“This is an Accepted Manuscript of an article published by Thieme Publishing Group in Synthesis on 14th November, 2016, available online at https://www.thiemeconnect.de/products/ejournals/abstract/10.1055/S-0036-1589408“

Concentration Effect in the Asymmetric Michael Addition of Ace- tone to βNitrostyrenes Catalyzed by Primary Amine Thioureas
Z. Inci Günler

a

a
Ignacio Alfonso
a
Ciril Jimeno*
Miquel A. Pericàs* b,c
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 

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

aldol and multi- component Biginelli reactions.3a,b
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

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 the Mannich reaction, α-alkylation of
aldehydes, cycliza- tions and cycloadditions, and vinylogous

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 βnitrostyrenes 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 improvement 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 experiments 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 diluted conditions (5 mL toluene added, [1]0 = 0.06 M). Further 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 Information.
Regarding conversion, it was also clear that higher concentrations (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 compromise between the optimal reagent concentration for enantioselectivity and conversion must be decided upon. An initial 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

the range 84–96% ee were obtained for a variety of
substituted β-nitrostyrenes, bearing electron-donating
(entries 2, 3 and 5) or electron-withdrawing (entries 4

and 6–8) groups. No particular dependence of
enantioselectivity on electronic effects was observed,
although the most modest result corr esponds to a β-

nitrostyrene containing a strong electron-withdrawing
group (p-CF3, entry 8). These results
demonstrate that IV is a simple yet reliable catalyst for this
particular reaction.
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.

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 or a reverse reaction of
the addition product with the free PAT catalyst was never

detected (see the Supporting Infor- mation).6
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, enantioselective, 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-

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 calculated, and showed a threefold increase in TOF by just diluting the initial β-nitrostyrene concentration from [1]0 = 0.45
M to 0.23 M (Table 2).

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 conversion 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.
All reagents were purchased and used without any further
purification.
4-Trifluoromethyl-β-nitrostyrene
was
18 Solvents
synthesized according to a literature procedure.
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.
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)-1,2diaminocyclohexane (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 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-d ): δ = 8.20 (br, 1 H, NHCS),
6
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).
13C NMR (100 MHz, DMSO-d ): δ = 182.1 (C=S), 142.7 (C
6
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).
Michael Addition Dilution Studies; General Procedure
In a vial, the catalyst (0.0335 mmol, 0.1 equiv) and βnitrostyrene (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).
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
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-(4Methoxyphenyl)-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.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 28.8 (major), 30.4
(minor) min.

1H NMR (400 MHz, CDCl ): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.82
3
(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)-4-(2-Methoxyphenyl)-5-nitropentan-2-one (2c)20

1H NMR (400 MHz, CDCl ): δ = 7.22 (m, 2 H), 7.02 (m, 2 H),
3
4.75–4.50 (m, 2 H), 4.01 (m, 1 H), 2.83 (m, 2 H), 2.12 (s, 3 H).
(R)-5-Nitro-4-(4
trifluoromethyl)phenyl)pentan-2-one
22
(2h)

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–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 21.0 (major), 23.2
(minor) min.
1H NMR (400 MHz, CDCl ): δ = 7.25–6.83 (m, 4 H), 4.70 (m,
3
2 H), 4.22 (m, 1 H), 3.80 (s, 3 H), 3.00 (m, 2 H), 2.08 (s, 3 H).
(R)-4-(4-Bromophenyl)-5-nitropentan-2-one (2d)20

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.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 13.7 (major), 14.9
(minor) min.
1H NMR (400 MHz, CDCl ): δ = 7.23 (m, 2 H), 7.01 (m, 2 H),
3
4.75–4.50 (m, 2 H), 4.01 (m, 1 H), 2.82 (m, 2 H), 2.10 (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).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1589408.
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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–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 26.8 (major), 31.1
(minor) min.
1H NMR (400 MHz, CDCl ): δ = 7.48 (d, J = 8.4 Hz, 2 H), 7.12
3
(d, J = 8.4 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).
(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.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 18.5 (major), 20.7
(minor) min.
1H NMR (400 MHz, CDCl ): δ = 7.30–6.80 (m, 4 H), 4.70 (m,
3
2 H), 4.21 (m, 1 H), 3.82 (s, 3 H), 3.05–2.85 (m, 2 H), 2.10 (s,
3 H).
(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.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 23.8 (major), 28.5
(minor) min.
1H NMR (400 MHz, CDCl ): δ = 7.45–7.10 (m, 3 H), 4.75 (m,
3
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.
HPLC (Phenomenex Lux 5 μm Amylose-2 column, hexane–iPrOH, 90:10, 1 mL/min, 209 nm): tR = 15.8 (major), 17.2
(minor) min.

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