Organocatalytic solvent-free hydrogen bonding-mediated asymmetric Michael additions under ball milling conditions

Article abstract of DOI:10.1039/c2gc36906k

An efficient, solvent-free protocol for asymmetric Michael additions of α-nitrocyclohexanone to nitroalkenes using thiourea derivatives as hydrogen bonding catalysts has been developed. By performing the organocatalytic reactions in a planetary ball mill, high yields (up to 97%) and excellent enantioselectivities (er up to 98 : 2) were achieved in short reaction times with low catalyst loadings.

Full text of DOI:10.1039/c2gc36906k

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Organocatalytic solvent-free hydrogen bonding-
mediated asymmetric Michael additions under ball
Cite this: Green Chem., 2013, 15, 612
Received 28th November 2012,
Accepted 2nd January 2013
milling conditions†
DOI: 10.1039/c2gc36906k
Manuel Jörres, Stefanie Mersmann, Gerhard Raabe and Carsten Bolm*
www.rsc.org/greenchem
An efficient, solvent-free protocol for asymmetric Michael preparation and modification of inorganic solids,8 and more
additions of α-nitrocyclohexanone to nitroalkenes using thiourea recently it was applied in solvent-free organic synthesis.9 It has
derivatives as hydrogen bonding catalysts has been developed. been argued that the latter is effective due to more efficient
By performing the organocatalytic reactions in a planetary ball mixing and enhancement of reagent surfaces rather than the
mill, high yields (up to 97%) and excellent enantioselectivities mechanical breaking of molecular bonds.10
(er up to 98 : 2) were achieved in short reaction times with low
catalyst loadings.
Applications of ball milling in organic synthesis predomi-
nantly relate to catalytic C–C bond formations.3,9,11–15
Although it was shown that, compared to the classical solu-
tion-based alternative, asymmetric organocatalytic reactions
under ball milling conditions can be performed with lower
catalyst loading and in shorter reaction times, only a few
examples have so far been studied in depth. Respective reports
include asymmetric anhydride openings,12 aldol-12,13 and
alkylation reactions14 and, only recently, Michael additions.3,15
Hydrogen bonding plays a major role in organocatalytic
activations.16 Many bifunctional organocatalysts that allow the
simultaneous activation of two reactants rely on that
concept.17 Along those lines, we recently reported the asym-
metric Michael addition of α-nitrocyclohexanone (1) to aryl
nitroalkenes 2 catalysed by natural amino acid-derived bifunc-
tional thioureas.18 Combining these recent results with our
long-lasting interest in asymmetric organocatalysis under
(solvent-free) ball milling conditions,12,13a,b we envisioned that
also this reaction could benefit from applying the mechano-
chemical technique. Three factors were expected to increase
the reaction efficiency: first, the high local reagent concen-
tration; second, the lack of solvent interference to hydrogen
bonding; and third, the efficient reagent mixing in the solvent-
free media. Here, we report on the validation of this
hypothesis.
1. Introduction
The concept of organocatalysis has gained significant interest
within the field of asymmetric organic synthesis over the last
decade.1,2 Besides its many advantages such as the use of air-
and water-stable catalysts, the avoidance of toxic metals, and
being environmentally benign in general, there are often still
severe limitations, as for example, high catalyst loadings, a
limited solvent choice and long reaction times, restricting the
potential of asymmetric organocatalysis for industrial appli-
cations.3 Attempts to overcome these boundaries include
attempted syntheses of more efficient organocatalysts,4 per-
forming organocatalysed reactions in ionic liquids or water,
the utilisation of solvent-free reaction conditions and the
application of non-classical energy sources such as microwave
irradiation, ultrasonication or high pressure and mechano-
chemical techniques.5
According to IUPAC,
a mechanochemical reaction is
defined as a “chemical reaction that is induced by the direct
absorption of mechanical energy”.6 Ball milling is a well-estab-
lished industrial technique,7 and its method of mechanical
activation is in accordance with this definition. It has been
used for the grinding of minerals into fine particles and the
2. Results and discussion
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany. E-mail: carsten.bolm@oc.rwth-aachen.de;
Fax: +49 241 80 92 391; Tel: +49 24 80 94 675
†Electronic supplementary information (ESI) available: Experimental proce-
To search for mechanochemical effects induced by ball
milling on the aforementioned thiourea-catalysed asymmetric
Michael addition reactions, the solvent-free coupling of
α-nitrocyclohexanone (1) and 2-furyl-substituted nitroalkene 2a
was initially chosen as a test reaction. First experiments with
dures, results of the reaction condition screening, full characterization of new
products, computational and experimental ECD and VCD spectra, and er deter-
minations. See DOI: 10.1039/c2gc36906k
612 | Green Chem., 2013, 15, 612–616
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Scheme 1 Michael addition of α-nitrocyclohexanone (1) to 2-furyl-substituted
nitroalkene 2a; ball milling conditions: 2 × 15 min at 300 rpm and 15 min
pause, 20 balls with a diameter of 0.4 cm.19
Table 1 Catalyst screeninga
Fig. 1 Screened organocatalysts.
Entry
Catalyst
Yieldb (%)
drc (anti : syn)
erc
1
2
3
4
5
6
7
8
Aa
B
83
69
71
78
66
57
64
77
92
85
67
95 : 5
90 : 10
92 : 8
80 : 20
55 : 45
85 : 15
89 : 11
93 : 7
92 : 8
76 : 24
85 : 15
78 : 22
82 : 18
81 : 19
90 : 10
93 : 7
92 : 8
95 : 5
20 : 80
and Ac, respectively) lowered the yield and the stereoselectiv-
ities in the formation of 3a (Table 1, entries 1, 6 and 7).21 The
latter, however, could be improved by applying piperidine-
based thioureas with bulky substituents (such as tert-butyl) at
the endocyclic nitrogen (Table 1, entry 1 versus entries 8
and 10). Consequently, the use of N-tert-butyl-containing
thiourea Af having a benzyl group as R2 gave the best results,
affording product 3a with an er of 95 : 5 in 85% yield
(entry 10).19
Ca
Cb
Cc
Ab
Ac
Ad
Ae
Af
9
10
11
92 : 8
96 : 4
95 : 5
D
a Reactions were carried out on a 0.2 mmol scale; ball milling
conditions: 2 × 15 min at 300 rpm and 15 min pause. b After aqueous
workup and flash chromatography.19 c Determined by HPLC of the
crude product using a chiral stationary phase.
Finally, Takemoto’s thiourea D22 was included in the
screening process, in order to compare the results obtained for
A–C with those achievable with an established thiourea-type
catalyst. With D, the diastereoselectivity remained high, but
piperidine-based thiourea Aa showed that the addition pro- the yield and the enantioselectivity dropped (Table 1, entry
ceeded smoothly leading to product 3a with an enantiomeric 11). Based on all results, thiourea Af became the catalyst of
ratio of 92 : 8 and a diastereomeric ratio of 95 : 5 in 83% yield choice for the subsequent investigations (Table 2).
after only 30 min (Scheme 1).19
The effect of the catalyst loading was studied next. To our
A subsequent screening of the reaction conditions includ- delight, the enantioselectivity increased when the amount of
ing total milling time and milling speed revealed that this the catalyst was reduced. Thus, with only 2.5 mol% (instead of
result could not be improved.20 To avoid overheating, the reac- the previously used 10 mol%) of Af, the er of 3a was 96 : 4, and
tions were typically carried out in milling cycles consisting of a the product was obtained in 83% yield (Table 2, entry 3).
15 min milling period followed by a 15 min pause. The neces- Notably, the reaction proceeded with very high stereoselectivity
sity of this procedure was validated following a 30 min test (er of 96 : 4, dr of 97 : 3) even with a catalyst loading as low as
reaction without any pause, which afforded the resulting 1 mol%, but under those conditions the yield dropped signifi-
product with an er of 90 : 10 in a yield of only 66%.19
cantly to 57% (Table 2, entry 4).
The use of neutral, acidic or basic additives as milling
To check for possible milling effects, the grinding balls in
auxiliaries was tested as well as the addition of DCM for the vessel were exchanged for balls with a smaller diameter.
liquid-assisted grinding. However, none of those changes led While the stereoselectivity of the reaction remained high,
to an improvement of the stereoselectivity and the yield.
lower yields of 3a were obtained, probably due to blind spots
Next, alternative thiourea catalysts were screened (Table 1, in the vessel (Table 2, entries 5–7).23
Fig. 1).19 Compared to Aa the use of pyrrolidine-based thiourea
In an attempt to overcome the problem of the α-nitrocyclo-
B led to a lower yield of 3a and a reduced enantioselectivity hexanone traces in the final product, an investigation into the
(entries 1 and 2). In the series of thiourea Ca, urea Cb and substrate ratio was carried out. Unfortunately, neither the use
selenurea Cc (entries 3–5), the first gave the best stereoselectiv- of stoichiometric reagent amounts nor applying an excess
ities (er and dr).20 None of those catalysts, however, reached of nitroalkene 2a proved superior to the aforementioned
the superior values obtained with thiourea Aa (entry 1).
conditions, where an excess of α-nitrocyclohexanone (1) was
Changing the substituent R2 from 3,5-bis(trifluoromethyl)- employed. While the enantioselectivities remained high, the
phenyl (as in Aa) to 2-naphthyl or benzyl (as in thioureas Ab yield dropped to 52%–65% (Table 2, entries 8–11).
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Table 2 Screening of reaction and milling conditions for the Michael addition of α-nitrocyclohexanone (1) to 2-furyl-substituted nitroalkene 2aa
Entry
Ratio of 1 : 2a
Catalyst loading (mol%)
Milling balls diameter (cm)
Milling time (min)
Yieldb (%)
drc (anti : syn)
erc
1
2
3
4
5
6
7
8
1.5 : 1
1.5 : 1
1.5 : 1
1.5 : 1
1.5 : 1
1.5 : 1
1.5 : 1
1 : 1
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
10
5
2.5
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0.4
0.4
0.4
0.4
0.1
0.2
0.3
0.4
0.4
0.4
0.4
0.4
30
30
30
30
30
30
30
30
30
60
80d
30
85
70
83
57
47
66
35
63
65
61
52
86
96 : 4
93 : 7
96 : 4
97 : 3
97 : 3
97 : 3
96 : 4
96 : 4
95 : 5
94 : 6
97 : 3
94 : 6
95 : 5
96 : 4
96 : 4
96 : 4
94 : 6
96 : 4
96 : 4
96 : 4
96 : 4
93 : 7
96 : 4
96 : 4
9
10
11
12e
a Reactions were carried out on a 0.4 mmol scale; ball milling conditions: 15 min at 300 rpm and 15 min pause. b After aqueous workup and
flash chromatography.19 c Determined by HPLC of the crude product using a chiral stationary phase. d Ball milling conditions: 8 cycles of 10 min
at 300 rpm and 5 min pause. e Crude product was directly transferred to flash chromatography.
Table 3 Investigation of substrate scopea
Entry
Nitroalkene
Ar
Product
Yieldb (%)
drc (anti : syn)
erc
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2-Furyl
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
86
95
91
88
91
93
86
80
91
94 : 6
96 : 4
96 : 4
94 : 6
96 : 4
98 : 2
96 : 4
95 : 5
95 : 5
96 : 4
98 : 2
97 : 3
97 : 3
99 : 1
98 : 2
97 : 3
97 : 3
97 : 3
o-FC6H4
p-FC6H4
o-ClC6H4
p-ClC6H4
p-BrC6H4
p-MeOC6H4
p-MeC6H4
a Reactions were carried out on a 0.4 mmol scale with 1.5 equiv. of 2a; ball milling conditions: 2 × 15 min at 300 rpm and 15 min pause. b After
flash chromatography. c Determined by HPLC of the crude product using a chiral stationary phase.
The final solution for the product purification came from
Similar results could also be obtained when the reaction
the work-up protocol. Pleasingly, we found that the yield and was run on a larger scale, whereby 1.024 g (97%) of product 3b
purity of the final product were improved by direct flash with an er of 98 : 2 was obtained from 3.6 mmol of α-nitro-
chromatography of the reaction mixture avoiding any styrene (2b).24
additional aqueous work-up step. Thus, with 1.5 equivalents of
nitroalkene 2a, the final product was obtained in pure form in ECD- and VCD-spectra of compound 3b the absolute configur-
86% yield (Table 2, entry 12).
ation of this product is very likely S,S.25 This result is in accord
According to a comparison of calculated and measured
To determine the substrate scope, the optimised reaction with the one obtained previously by X-ray crystal structure
conditions were applied to a range of nitroalkenes. All com- analysis.18
pounds reacted well, and the corresponding addition products
In summary, we developed a new protocol for the hydrogen
were obtained in yields ranging from 80% to 95% (Table 3). bond-mediated organocatalytic addition of α-nitrocyclohexa-
Neither electron-withdrawing nor electron-donating substitu- none to aryl nitroalkenes under solvent-free conditions in a
ents on the aryl unit of the nitroalkenes appeared to signifi- ball mill providing the corresponding addition products in
cantly affect the overall yields. The diastereoselectivities were high yields and with excellent stereoselectivities. The reactions
generally high, with dr values typically around 95 : 5. All enan- proceed with a remarkably low catalyst loading, and the pro-
tiomeric ratios were above 96 : 4. In that respect, the o-chloro- ducts can be purified by direct flash chromatography (without
substituted product 3e provided the best result (er of 99 : 1).
aqueous work-up). In comparison to the results achieved in
614 | Green Chem., 2013, 15, 612–616
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common solvent-phase reactions,18,26 the ones performed
(solvent-free) in a ball mill are faster and more stereoselective.
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Acknowledgements
We thank Ms Pirwerdjan and Ms Holthusen (both RWTH
Aachen University) for their experimental work in this project,
and we are grateful to Dr Schiffers and Dr Priebbenow (both
RWTH Aachen University) for proofreading the manuscript.
We also thank Ms Kallweit from the group of Prof. Haberhauer
(University Duisburg-Essen) for the measurement of the ECD
spectrum. Seed funds for the acquisition of a VCD instrument
provided by RWTH Aachen University through the Excellence
Initiative of the federal and state governments are highly
appreciated.
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19 Because at this initial stage, a small amount (1–5%) of 23 After opening the reaction vessel, substrate residues were
α-nitrocyclohexanone(1) remained in the product (isolated found in the blind spots.
by aqueous workup followed by flash chromatography), the 24 In this reaction, 1.78 mmol (0.49 equiv.) of nitroalkene 2b
“yield” reported here was “corrected” after analysis by
could be recycled following flash chromatography.
25 For computational and experimental details, see ESI.†
1H-NMR spectroscopy.
20 For details on the condition screening and synthetic 26 Reaction conditions and result: use of 0.3 mmol of 1 and
approaches, see the ESI.†
0.2 mmol of 2c in 1 mL of DCM, catalysed by 10 mol% of
Af at room temperature provided the addition product 3c
with a dr of 82 : 18 and an er of 97 : 3 in 90% yield
after 17 h.
21 For effects of electronic variations of thiourea moieties,
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616 | Green Chem., 2013, 15, 612–616
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