A Waste-Minimized Approach to Cassar-Heck Reaction Based on POLITAG-Pd0 Heterogeneous Catalyst and Recoverable Acetonitrile Azeotrope

Article abstract of DOI:10.1002/cssc.202101052

Three different Pd⁰-based heterogeneous catalysts were developed and tested in the Cassar–Heck reaction (i. e., copper-free Sonogashira reaction) aiming at the definition of a waste minimized protocol. The cross-linked polymeric supports used in this investigation were designed to be adequate for different reaction media and were decorated with different pincer-type ionic ligands having the role of stabilizing the formation and dimension of palladium nanoparticles. Among the ionic tags tested, bis-imidazolium showed the best performances in terms of efficiency and durability of the metal catalytic system. Eventually, aqueous acetonitrile azeotrope was selected as the reaction medium as it allowed the best catalytic efficiency combined with easy recovery and reuse. Finally, the synergy between the selected catalyst and reaction medium allowed to obtain highly satisfactory isolated yields of a variety of substrates while using a low amount of metal catalyst. The high performance of the designed POLymeric Ionic TAG (POLITAG)-Pd⁰, along with its good selectivity achieved in a copper-free process, also led to a simplified purification procedure allowing the minimization of the waste generated as also proven by the very low E-factor values (1.4–5) associated.

Full text of DOI:10.1002/cssc.202101052

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A Waste-Minimized Approach to Cassar-Heck Reaction
Based on POLITAG-Pd0 Heterogeneous Catalyst and
Recoverable Acetonitrile Azeotrope
Federica Valentini+,[a] Francesco Ferlin+,[a] Elena Tomarelli,[a] Hamed Mahmoudi,[b]
Mojtaba Bagherzadeh,[b] Massimo Calamante,[c, d] and Luigi Vaccaro*[a]
Three different Pd0-based heterogeneous catalysts were devel-
oped and tested in the Cassar–Heck reaction (i.e., copper-free
Sonogashira reaction) aiming at the definition of a waste
minimized protocol. The cross-linked polymeric supports used
in this investigation were designed to be adequate for different
reaction media and were decorated with different pincer-type
ionic ligands having the role of stabilizing the formation and
dimension of palladium nanoparticles. Among the ionic tags
tested, bis-imidazolium showed the best performances in terms
of efficiency and durability of the metal catalytic system.
Eventually, aqueous acetonitrile azeotrope was selected as the
reaction medium as it allowed the best catalytic efficiency
combined with easy recovery and reuse. Finally, the synergy
between the selected catalyst and reaction medium allowed to
obtain highly satisfactory isolated yields of
a variety of
substrates while using a low amount of metal catalyst. The high
performance of the designed POLymeric Ionic TAG (POLITAG)-
Pd0, along with its good selectivity achieved in a copper-free
process, also led to a simplified purification procedure allowing
the minimization of the waste generated as also proven by the
very low E-factor values (1.4–5) associated.
Introduction
and also of the product metal contamination, facilitating the
overall work-up/product isolation procedure.[3] This is even
more true if applied to the preparation of active pharmaceutical
ingredients, which have highly stringent regulations on their
metal contaminants.[4]
The design of high-performance durable and reusable catalysts
is one of the key challenges for aiming at a modern and more
sustainable chemical production.[1] Indeed, the replacement of
stoichiometric reagents with small amounts of catalysts is
crucial for the abatement of the waste generated in the
preparation of target molecular architectures.[2] In this context,
transition metal-based heterogeneous catalytic systems play a
crucial role: provided that they are truly recoverable and
reusable in easily reproducible conditions, their easy separation
from the reaction mixture can allow the minimization of waste
Among the industrially used methodologies for the con-
struction of CÀ C bond, Cassar–Heck or Sonogashira reactions
are among the most studied since their first report in the
literature in 1975. In fact, in the same year Heck[5] and Cassar[6]
with
a a
copper-free approach and Sonogashira[7] using
combined palladium/copper catalysis disclosed separately dif-
ferent protocols allowing the possibility to form a new bond
between a C(sp) (alkyne) with aromatic C(sp2).
[a] Dr. F. Valentini,+ Dr. F. Ferlin,+ E. Tomarelli, Prof. L. Vaccaro
Dipartimento di Chimica, Biologia e Biotecnologie
Università degli Studi di Perugia
Via Elce di Sotto, 8, 06124 Perugia (Italy)
E-mail: luigi.vaccaro@unipg.it
Homepage: http://greensoc.chm.unipg.it/
[b] Dr. H. Mahmoudi, Prof. M. Bagherzadeh
Chemistry Department
Sharif University of Technology
Tehran P.O Box 11155 3615 (Iran)
[c] Dr. M. Calamante
Institute of Chemistry of Organometallic Compounds (CNR-ICCOM)
Via Madonna del Piano 10, 50019 Sesto Fiorentino (Italy)
[d] Dr. M. Calamante
Department of Chemistry“U. Schiff”University of Florence
Via della Lastruccia 13, 50019 Sesto Fiorentino (Italy)
[+] These authors contributed equally to this work.
The interest in the resultant alkynyl compounds has made
these procedures widely important and investigated for the
preparation of target pharmaceuticals or natural products.[8] In
the literature, there are reports dealing with the definition of
environmentally friendly protocols for the preparation of
alkynes and more in detail, to make Sonogashira and related
reactions consistent with the current need of a more sustain-
able chemical production.[9]
Among the strategies adopted, several studies aimed at the
minimization of the palladium amount in combination with the
use of a ligand under homogeneous conditions[10] or by
supporting the catalytic system on a heterogeneous support,
aiming at its recovery and reuse.[11]
Overall green efficiency of a protocol depends also on the
use of the materials and solvents that directly influence the
waste generation. These are utilized in large amounts in all the
synthetic steps and especially at the purification stage.[12]
Therefore, the design and test of highly efficient heterogeneous
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cssc.202101052
© 2021 The Authors. ChemSusChem published by Wiley-VCH GmbH. This is
an open access article under the terms of the Creative Commons Attribution
Non-Commercial NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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catalysts[13] should consider the use of more sustainable media
able to replace the most commonly used toxic solvents.[9a,b,14]
Among the latter, a good option is offered by aqueous
recoverable azeotropes that, being easily recoverable, can also
be reused solving their dispersion and disposal issues.[15] The
possibility to recover the reaction medium is one of the key
pillars to aim for a waste minimization also according to the
EPA (Environmental Protection Agency) policies.[16] Furthermore,
the combination of an organic solvent with water can also be
an effective tool to improve the process efficiency by increasing
the combination of compounds soluble in different solvents.
Our continuous interest in the definition of waste-mini-
mized procedures, is based on both the design of heteroge-
neous catalysts[17] and use of green solvents,[18] and with this
aim we have developed our POLITAG-Pd0 (POLymeric Ionic-
TAG) for a waste-minimized Cassar–Heck (copper-free Sonoga-
shira) reaction.
We have previously proven that our crosslinked heteroge-
neous support decorated with pincer-type ionic tags is able to
influence the palladium catalytic efficiency by stabilizing its
nanoparticles[17e] as well as its anionic PdII complexes.[17a,d] By
tuning the ligand architecture, our polymeric POLITAG support,
and the reaction medium, we aim to regulate the reactivity and
also the metal leaching. Taking into consideration these
parameters, herein, we report a further example proving how
important the catalyst design is in the development of environ-
mentally friendly processes.
amounts of styrene and 4-vinylbenzyl chloride with 2% of 1,4-
bis (4-vinylphenoxy)benzene as crosslinker,[20] therefore featur-
ing chlorinated anchoring centers, SPÀ Cl This support was
designed considering the size and flexibility of the crosslinker in
order to be efficient in various polar reaction media.
Functionalization followed the polymerization by anchoring
one of the pincer-type ligands L1,[17d] L2,[17e] and L3[17a] that after
being subsequently quaternized, afforded three different
POLITAGs supports (Scheme 1). The loading of supported ionic
tags was determined by elemental analysis, and after palladium
nanoparticles
formed
(Scheme 1)
the
corresponding
POLITAGsÀ L-Pd0 heterogeneous catalysts could be achieved.
For the sake of an optimal comparison, we optimized the
conditions in order to prepare the three different catalysts with
comparable metal loadings (see Table S1 in the Supporting
Information), as well as the size distribution of Pd nanoparticles
for all the ionic tags employed as confirmed by transmission
electron microscopy (TEM) analysis (see Figure S1 in the
Supporting Information).
The difference of the ionic-tags was initially tested in terms
of catalytic efficiency and nanoparticles stabilization of resultant
POLITAGs-Pd0. The three catalysts were used in the Cassar–Heck
reaction of representative iodobenzene (1a) and phenylacety-
lene (2a) at different reaction times, and then palladium
leaching was measured after 4 h (Table 1).[9h] 0.5 mol% of
POLITAGs-Pd0 was used, together with DABCO (1,4-diazabicyclo
[2.2.2]octane) as base and in γ-valerolactone (GVL) as reaction
°
In this contribution we have reported that our catalyst
system can reach a high performance in promoting the Cassar–
Heck reaction by using a very low loading of Pd (0.01 mol%) in
a recoverable acetonitrile–water azeotrope allowing different
substrates to be processed. Moreover, the choice of this
reaction medium and the optimization of work-up procedure
has also led to a waste-minimized protocol as confirmed by the
low E-factor[19] values associated.
medium at 60 C.
Although triazolium-based ionic tags L2 and L3 showed
slightly higher catalytic efficiency after 2 h (Table 1, entries 3
and 5) the conversion at 4 h was comparable with the results
obtained employing POLITAG-L1-Pd0 catalyst (Table 1, entries 2,
4, and 6). The latter showed the best compromise between
catalytic performance and metal leaching and therefore was
selected for the further progress of this study.
The reaction conditions for Cassar-Heck cross-coupling with
POLITAG-L1-Pd0 were extended to different reaction media, and
palladium leaching was always measured in all the solvents
screened (Figure 1). As a result, it can be concluded that the
catalyst efficiency was maintained in almost all the media tested
while enormous differences in term of metal leached in solution
could be observed. The most common dipolar aprotic solvents
Results and Discussion
The cross-linked polymeric support developed by our group is a
gel-type spaced rigid (SPACER, SP) crosslinked polystyrene resin
obtained by suspension co-polymerization of equimolar
Scheme 1. Schematic representation of POLITAG-L-Pd0 synthesis.
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Table 1. Selection of POLITAG-Pd0.[a]
Under the same conditions, GVL gave better results
affording 3aa in 78 and 64%, with 0.05 and 0.01 mol% of
POLITAG-L1-Pd0, respectively (see the Supporting Information,
Table S2, entries 3 and 5). 80% conversion to 3aa could be
obtained by prolonging reaction time to 24 h (Supporting
Information, Table S2, entry 8). The retained catalytic efficiency
could be ascribable to the formation of solid precipitate,
consisted in quaternized organic base, which make the reaction
stirring difficult.
By plotting the conversion of 1a for the selected reaction
media when 0.01 mol% of POLITAG-L1-Pd0 is used (Figure 2), it
is evident that the best catalyst performances were observed in
aqueous acetonitrile azeotrope (Supporting Information, Ta-
ble S2 entries 10–12). After further optimization of the process
in this medium (base, temperature, and reaction time, Table S3)
Entry
Catalyst
t
[h]
Conv.[b]
[%]
Pd leaching[c]
[ppm]
1
2
3
4
5
6
POLITAG-L1-Pd0
POLITAG-L1-Pd0
POLITAG-L2-Pd0
POLITAG-L2-Pd0
POLITAG-L3-Pd0
POLITAG-L3-Pd0
2
4
2
4
2
4
90
97
96
98
96
>99
26
128
83
[a] Reaction conditions: POLITAG-Pd0 (0.5 mol%), 1a (1 mmol), 2a
(1.5 equiv.), DABCO (1.2 equiv.), GVL (1 mL), 60 C, 4 h. [b] Conversion was
measured by GC analysis. The remaining materials were 1a and 2a. [c] Pd
leaching was measured by MP-AES 4210 instrument.
°
°
we could achieve full conversion to 3aa after 7 h at 90 C by
using only 0.01 mol% of POLITAG-L1-Pd0 and DABCO as base
(see Table S3, entry 7).
To have more details on the design of our catalyst and on
the role of the support or the pincer-type ligand, we prepared
and tested three different Pd0-based polymer supported
catalysts (Figure 3), which differ in the support used in terms of
rigidity and accessibility of catalytic sites and on the single
imidazolium unit replacing the pincer-type unit.
Our bis-imidazolium ligand L1 was immobilized on commer-
cially available Janda Jel (a resin considered to act as flexible
solvent-like system) and classic polystyrene Merrifield’s featur-
ing a smaller divinylbenzene as cross-linker. After the immobili-
zation of Pd nanoparticles, JJ-L1-Pd0 and M-L1-Pd0 systems
were prepared, respectively. Beside the fact that these catalysts
showed fairly good conversions with our optimized reaction
conditions, it is clearly visible how the nature of the crosslinker
strongly influences the accessibility to the catalytic sites and
ultimately not allows to quantitatively reach product 3aa.
The catalyst obtained by immobilizing the single imidazo-
lium unit onto our SPACER support led to SP-imi-Pd0, which
showed a slightly better conversion in comparison with JJ-L1-
Pd0 and M-L1-Pd0 confirming the higher efficiency achieved by
Figure 1. Conversion/leaching comparison for Cassar–Heck reaction between
1a and 2a using POLITAG-L1-Pd0 catalysts. Reaction conditions: POLITAG-L1-
Pd0 (0.5 mol%), 1a (1 mmol), 2a (1.5 equiv.), DABCO (1.2 equiv.), solvent
°
(1 mL), 60 C, 4 h. Conversion was measured by GC analysis. The remaining
materials were 1a and 2a. Pd leaching was measured by MP-AES 4210
instrument.
N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),
and dimethyl sulfoxide (DMSO) showed high conversion in
product 3aa with Pd leaching in the range of 61–91 ppm. These
high values of metal were significantly decreased (from 26 to 5)
when also more sustainable alternatives were used. On the
base of these results, GVL, propylene carbonate, and CH3CN/
water azeotrope were selected for a further optimization.
The amount of POLITAG-L1-Pd0 catalyst was decreased in
these sustainable reaction media by varying temperatures and
times (see the Supporting Information, Table S2). Unfortunately,
when 0.05 mol% of catalyst was employed, the conversion was
°
low in propylene carbonate at 80 C (12%, see the Supporting
Figure 2. Conversion of 1a into 3aa during the time in the selected reaction
medium using 0.01 mol% of POLITAG-L1-Pd0. Conversion was measured by
GC analysis. The remaining materials were 1a and 2a. Reaction conditions:
POLITAG-L1-Pd0 (9.4 wt%, 0.01 mol%, 0.117 mg), 1a (1 mmol), 2a (1.5 equiv.),
Information, Table S2, entry 4), while no product 3aa at all was
detected when 0.01 mol% of the catalyst was used (see the
Supporting Information, Table S2, entry 9).
°
DABCO (1.2 equiv.), 1 mL of medium, 80 C.
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Table 2. Comparison of TON and TOF of POLITAG-L1-Pd0 with the best-
performing Pd-NPs based catalysts for the representative coupling
between 1a and 2a.
Pd
Medium
t
TON
TOF (h-1)
Ref.
[mol %]
0.158
0.05
1.00
0.2
0.005
0.05
0.04
0.01
0.06
0.01
0.05
0.002
EtOH/H2O
TPGS-750-M/H2O
CH3CN/H2O (1:1)
DMF
CH3CN
DMA
H2O
EtOH/H2O (1:1)
H2O
H2O
ethylene glycol
az. CH3CN/H2O
10 min 633
3750
79
600
240
358
73
4500
375
1583
4800
980
2806
[11a]
[11e]
[11d]
[11f]
[11 g]
[11i]
[11j]
[11k]
[11 l]
[11 m]
[11n]
this work
24 h
1900
10 min 100
2 h
480
48 h
24 h
0.5 h
24 h
1 h
2 h
2 h
17200
1760
2250
9000
1583
9600
1960
43500
16 h
DMA=N,N-Dimethylacetamide
Table 3. Comparison of E-factor values in sustainable alternative reaction
media for reaction between 1a and 2a.
Reaction medium
3aa yield
[%]
E-factor[a]
Ref.
Figure 3. Comparison of catalytic performance between POLITAG-L1-Pd0 and
other polymer-supported Pd0-based catalyst by changing support (JJ: Janda
Jel; M: Merrifield) or ionic ligand (imi: imidazolium moiety). Reaction
conditions: Pd0-catalyst (0.01 mol%), 1a (1 mmol), 2a (1.5 equiv.), DABCO
CH3CN/H2O az.
CH3CN/H2O az.
CH3CN/H2O az.
GVL
HEP
DES
97
77
82
70
97
98
1.4
this work
[9g]
[9g]
[9h]
[9b]
17[b]
90[c]
73[d]
173
°
(1.2 equiv.), 1 mL of CH3CN/H2O azeotrope, 90 C, 7 h. Conversion was
measured by GC analysis. The remaining materials were 1a and 2a.
24.4[e]
[9a]
[a] Calculated without considering product purification processes and
recovered catalysts. [b] Heterogeneous base. [c] Homogeneous base. [d]
Calculated considering 5 mL of petroleum ether and 3×1.5 mL of water
for extraction as optimized by the same authors in ref. [9g]. [e] 1a
substituted with 3-chloroiodobenzene.
combining the pincer-type ionic tag and our polymeric support
to obtain the best results and the full conversion of 1a.
Finally, the amount of POLITAG-L1-Pd0 was also tentatively
decreased to 0.002 mol%, obtaining 87% conversion to 3aa
after 16 h. This result makes our system competitive, in terms of
turnover number (TON) and frequency (TOF), with the best-
performing Pd-NP-based heterogeneous catalysts reported in
the literature (Table 2).
which negatively influences the E-factor calculation. The use of
a minimum-boiling-point azeotropic mixture allows an easy
recovery accompanied with solvents and energy saving.[15]
Moreover, the high catalyst efficiency and selectivity led us
to improve the purification protocol. Filtration and washing of
the solid reaction crude on silica pad with 10 mL of heptane
affords the pure product 3aa in 97% yield. The heptane used in
purification step was then recovered in 94%. When the
optimized conditions were scaled up to 10 mmol scale, similar
results were obtained.
The optimized reaction conditions were efficiently extended
to the Cassar–Heck coupling of different iodoarenes 1b–i
(Scheme 2) and 2a in good to excellent isolated yields (76–
98%). When electron-withdrawing substituted aryl iodides (1b–
e) were employed, high yields were obtained by filtering and
washing the reaction crude with toluene. The solvent used in
this purification procedure was recovered in 97%. For deacti-
The protocol was finally optimized using 0.01 mol% of
POLITAG-L1-Pd0, and a low Pd leaching (1 ppm) could be
achieved (Supporting Information, Table S2, entry 12).
At the end of the process, the catalyst was filtered and
washed with aqueous acetonitrile azeotrope. The latter could
be recovered by distillation leading to a protocol with an overall
E-factor value of 1.4 for the product 3aa. This value is extremely
low compared with some selected and best-performing proto-
cols also using sustainable reaction media in the literature
(Table 3). Although GVL,[9h] N-hydroxyethylpyrrolidone (HEP),[9b]
and glycerol-based deep eutectic solvent (DES)[9a] have been
shown to be valid alternatives to toxic dipolar aprotic solvents
by allowing high isolated yields and also being possibly
recoverable,[9a,b] they generally require an extraction work-up,
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Scheme 2. Substrate scope for the Cassar–Heck reaction between iodoarene
1a–i and phenyl acetylene 2a. Reaction conditions: POLITAG-L1-Pd0 (9.4 wt
%, 0.01 mol%, 0.117 mg), 1 (1 mmol), 2a (1.5 equiv.), DABCO (1.2 equiv.),
°
1 mL of CH3CN/H2O azeotrope, 90 C, 7 h. Isolated yields are given in
Scheme 3. Substrate scope for the Cassar–Heck reaction between iodoarene
1 and phenyl acetylene 2b–d. Reaction conditions: POLITAG-L1-Pd0 (9.4 wt
%, 0.01 mol%, 0.117 mg), 1 (1 mmol), 2 (1.5 equiv.), DABCO (1.2 equiv.), 1 mL
parentheses. [a] By conducting this reaction on 10 mmol scale, similar results
were obtained. [b] E-factor calculated without considering purification
process. [c] Reaction performed with 0.02 mol% of POLITAG-L1-Pd0 for 16 h.
°
of CH3CN/H2O azeotrope, 90 C, 7 h. Isolated yields are given in parentheses.
[a] E-factor calculated without considering purification process. [b] Reaction
performed with 0.03 mol% of POLITAG-L1-Pd0 for 16 h. [c] Reaction
performed with 0.02 mol% of POLITAG-L1-Pd0 for 24 h.
vated substrates 1f, 1h, and 1i a slightly higher amount of
POLITAG-L1-Pd0 was required together with 16 h of reaction
time, and filtration with heptane was employed to isolate
products.
The optimized reaction conditions and purification protocol
was revealed to be efficient also when different substituted
phenyl acetylenes 2b and c (Scheme 3) were employed, as well
as alkyl-substituted terminal alkyne 2d. The yields obtained for
these substrates (76–99%) are comparable with the reactions
performed with phenylacetylene 2a affording E-factor values in
the range from 1.6 to 3.1, very good values also considering the
most deactivated alkyne 2d.
The substrate scope was subsequently extended to different
iodo-heterocycles 4a–d (Scheme 4) which are rarely investi-
gated in this type of studies but are relevant to prove the
generality of the protocol. 2-Iodothiophene 4a gave good
isolated yields (60–80%) with our optimized reaction conditions
when both phenylacetylene 2a and p-tolyl acetylene 2b were
employed. When nitrogen-containing heterocycles were re-
acted with 2a, 0.02 or 0.03 mol% of POLITAG-L1-Pd0 was
required to satisfactorily afford the products 5ba, 5ca, and 5da.
Product 5ca, which contains an amino group, was successful
isolated by recrystallization. However, in these reaction con-
ditions 3-iodopyridine 5e gave the desired product only in
traces. It is worthy to note that the protocol here developed
showed good efficiency in terms of waste minimization (E-factor
range 3–27) even by including in the calculation the amount of
materials used for purification (solvents and SiO2) (see the
Supporting Information for further details).
Scheme 4. Substrate scope for the Cassar-Heck reaction between iodo-
heterocycles 4a–d and phenyl acetylenes 2a and b. Reaction conditions:
POLITAG-L1-Pd0 (9.4 wt%, 0.01 mol%, 0.117 mg), 1 (1 mmol), 2 (1.5 equiv.),
°
DABCO (1.2 equiv.), 1 mL of CH3CN/H2O azeotrope, 90 C, 7 h. Isolated yields
are given in parentheses. [a] E-factor calculated without considering
purification process. [b] Reaction performed with 0.02 mol% of POLITAG-L1-
Pd0 for 16 h. [c] Reaction performed with 0.03 mol% of POLITAG-L1-Pd0 for
16 h.
(8) (Scheme 5). Eniluracil is an inactivator of the enzyme
dihydropyrimidine dehydrogenase obtained by the coupling of
5-iodouracil (6) and trimethylsilyl acetylene (7) with subsequent
deprotection to remove trimethylsilyl group.[8g]
As an illustration of the applicability of our protocol in the
synthesis of API, we conducted the Cassar-Heck coupling with
our POLITAG-L1-Pd0 for the synthesis of Eniluracil intermediate
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good isolated yields for electron-withdrawing aryl bromides
(9b–d); while poor yields were observed with deactivated 4-
bromotoluene (6e) as well as with bromobenzene (9a) under
the same reaction conditions.
Conclusion
Three different POLITAG-L1-Pd0 have been developed and
tested in the Cassar–Heck reaction. Among the ionic tags
screened, bis-imidazolium pincer-type ligand L1 was selected
for giving the higher stabilization of Pd nanoparticles on
polymeric support in comparison with triazolium based coun-
terparts L2 and L3. Our polymeric support featuring a rigid and
spaced structure due to the cross-linker used (SPACER) plays a
crucial role in the overall efficiency of the Pd0 system especially
if compared to catalysts obtained from commercially available
supports (JJ-L1-Pd0, M-L1-Pd0). Aqueous acetonitrile azeotrope
has been identified as the best reaction medium to perform the
coupling with very low Pd amount (0.002 mol%). With these
conditions high turnover number (TON) and frequency (TOF)
values were measured (43500 and 2806 hÀ 1 respectively). The
optimized reaction conditions were selected to have the best
match between low catalyst amount (0.01 mol%) and reaction
time (7 h). These conditions allowed us to synthesize a wide
variety of alkynyl products with isolated yields ranging from
good to excellent values.
Scheme 5. Synthesis of Eniluracil intermediate (8) by Cassar-Heck reaction
between 5-iodouracil (6) and trimethylsilylacetylene (7) with POLITAG-L1-
Pd0. Isolated yield is given in parentheses. Reaction conditions: POLITAG-L1-
Pd0 (0.01 mol%) 6 (1 mmol), 7 (1.5 equiv.), DABCO (1.2 equiv.), 3 mL of
°
CH3CN/H2O azeotrope, 90 C, 16 h.
We found optimal solubility of the starting material 6 in our
selected aqueous acetonitrile azeotrope reaction medium,
which allowed us to obtain high conversion in product 8 with
only 0.01 mol% of POLITAG-L1-Pd0.
Interestingly, once the catalyst was separated by hot
filtration, the product 8 precipitated in the reaction mixture at
room temperature and could be easily obtained by filtration.
This optimized protocol led to an isolated yield of 82% and an
E-factor value of 3.
Notably, the use of aryl iodide is also widely exploited in
pharmaceutical industries. This choice is generally related to the
interest in developing highly efficient processes. We decided to
also perform the Cassar–Heck reaction with generally less-
reactive aryl bromides (Scheme 6).
Moreover, the synergy between the reaction medium
selected and high catalyst performance and selectivity led to an
effective and simple purification that allowed us to achieve a
minimal-waste production; in fact, low E-factor values have
been calculated in the range from 1.4 to 5 and from 3 to 27 if
also purification materials were considered. Our optimized
protocol was extended also to the synthesis of Eniluracil
intermediate with good isolated yield and low E-factor value.
Finally, the efficiency of our POLITAG-L1-Pd0 in the selected
reaction medium has been proved by employing generally less
reactive aryl bromides.
With the selected POLITAG-L1-Pd0 catalyst and CH3CN
aqueous azeotrope as reaction medium, we were able to obtain
Experimental Section
Unless otherwise stated, all chemicals were purchased and used
without any further purification. GLC analyses were performed by
using Hewlett-Packard HP 5890 SERIES II equipped with a capillary
column DB-5MS (30 m, 0.32 mm), a flame ionization detector (FID),
and helium as gas carrier. GC-EIMS analyses were carried out by
using a Hewlett-Packard HP 6890 N Network GC system/5975 mass
selective detector equipped with an electron impact ionizer at
70 eV. Melting points were measured on a Büchi 510 apparatus.
NMR spectra were recorded on a Bruker DRX-ADVANCE 400 MHz
(1H at 400 MHz, 13C at 100.6 MHz and 19F at 376.4 MHz) in CDCl3.
Chemical shifts are reported in ppm (δ), coupling constant (J) in
Hertz, and multiplicity are reported as follows: s=singlet, bs=
broad singlet, d=doublet, dd=double doublet, td=double triplet,
t=triplet, m=multiplet. Elemental analysis (EA) was conducted on
Elementar UNICUBE® elemental analyzer. Metal loading was meas-
ured using MP-AES 4210 instrument. Products purification was
performed through filtration on silica plug using 230–400 mesh
silica gel. TEM images were obtained using a PHILIPS CM 12
Scheme 6. Substrate scope for the Cassar–Heck reaction with aryl bromide 6.
Reaction conditions: POLITAG-L1-Pd0 (9.4 wt%, 0.5 mol%, 5.66 mg), 9
(1 mmol), 2 (1.5 equiv.), DABCO (1.2 equiv.), 1 mL of CH3CN/H2O azeotrope,
°
120 C, 15 h. Isolated yields are given in parentheses. [a] Reaction performed
with 0.01 mol%. [b] Reaction conducted in 8 h.
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°
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Acknowledgements
The Università degli Studi di Perugia and MIUR are acknowledged
for financial support for the project AMIS, through the program
“Dipartimenti di Eccellenza-2018-2022”.
Sterling SpA is acknowledged for useful discussion on the
synthesis of target APIs.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: azeotrope · CÀ C coupling · Cassar-Heck · polymer-
supported catalyst · waste minimization
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Manuscript received: May 19, 2021
Revised manuscript received: July 1, 2021
Accepted manuscript online: July 9, 2021
Version of record online: ■■■, ■■■■
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FULL PAPERS
Waste not: The Cassar-Heck reaction
affords the synthesis of different
alkynyl compounds in high isolated
yields and low E-factor values in a
waste-minimized protocol. The
Dr. F. Valentini, Dr. F. Ferlin, E.
Tomarelli, Dr. H. Mahmoudi, Prof. M.
Bagherzadeh, Dr. M. Calamante,
Prof. L. Vaccaro*
1 – 9
careful selection of POLITAG-Pd0
(POLymeric Ionic TAG) catalyst and
the reaction medium lead to high
turnover number (43500) and
A Waste-Minimized Approach to
Cassar-Heck Reaction Based on
POLITAG-Pd0 Heterogeneous
Catalyst and Recoverable
turnover frequency (2806 hÀ 1) values.
Most importantly, with the optimized
protocol, the Eniluracil API intermedi-
ate was synthetized in high yield.
Acetonitrile Azeotrope