Stereodivergent Synthesis of Alkenylpyridines via Pd/Cu Catalyzed C-H Alkenylation of Pyridinium Salts with Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c02679

The first Pd/Cu catalyzed selective C2-alkenylation of pyridines with internal alkynes has been developed via the pyridinium salt activation strategy. Importantly, the configuration of the product alkenylpyridines could be tuned by the choice of the proper N-alkyl group of the pyridinium salts, thus allowing for both the Z- and E-alkenylpyridines synthesized with good regio- and stereoselectivity. A plausible mechanism was proposed based on the Hammett study and KIE experiment.

Full text of DOI:10.1021/acs.orglett.0c02679

pubs.acs.org/OrgLett
Letter
Stereodivergent Synthesis of Alkenylpyridines via Pd/Cu Catalyzed
C−H Alkenylation of Pyridinium Salts with Alkynes
Wenjing Li, Juan Tang, Shun Li, Xueli Zheng, Maolin Yuan, Bin Xu, Weidong Jiang, Haiyan Fu,*
Ruixiang Li, and Hua Chen*
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ABSTRACT: The first Pd/Cu catalyzed selective C2-alkenylation of
pyridines with internal alkynes has been developed via the pyridinium salt
activation strategy. Importantly, the configuration of the product
alkenylpyridines could be tuned by the choice of the proper N-alkyl
group of the pyridinium salts, thus allowing for both the Z- and E-
alkenylpyridines synthesized with good regio- and stereoselectivity. A
plausible mechanism was proposed based on the Hammett study and KIE experiment.
he alkenylated pyridines have emerged as the core
Scheme 1. Transition-Metal-Catalyzed C−H Alkenylation of
Pyridine
T
substructure found in numerous medicinally relevant
1
molecules and biologically active compounds. Figure 1
showcases their occurrence in marketed drugs such as
2
Acrivastine, Montelukast, and Axitinib. Accordingly, much
effort has been focused on the development of the methods for
3
4a
the synthesis of alkenylpyridine. In 2003, Murakami’s group
reported a Ru-catalyzed alkenylation of pyridine with (alkyn-1-
yl)silanes, which involved a ruthenium vinylidene species
(Scheme 1a). Later, the Pd-catalyzed oxidative alkenylation of
pyridine using olefins was successively developed by the
4
b
4c
4d
4e
Chang, Yu, Huang, and Poli groups (Scheme 1b).
Transition-metal-catalyzed Fujiwara hydroarylation between
pyridine and alkynes provides an alternative approach for the
alkenylation of pyridine, which would be the most appealing
one from the viewpoint of step and atom economy. However,
the Fujiwara hydroarylation is usually limited to electron-rich
arenes, and C2-selective alkenylation of π-electron-deficient
pyridine with alkynes proved to be a challenging task; only two
5
examples have been reported to date.
In 2007, Nakao and Hiyama developed a Ni(cod) (cod =
2
1
,5-cyclooctadiene) catalyzed C2-alkenylation of pyridine by
internal alkynes using pyridine-N-oxides as a pyridine
surrogate; however, the resulting alkenylated pyridine-N-oxides
were required to be deoxygenated with PCl to provide free 2-
3
Received: August 12, 2020
Figure 1. Representative examples of bioactive compounds containing
2
-alkenylpyridine motif.
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02679
A
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a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Z-selective Alkenylation of Pyridinium Salts
b
entry
1
deviation from standard conditions
No change
No Pd catalyst
No Cu(I) additive
No phosphine Ligand
yield (Z/E)
88 (3:1)
N.R.
N.R.
c
2
c
3
c
4
5
N.R.
c
CuCl/CuI/Cu O/CuCN instead of CuBr
<36 (4:1)
<36 (4:1)
48 (4:1)
58 (4:1)
Trace
2
c
6
TFP/TPP/(Cy) P instead of (Cy) P·HBF
3
3
4
7
8
9
In absence of Et N
3
In absence of H O
2
d
DMAc
Fluorobenzene
d
1
0
33 (4:1)
a
Standard conditions: 1A (0.3 mmol), 2a (0.6 mmol), Pd(OAc) (10
2
mol %), CuBr (50 mol %), (Cy) P·HBF (30 mol %), PivOK (0.3
3
4
mmol), Et N (30 mol %), H O (50 uL), Fluorobenzene (0.25 mL),
3
2
b
c
and DMAc (0.1 mL), 120 °C, 20 h. Isolated yields (Z/E). DMAc
0.2 mL) and Toluene (0.5 mL). N.R. = no reaction observed.
PivOK (0.3 mmol).
(
d
6
a
alkenylpyridines. Later, they further developed a Ni(cod)2/
Lewis acid (LA) catalytic system, by which the direct C2-
alkenylation of pyridine with internal alkynes could be
6b
accomplished (Scheme 1c). Both methods rely on using
7
air- and moisture-sensitive Ni(cod) , which is operationally
2
inconvenient. Another distinctive feature of two systems was
that they both afforded the 2-alkenylpyridines in E-selective
fashion. To the best of our knowledge, no examples of the
successful Z-selective alkenylation of pyridine were reported.
Mechanistically, in the Nakao and Hiyama systems, both the
alkynes coordination and the pyridine C−H activation
occurred at the same Ni(0) center. Accordingly, the alkynes
prefer to insert to the resultant Ni−H bond in cis fashion,
hence leading to E-selective alkenylated pyridines. In recent
years, our group developed a Pd/Cu bimetallic system for
pyridine C−H arylation based on the pyridinium salt activation
8
strategy, which has two main advantages: (1) the ortho C−H
could be readily cleaved by Cu(I) to form 2-pyridiniumyl-
9
Cu(I) species due to the increased acidity; (2) the N-alkyl
group could be in situ removable via a N-dealkylation
1
0
process, thus obviating the requirement of an additional
synthetic step to remove it. The N-dealkylation could occur
immediately after the formation of 2-pyridiniumyl-Cu(I)
species or after the completion of the C−H functionalization.
We assume that in the coupling reaction of the pyridinium salt
with the alkynes using Pd/Cu system, if the in situ formed 2-
pyridiniumyl-Cu(I) species directly reacts with the alkynes, Z-
enriched alkenylpyridines would be formed due to the trans
5
attack by a pyridiniumyl anion on the Pd-bound alkynes;
whereas if the N-dealkylation occurred prior to the reaction of
pyridiniumyl-Cu(I) species with the alkynes, the free pyridine
nitrogen would coordinate to the Pd center, which would
enforce the pyridinyl-Cu to attack the triple bond of the
alkynes in a cis manner, leading to an E-configuration enriched
product. Since the reactivity of the N-dealkylation is influenced
by the type of the N-alkyl group on the pyridinium salt, the
product configuration would be tunable by the choice of
a
Reactions were conducted with 1a-1V (0.3 mmol) and 2a−2l (0.6
mmol), and all yields given are isolated.
proper N-alkyl group. Herein, we report the first example of
regio- and stereoselective pyridines alkenylation with internal
alkynes in a stereodivergent manner based on the pyridinium
salt activation strategy under Pd/Cu catalysis. Both the Z- and
B
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a
Scheme 3. E-Selective Alkenylation of Pyridinium Salts
Scheme 5. Hammett Analysis for the Reaction of Alkynes
We initiated our study with the reaction between N-methyl-
2
-phenylpyridinium iodide and diphenylacetylene. The optimal
conditions were established and gave a mixture of Z-1 (CCDC
984439) and E-1 (CCDC 1984437) in 88% combined yields
a
Reactions were conducted with 1W−1Y (0.3 mmol) and 2a−2j (0.6
1
mmol), and all yields given are isolated.
with a Z/E ratio of 3:1 (Table 1, entry 1), accompanied by a
trace amount of 2-phenylpyridine, which was produced from
the N-demethylation of pyridinium salts. No reaction was
observed in the absence of the Pd catalyst, Cu(I) salt, or
phosphine ligand (entries 2−4). Other Cu(I) sources gave
product in less than 36% yield, much lower than CuBr (entry
5
). Tricyclohexylphosphinium salt was the best ligand for this
reaction. Other investigated phosphine ligands afforded
product in less than 36% yield (entry 6). Et N and H O are
3
2
also important, as in the absence of either of them led to a
decrease in yield (entries 7 and 8). The fluorobenzene or
DMAc as the single solvent afforded lower yields than in the
case of mixed solvents of them (entries 9 and 10).
With the optimal reaction conditions in hand, we first
examined the scope of N-methylpyridinium salts (Scheme 2).
It was found that 2-(2-methylpentan-3-yl) pyridinium salt was
formed in an excellent yield of 90% with good stereoselectivity
(
2, Z/E > 9:1). The pyridinium salt bearing α-branched alkyl
Figure 2. Plot of N-dealkylation yields over time: (■) 2-phenyl-
pyridine; (red ●) 2-(p-tolyl)pyridine.
groups afforded much higher yields than those with straight
alkyl groups such as methyl, ethyl, butyl, and pentyl (2−8
versus 11−15). Note that the 2-cyclopropyl group and the
ester group on the alkyl chain were also tolerated and
generated the alkenylation products in moderate yields with Z-
selectivity (9−10). Furthermore, a good Z/E ratio of 7:1 was
obtained for 2-phenylpyridinium salts when it reacted with the
bulkier 3,5-dimethyl diphenylacetylene. By this approach,
various 2-aryl substituted pyridinium salts reacted smoothly
to give the alkenylated products 16−23 in 57−93% yields, with
the Z/E ratio ranging from 3:1 to 7:1. It should be noted that
electron-rich substituents on the 3-, 4-, or 5-position of the
pyridine ring were well tolerated (24−33). Even the more
sterically hindered 5-substituted pyridinium salts could also
give desired product 32 in 73% yield. However, the electron-
withdrawing groups on the pyridine ring were not compatible
and led to a complex mixture. A 2-heteroaryl group such as
furanyl, thiophenyl, or pyridinyl substituted pyridinium salts
also reacted well, providing products 34−36 in 24−65% yields
with moderate Z-selectivity. It is worth noting that pyrazole
can also be smoothly alkenylated via its corresponding
pyridinium iodide salt.
Scheme 4. Scale-up Reaction and Useful Transformation
E-selective C2-alkenylation of pyridine could be achievable just
by tuning the N-alkyl groups of the pyridinium salts (Scheme
Subsequently, we investigated the scope of alkynes. Both the
t
1
d).
electron-donating groups ( Bu, Me, OMe) and electron-
C
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Scheme 6. Proposed Mechanism
withdrawing groups (F, Cl, Br, CF ) of symmetrical aromatic
alkynes were well tolerated (38−44). However, the ortho
chlorinated diphenylacetylene only afforded the product in
disubstituted piperidine 51 in 48% yield via B(C F ) catalyzed
reduction.
A Hammett analysis was constructed via a series of para-
3
6 5 3
13
5
6% yield, with a 0.9:1 Z/E ratio, much lower than that for its
substituted aryl alkynes p-XC H CHCHC H X-p (X =
6
4
6
4
para counterpart, probably due to the steric hindrance (45
versus 42). Gratifyingly, the unsymmetrical 1-phenylpropyne
gave the corresponding products in which a small substituent
group is positioned on the carbon atom adjacent to a pyridine
ring of the substrate. It was worth noting that heteroaryl
alkyne 1-(p-tolylethynyl)-1H-indole could also be tolerated
and gave drug-like compound 48 in 20% yield, but the aliphatic
OMe, Me, H, Cl, CF ) under the standard conditions. A
3
+
plot of k /k vs σ shows a ρ value of −0.64. Evidently, the
X
H
electron-rich alkynes reacted much faster, indicating a buildup
of at least a partial positive charge on the alkynes in the
transition state of the product-determining step (Scheme 5).
11
14
The positive charge on the alkynes most likely emerged upon
its coordination to Pd, which would be beneficial for the
nucleophilic attack of the cuprated pyridiniumyl or pyridinyl
species to the coordinated alkynes. In addition, the kinetic
isotopic effect (KIE) of 1.48 determined from two parallel
reactions between 1A and d-1A with 1,2-di-p-tolylethyne
revealed that the C−H bond cleavage may not be the rate-
limiting step of this transformation (see Supporting Informa-
tion).
12
alkynes failed to react.
To our delight, the configuration of the product could be
switched from Z to E when the N-methyl group of the
pyridinium salts was replaced by an N-benzyl group (Scheme
3
). For example, the reaction of N-benzyl 2-phenylpyridinium
and N-benzyl 2-methylpyridinium iodide salts under the
standard condition afforded 58% and 20% yields of
alkenylation product 1 and 14 with an E/Z ratio of 3:1 and
On the basis of our mechanistic studies and previous
4
:1, respectively. Again, the E/Z ratios could be improved by
5,15
reports,
a plausible mechanism is proposed (Scheme 6).
using α-branched alkylpyridinium salts as the substrate. For
instance, the N-benzyl-2-(2-methylpentan-3-yl) pyridinium salt
reacted smoothly with various aryl alkynes, electron-neutral,
II
First, the PCy modified [Pd] complex A was generated in situ
3
from Pd(OAc)2 and PCy . Then, a well-known π-philic
3
activation of the triple bond of alkynes with A gave the
-rich, or -deficient, to deliver the corresponding products 2,
1
2a,16
intermediate B.
The acidic ortho C−H bond of the N-
3
8−44, and 46 in 41−60% yields with the E/Z ratio ranging
methylpyridinium salts was easily cleaved by CuBr through a
concerted metalation deprotonation (CMD) process assisted
by PivOK, affording a 2-pyridiniumyl Cu(I) complex. In the
case of N-methylpyridinium salts, the Cu(I) complex C
preferred to directly undergo a nucleophilic attack to the
coordinated alkynes in B in a trans manner. Protiodepallada-
from 5:1 to 8:1. It should be noted that the product yields
from the N-benzylpyridinium salts were significantly lower
than that obtained from N-methylpyridinium salts. The reason
may be ascribed to the more obvious steric hindrance of the
benzyl group, as well as its stronger debenzylation tendency.
Indeed, when equimolar amounts of N-benzyl and N-
methylpyridinium salts were heated under standard conditions
in the absence of alkynes, the rate of debenzylation was
invariably faster than that of demethylation (Figure 2).
8b
II
tion of the resulting Pd -alkenyl intermediate D led to the
formation of Z-alkenylpyridinium salts E and regenerated
II
[
Pd] complex A. Then compound E underwent demethyla-
tion to furnish the Z-alkenylpyridines as the major products. In
case of the N-benzylpyridinium salts, Cu(I) complex F tended
to first undergo debenzylation. The resultant 2-pyridyl-Cu(I)
species G then coordinated to the Pd center of intermediate B
via the lone pair of the pyridine nitrogen to form intermediate
H, wherein the 2-pyridinyl anion nucleophilically attacked the
coordinated CC bond in a cis manner to deliver the
intermediate I, which then underwent protiodepalladation to
afford the E-alkenylpyridines as the major product.
To demonstrate the applicability of this method, a gram-
scale reaction of 1A/1a and 2a was performed at 12−13 times
scale-up, and the reaction still proceeded smoothly to afford
the product 1 and 2 in 72% and 76% yields, respectively, with
the stereoselectivity being maintained (Scheme 4a). The
alkenylation products can readily undergo further trans-
formation. As shown in Scheme 4b, the C−C double bond
of Z-1 could be selectively hydrogenated to afford 50 in
excellent yield, which could be further transformed into 2,6-
D
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In conclusion, the first Pd/Cu-catalyzed C2-alkenylation of
pyridines with alkynes based on the pyridinium salt activation
strategy has been developed. With this protocol both the Z-
and E-alkenylpyridines could be synthesized in good regio- and
stereoselectivity from the corresponding pyridinium salts, just
by tuning the N-alkyl group. Probably by virtue of the different
dealkylation ability of N-alkylpyridinium salts, the N-
methylpyridinium salts delivered the Z-enriched alkenylpyr-
idines, whereas the N-benzylpyridinium salts gave the E-
enriched alkenylpyridines. The reaction features wide substrate
scope, good functional group compatibilities, and facile
scalability. Further investigations on the details of the
mechanism are ongoing in our laboratory.
Sichuan, Zigong 643000, P. R. China; orcid.org/0000-
0003-1775-6456
Ruixiang Li − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02679
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
Nos. 21871187 and 21572137), the Opening Project of Key
ASSOCIATED CONTENT
sı Supporting Information
■
(
*
Laboratory of Green Chemistry of Sichuan Institutes of Higher
Education (LZJ1901), and the Key Program of Sichuan
Science and Technology Project (2019YFG0146) for their
financial support. We also thank Chunchun Zhang from the
Centre of Testing & Analysis, Sichuan University, for NMR
measurements and the Comprehensive Training Platform of
Specialized Laboratory, College of Chemistry, Sichuan
University.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02679.
Experimental details and full spectroscopic data for all
new compounds (PDF)
Accession Codes
CCDC 1984437 and 1984439 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Haiyan Fu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China; orcid.org/0000-0002-7185-
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Hua Chen − Key Laboratory of Green Chemistry & Technology,
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