Self-assembly of an organocatalyst for the enantioselective synthesis of Michael adducts and α-aminoxy alcohols in a nonpolar medium

Article abstract of DOI:10.1016/j.tetasy.2013.08.008

A proline-thiourea host-guest complex is described as a self-assembled organocatalyst for the enantioselective Michael addition of aldehydes to nitroolefins and for the asymmetric α-aminoxylation of both aldehydes and ketones. The Michael adducts were obt

Full text of DOI:10.1016/j.tetasy.2013.08.008

Tetrahedron: Asymmetry 24 (2013) 1218–1224
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Self-assembly of an organocatalyst for the enantioselective synthesis
of Michael adducts and a-aminoxy alcohols in a nonpolar medium
Ayhan Sıtkı Demir , Sinan Basceken a,b,
a,
⇑
a
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Department of Chemistry, Hitit University, 19030 Corum, Turkey
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2013
Accepted 14 August 2013
A proline–thiourea host–guest complex is described as a self-assembled organocatalyst for the enantio-
selective Michael addition of aldehydes to nitroolefins and for the asymmetric a-aminoxylation of both
aldehydes and ketones. The Michael adducts were obtained in good yields of up to 80%, high diastereose-
lectivities of up to 5:95, and high enantiomeric excesses of up to 98%. The optically active aminoxy alco-
hols were synthesized in 60–85% yields with 94–99% enantiomeric excesses after reduction of the
oxidation products using NaBH
a-
4
.
Ó 2013 Elsevier Ltd. All rights reserved.
1
. Introduction
The first example of a self-assembled organocatalyst for the Mi-
tially positive nitrogen of the enamine and the partially negative
nitro group should be situated close to each other, due to favorable
electrostatic interactions.
5
chael addition of ketones to nitroalkenes was published by Clarke
and Fuentes et al. in 2007, wherein the addition of achiral guest
additives to a chiral organocatalyst host can transform an unselec-
tive catalyst into a highly effective one through hydrogen-bonding
2
. Results and discussion
We have previously shown the proof-of-principle results of pro-
1
interactions. Subsequently, Zhao and Mandal reported that organ-
line-catalyzed direct asymmetric aldol and Mannich reactions
using bipyridine derived achiral thioureas I or II as additives
ocatalysts formed through the self-assembly of simple
a-amino
7
acids and alkaloid thiourea derivatives could be used as efficient
(Scheme 1). The possibility of fine-tuning these proline–thiourea
catalysts for the nitro-Michael addition of ketones and nitroal-
interactions also presents a potential strategy for asymmetric cat-
alyst development.
2
3
kenes. In earlier work, we described a proline–thiourea self-
assembled organocatalyst for the enantioselective Michael
addition of aldehydes to nitroalkenes. The reaction was efficient
with 5% of the thiourea, with moderate to good enantioselectivity
2
.1. Michael reaction
(
up to 76% ee) being obtained.3
Herein we report the results of the enantioselective Michael
Barbas et al. reported on catalytic acetone addition reactions to
reaction of aldehydes to nitroolefins catalyzed by a self-assembled
b-nitroolefins and alkylidene malonates in DMSO, using (S)-proline
4
as the catalyst. However, only racemic products were obtained.
Most commonly, aprotic solvents are used in proline catalyzed
reactions. Enders et al. anticipated that alcohols, which can homog-
enize the reaction mixture, may be effective for this reaction by
B
host
5
O
A
increasing the amount of dissolved proline. To explain the syn-
N
O
diastereoselectivity and the absolute configuration observed, En-
ders et al. proposed an acyclic synclinal transition state (TS)-A
based on Seebach’s model (Fig. 1).6 In this, all bonds around the
newly formed bond are staggered, with a gauche relationship be-
N
O
O
O
N
H
H
CF3
H
N
O
O
O
R3
N
H
R2
Ar
N
S
R1
R2
tween the donor and the acceptor
p-systems. Additionally, the par-
CF3
N
⇑
Corresponding author. Tel.: +90 (0) 364 227 7000; fax: +90 (0) 364 227 7005.
E-mail address: sinanbasceken@hitit.edu.tr (S. Basceken).
Figure 1. (A) The Seebach model for (S)-proline catalyzed Michael reactions,5,6 (B)
the possible interaction of a bipyridine derived thiourea moiety with (S)-proline in
Deceased on June 24th, 2012.
the TS.
0
957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.08.008

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 1218–1224
1219
H
N
H
N
Table 1
CF3
a
Solvent screening for the enantioselective Michael reaction
Br
*
N
S
CF3
CF3
S
N
O
cocatalyst
O
NO2
I or II
NO2
F3C
N
H
N
H
+
*
solvent
Br
I
CF3
1a
2b
Cat. T [°C] Yield (%) dr (anti/syn)b
3b
eec (%) (Conf.)d
S
Entry Solvent
N
H
N
H
CF3
1
2
3
4
5
6
7
8
9
1
Hexane
Toluene
Benzene
Toluene
Toluene
Hexane
Toluene II
Benzene II
Toluene II
Toluene II
I
I
I
I
I
II
ꢀ30
ꢀ30
+5
+20
+20
ꢀ30
ꢀ30
+5
63 34/66
77 33/67
80 20/80
65 36/64
62 36/64
64 26/74
70 20/80
73 22/78
60 35/65
61 32/68
95
98
90
85
85
62
97
97
70
41
(2R,3S)
(2R,3S)
(2R,3S)
(2S,3R)
(2S,3R)
(2R,3S)
(2R,3S)
(2R,3S)
(2S,3R)
(2S,3R)
N
d
e
N
H
N
H
N
F3C
S
II
d
CF3
+20
+20
0e
Scheme 1. Bipyridine derived achiral thioureas.7
f
By comparison of their specific rotations with those reported.
a
The reactions were conducted with (S)-proline (10 mol %), thiourea I or II
(
(
10 mol %), propionaldehyde (2 equiv 10 lL), trans-4-bromo-b-nitrostyrene
organocatalyst that was formed through a chiral (S)-proline (host)
and bipyridine derived achiral thioureas (guest) I or II.
0.125 mmol), and solvent (1.2 mL) for 24 h.
b
Determined by chiral HPLC analysis of the mixture of the anti/syn product.
Determined by chiral HPLC with an AD-H column.
c
d
e
We began the investigations with acceptor trans-4-bromo-b-
nitrostyrene 2a and donor propionaldehyde 1a under proline catal-
ysis and bipyridine derived thioureas as the additive in a nonpolar
solvent. During the studies, some representative illustrative sol-
vents were screened and the results are summarized in Table 1.
The reactions were performed with 10 mol % of catalyst and
various nonpolar solvents at different temperatures. The yields at
low temperature (ꢀ30 °C) were moderate, but the ee was very high
(
(
S)-tert-Leucine was used as the catalyst.
S)-Tryptophan was used as the catalyst.
assembly with the bipyridine derived thiourea guest, in turn
enhancing the reactivity and selectivity of the catalyst.
(
98% ee). Toluene was the most favorable solvent but all of the
The proposed mechanism of the proline–thiourea catalyzed Mi-
chael reaction is depicted in Scheme 2. This mechanism reflects our
observation that both NH groups of the thiourea moiety and an
acidic proton of proline are required to catalyze this reaction.
The self-assembled host–guest complex of proline–thiourea may
facilitate each individual step of the mechanism, including the
nucleophilic attack of the amino group (a), the dehydration of
the carbinol amine intermediate (b), the carbon–carbon bond
forming step (c), and both steps of the hydrolysis of the imini-
um-Michael intermediate (d and e). Generally, syn-diastereoselec-
solvents gave comparable results. The syn-diastereomer was the
major diastereomer in all cases. We also used (S)-tert-leucine and
(S)-tryptophan as the catalyst and they furnished the same diaste-
reoselectivity but reversed enantioselectivity.
We assumed that the asymmetric Michael reaction occurs via
an enamine mechanism (Fig. 1). In analogy to the mechanism pub-
lished by Enders et al.,5 we proposed that the Michael reaction
6
would proceed according to a modified Seebach model in (TS)-B,
in which the carboxylate moiety of the proline host forms an
R = CH3, R' = Ar
O
R
-
H2O
b
N
+
HN
N
R
O
O
O
H
a
R
H
H
H
H
O
H
O
HO
O
L*
L*
R'
L*
O2N
R'
R
N
β
-nitrostyrene
N
O
N
O
H
O
c
R
O
O
R
O
N
O
O
L*
L*
TS
trans-enamine +trans-
+
H2O
d
β
-nitrostyrene
HN
CF3
L*
=
O2N
R'
O
HN
R'
e
O2N
HN
CF3
N
H
O
S
H
O
+
H
R
R
O
OH
O
L*
L*
syn
N
Scheme 2. Proposed mechanism of the Michael reaction.

1
220
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 1218–1224
Table 2
Michael reaction in good yield (57%) with high enantioselectivity
92%). We then continued to evaluate the scope of the reaction
Catalytic asymmetric Michael reaction of aldehydes to nitroalkenesa
(
R2
by testing the Michael addition of isovaleraldehyde 1c to a nitro-
alkene, which led to good isolated yields and high diastereoselec-
tivities with excellent enantioselectivities (Table 2, entries 7, 14).
We then decided to perform comparative experiments using
pyridine, 2,6-dimethyl pyridine, and bipyridine as additives in
the proline catalyzed enantioselective Michael reaction. However,
we did not obtain any product. This fact clearly demonstrates that
the hydrogen bonding effect of the proline–thiourea, and not the
basicity of the pyridine moiety, plays the most important role in
nonpolar solvents.
Concerning the reverse effect (Table 1, entries 4–5, 9–10), which
was seen with (S)-tert-leucine and (S)-tryptophan, several amino
acids were screened for the preparation of the catalyst and applied
to the Michael addition at different temperatures under unoptim-
ized conditions as shown in Table 3. The diastereoselectivities and
enantioselectivities were good and showed reverse enantioselec-
tivities compared to proline; among them, only (S)-cysteine
showed the same absolute configuration (Table 3, entry 4). The
screening of the amino acids and optimization of the reaction con-
ditions for modularity of the catalyst systems are topics of further
research in our laboratories.
O
cocatalyst
I or II
O
NO2
(
R)
NO2
+
(S)
toluene, -30°C
R1
R2
R1
1a-c
2a-e
3a-g
Entry Aldehyde Nitrostyrene Cat. Yield (%) dr (anti/syn)b eec (%)
1
2
R
R
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CH
CH
CH
CH
CH
CH
3
3
3
3
3
2
H
I
I
I
I
I
I
I
II
II
II
II
II
II
II
70 18/82
77 33/67
54 13/87
93
98
90
97
98
92
95
91
97
90
90
91
92
90
4-Br
4-OMe
2-OMe
2-Br
4-Br
4-Br
H
4-Br
4-OMe
2-OMe
2-Br
4-Br
4-Br
55
9/91
65 18/82
CH
3
57
60
8/92
5/95
CH(CH
3
)
2
CH
3
CH
3
CH
3
CH
3
CH
3
CH
2
60 15/85
70 20/80
55 13/87
45 10/90
60 22/78
50 10/90
0
1
2
3
4
CH
3
CH(CH
3
)
2
55
5/95
For application of the reverse effect, (S)-tert-leucine was used
for the Michael addition of propionaldehyde 1a to various b-nitro-
styrenes 2a–d. The products were isolated in high diastereo- and
enantioselectivities as summarized in Table 4. On the basis of the
experimental results, a possible transition state for this reaction
was proposed to account for the observed stereoselectivities, as
shown in Figure 2. Nitrogen atoms are located opposite to each
other, and the enamine is in an anti-conformation. The si-face of
the enamine is efficiently shielded by forming carboxyl group-
thiourea hydrogen bond interactions and the nucleophilic attack
comes preferentially from the re-face of the enamine to the-re face
of the trans-b-nitrostyrene to give the corresponding preferred syn-
Michael adduct with a (2S,3R)-absolute configuration. Neverthe-
less, the precise catalytic mechanism needs further investigation.
In summary, Michael adducts were obtained in high yields with
good diastereo- and high enantioselectivities (up to 5:95 dr and
a
The reactions were conducted with (S)-proline (10 mol %), thiourea I or II
(
(
10 mol %), aldehyde (2 equiv 10 lL), nitroalkene (0.125 mmol), and toluene
1.2 mL) for 24 h.
b
Determined by chiral HPLC analysis of the mixture of the anti/syn product.
Determined by a chiral HPLC column.
c
tivity was observed in the proline–thiourea catalyzed Michael
addition. Of course, other possible mechanisms cannot be ruled
out at this stage.
After the optimization experiments, various representative
aldehydes and nitroolefins were used with 10 mol % catalyst at
ꢀ
30 °C in toluene as shown in Table 2. The corresponding Michael
products were obtained with high stereoselectivities.
Unbranched aldehydes, such as propionaldehyde 1a (Table 2,
entries 1–5, 8–12), were added to various nitroalkenes in which
moderate to good yields with excellent enantioselectivities were
observed. Additionally, butanal 1b (Table 2, entry 6) gave the
9
8% ee). The experiments showed that only a simple amino acid-
thiourea catalyst was sufficient to obtain high selectivities. The
presence of primary and secondary amine functionalities showed
high catalytic activity and selectivity. By changing the modular
system from proline to other amino acids with a primary amino
group enabled us to achieve the reverse enantioselectivity. The
Table 3
Amino acid screening for the Michael reaction of propionaldehyde 1a to trans-4-
bromo-b-nitrostyrene 2b in toluene
a
Br
Table 4
a
O
(S)-tert-Leucine catalyzed Michael reaction
NO2
10 mol% I
R2
O
1
0 mol% amino acid
+
(S)
NO2
toluene
Br
(R)
O
O
1
a
NO2
cocatalyst
2
b
3
b
I
(
S)
NO2
+
(R)
toluene, -20 o
C
eec (%) (Conf.)d
R2
Entry Amino acid
T [°C] Yield (%) dr
(
anti/syn)b
3a,b,d,e
1
a
2a,b,d,e
1
2
3
4
5
6
(S)-Alanine
(S)-Valine
(S)-tert-Leucine
(S)-Cysteine
(S)-Tryptophan
(S)-Histidine
20
20
70 35/65
75 36/64
77 36/64
78 36/64
72 36/64
61 37/63
80
82
85
18
85
70
(2S,3R)
(2S,3R)
(2S,3R)
(2R,3S)
(2S,3R)
(2S,3R)
Entry
Nitrostyrene R2
Yield (%)
dr (anti/syn)b
eec (%)
(Conf.)d
ꢀ20
1
2
3
4
H
75
77
74
72
30/70
36/64
38/62
44/56
91
85
96
94
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
20
4-Br
2-OMe
2-Br
ꢀ5
20
a
a
The reactions were conducted with amino acid (10 mol %), thiourea I (10 mol %),
The reactions were conducted with (S)-tert-leucine (10 mol %), thiourea I
propionaldehyde (2 equiv 10
lL), trans-4-bromo-b-nitrostyrene (0.125 mmol), and
(10 mol %), propionaldehyde (2 equiv10 lL), nitroalkenes (0.125 mmol), and tolu-
toluene (1.2 mL) for 24 h.
ene (1.2 mL) for 24 h.
b
b
Determined by chiral HPLC analysis of the mixture of the anti/syn product.
Determined by chiral HPLC.
Determined by chiral HPLC analysis of the mixture of the anti/syn-product.
Determined by chiral HPLC.
c
c
d
d
By comparison of their specific rotations with those reported.
By comparison of their specific rotations with those reported in the literature.

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 1218–1224
1221
host
Table 5
F3C
Solvent screening for the direct asymmetric
a
-aminoxylationa
NaBH
trans-enamine
re-face
O
O
N
O
cocatalyst
I or II
O
4
H
N
+
(R)
O
(
S)
(R)
EtOH
N
H
N
CF3
O
HO
N
H
Ph
N
Ph
O
Ph
H
solvent, rt
H
H
S
1a
4
O
5a
6a
O
N
eeb (%)
Entry
Solvent
Cat.
Yield (%)
N
1
2
3
4
5
6
Hexane
Toluene
Benzene
Hexane
Toluene
Benzene
I
I
I
II
II
II
54
85
72
50
67
54
91
99
96
90
98
95
Ar
trans-β-nitrostyrene
re-face
Figure 2. The possible interaction of the bipyridine derived thiourea with (S)-tert-
leucine in the TS of the reverse enantioselective Michael reaction.
a
The reactions were conducted with (S)-proline (10 mol %), thiourea I or II
10 mol %), propionaldehyde (20 L, 2 equiv), nitrosobenzene (0.125 mmol), and
solvent (2 mL) for 6 h.
(
l
primary amine functionality may be responsible for the double
hydrogen bonding network with nitroolefin.2 Typically, catalyst
structures were modified by changing the amino acid in order to
obtain reverse enantioselectivities.2 This concept was based on
the self-assembly of the simple commercially available catalyst
by complementary hydrogen bonding between an amino acid
and an additive in order to alter the catalyst environment.
b
Determined by chiral HPLC with AD-H column.
et al.,13 Córdova,14 Jørgensen,15 and others to obtain products in
high yields and with excellent enantioselectivities. Cleavage of
the O–N bond was also carried out via catalytic hydrogenation to
obtain the diol without a loss of enantiomeric purity. Both Córdova
1
4
16
2
.2. a-Aminoxylation
et al. and Houk et al. conducted quantum mechanical computa-
tional studies to understand the mechanism of proline-catalyzed
The
target for the development of new enantioselective technologies.
-Oxygenated carbonyl compounds are important not only due
a-oxycarbonyl synthon remains an important structural
a-aminoxylation reactions as well as to explain the observed selec-
tivity of the aminoxylation products over hydroxyamination prod-
ucts. The (TS)-A for the attack at the nitrogen (N-anti) is higher in
energy (2.6 kcal/mol) than the one for the attack at oxygen
a
to their presence in many natural and non-natural biologically
active compounds, but also because of their utility for the synthesis
(
O-anti). The higher basicity of the nitrogen accounts for its prefer-
8
of other useful building blocks such as diols. Obtaining
a-hydroxy
ential protonation, rendering the oxygen atom electrophilic.
Among the two transition state structures for attack at the oxygen,
O-syn is 3.3 kcal/mol higher in energy than O-anti and gives the
minor enantiomeric product, as can be seen in Figure 3.16
carbonyl compounds in enantiomerically pure form is of interest to
synthetic organic chemists. With the applications of asymmetric
enamine catalysis in hand for the
a-functionalization of carbonyl
compounds with a variety of electrophiles, a natural extension
In order to explain the observed enantioselectivities with re-
spect to (S)-proline, we proposed (TS)-B based Houk model16 as
shown in Figure 3, which is analogous to the TS structures for
was to use this concept in combination with a suitable oxygen
8
electrophile.
2
The discovery by Yamamoto et al. of the use of nitrosobenzene
the proline-catalyzed intermolecular aldol reaction.
as an electrophilic source of oxygen in asymmetric metal-catalyzed
Our initial studies revealed that the proposed organocatalytic a-
9
a
-oxygenations of tin enolates in 2003, and the elegant work by
aminoxylation is indeed facile at room temperature and can be
accomplished with a supramolecular catalyst using a variety of
nonpolar solvents. Toluene furnished a higher yield than hexane
1
0
List, revealed a new application for the a-oxidation of aldehydes
and ketones. A number of aldehydes and ketones have been amin-
oxylated by using proline or proline-derived catalyst by different
research groups, that is, Zhong,11 MacMillan et al., Hayashi
12
Table 6
Direct asymmetric
a
-aminoxylation of various aldehydes 1a–d to nitrosobenzene 4a
O
O
O
cocatalyst
NaBH
EtOH
O
O
O
4
I or II
(R)
O
O
R
+
N
(R)
R
NH
Ph
HO
NH
Ph
Ph
N
O
N
O
N
O
R1 Ph
toluene, rt
R1
R1
H
H
O
N
H
Ph
N
N
O
A
O
4
1
a-e
5
a-e
6a-d
Ph
O-syn
O-anti
N-anti
R1
eeb (%)
Entry
R
Cat.
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
H
H
H
H
(CH2)4
H
H
H
H
(CH2)4
Me
Et
i-Pr
n-Pr
—
Me
Et
i-Pr
n-Pr
—
I
I
I
I
6a
6b
6c
6d
5e
6a
6b
6c
6d
5e
85
76
60
62
75
67
60
52
50
56
99
98
94
98
99
98
97
97
96
99
host
Ph
N
H
O
I
N
O
CF3
H
II
II
II
II
II
B
O
H
N
N
R
S
CF3
N
c
a
By comparison of their specific rotations with those reported in the literature.
The reactions were conducted with (S)-proline (10 mol %), thiourea I or II
(
10 mol %), aldehydes or cyclohexanone (20
lL, 2 equiv), nitrosobenzene
Figure 3. (A) Calculated TS models for the proline-catalyzed
a-aminoxylation of
aldehydes,16 (B) the possible interaction of the bipyridine derived thiourea with (S)-
(0.125 mmol), and toluene (2 mL) for 6 h.
b
Determined by chiral HPLC with an AD-H column.
proline in the TS.

1
222
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 1218–1224
O
-
H O
N
+
HN
N
2
O
O
O
a
H
b
H
H
H
N
HO
O
O
O
L*
L*
L*
Ph
HN
Ph
N
+ PhNO
c
O
N
O
N
O
H
O
H
O
O
O
O
L*
L*
L*
trans-enamine
si-face
+H O
2
d
Ph
HN
O
e
O
HN
N
H
O
Ph
O
O
N
H
+
H
OH
O
O
L*
L*
Scheme 3. Proposed mechanism for the a-aminoxylation reaction.
and benzene (Table 5, entry 2), while variation in the solvents had
a pronounced effect on the yield; excellent levels of enantioselec-
tion were observed for all three nonpolar solvents (up to 99% ee).
In terms of operational convenience, the use of 10 mol % (S)-pro-
line–thiourea ensures high levels of reaction efficiency and enanti-
knowledge, this is the first report of enantioselective Michael and
-aminoxylation reactions through an intermolecular hydrogen
a
bond network between bipyridine derived achiral thiourea guest
and chiral proline host. The success of this catalyst design will open
up new perspectives in asymmetric organocatalysis. More detailed
studies regarding the mechanism and synthetic applications of this
host–guest system on enantioselective organocatalytic reactions
are currently under investigation.
oselectivity. The
aminoxy alcohols by reduction with NaBH
pression of the homodimerization aldol and the
way was achieved by using toluene to provide the desired
-oxyaldehyde in high yield and with excellent enantioselectivity,
a
-oxidation products were converted into
in ethanol. The sup-
-amination path-
4
a
a
4
4
. Experimental
as shown in Table 6.
The enantioselective direct aminoxylation of nitrosoben-zene 4
with various unbranched aliphatic aldehydes 1a–d catalyzed by
proline–thiourea (10 mol %) proceeded in high yield and the amin-
oxy alcohols were obtained with 94–99% ee after reduction of the
.1. General procedure for the enantioselective Michael
reaction
A mixture of (S)-proline (0.0125 mmol, 1.4 mg, 10 mol %), thio-
urea I or II (0.0125 mmol, 9.1 mg, 10 mol %), and 2 mL toluene was
placed in a screw-capped vial. The aldehyde (10 L, 2 equiv) was
a-oxidation products by using NaBH
4
.
Cyclohexanone 1e was then examined in an asymmetric
a
-
l
aminoxylation reaction with nitrosobenzene 4 in toluene, and
moderate to good yields and excellent enantioselectivities (99%)
were obtained (Table 6, entries 5, 10).
then added and the resulting mixture was stirred for 30 min at
ambient temperature followed by the addition of nitroalkene
(
0.125 mmol), and then stirring was continued for 24 h (TLC mon-
The proposed mechanism for the proline–thiourea catalyzed a-
itoring). The reaction mixture was treated with a saturated aque-
ous ammonium chloride solution and the whole mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried, and concentrated to give a crude residue, which was
purified by column chromatography over silica gel using hexane–
ethyl acetate as an eluent to afford a pure product. The enantio-
meric excess (ee) of the products was determined by chiral-phase
HPLC analysis. The absolute configurations of the products were
determined by comparing the values with those previously re-
aminoxylation reaction is depicted in Scheme 3. The main steps of
this transformation are as follows: the nucleophilic attack of the
proline (a), the dehydration of the carbinol amine to give an enam-
ine (b), the carbon–oxygen bond forming between donor nitroso-
benzene and the acceptor enamine intermediate in the transition
state (c), and then the formation of the enantiomerically enriched
a-aminoxylation product followed by hydrolysis (d and e). The ob-
served enantioselectivitiy of the catalytic -aminoxylation of alde-
a
1
7
hydes can be rationalized by invoking an enamine mechanism
operating through a chair transition state where the si face of an
ported in the literature.
(
E)-enamine formed from the aldehyde and the proline approaches
the less-hindered oxygen atom of nitrosobenzene to provide a chi-
ral -aminoxyaldehyde with an R configuration. This mechanism is
4
.2. General procedure for the enantioselective a-aminoxylation
a
A mixture of (S)-proline (0.0125 mmol, 1.4 mg, 10 mol %), thio-
urea I or II (0.0125 mmol, 9.1 mg, 10 mol %), and nitrosobenzene
15 mg, 0.125 mmol) in toluene (2 mL) was placed in a screw-
capped vial. The aldehyde (20 L, 2 equiv) was added followed
completely in accord with the previously proposed models for pro-
line-catalyzed aldol reactions.2
(
l
3
. Conclusion
by stirring at room temperature for 6 h. After the aminoxylation
reaction was completed (TLC monitoring), ethanol (2 mL) was then
added and then sodium borohydride (20 mg). The reaction mixture
was stirred for 10 min at room temperature. Next, the reaction was
quenched with water (5 mL) and the resulting mixture was
extracted with ethyl acetate (10 mL ꢁ 2). The combined organic
In conclusion, we have developed asymmetric concepts in non-
polar organic solvents. The proline–thiourea self-assembled organ-
ocatalyst system demonstrated excellent reactivity,
diastereoselectivity, and enantioselectivity. To the best of our

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 1218–1224
1223
extracts were dried over anhydrous sodium sulfate and concen-
trated in vacuo after filtration. Purification by column chroma-
tography (silica gel, ethyl acetate–hexane as an eluent) gave
Spectroscopic data are in agreement with the published data. The
enantiomeric excess was determined by HPLC with an AS-H col-
umn (i-PrOH/hexanes: 5/95, flow rate: 1.0 mL/min, k = 230 nm,
(
2R)-2-anilinoxy alcohol. The enantiomeric excess (ee) of the prod-
anti/syn = 13/87); t
R
= 53.1 min (minor) and t
R
= 77.3 min (major).
1
ucts was determined by chiral-phase HPLC analysis. The absolute
configurations of the products were determined by comparing
the values with those previously reported in the literature.
H NMR (CDCl ): d 9.68 (d, J = 1.7 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H),
3
6.86 (d, J = 8.7, Hz, 2H), 4.78–4.72 (m, 1H), 4.64 (dd, J = 9.5,
12.6 Hz, 1H), 3.76 (s, 3H), 2.79–2.68 (m, 1H), 0.98 (d, J = 7.3 Hz,
1
8
1
3
3
H); C NMR (CDCl
3
): d 202.5, 159.3, 129.2, 114.4, 78.4, 55.2,
4
.3. Thioureas I and II are known compounds:7
48.6, 43.4, 12.0.
0
0
0
1
,1 -([2,2 -Bipyridine]-4,4 -diyl)bis(3-(3,5-bis(trifluoromet-
4.7. (2R,3S)-3-(2-Methoxyphenyl)-2-methyl-4-nitrobutyral-
dehyde 3d
1
hyl)phenyl)thiourea) I: H NMR (CD
3
COCD
3
): d 10.1 (br s, 2H), 8.6
(
(
1
app d, J = 2.0 Hz, 2H), 8.5 (app d, J = 5.5 Hz, 2H), 8.3 (app s, 4H), 7.9
app dd, J = 2.0, 5.5 Hz, 2H), 7.8 (app s, 2H); 13C NMR (CD
The title compound was prepared from trans-2-methoxy-b-
nitrostyrene 2d and propionaldehyde 1a according to the general
procedure; compound 3d was obtained with a maximum of 97%
ee. Spectroscopic data are in agreement with the published data.
The enantiomeric excess was determined by HPLC with an OD-H
column (i-PrOH/hexanes: 5/95, flow rate: 0.5 mL/min, k = 220 nm,
3
3
COCD ): d
0
81.1 (s, C@S), 150.7 (s, bipyridine-C-4, bipyridine-C-4 ), 142.2 (s,
0
ArC-NHR), 132.7 (d, bipyridine-C-6, bipyridine-C-6 ), 132.3, 131.9
s, ArC-CF ), 125.7 (s, C-F), 124.9, 122.9, 118.8, 117.3, 114.2 (d,
Ar-C).
(
3
0
0
0
1
,1 -([2,2 -Bipyridine]-4,4 -diylbis(methylene))bis(3-(3,5-
1
R R
= 39.9 min (minor); t H
= 41.4 min (major). 1
bis(trifluoromethyl)phenyl)thiourea) II: H NMR (CD
br s, 2H), 8.6 (app d, J = 5.0 Hz, 2H), 8.5 (app s, 2H), 8.4 (app d,
J = 4.8 Hz, 4H), 7.7 (app s, 2H), 7.4 (app dd, J = 1.5, 5.0 Hz, 2H),
3
3
COCD ): d 9.8
anti/syn = 9/91); t
NMR (CDCl ): d 9.70 (d, J = 1.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.06
(
3
(dd, J = 1.7, 7.5 Hz, 1H), 6.92–6.87 (m, 2H), 4.85 (dd, J = 9.0,
5
.07 (app d, J = 4.8 Hz, 4H); 13C NMR (CD
3
COCD
3
): d 183.2 (s,
12.6 Hz, 1H), 4.73 (dd, J = 9.0, 12.6 Hz, 1H), 3.82 (s, 3H), 3.02–
0
13
C@S), 156.9 (s, bipyridine-C-2, bipyridine-C-2 ), 150.1 (d, bipyri-
dine-C-6, bipyridine-C-6 ), 149.7 (s, bipyridine-C-4, bipyridine-C-
4
1
3
2.98 (m, 1H), 0.92 (d, J = 7.3 Hz, 3H). C NMR (CDCl ): d 202.9,
0
157.4, 130.3, 129.3, 124.5, 120.9, 111.1, 77.5, 55.3, 47.1, 40.6, 12.1.
0
3
), 142.8 (s, ArC-NHR), 132.2, 131.9 (s, ArC-CF ), 128.4 (d, Ar-C),
25.7 (s, C-F), 123.8, 123.5, 123.0, 120.2, 117.8 (d, Ar-C), 47.6 (t,
R).
4.8. (2R,3S)-(2-Bromophenyl)-2-methyl-4-nitrobutyraldehyde
(3e)
Ar-CH
2
4
.4. (2R,3S)-2-Methyl-4-nitro-3-phenylbutyraldehyde 3a
The title compound was prepared from trans-2-bromo-b-nitro-
styrene 2e and propionaldehyde 1a according to the general proce-
dure; compound 3e was obtained with a maximum of 98% ee.
Spectroscopic data are in agreement with the published data. The
enantiomeric excess was determined by HPLC with an AD-H col-
umn (i-PrOH/hexanes: 5/95, flow rate: 0.5 mL/min, k = 220 nm,
The title compound was prepared from trans-b-nitrostyrene 2a
and propionaldehyde 1a according to the general procedure; com-
pound 3a was obtained with a maximum of 93% ee. Spectroscopic
data are in agreement with the published data. The enantiomeric
excess was determined by HPLC with an OD-H column (i-PrOH/
anti/syn = 18/82); t
H NMR (CDCl
3
R
= 23.4 min (major) and t
): d 9.73 (d, J = 1.5 Hz, 1H), 7.57–7.62 (m, 1H),
7.34–7.27 (m, 1H), 7.23–7.14 (m, 2H), 4.88–4.72 (m, 2H), 2.98–
R
= 27.4 min (minor).
1
hexanes: 10/90; flow rate: 1.0 mL/min; k = 220 nm, anti/syn = 18/
1
8
(
(
2); t
CDCl
m, 2H), 4.78 (dd, J = 5.5, 12.7 Hz, 1H), 4.67 (dd, J = 9.5, 12.7 Hz,
R
= 22.2 min (minor) and t
R
= 31,4 min (major). H NMR
1
3
3
): d 9.68 (d, J = 1.6 Hz, 1H), 7.35–7.26 (m, 3H), 7.17–7.15
3
2.91 (m, 1H), 1.04 (d, J = 7.4 Hz, 3H); C NMR (CDCl ): d 201.9,
136.4, 133.9, 129.5, 128.2, 75.5, 48.0, 12.3.
1
3
4
H), 3.85–3.77 (m, 1H), 2.84–2.72 (m, 1H), 0.97 (d, J = 7.3 Hz,
H); 1 C NMR (CDCl
3
): d 202.4, 136.7, 129.1, 128.1, 78.2, 48.4,
4.9. (2R,3S)-2-Ethyl-4-nitro-3-(4-bromophenyl)butyraldehyde
3f
3
4.0, 12.1.
4
3
.5. (2R,3S)-3-(4-Bromophenyl)-2-methyl-4-nitrobutyraldehyde
b
The title compound was prepared from trans-4-bromo-b-nitro-
styrene 2b and butyraldehyde 1b according to the general proce-
dure; compound 3f was obtained with a maximum of 92% ee.
Spectroscopic data are in agreement with the published data. The
enantiomeric excess was determined by HPLC with an AD-H (i-
PrOH/hexanes: 1/99, flow rate: 1.0 mL/min, k = 220 nm, anti/
The title compound was prepared from trans-4-bromo-b-nitro-
styrene 2b and propionaldehyde 1a according to the general proce-
dure; compound 3b was obtained with a maximum of 97% ee.
Spectroscopic data are in agreement with the published data. The
enantiomeric excess was determined by HPLC with an AD-H col-
umn (i-PrOH/hexanes: 2/98, flow rate: 0.8 mL/min, k = 220 nm,
R R
= 22.2 min (major) and t H
= 31.3 min (minor). 1
syn = 8/92); t
NMR (CDCl ): d 9.68 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H),
3
7.08 (d, J = 8.5 Hz, 2H), 4.73 (dd, J = 4.8, 12.8 Hz, 1H), 4.58 (dd,
anti/syn = 33/67); t
R
= 34.9 min (major) and t
): d 9.69 (d, J = 1.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H),
.06 (d, J = 8.4 Hz, 2H), 4.78 (dd, J = 5.2, 12.8 Hz, 1H), 4.66 (dd,
J = 9.6, 12.8 Hz, 1H), 3.84–3.76 (m, 1H), 2.83–2.73 (m, 1H), 1.01
R
= 49.9 min (minor).
J = 9.9, 12.8 Hz, 1H), 3.82–3.75 (m, 1H), 2.69–2.63 (m, 1H), 1.56–
1.42 (m, 2H), 0.81 (t, J = 7.5 Hz, 3H); C NMR (CDCl ): d 202.8,
3
136.0, 132.3, 129.8, 122.1, 78.3, 54.6, 43.3, 42.1, 20.3, 10.5.
1
13
H NMR (CDCl
3
7
1
3
(
d, J = 7.3 Hz, 3H); C NMR (CDCl
3
): d 201.8, 135.7, 132.3, 129.8,
4.10. (2R,3S)-2-(Methylethyl)-4-nitro-3-(4-bromophenyl)butyr-
1
22.2, 77.8, 48.2, 43.5, 12.2.
aldehyde 3g
4
.6. (2R,3S)-3-(4-Methoxyphenyl)-2-methyl-4-nitrobutyral-
The title compound was prepared from trans-4-bromo-b-nitro-
styrene 2b and isovaleraldehyde 1c according to the general proce-
dure; compound 3g was obtained with a maximum of 95% ee.
Spectroscopic data are in agreement with the published data. The
enantiomeric excess was determined by HPLC with an AD-H col-
umn (i-PrOH/hexanes: 5/95, flow rate: 0.5 mL/min, k = 220 nm,
dehyde 3c
The title compound was prepared from trans-4-methoxy-b-
nitrostyrene 2c and propionaldehyde 1a according to the general
procedure; compound 3c was obtained in a maximum of 90% ee.

1
224
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 1218–1224
anti/syn = 5/95); t
R
= 27.0 min (major) and t
): d 9.9 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H),
.09 (d, J = 8.4 Hz, 2H), 4.68 (dd, J = 4.2, 12.7 Hz, 1H), 4.53 (dd,
J = 10.2, 12.6 Hz, 1H), 3.91-3.85 (m, 1H), 2.77–2.73 (m, 1H), 1.71–
R
= 41.8 min (minor).
4.15. (2R)-2-Anilinoxycyclohexanone 5e
1
H NMR (CDCl
3
7
After the aminoxylation reaction was complete, the reaction
mixture was quenched with water (5 mL) and the resulting mix-
ture was extracted with ethyl acetate (10 mL ꢁ 2). The combined
organic extracts were dried over anhydrous sodium sulfate and
concentrated in vacuo after filtration. Purification by column chro-
matography (silica gel, ethyl acetate–hexane as an eluent) gave
1
3
1
.66 (m, 1H), 1.10 (d, J = 7.2 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H);
C
3
NMR (CDCl ): d 204.0, 136.3, 132.3, 129.7, 122.0, 78.7, 58.5, 41.4,
2
7.9, 21.6, 16.9.
(
2R)-2-anilinoxycyclohexanone 5e. Following the procedure, com-
4
.11. (2R)-2-Anilinoxypropanol 6a
pound 5e was obtained with 99% ee. The enantiomeric purity was
determined by HPLC on an AD-H column, hexanes/i-PrOH = 90/10,
Following the general procedure, compound 6a was obtained in
9% ee. The enantiomeric purity was determined by HPLC on an
flow rate = 1.0 mL/min, UV = 254 nm, t
CDCl ): d 7.74 (s, 1H), 7.18 (t, J = 8.3 Hz, 2H), 6.87 (t, J = 7.8 Hz,
3H), 4.32 (dd, J = 6.2, 10.8 Hz, 1H), 2.47–2.24 (m, 3H), 2.01–1.89
(R) = 16.1 min. 1H NMR
R
9
(
3
AD-H column, hexanes/i-PrOH = 90/10, flow rate = 1.0 mL/min,
UV = 220 nm,
1
t
R
(S) = 10.7 min and
R
t (R) = 12.2 min.
H NMR
1
3
(
3
m, 2H), 1.79–1.57 (m, 3H); C NMR (CDCl ): d 209.9, 148.1,
(CDCl
(m, 1H), 3.79–3.69 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H); C NMR
(CDCl ): d 148.6, 129.0, 122.3, 114.7, 80.1, 66.4, 15.4.
3
): d 7.26 (t, J = 7.8 Hz, 2H), 6.98–6.95 (m, 3H), 4.12–4.06
1
3
128.9, 122.1, 114.4, 86.3, 40.9, 32.5, 27.3, 23.8.
3
Acknowledgments
4
.12. (2R)-2-Anilinoxybutanol 6b
Financial support from the Scientific and Technological Re-
search Council of Turkey (TÜBITAK), the Turkish Academy of Sci-
ences (TÜBA), and Middle East Technical University (METU) is
gratefully acknowledged.
Following the general procedure, compound 6b was obtained in
8% ee. The enantiomeric purity was determined by HPLC on an
9
AD-H column, hexanes/i-PrOH = 90/10, flow rate = 1.0 mL/min,
1
UV = 230 nm,
CDCl ): d 7.28 (dd, J = 7.2, 8.5 Hz, 2H), 7.03–6.97 (m, 3H), 3.93–
.75 (m, 2H), 2.53 (s, br s, 1H), 1.79–1.49 (m, 2H), 1.02 (t,
t
R
(S) = 10.8 min and
R
t (R) = 11.7 min.
H NMR
References
(
3
3
1.
(a) Clarke, M. L.; Fuentes, J. A. Angew. Chem., Int. Ed. 2007, 46, 930; (b) Jones, C.
E.; Turega, S. M.; Clarke, M. L. Tetrahedron Lett. 2008, 49, 4666.
1
3
3
J = 7.5 Hz, 3H); C NMR (CDCl ): d 148.4, 129.1, 122.5, 114.9,
8
5.3, 65.1, 22.9, 10.2.
2. Mandal, T.; Zhao, C.-G. Angew. Chem., Int. Ed. 2008, 47, 7714.
3
4
.
.
Eymur, S.; Demir, A. S. Tetrahedron: Asymmetry 2010, 21, 112.
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260.
4
.13. (2R)-3-Methyl-2-anilinoxybutanol 6c
5. Enders, D.; Seki, A. Synlett 2002, 26.
6.
(a) Blarer, S. J.; Seebach, D. Chem. Ber. 1983, 116, 2250; (b) Seebach, D.; Golinski,
J. Helv. Chim. Acta 1981, 64, 1413.
Following the general procedure, compound 6c was obtained in
4% ee. The enantiomeric purity was determined by HPLC on an
7.
Basceken, S.; Demir, A. S. Tetrahedron: Asymmetry 2013, 24, 515.
9
8. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038.
9.
AD-H column, hexanes/i-PrOH = 90/10, flow rate = 1.0 mL/min,
1
10. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656; (b) List, B. Synlett 2001, 1675; (c)
Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790; (d) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254.
UV = 254 nm, t
d 7.19 (dd, J = 7.3, 8.5 Hz, 2H), 6.93–6.88 (m, 3H), 3.78–3.76 (m,
H), 3.66–3.63 (m, 1H), 2.91 (s, br s, 1H), 1.99–1.86 (m, 1H), 0.96
R R 3
(S) = 9.1 min and t (R) = 10.0 min. H NMR (CDCl ):
2
(
d, 3H, J = 6.6 Hz) 0.91 (d, 3H, J = 6.6 Hz); 1 C NMR (CDCl
3
11. Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247.
3
): d
12. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
1
48.4, 129.0, 122.5, 115.1, 88.7, 63.7, 28.8, 18.8, 18.6.
125, 10808.
1
1
3. Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293.
4. (a) Córdova, A.; Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am.
Chem. Soc. 2002, 124, 1866; (b) Córdova, A.; Sundén, H.; Bøgevig, A.; Johansson,
M.; Himo, F. Chem. Eur. J. 2004, 10, 3673.
4
.14. (2R)-2-Anilinoxypentanol 6d
Following the general procedure, compound 6d was obtained in
8% ee. The enantiomeric purity was determined by HPLC on an
15. Bertelsen, S.; Dinér, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007,
29, 1536–1537.
1
9
1
1
6. Cheong, P. H.-Y.; Houk, K. N. J. Am. Chem. Soc. 2004, 126, 13912.
7. (a) Betancort, J. M.; Barbas, C. F., III Org. Lett. 2001, 3, 3737; (b) Gotoh, H.;
Hayashi, T.; Hayashi, Y.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212; (c)
Barros, M. T.; Phillips, A. M. F. Eur. J. Org. Chem. 2007, 178; (d) Reddy, R. J.; Kuan,
H. H.; Chou, T. Y.; Chen, K. Chem. Eur. J. 2009, 15, 9294; (e) Wiesner, M.; Revell,
J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871; (f) Xiao, J.; Xu, F. X.;
Lu, Y. P.; Loh, T. P. Org. Lett. 2010, 12, 1220.
AD-H column, hexanes/i-PrOH = 90/10, flow rate = 1.0 mL/min,
1
UV = 254 nm, t
d 7.26 (t, J = 7.7 Hz, 2H), 6.98–6.96 (m, 3H), 3.96–3.72 (m, 3H), 2.91
s, br s, 1H), 1.69–1.61 (m, 1H), 1.51–1.41 (m, 3H), 0.95 (t,
R R 3
(S) = 9.9 min, and t (R) = 11.4 min. H NMR (CDCl ):
(
1
3
J = 7.2 Hz, 3H); C NMR (CDCl
3.8, 65.3, 32.1, 19.1, 14.3.
3
): d 148.6, 129.1, 122.4, 114.8,
18. Huang, K.; Huang, Z. Z.; Li, X. L. J. Org. Chem. 2006, 71, 8320.
8