High pressure-assisted low-loading asymmetric organocatalytic conjugate addition of nitroalkanes to chalcones

Article abstract of DOI:10.1039/c8ob00561c

The application of high pressure (up to 9 kbar) allows for relatively fast (1-5 h) and highly enantioselective 1,4-addition of nitromethane and 2-nitropropane to chalcones at room temperature with substantial reduction of catalyst loading (0.2-1 mol% of cinchona alkaloid-based thioureas and squaramides). Various γ-nitroketones were obtained at 9 kbar with high yield and enantioselectivity (up to 98%), whereas in control experiments at atmospheric pressure usually only a small amount (<10%) of products were formed after 20 h.

Full text of DOI:10.1039/c8ob00561c

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PAPER
High pressure-assisted low-loading asymmetric organocatalytic
conjugate addition of nitroalkanes to chalcones
Agnieszka Cholewiak,† Kamil Adamczyk, Michał Kopyt, Adrian Kasztelan and Piotr Kwiatkowski*
Received 00th January 20xx,
The application of high-pressure (up to 9 kbar) allows for relatively fast (1-5 h) and highly enantioselective
1,4-addition of nitromethane and 2-nitropropane to chalcones at room temperature with substantial reduction of
catalyst loading (0.2-1 mol% of cinchona alkaloid-based thioureas and squaramides). Various -nitroketones were
obtained at 9 kbar with high yield and enantioselectivity (up to 98%), whereas in control experiments at atmospheric
pressure usually only a small amount (<10%) of products were formed after 20 h.
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Dedicated to Professor Jacek Gawroński on the occasion of his 75th birthday
asymmetric reaction catalysed by chiral amines performed
under high-pressure conditions. The Michael addition of
nitromethane to chalcone catalysed by cinchona alkaloids
Introduction
Asymmetric organocatalysis has grown rapidly since the
beginning of this century to become a powerful strategy in the
synthesis of chiral molecules.1 Despite unquestioned
advantages of this methodology still the most serious
limitations for a number of such reactions are high catalyst
loading and long reaction time.2 However efficiency of selected
types of catalytic organic processes can be improved by
application of non-classical methods of activation such as high
pressure,3 microwave heating, ultrasound irradiation, and ball
milling.4 Our laboratory has focused on the investigation of
pressure effects in asymmetric catalysis, with special attention
paid to organocatalysis.4a, 5 This method of activation can be
effectively used to accelerate reactions with negative volume
of activation.6 The application of high-pressure techniques in
asymmetric catalysis using chiral metal complexes7 and
organocatalysts4a is still weakly explored area. In the literature
there are several reports presenting examples of asymmetric
organocatalytic transformations involving high-pressure
were studied, and 10 mol% of quinidine (1f) under 9 kbar after
24 resulted in quantitative yield and moderate
h
enantioselectivity (up to 60%). Recently our group
demonstrated a significant effect of hydrostatic pressure on
difficult
nitromethane to sterically congested β,β-disubstituted enones
to form -nitroketones containing quaternary stereogenic
organocatalytic
1,4-conjugate
addition
of

centers with good yields and excellent enantioselectivities (up
to 99% ee).5a, 5c The Michael reaction of β-substituted cyclic
enones was effectively catalysed by cinchona-derived primary
amines and weak acid co-catalyst under 10 kbar.5a The
enantioselective addition of nitromethane to acyclic
β,β-disubstituted β-CF3 enones was remarkably accelerated by
pressure (8-10 kbar) in the presence of chiral tertiary amine-
thioureas (e.g. 1a-c, Fig. 1).5c
The pioneering work of Matsumoto8a and development of
highly enantioselective organocatalysts for Michael-type
reactions13 in recent years prompted us to examine the impact
of pressure also in typical variants of the 1,4-addition, which
could improve the efficiency of the process through significant
reduction of catalyst loading and reaction time.
Herein, we demonstrate the study on high-pressure
mediated asymmetric 1,4-conjugate addition of nitromethane
and 2-nitropropane to chalcones14,15,16 (Scheme 1) with low
activation e.g. in Michael,5a,
Baylis-Hillman,9 aldol,10
5c,
8
Mannich,11 Diels-Alder,12 and Friedel-Crafts5b,5d,5e reactions,
however high enantioselectivities (ee>90%) were observed in
only a few cases.5a-c, e, 8c,d, 11
In 1981 Matsumoto8a reported the first example of an
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
E-mail: pkwiat@chem.uw.edu.pl
loading (1 mol %) of bifunctional tertiary amine-thioureas or
-squaramides. This group of catalysts has been successfully
employed over the last decade in various types of asymmetric
reactions1,17,18 including Michael-type additions.13
† Present Address: Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Journal Name
Ar1
O
chiral
loading, concentration of reagents, temperature and the time
DOI: 10.1039/C8OB00561C
are important factors affecting the reaction rate.
O
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R
R
amine
O2N
+
NO2
Ar2
Ar1
Ar2
high pressure
R
R
R = H or CH3
Scheme 1. Michael addition of nitroalkanes to chalcones.
Table 1. Catalyst screening in the addition of nitromethane to
a
benzylideneacetophenone (2a
)
Among reported chiral tertiary amine-thioureas the most
organocatalyst
(0.5 mol %)
efficient and popular so far are cinchona alkaloid derived19
Ph
O
O
14d
thioureas20 and squaramides21,
as well as Takemoto
O2N
+
MeNO2
Ph
Ph
Ph
toluene, rt, 2 h
catalyst.22 One of the first examples of application of cinchona
alkaloid thioureas was the conjugate addition of nitromethane
to chalcones.14a The reaction with nitromethane in toluene at
room temperature require 10 mol% of 1a and 110 h to obtain
high yield (94% and 96% ee). However, Soós and co-workers
reduced notably the catalyst loading and reaction time (e.g. to
2 mol% and 45 h) by carrying out the reaction at higher
(3 equiv)
9 kbar
2a
3a
Entry
Catalyst Yield at 1bar Yield at 9 kbar
ee at
(0.5
(20 h) [%]b
(2 h) [%]b,c
9 kbar [%]d
(config.)e
mol%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4 (38)f
~0.5
~0.5
3
98 (94)c
93
95.5 (R)
95 (S)
95 (S)
98 (S)
97.5 (R)
57 (R)
48 (S)
91 (S)
temperature (50
Finally with 0.5 mol% of 1a at 50

C) without any solvent (94% and 92% ee).14a
C they were able to isolate

97
the product with 82% yield and 94% ee but after 171 h. Also
cinchona-based squaramides 1d (5 mol%) and 1e (2 mol%)
96 (93)c
turned out to be effective at 80

C in this reaction (94% after
revisited mechanistic and
60h, 95% ee).14d Recently
a
4
95
stereochemical model based on DFT calculations has been
<0.5
<0.5
~0.5
54 [90]g
20 [36]g
96
proposed for this reaction with catalysts of type 1a and 1e 23
.
1g
1h
8
R
N
OMe
N
a
OMe
N
Reaction conditions: 1a-h (0.5 mol%), 2a (1mmol, c=1.0 mol/L),
C, 2h
C, 20h). Determined by GC analysis with internal
N
N
N
nitromethane (3 equiv) in toluene (ca. 0.75 mL), 9 kbar, 20-25

b
(or 1 bar, 20-25

HN
HN
NH
c
standard. Isolated yield in parentheses; 5 mmol reaction scale.
d
e
HN
S
S
NH
Determined by HPLC analysis using Chiralpak® IC column. The
HN
O
absolute configuration was determined by comparison of the optical
f
O
F3C
rotation with a literature value (ref. 14a) 38% yield at 50
C after 5
days (1 bar). g Yield in square brackets after 20h at 9 kbar.
F3C
CF3
F3C
CF3
CF3
1b
1c
R = H
R = OMe
1a
1d
In contrast, under high-pressure conditions (9 kbar) we
observed remarkable acceleration of the 1,4-addition in the
OMe
OH
N
N
N
BnO
1g
OMe
N
presence of 0.5 mol% of tertiary amine-thioureas 1a-c
, 1h and
N
HO
1f
squaramides 1d 1e. The reaction under 9 kbar is relatively fast
,
N
NH
and after 2 h the product was formed with high yield (93-98%)
accompanied by high enantioselectivity (91-98%, Table 1,
CF3
O
NH
S
entries 1-5 and 8). Squaramides 1d, 1e offer slightly higher
O
CF3
N
N
CF3
H
H
enantioselectivities compared to thioureas 1a-c (97-98% ee vs
95-96% ee). For comparison we also used quinidine (1f) which
was tested by Matsumoto8a-b in this reaction. Alkaloid 1f (0.5
mol%) turned out to be less active and selective in comparison
to thiourea and squaramide derivatives, however high yield
was obtained after 20 h (entry 6). Additionally, with cupreidine
9-O-benzyl ether (1g) low conversion and opposite direction of
asymmetric induction was observed (entry 7).
Next we investigated how the reaction proceeds under
lower pressure in the presence of organocatalyst 1a (0.5
mol%) with prolonged reaction time (20 h, Figure 2). An
application of only 2-3 kbar for 20 h increased the yield from
3-4% to 35-64% (59-79%, 96% ee with 1 mol% of 1a). At the
4-6 kbar the product was formed with good yield (80-89%) but
application of 7 kbar or higher pressure resulted in very high
N
1e
F3C
1h
Figure 1. Organocatalysts examined in the Michael reaction.
Results and discussion
In our initial studies we examined the effect of pressure on the
reaction of benzylideneacetophenone (2a) with nitromethane in the
presence of chiral amines 1a-h (Figure 1 and Table 1). Control
experiments at atmospheric pressure and room temperature with
0.5 mol% of 1a-h in toluene resulted after 20 h in traces of products
(4%, Table 1). For the reaction carried out at 50 C for 5 days with
catalyst 1a (0.5 mol%) the yield increased to 38%. Results at
atmospheric pressure14a-d indicates that in this case catalyst
2 | J. Name., 2012, 00, 1-3
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The reaction is also efficient and highly enantioseleVciteiwveArtwicliethOn0lin.1e
DOI: 10.1039/C8OB00561C
mol% of 1a on a gram scale synthesis (10 mmol of 2a) after 20h
(entry 4). Typically 3 equiv of nitromethane was used, however with
1.5-2 equiv only slightly lower yields (91-94%) and unchanged
enantioselectivity were obtained with 0.5 mol% of catalysts after 2
hours (entries 5, 6 and 9).
conversion (>95%). The enantioselectivity is practically not
influenced by pressure and for all experiments presented in
Figure 2 enantiomeric excess in the range of 95-96% was
observed.
In order to evaluate the scope of enones24 in the high-pressure
addition of nitromethane we applied 0.5 mol% of thiourea 1a, and
to obtain opposite enantiomers squaramide 1d was used (Scheme
2, results in parentheses with 1d). Typically reactions were carried
out at 9 kbar for 2 h. This procedure works very well for products
with heteroaromatic rings attached to the carbonyl group (3b-d)
and adducts with ortho- and meta-substituted phenyls (3e-j) and
2-pyridyl (3n) in -position (Scheme 2, 10 examples). Those
compounds were isolated with enantioselectivities in the range
90.5-98% and yields usually over 90% (up to 97%).
Ar1
O
O
1a (0.5 mol%)
O2N
O2N
Ar2
3b-p
Ar2
Ar1
Ar2
Conditions: 1a (0.5 mol%), 2a (c=1.0 mol/L), MeNO2 (3 equiv.) in toluene,
232 ºC, 20h.
+
MeNO2
toluene
or
9 kbar, rt, 2h
(c = 1 mol/L)
Ar1
O
(3 equiv)
2
1d (0.5 mol%)
Figure 2. Effect of pressure on the model reaction.
(results with 1d are given in parentheses)
yield <10% at 1 bar, rt, 20h
[yield >10% for 3d, 3h in brackets]
Further optimisation studies were carried out under pressure
Ph
O
Ph
O
Ph
O
of 9 kbar with catalysts 1a, 1d and 1e (Table 2). The reaction
O2N
O2N
O2N
O
S
under hyperbaric conditions is very effective even after 1h
with 0.5 mol% of 1a and 1d. In those cases the product was
formed with yield exceeding 90% (entries 2 and 7). When the
catalysts loading was reduced to 0.2 mol% comparable
conversion was observed after 5h (entries 3, 8 and 10).
N
3b
3c
3d
95%, 96% ee
(93%, ent 97% ee)
96%, 95% ee
(95%, ent 97.5% ee)
92% [15%], 91.5% ee
(94% [22%], ent 95% ee)
Me
O
Cl
O
MeO
O2N
O
O2N
O2N
Table 2. Optimization studies in addition of nitromethane to
Ph
Ph
Ph
benzylideneacetophenone at 9 kbar a
3f
3g
96%, 94.5% ee
3e
95%, 93.5% ee
97%, 94.5% ee
(95%, ent 97.5% ee)
(91%, ent 96.5% ee)
(93%, ent 97.5% ee)
Catalyst
(mol%)
Time
Yield
[%]b,c
ee
Entry
Cl
[%]d
F3C
O
(config.)
O
O
O2N
O2N
O2N
Ph
Ph
Ph
1
1a (1%)
1a (0.5%)
1a (0.2%)
1a (0.1%)
1a (0.5%)
1a (0.5%)
1d (0.5%)
1d (0.2%)
1d (0.5%)
1e (0.2%)
1 h
1 h
5 h
20 h
2h
96
92 (88)
93 (88)
95 (90)e
94
95.5 (R)
95.5 (R)
96 (R)
3h
95% [29%], 95.5% ee
3i
3j
92%, 96% ee
(84%, ent 98% ee)
94%, 95% ee
(96% [28%], ent 96% ee)
2
(95%, 97.5% ee)
OMe
Me
F
3
4 e
5 f
6 g
7
95 (R)
O
O
O
O2N
O2N
O2N
95.5 (R)
95.5 (R)
98 (S)
Ph
Ph
Ph
72%, a) 93%, 94.5% ee
30%, b) 81%, 97% ee
3l
3m
3k
95%, 95% ee
2h
91
(94%, ent 96% ee)
(85%, ent 98% ee)
(
c) 79%, ent 98% ee)
1 h
5 h
2h
93
Ph
S
N
O
O
O
8
94 (90)
92
98 (S)
O2N
O2N
O2N
Ph
Ph
Ph
9 g
98 (S)
74%, a) 89%, 88% ee
(76%, d) 87%, ent 97.5 ee)
~30%, e) 82%, 96% ee
3p
3n
3o
88%, 90.5% ee
10
5 h
95
97 (R)
(83%, ent 97.5% ee)
(
c) 77%, ent 97.5% ee)
modifications: a) 1 mol% of 1a, b) 1 mol% of 1e, 5h c) 1 mol% of 1d, 5h
d) 1 mol% of 1d, 2h e) 2 mol% of 1a, 5h
a
Reaction conditions: 2a (1mmol, c=1.0mol/L), nitromethane (3
b
equiv) in toluene ( 0.75mL), 20-25 C, 9 kbar. Determined by GC
c
analysis with internal standard. Isolated yield in parentheses; 5-10
mmol reaction scale. Determined by HPLC analysis using Chiralpak®
d
Scheme 2. Scope of high-pressure 1,4-conjugate addition of
IC column. e 10 mmol scale reaction: 2.08g of 2a and 6.0 mg of 1a in 10
nitromethane to enones.
mL Teflon ampoule. f With 2 equiv of nitromethane
of nitromethane.
.
With 1.5 equiv
g
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Application of 9 kbar and 1 mol% of 1a after 5 h resulted in
DOI: 10.1039/C8OB00561C
formation of 4a with 92% yield and 91% ee. The decrease of
The high pressure Michael reaction is slower for selected
View Article Online
25
chalcones with para-substituted phenyls (see products 3k
, 3l;
2-nitropropane amount (1.5 equiv vs. 3 equiv) reduced the
reaction yield to 70%. Unfortunately, squaramide catalysts (1d and
1e) turned out to be considerably less effective in this reaction
under high pressure conditions (20-30% yield).
Having established the optimal reaction conditions for
high-pressure addition of 2-nitropropane to chalcone, we
extended investigations to other enones (Scheme 3). Products
4b-h were obtained after 5 h under 9 kbar in the presence of
catalyst 1a (1 mol%) with high yield, however
enantioselectivities were slightly lower (85-94% ee) compared
to corresponding reactions with nitromethane (90.5-96% ee).
Control experiments with 2-nitropropane under atmospheric
pressure yields after 20 hours less then 5% of products of type
except for 3m) and 2-thienyl (3o) in -position. Products 3k

and 3o were obtained with 72-85% yield, but with 1 mol% of
catalyst results were improved to 87-93%. Unexpectedly
reaction of chalcone having methyl group in para-position (see
product 3l) was relatively slow under hyperbaric conditions
with thiourea 1a (30% yield after 2 h). However use of 1
mol% of squaramide catalyst 1d and 1e at 9 kbar for 5 h
allowed to obtain the product 3l with much better yield (79-
81%). We also tested addition of nitromethane to
cinnamylideneacetophenone (see product 3p). This reaction
was reported by Silva14e with 20-30 mol% of catalyst 1a and
the product 3p was obtained with 78-97% yield and 93-96% ee
after 7 days. With 10 mol% of 1e at 80 C and atmospheric
pressure 3p was isolated after 4 days with 53% yield and 94%
ee (see ref. 14d). Under high pressure (9 kbar) with 0.5 mol%
4
.
Finally we examined the addition of nitroethane and
1-nitropropane to chalcone, which lead to products and
5
6
of 1a progress of the reaction was unsatisfactory (
2 h, however application of 2-1 mol% of catalysts 1a and 1d
over resulted in good yield (77-82%) and high
30%) after
with two stereogenic centers (Scheme 4). The primary
nitroalkanes turned out to be considerably more active then
2-nitropropane. Those reactions are relatively fast at 9 kbar
with 0.5 mol% of 1a or 1d and practically quantitative
5
h
enantioselectivity.
Further, we extended investigations to conjugate addition of
2-nitropropane to 1,3-diaryl-substituted enones, including
conversion was obtained after
2
hours with high
enantioselectivity (Scheme 4).26 As expected, the
diastereoselectivity in this type of Michael reaction is
moderate or low.14g The use of catalyst 1a favours the
heteroaryl substituents 14c, 15i-l
The reaction with chalcone under
.
ambient conditions require 10 mol% of 1a and 8 days to obtain
product 4a with 91% yield and 92% ee (see ref. 14c). In our trials
with 1 mol% of 1a, we observed only traces of nitroketone 4a under
atmospheric pressure after 20 h (Scheme 3). In this case application
of high pressure also effectively accelerates the addition. However,
compared to the corresponding reaction with nitromethane, higher
catalyst loading (1 mol%) and longer reaction time (5 h) is required
to obtain comparable conversion.
formation of anti-products (2:1 ratio for 5), but for catalyst 1d
syn-products were obtained with small predominance (1.2-1.4
:1).
(anti)
Ph
O
(syn)
Ph
O
1a
(0.5 mol%)
R
Ph
(3R,4R)-
+
R
Ph
(3R,4S)-
toluene
9 kbar, rt, 2h
NO2
NO2
NO2
O
O
Ar1
O
5 R=H
94% 95% ee
dr 2 : 1
94% ee
87.5% ee
1a (1 mol%)
Ar1
Ar2
Ph
+
NO2
6 R=CH3 96% 93.5% ee dr 1.7 : 1
+
Ph
O2N
Ar2
toluene
R
9 kbar, rt, 5h
4a-i
yield < 5% at 1 bar, rt, 20h
(with 1d and 1e : 20-30% of 4a, 97±0.5% ee)
(c = 1 mol/L)
(c = 1 mol/L)
(3 equiv)
R = H
1d
R = Me
Ph
O
Ph
O
(0.5 mol%)
(3 equiv)
Ph
O
R
Ph
(3S,4S)-
+
R
Ph
(3S,4R)-
98% ee
98% ee
toluene
9 kbar, rt, 2h
O2N
NO2
NO2
Ph
1 bar, 20h with 1a:
Ph
O
Ph
O
5
6
28% yield
~10% yield
5 R=H
93% 97% ee
6 R=CH3 95% 97% ee
dr 1 : 1.2
dr 1 : 1.4
O2N
O2N
O
S
4a 92%, 91% ee
27% after 1 h
< 2% at 1 bar, 20h
4b 84%, 89% ee
4c 94%, 87% ee
Scheme 4. High-pressure 1,4-cojugate addition of nitroethane and
1-nitropropane to chalcone.
(1.5 eq of iPrNO2: 70%, 91% ee)
Ph
O
MeO
O2N
O
Cl
O
O2N
O2N
Conclusions
Ph
Ph
N
This work demonstrates significant effect of hydrostatic
pressure on the rate of enantioselective addition of
nitromethane and 2-nitropropane to simple 1,3-diaryl-
substituted enones in the presence of chiral bifunctional
tertiary amine/hydrogen-bond donor-based catalysts.
The application of 9 kbar pressure at room temperature
and small amount (0.2-0.5 mol%) of cinchona-based thioureas
or squaramides allows for efficient synthesis of wide range of
4d 88%, 92% ee
4e 91%, 87% ee
4f 92%, 90.5% ee
~10% at 1 bar, 20h
S
N
O
O
F3C
O2N
O
O2N
O2N
Ph
Ph
Ph
4i 86%, 89% ee
(2% of 1a, 20h)
4g 84%, 94% ee
4h 88%, 85% ee

-nitroketones with high yield and enantioselectivities up to
Scheme 3. High-pressure 1,4-cojugate addition of 2-nitropropane to
98% ee in a relatively short time (1-5 h). The enantioselectivity
chalcones.
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ARTICLE
under high-pressure is slightly higher compared with results at
atmospheric pressure with heating (50-80 C, ref. 14a and
14d). Moreover, thermal method require higher catalyst
loading (2-10 mol%) and longer reaction time (usually 2 days)
to reach similar yields. The model reaction is also effectively
accelerated with 0.5 mol% of 1a at lower pressure (4-6 kbar)
Conflicts of interest
There are no conflicts of interest to declare
View Article Online
DOI: 10.1039/C8OB00561C

.
Acknowledgements
This work was financially supported by the Ministry of Science
and Higher Education of the Republic of Poland through
Iuventus Plus Programme (Grant No. IP2011 028671).
and room temperature to provide product 3a with
 80% yield
after 20 h, whereas the control experiments at atmospheric
pressure resulted in a very low conversion (<10%). Finally, the
high-pressure approach (9 kbar for 5h with 1 mol% of 1a) was
also successfully extended to more demanding addition of
2-nitropropane to selected chalcones.
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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6 | J. Name., 2012, 00, 1-3
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Page 7 of 7
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB00561C
Graphical Abstract – Table of Contents
High pressure-assisted low-loading asymmetric organocatalytic conjugate
addition of nitroalkanes to chalcones
Agnieszka Cholewiak, Kamil Adamczyk, Michał Kopyt, Adrian Kasztelan and Piotr Kwiatkowski*
Highly enantioselective and relatively fast (1-5 h) Michael reaction with substantial
reduction of organocatalyst loading (0.2-1 mol %) was developed under high-pressure
conditions (up to 9 kbar) and room temperature
.
Ar
O
Ar
O
organocatalyst 1a (or 1d to ent)
N
H
H
O2N
or
N
N
CF3
O2N
(0.2-1 mol%)
Ar
Ar
S
MeO
MeNO2
CF3
79-95%, 96.5-98% ee
88-97%, 88-96% ee
N
1a
(with 1d)
(with 1a)
HIGH PRESSURE
(up to 9 kbar)
O
(yield <10% at 1 bar, 20h)
25 oC, 1-5 h
Ar
Ar
F3C
Ar
O
H
N
N
NH
O2N
F3C
organocatalyst 1a
OMe
O
Ar
O
(1 mol%)
N
1d
i-PrNO2
84-96%, 85-94% ee
Low catalyst loading
Short reaction time
Ambient temperature