Silica gel-mediated catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl compounds to highly toxic methyl vinyl ketone without volatilization

Article abstract of DOI:10.1016/j.tetlet.2020.152142

Silica gel-mediated Michael addition of 1,3-dicarbonyl compounds to methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) was carried out to give the corresponding adducts in quite excellent yields. The reactions could be carried out without any catalysts and solvents. In addition, highly toxic MVK and EVK could be employed without significant volatilization. Silica gel could be recycled five times without the decrease of the yields.

Full text of DOI:10.1016/j.tetlet.2020.152142

Journal Pre-proofs
Silica gel-mediated catalyst-free and solvent-free Michael addition of 1,3-di‐
carbonyl compounds to highly toxic methyl vinyl ketone without volatiliza‐
tion
Kiyoshi Tanemura, Taoufik Rohand
PII:
DOI:
Reference:
S0040-4039(20)30602-X
https://doi.org/10.1016/j.tetlet.2020.152142
TETL 152142
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 April 2020
5 June 2020
9 June 2020
Please cite this article as: Tanemura, K., Rohand, T., Silica gel-mediated catalyst-free and solvent-free Michael
addition of 1,3-dicarbonyl compounds to highly toxic methyl vinyl ketone without volatilization, Tetrahedron
Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152142
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Silica gel-mediated catalyst-free and solvent-
free Michael addition of 1,3-dicarbonyl
compounds to highly toxic methyl vinyl
ketone without volatilization
Leave this area blank for abstract info.
Kiyoshi Tanemura, Taoufik Rohand
R1
R1
R2
O
O
O
O
O
O
SiO2
+
R3
R3
R3 = Me and Et
R2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Silica gel-mediated catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl
compounds to highly toxic methyl vinyl ketone without volatilization
Kiyoshi Tanemuraa,  and Taoufik Rohandb
a
Chemical Laboratory, School of Life Dentistry at Niigata, Nippon Dental University, Hamaura-cho, Niigata 951-8580, Japan
Laboratoire de Chimie Analytique et Moléculaire, Département de Chimie, Université Cadi Ayyad-Marrakech, Faculté Polydisciplinaire de Safi, 46000 Safi,
b
Morocco
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Fax: +81 25 267 1134; E-mail address: tanemura@ngt.ndu.ac.jp.
Article history:
Received
Silica gel-mediated Michael addition of 1,3-dicarbonyl compounds to methyl vinyl ketone
(MVK) and ethyl vinyl ketone (EVK) was carried out to give the corresponding adducts in quite
Received in revised form
Accepted
Available online
excellent yields. The reactions could be carried out without any catalysts and solvents. In
addition, highly toxic MVK and EVK could be employed without significant volatilization.
Silica gel could be recycled five times without the decrease of the yields.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Silica gel
Michael addition
Hydrogen bonding
Solvent-free conditions
Great interest has been taken in solvent-free reactions in order
to improve traditional methods from the economic and
environmentally benign viewpoints since the procedure does not
utilize harmful organic solvents [1, 2]. Convenient work-up and
many faster reactions are attractive and valuable advantages. In
relation to this methodology, silica gel and alumina-mediated
reactions under organic solvent-free conditions have attracted
much attention because of high selectivity, dramatic acceleration,
and mild conditions [3, 4]. During the course of our
investigations on the use of silica gel in chemical reactions [5-7],
we have found that highly volatile compounds do not volatilize
near and above their boiling points on heating in silica gel-
mediated self-aldol reactions [8].
compounds with highly toxic MVK and EVK proceeded with
suppressing volatilization to give the corresponding adducts in
quite excellent yields.
Scheme 1. Michael addition mediated by adsorbent.
First, we examined Michael addition of methyl 2-
oxocyclopentane-1-carboxylate (1a) with 3.0 equivalents of
MVK 2a at 70 °C for 8 h as a model reaction using some
adsorbents (Scheme 1). The results are summarized in Table 1.
The use of silica gel (Silica gel 60, 63-200 μm, spherical,
Nacalai) as an adsorbent gave the adduct 3a in the quite excellent
yield (>99%) (entry 1). Even when a reflux condenser was not
equipped, compound 3a was obtained in 99% yield (entry 2). The
use of the other silica gel gave almost the same results (entries 3-
6). Crushed silica gel also led to the similar results although it is
somewhat difficult to mix (entry 7). Michael addition mediated
by sea sand yielded 3a in the low yield (28%) (entry 8). Mixing
was difficult in sea sand-mediated reactions owing to the
formation of a large mass. Only 3% of 3a was obtained without a
reflux condenser, indicating that sea sand cannot adsorb a large
amount of MVK (entry 9). Recently, Michael addition of 1,3-
dicarbonyl compounds to nitroalkenes using quartz sand by a
grinding method has been reported [27]. The reactions mediated
by alumina, H-Mordenite, and Montmorillonite K10 resulted in
the lower yields of 3a together with the formation of complex
mixture or polymeric material because of the more acidic nature
of these solids (entries 10-12). The low yield (10%) of activated
carbon would be attributed to the much weaker acidic nature of
the adsorbent (entry 12). The reaction progressed in the absence
of adsorbents to give 3a in 12% yield (entry 14). Michael
addition of 1a in toluene hardly proceeded (entry 15). The
Michael addition is widely recognized as an efficient and
important reaction to form carbon-carbon bonds in organic
synthesis [9-13]. Generally, Michael addition was catalyzed by
strong bases such as alkali metal alkoxides and hydroxides or
some acids such as super acids, which remain environmentally
harmful residues or afford undesirable side products [14-17].
Recently, considerable attention has been focused on the
procedures under mild and environmentally friendly conditions.
From these points of view, some methods using weakly acidic or
basic solids have been devised [18-25]. However, frequently used
methyl vinyl ketone (MVK) (2a) and ethyl vinyl ketone (EVK)
(2b) are highly toxic and volatile compounds. MVK and EVK
causes central nervous system depression, the edema of the
lungs, and eye injury [26].
In this paper, we wish to report that silica gel-mediated
catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl
O
O
O
COOMe
O
COOMe
+
Adsorbent
1a
2a
3a

2
Tetrahedron
reaction in EtOH was more accelerated than those under neat
Michael acceptors 2c-f hardly gave the adducts at 90 °C (Fig. 1).
conditions and in toluene by the hydrogen-bonding activation
with EtOH (entry 16) [28].
The reactions at 120 °C resulted in exclusive polymerization.
We examined the volatilization of MVK (bp 81 °C) and EVK
(bp 103 °C) at 90 and 70 °C in the presence and absence of silica
gel equipped with a reflux condenser (Liebig condenser) and a
drying tube. The weight loss of MVK and EVK was determined
by the electronic balance. The results are shown in Table 3.
When silica gel was not employed, a large amount of MVK and a
small amount of EVK were volatilized after the heating at 90 and
70 °C although polymeric material was formed in the case of
EVK (entries 2, 4, 6, and 8). The reason for the larger weight loss
of MVK at 70 °C than that of 90 °C will be attributed to the fact
that a large amount of MVK attached at the joint between the
flask and the condenser at 70 °C, while the reflux of MVK was
observed inside the condenser and less amount of MVK attached
at the joint at 90 °C (entries 2 and 4). On the other hand, the
weight loss was not observed in the presence of silica gel
although a small amount of complex mixture was obtained
(entries 1, 3, 5, and 7).
Table 1
Michael addition of 1a mediated by some adsorbents.a
a Compound 1a (2.0 mmol), MVK 2a (6.0 mmol), adsorbent (6.0 g), 70 °C, 8
h.
b Isolated yields.
c Reflux condenser was not equipped.
d Silica gel 60 (63-200 μm, spherical, Nacalai) was used.
e Silica gel 60 (63-210 μm, spherical, Kanto) was used.
f Wakosil C-200 (64-210 μm, spherical, Wako) was used.
g Silica gel 60 (45-106 μm, spherical, Nacalai) was used.
h Wakosil C-300 (40-64 μm, spherical, Wako) was used.
i Silica gel 60 (63-200 μm, crushed, Nacalai) was used
j Sea sand C (40-80 mesh, Nakalai) was used.
k Alumina (activated, acidic, Brockmann I, 150 mesh, Aldrich) was used.
Entry
Adsorbent
Silica geld
Silica geld
Silica gele
Silica gelf
Yield (%)b
> 99
99
1
2c
3
In order to expand the scope of this system, the present
procedure was scaled up 20-fold for the addition of compound 1a
to MVK. The reactions proceeded without any difficulty to give
3a in 92% yield.
95
4
99
5
Silica gelg
Silica gelh
Silica geli
97
6
98
The recycle experiments of Michael addition of 1a with MVK
were carried out. The recovered silica gel was washed with
EtOAc and dried at 120 °C under reduced pressure (20 Torr) (1
Torr = 133.322 Pa) for 3 h. Silica gel could be reused five times
without significant decrease of the yields (Table 4).
7
> 99
28
8
Sea sandj
9c
10
11
12
13
14
15
16
Sea sandj
3
Aluminak
33q
27r
61r
10
A plausible mechanism for the formation of 3 is shown in
Scheme 2. The keto form 1 of the 1,3-dicarbonyl compounds is
in equilibrium with the enol form 4. Compound 4 would attack
the Michael acceptor 2 to give 3 via the enol form 5. The
function of silica gel is probably to shift the equilibrium to the
enol form 4 by the coordination of the weakly acidic hydrogen
atom of silica gel to the oxygen atom of the keto form 1. In
addition, the attack of the enol from 4 to 2 would be accelerated
by the coordination of the hydrogen atom of silica gel to the
oxygen atom of 2. Thus, hydrogen bonding between surface
hydroxy groups of silica gel and substrates would play an
important role.
H-Mordenitel
Montmorillonite K10m
Activated carbonn
−
12
o
−
1
p
−
25
l Hydrogen Mordenite (5-7 μm, Wako) was used.
m Montmorillonite K10 (surface area 220-270 m2/g, Aldrich) was used.
n Activated carbon (Darco, 100 mesh, Aldrich) was used.
o Dry toluene (6.0 mL) was used as a solvent.
p Dry EtOH (6.0 mL) was used as a solvent.
q Complex mixture was obtained.
In conclusion, we devised the silica gel-mediated Michael
addition of 1,3-dicarbonyl compounds with MVK and EVK. The
reactions proceeded without any catalysts and solvents. The
products were obtained in quite excellent yields. We could carry
out Michael addition with preventing the discharge of highly
toxic MVK and EVK compared to neat reactions. The products
could be separated only by filtration. Furthermore, silica gel
could be recycled without the significant decrease of the yields.
r Polymeric material was obtained.
Next, we tested the reactions of various 1,3-dicarbonyl
compounds 1a-k with MVK 2a and EVK 2b. The results are
summarized in Table 2. Compounds 1a-k reacted with 3.0
equivalents of MVK and EVK to give the corresponding adducts
3a-p in quite excellent yields because of the weakly acidic nature
of silica gel, respectively. One and a half equivalents of MVK
were enough to complete the reactions of 1a and 1b at 70 °C
(entries 1 and 2). It is interesting to note that compounds 1c and
1d possessing six-membered ring reacted considerably slower
than 1a and 1b possessing five-membered ring probably due to
the steric reason during the reaction although details are not clear
at the present time (entries 1-4, 12, and 13). EVK reacted more
slowly than MVK (entries 12-16). The reactions were sensitive to
steric hindrance of 1,3-dicarbonyl compounds (entries 5 and 6, 9-
11, 14 and 15). In spite of our extensive efforts, the other
Acknowledgments
We thank Center for Coordination of Research Facilities,
Institute for Research Promotion, Niigata University for NMR
measurements and high-resolution mass analysis. K. T. thanks
the Research Promotion Grant (NDU Grants N-20009) from
Nippon Dental University. T. R. thanks the University Cadi
Ayyad and specially the Faculty Polydisciplinaire of Safi for the
financial support to the LACM laboratory.
Table 2
Michael addition of various Michael donors 1 with 2.a

5
Entry
Donor
Acceptor
Time (h)
Product
Yield (%)b
Temp (
)
℃
O
O
COOMe
O
O
COOMe
1
2
70
70
8
8
> 99 (94)c (86)d
> 99 (95)c
3a
3b
1a
2a
O
O
O
COOEt
COOEt
2a
1b
O
O
O
O
COOMe
COOMe
3
4
2a
2a
90
90
24
24
92
96
3c
1c
O
COOEt
O
O
COOEt
3d
1d
O
O
O
OEt
5
6
2a
2a
90
90
8
> 99
99
OEt
3e
O
1e
O
O
Ph
O
O
OEt
16
Ph
OEt
3f
O
1f
O
O
O
COMe
COMe
1g
7
8
2a
2a
90
90
20
24
> 99
92
O
O
3g
O
COOMe
EtOOC
O
EtOOC
O
COOEt
3h
COOEt
O
COOEt
1h
O
9
10
11
12
2a
2a
2a
90
90
90
70
24
32
48
24
98
> 99
> 99
99
3i
O
1i
O
O
O
Ph
O
O
Ph
Ph
3j
O
1j
O
O
O
O
Ph
O
Ph
Ph
3k
1k
O
O
O
COOEt
COOEt
3l
1b
2b

4
Tetrahedron
Table 2 Continued
Entry
Donor
Acceptor
Time (h)
Product
Yield (%)b
Temp (
)
℃
O
O
COOEt
O
O
COOEt
13
14
2b
2b
90
90
64
36
> 99
> 99
3m
1d
O
O
O
OEt
OEt
3n
O
1e
O
O
Ph
O
O
OEt
15
16
2b
2b
90
90
64
72
> 99
92
Ph
OEt
O
3o
1f
O
O
O
O
3p
1i
O
a Compound 1 (2.0 mmol), acceptor 2 (6.0 mmol), Silica gel 60 (63-200 μm, spherical, Nacalai, 6.0 g).
b Isolated yields.
c Compound 1 (2.0 mmol), MVK 2a (3.0 mmol), Silica gel 60 (63-200 μm, spherical, Nacalai, 3.8 g), 70 °C, 24 h.
d Compound 1 (2.0 mmol), MVK 2a (3.0 mmol), Silica gel 60 (63-200 μm, spherical, Nacalai, 3.8 g), 90 °C, 8 h.
O
O
Table 4
Recycle experiments for the reaction mediated by silica gel.a
NO2
COOMe
2e
Ph
1st
94
2nd
96
3rd
99
4th
97
5th
98
2c
2f
2d
Yields (%)b
Fig. 1. Structure of some Michael acceptors.
a Compound 1a (2.0 mmol), MVK 2a (3.0 mmol), Silica gel 60 (63-200 μm,
spherical, Nacalai, 3.8 g), 70 °C, 24 h.
Table 3
b Isolated yields.
Entry
1a
Acceptor
MVK
MVK
MVK
MVK
EVK
Temp (°C)
Silica gelc
Weight loss (wt%)
90
90
70
70
90
90
70
70
+
−
+
−
+
−
+
−
0d
60
0e
R1
R2
R1
R2
O
2a
O
O
O
O
O
Si
O
3a
R3
O
H
4a
90
0f
3
5b
1
6b
EVK
15g
0h
8i
O
Si
O
H
O
7b
EVK
8b
EVK
R1
R2
R1
H
O
O
O
O
O
Effect of silica gel for the heating of MVK 2a and EVK 2b.
+
H
R3
a MVK 2a (3.0 mmol), Silica gel 60 (60-200 μm, spherical, Nacalai, 2.3 g), 8
h.
R3
O
R2
b EVK 2b (3.0 mmol), Silica gel 60 (60-200 μm, spherical, Nacalai, 2.3 g), 8
h.
2
5
4
c + (Silica gel was used), − (silica gel was not used).
d Complex mixture was obtained in 8 wt%.
e Complex mixture was obtained in 3 wt%.
f Complex mixture was obtained in 20 wt%.
g Polymeric material was obtained in 77 wt%.
h Complex mixture was obtained in 14 wt%.
i Polymeric material was obtained in 14 wt%.
Scheme 2. Mechanism for the formation of 3.
Supplementary data

5
Supplementary data associated with this article can be found,
in the online version.
References
[1] K. Yoshizawa, S. Toyota, F. Toda, Tetrahedron Lett. 42
(2001) 7983-7985.
[2] F. Toda, T. Suzuki, S. Higa, J. Chem. Soc., Perkin Trans. 1
(1998) 3521-3522.
[3] S. Onitsuka, Y. Z. Jin, A. C. Shaikh, H. Furuno, J. Inanaga,
Molecules 17 (2012) 11469-11483.
[4] H. Kotsuki, T. Shimanouchi, Tetrahedron Lett. 37 (1996)
1845-1848.
[5] K. Tanemura, T. Suzuki, Tetrahedron Lett. 59 (2018) 392-
396.
[6] K. Tanemura, Tetrahedron Lett. 59 (2018) 4293-4298.
[7] T. Rohand, J. Savary, I. E. Markó, Monat. Chem. 149
(2018) 1429-1436.
[8] K. Tanemura, Tetrahedron Lett. 60 (2019) 1924-1928.
[9] B. C. Ranu, S. S. Dey, A. Hajra, Arkivoc 7 (2002) 76-81.
[10] A. Prakasham, M. K. Gangwar, P. Ghosh, J. Organomet.
Chem. 859 (2018) 106-116.
[11] S. Ričko, J. Svete, B. Štefane, A. Perdih, A. Golobič, A.
Meden, U. Grošelj, Adv. Synth. Catal. 358 (2016) 3786-
3796.
[12] A. Lubineau, J. Augé, Tetrahedron Lett. 33 (1992) 8073-
8074.
[13] B. Movassagh, P. Shaygan, Arkivoc 12 (2006) 130-137.
[14] T. C. Wabnitz, J. B. Spencer, Org. Lett. 5 (2003) 2141-
2144.
[15] H. Kotsuki, K. Arimura, Tetrahedron Lett. 38 (1997) 7583-
7586.
[16] H. Kotsuki, K. Arimura, T. Ohishi, R. Maruzasa, J. Org.
Chem. 64 (1999) 3770-3773.
[17] Y. Mori, K. Kakumoto, K. Manabe, S. Kobayashi,
Tetrahedron Lett. 41 (2000) 3107-3111.
[18] B. C. Ranu, S. Bhar, R. Chakraborty, A. R. Das, M. Saha,
A. Sarkar, R. Chakraborti, D. C. Sarkar, J. Indian Inst. Sci.
74 (2013) 15-33.
[19] G. Bosica, R. Abdilla, Molecules 21 (2016) 815.
[20] M. Seifi, H. Sheibani, Catal. Lett. 126 (2008) 275-279.
[21] A. O. Terent'ev, V. A. Vil, I. A. Yaremenko, O. V.
Bityukov, D. O. Levitsky, V. V. Chernyshev, G. I.
Nikishin, F. Fleury, New J. Chem. 38 (2014) 1493-1502.
[22] H. Hagiwara, S. Inotsume, M. Fukushima, T. Hoshi, T.
Suzuki, Chem. Lett. 35 (2006) 926-927.
[23] B. C. Ranu, S. Bhar, Tetrahedron 48 (1992) 1327-1332.
[24] R. Sreekumar, P. Rugmini, R. Padmakumar, Tetrahedron
Lett. 38 (1997) 6557-6560.
[25] M. Saikia, D. Kakati, M. S. Joseph, J. C. Sarma, Lett. Org.
Chem. 6 (2009) 654-658.
[26] C. Y. Chen, J. T. Yeh, Environ. Toxicol. Water Quality 11
(1996) 83-90.
[27] Z.-B. Xie, N. Wang, M.-Y. Wu, T. He, Z.-G. Le, X.-Q. Yu,
Beilstein J. Org. Chem. 8 (2012) 534-538.
[28] S. Shirakawa, S. Shimizu, Synlett (2007) 3160-3164.
Declaration of interests

6
Tetrahedron
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Graphical Abstract
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
* Silica gel-mediated Michael addition was
developed.
* Highly toxic methyl vinyl ketone can be used
without volatilization.
* Reactions proceeded under catalyst-free and
solvent-free conditions.
free Michael addition of 1,3-dicarbonyl
Silica gel-mediated catalyst-free and solvent-
Leave this area blank for abstract info.
compounds to highly toxic methyl vinyl
ketone without volatilization
* Michael adducts can be obtained in quite
Kiyoshi Tanemura, Taoufik Rohand
excellent yields.
R1
R1
* Products can be separated by filtration.
O
O
O
O
O
SiO2
+
R3
R3
R3 = Me and Et
O
R2
R2