Palladium-Catalyzed Electrophilic Functionalization of Pyridine Derivatives through Phosphonium Salts

Article abstract of DOI:10.1002/anie.202006724

Herein, we report a highly efficient and practical method for pyridine-derived heterobiaryl synthesis through palladium-catalyzed electrophilic functionalization of easily available pyridine-derived quaternary phosphonium salts. The nice generality of this reaction was goes beyond arylation, enabling facile incorporation of diverse carbon-based fragments, including alkenyl, alkynyl, and also allyl fragments, onto the pyridine core. Notably, the silver salt additive is revealed to be of vital importance for the success of this transformation and its pivotal role as transmetallation mediator, which guarantees a smooth transfer of pyridyl group to palladium intermediate, is also described.

Full text of DOI:10.1002/anie.202006724

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Palladium-Catalyzed Electrophilic Functionalization of Pyridine
Derivatives through Phosphonium Salts
Authors: Yuan-Yuan Che, Yanni Yue, Ling-Zhi Lin, Bingbing Pei,
Xuezu Deng, and Chao Feng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202006724
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10.1002/anie.202006724
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Palladium-Catalyzed Electrophilic Functionalization of Pyridine
Derivatives through Phosphonium Salts
Yuan-Yuan Che,† Yanni Yue,† Ling-Zhi Lin, Bingbing Pei, Xuezu Deng, Chao Feng*
Dedication ((optional))
Y.-Y. Che,[†] Y. Yue,[†] L.-Z. Lin, B. Pei, X. Deng, Prof. Dr. C. Feng
Technical Institute of Fluorochemistry (TIF), Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering
Nanjing Tech University
30 South Puzhu Road, Nanjing 211816, P. R. China
E-mail: iamcfeng@njtech.edu.cn
[†]These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Herein, we report a highly efficient and practical method
for pyridine-derived heterobiaryls synthesis by resorting to
palladium-catalyzed electrophilic functionalization of easily available
pyridine-derived quaternary phosphonium salts. The nice generality
of the present reaction protocol is further extrapolated beyond
arylation regime by enabling facile incorporation of diverse carbon-
based fragments, including alkenyl, alkynyl and also allyl, onto
pyridine core. Notably, the silver salt additive is revealed to be of
vital importance for the success of this transformation and its pivotal
role as transmetallation mediator, which guarantees a smooth
transfer of pyridyl group to palladium intermediate, is also disclosed.
deficiency of effective while compatible aryl radical production
manifolds.[15] Furthermore, when it comes to the regioselective
arylation, the venerable cross-coupling reactions hold plenty of
benefits as both C-H activation and radical arylation protocols
always produce more than one regioisomers except for those
sterically or electronically biased substrates.[15,16] Under this
environment, the development of strategically novel method
which enables a nice merge of merit of site-specificity (as in
cross-coupling protocols) and substrate availability (as in C-H
functionalization protocols) would be highly desirable.
Pyridine frameworks represent a preeminent class of structural
motif which finds widespread occurrence in bioactive
compounds, functional materials, privileged ancillary ligands as
well as pharmaceutical molecules (Scheme 1a).[1] Therefore, the
development of efficient synthetic protocols for the expedient
construction of those sophisticated pyridine-containing molecular
structures has aroused considerable interest in the synthetic
community.[2] Among these, pyridine-based heterobiaryls
particularly caught much attention from synthetic chemists and
the continuing endeavors made in this domain have been
rewarded with diverse eligible methodologies for this aim.[3] In
this respect, while conventional cross-coupling scenarios that
harness the electronically matched reactivity between aryl
halides and aryl metallic reagents have oftentimes proved to be
applicable, the intrinsic limitations such as restricted availability
of pyridyl halides, especially for structurally complicated ones,
and low stability of many heterocylic organometallic species
have inevitably detracted from its wide applications in complex
molecular settings.[4-8] Also should be pointed out is that the
situation would become more critical when considering the
requirement of site-selective halogenation or metallation with
respect to pyridine cores.[9,10] This status, however, is ameliorate
to some extent with the evolvement of site-selective C-H
functionalization of pyridines[11] and also synthetic elaborations
based on radical type Minisci reactions.[12] Notwithstanding these
notable progresses, pre-installation of directing groups or
employment of super-stoichiometric amount of pyridine
substrates, often as reaction solvent, is always required in C-H
arylation scenarios.[13] On the other hand, compared with the
well-explored Minisci alkylation reactions,[14] the advancement of
arylation protocol lags far behind, probably owing to the
Scheme 1. Functionalization of pyridines.
1
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Very recently, by integrating C4-selective phosphonium
formation and C-P bond elaboration, ground-breaking
led to an increase of the yield to 80% (Table 1, entry 3).[20] The
substitution of CuCl for silver salt was also revealed to be
productive, albeit attenuating the reaction efficiency (Table 1,
entry 4). This result, however, indicates that silver salt may not
or solely act as the halogen scavenger and we believe that it
potentially works as pyridyl-shuttle by guaranteeing a facile
transmetallation process.[21] Further examination of parameters
revealed that using acetone as solevent, K2CO3 as base and
RuPhos as ligand was conducive to the reaction outcome (Table
1, entries 5-7). As expected, the reaction was totally impeded in
the absence of either ligands or bases (Table 1, entries 8 and 9).
Furthermore, the reaction between 1a and 2a could be readily
scaled up without obvious influence on the reaction efficiency,
demonstrating the practicability of this transformation. To the
best of our knowledge, this represents the first example of
transition metal-catalyzed electrophilic functionalization of
pyridylphosphonium salts.
Having established the optimized conditions, the reaction scope
exploration was subsequently conducted and the results were
presented in Scheme 2. Initially, the general applicability of aryl
iodide was inspected. Using pyridylphosphonium salt 1a as the
model substrate, we were delight to find that a wide spectrum of
aryl iodides containing both electron-donating and electron-
withdrawing substituents were nicely compatible (3aa-3an). The
silyl group which enables further synthetic manipulation for
structural elaboration remained intact during this transformation
(3ad). In addition, protic substituent such as amide was also
tolerated, suggesting that the in situ formed pyridyl anion
equivalent is not so reactive to undergo premature proton-
quenching (3ae). Notably, steric congested 2,6-disubstituted aryl
iodide such as 2f was amenable to this process, albeit
generating product 3af in moderate yield. Delightfully, poly-
advancement
for
pyridine/diazine-functionalization
was
disclosed by McNally and coworkers.[17,18] These transformations
formally allows smooth incorporation of a wide variety of external
nucleophiles and two distinctive working profiles pertaining to
nucleophile-coupling have been invoked: one proceeds through
oxidative addition with low-valent transition metal catalysts;[17]
the other takes place via nucleophilic addition onto phosphorus
atom, with the subsequent phosphorane ligand coupling
eventually accomplishing the formation of C-C or C-heteroatom
bond (Scheme 1b).[18a-18g] Despite these enticing advances, the
state-of-the-art
regarding
synthetic
elaboration
of
pyridylphosphonium salts is mainly restricted to nucleophilic
coupling protocols by capitalizing on the innate electrophilicity of
these versatile intermediates. In this regard, we were drawn by
elegant works from Anders, Sugimoto, Burton and Xiao, who
disclosed that tetraarylphosphonium salts could be transformed
into (hetero)arene anion equivalent in the presence of Brønsted
base.[19] Inspired by this decomposition mode, we envisage the
possibility of engaging the putative pyridyl anion equivalent in
transition metal-catalyzed cross-coupling reactions, for example
arylation using readily available arylhalides (Scheme 1c). We
believe that the successful development of this protocol would
engender a deep influence not only on pyridine-functionalization
chemistry but more importantly on transition metal-catalyzed
cross-coupling scenario by expanding the potential competent
nucleophilic coupling partners from conventional metallic
reagents to non-metallic main-group element-based species.
Table 1: Optimization of reaction conditions.[a]
halogen
decorated
substrates
were
competent
for
chemoselective reactions, thus offering potential synthetic
handles for structural complexity construction using traditional
cross-coupling protocols (3ag-3ai). Meanwhile, the nice
tolerance of functional groups such as CO2Me, CF3, NO2, CN,
COMe further showcased the applicability of this reaction (3aj-
3an). Furthermore, aryl iodide with extended aromatic systems
also engaged in this reaction uneventfully (3ao-3ap). Of note,
heterocyclic iodide substrates including benzofuran, oxazole,
pyrazole, carbazole, thiophene and imidazo[1,2-a]pyridine all
participated in this reaction without any issue, which provides a
straightforward avenue for the rapid construction of heterobiaryl
architecture with potential bioactivities (3aq-3aw). To further
challenge the utility of this protocol in more complicate settings,
late-stage modifications of pharmaceutical relevant molecules
were subsequently carried out. Gratifyingly, geraniol, menthol,
estrone, gemfibrozil, ibuprofen and tocopherol-derived aryl
iodide could readily undergo pyridination and gave rise to the
desired products in exceptional reaction efficiencies (3ax-3aac).
The reaction generality with respect heterocyclic phosphonium
salt was further scrutinized using 4-iodoanisole as the standard
reaction partner. It was found that pyridylphosphonium salts
possessing substituent such as phenyl, F, Cl at C2-position were
highly reactive, delivering the desired products in 85-93% yields.
Pleasingly, substrates containing 3- or 2,3-disubstituents were
also amenable to this reaction, as showcased in the examples of
3ea and 3fa, despite that the reactions would encounter
somewhat steric hindrance in these cases. Disappointedly,
inconsistent results were observed when we tried to apply the
Entry
Ligand
Additive
Base
Yieldb [%][b]
1
2
3
4
5
6
7
8
9
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
Ruphos
SPhos
/
/
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
/
0
AgOAc
AgClO4
CuCl
66
80
34
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
83[c]
85[c]
95[c,d]
0[c]
0[c]
K2CO3
[a] Standard conditions: 1a (0.25 mmol), 2a (0.10 mmol), Additive (0.12 mmol),
K2CO3 (0.30 mmol), Pd(OAc)2 (0.005 mmol), SPhos (0.010 mmol) in THF (1.0
mL) at 65 °C for 12 h. [b] NMR yield determined with 1,1,2,2-tetrachloroethane
as the internal standard. [c] Acetone as solvent. [d] Isolated yield.
To probe the feasibility of our hypothesis, the evaluation of
cross-coupling between pyridylphosphonium salts 1a with 4-
iodoanisole 2a was explored (Table 1). To our delight, the
desired product 3aa was obtained in 66% NMR yield under the
reaction conditions of 5 mol% of Pd(OAc), 10 mol% of SPhos,
o
3.0 equiv. of Cs2CO3 and 1.2 equiv. of AgOAc in THF at 65 C
for 12 h, whereas no any amount of 3aa could be formed in the
absence of silver salt (Table 1, entries 1 and 2). Among various
silver salts tested, AgClO4 proved to be the optimal choice which
2
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Scheme 2. Substrate scope. Standard conditions: 1 (0.25 mmol), 2 (0.10 mmol), AgClO4 (0.12 mmol), K2CO3 (0.30 mmol), Pd(OAc)2 (0.005 mmol), RuPhos
(0.010 mmol) in acetone (1.0 mL) at 65 °C for 12 h. [a] Ph2PCy (0.020 mmol). [b] Ph2PCy (0.050 mmol).
3
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Pd(OAc)2/RuPhos catalytic system to the arylation of substrates
the product 3ba was generated in 78% yield, accompanied by
with more electronically inductive substituents on the C3-position. the formation of byproduct 6 in 45% yield, with incorporation of
To our delight, modification of reaction condition using Ph2PCy
as the ancillary ligand was found to greatly improve the reaction
efficiency, thus enabling the nice accommodation of substituents
including OMe, Ph, F, CO2Me and CN on the C3-position (3ga-
3ka). Furthermore, substrate derived from azaindole 1l was
significant amount of deuterium on the C4-position and minor
extent on the C6-position being observed (Scheme 4a). This
result shows that once the nucleophilic phosphonium-derived
species is generated, it undergoes cross-coupling reaction
kinetically more favored than protonation, thus implicating that
compatible, which furnished the desired product 3la in 68% yield. direct participation of discreet pyridyl anion intermediate should
It is worth pointing out that 2-pyridylphosphonium salt was also
viable substrate, although diminished reaction efficiency was
always observed (3ma, 3ra). Notably, phosphonium salts
derived from diazine, such as pyrimidine and pyrazine, could
also be successfully employed, albeit generating the desired
products in attenuated reaction efficiencies (3na-3pa). Structural
modification of complex molecules was also feasible, which in
no small part underlines the competency of the present method
in the assembly of molecular complexity for pharmaceutical
research (3qa-3ua). Further examination of pyridylphosphonium
salts revealed that substrates 1v-1z were not suitable for this
reaction probably due to the following reasons: e.g. substrate-
decomposition, catalyst-deactivation, unfavorable intramolecular
coupling because of conformational restrain. It is worth pointing
not be the predominant pathway. With regard to silver additive,
two possible roles could be anticipated. First, it may act as
halogen-scavenger, which allows the generation of cationic
palladium intermediate, thus prompting
the ensuing
transmetallation step. Alternatively, the silver additive may also
function as transmetallation mediator by promoting transfer of
pyridyl group through in situ formation of organosilver
intermediate. To discern the working mode of silver additive,
control experiments using alternative halogen-scavengers, such
as NaBF4, KPF6, NaOTf, NaBARF, were launched (Scheme 4b).
However, in no case, did formation of the desired product 3aa
be observed. These negative results associated with the fact
that copper salt also enables the product formation pointed to
the strong likelihood of silver-mediated transmetallation process.
out that as phosphonium salts were used in excess in Scheme 2, At this stage, we were, however, not able to detect the formation
the competing fragmentation-protonation and phosphorane
ligand coupling would account for the remaining mass balance
of these reactions.
of pyridylsilver intermediate, probably because of its relative
unstability. Therefore, we diverted out attention from
pyridylphosphonium salt to tetraaryl analogue. Pleasingly, when
cross-coupling between tetraarylphosphonium salt 7 and 2a was
attempted, the desired product 8 could be obtained in 59% yield
(Scheme 4c). In addition, control reaction carried out using
arylsilver complex 9 indicated the viability of transmetallation
from silver to palladium, which in turn lend concrete support to
the argument of silver-mediated pyridyl-transfer process
(Scheme 4d).[21]
To further probe the applicability of this coupling method, the
pyridination of other potential electrophiles were examined.
Excitingly, slight modification of the reaction conditions allowed a
smooth cross-coupling with allyl carbonate. Functional groups
such as alkyl, alkoxyl, ester and fluorine atom were all well
tolerated and afforded the terminal allylation products in good to
excellent yields (5ba-5bd). In addition, allyl carbonate with
substituent on the C2-position was also reactive, which delivered
the desired product 5be in 60% yield. Further continuing
investigations demonstrated that alkynylation and alkenylation
reactions could also be brought about using the standard
reaction conditions in arylation reaction, although moderate
yields were obtained (5af, 5ag).
Scheme 3. Pyridination of other competent electrophiles.
Scheme 4. Control experiments.
In order to probe the reaction mechanism especially the function
of silver additive in the catalytic process, a set of control
experiments were carried out. Initially, when the reaction of 1b
and 2a was carried out with the addition of 10 equivalent of D2O,
In conclusion, upon activation by external Brønsted base, the
electronic property of pyridylphosphonium salt is reversed, and
its successful engagement in palladium-catalyzed cross-
4
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We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (21871138), the Natural
Science Foundation of Jiangsu Province (BK20170984),
“Thousand Talents Plan” Youth Program, the “Jiangsu Specially-
Appointed Professor Plan” and the “Innovation
&
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Entry for the Table of Contents
By taking advantage of the synergistic interaction of palladium catalyst and silver additive, a strategically novel synthetic protocol,
which enables the expedient site-selective elaboration of pyridine derivatives, was developed. The successful use of
pyridylphosphonium salts as the donor of pyridyl anion equivalent greatly expanded the repertoire of competent nucleophilic coupling
partner that is amenable to palladium-catalyzed cross-couplings.
7
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