Heterogeneous catalytic 1,4-addition of arylmagnesium compounds to chalcones

Article abstract of DOI:10.1016/j.tetlet.2018.07.016

Copper(II) on a 4 ? molecular sieve support catalyses the chemoselective addition of alkyl- and arylmagnesium halides to chalcones. Only the 1,4-addition products were obtained in high yields.

Full text of DOI:10.1016/j.tetlet.2018.07.016

Accepted Manuscript
Heterogeneous catalytic 1,4-addition of arylmagnesium compounds to chal-
cones
Kinga Juhász, Zoltán Hell
PII:
S0040-4039(18)30876-1
https://doi.org/10.1016/j.tetlet.2018.07.016
TETL 50125
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 May 2018
27 June 2018
3 July 2018
Please cite this article as: Juhász, K., Hell, Z., Heterogeneous catalytic 1,4-addition of arylmagnesium compounds
to chalcones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.016
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Graphical Abstract
Heterogeneous catalytic 1,4-addition of
arylmagnesium compounds to chalcones
Kinga Juhász, Zoltán Hell

Tetrahedron Letters
Heterogeneous catalytic 1,4-addition of arylmagnesium compounds to chalcones
Kinga Juhásza, Zoltán Hella*
aBudapest University of Technology and Economics, Department of Organic Chemistry and Technology, H-1111 Budapest, Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper(II) on a 4Å molecular sieve support catalyses the chemoselective addition of alkyl- and
arylmagnesium halides to chalcones. Only the 1,4-addition products were obtained in high
yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Grignard reaction
Chalcones
1,4-addition
Heterogeneous catalysis
Copper
4Å molecular sieve
1. Introduction
can be tedious. The application of heterogeneous catalytic
methods reduces some of these disadvantages, and thus the
The addition of nucleophiles to electron-deficient conjugated
systems is a widely used method for the formation of carbon-
carbon bonds in synthetic organic chemistry. Generally, the
reaction of α,β-unsaturated carbonyl compounds with
organometallic reagents affords the corresponding 1,2-addition
product. However, it was observed that the addition of a catalytic
amount of a copper salt to the reaction mixture leads to conjugate
addition.1-4
development of efficient heterogeneous catalytic processes
represents an interesting area of research.
2. Results and Discussion
Recently our research group developed new heterogeneous
copper-catalyzed methods for the preparation of propargylamines
via A3-coupling,9 and for the Chan-Lam-coupling of amines and
boronic acids.10
Kharasch and co-workers studied the reaction of
α,β-unsaturated carbonyl compounds with methylmagnesium
bromide. It was found that in the presence of a catalytic amount
of metal salts 1,4-addition occurred, instead of 1,2-addition,
yielding β-substituted carbonyl compounds (Fig. 1). Copper was
found to be the most efficient metal to perform the conjugate
addition.5
In continuation of our interest in the development of new
heterogeneous catalytic methods, we examined the reaction of
chalcones with Grignard compounds in the presence of copper(II)
on a 4Å molecular sieve support [Cu(II)-4Å MS]. In the reaction
of trans-chalcone (benzylideneacetophenone, 2a) with
ethylmagnesium iodide (1a), 3-ethyl-1,3-diphenyl-propan-1-one
(3a) was formed in good yield (80%, Fig. 2). GC-MS
examination of the reaction mixture showed that the 1,4-addition
product was formed exclusively, and the 1,2-addition product
(4a) was not observed. This was also confirmed by analysis of
the 1H and 13C NMR spectra. It is well known that during the
formation and reaction of Grignard compounds that
Figure 1. Conjugate addition of methylmagnesium bromide to
homocoupling with formation of the corresponding dialkyl/diaryl
compounds can occur. This side-reaction cannot be easily
avoided, thus, based on our previous experience during the study
of the Kumada-coupling, the halide derivatives were used in
excess. The effect of different solvents was examined, where in
case of tetrahydrofuran and diethyl ether no significant difference
was found. When the reaction was carried out in methyl-tert-
butyl-ether, no product was formed, and chalcone 2a was
recovered from the reaction mixture. Due to the simpler reaction
workup, diethyl ether was chosen as for further reactions. The
optimal reaction time was 6 h and longer reaction times did not
result in improved yields (Table 1). In case of a 3 h reaction time,
isophorone
This reaction was extensively developed, and the catalytic
activity of organocopper compounds6 and the reactivity of α,β-
unsaturated esters7 have also been demonstrated. Most recently
the stereochemistry of the reaction has been examined using
chiral catalysts and/or ligands.8
The above mentioned methods are homogeneous catalytic
processes. Homogeneous catalytic reactions have several
disadvantages: the metal catalysts often require ligands, and
during workup the separation of both the metal and the ligand
*Email: zhell@mail.bme.hu
Tel.: +36 1 463 1414

2
Tetrahedron
the chalcone could be still detected by TLC as well as in the 1H
Table 2. Reaction of chalcone 2a with Grignard compounds
NMR spectrum.
In order to demonstrate the need for the catalyst in this
reaction a control experiment was carried out, where no catalyst
was added. Upon analyzing the 1H NMR spectrum of the reaction
mixture a detectable amount of the 1,2-addition product as well
as several unknown by-products could be identified. Therefore, it
was proved that the selectivity of the reaction relies on the
application of the Cu(II)-4Å MS catalyst (Table 1).
in the presence of Cu(II)-4Å MSa
Yieldb
Entry
RMgX
Product
3 (%)
Table 1. Optimization of the reaction conditions
1
80
2
3
78
72
Time
(h)
Yielda
Entry
1
Catalyst
Solvent
Et2O
3a (%)
Cu(II)-4Å MS
6
80
2
-
Et2O
6
65b
4
5
83
60
3
4
5
6
Cu(II)-4Å MS
Cu(II)-4Å MS
Cu(II)-4Å MS
Cu(II)-4Å MS
Et2O
3
55b
79
80
0
Et2O
12
6
THF
6
7
83
67
MTBE
6
a Based on GC-MS
b Based on 1H NMR of the crude product
8
9
75
70
Figure 2. Reaction of ethylmagnesium iodide 1a with chalcone
2a in the presence of Cu(II)-4Å MS and the undesired product
4a.
Under the optimized reaction conditions chalcone 2a was
reacted with different Grignard compounds (Table 2). In all cases
the desired 1,4-addition products were obtained. As mentioned
above due to the excess of the halide reactant, in the case of
aromatic halides the corresponding biphenyl derivatives, arising
from homocoupling of the Grignard compounds, were detected in
the reaction mixture. Conversely, in the case of aliphatic
Grignard compounds the highly volatile homocoupled dimers
were removed from the reaction mixture either during the
reaction, during the workup, or during solvent evaporation. The
biphenyl derivatives could be separated from the products via
chromatographic purification.
10
88

3
a Reagents and conditions: magnesium (2 mmol), alkyl/aryl halide (2.3
mmol), chalcone (1 mmol), catalyst (0.1 g, 9 mol% Cu), diethyl ether (9 mL),
reflux, 6 h
11
20
b Based on GC-MS
a Reagents and conditions: magnesium (2 mmol), alkyl/aryl halide (2.3
Table 4. Reusability of the Cu(II)-4Å MS catalyst
mmol), chalcone (1 mmol), catalyst (0.1 g, 9 mol% Cu), diethyl ether (9 mL),
Yielda
Entry
Number of uses
reflux, 6 h
b Based on GC-MS
3a (%)
1
2
3
1
2
3
80
As shown in Table 2, good yields were obtained with both
aliphatic and aromatic Grignard compounds and no significant
steric effect was observed. Compound 1j, containing a
trifluoromethyl group also showed good activity. Because the
reactivity of phenylmagnesium bromide 1e toward chalcone is
lower than the reactivity of phenylmagnesium iodide 1d, the
amount of biphenyl increased in the reaction of 1e. This is the
reason for the different yields attained in entries 4 and 5. As
observed during our study of the Kumada coupling,11 a methoxy
substituent on the aryl halide may inhibit the Grignard reaction.
This is the reason for the poor yield in entry 11. It was also
observed, that the presence of a nitro group on the aryl halide
decreases the solubility of the aryl halide in diethyl ether, thus no
reaction occurred.
79
75
4
4
74
a Based on GC-MS
The method was also tested in the reaction of
ethylmagnesium iodide with 2-cyclohex-1-one. In this case a
complex reaction mixture was obtained, in which both the 1,2-
addition product and the 1,4-addition product were detected
together with undefined by-products in the 1H NMR spectrum
and the GC-MS chromatogram.
Next, we examined the reactivity of substituted chalcones
(Table 3). In these cases no significant differences were observed
in the reactivity of the different derivatives. The desired products
were obtained in good yields.
3. Conclusion
In conclusion, copper(II) on a 4Å molecular sieve support was
demonstrated to be an efficient catalyst for the selective 1,4-
addition of Grignard compounds to chalcones. The workup of the
reaction mixture is straightforward, and the products were
obtained in good yields. The preparation of the catalyst is simple,
and after washing with acetone and drying can be reused multiple
times without significant loss of activity.
The reusability or recyclability of the catalyst is an important
advantage of heterogenous catalytic methods. Thus, the
reusability of Cu(II)-4Å MS was tested in the reaction of
ethylmagnesium iodide 1a and chalcone 2a. The catalyst was
filtered from the reaction mixture, washed with acetone, and
dried at 120 °C for 1 h, then a second experiment was carried out
with the recovered catalyst The reusability was tested three times,
and it was found that the catalyst can be reused without
significant loss of activity (Table 4).
References and notes
1.
2.
Dieter, S. Angew. Chem. 1993, 105, 1738.
Rappoport, Z.; Marek, I. The Chemistry of Organocopper
Compounds, Wiley, 2009.
3.
4.
Lipshutz, B. H.; Sengupta, S. Organic Reactions 1992, 41, 135.
Ortiz, P.; Lanza, F.; Harutyunyan, S. Top Organomet. Chem.,
2016, 58, 99-134.
Table 3. Reaction of substituted chalcones 2b-e with
ethylmagnesium iodide 1a in the presence of Cu(II)-4Å MSa
5.
6.
7.
8.
Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc., 1941, 63,
2308-2316.
House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem.
1966, 31, 3128-3141.
(a) Munch-Petersen, J. J. Org. Chem. 1957, 22, 170-176; (b)
Munch-Petersen, J. Acta Chem. Scand. 1958, 12, 2007-2011.
(a) Krause, N.; Pamies, O. ; Dieguez, M. Chem. Rev. 2008, 108,
2796-2823; (b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824-2852;
(c) Jerphagnon, Th.; Pizzutti, M. G.; Minnaard, A. J.; Feringa, B.
L. Chem. Soc. Rev. 2009, 38, 1039-1075.
Yieldb
Entry
1
Chalcone
Product
(%)
80
9.
Fodor, A.; Kiss, Á.; Debreczeni, N.; Hell, Z.; Gresits, I. Org.
Biomol. Chem. 2010, 8, 4575-4581.
10. Debreczeni, N.; Fodor, A.; Hell, Z. Catal. Lett. 2014, 144, 1547-
1551.
11. Kiss, Á.; Hell, Z.; Bálint, M. Org. Biomol. Chem. 2010, 8, 331.
2
88
3
4
85
89

4
Tetrahedron
Highlights
 The method is simple and selective
 The workup of the reaction mixture is easy
 The catalyst can be simply prepared and can
be reused without loss of activity