Pd/C-catalyzed aerobic oxidative C–H alkenylation of arenes in γ-valerolactone (GVL)

Article abstract of DOI:10.1016/j.mcat.2021.111787

A novel methodology for the heterogeneous palladium-catalyzed C–H alkenylation of N-methoxybenzamides and anilides is presented. This approach is based on the use of commercially available Pd/C as catalyst and molecular oxygen as terminal oxidant, in comb

Full text of DOI:10.1016/j.mcat.2021.111787

Molecular Catalysis 513 (2021) 111787
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
Pd/C-catalyzed aerobic oxidative C–H alkenylation of arenes in
γ-valerolactone (GVL)
1
1
*
Ioannis Anastasiou , Francesco Ferlin , Orlando Viteritti, Stefano Santoro, Luigi Vaccaro
Laboratory of Green S.O.C. – Dipartimento di Chimica, biologia e Biotecnologie, Universit a` degli Studi di Perugia, Via Elce di Sotto 8, 06123, Perugia, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
A novel methodology for the heterogeneous palladium-catalyzed C–H alkenylation of N-methoxybenzamides and
anilides is presented. This approach is based on the use of commercially available Pd/C as catalyst and molecular
oxygen as terminal oxidant, in combination with a substoichiometric amount of benzoquinone. Furthermore, the
reaction can be conducted in non-toxic biomass-derived γ-valerolactone (GVL) as reaction medium. The catalytic
system exploited high activity leading to good isolated yields to several interesting products. In addition, the
catalyst showed a remarkable stability in the reaction conditions, allowing its recycling in consecutive reaction
runs.
2
C(sp )–H activation
C–H alkenylation
Green solvents
Oxygen
Heterogeneous catalysis
Fujiwara-Moritani reaction
Introduction
important process for the industrial production of fine chemicals [14].
Its oxidative variant, initially reported by Fujiwara and Moritani
The direct C–H functionalization for the construction of new C–C or
C–heteroatom bonds represents one of the most powerful, attractive and
desirable synthetic strategies for organic chemists. Combined with
transition metal catalysis, this methodology has attracted enormous
interest in recent years [1-12]. Considering the ubiquity of C–H bonds in
nature, as well as their inherent low reactivity and thermal stability, the
chemo-, regio-, and stereoselective functionalization of unactivated C–H
bonds is still a challenge.
[15-19], has some potential advantages both in terms of costs (no need
for pre-functionalization of the starting materials) and in the formation
of by-products (i.e. halogenated salt). Clearly, being an oxidative pro-
cess, the use of an oxidant is essential to obtain the aforementioned
direct coupling. Initial reports made use of stoichiometric Pd(II) [20],
later replaced by catalytic Pd in combination with a stoichiometric
oxidant, either organic or inorganic [21-24]. With a view to sustainable
development, the replacement of these oxidants with other ecologically
benign ones, such as molecular oxygen, would inevitably lead to a
further reduction in costs and waste generation. In this respect, several
examples involving different transition metals have been reported in
recent years [25-33]. Despite these advances, the loss of reactivity and
the poor recyclability shown in most homogeneous palladium-based
catalytic processes, mainly due to the inactivation of the catalysts,
represent a limitation. Therefore, the development of heterogeneous
catalysts, with the aim of increasing the recyclability of the catalyst
avoiding its deactivation, is certainly important. However, to date only
few examples of the use of heterogeneous catalysts for the oxidative
alkenylation of arenes have been reported [34-42]. Furthermore, there
is still large room for improvement in these methodologies, mainly
because of a general lack of recyclability of the catalyst, the use of toxic
solvents and the need for additives (such as ligands and stoichiometric
amounts of oxidants).
The oxidative coupling of two different C–H bonds, introduced as
cross-dehydrogenative coupling (CDC) by Li’s group in 2004, [13]
represents a straightforward and unique method for the construction of
new C–C bonds. This elegant strategy ideally allows a considerable
reduction in the formation of unwanted by-products, since no
pre-functionalization of the coupling partners is required. Consequently,
there is a reduction in the number of steps towards the desired molecule
with a resulting reduction in costs. The driving force of these processes is
usually supplied by a stoichiometric oxidant (benzoquinone, peroxides,
2
Ag(І) or Cu(ІІ) salts, hypervalent iodine, persulfates, O etc.). Among
these, molecular oxygen is particularly attractive in a sustainability
perspective, since ideally it leads to the exclusive formation of water as
by-product.
The palladium-catalyzed alkenylation of aryl halides or pseudo-
halides, known as the Mizoroki-Heck reaction, is
a particularly
*
Corresponding author.
E-mail addresses: luigi.vaccaro@unipg.it, greensoc.chm@unipg.it (L. Vaccaro).
1
Ioannis Anastasiou and Francesco Ferlin contributed equally to this work
https://doi.org/10.1016/j.mcat.2021.111787
Received 9 July 2021; Received in revised form 26 July 2021; Accepted 27 July 2021
Available online 5 August 2021
2
468-8231/© 2021 Elsevier B.V. All rights reserved.

I. Anastasiou et al.
Molecular Catalysis 513 (2021) 111787
obtained from commercial sources without further purification. N-
methoxybenzamides were synthesized and used with a purity of 98–99%
confirmed by NMR analysis. Acetanilides were commercially available
and were used with a purity of 95–99%. Acrylates were commercially
available and were used with a purity of 95–99%. GC analyses were
performed by using a Hewlett-Packard HP 5890A equipped with a
capillary column DB-35MS (30 m, 0.53 mm), a FID detector and helium
as gas carrier. GC-EIMS analyses were carried out using a Hewlett-
Packard HP 6890 N Network GC system/5975 Mass Selective Detector
equipped with an electron impact ionizer at 70 eV. NMR spectra were
1
13
recorded on a Bruker DRX-ADVANCE 400 MHz ( H at 400 MHz, C at
00.6 MHz and 19F at 376 MHz) using CDCl
or DMSO‑d as solvents
1
3
6
and TMS as the internal standard. Chemical shifts are reported in ppm
with multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), and coupling constants in Hertz. Elemental
Analysis (EA) were conducted on Elementar UNICUBE® elemental
analyzer. Palladium content was measured by using an Agilent 4210
MP-AES instrument. For all the catalytic test and for the substrates
scope, pyrex vials were used.
Fig. 1. Heterogeneous Pd-catalyzed ortho C–H alkenylations using benzoqui-
none (a) or molecular oxygen as oxidant (b, this work).
Within our research program on the development of sustainable C–H
functionalizations [43-52], we have recently reported the heteroge-
neous Pd-catalyzed olefination of acetanilides with electron-poor al-
kenes (Fig. 1a) [38]. The process relies on the use of commercially
available heterogeneous Pd/C as catalyst in a biomass derived reaction
medium such as γ-valerolactone (GVL) [53-55]. This catalytic system, as
well as demonstrating a high catalytic efficiency both in terms of yield
and selectivity, can be easily recovered and recycled for consecutive
runs without any loss of reactivity, and with very little release of
palladium in solution. Indeed, it has been proven that the use of het-
erogeneous catalysts in GVL as the reaction medium results in a reduced
metal leaching compared to common dipolar aprotic solvents, thus
improving the recyclability of the catalyst [43-45]. Furthermore,
recoverability and durability of the catalyst were further improved by
performing the reaction in continuous flow [38, 56-58].
General procedure for the synthesis of N-methoxybenzamides
Following a literature procedure (See supplementary material for
further information), methoxyamine hydrochloride (1 equiv.) and po-
tassium carbonate (2 equiv.) were dissolved in a mixture of H
2
O and
◦
EtOAc [0.13 M] (2:1 ratio), and cooled to 0 C. Acyl chloride (1 equiv.)
was added dropwise, the reaction was allowed to warm to r.t. and stirred
overnight. The mixture was diluted with EtOAc/H
separated. The organic phase was washed with brine and dried over
Na SO , filtered and concentrated to give the product which was then
2
O and the layers were
2
4
recrystallised (EtOAc/hexane) to give the desired compound (oily
products were purified by flash column chromatography).
A drawback of our previously reported methodology is the need of a
stoichiometric amount of benzoquinone as oxidant (Fig. 1a), which is
necessarily associated to the formation of a certain amount of organic
waste. In order to overcome this limitation, we explored the possibility
to use the aforementioned Pd/C catalytic system with molecular oxygen
as terminal oxidant in combination with a catalytic amount of benzo-
quinone. Herein, we report our results on the application of this strategy
for the oxidative alkenylation of N-methoxybenzamides and anilides
with electron-poor olefins allowing also recycle and reuse of the catalyst
with low leaching of metal contaminant (Fig. 1b).
General procedure for the C–H alkenylation of N-methoxybenzamides
reaction
N-methoxybenzamide (0.3 mmol), PS-TsOH (1 equiv.), p-benzoqui-
none (0.2 equiv.) and Pd/C 10 wt.% (10 mol%). were weighed and
placed into an 8 mL screw-capped vial equipped with a magnetic stirring
bar. The vial was evacuated and refilled with oxygen three times. A
balloon of oxygen was then attached to the reaction vial and acrylate
(1.5 equiv.) and GVL [0.05 M] (previously oxygenised by keeping it
Experimental section
under flow of O
2
for at least 30 min) were added. The reaction was
◦
General remarks
stirred at 120 C for 24 h under oxygen. After that time, the reaction
mixture was cooled down to room temperature and the catalyst was
′
Unless otherwise stated, all solvents and reagents were used as
recovered by centrifugation (6000 rpm, 15 ). Following distillation of
GVL, the crude mixture was directly purified by flash column chroma-
tography using petroleum ether/ethyl acetate as eluent to yield the
desired product.
Table 1
Optimization of reaction conditions for the C–H alkenylation of N-methox-
ybenzamide by n‑butyl acrylate. .
a
b
ꢀ
Entry
1
Acid
O
2
pressure
T (
GVL
[M]
C (%)
TOF (h
General procedure for the C–H alkenylation of anilides reaction
◦
1
(
atm)
C)
)
Benzoic
acid
1
120
0.5
NR
NR
-
Acetanilide (0.3 mmol), PS-TsOH (1 equiv.), p-benzoquinone (0.2
equiv.) and Pd/C 10 wt.% (7.5 mol%) were weighed and placed into a 4
mL screw-capped vial equipped with a magnetic stirring bar. The vial
was evacuated and refilled with oxygen three times. A balloon of oxygen
was then attached to the reaction vial and acrylate (1.5 equiv.) and GVL
2
3
4
5
6
7
8
9
PivOH
p-TsOH
p-TsOH
1
1
1
1
5
1
1
1
120
120
90
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.05
-
51(40)
20
0.16
-
c
p-TsOH
p-TsOH
PS-TsOH
PS-TsOH
PS-TsOH
120
120
120
120
120
NR
-
10
-
[
0.5 M] (previously oxygenised by keeping it under flow of O
2
for at
53 (44)
98 (78)
>99
0.18
0.33
0.35
◦
least 30 min) were added. The reaction was stirred at 85 C for 24 h
under oxygen. After that time, the reaction mixture was cooled down to
(
85)
room temperature and the catalyst was recovered by centrifugation
′
(
6000 rpm, 15 ). Following distillation of GVL, the crude mixture was
Reaction conditions: 1a (0.3 mmol), 2a (1.5 equiv.), Pd/C (10 mol%), BQ (0.2
b
equiv.), acid (1 equiv.), GVL, O
2
, 24 h. GC conversion based on the limiting
directly purified by flash column chromatography using petroleum
ether/ethyl acetate as eluent to yield the desired product.
c
reagent 1a (isolated yield). 0.3 equiv.
2

I. Anastasiou et al.
Molecular Catalysis 513 (2021) 111787
Scheme 1. Substrate scope for the alkenylation of N-methoxybenzamides. Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv.), Pd/C (10 mol%), BQ (0.2 equiv.), PS-TsOH
◦
(
1 equiv.), GVL [0.05M], 120 C, O
2
(1 atm), 24 h.
Results and discussion
performing the reaction at higher dilution had a major influence on the
reactivity, resulting in full conversion and high product yield (entries 8
and 9). Under these conditions, it is important to highlight the active p-
benzoquinone redox cycle. Indeed, p-benzoquinone used in catalytic
amount, is effectively needed as oxidant to reoxidize Pd(0) formed
during the reaction to the active Pd(II) species. The hydroquinone
reduced formed is then reoxidized by molecular oxygen to its active p-
We began our investigation by testing the feasibility of an aerobic
oxidative C–H alkenylation of N-methoxybenzamides. We were moti-
vated by the previously demonstrated efficiency of the N-methoxyamido
3
2
group in directing C–H activations on sp and sp carbons [59-62], and
more specifically in enabling a tandem C–H olefination/annulation to
form isoindolinones [63-68]. It is also noteworthy that only a handful of
methodologies have been reported to promote this kind of reactivity,
and that none of them make use of heterogeneous palladium sources
and/or investigates the applicability of environmentally friendly reac-
tion media. To this end, we first optimized the reaction conditions for
the tandem C–H olefination/annulation between N-methoxybenzamide
2
benzoquinone. Importantly, O pressure is also relevant and it must be
balanced to efficiently influence the p-benzoquinone redox cycle but
also prevent degradation of the product. As reported in other protocols,
acid additive (PS-TsOH) is needed as a coadjutant for the concerted
metalation deprotonation (CMD) step in which the C–H activation takes
place.
1
a and n‑butyl acrylate 2a (Table 1).
With the optimized conditions in hand, the scope of the alkenyla-
We began using 10 mol% of Pd/C, in combination with 20 mol% of
tion/heteroannulation reaction was examined with a variety of
◦
benzoquinone at 120 C in GVL as reaction medium and in 1 atm of O
2
.
substituted N-methoxybenzamides and alkenes (Scheme 1). Interest-
ingly, the reaction of N‑methoxy-4-methylbenzamide with 1b pro-
ceeded differently affording 3b in 85% yield. While in the case of 3a the
ring closure proceeds through an intramolecular aza-Michael addition,
the formation of 3b is probably the result of a sequential C–H activation/
intramolecular aza-Wacker reaction generating selectively the E-
configured isoindolinone product (vide infra) as also confirmed by 2D-
NMR (NOESY). For alkenes 2, few acrylates were tested giving the
corresponding unsaturated products 3c and 3d in moderate yield.
To further evaluate the scope of the reaction, a range of variously
substituted N-methoxybenzamides was reacted with butyl acrylate. A
good tolerability of the aryl ring to substitution was found, with the
desired products being obtained in generally moderate yield.
Initially we tested soluble carboxylic acids as additives, such as benzoic
acid and pivalic acid, but we could not observe any formation of the
desired product (Table 1, entries 1–2). Gratifyingly, using the more
acidic p-toluenesulfonic acid (p-TsOH) led to 51% conversion in other-
wise identical conditions (entry 3). Arguing that the relatively harsh
reaction conditions could lead to some product degradation, we per-
◦
formed the reaction at 90 C (entry 4) or with a lower amount of p-TsOH
(
entry 5), observing in both cases lower conversions. Similarly,
increasing the O pressure to 5 atm led to only 10% conversion (entry 6).
Substituting p-TsOH with a polystyrene-supported benzenesulfonic acid
PS-TsOH) had very little effect on the reactivity (cf. entries 3 and 7),
2
(
with PS-TsOH being preferable from a sustainability perspective for its
possible recoverability and recyclability. Finally, we found that
As mentioned above, the ring formation may proceed either via an
3

I. Anastasiou et al.
Molecular Catalysis 513 (2021) 111787
◦
Table 2
allowed obtaining full conversion in 24 h at 85 C under 5 atm of O
2
Optimization of reaction conditions for the C–H alkenylation of acetanilide by
(entry 3). Lower catalyst loadings led to incomplete conversions in
otherwise identical conditions (entries 1 and 2). Interestingly, even
when full conversion was achieved (entry 3), the isolated product yield
was rather low (38%). Hypothesizing that the low yield could derive
from some product degradation in the strongly oxidizing reaction con-
a
n‑butyl acrylate. .
Entry
Pd/C
mol%)
Acid
O
2
pressure
Conversion
TOF (h
b
ꢀ 1
(
(atm)
(%)
)
1
2
3
4
2.5
5
PS-TsOH
PS-TsOH
PS-TsOH
PS-TsOH
PS-TsOH
p-TsOH
5
5
5
1
1
1
1
1
60
-
85 (32)
>99 (38)
>99 (62)
>99 (65)
47
0.26
0.21
0.34
0.36
-
2
ditions, we conducted the reaction in 1 atm of O , which resulted indeed
7.5
7.5
7.5
7.5
7.5
7.5
in full conversion and significantly higher product yield (62%, entry 4).
◦
Finally, lowering the reaction temperature to 60 C resulted in a further
[
c]
5
6
7
8
slight increase of product yield (entry 5). Changing the reaction me-
dium, the stoichiometric ratios of the reactants (see Table S1 in the
Supplementary material) or the acid additive (Table S2 in the Supple-
mentary material and entries 6–8 in Table 2) did not improve the
outcome of the reaction.
Amberlyst®
Dowex®
93 (63)
>99 (64)
0.35
0.35
5
0WX4
Reaction conditions: 4a (0.3 mmol), 2a (1.5 equiv.), Pd/C (mol%), BQ (0.2
◦
equiv.), acid (1 equiv.), GVL [0.5 M], O
2
(atm), 85 C, 24 h. b GC conversion
With optimized conditions in hand, scope and limitations were
examined with a variety of substituted anilides and acrylates (Scheme
◦
based on the limiting reagent 4a (isolated yield). c Reaction performed at 60 C.
2
). The substitution pattern on the acetanilide substrate demonstrated to
intramolecular aza-Michael addition or through an aza-Wacker reaction.
Particularly, in the case of 3 h both saturated and unsaturated products
were obtained. In all examples, we observed the exclusive formation of
the E-configured alkene. Finally, the reactions also proceeded with
complete regioselectivity as shown by the reaction on N‑methoxy-3-
methylbenzamide 1 h.
have a significant impact on the efficacy of this oxidative coupling re-
action. Particularly, in the presence of an electron-donating substituent,
such as a methyl group, at the para position to the acetamide moiety, the
coupling reaction proceeded smoothly affording the product in good
yield (75%, 5b). On the other hand, the presence of a stronger electron-
donating methoxy group at the para position to the acetamide moiety
resulted in lower yields of the desired product 5c. The presence of
electron-withdrawing groups on the arene generally resulted in low
product yields (products 5d-f), while moderate yields were obtained
with the electron-withdrawing fluorine at the meta position to the
acetamide moiety (5 g). The halide functional groups were however
Next, we considered expanding the scope of the aerobic oxidative
alkenylation to acetanilides, beginning with a re-optimization of the
reaction conditions (Table 2) starting from those previously reported by
our research group [38]. First we optimized the catalyst loading, finding
that 7.5 mol% of Pd/C, in combination with 20 mol% of benzoquinone
Scheme 2. Substrate scope for the alkenylation of anilides. Reaction conditions: 4 (0.3 mmol), 2 (1.5 equiv.), Pd/C (7.5 mol%), BQ (0.2 equiv.), PS-TsOH (1 equiv.),
◦
a
GVL [0.5 M], O (1 atm) 60 C, 24 h. Isolated yields. 48 h.
2
4

I. Anastasiou et al.
Molecular Catalysis 513 (2021) 111787
Table 3
activation mechanism promoted by a heterogeneous palladium catalyst
with high stability and very little leaching of the metal.
Catalyst recycling for the reaction between N-methoxybenzamide 1a and butyl
a
acrylate 2a. .
b
Entry
Pd leaching (ppm)
Conversion (%)
Declaration of Competing Interest
1
2
3
6.0
5.8
5.7
>99
>99
>99
There are no conflicts of interest to declare under Conflicts of
interest.
a
Reaction conditions: 1a (0.3 mmol), 2a (1.5 equiv.), Pd/C (10 mol%), BQ
◦
(
0.2 equiv.), PS-TsOH (1 equiv.), GVL [0.05 M], 120 C, O
b
2
(1 atm), 24 h.
GC conversion to 3a.
Acknowledgments
well-tolerated and we could not observe the formation of any proto-
dehalogenation or other cross-coupling side products under these reac-
tion conditions.
The research leading to these results has received funding from the
NMBP-01-2016 Programme of the European Union’s Horizon 2020
◦
Framework Programme H2020/2014-2020/ under grant agreement n
In addition to n‑butyl acrylate, we also tested methyl and ethyl
acrylate as well as ethyl crotonate in the coupling with unsubstituted
acetanilide 4a. While the two acrylates provided the desired products in
slightly lower yields, compared to butyl acrylate, the ethyl crotonate
proved ineffective in this reaction (5k). It is noteworthy that we never
observed the formation of bis-olefination products and that the reaction
always proceeds selectively in the ortho position to the acetamido
directing group.
[720996]. The Universit
a` degli Studi di Perugia and MUR are
acknowledged for financial support to the project AMIS, through the
′
′
program “Dipartimenti di Eccellenza - 2018–2022 .
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.mcat.2021.111787.
Regarding the mechanism of the tandem oxidative C–H olefination/
annulation process, a plausible proposal can be suggested on the basis of
our experimental findings and by analogy with mechanisms established
for related processes [63-76]. Initially, the N-methoxyamido group di-
rects the ortho-C–H insertion of Pd(II) to generate a five-membered
palladacycle. Carbopalladation of the olefin followed by β-hydride
elimination gives the olefination intermediate (Fujiwara-Moritani
product).
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acrylate 2a (Table 3). After the first run, the catalyst/acid mixture was
separated from the reaction mixture by centrifugation, washed, dried
and re-used. High stability of the catalytic system was observed after at
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Conclusion
In the present study we demonstrated the feasibility of an oxidative
ortho-C–H olefination of N-methoxybenzamides and anilides catalyzed
by a commercially available heterogeneous Pd/C catalyst using molec-
ular oxygen as the terminal oxidant. The process is simple and represents
an advancement towards the development of a greener Fujiwara-
Moritani reaction, since it is performed in a biomass-derived reaction
medium (GVL) and benzoquinone is used in a substoichiometric
amount. Finally, the catalytic system can be easily recovered at the end
of the process and reused for consecutive reaction runs, and the release
of metal into solution is consistently very low. In addition, this protocol
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