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M. P. Darbem et al. / Tetrahedron Letters 55 (2014) 5179–5181
Table 1
Results and discussion
Protocol, Michael acceptor, solvent, and yields (%) for the thio-Michael reaction using
the Zn[Pro]2 as catalyst (10 mol %) and thiophenol
To prove our hypothesis and assess the catalytic ability of
Zn[Pro]2, we carried out the synthesis of the thio-Michael adduct
from cinnamaldehyde and thiophenol, using this synthesis as the
model reaction. A blank reaction (without Zn[Pro]2) was carried
out using equivalent molar amounts of cinnamaldehyde and thio-
phenol in a magnetic stirrer for 60 min. Three other reactions were
carried out for comparison. The first used the same amounts of
reagents as the blank reaction but also included 10 mol % Zn[Pro]2.
The second reaction differed from the blank reaction in that the
reaction flask was inserted into the ultrasound device. Finally, in
the last reaction, 10 mol % Zn[Pro]2 was used in combination with
the insertion of the reaction flask in the ultrasound device. All the
reactions were carried out for 1 h. Data are presented in Figure 1.
The compound obtained from the reaction with cinnamalde-
hyde was reduced using NaBH4 as the alcohol is more stable than
the aldehyde.
Entry Methodology Michael acceptor
Time
(min)
Yielda
(%)
1
2
3
4
5
US
Stirrer
US
Stirrer
US
Chalcone
Chalcone
Cyclohex-2-enone
Cyclohex-2-enone
3-Methyl-Cyclohex-3-
enone
5
10
15
60
60
89
85
96
80
50
6
Stirrer
3-Methyl-Cyclohex-3-
enone
60
30
7
8
US
Stirrer
Isophorone
Isophorone
60
60
0
0
a
Yields obtained after purification by chromatographic column.
O
As observed in Figure 1, when we concurrently used the
ultrasound device and 10 mol % of the catalyst, we obtained the
thio-Michael adduct in 80% in 1 h. It is worth noting that when
using a chiral hybrid catalyst, Zn[L-Pro]2, a dextro thio-Michael
adduct was obtained. This result is important and contrary to the
results from porcine pancreatic lipase.12
HN
O
Zn
O
NH
O
O
O
We expanded our methodology using other types of a,b-unsat-
HN
urated carbonyl compounds as described in Table 1. As expected,
the presence of the ultrasound device resulted in an improved pro-
cess by decreasing the reaction time (entries 1–2 and 3–4) and
increasing the yields by 12.4%, 16.7%, and 40.0% for the reactions
involving chalcone, cyclohex-2-enone, and 3-methyl-cyclohex-
3-enone, respectively.
O
Zn
O
O
NH
O
S
H
O
The reaction using isophorone did not produce the thio-Michael
adduct, and to the best of our knowledge, we attributed this effect
to the presence of dimethyl groups bonded to carbon 5, which
made it impossible for a nucleophilic attack to occur in the transi-
tion state following the reaction between Zn[Pro]2 and isophorone.
This fact was proven by data for 3-methyl-cyclohexen-2-one,
which also presented a hindered effect but in the C3 position. For
this compound, yields were lower when compared to the other
Michael acceptor. Considering all results, we proposed a mecha-
nism involving the cyclohexen-2-one and thiophenol (Fig. 2).
Aiming to expand the protocol described here, we used
40-substituted thiophenol in the thio-Michael reaction using
cyclohexen-2-one, and the resulting data are presented in Figure 3.
We also decided to use another hybrid heterogenic catalyst,
bis[glycinate-N,O]Zn or Zn[Gly]2, in the same reaction previously
executed for Zn[Pro]2; the resulting data are presented in Table 2.
Two unexpected and important facts were observed in the
O
S
Ph
HN
O
SPh
O
Zn
O
NH
O
Figure 2. Plausible mechanism for Zn [Pro]2 catalyzed the thio-Michael reaction.
Figure 3. Yields obtained or the reaction involving cyclohexen-2-one and some
4-substituted thiophenols.
reactions with Zn[Gly]2 when compared to Zn[Pro]2: the increase
in some reaction times (entries 1 and 3) and the decrease in the
yields (Tables 1 and 2). Both facts can be explained by the dissolu-
tion of the catalyst Zn[Gly]2 in the solvent media, which did not
occur with Zn[Pro]2. This shows that the process of purification
for the reactions using Zn[Gly]2 was more complex.
Finally, we carried out the reaction involving cyclohexanone
and 40-substituted thiophenol (4-OMe, 4-Cl, and 4-NO2) testing
the methodology with and without the ultrasound device and
using Zn[Gly]2 as catalyst. As observed for all the reactions
Figure 1. Yields obtained for the reaction using magnetic stirrer or ultrasound with
and without Zn[Pro]2.
Darbem, Mariana P.
