Palladium-Catalyzed Cascade Reactions of I-Ketonitriles with Arylboronic Acids: Synthesis of Pyridines

Article abstract of DOI:10.1021/acscombsci.9b00198

This study presents the first example of the Pd-catalyzed cascade reactions of 5-oxohexanenitrile with arylboronic acids, affording important synthon 2-methylpyridines that can be further translated through C(sp³)-H functionalization to construct pyridine derivatives. Furthermore, this chemistry allows 5-oxo-5-Arylpentanenitrile to react with arylboronic acids to provide unsymmetrical 2,6-diarylpyridines. This protocol paves the way for the practical and atom economical syntheses of valuable pyridines with broad functional groups in moderate to excellent yields under mild conditions.

Full text of DOI:10.1021/acscombsci.9b00198

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Letter
Palladium-Catalyzed Cascade Reactions of δ‑Ketonitriles with
Arylboronic Acids: Synthesis of Pyridines
Xinrong Yao, Linjun Qi, Renhao Li,* Qianqian Zhen, Jichao Liu, Zhiwei Zhao, Yinlin Shao, Maolin Hu,*
and Jiuxi Chen*
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ABSTRACT: This study presents the first example of the Pd-
catalyzed cascade reactions of 5-oxohexanenitrile with arylboronic
acids, affording important synthon 2-methylpyridines that can be
further translated through C(sp3)-H functionalization to construct
pyridine derivatives. Furthermore, this chemistry allows 5-oxo-5-
arylpentanenitrile to react with arylboronic acids to provide
unsymmetrical 2,6-diarylpyridines. This protocol paves the way
for the practical and atom economical syntheses of valuable
pyridines with broad functional groups in moderate to excellent yields under mild conditions.
KEYWORDS: carbopalladation, cascade coupling, ketonitrile, arylboronic acids, pyridine
he nitrile is a relatively stable functional group that is
Tusually used as a ligand or in a solvent in organometallic
reactions. However, nitriles can be flexibly transformed by
transition metal catalysis in organic syntheses.1−3 The nitrile
group can react in addition reactions with organoboron
reagents or other analogues4 to synthesize ketones and
derivatives. On the basis of this strategy, several groups have
disclosed the Pd-catalyzed C−C coupling to nitriles as the
initial step to afford five-membered heterocycles (Figure 1).
For example, the Shao group reported the carbopalladation of
arylboronic acids to nitriles, followed by intramolecular
cyclization to construct imidazoles.5 The Adhikari group
reported Pd(II)-catalyzed coupling substituted aliphatic nitriles
with arylboronic acids to synthesize 3-substituted 2-aryl-1H-
pyrroles.6 The Liao group described Pd-catalyzed addition of
arylboronic acids to carbonic ester substituted nitriles to
synthesize spirooxindolyl oxazol-2(5H)-ones.7 Our group
developed a one-step syntheses of 2-arylbenzo[b]furans and
2-aryl-1H-indoles via sequential addition and intramolecular
annulation reactions with hydroxy- or amino-substituted 2-
phenylacetonitriles.8,9
Our group’s study of novel Pd-catalyzed nitrile coordination
and subsequent cascade-coupling reactions with easily available
nitriles for the preparation of a wide variety of six-10,11 and
seven-12membered heterocycles, such as quinazolines, iso-
quinolines, and isoquinolones, has been reported. Despite the
notable advancement obtained to the synthesis of six-
membered heterocycles, the need for benzonitrile or 2-
phenylacetonitrile as substrates to construct fused six-member
ring compounds is a severe restriction. However, the synthesis
of six-membered heterocycles, such as pyridine, by carbopalla-
dation of alkyl nitrile is not known.
The 2,6-disubstituted pyridine constitutes privileged scaf-
folds of compounds with activities of relevance in a wide range
of natural products, pharmaceuticals, and functional materi-
als.13 The heteroarenes introduction into alkyl groups,
especially methyl groups, influences their drug metabolism
and pharmacokinetic profiles.14 On the other hand, the
interconversion of 2-methylpyridines with enamine tautomers
is a particular concern and plays an important role in the
C(sp3)-H functionalization of 2-methylpyridine to construct
pyridine derivates.15−18 In this context, potential bioactive
compounds, 2-methyl-6-arylpyridines, could serve as key units
in the syntheses of various pyridine derivates. 2-Methyl-6-
arylpyridines were prepared from various strategies,19−24
including methylation of 2-arylpyridine,19 coupling 2-halo-
gen-6-arylpyridine with organoborons or other surrogates,20
dehydrogenative condensation of amino alcohols,21 or intra-
molecular cyclizations with imine derivates.22 However, the
synthesis of 2-methyl-6-arylpyridines via cascade carbopallada-
tion/cyclization of alkylnitriles has not been reported. Inspired
by our recent findings, we present the Pd-catalyzed cascade
carbopalladation/cyclization/aromatization of arylboronic
acids with 5-oxohexanenitrile (commercial product, CAS
10412-98-3), leading to 2-methyl-6-arylpyridines. As an
extension, this strategy was also applied for 2,6-diarylpyridine
synthesis.
Received: November 24, 2019
Revised: February 8, 2020
Published: February 12, 2020
https://dx.doi.org/10.1021/acscombsci.9b00198
© XXXX American Chemical Society
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A

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Letter
Figure 1. Carbopalladation cascade cyclization with nitriles.
We commenced our studies with 5-oxohexanenitrile 1a and
phenylboronic acid 2a as the model substrates using a
combination of Pd(OAc)2, 2,2′-bipyridine (L1), and
CF3COOH in MeOH (Table 1, entry 1). In a preliminary
experiment, the desired product 2-methyl-6-phenylpyridine
(3a) was observed in 67% yield, determined from NMR data.
Encouraged by this result, we then surveyed various Pd-salts as
catalysts (entries 2−6), and the best outcome in terms of
efficiency was obtained in case of Pd2(dba)3. The reaction
conditions were evaluated with respect to various ligands to
improve the yield. However, the examination of L2−L9 (Table
1, entries 7−14) failed to show any improvement in the yield
of 3a. Next, solvent screening was undertaken (entries 15−26)
and demonstrated that other solvents were less effective.
Compared with MeOH, other alcohols, such as ethanol,
propanol, butanol, and pentanol, exhibited obviously different
performances by having low reaction activity, if any at all.
Finally, attempts to enhance the efficiency of product
formation further by elevated reaction temperature and shorter
reaction time were successful to obtain 3a in 90% yield (Table
1, entries 27−28). Hence, the optimum conditions involved
conducting the reaction in MeOH with Pd2(dba)3 as catalyst,
2,2′-bipyridine (L1) as ligand, CF3COOH as additive and a
temperature of 90 °C in air.
The catalyst was compatible with phenylboronic acids bearing
various functional groups, including tertiary butyl (3e), phenyl
(3f), methoxyl (3g-h), phenoxy (3i), and trifluoromethoxy
(3j). The selective synthesis of halide-substituted N-hetero-
cycles has received increasing attention because they could be
amenable to diverse functionalization. Fluoro-, chloro-, and
bromo-substituted products as useful handles for further cross-
coupling reactions, were obtained successfully in acceptable
yields (3k−n). Fused rings, such as 2-naphthyl and 1-naphthyl,
were also transformed smoothly (3o−p).
Unsymmetrical pyridines represent an important and
abundant class of heterocyclic receiving significant attention
as basic constituents of many biologically active pharmaceut-
icals, natural products, and functional materials. Thus,
developing versatile and flexible methodologies to construct
unsymmetrical pyridines using modularized building blocks are
still needed. Excitingly, unsymmetrical 2,6-diarylpyridines are
also obtained by carbopalladation cascade cyclization of 5-oxo-
5-arylpentanenitrile with organoboronic reagents.
Next, the substrate scope of the cyclization was subsequently
explored by employing various arylboronic acids with 5-oxo-5-
phenyl-pentanenitrile (Scheme 1). First, the compatibility of
different alkyl or aryl substituted arylboronic acids in the
present transformation was examined. To our delight, a wide
range of alkyl and aryl groups, including methyl, tertiary butyl,
isopropyl, naphthyl, and phenyl, were well compatible in this
transformation, giving access to the unsymmetrical pyridines in
good to excellent yields (4b−j). It should be mentioned that
the halogenated arylboronic acids were also suitable for the
transformation, the products (4k−n) were obtained in good
With the established procedure, the scope of arylboronic
acids in this tandem reaction was investigated (Scheme 1). The
methyl groups on the phenyl ring of boronic acid provided the
corresponding products 3b−d in good yields. The yield
reduced from 33 to 3c and 3b, which showed that the reaction
seemed sensitive to steric hindrance of the arylboronic acid.
B
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a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), cat. (5 mol %), ligand (10 mol %), CF3COOH (0.15 mL), solvent (2.0 mL), 80 °C, 24 h, air.
b
c
d
e
1
Determined by H NMR. NR = No reaction. At 90 °C. For 12 h.
yields. Substrates with various electron-donating groups
(−OMe, −OPh) and electron-drawing groups (−CHO,
−NO2, −CF3) were also tolerated in this reaction, as
demonstrated with 4o−t.
We performed the cyclization of other δ-ketonitriles to
display the synthetic utility of the transformation (Scheme 2).
The δ-ketonitriles bearing a variety of functional groups,
including electron-drawing groups or electron-donating groups
were well tolerated and the desired products were obtained in
moderate to good yields (4b−e, 4k−n, 4t). The 5-oxo-5-(p-
tolyl)-pentanenitrile, as substrate, also produced unsym-
metrical pyridines smoothly (4u−y).
A plausible mechanism for the reaction is proposed in
Scheme 3. First, the Pd(II) catalyst underwent transmetalation
with arylboronic acid to provide arylpalladium(II) intermedi-
ate A. The ketonitriles coordination with palladium then gave
intermediate B. Next, the intermediate C was acquired,
following 1,2-addition of the coordinated aryl group to the
cyano group. Once the Paal−Knorr intermediate C was
generated, it spontaneously underwent in situ cyclization,
followed by dehydration/aromatization to give the desired
products of unsymmetrical 2,6-diarylpyridines.
cascade coupling of alkylketonitrile with arylboronic acids,
affording important synthon 2-methylpyridines that can further
be translated through C(sp3)-H functionalization to construct
pyridine derivatives. Furthermore, unsymmetrical 2,6-diary-
lpyridines were also obtained through the cascade carbopalla-
dation/cyclization of 5-oxo-5-arylpentanenitrile with organo-
boronic reagents. This protocol paves the way for the practical
and atom economical syntheses of valuable pyridines in
moderate to excellent yields with a broad range of substituents
under mild condition.
EXPERIMENTAL PROCEDURES
■
General Procedures for the Synthesis of 5-Oxo-5-
penylpentanenitrile. Penylboronic acid (0.4 mmol, 0.5
equiv), Pd(acac)2 (5 mmol %), bpy (10 mol %), TsOH·H2O
(2 equiv), toluene (2.5 mL), H2O (0.5 mL), and glutaronitrile
(38 μL, 0.8 mmol, 1 equiv) were successively added to a 25
mL sealing tube. The reaction mixture was stirred vigorously at
80 °C for 24 h. After the reaction mixture was cooled to room
temperature, washed with saturated NaHCO3, and extracted
with ethyl acetate (3 × 10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and evaporated under a
vacuum. The residue was purified by flash column chromatog-
In summary, we have demonstrated the first example of
palladium complexes as effective catalyst for the C−C, N−C
C
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a
Scheme 1. Synthesis of 2-Methyl-6-arylpyridines and 2-Phenyl-6-arylpyridines
a
Reaction Conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd2(dba)3 (5 mol %), bpy (10 mol %), CF3COOH (0.15 mL), CH3OH (2.0 mL), 90 °C, 12
b
h, air. Isolated yield. For 24 h.
a
Scheme 2. Synthesis of Unsymmetrical Pyridines
a
Reaction Conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd2(dba)3 (5 mol %), bpy (10 mol %), CF3COOH (0.15 mL), CH3OH (2.0 mL), 90 °C, 12
b
h, air. Isolated yield. For 24 h.
D
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Letter
Jiuxi Chen − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China;
orcid.org/0000-0001-6666-9813; Email: jiuxichen@
wzu.edu.cn
Scheme 3. Proposed Mechanism
Authors
Xinrong Yao − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
Linjun Qi − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
Qianqian Zhen − College of Chemistry & Materials
Engineering, Wenzhou University, Wenzhou 325035, P. R.
China
Jichao Liu − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
Zhiwei Zhao − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
Yinlin Shao − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China;
orcid.org/0000-0003-1935-0345
raphy with petroleum ether/ethyl acetate (10:1) to afford 5-
oxo-5-penylpentanenitrile.
General Procedures for the Synthesis of 2-Methyl-6-
phenylpyridine. In air atmosphere, penylboronic acid (0.4
mmol, 2 equiv), Pd2(dba)3 (5 mmol %), bpy (10 mol %),
CH3OH (2 mL), 5-oxohexanenitrile (0.2 mmol, 1 equiv), and
CF3COOH (0.15 mL) were successively added to a 25 mL
sealing tube. The reaction mixture was stirred vigorously at 90
°C and observed by TLC point plate until the end of the
reaction. After the reaction mixture was cooled to room
temperature, washed with saturated NaHCO3, and extracted
with ethyl acetate (3 × 10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and evaporated under a
vacuum. The residue was purified by flash column chromatog-
raphy with petroleum ether/ethyl acetate (10:1) to afford 2-
methyl-6-phenylpyridine.
General Procedures for the Synthesis of 2,6-
Diphenylpyridine. In air atmosphere, penylboronic acid
(0.4 mmol, 2 equiv), Pd2(dba)3 (5 mmol %), bpy (10 mol %),
CH3OH (2 mL), 5−5-oxo-5-penylpentanenitrile (0.2 mmol, 1
equiv), and CF3COOH (0.15 mL) were successively added to
a 25 mL sealing tube. The reaction mixture was stirred
vigorously at 90 °C and observed by TLC point plate until the
end of the reaction. After the reaction mixture was cooled to
room temperature, washed with saturated NaHCO3, and
extracted with ethyl acetate (3 × 10 mL). The combined
organic layers were dried over anhydrous Na2SO4 and
evaporated under a vacuum. The residue was purified by
flash column chromatography with petroleum ether/ethyl
acetate (10:1) to afford 2,6-diphenylpyridine.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscombsci.9b00198
Author Contributions
X.Y. and L.Q. contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21572162) and the Natural Science Foundation of
Zhejiang Province (Nos. LY20B020015, LQ18B020006) for
financial support.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscombsci.9b00198.
■
sı
Details of experimental and analytical procedures, along
with spectroscopic data for synthesized compounds
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Renhao Li − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, P. R. China;
orcid.org/0000-0003-2451-2142; Email: lirh@
wmu.edu.cn
(8) Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding, J.; Wu, H.
Palladium-Catalyzed Addition of Potassium Aryltriflfluoroborates to
Aliphatic Nitriles: Synthesis of Alkyl Aryl Ketones, Diketone
Compounds, and 2-Arylbenzo[b]furans. J. Org. Chem. 2013, 78,
5273−5281.
Maolin Hu − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China;
Email: maolin@wzu.edu.cn
E
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