Applications of Thermal Activation, Ball-milling and Aqueous Medium in Stereoselective Michael Addition of Nitromethane to Enynones Catalyzed by Chiral Squaramides

Article abstract of DOI:10.1002/adsc.201801498

Stereoselective addition of nitromethane to conjugated en-ynones was performed through the application of chiral squaramides. Three non-classical approaches to promote the addition reaction were tested, including activation of the nucleophile by inorganic base in a biphasic aqueous system, thermal activation, and ball-milling. Hydrogen-bonding catalysis was effective in all these methods, providing 1,4-addition products in high yields and stereoselectivities of up to 98% requiring 1–5 mol% of Cinchona alkaloid squaramide. (Figure presented.).

Full text of DOI:10.1002/adsc.201801498

Title: Applications of thermal activation, ball-milling and aqueous
medium in Stereoselective Michael addition of nitromethane to
en-ynones catalyzed by chiral squaramides
Authors: Żaneta Ignatiuk, Mikołaj Janicki, Robert Góra, Krzysztof
Konieczny, and Rafał Kowalczyk
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801498
Link to VoR: http://dx.doi.org/10.1002/adsc.201801498

10.1002/adsc.201801498
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Applications of Thermal Activation, Ball-milling and Aqueous
Medium in Stereoselective Michael Addition of Nitromethane to
En-ynones Catalyzed by Chiral Squaramides
Żaneta A. Ignatiuka, Mikołaj J. Janickib, Robert W. Górab, Krzysztof Koniecznyc and
Rafał Kowalczyka*
a
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże
Wyspiańskiego 27, 50-370 Wrocław, Poland
Fax: (+48)-713202427; Phone: +4871 3203358; e-mail: rafal.kowalczyk@pwr.edu.pl
Department of Physical and Quantum Chemistry, Faculty of Chemistry, Wrocław University of Science and
b
Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370
c
Wrocław, Poland
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Stereoselective addition of nitromethane to Hydrogen-bonding catalysis was effective in all these
conjugated en-ynones was performed through the application methods, providing 1,4-addition products in high yields and
of chiral squaramides. Three non-classical approaches to stereoselectivities of up to 98% requiring 1–5 mol% of
promote the addition reaction were tested, including Cinchona alkaloid squaramide.
activation of the nucleophile by inorganic base in a biphasic
aqueous system, thermal activation, and ball-milling.
Keywords: hydrogen-bonding; Michael addition; thermal
activation; ball-milling; organocatalysis
reaction was exploited in an elegant synthesis of (+)-
α-lycorane, where transformations of the remaining
triple bond after conjugate addition were critical to the
overall synthesis.[9] Such Michael acceptors with a
triple bond in the conjugated system can react either in
the 1,4-[10] or 1,6-mode (Scheme 1).[11] In particular
for 1,3-enynones, the observed regioselectivity is
dependent on the reaction conditions and the nature of
the nucleophile.[12] Thus, en-ynones are an interesting
group of electrophiles offering various possible
regioisomeric products and giving access to
Introduction
Chiral squaramides have proven to be a highly
effective class of organocatalysts, providing access to
enantioenriched products in single[1] and tandem
reactions.[2] The most successful transformations
typically require only 1–2 mol% of catalyst.[3] Recent
reports suggest that chiral squaramides operate at the
water-organic interface[4] where they can act as phase-
transfer
catalysts.[5]
Moreover,
squaramides
successfully operate inside the organic phase on water
resulting in hydrophobic amplification in various
Michael additions.[6] The high activity of these
hydrogen-bond donors in stereoselective reactions has
also been noted in transformations for which heating
was necessary to obtain the expected products.
Surprisingly, no loss of optical purity was observed in
such reactions.[7] These examples indicate promise for
the development of new experimental methods where
hydrogen-bonding catalysis enables attaining
stereoselectivities observed under more standard
conditions for asymmetric catalysis. One potential
application is the addition of carbon nucleophiles to
conjugated electron-poor 1,3-enyne scaffolds.[8] This
(poly)cyclic
compounds
through
further
transformations of the triple bond.
However, the reactivity of en-ynones under
ambient conditions is rather limited. Here we report a
stereoselective addition of nitromethane to en-ynones
that requires the reaction to be performed either in a
biphasic water-dichloromethane medium, at elevated
temperatures, or with ball-milling.[13] Previously these
types of adducts were attainable via the addition of
acetophenones to nitroenyones. Further reaction of the
adducts led to 1,5-diketones with three contiguous
stereocenters after hydration/Michael cyclization
sequences.[14] This structural motif has also been found
in compounds exhibiting interesting bioactivities.[15]
1
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
While the application of 5 mol% of catalyst
promoted complete conversion of A1, the formation of
an unidentified byproduct was also noted, decreasing
the overall yield. Further tests (for details, see ESI) led
to the conclusion that reactions performed in the
Table 1. Stereoselective addition of nitromethane to en-
ynone A1 in biphasic system a)
Entry C-1 [mol%]
Conversion [%]b)
ee [%]c)
1
2
3
4
10
>99
>99
33
90
92
94
95
5.0
2.5
1.0
22
a)
Reaction was performed at 298 K applying 7 equiv of
nitromethane in 1 mL of dichloromethane, 1 equiv of
KH2PO4 in 1 mL of water. Determined by H NMR.
Determined by HPLC on AD-H column
b)
1
c)
Scheme 1. Regioselectivity in the addition to en-ynones.
However, such Michael additions relied on iminium-
ion catalysis and required as much as 15 mol% of
intricate chiral bifunctional primary amine-thiourea
catalysts.[16a] This approach is further complicated by
the limited stability of polyconjugated nitroalkenes.[17]
Therefore, the methods proposed herein are seen as
a valuable alternative approach to these interesting
adducts by combining stable, crystalline acceptors
together with low catalyst loadings.
biphasic system were strongly dependent on the
substrate and provided unsatisfactory results in terms
of stereoselectivity and conversions. Therefore, a
general approach with low catalyst loadings was
desirable. Among the very few non-classical methods
known in hydrogen bonding catalysis,[20] elevated
temperature could potentially support product
formation in the stereoselective reactions, which are
sluggish or required long reaction times to proceed
under
ambient
conditions.
Usually,
better
enantioselectivities are observed in reactions
performed at lower temperatures. However, when the
difference in free activation energies of competing
diastereomeric transition states is high, independence
of the enantioselectivity from temperature can be
expected.[21] Thankfully, the reaction performed in
neat nitromethane at 60 ºC provided the product with
high yield (90%) and enantioselectivity (95%) using 5
mol% of C-1. The excess of nitromethane was crucial
to achieve high conversions and allowed convenient
heating of the reaction mixture. It should also be
emphasized that neither DABCO (as a simple base)
nor 9-deoxy-epi-aminoquinine (activation of en-ynone
via iminium-ion catalysis)[22] gave any product.
Further catalyst screening proved squaramides to be
effective catalysts leading to the desired product with
76–95% ee (Scheme 2). The quinine based catalysts
C-1 to C-4 outperformed catalyst C-6. Among
squaramides with aliphatic amine moieties C-4 and C-
5, the former proved more efficient in the tested
reaction. Application of quinidine-derived catalyst C-
7 led to the product with the opposite absolute
configuration.
Results and Discussion
In our hands the conjugated π-electron system in en-
ynones exhibited rather limited reactivity, but proved
to be more susceptible to reactions with thiols than the
analogous dienones (Scheme 1).[18] Surprisingly, at
room temperature acceptor A1 remained unreactive to
nitromethane added in large excess and in the presence
of a Cinchona based squaramide (C-1, 10 mol%).
Therefore, additional activation was required.
Inspired by the high catalytic activity of squaramides
in a transformation occurring in the presence of
water,[19] we explored the possibility of mild
deprotonation of nitromethane in basic aqueous
solution without any unwanted background reaction of
the activated nucleophile. We found that the reaction
could be effectively performed in a two-phase system.
While the stereoselective addition of nucleophile
occurred in the dichloromethane layer, deprotonation
by the inorganic base took place in the aqueous phase.
The overall process led to the product with 90% ee by
applying 10 mol% of the catalyst. Interestingly,
lowering the squaramide C-1 loading to 1 mol%
provided higher enantioselectivities, but at the cost of
a dramatic drop in conversion (Table 1).
With the hypothesis that replacement of the oxygen
atoms in squaramides by sulfur might improve
catalytic efficiency,[23] we evaluated thiosquaramide
2
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
(DHQ)2AQN and quinine. Initially obtained rather
low conversions were improved by extensive
optimization of the conditions pertinent to friction
including the number of balls, their size and the speed
of milling (Table 2, for more details, see SI). The
optimized conditions required the addition of NaCl
and milling with two steel balls of 10 mm diameter and
led to product with 90% ee after 16 h. Further increase
in the milling time improved conversion to a small
extent (91 vs 86%) while the ee dropped to 88%.
Conversions increased with the power of milling
(tested 450 and 650 rpm, for further details, see SI),
but enantioselectivity remained practically unchanged.
Such observations could suggest that a high difference
between transition state (TS) energies causes
enantioselectivities to be only slightly affected by the
temperature, which increases with higher milling
power. While the conversions and stereoselectivities
achieved using thiourea C-9 and squaramide C-1 were
almost equal, no product was formed when the
thiosquaramide C-8 was used.
With the optimized milling protocol, the role of the
catalyst C-1 loading on both yield and stereoselectivity
in the tested reactions were studied (Table 3). It was
found that the additives (e.g. NaCl) were not necessary
to achieve high enantioselectivities. However, a
gradual decrease of the squaramide catalyst loading
from 10 mol% to 1 mol% resulted in a significant
decrease in yield. In contrast, only a slight variation in
the enantioselectivity was observed which ranged
from 93% for 10 mol% to 96% for 2 mol% of C-1.
Among the methods tested, the longest time
required to achieve high yields was found for the
reaction performed in neat nitromethane (Scheme 3).
While enantioselectivity reached 94% ee in a planetary
ball mill, ees up to 95% were achieved in solution
applying 5 mol% of C-1 in both cases. Hence, these
methods offered similar stereoselectivities. However,
the application of the ball-mill required 10 mol% of
catalyst to reach high conversions. Slightly lower
enantioselectivity (89% ee) was obtained using a
microwave reactor.
Scheme 2. Catalyst screen in the tested reaction of
nitromethane with acceptor A1.
C-8. Disappointingly, no product was observed
either at room temperature or at 333 K. Thiourea
catalyst C-9 performed the reaction successfully, but
the product was obtained with lower stereoselectivity
when compared to C-1.
Intrigued by the thermal effect, we also tested the
stereoselectivity of the reaction performed in a
microwave reactor. Michael additions were performed
analogously to those presented in Scheme 3, but at 393
K, leading to 69% conversion and 86% ee after 3 h
using catalyst C-1. The conversion was increased to
89% by doubling the reaction time, without
deterioration of enantioselectivity.
Next, we evaluated the impact of the acceptor’s
structure on stereochemical outcomes in addition of
nitromethane to various en-ynones. The acceptor
screen was performed with reactions at 333 K in
nitromethane using 5 mol% of C-1 (Table 4). Various
1,5-diaryl-2-en-4-ynone systems which differed in the
substitution of the aromatic rings were tested, giving
products with 85–98% ee. Introduction of electron
withdrawing substituents at the para position of the
aryl ketone unit led to lower enantioselectivities (entry
8 vs entries 1–7, Table 4). On the other hand, product
yield dramatically decreased when the electron density
of the conjugated system was increased with a para
methoxy group in either of the aryl groups in acceptors
A8 and A22. However, the impact of the electronic
character of the group on yield is not clear since the
para-fluoro substituent in A3 gave product with a
yield close to 50%. Conversely, meta- substituted
acceptors A2 and A4 reacted well to give the
corresponding alkyne products in high yields.
Results similar to microwave-assisted heating were
attained by ball-milling.[24] Highly efficient milling
allows very effective contact between solids without
the need of solvent. As the hydrogen bonds are
particularly sensitive to the solvent, the application of
ball milling could be the route to increase their strength
and, in consequence, the effectiveness of catalysis
involving hydrogen-bonding.[25] An additional effect
exerted on reaction kinetics stems from heating by
friction. These features of milling appeared relevant
to the studied Michael addition of nitromethane to en-
ynone A1.
In initial attempts, different activation methods of
the reagents were studied including chiral base
catalysis employing (DHQ)2AQN, quinine and finally,
two-centered hydrogen bond donors, such as quinine-
based thiourea C-9 and squaramide C-1.
Thiourea and squaramide catalysts provided product
P1 with higher enantioselectivity than obtained using
3
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
Table 2. Stereoselective Michael addition of nitromethane to en-ynone A1 performed in planetary ball-milla)
Entry catalyst
additive
Milling setupb) Milling speed [rpm] Time [h] Conversion [%]c)
ee [%]d
1
2
3
4
5
6
7
8
–
–
–
–
5×5
5×5
5×5
5×5
450
450
450
450
450
450
650
650
650
650
650
4
4
4
4
4
4
4
16
16
24
10
8
1
59
9
(DHQ)2AQN
quinine
C-9
C-1
C-1
C-1
C-1
C-1
C-1
23
14
24
43
27
83
86
91
0
84
83
81
21
91
88
90
88
–
silica gel 5×5
K2HPO4 5×5
NaCl
NaCl
NaCl
NaCl
NaCl
2×10
5×5
2×10
2×10
2×10
9
10
11
C-1
C-8
a) Reactions were performed in a 0.5 mmol scale with 10 equiv of nitromethane and 10 mol% of the respective catalyst and
100 mg of additive, where indicated. Milling was performed in a cycle of 1 h milling and 1 min break followed by the
change of the rotation direction in the 12 mL stainless steel container. b) Number of balls × ball diameter [mm]. c) Determined
by 1H NMR; d) Determined by HPLC on AD-H column
In general, the Michael reaction of the tested
acceptors A11–A22 with nitromethane occurred with
high enantioselectivity regardless of their structure.
Slightly lower stereoselectivity was noted only in the
case of acceptors with ortho-substituted phenyl rings
such as in A14, and particularly in 2,4-disubstituted
A17. The presence of a halogen group in the meta-
position in acceptors A12, A15 and A18 did not
influence either the yields or stereoselectivities of the
reactions in comparison to the results obtained for the
other acceptors.
reaction using 5 mol% of C-1 (Scheme 3). Thus, the
stereochemistry of the acceptor was extremely
important for achieving high enantioselectivity. In
addition, the 1,3-diketone system in acceptors A24 and
A25 would seem to offer additional groups amenable
to interaction with the two-centered hydrogen bond
system of squaramide. As a result, better control of the
chirality transfer might be expected. However, when
A24 was subjected to reaction with nitromethane
catalyzed by 10 mol% of C-2, the resulting adduct was
obtained in 91% yield but merely 67% ee, while
from1,3-ketoester A25 no product was obtained.
Table 3. Stereoselective Michael addition of nitromethane
to en-ynone A1 catalyzed by C-1 performed in planetary
ball-milla)
Entry Catalyst [mol%] Yield [%]b) ee [%]c)
1
2
3
4
10
94
85
24
30
93
94
96
95
5.0
2.0
1.0
a)
Reactions were performed on a 0.5-mmol scale with 10
equiv of nitromethane; Milling at 650 rpm was performed
for 24 h in cycles of 1 h milling and 1 min break followed
by the change of the rotation direction. Two 10 mm steel
b)
c)
balls were used.
After column chromatography.
Determined by HPLC on AD-H column.
Furthermore, experiments performed using the ball
mill (entries 4 and 18, Table 4) revealed that catalyst
activity remained unaffected by the choice of the
synthetic method and in both cases led to comparable
enantioselectivities. However, the addition of
nitromethane to en-ynones is limited to compounds in
which both ends of the conjugated system are
terminated by aryl substituents. Acceptor A23 (R1 = n-
hexyl) did not undergo transformation to the product
even at 353 K after a prolonged time.
Scheme 3. Further studies on the acceptor’s structure.
The Z-isomer of en-ynone A1 underwent
unselective transformation to the Michael adduct in a
4
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
Table 4. Scope of the acceptors in the Michael addition of nitromethane catalyzed by C-1a)
Entry acceptor R1
R2
Product Yield [%]b) ee [%]c)
1
Ph
Ph
90
92
47
99
98
90
76
66
23
98
92
91
88
95
83
89
60
97
82
65
96
70
99
97
39
35
0
92 (-95)d)
94
90
91
98
93
97
81
95
96
96
92
95
95
89
92
90
80.5
93
94
95
98
95
95
95
96
A1
P1
P2
P3
P4
P5
P5
P6
P7
2
Ph
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-CH3OC6H4
4-PhC6H4
2-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
A2
3
Ph
A3
4
Ph
A4
5
Ph
Ph
Ph
A5
A5
A6
6e)
7
8
Ph
A7
9
Ph
A8
P8
P9
10
11
12
13
14
15
16
17
18
19
20
21
22f)
23g)
24e)
25
26
27
Ph
Ph
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A20
A20
A20
A21
A22
A23
P10
P11
P12
P13
P14
P15
P16
P17
P18
P19
P20
P20
P20
P20
P21
P22
–
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
3-BrC6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
Ph
Ph
Ph
4-CH3OC6H4 Ph
2-Naphthyl
n-hexyl
Ph
Ph
–
a) Reaction was performed on a 0.25-mmol scale in 1 mL of nitromethane for 48 h applying 5 mol% of catalyst C-1 b) After
column chromatography; c) Determined by HPLC on chiral stationary phases; d) Catalyst C-7 was used. e) Reaction performed
in planetary ball mill with 10 mol% of C-1, 650 rpm, two 10 mm steel balls for 24 h; f) 2 mol% of C-1 was used; g) 1 mol%
of C-1 was used.
In contrast, application of squaramide C-1 (5 mol%)
to the reaction of nitromethane with an elongated π-
system, such as in acceptor A26, yielded 42% of the
1,4-adduct with high enantioselectivity (95%). This
addition product was previously obtained in a different
catalytic approach involving 15 mol% of a primary
amine-thiourea mixed system and was further
transformed into a 1,5-diketone with three contiguous
stereocenters.[14] Comparison of the degree of optical
rotation and the elution order in HPLC with the
reported data for the adducts P1[16] and P24[14] indicate
that the use of catalyst C-1 led to the adduct with (R)-
configuration. Moreover, the (R)-configuration for the
product P6 was assigned unequivocally (Figure 1)
based on the X-ray diffraction data with a low value of
Figure 1. X-ray structure of (R)-P6.
displacement parameters are drawn at 30% probability level.
The atomic
the Flack parameter (0.008(6)).[26] Tentatively, the
same configuration was ascribed to all adducts
obtained with epi-quinine-based catalysts. Hence, the
(S)-P1 adduct was obtained in reaction catalyzed by
the pseudoenantiomeric catalyst C-7 (Scheme 2).
Next, the scope with respect to nitroalkanes was tested
in reactions with acceptor A1 catalyzed by catalyst C-
1. The reactivity of such nucleophiles with Michael
5
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
acceptors[27] could be affected due to nitroalkane
anomaly effect.[28] Therefore, it was interesting to test
nitroethane, nitropropane, 2-nitropropane, and ethyl
nitroacetate for addition to en-ynone A1 (Table 5). 2-
Nitropropane reacted well, giving the desired
enantioenriched product in moderate yield (72%) but
with high enantioselectivity (96%).
When the
analogous reaction was performed at 353 K, a small
decrease in both yield and ee was observed.
Nitroethane reacted well at 353 K to give cleanly a
racemic mixture of diastereomeric products (1:1)
when achiral squaramide C-10 was used. A similar
result was obtained when 1-nitropropane was applied.
A stereoselective variant of the reaction catalyzed by
C-1 provided adducts of nitroethane and 1-
nitropropane with excellent enantioselectivities
ranging 91–97% ee, albeit with no diastereoselectivity.
The effect of the temperature was rather negligible
(Table 5, entries 2, 6, and 10). Although both
nitroethane and nitropropane are more susceptible to
deprotonation in comparison to nitromethane,[28] their
reactivity might be similar.[27] Ethyl nitroacetate
incorporates an additional α-EWG group and differs
from the previous nucleophiles. With reference to the
Mayr nucleophilicity scale,[29] which quantitatively
describes the reaction rates of various nucleophiles and
electrophiles with equation log k = s(N+E),
nucleophilicity parameter N = 15.74, and specific
slope parameter s = 0.74 were found for ethyl
nitroacetate.[30] For nitromethane, reported values of N
= 20.71 and s = 0.60 in DMSO indicate it to be a better
nucleophile. Thus, ethyl nitroacetate seems to be less
reactive than nitromethane, explaining the lack of
reaction with acceptor A1.
Scheme 4. Addition of nitromethane-d3 and the deuterium
distribution in the product based on NMR.
These models consisted of nitromethane, acceptor
A1 and catalyst C-1. In the initial activation step
deprotonation of nitromethane was considered to
provide the more reactive nucleophile together with
creation of a protonated quincylidene N–H unit. We
found that coordination of the substrate A1 in the next
step occurred by formation of a hydrogen bond with a
protonated amine moiety in catalyst C-1 which was
further stabilized by stacking interactions of the aryl
groups, while the nitronate anion was bound to the
squaramide system (Figure 2, R-TS).
Reactions of nitroethane, nitropropane and 2-
nitropropane were performed in a planetary ball mill
as a comparison to the results obtained in solution.
However, essentially the same outcome was achieved
(Table 4, entries 3, and 11 vs 1, 5 and 9, respectively).
An attempted reaction with a malonate resulted in
no Michael adduct leaving acceptor A1 unchanged.
In an attempt to better understand the nature of the
interactions between Michael acceptor and the catalyst
and to gain insight into the reaction mechanism,
additions were carried out in CD3NO2. Under
optimized conditions applying C-1, adduct P28 was
obtained in 99% yield and 90% ee. Both hydrogen
atoms in the α-position of the carbonyl group in P28
were substituted with deuterium.
Partial H/D
exchange at the α-position to the nitro group was also
observed according to analysis of NMR spectra of the
crude product. The observed H-D exchange suggests
proton abstraction from nitromethane followed by
further enol-ketone tautomerization. Additionally, to
propose a plausible molecular mechanism of
nucleophilic addition of nitromethane to en-ynone A1
in the presence of Cinchona-based squaramide C-1,
we performed Kohn–Sham density functional theory
(KS-DFT) calculations for the model systems shown
in Figure 2.[31]
Figure 2. The structure of transition states for addition of
nitronate to en-ynone A1 leading to (R)- or (S)-product P1
(top) located at the B3LYP-D3-PCM/def2-SVP level and
the proposed catalytic cycle (bottom).
The resulting Gibbs free energy profile is shown in
Figure 3. The stationary points were located using the
B3LYP-D3(BJ)/def2-SVP method. The free energies
6
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
Figure 3. The Gibbs energy profile for the Michael addition of nitromethane to en-ynone A1 in the presence of Cinchona
based squaramide C-1 calculated at the SCS-MP2/def2-TZVP//B3LYP-D3(BJ)-PCM/def2-SVP level. The abbreviations
refer to A - activation, R/S - addition, H- proton transfer, T- tautomerization, -SC substrate complex, -TS transition state,
-PC products complex
were estimated based on single-point SCS-MP2/def2-
TZVP electronic energy calculations, assuming the
B3LYP-D3(BJ)/def2-SVP geometries and the
corresponding thermal and PCM solvation free energy
corrections (cf. Supplementary Information for the
Cartesian coordinates of located stationary points and
the details of computational protocol abbreviated
further as SCS-MP2/def2-TZVP//B3LYP-D3(BJ)-
PCM/def2-SVP). Our calculations suggest that the
studied reaction is initiated by proton abstraction from
nitromethane by the basic unit of bifunctional catalyst
C-1. This appears to be the rate-limiting step (cf.
Figure 3 – activation step, A), which is characterized
by a free energy barrier of 17.3 kcal/mol. The
activation step results in a formation of nitronate (cf.
A-TS inset in Figure 3) with excess negative
chargelocated on the carbon atom (achieving −0.35 e
in the transition state and increased to −0.51 e in the
intermediate A-PC). The activated nucleophile can
subsequently attack the positively charged (+0.16 e) β-
carbon atom of the π-system of A1 (Figure 3 – addition
step, R) approaching the Si-face of the double bond
and resulting in the formation of the observed (R)-
adduct. The free energy barrier for the latter step of
5.9 kcal/mol should be easily accessible due to
significant energy excess after activation. Our
calculations indicate that the further steps involving
recapture of the proton from catalyst C-1 by the
carbonyl group of substituted en-ynone A1 and
subsequent tautomerization are virtually barrierless
and lead to further stabilization of the system (cf. H-
transfer and tautomerization steps in Figure 3).
The alternative possible orientation of nitronate and
the substrate A1 in the transition state (Figure 2 S-TS)
would lead to a product of opposite configuration. The
calculated free energy profile for the alternative
addition leading to the (S)-adduct (cf. Figure 3 –
addition step, S) shows a much higher free energy
barrier of 19.8 kcal/mol for this process, as well as a
negligible activation energy of about 1 kcal/mol for the
inverse direction (S-PS to S-TS). The calculated free
energy profiles are thus consistent with the observed
stereoselectivity of the studied reaction.
Finally, an arrangement in which the carbonyl group
in the substrate A1 is located opposite to the
protonated nitrogen atom of the quinuclidine moiety in
C-1, in comparison to the structure shown in Figure 2
(R-TS), is unproductive. Such an orientation of the
electrophilic center in Michael acceptor A1 should
also lead to the (S)-isomer.
7
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
Table 5. Scope of the nucleophiles in the reaction of acceptor A1a)
Entry
R1
R2
Catalyst
Product
Yield [%]b)
d.r.c)
ee [%]d)
1
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CO2Et
CH3
CH3
CH3
H
H
H
H
H
H
H
C-1
C-1
C-1
C-10
C-1
C-1
C-1
C-10
C-1
C-1
C-1
C-1
70
64
84
90
92
89
98
91
85
89
95
0
-
-
-
96
94
P25
P25
P25
P26
P26
P26
P26
P27
P27
P27
P27
-
2e)
3f)
4
96.5
-
97/97
94.5/94
95/95
-
91/93
92/91.5
94/91
-
1:1
1.1:1
1.1:1
1.1:1
1:1
1:1
1:1
1:1
-
5
6e)
7f)
8
9
10e)
11f)
12
H
H
a) Reactions were performed on a 0.25 mmol scale applying 5 mol% of catalyst and 1 mL of nitroalkane at 333 K for 48 h;
b) After column chromatography; c) Determined by 1H NMR integration; d) Determined by HPLC on chiral stationary phases;
e) Performed at 353 K; f) Reaction performed in planetary ball mill with 10 mol% of C-1, 650 rpm, two 10 mm steel balls
for 24 h
[1] a) X. Han, H. B. Zhou, C. Dong, Chem. Rec. 2016, 16,
897–906; b) B.-L. Zhao, J.-H. Li, D.-M. Du, Chem. Rec.
2017, 17, 994–1018
Conclusion
[2] P. Chauhan, S. Mahajan, U. Kaya, D. Hack, D. Enders,
We have demonstrated the efficiency of chiral
Adv. Synth. Catal. 2015, 357, 253–281
Cinchona alkaloid squaramides in three non-classical
techniques, i.e. performing the reaction in water-
organic biphasic mixtures, applying thermal activation
and mechanochemistry. Michael addition to poorly
reactive acceptors resulted in good yields and
enantioselectivities from 81 to 98%. Ball milling
performed equally well in terms of yield and
selectivity to reactions in solution but required shorter
reaction times and relatively low catalyst loadings.
Thus, we highlight ball-milling as an effective tool
compatible with stereoselective hydrogen bonding
catalysis in transformations where elevated
temperature does not impair the stereochemical
outcome. The observed nucleophile’s approach
directed by catalyst C-1 was rationalized by DFT
calculations.
[3] F. Giacalone, M. Gruttadauria, P. Agrigento, R. Noto,
Chem. Soc. Rev. 2012, 41, 2406–2447
[4] W. Guo, X. Liu, Y. Liu, C. Li, ACS Catal. 2018, 8, 328–
341
[5]W. Guo, B. Wu, X. Zhou, P. Chen, X. Wang, Y. G. Zhou,
Y. Liu, C. Li, Angew. Chem. Int. Ed. 2015, 54,
4522−4526
[6] a) C. M. Kleiner, P. R. Schreiner, Chem. Comm. 2006,
41, 4315–4317; b) H. Y. Bae, C. E. Song. ACS Catal.
2015, 5, 3613–3619
[7] W. Yang, D. -M. Du, Org. Lett. 2010, 12, 5450–5453
[8] X. Li, F. Peng, M. Zhou, M. Mo, R. Zhao, Z. Shao,
Chem. Comm. 2014, 50, 1745–1747
[9] X.-L. Meng, T. Liu, Z.-W. Sun, J.-C. Wang, F.-Z. Peng,
Acknowledgements
Z.-H. Shao, Org. Lett. 2014, 16, 3044–3047
[10] D. Hack, P. Chauhan, K. Deckers, G. N. Hermann, L.
Mertens, G. Raabe, D. Enders, Org. Lett. 2014, 16,
5188–5191
National Science Center, Poland is acknowledged for financial
support (Grant No. 2016/22/E/ST5/00046). Computational grant
from Wrocław Centre of Networking and Supercomputing (WCSS)
is also gratefully acknowledged. The authors are grateful to Mr.
Nicholas Swisher, Caltech, for comments on the article.
[11] a) H. Kuroda, E. Hanaki, H. Izawa, M. Kano, H.
Itahashi, Tetrahedron 2004, 60, 1913–1920; b) For a
recent example of interesting site-divergent and
stereoselective Michael addition to en-yne system in
enynyl N-acyl pyrazoles, see: D. Uraguchi, R. Shibazaki,
References
8
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10.1002/adsc.201801498
Advanced Synthesis & Catalysis
N. Tanaka, K. Yamada, K. Yoshioka, T. Ooi, Angew.
[22] P. Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 9748–
Chem. Int. Ed. 2018, 57, 4732–4736
9770
[12] A. A. Golovanov, D. M. Gusev, A. V. Vologzhanina,
V. V. Bekin, V. S. Pisareva, Russ. J. Org. Chem. 2014,
50, 13–20
[23] M. Rombola, C. S. Sumaria, T. D. Montgomery, V. H.
Rawal, J. Am. Chem. Soc. 2017, 139, 5297–5300
[24] A. Stolle, Technical Implications of Organic Synthesis
in Ball Mills in Ball Milling Towards Green Synthesis,
ed. B. Ranu, A. Stolle, The Royal Society of Chemistry,
Cambridge, 2015, pp. 241–276
[13] For a recent reviews, see: a) J. L. Howard, Q. Cao, D.
L. Browne, Chem. Sci. 2018, 9, 3080–3094; b) M. Obst,
B. König, Eur. J. Org. Chem. 2018, 4213–4232
[14] T. Liu, M. Zhou, T. Yuan, B. Fu, X. Wang, F. Peng,
[25] a) M. Hestericová, R. Šebesta, Tetrahedron 2014, 70,
901–905; b) M. Jorres, S. Mersmann, G. Raabe, C. Bolm,
Green Chem., 2013, 15, 612–616; c) Y.-F. Wang, R.-X.
Chen, K. Wang, B.-B. Zhang, Z.-B. Li, D.-Q. Xu, Green
Chem. 2012, 14, 893–895
Z. Shao, Adv. Synth. Catal. 2017, 359, 89–95
[15] C.-R. Chen, Y.-W. Liao, L. Wang, Y.-H. Kuo, H.-J.
Liu, W.-L. Shih, H.-L. Cheng, C.-I. Chang, Chem.
Pharm. Bull. 2010, 58, 1639–1642
[26] CCDC-1871638
contains
the
supplementary
[16] An example of lone reaction was provided: a) H. Ma,
K. Liu, F.-G. Zhang, C.-L. Zhu, J. Nie, J.-A. Ma, J. Org.
Chem. 2010, 75, 1402–1409; For examples of
analogous additions to nitrodienes, see: b) X.-T. Guo, F.
Sha, X.-Y. Wu, Synthesis 2017, 49, 647–656; c) S. Belot,
A. Massaro, A. Tenti, A. Mordini, A. Alexakis, Org. Lett.
2008, 10, 4557–4560
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.cdc.cam.ac.uk/da
ta_request/cif
Data
Centre
via
[27] T. Bug, T. Lemek, H. Meyr, J. Org. Chem. 2004, 69,
7565–7576
[17] R. Ballini, N. Araújo, M. V. Gil, E. Román, J. A.
Serrano, Chem. Rev. 2013, 113, 3493–3515
[28] A. J. Kresge, Can. J. Chem. 1974, 52, 1897–1903
[18] R. Kowalczyk, P. J. Boratyński, Adv. Synth. Cat. 2016,
358, 1289–1295
[29] P. Jaramillo, P. Pérez, R. Contreras, W. Tiznado, P.
Fuentealba, J. Phys. Chem. A, 2006, 110, 8181–8187
[19] F. Cruz-Acosta, P. de Armas, F. Garcia-Tellado, Chem.
Eur. J. 2013, 19, 16550–16554
[30] F. Corral-Bautista, R. Appel, J. S. Frickel, H. Meyr,
Chem. Eur. J. 2015, 21, 875–884
[20] P. Kwiatkowski, K. Dudziński, D. Łyżwa, Non-
Classical Activation of Organocatalytic Reactions in
Comprehensive Enantioselective Organocatalysis:
Catalysts, Reactions, and Applications, (Ed.: P. Dalko),
Wiley-VCH, Weinheim, 2013, 2-3, pp. 579–615.
[31] For other mechanistic investigations involving
squaramide catalyzed Michael addition, see: a) E. Varga,
L. T. Mika, A. Csámpai, T. Holczbauer, G. Kardos, T.
Soós, RSC Adv. 2015, 5, 95097–95086; b) B. Kótai, G.
Kardos, A. Hamza, V. Farkas, I. Pápai, T. Soós, Chem.
Eur. J. 2014, 20, 5631–5639
[21] P. Walsh, M. Kozlowski, in Fundamentals of
Asymmetric Catalysis, University Science Books,
Sausalito, California, 2009, pp. 5–14.
9
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Advanced Synthesis & Catalysis
FULL PAPER
Applications of thermal activation, ball-milling
and aqueous medium in Stereoselective Michael
addition of nitromethane to en-ynones catalyzed
by chiral squaramides
Adv. Synth. Catal. Year, Volume, Page – Page
Żaneta A. Ignatiuk, Mikołaj J. Janicki, Robert W.
Góra, Krzysztof Konieczny and Rafał Kowalczyk*
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