A Bifunctional Metal/Acid Catalyst for One-pot Multistep Synthesis of Pharmaceuticals

Article abstract of DOI:10.1134/S0965544120040106

Abstract: One inhibitor of the fatty acid transporter FATP4 was synthesized in a three steps one-pot process in the presence of a bifunctional metal/acid catalyst. This molecule which has potential interest for the treatment of the obesity in orlistat (Xenical ^TM) analogue-based therapies has a 3,4-dihydropyrimidin-2(1H)-one (DHPM) scaffold and was obtained by means of a three one-pot process through successive oxidation, cyclocondensation and transesterification reactions. The one-pot strategy was extended to the synthesis of a series of related ester DHPM derivatives.

Full text of DOI:10.1134/S0965544120040106

ISSN 0965-5441, Petroleum Chemistry, 2020, Vol. 60, No. 4, pp. 499–507. © Pleiades Publishing, Ltd., 2020.
A Bifunctional Metal/Acid Catalyst
for One-Pot Multistep Synthesis of Pharmaceuticals
Maria Victoria Lopez-Pradoa, María J. Sabatera, *, and Avelino Cormaa, **
aInstituto de Tecnología Química, Universitat Politècnica de València–Consejo Superior de Investigaciones Científicas,
Av. los Naranjos, s/n, 46022 Valencia, Spain
*e-mail: mjsabate@itq.upv.es
**e-mail: acorma@itq.upv.es
Received November 25, 2019; revised December 9, 2019; accepted December 10, 2019
Abstract—One inhibitor of the fatty acid transporter FATP4 was synthesized in a three steps one-pot process
in the presence of a bifunctional metal/acid catalyst. This molecule which has potential interest for the treat-
ment of the obesity in orlistat (Xenical TM) analogue-based therapies has a 3,4-dihydropyrimidin-2(1H)-one
(DHPM) scaffold and was obtained by means of a three one-pot process through successive oxidation, cyclo-
condensation and transesterification reactions. The one-pot strategy was extended to the synthesis of a series
of related ester DHPM derivatives.
DOI: 10.1134/S0965544120040106
INTRODUCTION
of reagents and catalysts supported on solid supports
has received much attention in recent years because of
the obvious simplification of the purification pro-
cesses together with a drastic decrease in the produc-
tion of waste and environmental impact [28–31].
3,4-Dihydropyrimidin-2(1H)-one
derivatives
(DHPMs) are molecules with a high potential for
pharmaceutical applications such as anti-tumor, anti-
viral, anti-inflammatory activity, calcium channel
blockers, antiparasitics, etc. [1–5].
In this line and going one step further, a more
ambitious and less frequent addressed challenge is the
synthesis of the dihydropyrimidinone ring (DHPM)
and its ulterior derivatization in a single step [32, 33].
There are several general methods for synthesizing
these structures, and virtually none to get more com-
plex derivatives in a straightforward manner [6].
Among the most modern methods to synthesize
DHPMs, the Biginelli reaction is one of the most
direct protocols, that involves the acid-catalyzed
three-component condensation of ureas, aldehydes
and β-oxoesters or 1,3-dicarbonyl compounds [6–8].
In general terms, when a particular derivative is
needed, a preliminary basic DHPM structure is pre-
pared which will lead to the target molecule with the
required structure-activity relationship.
For achieving this, the development of solid multi-
functional catalysts which promotes the Biginelli reac-
tion together with the direct derivatization of this N-
heterocycle under green conditions is required. There-
fore, in our aim to find multifunctional solid catalysts
that allow process intensification, we have chosen the
synthesis of a paradigmatic molecule that, while being
pharmacologically relevant, it requires different steps
for its preparation with the corresponding intermedi-
ate separation-purification procedures. This is the orl-
istat’s (Xenical TM) functional analogue (5-cyclopen-
tylcarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimi-
din2(1H)-one) (1), an inhibitor of the fatty acid
transporter FATP4 with potential interest for the treat-
ment of the obesity, in orlistat analogue-based thera-
To date, several improved reaction protocols have
been reported for the synthesis of basic DHPMs which
include, the direct modification of the classical one-
pot Biginelli approach itself, the implementation of
novel, but more complex synthetic strategies, the ben-
efits of using microwave heating, the use of a solid-
phase method, alternative green solvents or even the
non-use of solvent, etc [9–27]. In this context, the use pies (Scheme 1) [34].
499

500
LOPEZ-PRADO et al.
O
6
3
5
O
NH
O
1
N
H
H3C
2
4
1
Scheme 1. Chemical structure and molecular modelization of the orlistat’s functional analogue
(5-cyclopentylcarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin2(1H)-one) (1).
This molecule, which has the 3,4-dihydropyrimidin- three step one-pot reaction involving oxidation, cyclocon-
2(1H)-one scaffold and a lipophilic cyclopentyl ester densation and transesterification reactions catalyzed by a
group at the 5 position, will be obtained here through a bifunctional metal/acid catalyst as depicted in Scheme 2.
O
O
H+
B
H+
C
O2
A
EtO
H3C
NH
PhCH2OH
PhCHO
O
NH
N
H
O
H3C
N
H
O
O
1
O
O
+
H2N
NH2
H3C
OEt
Scheme 2. One-pot multistep catalytic process for the synthesis of dihydropyrimidin-2(1H)-one
derivative 1 starting from benzyl alcohol.
In a first approach benzaldehyde will be coupled synthesis were of HPLC grade. Pd/Al2O3 was pur-
with a α ß-ketoester and urea to afford the dihydropy-
rimidin-2(1H)-one ring (the well-known Biginelli
reaction). However, when stability or the handling of
the aldehyde is an issue, the catalysts presented here
allow starting the reaction from the corresponding
alcohol that will be oxidized to generate “in situ” the
aldehyde (steps A and B in Scheme 2). Thus, when the
basic DHPM heterocycle is formed, the intermediate
is transformed into a new dihydropyrimidin-2(1H)-
one ester derivative through a transesterification reac-
tion, still in a single pot multi-step process (step C, see
Scheme 2).
chased from Aldrich.
Catalyst preparation
1. (a) Pd(1%)/MCM41
Pd(1%)/MCM41 (Si/Al = 12.5) was prepared
according to a procedure reported in the literature
[35]: MCM-41 (Si : Al = 12.5) (1 g), PdCl2 (16.8 mg)
and H2O (50 ml) were mixed and stirred for 8 h. The
solid was filtered, dried at 120°C and calcined at
400°C for 2 h. The final catalyst was hidrogenated
during 2 h at 200°C (hydrogen flow: 100 ml/min).
2. (b) Pd(1%)/Al2O3
Pd/Al2O3 was purchased by Aldrich.
3. (c) Pd(0.5%)/Hβ
We will show that this multi-step one-pot route can
be performed with an optimized bifunctional
metal/acid solid catalyst.
The catalyst was prepared following procedure
reported in the literature [36]: PdCl2 (8.4 mg) and
NH4OH (12.5 mL, 0.1 M) were mixed and stirred at
room temperature for 24 h in the presence of Hβ
(2.5 g) (PQ Corporation). The resulting solid was fil-
tered, washed with distilled water (1 L/g), and dried in
an oven at 100°C overnight.
EXPERIMENTAL
Materials. A commercially available starting mate-
rials, (alcohols, urea, ethyl aceto acetate, inorganic
salts and carriers) were purchased from Sigma-
Aldrich, Strem, Fluka and Nanoscale and were used
4. Pd(0.5%)/ITQ-2
The delaminated material ITQ-2 was prepared fol-
without further purification. All solvents used for the lowing procedure reported in the literature [37–39].
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Then ITQ-2 (1 g) was mixed with an excess of HCl (0.25 mmol) as internal standard were placed in a
(0.2 M; 3 mL/g MCM41) and PdCl2 (8.4 mg). The batch microreactor being vigorously stirred at 100°C
under 5 bar O2 pressure. Once the oxidation of the
slurry was stirred for 24 h. The solid was filtered, dried
at 100°C overnight and calcined at 350°C for 3 h. alcohol was completed, ethyl acetoacetate (1 mmol)
Finally the catalyst was hidrogenated at 350°C for 1 h and urea (1.3 mmol) were incorporated into the vessel,
(hydrogen flow: 100 mL/min)
the temperature was decreased to 80°C and the reac-
tion was monitored by GC until reaction completion.
5. Pd(0.5%)/Amberlyst and Pd(1%)/Amberlyst
The catalyst was prepared by following the proce-
dure reported in the literature [40]: the required
amount of Pd(NH3)4Cl, deionized water (20 mL) and
Amberlyst-15 (1 g) (Fluka, 20–50 mesh) were mixed
and stirred at 80°C for 24 h. The solid was filtered,
washed with deionized water (15 mL), and dried at
100°C overnight. The as-made material thus obtained
was reduced under an H2 flow (100 mL/min) at 100°C
for 1 h just before use.
2. One pot reaction for the synthesis
of compounds 6−10
A mixture of alcohol (1 mmol), catalyst (1% mol
Pd), trifluorotoluene (1 mL), and n-dodecane
(0.25 mmol) as internal standard were placed in a
batch microreactor being vigorously stirred at 100°C
under 5 bar O2 pressure. Once the oxidation of the
alcohol was completed, ethyl acetoacetate (1 mmol)
and urea (1.3 mmol) were incorporated into the vessel,
the temperature was decreased to 80ºC and the reac-
tion was monitored by GC until reaction completion.
6. Pd(n%)/SAC-13 (n = 0.25, 0.5 and 1%)
The required amount of Pd(NH3)4NO2, solvent
(10 mL) and commercial SAC-13 (1 g) (Aldrich) were
mixed and stirred at 80°C for 24 h after which the cat-
alyst was filtered off, washed and dried at 100°C under
air. The obtained material was subsequently reduced at
200°C (heating rate 5°C/min) under H2 flow
(100 mL/min).
Then phosphotungstic acid PTA (1.75% mol with
respect to the amount of DHPM formed) an alcohol
excess were added and the temperature was increased
up to 140°C. The reaction was monitored by GC.
When the reaction was completed, the catalyst was
separated by filtration and the solvent was evaporated
under vacuo. The reaction product was purified by
column chromatography on silica gel with a mixture
hexane/Et2O (99 : 1) as eluent.
7. Pd(0.5%)/PVS-SiO2
PVS-SiO2 was prepared according to a reported
procedure [41, 42]. Then PdCl2 (8.4 mg), H2O
(10 mL) and PVS-SiO2 (1 g) were mixed and stirred at
80°C for 24 h, after which the catalyst was filtered off,
washed and dried at 100°C under air. The material was
subsequently reduced at 200°C (heating rate
5°C/min) under H2 flow (100 mL/min).
RESULTS AND DISCUSSION
Study of the Bifunctional Metal/Acid Catalyst
for the Synthesis of the DHPM Scaffold
Catalytic reactions
The possibility of developing a one-pot methodol-
ogy for the synthesis of the DHPM ester derivative 1
became evident to us by considering the retrosynthetic
1. One pot reaction for the synthesis of DHPMs
A mixture of alcohol (1 mmol), catalyst (1% mol
Pd), trifluorotoluene (1 mL), and n-dodecane analysis of the molecule (Scheme 3).
Scheme 3. Retrosynthetic analysis of bioactive structure (5-cyclopentylcarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimi-
din2(1H)-one) (1).
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LOPEZ-PRADO et al.
According to scheme 3 our target molecule 1 might The resulting catalyst Pd(0.5%)/Hβ was activated pre-
be transformed into two much simpler synthons viously by calcination at 200°C for 3 h followed by
derived from a nucleophilic cyclopentanoxide anion reduction at 200°C during 3 h with H2. The catalytic
and a primary DHPM ring (Scheme 3). This DHPM
nucleous might be obtained through three key discon-
nections that correspond to a known acid catalyzed
three-component condensation strategy between an
aldehyde, α,ß-ketoester and urea denoted as Biginelli
reaction (Scheme 3). Thus, our goal was the prepara-
tion of this DHPM ester 1 by planning the synthesis
forward and using a bifunctional catalyst (Scheme 2).
The catalyst should contain an acidic and a metal
function. The acid should be capable of assembling the
original three components (urea, oxoester and alde-
hyde) into the N-heterocycle DHPM, and the metal
function would allow starting the reaction from the
corresponding alcohol and to dehydrogenate it into
the aldehyde. This can be of interest when the alde-
hyde is not stable under reaction conditions or it is less
available (see Scheme 2).
To perform the alcohol dehydrogenation reaction
we thought on palladium nanoparticles supported on
a high surface area solid acid. The choice of the above
metal allows using molecular oxygen as green oxidant
in an oxidative dehydrogenation of the alcohol to the
aldehyde [44–51], while the solid acid support would
catalyze the consecutive cyclocondensation or Bigi-
nelli reaction leading to the final product DHPM
(Scheme 2). Preliminary tests revealed that the cata-
lytic results improved when the urea and α,ß-ketoester
reactants were incorporated sequentially after com-
pleting the formation of benzaldehyde, instead of add-
ing the three components simultaneously. Thus, tak-
ing into account these preliminary results, the experi-
mental procedure was adapted so that the urea and the
α,ß-ketoester were incorporated once the alcohol was
completely reacted.
In principle, since a solid with acid sites is required, and
taking into account the large size of the products, a struc-
tured mesoporous aluminosilicate MCM-41 (Si/Al = 15)
was selected as the solid acidic component of the bifunc-
tional catalyst [52]. Then palladium was deposited on
MCM-41 and the resulting catalyst Pd(1%)/
MCM41(Si/Al = 15) was tested for the benzyl alcohol,
urea and ethyl acetoacetate assembly to form 2-methyl-3-
ethylformiate-4-phenyl-3,4-dihydropyrimidin-2(1H)-
one (1) in TFT as solvent (entry 1, Table 1).
In this case the catalyst was active and selective for
performing the oxidative dehydrogenation step
(step a), but its activity and selectivity was low for the
cyclocondensation reaction step (step b) (entry 1,
Table 1). Notice that even Pd on γ-Al2O3 was a very
suitable catalyst for step a, and again better than
Pd/MCM41 for step b (entry 2, Table 1).
results in the two- step one-pot reaction in the pres-
ence of Pd(0.5%)/Hβ slightly increased though the
selectivity in the second step did not improve probably
due to steric limitations (entry 3, Table 1). Therefore,
it was decided to increase the reactant accessibility,
while maintaining a zeolitic acidity. For achieving this,
palladium was supported on a highly stable layered
zeolite precursor having structured readily accessible
external cups, as it is the case of ITQ-2 zeolite [54].
ITQ-2 was prepared with a Si/Al ratio of 12.5 [54]. In
this case the increased access to the catalytic sites for
large molecules contributed to improve the catalytic
results in the second step of the one-pot reaction,
although it was not so for the oxidation step (step a)
since in this case the results were significantly lower
than those obtained with zeolite β(entry 4, Table 1).
Besides this and in the search for new acid cata-
lysts, organic polymers with strong acidities such as
Amberlyst-15 were also tested with two different Pd
loadings [55, 56]. Unfortunately, with the highest
metal loading (1% Pd) the metal dispersion achieved
on this sulfonic resin was very low due to the low sur-
face area of Amberlyst-15 (45 m2/g), with the corre-
sponding poor results for the dehydrogenation step to
form benzaldehyde (see Table 1S in supplementary
material), while a competing acid catalyzed etherifica-
tion reaction giving rise to dibenzylether (2) as the
main product prevailed (entry 5 in Table 1, Fig. 1). In
accordance to this observation the catalytic results
improved considerably when the metal loading was
reduced by half (0.5%) (entry 6, Table 1) and the metal
dispersion was larger (see Table 1S in supplementary
material).
Other secondary products that were detected in
this sequential transformation were the imine N-ben-
cilidenurea (3), the aldol condensation product (4)
and traces of a dihydropyridine derivative (5) (Fig. 1)
described by Hantzsch in 1882. Formation of this
product 5 can be accounted for the condensation of
the aldehyde, the dicarbonylic compound and ammo-
nia derived from the thermal decomposition of urea
[42]. Taking that into account, it appears that the for-
mation of 5 could be completely avoided by keeping
the temperature of the multicomponent reaction at
80°C (see Fig. 1).
From these results presented in Fig. 1 the benefit of
using a catalyst with strong acidity when operating at
low temperatures is clear. Thus in the search for a solid
with strong acid groups (−SO3H) that, at the same
time, had a surface area large enough to achieve good
metal dispersion we selected the nanocomposite sil-
ica-Nafion named SAC-13 [52]. This material, which
is produced by the entrapment of nanometer sized
Nafion resin particles (having highly acidic fluoro sul-
phonic acid groups) in a highly porous silica network,
At this point we decided to modify the acidic com-
ponent of the catalyst increasing the acidity by using a
large pore high silica zeolite such as Beta, and to
disperse Pd on the surface. For achieving high Pd dis-
persions we followed the method of Zhang el al. [53]. has a BET surface area in the range of 150–500 m2/g
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A BIFUNCTIONAL METAL/ACID CATALYST
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Table 1. Results on the concurrent tandem oxidation/cyclization reaction to 2-methyl-3-ethylformiate-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one (1) in TFT
O
O
O
H2N
NH2
OEt
+
O
[O]
H+
PhCH2OH
PhCHO
a
b
EtO
NH
N
H
O
1
Step aa
Step bb
Entry
Catalyst
Conv, %c
S, %d
Conv, %e
S, %f
1
2
3
4
5
6
7
8
9
Pd(1%)/MCM41 (Si/Al : 15)
Pd(1%)/Al2O3
73
90
95
85
99
83
99
99
99
89
95
96
95
95
95
62
5
65
90
99
99
99
99
86
51
81
85
97
–
67
89
93
87
92
63
62
50
70
67
94
–
81
81
95
91
89
65
58
Pd(0.5%)/Hβ (Si/Al : 12.5)
Pd(0.5%/ITQ-2(Si/Al : 12.5)
Pd(1%)/Amberlyst
Pd(0.5%)/Amberlyst
Pd(0.25%)/SAC-13
Pd(0.5%)/SAC-13
Pd(1%)/SAC-13
Pd(0.5%)/PVS-SiO2
Pd(0.5%)/CeO2
Pd(0.5%)/ZrO2
10
11
12
a)
b)
Reaction conditions: alcohol (1 mmol), TFT (1 mL), catalyst (1% mol Pd), n-dodecane (0.25 mmol),
= 5 bar, T = 100°C; reaction
PO
2
c)
conditions: ethyl acetoacetate (1 mmol), urea (1.3 mmol), T = 80°C, N ; conversion (%) determined by GC on the amount of benzyl
2
d)
e)
f)
alcohol converted; selectivity (%); conversion (%): determined on the amount of benzaldehyde transformed; selectivity (%).
that, in principle, should allow a high metal disper- and b improved as compared to previous catalysts due
sion. Then 0.25, 0.5, and 1% weight Pd (see experi-
mental section) was incorporated on the Nafion com-
posite material to obtain three different bifunctional
Pd/SAC-13 catalysts with three different metal load-
ings for performing the two-step one-pot reaction
to the good metal dispersion achieved on this surface
(see characterization data in table 1S, supplementary
material).
HRTEM images and STEM-XEDS analysis of
Pd(0.5%)/SAC-13 (see Fig. 1S, supplementary mate-
rial) confirmed the existence of a homogeneous distri-
bution of relatively small palladium particles on the
Nafion-silica nanocomposite surface (see characteri-
(Pd(0.25%)/SAC-13,
Pd(1%)/SAC-13).
Pd(0.5%)/SAC-13,
and
Among them, Pd(0.5%)/SAC-13 afforded the best
catalytic results (entries 7−9, Table 1). In fact, the cat-
alytic performance of Pd(0.5%)/SAC-13 for steps a zation data in Table 1S supplementary material).
O
O
O
EtOOC
H3C
COOEt
CH3
O
N
H3C
O
CH3
Ph
N
2
3
4
5
Fig. 1. Secondary products detected during the one-pot reaction at 80°C.
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LOPEZ-PRADO et al.
In parallel, a high density sulfonic polymer supported
Thus, the final conclusion of this part of the work
is that a high metal Pd dispersion on strong solid acids
are required for a bifunctional catalyst that can per-
form successfully the synthesis of dihydropyrimidi-
onto SiO2 was also prepared, starting from the acid form of
a vinylsulfonic monomer [41]. Thus, vinylsulfonic acid was
polymerized giving poly(vinylsulfonic acid) (PVS), which
was deposited onto a silica surface (PVS/SiO2) providing a none derivatives working at relatively low reaction
temperatures. This can be achieved by Pd supported
on the composite Nafion (SAC-13).
new type of solid acid catalyst [41]. It is important to indi-
cate that as in the previous case with commercial Nafion
SAC-13 catalyst, this synthetic methodology does not
introduce sulfonic acid groups through an individual cova-
lent anchoring, but rather multiple sulfonic groups as a
polymer onto the carrier surface. We chose this catalyst
because the high polymerizability of the vinylsulfonic
monomer and the high acid density of the polymer PVS,
that usually results in a high density of catalytically active
acid sites on the heterogeneous catalyst [41]. In this case
the resulting Pd(0.5%)/PVS/SiO2 catalyst gave 297 m2/g
(see Table 1S, supplementary material).
Three-step One-pot Synthesis of DHPM Ester 1
Through Oxidation, Cyclocondensation
and Transesterification Reactions
Since the procedure described above is chemose-
lective and operates under relatively mild reaction
conditions, we thought in extending this protocol to
the synthesis of a dihydropirimidinone derivative with
therapeutic activity by means of a transterificacion
reaction on the newly formed DHPM structure.
The catalytic performance of Pd(0.5%)/PVS-SiO2
for the synthesis of the DHPM derivative 1 was only
slightly lower than that obtained with Pd(0.5%)/SAC-13
(entry 10, Table 1). This experimental fact can give the
clue for the two greatest demands of this one-pot reac-
tion. On the one hand, a reduced metal particle size
for an effective oxidation reaction and on the other
strongly acidic centers (as can be sulfonic groups) for
an effective multicomponent cyclization to take place.
This fact can be corroborated because other catalysts with cyclopentanol, which is also catalyzed by acid
with high Pd dispersion and lower acidity such as sites. Following the one-pot strategy described above,
Pd(0.5%)/CeO2 and Pd(0.5%)/ZrO2 failed at the level
of the cyclization step and gave lower yields of the het-
erocycle DHPM according to the last two entries of
the Table 1 (entries 11−12, Table 1).
For achieving this, benzyl alcohol was oxidized to
benzaldehyde in the presence of Pd(0.5%)/SAC-13 at
100°C. Then benzaldehyde was coupled in situ with
the α,ß-ketoester and urea to afford the dihydropy-
rimidin-2(1H)-one derivative 1 through a cyclocon-
densation reaction at 80°C temperature. Thus, the
remaining step would be the transesterification of 1
catalytic amounts of fresh heteropolyacid phospho-
tungstic acid PTA within cyclopentanol were incorpo-
rated to the reactor and the reaction was carried out at
140°C (see experimental section, Scheme 4).
O
O
O
H2N
NH2 H3C
PhCHO
OEt
EtOOC
H3C
ROOC
H3C
H+
NH
[O]
H+
NH
PhCH2OH
Pd(0.5%)/SAC-13
PTA
N
H
O
N
H
O
Compound
Yield (%)
40
1
R =
R =
CH (CH2)2 CH2
6
7
8
68
57
42
3
R = CH3 (CH2)3 CH2
CH (CH2)4 CH2
R =
R =
3
(CH )
C
9
20
20
3 3
10
R = Ph CH2
Scheme 4. One-pot reaction for the synthesis of new DHPM ester derivatives 1, 6−10 catalyzed by Pd(0.5%)-SAC13 and PTA.
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A BIFUNCTIONAL METAL/ACID CATALYST
505
It has to be pointed out that the synthesis of this be subjected to an ulterior BF3 catalysed Biginelli con-
compound has been described to occur in a two sepa-
rated reaction steps, involving the reaction of cyclo-
densation with urea and the appropriate aldehyde to
give the dihydropirimidinone structure [34]
pentanol with diketene to afford a ketoester, which will (Scheme 5).
TWO STEP CLASSICAL ROUTE [7]
Ph
O
O
2 C
O
NH
O
H3C
N
H
O
1
THREE STEP ONE-POT ROUTE
EtO2C
Ph
O
EtOOC
H3C
Ph
NH2
H2N
NH
Ph
OH
O
+
H
O
N
H
O
1
Scheme 5. Classical [34] versus one-pot routes for the synthesis of compound 1.
Through the one-pot strategy the yields of com- 100°C for 1 h. By following this procedure the solid could
pound 1 were moderated due to the existence of a be used at least four times with a reasonable activity and
competing reaction for forming dibenzyl ether. None- selectivity (Fig. 2).
theless, the final yields of the transesterification com-
pound 1 markedly increased when reacting less hin-
dered short chain primary alcohols such as n-butanol
acting as nucleophile in the one-pot strategy
(Scheme 4).
In this line the yield of the transesterification prod-
uct also decreased when the chain length of the
unbranched alcohols was elongated from n-butanol to
n-hexanol as well as when using a benzylic type alco-
hol or a tertiary alcohol such as tert-butanol (see one-
pot synthesis of compounds 6−10 in Scheme 4).
Nevertheless a gradual decrease in yield was observed
in the first and second recycling that has been seen to be
due to the leaching of a part of the less strongly attached
Pd. It is clear that further catalyst optimization will be
necessary to stabilize the Pd and control pore size distri-
bution in the SAC-13 material.
CONCLUSION
The catalytic activity of different metal/acid based
heterogeneous catalysts was studied in the one-pot
synthesis of a DHPM derivative of therapeutic inter-
est.
Then by proper modification of the catalyst and the
operating conditions, the production of this molecule
could be maximized following a strategy that can sub-
stitute a two separated reaction process with interme-
diate purification steps.
Reusability and Recyclability Experiments
with Bifunctional Metal/acid Catalysts Pd(0.5%)-SAC13
Given that Pd(0.5%)/SAC-13 afforded the best cata-
lytic results we explored the possibility of recycling and
reusing this solid metal/acid catalyst in subsequent runs
for the synthesis of DHPM. Then, Pd(0.5%)/SAC-13
which was recovered by filtration at the end of the global of a multiple catalyst will lead to the direct formation
process was exhaustively washed with TFT, dried and of diverse C–C and C–N bonds through different
calcined at 300°C for 2 h under air, and hydrogenated at successive transformations.
This complex approach, which is based on the use
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LOPEZ-PRADO et al.
Fig. 2. Reusability experiments for the synthesis of compound 1 in the presence of Pd(0.5%)/SAC-13 catalyst.
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FUNDING
16. C. O. Kappe, Eur. J. Med. Chem. 35, 1043 (2000).
Financial support by the Ministerio de Economia y
Competitividad, Programa Severo Ochoa (SEV2016-0683)
and Ministerio de Ciencia Innovacion y Universidades,
Programa Estatal de Generación de Conocimiento
(PGC2018-101247-B-100) are gratefully acknowledged.
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