Calixarene-derived chiral tertiary amine-thiourea organocatalyzed asymmetric Michael additions of acetyl acetone and dimethyl malonate to nitroolefins

Article abstract of DOI:10.1016/j.tetasy.2016.01.004

Novel bifunctional chiral thiourea-tertiary amines bearing a calix[4]arene scaffold were synthesized and applied in catalytic asymmetric Michael addition of acetyl acetone and dimethyl malonate to nitroolefins. The corresponding adducts were obtained in e

Full text of DOI:10.1016/j.tetasy.2016.01.004

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Calixarene-derived chiral tertiary amine–thiourea organocatalyzed
asymmetric Michael additions of acetyl acetone and dimethyl
malonate to nitroolefins
⇑
Mustafa Durmaz , Aysun Tataroglu, Horu Yilmaz, Abdulkadir Sirit
Department of Chemistry, Ahmet Kelesoglu Education Faculty, Necmettin Erbakan University, 42090 Konya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel bifunctional chiral thiourea-tertiary amines bearing a calix[4]arene scaffold were synthesized and
applied in catalytic asymmetric Michael addition of acetyl acetone and dimethyl malonate to nitroolefins.
The corresponding adducts were obtained in excellent yields (up to 99%) and with high enantioselectiv-
ities (up to 94% ee).
Received 21 December 2015
Accepted 6 January 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
Calixarenes, cyclic oligomers of phenolic units linked through
the ortho-positions, represent an important class of macrocyclic
Asymmetric organocatalysis through hydrogen bond activation
has become an efficient activation mode in many enantioselective
syntheses.1 Among the different hydrogen bonding moieties,
bifunctional organocatalysts, which incorporate both H-bond
donor and Lewis base functionalities into a single asymmetric
molecular scaffold, have emerged as efficacious catalysts and have
been successfully applied to various types of asymmetric reac-
tions2,3 since the pioneering work of Jacobsen,4 Schreiner5 and
Takemoto.6 The key to the high activity as well as selectivity of
these catalysts was assigned to their ability to activate both elec-
trophilic and nucleophilic centers of the reacting partners indepen-
dently and simultaneously in a controlled chiral environment.
The Michael reaction, the nucleophilic addition of appropriate
compounds due to their potential to form host–guest complexes
with numerous classes of compounds in supramolecular
chemistry.9 Chiral derivatives of these macrocycles, which can be
synthesized by attaching chiral substituents at one of the rims
(lower or upper) may have potential applications, such as being
organocatalysts,10 ionophores in catalysis, carriers in liquid mem-
brane technology, extractants for anions and cations, and chemical
sensors.11
As part of our ongoing studies to develop novel types of
organocatalysts for asymmetric transformations, we have recently
reported that calix[4]arene-based chiral primary amine–thioureas
can function as multiple H-bond donor organocatalysts and have
shown excellent performances in the catalytic asymmetric Michael
additions of aldehydes to nitroalkenes and maleimides.12 Herein
we report the synthesis of calixarene-based chiral bifunctional
tertiary amine–thiourea organocatalysts and their application in
the catalytic conjugate addition of 1,3-dicarbonyl compounds to
a variety of nitroolefins under mild conditions.
carboanionic reagents to
a,b-unsaturated carbonyl compounds,
represents a direct and attractive approach for the construction
of versatile intermediates by remote functionalization in organic
synthesis.7 Therefore, their catalytic asymmetric versions have
been studied extensively.8 In particular, the Michael addition of
1,3-dicarbonyl compounds to nitroalkenes is one of the most
important methods for the preparation of optically active nitro car-
bonyl compounds, which play an important role as precursors of
biologically active compounds or chiral building blocks in syn-
thetic and medicinal chemistry. Although significant progress has
been achieved in this area, there is still need for new strategies
to design efficient, recyclable chiral catalysts for asymmetric
Michael addition reactions.
2. Results and discussion
At first, calixarene-based primary amine–thioureas 1a–b were
readily prepared in two steps from p-tert-butylcalix[4]arene dia-
mine and chiral isothiocyanates according to our previous
method.12a The introduction of the methyl groups using HCHO/
NaBH3CN in AcOH/CH3CN solvent mixture afforded 2a–b in 87%
and 86% yields respectively (Scheme 1).
In the literature, conjugate additions were found to be suitable
reactions for evaluating the catalytic activities of these new chiral
⇑
Corresponding author. Tel.: +90 332 3238220/5820; fax: +90 332 3238225.
E-mail address: mdurmaz@konya.edu.tr (M. Durmaz).
http://dx.doi.org/10.1016/j.tetasy.2016.01.004
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Durmaz, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.004

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M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
N
NH2
H2N
N
*
*
*
*
*
*
*
*
NH
NH
HN
HN
NH
NH
HN
HN
S
S
S
S
O
O
O
O
HO OH
HO OH
HCHO, NaBH3CN
AcOH
CH3CN, rt, 24h
1a-1b
2
N
N
N
N
HN
HN
HN
HN
NH
NH
NH
NH
S
S
S
S
O
O
O
HO OH
O
HO OH
2a
2b
Scheme 1. Synthesis of calix[4]arene-based tertiary amine–thiourea organocatalysts 2a, 2b.
tertiary amine–thioureas.13 Hence, the conjugate addition reaction
of 2,4-pentanedione to trans-b-nitrostyrene was chosen as the
model reaction to examine the efficacy of 2a–b as organocatalysts.
In the presence of 10 mol % of 2a, the reaction of trans-b-nitrostyr-
ene 9a with 2,4-pentanedione in CH2Cl2, afforded the Michael
adduct (S)-11a in 95% yield and with 76% ee in 24 h (Table 1, entry
1). From the results of recent studies14 we expected reversed
senses of asymmetric induction with catalyst 2b. However,
thiourea 2b catalyzed the Michael addition with great efficiency
to yield the product in 93% yield but with a poor enantioselectivity
of 15% (Table 1, entry 2). Similar results were obtained when the
solvent was changed to toluene (Table 1, entries 3 and 4). In further
experiments, other influencing factors, such as solvent, reaction
temperature and catalyst loading were thoroughly investigated,
employing 2a as the catalyst (Table 1, entries 5–15). Solvent eval-
uation revealed that the enantioselectivity was highly dependent
on the solvent, with acetonitrile being found as the best solvent.
We expected that the resulting ee would be higher at a lower tem-
perature. However, reducing the reaction temperature from room
temperature to 0 °C did not improve the enantioselectivity (Table 1,
entry 14). When the catalyst loading was reduced to 5 mol %, the
yield and enantioselectivity were not significantly affected, but
the reaction time was prolonged (Table 1, entry 15). Thus, the opti-
mized catalyst loading was chosen as 10 mol %.
typical acids, bases, and water were employed. Among the
screened additives, reduced reaction times and good yields were
obtained with H2O and Et3N (Table 2, entries 1 and 5), but the
enantioselectivity was poor. In the presence of AcOH and PhCO2H,
prolonged reaction times, lower yields, and enantioselectivities
were observed (Table 2, entries 2 and 3).
In order to confirm the role of the achiral calixarene backbone
of 2a, the monomeric analogue 8 was also prepared in order to
carry out key control reactions since simple tertiary amine–thiour-
eas are known to be good catalysts for the asymmetric Michael
additions of 1,3-dicarbonyl compounds to nitroalkenes. The chiral
tertiary amine–thiourea 8 was synthesised starting from p-tert-
butyl phenol in five steps and 50% overall yield by the procedure
shown in Scheme 2. In the first control experiment, catalyst 8
afforded the Michael adduct in lower yield and enantioselectivity
(Table 1, entry 16) than the calixarene-based chiral tertiary
amine–thiourea derivatives. In another experiment to mimic the
effect of calixarene-thiourea 2a, 20 mol % of catalyst 8 was used
(Table 1, entry 17). Only a slight increase in the enantioselectivity
and chemical yield was observed. In order to explain the role of the
bulky calixarene moiety of thiourea and the phenolic hydroxy
groups on the calixarene scaffold, we performed a conjugate addi-
tion using 8 as the catalyst and p-tert-butyl phenol as an acidic
additive (Table 2, entry 6). Even in this case, the employment of
8-p-tert-butyl phenol system did not provide a better enantioselec-
tivity than that achieved with chiral calix[4]arene thiourea 2a.
With the optimized reaction conditions in hand, we next evalu-
ated the scope of the Michael addition reaction with a number of
In the literature, it has been reported that the presence of addi-
tives, bases, or acids has a significant influence on asymmetric
reactions.15 We were thus inspired to carry out the enantioselec-
tive conjugate addition in the presence of additives to determine
the optimal reaction conditions. As depicted in Table 2, various
nitroolefins
9 with 2,4-pentanedione 10 in the presence of
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M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
withdrawing groups reacted well with acetylacetone to give the
desired Michael adducts 11b–11l in generally high yields (59–
98%) and with moderate to good enantioselectivities (48–89%).
To further extend the application of our new organocatalyst, we
examined the catalytic properties of 2a in the conjugate addition of
dimethylmalonate to nitroalkenes. Parameters such as solvent
(Table 4, entries 1–11), temperature (Table 4, entry 12) and cata-
lyst loading (Table 4, entry 13) were also examined.
Optimization of the reaction conditions for the asymmetric Michael addition of
acetylacetone to trans-b-nitrostyrene catalyzed by 2a–b and 8a
O
O
NO2
O
O
NO2
catalyst (10 mol %)
solvent
*
+
Table 5 shows the generality and scope of the Michael addition
reaction with a variety of nitroolefins and dimethyl malonate. As
demonstrated in Table 5 using 10 mol % of 2a, the reactions of all
nitrostyrenes, bearing ortho-, meta- or para-electron-donating or
electron-withdrawing substituents, with dimethylmalonate 12
proceeded smoothly and gave the corresponding products 13b–
m in high yields (up to 98%) and with good enantioselectivities
(up to 88%).
Although the real catalytic mechanism still needs further study
to explain the observed enantioselectivity in Michael additions cat-
alyzed by calix[4]arene-based chiral tertiary amine–thiourea
derivatives, we propose a plausible synergistic dual activation
model for the reaction. First, the scaffold of the calixarene catalyst
was assumed to create reaction sites surrounded by two thioureas,
which interact through hydrogen bonding with the nitro group of
the nitrostyrene and enhance their electrophilicity, while the ter-
tiary amine deprotonates an acidic proton of 1,3-dicarbonyl com-
pound, to generate a ternary complex. From the observed (S)-
absolute configuration of the conjugate adduct 11a, the new C–C
bond was formed by the nuclephilic attack on the re-face of nitros-
tyrene 9a.
9a
10
11a
Entry
Catalyst
Solvent
Time (h) Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
8
CH2Cl2
CH2Cl2
Toluene
Toluene
CHCl3
ClCH2CH2Cl
EtOAc
CCl4
CH3CN
THF
MTBE
MeOH
DMF
CH3CN
CH3CN
CH3CN
CH3CN
24
24
24
24
24
24
24
24
24
24
24
4
95
93
93
95
91
97
98
97
99
98
95
82
64
94
98
87
91
76 (S)
15 (R)
81 (S)
10 (R)
72 (S)
79 (S)
82 (S)
71 (S)
94 (S)
77 (S)
75 (S)
12 (S)
55 (S)
85 (S)
93 (S)
38 (S)
44 (S)
9
10
11
12
13
14d
15e
16
17f
4
36
40
30
24
8
a
The reactions were performed with 0.05 mmol of 9a, and 0.1 mmol of 10 in
0.125 mL of solvent in the presence of 10 mol % of catalyst.
b
Isolated yields.
c
Determined by chiral HPLC analysis (Chiralpak AS-H), and the configuration
was assigned by comparison of the retention time and specific rotation with liter-
ature data.
3. Conclusion
d
Reaction performed at 0 °C.
5 mol % catalyst was used.
e
In conclusion, we have developed novel calix[4]arene-based
chiral bifunctional tertiary amine–thiourea catalysts as multiple
H-bond donor–acceptor organocatalysts for the asymmetric
Michael additions of nitroolefins to 1,3-dicarbonyl compounds.
The reaction was efficient in terms of productivity (up to 99% yield)
and enantioselectivity (up to 94% ee). These results might pave the
way for immobilizing these calixarene derivatives either onto poly-
mers or magnetic nanoparticles for batch and continuous flow
applications.
f
20 mol % catalyst was used.
Table 2
Screening of conditions for the asymmetric Michael addition of acetylacetone 10 and
trans-b-nitrostyrene 9aa
O
O
NO2
O
O
NO2
catalyst (10 mol %)
additive, CH3CN
(S)
+
4. Experimental
4.1. General
9a
10
11a
Entry
Catalyst
Additive
Time (h) Yieldb (%)
eec (%)
Melting points were determined on an Electrothermal 9100
apparatus in a sealed capillary. 1H and 13C NMR spectra were
recorded in CDCl3 at room temperature on Varian 400 instrument.
Chemical shifts are reported in ppm. Data were reported as fol-
lows: chemical shift (ppm), multiplicity (s = singlet, d = doublet,
t = triplet, m = multiplet, br = broad), coupling constants (Hz).
Infrared (IR) spectra were recorded on a Termo Scientific Nicolet
iS5 spectrometer equipped with an ATR unit and are reported in
wavenumbers (cmÀ1). The HPLC measurements were carried out
on Agilent 1100 equipment connected with Chiralpak Daicel AD-
H, OD-H and AS-H columns. Optical rotations were measured on
an Atago AP-100 digital polarimeter using a 1 dm cell. Elemental
analyses were performed using a Leco CHNS-932 analyzer. Analyt-
ical TLC was performed using Merck prepared plates (silica gel 60
F254 on aluminum). Flash chromatography separations were per-
formed on a Merck Silica Gel 60 (230–400 Mesh). All starting mate-
rials and reagents used were of standard analytical grade from
Fluka, Merck, Aldrich, Acros or TCI and used without further purifi-
cation. Dichloromethane was dried (CaCl2), distilled from CaH2 and
1
2
3
4
5
6
2a
2a
2a
2a
2a
8
H2O
AcOH
PhCO2H
Pyridine
Et3N
4
96
48
24
4
96
88
75
98
93
98
59
61
73
83
31
59
p-t-Butylphenol
24
a
The reactions were performed with 0.05 mmol 9a 0.1 mmol 10 in 0.125 mL of
solvent in the presence of 10 mol % of catalyst and 15 mol % additive at room
temperature.
b
Isolated yields.
c
Determined by chiral HPLC analysis (Chiralpak AS-H), and the configuration
was assigned by comparison of the retention time and specific rotation with liter-
ature data.
10 mol % catalyst 2a at room temperature. The results are summa-
rized in Table 3. It appears that the position and the electronic
properties of the substituents for aromatic rings of nitroolefins
are well tolerated by the conjugate addition reactions. A wide
range of nitroolefins bearing either electron donating or electron
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M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
O
NH2
N
O
OH
O
iii
i
ii
5
3
4
O
N
H2N
HN
N
O
HN
HN
HN
S
HN
S
HN
S
v
iv
O
O
O
7
6
8
Scheme 2. Synthesis of chiral p-tert-butylphenol analogue 8. Reagents and conditions: (i) K2CO3, N-(3-bromopropyl)phthalimide, dry DMF, rt; (ii) N2H4ÁH2O, EtOH, reflux; (iii)
chiral isothiocyanate, CH2Cl2, rt, 24 h; (iv) N2H4ÁH2O, EtOH, reflux; (v) HCHO, NaBH3CN, AcOH, CH3CN, rt, 4 h.
Table 3
4.2. Synthesis of catalysts
Asymmetric Michael addition of acetylacetone with different nitrostyrenes catalyzed
by organocatalyst 2aa
4.2.1. General procedure for the synthesis of chiral calix[4]
arene-based tertiary amine thioureas 2a and 2b
O
R
O
To
a solution of 1a/1b (1.48 g, 1.38 mmol) in 20 mL of
O
O
2a (10 mol %)
acetonitrile, formaldehyde (0.48 g, 16.13 mmol) was added and
the resulting mixture was stirred at room temperature for
15 min. Next, NaBH3CN (0.60 g, 9.49 mmol) was added, followed
15 min later by AcOH (1.79 mL, 18.32 mmol). After for stirring
24 h at room temperature, the reaction mixture was diluted with
2% CH3OH–CHCl3 (100 mL) and washed with 1 M NaOH
(4 Â 50 mL). The aqueous layer was re-extracted with CHCl3
(3 Â 30 mL), the combined organic layer was dried over MgSO4
and the solvent was removed under reduced pressure. The residue
was purified by flash chromatography on silica gel eluting with
CHCl3–MeOH mixtures.
NO2
NO2
+
R
(S)
CH3CN
9
10
11
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2-Br-C6H4 9b
3-Br-C6H4 9c
4-Br-C6H4 9d
2-MeO-C6H4 9e
3-MeO-C6H4 9f
4-MeO-C6H4 9g
2-F-C6H4 9h
11b
11c
11d
11e
11f
11g
11h
11i
61
86
78
97
98
97
59
87
90
75
62
89
77
78
72
84
81
48
89
70
70
80
4-F-C6H4 9i
9
4-Me-C6H4 9j
4-Cl-C6H4 9k
2,4-Cl-C6H3 9l
11j
11k
11l
4.2.1.1. Catalyst 2a.
White solid; 87% yield; mp 145–147 °C,
10
11
[a]
25 = À14.5 (c 1.0, CHCl3); Catalyst 2b: White solid; 86% yield;
D
mp 144–146 °C; [a]
25 = +15.4 (c 1.0, CHCl3); IR (cmÀ1): 3328,
D
a
The reactions were performed with 2 equiv of acetylacetone and 1 equiv of 9 in
0.125 mL of CH3CN in the presence of 10 mol % 2a at room temperature for 4–24 h.
2931, 2861, 1772, 1734, 1717, 1653, 1636, 1540, 1484, 1361,
1299, 1194, 1123, 1094; 1H NMR (400 MHz, CDCl3): d = 8.20 (br
s, 2H), 6.97 (s, 4H), 6.88 (s, 4H), 4.32–3.81 (m, 12H), 3.29 (t,
J = 11.9 Hz, 4H), 2.56–1.91 (m, 20H), 1.83–1.63 (m, 4H), 1.62–
1.45 (m, 4H), 1.17 (s, 22H), 1.04–1.13 (m, 4H), 1.01 (s, 18H) ppm;
NH-signals could not be detected; 13C NMR (100 MHz, CDCl3):
d = 149.3, 147.5, 132.8, 132.6, 127.6, 127.5, 125.9, 125.8, 125.7,
125.4, 40.1, 34.1, 33.8, 33.2, 32.9, 32.5, 32.3, 32.0, 31.6, 31.4,
b
Isolated yields.
c
Determined by chiral HPLC analysis, and the configuration was assigned by
comparison of the retention time and specific rotation with literature data.
stored over molecular sieves. Other commercial grade solvents
were distilled, and then stored over molecular sieves. The drying
agent employed was anhydrous MgSO4.
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M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Table 4
propyl)phthalimide (1.34 g, 5.0 mmol) was added. After stirring
for 12 h at room temperature, the reaction was quenched with
water (10 mL) and extracted with EtOAc (5 mL) three times. The
combined organic phase was dried over MgSO4 and concentrated
to give the crude product, which was purified by flash chromatog-
raphy on silica gel eluting with hexane–ethyl acetate mixtures.
Yellow oil; 91% yield; IR (cmÀ1): 2960, 2868, 2253, 1772, 1708,
1610, 1513, 1393, 1245, 1038, 907; 1H NMR (400 MHz, CDCl3):
d = 7.84–7.82 (m, 2H, ArH), 7.71–7.69 (m, 2H, ArH), 7.26–7.24 (m,
2H, ArH), 6.77–6.75 (m, 2H, ArH), 4.01 (t, 2H, J = 6.0 Hz, –OCH2CH2),
3.90 (t, 2H, J = 6.9, –NCH2CH2), 2.21–2.14 (m, 2H, CH2CH2CH2), 1.28
(s, 9H, t-Bu) ppm; 13C NMR (100 MHz, CDCl3): d = 169.1, 157.2,
144.1, 134.8, 134.6, 132.9, 126.9, 124.1, 123.9, 114.7, 66.3, 36.3,
34.8, 32.3, 29.2 ppm. Anal. Calcd for: C21H23NO3 (337.41): C,
74.75, H, 6.87, N, 4.15. Found: C, 74.71; H, 7.01; N, 4.12.
Asymmetric Michael addition of dimethyl malonate to trans-b-nitrostyrene catalyzed
by 2aa
O
O
MeO
OMe
NO2
NO2
O
O
2a
(10 mol %)
solvent
+
MeO
OMe
9a
12
13a
Entry
Solvent
Time (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
CH2Cl2
Toluene
CHCl3
6
4
6
4
6
6
4
4
4
2
2
10
5
95
99
94
91
92
98
97
98
89
93
96
98
95
71
79
64
72
74
74
65
68
75
16
7
CCl4
ClCH2CH2Cl
EtOAc
CH3CN
THF
MTBE
MeOH
DMF
4.2.3. 3-(4-(tert-Butyl)phenoxy)propan-1-amine 5
Compound
4 (7.5 g, 22.23 mmol) and hydrazine hydrate
(7.5 mL, 85% in H2O) were dissolved in EtOH (40 mL) and refluxed
for 4 h. The mixture was cooled to room temperature and filtered.
The solvent was then removed under vacuum. The residue was dis-
solved in CH2Cl2 (50 mL), washed with water (50 mL), dried over
MgSO4 and purified by flash chromatography on silica gel eluting
with hexane–ethyl acetate mixtures. Green oil; 88% yield; IR
(cmÀ1): 3307, 2958, 2867, 1608, 1513, 1473, 1246, 1184, 588. 1H
NMR (400 MHz, CDCl3): d = 7.31–7.26 (m, 2H, ArH), 6.84 (d,
J = 8.8 Hz, 2H, ArH), 4.03 (t, J = 6.0 Hz, 2H, –OCH2CH2), 2.91 (t,
J = 6.7 Hz, 2H, NH2CH2CH2), 1.96–1.89 (m, 2H, CH2CH2CH2), 1.62
(s, 2H, NH2), 1.30 (s, 9H, t-Bu) ppm; 13C NMR (100 MHz, CDCl3):
d = 126.3, 126.2, 113.9, 65.8, 39.3, 34.0, 34.9, 31.5, 31.3,
29.7 ppm. Anal. Calcd for: C13H21NO (207.31): C, 75.32, H, 10.21,
N, 6.76. Found: C, 75.26, H, 10.40, N, 6.70.
9
10
11
12d
13e
Toluene
Toluene
74
73
a
The reactions were performed with 0.05 mmol of 9a, 0.15 mmol of 12 in 0.2 mL
of solvent in the presence of 10 mol % of catalyst.
b
Isolated yields.
c
Determined by chiral HPLC analysis (Chiralpak AD-H), and the configuration
was assigned by comparison of the retention time and specific rotation with liter-
ature data.
d
Reaction performed at 0 °C.
5 mol % catalyst was used.
e
Table 5
Asymmetric Michael addition of dimethylmalonate with different nitrostyrenes
catalyzed by organocatalyst 2aa
4.2.4. 1-(3-(4-(tert-Butyl)phenoxy)propyl)-3-((1S,2S)-2-(1,3-dioxo-
isoindolin-2-yl)-cyclohexyl)thiourea 6
To a solution of chiral isothiocyanate16 (0.143 g, 0.5 mmol) in
dry CH2Cl2 (15 mL) was added 3-(4-(tert-butyl)phenoxy)propan-
1-amine 5 (0.104 g, 0.5 mmol). The reaction mixture was stirred
for 24 h at rt. After removal of the solvent, the crude product was
purified by flash chromatography (hexane–EtOAc) to afford 6. Yel-
O
R
O
MeO
OMe
NO2
O
O
2a (10 mol %)
NO2
+
R
(S)
MeO
OMe
toluene
12
13
9
low oil; 87% yield; [
a
]
25 = À2.1 (c 1.0, CHCl3); IR (cmÀ1): 3354,
D
2938, 2864, 1767, 1704, 1390, 1241, 1046, 639. 1H NMR
(400 MHz, CDCl3): d = 7.74–7.72 (m, 2H), 7.63–7.61 (m, 2H),
7.31–7.28 (m, 2H), 6.87–6.85 (m, 2H), 6.34–6.22 (m, 1H), 6.00–
5.97 (m, 1H), 4.70 (br s, 2H), 3.98–3.89 (m, 2H), 3.48–3.29 (m,
2H), 2.46–2.13 (m, 2H), 2.02–1.65 (m, 6H), 1.44–1.34 (m, 2H),
1.28 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): d = 181.5, 168.8,
156.0, 143.8, 134.0, 131.7, 126.3, 123.2, 114.0, 54.7, 34.1, 32.9,
31.5, 28.9, 28.7, 25.2, 24.4 ppm. Anal. Calcd for: C28H35N3O3S
(493.66): C, 68.12, H, 7.15, N, 8.51. Found: C, 68.18, H, 7.83, N, 8.44.
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2-Br-C6H4 9b
3-Br-C6H4 9c
4-Br-C6H4 9d
2-MeO-C6H4 9e
3-MeO-C6H4 9f
4-MeO-C6H4 9g
2-F-C6H4 9h
13b
13c
13d
13e
13f
13g
13h
13i
86
92
95
96
97
98
91
97
91
84
91
96
86
75
84
81
50
67
81
80
84
79
88
79
4-F-C6H4 9i
9
4-Me-C6H4 9j
4-Cl-C6H4 9k
2,4-Cl-C6H3 9l
2-NO2-C6H4
13j
13k
13l
10
11
12
4.2.5. 1-((1S,2S)-2-Aminocyclohexyl)-3-(3-(4-(tert-butyl)phen-
oxy)propyl)thiourea 7
13m
a
The reactions were performed with 3 equiv of dimethylmalonate and 1 equiv of
The protected thiourea–amine 6 (1.35 g, 2.73 mmol) and hydra-
zine hydrate (1.35 mL mL, 85% in H2O) were dissolved in EtOH
(35 mL) and refluxed for 6 h. The solvent was evaporated under
vacuum and the residue was dissolved in CHCl3 (20 mL), washed
with water (3 Â 15 mL) and brine (20 mL), dried over MgSO4 and
concentrated to yield a greenish oil (0.834 g, 84%), which was used
in the next step without further purification.
9 in 0.2 mL of toluene in the presence of 10 mol % 2a at room temperature.
b
Isolated yields.
c
Determined by chiral HPLC analysis, and the configuration was assigned by
comparison of the retention time and specific rotation with literature data.
31.1, 29.7, 29.4, 25.0, 24.9, 24.7, 24.6 ppm. Anal. Calcd for:
C68H102N6O4S2 (1131.71): C, 72.17, H, 9.08, N, 7.43. Found: C,
72.15, H, 9.09, N, 7.44.
4.2.6. 1-(3-(4-(tert-Butyl)phenoxy)propyl)-3-((1S,2S)-2-(dime-
thylamino)cyclohexyl)-thiourea 8
4.2.2. 2-(3-(4-(tert-Butyl)phenoxy)propyl)isoindoline-1,3-dione 4
To a stirred suspension of p-tert-butylphenol (0.90 g, 6.0 mmol)
and K2CO3 (1.38 g, 10.0 mmol) in dry DMF (10 mL), N-(3-bromo-
To a solution of 7 (40.0 mg, 0.11 mmol) in 10 mL of acetonitrile,
formaldehyde (0.107 mL, 3.9 mmol) was added and the resulting
mixture was stirred at room temperature for 15 minute. Next,
Please cite this article in press as: Durmaz, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.004

6
M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
NaBH3CN (49.0 mg, 0.78 mmol) was added, followed 15 min later
by AcOH (0.144 mL, 2.52 mmol). After stirring for 4 h at room tem-
perature, the reaction mixture was diluted with 2% CHCl3–CH3OH
(30 mL), and washed with 1 M NaOH (4 Â 25 mL). The aqueous
layer was re-extracted with CHCl3 (3 Â 20 mL), the combined
organic layer was dried over MgSO4 and the solvent was removed
under reduced pressure. The residue was purified by flash chro-
matography on silica gel eluting with CHCl3–MeOH mixtures. Pale
1.0 mL/min, wavelength = 210 nm: tR (major) = 18.4 min, tR
(minor) = 37.3 min]. [
25 = +132.6 (c 1.0, CHCl3).
a]
D
4.3.4. (S)-3-[1-(4-Bromophenyl)-2-nitroethyl)]-pentane-2,4-dione
11d17c
White solid; yield 78%; 78% ee; mp 71 °C; IR (cmÀ1): 1729,
1699, 1547, 1490, 1431, 1362, 1264, 1140, 818. 1H NMR
(400 MHz, CDCl3): d = 7.46 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.4 Hz,
2H), 4.61–4.59 (m, 2H), 4.33 (d, J = 10.8 Hz, 1H), 4.24–4.18 (m,
1H), 2.30 (s, 3H), 1.98 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d = 201.4, 200.6, 135.0, 132.5, 129.6, 122.7, 77.8, 70.4, 42.2, 30.5,
29.7 ppm. HPLC analysis [Chiralpak AS-H column, hexane–2-pro-
panol = 85:15, flow rate: 1.0 mL/min, wavelength = 210 nm: tR
yellow oil; 85% yield; [
a
]
D
25 = À3.2 (c 1.2, CHCl3); IR (cmÀ1): 3218,
2933, 2862, 1608, 1512, 1362, 1240, 1060, 734. 1H NMR
(400 MHz, CDCl3): d = 7.26–7.24 (m, 2H), 6.80–6.78 (m, 2H), 6.60
(br s, 2H), 4.09–3.97 (m, 3H), 3.69–3.48 (m, 3H), 2.41–2.28 (m,
2H), 2.18 (s, 6H), 2.00–1.58 (m, 5H), 1.25 (s, 9H), 1.16–0.98 (m,
3H) ppm; 13C NMR (100 MHz, CDCl3): d = 182.1, 156.2, 143.6,
126.2, 113.9, 66.8, 65.4, 55.7, 40.2, 34.0, 33.0, 31.5, 29.0, 25.0,
24.6, 21.6 ppm. Anal. Calcd for: C22H37N3OS (391.61): C, 67.47, H,
9.52, N, 10.73. Found: C, 67.24, H, 9.88, N, 10.71.
(major) = 17.7 min, tR (minor) = 32.5 min]. [a]
25 = +137.1 (c 1.0,
D
CHCl3).
4.3.5. (S)-3-[1-(2-Methoxyphenyl)-2-nitroethyl]-pentane-2,4-dione
11e17c
4.3. Representative procedure for the asymmetric addition of
2,4–pentanedione to nitroalkenes
Colorless oil; yield 97%; 72% ee; IR (cmÀ1): 1727, 1702, 1596,
1552, 1494, 1359, 1247, 1159, 1024, 758. 1H NMR (400 MHz,
CDCl3): d = 7.29–7.24 (m, 1H), 7.09–7.07 (m, 1H), 6.91–6.87 (m,
2H), 4.86–4.75 (m, 1H), 4.61–4.56 (m, 2H), 4.51–4.45 (m, 1H),
3.88 (s, 3H), 2.28 (s, 3H), 1.93 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d = 202.3, 201.5, 130.2, 129.7, 123.5, 121.2, 111.2, 69.1,
55.4, 38.9, 30.4, 29.7, 28.7 ppm. HPLC analysis [Chiralpak AD-H col-
umn, hexane–2-propanol = 97:3, flow rate: 0.5 mL/min, wave-
length = 210 nm: tR (major) = 38.4 min, tR (minor) = 40.6 min].
To a stirred solution of nitroalkene (0.05 mmol) and chiral
catalyst (0.005 mmol, 10 mol %) in 0.125 mL of solvent was added
2,4-pentanedione (0.1 mmol). After the reaction was complete
(monitored by TLC), the resulting mixture was concentrated and
the residue was purified through column chromatography on silica
gel (eluent, ethyl acetate/hexane 1:4 to 1:1) to afford product
11a–11l. The enantiomeric purity of the product was determined
by using chiral HPLC analysis. Racemic samples of the Michael
adducts were prepared using a racemic catalyst.
[a]
25 = +186.1 (c 0.5, CHCl3).
D
4.3.6. (S)-3-[1-(3-Methoxyphenyl)-2-nitroethyl]-pentane-2,4-
dione 11f17c
4.3.1. (S)-3-(2-Nitro-1-phenylethyl)-pentane-2,4-dione 11a17a
White solid; yield 99%; 94% ee; mp 112–113 °C; IR (cmÀ1):
1732, 1703, 1550, 1496, 1433, 1361, 1272, 1140, 702. 1H NMR
(400 MHz, CDCl3): d = 7.26–7.19 (m, 3H), 7.12–7.10 (m, 2H),
4.58–4.55 (m, 2H), 4.30 (d, J = 10.5 Hz, 1H), 4.21–4.17 (m, 1H),
2.23 (s, 3H), 1.87 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d
201.8, 201.0, 135.9, 129.3, 128.6, 127.9, 78.2, 70.7, 42.7, 30.5,
29.6 ppm. HPLC analysis [Chiralpak AS-H column, hexane–2-
propanol = 85:15, flow rate: 1.0 mL/min, wavelength = 210 nm: tR
White solid; yield 98%; 84% ee; mp 95 °C; IR (cmÀ1): 1732,
1703, 1600, 1554, 1543, 1495, 1437, 1361, 1262, 1141, 1040,
793, 704. 1H NMR (400 MHz, CDCl3): d = 7.24 (s, 1H), 6.82–6.70
(m, 3H), 4.64–4.57 (m, 2H), 4.36 (d, J = 10.8 Hz, 1H), 4.23–4.18
(m, 1H), 3.77 (s, 3H), 2.29 (s, 3H), 1.96 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d = 201.8, 201.0, 160.0, 137.5, 130.4, 119.9,
114.1, 113.6, 78.1, 70.6, 55.2, 42.7, 30.4, 29.6 ppm. HPLC analysis
[Chiralpak AD-H column, hexane–2-propanol = 85:15, flow rate:
1.0 mL/min, wavelength = 210 nm: tR (major) = 9.7 min, tR
(major) = 15.1 min, tR (minor) = 24.1 min]. [
a
]
D
25 = +196.2 (c 1.0,
(minor) = 12.4 min]. [a]
25 = +207.3 (c 0.25, CHCl3).
D
CHCl3).
4.3.7. (S)-3-[1-(4-Methoxyphenyl)-2-nitroethyl]-pentane-2,4-
dione 11g17a
4.3.2. (S)-3-[1-(2-Bromophenyl)-2-nitroethyl]-pentane-2,4-dione
11b17b
White solid; yield 97%; 81% ee; mp 116–118 °C; IR (cmÀ1):
1733, 1705, 1614, 1549, 1515, 1438, 1363, 1261, 1171, 1141,
812. 1H NMR (400 MHz, CDCl3) d = 7.09 (d, J = 8.7 Hz, 2H), 6.83
(d, J = 8.8 Hz, 2H), 4.58–4.55 (m, 2H), 4.32 (d, J = 10.9 Hz, 1H),
4.21–4.15 (m,1H), 3.76 (s, 3H), 2.28 (s, 3H), 1.93 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3): d = 201.9, 201.2, 159.4, 129.0, 127.6,
114.6, 78.4, 70.8, 55.2, 42.1, 30.4, 29.5 ppm. HPLC analysis [Chiral-
pak AD-H column, hexane–2-propanol = 90:10, flow rate: 1.0 mL/
min, wavelength = 210 nm: tR (major) = 15.4 min, tR (minor)
Orange solid; yield 61%, 89% ee; mp 87 °C; IR (cmÀ1): 1727,
1702, 1553, 1472, 1433, 1359, 1259, 1154, 762. 1H NMR
(400 MHz, CDCl3): d = 7.63 (d, J = 7.9 Hz, 1H), 7.30–7.26 (m, 1H),
7.19–7.12 (m, 2H), 4.85–4.71 (m, 2H), 4.68–4.64 (m, 1H), 4.59 (d,
J = 9.4 Hz, 1H), 2.29 (s, 3H), 2.04 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d = 201.9, 200.8, 135.0, 134.0, 129.9, 128.3, 76.2, 69.1,
41.0, 30.9, 28.3 ppm. HPLC analysis [Chiralpak AD-H column,
hexane–2-propanol = 97:3, flow rate: 0.5 mL/min, wave-
length = 210 nm: tR (major) = 21.8 min, tR (minor) = 27.3 min].
= 24.0 min]. [a]
25 = +119.7 (c 2.5, CHCl3).
D
[a]
25 = +209.3 (c 1.0, CHCl3).
D
4.3.8. (S)-3-[1-(2-Fluorophenyl)-2-nitroethyl]-pentane-2,4-dione
11h17b
4.3.3. (S)-3-[1-(3-Bromophenyl)-2-nitroethyl]-pentane-2,4-dione
11c17b
White solid; yield 59%; 48% ee; mp 57–58 °C; IR (cmÀ1): 1730,
1704, 1554, 1494, 1426, 1361, 1267, 1234, 1178, 1144, 767. 1H
NMR (400 MHz, CDCl3): d = 7.32–7.27 (m, 1H), 7.20–7.03 (m, 3H),
4.75–4.60 (m, 2H), 4.49–4.47 (m, 2H), 2.29 (s, 3H), 2.01 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): d = 201.3, 200.7, 130.5, 124.9,
116.4, 76.6, 69.0, 37.9, 30.4, 29.2 ppm. HPLC analysis [Chiralpak
AD-H column, hexane–2-propanol = 90:10, flow rate: 1.0 mL/min,
White solid; yield 86%; 77% ee; mp 102–103 °C; IR (cmÀ1):
1727, 1703, 1550, 1477, 1433, 1383, 1367, 1252, 1141, 790, 699.
1H NMR (400 MHz, CDCl3): d = 7.43 (d, J = 8.9 Hz, 1H), 7.35 (s,
1H), 7.26–7.11 (m, 2H), 4.63–4.61 (m, 2H), 4.33 (d, J = 10.6 Hz,
1H), 4.23–4.18 (m, 1H), 2.29 (s, 3H), 2.00 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d = 201.3, 200.4, 138.5, 131.8, 131.0, 130.8,
126.6, 123.3, 77.7, 70.3, 42.3, 30.5, 29.8 ppm. HPLC analysis
[Chiralpak AS-H column, hexane–2-propanol = 85:15, flow rate:
wavelength = 210 nm:
tR
(major) = 10.4 min,
tR
(minor)
= 11.8 min]. [
a]
D
25 = +186.8 (c 0.4, CHCl3).
Please cite this article in press as: Durmaz, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.004

M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
4.3.9. (S)-3-[1-(4-Fluorophenyl)-2-nitroethyl]-pentane-2,4-dione
11i17c
4.4.1. Dimethyl (S)-2-(2-nitro-1-phenylethyl)malonate 13a18a
White solid; yield 99%; 79% ee; mp 59–61 °C; IR (cmÀ1): 2985,
1727, 1557, 1498, 1456, 1435, 1380, 1266, 1082, 985, 756, 699.
1H NMR (400 MHz, CDCl3): d = 7.34–7.21 (m, 5H), 4.95–4.84 (m,
2H), 4.26–4.22 (m, 1H), 3.86 (d, J = 9.1 Hz, 1H), 3.75 (s, 3H), 3.55
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3): d = 167.8, 167.2, 136.1,
129.0, 128.4, 127.8, 77.4, 54.7, 53.0, 52.8, 42.9 ppm. HPLC analysis
[Chiralpak AD-H column, hexane–2-propanol = 90:10, flow rate:
1.0 mL/min, wavelength = 220 nm: tR (minor) = 17.0 min, tR
Colorless oil; yield 87%; 89% ee; IR (cmÀ1): 1733, 1704, 1550,
1513, 1437, 1363, 1267, 1141, 827. 1H NMR (400 MHz, CDCl3):
d = 7.19–7.15 (m, 2H), 7.04–6.99 (m, 2H), 4.61–4.59 (m, 2H), 4.33
(d, J = 10.8 Hz, 1H), 4.26–4.21 (m, 1H), 2.29 (s, 3H), 1.96 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): d = 201.5, 200.8, 163.7, 161.2,
131.7, 131.7, 129.7, 129.6, 116.5, 116.3, 78.1, 70.6, 42.0, 30.5,
29.6 ppm. HPLC analysis [Chiralpak AD-H column, hexane–2-pro-
panol = 90:10, flow rate: 1.0 mL/min, wavelength = 210 nm: tR
(major) = 28.1 min]. [
a]
25 = À3.7 (c 1.0, CH2Cl2).
D
(major) = 13.0 min, tR (minor) = 26.4 min].
[a]
25 = +12.9 (c 1.0,
D
CHCl3).
4.4.2. Dimethyl (S)-2-(1-(2-bromophenyl)-2-nitroethyl)malonate
13b18b
Colorless oil; yield 86%; 86% ee; IR (cmÀ1): 2958, 1740, 1558,
1435, 1379, 1159, 1025, 756. 1H NMR (400 MHz, CDCl3):
d = 7.61–7.59 (m, 1H), 7.32–7.20 (m, 2H), 7.19–7.11 (m, 1H),
5.15–5.10 (m, 1H), 4.98–4.94 (m, 1H), 4.79–4.74 (m, 1H), 4.10 (d,
J = 7.9 Hz, 1H), 3.72 (s, 3H), 3.65 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): d = 167.7, 167.2, 135.2, 133.9, 129.8, 127.9, 124.7, 75.5,
53.0, 52.9 (2C), 41.4 ppm. HPLC analysis [Chiralcel OD-H column,
hexane–2-propanol = 80:20, flow rate: 0.9 mL/min, wave-
length = 220 nm: tR (major) = 11.7 min, tR (minor) = 19.1 min].
4.3.10. (S)-3-[1-(4-Methylphenyl)-2-nitroethyl]-pentane-2,4-
dione 11j17a
White solid; yield 90%; 70% ee; mp 88–90 °C; IR (cmÀ1): 1731,
1702, 1548, 1430, 1362, 1267, 1140, 813. 1H NMR (400 MHz,
CDCl3): d = 7.13–7.07 (m, 4H), 4.61–4.58 (m, 2H), 4.33 (d,
J = 10.8 Hz, 1H), 4.23–4.17 (m, 1H), 2.29 (s, 6H), 1.94 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): d = 201.9, 201.1, 138.3, 132.8,
130.0, 127.8, 78.3, 70.8, 42.4, 30.4, 29.4, 21.0 ppm. HPLC analysis
[Chiralpak AD-H column, hexane–2-propanol = 90:10, flow rate:
1.0 mL/min, wavelength = 210 nm: tR (major) = 10.2 min, tR
[a]
25 = +5.1 (c 1.0, CHCl3).
D
(minor) = 16.5 min]. [a]
25 = +78.2 (c 2.8, CHCl3).
D
4.4.3. Dimethyl (S)-2-(1-(3-bromophenyl)-2-nitroethyl)malonate
13c18c
Colorless oil; yield 92%; 75% ee; IR (cmÀ1): 2956, 1736, 1556,
1437, 1379, 1237, 1042. 1H NMR (400 MHz, CDCl3): d = 7.43–7.39
(m, 2H), 7.22–7.16 (m, 2H), 4.94–4.83 (m, 2H), 4.24–4.18 (m,
1H), 3.82 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 3.59 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3): d = 167.6, 167.0, 138.5, 131.6, 131.1,
130.5, 126.5, 122.9, 76.9, 54.5, 53.1, 53.0, 42.4 ppm. HPLC analysis
[Chiralcel OD-H column, hexane–2-propanol = 90:10, flow rate:
1.0 mL/min, wavelength = 220 nm: tR (minor) = 21.1 min, tR
4.3.11. (S)-3-[1-(4-Chlorophenyl)-2-nitroethyl]-pentane-2,4-dione
11k17a
White solid; yield 75%; 70% ee; mp 110–111 °C; IR (cmÀ1):
1732, 1701, 1549, 1482, 1361, 1332, 1270, 1141, 821. 1H NMR
(400 MHz, CDCl3): d = 7.26–7.23 (m, 2H), 7.08–7.06 (m, 2H),
4.55–4.53 (m, 2H), 4.27 (d, J = 10.5 Hz, 1H), 4.19–4.13 (m, 1H),
2.23 (s, 3H), 1.91 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d = 201.4, 200.6, 134.5, 134.5, 129.6, 129.3, 77.9, 70.5, 42.1, 30.5,
29.7 ppm. HPLC analysis [Chiralpak AS-H column, hexane–2-pro-
panol = 85:15, flow rate: 1.0 mL/min, wavelength = 210 nm: tR
(major) = 23.5 min]. [a]
25 = +3.1 (c 1.0, CHCl3).
D
(major) = 16.4 min, tR (minor) = 34.0 min].
[a]
25 = +19.2 (c 0.5,
D
4.4.4. Dimethyl (S)-2-(1-(4-bromophenyl)-2-nitroethyl)malonate
13d18c
CHCl3).
White solid; yield 95%; 84% ee; mp 92–94 °C; IR (cmÀ1): 2956,
2922, 1751, 1732, 1554, 1489, 1435, 1344, 1257, 1157, 1013,
829. 1H NMR (400 MHz, CDCl3): d = 7.47–7.44 (m, 2H), 7.13–7.11
(m, 2H), 4.93–4.81 (m, 2H), 4.24–4.18 (m, 1H), 3.82 (d, J = 9.0 Hz,
1H), 3.76 (s, 3H), 3.59 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d = 167.6, 167.0, 135.1, 132.2, 129.6, 122.5, 77.1, 54.4, 53.1, 53.0,
42.3 ppm. HPLC analysis [Chiralpak AD-H column, hexane–2-pro-
panol = 75:25, flow rate: 1.5 mL/min, wavelength = 220 nm: tR
4.3.12. (S)-3-[1-(2,4-Dichlorophenyl)-2-nitroethyl]-pentane-2,4-
dione 11l17b
Colorless oil; yield 62%; 80% ee; IR (cmÀ1): 1730, 1704, 1550,
1475, 1378, 1360. 1H NMR (400 MHz, CDCl3): d = 7.45 (d,
J = 2.1 Hz, 1H), 7.24–7.21 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.84–
4.80 (m, 1H), 4.71–4.61 (m, 2H), 4.54 (d, J = 9.7 Hz, 1H), 2.29 (s,
3H), 2.06 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d = 201.6,
200.5, 135.1, 134.5, 132.1, 130.5, 128.0, 76.0, 68.8, 38.4, 30.9,
28.6 ppm. HPLC analysis [Chiralpak AD-H column, hexane–2-pro-
panol = 90:10, flow rate: 1.0 mL/min, wavelength = 210 nm: tR
(minor) = 7.3 min, tR (major) = 10.7 min]. [a]
25 = +4.9 (c 1.0, CHCl3).
D
4.4.5. Dimethyl (S)-2-(1-(2-methoxyphenyl)-2-nitroethyl)mal-
onate 13e18c
(minor) = 10.0 min, tR (major) = 13.8 min]. [a]
25 = +59.1 (c 2.25,
D
Colorless oil; yield 96%; 81% ee; IR (cmÀ1): 2923, 2254, 1793,
1700, 1554, 1493, 1381, 1247, 1158, 1095, 908, 734, 651. 1H
NMR (400 MHz, CDCl3): d = 7.27–7.22 (m, 1H), 7.13 (dd,
J = 1.6 Hz, 7.8 Hz, 1H), 6.88–6.85 (m, 2H), 5.05–4.99 (m, 1H),
4.90–4.85 (m, 1H) 4.42–4.36 (m, 1H), 4.17 (d, J = 9.9 Hz, 1H), 3.85
(s, 3H), 3.74 (s, 3H), 3.50 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d = 168.2, 167.6, 157.3, 130.5, 129.7, 123.6, 120.8, 111.1, 76.0, 55.4,
52.8, 52.6, 52.5, 40.3 ppm. HPLC analysis [Chiralcel OD-H column,
hexane–2-propanol = 70:30, flow rate: 0.5 mL/min, wave-
length = 220 nm: tR (major) = 14.1 min, tR (minor) = 18.3 min].
CHCl3).
4.4. Representative procedure for the asymmetric addition of
dimethyl malonate to nitroalkenes
A
solution of nitroalkene (0.05 mmol), dimethylmalonate
(19.82 mg, 0.15 mmol) and chiral catalyst (0.005 mmol, 10 mol %)
in 0.2 mL of the desired solvent was stirred at a certain tempera-
ture and for the appropriate time (monitored by TLC). The resulting
mixture was concentrated and the residue was purified via column
chromatography on silica gel (eluent, ethyl acetate/hexane 1:10 to
1:2) to afford product 13a–13m. The enantiomeric purity of the
product was determined by using chiral HPLC analysis. Racemic
samples of the Michael adducts were prepared using racemic
catalyst.
[a]
25 = +4.4 (c 1.0, CHCl3).
D
4.4.6. Dimethyl (S)-2-(1-(3-methoxyphenyl)-2-nitroethyl)mal-
onate 13f18c
White solid; yield 97%; 50% ee; mp 53–55 °C; IR (cmÀ1): 2922,
2852, 1737, 1602, 1552, 1460, 1258, 1040. 1H NMR (400 MHz,
Please cite this article in press as: Durmaz, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.004

8
M. Durmaz et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
CDCl3): d = 7.24–7.20 (m, 1H), 6.81–6.76 (m, 3H), 4.93–4.83 (m,
2H), 4.24–4.18 (m, 1H), 3.85 (d, J = 8.9 Hz, 1H), 3.76 (s, 3H), 3.75
(s, 3H), 3.58 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): d = 167.8,
167.2, 159.8, 137.7, 130.0, 119.8, 113.9, 113.6, 77.3, 55.2, 54.7,
53.0, 52.8, 42.9 ppm. HPLC analysis [Chiralcel OD-H column, hex-
2H), 4.93–4.82 (m, 2H), 4.25–4.20 (m, 1H), 3.82 (d, J = 9.0 Hz,
1H), 3.76 (s, 3H), 3.59 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d = 167.6, 167.0, 134.6, 134.4, 129.3, 129.2, 77.2, 54.5, 53.1, 53.0,
42.3 ppm. HPLC analysis [Chiralcel OD-H column, hexane–2-pro-
panol = 85:15, flow rate: 0.5 mL/min, wavelength = 220 nm: tR
ane–2-propanol = 70:30,
length = 220 nm: tR (minor) = 23.7 min, tR (major) = 27.3 min].
25 = +1.4 (c 1.0, CHCl3).
flow
rate:
0.5 mL/min,
wave-
(major) = 34.7 min, tR (minor) = 39.2 min]. [a]
25 = +3.7 (c 1.0,
D
CHCl3).
[a]
D
4.4.12. Dimethyl (S)-2-(1-(2,4-dichlorophenyl)-2-nitroethyl)mal-
onate 13l
4.4.7. Dimethyl (S)-2-(1-(4-methoxyphenyl)-2-nitroethyl)mal-
onate 13g18c
Yellowish oil; yield 91%; 88% ee; IR (cmÀ1): 2955, 2917, 2848,
1733, 1598, 1377, 1232, 1052. 1H NMR (400 MHz, CDCl3):
d = 7.43 (d, J = 1.8 Hz, 1H), 7.24–7.18 (m, 2H), 5.12–5.07 (m, 1H),
4.96–4.91 (m, 1H), 4.73–4.67 (m, 1H), 4.07 (d, J = 8.3 Hz, 1H),
3.74 (s, 3H), 3.66 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d = 167.6, 167.1, 134.9, 134.8, 132.2, 130.4, 129.4, 127.7, 75.2,
53.11, 53.08, 52.6, 38.9 ppm. HPLC analysis [Chiralcel OD-H col-
umn, hexane–2-propanol = 70:30, flow rate: 0.8 mL/min, wave-
length = 220 nm: tR (major) = 10.1 min, tR (minor) = 21.5 min].
Colorless oil; yield 98%; 67% ee; IR (cmÀ1): 3011, 2957, 2841,
1733, 1557, 1516, 1436, 1258, 1032. 1H NMR (400 MHz, CDCl3):
d = 7.15–7.12 (m, 2H), 6.84–6.81 (m, 2H), 4.90–4.78 (m, 2H),
4.21–4.15 (m, 1H), 3.82 (d, J = 9.2 Hz, 1H), 3.76 (s, 3H), 3.74 (s,
3H), 3.55 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): d = 168.7,
168.0, 160.2, 129.8, 128.6, 115.1, 78.4, 55.9, 55.6, 53.8, 53.6,
43.0 ppm. HPLC analysis [Chiralpak AD-H column, hexane–2-pro-
panol = 70:30, flow rate: 1.0 mL/min, wavelength = 220 nm: tR
(minor) = 10.3 min, tR (major) = 18.2 min].
[
a]
25 = +1.9 (c 1.0,
[a]
25 = +5.6 (c 1.0, CHCl3).
D
D
CHCl3).
4.4.13. Dimethyl (S)-2-(2-nitro-1-(2-nitrophenyl)ethyl)malonate
13m18d
4.4.8. Dimethyl (S)-2-(1-(2-fluorophenyl)-2-nitroethyl)malonate
13h18d
Yellowish oil; yield 96%; 79% ee; IR (cmÀ1): 3018, 2958, 1733,
1558, 1436, 1361. 1H NMR (400 MHz, CDCl3): d = 7.95 (dd,
J = 1.2 Hz, 8.1 Hz, 1H), 7.61–7.57 (m, 1H), 7.50–7.46 (m, 1H),
7.42–7.40 (m, 1H), 5.17 (dd, J = 8.2 Hz, 13.9 Hz, 1H), 5.05 (dd,
J = 4.3 Hz, 14.0 Hz, 1H), 4.77 (td, J = 4.5 Hz, 8.1 Hz, 1H), 4.24 (d,
J = 7.9 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): d = 167.7, 167.1, 149.9, 133.3, 131.1, 129.3, 128.8, 125.5,
75.9, 53.4, 53.2, 53.1, 37.5 ppm. HPLC analysis [Chiralcel OD-H col-
umn, hexane–2-propanol = 70:30, flow rate: 0.9 mL/min, wave-
length = 220 nm: tR (major) = 12.8 min, tR (minor) = 19.4 min].
Colorless oil; yield 91%; 81% ee; IR (cmÀ1): 2958, 2848, 1733,
1557, 1495, 1436, 1259. 1H NMR (400 MHz, CDCl3): d = 7.32–7.21
(m, 2H), 7.13–7.04 (m, 2H), 4.93 (d, J = 6.9 Hz, 2H), 4.48–4.42 (m,
1H), 4.00 (d, J = 9.7 Hz, 1H), 3.77 (s, 3H), 3.55 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3): d = 167.7, 167.1, 162.1, 159.7, 130.49,
130.45, 130.34, 130.3, 124.62, 124.58, 123.0, 122.9, 116.2, 116.0,
76.00, 75.98, 53.10, 53.07, 52.99, 52.97, 52.86, 52.84, 38.6 ppm.
HPLC analysis [Chiralpak AD-H column, hexane–2-propa-
nol = 70:30, flow rate: 1.0 mL/min, wavelength = 220 nm: tR
(minor) = 7.4 min, tR (major) = 9.8 min]. [
a
]
D
25 = À4.2 (c 1.0, CHCl3).
[a]
25 = +3.4 (c 1.0, CHCl3).
D
4.4.9. Dimethyl (S)-2-(1-(4-fluorophenyl)-2-nitroethyl)malonate
13i18a
Acknowledgements
Colorless oil; yield 97%; 80% ee; IR (cmÀ1): 3015, 2956, 2915,
1735, 1702, 1555, 1473, 1381, 1096, 908, 734, 650. 1H NMR
(400 MHz, CDCl3): d = 7.23–7.20 (m, 2H), 7.03–6.99 (m, 2H),
4.93–4.80 (m, 2H), 4.26–4.20 (m, 1H), 3.82 (d, J = 9.1 Hz, 1H),
3.75 (s, 3H), 3.56 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d = 167.6, 167.1, 163.7, 161.2, 131.9, 131.8, 129.7, 129.6, 116.1,
115.9, 77.4, 54.6, 53.0, 52.9, 42.2 ppm. HPLC analysis [Chiralpak
AD-H column, hexane–2-propanol = 70:30, flow rate: 1.0 mL/min,
wavelength = 220 nm: tR (minor) = 8.1 min, tR (major) = 14.6 min].
This work was supported by the Scientific and Technological
Research Council of Turkey (TUBITAK-113Z696) and Research
Foundation of Necmettin Erbakan University (BAP–141110003).
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D
4.4.11. Dimethyl (S)-2(1-(4-chlorophenyl)-2-nitroethyl)malonate
13k18c
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Please cite this article in press as: Durmaz, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.004

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