A study of chiral oxazoline ligands with a 1,2,4-triazine and other six-membered aza-heteroaromatic rings and their application in Cu-catalysed asymmetric nitroaldol reactions

Article abstract of DOI:10.1016/j.tetasy.2014.10.001

Enantiomerically pure oxazoline ligands with variously substituted 1,2,4-triazine rings have been synthesized using the Pd-catalysed cross-coupling amination of 3-halo-1,2,4-triazines. The catalytic efficiency of the ligands was studied in the asymmetric

Full text of DOI:10.1016/j.tetasy.2014.10.001

Tetrahedron: Asymmetry 25 (2014) 1478–1487
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A study of chiral oxazoline ligands with a 1,2,4-triazine and other
six-membered aza-heteroaromatic rings and their application in
Cu-catalysed asymmetric nitroaldol reactions
⇑
´
Ewa Wolinska
Department of Chemistry, Siedlce University, 08-110 Siedlce, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 September 2014
Accepted 2 October 2014
Enantiomerically pure oxazoline ligands with variously substituted 1,2,4-triazine rings have been synthe-
sized using the Pd-catalysed cross-coupling amination of 3-halo-1,2,4-triazines. The catalytic efficiency of
the ligands was studied in the asymmetric Henry reaction of nitromethane with several aldehydes. The
appropriate b-nitro alcohols were formed in good yields (up to 93%) and with up to 78% ee. The impact of
the substitution of the 1,2,4-triazine ring on the nitroaldol reaction is discussed. In order to investigate
the influence of the 1,2,4-triazine ring on the catalytic activity of the ligands, ligands where the
1,2,4-triazine ring was replaced by a pyridine, pyrimidine, pyrazine or pyridine N-oxide ring were synthe-
sized and applied to asymmetric nitroaldol reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
In line with our interests in 1,2,4-triazine-oxazoline ligands, we
have reported on novel ligands 1 bearing a 1,2,4-triazine ring, an
Metal-based asymmetric catalysis1 constitutes a large research
area, and the field is still being rapidly developed along with an
expansion of organocatalysis.2 Since the selectivity of metal cata-
lysts is largely determined by the ligands, ligand design is a major
topic in asymmetric catalysis. In 1986, Brunner first described the
use of chiral oxazoline (4,5-dihydrooxazole) based ligands in
the asymmetric monophenylation of cis-cyclohexan-1,2-diol and
meso-butan-2,3-diol.3 Since then such ligands have been found to
be very active in numerous metal-catalysed enantioselective pro-
cesses.4 The structures of the oxazoline ligands differ depending
on the number of oxazoline rings, additional chiral elements and
specific structural features. Among them, C2-symmetric bis(oxazo-
lines) are one of the most popular classes of chiral ligands and have
been extensively studied by many research groups.4c,e In contrast,
monooxazoline ligands, although represented by a large number of
various structures, are much less explored. Many additional het-
eroatom donors such as nitrogen, oxygen, sulfur and phosphorus
are incorporated into different structures of the oxazoline ligands
thus forming many mono-, bi- and tridentate ligands.4 The addi-
tional electron donor can be derived either from a functional group
or heterocyclic ring.
NH group and a chiral oxazoline moiety (Fig. 1).5
N
R3
R4
N
N
N
N
Ph
N
N
H
N
H
N
O
N
O
∗
R1
∗
R2
1a - l
1m
a: R3 = R4 = Ph, R2 = H, R1 = t-Bu (S)
b: R3 = R4 = Ph, R2 = H, R1 = Ph (S)
c: R3 = R4 = Ph, R2 = H, R1 = i-Pr (S)
d: R3 = R4 = Ph, R2 = H, R1 = Bn (R)
e: R3 = H, R4 = Ph, R2 = H, R1 = t-Bu (S)
f: R3 = H, R4 = Ph, R2 = H, R1 = Ph (S)
g: R3 = H, R4 = Ph, R2 = H, R1 = i-Pr (S)
h: R3 = H, R4 = t-Bu, R2 = H, R1 = t-Bu (S)
i: R3 = H, R4 = t-Bu, R2 = H, R1 = Ph (S)
j: R3 = H, R4 = t-Bu, R2 = H, R1 = i-Pr (S)
k: R3 = H, R4 = t-Bu, R2 = H, R1 = Bn (R)
l: R3 = H, R4 = R2 = R1 = Ph (4R, 5S)
Figure 1. Previous work: 1,2,4-triazine-oxazoline ligands with a flexible substi-
tuent in the oxazoline ring and with an indane moiety.
Ligands with two differentiated sp2-hybridized coordinating
nitrogen atoms have found wide application in enantioselective
metal-catalysed reactions6 and may also serve as ligands able to
form bifunctional catalysts with metals.7 Thus, the structures of
ligands 1 have been designed on the assumption that (1) both
the nitrogen atoms of the 1,2,4-triazine moiety and the oxazoline
⇑
Tel.: +48 25 6431116; fax: +48 25 6442095.
E-mail address: ewol@uph.edu.pl
http://dx.doi.org/10.1016/j.tetasy.2014.10.001
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

´
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E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
nitrogen atom would be responsible for coordination to a metal
ion, together with the NH group; and (2) the 1,2,4-triazine nitrogen
atom can act as a Lewis base in the complexes formed by these
ligands. Ligands 1 were found to be active stereocontrollers in
Cu-catalysed asymmetric nitroaldol reactions of a series of aro-
matic and aliphatic aldehydes, providing the products with enanti-
oselectivities of up to 92%.5 The enantiomeric excesses thus
obtained were due to the substitution pattern in the oxazoline ring,
while the substituents in the 1,2,4-triazine ring of ligands 1a–l
affect the solubility of the ligands or their Cu-complexes have an
impact on the course of the asymmetric reaction. Ligands 1a–d
with two phenyl substituents in the 1,2,4-triazine ring afforded
Henry adducts in lower yields than their counterparts with one
phenyl ring at the 5-position of the 1,2,4-triazine. This observation
prompted us to design ligands 2 and 3 with a 1,2,4-triazine having
a phenyl ring at the 6-position and an unoccupied 5-position. In
order to further investigate the influence of the substitution
in the 1,2,4-triazine ring on ligand activity we also prepared
ligand 4 characterized by the presence of a phenanthro-fused
1,2,4-triazine unit (Fig. 2). The phenanthrene moiety prevents free
rotation of the phenyl at the 5-position and provides its coplanar
arrangement with the triazine ring in comparison to ligands 1,8
which may affect the geometry of the active complex.
group into the ligand structure provides suitable electronic envi-
ronments for a central metal ion.9 Unfortunately, the number of
ligands combining a pyridine N-oxide and oxazoline in the mole-
cule is very limited. A detailed search allowed us to find only
two papers devoted to this type of ligand. Ma and Andrus have
reported on the synthesis and application of oxazoline-pyridine
N-oxide ligands in the asymmetric allylation of aldehydes with
allylchlorosilanes.10a Another ligand was synthesized by Reiser,
but there is no information on its application in asymmetric
catalysis.10b This area remains very attractive for development,
thus oxazoline ligands 5e–f with a pyridine N-oxide moiety were
also synthesized and used in the asymmetric Henry reaction
(Fig. 3).
2. Results and discussion
2.1. Synthesis of ligands
Ligands 2, 3 and 4 were prepared based on the synthetic strat-
egy outlined in Scheme 1. Initially, appropriate 2-(o-aminophe-
nyl)oxazolines 12a–b and 13 were obtained by condensation of
enantiomerically pure aminoalcohols 10a–b and 11 with the CN
group of 2-aminobenzonitrile 9 in the presence of a threefold
excess of ZnCl2 in chlorobenzene at reflux over 24 h.11 Subse-
quently, the Buchwald-Hartwig amination12 of 3-chloro-1,2,4-tria-
zines 14a and 14b with 2-(o-aminophenyl)oxazolines 12a–b and
13 was conducted to furnish the desired chiral ligands 2a–b, 3
and 4. The conditions of the reaction, in terms of the amount of pal-
ladium source and ligand were elaborated by us previously.5a Thus
the Buchwald–Hartwig reactions were carried out in boiling diox-
ane using Pd2dba3 (10 mol %) as the palladium source, Xantphos
(20 mol %) as the ligand and K2CO3 as the base.
Herein we report the synthesis of ligands 2, 3 and 4 and their
application in enantioselective Henry reactions. Since the actual
contribution of a 1,2,4-triazine ring to the activity of the 1,2,4-
triazine-oxazoline ligands is not clearly defined, several analogous
ligands with pyridine 5a, 6a, pyrimidine 5b, 6b, 7, 8 and pyrazine
5c, 6c instead of a 1,2,4-triazine ring were also synthesized and
tested in the asymmetric nitroaldol reaction for comparison
studies (Fig. 3). It is well documented that amine N-oxides act as
powerful electron-pair donors and that the introduction of such a
Ph
N
N
Ph
N
N
N
N
N
N
N
H
N
H
N
N
H
N
O
N
O
N
O
R
2a-b
Ph
a: R = Ph (S)
4
3
b: R = i-Pr (S)
Figure 2. New 1,2,4-triazine oxazoline chiral ligands.
N
N
N
H
N
N
H
N
Cl
N
H
N
O
O
N
N
O
Ph
R
6a-c
d: R = i-Pr
7
5a-f
N
N
=
N
=
a: R = Ph
b: R = Ph
N
N
N
H
N
N
H
N
e: R = Ph
f: R = i-Pr
N
=
N
=
N
N
O
N
N
O
N
N
O
O
c: R = Ph
N
=
N
=
Ph
Ph
8
N
Figure 3. Chiral oxazoline ligands with pyridine, pyrimidine, pyrazine and pyridine N-oxide rings.

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E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
R
HO
H2N
O
R
HO
NH2
10a-b
CN
H2N
N
O
11
N
ZnCl2
chlorobenzene
reflux
ZnCl2
NH2
NH2
chlorobenzene
reflux
9
12a-b
13
a: R = Ph
b: R = i-Pr
Ph
N
N
N
Ph
N
N
N
N
Ph
N
H
13
12a-b
N
N
N
H
Pd2dba3, Xantphos
K2CO3
N
O
Pd2dba3, Xantphos
K2CO3
Cl
dioxane
reflux
N
O
dioxane
reflux
14a
R
2a, 45%
2b, 32%
3, 15%
N
N
N
Pd2dba3, Xantphos
N
12a
+
K2CO3
dioxane
reflux
N
N
H
N
Cl
N
O
Ph
14b
4, 45%
Scheme 1. Synthesis of ligands 2a–b, 3 and 4.
The Pd-catalysed C–N bond formation was also a key step in the
synthesis of ligands with a pyridine, pyrimidine or pyrazine ring
(Scheme 2). Compounds 5a and 5d have already been synthesized
from 2-bromopyridine by Guiry using a palladium catalysed aryl
amination. After 1 h of microwave irradiation, the compounds
were isolated in 60% and 83% yields.13 In our case, ligands 5a
and 5d were formed in 54% and 21% yields, respectively, from
2-bromopyridine 15a and 2-(o-aminophenyl)oxazolines 12a–b
upon conventional heating at 108 °C. Heating for 19 h was
necessary to obtain ligand 5b in 55% yield. The Buchwald–Hartwig
aminations of 2-chloropyrazine 15c with 12a were completed after
3.5 h to give ligand 5c in a yield of 92%. In an analogous manner,
ligands 6a–c with an indanol-derived substituent in the oxazoline
ring were prepared. Continued efforts were directed towards the
synthesis of C1-symmetrical bisoxazoline ligand 8 derived from
2,4-dichlopyrimidine 16. Amination of 2,4-dichloropyrimidine 16
with 2.2 equiv of 2-(o-aminophenyl)oxazoline 12a after 18 h of
heating in boiling dioxane resulted in the formation of monosub-
stituted product 7 in 57% yield. When the reaction time was pro-
longed to 30 h, ligand 8 was obtained in 16% yield in addition to
compound 7 being isolated in a yield of 37%. Further extension of
the time or the addition of a larger amount of catalyst did not
increase the yield of the desired ligand 8. Ligands 5e and 5f with
an N-oxide function in the pyridine ring were synthesized by the
oxidation of 5a and 5d with m-chloroperbenzoic acid (Scheme 2).
We decided to conduct the oxidation process at a low temperature
in order to avoid any oxidation of the oxazoline ring.14 However,
when the reaction was carried out at À20 °C in dichloromethane
the products did not form. We found that 0 °C was the optimal
temperature for the oxidation reaction. Thus, N-oxides 5e and 5f
were obtained in yields of 51 and 54%, respectively.
2.2. Enantioselective Henry reactions
For a preliminary study, ligands with the 1,2,4-triazine ring
were applied as catalysts in the asymmetric nitroaldol reaction,
in which m-nitrobenzaldehyde and nitromethane were used as
model substrates. The results of the reactions carried out in the
presence of 5 mol % of Cu(OAc)2ÁH2O in different solvent systems
are shown in Table 1.
In 2-propanol, the highest yield was observed in reactions car-
ried out in the presence of ligands 2a and 2b (Table 1, entries 1 and
2). Unfortunately the enantiomeric purity of the products obtained
was low. Ligands 3 and 4 were found to be strongly insoluble in 2-
propanol which affected their efficiency in the reaction (Table 1,
entries 3 and 6). Changing the solvent to THF improved the chem-
ical yield of both ligands, especially for ligand 4, but it had a neg-
ative effect on the enantioselectivity (Table 1, entries 4 and 7). In
the reaction catalysed by 3, a racemic product was obtained in
THF. A 2-propanol/THF (1:1) solvent system did not increase the
reaction yield in which ligand 3 was used as a catalyst; however
the enantioselectivity increased to 17% (Table 1, entry 5). This
was the best result that we managed to obtain for ligand 3. There-
fore, we turned our attention to ligand 4 since we were interested
in determining the influence of the phenanthrene unit on the prop-
erties of ligands. The reaction conducted in the presence of the
ligand in a 2:1 mixture of 2-propanol/THF yielded the product at
73% conversion and 37% ee (Table 1 entry 8). A reversal in the ratio
of the reaction medium components (2-propanol/THF, 1:2)
allowed us to obtain the product in a better yield of 87%, while
the enantiomeric purity remained almost the same (Table 1 entry
10). A significant improvement of the yield and enantioselectivity
was achieved when a mixture of 2-propanol/THF in a ratio of 1:1

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E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
13
12a
N
N
Pd2dba3, Xantphos
Pd2dba3, Xantphos
N
N
H
N
H
K2CO3
dioxane
reflux
K2CO3
dioxane
reflux
X
15a-c
N
O
N
O
=
N
Ph
a: X = Br,
N
5a, 54%, 18 hr
5b, 55%, 19 hr
5c, 92%, 3.5 hr
N
b: X = Cl,
c: X = Cl,
N
=
N
N
6a, 47%, 19 hrs
6b, 62%, 16 hrs
6c, 87%, 4 hrs
=
N
N
12b
Pd2dba3, Xantphos
N
N
H
K2CO3
dioxane
reflux
N
Br
N
O
15a
5d, 21%, 24 hr
18 hrs, 57%, sole product
N
12a, 2.2 equiv
N
N
Pd2dba3, Xantphos
N
H
N
N
H
Cl
N
N
+
H
K2CO3
dioxane
reflux
Cl
N
Cl
O
N
N
O
N
O
16
30 hr
Ph
Ph
Ph
7, 37%
8, 16%
mCPBA
CH2Cl2
0 °C
5a or 5d
N
N
H
O
N
O
R
5e, R = Ph, 51%, 24 hr
5f, R = i-Pr, 54%, 24 hr
Scheme 2. Synthesis of ligands with a pyridine, pyrimidine, pyrazine or pyridine N-oxide ring.
was applied as the solvent. Under these conditions, the reaction
proceeded in 92% yield and with an enantioselectivity of 41%
(Table 1, entry 9).
Having obtained the optimal solvent conditions, we decided to
check the scope of the reaction. For these studies, ligands 2a and 4
were chosen due to the different substitution pattern in the
1,2,4-triazine ring. The results of the asymmetric addition of nitro-
methane to a series of aldehydes in the presence of ligands 2a and
4 are collected in Table 2.
Analysing the results obtained by using ligand 2a, it can be seen
that the enantioselectivity varied in the range of 18 to 78% (Table 2,
entries 1–16). The yield of the products significantly depends on
the nature of the aldehydes. Benzaldehydes with electron-
withdrawing groups in the phenyl ring reacted faster (Table 2,
entries 1 and 3–8) than aldehydes substituted with electron-
donating ones (Table 2, entries 9–15). However, the electronic
nature of the substituents does not have an influence on the
enantioselectivity. The reaction of an aliphatic aldehyde, hydrocin-
namaldehyde 17p afforded the product with enantioselectivity of
50% and a low yield (Table 2, entry 16). In some cases, precipitation
of a 2a-Cu complex was observed. Unfortunately isolation of the
complex and preparation of a crystal suitable for X-ray analysis
were not successful. When ligand 4 was used as the catalyst, the
nitroaldol reactions proceeded with better enantioselectivities
and higher yields (Table 2, entries 17–21). In the reactions tested
(S)-enriched b-nitro alcohols were produced, with the exception
of the reaction of 4-chlorobenzaldehyde 17g catalysed by 2a, when
the formation of the (R)-enantiomer of 19g was favoured (Table 2,
entry 7). Conversely, in the reaction of 4-chlorobenzaldehyde con-
ducted in the presence of ligand 4, the (S)-enantiomer was formed
predominantly (Table 2, entry 20). Both ligands 2a and 4 possess
an (S)-configured stereocenter at the 4-position of the oxazoline
ring; therefore the stereodifferentiation in the reaction may be
due to the substitution in the 1,2,4-triazine ring. It is worth noting
that our previously described (R)-configured ligands 1l and 1m
with a phenyl substituent at the 5-position of the 1,2,4-triazine ini-
tiated the formation of an (R)-enriched product in the reaction of
4-chlorobenzaldehyde.5b
In subsequent studies, we undertook efforts to examine the role
of the 1,2,4-triazine moiety on the catalytic efficiency of our
triazine-oxazoline ligands. Comparison experiments involving
ligands 5a–c, 5e–f, 6a–c, 7, and 8, where the 1,2,4-triazine ring is

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E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
Table 1
Table 3
Screening of ligands 2a–b, 3 and 4a
Screening of ligands 5a–c, 5e–f, 6a–c, 7 and 8a
O
Cu(OAc)2·H2O (5 mol%)
ligand (5 mol%)
OH
*
OH
O
Cu(OAc)2·H2O (5 mol%)
NO2
CH3NO2
+
H
NO2
ligand (5 mol%)
solvent, rt
∗
i-PrOH
R
R
H
CH3NO2
+
rt
19a, 19f-j, 19l
18
17a, 17f-j, 17l
NO2
NO2
Product Yieldb (%)
eec (%)
19a
17a
18
R
Aldehyde
Ligand
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-ClC6H4
17a
17a
17a
17a
17a
17a
17a
17a
17g
17f
17j
17l
17h
17i
17h
17a
17a
5a
5b
5c
6a
6b
6c
7
19a
19a
19a
19a
19a
19a
19a
19a
19g
19f
19j
19l
19h
19i
19h
19a
19a
37
63
57
80
71
58
65
87
15
35
9
39
44
22
22
81
88
4 (S)
11 (S)
8 (S)
23 (S)
29 (S)
11 (S)
rac
12 (S)
23 (S)
34 (S)
17 (S)
34 (S)
64 (R)
63 (R)
67 (R)
14 (S)
11 (S)
Ligand
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2a
2b
3
3
3
4
4
4
4
i-PrOH
i-PrOH
i-PrOH
THF
i-PrOH/THF (1:1)
i-PrOH
THF
i-PrOH/THF (2:1)
i-PrOH/THF (1:1)
i-PrOH/THF (1:2)
88
77
51
68
68
38
85
73
92
87
18 (S)
14 (S)
4 (R)
rac
17 (S)
32 (S)
13 (S)
37 (S)
41 (S)
36 (S)
8
5a
5b
5b
5b
6a
6a
6b
5e
5f
3-ClC6H4
3-MeC6H4
2-MeOC6H4
2-BrC6H4
2-MeC6H4
2-BrC6H4
10
4
a
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and
5 mol % of Cu(OAc)2ÁH2O at room temperature for 98 h.
b
Yields of isolated products.
3-NO2C6H4
3-NO2C6H4
c
Enantiomeric excess was determined by HPLC using Chiracel OD-H column. The
absolute configuration was assigned by comparing their specific rotations or the
HPLC elution order with data from the literature.
a
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and
5 mol % of Cu(OAc)2ÁH2O in 2-propanol at room temperature for 98 h.
b
Yields of isolated products.
Enantiomeric excess was determined by HPLC using Chiracel OD-H column. The
c
replaced by a pyridine, pyrimidine, pyrazine or pyridine N-oxide
ring were conducted. The results of the asymmetric addition of
nitromethane to several aldehydes are presented in Table 3.
absolute configuration was assigned by comparing their specific rotations or the
HPLC elution order with data from the literature.
Table 2
Scope of aldehydes in the catalytic enantioselective Henry reactiona
Cu(OAc)2·H2O (5 mol%)
ligand (5 mol%)
OH
O
CH3NO2
+
NO2
i-PrOH (A)
i-PrOH/THF 1:1 (B)
rt
∗
R
R
H
17a-p
18
19a-p
R
Aldehyde
Ligand
Solvent
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
21
3-NO2C6H4
Ph
17a
17b
17c
17d
17e
17f
17g
17h
17i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
4
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
19a
19b
19c
19d
19e
19f
19g
19h
19i
88
35
85
93
63
41
48
70
45
20
Traces
16
33
19
34
17
92
55
87
35
68
51
25
18 (S)
30 (S)
43 (S)
23 (S)
55 (S)
29 (S)
78 (R)
68 (S)
39 (S)
38 (S)
—
56 (S)
22 (S)
30 (S)
41 (S)
50 (S)
41 (S)
60 (S)
42 (S)
65 (S)
77 (S)
63 (S)
61 (S)
2-NO2C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
1-naphthyl
PhCH2CH2
3-NO2C6H4
Ph
17j
17k
17l
19j
19k
19l
17m
17n
17o
17p
17a
17b
17d
17g
17g
17i
19m
19n
19o
19p
19a
19b
19d
19g
19g
19i
4
4
4
4
4
4
4-NO2C6H4
4-ClC6H4
2-BrC6H4
2-MeC6H4
3-MeC6H4
17j
19j
a
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and 5 mol % of Cu(OAc)2ÁH2O in 2 mL of i-PrOH (A) or iPr/THF 1:1 (B) at room temperature for
98 h.
b
Yields of isolated products.
c
Enantiomeric excess was determined by HPLC using Chiracel OD-H column. The absolute configuration was assigned by comparing their specific rotations or the HPLC
elution order with data from the literature.

´
1483
E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
The addition to m-nitrobenzaldehyde was carried out in moder-
ate to good yield whereas the enantioselectivities were very low
and did not exceed 29% for ligand 6b (Table 3, entries 1–8). For
comparison, phenanthro-1,2,4-triazine ligand 4 generated the
b-nitro alcohol 19a with an enantiomeric purity of 41%. The use
of other 1,2,4-triazine-oxazoline ligands 1 investigated before
afforded b-nitro alcohol 19a with higher enantioselectivities of
up to 49%.5 In the presence of ligands 6a–b possessing an indane
moiety, benzaldehydes with a substituent at the ortho-position
underwent the addition of nitromethane with relatively good
enantioselection, but this was accompanied by low chemical yield
(Table 3, entries 13–15). Previously examined 1,2,4-triazine-oxaz-
oline ligand 1m also with an indane unit catalysed the addition to
o-bromo- and o-methylbenzaldehyde in yields of 81% and 66% and
enantioselectivities of 77% and 92%, respectively.5b Although
ligands 5e and 5f with an N-oxide moiety promoted the addition
in good yield, the enantioselectivities obtained were very low
(Table 3, entries 16 and 17). Thus, ligands with other than 1,2,4-tri-
azine six-membered azaheteroaromatics were found to be less
active in the asymmetric nitroaldol reaction than the 1,2,4-tri-
azine-oxazoline ones. This suggests that the presence of a 1,2,4-tri-
azine ring in the ligand structure is essential in promoting high
levels of yield and enantioselection.
using Merck Kieselgel 60 (0.040–0.060 mm). Solvents were dried
and distilled according to standard procedures. 3-Chloro-6-phe-
nyl-1,2,4-triazine15 14a and 3-chlorophenanthro[9,10-e]-1,2,4-tri-
azine16 14b were synthesized according to literature procedures.
4.2. General procedure for the synthesis of 2-(o-aminophenyl)
oxazolines 12a–b and 13
An oven dried two-necked flask was washed with argon and
charged with 2-aminobenzonitrile (118 mg, 1 mmol), the appro-
priate amino alcohol, freshly flame dried ZnCl2 (405 mg, 3 mmol)
and anhydrous chlorobenzene (6 mL). The mixture was stirred at
reflux for 24 h. The solvent was then removed under reduced pres-
sure and the residue was stirred with 30% NaOH for 0.5 h. The
product was extracted with dichloromethane and purified by flash
column chromatography on silica gel.
4.2.1. 2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12a
Compound 12a was prepared from (S)-phenylglycinol (205 mg,
1.5 mmol) after purification by silica gel chromatography (hexane/
EtOAc, 5:1), yield 90% (210 mg). All of the physical and spectro-
scopic data are with agreement with the published data.17
4.2.2. 2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12b
Compound 12b was prepared from (S)-valinol (155 mg,
1.5 mmol) after purification by silica gel chromatography (hex-
ane/EtOAc, 5:1), yield 74% (150 mg). All of the physical and spec-
troscopic data are with agreement with the published data.17
3. Conclusion
In conclusion, we have synthesised new 1,2,4-triazine-oxazo-
line ligands 2a–b and 3 with a phenyl substituent at the 6-posision
of the 1,2,4-triazine ring and ligand 4 with a phenanthro-fused
1,2,4-triazine. The ligands have been applied in the asymmetric
addition of nitromethane to various aldehydes with enantioselec-
tivities of up to 78%. The substitution mode of the 1,2,4-triazine
ring was crucial in terms of the reactivity of the ligands mostly
due to their solubility. Several ligands with different six-membered
azaheteroaromatic rings instead of a 1,2,4-triazine ring have been
synthesized. Two oxazoline ligands with an N-oxide function in
the pyridine ring have also been obtained. Using these ligands in
asymmetric nitroaldol reactions gave products with lower enantio-
meric purities or yields, which indicates the important role of the
1,2,4-triazine ring in the enantioinduction. Studies to clarify the
differences in the activity of the oxazoline ligands with a 1,2,4-tri-
azine and with other azaheteroaromatics are currently in progress.
4.2.3. 2-[(3aR,8aS)-8,8a-Dihydro-3aH-indeno[1,2-d]oxazol-2-yl]-
aniline 13
Compound 13 was prepared from (1R,2S)-1-amino-2-indanol
(179 mg, 1.2 mmol) after purification by silica gel chromatography
(hexane/EtOAc, 8:1), yield 58% (87 mg). All of the physical and
spectroscopic data are in agreement with the published data.18
4.3. General procedure for the preparation of ligands 2a–b, 3, 4,
5a–d, 6a–c, 7, and 8
An oven dried three-necked flask was washed with argon and
charged with Pd2dba3 (45.8 mg, 10 mol %), Xantphos (57.8 mg,
20 mol %), 2-(o-aminophenyl)oxazoline 12a–b or 13 (0.6 mmol),
heteroaromatic halide 14a–b or 15a–c, 16 (0.5 mmol) and K2CO3
(1.38 g, 10 mmol). The flask was then evacuated and backfilled
with argon. Dioxane (10 mL) was added through the septum. The
mixture was refluxed for the indicated period of time. After cool-
ing, the solid material was filtered off and washed with CH2Cl2.
The solvent was evaporated, and the resulting crude products were
purified as described below.
4. Experimental
4.1. General
1H and 13C NMR spectra were determined at 400 and 100 MHz,
respectively, with a Varian 400 MR spectrometer. Chemical shifts
(d) are reported in part per million from tetramethylsilane with
the solvent resonance as the internal standard. Coupling constants
are given as absolute values expressed in Hertz. Mass spectra were
obtained by using AMD 604 (AMD Intectra GmbH, Germany) and
GC/MS QP 5050 Shimadzu (30 m  0.25 mm ID-BPX 5 0.25 mm)
spectrometers. Infrared spectra were obtained by using a Shima-
dzu FT IR Affinity-1 Spectrometer. Elemental analyses were
recorded with an Elementar Vario EL III CHNS analyser and the
results for indicated elements were within 0.3% of the calculated
values. Optical rotation values were measured at room tempera-
ture with a Perkin-Elmer polarimeter. The ee values were deter-
mined by HPLC (Knauer) analysis by using a chiral stationary
phase column (Chiralcel OD-H or Chiralcel AD-H), and elution with
isopropanol–hexanes. Thin layer chromatography (TLC) was car-
ried out on aluminium sheets percolated with silica gel 60 F254
(Merck). Column chromatography separations were performed by
4.3.1. 3-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
amino-6-phenyl-1,2,4-triazine 2a
The product was obtained from 3-chloro-6-phenyl-1,2,4-
triazine 14a and 2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]
aniline 12a after 24 h of heating as a yellow solid. The product was
purified by column chromatography using hexanes/ethyl acetate
10:1 and recrystallized from ethanol, yield 45% (88 mg). Mp 124–
125 °C. [
a]
20 = +33.4 (c 0.55, CH2Cl2). IR (ZnSe)
m
max: 2999, 1627,
D
1543, 1442, 1425, 1041, 748, 690 cmÀ1
.
1H NMR (400 MHz, CDCl3)
d: 12.73 (s, 1H), 9.01 (dd, J = 1.2, 8.8 Hz, 1H), 8.73 (s, 1H), 8.03–7.99
(m, 3H), 7.58–7.47 (m, 4H), 7.40–7.28 (m, 5H), 7.10 (dt, J = 1.2,
8.0 Hz, 1H), 5.62 (dd, J = 8.4, 10.4 Hz, 1H), 4.79 (dd, J = 8.4, 10.4 Hz,
1H), 4.25 (t, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 164.8,
159.3, 150.4, 147.1, 142.0, 140.6, 133.9, 132.7, 129.7, 129.6, 129.1,
128.8, 127.6, 126.5, 125.7, 121.1, 119.1, 112.7, 73.4, 69.9, 29.7. HRMS
(ESI, m/z): calcd for C24H20N5O ([M+H]+), 394.1662, found 394.1652.

´
E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
1484
4.3.2. 3-{2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
amino-6-phenyl-1,2,4-triazine 2b
18 h of heating as a white solid. The product was purified by col-
umn chromatography using hexanes/ethyl acetate 9:1, yield 54%
(85 mg). All of the physical and spectroscopic data of compound
5a are in agreement with the published data.13
The product was obtained from 3-chloro-6-phenyl-1,2,4-
triazine 14a and 2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-
2-yl]aniline 12b after 24 h of heating as a yellow solid. The product
was purified by column chromatography using hexanes/ethyl ace-
tate 10:1 and recrystallized from ethanol, yield 32% (29 mg). Mp
4.3.6. 2-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminopyrimidine 5b
138–139 °C. [
a
]
D
20 = À7.1 (c 0.50, CH2Cl2). IR (ZnSe)
m
max: 2958,
The product was obtained from 2-chloropyrimidine 15b and 2-
[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12a after 19 h
of heating as a white solid. The product was purified by column
chromatography using hexanes/ethyl acetate 7:1, yield 55%
1633, 1543, 1423, 1039, 744 cmÀ1
.
1H NMR (400 MHz, CDCl3) d:
12.89 (s, 1H), 8.96 (dd, J = 0.8, 8.8 Hz, 1H), 8.76 (s, 1H), 8.04–8.02
(m, 2H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H), 7.55–7.48 (m, 4H), 7.06 (dt,
J = 1.2, 8.0 Hz, 1H), 4.43 (dd, J = 8.4, 9.6 Hz, 1H), 4.28–4.24 (m,
1H), 4.11 (t, J = 8.0 Hz, 1H), 1.88 (o, J = 6.8 Hz, 1H), 1.13 (d,
J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d: 163.3, 159.4, 150.3, 147.1, 143.3, 140.4, 134.0, 132.3, 130.5,
129.6, 129.4, 129.1, 128.9, 128.4, 125.7, 125.4, 120.9, 118.9,
113.0, 72.8, 69.3, 33.3, 19.0, 18.7. HRMS (ESI, m/z): calcd for
(87 mg). Mp 83–84 °C. [
3230, 3062, 2971, 2900, 1635, 1608, 1558, 1531, 1436, 1406, 746,
696 cmÀ1 1H NMR (400 MHz, CDCl3) d: 12.30 (s, 1H), 8.93 (d,
a] :
20 = +376.5 (c 1.0, CH2Cl2). IR (ZnSe) mmax
D
.
J = 8.4 Hz, 1H), 8.45 (d, J = 4.8 Hz, 2H), 7.96 (dd, J = 1.2, 8.0 Hz,
1H), 7.49 (dt, J = 1.2, 8.4 Hz, 1H), 7.36–7.28 (m, 5H), 7.02 (dt,
J = 0.4, 7.6 Hz, 1H), 6.73 (t, J = 4.8 Hz, 1H), 5.60 (dd, J = 8.0,
10.0 Hz, 1H), 4.74 (dd, J = 8.8, 10.0 Hz, 1H), 4.20 (t, J = 8.0 Hz, 1H).
13C NMR (100 MHz, CDCl3) d: 164.8, 160.2, 157.8, 142.3, 141.6,
132.4, 129.6, 128.7, 127.5, 126.5, 120.1, 118.5, 112.9, 112.3, 73.3,
70.0. HRMS (ESI, m/z): calcd for C19H17N4O ([M+H]+), 317.1397,
found 317.1394.
C
21H22N5O ([M+H]+), 360.1819, found 360.1807. Anal. Calcd for
C21H21N5O (359.17): C, 70.17; H, 5.89; N, 19.48. Found: C, 70.20;
H, 5.98; N, 19.53.
4.3.3. 3-{2-[(3aR,8aS)-8,8a-Dihydro-3aH-indeno[1,2-d]oxazol-2-
yl]phenyl}amino-6-phenyl-1,2,4-triazine 3
The product was obtained from 3-chloro-6-phenyl-1,2,4-
triazine 14a and 2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxa-
zol-2-yl]-aniline 13 after 24 h of heating as a yellow solid. The
product was purified by column chromatography using hexanes/
ethyl acetate 4:1 and recrystallized from ethanol, yield 15%
4.3.7. 2-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminopyrazine 5c
The product was obtained from 2-chloropyrazine 15c and 2-
[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12a after 3.5 h
of heating as a white solid. The product was purified by column
chromatography using hexanes/ethyl acetate 7:1, yield 92%
(28 mg). Mp 269–270 °C. [
m
a
]
D
20 = À487.6 (c 0.25, CH2Cl2). IR (ZnSe)
max: 3037, 1627, 1541, 1442, 1421, 1043, 746 cmÀ1
.
1H NMR
(145 mg). Mp 71–72 °C. [
m
a]
20 = +351.5 (c 1.0, CH2Cl2). IR (ZnSe)
D
(400 MHz, CDCl3) d: 12.71 (s, 1H), 8.89 (d, J = 7.6 Hz, 1H), 8.78 (s,
1H), 8.05–8.03 (m, 2H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H), 7.68–7.66
max: 3176, 2966, 2900, 1626, 1521, 1448, 746 cmÀ1 1H NMR
.
(400 MHz, CDCl3) d: 12.09 (s, 1H), 8.85 (dd, J = 0.8, 8.8 Hz, 1H),
8.17–8.14 (m, 2H), 7.97–7.96 (m, 1H), 7.94 (d, J = 1.6 Hz, 1H),
7.51 (ddd, J = 1.6, 7.2, 8.8 Hz, 1H), 7.41–7.30 (m, 5H), 7.01 (dt,
J = 1.2, 8.4 Hz, 1H), 5.55 (dd, J = 8.4, 10.0 Hz, 1H), 4.77 (dd, J = 8.4,
10.0 Hz, 1H), 4.22 (t, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d:
165.2, 152.0, 142.1, 141.9, 141.1, 136.6, 134.9, 132.6, 129.7,
128.9, 127.8, 126.4, 120.0, 117.7, 111.9, 73.3, 69.9. HRMS (ESI, m/
z): calcd for C19H17N4O ([M+H]+), 317.1397, found 317.1395.
(m, 1H), 7.56
– 7.47 (m, 4H), 7.29–7.27 (m, 2H), 7.03 (t,
J = 7.6 Hz, 1H), 5.93 (d, J = 7.6 Hz, 1H), 5.45 (dt, J = 1.6, 8.0 Hz,
1H), 3.54 (dd, J = 7.2, 18 Hz, 1H), 3.42 (d, J = 18.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3) d: 164.0, 159.4, 150.3, 147.0, 141.8, 140.3,
139.5, 134.0, 132.4, 129.6, 129.5, 129.1, 128.6, 127.6, 125.7,
125.3, 120.9, 118.9, 113.1, 81.9, 76.8, 39.5. HRMS (ESI, m/z): calcd
for C25H20N5O ([M+H]+), 406.1662, found 406.1662. Anal. Calcd
for C25H19N5OÁ1/2H2O (414.16): C, 72.45; H, 4.86; N, 16.90. Found:
C, 72.36; H, 4.82; N, 16.82.
4.3.8. 2-{2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminopyridine 5d
4.3.4. 3-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminophenanthro[9,10-e]1,2,4-triazine 4
The product was obtained from 2-bromopyridine 15a and
2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12b after
21 h of heating as a white solid. The product was purified by col-
umn chromatography using hexanes/ethyl acetate 20:1, yield
21% (30 mg). All of the physical and spectroscopic data of com-
pound 5d are in agreement with the published data.13
The product was obtained from 3-chlorophenanthro[9,10-e]-
1,2,4-triazine 14b and 2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-
2-yl]aniline 12a after 20 h of heating as a yellow solid. The product
was purified by washing with hot ethanol, yield 45% (105 mg). Mp
255–256 °C. [
a]
20 = +259.2 (c 0.25, CH2Cl2). IR (ZnSe)
m
max: 3211,
.
D
3117, 2882, 1616, 1602, 1514, 1448, 1041, 748 cmÀ1
1H NMR
4.3.9. 2-{2-[(3aR,8aS)-8,8a-Dihydro-3aH-indeno[1,2-d]oxazol-2-
yl]phenyl}aminopyridine 6a
(400 MHz, CDCl3) d: 13.14 (s, 1H), 9.33–9.30 (m, 1H), 9.22 (d,
J = 8.4 Hz, 1H), 9.17 (dd, J = 1.2, 8.0 Hz, 1H), 8.59 (d, J = 8.4 Hz,
1H), 8.57–8.54 (m, 1H), 8.05 (dd, J = 1.6, 8.0 Hz, 1H), 7.87 (dt,
J = 1.2, 8.4 Hz, 1H), 7.77–7.69 (m, 4H), 7.45–7.38 (m, 4H), 7.33–
7.30 (m, 1H), 7.15 (t, J = 7.2 Hz, 1H), 5.69 (t, J = 8.4 Hz, 1H), 4.84
(dd, J = 8.4, 10.4 Hz, 1H), 4.29 (t, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, TFA/benzene-d6) d: 172.3, 163.1, 154.6, 152.5, 139.2,
138.7, 138.6, 135.6, 133.7, 133.2, 132.9, 131.8, 131.0, 130.7,
130.1, 130.0, 129.8, 129.2, 128.7, 126.7, 125.4, 125.2, 124.7,
124.2, 79.7, 62.4. HRMS (ESI, m/z): calcd for C30H22N5O ([M+H]+),
468.1819, found 468.1804.
The product was obtained from 2-bromopyridine 15a and
2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]-aniline
13 after 19 h of heating as a white solid. The product was purified
by column chromatography using hexanes/ethyl acetate 10:1 and
recrystallized from ethanol, yield 47% (78 mg). Mp 156–157 °C.
[a]
20 = À388.1 (c 0.52, CH2Cl2). IR (ZnSe)
mmax: 3024, 1622, 1477,
D
1448, 1415, 746 cmÀ1
.
1H NMR (400 MHz, CDCl3) d: 11.52 (s, 1H),
8.70–8.67 (m, 1H), 8.28–8.26 (m, 1H), 7.82 (dd, J = 1.8, 8.0 Hz,
1H), 7.55–7.51 (m, 2H), 7.40–7.36 (m, 1H), 7.31–7.25 (m, 3H),
6.87–6.83 (m, 2H), 6.77 (ddd, J = 1.0, 5.0, 6.0 Hz, 1H), 5.84 (d,
J = 7.8 Hz, 1H), 5.42 (ddd, J = 1.7, 6.7, 8.3 Hz, 1H), 3.52 (dd, J = 6.8,
18 Hz, 1H), 3.49 (dd, J = 1.2, 17.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d: 164.2, 155.3, 147.7, 142.7, 142.0, 139.7, 137.1, 132.2, 129.5,
128.5, 127.5, 125.4, 125.3, 118.8, 117.2, 115.4, 112.6, 111.5, 81.4,
4.3.5. 2-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminopyridine 5a
The product was obtained from 2-bromopyridine 15a and
2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12a after
76.8, 39.7. HRMS (ESI, m/z): calcd for
C
21H18N3O ([M+H]+),

´
1485
E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
328.1444, found 328.1436. Anal. Calcd for C21H17N3O (327.13): C,
77.04; H, 5.23; N, 12.84. Found: C, 77.06; H, 5.25; N, 12.90.
of heating as a white solid. The product was purified by column
chromatography using hexanes/ethyl acetate 8:1, yield 16%
(45 mg). Mp 64–65 °C. [a]
20 = +349.7 (c 0.45, CH2Cl2).1H NMR
D
4.3.10. 2-{2-[(3aR,8aS)-8,8a-Dihydro-3aH-indeno[1,2-d]oxazol-
2-yl]phenyl}aminopyrimidine 6b
(400 MHz, CDCl3) d: 12.05 (s, 1H), 11.87 (s, 1H), 8.94 (dd, J = 0.8,
8.4 Hz, 1H), 8.86–8.84 (m, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.94 (dd,
J = 1.6, 8.0 Hz, 1H), 7.90–7.87 (m, 1H), 7.49–7.29 (m, 11H), 7.00–
6.89 (m, 3H), 6.14 (d, J = 5.6 Hz, 1H), 5.62 (t, J = 9.6 Hz, 1H), 5.53
(dd, J = 8.4, 9.6 Hz, 1H), 4.80–4.73 (m, 2H), 4.20–4.15 (m, 2H). 13C
NMR (100 MHz, CDCl3) d: 165.1, 164.9, 160.3, 159.6, 156.2, 142.4,
142.1, 142.0, 141.5, 132.3, 132.2, 129.5, 129.4, 128.9, 128.8,
127.7, 127.5, 126.5, 126.4, 120.4, 120.1, 119.6, 118.9, 112.4,
112.0, 101.5, 77.2, 73.3, 70.1, 69.9. HRMS (ESI, m/z): calcd for
The product was obtained from 2-chloropyrimidine 15b and
2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]-aniline
13 after 16 h of heating as a white solid. The product was purified
by column chromatography using hexanes/ethyl acetate 8:1 and
recrystallized from ethanol, yield 62% (102 mg). Mp 225–227 °C.
[
a]
D
20 = À408.2 (c 0.53, CH2Cl2). IR (ZnSe)
mmax: 3068, 1625, 1558,
1436, 1411, 744 cmÀ1
.
1H NMR (400 MHz, CDCl3) d: 12.08 (s, 1H),
8.83 (dd, J = 0.8, 8.4 Hz, 1H), 8.49 (d, J = 4.8 Hz, 2H), 7.86 (dd,
J = 1.6, 8.0 Hz, 1H), 7.66–7.64 (m, 1H), 7.43 (ddd, J = 1.6, 7.6,
8.8 Hz 1H), 7.30–7.25 (m, 3H), 6.94 (t, J = 8.0 Hz, 1H), 6.74 (t,
J = 4.8 Hz, 1H), 5.91 (d, J = 8.0 Hz, 1H), 5.41 (ddd, J = 1.6, 6.4,
8.0 Hz, 1H), 3.52 (dd, J = 6.4, 18.0 Hz, 1H), 3.41 (d, J = 18.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) d: 164.0, 160.3, 157.8, 142.0,
141.3, 139.6, 132.1, 129.5, 128.5, 127.5, 125.8, 125.2, 120.0,
118.4, 112.8, 112.6, 81.7, 76.8, 39.5. HRMS (ESI, m/z): calcd for
C
34H29N6O2 ([M+H]+), 553.2347, found 553.2344.
4.4. General procedure for the preparation of ligands 5e and 5f
2-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}ami-
nopyridine 5a or 2-{2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-
2-yl]phenyl}aminopyridine 5d (0.5 mmol) was dissolved in
dichloromethane (13 mL) and the solution was cooled to 0 °C. Next
m-chloroperbenzoic acid (145 mg, 0.7 mmol) in dichloromethane
(3 mL) was added dropwise and the mixture was stirred at 0 °C
for 24 h. The mixture was then washed with sat. sodium bicarbon-
ate three times. The organic layers were collected and dried over
magnesium sulfate. After evaporation of the solvent, the crude
products were purified by column chromatography (dichlorometh-
ane/methanol 80:1).
C
C
20H17N4O ([M+H]+), 329.1397, found 329.1390. Anal. Calcd for
20H16N4O (328.13): C, 73.15; H, 4.91; N, 17.06. Found: C, 73.12;
H, 5.01; N, 17.06.
4.3.11. 2-{2-[(3aR,8aS)-8,8a-Dihydro-3aH-indeno[1,2-d]oxazol-
2-yl]phenyl}aminopyrazine 6c
The product was obtained from 2-chloropyrazine 15c and
2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]-aniline
13 after 4 h of heating as a white solid. The product was purified by
column chromatography using hexanes/ethyl acetate 8:1 and
recrystallized from ethanol, yield 87% (143 mg). Mp 217–218 °C.
4.4.1. 2-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminopyridine 1-oxide 5e
The product was obtained from 2-{2-[(4S)-4-phenyl-4,5-dihy-
dro-1,3-oxazol-2-yl]phenyl}aminopyridine 5a as a greenish oil,
[
a]
D
20 = À363.6 (c 0.55, CH2Cl2). IR (ZnSe)
mmax: 3039, 1622, 1519,
1446, 1001, 746 cmÀ1
.
1H NMR (400 MHz, CDCl3) d: 12.04 (s, 1H),
yield 51% (85 mg).
m
[a]
20 = +279.8 (c 0.50, CH2Cl2). IR (ZnSe)
D
8.76 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.97 (d,
J = 2.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 6.0 Hz, 1H),
7.43 (t, J = 7.6 Hz, 1H), 7.31–7.25 (m, 3H), 6.95 (t, J = 7.6 Hz, 1H),
5.86 (d, J = 8.0 Hz, 1H), 5.45 (t, J = 6.8 Hz, 1H), 3.54 (dd, J = 6.8,
18.0 Hz, 1H), 3.39 (d, J = 18.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d: 164.3, 152.1, 141.7, 141.6, 141.3, 139.6, 136.2, 134.3, 132.4,
129.6, 128.7, 127.7, 125.4, 125.2, 120.1, 117.8, 112.3, 81.8, 76.5,
39.7. HRMS (ESI, m/z): calcd for C20H17N4O ([M+H]+), 329.1397,
found 329.1388. Anal. Calcd for C20H16N4O (328.13): C, 73.15; H,
4.91; N, 17.06. Found: C, 79.96; H, 5.28; N, 17.06.
max: 3061, 1519, 1274, 1197, 742, 698 cmÀ1 1H NMR (400 MHz,
.
CDCl3) d: 11.92 (br s, 1H), 8.26 (dd, J = 5.6, 1.2 Hz, 1H), 8.00 (dd,
J = 6.0, 1.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.50–7.46 (m, 2H),
7.44–7.41 (m, 3H), 7.37–7.33 (m, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.08
(dt, J = 1.2, 8.0 Hz, 1H), 6.74 (dt, J = 1.6, 6.4 Hz, 1H), 5.63 (t,
J = 10.0 Hz, 1H), 4.79 (dd, J = 8.4, 2.0 Hz, 1H), 4.25 (t, J = 8.4 Hz,
1H). 13C NMR (100 MHz, CDCl3) d: 164.0, 148.1, 142.6, 140.5,
139.2, 132.5, 131.3, 129.3, 127.9, 127.7, 127.0, 122.1, 117.5,
116.0, 115.4, 110.2, 73.6, 70.2. HRMS (ESI, m/z): calcd for
C
20H18N3O2 ([M+H]+), 553.2347, found 553.2344.
4.3.12. 2-Chloro-4-{2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-
yl]phenyl}aminopyrimidine 7
4.4.2. 2-{2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
aminopyridine 1-oxide 5f
The product was obtained from 2,4-dichloropyrimidine 16 and
2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12a after
18 h of heating as a white solid. The product was purified by col-
umn chromatography using hexanes/ethyl acetate 7:1, yield 57%
The product was obtained from 2-{2-[(4S)-4-isopropyl-4,5-
dihydro-1,3-oxazol-2-yl]phenyl}aminopyridine 5d as a greenish
oil, yield 54% (80 mg). [
a] :
20 = +43.2 (c 0.54, CH2Cl2). IR (ZnSe) mmax
D
3061, 1519, 1275, 1197, 743, 698 cmÀ1
.
1H NMR (400 MHz, CDCl3)
(100 mg). Mp 84–85 °C. [
a]
20 = +268.7 (c 0.45, CH2Cl2). IR (ZnSe)
d: 12.10 (br s, 1H), 8.28 (dd, J = 4.0, 1.4 Hz, 1H), 7.90 (dd, J = 6.4,
1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 7.2, 1.6 Hz, 1H),
7.41 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 8.2 Hz, 1H), 7.03 (t, J = 7.2 Hz,
1H), 6.73 (t, J = 6.0 Hz, 1H), 4.40 (dd, J = 8.4, 0.8 Hz, 1H), 4.20 (t,
J = 8.0 Hz, 1H), 4.10 (t, J = 8.0 Hz, 1H), 1.83 (o, J = 6.8 Hz, 1H), 1.16
(d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d: 161.9, 147.8, 139.7, 138.5, 131.5, 130.3, 127.1, 121.3,
116.6, 115.5, 114.7, 109.6, 73.2, 69.5, 33.4, 18.9, 18.8. HRMS (ESI,
m/z): calcd for C17H20N3O2 ([M+H]+), 298.1550, found 298.1549.
D
m
max: 3288, 3028, 2920, 1620, 1575, 1504, 1458, 1444, 1332,
1267, 981, 748, 700 cmÀ1
.
1H NMR (400 MHz, CDCl3) d: 12.36 (s,
1H), 8.84 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.96 (dd,
J = 2.0, 8.0 Hz, 1H), 7.57 (ddd, J = 2.0, 7.6, 9.2 Hz, 1H), 7.42–7.29
(m, 5H), 7.11 (ddd, 0.8, 7.6, 8.4 Hz, 1H), 6.50 (d, J = 6.0 Hz, 1H),
5.53 (dd, J = 8.4, 10.0 Hz, 1H), 4.78 (dd, J = 8.4, 10.0 Hz, 1H), 4.22
(t, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 165.1, 161.1,
160.5, 156.8, 141.7, 140.3, 132.8, 129.6, 128.9, 127.9, 126.3,
121.8, 119.8, 113.0, 107.3, 73.5, 69.8. HRMS (ESI, m/z): calcd for
C
19H16N4OCl ([M+H]+), 351.1007, found 351.1005.
4.5. General procedure for the catalytic enantioselective Henry
reaction
4.3.13. 2,4-Di-{[2-((4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl)
phenyl]amino}pyrimidine 8
The product was obtained from 2,4-dichloropyrimidine 16 and
2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline 12a after 30 h
A mixture of Cu(OAc)2ÁH2O (5 mg, 0.025 mmol, 5 mol %) and
ligand (0.025 mmol, 5 mol %) in anhydrous 2-propanol (2 mL) or
2-propanol/THF, 1:1 was stirred at room temperature for 4 h under

´
E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
1486
argon atmosphere to give a red-brown solution. The aldehyde
(0.5 mmol) and the nitromethane (270 L, 5 mmol) were then
HPLC20a (Chiralcel OD-H, Hexane/i-PrOH = 90:10, flow rate:
0.5 mL/min, k = 215 nm), tminor = 27.9, tmajor = 22.1, 78% ee.
l
added and the reaction was conducted at room temperature for
4 days. The solvent was then removed under reduced pressure
and the product was isolated by column chromatography. All spec-
troscopic data of the nitroaldol adducts 19a–p were in good agree-
ment with those reported previously.5 The ee values of the b-nitro
alcohols 19a–p were determined by chiral HPLC analysis. The abso-
lute configurations of the products were assigned by comparing
their specific rotations or the HPLC elution order with literature
data.
4.5.8. (S)-1-(2-Bromophenyl)-2-nitroethanol 19h
Compound 19h was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
tate 8:1) to give a colourless oil (85 mg, 68% yield). [
a]
20 = +38.2 (c
D
0.90, CH2Cl2). {Lit.20c 20 = +46.2 (c 0.90, CH2Cl2), 98% ee}. HPLC20d
[a]
D
(Chiralcel OD-H, Hexane/i-PrOH = 96:4, flow rate: 0.5 mL/min,
k = 215 nm), tminor = 25.1, tmajor = 26.6, 77% ee.
4.5.9. (S)-1-(2-Methylphenyl)-2-nitroethanol 19i
Compound 19i was obtained according to the general procedure
and purified by column chromatography (hexanes/ethyl acetate
4.5.1. (S)-2-Nitro-1-(3-nitrophenyl)ethanol 19a
Compound 19a was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
10:1) to give a yellow oil (54 mg, 51% yield). [
a]
20 = +30.8 (c 1.01,
D
CH2Cl2). {Lit.20c 20 = +52.8 (c 1.01, CH2Cl2), 99% ee}. HPLC6b (Chi-
[a]
D
tate 2.5:1) to give
a colourless solid (97 mg, 92% yield).
[a] [a]
20 = +17.1 (c 1.25, CH2Cl2). {Lit.19a 20 = +36.2 (c 1.25, CH2Cl2),
D D
ralcel OD-H, Hexane/i-PrOH =90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 10.3, tmajor = 16.5, 63% ee.
81% ee}. HPLC20c (Chiralcel OD-H, Hexane/i-PrOH = 90:10, flow
rate: 1.0 mL/min, k = 215 nm), tminor = 21.1, tmajor = 24.2, 41% ee.
4.5.10. (S)-1-(3-Methylphenyl)-2-nitroethanol 19j
Compound 19j was obtained according to the general procedure
and purified by column chromatography (hexanes/ethyl acetate
4.5.2. (S)-2-Nitro-1-phenylethanol 19b
Compound 19b was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
8:1) to give a yellow oil (23 mg, 25% yield). [
a]
20 = +23.2 (c 0.5, CH2-
D
Cl2). {Lit.20c 20 = +38.8 (c 0.50, CH2Cl2), 98% ee}. HPLC6b (Chiralcel
[a]
D
tate 7:1) to give a colourless oil (46 mg, 55% yield). [
a]
20 = +28.1 (c
D
OD-H, Hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, k = 215 nm),
tminor = 10.1, tmajor = 11.8, 61% ee.
1.00, CH2Cl2). {Lit.20c 20 = +40.2 (c 0.96, CH2Cl2), 98% ee}. HPLC20c
[a]
D
(Chiralcel OD-H, Hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 11.8, tmajor = 14.5, 60% ee.
4.5.11. (S)-1-(2-Methoxyphenyl)-2-nitroethanol 19l
Compound 19l was obtained according to the general procedure
and purified by column chromatography (hexanes/ethyl acetate
4.5.3. (S)-2-Nitro-1-(2-nitrophenyl)ethanol 19c
Compound 19c was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
10:1) to give a yellow oil (16 mg, 16% yield). [
a]
20 = +29.2 (c 1.04,
D
CH2Cl2). {Lit.20c 20 = +45.0 (c 1.05, CH2Cl2), 96% ee}. HPLC6b (Chi-
[a]
D
tate 5:1) to give a brown solid (90 mg, 85% yield). [a]
20 = À98.5 (c
D
1.05, CH2Cl2). {Lit.20c
[
a
]
20 = À169.4 (c 0.22, CH2Cl2), 87% ee}.
ralcel OD-H, Hexane/i-PrOH =90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 10.8, tmajor = 13.1, 56% ee.
D
HPLC20d (Chiralcel OD-H, Hexane/i-PrOH = 90:10, flow rate:
1.0 mL/min, k = 215 nm), tminor = 11.7, tmajor = 13.0, 43% ee.
4.5.12. (S)-1-(3-Methoxyphenyl)-2-nitroethanol 19m
Compound 19m was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
4.5.4. (S)-2-Nitro-1-(4-nitrophenyl)ethanol 19d
Compound 19d was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
tate 7:1) to give a yellow oil (32 mg, 33% yield). [
a]
20 = +10.7 (c
D
0.60, CH2Cl2). {Lit.20c 20 = +36.3 (c 0.60, CH2Cl2), 92% ee}. HPLC6b
[a]
D
tate 5:1) to give a colourless solid (90 mg, 87% yield). [a]
20 = +18.2
D
(Chiralcel OD-H, Hexane/i-PrOH =90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 22.2, tmajor = 30.0, 22% ee.
(c 1.00, CH2Cl2). {Lit.20c 20 = +36.1 (c 0.98, CH2Cl2), 95% ee}.
[a]
D
HPLC20b (Chiralcel OD-H, Hexane/i-PrOH = 85:15, flow rate:
1.0 mL/min, k = 215 nm), tminor = 13.5, tmajor = 16.9, 42% ee.
4.5.13. (S)-1-(4-Methoxyphenyl)-2-nitroethanol 19n
Compound 19n was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
4.5.5. (S)-1-(2-Chlorophenyl)-2-nitroethanol 19e
Compound 19e was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
tate 7:1) to give a yellow oil (19 mg, 19% yield). [
a]
20 = +15.3 (c
D
0.50, CH2Cl2). {Lit.6b 20 = +43.5 (c 0.95, CH2Cl2), 98% ee}. HPLC6b
[a]
D
tate 7:1) to give a colourless oil (63 mg, 63% yield). [
a]
20 = +55.6 (c
D
(Chiralcel OD-H, Hexane/i-PrOH =90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 17.0, tmajor = 21.5, 30% ee.
1.03, CH2Cl2). {Lit.20c 20 = +47.7 (c 1.07, CH2Cl2), 99% ee}. HPLC6b
[a]
D
(Chiralcel OD-H, Hexane/i-PrOH = 98:2, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 20.5, tmajor = 22.0, 55% ee.
4.5.14. (S)-1-(1-Naphthyl)-2-nitroethanol 19o
Compound 19o was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
4.5.6. (S)-1-(3-Chlorophenyl)-2-nitroethanol 19f
Compound 19f was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
tate 10:1) to give a yellow oil (36 mg, 34% yield). [
a]
20 = +26.8 (c
D
1.00, CH2Cl2). {Lit.20c 20 = +26.0 (c 1.06, CH2Cl2), 98% ee}. HPLC20c
[a]
D
tate 7:1) to give a colourless oil (41 mg, 41% yield). [
a]
20 = +17.4 (c
D
(Chiralcel OD-H, Hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 15.0, tmajor = 24.6, 41% ee.
0.53, CH2Cl2). {Lit.20c 20 = +73.7 (c 0.48, CH2Cl2), 97% ee}. HPLC20c
[a]
D
(Chiralcel OD-H, Hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min,
k = 215 nm), tminor = 12.5, tmajor = 16.0, 29% ee.
4.5.15. (S)-1-Nitro-4-phenylbutan-2-ol 19p
Compound 19p was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
4.5.7. (R)-1-(4-Chlorophenyl)-2-nitroethanol 19g
Compound 19g was obtained according to the general proce-
dure and purified by column chromatography (hexanes/ethyl ace-
tate 5:1) to give a colourless solid (16 mg, 17% yield). [
a]
20 = À4.8
D
(c 1.00, CH2Cl2). {Lit.20c
[
a]
20 = À14.2 (c 1.00, CH2Cl2), 92% ee}.
D
tate 7:1) to give a colourless oil (48 mg, 48% yield). [
a]
20 = À36.4 (c
HPLC6b (Chiralpak AD-H, Hexane/i-PrOH = 95:5, flow rate: 0.7 mL/
min, k = 215 nm), tminor = 27.9, tmajor = 35.2, 50% ee.
D
1.02, CH2Cl2). {Lit.19b
[a]
20 = À48.1 (c 1.01, CH2Cl2), 95% ee}.
D

´
1487
E. Wolinska / Tetrahedron: Asymmetry 25 (2014) 1478–1487
C.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638; (e) Shibasaki, M.;
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Acknowledgment
We would like to thank Prof. Andrzej Rykowski for profound
scientific discussion.
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