Cobalt-Catalyzed Aerobic Oxidative C-H/C-H Cross-Coupling of Unactivated Arenes for the Synthesis of Biaryls

Article abstract of DOI:10.1021/acs.orglett.8b02526

A mild and efficient protocol for the synthesis of 2,2′-difunctional biaryls from readily available benzamides and oximes by Co(OAc)₂·4H₂O catalysis has been developed. The catalytic cycle that includes aerobic oxidation of Co(I) to Co(III) is successfully achieved for the first time through dual-chelation-assisted C-H/C-H coupling with the assistance of catalytic Mn(acac)₃. The catalytic system exhibits powerful reactivity and tolerates a large number of sensitive functional groups.

Full text of DOI:10.1021/acs.orglett.8b02526

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Cobalt-Catalyzed Aerobic Oxidative C−H/C−H Cross-Coupling of
Unactivated Arenes for the Synthesis of Biaryls
Ningning Lv, Zhengkai Chen, Yue Liu, Zhanxiang Liu, and Yuhong Zhang*
†
‡
†
†
,†,§
†
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China
§
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
*
S Supporting Information
ABSTRACT: A mild and efficient protocol for the synthesis of 2,2′-
difunctional biaryls from readily available benzamides and oximes by
Co(OAc) ·4H O catalysis has been developed. The catalytic cycle that
2
2
includes aerobic oxidation of Co(I) to Co(III) is successfully achieved for
the first time through dual-chelation-assisted C−H/C−H coupling with the
assistance of catalytic Mn(acac) . The catalytic system exhibits powerful
3
reactivity and tolerates a large number of sensitive functional groups.
he prevalence of the biaryl structural motif has prompted
readily available benzamides and oximes. This new reaction
takes place at 65 °C in air and requires 20 mol % Co(OAc)2·
4H O and 20 mol % Mn(acac) as catalysts.
T
intense research directed at discovering efficient and
1
,2
high-yielding methods for its preparation. Direct arylation of
2
3
2
arenes, achieved via cross-coupling of C(sp )−H bonds, has
The low cost cobalt catalysts have attracted much interest
recently due to their unique catalytic properties, low toxicity,
featured prominently in these efforts, leading to the establish-
14
ment of a range of useful transition-metal-catalyzed C−H/C−
and industrial prospects. Inspired by our continuous interests
3
15
H coupling reactions. For example, by exploiting the
in cobalt-catalyzed C−H bond activation, we initially focused
advantages of chelation-assisted C−H activation, the biaryl
motifs are constructed successfully through the assistance of a
directing group to control the regioselectivity and achieve the
on the examination of a cobalt catalytic system without the use
of oxidant in air by the use of benzamide 1a and oxime 2a as
model substrates. Unfortunately, no reaction was observed (see
the Supporting Information (SI)). Based on the fact that the
metal catalyst is often used to promote the reaction rate in the
transformation using oxygen as the oxidant, a series of
metals, such as Cu, Ag, Pd, and Mn, were subjected to the
reaction (see the SI). To our delight, the coupling product 3a
4
−9
reactivity. These reactions substitute the preactivated arenes
with a simple arene and, therefore, avoid the expense and
difficulty in preparing organometallic or halide coupling
partners. Over the past decade, many catalyst systems have
16
4
5
6
been applied to these transformations, including Pd, Rh, Co,
7
8
9
was obtained in 42% yield by the use of 20 mol % Mn(acac)3.
Cu, Ni, and Ru. A common element in all of these processes
is the need for distinct electronic effect or sterically controlled
substrates, which greatly limits their wider application.
In recent years, the use of a dual-chelation-assisted strategy
for the synthesis of biaryls, especially difunctional biaryls which
Other metals, including Cu(OAc) , AgOAc, and Pd(OAc) ,
2
2
failed to catalyze the reaction. There was no desired product in
a nitrogen atmosphere in the presence of 0.2 equiv or 2 equiv
of Mn(acac) , implicating that Mn(acac) itself is unable to
3
3
10
promote the reaction as an oxidant. Intriguingly, the
homocoupling products were not detected by TLC and GC-
MS. In order to confirm this result, the parallel experiment was
performed to evaluate the reactivity of the homocoupling by
subjecting only one substrate under the current catalytic
system (see the SI). Unexpectedly, both substrates benzamide
show broad and unique biological activities, has attracted
11
significant scientific attention. The dual-chelation-assisted
strategy is expected to precisely control the regioselectivity of
both arenes and greatly extend the substrate scope to
difunctional biaryls. In this regard, the homocoupling is first
12
explored to successfully attain a high level of regioselectivity.
1
a and oxime 2a are inactive and fail to give the homocoupling
However, the application of the strategy to cross-coupling is
relatively limited due to the inevitable formation of undesirable
homocoupling byproducts. The large excess of one substrate is
often required to increase the chemoselectivity. Another
disadvantage is that most of these coupling reactions require
a significant excess of hazardous or expensive oxidants such as
products under the standard reaction conditions, which result
in high chemoselectivity for this cross-coupling reaction.
Further optimization toward the base and solvent revealed
that NaOPiv·H O showed optimal efficiency and t-AmylOH
2
was the best solvent. No reaction was observed in the absence
1
1b,d
11b,d
11a
11d
of Co(OAc) ·4H O, and the yield decreased obviously when
K S O ,
NaIO4,
AgNO3, and Ag CO . Because it
2
2
2
2
8
2
3
is abundant and environmentally benign, oxygen would be a
13
preferred oxidant in these transformations. Herein, we report
a new protocol for the synthesis of difunctional biaryls from
Received: August 7, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02526
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Oximes ,
a b
less catalyst was employed (see the SI). The reaction could be
performed at 65 °C smoothly.
Various benzamides could be used in this reaction, and some
representative results was summarized in Scheme 1. In general,
Scheme 1. Scope of Benzamidesa,b
a
b
Reaction conditions were optimal conditions in the SI. Isolated
yields.
was used in the reaction, the deiodination had not been
observed (4d). The comparable reactivity was attained with
diverse meta substituted, disubstituted, or ortho substituted
oximes (4m−4t), exhibiting the good compatibility of the
methodology. With respect to the 1-naphthoxime substrate,
the reaction proceeded well to provide the coupling product
a
b
Reaction conditions were optimal conditions in the SI. Isolated
c
yields. 1 mmol scale.
4
u in 60% yield. The other complicated aryl oximes could
participate in the reaction to deliver the desired products in
good yields as well (4v−4x).
the electronic effect and steric effect on benzamides exerted no
obvious influence upon the reaction. For example, the electron-
rich benzamides showed good reactivity to afford the
corresponding biaryls (3k−3m, 3p−3s). At the same time,
the benzamides with electron-withdrawing substituents,
As part of a research program targeted at the development of
general direct arylation reactions, we explored the reactivity of
the current catalytic system to verify the availability of an
efficient reaction with various directing group substrates. We
first explored 2-phenylpyridine, which is a popular model
molecule for the chelation assisted C−H activation reaction.
Initial investigations revealed that the current catalytic system
enabled the selective formation of the corresponding cross-
coupling biaryls in moderate yield (Scheme 3, 6a). Encouraged
including −F, −Cl, −Br, −I, −CF , and −COOMe,
3
participated in the reaction smoothly (3b, 3d−3j, 3n−3o,
3
t−3w). When an −I substituted substrate was performed in
the reaction, the deiodination had not been observed (3g, 3n).
However, the substitution with a strong electron-withdrawing
nitro group gave the corresponding biaryls in low yield (3h). It
is worth mentioning that only monoarylation products were
obtained for para-substituted benzamide substrates (3c−3m).
And a mixture of biaryls was isolated with regard to several
meta halo-substituted substrates (3u−w), which might be
attributed to relatively less steric hindrance. Multisubstituted
benzamides were successfully converted to their corresponding
multisubstituted biaryls under the standard reaction conditions
,
a b
Scheme 3. Scope of Variant Directing Groups
(3s and 3t). Naphthalenecarboxamide was applicable under
the standard conditions as well and afforded the desired
product (3x) in 58% yield. The thiophene-2-carboxamide
could serve as a viable substrate in the reaction with lower
efficiency (3y). Significantly, the transformation could be
carried out on a 1 mmol scale in reasonable yield (3a), and the
structure of the biaryl (3a) is clearly confirmed by single-
crystal X-ray diffraction (CCDC 1826163).
a
b
Reaction conditions were optimal conditions in the SI. Isolated
c
yields. Using TFE as solvent.
After examining the compatibility of the coupling reaction
with various benzamides, then we explored the reactivity of
different oximes (Scheme 2). A series of para substituted
oximes bearing electron-withdrawing or -donating groups were
reactive to furnish the biaryl products in moderate to good
yields (4a−4l). The tolerance of several halogen substituents
offered the opportunity of further derivatization of the
obtained biaryls. When the −I substituted oxime substrate
by this initial discovery, the scope with variant chelation
substrates was investigated. To our delight, most nitrogen-
containing directing groups, including benzimidate, hydrazone,
O-acetyl/pivaloyloxime, and acethydrazide showed reactivity to
give diverse difunctional biaryls (6b−d), greatly highlighting
the good compatibility of the protocol. The homocoupling
byproduct was not observed in these transformations.
B
DOI: 10.1021/acs.orglett.8b02526
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To gain insight into the reaction mechanism, the
intermolecular competition experiment of electronically differ-
entiated 1h and 1k with 2a was performed. It is observed that
the electronic effect of benzamides does not significantly
impact the reaction. In contrast, the electron-donating group
on the oximes facilitates the transformation (see the SI). The
The reductive elimination of species C produces the cross-
coupling biaryl product and liberates Co(I) species. The latter
could be oxidized to Co(III) through the O /Mn(acac)
2
3
system to fulfill the catalytic cycle.
The obtained coupling product could undergo Beckmann
rearrangement to give the useful 2-amino-2′-carboxybiaryls,
which possess versatile biological activities and medicinal
experiments in the presence of 20 equiv of D O led to the
2
17
formation of a 19% H/D exchange of benzamide, suggesting a
reversible process of C−H cleavage of benzamide. In contrast,
no H/D exchange was observed for the oxime substrate. The
intermolecular deuterium-labeling experiments with respect to
benzamide and oxime were performed as shown in the SI. A
kinetic isotope effect (KIE) value of 4.0 was observed from the
properties (Scheme 5, eq 1). Furthermore, by using our
Scheme 5. Further Applications
competitive reaction of 1c and D -1c. These data demonstrate
5
that the C−H activation process might be involved in the rate-
determining step.
Song and Niu recently reported a cobalt-catalyzed SET and
CMD C−H/C−H coupling reaction for biaryl synthesis and
the addition of a radical scavenger drastically suppressed the
1
1c
reaction.
However, it was found that the addition of an
biaryl product, the key intermediate 9 for the synthesis of
excessive amount of TEMPO (2,2,6,6-tetramethylpiperidine 1-
oxyl) did not influence the reaction at all and a good yield was
always obtained (see the SI). This result indicated that a
radical catalytic pathway might not be involved in our reaction.
It should be emphasized that the reaction was totally inhibited
with the addition of 2 equiv of BHT (2,4-ditert-butyl-4-
methylphenol) due to the reaction between the oxime and
BHT (see the SI).
1
8
valuable pharmaceutical 5-methyl-6,7-dihydro-5H-dibenz-
c,e]azepine, which is often synthesized through Suzuki
[
coupling reaction, could be prepared by hydrolysis and
esterification (Scheme 5, eq 2). The preparation of the Suzuki
coupling partners for compound 9 is quite complicated with
19
multiple steps.
In summary, we have developed a new protocol for synthesis
of difunctional biaryls by cobalt-catalyzed aerobic oxidative
cross-coupling of C−H/C−H from readily available benza-
mides and oximes. For the first time, hazardous and expensive
oxidants, such as K S O , NaIO , AgNO , and Ag CO , have
11,16
Based on previous reports
and preliminary mechanistic
studies, a plausible mechanism is proposed as shown in
Scheme 4. Because the reaction failed in the presence of 20
2
2
8
4
3
2
3
been successfully replaced by oxygen/cat.Mn(III). In view of
the rare utility of oxygen as an oxidant in biaryl synthesis, the
current results should provide a meaningful opportunity for
process development in avoiding the use of large amounts of
oxidants. This protocol is distinguished by its broad substrate
scope and intriguing chemoselectivity in cross-coupling.
Furthermore, this catalytic system is compatible with a few
variant directing group substrates, which provides a pathway to
obtain diverse difunctional biaryls. Further investigations on a
related mechanism will be reported in due course.
Scheme 4. Proposed Reaction Mechanism
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02526.
Experimental and characterization details; mechanistic
1
13
investigations; synthetic application; H and C NMR
spectra (PDF)
mol % Co(OAc) ·4H O and 2 equiv Mn(acac) in a nitrogen
2
2
3
atmosphere, it is presumed that the key oxidant for the
oxidation of Co(II) to Co(III) cycle is the O /Mn(acac)
Accession Codes
2
3
CCDC 1826163 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.
system. The formed Co(III) reacts with benzamide with the
assistance of an 8-aminoquinolyl auxiliary to enable the
formation of intermediate A through an ortho-C−H cleavage
by a concerted metalation deprotonation process (CMD),
which was detected by ESI-HRMS (see the SI). The H/D
exchange experiment revealed that this activation process is
reversible. The subsequent ligand exchange of oxime into
Co(III) provides the species B (detected by ESI-HRMS; see
the SI), which undergoes the second CMD process to abstract
the inert ortho-hydrogen of the oxime to generate species C.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail:yhzhang@zju.edu.cn
C
DOI: 10.1021/acs.orglett.8b02526
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
2016, 8, 1242. (f) Yoshino, T.; Matsunaga, S. Adv. Synth. Catal. 2017,
3
(
59, 1245.
Zhengkai Chen: 0000-0002-5556-6461
Yuhong Zhang: 0000-0002-1033-3429
Notes
15) (a) Zhang, J.; Chen, H.; Lin, C.; Liu, Z.; Wang, C.; Zhang, Y. J.
Am. Chem. Soc. 2015, 137, 12990. (b) Liu, Y.; Wang, C.; Lv, N.; Liu,
Z.; Zhang, Y. Adv. Synth. Catal. 2017, 359, 1351. (c) Yu, W.; Zhang,
W.; Liu, Z.; Zhang, Y. Chem. Commun. 2016, 52, 6837. (d) Lv, N.;
Liu, Y.; Xiong, C.; Liu, Z.; Zhang, Y. Org. Lett. 2017, 19, 4640.
The authors declare no competing financial interest.
(
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ACKNOWLEDGMENTS
■
8
Funding from Natural Science Foundation of China (Nos.
1472165, 21672186, 21602202) and Important Project of
Zhejiang province (2017C03049) is highly acknowledged.
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Org. Lett. XXXX, XXX, XXX−XXX