Concentration Effect in the Asymmetric Michael Addition of Acetone to β-Nitrostyrenes Catalyzed by Primary Amine Thioureas

Article abstract of DOI:10.1055/s-0036-1589408

Bifunctional primary amine thiourea (PAT) organocatalysts show remarkable improvement in enantioselectivity and catalytic activity (turnover frequency) in the asymmetric Michael addition of acetone to β-nitrostyrenes upon dilution. Mechanistic investigati

Full text of DOI:10.1055/s-0036-1589408

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
Z. I. Günler et al.
Paper
Synthesis
Concentration Effect in the Asymmetric Michael Addition of Ace-
tone to β-Nitrostyrenes Catalyzed by Primary Amine Thioureas
Z. Inci Günlera
Ignacio Alfonsoa
Ciril Jimeno*a
S
Ph
X
(10 mol%)
O
N
N
Ph
X
H
H
Miquel A. Pericàs*b,c
NO2
NO2
NH2
8 examples
up to 81% yield
up to 96% ee
a Department of Biological Chemistry and Molecular Modelling,
Institute of Advanced Chemistry of Catalonia (IQAC-CSIC),
Jordi Girona 18-26, 08034 Barcelona, Spain
ciril.jimeno@iqac.csic.es
AcOH (10 mol%), acetone
toluene, rt, < 0.2 M
b Institute of Chemical Research of Catalonia (ICIQ), The Barcelona
Institute of Science and Technology, Av. Països Catalans 16,
43007 Tarragona, Spain
c Departament de Química Inorgànica i Orgànica, Universitat de
Barcelona, 08028 Barcelona, Spain
mpericas@iciq.es
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday
Received: 28.09.2016
Accepted after revision: 07.10.2016
Published online: 14.11.2016
the Mannich reaction, α-alkylation of aldehydes, cycliza-
tions and cycloadditions, and vinylogous aldol and multi-
component Biginelli reactions.3a,b
DOI: 10.1055/s-0036-1589408; Art ID: ss-2016-z0665-op
During mechanistic analysis of the catalytic system
comprising I, we disclosed the subtle yet decisive effects
that acetic acid and water exert over PAT catalysts in the
asymmetric Michael addition of acetone to β-nitrostyrene
(1, Scheme 1).6 These additives modify the reaction mecha-
nism: water minimizes catalyst deactivation by the nitro-
styrene, and acetic acid, which provides the catalyst turn-
over, prevents the formation of an undesired double addi-
tion side product. Although water actually slows down the
reaction rate, the overall result is an enhancement in the
yield of the desired Michael adduct 2a.6
Abstract Bifunctional primary amine thiourea (PAT) organocatalysts
show remarkable improvement in enantioselectivity and catalytic activ-
ity (turnover frequency) in the asymmetric Michael addition of acetone
to β-nitrostyrenes upon dilution. Mechanistic investigations indicate
that this behavior corresponds to the inhibition of off-cycle catalyst de-
activation at low concentration, rather than to the operation of aggre-
gation phenomena at high concentration. Reaction at low concentra-
tion (≤0.2 M in β-nitrostyrene) leads to the minimization of catalyst
deactivation and, thus, to the optimization of yield and ee of the
Michael addition products.
Key words primary amine thioureas, Michael addition, asymmetric
catalysis, organocatalysis, concentration effect
I–IV (10 mol%)
AcOH (10 mol%)
O
Ph
∗
NO2
The bifunctional primary amine thiourea (PAT) catalysts
developed by Tsogoeva1 and Jacobsen2 and their co-workers
in 2006 represented the first truly effective organocatalysts
for the asymmetric Michael addition of challenging sub-
strates like ketones and hindered aldehydes to α,β-unsatu-
rated nitro compounds. Indeed, the use of additives (water
and/or organic acids) was found to be crucial for the devel-
opment of efficient and highly enantioselective Michael ad-
ditions of such challenging substrates. Since then, many ex-
amples have been described, due to the interest of the
asymmetric Michael addition in organic synthesis and as a
benchmark for the development of new catalysts.3,4 Like-
wise, the occurrence of primary amines in the active site of
enzymes such as class I aldolases and pyridoxal phosphate
dependent enzymes, among many others, has also contrib-
uted to stimulating the interest in this kind of catalyst.5 Fur-
thermore, this type of catalyst can perform efficiently in re-
actions not belonging to the 1,4-addition archetype, such as
NO2
Ph
acetone (10 equiv)
toluene
2a
1
I, R =
Ph
S
H2N
HN
epi-I, R =
III, R =
HN
R
Ph
II, R =
Ph
Ph
IV, R =
Ph
Scheme 1 Michael addition of acetone to β-nitrostyrene catalyzed by
bifunctional PAT catalysts I–IV
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
Z. I. Günler et al.
Paper
Synthesis
In continuation of our efforts in asymmetric organoca-
talysis in general, and Michael additions in particular,7 we
now show that PAT catalysis results in significant changes
in conversion and enantioselectivity upon changes in the
reactants concentration. Essentially, dilution leads consis-
tently to Michael adducts with higher ee values. This behav-
ior was found to be identical for the five PAT catalysts stud-
ied herein (Scheme 1). Finally, we show that, under these
new reaction conditions, catalyst IV behaves as a simple yet
efficient PAT catalyst for the Michael addition of acetone to
β-nitrostyrenes without the need for a precise control of
the amount of water present in the reaction medium.
Several PAT organocatalysts were synthesized according
to literature methods and evaluated under the reaction
conditions outlined in Scheme 1. It is important to note that
water did not need to be added to the reaction mixture,
since the presence of sufficient water was secured by ad-
ventitious traces present in solvents, reagents and the at-
mosphere.8 Catalysts I, epi-I and II were successfully devel-
oped for this reaction by Tsogoeva and co-workers.1 Cata-
lyst III, developed initially by Yan and co-workers, lacks
additional stereocenters and therefore can be considered a
simplified version of I and epi-I.9 Finally, catalyst IV, at first
designed and tested for asymmetric hydrocyanation reac-
tions by Fuerst and Jacobsen, with little success,10 features a
bulkier benzhydryl side moiety, again with no additional
stereocenters (Scheme 1).
Hence, acetic acid was used as the only controlled addi-
tive to promote the Michael addition. The amount of AcOH
was re-optimized for catalyst I. Indeed, Figure 1 shows that
it is important not to surpass 10 mol% AcOH; above this val-
ue, a decrease in conversion takes place. We also observed
that the ee remained unaffected by the amount of acid (83–
86% ee). Therefore, the optimal amount of AcOH must be
set in a narrow range of 5–10 mol%. Thereafter, 10 mol%
AcOH was used in our work to ensure that there was always
enough acid, but being especially accurate not to surpass
that amount (Figure 1).
Then, the benchmark Michael addition was studied at
several concentrations with PAT catalysts I–IV, using 10
mol% catalyst and 10 mol% AcOH. In all cases, a clear im-
provement in ee was observed upon dilution, the amount
of solvent being the only variable. For reactions using 0.335
mmol of β-nitrostyrene, enantioselectivity increased
asymptotically for all catalysts studied (Figure 2) from ex-
periments performed at high concentration (toluene vol-
ume of 0.15 mL plus acetone volume of 0.25 mL, [1]0 = 0.84
M) to experiments at low concentration (toluene volume of
5 mL plus acetone volume of 0.25 mL, [1]0 = 0.06 M). For
catalyst I, the increase in ee was 14%, whereas for epi-I it
was 24%. Catalyst II also exhibited an improvement of 14%
ee. For catalyst III, the improvement was 17% ee, and for
catalyst IV, up to 15% ee. Clearly, the stereoselectivity of the
Michael addition significantly increased, reaching above
90% ee (product 2a) for most catalysts under the more di-
luted conditions (5 mL toluene added, [1]0 = 0.06 M). Fur-
ther dilution below 0.06 M (not shown) led to poorer re-
sults, though, likely due to a decrease in catalytic efficiency.
For the analogous results for epi-I, see the Supporting Infor-
mation.
Regarding conversion, it was also clear that higher con-
centrations (0.15 mL toluene, [1]0 = 0.84 M) are not suitable
for running this reaction with any of the catalysts studied.
Dilution improved the conversion as well, with best results
being obtained for an initial concentration of β-nitrosty-
rene around 0.3 M (1 mL toluene added). Further dilution
led, in general, to a slight but still acceptable decrease in
conversion. Finally, ≥95% conversion can be safely achieved
for all five catalysts I–IV in the range of [1]0 = 0.06–0.30 M
(1–5 mL toluene added, Figure 2).
In this way, these experiments show the importance of
optimizing the reactant concentration as a key parameter in
PAT catalysis. For the catalysts studied herein, a compro-
mise between the optimal reagent concentration for enan-
tioselectivity and conversion must be decided upon. An ini-
tial concentration of β-nitrostyrene of 0.15 M seems a good
choice in view of our results (2 mL toluene plus acetone for
0.335 mmol β-nitrostyrene), and this value was therefore
used as the optimal conditions to test the synthetic utility
and substrate scope of catalyst IV (vide infra). Our data also
suggest that the side moiety of the thiourea in PAT catalysts
might not be of great importance in determining activity
and enantioselectivity, once a catalytic scaffold (enantio-
pure trans-1,2-diaminocyclohexane) has been set. Reaction
conditions, including additives and concentration, might
play a much more important role in defining the final re-
sults of PAT-based catalytic systems.
Then, we evaluated the substrate scope under the opti-
mal concentration (initial concentration of nitrostyrene of
0.15 M, 10 mol% catalyst IV and 10 mol% AcOH), as shown
in Table 1. High isolated yields and enantioselectivities in
Figure 1 Effect of the AcOH amount in the Michael addition of ace-
tone to β-nitrostyrene (1). Reagents and conditions: catalyst I (10 mol%),
[1]0 = 0.45 M, acetone (10 equiv), toluene, r.t., 24 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
Z. I. Günler et al.
Paper
Synthesis
Table 1 Asymmetric Michael Addition of Acetone to Substituted β-Ni-
trostyrenesa
Entry Product
Yieldb (%) eec (%)
O
Ph
1
2
2a
2b
72
93
NO2
OMe
76
96
O
O
NO2
3
4
2c
80
81
91
89
OMe
NO2
Br
2d
O
O
O
O
O
NO2
CH3
5
6
7
8
2e
2f
55
77
80
54
87
92
92
84
NO2
Cl
Cl
NO2
F
2g
2h
NO2
CF3
Figure 2 Effect of reactant concentration on ee (left y axis) and con-
version (right y axis) for the addition of acetone to β-nitrostyrene (1; 50
mg, 0.335 mmol) catalyzed by I–IV, plotted against the amount of tolu-
ene added to the reaction. Reagents and conditions: catalyst (10 mol%),
AcOH (10 mol%), acetone (10 equiv), toluene, r.t., 24 h. Conversion de-
termined by 1H NMR spectroscopy of the crude samples; ee determined
by HPLC on a chiral stationary phase.
NO2
a Reaction conditions: [nitrostyrene]0 = 0.15 M, catalyst IV (10 mol%),
AcOH (10 mol%), acetone (10 equiv), toluene, r.t., 24 h.
b Isolated yield after purification by flash chromatography on silica gel.
c Determined by chiral-phase HPLC.
groups. No particular dependence of enantioselectivity on
electronic effects was observed, although the most modest
result corresponds to a β-nitrostyrene containing a strong
electron-withdrawing group (p-CF3, entry 8). These results
the range 84–96% ee were obtained for a variety of substi-
tuted β-nitrostyrenes, bearing electron-donating (entries 2,
3 and 5) or electron-withdrawing (entries 4 and 6–8)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
Z. I. Günler et al.
Paper
Synthesis
demonstrate that IV is a simple yet reliable catalyst for this
particular reaction.
or a reverse reaction of the addition product with the free
PAT catalyst was never detected (see the Supporting Infor-
mation).6
The most common explanation for the correlation be-
tween dilution and enantioselectivity observed in this
study would invoke catalyst self-aggregation, since some
thioureas and squaramides are known to undergo concen-
tration-dependent aggregation that has a strong impact on
their performance as asymmetric catalysts.11,12 High aggre-
gation phenomena because of gelation can even lead to in-
version of stereoselectivity.13 In these compounds, aggrega-
tion usually takes place through the establishment of inter-
molecular hydrogen bonds between thiourea (or
squaramide) groups.
However, we have discarded catalyst aggregation phe-
nomena in PAT catalysis because NMR dilution experiments
on I proved specifically that no aggregation takes place in
solution in the presence of AcOH, although a weak di-
merization constant (Kdimer = 25 M–1 at 25 °C) can be associ-
ated with the acid-free catalyst in solution (see the Sup-
porting Information for details). Moreover, the absence of
nonlinear effects in the asymmetric Michael addition cata-
lyzed by IV (see the Supporting Information), as also occurs
with Takemoto’s catalyst (a tertiary amine thiourea cata-
lyst), further supports this observation.14 Finally, we were
able to obtain single crystals of IV·AcOH suitable for X-ray
diffraction analysis (Figure 3). No thiourea–thiourea con-
tacts were observed in the solid state either; instead,
thiourea–acetate and thiourea–ammonium hydrogen
bonding are the norm.
It could be argued that these changes in conversion and
enantioselectivity can be due to changes in pH due to dif-
ferent concentrations of AcOH that might affect a non-
asymmetric background reaction. However, assuming an
aqueous solution, it can be calculated that the pH would
only decrease from 3.5 to 2.9 when going from the most di-
luted conditions to the most concentrated ([1]0 = 0.06 M to
0.84 M). Moreover, Michael addition was never observed in
the absence of a PAT catalyst.
Therefore, once the occurrence of product inhibition is
discarded,6 the most likely explanation for the observed
concentration effect must rely on the higher stability of the
PAT catalyst at low concentration. Indeed, catalyst deactiva-
tion by the nitrostyrene is an off-cycle process in direct
competition with the main catalytic cycle leading to the
Michael adduct.6 If dilution makes this process kinetically
disfavored (e.g., upon dilution, a second order reaction like
nitrostyrene polymerization should be disfavored ahead of
a first order reaction),16 a higher amount of active catalyst
would be available at a given reaction time for the main, en-
antioselective, cycle.
To further prove this assumption, we used quantitative
1H NMR analysis to study changes in the concentration of β-
nitrostyrene (1) with time for three different initial concen-
trations ([1]0 = 0.45, 0.34 and 0.23 M) using catalyst I. In or-
der to check the effect of the β-nitrostyrene concentration
exclusively, all other concentrations (catalyst, acetone,
AcOH and water) were kept constant. By applying reaction
progress kinetic analysis,17 we were able to construct turn-
over frequency (TOF) vs [1] plots for the three sets of reac-
tions (Figure 4 and Supporting Information). The results of
this study are clear: reactions performed under more dilut-
ed conditions are faster and exhibit higher TOF. This is in-
deed in agreement with our previous conclusion that cata-
Figure 3 Unit cell of IV·AcOH showing intra- and intermolecular hy-
drogen bonding. Sulfur, yellow; nitrogen, blue; oxygen, red; carbon,
gray. Non-H-bonding hydrogen atoms have been omitted for clarity. El-
lipsoid probability level set at 50%. CCDC 1437478.
Therefore, the explanation for such a concentration ef-
fect must respond to other mechanistic aspects of the reac-
tion. Reversibility, which has a decisive impact on yield and
stereoselectivity of the Michael addition of α,α-disubstitut-
ed aldehydes to nitroolefins,15 must be of negligible impor-
tance for the Michael addition of acetone since, for exam-
ple, the ee of the reaction product remains constant over
time when catalyst IV is used. Likewise, product inhibition
Figure 4 Effect of the initial concentration of 1 on TOF in the Michael
addition of acetone to β-nitrostyrene (1). Reagents and conditions:
[I]0 = 0.045 M, [acetone]0 = 4.5 M, [AcOH]0 = 0.011 M, [water]0 = 0.045
M, toluene, r.t. [1]0 = 0.45 M, diamonds; [1]0 = 0.34 M, squares;
[1]0 = 0.23 M, circles.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
Z. I. Günler et al.
Paper
Synthesis
lyst deactivation by the nitrostyrene takes place at high
concentration. From these results, the apparent first-order
kinetic constants for the three concentrations could be cal-
culated, and showed a threefold increase in TOF by just di-
luting the initial β-nitrostyrene concentration from
[1]0 = 0.45 M to 0.23 M (Table 2).
silica gel eluting with hexane–EtOAc mixtures of increasing polarity.
Catalyst IV was isolated as a white foam; yield: 2.3 g (6.83 mmol,
78%). The spectroscopic characterization of IV matched the literature
data.
1H NMR (400 MHz, DMSO-d6): δ = 8.20 (br, 1 H, NHCS), 7.42 (br d, J =
6.0 Hz, 1 H, NHCS), 7.40–7.20 (m, 10 H, CH Ar), 6.68 (s, 1 H, CHPh2),
3.75 (br, 1 H, CHNH), 2.43 (m, 1 H, CHNH2), 2.00 (m, 1 H, CH Cy), 1.78
(m, 1 H, CH Cy), 1.58 (m, 2 H, CH Cy), 1.25–0.95 (m, 4 H, CH Cy).
Table 2 Observed First-Order Kinetic Constants for the Reactions Plot-
ted in Figure 4
13C NMR (100 MHz, DMSO-d6): δ = 182.1 (C=S), 142.7 (C Ar), 128.4
(CH Ar), 127.2 (CH Ar), 126.9 (CH Ar), 60.4 (CHNH), 59.8 (CHPh2), 54.3
(CHNH2), 34.7 (CH2 Cy), 31.4 (CH2 Cy), 24.5 (CH2 Cy), 24.3 (CH2 Cy).
[1]0 [M]
k
obsd [M–1·h–1
]
Error
± 0.11
Michael Addition Dilution Studies; General Procedure
0.45
0.34
0.23
2.20
3.96
7.00
In a vial, the catalyst (0.0335 mmol, 0.1 equiv) and β-nitrostyrene (50
mg, 0.335 mmol, 1 equiv) were weighed, then dissolved in toluene (2
mL, varied for other reaction concentrations). To this solution, AcOH
(0.1 equiv) was added [10 μL of a stock solution of AcOH (200 μL, 3.5
mmol) in toluene (1 mL)]. Finally, acetone (250 μL, 3.35 mmol, 10
equiv) was added and the reaction mixture was stirred at r.t. for 24 h.
To quench the reaction, water was added, and the organic phase was
extracted with EtOAc and dried over MgSO4. The solvent was evapo-
rated in vacuo and the crude mixture was analyzed by 1H NMR spec-
troscopy to determine the conversion. HPLC samples were prepared
from the crude reaction mixture and analyzed using a Phenomenex
Lux 5 μm Amylose-2 column (hexane–i-PrOH, 90:10, 1 mL/min, 209
nm).
± 0.11
± 0.02
The observed increase in ee of the Michael adduct upon
dilution can be simply attributed to this increase in TOF of
the catalytic asymmetric process ahead of non-asymmetric
background reactions. The conclusion is that a reaction run
under diluted conditions keeps side reactions hampering
the Michael addition under control, resulting in an efficient
process.
To sum up, we have found a remarkable and general
concentration effect in the asymmetric Michael addition of
acetone to β-nitrostyrenes catalyzed by primary amine
thioureas. When the reactant concentration is decreased
(dilution), the ee values increase significantly while conver-
sion remains high. Under the optimal concentration
([1]0 = 0.15 M), excellent results can be obtained. Finally, we
have successfully applied catalyst IV to the asymmetric
Michael addition of acetone to β-nitrostyrenes for the first
time. It thus has become apparent that, in these PAT-cata-
lyzed Michael additions, reaction concentration plays a fun-
damental role and must be thoroughly optimized to ensure
the highest performance of the catalyst.
Preparative Michael Addition ([Nitroalkene]0 = 0.15 M); General
Procedure
In a 10-mL flask, catalyst IV (34 mg, 0.1 mmol, 0.1 equiv) and the cor-
responding nitroalkene (1 mmol, 1 equiv) were weighed, then dis-
solved in toluene (6 mL). To this solution, AcOH (5.7 μL, 0.1 mmol, 0.1
equiv) and acetone (0.75 mL, 10 mmol, 10 equiv) were added. The re-
action mixture was stirred at r.t. for 24 h. Then, water was added, and
the mixture was transferred to a separation funnel. The organic phase
was extracted with EtOAc and dried over MgSO4. The solvent was
evaporated in vacuo and the crude mixture was purified by flash
chromatography on silica gel (EtOAc–hexane, 1:4). All adducts are
known compounds, and our spectroscopic data match the literature
data.
(R)-5-Nitro-4-phenylpentan-2-one (2a)1a,19
All reagents were purchased and used without any further purifica-
tion. 4-Trifluoromethyl-β-nitrostyrene was synthesized according to
a literature procedure.18 Solvents were directly used from the bottle,
unless otherwise indicated. Unless otherwise stated, all reactions
were performed in air. Column chromatography and TLC were per-
formed on silica gel using UV light and/or indicator stains to visualize
the products. 1H and 13C NMR spectra were measured in the indicated
deuterated solvent at 25 °C on an Automatic Varian VNMRS 400 MHz
spectrometer with OneNMR Probe. Chemical shifts are reported in
ppm downfield and upfield from TMS, and referenced to solvent reso-
nances.
The preparative Michael addition procedure was followed using
trans-β-nitrostyrene (149 mg, 1 mmol). Product 2a (149 mg, 0.72
mmol, 72% isolated yield; 93% ee (R)) was obtained as a white solid.
[α]D20 –6.8 (c 0.4, CHCl3).
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 19.8 (major), 22.4 (minor) min.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.10 (m, 5 H), 4.75–4.55 (m, 2 H),
4.02 (m, 1 H), 2.90 (d, J = 7.0 Hz, 2 H), 2.12 (s, 3 H).
(R)-4-(4-Methoxyphenyl)-5-nitropentan-2-one (2b)1a,19
The preparative Michael addition procedure was followed using
trans-4-methoxy-β-nitrostyrene (179 mg, 1 mmol). Product 2b (180
mg, 0.76 mmol, 76% isolated yield; 96% ee (R)) was obtained as a
white solid.
Synthesis of Catalyst IV1a,10
Benzhydryl isothiocyanate (1.97 g, 8.75 mmol) was added over a peri-
od of 1 h to a stirred solution of (S,S)-1,2-diaminocyclohexane (1 g,
8.75 mmol) in anhyd CH2Cl2 (17 mL). The reaction mixture was
stirred for a further 3 h at r.t. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography on
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 28.8 (major), 30.4 (minor) min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
Z. I. Günler et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.82 (d, J = 8.6
Hz, 2 H), 4.70–4.50 (m, 2 H), 3.90 (m, 1 H), 3.75 (s, 3 H), 2.89 (m, 2 H),
2.08 (s, 3 H).
(R)-5-Nitro-4-(4-(trifluoromethyl)phenyl)pentan-2-one (2h)22
The preparative Michael addition procedure was followed using
trans-4-trifluoromethyl-β-nitrostyrene (217 mg, 1 mmol). Product
2h (149 mg, 0.54 mmol, 54% isolated yield; 84% ee (R)) was obtained
as a white solid.
(R)-4-(2-Methoxyphenyl)-5-nitropentan-2-one (2c)20
The preparative Michael addition procedure was followed using
trans-2-methoxy-β-nitrostyrene (179 mg, 1 mmol). Product 2c (190
mg, 0.80 mmol, 80% isolated yield; 91% ee (R)) was obtained as a
white solid.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 13.7 (major), 14.9 (minor) min.
1H NMR (400 MHz, CDCl3): δ = 7.23 (m, 2 H), 7.01 (m, 2 H), 4.75–4.50
(m, 2 H), 4.01 (m, 1 H), 2.82 (m, 2 H), 2.10 (s, 3 H).
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 21.0 (major), 23.2 (minor) min.
1H NMR (400 MHz, CDCl3): δ = 7.25–6.83 (m, 4 H), 4.70 (m, 2 H), 4.22
(m, 1 H), 3.80 (s, 3 H), 3.00 (m, 2 H), 2.08 (s, 3 H).
Acknowledgment
Financial support from MINECO (Grants CTQ2015-70117-R and
CTQ2015-69136-R), Generalitat de Catalunya (Grants 2014SGR231
and 2014SGR827) and the ICIQ Foundation is acknowledged. We also
thank MINECO for a Severo Ochoa Excellence Accreditation 2014–
2018 (SEV-2013-0319). C.J. thanks the Ramón y Cajal program (RYC-
2010-06750) for financial support. Z.I.G. holds a FI-DGR predoctoral
fellowship (2013FI_B 00395).
(R)-4-(4-Bromophenyl)-5-nitropentan-2-one (2d)20
The preparative Michael addition procedure was followed using
trans-4-bromo-β-nitrostyrene (228 mg, 1 mmol). Product 2d (232
mg, 0.81 mmol, 81% isolated yield; 89% ee (R)) was obtained as a
white solid.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 26.8 (major), 31.1 (minor) min.
1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.4
Supporting Information
Hz, 2 H), 4.70–4.50 (m, 2 H), 4.02 (m, 1 H), 2.88 (m, 2 H), 2.14 (s, 3 H).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1589408.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(R)-5-Nitro-4-(p-tolyl)pentan-2-one (2e)21
The preparative Michael addition procedure was followed using
trans-4-methyl-β-nitrostyrene (163 mg, 1 mmol). Product 2e (122
mg, 0.55 mmol, 55% isolated yield; 87% ee (R)) was obtained as a
white solid.
References
(1) (a) Tsogoeva, S. B.; Wei, S. W. Chem. Commun. 2006, 1451.
(b) Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Adv. Synth. Catal.
2006, 348, 826.
(2) (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 6366.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 18.5 (major), 20.7 (minor) min.
1H NMR (400 MHz, CDCl3): δ = 7.30–6.80 (m, 4 H), 4.70 (m, 2 H), 4.21
(m, 1 H), 3.82 (s, 3 H), 3.05–2.85 (m, 2 H), 2.10 (s, 3 H).
(3) For reviews, see: (a) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B.
Org. Biomol. Chem. 2013, 11, 7051. (b) Tsakos, M.; Kokotos, C. G.
Tetrahedron 2013, 69, 10199. (c) Peng, F.; Shao, Z. J. Mol. Catal.
A: Chem. 2008, 285, 1.
(R)-4-(2,4-Dichlorophenyl)-5-nitropentan-2-one (2f)22
The preparative Michael addition procedure was followed using
trans-2,4-dichloro-β-nitrostyrene (218 mg, 1 mmol). Product 2f (213
mg, 0.77 mmol, 77% isolated yield; 92% ee (R)) was obtained as a
white solid.
(4) For selected examples, see: (a) Tsakos, M.; Kokotos, C. G.;
Kokotos, G. Adv. Synth. Catal. 2012, 354, 740. (b) Kokotos, C. G.;
Kokotos, G. Adv. Synth. Catal. 2009, 351, 1355. (c) Dudzinski, K.;
Pakulska, A. M.; Kwiatkowski, P. Org. Lett. 2012, 14, 4222.
(5) (a) John, R. A. Biochim. Biophys. Acta 1995, 1248, 81.
(b) Maegley, K. A.; Admiraal, S. J.; Herschlag, D. Proc. Natl. Acad.
Sci. U.S.A. 1996, 93, 8160. (c) Jornvall, H.; Persson, B.; Krook, M.;
Atrian, S.; Gonzalez-Duarte, R.; Jeffery, J.; Ghosh, D. Biochemis-
try 1995, 34, 6003. (d) Shuman, S.; Schwer, B. Mol. Microbiol.
1995, 17, 405. (e) Radominska-Pandya, A.; Czernik, P. J.; Little, J.
M.; Battaglia, E.; Mackenzie, P. I. Drug Metab. Rev. 1999, 31, 817.
(f) Gefflaut, T.; Blonski, C.; Perie, J.; Willson, M. Prog. Biophys.
Mol. Biol. 1995, 63, 301.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 23.8 (major), 28.5 (minor) min.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.10 (m, 3 H), 4.75 (m, 2 H), 4.41
(m, 1 H), 3.10–2.80 (m, 2 H), 2.16 (s, 3 H).
(R)-4-(4-Fluorophenyl)-5-nitropentan-2-one (2g)20
The preparative Michael addition procedure was followed using
trans-4-fluoro-β-nitrostyrene (167 mg, 1 mmol). Product 2g (180 mg,
0.80 mmol, 80% isolated yield; 92% ee (R)) was obtained as a white
solid.
(6) Günler, Z. I.; Companyó, X.; Alfonso, I.; Burés, J.; Jimeno, C.;
Pericàs, M. A. Chem. Commun. 2016, 52, 6821.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–i-PrOH,
90:10, 1 mL/min, 209 nm): tR = 15.8 (major), 17.2 (minor) min.
(7) For recent examples, see: (a) Serra-Pont, A.; Alfonso, I.; Jimeno,
C.; Solà, J. Chem. Commun. 2015, 51, 17386. (b) Kasaplar, P.;
Ozkal, E.; Rodríguez-Escrich, C.; Pericàs, M. A. Green Chem.
2015, 17, 3122. (c) Sagamanova, I. K.; Sayalero, S.; Martínez-
Arranz, S.; Albéniz, A. C.; Pericàs, M. A. Catal. Sci. Technol. 2015,
5, 754. (d) Jimeno, C.; Cao, L.; Renaud, P. J. Org. Chem. 2016, 81,
1251.
1H NMR (400 MHz, CDCl3): δ = 7.22 (m, 2 H), 7.02 (m, 2 H), 4.75–4.50
(m, 2 H), 4.01 (m, 1 H), 2.83 (m, 2 H), 2.12 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
Z. I. Günler et al.
Paper
Synthesis
(8) Jimeno, C. Org. Biomol. Chem. 2016, 14, 6147.
(9) Zhang, X.-J.; Liu, S.-P.; Lao, J.-H.; Du, G.-J.; Yan, M.; Chan, A. S. C.
Tetrahedron: Asymmetry 2009, 20, 1451.
(14) (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119. (b) Takemoto, Y. Chem. Pharm.
Bull. 2010, 58, 593.
(10) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964.
(11) (a) Jang, H. B.; Rho, H. S.; Oh, J. S.; Nam, E. H.; Park, S. E.; Bae, H.
Y.; Song, C. E. Org. Biomol. Chem. 2010, 8, 3918. (b) Lee, J. W.;
Ryu, T. H.; Oh, J. S.; Bae, H. Y.; Jang, H. B.; Song, C. E. Chem.
Commun. 2009, 7224. (c) Oh, J.-S.; Lee, J.-W.; Ryu, T. H.; Lee, J.
H.; Song, C. E. Org. Biomol. Chem. 2012, 10, 1052. (d) Oh, S. H.;
Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E.
Angew. Chem. Int. Ed. 2008, 47, 7872. (e) Rho, H. S.; Oh, S. H.;
Lee, J. W.; Lee, J. Y.; Chin, J.; Song, C. E. Chem. Commun. 2008,
1208.
(15) (a) Ji, Y.; Blackmond, D. G. Catal. Sci. Technol. 2014, 4, 3505.
(b) Burés, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc.
2011, 133, 8822.
(16) (a) Barbier, V.; Couty, F.; David, O. R. P. Eur. J. Org. Chem. 2015,
3679. (b) Berry, R. W. H.; Mazza, R. J. Polymer 1973, 14, 172.
(17) Blackmond, D. G. Angew. Chem. Int. Ed. 2005, 44, 4302.
(18) Simpson, A. J.; Lam, H. W. Org. Lett. 2013, 15, 2586.
(19) Morris, D. J.; Partridge, A. S.; Manville, C. V.; Racys, D. T.;
Woodward, G.; Docherty, G.; Wills, M. Tetrahedron Lett. 2010,
51, 209.
(12) Retini, M.; Bergonzinia, G.; Melchiorre, P. Chem. Commun. 2012,
48, 3336.
(20) Xue, F.; Zhang, S.; Duan, W.; Wang, W. Adv. Synth. Catal. 2008,
350, 2194.
(13) Rodríguez-Llansola, F.; Miravet, J. F.; Escuder, B. Chem. Eur. J.
2010, 16, 8480.
(21) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008, 3302.
(22) Gu, Q.; Guo, X.-T.; Wu, X.-Y. Tetrahedron 2009, 65, 5265.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G