Chiral oxazoline ligands containing a 1,2,4-triazine ring and their application in the Cu-catalyzed asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tet.2013.06.084

Eleven members of new ligand class incorporating a chiral oxazoline and a 1,2,4-triazine ring have been synthesized via Pd-catalyzed amination reaction of 3-halo-1,2,4-triazines with 2-(o-aminophenyl)oxazolines. Buchwald-Hartwig amination of 3-halo-1,2,4-triazines was investigated to establish the best conditions for synthesis of the title ligands. Catalytic activity of the new ligands was evaluated in the asymmetric Henry reaction of nitromethane with a variety of aromatic and aliphatic aldehydes. The β-hydroxy nitroalkanes were obtained in high yields (up to 95%), and moderate-to-good enantioselectivity (up to 82% ee).

Full text of DOI:10.1016/j.tet.2013.06.084

Tetrahedron 69 (2013) 7269e7278
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral oxazoline ligands containing a 1,2,4-triazine ring and their
application in the Cu-catalyzed asymmetric Henry reaction
*
ꢀ
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:
Eleven members of new ligand class incorporating a chiral oxazoline and a 1,2,4-triazine ring have been
synthesized via Pd-catalyzed amination reaction of 3-halo-1,2,4-triazines with 2-(o-aminophenyl)ox-
azolines. BuchwaldeHartwig amination of 3-halo-1,2,4-triazines was investigated to establish the best
conditions for synthesis of the title ligands. Catalytic activity of the new ligands was evaluated in the
Received 27 February 2013
Received in revised form 9 June 2013
Accepted 24 June 2013
Available online 29 June 2013
asymmetric Henry reaction of nitromethane with a variety of aromatic and aliphatic aldehydes. The b-
hydroxy nitroalkanes were obtained in high yields (up to 95%), and moderate-to-good enantioselectivity
(up to 82% ee).
Keywords:
Asymmetric catalysis
Chiral oxazoline ligands
1,2,4-Triazine
Ó 2013 Elsevier Ltd. All rights reserved.
Enantioselective Henry reaction
BuchwaldeHartwig amination
1. Introduction
chiral oxazolines and bisoxazolines have been used as ligands for
metal-catalyzed enantioselective transformations.6 Oxazoline li-
The nitroaldol (Henry)1 reaction has become a powerful syn-
thetic method for carbonecarbon bond formation in which
a nitroalkane compound is added to an aldehyde or ketone to give
gands containing thiophene,8 quinoline,9 quinazoline,10 pyrroli-
dine11 and phthalazine12 rings have also been described. Very
recently, new pyrrole-oxazoline ligands have been synthesized and
tested in an asymmetric nitroaldol reaction.7a
a
b
-nitro alcohol. The resulting
b
-nitro alcohols can be further
-amino
-hydroxycarboxylic
converted into valuable bifunctional compounds, such as
b
Therefore, the chiral oxazolines with an appropriate function-
ality offer an excellent framework for the design of novel ligands,
which can form catalysts with metals containing more than one
active centre. Such catalysts exhibit both Lewis acidity and Lewis
basicity and have been developed as highly active and stereo-
selective bifunctional catalysts. The concept of bifunctional activa-
tion has recently become a fast growing area of asymmetric
catalysis.13 Surprisingly, there are only a few examples of oxazoline-
containing complexes with different metals showing synergistic
activation of electrophilic and nucleophilic centres.14 New types of
oxazoline-pyridine-based bifunctional complexes have been de-
scribed by Guiry.14a
To the best of our knowledge, chiral oxazolines containing
a 1,2,4-triazine ring have not been synthesized and used as ligands
in asymmetric synthesis. It is well known that 1,2,4-triazines are
powerful metal chelators15 and have been used, inter alia, as se-
lective extractants of rare elements from nuclear waste.16 So, we
envisaged that 1,2,4-triazine nitrogen atoms can coordinate to-
gether with an oxazoline nitrogen atom to form stable complexes.
Moreover, 1,2,4-triazine nitrogen atoms can act as Lewis bases, thus
the oxazoline-1,2,4-triazine ligands can form bifunctional catalysts
with metals.
alcohols by reduction of the nitro group, and
a
acids by the Nef reaction.2 Furthermore, the enantioselective ad-
dition of nitroalkanes to carbonyl compounds provides optically
active
b-nitroalkanols, which are useful intermediates in the
asymmetric synthesis of pharmacologically important com-
pounds.3 Since the first asymmetric version of the Henry reaction
was reported by Shibasaki,4 metal-catalyzed enantioselective
nitroaldol reaction has attracted much attention and various effi-
cient chiral ligands have been elaborated for this synthetically
useful method.5
Chiral oxazolines are a type of ‘privileged ligands’ and their
applicability was proven with great success in various asymmetric
metal-catalyzed transformations including enantioselective dieth-
ylzinc additions to aldehydes, DielseAlder reactions, cyclopropa-
nations, hydrosilylations, hydrogenations and allylic alkylations.6
Modular oxazoline ligands have also been applied with great suc-
cess in the asymmetric Henry reaction.7 A large number of pyridyl
* Tel.: þ48 25 6431116; fax: þ48 25 6442095; e-mail addresses: ewol@uph.
edu.pl. ewawoli@yahoo.com.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.084

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E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7270
Here, we report on the synthesis of ligand class 9 in which an
5b. Thus, the bromination reaction was carried out in boiling
dichloromethane using 1.5 equiv of POBr3 in the presence of N,N-
dimethylaniline. After 1 h of heating 3-bromo-5,6-diphenyl-1,2,4-
triazine (5b) was formed in 72% yield. Addition of a larger amount
of POBr3 or extension of time did not increase theyield of the reaction.
High reactivity of 3-bromo-5,6-diphenyl-1,2,4-triazine (5b) in
aromatic nucleophilic substitution was proved in reactions with
some aliphatic amines 10aec. Reactions carried out in the presence
of potassium carbonate gave the appropriate products of sub-
stitution 11aec in good or excellent yield (Scheme 2).
N-phenylamine unit links the 1,2,4-triazine and chiral oxazoline
rings. The application of these ligands as chiral auxiliaries in the
asymmetric Henry reaction is also described.
2. Results and discussion
2.1. Synthesis of chiral ligands
Two possible synthetic approaches leading to ligands 9 are
outlined in Scheme 1. Our initial strategy was based on the
palladium-catalysed cross-coupling reaction of 2-chlorobenzon-
itrile (2) and 3-amino-1,2,4-triazine (1a, R2¼R3¼H) followed by
generation of the chiral oxazoline ring by condensation of an
enantiomerically pure amino alcohol and the nitrile group of
compound 3 (Scheme 1, route A). It was reported by Guillaument
et al.17 that electron poor 3-amino-1,2,4-triazine (1a R2¼R3¼H)
easily coupled with a variety of heteroaryl chlorides employing
BuchwaldeHartwig amination18 using mixtures of Xantphos and
Pd(OAc)2 or Pd2dba3 as the palladium source. Unfortunately, at-
tempts to extend this protocol to the Pd-catalysed amination
starting from 2-chlorobenzonitrile (2) and 3-amino-1,2,4-triazine
(1a, R2¼R3¼H) were unsuccessful and only 3-amino-1,2,4-triazine
was recovered unchanged. It seems likely that the chloro sub-
stituent in 2-chlorobenzonitrile does not act as a good leaving
group under BuchwaldeHartwing amination conditions with poor
nucleophile 1a. Therefore, we directed our attention to the Pd-
catalysed cross-coupling reaction of the corresponding 3-halo-
1,2,4-triazines 5 and anilines 6 bearing a chiral oxazoline unit
(Scheme 1, route B). Our ongoing research on nucleophilic sub-
stitution of 1,2,4-triazines revealed that 3,30-dichloro-5,50-bi-1,2,4-
triazine easily undergoes nucleophilic displacement of chlorines
with primary and secondary alkylamines.19 Thus application of
3-halo-1,2,4-triazines 5 to reaction with (oxazol-2-yl)anilines 6
should provide the expected ligands 9.
Scheme 2. Reaction of 3-bromo-5,6-diphenyl-1,2,4-triazine (5b) with pyrrolidine
(10a), ethanolamine (10b) and p-amino-benzylamine (10c).
However, for the reaction of 3-halo-1,2,4-triazines 5 with aro-
matic amines such as 6 application of BuchwaldeHartwig Pd-
catalysis was necessary. When these amines were reacted in typi-
cal SNAr conditions no products were formed. First, we studied the
cross-coupling reaction of 5a, b with some simple aromatic amines
such as aniline and several heterocyclic amines to optimize the
cross-coupling conditions (Table 1).
Amination of 3-choro-5,6-diphenyl-1,2,4-triazine (5a) with an-
iline (12a), and with three isomeric aminopyridines 12bed or
aminopyrazine (12e) using Pd(OAc)2 as the palladium source and
Xantphos (Pd/L 10/20 mol %) resulted in the formation of the
Scheme 1. Two possible synthetic strategies to chiral ligands 9.
Initially, we considered using 3-chloro-5,6-diphenyl-1,2,4-triazine
(5a). Thelattercanbeeasily prepared accordingtoa knownprocedure
by refluxing 3-hydroxy-1,2,4-triazine in POCl3.20 Since bromine is
a better leaving group in cross-coupling reactions catalysed by pal-
ladium we decided to synthesise 3-bromo-5,6-diphenyl-1,2,4-
triazine (5b). Published synthesis of analogue, 3-bromo-5-phenyl-
1,2,4-triazine was afforded by melting 3-hydroxy-5-phenyl-1,2,4-
triazine with POBr3, which is a solid.21 Application of this method to
the synthesis of 5b appeared inconvenient and not effective. To make
the bromination reaction more practicable we were looking for
a solvent in which both 3-hydroxy-1,2,4-triazine and phosphorus
oxybromide are soluble. We found out that benzene or dichloro-
methane dissolves both the reagents and can be useful in synthesis of
desired products 13aee in 47e83% yield (Table 1, entries 1e5).
Palladium acetate and Pd2dba3 appeared not active in amination of
5a, b with aminobenzonitrile (12f). No product was detected after
the reaction. Amination of chlorotriazine 5a with achiral 2-(4,5-
dihydro-1,3-oxazol-2-yl)aniline (12g) was also examined. The ex-
pected product 13g was obtained in a small amount (9%) when
Pd(OAc)2 was used as the palladium source (Table 1, entry 9). Use of
Pd2dba3 instead of palladium acetate gave the coupling product 13g
in 36% yield (Table 1, entry 10). When 3-bromo-5,6-diphenyl-1,2,4-
triazine (5b) was chosen as the coupling partner and subjected to
reaction with 12g in the presence of Pd2dba3 (10 mol %), Xantphos
(20 mol %) and K2CO3 in boiling dioxane N-arylation product 13g
was isolated in 68% yield (Table 1, entry 11).

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E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7271
Table 1
a catalytic amount (20 mol %) of ZnCl2 the substrate was consumed
after 5 days and the product 6a was formed in 74% yield. The re-
action proceeded faster when three-fold excess of ZnCl2 was used.
In these modified conditions, product 6a was obtained in 99% yield
after heating for 24 h. Similarly, oxazolylaniline 6b was formed in
73% and 87% yield when 20 mol % or excess of ZnCl2 was used.
Condensations of valinol and phenylalaninol with 2-amino-
benzonitrile were carried out using excess of ZnCl2 and yielded
the required (o-aminophenyl)oxazolines 6c and 6d in 70 and 72%
yield, respectively.
Optimization of BuchwaldeHartwig amination reaction conditions of 5aeb with
aromatic and heteroaromatic amines 12aeg
Next, we conducted cross-coupling reactions of oxazolylanilines
6aed with 3-halo-1,2,4-triazines 5bed using the optimised con-
ditions (Scheme 4, Table 2).
Entry
Amine
X
Pd
Product
Yield (%)
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
12f
12f
12g
12g
12g
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Br
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
Pd2dba3
Pd(OAc)2
Pd2dba3
Pd2dba3
13a
13b
13c
13d
13e
d
68
58
47
83
75
d
d
d
9
Scheme 4. Synthesis of chiral ligands 9aek.
d
d
Table 2
9
10
11
13g
13g
13g
Synthesis of chiral ligands 9aek
36
68
Ligand
R1
R2
R3
Yield (%)
1
2
3
4
5
6
7
8
9aa
9b
9c
9d
9e
9f
9g
9h
9i
t-Bu
Ph
i-Pr
Bn
t-Bu
Ph
i-Pr
t-Bu
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
42 (S)
54 (S)
68 (S)
43 (R)
28 (S)
56 (S)
54 (S)
35 (S)
49 (S)
70 (S)
60 (R)
Our protocol of synthesis of 3-arylamino- and 3-heteroaryla-
mino- derivatives of 1,2,4-triazine utilizes easily obtained 3-halo-
1,2,4-triazines as the starting material. Such compounds were not
tested in BuchwaldeHartwig amination previously. In comparison
with the amination of 3-methylsulfanyl-1,2,4-triazine22 published
by Routier our methodology is simpler, and works for less active
heteroaromatic amines and sterically hindered aniline 12g. Rout-
ier’s desulfurative procedure is limited to simple aliphatic amines
and anilines without a substituent in ortho position. The methyl-
sulfanyl group in 1,2,4-triazine is active in BuchwaldeHartwig
amination under microwave irradiation only in the presence of
a complex catalytic system.
A reasonable yield of Pd-coupling between 5b and 12g persuaded
us to adopt the optimized conditionsdescribedabove tothetwo-step
synthesis of the titled ligand class 9 according to route B depicted in
Scheme 1. The synthesis of ligands began with the preparation of
enantiopure 2-(o-aminophenyl)oxazolines 6aed by condensation of
chiral amino alcohols 4aed with 2-aminobenzonitrile in the pres-
ence of ZnCl2 in boiling chlorobenzene (Scheme 3).23
9
10
11
9j
9k
i-Pr
Bn
H
H
a
The synthesis of ligand 9a was presented previously.24
Thus, the BuchwaldeHartwig aryl aminations between 5bed
and 6aed were carried out in boiling dioxane using K2CO3 as the
base, Pd2dba3 (10 mol %) as the palladium source and Xantphos
(20 mol %) as the ligand. The amination required 24 h reaction time
to get complete consumption of 3-halo-1,2,4-triazines 5bed. After
this time, ligands 9aek were obtained in 28e70% yield (Scheme 4,
Table 2).
2.2. Enantioselective Henry reactions
With the enantiopure oxazoline ligands 9aek in hand, we ex-
amined their asymmetric induction properties in the Cu-catalyzed
enantioselective Henry reaction between 3-nitrobenzaldehyde
(14a) and nitromethane (15) in the presence of Cu(OAc)2$H2O,
which was already known as a very good catalyst for the enantio-
selective nitroaldol reaction in the absence of any base. The results
are summarized in Table 3. All reactions were performed at room
temperature in isopropanol to afford the
good yields of 57e95% and enantioselectivity 24e51%. Considering
the relationship between the structure of the tested ligands 9aek
b-nitro alcohol 16a in
Scheme 3. Synthesis of enantiopure 2-(o-aminophenyl)oxazolines 6aed.
and the enantiopurity of the obtained b-nitro alcohol 16a, it is ev-
When reaction of 2-aminobenzonitrile with tert-leucinol was
ident that presence of phenyl group in the oxazoline ring of ligands
results in higher enantioselectivity (Table 3, entries 2, 6 and 9).
carried out according to a literature procedure23a in the presence of

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E. Wolinska / Tetrahedron 69 (2013) 7269e7278
Table 3
Table 4
Screening of ligands 9aeka
Optimization of reaction conditionsa
R1
R2
R3
Yieldb (%)
eec (%)
Solvent
Precatalyst
Yieldb (%)
eec (%)
Ligand
1
2
3
4
5
6
7
8
9
i-PrOH
THF
CH2Cl2
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
CuCl2
95
82
10
82
0
82
91
77d
83e
46 (S)
20 (S)
d
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
t-Bu
Ph
i-Pr
Bn
t-Bu
Ph
i-Pr
t-Bu
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
68
76
85
87
82
95
95
57
73
71
70
27 (S)
40 (S)
34 (S)
25 (R)
31 (S)
46 (S)
35 (S)
24 (S)
51 (S)
33 (S)
26 (R)
37 (S)
d
Cu(OAc)2
41 (S)
39 (S)
34 (S)
41 (S)
Copper(I) thiopheno-2-carboxylate
Cu(OAc)2$H2O
Cu(OAc)2$H2O
9
10
11
9j
9k
i-Pr
Bn
H
H
a
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and
5 mol % of precatalyst in 2 mL of 2-propanol at room temperature for 98 h.
b
a
Yields of isolated products.
Enantiomeric excess was determined by HPLC using Chiracel OD-H column. The
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and
c
5 mol % of Cu(OAc)2$H2O in 2 mL of 2-propanol at room temperature for 98 h.
b
absolute configuration was assigned by comparing their specific rotations or the
Yields of isolated products.
Enantiomeric excess was determined by HPLC using Chiracel OD-H column. The
HPLC elution order with data from the literature.3e
c
d
Reaction was carried out for 40 h.
Reaction was carried out in the presence of 3 mol % of ligand and 3 mol % of
absolute configuration was assigned by comparing their specific rotations or the
e
HPLC elution order with data from the literature.3e
Cu(OAc)2$H2O.
This is probably due to possible favourable
pep interaction be-
results in reduction of efficiency and enantioselectivity to 77 and
34%, respectively (Table 4, entry 8). Finally, it was found that the
reaction gave slightly decreased yield and enantiopurity of product
when the catalyst loading was lowered to 3 mol % (Table 4, entry 9).
After determining the best conditions, the scope and limitation of
the substrates were investigated. A variety of aldehydes were
employed as substrates to afford the corresponding nitroaldol
products with varied yield and enantioselectivity. The results are
presented in Table 5. Aldehydes 14a, 14cef and 14h possessing
tween aldehyde and phenyl group in the oxazoline moiety. The
lowest asymmetric induction was achieved when ligands with
bulky tert-butyl group 9a, 9e and 9h (Table 3, entries 1, 5 and 8) and
flexible benzyl group 9d and 9k were used (Table 3, entries 4 and
11). The results obtained indicate that the nature of substituents in
positions 5 and 6 of the 1,2,4-triazine ring does not affect the
enantioselective outcome of the reaction. On the other hand, the
substituents in 1,2,4-triazine strongly influence a chemical yield of
the investigated reaction. The highest yield of b-nitro alcohol 16a
was observed in reactions catalyzed by complexes of ligands 9eeg
possessing a phenyl substituent in position 5 of the 1,2,4-triazine
ring (Table 3, entries 5e7). Application of ligands 9aed with two
phenyl rings in 1,2,4-triazine and ligands 9hek with a tert-butyl
substituent in position 5 of 1,2,4-triazine afforded product with
significantly lower yield (Table 3, entries 1e4 and 8e11). The (S)-
enriched products were obtained by using the (S)-configured
ligands (Table 3, entries 1e3 and 5e10) while ligands 9d and 9k
Table 5
Scope of aldehydes in the catalytic enantioselective Henry reactiona
with R configuration of stereogenic centre gave R-enriched b-nitro
alcohols (Table 3, entries 4 and 11).
R
Aldehyde
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
3-NO2C6H4
Ph
2-NO2C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H4
1-Naphthyl
PhCH2CH2
CH3(CH2)3
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
14o
14p
14q
14r
16a
16b
16c
16d
16e
14f
16g
16h
16i
16j
16k
16l
16m
16n
16o
16p
16q
16r
95
60
90
82
87
65
0
76
47
59
47
20
56
Traces
16
41
13
20
46 (S)
52 (S)
69 (S)
46 (S)
75 (S)
58 (S)
d
In the subsequent studies, the reaction parameters, including
metal salts, solvent and catalyst loadings, were optimized. To de-
termine the optimal conditions the asymmetric Henry reaction of
3-nitrobenzaldehyde (14a) with nitromethane (15) in the presence
of ligand 9f was tested (Table 4). A remarkable effect of the coun-
terions on the yield and enentioselectivity was observed. Among
the copper precatalysts, Cu(OAc)2$H2O, Cu(OAc)2 and copper(I)
thiopheno-2-carboxylate, provided the best results (Table 4, entries
1, 6 and 7). The application of CuCl2 yielded no product. Next, the
influence of solvent was investigated. Several protic and aprotic
solvents were tested. It was observed that the type of solvent had
a significant effect on both the chemical yield and enantiose-
lectivity of the Henry products (Table 4, entries 1e4). 2-Propanol
was found to be the best solvent for the reaction. Running the re-
action in ethanol gave the product in 82% yield and 41% ee, while
THF resulted in only 20% ee. When the reaction was carried out in
a non-coordinating solvent such as dichloromethane the yield
dramatically dropped to 10%. It is possible that 2-propanol co-
ordinates the copper metal, and this process might enhance the
yield and enantioselectivity. Shortening the reaction time to 40 h
82 (S)
52 (S)
48 (S)
43 (S)
67 (S)
48 (S)
d
9
10
11
12
13
14
15
16
17
18
35 (S)
50 (S)
55 (S)
56 (S)
a
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and
5 mol % of Cu(OAc)2$H2O in 2 mL of 2-propanol at room temperature for 98 h.
b
Yields of isolated products.
Enantiomeric excess was determined by HPLC using Chiracel OD-H or AD-H
c
column. The absolute configuration was assigned by comparing their specific ro-
tations or the HPLC elution order with data from the literature.3e, f, 5a, 25

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E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7273
electron-withdrawing groups in the phenyl ring formed the Henry
adduct in higher yield than benzaldehyde (Table 5, entries 1, 3e6 and
8). Conversely, the reactions of aldehydes with electron-donating
substituents afforded the appropriate products 16ieo in lower
chemical yields (Table 5, entries 9e15). Position of chlorine sub-
stituent in the three positional isomers of chlorobenzaldehyde
ring to asymmetric nitroaldol reactions. The enantioselectivity was
controlled by the substituents on the oxazoline ring. It was found
that the best chiral induction was achieved by ligand 9f possessing
phenyl group in the oxazoline ring. Using this ligand high yields (up
to 95%) and moderate and good enantioselectivities (up to 82%)
were obtained for both aromatic and aliphatic aldehydes. It has
been proven that substituents on the 1,2,4-triazine ring strongly
affected reaction rate of nitromethane addition to 3-nitro-
benzaldehyde. Investigation of the detailed reaction mechanism
is currently in progress.
14eeg has a remarkable influence on the yield of the b-nitro alcohols
(Table 5, entries 5e7). 2-Chlorobenzaldehyde gave the product in the
highest yield among them. It is interesting to note that in the reaction
of 4-chlorobenzaldehyde, no product was obtained. Only traces of
product 16n were detected in the reaction of 4-methoxyben-
zaldehyde, while 2- and 3-methoxybenzaldehydes gave the appro-
priate products in better yield (Table 5, entries 12e14). Decreased
yield was also observed for 4-nitrobenzaldehyde in comparison to 2-
and 3-nitrobenzaldehydes (Table 5, entries 1, 3 and 4). In addition,
the position of the substituent plays a crucial role in induction of
enantioselectivity. Aromatic aldehydes substituted in the ortho po-
sitionproduced the Henryadducts inhigherenantioselectivity(Table
5, entries 3, 5, 8, 9 and 12) than those with para (Table 5, entries 4,
11 and 14) or meta (Table 5, entries 1, 6, 10 and 13) substituents.
Electronic properties of substituents on the aromatic ring had a slight
influence on the enantioselectivity. When aliphatic aldehydes 14q
and 14r were chosen as substrates the reactionwas much slower due
4. Experimental
4.1. General
1H and 13C NMR spectra were determined at 400 and 100 MHz,
respectively, with a Varian Gemini spectrometer. Chemical shifts (d)
were 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 LTQ Orbitrap Velos (Thermo Scientific) spec-
trometer. Infrared spectra were obtained by using a Magna
FTIRd760 Nicolet apparatus. Elemental analyses were recorded
with a PerkineElmer 2400-CHN analyzer and the results for in-
dicated elements were within 0.3% of the calculated values. Optical
rotation values were measured at room temperature with a Per-
kineElmer polarimeter. The ee values were determined by HPLC
(Knauer) analysis by using a chiral stationary phase column (Chir-
alcel OD-H or Chiralcel AD-H), and elution with isopropanol/hex-
anes. Thin layer chromatography (TLC) was carried out on
aluminium sheets percolated with silica gel 60 F254 (Merck). Col-
umn chromatography separations were performed by using Merck
Kieselgel 60 (0.040e0.060 mm). Solvents were dried and distilled
according to standard procedures. 3-Chloro-5,6-diphenyl-1,2,4-
triazine20 (5a), 3-bromo-5-phenyl-1,2,4-triazine21 (5b) and 3-
chloro-5-tert-butyl-1,2,4-triazine26 (5e) were synthesised accord-
ing to literature procedures.
to the electronic and steric effect of the sp3-hybridized
atom (Table 5, entries 17 and 18).
a-carbon
To examine the role of the 1,2,4-triazine moiety on the catalytic
efficiency, we designed analogous ligands 9l and 9m for control ex-
periments. Comparison studies using these ligands revealed that the
presence of the 1,2,4-triazine ring in the ligand structure is crucial for
the reaction efficiency and enantioselectivity (Table 6). Product 16a
was obtained in significantly lower yield and ee in reactions cata-
lyzed by ligands 9l and 9m (Table 6, entries 1 and 2). Only traces of
Henry adduct 16e were detected when 2-chlorobenzaldehyde (14e)
was subjected to addition of nitromethane in the presence of catalyst
derived from 9m (Table 6, entry 3). Utility of triazine ligand 9f led to
product 16e in 87% yield and 75% ee.
Table 6
The Henry reaction in the presence of ligands 9l and 9ma
4.2. Synthesis of 3-bromo-5,6-diphenyl-1,2,4-triazine 5b
5,6-Diphenyl-3-hydroxy-1,2,4-triazine (2 g, 8.0 mmol) was dis-
solved in dichloromethane (32 mL) and solution of phosphorus
oxybromide (3.5 g, 12.0 mmol) in dichloromethane (5 mL) was
added dropwise followed by addition of N,N-dimethylaniline
(1.1 mL, 8.8 mmol). The reaction mixture was refluxed for 1 h, then
the solvent was removed by distillation and the residue was poured
into iced-water. The formed precipitate was filtered of and the
product was purified by silica gel column chromatography using
hexanes/EtOAc (5:1) to produce 5b as a yellow solid, yield 72%
(1.8 g). Mp 154e155 ꢀC. 1H NMR (400 MHz, CDCl3)
(m, 10H). 13C NMR (100 MHz, CDCl3)
: 158.2, 157.0, 154.9, 134.6,
134.3, 131.9, 130.5, 130.3, 129.7, 129.2, 129.0. Anal. Calcd for
15H10BrN3 (311.01): C, 57.71; H, 3.23; N, 13.46; found: C, 57.65; H,
d: 7.58e7.32
d
Ligand
R
Aldehyde
Product
Yieldb (%)
eec (%)
C
1
2
3
9l
9m
9m
3-NO2C6H4
3-NO2C6H4
2-ClC6H4
14a
14a
14e
16a
16a
16e
21
44
Traces
27 (S)
33 (S)
d
3.13; N, 13.46.
4.3. General procedure for the reaction of 3-bromo-5,6-
diphenyl-1,2,4-triazine (5b) with amines 11aec
a
All reactions were performed on a 0.5 mmol scale with 5 mol % of ligand and
5 mol % of Cu(OAc)2$H2O in 2 mL of 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
3-Bromo-5,6-diphenyl-1,2,4-triazine (5b) (100 mg, 0.32 mmol),
amine 10aec (0.64 mmol) and K2CO3 (132 mg, 0.96 mmol) were
refluxed in dioxane (5 mL) until the triazine substrate was con-
sumed (TLC control). The mixture was filtered off and the products
11aec were purified as described below.
absolute configuration was assigned by comparing their specific rotations or the
HPLC elution order with data from the literature.3e
3. Conclusion
In conclusion, we have demonstrated the synthesis and appli-
cation of new chiral oxazoline ligands incorporating a 1,2,4-triazine
4.3.1. 5,6-Diphenyl-3-(pyrrolidin-1-yl)-1,2,4-triazine
compound was prepared according to the General Procedure and
(11a). This

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E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7274
purified by column chromatography (CH2Cl2/acetone 100:1) and
recrystallized from ethanol to give a yellow solid (89 mg, 92% yield).
Mp 187e188 ꢀC. IR (KBr) nmax: 3055, 2976, 2946, 2864, 1540,
DMSO-d6) d: 185.12, 181.03, 175.7, 168.7, 158.0, 147.9, 137.9, 135.9,
135.6, 130.2, 129.4, 128.9, 128.2, 128.1, 118.1, 113.1.
1477 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d: 7.53e7.52 (m, 1H),
4.4.2. 5,6-Diphenyl-3-[(pyridin-2-yl)amino]-1,2,4-triazine
(13b). Compound 13b was prepared from 2-aminopyridine accord-
ing to Method A as a yellow solid (yield 58%, 94 mg). Mp 138e139 ꢀC.
IR (KBr) nmax: 3217, 2993,1590,1508 cmꢁ1.1H NMR (400 MHz, DMSO-
7.51e7.50 (m, 1H), 7.45e7.42 (m, 2H), 7.39e7.36 (m, 1H), 7.32e7.31
(m, 1H), 7.31e7.27 (m, 4H), 3.40 (br s, 4H), 2.07 (br s, 4H). 13C NMR
(100 MHz, CDCl3) d: 158.3, 156.0, 147.8, 136.9, 136.7, 129.9, 129.6,
129.1, 128.1, 127.9, 46.5, 25.4. Anal. Calcd for C19H18N4 (302.37): C,
75.47; H, 6.00; N, 18.53; found: C, 75.36; H, 6.06; N, 18.43.
d6)
d
: 10.65 (s,1H), 8.40 (ddd, J¼0.8,1.6, 4.8 Hz,1H), 8.29 (d, J¼8.4 Hz,
1H), 7.87 (ddd, J¼2.0, 7.2, 8.4 Hz, 1H), 7.56e7.41 (m, 10H), 7.11 (ddd,
J¼0.8, 4.8, 7.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d: 162.1, 158.1,
4.3.2. 2-(5,6-Diphenyl-1,2,4-triazin-3-ylamino)ethanol (11b). This
compound was prepared according to the General Procedure and
purified by column chromatography (CH2Cl2/MeOH 20:1) and
recrystallized from ethanol to give a yellow solid (85 mg, 91% yield).
Mp 162e164 ꢀC. IR (KBr) nmax: 3423, 3255, 3083, 2933, 1595,
155.9, 152.4, 150.9, 148.1, 137.9, 135.9, 135.7, 130.3, 129.5, 129.1, 128.6,
128.3,118.2,113.2. Anal. CalcdforC20H15N5 (325.13): C, 73.83;H, 4.65;
N, 21.52; found C, 73.59; H, 4.63; N, 21.39.
4.4.3. 5,6-Diphenyl-3-[(pyridin-3-yl)amino]-1,2,4-triazine
(13c). Compound 13c was prepared from 3-aminopyridine
according to Method A as a yellow solid (yield 47%, 76 mg). Mp
1524 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6)
d
: 7.83 (br s, 1H),
7.42e7.33 (m, 10H), 4.74 (t, J¼5.2 Hz, 1H), 3.63e3.60 (m, 2H), 3.53
(br s, 2H). 13C NMR (100 MHz, DMSO-d6)
: 159.1, 157.8, 155.3, 136.9,
136.8, 131.2, 130.1, 129.7, 129.2, 129.1, 60.2, 43.7. Anal. Calcd for
17H16N4O$1/4H2O (296.84): C, 68.79; H, 5.60; N, 18.87; found: C,
d
202e203 ꢀC. IR (KBr) nmax: 3255, 3057, 3023, 2912, 1616, 1518 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6)
8.30 (ddd, J¼1.6, 2.4, 8.4 Hz, 1H), 8.24 (dd, J¼1.2, 4.8 Hz, 1H),
7.51e7.37 (m, 11H). 13C NMR (100 MHz, DMSO-d6)
: 158.6, 156.1,
d: 10.54 (s, 1H), 9.0 (d, J¼2.4 Hz, 1H),
C
68.77; H, 5.41; N, 18.85.
d
150.6, 143.1, 141.1, 136.4, 135.9, 135.8, 130.3, 129.4, 129.0, 128.5,
128.3, 128.2, 125.9, 123.5. Anal. Calcd for C20H15N5 (325.13): C,
73.83; H, 4.65; N, 21.52; found C, 73.82; H, 4.69; N, 21.42.
4.3.3. N-(4-Aminobenzyl)-5,6-diphenyl-1,2,4-triazin-3-amine
(11c). This compound was prepared according to the General
Procedure. After filtration the product precipitated from
dioxane was filtered of and washed with dioxane. Yield 79%
(89 mg). Mp 196e197 ꢀC. IR (KBr) nmax: 3460, 3373, 3228, 3069,
4.4.4. 5,6-Diphenyl-3-[(pyridin-4-yl)amino]-1,2,4-triazine
(13d). Compound 13d was prepared from 4-aminopyridine
according to Method A as a yellow solid (yield 83%, 135 mg). Mp
235e236 ꢀC. IR (KBr) nmax: 3263, 3032, 2923, 1597, 1509 cmꢁ1. 1H
2995, 1595, 1519 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 8.30 (br s,
1H), 7.41e7.34 (m, 10H), 7.07 (d, J¼8.4 Hz, 2H), 6.51 (d, J¼8.4 Hz,
2H), 4.93 (s, 2H), 4.24 (br s, 2H). 13C NMR (100 MHz,
NMR (400 MHz, DMSO-d6)
d
: 10.83 (s, 1H), 8.48 (d, J¼6.2 Hz, 2H),
CF3COODebenzene)
d: 168.3, 152.3, 149.5, 138.8, 134.9, 133.3, 132.0,
7.89 (d, J¼6.2 Hz, 1H), 7.57e7.42 (m, 10H). 13C NMR (100 MHz,
131.5, 131.0, 130.2, 129.3, 129.1, 128.7, 128.2, 128.0, 44.8. Anal. Calcd
for C22H19N5 (353.42): C, 74.77; H, 5.42; N,19.82; found: C, 74.54; H,
5.52; N, 19.59.
DMSO-d6) d: 159.4, 157.1, 152.2, 151.1, 147.3, 136.7, 136.5, 131.4, 130.4,
130.0, 129.6, 129.3, 129.2, 113.8. Anal. Calcd for C20H15N5$1/4H2O
(329.63): C, 72.82; H, 4.73; N, 21.23; found C, 72.96; H, 4.85; N,
21.28.
4.4. General procedure for the BuchwaldeHartwig palladium
amination of 3-halo-5,6-diphenyl-1,2,4-triazines 5a and 5b
4.4.5. 5,6-Diphenyl-3-[(pyrazinyl)amino]-1,2,4-triazine
(13e). Compound 13e was prepared from aminopyrazine according
to Method A as a yellow solid (yield 75%, 122 mg). Mp 215e216 ꢀC.
Method A. A two-necked flask flushed with argon was charged
with anhydrous dioxane (4 mL) and Xantphos (57.8 mg, 20 mol %).
After degassing, Pd(OAc)2 (11.2 mg, 10 mol %) was added and the
mixture was stirred under argon for 15 min at room temperature to
generate the catalyst. In a second flask, 3-chloro-5,6-diphenyl-
1,2,4-triazine (134 mg, 0.5 mmol), appropriate heteroamine
(0.55 mmol), K2CO3 (1.38 g, 10 mmol) and dioxane (5 mL) were
placed. The solution of generated catalyst was transferred and the
resulting mixture was subsequently heated at reflux under argon
until 3-chloro-5,6-diphenyl-1,2,4-triazine was consumed (TLC).
After cooling, the residue was filtered off through Celite and the
product was purified by column chromatography.
Method B. 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 %), heteroarylamine (0.6 mmol), 3-halo-5,6-
diphenyl-1,2,4-triazine 5a or 5b (0.5 mmol) and K2CO3 (1.38 g,
10 mmol). Then, the flask was evacuated and backfilled with argon.
Dioxane (10 mL) was added trough the septum. The mixture was
refluxed until the 3-halo-5,6-diphenyl-1,2,4-triazine disappeared
(TLC). After cooling, the solid material was filtered off and washed
with CH2Cl2. The solvent was evaporated, and the resulting crude
product was purified by column chromatography.
IR (KBr) nmax: 3214, 3058, 1571, 1510 cmꢁ1 1H NMR (400 MHz,
.
DMSO-d6)
d
: 11.05 (s, 1H), 9.49 (d, J¼1.3 Hz, 1H), 8.41 (dd, J¼1.5,
2.4 Hz, 1H), 8.30 (d, J¼2.6 Hz, 1H), 7.52e7.38 (m, 10H). 13C NMR
(100 MHz, DMSO-d6) d: 158.7, 157.1, 152.5, 150.3, 143.4, 139.2, 137.2,
136.7,136.5,131.4,130.4,130.0,129.7,129.3. Anal. Calcd for C19H14N6
(326.13): C, 69.92; H, 4.32; N, 25.75; found C, 69.81; H, 4.26; N,
25.61.
4.4.6. 5,6-Diphenyl-3-[2-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]
amino-1,2,4-triazine (13g). Compound 13g was prepared from 2-
(4,5-dihydro-1,3-oxazol-2-yl)aniline (12g) and 3-bromo-5,6-
diphenyl-1,2,4-triazine according to Method B as a yellow solid
(yield 68%,134 mg). Mp 213e214 ꢀC. IR (KBr) nmax: 2908, 1637, 1556,
1509 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d: 12.69 (s, 1H), 9.02 (d,
J¼8.6 Hz, 1H), 7.93 (dd, J¼1.6, 8.0 Hz, 1H), 7.59e7.57 (m, 2H),
7.54e7.49 (m, 3H), 7.43e7.41 (m, 1H), 7.37e7.33 (m, 5H), 7.07e7.03
(m, 1H), 4.41 (t, J¼8.8 Hz, 2H), 4.24 (t, J¼8.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d: 164.6, 158.9, 156.2, 150.9, 140.6, 136.1, 136.0,
132.3, 130.4, 129.8, 129.5, 129.2, 128.6, 128.3, 120.8, 118.9, 113.0, 66.1,
54.9. Anal. Calcd for C24H19N5O (393.16): C, 73.27; H, 4.87; N, 17.80;
found C, 73.17; H, 4.79; N, 17.60.
4.4.1. 5,6-Diphenyl-3-phenylamino-1,2,4-triazine (13a). Compound
13a was prepared from aniline according to Method A as a yellow
solid (yield 68%, 110 mg). Mp 225e226 ꢀC. (Lit.27 mp 230 ꢀC). 1H
4.5. General procedure for the synthesis of 2-(o-amino-
phenyl)oxazolines 6aed
NMR (400 MHz, DMSO-d6)
d
: 10.34 (s, 1H), 7.85 (d, J¼7.6 Hz, 1H),
Method A. An oven dried two-necked flask was washed with
argon and charged with 2-aminobenzonitrile (118 mg, 1 mmol), the
7.50e7.34 (m, 13H), 7.03 (t, J¼7.2 Hz, 1H). 13C NMR (100 MHz,

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E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7275
appropriate amino alcohol (1.5 mmol), 1 M solution of ZnCl2 in Et2O
(0.2 mL, 0.2 mmol) and anhydrous chlorobenzene (6 mL). The
mixture was stirred under reflux for 5 days. The solvent was then
removed under reduced pressure and the product was purified by
flash column chromatography on silica gel.
Method B. An oven dried two-necked flask was washed with
argon and charged with 2-aminobenzonitrile (118 mg, 1 mmol), the
appropriate amino alcohol (1.5 mmol), freshly flame dried ZnCl2
(405 mg, 3 mmol) and anhydrous chlorobenzene (6 mL). The
mixture was stirred under reflux for 24 h. The solvent was then
removed under reduced pressure and the residue was stirred with
30% NaOH for 0.5 h. The product was extracted with dichloro-
methane and purified by flash column chromatography on
silica gel.
3-bromo-5,6-diphenyl-1,2,4-triazine (5b) and 2-[(4S)-4-phenyl-
4,5-dihydro-1,3-oxazol-2-yl]aniline (6b) as a yellow solid, yield 54%
(127 mg). Mp 164e165 ꢀC. IR (KBr) nmax: 3031, 1631, 1612, 1550,
1514 cmꢁ1. [
a
]
D
20 þ270.5 (c 0.85, CHCl3). 1H NMR (400 MHz, CDCl3)
d
: 12.64 (s, 1H), 8.94 (d, J¼8.4 Hz, 1H), 8.03 (dd, J¼1.6, 8.0 Hz, 1H),
7.60e7.54 (m, 3H), 7.50e7.48 (m, 2H), 7.44e7.30 (m, 11H), 7.13 (t,
J¼7.2 Hz, 1H), 5.66 (dd, J¼8.4, 10.0 Hz, 1H), 4.87 (dd, J¼10.0, 8.4 Hz,
1H), 4.34 (t, J¼8.4 Hz,1H). 13C NMR (100 MHz, CDCl3)
d: 164.7,158.8,
156.1, 150.9, 142.0, 140.9, 136.1, 136.0, 132.6, 130.4, 129.8, 129.6,
129.2, 128.7, 128.6, 128.4, 128.3, 127.5, 126.4, 120.9, 119.1, 112.9, 73.2,
69.8. Anal. Calcd for C30H23N5O (469.54): C, 76.74; H, 4.94; N, 14.92;
found C, 76.74; H, 4.98; N, 14.88.
4.6.3. 5,6-Diphenyl-3-{2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-
2-yl]phenyl}amino-1,2,4-triazine (9c). The product was obtained
from 3-bromo-5,6-diphenyl-1,2,4-triazine (5b) and 2-[(4S)-4-
4.5.1. 2-[(4S)-4-tert-Butyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(6a). Compound 6a was prepared from S-tert-leucinol (175 mg,
1.5 mmol) according to method A (yield 74%, 161 mg) or method B
(yield 99%, 216 mg) after purification by silica gel chromatography
(hexane/EtOAc, 5:1). All the physical and spectroscopic data are
with agreement with the published ones.23b
isopropyl-4,5-dihydro-1,3-oxazol-2-yl]aniline (6c) as
a yellow
solid, yield 68% (148 mg). Mp 172e173 ꢀC. IR (KBr) nmax: 2958, 1630,
20
1551, 1519 cmꢁ1. [
a
]
ꢁ11.9 (c 1.02, CHCl3). 1H NMR (400 MHz,
D
CDCl3)
d
: 12.98 (s, 1H), 9.03 (d, J¼8.4 Hz, 1H), 7.91 (dd, J¼1.2, 8.0 Hz,
1H), 7.61e7.59 (m, 2H), 7.54e7.50 (m, 3H), 7.44e7.40 (m, 1H),
7.36e7.31 (m, 5H), 7.04 (t, J¼8.0 Hz, 1H), 4.45 (t, J¼8.4 Hz, 1H),
4.26e4.20 (m, 1H), 4.10 (t, J¼8.4 Hz, 1H), 1.85 (m, 1H), 1.18 (d,
4.5.2. 2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(6b). Compound 6b was prepared from S-phenylglycinol (205 mg,
1.5 mmol) according to method A (yield 73%, 174 mg) or method B
(yield 87%, 207 mg) after purification by silica gel chromatography
(hexane/EtOAc, 5:1). All the physical and spectroscopic data are
with agreement with the published ones.23b
J¼6.6 Hz, 3H), 1.04 (d, J¼6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d:
163.7, 159.2, 156.4, 151.2, 141.1, 136.5, 136.4, 132.7, 130.7, 130.1, 129.7,
129.6, 128.9, 128.7, 128.6, 121.0, 119.2, 113.3, 73.2, 70.0, 33.9, 19.35,
19.32. Anal. Calcd for C27H25N5O (435.52): C, 74.46; H, 5.79; N,
16.08; found: C, 74.38; H, 5.70; N, 15.97.
4.5.3. 2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(6c). Compound 6c was prepared from S-valinol (155 mg,
1.5 mmol) according to method A (yield 73%, 149 mg) after purifi-
cation by silica gel chromatography (hexane/EtOAc, 5:1). All the
physical and spectroscopic data are with agreement with the
published ones.23b
4.6.4. 5,6-Diphenyl-3-{2-[(4R)-4-benzyl-4,5-dihydro-1,3-oxazol-2-
yl]phenyl}amino-1,2,4-triazine (9d). The product was obtained from
3-bromo-5,6-diphenyl-1,2,4-triazine (5b) and 2-[(4R)-4-benzyl-
4,5-dihydro-1,3-oxazol-2-yl]aniline (6d) as a yellow solid, yield 43%
(104 mg). Mp 181e182 ꢀC. IR (KBr) nmax: 3057, 3028, 2931, 1627,
20
1553, 1508 cmꢁ1. [
a]
ꢁ37.0 (c 0.96, CHCl3). 1H NMR (400 MHz,
D
CDCl3)
d
: 12.65 (s, 1H), 9.02 (d, J¼8.4 Hz, 1H), 7.91 (dd, J¼8.0, 1.6 Hz,
4.5.4. 2-[(4R)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(6d). Compound 6d was prepared from R-phenylalaninol (155 mg,
1.5 mmol) according to method A (yield 71%, 179 mg) after purifi-
cation by silica gel chromatography (hexane/EtOAc, 5:1). All the
physical and spectroscopic data are with agreement with the
published ones.23b
1H), 7.59e7.54 (m, 2H), 7.53e7.50 (m, 3H), 7.46e7.43 (m, 1H),
7.37e7.31 (m, 7H), 7.27e7.24 (m, 2H), 7.20e7.16 (m, 1H), 7.07e7.03
(m, 1H), 4.80e4.72 (m, 1H), 4.39 (t, J¼9.0 Hz, 1H), 4.14 (t, J¼9.0 Hz,
1H), 3.28 (dd, J¼6.0, 14.0 Hz, 1H), 2.86 (dd, J¼7.6, 14 Hz, 1H). 13C
NMR (100 MHz, CDCl3) d: 163.8, 159.0, 156.2, 150.9, 140.7, 137.8,
136.1, 136.1, 132.4, 130.3, 129.8, 129.4, 129.3, 129.2, 128.6, 128.5,
128.3, 126.5, 120.8, 118.9, 112.9, 70.5, 67.9, 41.8. Anal. Calcd for
4.6. General procedure for the preparation of ligands 9aek, 9l
C31H25N5O (483.56): C, 77.00; H, 5.21; N, 14.48; found: C, 76.97; H,
and 9m
5.23; N, 14.42.
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-(4,5-dihydro-1,3-oxazol-2-yl)aniline 6aed (0.6 mmol),
3-halo-1,2,4-triazine 5bed (0.5 mmol) and K2CO3 (1.38 g,10 mmol).
Then, the flask was evacuated and backfilled with argon. Dioxane
(10 mL) was added through the septum. The mixture was refluxed
for 24 h. After cooling, the solid material was filtered off and
washed with CH2Cl2. The solvent was evaporated, and the resulting
crude product was purified by column chromatography using
hexanes/ethyl acetate (10:1) as eluent.
4.6.5. 3-{2-[(4S)-4-tert-Butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
amino-5-phenyl-1,2,4-triazine (9e). The product was obtained from
3-bromo-5-phenyl-1,2,4-triazine (5c) and 2-[(4S)-4-tert-butyl-4,5-
dihydro-1,3-oxazol-2-yl]aniline (6a) as a yellow solid, yield 28%
(53 mg). Mp 151e152 ꢀC. IR (KBr) nmax: 2965, 2903, 2868, 1641,
20
1525, 1507 cmꢁ1. [
a
]
þ21.3 (c 1.02, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3)
d
: 12.93 (s, 1H), 9.23 (s, 1H), 9.03 (d, J¼8.4 Hz, 1H), 8.18 (dd,
J¼1.6, 7.6 Hz, 2H), 7.90 (dd, J¼1.6, 8.0 Hz, 1H), 7.59e7.52 (m, 4H),
7.05 (dt, J¼0.8, 7.6 Hz, 1H), 4.39e4.19 (m, 3H), 1.06 (s, 1H). 13C NMR
(100 MHz, CDCl3) d: 163.3, 160.4, 155.5, 140.8, 139.0, 134.0, 132.3,
132.1, 129.3, 129.1, 127.4, 120.7, 119.0, 112.9, 76.2, 67.4, 34.0, 25.9.
Anal. Calcd for C22H23N5O (373.45): C, 70.76; H, 6.21; N, 18.75;
found: C, 70.78; H, 6.19; N, 18.68.
4.6.1. 5,6-Diphenyl-3-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-
2-yl]phenyl}amino-1,2,4-triazine (9a). The product was obtained
from 3-bromo-5,6-diphenyl-1,2,4-triazine (5b) and 2-[(4S)-4-tert-
butyl-4,5-dihydro-1,3-oxazol-2-yl]aniline (6a) as a yellow solid,
yield 42% (95 mg). All the physical and spectroscopic data were
published by us previously.24
4.6.6. 3-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
amino-5-phenyl-1,2,4-triazine (9f). The product was obtained from
3-bromo-5-phenyl-1,2,4-triazine (5c) and 2-[(4S)-4-phenyl-4,5-
dihydro-1,3-oxazol-2-yl]aniline (6b) as a yellow solid, yield 56%
(112 mg). Mp 147e148 ꢀC. IR (KBr) nmax: 3026, 1636, 1618,
4.6.2. 5,6-Diphenyl-3-{2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-
yl]phenyl}amino-1,2,4-triazine (9b). The product was obtained from
1522 cmꢁ1. [
a
]
20 þ321.6 (c 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d:
D

ꢀ
E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7276
12.68 (s, 1H), 9.23 (s, 1H), 9.02 (d, J¼8.4 Hz, 1H), 8.15 (dd, J¼1.6,
8.0 Hz, 2H), 7.99 (dd, J¼1.6, 8.0 Hz, 1H), 7.61e7.51 (m, 4H), 7.43e7.36
(m, 4H), 7.33e7.28 (m, 1H), 7.10 (dt, J¼0.8, 8.0 Hz, 1H), 5.65 (dd,
J¼8.8, 10.0 Hz, 1H), 4.82 (dd, J¼8.4, 10.0 Hz, 1H), 4.27 (t, J¼8.4 Hz,
28.7, 19.1, 18.9. HRMS (ESI, m/z): Calcd for C19H25N5ONa ([MþNa]þ),
362.1951, found 362.1942.
4.6.11. 5-tert-Butyl-3-{2-[(4R)-4-benzyl-4,5-dihydro-1,3-oxazol-2-
yl]phenyl}amino-1,2,4-triazine (9k). The product was obtained from
3-chloro-5-tert-butyl-1,2,4-triazine (5d) and 2-[(4R)-4-benzyl-4,5-
dihydro-1,3-oxazol-2-yl]aniline (6c) as a yellow solid, yield 60%
(116 mg). Mp 89e90 ꢀC. IR (KBr) nmax: 3029, 2967, 1633, 1608,
1H). 13C NMR (100 MHz, CDCl3)
d: 164.7, 160.5, 155.5, 142.0, 140.8,
139.2, 134.0, 132.6, 132.1, 129.6, 129.2, 128.8, 127.5, 126.4, 121.0,
119.2, 113.0, 73.2, 70.0. Anal. Calcd for C24H19N5O (393.44): C, 73.27;
H, 4.87; N, 17.80; found: C, 73.29; H, 4.90; N, 17.64.
1528 cmꢁ1. [
a]
20 ꢁ12.7 (c 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d:
D
4.6.7. 3-{2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}
amino-5-phenyl-1,2,4-triazine (9g). The product was obtained from
3-bromo-5-phenyl-1,2,4-triazine (5c) and 2-[(4S)-4-isopropyl-4,5-
dihydro-1,3-oxazol-2-yl]aniline (6c) as a yellow solid, yield 54%
(98 mg). Mp 138e139 ꢀC. IR (KBr) nmax: 2957, 2895, 2872, 1638,
12.53 (s, 1H), 8.89 (dd, J¼0.4, 8.8 Hz, 1H), 7.87 (dd, J¼1.6, 7.2 Hz, 1H),
7.50 (ddd, J¼1.6, 7.2, 8.8 Hz, 1H), 7.31e7.28 (m, 4H), 7.25e7.21 (m,
1H), 7.02 (ddd, J¼1.2, 8.0, 8.4 Hz, 1H), 4.79e4.72 (m, 1H), 4.35 (t,
J¼8.4 Hz, 1H), 4.11 (t, J¼8.4, 1H), 3.29 (dd, J¼5.4, 14.0 Hz, 1H), 2.85
(dd, J¼8.0, 14.0 Hz, 1H), 1.41 (s, 1H). 13C NMR (100 MHz, CDCl3)
d:
1508 cmꢁ1. [
a
]
D
20 þ20.2 (c 1.01, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d:
169.4, 163.8, 160.1, 140.8, 139.9, 137.7, 132.2, 129.4, 129.3, 128.6,
126.6, 120.6, 118.8, 112.9, 70.4, 67.9, 41.7, 36.7, 28.8. Anal. Calcd for
12.87 (s, 1H), 9.23 (s, 1H), 9.01 (d, J¼8.0 Hz, 1H), 8.17 (d, J¼7.2 Hz,
2H), 7.90 (dd, J¼1.6, 7.6 Hz, 1H), 7.58e7.52 (m, 4H), 7.05 (dt, J¼0.8,
8.4 Hz, 1H), 4.45 (dd, J¼8.4, 9.6 Hz, 1H), 4.27e4.21 (m, 1H), 4.10 (t,
J¼8.4, Hz, 1H), 1.88e1.81 (m, 1H), 1.19 (d, J¼6.4 Hz, 3H), 1.05 (d,
C23H25N5O (387.48): C, 71.29; H, 6.50; N, 18.07; found: C, 71.30; H,
6.43; N, 17.99.
J¼6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
: 163.3, 160.4, 155.4,
4.6.12. N-Phenyl-2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]ani-
line (9l). The product was obtained from bromobenzene and 2-
[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline (6b) as a col-
140.7,139.0,134.0,132.3, 132.1, 129.3,129.1, 127.5, 120.8, 119.0,113.0,
73.0, 69.6, 33.5, 19.0, 18.9. Anal. Calcd for C21H21N5O (359.42): C,
70.17; H, 5.89; N, 19.48; found: C, 70.09; H, 5.88; N, 19.48.
ourless viscous oil, yield 84% (132 mg). IR (KBr) nmax: 3233, 3170,
20
3029, 2923, 2852, 1629, 1592, 1518 cmꢁ1. [
a
]
þ352.3 (c 1.9,
D
4.6.8. 5-tert-Butyl-3-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-
yl]phenyl}amino-1,2,4-triazine (9h). The product was obtained from
3-chloro-5-tert-butyl-1,2,4-triazine (5d) and 2-[(4S)-4-tert-butyl-
4,5-dihydro-1,3-oxazol-2-yl]aniline (6a) as a yellow solid, yield 35%
CH2Cl2). 1H NMR (400 MHz, CDCl3)
d: 10.51 (br s, 1H), 7.90 (dd,
J¼1.2, 7.6 Hz, 1H), 7.39e7.25 (m, 11H), 7.07e7.03 (m, 1H), 6.79 (ddd,
J¼1.2, 6.8, 8.0 Hz, 1H), 5.50 (dd, J¼8.4, 10.0 Hz, 1H), 4.74 (dd, J¼8.0,
10.0 Hz, 1H), 4.17 (t, J¼8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d:
(62 mg). Mp 127e128 ꢀC. IR (KBr) nmax: 3234, 3028, 2958, 2901,
165.1,146.1,142.4,141.3,132.3,130.2,129.2,128.7,127.6,126.5,123.0,
20
2867, 1639, 1615, 1548 cmꢁ1. [
a
]
D
ꢁ0.76 (c 1.02, CH2Cl2). 1H NMR
122.1, 116.9, 113.3, 109.9, 73.2, 70.0. HRMS (ESI, m/z): calcd for
(400 MHz, CDCl3)
d
: 12.72 (s, 1H), 8.98 (d, J¼8.8 Hz, 1H), 8.84 (s, 1H),
C
21H19N2O ([MþH]þ), 315.1492, found 315.1490.
7.87 (dd, J¼1.6, 8.0 Hz,1H), 7.50 (ddd, J¼1.6, 7.2, 8.8 Hz,1H), 7.02 (dt,
J¼0.8, 7.6 Hz, 1H), 4.37e4.33 (m, 1H), 4.25e4.17 (m, 2H), 1.38 (s, 1H),
4.6.13. 3-{2-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}ami-
nobiphenyl (9m). The product was obtained from 3-bromobiphenyl
and 2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]aniline (6b) as
1.02 (s, 1H). 13C NMR (100 MHz, CDCl3)
d: 169.6, 163.3, 159.8, 140.8,
140.1, 132.3, 129.2, 120.5, 119.0, 112.7, 76.2, 67.4, 36.6, 34.0, 28.7,
25.8. Anal. Calcd for C20H27N5O (353.46): C, 67.96; H, 7.70; N, 19.81;
found: C, 67.79; H, 7.61; N, 19.49.
a colourless viscous oil, yield 44% (85 mg). IR (KBr) nmax: 3225, 3057,
20
3028, 2919, 2897, 1629, 1601, 1579 cmꢁ1. [
a]
þ303.1 (c 0.92,
D
CH2Cl2). 1H NMR (400 MHz, CDCl3)
d: 10.58 (br s, 1H), 7.91 (dd,
4.6.9. 5-tert-Butyl-3-{2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]
phenyl}amino-1,2,4-triazine (9i). The product was obtained from 3-
chloro-5-tert-butyl-1,2,4-triazine (5d) and 2-[(4S)-4-phenyl-4,5-
dihydro-1,3-oxazol-2-yl]aniline (6b) as a yellow solid, yield 49%
J¼1.6, 8.0 Hz, 1H), 7.60e7.58 (m, 2H), 7.49 (t, J¼1.6 Hz, 1H),
7.45e7.24 (m, 13H), 6.83e6.79 (m, 1H), 5.51 (dd, J¼8.4, 10.0 Hz, 1H),
4.75 (dd, J¼8.4, 10.0 Hz, 1H), 4.19 (t, J¼8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d: 163.6, 146.1, 142.4, 142.3, 141.7, 140.9, 132.4,
(92 mg). Mp 160e162 ꢀC. IR (KBr) nmax: 3232, 3095, 3020, 2962,
130.3, 129.6, 128.8, 128.7, 127.6, 127.3, 127.1, 126.5, 121.9, 120.9,
20
2904, 1632, 1616, 1525 cmꢁ1. [
a]
þ238.6 (c 1.0, CH2Cl2). 1H NMR
120.8, 117.1, 113.5, 110.1, 73.2, 70.0. HRMS (ESI, m/z): calcd for
D
(400 MHz, CDCl3)
d
: 12.57 (s, 1H), 8.95 (dd, J¼0.6, 8.4 Hz, 1H), 8.85
C
27H23N2O ([MþH]þ), 391.1805, found 391.1804.
(m, 1H), 7.96 (dd, J¼1.6, 8.0 Hz,1H), 7.53 (ddd, J¼2.0, 7.6, 8.8 Hz, 1H),
7.41e7.34 (m, 4H), 7.31e7.29 (m, 1H), 7.06 (ddd, J¼0.8, 7.6, 8.0 Hz,
1H), 5.63 (dd, J¼8.6, 10.2 Hz, 1H), 4.81 (dd, J¼8.6, 10.2 Hz, 1H), 4.25
4.7. General procedure for the catalytic enantioselective
Henry reaction
(t, J¼8.6 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3)
d: 169.5,
164.6, 160.0, 142.0, 140.9, 140.0, 132.5, 129.6, 128.7, 127.5, 126.3,
120.7, 119.0, 112.8, 73.1, 69.8, 36.7, 28.8. Anal. Calcd for C22H23N5O
(373.45): C, 70.76; H, 6.21; N, 18.75; found: C, 70.54; H, 6.17; N,
18.62.
A mixture of Cu(OAc)2$H2O (5 mg, 0.025 mmol, 5 mol %) and
ligand 9aek (0.025 mmol, 5 mol %) in anhydrous 2-propanol (2 mL)
was stirred at room temperature for 4 h under argon atmosphere to
give a red-brown solution. The aldehyde (0.5 mmol) and the ni-
tromethane (270 mL, 5 mmol) were added and the reaction was
4.6.10. 5-tert-Butyl-3-{2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-
2-yl]phenyl}amino-1,2,4-triazine (9j). The product was obtained
from 3-chloro-5-tert-butyl-1,2,4-triazine (5d) and 2-[(4S)-4-
conducted at room temperature for 4 days. Then the solvent was
removed under reduced pressure and the product was isolated by
column chromatography. The ee values of the nitroalcohols 16aer
were determined by chiral HPLC analysis. The absolute configura-
tions of the products were assigned by comparing their specific
rotations or the retention times in HPLC with literature data.3e,25
isopropyl-4,5-dihydro-1,3-oxazol-2-yl]aniline (6c) as
a yellow
solid, yield 70% (119 mg). Mp 89e90 ꢀC. IR (KBr) nmax: 3029, 2956,
2899, 2868, 1636, 1617, 1510 cmꢁ1. [
a
]
D
ꢁ76.3 (c 1.01, CH2Cl2). 1H
20
NMR (400 MHz, CDCl3)
d
: 12.68 (s, 1H), 8.95 (d, J¼8.4 Hz, 1H), 8.83
(s, 1H), 7.87 (dd, J¼1.7, 7.8 Hz, 1H), 7.49 (ddd, J¼1.7, 7.4, 8.8 Hz, 1H),
7.01 (dt, J¼0.9, 8.0 Hz,1H), 4.43 (dd, J¼8.1, 9.4 Hz,1H), 4.22e4.15 (m,
1H), 4.06 (t, J¼8.1 Hz, 1H), 1.87e1.76 (m, 1H), 1.16 (d, J¼6.7, 1H), 1.01
4.7.1. (S)-2-Nitro-1-(3-nitrophenyl)ethanol (16a). Compound 16a
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 2.5:1) to give
(d, J¼6.7 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d: 169.6, 163.4, 159.8,
a colourless solid (100 mg, 95% yield). [
a]
þ20.5 (c 1.25, CH2Cl2).
20
D
20
140.8, 140.0, 132.2, 129.3, 120.5, 118.9, 112.8, 72.9, 69.7, 36.2, 33.6,
[Lit.7h
[a
]
þ36.2 (c 1.25, CH2Cl2), 81% ee]. 1H NMR (400 MHz,
D

ꢀ
E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7277
CDCl3)
d
: 8.33 (s, 1H), 8.23 (d, J¼8.0 Hz, 1H), 7.77 (d, J¼7.6 Hz, 1H),
1H). HPLC3e (Chiralcel OD-H, hexane/i-PrOH 90:10, flow rate:
1.0 mL/min,
¼215 nm), tminor¼10.6, tmajor¼11.0, 82% ee.
7.62 (t, J¼8.0 Hz, 1H), 5.62e5.59 (m, 1H), 4.66e4.56 (m, 2H), 3.12 (d,
l
J¼4.0 Hz, 1H). HPLC3e (Chiralcel OD-H, hexane/i-PrOH 90:10, flow
rate: 1.0 mL/min,
l¼215 nm), tminor¼28.2, tmajor¼32.4, 46% ee.
4.7.8. (S)-1-(2-Methylphenyl)-2-nitroethanol (16i). Compound 16i
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 10:1) to give
4.7.2. (S)-2-Nitro-1-phenylethanol (16b). Compound 16b was ob-
tained according to the general procedure and purified by column
chromatography (hexanes/ethyl acetate 7:1) to give a colourless oil
20
a yellow oil (50 mg, 47% yield). [
a
]
þ28.0 (c 1.01, CH2Cl2). [Lit.3e
D
20
[a
]
þ52.8 (c 1.01, CH2Cl2), 99% ee]. 1H NMR (400 MHz, CDCl3)
d:
D
(50 mg, 60% yield). [
a
]
20 þ23.1 (c 0.96, CH2Cl2). [Lit.3e
[
a
]
20 þ40.2 (c
7.54e7.52 (m, 1H), 7.31e7.25 (m, 2H), 7.20e7.18 (m, 1H), 5.71e5.68
(m, 1H), 4.57 (dd, J¼9.6, 13.4 Hz, 1H), 4.46 (dd, J¼2.8, 13.4 Hz, 1H),
2.64 (d, J¼3.6 Hz, 1H), 2.39 (s, 3H). HPLC3e (Chiralcel OD-H, hexane/
D
D
0.96, CH2Cl2), 98% ee]. 1H NMR (400 MHz, CDCl3)
d
: 7.43e7.34 (m,
5H), 5.45 (dd, J¼4.0, 8.0 Hz, 1H), 4.59 (dd, J¼12.0, 16.0 Hz, 1H), 4.50
(dd, J¼4.0, 12.0 Hz, 1H), 2.85 (br s, 1H). HPLC25a (Chiralcel OD-H,
i-PrOH 90:10, flow rate: 1.0 mL/min,
tmajor¼17.9, 52% ee.
l¼215 nm), tminor¼11.7,
hexane/i-PrOH 85:15, flow rate: 1.0 mL/min,
tminor¼10.3, tmajor¼12.2, 52% ee.
l¼215 nm),
4.7.9. (S)-1-(3-Methylphenyl)-2-nitroethanol (16j). Compound 16j
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 8:1) to give a yel-
4.7.3. (S)-2-Nitro-1-(2-nitrophenyl)ethanol (16c). Compound 16c
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 5:1) to give
20
20
low oil (54 mg, 59% yield). [
a
]
þ21.2 (c 0.5, CH2Cl2). [Lit.3e
[a]
D
D
þ38.8 (c 0.50, CH2Cl2), 98% ee]. 1H NMR (400 MHz, CDCl3)
d: 7.29 (t,
20
a brown solid (95 mg, 90% yield). [
a
]
D
ꢁ121.9 (c 0.23, CH2Cl2).
[Lit.7h
[a]
ꢁ169.4 (c 0.22, CH2Cl2), 87% ee]. 1H NMR (400 MHz,
20
J¼7.6 Hz, 1H), 7.22e7.17 (m, 3H), 5.43 (dd, J¼3.2, 9.6 Hz, 1H), 4.61
(dd, J¼9.6, 13.6 Hz, 1H), 4.51 (dd, J¼3.2, 13.6 Hz, 1H), 2.75 (br s, 1H),
2.38 (s, 3H). HPLC3e (Chiralcel OD-H, hexane/i-PrOH 90:10, flow
D
CDCl3)
d
: 8.08 (dd, J¼1.2, 8.0 Hz, 1H), 7.95 (dd, J¼1.2, 8.0 Hz, 1H),
7.77e7.73 (m, 1H), 7.58e7.54 (m, 1H), 6.08e6.04 (m, 1H), 4.87 (dd,
J¼2.4, 14.0 Hz, 1H), 4.55 (dd, J¼8.8, 14.0 Hz, 1H), 3.14 (d, J¼4.0 Hz,
1H). HPLC25b (Chiralcel OD-H, hexane/i-PrOH 90:10, flow rate:
rate: 1.0 mL/min,
l¼215 nm), tminor¼12.0, tmajor¼13.9, 48% ee.
1.0 mL/min,
l¼215 nm), tminor¼15.9, tmajor¼17.9, 69% ee.
4.7.10. (S)-1-(4-Methylphenyl)-2-nitroethanol
16k was obtained according to the general procedure and purified
(16k). Compound
by column chromatography (hexanes/ethyl acetate 5:1) to give
4.7.4. (S)-2-Nitro-1-(4-nitrophenyl)ethanol (16d). Compound 16d
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 5:1) to give a col-
20
a yellow oil (43 mg, 47% yield). [
a
]
þ10.9 (c 1.10, CH2Cl2). [Lit.3e
D
20
[a
]
þ24.8 (c 1.10, CH2Cl2), 98% ee]. 1H NMR (400 MHz, CDCl3)
d:
D
ourless solid (85 mg, 82% yield). [
a
]
D
þ21.0 (c 1.0, CH2Cl2). [Lit.3e
20
7.29 (d, J¼8.0 Hz, 2H), 7.21 (d, J¼8.0 Hz, 2H), 5.43 (dd, J¼2.8, 9.6 Hz,
1H), 4.61 (dd, J¼9.6, 13.2 Hz, 1H), 4.50 (dd, J¼2.8, 13.2 Hz, 1H), 2.69
(br s, 1H), 2.37 (s, 3H). HPLC3e (Chiralcel OD-H, hexane/i-PrOH
20
[
a]
þ36.1 (c 0.98, CH2Cl2), 95% ee]. 1H NMR (400 MHz, CDCl3)
d:
D
8.27 (d, J¼8.4 Hz, 2H), 7.62 (d, J¼8.4 Hz, 2H), 5.61e5.58 (m, 1H),
4.64e4.55 (m, 2H), 3.08 (d, J¼4.0 Hz, 1H). HPLC25b (Chiralcel OD-H,
90:10, flow rate: 1.0 mL/min,
43% ee.
l¼215 nm), tminor¼14.4, tmajor¼18.4,
hexane/i-PrOH 85:15, flow rate: 1.0 mL/min,
tminor¼17.8, tmajor¼22.3, 46% ee.
l¼215 nm),
4.7.11. (S)-1-(2-Methoxyphenyl)-2-nitroethanol (16l). Compound
16l was obtained according to the general procedure and purified
by column chromatography (hexanes/ethyl acetate 10:1) to give
4.7.5. (S)-1-(2-Chlorophenyl)-2-nitroethanol (16e). Compound 16e
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 7:1) to give a col-
20
a yellow oil (20 mg, 20% yield). [
a
]
D
þ15.7 (c 1.05, CH2Cl2). [Lit.3e
20
þ45.0 (c 1.05, CH2Cl2), 96% ee]. 1H NMR (400 MHz, CDCl3)
d:
20
ourless oil (87 mg, 87% yield). [a]
þ42.8 (c 1.03, CH2Cl2). [Lit.3e
[a
]
D
D
20
[
a]
þ47.7 (c 1.07, CH2Cl2), 99% ee]. 1H NMR (400 MHz, CDCl3)
d:
7.46e7.43 (m, 1H), 7.35e7.31 (m, 1H), 7.04e6.99 (m, 1H), 6.91 (d,
J¼8.4 Hz, 1H), 5.64 (dd, J¼3.2, 9.2 Hz, 1H), 4.65 (dd, J¼3.2, 13.2 Hz,
1H), 4.58 (dd, J¼9.2, 13.2 Hz, 1H), 3.89 (s, 3H), 3.12 (br s, 1H). HPLC3e
(Chiralcel OD-H, hexane/i-PrOH 90:10, flow rate: 1.0 mL/min,
D
7.66 (dd, J¼2.0, 7.6 Hz, 1H), 7.40e7.31 (m, 3H), 5.87e5.84 (m, 1H),
4.69 (dd, J¼2.4, 14.0 Hz, 1H), 4.46 (dd, J¼9.6, 14.0 Hz, 1H), 2.93 (d,
J¼4.4 Hz, 1H). HPLC3f (Chiralcel OD-H, hexane/i-PrOH 98:2, flow
l¼215 nm), tminor¼11.8, tmajor¼13.9, 67% ee.
rate: 1.0 mL/min,
l
¼215 nm), tminor¼25.0, tmajor¼27.2, 75% ee.
4.7.6. (S)-1-(3-Chlorophenyl)-2-nitroethanol (16f). Compound 16f
was obtained according to the general procedure and purified by
4.7.12. (S)-1-(3-Methoxyphenyl)-2-nitroethanol (16m). Compound
16m was obtained according to the general procedure and purified
column chromatography (hexanes/ethyl acetate 7:1) to give a col-
by column chromatography (hexanes/ethyl acetate 7:1) to give
20
20
ourless oil (65 mg, 65% yield). [
a]
20 þ44.4 (c 0.5, CH2Cl2). [Lit.3e
[a
]
a yellow oil (55 mg, 56% yield). [
a]
þ23.8 (c 0.6, CH2Cl2). [Lit.3e
D
D
D
20
þ73.7 (c 0.48, CH2Cl2), 97% ee]. 1H NMR (400 MHz, CDCl3)
d:
[a
]
þ36.3 (c 0.60, CH2Cl2), 92% ee]. 1H NMR (400 MHz, CDCl3)
d:
D
7.44e7.43 (m, 1H), 7.35e7.34 (m, 2H), 7.30e7.27 (m, 1H), 5.46 (dd,
J¼2.8, 9.2 Hz, 1H), 4.59 (dd, J¼2.8, 9.2 Hz, 1H), 4.52 (dd, J¼3.2,
13.6 Hz, 1H), 2.88 (br s, 1H). HPLC3e (Chiralcel OD-H, hexane/i-PrOH
7.33e7.29 (m, 1H), 6.97e6.95 (m, 2H), 6.91e6.88 (m, 1H), 5.44 (dd,
J¼3.2, 9.6 Hz, 1H), 4.60 (dd, J¼9.6, 13.6 Hz, 1H), 4.50 (dd, J¼3.2,
13.6 Hz, 1H), 3.82 (s, 3H), 2.31 (br s, 1H). HPLC3e (Chiralcel OD-H,
90:10, flow rate: 1.0 mL/min,
58% ee.
l¼215 nm), tminor¼14.1, tmajor¼17.9,
hexane/i-PrOH 90:10, flow rate: 1.0 mL/min,
tminor¼23.9, tmajor¼31.5, 48% ee.
l¼215 nm),
4.7.7. (S)-1-(2-Bromophenyl)-2-nitroethanol (16h). Compound 16h
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 8:1) to give a col-
4 . 7 .13 . ( S ) - 1 - ( 3 , 4 - D i m e t h o x y p h e nyl ) - 2 - n i t r o e t h a n o l
(16o). Compound 16o was obtained according to the general pro-
cedure and purified by column chromatography (hexanes/ethyl
20
ourless oil (94 mg, 76% yield). [
a
]
D
20 þ38.7 (c 0.9, CH2Cl2). [Lit.3e
[a
]
acetate 2.5:1) to give a yellow oil (18 mg, 16% yield). [
a
]
20 þ12.5 (c
D
D
20
þ46.2 (c 0.90, CH2Cl2), 98% ee]. 1H NMR (400 MHz, CDCl3)
d
: 7.67
1.32, CH2Cl2). [Lit.25a
(400 MHz, CDCl3)
[
a]
þ28.1 (c 1.2, CH2Cl2), 82% ee]. 1H NMR
D
(dd, J¼1.6, 7.6 Hz, 1H), 7.57 (dd, J¼1.2, 8.0 Hz, 1H), 7.41 (dt, J¼0.8,
7.2 Hz, 1H), 7.23 (dt, J¼1.6, 7.6 Hz, 2H), 5.83e5.79 (m, 1H), 4.69 (dd,
J¼1.6, 13.6 Hz, 1H), 4.44 (dd, J¼9.6, 13.6 Hz, 1H), 2.94 (d, J¼4.4 Hz,
d
: 6.94e6.85 (m, 3H), 5.42 (dd, J¼4.0, 12.0 Hz,
1H), 4.61 (dd, J¼12.0, 16.0 Hz, 1H), 4.50 (dd, J¼4.0, 12.0 Hz, 1H), 3.90
(s, 3H), 3.89 (s, 3H), 2.74 (br s, 1H). HPLC25a (Chiralcel OD-H,

ꢀ
E. Wolinska / Tetrahedron 69 (2013) 7269e7278
7278
2012, 68, 9119e9124; (c) Gu, L.; Zhou, Y.; Zhang, J.; Gong, Y. Tetrahedron:
Asymmetry 2012, 23, 124e129; (d) Zhou, Y.; Gong, Y. Eur. J. Org. Chem. 2011,
6092e6099; (e) Ji, Y. Q.; Qi, G.; Judeh, Z. M. A. Tetrahedron: Asymmetry 2011, 22,
2065e2070; (f) Kodama, K.; Sugawara, K.; Hirose, T. Chem.dEur. J. 2011, 17,
13584e13592; (g) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007,
2561e2574; (h) Boruwa, J.; Gogoi, P. N.; Saikia, P. P.; Barua, N. C. Tetrahedron:
Asymmetry 2006, 17, 3315e3326.
hexane/i-PrOH 85:15, flow rate: 1.0 mL/min,
tminor¼29.0, tmajor¼38.7, 35% ee.
l
¼215 nm),
4.7.14. (S)-1-(1-Naphthyl)-2-nitroethanol (16p). Compound 16p
was obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 10:1) to give
6. (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505e2550; (b) Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561e3651.
20
a yellow oil (44 mg, 41% yield). [
a]
þ7.57 (c 1.08, CH2Cl2). [Lit.3e
D
20
[
a]
þ26.0 (c 1.06, CH2Cl2), 98% ee]. 1H NMR (400 MHz, CDCl3)
d:
7. (a) Aydin, A. E.; Yuksekdanaci, S. Tetrahedron: Asymmetry 2013, 24, 14e22; (b)
Angulo, B.; García, J. I.; Herrerías, C. I.; Mayoral, J. A.; Mineana, A. C. J. Org. Chem.
2012, 77, 5525e5532; (c) Li, Z.-H.; Zhou, Z.-M.; Hao, X.-Y.; Zhang, J.; Dong, X.;
Liu, Y.-Q. Chirality 2012, 24, 1092e1095; (d) Balaraman, K.; Vasanthan, R.; Ke-
savan, V. Synthesis 2012, 44, 2455e2462; (e) Mao, J.; Nie, X.; Wang, M.; Wang,
Q.; Zheng, B.; Bian, Q.; Hong, J. Tetrahedron: Asymmetry 2012, 23, 965e971; (f)
Zhou, Z.-M.; Li, Z.-H.; Hao, X.-Y.; Zhang, Y.; Dong, X.; Liu, Y.-Q.; Sun, W.-W.;
Caoa, D.; Wanga, J.-L. Org. Biomol. Chem. 2012, 10, 2113e2118; (g) Maggi, R.;
Lanari, D.; Oro, C.; Sartori, G.; Vaccaro, L. Eur. J. Org. Chem. 2011, 5551e5554; (h)
Yang, W.; Du, D.-M. Eur. J. Org. Chem. 2011, 1552e1556; (i) Reddy, B. V. S.;
George, J. Tetrahedron: Asymmetry 2011, 22, 1169e1175; (j) Didier, D.; Magnier-
Bouvier, C.; Schulz, E. Adv. Synth. Catal. 2011, 353, 1087e1095; (k) Lang, K.; Park,
J.; Hong, S. J. Org. Chem. 2010, 75, 6424e6435; (l) Gaab, M.; Bellemin-Laponnaz,
S.; Gade, L. H. Chem.dEur. J. 2009, 15, 5450e5462.
D
8.05 (d, J¼8.8 Hz, 1H), 7.92 (d, J¼8.8 Hz, 1H), 7.87 (d, J¼8.4 Hz, 1H),
7.77 (d, J¼8.8 Hz,1H), 7.62e7.51 (m, 3H), 6.27 (dd, J¼3.6, 8.4 Hz,1H),
4.72e4.64 (m, 2H), 2.87 (br s,1H). HPLC25b (Chiralcel OD-H, hexane/
i-PrOH 90:10, flow rate: 1.0 mL/min,
tmajor¼28.1, 50% ee.
l¼215 nm), tminor¼18.9,
4.7.15. (S)-1-Nitro-4-phenylbutan-2-ol (16q). Compound 16q was
obtained according to the general procedure and purified by
column chromatography (hexanes/ethyl acetate 5:1) to give a col-
20
ourless solid (13 mg, 14% yield). [
a
]
ꢁ8.2 (c 1.00, CH2Cl2). [Lit.3e
D
8. (a) Hargaden, G. C.; O’Sullivan, T. P.; Guiry, P. J. Org. Biomol. Chem. 2008, 6,
562e566; (b) Chai, Z.; Liu, Z.-Y.; Wu, X.-Y.; Zhao, G. Tetrahedron: Asymmetry
2006, 2442e2447; (c) Benaglia, M.; Benincori, T.; Mussini, P.; Pilati, T.; Rizzo, S.;
Sannicolo, F. J. Org. Chem. 2005, 70, 7488e7495; (d) Bonini, B.-F.; Giordano, L.;
20
[
a]
ꢁ14.2 (c 1.00, CH2Cl2), 92% ee]. 1H NMR (400 MHz, CDCl3)
d:
D
7.33e7.29 (m, 2H), 7.24e7.19 (m, 3H), 4.41e4.39 (m, 2H), 4.36e4.28
(m, 1H), 2.90e2.83 (m, 1H), 2.79e2.71 (m, 1H), 2.48 (br s, 1H),
1.92e1.75 (m, 2H). HPLC5a (Chiralpak AD-H, hexane/i-PrOH 95:5,
ꢁ
Fochi, M.; Comes-Franchini, M.; Bernardi, L.; Capito, E.; Ricci, A. Tetrahedron:
ꢁ
Asymmetry 2004, 15, 1043e1051; (e) Bonini, B. F.; Capito, E.; Comes-Franchini,
M.; Ricci, A.; Bottoni, A.; Bernardi, L.; Miscione, G. P.; Giordano, L.; Cowley, A. R.
Eur. J. Org. Chem. 2004, 4442e4451.
flow rate: 0.7 mL/min,
l¼215 nm), tminor¼28.6, tmajor¼36.5, 55% ee.
9. Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076e3077.
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11. McManus, H. A.; Barry, S. M.; Andersson, P. G.; Guiry, P. J. Tetrahedron 2004, 60,
4.7.16. (S)-1-Nitroheksan-2-ol (16r). Compound 16r was obtained
according to the general procedure and purified by column chro-
matography (hexanes/ethyl acetate 5:1) to give a yellow oil (15 mg,
€
3405e3416.
12. Zhang, L.; Yang, G.; Shen, C.; Arghib, S.; Zhang, W. Tetrahedron Lett. 2011, 52,
2375e2378.
20
20
20% yield). [
a
]
þ6.0 (c 0.70, CH2Cl2). [Lit.28
[
d
a
]
þ10.5 (c 0.70,
D
D
CH2Cl2), 98% ee]. 1H NMR (400 MHz, CDCl3)
: 4.44 (dd, J¼2.8,
13. (a) Shibasaki, M.; Matsunaga, S.; Kumagi, N. Synlett 2008, 1583e1602; (b) Kanai,
M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491e1508; (c) Shibasaki,
M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187e2209; (d) Denmark, S. C.;
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Scerba, M. T.; Alden-Danforth, A.; Lectka, T. Acc. Chem. Res. 2008, 41, 655e663.
12.8 Hz, 1H), 4.40e4.28 (m, 2H), 2.01 (br s, 1H), 1.59e1.42 (m, 3H),
1.41e1.32 (m, 3H), 0.92 (t, J¼6.8 Hz, 3H). HPLC25c (Chiralpak AD-H,
hexane/i-PrOH 98:2, flow rate: 0.8 mL/min,
tmajor¼40.6, 56% ee.
l¼215 nm), tminor¼30.4,
€
14. (a) Coeffard, V.; Muller-Bunz, H.; Guiry, P. J. Org. Biomol. Chem. 2009, 7,
1723e1734; (b) Griffit, J. A.; Rowlands, G. J. Synthesis 2005, 3446e3450; (c)
Chang, Y.-W.; Yang, J.-J.; Dang, J.-N.; Xue, Y.-X. Synlett 2007, 2283e2285; (d)
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A. Eur. J. Org. Chem.
2003, 1428e1432; (e) Takacs, J. M.; Reddy, D. S.; Moteki, S. A.; Wu, D.; Palencia,
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Acknowledgements
The authors are grateful to Prof. Andrzej Rykowski for helpful
discussions and to Prof. Zbigniew Ka1uza and his group from the
_
15. (a) Lindsey, C. W.; Layton, M. E. In “Science of Synthesis”, HoubeneWeyl Methods
of Molecular Transformation; Weinreb, S. M., Ed.; Georg Thieme: Stuttgart,
Germany, 2004; Vol. 17, p 357e447; (b) Neunhoeffer, H. In HoubeneWeyl
Methods of Organic Chemistry, 4th ed.; Schaumann, E., Ed.; Thieme: Stuttgart,
Germany, 1998; Vol. E9c, p 582e666.
Institute of Organic Chemistry, Polish Academy of Sciences for the
help in HPLC analyses.
Supplementary data
16. Hudson, M. J.; Drew, M. G. B.; Foreman, M. R. StJ.; Hill, C.; Huet, N.; Madic, C.;
Youngs, T. G. A. Dalton Trans. 2003, 1675e1685.
17. Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, B. L.; Guillaument, G.
J. Org. Chem. 2004, 69, 7809e7815.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.06.084.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
18. (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27e50; (b) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338e6361; (c) Hartwig, J. F. Acc.
Chem. Res. 2008, 41, 1534e1544; (d) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125e146.
ꢀ
19. Wolinska, E. Heterocycles 2009, 78, 623e633.
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