Palladium-Catalyzed Secondary C(sp3)?H Arylation of 2-Alkylpyridines

Article abstract of DOI:10.1002/adsc.202000306

A pyridyl group-assisted palladium-catalyzed secondary C(sp³)?H arylation protocol was developed. A substituent at the 3-position of the pyridyl group is proved to be important for promoting C?H arylation and controlling the regioselectivity. Aryl iodides can be used as coupling partners. The reaction proceeded in good to excellent yields with good functional group tolerance, even on the gram-scale. The preliminary asymmetric reaction was investigated using an L-proline derivative as a chiral ligand. (Figure presented.).

Full text of DOI:10.1002/adsc.202000306

Title: Palladium-catalyzed Secondary C(sp3)-H Arylation of 2-
Alkylpyridines
Authors: Hong-Liang Li and Yoichiro Kuninobu
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10.1002/adsc.202000306
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Palladium-catalyzed Secondary C(sp3)-H Arylation of 2-
Alkylpyridines
Hong-Liang Li,*,† Yoichiro Kuninobu*,‡,§
† Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Tianjin University,
92Weijin Road, Nankai District, Tianjin 300072, China, E-mail: lhl522508@126.com
‡
Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580,
Japan, E-mail: kuninobu@cm.kyushu-u.ac.jp
§
Department of Molecular and Material Sciences, Interdisciplinary Graduate School of Engineering Sciences, Kyushu
University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A pyridyl group-assisted palladium-catalyzed
secondary C(sp3)-H arylation protocol was developed.
A substituent at the 3-position of the pyridyl group is
proved to be important for promoting C-H arylation and
controlling the regioselectivity. Aryl iodides can be
used as coupling partners. The reaction proceeded in
good to excellent yields with good functional group
tolerance, even on the gram-scale. The preliminary
asymmetric reaction was investigated using an L-
proline derivative as a chiral ligand.
Keywords: C(sp3)-H Arylation; Secondary C-H
Activation; 2-Alkylpyridine; Aryl Iodide; Palladium
2-Phenethylpyridine moieties are very important
skeletons that are commonly found in pharmaceuticals,
agricultural chemicals, and natural products (Figure 1).[1]
Many pharmaceuticals containing the 2-phenethylpyridine
motif have been applied in many fields, such as clinical
treatments. However, traditional methods of synthesizing
this motif usually require complicated routes.[2]
Figure 2. Examples of C(sp3)-H transformations using
pyridine directing group.
Recently, the development of direct C-H transformations
has provided a unique solution for this problem. As is well
known,direct C(sp2)-H transformations have been rapidly
developed over the past few decades.[3] Direct C(sp3)-H
transformations catalyzed by a transition metal have also
been reported.[4] In 2004, Sanford achieved the first
example of palladium(II)-catalyzed C(sp3)-H acetoxylation
using an oxime or pyridine moiety as a directing group
(Figure 2a).[5] Subsequently, Daugulis and co-workers
reported the palladium(II)-catalyzed arylation of 2-
ethylpyridine (Figure 2b).[6] Maes and Mihovilovic
independently reported pyridyl group-assisted arylation of
Figure 1. Bioactive compounds containing
phenethylpyridine moiety.
a
2-
the C(sp3)-H bond adjacent to a heteroatom or in the
1
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10.1002/adsc.202000306
Advanced Synthesis & Catalysis
benzylic position (Figure 2c).[7,8] However, many reactions
proceed at the terminal and/or activated C(sp3)-H bond.
Pyridyl group-assisted secondary C(sp3)-H activation is
still rare. The poor reactivity of the secondary C(sp3)-H
compared to activated and terminal C(sp3)-H bonds is
attributed to the higher bond energy and steric hindrance of
the former.[9] In addition, pyridyl groups are strongly
chelating directing groups that generally form
thermodynamically stable cyclometalated intermediates
that are less reactive in the subsequent functionalization
steps.[10]
Herein, we report pyridyl group-assisted secondary
C(sp3)-H arylation process catalyzed by Pd(II). It was
envisioned that an acid additive could decrease the
coordination ability of the nitrogen atom of the pyridyl
group and therefore enhance the reactivity of the
cyclometalated intermediates in the arylation step.[11]
The reaction of 3-methyl-2-propylpyridine (1a) with 4-
methyliodobenzene (2a) in the presence of Pd(OAc)2 (5.0
mol%) and acetic acid (1.5 equiv) as an additive resulted in
25% yield of the arylated product 3a (Table 1, entry 1).
The yield of 3a increased slightly when trifluoroacetic acid
was used (Table 1, entry 2). Other acid additives, however,
did not give better results (Table 1, entries 3 and 4).
Several palladium(II) salts were further investigated (Table
1, entries 5-7), where the yield of 3a improved
dramatically with the use of Pd(OPiv)2 as a catalyst (Table
1, entry 6). Several solvents were also screened along with
position of the pyridine directing group is crucial for
promoting C-H arylation and controlling the
regioselectivity.[12] They speculated that the substituent at
the 3-position of the pyridine directing group could shorten
the distance between the nitrogen atom of the pyridyl
group and the -position of the alkyl chain. To our delight,
arylated product 3b was obtained in 82% yield in the
reaction of a substrate bearing a phenyl group at the 3-
position with 4-iodobiphenyl. Several aryl iodides having a
substituent at the para- or meta-positions were also
investigated. The corresponding arylated products 3c-3i
were produced in 58-69% yield without loss of the
functional groups (electron-donating or -withdrawing
groups).[13,14] Biaryl iodides showed higher reactivity than
monoaryl iodides and provided the corresponding arylated
products 3j-3w in 70-90% yield. The reaction also
proceeded smoothly using 3-methyl-2-butylpyridine and 3-
methyl-2-hexylpyridine to give arylated products 3x and
3y in 80% and 72% yields, respectively. The desired
products were afforded with good functional group
tolerance using substrates with an electron-donating or
electron-withdrawing group. However, the desired arylated
products were not obtained using 2-(sec-butyl)-3-
methylpyridine and 2-isopentyl-3-methylpyridine, and
ortho-substituted aryl iodides, probably due to the steric
hindrance.
Table 2. Substrate scope of 2-alkylpyridines and aryl
iodides[a]
neat
conditions
(Table
1,
entries
8-11).
Hexafluoroisopropanol (HFIP) was the best solvent (Table
1, entry 6). In order to further increase the yield of 3a, we
also screened the amount of catalyst and acid additive. The
reaction conditions in entry 6 gave the best result (see the
Supporting Information for details).
Table 1. Optimization of reaction conditions.[a]
[a]2a (1.5 equiv).[b]Yield was determined by 1H NMR using
1,1,2,2-tetrachloroethane as an internal standard.
With the optimized conditions in hand, we investigated
the substrate scope of pyridine derivatives 1 and aryl
iodides 2 (Table 2). 2-Propylpyridine, with no substituent
at the 3-position, did not give the desired arylation product.
Jun and Mihovilovic reported that a substituent at the 3-
2
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10.1002/adsc.202000306
Advanced Synthesis & Catalysis
Scheme 1. Gram-scale and asymmetric reactions.
We applied this reaction to the synthesis of histamine
antagonist.[16] Treatment of 1a with iodobenzene under the
standard reaction conditions gave 3c in 67% yield. Product
4 was obtained by oxidation using m-CPBA, then a
successive [3,3]-sigamatropic rearrangement produced the
histamine antaonist 5 in 88% yield. This method was not
only enhanced the yield of 5 dramatically, but also
provided an easy way to synthesize derivatives of 5 with
different aryl group at the -position.[17,18]
[a] 2 (1.5 equiv).[b] Pd(OPiv)2 (5.0 mol %), CF3COOH (1.5
equiv), HFIP, 120 oC, 30 h.
The secondary C(sp3)-H arylation reaction proceeded in
good yield, even on the gram-scale (Scheme 1a).
Treatment of 1.00 g of 3-methyl-2-propylpyridine (2a)
with biaryl iodide 2j in the presence of a Pd(OPiv)2 (5.0
mol%) catalyst, AgOAc (1.5 equiv), and CF3COOH (1.5
equiv) gave 1.46 g of arylated product 3j in 69% yield.
We also investigated asymmetric secondary C(sp3)-H
arylation (Scheme 1b).[15] After screening a series of chiral
ligands, the preliminary result was obtained using N-Boc-
2-methyl-L-proline as a chiral ligand. To the best of our
knowledge, this is the first example of pyridine-directed
enantioselective secondary C(sp3)-H arylation. Efforts to
improve the enantioselectivity are underway in our
laboratory.
Scheme 2. Application for synthesizing Histamin
Antagnist.
We investigated
a
kinetic isotope effect (KIE)
experiment to confirm whether C-H activation step is the
rate-determing step (scheme 3). When we performed a
reaction of 3-methyl-2-(propyl-2-d)-pyridine (6) with 4-
iodobiphenyl (2j), the arylated proudct 7 was obtained in
81% yield with 63% of deuterium. This result showed the
KIE valuse was 1.18, which indicated that the C-H
activation is not the rate-determing step.
3
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10.1002/adsc.202000306
Advanced Synthesis & Catalysis
3-Methyl-2-propylpyridine (1a, 0.250 mmol), substituted
iodobenzene (2, 0.375 mmol, 1.50 equiv), Pd(OPiv)2 (3.86
mg, 0.0125 mmol, 5.0 mol%), CF3COOH (42.8 mg, 0.375
mmol, 1.5 equiv), and HFIP (2.0 mL) were added into a 10
mL sealed tube. The mixture was stirred at 100 oC for 20 h.
Then, the solvent was removed under vacuum, and the
arylation products were separated by column
chromatography on silica gel (hexane/ethyl acetate = 10:1).
Scheme 3. KIE experiment
Acknowledgements
The proposed reaction mechanism is as follows (Figure
3):[11d,19-21] (1) A nitrogen atom of the pyridine moiety of 1
coordinates to the palladium catalyst to form intermediate
A and the palladium center approaches the -position of
the alkyl chain. In this step, the substituent at the 3-
position of the pyridine directing group is very important
for promoting the reaction and controllingthe
regioselectivity; (2) formation of intermediate B proceeds
This work was partially supported by the 64th China Postdoctoral
Science Foundation Grant Number 2018M641642 and JSPS
KAKENHI Grant Numbers JP 17H03016 and 18H04656.
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5
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10.1002/adsc.202000306
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-catalyzed Secondary C(sp3)-H Arylation
of 2-Alkylpyridines
Adv. Synth. Catal. Year, Volume, Page – Page
Hong-Liang Li,* Yoichiro Kuninobu*
6
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