Ligand-Enabled Palladium-Catalyzed Through-Space C?H Bond Activation via a Carbopalladation/1,4-Pd Migration/C?H Functionalization Sequence

Article abstract of DOI:10.1002/chem.202001582

We report, herein, a palladium-catalyzed cascade comprising carbopalladation, 1,4-Pd-migration and C(sp²)?C(sp²) bond formation to construct a variety of bis-heterocyclic frameworks in a single operational step. The methodology provi

Full text of DOI:10.1002/chem.202001582

Accepted Article
Accepted Article
Title: Ligand Enabled Palladium–Catalysed Through-Space C-H
Bond Activation via a Carbopalladation/1,4-Pd Migration/C-H
Functionalization Sequence
Authors: Su Chen, Prabhat Ranjan, Nagarajan Ramkumar, Luc Van
Meervelt, Erik V. Van der Eycken, and Upendra K. Sharma
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001582
Link to VoR: https://doi.org/10.1002/chem.202001582
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1/2020

Chemistry - A European Journal
10.1002/chem.202001582
COMMUNICATION
Ligand Enabled Palladium-Catalysed Through-Space C-H Bond
Activation
via
a
Carbopalladation/1,4-Pd
Migration/C-H
Functionalization Sequence
[a]
[a]
[a]
[b]
[a,c]
Su Chen, Prabhat Ranjan, Nagarajan Ramkumar, Luc Van Meervelt, Erik V. Van der Eycken,*
Upendra K. Sharma*[a]
Abstract: We report, herein,
a palladium-catalysed cascade
2
2
comprising carbopalladation, 1,4-Pd-migration and C(sp )-C(sp )
bond formation to construct a variety of bis-heterocyclic frameworks
in a single operational step. The methodology provides a direct
approach to introduce an oxadiazole core at a remote location without
any functional group obligation, with moderate to good yields.
Palladium-catalysed cross coupling has remained in the forefront
of organometallic chemistry to form C-C, C-O and C-N bonds and
is characterized by versatility, extensive scope, and high
tolerance to many functional groups.[1,2] Among this class of
reactions, the Heck-Mizoroki reaction[3a] has been particularly well
studied for forming carbo- and heterocyclic scaffolds such as
indoles, benzofurans, and oxindoles.[3b] The σ–alkyl palladium
intermediates lacking a syn-β-hydrogen, generated after an
intramolecular insertion reaction (scheme 1B), are often termed
as living species and have been extensively explored in domino
processes with a variety of nucleophiles[4] following the early work
by Grigg et al.[5] The whole concept revolves around designing
substrates where β-hydride elimination is blocked to promote the
development of both intra- as well as intermolecular cascades to
form complex molecular architectures especially involving C-H
activation as key step (scheme 1B).[6]
Recent advances in C-H functionalization of (hetero)arenes
via transition-metal catalysis have transformed the way organic
chemists execute the synthesis of complex structures[7] as it
circumvents the need for pre-functionalization of the starting
materials. One such interesting approach is the incorporation of
palladium-migration to its neighbouring position via activating a
Scheme 1: Background on σ–alkyl palladium intermediates and the oxadiazole
framework.
2
3
C(sp )-H or C(sp )-H bond and followed by functionalization with
another C-H bond, thus mimicking a dehydrogenative coupling
Such 1,4-palladium migration after a usual carbopalladation step,
is able to trigger a domino reaction from a simple starting material,
allowing the rapid generation of molecular diversity and
complexity in a minimum number of steps (Scheme 1C).[10]
The (hetero)aryl or alkyl 1,3,4-oxadiazole skeleton is a key
structural unit in various biologically active compounds and finds
remote location.[8] Larock and co-workers[9]
pathway at
a
pioneered the study on palladium catalyzed through-space
2
C(sp )-H bond activation by 1,4-alkyl to aryl palladium migration.
[
a]
S. Chen, P. Ranjan, Dr. N. Ramkumar, Prof. Dr. E. V. Van der Eycken
and Dr. U. K. Sharma
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Email: erik.vandereycken@kuleuven.be, usharma81@gmail.com,
upendrakumar.sharma@kuleuven.be.
Biomolecular Architecture, Department of Chemistry, KU Leuven,
Celestijnenlaan 200F, B-3001 Leuven, Belgium
profound applications in medicinal chemistry as well as in material
sciences.[11] In addition, oxadiazoles are known as bioisosteres of
amides and esters with superior hydrolytic and metabolic stability,
improved pharmacokinetics as well as in vivo performance.[
Raltegravir,
12]
[13]
is an antiretroviral drug for the treatment of HIV
[14]
infection containing the 1,3,4-oxadiazole moiety (Figure 1A).
Some other significant molecules possessing the 1,3,4-
oxadiazole core include butyl PBD or ß-PBD (2-(4-tert-
butylphenyl)-5-(4-biphenyl)-1,3,4-oxadiazole) which is used in the
liquid scintillator neutrino detector (LSND).[15]
[
[
b]
c]
Peoples’ Friendship University of Russia (RUDN University),
Miklukho -Maklaya street 6, RU-117198 Moscow, Russia
Additional data related to this publication is available at the
https://doi.org/ data repository.
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Chemistry - A European Journal
10.1002/chem.202001582
COMMUNICATION
In continuation of
our previous work on C-H bond
was the best choice (entries 9-11). Slightly higher yields were
obtained by increasing the amount of ligand JohnPhos to 30 mol%
(entry 12). Inspired by the work of Yu’s lab on C(sp )-H
[
16]
functionalization of (hetero)arenes (Scheme 1D), we wondered
if such transient alkylpalladium(II) species could activate the
2
2
activation,[18] we decided to investigate the effect of 2-pyridone-
based ligands on the desired C-H activation at remote location.
Thus, when 30 mol% 2-hydroxy-5-nitropyridine was employed
instead of 30 mol% Ac-Leu-OH, the desired product 3a was
obtained in 72% yield (entry 13). Other pyridone-based ligands
displayed decreased activity (entry 14 and supporting
information). We finally established the optimized conditions as
C(sp )-H bond of the neighbouring benzene ring via 1,4-Pd-
migration. This could be followed by trapping the nascent Pd-
intermediate via another intermolecular C-H functionalization step
with an oxadiazole. Herein we report a Pd-catalysed cascade
comprising of carbopalladation, 1,4-Pd-migration, C(sp )-C(sp )
bond formation to construct bis-heterocyclic frameworks in a
single operational step.
2
2
3 5 2
1a (0.4 mmol), 2a (0.2 mmol), [PdCl(C H )] (10 mol%),
Table 1: Optimization of the reaction conditions.a
CyJohnPhos (30 mol%), 2-hydroxy-5-nitropyridine (30 mol%) and
CsOAc (2 equiv) in DMA at 110°C for 10h (entry 13).
With the optimized reaction conditions in hand, we then
explored the substrate scope (table 2). First, various oxadiazoles
were examined and most of the functional groups were well
tolerated under the optimized conditions. With
a methyl
Entry
Catalyst
Base
Ligand
Yield 3a:3a' (%)
substituent on the phenyl ring of 2-phenyl-1,3,4-oxadiazole, the
compound reacted efficiently to give the desired products 3b in
72% yields. Electron donating functional groups (methoxy and
tert-butyl) were also investigated whereby a methoxy group
resulted in 75% yield (3c) contrary to only 32% yield with the
bulkier tert-butyl group on the aromatic ring (3d). Potentially useful
groups for further functionalization like an N,N-dimethyl amino
and hydroxyl group on the phenyl ring were also examined, and
the desired products 3e and 3f were obtained in moderate yields.
In addition, a chloro-substituent resulted in a moderate yield of
65% for 3g, while we observed a lower yield of 28% for 3h bearing
a bromine, due to the formation of some unidentified side products.
1
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CyJohnPhos
JohnPhos
MePhos
XPhos
dppb
37:24
30:35
20:35
15:35
30:40
20:25
49:34
58:30
40:17
60:25
45:20
62:13
72:11
60:17
b
2
2
2
2
2
2
2
2
b
3
b
4
5
b
b
6
DPEPhos
7
CyJohnPhos
CyJohnPhos
CyJohnPhos
CyJohnPhos
CyJohnPhos
CyJohnPhos
CyJohnPhos
CyJohnPhos
c
8
c
9
2
Pd (dba)
3
1
1
1
1
1
0c
1
2
3
4
[PdCl(C
3
H
5 2
)]
c
Pd(OAc)
2
(PPh
)]
)]
)]
3 2
)
c,d
[PdCl(C
[PdCl(C
[PdCl(C
3
H
5
2
c,d,e
3
H
5
2
c,d,f
3
H
5
2
3 2
Substrates bearing electron-withdrawing (CF and NO ) groups
on the phenyl ring were also investigated and successfully
converted into products 3i−3j in good yields.
aReaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), and catalyst (10 mol %),
ligand (20 mol %), base (2 equiv), Ac-Leu-OH additive (30 mol %) in DMA (1.5
mL) under N
o
b
2
for 10h at 110 C, isolated yield. Determined by 1H NMR using
c
d
2,4,6-trimethoxybenzaldehyde as an internal standard. 2 equiv of 1a. 30 mol %
Table 2: Substrate scope for various oxadiazoles.a
e
f
CyJohnPhos. 30 mol % 2-hydroxy-5-nitropyridine additive, 30 mol % 5-
trifluoromethyl)-2-pyridinol additive.
(
This reaction was first tested by applying 1-iodo-2-(((2-
methylallyl)oxy)methyl)benzene (1a) and 2-phenyl-1,3,4-
oxadiazole (2a) as model substrates (Table 1). Earlier attempts
on the concept of 1,4-Pd-migration and trapping via thiophene
forged the ground work for these initial optimization studies[17] but
mostly resulted in 1:1 mixtures or reaction decomposition (for
details, See table S1, SI). Attempts were performed in the
2
presence of Pd(OAc) (10 mol %), Ac-Leu-OH (30 mol %) and
CsOPiv (2 equiv) as base in DMA at 110 oC affording 2-(4,4-
dimethylisochroman-5-yl)-5-phenyl-1,3,4-oxadiazole (3a) further
confirmed by X-ray crystal structure analysis (see the Supporting
Information) in 37% yield (Table 1, entry 1), along with direct
coupling (no 1,4-Pd shift) product 2-((4-methylisochroman-4-
yl)methyl)-5-phenyl-1,3,4-oxadiazole (3a') in 24% yield.
Thereafter, several Pd-ligands were screened (Table 1, entries 2-
6), but the reaction did not work well under these conditions.
Among the choice of bases, different inorganic bases were
screened (see entry 7 and Supporting Information, Scheme 3).
CsOAc proved to be superior to CsOPiv with less side product
aReaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), [PdCl(C
CyJohnPhos (30 mol %), 2-hydroxy-5-nitropyridine (30 mol %) and CsOAc (2
equiv) in DMA (1.5 mL) under N at 110°C for 10h.
3
5 2
H )] (10 mol %),
(
3a') formation. Moreover, when the amount of 1a was increased
to 2 equiv (entry 8), the desired product 3a was obtained in 58%
yield. Screening of other palladium-catalysts, such as Pd (dba)
3 5 2
PdCl(C )] and Pd(OAc) (PPh revealed that [PdCl(C H )]
2
2
3
,
[
3
H
5
2
2
3
)
2
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Chemistry - A European Journal
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COMMUNICATION
Interestingly, the replacement of the phenyl group in oxadiazole
with more challenging heterocycles such as thiophene, furan or
pyridine, delivered the expected products 3k−3m in moderate
yields. Moreover, the 1,3-di(1,3,4-oxadiazol-2-yl)benzene
framework led to the desired product 3n in satisfactory yield,
providing the opportunity to generate complex scaffolds in
minimal steps. Surprisingly, methyl oxadiazole did not result in the
desired product.
The practical applicability of the process for the synthesis of
3i has been demonstrated by performing the reaction at 1 mmol
scale, affording 3i in 78% yield (Scheme 2). However, in order to
fully consume the starting material 2i, an additional equivalent of
1a was added to the reaction after 12h. To gain more insight into
the mechanism via deuterium-labelling studies, we employed 20
2
equiv of D O under our optimized conditions (Scheme 3a). Since
the reaction undergoes Pd migration from the intermediate B to
C, we expected deuteration at the terminal methyl group. To our
delight, we observed 64% deuterium incorporation in d-3a,
Table 3: Substrate scope.a
1
13
confirmed by HNMR and CNMR (see supporting information).
This result is in line with the previous reports and supports the
formation of a five-membered palladacycle intermediate towards
intramolecular C-H activation via 1,4-Pd-migration.[19]
A
competition experiment with substituted oxadiazoles was also
performed (Scheme 3b). The formation of 3c and 3j in a 2:3 ratio
suggested that the oxadiazole bearing an electron withdrawing
substituent reacts preferably with the 1,4-Pd-migration
intermediate D, which could be accounted for preferential
deprotonation as compared to electron-rich 3c.[20]
aReaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), [PdCl(C
CyJohnPhos (30 mol %), 2-hydroxy-5-nitropyridine (30 mol %) and CsOAc (2
equiv) in DMA (1.5 mL) under N at 110°C for 10h.
3 5 2
H )] (10 mol %),
2
Scheme 3: Control experiments.
Next, we turned our attention to explore various heterocyclic
skeletons under standard conditions. First, 1-iodo-2-((3-
methylbut-3-en-1-yl)oxy)benzene and N-(2-iodophenyl)- N-(3-
methylbut-3-en-1-yl)methanesulfonamide were examined and
provided the desired products 4a and 4b in 38% and 47% yield
respectively. In addition, substrates with the phenyl group of the
methallyl ether bearing a methoxy- or a bromo-substituent were
also investigated. These compounds reacted efficiently to give the
desired products 4c and 4d in 67% and 66% yield respectively.
Unfortunately, the substrate bearing a chloro group at the meta-
position of the aryl iodide did not afford the desired product, as
solely the side product 4e' (no 1,4-Pd-shift) was formed in 72%
yield. This might be attributed to an increased steric hindrance for
the C−H functionalization step. Additionally, substitution of the
vinylic methyl group by a bulkier ethyl-group resulted in a slightly
lower yield of 4f. The flexibility of the reaction was further
demonstrated by the synthesis of 4g, 4h and 4i in 81%, 88% and
67% yield, respectively.
Scheme 4: Proposed mechanism.
Scheme 2: Millimole scale synthesis of 3i.
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Chemistry - A European Journal
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COMMUNICATION
Based on the previous reports[21] and control experiments, a
plausible catalytic cycle of this reaction is outlined in scheme 4.
The reaction begins with the oxidative addition of Pd(0) to the C-I
bond of 1-iodo-2-(((2-methylallyl)oxy)methyl)benzene 1a, forming
the arylpalladium species A, which undergoes intramolecular
carbopalladation to generate intermediate B. The 2-hydroxy-5-
nitropyridine could serve as a ligand or as an internal base[18] to
assist a tandem intramolecular C−H activation and 1,4-Pd-shift to
generate species C and D, respectively. Afterwards, the attack of
Chaloner, C. H. Heath, L. Tietze, S. G. Stewart, Eur. J. Org. Chem. 2012,
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delivers the desired product 3a after reductive elimination, and
simultaneously liberates the Pd(0) species for the next catalytic
cycle.
[7]
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In summary, we have developed an efficient methodology
2
2
involving carbopalladation, 1,4-Pd-migration, and C(sp )-C(sp )
bond formation to construct variety of bis-heterocyclic
a
frameworks. Over 22 examples of structurally and functionally
diverse products were successfully synthesized. The substrate
scope along with relatively mild reaction conditions and the good
yields make this method synthetically useful. This new azole
activation method should enable the mild synthesis of these
biologically relevant molecules in a more sustainable manner.
[8]
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Acknowledgements
The authors wish to thank the FWO Fund for Scientific Research-
Flanders (Belgium) and the Research Fund of the University of
Leuven (KU Leuven) for financial support. S.C. is grateful to the
University of Leuven for the doctoral funding. PR is thankful to
Marie–Curie action (Grant No. 721290). R.K. is thankful to the
SERB India for postdoctoral fellowship. L.V.M. thanks the
Hercules Foundation for supporting the purchase of the
diffractometer through project AKUL/09/ 0035. We acknowledge
the support of “RUDN University Program 5-100”.
[
[
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3
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[11]
Keywords: 1,4-Pd migration • oxadiazoles • C-H activation • Pd-
5
catalysis
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[
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