Rhodium-Catalyzed Pyridine N-Oxide Assisted Suzuki-Miyaura Coupling Reaction via C(O)-C Bond Activation

Article abstract of DOI:10.1021/acs.orglett.9b04068

A rhodium-catalyzed Suzuki-Miyaura coupling reaction via C(O)-C bond activation to form 2-benzoylpyridine N-oxide derivatives is reported. Both the C(O)-C(sp²) and C(O)-C(sp³) bond could be activated during the reaction with yields up to 92%. The N-oxide moiety could be employed as a traceless directing group, leading to free pyridine ketones.

Full text of DOI:10.1021/acs.orglett.9b04068

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Pyridine N‑Oxide Assisted Suzuki−Miyaura
Coupling Reaction via C(O)−C Bond Activation
Jing Zhong, Yang Long, Xufei Yan, Shiyu He, Runyou Ye, Haifeng Xiang, and Xiangge Zhou*
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P.R. China
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed Suzuki−Miyaura coupling
reaction via C(O)-C bond activation to form 2-benzoylpyr-
idine N-oxide derivatives is reported. Both the C(O)−C(sp2)
and C(O)−C(sp3) bond could be activated during the
reaction with yields up to 92%. The N-oxide moiety could
be employed as a traceless directing group, leading to free
pyridine ketones.
he Suzuki−Miyaura coupling reaction was first discov-
ered by Suzuki and co-workers to achieve a C(sp2)−
Scheme 1. Examples of Suzuki−Miyaura Coupling via
C(O)−C Bond Activation
T
C(sp2) single bond in the presence of palladium catalyst in
1979.1a It has become one of the most general and
straightforward synthetic methods to form carbon−carbon
bonds as well as new functional groups in organic synthesis.1
Several transition-metal catalysts including palladium,2a
rhodium,2b nickel,2c iron,2d or cobalt2e have been applied in
this transformation during the past decades.
On the other hand, it is well-known that the C−C bond of
three- or four-membered ring molecules can be successfully
activated, accompanyed by the release of ring strain.3 In the
case of unstrained molecules, special driving forces are usually
required to overcome the high kinetic barriers associated with
the activation step of generating stable intermediates.4,5
Among various unstrained C−C bond activations, the cleavage
of C−C bonds adjacent to the carbonyl group (C(O)−C bond
cleavage) has been extensively investigated due to its weakness
and wide availability of ketone derivatives. Pioneering works
have been reported by Jun,5a Lee,5b Murai,5c Douglas,5d Shi,5e
Dong,5f Johnson,5g Wei,5h and Chatani5i and other groups.
Furthermore, N-heteroaryl ketones are important structural
units usually found in drug molecules, natural products, and
functional materials. However, the functionalization of
pyridines is quite difficult due to its electron-poor nature.
Wang and co-workers reported a rhodium(I)-catalyzed cross-
coupling reaction of 8-quinolinyl ketones with a broad scope of
boronic acid reagents.6 Johnson further proved that the
reaction could be tolerant to a variety of electron-deficient
aryl boronic reagents (Scheme 1a).7 Utilizing a similar strategy,
Dong and co-workers merged the imine-directed C−C
activation in one-pot transmetalation process (Scheme 1b).8
However, the direct pyridine assisted ortho position C(O)−C
bond activation has not been reported, which might be caused
by the difficulty in forming a stable four-membered ring
intermediate (Scheme 1c). Meanwhile, pyridine N-oxides have
been reported as activated starting substances for versatile
derivations and also as the directing groups for selective C−H9
or C−C bond activation.10 In continuation of our work on C−
H bond activation11 and C−C bond activation,12 herein is
reported the development of a rhodium-catalyzed Suzuki−
Miyaura-type coupling reaction of 2-benzoylpyridine N-oxides
with boronic acids (Scheme 1c). This work reported the first
example of utilization of N-oxide moiety as a traceless directing
group to achieve C−C bond activation, which could be
subsequently easily removed in a one-pot process.13
Initially, 2-benzoylpyridine 1-oxide (1a) was chosen as a
model substrate to be coupled with 4-methoxyphenylboronic
acid (2a) in the presence of 10 mol % of [Rh(CO)2(acac)] as
catalyst in toluene at 140 °C under N2 atmosphere. As shown
in Table 1, 23% yield of the desired product 3a was detected
(Table 1, entry 1). Then the solvent effect studies showed that
Received: November 13, 2019
© XXXX American Chemical Society
A
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Organic Letters
Letter
a
a,b
Table 1. Screening for Optimal Catalytic System
Scheme 2. Scope of Arylboronic Acids
c
d
b
entry
[Rh]
additive (mol %)
solvent
toluene
DMSO
yield (%)
e
1
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2Cl]2
23
17
27
34
53
55
51
32
42
50
36
NR
25
NR
55
35
27
65
75
77
82
e
2
e
3
PhCl
e
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
5
6
f
7
8
9
K2CO3 (120)
NaOAc (120)
NaF (120)
K3PO4 (120)
dppb (20)
dppp (20)
X-phos (20)
ICy (20)
10
11
12
13
14
15
16
17
[Rh(PPh3)3Cl]2
[Rh(C2H4)2Cl]2
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
[Rh(CO)2(acac)]
g
18
g
19
20
H2O (250)
H2O (500)
H2O (750)
g
g
21
a
General conditions: 1a (0.2 mmol), 2a (0.5 mmol), [Rh] (10 mol
%), additive, and solvent (1.0 mL) were stirred at 140 °C for 24 h in
b
c
d
air. Isolated yields. acac: acetylacetonato. dppb: 1,4-bis-
(diphenylphosphino)butane. dppp: 1,3-bis(diphenylphosphino)-
propane. X-phos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbi-
e
phenyl. ICy: 1,3-dicyclohexylimidazolium chloride. Under N2.
Under O2. 1,4-Dioxane (2.0 mL).
f
g
a
1,4-dioxane was better than others including toluene, DMSO,
and PhCl (Table 1, entries 2−4). It is worth noting that the N-
oxide compound (1a) was found to be partially reduced under
N2 atmosphere, which would cause the decreased yields (Table
1, entry 4). Therefore, air and oxygen atmosphere were tried in
the reaction, and air atmosphere was proved to be enough to
suppress the reduction with yield of 53% (Table 1, entries 5
and 6). Different bases including K2CO3, NaOAc, NaF, K3PO4,
and ligands including phosphine and NHC were also tested,
resulting in similar or inferior effects (Table 1, entries 7−
14).14,15 With regard to the rhodium salts, [Rh(CO)2(acac)]
was the best one (Table 1, entries 15−17). After extensive
screening of the reaction parameters, addition of a small
amount of H2O was found to be beneficial to the reaction,8,16
and the desired coupling product (3a) was ultimately obtained
in 82% yield in the presence of 7.5 equiv of H2O (Table 1,
entry 21).
With the optimized reaction conditions in hand, the scope of
arylboronic acids was then explored (Scheme 2). In general,
electron-rich substituents were found to be beneficial to the
reactions, which was probably due to a faster transmetalation
process.1e For example, arylboronic acid with a p-methyl or
chloro group resulted in yields of 91% and 61%, respectively
(3b and 3k). Meanwhile, steric effects seemed to be an
important factor for the results. The arylboronic acid with a
substituent at the ortho position gave low yields (3p and 3q).
Polysubstituted arylboronic acids also smoothly delivered the
corresponding products in moderate to good yields (3r−3u).
1 (0.2 mmol), 2 (0.5 mmol), [Rh(CO)2(acac)] (10 mol %), H2O
(7.5 equiv), and 1,4-dioxane (2.0 mL) were stirred at 140 °C for 24 h
b
in air. Isolated yields.
Further studies showed that 2-acetylpyridine N-oxide, which
contains a C(sp3)−C(O) bond, could undergo similar
conversions when it was reacted with an array of electron-
rich and electron-deficient aryl boronic acid moieties under the
standard conditions albeit in decreased yields (37%−53%),
indicating that C(O)−C(sp2) activation might be easier than
C(O)−C(sp3) activation. The structure of 3f was confirmed
via X-ray single-crystal determination.
Next, the limitation and generality of the pyridine N-oxides
was examined. As shown in Scheme 3, the electronic and steric
effects of some substituents were studied and seemed to have
few effects on the results. For example, the o-, m-, and p-
methyl-substituted substrates gave similar results around 80%
yields (3v−3x). Meanwhile, methoxy- or chloro-substituted
substrates also afforded the desired products in yields around
70% (3z and 3aa). Additionally, 2-benzoylquinoline 1-oxide
was applied as substrate to form the corresponding product 3y
in 66% yield.
To gain insight into the possible catalytic pathway, a series
of control experiments were carried out as shown in Scheme 4.
At first, no product was detected in the reaction between 2-
benzoylpyridine (4) and 4-methoxyphenylboronic acid (2a)
(Scheme 4a) under the standard conditions, indicating the
B
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Letter
a,b
Scheme 3. Scope of 2-Benzoylpyridine N-Oxides
Scheme 5. Plausible Mechanistic Pathway
a
1 (0.2 mmol), 2a (0.5 mmol), [Rh(CO)2(acac)] (10 mol %), H2O
(7.5 equiv), and 1,4-dioxane (2.0 mL) were stirred at 140 °C for 24 h
oxide with rhodium(I) and a formal oxidative addition process
generates a five-membered rhodacyclic C and thereby sets the
stage for the key C−C activation. Reductive elimination can
form intermediate D, and subsequent dissociation would
generate the desired product 3 and rhodium(I) complex E.
Proton exchange of intermediate E with arylboronic 2 is
feasible to give the intermediate F and R-H,17 from which β-
aryl elimination might take place to regenerate intermediate A.
On the other hand, partial intermediate E would also be
reacted with another arylboronic acid 2 in the presence of
oxygen to generate Rh(III) complex G, releasing Rh(I) and the
byproduct R-R′ by reductive elimination to complete the
catalytic cycle.
b
in air. Isolated yields.
Scheme 4. Mechanistic Studies
To explore the efficiency and practical utility of this method,
the scale-up experiment and synthetic transformation reactions
were carried out. As shown in Scheme 6a, the gram-scale
Scheme 6. Gram-Scale Experiment and Synthetic
Transformations
pyridine N-oxides to be crucial for the reaction as a directing
group. Then, analysis of the crude product mixture of the
reaction between 1a and 2a by GC−MS and NMR revealed
the existence of 4-methoxyl-1,1′-biphenyl (5), which proved
the possibility of involvement of carbon−carbon activation and
transmetalation steps during the reaction (Scheme 4b).
Furthermore, a certain amount of protonated aryl product 7
from the starting substrate 3u was detected by GC−MS
(Scheme 4c). According to Hartwig’s work,17 the deuterium-
labeling experiments have also been performed, indicating the
source of proton might come from arylboronic acid (Scheme
4d). When the deuterated (at the 85% D level) phenylboronic
acid (2aa-d2) and 3ab were subjected to the standard reaction
conditions, more than 80% deuterium incorporation was
observed at the C4 position of N,N-dimethylaniline (9a-d1).
On the basis of the experimental results and literature
precedence,6,7,17 a plausible catalytic cycle for the rhodium-
catalyzed C(O)−C activation was proposed as depicted in
Scheme 5. Initial transmetalation of the boronic acid 2 with
rhodium catalyst forms rhodium(I) aryl intermediate A. Next,
coordination of substrate 1 through the oxygen atom of N-
experiment (5 mmol) was conducted by using 1a and 2a as
substrates, and 3a was obtained in 72% yield. More
importantly, after addition of PBr3 into the reaction mixture,
the free pyridine ketone (4a) could be obtained in a total yield
of 69% in one-pot reaction (Scheme 6b), indicating that N-
oxide moiety could be removed as a traceless directing group
in the reaction. At last, this protocol could be successfully
applied in the synthesis of 2-(3,4,5-trimethoxybenzoyl)-
quinolone (10b), which was reported to show potent
antiproliferative activity against various human cancer cells
(Scheme 6c).18
C
DOI: 10.1021/acs.orglett.9b04068
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Catal. 2017, 7, 1340. (g) Fumagalli, G.; Stanton, S.; Bower, J. F.
Chem. Rev. 2017, 117, 9404.
In summary, a protocol of efficient cross-coupling of alkyl
and 2-benzoylpyridine N-oxides with boronic acids via C(O)−
C(sp3) or C(O)−C(sp2) activation was developed. The
pyridine N-oxides proved to be crucial to realize the reaction,
which was used as a traceless directing group and could be
removed under PBr3 conditions in one-pot reaction. The
development of new reactions based on this strategy is
currently in progress.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04068.
Experimental procedures; crystallographic data; spectral
data (PDF)
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CCDC 1956268 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhouxiangge@scu.edu.cn.
ORCID
Haifeng Xiang: 0000-0002-4778-2455
Xiangge Zhou: 0000-0001-5327-6674
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant No. 21472128) and Sichuan Science and
Technology Program (No. 2018JY560) for financial support.
We also acknowledge the Comprehensive Training Platform of
Specialized Laboratory, College of Chemistry, Sichuan
University, for HRMS analysis.
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