Fast, solvent-free and hydrogen-bonding-mediated asymmetric Michael addition in a ball mill

Article abstract of DOI:10.1039/c2gc16521j

The chiral squaramide derivatives as hydrogen bonding catalyst for the Michael addition reactions of 1,3-dicarbonyl compounds to nitroolefins under solvent-free conditions was developed using a planetary ball mill. High yields, high enantioselectivities a

Full text of DOI:10.1039/c2gc16521j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 893
www.rsc.org/greenchem
COMMUNICATION
Fast, solvent-free and hydrogen-bonding-mediated asymmetric Michael
addition in a ball mill†
a
a
a
a
b
a
Yi-Feng Wang, Ru-Xiang Chen, Ke Wang, Bin-Bin Zhang, Zhao-Bo Li and Dan-Qian Xu*
Received 28th November 2011, Accepted 9th January 2012
DOI: 10.1039/c2gc16521j
The chiral squaramide derivatives as hydrogen bonding cata-
lyst for the Michael addition reactions of 1,3-dicarbonyl com-
pounds to nitroolefins under solvent-free conditions was
developed using a planetary ball mill. High yields, high enan-
tioselectivities and shorter reaction times were achieved with
low catalyst loading.
ball mill. Enantioselective Michael addition using a bifunctional
25,26
cinchona-based squaramide organocatalyst
was dramatically
accelerated in a ball mill compared to the reaction in organic sol-
25
vents. Remarkably, catalyst loading at 0.5 mol% was sufficient
to complete most reactions within 30 min, affording the Michael
adduct in up to 95% yield and >99% ee.
To investigate the effect of the solvent-free ball milling on the
hydrogen bonding mediated asymmetric transformations, the
addition of 2,4-pentanedione 1a to β-nitrostyrene 2a in the pres-
ence of differently substituted types of sqaramides was carried
out in a ball mill (Fig. 1). A milling cycle consisting of a 10 min
milling period at a rotational speed of 400 rpm, followed by a
5 min pause to avoid overheating, was used (Table 1). Gratify-
ingly, preliminary results showed that good yields and enantio-
selectivities were obtained when only 0.5 mol% of
diaminocyclohexane/diphenylethylamino-derived squaramides
used as catalysts after 4 cycles of milling (entries 1–2). To our
delight, high enantioselectivity and especially high efficiency
was achieved when cinchona-derived squaramides IIa and IIb
were employed, which provided 87–89% yields and 89–95% ee
values after only 1 cycle (entries 3–4). Further investigation of
the effect of the substituent on one end of squaramide led to the
discovery of the suitable catalyst IIIg, affording an excellent
level of enantioselectivity (97% ee) and yield (91%) (entry 9).
Notably, the reaction proceeds well even at 0.1 mol% catalyst
loading with only slightly decreased result (entry 10). Further,
the reaction rate of the hydrogen-bonding-mediated Michael
Organocatalysis has been the subject of intensive development
during the last decade due to its special features such as being
environmentally benign, having atom economy and convenient
operation. However, there are still several drawbacks that are
limiting industrial applications of organocatalysis; typical pro-
blems are the high catalyst loading, long reaction time and
solvent limitations. In the pursuit of a more efficient and greener
1,2
process, performing the reactions in the absence of any solvent
3
appeared promising. In this contribution,
a solvent-free
4
implementation of the Michael addition of 1,3-dicarbonyl com-
pounds to nitroolefins in a planetary ball mill is reported.
Ball milling as a mechanochemical technique in synthetic
5
–7
chemistry
has been received widespread research interest;
among them catalyzed bond forming reactions has become par-
ticularly noteworthy, mainly including metal-mediated cross-
8
–14
15,16
coupling reactions
and organocatalysis.
The latter group
of reactions caught our attention as it allows a significant
decrease in the amount of harmful chemicals (toxic metals and
solvent). However, to the best of our knowledge, their appli-
cation in asymmetric organocatalysis was mainly limited to
1
7–22
asymmetric aldol reactions
derivatives.
catalyzed by proline or its
Hydrogen bonding is the most important of all directional
intermolecular interactions determining molecular conformation,
2
3,24
molecular aggregation in solid phase,
and introducing this
function into solvent-free asymmetric catalysis may enhance the
catalytic activity by the high concentration of the reagents and
the avoidance of solvent interference to hydrogen bonding. We
report here the successful results of H-bonding-mediated enan-
tioselective organocatalysis under solvent-free conditions in a
a
Catalytic Hydrogenation Research Center, Zhejiang University of
Technology, Hangzhou, 310014, China. E-mail: chrc@zjut.edu.cn;
Fax: (+86) 0571 88320066
b
Hangzhou Minsheng Pharmaceutical Group Co., Ltd., Hangzhou,
China
†
1
Electronic supplementary information (ESI) available. See DOI:
0.1039/c2gc16521j
Fig. 1 Screened organocatalysts.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 893–895 | 893

View Article Online
a
Table 1 Screening of the catalysts for the Michael reaction of 2,4-
pentanedione with β-nitrostryrene
Table 3 Variation of electrophiles
a
b
c
d
Product
3
Time
Yield
(%)
ee
b
c
d
Entry
Catalyst
Time (min)
Yield (%)
ee (%)
Entry
R
(min)
(%)
1
2
3
4
5
6
7
8
I
II
40
40
10
10
10
10
10
10
10
10
480
65
61
87
89
86
87
89
49
91
86
95
76
83
89
95
80
81
87
73
97
93
98
1
2
3
4
5
6
7
8
9
10
11
1
13
Ph (2a)
3a
3b
(2c) 3c
(2d) 3d
5
5
25
5
10
10
10
10
20
10
10
15
30
95
93
94
89
88
89
93
91
83
87
93
75
72
99
96
98
98
99
99
99
95
98
99
94
99
98
4-MeC
6
H
6
4
(2b)
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIg
IIIg
2-MeOC
4-MeOC
H
H
4
6
4
4-FC
6
H
4
(2e)
3e
3f
3g
3h
3i
3j
3k
3l
2-ClC
3-ClC
4-ClC
6
H
6
H
6
H
4
(2f)
(2g)
(2h)
(2i)
(2j)
(2k)
4
4
9
2-BrC
3-BrC
4-BrC
6
H
6
H
6
H
4
4
4
e
1
0
f
11
2
2-NO
2 6 4
C H (2l)
a
Reactions were carried out with 2a (8.00 mmol), 1a (2.0 equiv.) and
catalyst I–III (0.5 mol%); ball-milling conditions: 10 min at 400 rpm,
2, 4-Cl C H
3m
2
6 3
(2m)
naphthalen-2-yl
(2n)
furan-2-yl (2o)
thien-2-yl (2p)
b
c
d
and 5 min pause. Time for milling. Isolated yields. Determined by
HPLC analysis using a chiral stationary phase. With 0.1 mol% catalyst
loading. Reaction was carried out with 2a (0.5 mmol), 1a (2.0 equiv.),
2 2
and IIIg (0.5 mol%) in 1.5 mL of CH Cl .
14
3n
10
86
91
e
f
15
16
3o
3p
25
30
63
92
94
92
a
Reactions were carried out with 2 (8.00 mmol), 1a (2.0 equiv.) and
catalyst IIIg (0.5 mol%); ball-milling conditions: 5 min at 400 rpm, and
b
c
d
2
min pause. Time for milling. Isolated yields. Determined by
HPLC analysis using a chiral stationary phase.
Table 2 Optimization of the milling conditions for the Michael
reaction of 2,4-pentanedione with β-nitrostryrene
a
b
c
Entry
Milling speed (rpm)
Time (min)
Yield (%)
ee (%)
β-nitroolefins, which bear electron-rich, electron–neutral and
electron-withdrawing groups or heteroaryl β-nitroolefins as the
electrophiles reacted smoothly with 2,4-pentanedione 1a in a
very short reaction time to afford the corresponding products
3a–3p with high levels of yield (63–95%) and enantioselectivity
1
2
3
4
5
6
200
400
600
400
400
400
10
10
10
20
30
5
88
91
85
90
88
95
92
97
93
95
95
99
(91–99% ee). Next, various 1,3-dicarbonyl compounds as
a
nucleophiles was probed (Table 4). Of the cases studied, all give
rise to the corresponding products in good yields and high
enantioselectivities. Notably, some less active nucleophiles need
relatively long milling time, and slightly erosion in yields and
ee’s was observed in these cases, perhaps as a result of tempera-
ture increasing during the long milling time.
Reactions were carried out with 2a (8.00 mmol), 1a (2.0 equiv.) and
b
c
catalyst IIIg (0.5 mol%) in the ball mill. Isolated yields. Determined
by HPLC analysis using a chiral stationary phase.
addition was remarkably accelerated due to the intense mixing
by the ball milling and the absence of solvent interference,
although the yield and enantioselectivity was slightly lower than
the conventional process (entry 11).
In summary, a highly efficient H-bonding mediated enantio-
selective organocatalysis under solvent-free conditions in a ball
mill was reported. The intense mixing of the reactants in the ball
mill accelerates the reaction efficiently, but the diastereo- and
With IIIg showing the best results, a screening of the milling
conditions was performed. As shown in Table 2, varying the
milling speed from 200 to 600 rpm (entries 1–3) reveals that
neither decreasing nor increasing the milling speed resulted in
better results. Further optimization of the milling times shows
that even 5 min rotation is enough for the completion of the reac-
tion with the excellent results (entry 6, 95% yield, 99% ee). The
observed results are probably due to that the higher speed and
longer milling time resulted in the temperature increase, and the
lower speed led to the inefficient mixing.
25
enantioselectivities do not decrease. The results suggest that
H-bonding interactions, which are enhanced in the absence of
solvents, are crucial for the course of the reaction. Simplicity of
the reaction, solvent-free conditions, fast reaction times, high
yields and selectivities lead us to conclude that the ball mill
procedure is a significant version of the described reaction.
Acknowledgements
Once the optimum reaction conditions were found, the scope
and limitations of this methodology were explored (Tables 3
and 4). As shown in Table 3, a variety of substituted aromatic
This work was supported by the Zhejiang Provincial Natural
Science Foundation of China (No. Y4110373) and Foundation
of Zhejiang Education Committee (No. Y201018458).
894 | Green Chem., 2012, 14, 893–895
This journal is © The Royal Society of Chemistry 2012

View Article Online
a
Table 4 Variation of nucleophiles
3 K. Tanaka, Solvent-Free Organic Synthesis, Wiley VCH, Weinheim,
2009.
4
5
G. Choudhary and R. K. Peddinti, Green Chem., 2011, 13, 276–282.
S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić,
F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack,
L. Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed and
D. C. Waddell, Chem. Soc. Rev., 2012, 41, 413–447.
6
7
A. Stolle, T. Szuppa, S. E. S. Leonhardt and B. Ondruschka, Chem. Soc.
Rev., 2011, 40, 2317–2329.
B. Rodríguez, A. Bruckmann, T. Rantanen and C. Bolm, Adv. Synth.
Catal., 2007, 349, 2213–2233.
b
c
d
Product
4
Time
Yield (%) ee
(dr)
d
Entry Nucleophile
1
(min)
(%)
8 R. Thorwirth, A. Stolle, B. Ondruschka, A. Wild and U. S. Schubert,
Chem. Commun., 2011, 47, 4370–4372.
4a
4b
4c
4d
4e
4f
10
90
99
99
9 R. Schmidt, R. Thorwirth, T. Szuppa, A. Stolle, B. Ondruschka and
H. Hopf, Chem.–Eur. J., 2011, 17, 8129–8138.
1
.6 : 1
10 R. Thorwirth, A. Stolle and B. Ondruschka, Green Chem., 2010, 12,
2
3
4
5
6
5
99
99
985–991.
11 D. A. Fulmer, W. C. Shearouse, S. T. Medonza and J. Mack, Green
Chem., 2009, 11, 1821–1825.
1
2 F. Schneider, T. Szuppa, A. Stolle, B. Ondruschka and H. Hopf, Green
Chem., 2009, 11, 1894–1899.
3 F. Schneider, A. Stolle, B. Ondruschka and H. Hopf, Org. Process Res.
Dev., 2009, 13, 44–48.
4 F. Schneider and B. Ondruschka, ChemSusChem, 2008, 1, 622–625.
5 S. Toma, R. Sebesta and M. Meciarova, Curr. Org. Chem., 2011, 15,
25
30
50
20
90
93
1
91
1
1
2
257–2281.
6 A. Bruckmann, A. Krebs and C. Bolm, Green Chem., 2008, 10, 1131–
141.
96
85
1
1
1
7 B. Rodríguez, T. Rantanen and C. Bolm, Angew. Chem., Int. Ed., 2006,
45, 6924–6926.
96
92
18 B. Rodríguez, A. Bruckmann and C. Bolm, Chem.–Eur. J., 2007, 13,
710–4722.
9 J. G. Hernández and E. Juaristi, Tetrahedron, 2011, 67, 6953–6959.
20 J. G. Hernández and E. Juaristi, J. Org. Chem., 2011, 76, 1464–1467.
4
1
a
Reactions were carried out with 2a (8.00 mmol), 1 (2.0 equiv.) and
catalyst IIIg (0.5 mol%); ball-milling conditions: 5 min at 400 rpm, and
min pause. Time for milling. Isolated yields. Determined by
2
1 J. G. Hernández, V. García-López and E. Juaristi, Tetrahedron, 2012, 68,
92–97.
2 A. Bañón-Caballero, G. Guillena and C. Nájera, Green Chem., 2010, 12,
b
c
2
2
HPLC analysis using a chiral stationary phase.
1599–1606.
2
2
3 T. Steiner, Angew. Chem., Int. Ed., 2002, 41, 48–76.
4 T. Friščić, A. V. Trask, W. D. S. Motherwell and W. Jones, Cryst. Growth
Des., 2008, 8, 1605–1609.
Notes and references
25 J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem. Soc., 2008,
1
A. Berkessel and H. Gröger, Asymmetric Organocatalysis, Wiley VCH,
Weinheim, 2005.
P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH, Weinheim, 2007.
130, 14416–14417.
26 H. Y. Bae, S. Some, J. S. Oh, Y. S. Lee and C. E. Song, Chem. Commun.,
2011, 47, 9621–9623.
2
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 893–895 | 895