Cu(OAc)2-catalyzed coupling of aromatic C-H bonds with arylboron reagents

Article abstract of DOI:10.1021/ol5027377

Cu-catalyzed coupling of aryl C-H bonds with arylboron reagents was accomplished using a readily removable directing group, which provides a useful method for the synthesis of biaryl compounds. The distinct transmetalation step in this Cu-catalyzed C-H coupling with aryl borons provides unique evidence for the formation of an aryl cupperate intermediate.

Full text of DOI:10.1021/ol5027377

Letter
pubs.acs.org/OrgLett
Cu(OAc)2‑Catalyzed Coupling of Aromatic C−H Bonds with Arylboron
Reagents
Ming Shang,† Shang-Zheng Sun,§ Hui-Xiong Dai,*,† and Jin-Quan Yu*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§Department of Chemistry, Innovative Drug Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, China
S
* Supporting Information
ABSTRACT: Cu-catalyzed coupling of aryl C−H bonds with
arylboron reagents was accomplished using a readily removable
directing group, which provides a useful method for the synthesis of
biaryl compounds. The distinct transmetalation step in this Cu-
catalyzed C−H coupling with aryl borons provides unique evidence for
the formation of an aryl cupperate intermediate.
a
Table 1. Reaction Development
espite the remarkable success of Pd(0)-catalyzed cross-
1
Dcoupling reactions of aryl halides,
development of
b
Cu(OAc)2
(mol %)
yield
entry
[Ag] (equiv)
base
(%)
Scheme 1. Transition-Metal-Catalyzed C−H Coupling with
1
20
20
20
20
20
20
20
20
30
30
30
30
30
30
AgOAc (1.0) Na2CO3
Ag2CO3 (1.0) Na2CO3
AgNO3 (1.0) Na2CO3
21
30
29
50
33
25
22
55
62
66
63
65
69
73
Organometallic Reagent
2
3
4
5
6
7
8
9
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.5)
Ag2O (2.0)
Ag2O (1.5)
Ag2O (1.5)
Ag2O (1.5)
Na2CO3
K2CO3
KOAc
NaOAc
c
c
Na2CO3
Na2CO3
c
c
c
c
c
10
11
12
13
14
Na2CO3
Na2CO3
,
,
,
d
d
d
Na2CO3
e
e
Na2CO3+ KOAc
Na2CO3+ KOAc
,f
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), base (0.2
b
1
mmol), DMSO (1.0 mL), 80 °C, Ar, 12 h. Yield determined by H
Pd(II)-catalyzed cross-coupling of C−H bonds with organo-
metallic reagents2 has remained a great challenge due to the
lack of reactivity of C−H bonds and difficulty in closing the
oxidative catalytic cycle. From a historical perspective, the
direct coupling of C−H bonds with organometallic reagents has
long attracted the attention of organic chemists.3−6 In 1998, Oi
et al. reported the first catalytic cross-coupling of 2-
arylpyridines with arylstannanes using RhCl(Ph3P)3 as a
catalyst.4a In 2003, Murai et al. reported a ruthenium(0)-
catalyzed ortho-arylation of aromatic ketones with arylbor-
onates.5a Inspired by Pd(0)-catalyzed cross-coupling reactions,
we embarked on the development of a series of Pd(II)-
catalyzed oxidative cross-couplings of C−H bonds with
organotin and organoboron reagents.2a−d While this newly
established catalytic cycle has gained considerable interest,2,3
NMR analysis of crude reaction mixture using CH2Br2 as an internal
c
d
e
standard. 2a (0.25 mmol). 4 h. Na2CO3 (0.2 mmol), KOAc (0.2
f
mmol). 70 °C.
the use of Cu(II) catalysts for catalytic C−H activation
reactions could be complementary and sometimes desir-
able.7−10 We and others have previously reported a diverse
range of Cu(OAc)2-catalyzed or -mediated C−H activation
reactions using directing groups.7−10 Interestingly, a single
example of C−H coupling of an electron-rich trimethoxyarene
with arylboronic acids using stoichiometric Cu(TFA)2 was also
Received: September 16, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
a b
,
a b
,
Scheme 2. Scope of Benzamide Substrates
Scheme 3. Scope of Arylboronates
a
a
Reaction conditions: 1a−1p (0.1 mmol), 2a (0.25 mmol), Cu(OAc)2
Reaction conditions: 1a (0.1 mmol), 2b−2m (0.25 mmol),
(0.03 mmol), Ag2O (0.15 mmol), Na2CO3 (0.2 mmol), KOAc (0.2
mmol), DMSO (1.0 mL), 70 °C, Ar, 4 h. Isolated yield. 2a (0.4
mmol), Cu(OAc)2 (0.04 mmol), 12 h. Cu(OAc)2 (0.02 mmol).
Cu(OAc)2 (0.03 mmol), Ag2O (0.15 mmol), Na2CO3 (0.2 mmol),
b
c
b
KOAc (0.2 mmol), DMSO (1.0 mL), 70 °C, Ar, 4 h. Isolated yield.
d
c
d
12 h. 2 (0.4 mmol), Cu(OAc)2 (0.04 mmol), 12 h
Scheme 4. Synthetic Elaboration of the Directing Group
reported by Itami.11 Herein, we report the first example of
Cu(II)-catalyzed cross-coupling of inert aryl C−H bonds with
organoboron reagents using a readily removable directing
group.
In our initial report on the Cu(II)-catalyzed C−H
functionalization of 2-phenylpyridine, we demonstrated the
feasibility of forging C−N and C−C bonds using nucleophilic
amines and cyanides,7a though subsequent efforts to develop
Cu(II)-catalyzed C−H couplings with organoboron reagents
using this directing group proved unsuccessful. However, our
recent discovery of a superior, easily removable amide−
oxazoline directing group for Cu(II)-mediated aminations9a
prompted us to revisit this subject (Scheme 1). Encouragingly,
we found that substrate 1a was arylated with 21% yield in the
presence of 2 equiv of PhBpin, 20 mol % of Cu(OAc)2, 1 equiv
of AgOAc, and 2 equiv of Na2CO3 at 80 °C (Table 1, entry 1).
The yield was improved to 50% when Ag2O was used as
oxidant (Table 1, entries 2−4), which is similar to our Pd-
catalyzed C−H coupling reactions in which Ag2O was found to
promote transmetalation in addition to reoxidizing the low-
valent metal.2b,d After a brief screening of bases, Na2CO3
remained the optimal choice (Table 1, entries 5−7). Alternative
copper salts proved to be ineffective for this transformation
(see the Supporting Information). A moderate improvement in
yield was also obtained by increasing the amount of PhBpin to
2.5 equiv (Table 1, entry 8). The coupling reaction proceeded
in the presence of 30 mol % of Cu(OAc)2 and 1.5 equiv of
Ag2O to afford the product in 66% yield (Table 1, entries 9−
Figure 1. Plausible catalytic cycle.
B
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Organic Letters
Letter
Notes
11). Additionally, the reaction time could be shortened to 4 h
without affecting the yield (Table 1, entry 12). The use of a
combination of Na2CO3 and KOAc as the bases and decreasing
the reaction temperature to 70 °C further improved the yield to
73%.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, the CAS/SAFEA
International Partnership Program for Creative Research
Teams, NSFC-21121062, and The Recruitment Program of
Global Experts for financial support. We gratefully acknowledge
The Scripps Research Institute, for financial support. This work
was supported by NSF under the CCI Center for Selective C−
H Functionalization, CHE-1205646.
The scope of this reaction with respect to the benzamide
substrate was examined under these conditions. As shown in
Scheme 2, electron-rich methyl-, methoxy-, tert-butyl-, 2,4-
dimethyl-, and phenyl-substituted arenes undergo C−H
arylation well, affording the desired products in good yields
(3b−i, 56−70% yields). Electron-deficient halogen and
trifluoromethyl substituents are tolerated (3j−m), although
lower yields were observed. In these cases, a majority of the
starting materials were recovered and a small amount of ortho-
hydroxylated side products were obtained. Arylation of the
vinylated arene produced the desired product in 65% yield
(3n). Indole and pyridine substrates are also arylated in 51%
and 26% yields, respectively (3o,p).
A variety of arylboronates were investigated as coupling
partners using 1a as the substrate (Scheme 3). The coupling of
1a with electron-rich arylboronates afforded the arylated
products in 57−73% yields (4a−e). Arylboron reagents
containing electron-withdrawing groups such as fluoro, chloro,
trifluoromethyl, and methoxycarbonyl moieties are also
compatible, providing the coupling products in 53−61% yields
(4f−i). The presence of a nitro group reduced the yield to 39%
(4j). Coupling with heterocyclic arylboronates also proceeds,
albeit in moderate yields (4k,l).
To improve the synthetic applicability of this reaction, we
treated the Boc-protected product 5 with EtSH in the presence
of LiHMDS at room temperature to give the thioester 6
(Scheme 4).12 The thioester 6 can be readily converted to the
corresponding aldehyde 7 and carboxyl acid 8 in good yields.
Despite the rapid development of Cu-catalyzed various C−H
activation reactions,7−10 evidence for the involvement of a C−
H cupperation intermediate remains scarce (Figure 1). The
distinct catalytic cycle of C−H coupling with aryl borons
proceeding through a transmetalation step supports the
formation of an aryl cupperate intermediate, although the
involvement of Cu(III) remains to be elucidated. In addition,
the intra- (kH/kD = 3.3) and intermolecular (kH/kD = 4.3)
kinetic isotope effects also ruled out an electrophilic aromatic
substitution pathway (SEAr) (see the Supporting Information).
In summary, we have developed a copper(II)-catalyzed cross-
coupling reaction of aryl C−H bonds using a readily removable
directing group. Both the benzamide substrates and the
coupling partners tolerate a wide range of functional groups.
This finding paves the way for developing Cu-catalyzed cross-
coupling of C−H bonds with organometallic reagents using
directing groups.
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ASSOCIATED CONTENT
■
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* Supporting Information
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hxdai@sioc.ac.cn.
*E-mail: yu200@scripps.edu.
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