A heterogeneous and recoverable palladium catalyst to access the regioselective C-H alkenylation of quinoline: N -oxides

Article abstract of DOI:10.1039/d0gc02634d

Herein, we disclose the first C-2-selective C-H alkenylation of quinoline N-oxides catalyzed using a heterogeneous palladium catalyst. The protocol does not require the use of an external oxidant and it is applicable to an ample substrate scope always showing excellent site selectivity. This process is made accessible by the use of a specific 1,2,3-triazolium-tagged heterogeneous polymeric catalytic system. The catalyst can be efficiently recovered and reused with no decrease of its catalytic performance and hot filtration and mercury poisoning tests suggest that its mechanism of action is operatively heterogeneous. In addition, mechanistic studies revealed that C-H activation reaction pathways are operative, setting the stage for the direct synthesis of 2-functionalized quinolines using N-oxide functionality as both a directing group and an oxidant.

Full text of DOI:10.1039/d0gc02634d

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DOI: 10.1039/D0GC02634D
ARTICLE
Heterogeneous and Recoverable Palladium Catalyst to access
Regioselective C–H Alkenylation of Quinoline N–oxides
Daniele Sciosci,‡a Federica Valentini,‡a Francesco Ferlin,a Shaomin Chen,b Yanlong Gu,b Oriana
Received 00th January 20xx,
Accepted 00th January 20xx
Piermatti,a Luigi Vaccaro*a
DOI: 10.1039/x0xx00000x
Herein, we disclose the first C–2-selective C–H alkenylation of quinoline N–oxides catalyzed by a heterogeneous palladium
catalyst. The protocol does not require the use of an external oxidant and it is applicable to an ample substrates scope always
showing excellent site selectivity. This process is made accessible by the use of a specific 1,2,3-triazolium tagged
heterogeneous polymeric catalytic system. Catalyst can be efficiently recovered and reused with no decrease of its catalytic
performance and hot filtration and mercury poisoning tests suggest that its mechanism of action is operatively
heterogeneous. In addition, mechanistic studies revealed that a C–H activation reaction pathways is operative setting the
stage for the direct synthesis of 2-functionalized quinolines using N–oxide functionality as both directing group and oxidant.
oxide moiety has been solely restricted to the use of
homogeneous catalysts.8
Previous contributions reported that the reaction of quinoline
Introduction
The methods for the direct transformation of the C–H bonds
commonly considered non-reactive are in constant
development, proving more and more convincingly to be an
extremely useful tool in organic synthesis.1 Efficient C–H
functionalization procedures enable important applications in
the preparation of key molecules for material sciences, crop
N–oxides 1 with acrylates 2 or styrenes 5, proceeding via a C–H
functionalization path, may give alkenylation products at C–2
and/or at C–8 depending on the catalyst used and its actual
ability together with N-oxide functionality, to steer selectively
the process9 (Scheme 1). It is worthy to mention, that this
reaction may also proceed in absence of transition-metal
catalyst,10 and/or with a completely different cycloaddition
path, leading to an hydroxylated compound 4 that undergoes
water elimination to give the desired alkenylated product 3.
science, natural products and pharmaceuticals.2 As
consequence, large number of C–H functionalization
a
a
protocols of arenes have been realized exploiting the ability of
functional groups to create weak interactions with C–H bonds
positioned in their vicinity.3 Among these, N–Oxide
functionality is peculiarly intriguing,4 being also capable to steer
C–H activation processes. Notably, it has been demonstrated
that the presence of N–oxide bond may lead to a specific
regioselectivity during the C–H metalation step.5 It is also
possible to exploit this functionality as an internal oxidant
opening a smart access to an “external-oxidant-free” process.
Compared to homogeneous C–H functionalizations,
heterogeneous C–H activation protocols continue to be
relatively scarce,6 with notable recent progress realized with
the aid of heterogeneous or heterogenized catalytic systems.7
Despite these considerable advances, so far the palladium-
catalyzed C-2 selective C–H functionalization of quinoline N–
Previous works
Homogeneous
Pd, Rh, Cu
catalyst
and/or
N
O
H
N
O
H
N
O
FG
FG
H
FG
H
This work
- Ligand-specific
catalytic efficiency
Heterogeneous
Pd-complex
- fully recoverable
catalytic system
N
H
N
R
- Broad substrate
scope
H
O
H
R
Scheme 1. Features of current work.
Within our research program devoted to the design and
definition of recoverable catalytic systems for C–H activation
reactions,11 we have developed the first heterogeneous catalyst
for the C-2 selective alkenylation of quinoline N–oxide.
Accordingly, we report herein the design and preparation of a
polymeric systems decorated with specific ionic-tag ligands that
have allowed the first C–H functionalization on quinoline N–
oxide using recoverable and heterogeneous palladium
catalysts.
a. Laboratory of Green S.O.C. – Dipartimento di Chimica, biologia e Biotecnologie,
Università degli Studi di Perugia, Via Elce di Sotto 8, 06123 – Perugia, Italy.
E-mail: luigi.vaccaro@unipg.it; http://www.dcbb.unipg.it/greensoc
b. Hubei Key Laboratory of Material Chemistry and Service Failure, School of
Chemistry and Chemical Engineering, Huazhong University of Science and
Technology, Wuhan, China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
‡Both authors contributed equally to this work.
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In the design and preparation of our heterogeneous palladium Among a variety of reaction conditions,14 the useVoiefw5ArmticloelO%nlionef
DOI: 10.1039/D0GC02634D
catalytic system, we decided to exploit the ability of ionic POLITAG-Pd(II)-L3 in highly concentrated toluene condition
organic moieties to stabilize palladium catalytic species and also [20M] and in the presence of 2 equivalents of ethyl acrylate
the use of specific ligands to modulate and accelerate catalytic (2a), allowed to access the best results. Also, the other POLITAG
reactions.12 In addition, we have also aimed at the catalysts showed good results (Table 1 entries 1-2), but
immobilization of the ligands onto polymeric supports and POLITAG-Pd(II)-L3 enabled the C-2 alkenylation with the
following previous eminent examples to accomplish also the highest positional selectivity and unique catalytic efficacy (Table
recover and reuse of the catalyst.13
1, entry 3). Interestingly, POLITAG-Pd(II)-L3 catalyst showed its
superiority compared to the homogeneous PdCl2 both in terms
of conversion to products and of C–2 selectivity (entry 3 vs 8).
Similarly, other typically used palladium catalytic systems
showed inferior results both in terms of conversions and
selectivity. (Table 1, entries 5-9).
Results and discussion
We started with the preparation of three different pincer-type
ligands (L1-L3, Scheme 2) and explored different reaction
conditions for the C-2 alkenylation of quinoline N–oxide.14
We also focused on the use of “spaced” polystyrene resins a
class of gel-type resin developed in our laboratories that proved
to give superior results in terms of catalytic site accessibility
under acid, base or metal catalysis.15
Table 1. Catalytic tests for the C–2 selective alkenylation of quinoline N–oxide (1a).a
Catalyst
(5 mol%)
OH
CO2Et
CO2Et
+
+
N
O
H
Toluene [20M]
110 °C, 4h
N
CO2Et
N
2a
1a
3a
4a
The key structures of our immobilized catalytic systems are
presented in Scheme 2 and the results of their use in the
optimization of the conditions for the reaction of 1a and 2a are
reported in Table 1 (and also in Tables S1- S3, in the supporting
information).
entry
1
Catalyst
Conv (%)b
75
3a:4a
59:41
70:30
92:8
POLITAG-Pd(II)-L1
POLITAG-Pd(II)-L2
POLITAG-Pd(II)-L3
POLITAG-Pd(II)-L3
Pd-EnCat 30e
Pd-EnCat 40e
Pd(OAc)2
2
>99
>99
85c,d
80
N
3
N
N
N
HO
N
HO
N
HO
N
N
N
4
53:47
55:45
40:60
60:40
80:20
30:70
18:82
10:90
50:50
94:6
N
N
N
L3
L1
N
L2
N
N
N
5
6
70
N
N
N
I
N
I
O
N
N
I
O
O
N
7
40
N
N
N
N
N
N
8
PdCl2
85
N
N
N
I
I
I
POLITAG-L1
POLITAG-L2
POLITAG-L3
9
Bis(triphenylphosphino)Pd(II)Cl2
Pd/C
20
10
11
12
13
14
15
19
N
N
N
N
O
N
Pd(dba)2
17
N
O
O
N
N
N
[PdCl4] 2
[PdCl4] 2
[PdCl4] 2
N
N
N
Pd(Ph3)4 (Pd-Tetrakis)
Na2PdCl4
32
N
N
N
N
60
POLITAG-Pd(II)-L3
POLITAG-Pd(II)-L2
POLITAG-Pd(II)-L1
Without POLITAG-Pd(II)-L3
POLITAG-L3
28
2:98d
10:90f
Scheme 2. Ligands and heterogeneous catalytic sys-tems used in this work.
50
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pd(II) (5 mol%), toluene (20 M),
110 °C, 4h. b Conversion to 3a/4a, determined using samples of pure compounds
as references. Solvent-free conditions. quinoline and 2-methyl quinoline were
detected as degradation products in 8 and 6%, respectively. e Pd-EnCat = Palladium
acetate microencapsulated in polyurea matrix at different percentage of matrix
content (30 or 40). fquinoline and 2-methyl quinoline were detected as
degradation products in 12 and 10%, respectively
Initially, we have prepared the N-containing ligands based on
imidazo-derivative (L1), 1,2,4-triazo-derivative (L2) and 1,2,3-
triazo-derivative (L3) (Scheme 2) and immobilized onto our
polystyrene resin. Then the heterogeneous ligands have been
quaternized using iodomethane, and the desired polymeric
featuring the corresponding ionic tags (POLITAG), have been
accessed. The final catalytic systems have been synthetized by
gently stirring POLITAG systems in an aqueous solution of
PdCl42-, generated in situ from PdCl2 and NaCl. 15a, 15b
The final palladium loading of the heterogeneous systems, was
measured by MP-AES (Microwave Plasma Atomic Emission
Spectroscopy) which showed a comparable palladium amount
for all three catalysts (POLITAG-Pd(II)-L1: 8.0 wt%; POLITAG-
Pd(II)-L2: 8.5 wt%; POLITAG-Pd(II)-L3: 8.5 wt%).
c
d
When the reaction of 1a with 2a was carried out without
catalyst (Table 1, entry 10) or in the presence of the
heterogeneous support only (Table 1, entry 11), formation of
hydroxylated product (4a) and the related degradation
products quinoline and 2-methyl quinoline, were detected.
These results confirm the necessary role of both ligand L3 and
Pd for steering the C–H alkenylation reaction and minimize the
2 | J. Name., 2012, 00, 1-3
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competitive formation of the hydroxylated product (4a), information, section 5, for further details). ImpVoierwtaAnrtticllye,Ontlhinee
DOI: 10.1039/D0GC02634D
deriving from a cycloaddition/ring opening sequence. It is also feasibility of acid-labile substrates has been demonstrated also
noteworthy that we also tried several variations of the optimal by comparing our site-selective methodology with acid-
conditions reported in entry 3, but with no success, including promoted literature available protocols10e-f (Scheme 5).
the change of medium and dilution (see also Tables S1- S3, in
the supporting information).
The optimized reaction conditions used for C–2 alkenylation of
R2
POLITAG-Pd(II)-L3
(5 mol%)
R1
R1
R2
+
quinoline N–oxide were then extended to a variety of substrates
to explore the versatility of the synthetic technology proposed
(Scheme 3). Several quinoline N–oxide derivatives 1 successfully
underwent the alkenylation catalyzed by POLITAG-Pd(II)-L3
catalyst, which selectively proceeded at C–2 position in all the
cases allowing to isolate the products with good to excellent
yields (Scheme 3).
Toluene [20M]
110° C, 4h
N
O
H
N
6
5
1
MeO
N
N
N
Cl
6a
: 75%
6b
: 73%
6c
: 83%
Cl
Cl
MeO
POLITAG-Pd(II)-L3 (5 mol%)
R
R
CO2R
+
N
O
H
N
3
CO2R
Toluene [20M]
110° C, 4h
N
N
N
Cl
Cl
Cl
Cl
2
1
6d
: 78%
6e
: 70%
6f
: 77%
N
N
N
CO2Bu
N
CO2Me
N
CO2Et
N
N
3b
: 75%
3c
: 73%
3a
: 85%
Cl
6g
6h
: 68%
: 72%
MeO
MeO
MeO
Scheme 4. Substrates scope of the reaction of quinoline N-oxides 1 with styrenes 5. a
Reaction conditions: 1 (1 mmol), 5 (2 mmol), Pd(II) (5 mol%), toluene (50 µL, 20 M), 110
°C, 4h.
N
CO2Et
N
N
CO2Me
CO2Bn
CO2Bu
CO2Bn
CO2Bu
CO2Et
3d
3e
3f
: 73%
: 68%
: 74%
Cl
MeO
N
Cl
CO2Me
N
N
3g
3h
3i
: 80%
: 78%
Cl
: 67%
Reaction for acid-labile substrates
Cl
N
POLITAG-Pd(II)-L3 (5 mol%)
Ph
+
N
CO2Me
N
N
Cl
Cl
N
O
H
N
Ph
Toluene [20M]
110 °C, 4h
O
O
3l
: 65%
Si
3j
3k
Si
: 82%
: 82%
6i:
84 %
6i
conditions from ref 10e: not detected
6i
conditions from ref 10f: detected in traces (ca 2%)
N
N
N
N
N
CO2Bu
CO2Bn
N
CO2Et
POLITAG-Pd(II)-L3 (5 mol%)
Ph
+
3m
3n
3o
: 72%
: 68%
: 62%
N
O
H
Toluene [20M]
110 °C, 4h
N
Ph
O
O
O
O
O
O
Scheme 3. Substrate scope for the reaction of quinoline N-oxides 1 with acrylates 2.a a
Reaction conditions: 1 (1 mmol), 2 (2 mmol), Pd(II) (5 mol%), toluene (50 µL, 20 M), 110
°C, 4h.
78 %
6j:
6j
conditions from ref 10e: not detected
6j
conditions from ref 10f: not detected
POLITAG-Pd(II)-L3 (5 mol%)
CO2Bn
+
The scope of the process is not restricted to the use of acrylates,
but also variously substituted styrenes 5 can be used for the
efficient C–2-alkenyation (Scheme 4). Notably, POLITAG-Pd(II)-
L3 being able to promote the direct access to quinoxalines 6g-
h, to the best of our knowledge, also offers an unique and step
economical access to these class of compounds.
N
H
Toluene [20M]
110 °C, 4h
N
CO2Bn
O
3d:
68 %
3d
3d
conditions from ref 10e:
conditions from ref 10f:
12 %
not detected
a Reaction conditions: 1 (1 mmol), 2 (2 mmol), Pd(II) (5 mol%), toluene (50 µL, 20 M), 110
°C, 4h.
The use of chlorostyrenes also open the route towards a
subsequent late stage functionalization for the preparation of
even more complex molecular moieties. Although, main
limitations of the reported catalytic system are found when 6-
nitro quinoline N-oxide, isoquinoline N-oxide and pyridines N-
oxide have been used as substrates (See supporting
Scheme 5. Scope for acid-labile substrates a
The representative reaction of 1a and 2a in presence of
POLITAG-Pd(II)-L3, was also performed on a larger scale for
checking the viability of a symbolic gram-scale synthesis. On 5.0
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mmol scale the results were also better allowing to slightly mechanism. However, no fragment featuring VitehweArtiTclEeMOnPlinOe
DOI: 10.1039/D0GC02634D
increase the yield for isolated product 3a (Scheme 6).
moiety has been detected.
Furthermore, additional experiments have been done to
hypothesize if the catalytic mechanism can be considered
homogeneous or heterogeneous.14 Hot-filtration test strongly
Gram scale reaction
suggests that
a heterogeneous mechanism is operative
underlining also the important role playing the polymeric
support and the pincer ligand L3, on efficiency of POLITAG-
Pd(II)-L3 in this process. Indeed, after the hot-filtration the
reaction proceed in favour of the cycloaddition path leading to
product 4a rather than C–H activation. Consistent results were
also obtained with mercury poisoning test that also suggest an
operative heterogeneous mechanism (see Table S5 in
Supporting Information for details).
We have also attempted the isolation of the actual
organometallic complex formed by placing quinoline N–oxide
1a in the presence of homogeneous bis-1,2,3-triazolium ligand
(L3) and Na2PdCl4, generated in-situ, under stirring at 110 °C.
After 2h a yellow solid precipitated from solution. The complex
was analyzed by NMR spectroscopy suggesting the structure in
Scheme 7 in which C-8 palladated species is formed. Actually,
the presence of homogeneous ligand L3 was not detected.
POLITAG-Pd(II)-L3 (5 mol%)
H
N
O
N
CO2Et
Toluene [20M]
110° C, 4h
3a
1a
(5.0 mmol, 0.75 g)
CO2Et
(4.5 mmol, 1.02 g)
90 % Yield
2a
Scheme 6. Gram scale synthesis of 3a.
Importantly, the synthetical utility of the heterogeneous
catalyst was reflected by its facile recovery and reuse when the
reaction is performed at full conversion of the reactant. The
reuse test was performed for representative 5 runs and then
the loss of palladium was measured by MP-AES analysis
revealing the high stability of POLITAG-Pd(II)-L3 catalyst (Table
S4 in the Supporting information). Although, even when the
recycling tests have been conducted by shortening the reaction
time to 2h, the catalytic efficiency is totally preserved for three
consecutive runs whit a negligible decrease in conversion from
the 4th run (Table 2).
Homogeneous ligand
I
N
N
N
Table 2. Palladium leaching and reuse of POLITAG-Pd(II)-L3 catalyst in the reaction of 1a
and 2a.a
N
N
O
N
I
N
Na2PdCl4
H2O, 110°C
O
Pd
O
POLITAG-Pd(II)-L3
O
OH
N
O
N
CO2Et
+
N
+
CO2Et
N
O
H
N
N
CO2Et
7a
1a
recovery/reuse
- Homogeneous ligand not detected
3a
4a
2a
1a
CO2Et
2a
N
O
- No reaction
Pd
Run
1
Conv (%)[b]
3a:4a
90:10
91:9
Leaching (ppm)[c]
O
7a
- Complex
recovered
N
O
Toluene [20M]
110°C, 4h
N
7a
75
80
75
60
56
4
5
4
2
2
2
Scheme 7. Synthesis of the homogeneous palladium quinoline N–oxide complex 7a.
3
92:8
The isolated complex 7a was used under the reaction
conditions, i.e. in the presence of acrylate 2a for 4h at 110 °C in
toluene [20M], but no reaction occurred. This result confirms
that the isolated complex 7a possesses a different reactivity
compared to the actual catalytic species operative when the
POLITAG-Pd(II)-L3 catalyst is used.
Recent DFT calculations showed that the free-energy barrier for
C-H activation at C–2 is 4.0 kcal/mol lower than that at C-8
position, making the formation of the C–2 alkenylated product
kinetically preferred.16, 9i Accordingly, complex 7a, is probably
not reactive as the most thermodynamically stable complex and
not the actual reactive one.
In addition, we have also studied in details the C–H bond
cleavage event by conducting the C–H alkenylation on the
isotopically labelled substrates 1a-d7 (Scheme 8). In both cases,
by independent and competition experiments, a kinetic isotope
effect was observed (kH/kD = 1.5),14 indicating that C–H bond
cleavage is occurring during or before the rate determining step
4
90:10
91:9
5
a
Reaction conditions: 1a (1 mmol), 2a (2 mmol), POLITAG-Pd(II)-L3 (5 mol%),
b
toluene (50 µL, 20 M), 110 °C, 2h. Conversion to products, determined using
samples of pure compounds as references c loss of palladium has been quantified
using MP-AES.
We performed XRD and TEM analyses of the catalyst POLITAG-
Pd(II)-L3 prior and after its use in the C–H alkenylation reaction.
These investigations revealed that no substantial changes in the
morphology or palladium nanoparticles formation occurs after
the recovery (Figure S1 and S2 in Supporting information).
Besides, the reaction conducted in the presence of TEMPO as
radical scavenger (see supporting information, section 4.5) gave
results comparable to that of the blank experiment, indicating
that radical generation may have an influence on the
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of the process.17 To further distinguish the C–H activation
mechanism to hypothetically possible cycloaddition pathways,
we have isolated hydroxylated product (4a) and subsequently,
submitted this product to our standard optimized conditions.
Even after 16h, the elimination of water is not complete
achieving a 6:4 mixture of 3a and 4a, respectively.
Conclusions
View Article Online
In conclusion, we have reported the firsDt OCI–: 210r.1e0g3i9o/sDe0lGeCct0i2v6e3C4D–
H alkenylation of synthetically useful quinoline N–oxides 1
promoted by a heterogeneous recoverable catalytic system.
The process can be uniquely accessed by the use of a
heterogeneous recoverable palladium(II) catalyst, which is
based on a bis-1,2,3-triazolium ligand immobilized on a spaced
cross-linked polystyrene support (POLITAG). The process is
selective towards the C–H activation mechanism and towards
the functionalization at the C–2 position of the quinoline N-
oxide moiety. Mechanistic studies suggest that the operative
mechanism is heterogeneous and exist a remarkable difference
in terms of reactivity and regioselectivity, between the
homogeneous and heterogeneous reaction pathways.
The POLITAG-Pd(II)-L3 catalyst can be effectively recovered and
reused without any loss of efficiency both in terms of reactivity
and selectivity.
Intermolecular KIE (independent reaction)
POLITAG-Pd(II)-L3
(5 mol%)
D7/H7
D7/H7
N
O
H/D
N
CO2Et
Toluene [20M]
CO2Et
3a/3a-d7
2a
1a/1a-d7
kH/kD= 1.5
Intermolecular KIE (one pot)
POLITAG-Pd(II)-L3
(5 mol%)
D7/H7
D7/H7
N
O
H/D
N
CO2Et
Toluene [20M]
These results set the stage for the direct decoration and
diversification of the quinoline moiety via a modern atom
economical and chemically effective strategy. The versatility of
the proposed process is demonstrated by the broad substrate
scope featuring a good functional group tolerance and excellent
positional selectivity.
CO2Et
2a
3a/3a-d7
1a/1a-d7
kH/kD= 1.5
Scheme 8. KIE determination via independent and competitive reactions.
Therefore, POLITAG-Pd(II)-L3 catalyst is not able to catalyse the
elimination additionally excluding the cycloaddition
mechanism. An additional confirmation of the role of the metal
catalytic system was also obtained by performing the reaction
Conflicts of interest
There are no conflicts to declare.
in the presence of
bis(trimethylsilyl)trifluoroacetamide,
a
silylating agent (N,O-
BTSFA) as the
corresponding silylated 4a is stable towards the elimination. In
the absence of our catalyst the reaction proceeded with a 70%
conversion after 24 hours to the silylated 4a.14 The same
reaction in the presence of POLITAG-Pd(II)-L3 gives the
opposite selectivity with the formation of the 3a (See Table S6
in Supporting information for further details). Based on these
experimental evidences a plausible mechanism involving the
initial C–H activation on the quinoline N-oxide, followed by
olefin insertion and β-hydride elimination can be rationalized
(Scheme 9).
Acknowledgements
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 nº [720996]. The Università degli Studi
di Perugia and MIUR are acknowledged for financial support to
the project AMIS, through the program “Dipartimenti di
Eccellenza - 2018-2022”.
2-
N
Cl
Cl
Cl
Cl
Pd
N
Notes and references
1
N
N
N
N+
O-
H
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N
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O-
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H
Pd
N+
N
N
N
N
N
N
Cl
Cl
R
N
Pd
Cl
N
O
N
N
N
N
N
Cl
Cl
N
Pd
O
N
Cl
HCl
N
N
2
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Cl
Scheme 9. Plausible mechanism of reaction.
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14 See Electronic Supporting Information for detailed
experimental results regarding optimization of reaction
conditions and further mechanistic studies.
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