Asymmetric Henry reactions catalyzed by metal complexes of chiral oxazoline based ligands

Article abstract of DOI:10.1016/j.tetasy.2012.11.022

Chiral oxazolines have been synthesized from norephedrine and pyrrole nitrile or benzoyl chloride and applied to the catalytic asymmetric Henry reactions of p-nitro aldehydes with nitromethane to provide β-hydroxy nitroalkanols in high conversion (up to 92%). The reaction was then optimized in terms of the metal, solvent, temperature, and amount of chiral ligand. The corresponding catalyst with Cu(OTf)₂ and isopropanol as the solvent gave the best enantioselectivities (up to 84% ee) of the corresponding β-nitroalkanol for p-nitrobenzaldehyde.

Full text of DOI:10.1016/j.tetasy.2012.11.022

Tetrahedron: Asymmetry 24 (2013) 14–22
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric Henry reactions catalyzed by metal complexes of chiral
oxazoline based ligands
⇑
A. Ebru Aydin , Seda Yuksekdanaci
Department of Chemistry, Mustafa Kemal University, 31040 Hatay, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 October 2012
Accepted 27 November 2012
Chiral oxazolines have been synthesized from norephedrine and pyrrole nitrile or benzoyl chloride and
applied to the catalytic asymmetric Henry reactions of p-nitro aldehydes with nitromethane to provide
b-hydroxy nitroalkanols in high conversion (up to 92%). The reaction was then optimized in terms of
the metal, solvent, temperature, and amount of chiral ligand. The corresponding catalyst with Cu(OTf)2
and isopropanol as the solvent gave the best enantioselectivities (up to 84% ee) of the corresponding
b-nitroalkanol for p-nitrobenzaldehyde.
We dedicate this paper to the memory of
Professor Dr. Ayhan S. DEMIR who died on
24 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
aminophenyloxazoline and oxazoline-Schiff base and their applica-
tions in enantioselective Henry reactions. When aminophenyl
The Henry reaction is an important organic reaction involving
the formation of a C–C bond.1 The resulting product of this reaction
is a b-nitro alcohol, which can be converted into the essential
building blocks of natural products or pharmaceuticals such as b-
oxazoline ligands were used as a ligand with Cu(OAc)2 in the Henry
reaction of p-nitrobenzaldehyde, the corresponding products were
obtained in moderate chemical yields (67–72%) but with low
enantioselectivities (21–46% ee).
amino alcohols, aziridines,
a
-hydroxy carboxylic acids,
a
-hydroxy
In contrast to the large number of chiral pyridyl oxazolines and
bisoxazolines used as ligands for metal catalyzed asymmetric reac-
tions, only a few examples of chiral pyrrole oxazoline ligands have
been reported so far. The first chiral pyrrole oxazoline ligands that
used free pyrrole nitrogen were synthesized and applied to copper-
catalyzed asymmetric cyclopropanations by Brunner in 1998.
However, the corresponding product was obtained with low enan-
tiomeric excess (3–14% ee).20
To the best of our knowledge, chiral oxazolines containing a
pyrrole ring have not been used before as ligands in Henry reac-
tions. Herein we report their first application in this reaction. We
synthesized chiral oxazoline-based ligands from pyrrole-2-carbo-
nitrile and 2-hydroxy benzoyl chloride. The chiral ligands synthe-
sized were applied as catalysts in Cu-catalyzed asymmetric
Henry reactions. Under the optimized conditions, aromatic and ali-
phatic aldehydes gave the corresponding products in moderate to
good yields and with high enantioselectivities. Moreover, when
nitroethane was used instead of nitromethane in the asymmetric
Henry reaction, products with two stereogenic centers were
obtained successfully.
ketones,
a
-nitro ketones, aldehydes, and sulfides.2 Shibasaki re-
ported the first asymmetric version of the Henry reaction in
1992.3 Since then, a very large number of chiral catalysts contain-
ing chiral ligands with metal atoms and also organocatalyst have
been synthesized and applied to the asymmetric Henry reaction.4
Oxazolines are an important class of heterocyclic compounds
and are versatile intermediates in synthetic organic chemistry.5
These compounds are used as protecting groups for carboxylic
acids6 and hydroxylamines. Chiral oxazolines have also been
extensively used in asymmetric syntheses as both auxiliaries and
ligands.7
A very large number of chiral ligands containing one or more
oxazoline rings have been synthesized and employed to prepare
enantiomerically pure compounds using chiral ligands in many
metal-catalyzed asymmetric reactions. Examples of widely used li-
gands of this type are pyridinooxazoline,8 bisoxazoline,9 bisoxazo-
linopyridine,10 BINOL-oxazoline,11 and phosphine-oxazoline12
derivatives. These chiral ligands have been applied to a wide range
of catalytic reactions including hydrosilylations13 Diels Alders
reactions,14 cyclopropanations,10a,15 allylic alkylation,16 enantiose-
lective diethylzinc additions to aldehydes,17 and the asymmetric
Henry reactions.18 Du et al.19 reported the synthesis of chiral
2. Result and discussion
2.1. Preparation of chiral 2-oxazoline ligand
A number of methods have been developed for the preparation
of 2-oxazolines from carboxylic acid,21 esters,22 nitriles,23
⇑
Corresponding authors. Tel.: +90 326 245 55 10; fax: +90 312 299 2163 (A.E.A.).
E-mail addresses: aebruaydin@gmail.com, aydin@mku.edu.tr (A. Ebru Aydin).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.022

A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
15
aldehydes,24 amino alcohols,25 and hydroxyamides.26 Herein chiral
2-oxazolines 3a,b and 4a,b were synthesized from both enantio-
mers of norephedrine with pyrrole-2-carbonitrile or an acyl chlo-
at room temperature. As can be seen from Table 1, the addition
of CH3NO2 to p-nitrobenzaldehyde led to the corresponding prod-
uct in 57–75% yield with 2-46% ee. In the presence of only a chiral
ligand, the observed enantioselectivities were very low. Compound
(4S,5R)-3a, which has an (R)-configuration at the oxygen bearing
stereogenic center gave the (S)-product, whereas (4R,5S)-3b with
an (S)-configuration at the same stereogenic center, gave the (R)-
product. Thus, ligands (4S,5R)-3a and (4S,5R)-4a induced enantio-
meric excess in the (S)-configured product, while (4R,5S)-3b and
(4R,5S)-4b led to enantiomeric excess in the (R)-configured prod-
uct. These results indicate that the configuration of the chiral b-
nitroalkanol depends on the configuration of the oxygen bearing
stereogenic center. The enantiomeric oxazoline ligand pairs in-
duced an opposite enantioselectivity in the Henry reaction (Table 1,
entries 1–2, 3–4).
With the aim of improving the enantioselectivity different pro-
cedures were tested and the results are summarized in Table 1. We
next attempted to improve further the enantioselectivity using
Et2Zn. Trost reported the first dinuclear zinc-amino alcohol cata-
lyzed asymmetric Henry reaction and the corresponding products
were obtained with high enantiomeric excess and yields (up to
93% ee and 90% yield).30 Since then, several zinc catalytic systems
such as N-methylephedrine-Zn,31 bicyclo[3.3.0]octane based b-
amino alcohol-Zn,32 ferrocenyl-substituted aziridinylmethanol-
Zn,33 and brucine-derived amino alcohol-Zn34 have been prepared
for asymmetric Henry reactions and afforded poor to good enanti-
oselectivities but with moderate chemical yields.
ride by the two methods shown in Schemes
1 and 2,
respectively. In the retrosynthetic plan in Scheme 1, pyrrole was
formylated by the Vilsmeier Haack method27 and the formylated
pyrrole (75% yield) was treated with NMP, NH2OHꢀHCl to form pyr-
role-2-carbonitrile 128 (70% yield). In the first method used for the
chiral oxazoline ligands, pyrrole-2-carbonitrile was treated with
both enantiomers of norephedrine 2 to give ligand 3 as shown in
Scheme 1.29 The stereochemistry of the starting material was
maintained throughout the course of the reaction; thus, (1R,2S)-
norephedrine gave (4S,5R)-3a, while (1S,2R)-norephedrine gave
(4R,5S)-3b (Cl, C2 in the starting material corresponds to C5, C4
in the product). Ligands (4S,5R)-3a and (4R,5S)-3b were obtained
by using (1R,2S)- and (1S,2R)-norephedrine 2a,b in 68% and 63%
yields, respectively. The synthesis of pyrrole oxazoline (4S,5R)-3a
was performed from the corresponding starting materials using
activated ZnCl2 in chlorobenzene at 80 °C with 29% yield using
the method reported by Brunner et al.20a
In the second method used for chiral ligands (Scheme 2), sali-
cylic acid was reacted with thionyl chloride to give 2-hydrox-
ybenzoyl chloride. Without further purification, the acid chloride
was treated with both enantiomers of norephedrine 2a and 2b
and Et3N in CH2Cl2 and then refluxed under basic conditions to
yield oxazolines (4S,5R)-4a and (4R,5S)-4b.
2.2. Enantioselective Henry reactions
A solution of Et2Zn was added to a solution of the chiral 2-oxaz-
oline ligands 3a,b and 4a,b in dry toluene at 0 °C under an atmo-
sphere of nitrogen and then stirred for 30 min to form chiral
zinc-catalyst at 0 °C. Next, CH3NO2 and p-nitrobenzaldehyde were
added into the mixture. The reaction mixture was stirred at room
temperature for 48 h to give 2-nitro-1-(4-nitrophenyl)ethanol in
moderate yield and with low ee in the presence of (4S,5R)-3a or
We examined the catalytic performance of these chiral oxazo-
line based ligands in the enantioselective Henry reaction. For this
purpose, p-nitrobenzaldehyde and nitromethane were selected as
the model substrate and nitroalkane (Scheme 3). The reaction
was performed in THF in the presence of 10 mol % chiral ligand
H2N
HO
∗
O
K2CO3, ethylene
glycol:glycerol=2:1
∗
∗
N
H
CN
+
N
H
N
120 oC, 24h
∗
(4S,5R)-3a
2a
1
(1R,2S)-
3b
(4R,5S)-
(1S,2R)-2b
Scheme 1. Synthesis of chiral oxazoline ligands (4S,5R)-3a and (4R,5S)-3b.
O
O
Ph
O
N
H2N
HO
*
*
rt
SOCl2
DCM
OH
Cl
+
*
*
OH
OH
HO
(4S,5R)-4a
(4R,5S)-4b
2a
(1R,2S)-
(1S,2R)-2b
Scheme 2. Synthesis of chiral oxazoline ligands (4S,5R)-4a and (4R,5S)-4b.
O
OH
10 mol% ligand
Cu(OAc)2.H2O
NO2
H
+
MeNO2
THF, rt
O2N
O2N
5a
6a
Scheme 3. Henry reaction of nitromethane with p-nitrobenzaldehyde.

16
A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
Table 1
Table 2
Enantioselective Henry reaction of nitromethane with p-nitrobenzaldehyde under
Screening metal salts in the asymmetric Henry reactiona
different reaction conditionsa
O
OH
O
OH
10 mol% ligand
NO2
H
+
Cu(OTf)2
NO2
10 mol% ligand
solvent, rt
H
∗
MeNO2
solvent, rt
O2N
+
MeNO2
O2N
O2N
O2N
5a
6a
Metal salt: ligand Yieldb (%) eec (%)
5a
6a
Entry Metal salt
Ligand
Entry
Ligand
Method
Yielde (%)
ee (%)
Conff
1
2
3
4
5
6
7
8d
9
Cu(OAc)2ꢀH2O (4S,5R)-4a
Ni(OAc)2ꢀH2O (4S,5R)-4a
Zn(OAc)2ꢀH2O (4S,5R)-4a
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
58
70
75
75
69
59
79
80
78
75
12
15
27
42
29
70
58
59
1
2
3
4
5
6
7
8
(4S,5R)-3a
(4R,5S)-3b
(4S,5R)-4a
(4R,5S)-4b
(4S,5R)-3a
(4R,5S)-3b
(4S,5R)-4a
(4R,5S)-4b
(4S,5R)-3a
(4R,5S)-3b
(4S,5R)-4a
(4R,5S)-4b
Ligandb
Ligandb
Ligandb
Ligandc
57
59
72
75
66
64
65
63
53
66
58
61
30
25
43
46
8
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
Zn(OTf)2
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-3a
(4R,5S)-
3b
CoCl2ꢀ2H2O
NiCl2ꢀ6H2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Et2Zn–ligandc
Et2Zn–ligandc
4
Et2Zn–ligandc
51
47
51
53
75
69
Et2Zn–ligandc
9
Cu(OAc)2ꢀH2O–Ligandd
Cu(OAc)2ꢀH2O–Ligandd
Cu(OAc)2ꢀH2O–Ligandd
Cu(OAc)2ꢀH2O–Ligandd
10d
11d
12d
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(4S,5R)-4a
(4S,5R)-3a
(4R,5S)-
3b
1:2
1:2
1:2
80
81
78
75
65
63
10
11
12
a
The reactions were carried out with 1 mmol of p-nitro benzaldehyde and
10 mmol nitromethane in 2 mL of THF in the presence of 10 mol % ligand at room
temperature for 48 h.
a
The reactions were carried out with 1 mmol of p-nitrobenzaldehyde and
10 mmol of nitromethane in 2 mL of THF in the presence of 10 mol % ligand and
10 mol % metal salt at room temperature.
b
With 10 mol % ligand, entries 1–4.
With 10 mol % ligand and 3 mmol Et2Zn, entries 5–8.
With 10 mol % ligand, and Cu(OAc)2 entries 9–12.
Values are isolated yields after chromatographic purification.
c
b
Values are isolated yields after chromatographic purification.
Enantiomeric excesses were determined by HPLC using
d
c
a Chiralcel OD-H
e
column.
f
d
Enantiomeric excesses were determined by HPLC using a Chiralcel OD-H col-
With 10 mol % ligand and 5 mol % Cu(OTf)2, entries 9 and 13.
umn. The absolute configuration was determined by comparison of the retention
time (chiral HPLC) with the literature values.10e,4k,l
Solvents always play an important role with regard to the
enantioselectivity. The influence of different solvents, such as
i
(4R,5S)-3b (Table 1, entry 5, 6). As shown in Table 1, the best re-
sults were obtained using (4S,5R)-4a (65% yield, 51% ee) and
(4R,5S)-4b (63% yield, 47% ee).
EtOH, MeOH, THF, PrOH, DCM, and toluene were tested in the
enantioselective Henry reaction between p-nitrobenzaldehyde
and nitromethane in combination with Cu(OAc)2.H2O and ligand
(4S,5R)-4a. As can be seen in Table 3, protic solvents (MeOH, EtOH,
and PrOH) proved to be better than aprotic solvents (THF and
DCM), giving higher enantiomeric excesses (entries 1, 2, 4 and 3,
To increase the yield and enantioselectivity of the chiral 2-ni-
tro-1-(4-nitrophenyl) ethanol 6a, Cu(OAc)2ꢀH2O was used as the
metal source. The combination of ligand (4S,5R)-3a with
Cu(OAc)2ꢀH2O gave the product in 53% yield with 51% ee for the
major (S)-enantiomer (Table 1, entry 9). In the presence of
(4R,5S)-3b, the corresponding product was obtained in 66% yield
with 53% ee for the major (R)-enantiomer (entry 10). Ligands
(4S,5R)-4a and (4R,5S)-4b gave nitroalkanols 6a with a higher
enantimeric excess (75% and 69%, respectively) (entries 11, 12).
In order to determine the optimum reaction conditions, the effect
of different reaction parameters, such as the metal source, solvent,
catalyst loading, and reaction temperature, were investigated by
using chiral ligands (4S,5R)-3a, (4R,5S)-3b and (4S,5R)-4a.
The effects of various metal sources were examined using
ligands (4S,5R)-3a, (4R,5S)-3b and (4S,5R)-4a. The results are
summarized in Table 2. When the reaction was performed
with Ni(OAc)2ꢀH2O, Zn(OAc)2ꢀH2O, Zn(OTf)2, CoCl2ꢀ2H2O, and
NiCl2ꢀ6H2O, the product was obtained in moderate to good yield,
but with low ee values (Table 2, entries 2–6). In the presence of
10 mol % Cu(OTf)2 and ligands (4S,5R)-4a, (4S,5R)-3a, and (4R,5S)-
3b, the corresponding products were obtained in 79%, 80%, and
78% yield with 70%, 58%, and 59% ee, respectively (entries 7–9).
By keeping the ligand (4S,5R)-4a ratio at 10 mol % and reducing
the Cu(OTf)2 ratio from 10 to 5 mol %, the enantioselectivity in-
creased to 75% ee, without any changes in the yield (entries 7,
10). When ligands (4S,5R)-3a and (4R,5S)-3b were used as cata-
lysts, the nitroalkanols were obtained in 81% and 78% yields with
65% and 63% ee, respectively (entries 11, 12). As shown in Table 2,
the most suitable ratio of metal to ligand proved to be 1:2 (entries
7, 10).
i
i
5). The highest enantiomeric excess (82%) was observed in PrOH.
The use of the aprotic solvent DCM gave 39% enantiomeric excess.
The lowest enantiomeric excess (25%) was observed when toluene
was used as the solvent. It was found that the enantioselectivity in-
creased in the order MeOH < EtOH < iPrOH (Table 3). It is possible
that these alcoholic solvents might coordinate with the copper me-
tal, and this process could increase the enantioselectivity. The low
chemical yields and enantioselectivities could be explained using
non-coordinating solvents such as DCM, and toluene. In the pres-
ence of (4S,5R)-3a, the nitroalkanol 6a was obtained in 84% yield
with 65% ee (Table 3, entry 8).
Since the reaction temperature has a significant effect on the
chemical yield and ee values of the nitroaldol product,35 the opti-
mization of temperature was carried out. Decreasing the tempera-
ture of the reaction from room temperature to 0 °C, caused the ee
value to increase considerably (Table 3, entries 9, 10). The
asymmetric Henry reaction was performed using (4S,5R)-4a at
0 °C and the highest enantioselectivity was obtained with an (S)-
configuration in 84% ee (entry 9). However, at ꢁ20 °C, the selectiv-
ity was decreased (Table 3, entries 10, 12).
It has been reported that a chiral catalyst in the presence of base
has an enhancement effect on the enantioselectivity.4e,k,8a,10d,36
Therefore, a series of experiments were performed by using a base,
such as K2CO3, DBU, Et3N, DMAP, DBU, Na2CO3, and DABCO. These
bases were tested in the reaction between p-nitrobenzaldehyde
and nitromethane in the presence of 10 mol % ligand, 5 mol %
Cu(OTf)2, and 50 mol % base. As can be seen in Table 4, when

A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
17
Table 3
afforded the (S)-enantiomer, the opposite (R)-enantiomer of the
corresponding products was obtained with ligand (4R,5S)-3b. Elec-
tron-withdrawing substitutents gave higher enantioselectivities
when compared to electron-donating substituents (Table 5). It is
known that the presence of electron-withdrawing groups leads
to an increase in the electrophilicity of carbonyl carbon atom in
aryl aldehydes, while the presence of electron-donating groups de-
creases it. We expected that the substrates with an electron-with
drawing substituent afforded a faster reaction leading to higher
enantioselectivity. With both ligands, high enantiomeric excesses
were observed for aromatic aldehydes bearing substituents at the
ortho position. The reason for this appears to be more due to steric
hindrance. In the presence of ligands (4S,5R)-3a, (4R,5S)-3b, and
(4S,5R)-4a, the hetereoaromatic aldehyde furan-2-carbaldehyde
also gave the nitroaldol product with 67%, 65%, and 85% ee, respec-
tively (Table 5, entry 14). Next, the scope of the asymmetric Henry
reaction was studied with aliphatic aldehydes using (4S,5R)-3a and
(4R,5S)-3b and ligand (4S,5R)-4a. The aliphatic aldehydes provided
the corresponding adduct with higher enantioselectivity than the
aromatic aldehydes. For aliphatic aldehydes, the enantioselectivity
increased with an increase in the chain length of the aldehydes.
The branched aliphatic aldehydes afforded optically Henry adducts
in moderate yield and with good enantiomeric excess.
The optimized catalyst was also applied to the diastereoselec-
tive Henry reaction with nitroethane used as the nucleophile.38
As shown in Table 6, aliphatic aldehydes showed lower selectivity
than aromatic aldehydes, under the optimized reaction conditions,
all aldehydes (both aromatic and aliphatic) afforded the corre-
sponding products in moderate to good diastereoselectivity. High
enantioselectivities were obtained for the syn-products (up to
78%). p-Nitrobenzaldehyde led to the corresponding product in
72% yield with 65:35 syn:anti diastereoselectivity. Aldehydes with
an electron-withdrawing subtitutent such as NO2 showed lower
diastereoselectivity than 2-methoxybenzaldehyde (Table 6, entries
1, 2). Isobutyraldehyde gave the corresponding product in 75%
yield with 64:36 syn:anti selectivity, with 63% enantiomeric excess
of the syn-product (Table 6, entry 3).
Effects of the solvents and reaction temperature on the asymmetric Henry reactiona
O
OH
10 mol% Ligand
Cu(OTf)2 (5 mol %)
NO2
H
+
MeNO2
O2N
O2N
solvent, rt
5a
6a
Entry
Ligand
Solvent
EtOH
Temp. (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
(4S,5R)-4a
(4S,5R)-4a
(4S,5R) 4a
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-3a
(4S,5R)-4a
(4S,5R)-4a
(4S,5R)-3a
(4S,5R)-3a
rt
rt
rt
rt
rt
rt
rt
rt
0
75
75
80
92
75
51
68
81
80
83
84
78
80
78
75
82
39
25
56
65
84
68
76
52
MeOH
THF
iPrOH
DCM
Toluene
MeCN
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
9
10
11
12
ꢁ20
0
ꢁ20
a
The reactions were carried out with 1 mmol of p-nitro benzaldehyde and
10 mmol of nitromethane in 2 mL of solvent in the presence of 10 mol % ligand and
5 mol % metal salt.
b
Values are isolated yields after chromatographic purification.
Enantiomeric excesses were determined by HPLC using
c
a Chiralcel OD-H
column.
K2CO3, DBU, or Et3N were used as the base, the yield of the asym-
metric Henry reaction increased while the ee value decreased (en-
tries 2, 3, and 4). Bases such as DIPEA and DMAP gave the product
in low yields but with moderate enantiomeric excess (entries 5, 6).
Bases such as Na2CO3 and DABCO gave the highest yield although
the ee values are moderate (Table 4, entries 7, 8).
The asymmetric Henry reaction was performed with different
aromatic aldehydes with electron-withdrawing and electron-
donating substituents under the optimized conditions: 10 and,
We propose a mechanism in which the aldehyde coordinates to
the copper, followed by nucleophilic attack of CH3NO2 onto the less
sterically hindered face of the carbonyl group, affording products
with high enantioselectivity. We were unable to obtain crystals
of the copper complexes with these ligands suitable for X-ray
i
5 mol % Cu(OTf)2 in PrOH for ligands (4S,5R)-3a (4R,5S)-3b, and
(4S,5R)-4a. The results are summarized in Table 5. Both chiral li-
gands (4S,5R)-3a and (4R,5S)-3b afforded the opposite enantiomers
with all of the aldehydes tested, that is while ligand (4S,5R)-3a
Table 4
Effects of organic base on the asymmetric Henry reactiona
O
OH
(4S,5R)-4a (10 mol %)
Cu(OTf)2 (5 mol %), base
NO2
H
+
MeNO2
iPrOH, 0 oC
O2N
O2N
5a
6a
Entry
Base additive
Loading of base (mol %)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
—
80
85
87
90
47
53
92
95
92
55
17
65
69
62
65
62
K2CO3,
DBU
Et3N
DIPEA
DMAP
Na2CO3
DABCO
50
50
50
50
50
50
50
a
The reactions were carried out with 1 mmol of p-nitro benzaldehyde and 10 mmol of nitromethane in 2 mL of iPrOH in the
presence of 10 mol % ligand, 5 mol % Cu(OTf)2, and 50 mol % base at 0 °C.
b
Values are isolated yields after chromatographic purification.
Enantiomeric excesses were determined by HPLC using a Chiralcel OD-H column.
c

18
A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
Table 5
Enantioselective Henry reaction of various aldehydes with nitromethane under optimal conditionsa
O
OH
Ligand (10 mol %)
Cu(OTf)2 (5 mol %)
NO2
+
MeNO2
R
H
R
iPrOH, 0 o
C
6
5
Entry
Aldehyde
Product 9
(4S,5R)-3a
(4R,5S)-3b
(4S,5R)-4a
Yieldb (%)
Yieldb (%)
eec,d (%)
Yieldb (%)
eec,e (%)
eec,d (%)
1
2
3
4
5
6
7
8
4-NO2C6H4
2-NO2C6H4
PhCHO
6a
6b
6d
6e
6f
6h
6i
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
80
75
78
75
78
80
82
72
78
80
72
75
78
80
74
59
54
58
54
76
78
75
60
70
65
68
66
72
69
70
68
65
67
66
57
60
63
65
84
83
78
72
76
80
75
68
92
78
65
63
76
78
72
56
47
56
57
74
76
73
58
74
63
70
64
77
67
68
66
63
65
65
55
58
60
64
80
83
76
79
92
76
78
73
88
84
92
80
65
72
65
67
63
58
53
84
86
80
78
82
79
78
80
82
78
75
77
78
80
74
84
86
88
90
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
2- MeC6H4
4-ClC6H4
2-ClC6H4
2-FC6H4
1-Naphthyl
2-Naphthyl
PhCH2CH2
2-Furfuryl
Cyclohexyl
nPr
9
10
11
12
13
14
15
16
17
18
19
iPr
nBu
iBu
a
i
The reactions were carried out with 1 mmol of p-nitro benzaldehyde and 10 mmol of nitromethane in 2 mL of PrOH in the presence of 10 mol % ligand and 5 mol %
Cu(OTf)2 at 0 °C.
b
Values are isolated yields after chromatographic purification.
Enantiomeric excesses were determined by HPLC using Chiralcel OD-H column. The absolute configurations are determined by comparison of retention time (chiral HPLC)
c
with the literature values.10e,4k,l
d
The (S)-enantiomer was obtained.
The (R)-enantiomer was obtained.
e
Table 6
Diastereoselective Henry reaction of various aldehydes with nitroethanea
O
(4S,5R)-4a (10 mol %)
OH
OH
Cu(OTf)2 (5 mol %)
+
NO2
+
R
H
R
R
iPrOH, 0 o
C
NO2
anti-7
NO2
syn-7
5
Entry
Aldehyde
Product
Yieldb (%)
syn:antic
eed (%)
syn
anti
1
2
3
4
5
6
p-Nitrobenzaldehyde
p-Methoxybenzaldehyde
Isobutyraldehyde
2-Methylbutyraldehyde
Cyclohexanecarbaldehyde
3-Phenylpropionaldehyde
7a
7b
7c
7d
7e
7f
72
78
75
74
75
77
65:35
62:38
64:36
61:39
63:37
68:32
78
68
63
68
58
73
46
49
48
52
50
60
a
All reactions were carried out with 1 mmol of p-nitro benzaldehyde and 10 mmol of nitromethane in 2 mL of iPrOH in the presence of 10 mol % ligand and 5 mol %
Cu(OTf)2 at 0 °C.
b
Values are isolated yields after chromatographic purification.
c
Diastereoselectivity was determined from 1H NMR spectrum.
d
Enantiomeric excesses were determined by HPLC using Chiralcel OD-H column. The absolute configurations ere determined by comparison of retention time (chiral HPLC)
with the literature values.37g,l
analysis. However, based on our experimental observations and
the previously reported steric and electronic consideration,10c,e,39
we propose two transition state models, which account for the
absolute configuration of the products obtained ligands (4S,5R)-
3a and (4S,5R)-4a (Fig. 1). According to the model proposed by
Evans,10e in the favorable transition state, the nucleophilic carbon
of the nitronate ion is formed in situ by deprotonation of nitro-
methane with a [OTf]ꢁ anion that approaches the aldehyde from
the Si face to give the (S)-isomer as the major product. The Re face
attack is not favored due to severe non-bonding interactions be-
tween the aromatic group, or aliphatic chain, of the corresponding
aldehyde with the chiral ligands (4S,5R)-3a and (4S,5R)-4a.

A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
19
(parts per million) are reported relative to TMS. Coupling constant
are expressed as J values in Hertz. Thin layer chromatography (TLC)
was performed using Merck Kieselgel 60 F254. Crude compounds
were purified with column chromatography using silica gel (60–
200 mesh except if stated different). All IR spectra were recorded
on a 2000 Perkin–Elmer spectrometer. Optical rotations were re-
corded on a Autopol IV polarimeter. All melting points were mea-
sured with an Electrothermal melting point instrument. Elemental
analyses were carried out on a LECO CHNS-932 series analyzer.
Enantiomeric excesses were determined by HPLC analysis using a
Shimadzu and Thermo Finnigan analyzer. All reactions were car-
ried out under an N2 atmosphere.
OTf
O
N
OTf
Cu
O
N
N
N
Cu
O
O
O
OTf
O
N
H
O
OTf
N
R
H2C
SH
H2C
R
H
OH
OH
NO2
NO2
4.2. Synthesis of chiral oxazolines
R
R
(S)
(R)
4.2.1. Experimental procedure for the synthesis of pyrrole-2-
carbonitrile 1
Re-unfavoured
Si-favoured
Pyrrole-2-carbaldehyde (10 mmol), NMP (15 mL), and
NH2OHꢀHCl (12 mmol) were refluxed at 110–115 °C. After cooling
to room temperature, H2O (50 mL) was added. The mixture was
then extracted with ethyl acetate (3 ꢂ 20 mL), dried over MgSO4,
and filtered. After evaporation of the solvent, the crude product
was purified by flash column chromatography (EtOAc/hexane,
1:6) to give compound 2 in 70% yield; bp: 92–94 °C; Rf: 0.70
(EtOAc/Hex, 1:3); 1H NMR (400 MHz, CDCl3) d (ppm) 6.18 (br s,
1H) 6.80 (br s,1H) 6.94 (br ss, 1H) 9,43 (s, 1H); 13C NMR
(100 MHz, CDCl3) d (ppm) 100.41, 110.29, 115.08, 120.64, 124.11.
OTf
OTf
O
O
N
N
O
O
O
Cu
O
Cu
O
O
O
OTf
OTf
N
R
N
O
H2C
H2C
H
4.2.2. Experimental procedure for the synthesis of chiral
oxazoline ligands (4S,5R)-3a and (4R,5S)-3b
H
R
Ethylene glycol/glycerol (2:1) (30 mL), anhydrous K2CO3
(2.68 mmol), pyrrole-2-carbonitrile 2 (2.76 mmol), and norephe-
drine 2a,b (2.71 mmol) were combined in a 100-mL round bot-
tomed flask. The mixture was stirred at 120 °C for 24 h. After the
reaction, it was cooled to room temperature, and ethyl acetate
(30 mL) and brine (30 mL) were added, collection of the organic
layer and water was carried out with ethyl acetate (3 ꢂ 30 mL).
The combined organic phases were dried over MgSO4 and filtered.
After evaporation of the solvent the crude product was purified by
flash column chromatography (EtOAc/hexane, 1:6).
OH
OH
NO2
NO2
R
R
(S)
(R)
Re-unfavoured
Si-favoured
Figure 1. Proposed transition state models for the enantioselective Henry reaction.
3. Conclusion
4.2.2.1. (4S,5R)-4-Methyl-5-phenyl-2-(1H-pyrrol-2-yl)-4,5-dihy-
drooxazole (4S,5R)-3a. Yield (68%, 0.41 g): mp 108–110 °C; Rf:
0.20 (EtOAc/Hex, 1:3); ½a D20
ꢃ
¼ ꢁ322 (c 1.94, CHCl3); 1H NMR
In conclusion, we have synthesized novel chiral ligands from
pyrrole-2-carbonitrile, salicylic acid, and norephedrine using two
different methods and applied them as catalysts for enantioselec-
tive Henry reactions. The reactions proceeded smoothly to provide
the corresponding adducts in good enantioselectivities for a wide
range of substrates. The best result (86.0% ee) was obtained when
the reactions were carried out with ligands where the free hydro-
xyl group had a phenyl ring. We determined the optimum condi-
tions for the Henry reaction by using different Lewis acids,
solvents, temperatures, and ligand ratios. The applications of these
chiral oxazoline ligands in other asymmetric reactions are cur-
rently underway.
(400 MHz, CDCl3)
d (ppm) 0.79 (d, J = 6.7 Hz, 3H) 4.56 (dq,
J = 7.2 Hz, 1H, J = 6.8, 1H) 5.65 (d, J = 9.6 Hz, 1H) 6.22 (t,
J = 3.2 Hz, 1H) 6.79 (dd, J = 3.6 Hz, J = 1.6 Hz, 1H) 6.87 (s, 1H)
7.17–7.25 (m, 2H) 7.26–7.32 (m, 3H) 10.03 (s, 1H); 13C NMR
(100 MHz, CDCl3) d (ppm) 17.95, 64.80, 83.93, 109.90, 113.11,
119.96, 122.21, 126.22, 127.95, 128.07, 128.34, 136.93, 158.01; IR
(KBr)
m 612, 1656, 2845, 3090, 3153; Anal. Calcd for C14H14N2O:
C 74.31, H 6.24, N 12.38, O 7.07; found: C 74.39, H 6.31, N 12.41,
O 6.89.
4.2.2.2. (4R,5S)-4-Methyl-5-phenyl-2-(1H-pyrrol-2-yl)-4,5-dihy-
drooxazole (4R,5S)-3b. Yield (63%, 0.38 g): mp 109–111 °C; Rf:
0.20 (EtOAc/Hex, 1:3); ½a D20
ꢃ
¼ þ322 (c 1.94, CHCl3); 1H NMR
4. Experimental
(400 MHz, CDCl3)
d (ppm) 0.78 (d, J = 7.2 Hz, 3H) 4.53 (dq,
4.1. General methods
J = 9.2 Hz, 1H, J = 6.8, 1H) 5.65 (d, J = 9.2 Hz, 1H) 6.22 (t,
J = 3.6 Hz, 1H) 6.79 (dd, J = 3.6 Hz, J = 1.2 Hz, 1H) 6.88 (d,
J = 1.2 Hz, 1H) 7.14 (m, 2H) 7.22–7.31 (m, 3H) 9.5 (s, 1H); 13C
NMR (100 MHz, CDCl3) d (ppm) 17.92, 64.77, 83.96, 109.96,
113.15, 119.93, 122.19, 126.22, 127.96, 128.34, 136.90, 157.95; IR
Reagents and solvents were purchased from Aldrich, Merck and
Fluka. All solvents were dried before use according to the standard
procedures. All NMR spectra were recorded on a Bruker DPX-
400 MHz spectrometer at room temperature. Chemical shifts
(KBr)
m 608, 1652, 2861, 3078, 3157.

20
A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
4.2.3. Experimental procedure for the synthesis of chiral
oxazoline ligands with carboxylic acid and amino alcohol
(4S,5R)-4a and (4R,5S)-4b
HPLC analysis. The absolute configuration of the products was as-
signed by comparison to the literature data.11a,33a,d,38g–l
Thionyl chloride/dichloromethane = 1:1 (2 mL) and salicylic
acid (10 mmol) were stirred until gas production ceased. The sol-
vent and excess of thionyl chloride were then removed under re-
duced pressure and 2-hydroxybenzoyl chloride was obtained.
Under a nitrogen atmosphere, norephedrine (10 mmol) and Et3N
(40 mmol) were added to DCM (100 mL) and cooled to 0 °C. Next,
2-hydroxybenzoyl chloride (10 mmol) in DCM (10 mL) was added.
The mixture was stirred at room temperature until reaction was
complete. Next, MsCl (15 mmol) was added and stirred for 5 h after
which NH4Cl was added. Collection of the organic layer and water
was carried out with DCM (3 ꢂ 30 mL). The combined organic
phases were dried over MgSO4 and filtered. After evaporation of
the solvent, the crude product was purified by flash column chro-
matography (EtOAc/hexane, 1:6).
4.3.2.1. (S)-2-Nitro-1-(4-nitrophenyl)ethanol 6a. For the Chiral-
cel OD-H column, solvent: n-hexane/iPrOH (85:15), flow rate:
1.0 mL/min, UV 215 nm, retention times: major enantiomer (S) tr
28.21 min, minor enantiomer (R) tR: 18.80 min for (R).
4.3.2.2. (S)-2-Nitro-1-(2-nitrophenyl)ethanol 6b. For the Chiral-
cel OD-H column, solvent: n-hexane/iPrOH (90:10), flow rate:
0.8 mL/min, UV 215 nm, retention times: major enantiomer (S) tr
26.40 min, minor enantiomer (R) tR: 20.25 min for (R).
4.3.2.3. (S)-1-Phenyl-2-nitroethanol 6c. For the Chiralcel OD-H
column, solvent: n-hexane/iPrOH, (90:10), flow rate: 0.6 mL/min,
UV 215 nm, retention times: major enantiomer (S) tr: 18.41 min,
minor enantiomer (R) tR: 15.47 min.
4.2.3.1.
2-((4S,5R)-4-Methyl-5-phenyl-4,5-dihydrooxazole-2-
yl)phenol (4S,5R)-4a. Yield (68%, 1.72 g); ½a D20
¼ þ67:1 (c 0.149,
ꢃ
4.3.2.4. (S)-1-(4-Methoxyphenyl)-2-nitroethanol 6d. For the
Chiralcel OD-H column, solvent: n-hexane/iPrOH, (90:10), flow
rate. 0.8 mL/min, UV 215 nm retention times: major enantiomer
(S) tr: 16.20 min, minor enantiomer (R) tr: 13.7 min.
CHCl3); 1H NMR (400 MHz, CDCl3) d (ppm) 1.5 (d, J = 6.7 Hz, 3H)
4.28 (dq, J = 6.7 Hz, J = 6.7 Hz, 1H) 5.10 (d, J = 7.7 Hz, 1H) 6.90 (dt,
J = 1.0 Hz, J = 7.6 Hz, 1H) 7.06 (m, 1H) 7.35–7.43 (m, 6H) 7.75 (m,
1H) 12.19 (s, 1H); 13C NMR (100 MHz, CDCl3) d (ppm) 21.7, 69.9,
87.6, 110.9, 117.0, 118.9, 126.0, 128.4, 128.9, 129.2, 133.7, 139.9,
4.3.2.5. (S)-1-(2-Methoxyphenyl)-2-nitroethanol 6e. For the
Chiralcel OD-H column, solvent: n-hexane/iPrOH (90:10), flow
rate: 0.8 mL/min, UV 215 nm, retention times: major enantiomer
(S) tr: 24.29 min, minor enantiomer (R) tr: 23.43 min.
160.3, 164.5; IR (CHCl3, Salt plate)
2927, 2967, 3032, 3064; Anal. Calcd for C16H15NO2: C 75.87, H
5.97, N 5.53, O 12.63; found: C 75.92, H 5.99, N 5.41, O 12.68.
m 1492, 1617, 1642, 2869,
4.3.2.6. (S)-1-(4-Methylphenyl)-2-nitroethanol 6f. For the Chi-
ralcel OD-H column, solvent: n-hexane/iPrOH, (90:10), flow rate.
0.5 mL/min, UV 215, retention times: major enantiomer (S) tr:
32.00 min, minor enantiomer (R) tr: 27.10 min.
4.2.3.2.
2-((4R,5S)-4-Methyl-5-phenyl-4,5-dihydrooxazole-2-
yl)phenol (4R,5S)-4b. Yield (68%, 1.72 g); ½a D20
¼ ꢁ67:1 (c 0.149,
ꢃ
CHCl3); 1H NMR (400 MHz, CDCl3) d (ppm) 1.6 (d, J = 6.7 Hz, 3H)
4.27 (dq, J = 6.7 Hz, J = 6.7 Hz, 1H) 5.10 (d, J = 7.7 Hz, 1H) 6.90 (m,
1H) 7.06 (m, 1H) 7.35–7.43 (m, 6H) 7.75 (m, 1H) 12.19 (s, 1H);
13C NMR (100 MHz, CDCl3) d (ppm) 21.8, 70.1, 87.6, 110.7, 117.3,
119.1, 126.2, 128.4, 129.1, 129.4, 133.9, 140.2, 160.3, 164.7.
4.3.2.7. (S)-1-(2-Methylphenyl)-2-nitroethanol 6g. For the Chi-
ralcel OD-H column, solvent: n-hexane/iPrOH (90:10), flow rate:
0.5 mL/min, UV 215 nm, retention times: major enantiomer (S) tr:
30.12 min, minor enantiomer (R) tr: 22.50 min.
4.3. Asymmetric Henry reactions
4.3.2.8. (S)-1-(4-Chlorophenyl)-2-nitroethanol 6h. For the Chi-
ralcel AD-H column, solvent: n-hexane/iPrOH (90:10), flow rate:
0.8 mL/min, UV 215 nm, retention times: major enantiomer (S) tr:
26.29 min, minor enantiomer (R) tr: 22.50 min.
4.3.1. Asymmetric Henry reaction in the presence of Et2Zn
To a solution of chiral ligands (0.1 mmol) in dry toluene (2 mL)
at 0 °C under a nitrogen atmosphere was added a solution of dieth-
ylzinc (3 mL, 1.0 M in hexane) via syringe. After stirring for 15 m at
0 °C, CH3NO2 (10 mmol) and p-nitrobenzaldehyde (1 mmol) were
added. The reaction mixture was stirred at 0 °C and monitored
by TLC. When the reaction was finished, NH4Cl was added at
ꢁ15 °C. When the mixture’s temperature reached room tempera-
ture, the mixture was extracted with chloroform (3 ꢂ 10 mL), dried
over MgSO4, and filtered. After evaporation of the solvent, the
crude product was purified by flash column chromatography
(EtOAc/hexane, 1:6).
4.3.2.9. (S)-1-(2-Chlorophenyl)-2-nitroethanol 6i. For the Chi-
ralcel OJ-H column, solvent: n-hexane/iPrOH (97:3), flow rate:
0.8 mL/min, UV 215 nm, retention times: major enantiomer (S) tr:
29.25 min, minor enantiomer (R) tr: 23.44 min.
4.3.2.10. (S)-1-(4-Fluorophenyl)-2-nitroethanol 6j. For the Chi-
ralcel OB-H column, solvent: n-hexane/iPrOH (90:10), flow rate.
0.8 mL/min, UV 215 nm, retention times: major enantiomer (S) tr:
12.60 min, minor enantiomer (R) tr: 11.50 min.
4.3.2. Asymmetric Henry reaction in the presence of
Cu(OAc)2ꢀH2O
4.3.2.11. (S)-1-(4-Trifluoromethyl)phenyl)-2-nitroethanol 6k. For
the Chiralcel OD-H column, solvent: n-hexane/iPrOH (85:15), flow
rate: 0.8 mL/min, UV 215 nm, retention times: major enantiomer
(S) tr: 15.67 min, minor enantiomer (R) tr: 12.45 min.
Under an nitrogen atmosphere, the chiral ligand (0.1 mmol) and
Cu(OAc)2ꢀH2O (0.1 mmol) in the solvent (2 mL) was stirred for 1 h
at room temperature. Next, CH3NO2 (10 mmol) and substituted
benzaldehyde (1 mmol) were added. When the reaction was com-
plete, the solvent was removed under reduced pressure and the
mixture was extracted with chloroform (3 ꢂ 10 mL), dried over
MgSO4, and filtered. After evaporation of the solvent, the crude
product was purified by flash column chromatography (EtOAc/
hexane, 1:6). The adducts were fully characterized by comparison
of their spectroscopic data with those reported in the literature.
The diastereoselectivity was determined from the 1H NMR spec-
trum. The enantiomeric purity of the product was determined by
4.3.2.12. (S)-1-(1-Naphthyl)-2-nitroethanol 6l. For the Chiralcel
OD-H column, solvent: n-hexane/iPrOH (85:15), flow rate:
0.8 mL/min, UV 215 nm, retention times: major enantiomer (S) tr:
28.30 min, minor enantiomer (R) tr: 23.45 min.
4.3.2.13. (S)-1-(2-Naphthyl)-2-nitroethanol 6m. For the Chiral-
cel AD-H column, solvent: n-hexane/iPrOH (85:15), flow rate:

A. Ebru Aydin, S. Yuksekdanaci / Tetrahedron: Asymmetry 24 (2013) 14–22
21
0.8 mL/min, UV 215 nm, retention times: major enantiomer (S) tr:
23.30 min, minor enantiomer (R) tR: 18.00 min.
synminor (1R,2R) tr:15.45 min. Diastereomeric ratio (syn/anti) was
determined by 1H NMR. The absolute configuration of both diaste-
reomers was assigned by comparison of the retention time in HPLC
with the literature data.38g–j 1H NMR spectroscopic data were in
agreement with the literature.
4.3.2.14. (S)-1-(2-Furyl)-2-nitroethanol 6n. For the Chiralcel AD-
H column, solvent: n-hexane/iPrOH, (85:15), flow rate: 0.8 mL/min,
UV 215 nm, retention times: major enantiomer (S) tr: 24.22 min,
minor enantiomer (R) tr: 18.40 min.
4.3.2.24. (1S,2S)-1-Cyclohexyl-2-nitropropan-1-ol 7e. For the
Chiralcel AD-H column, solvent: hexane/iPrOH (95:5), flow rate:
0.8 mL/min, UV 225 nm, retention times: synmajor (1S,2S) tr:
18.50 min, synminor (1R,2R) tr: 15.70 min. Diastereomeric ratio
(syn/anti) was determined by 1H NMR. The absolute configura-
tion of both diastereomers was assigned by comparison of
the retention time in HPLC with the literature data.38g–j 1H
NMR spectroscopic data were in agreement with the literature
values.
4.3.2.15. (S)-1-Cyclohexyl-2-nitroethanol 6o. For the Chiralpak
AD-H column, solvent: n-hexane-iPrOH (97:3), flow rate: 0.8 mL/
min, UV 215 nm,. retention times: major enantiomer (S) tr:
22.15 min, minor enantiomer (R) tR: 24.50 min.
4.3.2.16. (S)-1-Nitropentan-2-ol 6p. For the Chiralpak AD-H col-
umn, solvent: n-hexane-iPrOH (98:2), flow rate: 1 mL/min, UV
215 nm, retention times: major enantiomer (S) tr: 45.30 min, min-
or enantiomer (R) tr: 34.30 min.
4.3.2.25. (3S,4S)-4-Nitro-1-phenylpentan-3-ol 7f. For the Chiral-
cel AD-H column, solvent: hexane/iPrOH (95:5), flow rate: 1.0 mL/
min, 210 nm, retention times: synmajor (1S,2S) tr: 26.20 min,
synminor (1R,2R) tr: 18.45 min. Enantiomeric excess was determined
by HPLC with a Chiralcel AD-H column (hexane/isopropanol =
96:4, 1.0 mL/min, 220 nm), for syn-product, tmajor = 18.7 min,
tminor = 17.3 min. Diastereomeric ratio (syn/anti) was determined
by 1H NMR. The absolute configuration of both diastereomers
was assigned by comparison of the retention time in HPLC with
the literature data.38g–j 1H NMR spectroscopic data were in agree-
ment with the literature values.38k,l
4.3.2.17. (S)-3-Methyl-1-nitrobutan-2-ol 6r11a,33a
. For the Chi-
ralcel OD-H column, solvent: n-hexane/iPrOH (97:3), flow rate:
0.6 mL/min, UV 220 nm, retention times: major enantiomer (S) tr:
31.20 min, minor enantiomer (R) tr: 27.90 min.
4.3.2.18. (S)-1-Nitrohexan-2-ol 6s. For the Chiralcel AD–H col-
umn, solvent: hexane/iPrOH (98:2), flow rate: 0.8 mL/min, UV
215 nm, retention times: major enantiomer (S) tr: 37.60 min, min-
or enantiomer (R) tr: 28.75 min.
4.3.2.19. (S)-4-Methyl-1-nitropentan-2-ol 6t. For the Chiralcel
OJ-H column, solvent: n-hexane/iPrOH (98:2), flow rate: 0.6 mL/
min, UV 215 nm, retention times: major enantiomer (S) tr:
41.70 min, minor enantiomer (R) tr: 36.20 min.
Acknowledgments
This research (04Y0127) is financially supported by the Scien-
tific Research Commission of Mustafa Kemal University. The
authors would like to thank the Scientific Research Commission
of Mustafa Kemal University.
4.3.2.20. (1S,2S)-1-(4-Nitrophenyl)-2-nitropropan-1-ol 7a. For
the Chiralcel OD-H and Chiralpak AD-H column, solvent: hex-
ane/iPrOH (80:20), flow rate: 1.0 mL/min, UV 210 nm, retention
times: synmajor (1S,2S) tr = 24.81 min, synminor (1R,2R) tr = 21.60 min.
Diastereomeric ratio (syn/anti) was determined by 1H NMR. The
absolute configuration of both diastereomers was assigned by
comparison of the retention time in HPLC with the literature
data.1b,33,38g–j 1H NMR spectroscopic data were in agreement with
the literature values.38k,38l
References
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