Copper-mediated C-H/C-H biaryl coupling of benzoic acid derivatives and 1,3-azoles

Article abstract of DOI:10.1002/anie.201300587

Hot couple: A precious-metal-free copper-mediated intermolecular direct biaryl coupling of benzoic acid derivatives and 1,3-azoles has been developed. The key to success is the installation of an amide-based bidentate coordinating group, which is easily removed and transformed into the parent ester groups after the coupling reaction. Kinetic studies indicate that the rate-limiting step is the aromatic C-H bond cleavage of benzoic acid derivatives. Copyright

Full text of DOI:10.1002/anie.201300587

Angewandte
Chemie
DOI: 10.1002/anie.201300587
Synthetic Methods
À
À
Copper-Mediated C H/C H Biaryl Coupling of Benzoic Acid
Derivatives and 1,3-Azoles**
Mayuko Nishino, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Over the last two decades, the use of metal-mediated direct
benzoic acid derivatives and 1,3-azoles involving an amide-
À
C H functionalization has grown rapidly as it enables the
based double N,N-coordination strategy. The directing group
is readily attachable and detachable, and parent carbonyl
functional groups are easily recovered. The present reaction
system is one of a few successful applications of the double
À
conversion of ubiquitous C H bonds of organic molecules
into diverse functional groups in a single synthetic opera-
tion.[1] In particular, since the pioneering work by Murai
et al.,[2] methods involving directing groups have received
significant attention because they enable the efficient and
À
coordination strategy to copper-mediated C H functionali-
zation of nonacidic arenes.[15]
À
selective cleavage of the proximal C H bond through a cyclo-
Our optimization studies commenced with the identifica-
tion of a suitable carbonyl-based directing group. After
extensive screening of potential functional groups, we were
pleased that an 8-aminoquinoline-containing secondary
amide, which was originally developed by Daugulis and co-
metalation reaction. In many cases, groups containing neutral
or anionic heteroatoms such as nitrogen, oxygen, and sulfur
work as monodentate directing groups. Additionally, the
groups of Sames,[3] Daugulis,[4] Yu,[5] and Chatani,[6] have
independently developed a double coordination strategy, in
which bidentate systems, including N,N and N,S systems, were
workers,[4] enabled the direct C H/C H coupling with 1,3-
azoles.[16] In a typical experiment, treatment of the benzamide
1a with benzoxazole (2a) in the presence of Cu(OAc)2·OH2
in o-xylene heated to 1358C afforded the corresponding
heterobiaryl 3aa in 83% yield (Scheme 1). A trace amount of
the homocoupling product of 2a was detected by GC and
À
À
À
used to activate otherwise unreactive Csp2 H bonds and the
even more challenging Csp3 H bonds. Such a double coordi-
nation system has mainly been applied to palladium- and
À
ruthenium-catalyzed processes.[7,8]
Meanwhile, owing to their ubiquity in biologically active
compounds, natural products, and functional materials, the
efficient construction of (hetero)biaryl structures is a long-
standing focus for synthetic chemists.[9] In this context, direct
À
biaryl coupling by double C H bond cleavage of two different
À
À
arenes (C H/C H coupling) is now a highly active research
À
area in the metal-promoted C H functionalization. In gen-
eral, precious-metal complexes, such as palladium[10] and
rhodium[11] complexes, are highly active catalysts for this type
of transformation. We have recently focused on the potential
of copper salts and complexes[12] as more efficient and unique
promoters as well as less expensive and abundant alternatives
to the above-mentioned precious metals, and thus, we have
À
À
developed copper-mediated and copper-catalyzed C H/C H
coupling of arenes and heteroarenes.[13,14] However, the
substrate scope with regard to the arenes is limited to
pyridine- or pyrimidine-containing arenes. Thus, there still
remains a large demand for further development of copper-
mediated direct biaryl couplings by using more ubiquitous
and productive directing groups such as a carbonyl groups.
Scheme 1. Screening of directing groups.
GCMS analysis, but was readily separated from 3aa by silica
gel column chromatography. Results of control experiments
with some structurally similar but monodentate directing
groups suggest that an N,N-bidentate directing group is
crucial for good conversion (A–C). Also notable is the
inefficiency of other bidentate coordinating groups, such as
(2-pyridylmethyl)amino[6a,b,e,8] and (2-methylthiophenyl)a-
mino groups[4b,d,7e] (D and E). In addition to the bidentate
nature, the relatively acidic NH in 1a is also believed to play
a pivotal role in the coupling.[17]
À
À
Herein, we report a copper-mediated C H/C H coupling of
[*] M. Nishino, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry, Faculty of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from MEXT and
JSPS (Japan). M.M. acknowledges Kansai Research Foundation for
technology promotion.
By using the above-mentioned bidentate directing group,
we investigated the substrate scope of benzoic acid deriva-
tives with benzoxazole (2a) as a coupling partner (Scheme 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300587.
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Scheme 3. Products of copper-mediated C H/C H coupling of various
1,3-azoles under the reaction conditions shown in Scheme 2. The ratio
of monoheteroarylated product to bisheteroarylated product is in
parenthesis. [a] With Cu(OAc)2 instead of Cu(OAc)2·OH2. [b] With
0.75 mmol of Cu(OAc)2. [c] About 5% of the corresponding bisheter-
oarylated products 4’ were observed but not isolated. [d] With
1.0 mmol of 2-phenyl-1,3,4-oxadiazole at 1108C.
À
À
Scheme 2. Copper-mediated C H/C H coupling of various benzoic
acid derivatives 1 with benzoxazole (2a). Reaction conditions:
Cu(OAc)2·OH2 (0.50 mmol), 1 (0.25 mmol), 2a (0.50 mmol), o-xylene
(1.5 mL), 1358C, 4 h, N2. The combined yield of monoheteroarylated
product 3 and bisheteroarylated product 3’ is given. The ratio of 3/3’ is
in parenthesis; 3 and 3’ were readily separated by silica gel column
chromatography. [a] With Cu(OAc)2 instead of Cu(OAc)2·OH2. [b] At
1508C. [c] The protiodechlorinated bisheteroarylated product 3ha’’ was
obtained instead of 3ha’, in the indicated ratio. [d] With 0.75 mmol of
Cu(OAc)2. HetAr=2-benzoxazolyl, Q=8-quinolinyl.
aryloxazoles as well as substituted benzoxazoles underwent
the arylation smoothly (3 and 4). In particular, cyano and
nitro groups were tolerated under the reaction conditions (see
3pd, 4ad, and 4ae). Biheteroaryls containing thiophene,
oxazole, thiazole, imidazole, caffeine, and 1,3,4-oxadiazole
were also synthesized (see 3pc, 3pd, 4pf, 4pg, 5, 6pb, and
7ap). Again, the prevalence of such conjugated heteroaro-
matic cores in many biologically active molecules highlights
the synthetic utility of this method.[9,18] Additionally, the use
of the 8-aminoquinoline-based bidentate directing group
broadened the scope of the 1,3-azole coupling partner as
well as the arene itself. For example, thiazole, imidazole, and
oxadiazole derivatives were not suitable substrates in our
previous work involving the use of pyridine as a monodentate
directing group.[13] The beneficial effect of the bidentate
directing group can be attributed to the more rapid cyclo-
cupration between 1 and an azolylcopper and the more rigid
intermediate formed after the first cupration of 1,3-azoles
(see below).
To gain more insight into the mechanism, we conducted
the following experiments with deuterium-labeled benzamide
[D5]-1a and benzoxazole [D1]-2a. At an early stage in the
reaction (10 min), a rapid H/D exchange reaction of [D1]-2a
was observed in both the absence and presence of benzamide
1a [Eq. (1)]. On the other hand, [D5]-1a did not undergo H/D
scrambling in the presence of benzoxazole (2a), although in
the absence of 2a, a significant loss of deuterium content
Notably, a better result was often achieved when anhydrous
Cu(OAc)2 was used rather than Cu(OAc)2·OH2. The copper-
based system tolerated electronically and sterically diverse
substituents at the ortho, meta, and para positions of benzoic
acid derivatives including methyl, tert-butyl, methoxy, chloro,
fluoro, and trifluoromethyl groups (3ba–la). For substrates
À
that bear two potentially reactive C H bonds, the doubly
heteroarylated products 3’ were detected, and the reaction of
meta-substituted benzoic acid derivatives occurred predom-
inantly at the less congested site. The naphthalene ring was
also compatible; 2-naphthamide reacted with 2a regioselec-
tively at the 3-position (3ma and 3na). Moreover, some
representative heteroaromatic compounds including furan,
thiophene, pyrrole, indole, and pyridine were transformed
into the corresponding biheteroaryls (3oa, 3pa, 3qa, 3ra, and
3sa, respectively) in synthetically useful yields. These reac-
tions are particularly notable as such heteroarene-1,3-azole
moieties frequently occur in biologically active natural
products.[18]
Facilitated by the doubly coordinated directing group,
a variety of 1,3-azoles were applicable to the direct C H/C H
coupling (Scheme 3). Electron-rich and electron-deficient 5-
À
À
À
occurred [Eq. (2)]. These outcomes suggest that the C H
2
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Finally, we attempted a removal of the 8-aminoquinoline
directing group. As shown in Scheme 5, Boc protection of the
secondary amide moiety of 3aa followed by ethanolysis with
bond cleavage of benzoxazole (2a) occurs reversibly, whereas
that of benzamide (1a) is an irreversible process under these
À
reaction conditions, also the C H bond cleavage of 2a occurs
much more readily than that of 1a. Based on the above
considerations and the necessity for two equivalents of
Cu(OAc)2 to achieve a good conversion, we propose the
following mechanism for the reaction of 1a and 2a
(Scheme 4). An initial acetate-ligand-assisted cupration[19] of
Scheme 5. Removal of directing group.
NaOEt in a Et2O/EtOH (4:1, v/v) mixed solvent system
produced the corresponding ethyl ester 12 in a good overall
yield. The same reaction conditions could be applied to the
reaction of substituted benzoxazole systems 3ea and 3 fa.
Ethyl benzoates and thiophenecarboxylate bearing oxazole,
thiazole, and imidazole-conjugated p systems were also
obtained by the same procedure (see the Supporting Infor-
mation for the complete substrate scope). The resultant ester
group can act as a synthetic handle for further manipulations.
In conclusion, we have developed a precious-metal-free,
À
À
copper-mediated C H/C H coupling of benzoic acid deriv-
atives and 1,3-azoles with the aid of 8-aminoquinoline-based
double N,N-coordination strategy. Such a bidentate coordi-
nation system broadens the substrate scope of both nonacidic
arenes and 1,3-azoles in the copper-promoted direct hetero-
biaryl coupling. Moreover, the directing group is easily
removed after the coupling, and parent ester groups are
recovered. Further elucidation of the detailed mechanism,
application to other arene systems, and development of
catalytic variants with copper[28] are under investigation in our
laboratory.
Scheme 4. Plausible reaction mechanism.
[20]
À
the relatively acidic C H of 2a
generates azolylcopper
intermediate 8;[21] this step is believed to be reversible, as
indicated by the result shown in Equation (1). Subsequent
ligand exchange with 1a occurs to form anionic and neutral
doubly N,N-chelated complex 9. The corresponding hetero-
biaryl 3aa is formed after an additional Cu(OAc)2-promoted,
À
Received: January 23, 2013
Revised: February 7, 2013
Published online: && &&, &&&&
oxidation (disproportionation) induced C H cupration of the
benzene ring[22] and reductive elimination via CuIII complexes
10 and 11.[23] Such a tight double coordination can allow
relatively unreactive thiazoles and imidazoles to be used in
this type of coupling; in the absence of this double coorodi-
nation the reverse protonation is favored over the subsequent
À
Keywords: copper · cross-coupling · C H cleavage ·
.
heterobiaryls · synthetic methods
À
oxidation and C H cupration processes. The postulated order
of metalation is supported by the results shown in Equa-
tions (1) and (2). The highly electron-withdrawing nature of
the azolyl ligand in 8[24] is believed to be the key to the cross-
coupling occurring in preference to the homocoupling,
although the exact reason is not clear at the present.[25]
Kinetic studies with [D1]-2a and [D5]-1a provided kinetic
isotope effect (KIE) values of 1.0 and 2.0, respectively
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À
cleavage of 1a.[27]
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À
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[16] See the Supporting Information for detailed optimization
studies.
1
[17] The H NMR chemical shifts of NH in 1a, D, and E are 10.76,
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À
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[22] The disproportionation into CuIII prior to the second C H
À
cupration can also explain the finding that no H/D exchange of
[D5]-1a proceeded under the reaction conditions [Eq. (2)]; the
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À
cupration and reductive elimination. For the rapid reductive
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À
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À
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[24] A similar intermediate is proposed in the copper-mediated
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alternative pathway that includes: 1) formation of an arylcopper
species through double N,N-N,N-coordination assistance,
=
À
2) insertion of the C N bond of 1,3-azoles into the C Cu
bond, and 3) oxidation leading to rearomatization of azole cores.
Also see: S. Ranjit, R. Lee, D. Heryadi, C. Shen, J. Wu, P. Zhang,
K.-W. Huang, X. Liu, J. Org. Chem. 2011, 76, 8999.
[25] Another disproportionation of CuI into CuII and Cu0 would not
be involved as a Cu0 mirror (metallic copper) was not observed
at the end of the reaction; see Ref. [14a].
[28] A preliminary attempt to apply catalytic conditions (20 mol%
Cu(OAc)2, 4.0 equiv of AcOH, mesitylene, 1708C, air) afforded
the desired heterobiaryl 3aa in 50% yield (71% brsm, versus
Scheme 1).
[26] See the Supporting Information for details.
À
[27] Because of the possibility of an off-cycle C H cupration of 1,3-
azoles, at the present, we cannot completely exclude an
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
M. Nishino, K. Hirano,* T. Satoh,
M. Miura*
&&&& — &&&&
À
À
Copper-Mediated C H/C H Biaryl
Coupling of Benzoic Acid Derivatives and
1,3-Azoles
Hot couple: A precious-metal-free
group, which is easily removed and
copper-mediated intermolecular direct
biaryl coupling of benzoic acid derivatives
and 1,3-azoles has been developed. The
key to success is the installation of an
amide-based bidentate coordinating
transformed into the parent ester groups
after the coupling reaction. Kinetic stud-
ies indicate that the rate-limiting step is
À
the aromatic C H bond cleavage of
benzoic acid derivatives.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!