Palladium(II)-Catalyzed Substituted Pyridine Synthesis from ?±,?-Unsaturated Oxime Ethers via a C-H Alkenylation/Aza-6?-Electrocyclization Approach

Article abstract of DOI:10.1021/acs.orglett.1c00061

An efficient synthetic method for multisubstituted pyridines from β-aryl-substituted α,β-unsaturated oxime ethers and alkenes via Pd-catalyzed C-H activation has been developed. Systematic optimization of catalyst ligands revealed that sterically hindered

Full text of DOI:10.1021/acs.orglett.1c00061

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Letter
Palladium(II)-Catalyzed Substituted Pyridine Synthesis from α,β-
Unsaturated Oxime Ethers via a C−H Alkenylation/Aza-6π-
Electrocyclization Approach
Takahiro Yamada, Yoshimitsu Hashimoto, Kosaku Tanaka, III, Nobuyoshi Morita, and Osamu Tamura*
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ABSTRACT: An efficient synthetic method for multisubstituted
pyridines from β-aryl-substituted α,β-unsaturated oxime ethers and
alkenes via Pd-catalyzed C−H activation has been developed.
Systematic optimization of catalyst ligands revealed that sterically
hindered pyridines increased the reactivity. Mechanistic studies
suggested that the products are formed by Pd-catalyzed β-alkenylation
of α,β-unsaturated oxime followed by aza-6π-electrocyclization.
Various oximes and alkenes could be utilized to afford multisubstituted
pyridines with complete regioselectivity. The usefulness of this
methodology was showcased by the synthesis of 4-aryl-substituted pyridine derivatives, which are difficult to access with previously
reported Rh-catalyzed approaches with alkenes.
Scheme 1. Transition-Metal-Catalyzed Substituted Pyridine
Synthesis from α,β-Unsaturated Oximes
ubstituted pyridine scaffolds are widely encountered in
1
Smedicinal chemistry, and several approaches are available
to obtain pyridines with different substitution patterns.2 The
Rh-catalyzed approaches are particularly useful3 and can
provide access to multisubstituted pyridines from α,β-
unsaturated oximes and symmetrical internal alkynes (Scheme
1a).3a−d However, the reactions with terminal and unsym-
metrical internal alkynes suffer from low regioselectivity.
Rovis’s group reported that Rh(III)-catalyzed coupling of
α,β-unsaturated oximes with activated alkenes is a useful
approach to synthesize substituted pyridines with good
regioselectivity (Scheme 1b).3e Interestingly, this reaction
involves a 7-membered rhodacycle intermediate, which
undergoes C−N bond formation/N−O bond cleavage to
furnish the pyridine product. Unfortunately, high yields are
obtained only with β-unsubstituted α,β-unsaturated oximes.3e,f
Therefore, there remains a need for a versatile and efficient
approach to synthesize multisubstituted pyridines from readily
accessible β-aryl-substituted α,β-unsaturated oximes with high
regioselective control.
We have already reported the Pd-catalyzed β-selective C−H
arylation of α,β-unsaturated oxime ethers with arylboronic
acids, featuring the use of cationic Pd(II) catalyst.4 We
envisioned that the use of alkenes in place of arylboronic acids
might provide 1-azatrienes, which would undergo aza-6π-
electrocyclization and subsequent aromatization via the release
of alcohol along with N−O bond cleavage to furnish the
desired pyridine products.5 Herein, we report the results of this
new approach for the synthesis of multisubstituted pyridines
via Pd-catalyzed C−H alkenylation of α,β-unsaturated oximes
followed by aza-6π-electrocyclization. A key feature of our
Received: January 10, 2021
Published: February 10, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00061
© 2021 American Chemical Society
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method is the use of a general Pd(OAc)2 catalyst to obtain 4-
substituted pyridine derivatives, which are difficult to
synthesize with Rh-catalyzed methodology. This work comple-
ments previously reported pyridine synthetic methods, since 4-
unsubstituted pyridines can already be easily prepared with
alkenes by using a commercially available Rh-catalyst (Scheme
1b vs 1c).
We first examined the reaction between symmetrical α,β-
unsaturated O-methyl oxime 1a (Me) and methyl acrylate (2a)
in the presence of Pd(OAc)2 as a catalyst.6 With AgTFA as an
oxidant and dioxane as a solvent, the desired pyridine 3aa was
obtained in 17% yield, and no β-alkenylation product was
observed.
Based on our experience in the development of Pd-catalyzed
β-selective C−H functionalization of α,β-unsaturated oximes,4
we expected that the identification of a suitable catalyst ligand
would be the key to establish the optimal protocol. We chose
to examine the effect of pyridine derivatives, since they are
known to be useful ligands for Pd-catalyzed C−H alkenylation
of oxime derivatives (Table 1).7 Although simple organic
reactivity. Tricyclic quinoline-derived ligand L8 and acridine
(L9), developed by Yu and co-workers,8 led to loss of
reactivity. Anticipating a positive effect of a bulkier ligand, we
prepared L10 in one step from 2,6-difluoropyridine and 1-
adamantanol. To our delight, the use of L10 significantly
improved the reactivity and afforded 3aa in 50% yield. The
yield could not be further improved despite extensive ligand
screening with substrate 1a (Me).
Having identified two suitable ligands L4 and L10, we
turned our attention to exploring the structure−reactivity
relationship of the oxime ether moiety. Although various
oximes 1a bearing O-acetyl, O-pivaloyl, O-silyl, and O-SEM4
groups were examined, the reaction did not proceed at all (see
the Supporting Information). Indeed, with the highly sterically
hindered O-tert-butyl oxime 1a (tBu), only the starting material
was recovered (Table 2, entry 2). However, O-isopropyl oxime
a
Table 2. Reaction Optimization
a
Table 1. Ligand Optimization
entry
R
1a
ligand
AgTFA (x equiv)
yield (%)
1
2
3
4
5
Me
tBu
iPr
iPr
iPr
1a (Me)
1a (tBu)
1a (iPr)
1a (iPr)
1a (iPr)
L4
L4
2.5
2.5
2.5
2.5
5.0
47
0
L4
69
76
85
L10
L10
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (3.0 equiv),
Pd(OAc)2 (10 mol %), ligand (30 mol %), AgTFA (x equiv), dioxane
(2.0 mL), 90 °C, 24 h. Isolated yield.
1a (iPr) improved the reactivity and the yield increased to 69%
(entry 3). To our delight, the use of the ligand L10 in place of
L4 further improved the yield from 69% to 76% (entry 4).
Finally, further screening of reaction conditions revealed that
5.0 equiv of AgTFA was optimal, affording 3aa in 85% yield
(entry 5).
With the optimal oxime moiety as well as reaction
conditions in hand, we surveyed the generality of this
multisubstituted pyridine synthesis by examining the reaction
of various α,β-unsaturated oximes with methyl acrylate (2a)
(Table 3). Symmetrical oximes bearing an electron-donating
group (1b and 1c), halogens (1d and 1e) and an electron-
withdrawing CF3 group (1f) at the para position of the phenyl
ring afforded the expected 2-allylpyridines (3ba−3fa) in good
yields (65−91%). Notably, unsymmetrical ketoximes were
available, affording the pyridines (3ga−3ka) in good yields
(64−80%). Oximes with heteroaromatics such as dibenzothio-
phene (1l) and carbazole (1m) were also acceptable and
furnished the desired pyridines 3la and 3ma in 48% and 55%
yields, respectively. This reaction also worked well with
cyclized oximes derived from benzylidene cyclopentanone
derivatives (1n−1p), giving the desired 2,3,4,6-tetrasubstituted
pyridines (3na−3pa) in good yields. Unfortunately, with the
exception of the cyclized oximes (1n−1p), neither α-
substituents nor β-alkyl substituents were generally tolerated
(see the Supporting Information).
a
Reaction conditions: 1a (Me) (0.2 mmol, 1.0 equiv), 2a (3.0 equiv),
Pd(OAc)2 (10 mol %), ligand (30 mol %), AgTFA (2.5 equiv),
dioxane (2.0 mL), 90 °C, 24 h. Isolated yield.
bases, pyridine (L1)7a,b and 2,6-lutidine (L2), inhibited the
reaction, 2,6-dimethoxypyridine (L3)7c slightly improved the
reactivity and afforded the desired pyridine in 29% yield.
Interestingly, more sterically hindered 2,6-di-tert-butylpyridine
(L4) significantly increased the reactivity and 3aa was obtained
in 47% yield. Next, we tested a series of 2-alkoxylquinoline
derivatives (L5−L8), which are more electron-rich than the
pyridine series ligands (L1−L4). The use of 2-methoxyquino-
line (L5) did not improve the reactivity, but the product yield
was increased when a quinoline ligand bearing a bulkier side
chain, tert-butoxy (L6) or 1-adamantyloxy (L7), was used.
This substituent effect suggests that steric hindrance around
the nitrogen atom of the quinoline ligand is crucial for high
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a
and the corresponding pyridines (3hb−3hd) were obtained in
good yields. Notably, acrylates bearing sterically bulky alkyl
groups, such as isopropyl (2e), cyclohexyl (2f), and 1-
adamantyl (2g) groups, worked well, affording the desired
products (3he−3hg) in excellent yields. Unexpectedly, the use
of phenyl acrylate (2h) as a partner olefin gave not pyridine
3hh but pyridine with an isopropyl ester 3he as the major
product. This product was probably produced by ester
exchange reaction between the corresponding pyridine 3hh
and in situ generated 2-propanol.
Table 3. Scope of α,β-Unsaturated Oxime Ethers
Other acrylate derivatives such as acrylamides were also
tolerated and provided the corresponding pyridines in
moderate yields (3hi and 3ji). To our surprise, cyclized
oximes 1o and 1p reacted efficiently with N,N-dimethyl
acrylamide (2i), giving the desired tetrasubstituted pyridines
3oi and 3pi in excellent yields. To demonstrate the generality
and utility of this multisubstituted pyridine synthesis, the
reactions of cyclized oximes 1o and 1p with other unsaturated
olefins were also tested. Various acrylamide derivatives such as
phenyl acrylamide (2j), n-butyl acrylamide (2k), and 4-
acryloylmorpholine (2l) were found to be suitable coupling
partners, giving the desired products (3oj−3ol) in 58%, 84%,
and 90% yields, respectively. Weinreb amide-derived acryl-
amide 2m was also tolerated, giving the corresponding pyridine
3om in moderate yield. Various styrene derivatives containing
electron-withdrawing groups such as nitro and ester were also
tolerated and afforded the expected pyridines (3on−3or) in
moderate to excellent yields. Notably, 4-trifluoromethylstyrene
(2q) and pentafluorostyrene (2r) reacted smoothly with
cyclized oximes, providing the corresponding pyridines 3oq,
3or, and 3pr in excellent yields. Further, this pyridine synthesis
is effective not only for monosubstituted olefins but also for
disubstituted olefins. Oxime 1o with dimethyl maleate (2s)
and N-methyl maleimide (2t) were successfully converted into
the corresponding pentasubstituted pyridines (3os and 3ot) in
36% and 52% yields, respectively.
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (3.0 equiv),
Pd(OAc)2 (10 mol %), L10 (30 mol %), AgTFA (5.0 equiv), dioxane
(2.0 mL), 90 °C, 24 h. Isolated yield.
Next, we examined the scope with respect to the partner
olefins (Table 4). Acrylates bearing ethyl (2b), benzyl (2c),
and methoxy ethyl (2d) substituents were found to react
smoothly, giving the expected 2-phenylethenylpyridines (3bb−
3bd) in 86%, 79%, and 93% yields, respectively. Unsym-
metrical ketoximes with various acrylates were also compatible,
a
Table 4. Scope of Various Alkenes
a
Reaction conditions: 1 (0.1−0.2 mmol, 1.0 equiv), alkene 2 (1.5 equiv), Pd(OAc)2 (10 mol %), L10 (30 mol %), AgTFA (5.0 equiv), dioxane
b
c
(2.0 mL), 90 °C, 24 h. Isolated yield. 3.0 equiv of alkene was used. 3he was obtained in 48% yield.
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To gain insight into the mechanism of this pyridine
formation, additional experiments were conducted (Table 5).
plausible mechanism for this reaction is depicted in Scheme 3.
After the generation of palladium trifluoroacetate in situ,
Table 5. Reaction of β-Unsubstituted α,β-Unsaturated
Oxime with Alkene
Scheme 3. Proposed Reaction Mechanism
a
entry
time (h)
3qb (%)
4qb (%)
1
2
4
36
0
28
36 (E/Z = 1.3/1)
11 (E-isomer only)
a
Conditions: see Table 3. Isolated yield.
When the reaction was performed with β-unsubstituted oxime
1q and ethyl acrylate (2b) under the same reaction conditions
for 4 h, 1-azatriene 4qb was obtained in 36% yield as a 1.3:1
mixture of E/Z isomers, but the expected pyridine was not
detected (Table 5, entry 1). However, when the reaction time
was extended to 36 h, the pyridine 3qb was obtained in 28%
yield along with 1-azatriene 4qb in 11% yield (Table 5, entry
2). It should be noted that only (E)-4qb was recovered,
suggesting that (Z)-4qb undergoes much faster electro-
cyclization than (E)-4qb. To confirm this, (Z)-4qb was stirred
in dioxane at 90 °C for 36 h. As expected, the corresponding
pyridine 3qb was obtained in 84% yield and a small amount of
E/Z mixture of 4qb was recovered (Scheme 2, eq 1). In
electrophilic C−H activation with α,β-unsaturated oxime 1
forms β-palladated intermediate A. Olefin coordination and
1,2-migratory insertion provides intermediate C, which
undergoes β-hydride elimination and reductive elimination to
form the 1-azatriene 4 with liberation of trifluoroacetic acid
and Pd(0) species. The formed Pd(0) is oxidized to Pd(II) by
Ag oxidant to complete the catalytic cycle. Then, aza-6π-
electrocyclization and subsequent aromatization proceed
rapidly to furnish the pyridine 3. The C4-substituent of 1-
azatriene intermediate 4 may contribute to the acceleration of
this aza-6π-electrocyclization step.
Scheme 2. Mechanistic Experiment
In conclusion, we have developed an efficient Pd-catalyzed
synthesis of 4-aryl-substituted pyridines from β-aryl-substituted
α,β-unsaturated oxime ethers. The catalyst ligand significantly
affected the reactivity, with the sterically hindered pyridine-
based ligand L10 being optimal. Various olefins could be
utilized to synthesize multisubstituted pyridines with complete
regioselectivity. Mechanistic studies indicate that the pyridine
formation proceeds via aza-6π-electrocyclization of β-alkeny-
lated α,β-unsaturated oximes. Considering the difficulties
inherent in the synthesis of 4-aryl-substituted pyridines with
previously developed Rh-catalyzed approaches with alkenes,
we believe this transformation will prove useful as a
complementary synthetic method.
contrast, similar treatment of (E)-4qb gave 3qb in only 18%
yield and most of the (E)-4qb was recovered (Scheme 2, eq 2).
These results clearly indicate that pyridines 3 were formed
from 1-azatriene intermediates via aza-6π-electrocyclization.
Considering that pyridine 3qb was also formed from the E-
isomer of 4qb to some extent, E/Z isomerization of 1-azatriene
appears to proceed to some extent under these reaction
conditions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00061.
Experimental procedures, characterization data for all
new compounds, additional experiments, and spectral
data (PDF)
Based on these observations and the results of our previous
investigation of Pd-catalyzed electrophilic C−H activation,4,9
a
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Letter
(c) Liu, S.; Liebeskind, L. S. A simple, modular synthesis of
substituted pyridines. J. Am. Chem. Soc. 2008, 130, 6918−6919.
(d) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. Significant
acceleration of 6π-azaelectrocyclization resulting from a remarkable
substituent effect and formal synthesis of the ocular age pigment A2-E
by a new method for substituted pyridine synthesis. J. Org. Chem.
2001, 66, 3099−3110.
AUTHOR INFORMATION
Corresponding Author
■
Osamu Tamura − Showa Pharmaceutical University, Tokyo
194-8543, Japan; Email: tamura@ac.shoyaku.ac.jp
Authors
(6) Based on our experience in the development of oxime chemistry,
E/Z isomerization of oxime ethers of β-substituted α,β-unsaturated
oximes should proceed easily, but E/Z isomerism might interfere with
the reaction optimization. Therefore, we chose a symmetrical oxime
1a as a pilot substrate.
(7) (a) Fu, X.; Yang, J.; Deng, K.; Shao, L.; Xia, C.; Ji, Y. Tandem
C−C/C−N formation via palladium-catalyzed C−H activation/
styrenation and sequential annulation of O-methylketoximes with
styrenes. Org. Lett. 2019, 21, 3505−3509. (b) Fu, X.-P.; Tang, S.-B.;
Yang, J.-Y.; Zhang, L.-L.; Xia, C.-C.; Ji, Y.-F. Cascade reaction for the
synthesis of carbolines from O-methylketoximes and styrenes via
palladium-catalyzed C−H activation and sequential annulation. Eur. J.
Org. Chem. 2019, 2019, 5974−5977. (c) Sun, C.-L.; Liu, N.; Li, B.-J.;
Yu, D.-G.; Wang, Y.; Shi, Z.-J. Pd-catalyzed C−H functionalization of
O-methyl oximes with arylboronic acids. Org. Lett. 2010, 12, 184−
187.
Takahiro Yamada − Showa Pharmaceutical University, Tokyo
194-8543, Japan
Yoshimitsu Hashimoto − Showa Pharmaceutical University,
Tokyo 194-8543, Japan; orcid.org/0000-0002-2868-
901X
Kosaku Tanaka, III − Showa Pharmaceutical University,
Tokyo 194-8543, Japan
Nobuyoshi Morita − Showa Pharmaceutical University,
Tokyo 194-8543, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00061
Notes
The authors declare no competing financial interest.
(8) (a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J.
E.; Homs, A.; Yu, J.-Q. Ligand-controlled C(sp3)−H arylation and
olefination in synthesis of unnatural chiral α-amino acids. Science
2014, 343, 1216−1220. (b) Li, S.; Zhu, R.-Y.; Xiao, K.-J.; Yu, J.-Q.
Ligand-enabled arylation of γ-C−H bonds. Angew. Chem., Int. Ed.
2016, 55, 4317−4321. (c) Zhu, R.-Y.; He, J.; Wang, X.-C.; Yu, J.-Q.
Ligand-promoted alkylation of C(sp3)−H and C(sp2)−H bonds. J.
Am. Chem. Soc. 2014, 136, 13194−13197.
(9) For selected examples of Pd-catalyzed electrophilic C−H
activation, see: (a) Fujiwara, Y.; Takaki, K.; Taniguchi, Y. Exploitation
of synthetic reactions via C−H bond activation by transition metal
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Synlett 1996, 591−599. (b) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.;
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(c) Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Pd-catalyzed selective
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