Enantioselective Henry reaction catalyzed with copper(II)-iminopyridine complexes

Article abstract of DOI:10.1016/j.tetasy.2007.06.023

Copper complexes of chiral iminopyridines prepared from camphane-derived ketones and picolylamine catalyzed the enantioselective Henry (nitroaldol) reaction between nitromethane and a number of aromatic and aliphatic aldehydes with high yields and good en

Full text of DOI:10.1016/j.tetasy.2007.06.023

Tetrahedron: Asymmetry 18 (2007) 1603–1612
Enantioselective Henry reaction catalyzed
with copper(II)–iminopyridine complexes
*
´
´
´
Gonzalo Blay, Estela Climent, Isabel Fernandez, Victor Hernandez-Olmos and Jose R. Pedro
` ` `
´
Departament de Quı´mica Organica, Facultat de Quımica, Universitat de Valencia, Dr. Moliner 50, E-46100-Burjassot, Valencia, Spain
Received 12 June 2007; accepted 20 June 2007
Available online 16 July 2007
Abstract—Copper complexes of chiral iminopyridines prepared from camphane-derived ketones and picolylamine catalyzed the enantio-
selective Henry (nitroaldol) reaction between nitromethane and a number of aromatic and aliphatic aldehydes with high yields and good
enantioselectivities. Iminopyridines derived from (1R)-(+)-camphor and (1S)-(+)-ketopinic acid gave the best results to afford the oppo-
site enantiomers in each case, despite the fact they have the same stereochemical pattern at the camphane skeleton. The reactions were
carried out without air or moisture exclusion.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
between nitromethane and o-anisaldehyde, without the
need for air or moisture exclusion. Herein we report in
detail the development of the enantioselective Henry reac-
tion between nitromethane and aromatic and aliphatic
aldehydes catalyzed by copper(II) salts in combination
with iminopyridines.
The addition of a nitroalkane to a carbonyl compound to
give a b-nitroalkanol, known as the Henry or nitroaldol
reaction, constitutes as one of the most useful methodolo-
gies for generating C–C bonds and obtaining polyfunction-
alized molecules.1 Due to the versatile chemistry of the
nitro group,2 the b-nitroalkanols that are obtained can be
transformed into a plethora of key molecular frameworks,
such as 1,2-amino alcohols, a-hydroxyacids, and others, by
reduction, Nef reaction or nucleophilic displacement,3
respectively. Consequently, considerable effort has been di-
rected over the last few years towards development of the
catalytic asymmetric version of this reaction.4 This goal
has been achieved with a number of organocatalytic meth-
ods,5 and most often with the use of metal complexes with
chiral ligands. Examples include rare-earth-BINOL,6 zinc–
aminoalcohol,7 or cobalt–ketoimine8 complexes, although
copper complexes with nitrogenated ligands have attracted
most attention as catalysts for this reaction.9 Despite all the
advances produced in this area, some of these catalytic
systems still show limitations such as moisture or air
sensitivity, high catalyst loading, low enantioselectivity,
or a difficult preparation of the catalyst. In a previous com-
munication,10 we reported that complexes of Cu(II) with
iminopyridine ligands derived from monoterpene ketones
and pyridylalkylamines catalyzed the Henry reaction
2. Results and discussion
2.1. Design and synthesis of iminopyridine ligands
A set of ligands 5–7, 9, 11, 13 and 15 with two coordinating
N atoms with sp2 hybridization were synthesized according
to the design in Figure 1. N,N-Ligands have been exten-
sively used in Lewis-acid catalyzed enantioselective reac-
tions. Thus, besides bis-imines11 and the omnipresent
group of C2-symmetric bis-oxazolines (BOX),12 a number
of ligands, which incorporate a coordinating pyridine ring
have been described. This class includes C2-symmetric bis-
pyridines,13 but also C1-symmetric oxazolinylpyridines14
and iminopyridines derived from aldehydes and chiral
spacer
spacer
Mn
+
N
N
Chiral
Chiral
N
N
ketone
Mn
+
ketone
R
R
*
Corresponding author. Tel.: +34 9635 44329; fax: +34 9635 44328;
e-mail: jose.r.pedro@uv.es
Figure 1. Design of chiral iminopyridine ligands.
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.023

1604
G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
amines.15 Three factors have been considered in our design.
A monoterpene ketone with a camphane skeleton was used
as the source of chirality.16 A spacer of variable length and
substitution is used to modify the bite angle of the ligands,
and finally, different ketones or substituted pyridylamines
can be used to modify the steric hindrance around the
proximities of the metal ion.
2.2. Nitroaldol reaction between nitromethane and aldehydes
2.2.1. Optimization of the reaction conditions. The reac-
tion between nitromethane and o-anisole 16b was used to
test the ability of these ligands to induce enantioselectivity
in the metal catalyzed Henry reaction (Scheme 2).
OH
OMe
OMe
In general, the synthesis of these ligands involved short
synthetic sequences (only one step in most cases) starting
from commercial or readily available materials. Ligands
5–7 were prepared by condensation between (1R)-(+)-cam-
phor 1 and the corresponding pyridylalkylamines 2–4 in
the presence of a catalytic amount of BF3ÆEt2O with azeo-
tropic removal of toluene–water (Dean–Stark). Ligand 9,
which has a double alkylated spacer chain was prepared
in two steps from ligand 5 via a double alkylation at the
benzylic position with BuLi and MeI in 29% overall yield
Ligands 11 and 15 were prepared in a similar way as 5–7
starting from (1S)-(+)-ketopinic acid (10) and (1S)-(+)-
camphorsulfonic acid (14), respectively. In these cases the
reaction proceeded faster than with camphor, probably
as a result of an intramolecular acid catalysis by the car-
boxylic or sulfonic acid during imine condensation. Final-
ly, ligand 13 was prepared starting from alcohol 12, which
can be prepared by addition of 2 equiv of phenylmagne-
sium bromide to ketopinic acid methyl ester17 (Scheme 1).
NO2
CHO
L, M(OAc)n
+
CH3NO2
Base, solvent
16b
17b
Scheme 2.
2.2.1.1. Screening of Lewis acids and ligands. Using the
reaction conditions described by Evans9a for the copper–
BOX catalyzed Henry reaction as a starting point, the reac-
tion was initially carried out at room temperature in etha-
nol as the solvent and in the presence of 11 mol % of ligand
5 and 10 mol % acetate as the source for the metal ion. The
reactions were performed in test tubes stopped with a sep-
tum with no special attention given for air or moisture
exclusion (Table 1). A screening of some late transition me-
tal acetates showed copper acetate to be the best promoter
for this reaction (entry 5). Copper(II) triflate was also
tested, but under these conditions, the nitroaldol reaction
took place with concomitant dehydration to give ortho-
methoxynitrostyrene as the main product (Table 1, foot-
note f). The reaction was also tested in different protic
and aprotic solvents. Ethanol was found to be the best
solvent for this reaction. Quite surprisingly, the use of
nitromethane as the solvent, resulted in a slower reaction
than with ethanol.
NH2
(CH2)n
(CH2)n
N
BF Et2O
3
N
N
+
R
Tol (-H2O)
O
R
1
2 n = 1, R = H
3 n = 1, R = Me
4 n = 2, R = H
5 n = 1, R = H (88%)
6 n = 1, R = Me (60%)
7 n = 2, R = H (90%)
Once we had determined the best solvent and metal ion, we
screened the different iminopyridines 6, 7, 9, 11 and 13 as
chiral ligands in combination with copper(II) acetate. None
of these ligands gave better results than ligand 5. Thus, it
was observed that the elongation (ligand 7, entry 11) and
the introduction of substituents (ligand 9, entry 12) on
the spacer, which alter the bite angle of the ligand had a
deleterious effect. Similarly, the introduction of steric
hindrance in the proximities of the pyridine nitrogen as
in ligand 6 (entry 10) or in the proximities of the imine as
in ligand 13 (entry 14), brought about a decrease in the
enantioselectivity, these ligands being less effective than
ligand 5. Only iminopyridine 11 (entry 13), which derives
from (+)-ketopinic acid, was able to induce a considerable
level of enantioselectivity (50%) in this reaction, although it
was lower than that obtained with ligand 5. An important
aspect of the reaction catalyzed with 11 is that, unlike the
other ligands that yielded (S)-(+)-17b as the product, the
reaction with ligand 11 afforded the opposite enantiomer
(R)-(ꢀ)-17b. This was quite surprising, considering that
all ligands share the same stereochemical pattern in the
chiral ketone. Therefore, the optimization process was
continued with ligands 5 and 11.
1. BuLi
2. MeI
1. BuLi
2. MeI
5
N
N
N
N
29%
9
8
overall
NH2
BF Et2O
3
+
N
N
N
HO2C
O
CHCl3 (-H2O)
80%
CO2H
11
13
10
2
NH2
N
N
N
+
+
BF Et2O
3
Ph
Ph
Tol (-H2O)
54%
OH
Ph
O
Ph
OH
12
2
NH2
N
BF Et2O
3
N
N
Tol (-H2O)
98%
O
SO3H
SO3H
2.2.1.2. Lewis acid–Brønsted base dual activation. To
increase the enantiomeric excess of the reaction product,
we decided to lower the reaction temperature. Using the
14
2
15
Scheme 1. Synthesis of iminopyridine ligands.

G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
1605
Table 1. Henry reaction between nitromethane and o-anisole according to
Lewis acids and Brønsted bases as independent entities has
some precedent in the literature, and the combined use of
amines with copper or zinc complexes has been descri-
bed.7d,8,9c,18 Accordingly, the use of different amines as
additives was tested using complex 5–Cu(OAc)2 as the
Lewis acid (Table 2). The use of the heterocyclic amine
2,6-lutidine (entry 2) decreased the reactivity with respect
to the amine-free reaction, to afford the expected product
in similar ee. The use of alkylamines was tested next
(entries 3–9). With these additives, the reaction tempera-
ture could be lowered to ꢀ65 °C, while maintaining accept-
able reaction times. Under these conditions, a noticeable
increase in the ee of the product could be attained.
Scheme 2a: Lewis acid and ligand screening
Entry
L
Metal salt
Solvent t (h) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5
Co(OAc)2Æ4H2O EtOH
Ni(OAc)2Æ4H2O EtOH
Zn(OAc)2Æ2H2O EtOH
24
24
93
70
24
94
94
rac
rac
10d
37
61
53
48
49
52
16
19
21
50d
7
5
5
5
5
5
5
5
5
6
7
9
77
Pd(OAc)2
EtOH
40e
93
Cu(OAc)2ÆH2Of EtOH
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
MeOH 24
MeNO2 70
CH2Cl2 70
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
95
90
62e
54e
47e
62
24
64
26
64
24
70
45e
70
Diisopropylethylamine (DIPEA) gave the best results
(up to 86% ee) either when used in stoichiometric (entry
6) or catalytic amounts (entry 7), although in this case,
the reaction required higher temperature to start. Finally,
variations in the catalyst load (entries 8 and 9) did not give
a significant variation on the result of the reaction.
11 Cu(OAc)2ÆH2O
13 Cu(OAc)2ÆH2O
95
a All reactions carried out at 0.5 mmol scale, using 11 mol % L, 10 mol %
M(OAc)n at rt.
b Yields refer to isolated product after column chromatography.
c Determined by HPLC analysis using a Chiralcel OD–H column. The (S)-
enantiomer was obtained unless if otherwise stated.
d The (R)-enantiomer was obtained.
The results obtained with ligand 5 were used as a starting
point for the optimization with ligand 11, which affords
the opposite enantiomer. When DIPEA (1 equiv) was used
as an additive with the catalyst formed by 11 and
Cu(OAc)2, the reaction could be carried out at ꢀ65 °C.
However, the product obtained under these conditions
showed an ee similar to that obtained with the amine-free
system at rt (Table 1, entry 13 vs Table 2, entry 11). Since
ligand 11 bears a carboxylic acid functionality, which can
form hydrogen bonds with EtOH, we decided to test the
use of aprotic solvents with ligand 11. Diethyl ether, which
can act as an acceptor for hydrogen bond formation gave a
sluggish reaction at ꢀ45 °C affording the expected product
in very low yield and only 30% ee. However, with the use of
chlorinated solvents, increased enantiomeric excesses could
e Uncompleted reaction after the indicated time.
f Under similar reaction conditions, Cu(OTf)2 gave ortho-methoxynitro-
styrene.
catalyst formed by 5–Cu(OAc)2 at 0 °C, the enantiomeric
excess of the product increased up to 67% (Table 2, entry
1). Unfortunately, when we attempted a further decrease
of the reaction temperature to ꢀ20 °C, it resulted in
impractical reaction times.
The concurrent activation of the aldehyde and nitrometh-
ane in the Henry reaction by the combined use of discrete
Table 2. Henry reaction between nitromethane and o-anisole according to Scheme 2 in the presence of aminesa
Entry
L
Solvent
Base
T (°C)
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CHCl3
EtOH
Et2O
CH2Cl2
(ClCH2)2
CHCl3
CHCl3
CHCl3
—
0
0d
88
117
45
45
88
48
70
70
70
46
20
144
74
46
22
46
48
98
90
85
84
56
90
92
96
94
94
76
5
88
83
83
98
90
67
66
77
80
83
85
83
86
5
2,6-Lutidine
i-PrNH2
Cy2NH
Et3N
5
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ55
ꢀ65
ꢀ65
ꢀ40
ꢀ65
ꢀ45
ꢀ45
ꢀ45
ꢀ45
ꢀ65
ꢀ45
5
5
5
DIPEA
DIPEA (0.1 equiv)
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
5
5e (22 mol %)
5f (6 mol %)
5
84
78
11
54g
30g
73g
67g
79g
84g
68
11
11
11
11
11
15
a All reactions carried out at 0.5 mmol scale, using 11 mol % L, 10 mol % Cu(OAc)2Æ2H2O, and 0.5 mmol of base, unless if otherwise stated.
b Yields refer to isolated product after column chromatography.
c Determined by HPLC analysis using a Chiralcel OD–H column. The (S)-enantiomer was obtained unless if otherwise stated.
d No reaction was observed at ꢀ20 °C.
e 20 mol % of Cu(OAc)2Æ2H2O.
f 5 mol % of Cu(OAc)2Æ2H2O.
g The (R)-enantiomer was obtained.

1606
G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
be obtained. Chloroform was found to be the most effective
solvent, which allowed us to decrease the reaction temper-
ature to ꢀ65 °C and afforded the reaction product almost
quantitatively with 84% ee (entry 16).
all the aldehydes tested. Thus, while ligand 5 primarily
afforded the (S)-enantiomer, the opposite (R)-enantiomer
of the nitroaldol products were obtained with ligand 11.
The reaction was carried out with several substituted benz-
aldehydes (entries 1–17 and 21–37). With both catalysts,
the best results were obtained with ortho-substitued benz-
aldehydes bearing electron-releasing substituents with lone
electron pairs (RO– and RS–, entries 2–4 and 22–24) or
simple alkyl groups (Me, Et, entries 5, 6 and 25, 26). The
presence of electron-withdrawing atoms, such as halogens
at this position, brought about a decrease in the enantiose-
lectivity of the reaction (entries 7–9 and 27–29), which was
especially important with the strongly electron-withdraw-
ing nitro group (entries 10 and 30). Benzaldehydes substi-
tuted at the para- and meta-positions followed a similar
behaviour and the products were obtained with somehow
lower enantiomeric excesses than their ortho-substituted
analogues (entries 11–17 and 31–37). With aliphatic alde-
hydes, both catalysts showed significant differences. Thus
the reaction of nitromethane with 3-phenylpropanal cata-
lyzed by the Cu(II)–5 complex (entry 18) was very sluggish
and was still incomplete after 10 days at ꢀ20 °C, affording
the expected nitroaldol product with low yield (44%) and ee
(43%). On the other hand, the Cu(II)–11 complex was able
A last assay was made using ligand 15 derived from (1S)-
(+)-camphorsulfonic acid, which incorporates a sulfonic
acid instead of a carboxylic acid moiety. Under the opti-
mized reaction conditions developed for ligand 11, the
reaction in the presence of 15 afforded (S)-(+)-17b in 68%
ee, showing that the presence of an acidic function at this
particular position of the terpene ketone is not responsible
for the inversion of the enantioselectivity observed with
ligand 11.
2.2.2. Substrate scope. A representative selection of alde-
hydes were evaluated under the optimized conditions:
11 mol % L, 10 mol % Cu(OAc)2ÆH2O in EtOH for ligand
5 and CHCl3 for ligand 11. The reaction temperature was
adjusted according to the reactivity of the aldehyde. The
results are summarized in Table 3 (Scheme 3).
As already noticed during the optimization process, both
ligands 5 and 11 yielded the opposite enantiomers with
N
N
N
N
5 (11 mol %)
11 (11 mol %)
CO2H
OH
Cu(OAC)2 2H2O
(10 mol%)
OH
Cu(OAC)2 2H2O
(10 mol%)
NO2
NO2
R
+
CH3NO2
R
R-CHO
DIPEA (1 eq)
EtOH
DIPEA (1 eq)
CHCl3
16
(S)-17
(R)-17
Scheme 3. Henry reaction between nitromethane and aldehydes in the presence of Cu(OAc)2Æ2H2O and ligands 5 or 11.
Table 3. Henry reaction between nitromethane and aldehydes according to Scheme 3: Substrate scope
Entry Aldehyde 16
Reaction with ligand 5
Entry
Reaction with ligand 11
T (°C) t (h) Yielda (%) (S)-17 eeb (%)
T (°C) t (h) Yielda (%) (R)-17 eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Benzaldehyde
a
b
c
d
e
f
ꢀ40
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ40
ꢀ40
ꢀ50
ꢀ45
ꢀ25
ꢀ40
ꢀ40
ꢀ40
ꢀ20
—
90
50
64
72
96
114
141
90
90
70
120
67
69
93
90
74
99
200
—
—
81
90
97
89
95
80
54
65
75
70
75
81
76
85
81
88
84
44
—
—
72
85
85
79
82
84
65
68
71
27
78
73
56
17
76
72
51
43
—
—
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
ꢀ65
ꢀ65
ꢀ65
ꢀ50
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ65
ꢀ50
ꢀ50
ꢀ65
ꢀ50
ꢀ50
ꢀ50
ꢀ65
ꢀ40
ꢀ50
ꢀ50
ꢀ50
140
46
90
67
50
115
140
50
46
20
120
67
90
67
70
120
93
120
120
120
84
98
96
83
97
82
90
98
95
89
80
80
90
99
83
91
95
83
99
94
80
84
83
83
83
84
75
78
77
31
78
81
74
27
75
72
63
74
73
79
2-Methoxybenzaldehyde
2-(Benzyloxy)benzaldehyde
2-(Methylthio)benzaldehyde
2-Methylbenzaldehyde
2-Ethylbenzaldehyde
2-Chlorobenzaldehyde
2-Bromobenzaldehyde
2-Iodobenzaldehyde
2-Nitrobenzaldehyde
4-Methoxybenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
4-Nitrobenzaldehyde
3-Methoxybenzaldehyde
3-Methylbenzaldehyde
3-Chlorobenzaldehyde
3-Phenylpropanal
g
h
i
j
k
l
m
n
o
p
q
r
Cyclohexancarbaldehyde
3-Methylbutanal
s
t
—
a Yields refer to isolated product after column chromatography.
b Determined by HPLC analysis using chiral stationary phase columns.

G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
1607
to promote the reaction at ꢀ50 °C yielding the expected
product with 74% ee (entry 38). Similar results were ob-
tained with other branched or sterically hindered aliphatic
aldehydes (entries 39 and 40) using ligand 11.
bonyl group giving the nitroaldol product with the (S)-
configuration.
3. Conclusion
2.2.3. Stereochemical considerations. As we have seen,
ligands 5 and 11 lead to opposite enantiomers, although
they have the same stereochemical pattern in the mono-
terpene ketone. Unfortunately, we have not been able to
obtain crystals of the copper complexes with these ligands
suitable for X-ray analysis. However, based on our exper-
imental observations and the previously reported steric
and electronic considerations,9a we propose two transition
state models, which account for the absolute configuration
of the products obtained with ligands 5 and 11. The active
species simultaneously binds the two reaction partners with
the nucleophile positioned perpendicular to the ligand
plane, while the electrophile, for maximum activation,
should be positioned in one of the more Lewis acidic equa-
torial sites in the ligand plane. With ligand 11, the ligand
plane should be defined by the two nitrogen atoms and
the deprotonated carboxyl group, which would bind to
the copper centre giving the expected distorted square pla-
nar complex (Fig. 2b). The fourth equatorial position
should be occupied by the aldehyde and transfer of the
nitronate from the less hindered apical position to the Si
face of the carbonyl group would lead to the (R)-nitroaldol
product. On the other hand, the complex with ligand 5
should have a more distorted geometry around the metal
centre in order to avoid the repulsive interaction between
the methyl group at C1 of the camphor skeleton and one
of the acetate molecules, which occupies the vacant equato-
rial coordination site (Fig. 2a). In this distorted complex
the C1-Methyl group would shield one of the apical posi-
tions of the copper complex and attack of the nitronate
would take place preferentially to the Re face of the car-
In conclusion, we have developed a new catalytic system
for the copper(II)-catalyzed enantioselective Henry reac-
tion between nitromethane and aldehydes. This system uses
a new family of N,N-ligands, namely iminopyridines, which
can be easily prepared in a modular way from readily avail-
able monoterpene ketones and pyridylalkylamines. Two
iminopyridines 5 and 11 derived from picolylamine and
(1R)-(+)-camphor and (1S)-(+)-ketopinic acid, respec-
tively, showed the maximum efficiency providing the corre-
sponding nitroalkanols with good yields and moderate to
high ee values. Both ligands provide opposite enantiomers,
despite the fact they have the same stereochemical pattern
in the terpene ketone. Finally, the reaction is carried out
without the need of air or moisture exclusion.
4. Experimental
4.1. General
Commercial reagents were used as purchased. Reagent
quality EtOH and CHCl3 were used for all enantioselective
reactions, which were carried out in test tubes stopped with
a septum. No special precautions were observed for air or
moisture exclusion. Reactions were monitored by TLC
analysis using Merck Silica Gel 60 F-254 thin layer plates.
Flash column chromatography was performed on Merck
silica gel 60, 0.040–0.063 mm. Optical rotations were mea-
sured using sodium light (D line 589 nm) on a Perkin Elmer
243 polarimeter. 1H NMR (Bruker Avance 300 DPX spec-
1
trometer) were run at 300 MHz for H and at 75 MHz for
13C NMR, in CDCl3 and referenced to the residual non-
deuterated solvent as internal standard (d 7.26 ppm for
1H and 77.0 ppm for 13C NMR, respectively). The carbon
type was determined by DEPT experiments. MS(EI) were
run at 70 eV. MS(FAB) were carried out on a Fisons
instruments VG autospec GC8000 series spectrometer at
30 kV in a MNBA matrix. Chiral HPLC analyses were per-
formed in an Agilent 1100 series instrument equipped with
a refraction index detector or in a Hitachi ELITE
LaChrom L-2130 instrument equipped with a UV diode-
array L-4500 detector. Retention times are given in min.
O
a
N
O
N
O
Me
N
Me
O
O
H
R
N
b
4.2. Synthesis of ligand 5
A solution of (+)-camphor 1 (6.0 g, 41.8 mmol), picolyl-
amine 2 (4.27 mL, 41.8 mmol) and BF3ÆEt2O (0.24 mL) in
toluene (95 mL) in a round bottom flask with a Dean–Stark
system was refluxed overnight under nitrogen. The reaction
mixture was diluted with EtOAc (50 mL), washed with
saturated aqueous NaHCO3 and dried over MgSO4. Sol-
vent removal was followed by column chromatography
eluting with hexane–EtOAc (8:2) to give 8.9 g (88%) of
O
N
O
O
R
H
O
O
N
25
25
ligand 5: ½aꢁD ¼ ꢀ24:2 (c 0.91, CHCl3), ½aꢁD ¼ ꢀ30:4 (c
0.81, MeOH); MS(EI) 242 (M+, 58), 241 (100), 92 (78);
HRMS 242.1772, C16H22N2 required 242.1783; H NMR
Figure 2. Proposed transition state models for the copper-catalyzed
enantioselective Henry reaction with ligands 5 (a) and l1 (b).
1

1608
G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
(300 MHz, CDCl3) d 8.50 (dd, J = 5.0, 1.8 Hz, 1H), 7.66
(td, J = 7.5, 1.8 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.14
(dd, J = 7.5, 5.0 Hz, 1H), 4.65 (d, J = 16.2 Hz, 1H), 4.61
(d, J = 16.2 Hz, 1H), 2.54 (dt, J = 17.4, 3.3 Hz, 1H), 2.03–
1.83 (m, 3H), 1.74 (td, J = 12.0, 4.2 Hz, 1H), 1.44 (ddd,
J = 12.0, 9.0, 4.2 Hz, 1H), 1.24 (ddd, J = 12.0, 9.0,
4.2 Hz), 1.11 (s, 3H), 0.95 (s, 3H), 0.78 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 184.5 (s), 160.6 (s), 148.8 (d), 136.4
(d), 121.4 (d), 121.4 (d), 57.5 (t), 53.9 (s), 47.2 (s), 43.8 (d),
35.9 (t), 32.1 (t), 27.3 (t), 19.5 (q), 18.9 (q), 11.3 (q).
phy eluting with hexane–EtOAc (9:1) gave 214 mg (29%)
25
of ligand 9: ½aꢁD ¼ ꢀ5:6 (c 0.99, CHCl3); MS(EI) 270
(M+, 11), 255 (100), 120 (57); HRMS 270.2085,
C18H26N2 required 270.2096; 1H NMR (300 MHz, CDCl3)
d 8.51 (d, J = 3.6 Hz, 1H), 7.58 (td, J = 7.8. 2.1 Hz, 1H),
7.45 (d, J = 7.8 Hz, 1H), 7.11–7.07 (m, 1H), 1.69–0.78
(m, 7H), 1.61 (s, 3H), 1.60 (s, 3H), 1.01 (s, 3H), 0.86 (s,
3H), 0.65 (s, 3H); 13C NMR (75 MHz, CDCl3) d 180.6
(s), 168.7 (s), 148.0 (d), 135.9 (d), 121.5 (d), 121.0 (d),
62.2 (s), 54.7 (s), 46.5 (s), 44.3 (d), 37.9 (t), 32.1 (t), 29.1
(q), 28.4 (q), 27.3 (t), 19.5 (q), 19.1 (q), 11.9 (q).
4.3. Synthesis of ligand 6
4.6. Synthesis of ligand 11
By using the same procedure as for the synthesis of 5, from
(+)-camphor (717 mg, 4.7 mmol) and amine 3 (593 mg,
4.9 mmol), after 21 h, and column chromatography eluting
The same procedure as for the synthesis of 5, in CHCl3
instead of toluene was used. Starting from (1S)-(+)-keto-
pinic acid 10 (2.5 g, 13.7 mmol) and picolylamine 2
(1.5 mL, 14.6 mmol), after 4 h, the reaction mixture was
concentrated under reduced pressure. Crystallization from
with hexane–EtOAc (4:6) were obtained 723 mg (60%) of
25
ligand 6: ½aꢁD ¼ ꢀ23:9 (c 0.92, CHCl3); MS(EI) 256 (M+,
75), 255 (100), 107 (70), 106 (81); HRMS 256.1901,
C17H24N2 required 256.1939; 1H NMR (300 MHz, CDCl3)
d 7.53 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.97 (d,
J = 7.8 Hz, 1H), 4.56 (d, J = 17.1 Hz, 1H), 4.50 (d,
J = 17.1 Hz, 1H), 2.50 (s, 3H), 2.40 (dt, J = 17.4, 4.2 Hz,
1H), 1.96–1.79 (m, 3H), 1.69 (td, J = 12.9, 4.2 Hz, 1H),
1.41 (ddd, J = 12.9, 9.0, 4.2 Hz, 1H), 1.26–1.16 (m, 1H),
1.04 (s, 3H), 0.93 (s, 3H), 0.76 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 184.6 (s), 159.9 (s), 157.3 (s), 136.7
(d), 121.0 (d), 118.3 (d), 57.5 (t), 54.0 (s), 47.2 (s), 43.8
(d), 36.0 (t), 32.1 (t), 27.3 (t), 24.4 (q), 19.6 (q), 18.9 (q),
11.4 (q).
hexane–CH2Cl2 afforded 2.99 g (80%) of ligand 11:
25
½aꢁD ¼ þ64:8 (c 1.11, CHCl3); MS(EI) 272 (M+, 55), 257
(49), 92 (100); HRMS 272.1425, C16H20N2O2 required
1
272.1525; H NMR (300 MHz, CDCl3) d 8.53 (d, J = 4.8,
1H), 7.70 (td, J = 7.5, 1.8 Hz, 1H), 7.33 (d, J = 7.5 Hz,
1H), 7.21 (m, 1H), 4.79 (s, 2H), 2.76 (dt, J = 18.0,
3.3 Hz, 1H), 2.50 (td, J = 12.3, 3.9 Hz, 1H), 2.26–2.04
(m, 3H), 1.77 (ddd, J = 13.8, 9.0, 3.9 Hz, 1H), 1.41 (ddd,
J = 12.0, 9.0, 3.9 Hz, 1 H), 1.31 (s, 3H), 0.97 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 185.3 (s), 173.2 (s), 157.2
(s), 149.3 (d), 137.0 (d), 122.4 (d), 121.7 (d), 60.7 (s), 56.5
(t), 50.6 (s), 43.9 (d), 35.7 (t), 31.4 (t), 28.0 (t), 20.2 (q),
19.9 (q).
4.4. Synthesis of ligand 7
By using the same procedure as for the synthesis of 5, from
4.7. Synthesis of ligand 13
camphor (1.0 g, 7.0 mmol) and amine
4
(890 mg,
7.35 mmol), after 27 h, and column chromatography elut-
By using the same procedure as for the synthesis of 5, from
ing with hexane–EtOAc (2:8) were obtained 1.61 g (90%)
ketone 12 (480 mg, 1.5 mmol) and picolylamine 2
(0.160 mL, 1.58 mmol), after 20 h and column chromatog-
25
of ligand 7: ½aꢁD ¼ ꢀ28:4 (c 1.01, CHCl3); MS(EI) 256
(M+, 44), 106 (100); HRMS 256.1925, C17H24N2 required
256.1939; 1H NMR (300 MHz, CDCl3) d 8.49 (d,
J = 4.8 Hz, 1H), 7.53 (td, J = 6.0, 1.2 Hz, 1H), 7.15 (d,
J = 7.8 Hz, 1H), 7.09–7.05 (m, 1H), 3.71–3.53 (m, 2H),
3.11–3.07 (m, 2H) 2.19 (dt, J = 17.1, 3.6 Hz, 1H), 1.82–
1.52 (m, 4H), 1.21–1.14 (m, 1H), 1.01–0.96 (m, 1H), 0.96
(s, 3H), 0.84 (s, 3H), 0.54 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 182.8 (s), 160.5 (s), 149.2 (d), 136.0 (d), 124.0
(d), 121.0 (d), 53.5 (s), 52.1 (t), 46.7 (s), 43.6 (d), 39.3 (t),
35.5 (t), 32.1 (t), 27.3 (t), 19.3 (q), 18.8 (q), 11.4 (q).
raphy eluting with hexane–EtOAc (6:4) were obtained
25
335 mg (54%) of ligand 13: mp 172–176 °C; ½aꢁD
¼
þ163:7 (c 0.97, CHCl3); MS(EI) 410 (M+, 1.0), 341 (35),
318 (100); HRMS 410.2353, C28H30N2O required
1
410.2358; H NMR (300 MHz, CDCl3) d 8.48 (d, J = 4.2,
1H), 7.56–7.46 (m, 5H), 7.28–7.09 (m, 8H), 6.98 (d,
J = 8.1 Hz, 1H), 4.69 (d, J = 17.4 Hz, 1H), 4.58 (d,
J = 17.4 Hz, 1H), 2.64–2.50 (m, 2H), 2.43–2.32 (m, 1H),
2.01 (d, J = 17.4 Hz, 1H), 1.91–1.79 (m, 1H), 1.66 (t,
J = 4.5 Hz, 1H), 1.37–1.29 (m, 1H), 1.11 (s, 3H), 0.12 (s,
3H); 13C NMR (75 MHz, CDCl3) d 184.9 (s), 159.5 (s),
149.1 (s), 148.2 (d), 144.9 (s), 137.0 (d), 129.4 (d), 128.4
(d), 127.0 (d), 126.8 (d), 126.5 (d), 125.9 (d), 122.1 (d),
121.7 (d), 80.2 (s), 64.2 (s), 56.7 (t), 50.3 (s), 45.4 (d), 35.4
(t), 27.4 (t), 26.9 (t), 22.3 (q), 21.1 (q).
4.5. Synthesis of ligand 9
BuLi (2 M) in cyclohexane (2.1 mL, 4.2 mmol) was added
dropwise to a solution of ligand 5 (0.7 g, 2.73 mmol) in
dry THF at ꢀ78 °C under nitrogen. After 5 min, a solution
of MeI (0.77 g, 5.46 mmol) was added and the mixture stir-
red for 45 min. The reaction was quenched by the addition
of water (10 mL), diluted with EtOAc (120 mL) and
washed with brine (50 mL). After drying over MgSO4,
the solvent was removed under reduced pressure to give
673 mg (93%) of a mixture of diastereomers 8. The proce-
dure was repeated with this diastereomeric mixture for
5 h. The usual workup followed by column chromatogra-
4.8. Synthesis of ligand 15
By using the same procedure as for the synthesis of 11,
from (1S)-(+)-camphorsulfonic acid 14 (2.5 g, 10.8 mmol)
and picolylamine (2, 1.15 mL, 11.3 mmol), after 20 h, were
obtained 3.4 g (98%) of ligand 15: mp 172–176 °C;
25
½aꢁD ¼ ꢀ39:6 (c 1.03, CHCl3); MS(FAB) 323 (M++1, 45);
HRMS 323.1421, C16H23N2O3S required 323.1429; 1H

G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
1609
NMR (300 MHz, CDCl3) d 8.60 (d, J = 3.9, 1H), 7.92 (td,
J = 7.5, 2.1 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.45 (m,
1H), 5.11 (s, 2H), 3.45 (d, J = 14.7 Hz, 1H), 3.30–3.19
(m, 1H), 3.08 (d, J = 14.7 Hz, 1H), 2.73–2.05 (m, 5H),
1.56–1.51 (m, 1H), 1.02 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 202.7 (s), 151.9 (s), 149.7 (d), 137.5 (d), 123.7
(d), 123.1 (d), 58.4 (s), 53.2 (t), 52.8 (s), 49.2 (t), 43.0 (d),
38.0 (t), 28.8 (t), 26.2 (t), 19.9 (q), 18.7 (q).
273.1001; 1H NMR (300 MHz, CDCl3) d 7.49–7.29 (m,
7H), 7.04 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H),
5.71 (dd, J = 9.0, 2.7 Hz, 1H), 5.17 (d, J = 12.1 Hz, 1H),
5.13 (d, J = 12.1 Hz, 1H), 4.68 (dd, J = 12.9, 2.7 Hz, 1H),
4.57 (dd, J = 12.9, 9.0 Hz, 1H), 3.03 (sample, 1H); 13C
NMR (75.5 MHz, CDCl3) d 155.0 (s), 136.1 (s), 129.7 (d),
128.8 (d), 128.3 (d), 127.2 (d), 127.1 (d), 126.3 (d), 121.4
(d), 111.9 (d), 79.8 (t), 70.2 (t), 67.6 (d).
4.9. General procedure for the enantioselective Henry
reaction
4.9.4. (R)-(ꢀ)-1-(2-Methylthiophenyl)-2-nitroethanol 17d.
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (83%) was determined
by HPLC (Chiralpak AD–H), hexane–i-PrOH 90:10,
Cu(OAc)2ÆH2O (9.9 mg, 0.05 mmol) was added to a solu-
tion of ligand 5 (13.3 mg, 0.055 mmol) in absolute EtOH
(1.5 mL) and the mixture stirred for 1 h. To the resulting
blue solution was added nitromethane (0.27 mL, 5 mmol)
and the recipient introduced in a bath at the required tem-
perature. Aldehyde 16 (0.5 mmol) dissolved in absolute
ethanol (1.5 mL) was added followed by DIPEA (82 lL,
0.5 mmol) and the reaction mixture stirred until comple-
tion (TLC). The solvent was removed under reduced pres-
sure and the residue chromatographed on silica gel to give
nitroalkanol 17. The same procedure was followed with
ligand 11 (15.0 mg) but using CHCl3 instead of EtOH.
Yields and enantiomeric excesses for compounds 17 are
shown in Table 3.
0.5 mL/min, major enantiomer (R) tr = 27.8, minor enan-
25
tiomer (S) tr = 28.8; ½aꢁD ¼ ꢀ62:6 (c 1.09, CH2Cl2, ee
83%, obtained with ligand 11); MS(EI) 213 (M+, 18), 151
(100), 91 (66); HRMS 213.0469, C9H11NO3S required
213.0460; 1H NMR (300 MHz, CDCl3) d 7.54 (dd,
J = 7.2, 1.5 Hz, 1H), 7.34–7.29 (m, 1H), 7.20–7.14 (m,
2H), 5.81 (dd, J = 9.6, 2.4 Hz, 1H), 4.61 (dd, J = 13.5,
2.4 Hz, 1H), 4.44 (dd, J = 13.5, 9.6 Hz, 1H), 2.81 (br s,
1H), 2.49 (s, 3H); 13C NMR (75.5 MHz, CDCl3) d 135.9
(s), 135.5 (s), 129.2 (d), 126.3 (d), 126.1 (d), 125.8 (d),
79.6 (t), 67.9 (d), 16.1 (q).
4.9.5.
(S)-(+)-1-(2-Methylphenyl)-2-nitroethanol
17e.
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (82%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
4.9.1. (S)-(+)-2-Nitro-1-phenylethanol 17a. Purified by
chromatography eluting with hexane–diethyl ether (9:1).
Enantiomeric excess (72%) was determined by HPLC (Chi-
ralcel OD–H), hexane–i-PrOH 90:10, 1 mL/min, major
min, major enantiomer (S) tr = 17.1, minor enantiomer
25
(R) tr = 11.5; ½aꢁD ¼ þ41:7 (c 1.07, CH2Cl2, ee 82%,
1
enantiomer (S) tr = 16.6, minor enantiomer (R) tr = 14.1;
obtained with ligand 5); H NMR (300 MHz, CDCl3) d
25
½aꢁD ¼ þ33:7 (c 1.05, CH2Cl2, ee 72%, obtained with ligand
7.50–7.46 (m, 1H), 7.25–7.22 (m, 2H), 7.17–7.15 (m, 1H),
5.64 (dd, J = 9.6, 2.7 Hz, 1H), 4.51 (dd, J = 13.5, 9.6 Hz,
1H), 4.39 (dd, J = 13.5, 2.7 Hz, 1H), 2.79 (br s, 1H), 2.35
(s , 3H); 13C NMR (75.5 MHz, CDCl3) d 136.2 (s), 134.4
(s), 130.8 (d), 128.7 (d), 126.7 (d), 125.6 (d), 80.2 (t), 67.9
(d), 18.8 (q).
1
5); H NMR (300 MHz, CDCl3) d 7.42–7.40 (m, 5H), 5.47
(dd, J = 9.3, 3.6 Hz, 1H), 4.62 (dd, J = 13.8, 9.3 Hz, 1H),
4.52 (dd, J = 13.8, 3.6 Hz, 1H), 2.77 (br s, 1H); 13C
NMR (75.5 MHz, CDCl3) d 138.0 (s), 129.0 (d), 128.9 (s),
125.9 (d), 81.1 (t), 70.9 (d).
4.9.2. (S)-(+)-1-(2-Methoxyphenyl)-2-nitroethanol 17b.
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (78%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
4.9.6. (S)-(+)-1-(2-Ethylphenyl)-2-nitroethanol 17f. Puri-
fied by chromatography eluting with hexane–diethyl ether
(9:1). Enantiomeric excess (84%) was determined by HPLC
(Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/min, major
min, major enantiomer (S) tr = 13.6, minor enantiomer
enantiomer (S) tr = 13.3, minor enantiomer (R) tr = 10.7;
25
25
(R) tr = 12.1; ½aꢁ ¼ þ39:8 (c 1.05, CH2Cl2, ee 85%, ob-
tained with ligaDnd 5); 1H NMR (300 MHz, CDCl3) d
7.44 (dd, J = 7.5, 1.5 Hz, 1H), 7.33 (td, J = 7.5, 1.5 Hz,
1H), 7.04–6.99 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.63
(dd, J = 9.0, 3.3 Hz, 1H), 4.65 (dd, J = 13.2, 3.3 Hz, 1H),
4.57 (dd, J = 13.2, 9.0 Hz, 1H), 3.88 (s, 3H), 2.87 (br s,
1H); 13C NMR (75.5 MHz, CDCl3) d 155.9 (s), 129.7 (d),
127.1 (d), 125.9 (s), 121.0 (d), 110.5 (d), 79.8 (t), 67.7 (d),
55.3 (q).
½aꢁD ¼ þ33:6 (c 0.96, CH2Cl2, ee 84%, obtained with ligand
5); MS(EI) 195 (M+, 0.2), 133 (100), 131 (87), 91 (58), 79
1
(46); HRMS 195.0896, C10H13NO3 required 195.0895; H
NMR (300 MHz, CDCl3) d 7.48 (dd, J = 9.0, 2.4 Hz,
1H), 7.29–7.19 (m, 3H), 5.70 (dd, J = 9.6, 2.7 Hz, 1H),
4.56 (dd, J = 13.2, 9.6 Hz, 1H), 4.38 (dd, J = 13.2,
2.7 Hz, 1H), 3.02 (sample, 1H), 2.69 (m, 2H), 1.24 (t,
J = 7.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d 140.7
(s), 135.5 (s), 129.0 (d), 128.9 (d), 126.7 (d), 125.8 (d),
80.8 (t), 67.3 (d), 25.1 (t), 15.5 (q).
4.9.3. (R)-(ꢀ)-1-(2-Benzyloxyphenyl)-2-nitroethanol 17c.
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (83%) was determined
by HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10,
4.9.7. (S)-(+)-1-(2-Chlorophenyl)-2-nitroethanol 17g. Puri-
fied by chromatography eluting with hexane–diethyl ether
(9:1). Enantiomeric excess (65%) was determined by HPLC
(Chiralcel OD–H), hexane–i-PrOH 95:5, 0.5 mL/min,
1 mL/min, major enantiomer (R) tr = 13.8, minor enantio-
25
mer (S) tr = 17.6; mp 65–67 °C; ½aꢁD ¼ ꢀ33:8 (c 1.10,
major enantiomer (S) tr = 29.9, minor enantiomer (R)
25
CH2Cl2, ee 83%, obtained with ligand 11); MS(EI) 273
tr = 28.2; ½aꢁD ¼ þ40:3 (c 1.10, CH2Cl2, ee 65%, obtained
(M+, 3), 91 (100). HRMS: 273.0985 C15H15NO4 required
with ligand 5); H NMR (300 MHz, CDCl3) d 7.67 (dd,
1

1610
G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
J = 7.5, 2.1 Hz, 1H), 7.40–7.27 (m, 3H), 5.85 (dd, J = 9.6,
2.4 Hz, 1H), 4.68 (dd, J = 13.5, 2.4 Hz, 1H), 4.45 (dd,
J = 13.5, 9.6 Hz, 1H), 2.88 (br s, 1H); 13C NMR
(75.5 MHz, CDCl3) d135.4 (s), 131.5 (s), 129.9 (d), 129.7
(d), 127.6 (d), 127.5 (d), 79.3 (t), 67.8 (d).
4.9.12.
(R)-(ꢀ)-1-(4-Methylphenyl)-2-nitroethanol
17l.
Purified by chromatography eluting with hexane–diethyl
ether (8:2). Enantiomeric excess (81%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
min, major enantiomer (R) tr = 14.1, minor enantiomer
25
(S) tr = 18.6; ½aꢁD ¼ ꢀ37:2 (c 1.14, CH2Cl2, ee 81%, ob-
4.9.8.
(R)-(ꢀ)-1-(2-Bromophenyl)-2-nitroethanol
17h.
tained with ligand 11); 1H NMR (300 MHz, CDCl3) d
7.33 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 5.46
(dd, J = 9.3, 3.0 Hz, 1H), 4.64 (dd, J = 13.2, 9.3 Hz, 1H),
4.52 (dd, J = 13.2, 3.0 Hz, 1H), 2.82 (br s, 1H), 2.41 (s,
3H); 13C NMR (75.5 MHz, CDCl3) d 138.9 (s), 135.1 (s),
129.6 (d), 125.8 (d), 81.2 (t), 70.8 (d), 21.1 (q).
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (78%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 95:5, 0.5 mL/
min, major enantiomer (R) tr = 29.4, minor enantiomer
25
(S) tr = 33.3; ½aꢁD ¼ ꢀ29:2 (c 1.06, CH2Cl2, ee 78%, ob-
tained with ligand 11); 1H NMR (300 MHz, CDCl3) d
7.66 (dd, J = 7.8, 1.8 Hz, 1H), 7.56 (dd, J = 7.8, 1.2 Hz,
1H), 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.23 (td, 7.8, 1.8 Hz,
1H), 5.81 (dd, J = 9.6, 2.4 Hz, 1H), 4.69 (dd, J = 13.8,
2.4 Hz, 1H), 4.32 (dd, J = 13.8, 9.6 Hz, 1H), 2.85 (br s,
1H); 13C NMR (75.5 MHz, CDCl3) d 137.0 (s), 133.0 (d),
130.2 (d), 128.2 (d), 127.8 (d), 121.4 (s), 79.3 (t), 70.0 (d).
4.9.13. (S)-(+)-1-(4-Chlorophenyl)-2-nitroethanol 17m.
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (56%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
min, major enantiomer (S) tr = 17.2, minor enantiomer
25
(R) tr = 14.1; ½aꢁD ¼ þ24:7 (c 1.13, CH2Cl2, ee 56%, ob-
tained with ligand 5); 1H NMR (300 MHz, CDCl3) d
7.39–7.31 (m, 4H), 5.43 (dd, J = 9.0, 3.3 Hz, 1H), 4.56
(dd, J = 13.2, 9.0 Hz, 1H), 4.47 (dd, J = 13.2, 3.3 Hz,
1H), 3.11 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) d
136.5 (s), 134.7 (s), 129.2 (d), 127.3 (d), 80.9 (t), 70.2 (d).
4.9.9. (S)-(+)-1-(2-Iodophenyl)-2-nitroethanol 17i. Purified
by chromatography eluting with hexane–diethyl ether (9:1).
Enantiomeric excess (71%) was determined by HPLC
(Chiralpak AD–H), hexane–i-PrOH 95:5, 0.5 mL/min,
major enantiomer (S) tr = 33.8, minor enantiomer (R)
25
tr = 35.6; ½aꢁD ¼ þ24:2 (c 1.08, CH2Cl2, ee 71%, obtained
4.9.14.
(R)-(ꢀ)-2-Nitro-1-(4-nitrophenyl)ethanol
17n.
with ligand 5); MS(EI) 293 (M+, 72), 246 (100), 233 (72),
91 (95); HRMS 292.9539, C8H8INO3 required 292.9549;
1H NMR (300 MHz, CDCl3) d 7.84 (dd, J = 7.8, 1.5 Hz,
1H), 7.62 (dd, J = 7.8, 1.2 Hz, 1H), 7.43 (td, J = 7.8,
1.5 Hz, 1H), 7.07 (td, 7.8, 1.2 Hz, 1H), 5.67 (dd, J = 9.9,
2.4 Hz, 1H), 4.65 (dd, J = 13.5, 2.4 Hz, 1H), 4.40 (dd,
J = 13.5, 9.9 Hz, 1H), 2.97 (br s, 1H); 13C NMR
(75.5 MHz, CDCl3) d 139.9 (s), 139.7 (d), 130.5 (d), 129.0
(d), 127.6 (d), 96.7 (s), 79.4 (t), 74.3 (d).
Purified by chromatography eluting with hexane–diethyl
ether (8:2). Enantiomeric excess (27%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
min, major enantiomer (R) tr = 26.7, minor enantiomer
25
(S) tr = 34.1; ½aꢁD ¼ ꢀ10:0 (c 1.06, CH2Cl2, ee 27%, ob-
tained with ligand 11); 1H NMR (300 MHz, CDCl3) d
8.24 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 5.61
(dd, J = 7.5, 4.7 Hz, 1H), 4.59 (1H, d, J = 7.5 Hz, 1H),
4.58 (d, J = 4.7 Hz, 1H), 3.30 (br s, 1H); 13C NMR
(75.5 MHz, CDCl3) d 148.0 (s), 145.0 (s), 126.9 (d), 124.1
(d), 80.6 (t), 69.9 (d).
4.9.10. (S)-(ꢀ)-2-Nitro-1-(2-nitrophenyl)ethanol 17j. Puri-
fied by chromatography eluting with hexane–diethyl ether
(8:2). Enantiomeric excess (27%) was determined by HPLC
(Chiralcel OD–H), hexane–i-PrOH 90:10, 0.8 mL/min,
4.9.15. (S)-(+)-1-(3-Methoxyphenyl)-2-nitroethanol 17o.
Purified by chromatography eluting with hexane–diethyl
ether (8:2). Enantiomeric excess (76%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
major enantiomer (S) tr = 19.6, minor enantiomer (R)
25
tr = 18.0; ½aꢁD ¼ ꢀ50:3 (c 0.38, CH2Cl2, ee 27%, obtained
1
with ligand 5); H NMR (300 MHz, CDCl3) d 8.07 (dd,
min, major enantiomer (S) tr = 36.1, minor enantiomer
25
J = 8.1, 1.2 Hz, 1H), 7.95 (dd, J = 8.1, 1.2 Hz, 1H), 7.75
(td, J = 7.8, 1.2 Hz, 1H), 7.55 (td, J = 7.8, 1.2 Hz, 1H)
6.04 (dd, J = 9.3, 2.4 Hz, 1H), 4.86 (dd, J = 13.8, 2.4 Hz,
1H), 4.55 (dd, J = 13.8, 9.3 Hz, 1H), 3.28 (br s, 1H); 13C
NMR (75.5 MHz, CDCl3) d 147.1 (s), 134.3 (d), 134.0 (s),
129.7 (d), 128.7 (d), 125.0 (d), 80.0 (t), 66.7 (d).
(R) tr = 25.2; ½aꢁD ¼ þ26:6 (c 0.97, CH2Cl2, ee 76%, ob-
tained with ligand 5); 1H NMR (300 MHz, CDCl3) d
7.31 (t, J = 8.1, 1H), 6.96 (m, 2H), 6.89 (dd, J = 8.1,
2.4 Hz, 1H), 5.44 (dd, J = 9.3, 3.3 Hz, 1H), 4.60 (dd,
J = 13.2, 9.3 Hz, 1H), 4.51 (dd, J = 13.2, 3.3 Hz, 1H),
3.82 (s, 3H), 2.59 (br s, 1H); 13C NMR (75.5 MHz, CDCl3)
d 160.0 (s), 139.7 (s), 130.0 (d), 118.0 (d), 114.3 (d), 111.4
(d), 81.1 (t), 70.8 (d), 55.3 (t).
4.9.11. (S)-(+)-1-(4-Methoxyphenyl)-2-nitroethanol 17k.
Purified by chromatography eluting with hexane–diethyl
ether (8:2). Enantiomeric excess (78%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
4.9.16. (R)-(ꢀ)-1-(3-Methylphenyl)-2-nitroethanol 17p.
Purified by chromatography eluting with hexane–diethyl
ether (8:2). Enantiomeric excess (72%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
min, major enantiomer (S) tr = 25.2, minor enantiomer
25
(R) tr = 20.2; ½aꢁD ¼ þ32:3 (c 1.05, CH2Cl2, ee 78%, ob-
tained with ligand 5); 1H NMR (300 MHz, CDCl3) d
7.32 (d, J = 8.7, 2H), 6.92 (d, J = 8.7, 2H), 5.41 (dd,
J = 9.3, 3.0 Hz, 1H), 4.60 (dd, J = 13.2, 9.3 Hz, 1H), 4.47
(dd, J = 13.2, 3.0 Hz, 1H), 3.81 (s, 3H), 2.35 (br s, 1H);
13C NMR (75.5 MHz, CDCl3) d 159.9 (s), 130.2 (s), 127.2
(d), 114.3 (d), 81.2 (t), 70.6 (d), 55.3 (q).
min, major enantiomer (R) tr = 11.8, minor enantiomer
25
(S) tr = 14.2; ½aꢁD ¼ ꢀ36:8 (c 1.09, CH2Cl2, ee 72%, ob-
tained with ligand 11); 1H NMR (300 MHz, CDCl3) d
7.20 (t, J = 7.5 Hz, 1H), 7.12–7.08 (m, 3H), 5.32 (dd,
J = 9.3, 3.0 Hz, 1H), 4.50 (dd, J = 13.2, 9.3 Hz, 1H), 4.40
(dd, J = 13.2, 3.0 Hz, 1H), 2.79 (br s, 1H), 2.29 (s, 3H);

G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
1611
13C NMR (75.5 MHz, CDCl3) d 138.8 (s), 138.0 (s), 129.6
References
(d), 128.8 (d), 126.5 (d), 122.9 (d), 81.2 (t), 71.0 (d), 21.3 (q).
1. (a) Rosini, G. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 2, pp
321–340; (b) Luzzio, F. A. Tetrahedron 2001, 57, 915–
945.
2. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
3. (a) Breslow, R. Science 1982, 218, 532; (b) Kirby, A. J.
Angew. Chem., Int. Ed. 1996, 35, 707.
4. (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.
5. Guanidine catalysis: (a) Sohtome, Y.; Hashimoto, Y.;
Nagasawa, K. Adv. Synth. Catal. 2005, 347, 1643–1648; (b)
Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Chem.
2006, 2894–2897; Cinchona alkaloids: (c) Marcelli, M.; van
der Haas, R. N. S.; van Maarseveen, J.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 929–931; (d) Li, H.; Wang, B.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 732–733; Phase transfer
conditions: (e) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 2054–2055; (f) Corey, E. J.; Zhang, F.-Y.
Angew. Chem., Int. Ed. 1999, 38, 1931–1934; Biocatalytic: (g)
Purkarthofer, T.; Gruber, K.; Gruber-Khadjawi, M.; Waich,
K.; Skrank, W.; Mink, D.; Griengl, H. Angew. Chem., Int.
Ed. 2006, 45, 3454–3456.
4.9.17. (R)-(ꢀ)-1-(3-Chlorophenyl)-2-nitroethanol 17q.
Purified by chromatography eluting with hexane–diethyl
ether (9:1). Enantiomeric excess (63%) was determined by
HPLC (Chiralcel OD–H), hexane–i-PrOH 90:10, 1 mL/
min, major enantiomer (R) tr = 13.3, minor enantiomer
25
(S) tr = 16.6; ½aꢁD ¼ ꢀ27:2 (c 1.05, CH2Cl2, ee 63%,
obtained with ligand 11); 1H NMR (300 MHz, CDCl3)
d 7.42 (m, 1H), 7.35–7.26 (m, 3H), 5.44 (dd, J = 9.3,
3.6 Hz, 1H), 4.58 (dd, J = 13.5, 9.3 Hz, 1H), 4.50 (dd,
J = 13.5, 3.6 Hz, 1H), 3.01 (br s, 1H); 13C NMR
(75.5 MHz, CDCl3) d 140.0 (s), 134.9 (s), 130.3 (d), 129.1
(d), 126.2 (d), 124.0 (d), 80.9 (t), 70.2 (d).
4.9.18. (R)-(+)-1-Nitro-4-phenyl-2-butanol 17r. Purified
by chromatography eluting with hexane–diethyl ether
(9:1). Enantiomeric excess (74%) was determined by HPLC
(Chiralpak AD–H), hexane–i-PrOH 90:10, 1 mL/min,
major enantiomer (R) tr = 12.0, minor enantiomer (S)
25
tr = 13.1; ½aꢁD ¼ þ13:1 (c 0.51, CH2Cl2, ee 74%, obtained
1
with ligand 11); H NMR (300 MHz, CDCl3) d 7.25–7.10
(m, 5H), 4.33–4.30 (m, 2H), 4.26–4.20 (m, 1H), 2.83–260
(m, 3H), 1.80–1.69 (m, 2H); 13C NMR (75.5 MHz, CDCl3)
d 140.6 (s), 128.6 (d), 128.4 (d), 126.3 (d), 80.5 (t), 67.7 (d),
35.1 (t), 31.3 (t).
6. (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibashaki, M. J.
Am. Chem. Soc. 1992, 114, 4418–4420; (b) Arai, T.; Yamada,
Y. M. A.; Yamamoto, N.; Sasai, H.; Shibashaki, M. Chem.
´
´
Eur. J. 1996, 2, 1368–1372; (c) Saa, J. M.; Tur, F.; Gonzalez,
J.; Vega, M. Tetrahedron: Asymmetry 2006, 17, 99–106.
7. (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002,
41, 861–863; (b) Trost, B. M.; Yeh, V. S. C.; Ito, H.;
Bremeyer, N. Org. Lett. 2002, 4, 2621–2623; (c) Zhong, T.-U.;
Tian, P.; Lin, G.-Q. Tetrahedron: Asymmetry 2004, 15, 771–
776; (d) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem.,
Int. Ed. 2005, 44, 3881–3884.
8. (a) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.;
Ikeno, T.; Yamada, T. Chem. Lett. 2004, 614–615; (b)
Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis
2004, 1947–1950.
9. (a) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw,
J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–
12693; (b) Risgaard, T.; Gothelf, K. V.; Jørgensen, K. A. Org.
Biomol. Chem. 2003, 1, 153–156; (c) Lu, S.-F.; Du, D.-M.;
Zhang, S.-W.; Xu, J. Tetrahedron: Asymmetry 2004, 15,
3433–3441; (d) Bures, F.; Szotkowski, T.; Kulha´nek, J.;
Pytela, O.; Ludwig, M.; Holcapek, M. Tetrahedron: Asym-
metry 2006, 17, 900–907; (e) Gan, C.; Lai, G.; Zhang, Z.;
Wang, Z.; Zhou, M.-M. Tetrahedron: Asymmetry 2006, 17,
725–728; (f) Maheswaran, H.; Prasant, K. L.; Krishna, G. G.;
Ravikumar, K.; Sridhar, B.; Kantam, M. L. Chem. Commun.
2006, 4066–4068; (g) Xiong, Y.; Wang, F.; Huang, X.; Wen,
Y.; Feng, X. Chem. Eur. J. 2007, 13, 829–833; (h) Bandini,
M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici,
C. Chem. Commun. 2007, 616–618; (i) Ma, K.; You, J. Chem.
Eur. J. 2007, 13, 1863–1871.
4.9.19. (R)-(ꢀ)-1-Cyclohexyl-2-nitroethanol 17s. Purified
by chromatography eluting with hexane–diethyl ether
(9:1). Enantiomeric excess (73%) was determined by HPLC
(Chiralpak AD–H), hexane–i-PrOH 95:5, 0.7 mL/min,
major enantiomer (R) tr = 21.6, minor enantiomer (S)
25
tr = 23.3; ½aꢁD ¼ ꢀ14:7 (c 1.03, CHCl3, ee 73%, obtained
1
with ligand 11); H NMR (300 MHz, CDCl3) d 4.48 (dd,
J = 12.9, 3.3 Hz, 1H), 4.41 (dd, J = 12.9, 8.7 Hz, 1H),
4.11–4.05 (m, 1H), 2.68 (sample, 1H), 1.84–1.75 (m, 3H),
1.70–1.58 (m, 2H), 1.50–1.37 (m, 1H), 1.28–1.05 (m, 5H);
13C NMR (75.5 MHz, CDCl3) d 79.3 (t), 72.8 (d), 41.3
(d), 28.8 (t), 27.9 (t), 26.0 (t), 25.8 (t), 25.7 (t).
4.9.20. (R)-(+)-4-Methyl-1-nitro-2-pentanol 17t. Purified
by chromatography eluting with hexane–diethyl ether
(9:1). Enantiomeric excess (79%) was determined by HPLC
(Chiralpak AD–H), hexane–i-PrOH 95:5, 1 mL/min, major
enantiomer (R) tr = 11.2, minor enantiomer (S) tr = 15.6;
25
½aꢁD ¼ þ1:4 (c 1.01, CH2Cl2, ee 79%, obtained with ligand
11); 1H NMR (300 MHz, CDCl3) d 4.43–4.33 (m, 3H), 2.41
(sample, 1H), 1.87–1.78 (m, 1H), 1.53–1.45 (m, 1H), 1.26–
1.17 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz,
3H); 13C NMR (75.5 MHz, CDCl3) d 81.0 (t), 66.9 (d), 42.4
(t), 24.3 (d), 23.1 (q), 21.7 (q).
´
´
10. Blay, G.; Climent, E.; Fernandez, I.; Hernandez-Olmos, V.;
Pedro, J. R. Tetrahedron: Asymmetry 2006, 17, 2046–2049.
11. Evans, D. A.; Lectka, T.; Miller, S. J. Tetrahedron Lett. 1993,
49, 7027–7030.
Acknowledgements
12. Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006,
106, 3561–3651.
13. Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129–
3170.
´
Financial support from the Ministerio de Educacion y
Ciencia (CTQ 2006-14199) and the Generalitat Valenciana
(GV 05/10) is gratefully acknowledged. V.H.-O. thanks the
`
Universitat de Valencia by a pre-doctoral grant (V Segles
program).
14. Brunner, H.; Obermann, U. Chem. Ber. 1989, 122, 499–
507.

1612
G. Blay et al. / Tetrahedron: Asymmetry 18 (2007) 1603–1612
15. (a) Chelucci, G. Tetrahedron: Asymmetry 1997, 8, 2667–2670;
(b) Nordstrom, K.; Macedo, E.; Moberg, C. J. Org. Chem.
1997, 62, 1604–1609; (c) Chelucci, G.; Sanna, M. G.; Gladiali,
S. Tetrahedron 2000, 56, 2889–2893; (d) Brunner, H.; Kagan,
H.; Kreutzer, G. Tetrahedron: Asymmetry 2003, 14, 2177–
2187; (e) Wu, X.-Y.; Xu, H.-D.; Tang, F.-Y.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2001, 12, 2565–2569; (f) Davenport,
A. J.; Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R.
Dalton Trans. 2000, 23, 4432–4441.
1998, 54, 5651–5666; (f) Jang, D.-P.; Chang, J.-W.; Uang, B.-
J. Org. Lett. 2001, 3, 983–985; (g) Yang, K.-S.; Lee, W.-D.;
Pan, J.-F.; Chen, K. J. Org. Chem. 2003, 68, 915–919; (h)
´
Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284–
287; (i) Bulanksananusorn, T.; Knochel, P. J. Org. Chem.
´
2004, 69, 4595–4601; (j) Jeon, S.; Li, H.; Garcıa, C.;
LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70,
448–455; (k) Chen, J.-H.; Venkatesham, U.; Lee, L.-C.; Chen,
k. Tetrahedron 2006, 62, 887–893.
16. For some examples on the use of camphor derivatives as
chiral auxiliaries and catalysts see: (a) Kitamura, M.; Suga,
S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–
6072; (b) Oppolzer, W. Tetrahedron 1987, 43, 1969–2004; (c)
17. Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J.; Yang, K.-S.; Lain,
J.-C.; Lin, C.-H.; Chen, K. J. Org. Chem. 1999, 64, 6993–
6998.
18. (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem.
Commun. 2001, 2222–2223; (b) Christensen, C.; Juhl, K.;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875–
4881.
´
Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 1997, 8,
´
2479–2496; (d) Ramon, D. J.; Yus, M. Tetrahedron Lett.
´
1998, 39, 1239–1242; (e) Ramon, D. J.; Yus, M. Tetrahedron