Integration of heterogeneous catalysts into complex synthetic routes: Sequential vs. one-pot reactions in a (Knoevenagel + Mukaiyama-Michael + hydrogenation + transesterification) sequence

Article abstract of DOI:10.1039/c2cy20442h

Heterogeneous catalysts of different nature can be combined in one-pot tandem reactions, but the compatibility issues of catalysts with reagents, products, and by-products make more convenient the application of a sequential procedure, in which the catalyst is filtered after each reaction and the crude is used in the following reaction without purification. In this way the recovery and reuse of each catalyst can be optimized to obtain the maximum productivity. The nature of the reactions, and the catalysts involved in them, conditions the maximum number of successive steps in the sequence. In the case of the (Knoevenagel + Mukaiyama-Michael + hydrogenation + transesterification) process tested in this work, the optimal results are obtained when the sequential method is applied to only three reactions, whereas the four reactions sequence shows limitations in the yield of the last transesterification step. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cy20442h

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Integration of heterogeneous catalysts into complex
synthetic routes: sequential vs. one-pot reactions in a
Cite this: Catal. Sci. Technol., 2013,
, 436
3
(Knoevenagel + Mukaiyama–Michael + hydrogenation +
transesterification) sequence†
Jos e´ M. Fraile,* Nuria Garc ´ı a, Clara I. Herrer ´ı as and Jos e´ A. Mayoral
Heterogeneous catalysts of different nature can be combined in one-pot tandem reactions, but the
compatibility issues of catalysts with reagents, products, and by-products make more convenient the
application of a sequential procedure, in which the catalyst is filtered after each reaction and the crude is
used in the following reaction without purification. In this way the recovery and reuse of each catalyst
can be optimized to obtain the maximum productivity. The nature of the reactions, and the catalysts
involved in them, conditions the maximum number of successive steps in the sequence. In the case of the
Received 27th June 2012,
Accepted 19th September 2012
(Knoevenagel + Mukaiyama–Michael + hydrogenation + transesterification) process tested in this work,
DOI: 10.1039/c2cy20442h
the optimal results are obtained when the sequential method is applied to only three reactions, whereas
the four reactions sequence shows limitations in the yield of the last transesterification step.
www.rsc.org/catalysis
In some cases multifunctional catalysts have been prepared
1. Introduction
1
1,12
and applied in tandem reactions,
but in general the combi-
The substitution of conventional stoichiometric methodologies nation of two or more single-site catalysts is simpler. In spite of
by catalytic processes, together with the possibility of process the interest in this strategy, the examples in the literature are
intensification by combining several catalytic steps into a one-pot rather scarce, and include one-pot combinations of solid acids
1,2
13–17
18–21
catalytic system, provides a means to improve the economical and and bases,
environmental aspects of the chemical processes by minimizing the and biocatalysts with chemical catalysts.22–24 Even if compatibility
use of chemicals, the waste production and the processing time.
between catalysts is not an issue, their compatibility with the
various types of heterogeneous catalysts,
Although it is possible to carry out tandem reactions with a single components of the other reaction (solvent, reagents, concomitant
catalyst, as in the case of tandem coupling reactions with Pd products) may condition the applicability of this methodology.
3,4
catalysts, in most cases several different catalysts are needed. Furthermore, the need for compatibility would be even more
Soluble chemical catalysts have been employed in some tandem difficult in the synthesis of highly functionalized molecules.
5,6
catalysis processes, but the site isolation provided by hetero-
In a previous work, we studied the combination of Mukaiyama–
geneous catalysis should avoid the interaction between incompatible Michael addition and hydrogenation reaction with heterogeneous
7
–10
sites.
As an additional advantage, heterogeneous catalysts can be catalysts, a copper-exchanged laponite and Pd/alumina respec-
25
easily separated and reused, with the subsequent increase in tively. It was shown that both reactions were compatible for a
productivity and operational simplicity. Thus tandem heterogeneous one-pot process, but by-products generated in the hydrogenation
catalysis should constitute a powerful tool in applied chemistry, reaction were detrimental for recovery of the mixture of solids. In
allowing extremely complex chemical transformations to take place contrast, a sequential procedure that uses the crude of the first
in cleaner and more efficient processes.
reaction in the second one allows the optimization of each catalyst
used individually whereas the separation and purification steps are
minimized. In our current work, we intend to use heterogeneous
catalysts in combinations of more than two reactions that include,
in addition to Mukaiyama–Michael and hydrogenation, both the
synthesis of the a,b-unsaturated substrate of the Mukaiyama–
Michael addition, and the transformation of the lactone products
by transesterification with methanol (Scheme 1).
Instituto de S ´ı ntesis Qu ´ı mica y Cat a´ lisis Homog ´e nea (ISQCH) and Instituto
Universitario de Cat a´ lisis Homog ´e nea (IUCH), C.S.I.C. – Universidad de Zaragoza,
E-50009 Zaragoza, Spain. E-mail: jmfraile@unizar.es
†
Electronic supplementary information (ESI) available: IR spectra of freshly
13
prepared and used Lap-Mn(salen), and C CP-MAS-NMR spectra of TBD-PS
unused and treated with HFIP and HFIP + 2-(trimethylsilyloxy)furan. See DOI:
1
0.1039/c2cy20442h
4
36 Catal. Sci. Technol., 2013, 3, 436--443
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Scheme 1 Insertion of the (Mukaiyama–Michael + Hydrogenation) tandem reaction in a longer synthetic pathway with heterogeneous catalysts.
2
. Experimental section
the products were purified by column chromatography using a
mixture of hexanes–ethyl acetate (9 : 1) as an eluent. Isolated
yield was always over 90%.
1,5,7-Triazabicyclo[4.4.0]dec-5-ene supported on silica (TBD-SiO2)
and on poly(styrene-divinylbenzene) (TBD-PS) and Pd/alumina were
purchased from Aldrich. Laponite was a generous gift from
Rockwood additives and it was dried at 120 1C for at least 12 h
before use. Lap-Cu was prepared by cationic exchange of
2.2.2 Transesterification. Diethyl 2-[(5-oxotetrahydrofuran-
2-yl)(phenyl)methyl]malonate (3, syn + anti mixture) was
obtained from diethyl benzylidenemalonate and 2-(trimethyl-
25
silyloxy)furan as described elsewhere. A mixture of 3 (334 mg,
2
5
2
laponite with Cu(OTf) in methanol. All reagents were also
1
mmol) and TBD-catalyst (TBD-PS or TBD-SiO2, 0.1 mmol) in
purchased from Aldrich and used without further purification,
except benzaldehydes that were distilled under vacuum prior to
use. Solvents were dried following conventional procedures.
methanol (5 mL) was stirred at rt for 24 h. Then, the catalyst
was filtered off and washed with 2 mL of dry dichloromethane.
The solid was dried under vacuum for 12 h prior to reuse. The
1
yield was determined by H-NMR using mesitylene as the
2
5
2.1 Preparation of Lap-Mn(salen)
standard. The same procedure with pure syn-3 led to syn-4
as a single product.
2.1.1 Preparation of Mn(salen)(OAc). 20 mmol of salicyl-
(
3S*,4S*,5R*)-Methyl
phenyl-tetrahydrofuran-3-carboxylate (syn-4). H-RMN (CDCl
d ppm, 400 MHz): 7.39–7.29 (m, 3H), 7.16–7.14 (m, 2H),
5-(2-methoxycarbonylethyl)-2-oxo-4-
aldehyde (2.44 g) and 10 mmol of ethylenediamine (600 mg) were
mixed with 25 mL of ethanol at rt for 1 h. The bright yellow
precipitate was filtered and recrystallized in ethanol to obtain N,N -
1
3
,
0
4
3
.95–4.90 (m, 1H), 4.24–4.20 (m, 1H), 3.90 (d, J=7.5 Hz, 1H),
bis(salicylidene)-ethylenediamine in quantitative yield. A solution
of this ligand (1.073 g, 4 mmol) in ethanol (40 mL) was treated with
a solution of KOH (450 mg, 8 mmol) in ethanol (10 mL). A solution
.80 (s, 3H), 3.63 (s, 3H), 2.47–3.30 (m, 2H), 1.55–1.47 (m, 2H).
1
3
C-RMN (CDCl , d ppm, 100 MHz): 172.9, 171.0, 167.5, 135.4,
3
1
29.2, 128.2, 127.6, 82.0, 53.3, 51.9, 51.7, 48.1, 30.0, 26.7. HR-
of Mn(OAc)
3
ꢀ2H
2
O (1.072 g, 4 mmol) in ethanol (30 mL) was then
+
+
MS (ESI ): m/z =307.1184 [MH ], calcd for C16
Methyl 5-(2-methoxycarbonylethyl)-2-oxo-4-phenyl-tetra-
hydrofuran-3-carboxylate (minor-4). (from the spectrum of the
19 6
H O : 307.1181.
added and the resulting mixture was stirred for 1 hour at rt and
heated under reflux for 4 h. The reaction was monitored by TLC on
silica using CH Cl as an eluent. The brown solid was washed with
2 2
1
transesterification product mixture) H-RMN (CDCl
00 MHz): 7.39–7.28 (m, 3H), 7.16–7.14 (m, 2H), 4.57 (td, J
=2.9 Hz, 1H), 4.26–4.16 (m, 1H), 3.83 (d, J=11.9 Hz, 1H), 3.76 (s,
3
, d ppm,
20 mL of H O and 20 mL of acetone. Yield: 54%.
2
4
J
2
1
=9.2 Hz,
2.1.2 Cationic exchange. A solution of Mn(salen)(OAc)
(0.5 mmol, 205.2 mg) in methanol (1 mL) was added to a suspen-
13
3H), 3.47 (s, 3H), 2.47–3.31 (m, 2H), 1.30–1.19 (m, 2H). C-RMN
sion of laponite (1 g) in methanol (10 mL). The suspension was
stirred at rt for 24 h and the brown solid was filtered and washed
with methanol (10 mL). Subsequently, the solid was washed with
acetonitrile in a Soxhlet apparatus for 72 h. The catalyst was dried
at 60 1C under vacuum overnight prior to use. The manganese
(CDCl , d ppm, 100 MHz): 172.7, 169.9, 167.2, 135.7, 129.3, 128.4,
3
127.5, 83.4, 55.1, 53.1, 51.4, 48.2, 29.6, 28.5.
2
.3 Combinations of catalytic reactions
ꢁ1
content (0.49 mmol g ) was determined by plasma emission
spectroscopy on a Perkin-Elmer Plasma 40 emission spectrometer.
2.3.1 Knoevenagel + Mukaiyama–Michael. In the one-pot
process, Knoevenagel reaction was carried out as described above,
but at the end of the reaction (72 h) Lap-Cu (143 mg) and HFIP
2.2 Catalytic tests
(
1.5 mmol, 109 mL) were added to the cooled (rt) reaction mixture.
.2.1 Knoevenagel condensation. Lap-Mn(salen) (135 mg, Then, a solution of 2-(trimethylsilyloxy)furan (2 mmol, 347 mL) in
.066 mmol) was added to a mixture of the corresponding 10 mL of toluene was slowly added to the suspension over 5 h. The
2
0
distilled benzaldehyde (1 mmol) and diethyl malonate (152 mL, reaction was monitored by GC and was stirred at rt for 24 h. After
mmol) in 5 mL of toluene. The mixture was stirred under this time, the mixture of catalysts was filtered off, washed with dry
1
argon at 120 1C for 72 h. The reaction was monitored by GC. At dichloromethane, and dried under vacuum for 12 h prior to reuse.
1
the end of the reaction, the mixture was cooled down to rt, the The overall yield was determined by H-RMN using mesitylene as
catalyst was filtered off and washed with dry dichloromethane. the standard. In the sequential process, the procedure was similar,
The solid was dried under vacuum for 12 h prior to reuse. except that Lap-Mn(salen) was filtered off once the Knoevenagel
Benzylidene- and p-chlorobenzylidene malonates were obtained reaction had finished and the crude was used in Mukaiyama–
by simple evaporation of the solvent under vacuum. The rest of Michael addition without purification.
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2.3.2 Hydrogenation + transesterification. Diethyl 2-[(5-oxo-2,5-
dihydrofuran-2-yl)(phenyl)methyl]malonate (2) was hydrogenated
25
in the presence of Pd/alumina as described elsewhere. Once the
reaction had finished, the palladium catalyst was filtered off. Then
TBD-PS (37.4 mg, 0.1 mmol) and 15 mL of methanol were added to
the crude and the mixture was stirred at rt for 24 h. After this time,
TBD-PS was filtered off and washed with dichloromethane.
Scheme 3 Synthesis of Lap-Mn(salen) from homogeneous (salen)MnX complexes.
1
The overall yield was determined by H-RMN using mesitylene as
the standard.
expected diethyl benzylidenemalonate in 24 h. As the homo-
geneous nature of this catalyst precluded its use in a multistep
2.3.3 Combinations of Knoevenagel + Mukaiyama–Michael +
35
sequence, it was immobilized onto laponite clay. A simple
hydrogenation + transesterification. The combination of three or
four reactions was carried out sequentially. The first reaction was
carried out as described above for Knoevenagel condensation
cation exchange in methanol (Scheme 3) led to Lap-Mn(salen)
with a functionalization of 0.49 mmol Mn per gram. This
catalyst was also efficient in the Knoevenagel condensation
but less active (57% yield after 24 h) than the homogeneous
complex and it required longer reaction times (3 days) to reach
quantitative yield. The efficiency was similar with different para
substituted benzaldehydes (Table 1). The catalyst was also
recoverable once with similar performance, but the activity
was significantly reduced in the third use (Table 1). The IR
analysis of the used catalyst (ESI†) shows the presence of
additional bands, probably due to the adsorption of reagents
or products, and even a chemical modification of the salen
ligand cannot be discarded.
2
5
or elsewhere for Mukaiyama–Michael addition. The hetero-
geneous catalyst was filtered off at the end of each reaction and
the catalyst and reagents of the following reaction were added to
the crude without purification.
3. Results and discussion
3.1 Heterogeneous catalysis for diethyl benzylidenemalonate
synthesis by Knoevenagel condensation
The synthesis of diethyl benzylidenemalonate (1) can be envisaged
through Knoevenagel condensation of diethyl malonate with
benzaldehyde (Scheme 2), a reaction typically catalyzed by bases.
Several heterogeneous catalysts have been described for model
Knoevenagel reactions, for example mixed oxides derived from
One possible explanation for the loss in catalytic activity
upon immobilization by cationic exchange may be the change
of counterion from acetate to laponite. In order to check this
ꢁ
hypothesis the analogous homogeneous complexes with BF
4
2
6,27
28
29
ꢁ
III
hydrotalcites,
additions in the case of guanidine-like organic bases, such as
,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) supported on mesoporous
alumina, and KF–alumina, or for Michael
and PF
6
anions were prepared by reaction of Mn (salen)(OAc)
3
6
with KBF4 and KPF6 respectively. These complexes were
poorly active in the Knoevenagel reaction, leading up to
only 10% yield of diethyl benzylidenemalonate, as well as
Mn (salen)Cl. On the contrary, when the immobilized catalyst
4
was prepared by exchange of Mn (salen)(BF ), the solid was
1
30
materials. Mixed oxides had been tested in the condensation of
cyanoacetate or malononitrile with benzaldehyde, but in our hands
Mg/Al and Mg/La mixed oxides were totally ineffective for
condensation of diethyl malonate. Three types of alumina (basic,
acidic and neutral) were also tested, with only 16% yield at most in
the case of basic alumina at 120 1C, in spite of the excellent results
III
31
32
III
nearly as active as that prepared from acetate, showing that the
species on laponite is the same irrespective of the anion of the
starting complex. The important role of the additional anion/
ligand is then evident, which explains the loss of activity upon
immobilization. However the acetate itself is not responsible for the
catalysis, as different acetate species demonstrated to be almost
28
described in the literature with the same substrate. These results
were not improved by microwaves activation. KF–alumina was also
ineffective, even at temperatures as high as 140 1C. With respect to
TBD, the two commercially available supported catalysts, on silica
and on a polystyrene–divinylbenzene resin, were completely unsuc-
37
completely inactive for this reaction.
The proposed mechanism for this reaction is the abstraction
of a proton from malonate by one of the phenoxide groups of
cessful. Ni(NO ) /SiO has recently been described as an efficient
3
2
2
33
catalyst for Knoevenagel reactions, but again in our hands very
low yields were obtained with diethyl malonate (up to 5%), and in
addition an important amount of the dicondensation product was
observed (Scheme 2).
Table 1 Knoevenagel condensation of diethyl malonate with different para
a
substituted benzaldehydes catalyzed by Lap-Mn(salen)
One of the best catalysts described for this reaction is the
Mn (salen)OAc complex (Scheme 3). Our tests using this
catalyst with diethyl malonate showed total conversion to the
ArCHO
Yield (%)
III
34
PhCHO
p-Cl-PhCHO
p-NO -PhCHO
2
100
100
98
p-tBu-PhCHO
p-Ph-PhCHO
95
90
PhCHO (2nd use)
PhCHO (3rd use)
92
54
a
Reaction conditions: 1 mmol of aldehyde, 1.2 mmol of diethyl
malonate, 135 mg of Lap-Mn(salen) (0.066 mmol Mn), 5 mL of toluene
under reflux, 72 h.
Scheme 2 Knoevenagel condensation of diethyl malonate with benzaldehydes.
4
38 Catal. Sci. Technol., 2013, 3, 436--443
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the salen ligand. In such a case, any complex of salen with a the sequence. Another point to be checked was the need for
trivalent metal should be suitable at the same time for immo- heterogeneous catalysts for this combination of reactions. In
bilization by cationic exchange and catalysis of the Knoevenagel fact a mixture of Mn(salen)(OAc) and Cu(OTf) was poorly active
2
condensation. Complexes of salen with Sc(OTf) , Cr(NO ) , and in Knoevenagel (26% yield) and Mukaiyama–Michael
3
3 3
V(acac) were prepared and tested in Knoevenagel condensation, (10% yield), in contrast with the isolated catalysts that are able
3
but very low yield of diethyl benzylidenemalonate was obtained to reach total conversions. The presence of Cu(OTf)
2
also
II
in all cases. The same happened with Mn (salen), demon- deactivated Lap-Mn(salen) (40% Knoevenagel yield after 4 days)
III
strating that the combination of Mn , salen and acetate (or and Mn(salen)(OAc) was able to deactivate Lap-Cu (only 20%
laponite) is mandatory to obtain good results.
.2 Heterogeneous catalysis for transesterification
Mukaiyama–Michael yield after 24 h).
In the compatibility study with the heterogeneous catalysts,
a Lap-Mn(salen) catalyzed Knoevenagel condensation was carried
out in the presence of Lap-Cu, and the reaction proceeded in the
same way as in the absence of the heterogeneous copper catalyst
3
As in the case of Knoevenagel condensation, many different basic
heterogeneous catalysts had been described for transesterification
(Scheme 5A). When the Lap-Cu catalyzed Mukaiyama–Michael
38
reactions, mainly related with biodiesel production. In our case
Mg–La mixed oxide and KF–alumina were unable to promote the
transesterification under reflux of methanol. Given that supported
addition was tested in the presence of Lap-Mn(salen) (Scheme 5B),
no negative effect was observed, demonstrating the total
compatibility between both heterogeneous catalysts.
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) had been successfully used
Apart from the compatibility between catalysts, it was also
necessary to check the compatibility between the Mukaiyama–
Michael reaction and the reagents of Knoevenagel condensa-
tion, since diethyl malonate is generally used in a slight excess
over benzaldehyde. When the Mukaiyama–Michael reaction
was carried out in the presence of diethyl malonate the yield
decreased to 80%, probably due to coordination of this reagent
to the copper catalyst (Lewis acid). Therefore, the possibility of
carrying out Knoevenagel condensation with only the stoichio-
metric amount of diethyl malonate was studied and under
those conditions the reaction also proceeded with quantitative
yield in 72 h.
17
as a transesterification catalyst in a multistep process, silica-
supported and polystyrene-divinylbenzene (PS)-supported TBD
were tested and both of them showed to be active in the trans-
esterification of the hydrogenated product 3 (Scheme 4). In this
reaction all ester and lactone groups underwent transesterification
and the final product (4) was a new more substituted lactone
obtained by cyclization between the hydroxyl group and one of the
starting ester groups with nearly quantitative yield after 24 h. Two
diastereomeric products were obtained. The major isomer was
prepared by transesterification of the pure major syn-3, whose
stereochemistry controls the relative cis position of b and g sub-
stituents, and the relative stereochemistry of a and b substituents
was determined to be trans by NMR. It was not possible to
determine the relative configuration of the minor product. The
behavior of both supported catalysts upon recovery was completely
different. TBD-PS was fully recoverable once and deactivated for the
On the other hand, it is well known that benzaldehyde in the
presence of an enol silane (as 2-(trimethylsilyloxy)furan) and a
3
9
Lewis acid may result in the Mukaiyama aldol reaction
Scheme 6) consuming the corresponding amount of furan
(
and decreasing the yield of the Mukaiyama–Michael addition.
In fact catalysts similar to Lap-Cu have shown to be efficient in
2
third cycle (yields: 100–99–20%), whereas TBD-SiO was deactivated
after the first reaction. Hence TBD-PS was chosen for compatibility
studies and combined reactions.
4
0
Mukaiyama aldol reactions.
However, the reaction with
benzaldehyde proceeds more slowly (10% yield at 24 h) than
3.3 Combination of Knoevenagel condensation +
Mukaiyama–Michael addition
Before combining Mukaiyama–Michael and Knoevenagel con-
densation, several compatibility studies between both reactions
were carried out. Firstly it was checked if the manganese
catalyst was able to promote the Mukaiyama–Michael reaction.
It was found that this solid did not catalyze the Mukaiyama–
Michael addition and thus, Lap-Cu was required to complete
Scheme 5 Compatibility between Knoevenagel and Mukaiyama–Michael catalysts.
Scheme 6 Mukaiyama aldol reaction of benzaldehyde with 2-(trimethyl-
Scheme 4 Transesterification of the hydrogenated product (3).
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silyloxy)furan.
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a
Table 3 Sequential tandem Knoevenagel + Mukaiyama–Michael
Yield (%)
Cycle
Knoevenagel
Mukaiyama–Michael
Overall
1
2
3
99
92
54
90
60
10
99
54
5
Scheme 7 (Knoevenagel + Mukaiyama–Michael) combination.
b
a
the Mukaiyama–Michael addition under the same conditions,
and the impact of a small amount of benzaldehyde would not
be very important.
Knoevenagel reaction conditions as in Table 1. Lap-Mn(salen) filtered
off after 72 h. Reagents and catalyst for Mukaiyama–Michael (ref. 20)
b
added to the crude. Lap-Cu washed with THF in a Soxhlet extractor
after the second cycle.
The combined process was tried by adding Lap-Cu to the
Knoevenagel condensation, carried out under reflux, and sub-
sequent addition of HFIP and 2-(trimethylsilyloxy)furan at room
temperature once the first reaction had finished. Although the
compatibility studies had been positive, the global yield of the
combination of both reactions (Scheme 7) dropped to 53%, due
to a yield decrease in the Mukaiyama–Michael addition (Table 2).
This deactivation of Lap-Cu is even stronger when the mixture of
catalysts is recovered under the same conditions. The difference
in behavior between fresh and aged Lap-Mn(salen) was checked
by stirring this catalyst in toluene under reflux and then addition
of all the components of the Mukaiyama–Michael reaction. The
significant reduction in yield (only 20%, Table 2) demonstrated
the role of aging of Lap-Mn(salen). Leaching of Mn, favored by
the long stirring period under reflux, was considered as the
potential origin of this effect. Two consecutive washings of
Lap-Mn(salen) with toluene under reaction conditions (and hot
filtration) demonstrated the existence of leaching: the activity of
was almost quantitative (Table 3). However, as conversion of the
second Knoevenagel reaction is not complete (92% yield), the
presence of unreacted diethyl malonate and benzaldehyde
causes a drop in the yield of the Mukaiyama–Michael addition
(60%, Table 3) due to the competition for coordination to the
copper catalyst. This fact was even more evident in the third
cycle, when the Knoevenagel reaction proceeded with lower
yield (54%).
Therefore, to carry out the combination of both reactions, the
best results are obtained in a sequential tandem process, including
filtration of the manganese catalyst and use of the reaction crude
in the next reaction without further purification. Furthermore, it is
necessary to obtain diethyl benzylidenemalonate with 100% yield,
because the presence of small amounts of unreacted reagents
competes with the catalyst of the second reaction.
the resulting solid was significantly reduced (45% yield, Table 2) 3.4 Combination of hydrogenation + transesterification
whereas the two toluene extracts were active in the Knoevenagel
condensation (Table 2). Surprisingly, Lap-Cu catalyzed Mukaiyama–
As transesterification is carried out in a different solvent
(methanol), it was necessary to check the effect of the presence
Michael addition proceeded with total conversion when the com-
ponents were added to the toluene extracts from Lap-Mn(salen),
showing that the origin of Lap-Cu deactivation is not (only) Mn
leaching.
Finally, in view of the incompatibilities between the catalysts,
a sequential process was envisaged. The catalysts were separated
after each reaction by filtration, and the reaction crude was used
in the following reaction without further purification. Under
such conditions, when the manganese catalyst was filtered off
after Knoevenagel condensation, the yield of the global process
of toluene. It was shown that toluene was not detrimental up to
a 50/50 (v/v) methanol/toluene ratio.
The hydrogenation was carried out in the presence of the
transesterification catalyst (TBD-PS) that did not have any
negative effect on the hydrogenation yield (Scheme 8A). On
the contrary, the presence of Pd/Al O in the transesterification
2
3
inhibited the formation of 4 (Scheme 8B). By increasing the
reaction temperature to 85 1C, 67% yield of 4 was obtained, but
this value could not be improved by increasing the amount of
TBD-PS or the reaction time.
Due to these problems found in the compatibility studies,
Table 2 Effect of Mn catalyst on (Knoevenagel + Mukaiyama–Michael) combination the combination of reactions was carried out in a sequential
way, that is, with filtration of the first catalyst and using the
Yield (%)
Individual
Mukaiyama–Michael
Mn catalyst
Knoevenagel in the presence of Mn cat.
Lap-Mn(salen) fresha
Combined reactions
99
99
99
–
100
53
15
20
–
100
100
(
2nd run)
b
Lap-Mn(salen) aged
c
Hot toluene washing twice 45
d
Toluene extract 1d
38
37
Toluene extract 2
a
Knoevenagel reaction in the presence of Lap-Cu and addition of HFIP
b
and TMSO-furan at the end of the first reaction. Stirred in toluene
c
under reflux for 72 h. Lap-Mn(salen) washed twice with hot toluene.
d
Extracts of each hot washing.
Scheme 8 Compatibility between hydrogenation and transesterification catalysts.
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associated with the combination of the four reactions, the two
possible combinations of three reactions were studied.
3
.6 Sequential processes involving three reactions
Firstly, the combination of the last three reactions was studied
Scheme 11). When purified diethyl benzylidenemalonate was
Scheme 9 Sequential (hydrogenation + transesterification) tandem process.
(
used as the starting material, the overall yield of the three-
reaction sequential process was close to 90% (Table 5, cycle 1).
Thereby, the components of the Knoevenagel reaction proved
to be responsible for the yield drop of the transesterification
reaction. Unfortunately, TBD-PS was deactivated in each cycle
of the reaction, as observed in the combined (hydrogenation +
transesterification) system, so a new batch of catalyst had to be
crude in the second reaction. Under such conditions, the final
product (4) was obtained at rt with high yield (97%) (Scheme 9).
Although the palladium catalyst could be reused for 4 cycles
of the reaction, the transesterification catalyst was deactivated
after the first cycle and it could not be regenerated by continuous
extraction with toluene in a Soxhlet apparatus. Thus, a new batch
of catalyst must be added in each reaction cycle.
13
used in every reaction. Characterization by C CP-MAS-NMR
(ESI†) shows that the TBD moiety is modified under reaction
3
.5 Knoevenagel + Mukaiyama–Michael + hydrogenation +
conditions, and it has been shown that in particular the
combination of 2-(trimethylsilyloxy)furan and HFIP is highly
detrimental for activity. This question is currently under study.
As previously described Lap-Cu could be reused at least ten
times, provided that it is Soxhlet extracted every two cycles, and
Pd/alumina could be reused 4 times but it could not be
regenerated (Table 5, cycles 2–10).
transesterification sequential process
Due to previously observed incompatibilities between some
catalysts and taking advantage of the heterogeneous nature of
the catalysts, a sequential process was envisaged (Scheme 10).
Thus, the catalysts must be separated after each reaction by
filtration and reused in subsequent reaction cycles.
When the crude after three sequential reactions was used, the
transesterification yield dropped to 48% (Table 4). Moreover, the
catalyst of this reaction was fully deactivated, as it happened
in the combination of hydrogenation–transesterification
2
5
The second tested combination was Knoevenagel + Mukaiyama–
Michael + hydrogenation (Scheme 12), whose results are gathered
(Table 4, cycle 2). A new batch of Lap-Mn(salen) was used in
the third cycle, to prevent the drop in yield of Mukaiyama–
Michael, as a consequence of the lower Knoevenagel conversion.
The use also of a new batch of TBD-PS allowed recovering
the initial results (Table 4, cycle 3). In view of the problems
Scheme 11 Sequential (Mukaiyama–Michael + hydrogenation + transesterification)
tandem process.
Table 5 Results of the sequential (Mukaiyama–Michael + hydrogenation +
transesterification) tandem process
a
Scheme 10 Sequential (Knoevenagel + Mukaiyama–Michael + hydrogenation +
Yield (%)
transesterification) tandem process.
Cycle
Mukaiy.
Hydrogen.
Transesterif.
Overall
1
2
3
4
5
6
7
8
9
100
99
100
100
100
100
100c
100
100
100
100c
100
100
89
0
90
88
89
89
91
88
87
89
0
Table 4 Results of the sequential (Knoevenagel + Mukaiyama–Michael +
b
d
90
88
88
85
88
83
85
86
d
hydrogenation + transesterification) tandem process
100
b
d
99
a
d
Yield (%)
95
b
d
97
Cycle
Knoev.
Mukaiy.
Hydrog.
Transest.
Overall
d
94
b
d
1
2
3
99
92
99
99
60
98
100
100
100
48
0
48
47
0
47
98
d
10
95
91
b
c
d
a
Determined by NMR in the two first reactions. Isolated in the case of
a
b
b
Determined by NMR. A new batch of Lap-Mn(salen) was used. transesterification and overall yields. Lap-Cu washed with THF in a
c
c
Lap-Cu washed with THF in a Soxhlet extractor after the second cycle. Soxhlet extractor every two cycles. A new batch of Pd/alumina was
d
d
A new batch of TBD-PS was used.
used every four cycles. A new batch of TBD-PS was used every cycle.
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minimizes the incompatibility issues, while optimizing at the
same time the recovery and reuse of each catalyst, and hence its
productivity. The elimination of intermediate purification steps
is an additional practical advantage of this approach.
The full sequence of four reactions shows inherent limita-
tions that drastically reduce the overall yield by deactivation of
the last reaction catalyst. On the contrary, different sequences
reactions, either two (Knoevenagel + Mukaiyama–Michael;
Mukaiyama–Michael + hydrogenation; hydrogenation + trans-
esterification) or three (Mukaiyama–Michael + hydrogenation +
Scheme 12 Sequential (Knoevenagel + Mukaiyama–Michael + hydrogenation)
tandem process.
transesterification; Knoevenagel
+ Mukaiyama–Michael +
hydrogenation) have led to very high yields, with optimal
recovery of the catalysts in subsequent cycles of the reaction.
Table 6 Results of the sequential (Knoevenagel + Mukaiyama–Michael +
hydrogenation) tandem process
a
Yield (%)
Acknowledgements
Cycle
Knoeven.
Mukaiy.
Hydrogen.
Overall
Financial support from the Spanish Ministerio de Econom ´ı a y
Competitividad (Project CTQ2011-28124) and the Diputaci o´ n
General de Arag o´ n (E11 Group co-financed by the European
Regional Development Funds) is gratefully acknowledged.
1
2
3
4
5
6
7
8
9
99
100
99
100
100
100
100
100
97
96
97
94
95
93
91
91
94
92
b
99
b
c
99
b
98
98
99
b
c
d
98
100
b
99
97
96
96
100
100
100
b
c
b
Notes and references
98
95
97
b
c
d
99
100
b
1
0
99
95
100
1 A. Bruggink, R. Schoevaart and T. Kieboom, Org. Process Res.
Dev., 2003, 7, 622.
2 J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C. Bazan, Chem.
Rev., 2005, 105, 1001.
a
b
Determined by NMR except in the case of isolated overall yield.
A
c
new batch of Lap-Mn(salen) was used every cycle. Lap-Cu washed with
THF in a Soxhlet extractor every two cycles. A new batch of Pd/
alumina was used every four cycles.
d
3
M. Gruber, S. Chouzier, K. Koehler and L. Djakovitch, Appl.
Catal., A, 2004, 265, 161.
in Table 6. Given the problems encountered with recovery of the
Lap-Mn(salen) catalyst, a new batch of the catalyst was used in each
cycle, whereas Lap-Cu and Pd/alumina were recovered as described
above without any loss of performance. Under such conditions,
overall yields in the range of 93–99% were obtained in ten
consecutive runs, with no purification intermediate steps,
except the simple catalyst filtration.
This is the most suitable three-reaction sequential process
when compared with the ‘‘classical’’ approach. In such a case the
isolated yields are 88% for Knoevenagel, 96% for Mukaiyama–
4 L. Joucla, G. Cusati, C. Pinel and L. Djakovitch, Adv. Synth.
Catal., 2010, 352, 1993.
5 H. Lebel and V. Paquet, J. Am. Chem. Soc., 2004, 126, 11152.
6 H. Lebel, C. Ladjel and L. Br ´e thous, J. Am. Chem. Soc., 2007,
129, 13321.
7 S. J. Broadwater, S. L. Roth, K. E. Price, M. Koba ˇs lija and
D. T. McQuade, Org. Biomol. Chem., 2005, 3, 2899.
8 S. L. Poe, M. Koba ˇs lija and D. T. McQuade, J. Am. Chem. Soc.,
2006, 128, 15586.
9 F.-X. Felpin and E. Fouquet, ChemSusChem, 2008, 1, 718.
Michael and 100% for hydrogenation, with an overall yield of 10 M. J. Climent, A. Corma and S. Iborra, Chem. Rev., 2011,
4% after three filtrations and evaporations, and two chromato-
111, 1072.
graphy columns on silica. On the contrary, the sequential 11 B. M. Choudary, N. S. Chowdari, S. Madhi and
process allows an overall isolated yield of 97% with only three
M. L. Kantam, Angew. Chem., Int. Ed., 2001, 40, 4620.
filtrations and one evaporation and silica column chromato- 12 B. M. Choudary, N. S. Chowdari, S. Madhi and
graphy. In addition to the higher overall yield, an additional
M. L. Kantam, J. Org. Chem., 2003, 68, 1736.
advantage of the Knoevenagel + Mukaiyama–Michael + hydroge- 13 K. Motokura, N. Fujita, K. Mori, T. Mizugaki, K. Ebitani and
nation is that purification of the final product 3 should allow the
K. Kaneda, J. Am. Chem. Soc., 2005, 127, 9674.
transesterification catalyst to be recovered once, doubling in this 14 N. T. S. Phan, C. S. Gill, J. V. Nguyen, Z. J. Zhang and
8
way its productivity.
C. W. Jones, Angew. Chem., Int. Ed., 2006, 45, 2209.
15 K. K. Akagawa, S. Sakamoto and K. Kudo, Tetrahedron Lett.,
2
007, 48, 985.
4
. Conclusions
1
6 A. W. Pilling, J. Boehmer and D. J. Dixon, Angew. Chem., Int.
Ed., 2007, 46, 5428.
One-pot fine chemistry catalytic processes present some limita-
tions due to incompatibilities between the different components 17 J. M. Fraile, R. Mallada, J. A. Mayoral, M. Men ´e ndez and
of the reactions. On the contrary the sequential methodology
L. Rold ´a n, Chem.–Eur. J., 2010, 16, 3296.
4
42 Catal. Sci. Technol., 2013, 3, 436--443
This journal is c The Royal Society of Chemistry 2013

View Article Online
Paper
Catalysis Science & Technology
1
1
2
2
8 F. Gelman, J. Blum and D. Avnir, J. Am. Chem. Soc., 2000, 30 Y. V. Subba Rao, D. E. De Vos and P. A. Jacobs, Angew.
22, 11999. Chem., Int. Ed. Engl., 1997, 36, 2661.
9 R. Abu-Reziq, D. Wang, M. Post and H. Alper, Chem. Mater., 31 J. M. Fraile, N. Garc ´ı a, J. A. Mayoral, E. Pires and L. Rold ´a n,
008, 20, 2544. Appl. Catal., A, 2009, 364, 87.
0 J. M. Fraile, N. Garc ´ı a, C. I. Herrer ´ı as and J. A. Mayoral, 32 J. M. Fraile, N. Garc ´ı a, J. A. Mayoral, E. Pires and L. Rold ´a n,
Catal. Today, 2011, 173, 15. Appl. Catal., A, 2010, 387, 67.
1 M. Genelot, V. Dufaud and L. Djakovitch, Tetrahedron, 2011, 33 V. S. R. R. Pullabhotla, A. Rahman and S. B. Jonnalagadda,
1
2
67, 976.
Catal. Commun., 2009, 10, 365.
2
2
2 L. Veum and U. Hanefeld, Chem. Commun., 2006, 825.
3 P. M ¨a ki-Arvela, S. Sahin, N. Kumar, J.-P. Mikkola, K. Er ¨a nen, 35 J. M. Fraile, J. I. Garc ´ı a, J. Masam and J. A. Mayoral, J. Mol.
34 M. L. Kantam and B. Bharathi, Catal. Lett., 1998, 55, 235.
T. Salmi and D. Y. Murzin, React. Kinet. Catal. Lett., 2008,
4, 281.
Catal. A: Chem., 1998, 136, 47.
36 A. Miyafuji and X. Katsuki, Tetrahedron, 1998, 54, 10339.
9
2
2
2
2
4 A. Caiazzo, P. M. L. Garcia, R. Wever, J. C. M. van Hest, 37 Knoevenagel condensation was tested under the same con-
A. E. Rowan and J. N. H. Reek, Org. Biomol. Chem., 2009, 7, 2926.
5 J. M. Fraile, N. Garc ´ı a, C. I. Herrer ´ı as, M. Mart ´ı n and
J. A. Mayoral, ACS Catal., 2012, 2, 56.
ditions using as catalysts NaOAc, (18-crown-6)NaOAc,
Mn(OAc) , (18-crown-6)Mn(OAc) , and laponite (Na form).
Yields in the range of 5–15% were obtained in all cases.
3
3
6 M. J. Climent, A. Corma, S. Iborra, K. Epping and A. Velty, 38 M. Di Serio, R. Tesser, L. Pengmei and E. Santacesaria,
J. Catal., 2004, 225, 316. Energy Fuels, 2008, 22, 207.
7 U. Costantino, M. Curini, F. Montanari, M. Nocchetti and 39 M. Szlosek and B. Figadere, Angew. Chem., Int. Ed., 2000,
O. Rosati, Microporous Mesoporous Mater., 2008, 107, 16. 39, 1799.
8 Y. Moussaoui and R. Ben Salem, C. R. Chim., 2007, 10, 1162. 40 J. M. Fraile, I. P ´e rez and J. A. Mayoral, J. Catal., 2007,
9 B. E. Blass, Tetrahedron, 2002, 58, 9301. 252, 303.
2
2
This journal is c The Royal Society of Chemistry 2013
Catal. Sci. Technol., 2013, 3, 436--443 443