and pinane based terpenes are examples of convenient building blocks
for the development of effective chiral auxiliaries. For instance, the copper complexes with
camphor-based dinitrogen ligands 1a [40], 1b [7], 1c [47] and 1d [48] have been reported to give high
level (up to 98%) of asymmetric induction when reacting nitromethane with a broad range of aldehydes,
including aliphatic ones (Figure 1).
N
NH
1a
N
N
H
NH
1b
N
NH
1c
N
H
N
H
N
H
N
H
1d
1e
Figure 1. Some camphor and pinane-derived N,N-ligands.
Compounds bearing a pinane core have been utilized in some asymmetric transformations such as the
enantioselective addition of diethylzinc to aldehydes [51–53], aldol condensation [54] and reduction of
ketones [55]. Recently, the copper complex of C2-symmetric ligand 1e was reported to promote the
asymmetric Henry reaction between nitromethane and aliphatic aldehydes affording nitroaldol products
with enantiomeric excess from 57% to 93% ee [56]. Based on the synthesis of 1c [47], we designed
the novel pinane-derived C1-symmetric ligand 4 (Scheme 1). Herein, we describe its application in a
copper-catalyzed asymmetric nitroaldol reaction.

Molecules 2015, 20
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2. Results and Discussion
The C1-symmetric ligand 4 was easily prepared from commercially available (1R,2R,3R,5S)-(−)-
isopinocampheylamine (2) and 1-methyl-2-imidazolecarboxalehyde in a one-pot reaction as outlined in
Scheme 1.
Reagents and conditions: (i) 1-methyl-2-imidazolecarboxaldehyde (1 equiv.), MeOH, rt; (ii) NaBH4 (3 equiv),
MeOH, 0 °C to rt.
Scheme 1. Synthesis of the ligand 4.
Initially, in connection with our interest in the synthesis of aliphatic nitroalcohols, we examined the
ability of 4 to promote the nitroaldol reaction between valeraldehyde (5a) and nitromethane in the
presence of CuCl2∙2H2O (5 mol %) at 0 °С with DIPEA (1 equiv.) as base additive. The results are
summarized in Table 1. When THF was used as solvent, the reaction proceeded smoothly resulting in
high yield (92%), but moderate enantioselectivity was observed (Table 1, entry 1). Then Cu(OAc)2∙H2O
was tested to see if there were any influence of the counterions on the reaction. Both copper salts gave
similar results in terms of enantioselectivity, but the yields varied significantly depending on the solvent
(Table 1, entries 1–4). Most likely, this is due to differences in the solubility of the formed complexes.
Hence, the use of other solvents was investigated. Of the solvents tested, i-PrOH was the best choice
(Table 1, entry 6, 97% yield, 55% ee). Lowering the temperature of the reaction to −20 °С resulted in a
significant decrease of the reaction rate with no improvements in enantioselectivity (Table 1, entries 8
and 9). The absolute configuration in the product 6a was determined based on comparison of the specific
optical rotation value with literature [24–32].
Table 1. Selected experimental conditions for asymmetric Henry reaction between pentanal
and nitromethane.
Entry a Copper Salt Solvent T (°C) Time (h) DIPEA (mol %) Yield (%) b e.e. (%) c
1
2
3
4
5
6
7
8
CuCl2∙2H2O
Cu(OAc)2∙H2O
CuCl2∙2H2O
THF
THF
4
4
20
20
20
20
20
20
20
20
100
100
100
100
100
100
100
100
90
52
88
92
68
97
63
<5
53
52
EtOH
4
33
Cu(OAc)2∙H2O EtOH
Cu(OAc)2∙H2O CH2Cl2
Cu(OAc)2∙H2O i-PrOH
4
37
4
47
4
55
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Et2O
THF
4
46
n.d. d
−25

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Table 1. Cont.
Entry a Copper Salt Solvent T (°C) Time (h) DIPEA (mol %) Yield (%) b e.e. (%) c
9
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
Cu(OAc)2∙H2O i-PrOH
−25
4
72
2
100
100
100
100
100
0
88
68
88
85
89
36
88
98
57
57
56
55
57
56
57
56
10
11
12
13
15
16
17
4
4
4
6
4
8
4
20
20
20
4
5
4
10
a The reactions were carried out on 0.5 mmol scale of valeraldehyde with 10 equiv. of nitromethane in 2 mL of
solvent. b Isolated product. c Enantiomeric excesses by HPLC analyis using a column with a chiral stationary
phase. d Not determined.
The Henry reaction is reversible [1]. The enantiomeric excess of the nitroaldol adducts can decrease
as a result of the retro-nitroaldol reaction. Hence, a time-course study was performed to investigate the
possibility of reversibility. The reaction was almost complete within four hours, while the ee-values of
the product 6a remained constant in the conditions explored (Table 1, entry 10–13), indicating the
absence of reversibility.
An external base is usually added to promote the reaction. Considering the still low ee of the product
observed, and the fact that the excess of additional base can enhance the non-enantioselective reaction
pathway [26], the effect of base loading was examined. The addition of even small amounts of external
base noticeably improved the reaction rate, while the ee-values of the products were unchanged with
increasing amounts of base added. These experiments verified that inhibition of an unselective pathway
occurred (Table 1, entries 15–17). The loading of 10 mol % of external base was sufficient to promote
the reaction until completion.
Based on the conditions investigated, different aliphatic aldehydes were tested. As shown in Table 2,
all of the aldehydes smoothly converted into the nitroaldol products with good to excellent yields.
Moderate ee-values ranging from 49% to 67% were observed; the highest ee-value was observed with
2,2-dimethylpropanal (5c) (Table 2, entry 3, 67% ee). Again, the absolute configuration in the products
6a–6h was assigned based on specific optical rotation values.
Then we tested the catalyst system with benzaldehyde (5h) (Table 2, entries 8–10). The reaction
between 5h and nitromethane in the presence of ligand 4 and CuCl2∙2H2O did not reach completion even
after 20 hours at 4 °С (Table 2, entry 8). Lowering the temperature of the reaction improved the level of
enantioinduction to 76% ee, but drastically diminished the yields to impractical values (Table 2, entries
9–10). Hence, other aromatic aldehydes were not investigated.
Finally, in view to explore the nitroalkane substrate scope, nitroethane was reacted with aliphatic
aldehydes employing optimized catalytic procedure (Table 3). The corresponding nitroaldol adducts
bearing two stereogenic centers were obtained in high yields (up to 94%) albeit moderate
diastereoselectivities favoring syn-product and enantioselectivities were observed. Diastereoselectivity
was improved when α-branched aldehyde was used (Table 3, entry 2).

Molecules 2015, 20
Table 2. Enantioselective Henry reaction of various aldehydes with nitromethane.
6228
Entry a
R
n-Bu
Aldehyde Product Yield (%) b e.e. (%) c
1
2
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
91
89
88
83
75
82
65
80
63
10
57
49
67
60
55
53
47
38
45
76
i-Bu
3
t-Bu
4
i-Pr
5
n-nonyl
n-undecyl
trans-2-decenyl
phenyl
phenyl
phenyl
6
7
5g
5h
5h
5h
6g
6h
6h
6h
8 d
9 e
10 f
a The reactions were performed on 0.5 mmol scale. b Isolated yield. c Determined by HPLC using a column with
a chiral stationary phase. d CuCl2∙2H2O was used as a copper source. e The reaction was carried out at −20 °С
for 48 h in the presence of 1 equiv. of DIPEA. f The reaction was carried out at −40 °С for 48 h in the presence
of 1 equiv. of DIPEA.
Table 3. Diastereoselective Henry reaction using nitroethane.
OH
OH
5 mol% 4/Cu(OAc)2 H2O,
O
DIPEA 1.0 equiv.
+
EtNO2
+
R
R
R
H
i-PrOH, 4 °C, 24 h
NO2
anti-7
NO2
syn-7
5
Entry a
R
Product Yield (%) b syn/anti (%) c ee (%) d
1
2
i-Bu
i-Pr
7a
7b
93
94
58/42
54/38
81:19
c
66/34
The reactions were performed on 0.5 mmol scale. b Isolated yield. Determined by H-NMR spectroscopy
a
1
analysis of isolated compound. d Determined by HPLC analysis using a column with a chiral stationary phase.
3. Experimental Section
All starting reagents and solvents were obtained from Sigma Aldrich and used as purchased without
further purification. Analytical TLC was performed using silica gel 60 F254 plates (Merck). Flash column
chromatography was performed on silica gel 60 (40–63 nm). NMR spectra were recorded on Varian
Gemini and Bruker AscendTM 400 spectrometers 300 MHz and 400 MHz for 1H-NMR and 75 MHz and
100 MHz for 13C-NMR, respectively. Chemical shifts are reported in ppm downfield from
tetramethylsilane relative to CDCl3 as internal standard (7.24 ppm for 1H and 77.00 for 13C). IR spectra
(4000–600 cm−1) were recorded on a Perkin-Elmer Spectrum BX series FT-IR spectrophotometer using
a reflectance cell (HATR). Optical rotations were measured using a 1 mL cell with 1.0 dm path length

Molecules 2015, 20
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on Perkin Elmer 341 polarimeter in dedicated solvent. HPLC analyzes were performed on Agilent 1200
Series instrument using chiral OD-H or AD-H columns.
3.1. Preparation of Ligands
3.1.1. Synthesis of (E)-1-(1-Methyl-1H-imidazol-2-yl)-N-((1S,2S,3S,5R)-2,6,6-
trimethylbicyclo[3.1.1]heptan-3-yl)methanimine (3)
To (1R,2R,3R,5S)-(−)-isopinocampheylamine (2) (612 mg, 4.0 mmol) was added of 1-methyl-2-
imidazolecarboxaldehyde (440 mg, 4.0 mmol) in 20 ml of dry methanol. The reaction mixture was left
stirring at room temperature until no more starting material was detected (controlled by TLC, visualized
by ninhydrine stain). Then mixture was directly concentrated under reduced pressure and purified by
column chromatography eluting with hexane and ethyl acetate to obtain 930 mg of compound 3 as
ꢀ ꢂꢄꢅ
colourless oil (95% yield). ꢁ = −45.1 (c = 2.0, EtOH). 1H-NMR (CDCl3, 400MHz, TMS): δ = 8.16
ꢃ
(s, 1H), 7.07 (s, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.36–3.33 (m, 1H), 2.38–2.25 (m, 2H), 2.10–2.01 (m,
1H), 1.98–1.91 (m, 1H), 1.89–1.81 (m, 2H), 1.22 (s, 3H), 1.47 (d, J = 9.3 Hz, 1H), 1.03 (s, 3H), 0.98 (d,
13
J = 8.7 Hz, 3H) ppm. C-NMR (75 MHz, CDCl3, TMS): δ = 149.7, 143.2, 128.9, 124.4, 70.5, 47.5,
44.1, 41.6, 38.7, 36.2, 35.4, 33.6, 27.9, 23.5, 19.8 ppm.
3.1.2. Synthesis of (1S,2S,3S,5R)-2,6,6-Trimethyl-N-((1-methyl-1H-imidazol-2-yl)methyl)-
bicyclo[3.1.1]heptan-3-amine (4)
Sodium borohydride (456 mg, 12.1 mmol, 3.2 equiv.) was added in portions to a chilled 0 °C solution
of 2 (930 mg, 3.8 mmol) in methanol. The mixture then was allowed to warm to room temperature and
left stirred until no more starting material was detected (controlled by TLC, UV detection). The reaction
was quenched with aqueous HCl, and MeOH solvent was removed under reduced pressure. The aqueous
part was basified until pH = 9–10 and extracted by ethyl acetate, dried over anhydrous Na2SO4 and
evaporated. The crude product was purified by flash column chromatography (hexane: EtOAc 7:3) to
ꢀ ꢂꢄꢅ
obtain 884 mg (94% yield) of 4 as a solid compound. ꢁ = −66.9 (c = 1.85, EtOH). 1H-NMR (CDCl3,
ꢃ
400 MHz, TMS): δ = 6.88 (s, 1H), 6.78 (s, 1H), 3.80 (dd, J1 = 13.2 Hz, J2 = 24.5 Hz, 2H), 3.69 (s, 3H),
2.88–2.81 (m, 1H), 2.41–2.24 (m, 2H), 1.93–1.90 (m, H), 1.78–1.74 (m, H), 1.64–1.57 (m, H), 1.18 (s,
3H), 1.06 (d, J = 7.5 Hz, 3H), 0.93 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3, TMS): δ = 147.5, 127.7,
121.7, 57.6, 48.4, 45.7, 44.9, 42.3, 39.1, 37.1, 34.3, 33.3, 28.4, 24.0, 22.1 ppm. HRMS (TOF ES+): exact
mass calculated for C15H26N3 [M + H]+ 248.2126; found 248.2124.
3.2. General Procedure for the Enantioselective Henry Reaction
Ligand 4 (6.2 mg, 5 mol %) and Cu(OAc)2∙H2O (5 mg, 5 mol %) were added to the test tube containing
2 mL of i-PrOH and stirred for an hour to obtain a blue solution. Then the test tubes were transferred to
a bath at the given reaction temperature and 0.5 mmol of aldehyde, 10 equivalents of nitroalkane and 0.1
equivalent of DIPEA (9 μL) were added. The reaction mixture was left stirring for the 24 h, after that
the volatile compounds were removed under reduced pressure and the residue was directly purified on
silica gel column eluting with hexane:EtOAc to afford the corresponding product.

Molecules 2015, 20
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3.2.1. R-(−)-1-Nitro-2-hexanol (6a)
Purified by column chromatography on silica (hexane:EtOAc 9:1), colorless oil, 90% yield, 57% ee.
Enantiomeric excess was determined by HPLC (Chiralcel OD-H column, hexane/isopropanol, 90/10 v/v,
ꢀ ꢂꢄꢅ
0.5 mL/min, 210 nm): tR (major) = 8.34 min, tR (minor) = 9.95 min; ꢁ = −6.5° (c = 1.2, CH2Cl2), (lit. [21]
ꢃ
ꢀ ꢂꢄꢅ
ꢁ
= −9.3° (c = 2.73, CH2Cl2, 93% ee (R))).1H-NMR (CDCl3, 300 MHz, TMS): δ = 4.44–4.25 (m, 3H),
ꢃ
2.51 (d, J = 4.7 Hz, 1H), 1.49–1.31 (m, 6H), 0.90 (t, J = 7.0 Hz, 3H). 13C-NMR (100 MHz, CDCl3, TMS):
δ = 80.6, 68.7, 33.4, 27.3, 22.4, 13.9 ppm.
3.2.2. R-(+)-4-Methyl-1-nitropentan-2-ol (6b)
Purified by column chromatography (hexane:EtOAc 10:1), colourless oil, 89% yield, 49% ee.
Enantiomeric excess was determined by HPLC (Chiralcel AD-H column, hexane/isopropanol, 90/10 v/v,
ꢀ ꢂꢄꢅ
0.5 mL/min, 23 °C, 210 nm): tR (major) = 13.53 min, tR (minor) = 17.72 min; ꢁ = +1.0° (c = 1.0, CH2Cl2),
ꢃ
ꢀ ꢂꢄꢅ
(lit. [4] ꢁ = +2.3° (c = 2.5, CH2Cl2, 82% ee (R))). 1H-NMR (CDCl3, 400 MHz, TMS): δ = 4.40–4.32
ꢃ
(m, 3H), 2.53 (d, J = 4.0 Hz, 1H), 1.84–1.78 (m, 1H), 1.51–1.44 (m, 1H), 1.23–1.17 (m, 1H), 0.94
(app t, J = 6.2 Hz, 6H). 13C-NMR 100 MHz, CDCl3, TMS): δ = 81.0, 67.0, 42.4, 24.3, 23.2, 21.7.
3.2.3. R-(−)-3,3-Dimethyl-1-nitrobutan-2-ol (6c)
Purified by column chromatography (hexane:EtOAc 10:1), colourless oil, 88% yield, 67% ee.
Enantiomeric excess was determined by HPLC (Chiralcel OD-H column, hexane/isopropanol, 98/2 v/v,
ꢀ ꢂꢄꢅ
1.0 mL/min, 23 °C, 210 nm): tR (major) = 16.39 min, tR (minor) = 19.31 min; ꢁ
= −29.3° (c = 0.15,
ꢃ
ꢀ ꢂꢄꢅ
CH2Cl2), (lit. [57] ꢁ = −28.1° (c = 1.78, CH2Cl2, 69% ee (R))). 1H-NMR (CDCl3, 400 MHz, TMS):
ꢃ
δ = 4.5 (dd, J1 = 13.0 Hz, J2 = 2.0 Hz, 1H), 4.35 (dd, J1 = 13 Hz, J2 = 10.1 Hz, 1H), 4.01 (ddd, J1 = 10.1 Hz,
J2 = 4.7 Hz, J3 = 2 Hz), 2.39 (d, J = 4.7 1H), 0.96 (s, 9H). 13C-NMR (75 MHz, CDCl3, TMS):
δ = 78.2, 76.2, 34.3, 25.6.
3.2.4. R-(−)-3-Methyl-1-nitrobutan-2-ol (6d)
Purified by column chromatography (hexane:EtOAc 10:1), colourless oil, 83% yield, 60% ee.
Enantiomeric excess was determined by HPLC (Chiralcel OD-H column, hexane/isopropanol, 98/2 v/v,
ꢀ ꢂꢄꢅ
1.0 mL/min, 23 °C, 210 nm): tR (major) = 20.46 min, tR (minor) = 22.90 min; ꢁ = −17.9° (c = 0.2, CH2Cl2),
ꢃ
ꢀ ꢂꢄꢅ
(lit. [45] ꢁ = −30.6° (c = 0.69, CH2Cl2, 99% ee (R))). 1H-NMR (CDCl3, 400 MHz, TMS): δ = 4.53–4.36
ꢃ
13
(m, 2H), 4.10–4.07 (m, 1H), 2.51 (br s, 1H), 1.82–1.74 (m, 1H), 0.97 (app t, J = 6.3 Hz). C-NMR
(100 MHz, CDCl3, TMS): δ = 79.3, 73.4, 31.7, 18.4, 17.5.
3.2.5. R-(−)-1-Nitroundecan-2-ol (6e)
Purified by column chromatography (hexane:EtOAc 10:1), yellowish oil, 82% yield; 55% ee.
Enantiomeric excess was determined by HPLC (Chiralcel AD-H column, hexane/isopropanol, 90/10 v/v,
ꢀ ꢂꢄꢅ
0.5 mL/min, 23 °C, 210 nm): tR (major) = 13.19 min, tR (minor) = 17.99 min; ꢁ = −2.8° (c = 1.9, CH2Cl2),
ꢃ
ꢀ ꢂꢄꢅ
(lit. [45] ꢁ = −4.9° (c = 1.04, CH2Cl2, 97% ee (R))). 1H-NMR (CDCl3, 400 MHz, TMS): δ = 4.43–4.28
ꢃ

Molecules 2015, 20
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(m, 3H), 2.47 (d, J = 4.5 Hz, 1H), 1.57–1.44 (m, 3H), 1.37–1.24 (m, 13H), 0.86 (t, J = 6.7 Hz, 3H).
13C-NMR (100 MHz, CDCl3, TMS): δ = 80.6, 68.7, 33.7, 31.9, 29.5, 29.4, 29.3, 29.3, 25.2, 22.7, 14.1.
3.2.6. R-(−)-1-Nitrotridecan-2-ol (6f)
Purified by column chromarography (hexane:EtOAc 10:1), pale yellow oil, 75% yield, 57% ee.
Enantiomeric excess was determined by HPLC (Chiralcel AD-H column, hexane/isopropanol, 90/10 v/v,
ꢀ ꢂꢄꢅ
0.5 mL/min, 23 °C, 210 nm): tR (major) = 11.51 min, tR (minor) = 14.79 min; ꢁ = −2.5° (c = 0.4, CH2Cl2).
ꢃ
1H-NMR (CDCl3, 400 MHz, TMS): δ = 4.35–4.32 (m, 2H), 4.31–4.27 (m, 1H), 2.47 (d, J = 4.6 Hz, 1H),
13
1.56–1.44 (m, 2H), 1.34–1.24 (m, 18H), 0.86 (t, J = 6.7 Hz). C-NMR (100 MHz, CDCl3, TMS):
δ = 80.6, 68.7, 33.7, 31.9, 29.6, 29.5, 29.4, 29.3 (2H), 25.2, 22.7, 14.1.
3.2.7. R-(−)-(E)-1-Nitroundec-3-en-2-ol (6g)
Purified by column chromatography (hexane:EtOAc 95:5), yellow oil, 65% yield, 47% ee.
Enantiomeric excess was determined by HPLC (Chiralcel AD-H column, hexane/isopropanol, 98/2 v/v,
ꢀ ꢂꢄꢅ
0.8 mL/min, 23 °C, 210 nm): tR (major) = 28.80 min, tR (minor) = 30.60 min; ꢁ = −0.4° (c = 0.7, CH2Cl2).
ꢃ
1H-NMR (CDCl3, 400 MHz, TMS): δ = 5.86 (dtd, J1 = 15.4 Hz, J2 = 6.8 Hz, J3 = 1.1 Hz, 1H), 5.42 (ddt,
J1 = 15.4 Hz, J2 = 6.6 Hz, J3 = 1.5 Hz, 1H), 4.79 (pentet, J = 5.6 Hz, 1H), 4.40 (d, J = 5.7 Hz, 2H), 2.40
(d, J = 4.4 Hz, 1H), 2.03 (dd, J1 = 14.2 Hz, J2 = 7.2 Hz, 2H), 1.37–1.25 (m, 10H), 0.86 (t, J = 6.7 Hz, 3H).
13C-NMR (100 MHz, CDCl3, TMS): δ = 136.3, 126.0, 8.1, 70.0, 32.2, 31.8, 29.1, 29.1, 28.8, 22.6, 14.1.
3.2.8. (R)-(−)-1-Phenyl-2-nitroethanol (6h)
Prepared according general procedure and purified by column chromatography (hexane:EtOAc, 8:1),
colorless oil, 63% yield, 45% ee. Enantiomeric excess was determined by HPLC (Chiralcel OD-H
column, hexane/isopropanol, 90/10 v/v, 0.5 mL/min, 254 nm): tR (major) = 19.88 min, tR (minor) = 24.00 min.
ꢀ ꢂꢄꢅ
ꢀ ꢂꢄꢅ
1
ꢁ
= −23.1° (c = 1.2 CH2Cl2), (lit. [45] ꢁ = −53.1° (c = 1.06 CH2Cl2, 96% ee (R))). H-NMR
ꢃ
ꢃ
(CDCl3, 300MHz, TMS): δ = 7.40–7.34 (m, 5H), 5.46 (dt, J1 = 9.4 Hz, J2 = 3.5 Hz, 1H), 4.60 (dd,
13
J1 = 13.3 Hz, J2 = 9.3 Hz, 1H), 4.50 (dd, J1 = 13.4 Hz, J2 = 3.2 Hz, 1H), 2.78 (br s, 1H). C-NMR
(75 MHz, CDCl3, TMS): δ = 138.2, 129.0, 128.9, 126.0, 81.2, 71.0.
3.2.9. (2R,3R)-5-Methyl-2-nitrohexane-3-ol (7a)
Prepared according general procedure and purified by column chromatography (hexane:EtOAc 10:1),
colourless oil, 93% yield. Enantiomeric excess was determined by HPLC (Chiralcel AD-H column,
hexane/isopropanol, 98/2 v/v, 1.0 mL/min, 23 °C, 220 nm): tR (anti minor) = 16.40 min, tR (anti major)
ꢀ ꢂꢄꢅ
= 17.62 min, tR (syn major) = 21.28 min, tR (syn minor) = 22.85 min. ꢁ = +15.2° (c = 0.91 EtOH),
ꢃ
ꢀ ꢂꢄꢅ
(lit. [58] ꢁ = +12.5° (c = 0.96 EtOH, syn/anti 93/7, 99% ee)). Diastereomeric ratio (syn/anti) was
determined by 1H-NMR (CDCl3, 400 MHz, TMS): δ = 4.52–4.43 (m, 1H), 4.25–4.22 (m, 0.42H, anti),
ꢃ
3.96–3.91 (m, 0.58H, syn), 2.18 (br s, 1H), 1.88–1.76 (m, 1H), 1.53 (dd, J1 = 6.7 Hz, J2 = 3.8 Hz, 3H),
1.42–1.35 (m, 1H), 1.24–1.16 (m, 1H), 0.95–0.90 (m, 6H). 13C-NMR (100 MHz, CDCl3, TMS): δ = 88.1
(syn), 86.7 (anti), 71.2 (syn), 70.2 (anti), 42.0 (syn), 41.8 (anti), 24.6 (anti), 24.3 (syn), 23.6 (syn), 23.3
(anti), 21.7 (anti), 21.4 (syn), 16.2 (syn), 12.4 (anti).

Molecules 2015, 20
6232
3.2.10. (3R, 4R)-2-methyl-4-nitropentan-3-ol (7b)
Prepared according general procedure and purified by column chromatography (hexane:EtOAc 10:1),
colourless oil, 94% yield. Enantiomeric excess was determined by HPLC (Chiralcel OD-H column,
hexane/isopropanol, 99/1 v/v, 1.0 mL/min, 23 °C, 220 nm): tR (anti major) = 18.56 min, tR (syn major)
ꢀ ꢂꢄꢅ
= 19.26 min, tR (anti minor) = 21.66 min, tR (anti minor) = 22.36 min. ꢁ = −3.4° (c = 1.12 CHCl3),
ꢃ
ꢀ ꢂꢄꢅ
(lit. [58] ꢁ = −2.0° (c = 0.85 CHCl3, syn/anti 97/3, 90% ee)). Diastereomeric ratio (syn/anti) was
determined by H-NMR (CDCl3, 400 MHz, TMS): δ = 4.68–4.61 (m, 1H), 3.86 (dd, J1 = 8.0 Hz,
ꢃ
1
J2 = 3.2 Hz, 0.19H, anti), 3.67 (dd, J1 = 7.2 Hz, J2 = 4.5 Hz, 0.81H, syn), 2.18 (br s 1H), 1.82–1.74 (m,
0.81H, syn), 1.72–1.64 (m, 0.19H, anti), 1.53 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.91 (d,
J = 6.7 Hz, 3H). 13C-NMR (100 MHz, CDCl3, TMS): δ = 86.2 (syn), 84.6 (anti), 77.3 (syn), 77.2 (anti),
30.8 (anti), 29.9 (syn), 19.8 (anti), 18.8 (syn), 18.6 (anti), 16.4 (syn), 15.5 (syn), 12.1 (anti).
4. Conclusions
In conclusion, a new pinane-based dinitrogen C1-symmetric ligand has been synthesized via an
experimental simple one pot procedure. This ligand was found to be reasonably selective for the copper
catalyzed asymmetric Henry reaction between nitromethane and aliphatic aldehydes. Of merit, high
yields were observed for this class of aldehydes. The ease of availability of ligand 4 in both enantiomeric
forms, together with the simple and scalable procedure for its preparation, is of advantage for the present
catalytic system. Currently, this catalyst system is investigated towards the synthesis of vicinal
amino-alcohol derived lipids.
Acknowledgments
Financial support from the University of Life Sciences to L.F. (Quota Scheme) and a grant from the
Norwegian Research Council, NFR 209335 are acknowledged.
Author Contributions
LF performed all the experiments. TVH designed the concept of the study. LF, YS, and TVH wrote
the paper.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Ono, N. The Nitrogroup in Organic Synthesis; Wiley-VCH: New York, USA, 2001.
2. Luzzio, F.A. The Henry reaction: Recent examples. Tetrahedron 2001, 57, 915–945.
3. Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. Basic character of rare earth metal alkoxides.
Utilization in catalytic C-C-bond-forming reactions and catalytic asymmetric nitroaldol reactions.
J. Am. Chem. Soc. 1992, 114, 4418–4420.

Molecules 2015, 20
6233
4. Trost, B.M.; Yeh, V.S.C.; Ito, H.; Bremeyer, N. Effect of ligand structure on zinc-catalyzed Henry
reaction. Asymmertic synthesis of (−)-denopamine and (−)-arbutamine. Org. Lett. 2002, 4, 2621–2623.
5. Roy, A.; Reddy, L.A.; Dwivedi, N.; Naram, J.; Swapna, R.; Malakondaiah, G.C.; Ravikumar, M.;
Bhalerao, D.; Pratap, T.P.; Reddy, P.P.; et al. Diastereoselective synthesis of a core fragment of
ritonavir and lopinavir. Tetrahedron Lett. 2011, 52, 6968–6970.
6. Guo, Z.L.; Deng, Y.Q.; Zhong, S.; Lu, G. Enantioselective synthesis of (R)-salmeterol employing
an asymmetric Henry reaction as the key step. Tetrahedron: Asymmetry 2011, 22, 1395–1399.
7. Zhou, Y.; Dong, J.; Zhang, F.; Gong, Y. Synthesis of C1-symmetric chiral secondary diamines and
their applications in the asymmetric copper(II)-catalyzed Henry (nitroaldol) reactions. J. Org. Chem.
2011, 76, 588–600.
8. Uraguchi, D.; Nakamura, S.; Ooi, T. Catalytic asymmetric direct Henry reaction of ynals: Short
synthesis of (2S,3R)-(+)-xestoaminol C and (−)-codonopsinines. Angew. Chem. Int. Ed. 2010, 49,
7562–7565.
9. Xu, K.; Lai, G.; Zha, Z.; Pan, S.; Chen, H.; Wang, Z. A highly anti-selective asymmetric Henry
reaction catalyzed by a chiral copper complex: Applications to the syntheses of spisulisine and a
pyrroloisoquinoline derivative. Chem. Eur. J. 2012, 18, 12357–12362.
10. Palomo, C.; Oiarbide, M.; Laso, A. Recent advances in catalytic asymmetric nitroaldol (Henry)
reaction. Eur. J. Org. Chem. 2007, 2561–2574.
11. Boruwa, J.; Gogoi, N.; Saikia, P.P.; Barua, N.C. Catalytic asymmetric Henry reaction.
Tetrahedron: Asymmetry 2006, 17, 3315–3326.
12. Alvarez-Casao, Y.; Marques-Lopez, E.; Herrera, R.P. Organocatalytic enantioselective Henry
reaction. Symmetry 2011, 3, 220–245.
13. Ube, H.; Terada, M. Enantioselective Henry (nitroaldol) reaction catalyzed by axially chiral
guanidines. Bioorg. Med. Chem. Lett. 2009, 19, 3895–3898.
14. Liu, L.; Zhang, F.; Xue, F.; Lou, G.; Zhang, H.; Ma, S.; Duan, W.; Wang, W. Catalytic enantioselective
Henry reaction of isatins: Application in concise synthesis of (S)-(−)-spirobrassinin. Chem. Eur. J.
2011, 17, 7791–7795.
15. Marcelli, T.; Haas, R.N. S.; Maarseveen, J.H.; Hiemstra, H. Asymmetric organocatalytic Henry
reaction. Angew. Chem. Int. Ed. 2006, 45, 929–931.
16. Trost, B.; Yeh, V. A dinuclear Zn calalyst for the asymmetric nitroaldol (Henry) reaction.
Angew. Chem. Int. Ed. 2002, 41, 861–863.
17. Lang, K.; Park, J.; Hong, S. Urea/transition-metal cooperative catalyst for anti-selective asymmetric
nitroaldol reaction. Angew. Chem. Int. Ed. 2012, 51, 1620–1624.
18. Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Enantioselective Henry reaction catalyzed by
salen-cobalt complexes. Synthesis 2004, 1947–1950.
19. Zulauf, A.; Mallah, M.; Schulz, E. New chiral thiophene chromium complexes for asymmetric
Henry reaction. J. Org. Chem. 2009, 74, 2242–2245.
20. Kowalczyk, R.; Sidorowicz, L.; Skarzewski, J. Asymmetric nitroaldol reaction catalyzes by a
chromium(III)-salen system. Tetrahedron: Asymmetry 2007, 18, 2581–2586.
21. Evans, D.A.; Seidel, D.; Rueping, M.; Lam, H.W.; Shaw, J.T.; Downey, C.W. A new copper
acetate-bis(oxazoline)-catalyzed, enantioselective Henry reaction. J. Am. Chem. Soc. 2003, 125,
12692–12693.

Molecules 2015, 20
6234
22. Ginotra, S.K.; Singh, V.K. Enantioselective Henry reaction catalyzed by a C2-symmetric
bis(oxazoline)- Cu(OAc)2∙H2O complex. Org. Biomol. Chem. 2007, 5, 3932–3937.
23. Lee, J.M.; Kim, J.; Shin, Y.; Yeom, C.E.; Lee, J.E.; Hueon, T.; Kim, B.M. Heterogeneous
asymmetric Henry reaction using a chiral bis(oxazoline)-copper complex immobilized in
magnetically separable mesocellular mesoporous silica support. Tetrahedron: Asymmetry 2010, 21,
285–291.
24. Kowalczyk, R.; Sidirowicz, L.; Skarzewski, J. Asymmetric Henry reaction catalyzed by chiral
secondary diamine-copper(II) complexes. Tetrahedron: Asymmetry 2008, 19, 2310–2315.
25. Luo, M.; Yan, B. Enantioselective Henry reaction catalyzed cy chiral N-metal complexes containing
R(+)/S(−)-α-ethylphenyl amines. Tetrahedron Lett. 2010, 51, 5577–5580.
26. Kodama, K.; Sugawara, K.; Hirose, T. Benzylidene acetal type bridged nucleic acids: Changes in
properties upon cleavage of the bridged triggered by external stimuli. Chem. Eur. J. 2011, 17,
7918–7926.
27. Selvakumar, S.; Sevasankaran, D.; Singh, V.K. Enantioselective Henry reaction catalyzed by
C2-symmetric chiral diamine-copper(II) complex. Org. Biomol. Chem. 2009, 7, 3156–3162.
28. Arai, T.; Watanabe, M.; Yanadisawa, A. Practical Asymmetric Henry reaction catalyzed by a chiral
diamine- Cu(OAc)2 complex. Org. Lett. 2007, 9, 3595–3597.
29. Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. Enantioselective Henry reaction catalyzed
by Cu (II) salt and bipiperidine. J. Org. Chem. 2010, 75, 1313–1316.
30. Chougnet, A.; Zhang, G.; Liu, K.; Haussinger, D.; Kagi, A.; Allmendinger, T.; Woggon, W.D.
Diastereoselective and highly enantioselective Henry reactions using C1-symmertical copper(II)
complexes. Adv. Synth. Catal. 2011, 353, 1797–1806.
31. Chunhong, Z.; Liu, F.; Gou, S. Application of chiral N,N'-dialkyl-1,2-cyclohexanediamine
derivatives in asymmetric copper(II)- catalyzed Henry reactions. Tetrahedron: Asymmetry 2014,
25, 278–283.
32. Liu, F.; Gou, S.; Li, L. Asymmetric Henry reaction of aldehydes vith various nitroalkanes
catalyzed by copper(II) complexes on novel chiral N-monoalkyl cyclohexane-1,2-diamines.
Appl. Organometal. Chem. 2014, 28, 186–193.
33. Wei, Y.; Yao, L.; Zhang, B.; He, W.; Zhang, S. Novel Schiff base ligand derived from cinchona
alkaloids for Cu(II)-catalyzed asymmetric Henry reaction. Tetrahedron 2011, 67, 8552–8558.
34. Boobalan, R.; Lee, G.H.; Chen, C. Copper complex of aminoisoborneol Schiff base Cu2(SBAIB-d)2:
An efficient catalyst for direct catalytic asymmetric nitroaldol (Henry) reaction. Adv. Synth. Catal.
2012, 354, 2511–2520.
35. Yang, W.; Liu, H.; Du, D.M. Efficient in situ three-component formation of chiral oxazoline-Schiff
base copper(II) complexes: Towards combinatorial library of chiral catalysts for asymmetric Henry
reaction. Org. Biomol. Chem. 2010, 8, 2956–2960.
36. Lai, G.; Guo, F.; Zheng, Y.; Fang, Y.; Song, H.; Xu, K.; Wang, S.; Zha, Z.; Wang, Z. Highly
enantioselective Henry reactions in water catalyzed by a copper tertiary amine complex and applied
in the synthesis of (S)-N-trans-feruloylctopamine. Chem. Eur. J. 2011, 17, 1114–1117.
37. Guo, Z.L.; Zhong, S.; Li, Y.B.; Lu, G. Chiral 1,1'-binaphthylazepine derived amino-alcohol
catalyzed asymmetric Henry reaction. Tetrahedron: Asymmetry 2011, 22, 238–245.

Molecules 2015, 20
6235
38. Qin, D.D.; Yu, W.; Zhou, J.D.; Zhan, Y.C.; Ruan, Y.P.; Zhou, Z.H.; Chen, H.B. Syn- and
enantioselective Henry reactions of aliphatic aldehydes and application to the synthesis of safingol.
Chem. Eur. J. 2013, 19, 16541–16544.
39. Reddy, B.S.; Reddy, S.M.; Manisha, S.; Madan, C. Asymmetric Henry reaction catalyzed
by a chiral Cu(II) complex: A facile enantioselective synthesis of (S)-2-nitro-1-arylethanols.
Tetrahedron: Asymmetry 2011, 22, 530–535.
40. Blay, G.; Climent, E.; Fernandez, I.; Hernandez-Olmos, V.; Pedro, J.R. Enantioselective Henry
reaction catalyzed with copper(II)-iminopyridine complexes. Tetrahedron: Asymmetry 2007, 18,
1603–1612.
41. Blay, G.; Domingo, L.R.; Hernandez-Olmos, V.; Pedro, J.R. New highly asymmetric Henry
reaction catalyzed by CuII and a C1-symmetric aminopyridine ligand, and its application to the
synthesis of miconazole. Chem. Eur. J. 2008, 14, 4725–4730.
42. Ji, Y.Q.; Qi, G.; Judeh, Z.M.A. Efficient asymmetric copper(I)-catalyzed Henry reaction using
chiral N-alkyl-C1-tetrahydro-1,1'-bisisoquinolines. Eur. J. Org. Chem. 2011, 4892–4898.
43. Ji, Y.Q.; Qi, G.; Judeh, Z.M.A. Catalytic anti-selective asymmetric Henry (nitroaldol) reaction
catalyzed by Cu(I)-amine-imine complexes. Tetrahedron: Asymmetry 2011, 22, 2065–2070.
44. Blay, G.; Hernandez-Olmos, V.; Pedro, J.R. Synthesis of (S)-(+)-sotalol and R-(−)-isoproterenol via
a catalytic enantioselective Henry reaction. Tetrahedron: Asymmetry 2010, 21, 578–581.
45. Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. A highly effective bis(sulfonamide)-diamine ligand: A
unique chiral skeleton for the enantioselective Cu-catalyzed Henry reaction. Chem. Eur. J. 2010,
16, 8259–8261.
46. Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. Asymmetric syn-selective Henry
reaction catalyzed by the sulfonyldiamine-CuCl-pyridine system. J. Org. Chem. 2008, 73,
4903–4906.
47. Zhou, Y.; Gong, Y. Asymmetric copper(II)-catalysed nitroaldol (Henry) reactions utilizing a chiral
C1-symmetric dinitrogen ligand. Eur. J. Org. Chem. 2011, 6092–6099.
48. Sanjeevakumar, N.; Periasamy, M. Highlly enantioselective Henry reaction catalyzed by a new
chiral C2-symmetric N,N'-bis(isobornyl)ethylendiamine-copper complex. Tetrahedron: Asymmetry
2009, 20, 1842–1847.
49. Ni, B.; He, J. Highly asymmetric Henry reaction catalyzed by chiral copper(II) complexes.
Tetrahedron Lett. 2013, 54, 462–465.
50. Sema, H.A.; Bez, G.; Karmakar, S. Asymmetric Henry reaction catalyzed by L-proline derivatives
in the presence of Cu(OAc)2: Isolation and characterization of an in situ formed Cu(II) complex.
Appl. Organometal. Chem. 2014, 28, 290–297.
51. Csillag, K.; Nemeth, L.; Martinek, T.A.; Szakonyi, Z.; Fulop, F. Stereoselective synthesis of
pinane-type tridentate aminodiols and their application in the enantioselective addition of
diethylzinc to benzaldehyde. Tetrahedron: Asymmetry 2012, 23, 144–150.
52. Binder, C.M.; Bautista, A.; Zaidlewicz, M.; Krzeminski, M.P.; Oliver, A.; Singaram, B. Dual
stereoselectivity in the dialkylzinc reaction using (−)-β-pinene derived amino alcohol chiral
auxiliaries. J. Org. Chem. 1999, 74, 2337–2343.
53. Cherng, Y.J.; Fang, J.M.; Lu, T.J. Pinane-type reagents for enantioselective reactions: Reduction of
ketones and addition of diethylzinc to aldehydes. J. Org. Chem. 1999, 64, 3207–3212.

Molecules 2015, 20
6236
54. Siyutkin, D.E.; Kucherenko, A.S.; Frolova, L.L.; Kuchin, A.V.; Zlotin, S.G. 2-Hydroxy-3-[(S)-
prolinamido]pinanes as novel bifunctional organocatalysts for asymmetric aldol reactions in
aqueous media. Tetrahedron: Asymmetry 2011, 22, 1320–1324.
55. Krzeminski, M.P.; Cwiklinska, M. Chiral terpene auxiliaries II. Spiroborate esters derived from
α-pinene—new catalysts for asymmetric borane reduction of prochiral ketones. Tetrahedron Lett.
2011, 52, 3919–3921.
56. Malhotra, S.V.; Brown, H.C. C2-symmetric N,N'-bis(terpenyl)ethylenediamines synthesis and
application in the enantioselective nitroaldol reaction. RSC Adv. 2014, 4, 14264–14269.
57. Dhahagani, K.; Rajesh, J.; Kanan, R.; Rajagopal, G. Asymmetric Henry reaction of aldehydes
catalyzed by recyclable MCM-41 supported copper(II) salen complex. Tetrahedron: Asymmetry
2011, 22, 857–865.
58. Sohtome, Y.; Hasimoto, Y.; Nagasawa, K. Diastereoselective and enantioselective Henry
(nitroaldol) reaction utilizing a guanidine-thiourea bifunctional organocatalyst. Eur. J. Org. Chem.
2006, 13, 2894–2897.
Sample Availability: Sample of the ligand 4 is available from the authors.
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