Copper-mediated intermolecular direct biaryl coupling

Article abstract of DOI:10.1021/ja111401h

Copper-mediated intermolecular direct biaryl coupling of arylazines and azoles via dual C-H bond cleavage proceeds even without palladium catalysts. The reaction system shows the high potential of copper salts in direct C-H arylation chemistry and provides a new approach to biaryl motifs, which are ubiquitous in pharmaceuticals and functional materials.

Full text of DOI:10.1021/ja111401h

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pubs.acs.org/JACS
Copper-Mediated Intermolecular Direct Biaryl Coupling
Masanori Kitahara, Nobuyoshi Umeda, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S Supporting Information
b
Scheme 1
ABSTRACT: Copper-mediated intermolecular direct biar-
yl coupling of arylazines and azoles via dual C-H bond
cleavage proceeds even without palladium catalysts. The
reaction system shows the high potential of copper salts in
direct C-H arylation chemistry and provides a new ap-
proach to biaryl motifs, which are ubiquitous in pharma-
ceuticals and functional materials.
Scheme 2
iaryl structures are a ubiquitous motif in biological, pharma-
ceutical, and material sciences.1 The transition-metal-cata-
B
lyzed cross-coupling reactions of aryl halides with arylmetals,
such as the Kumada-Tamao-Corriu, Suzuki-Miyaura,
Negishi, Migita-Kosugi-Stille, and Hiyama couplings, rank as
one of the most reliable approaches to the target molecules. On
the other hand, recent advances in metal-mediated direct C-H
functionalization provide an alternative and potentially more
efficient synthetic methodology.2 In particular, the direct biaryl
coupling of two different arenes via dual C-H bond cleavage,
though difficult to achieve in a general way, is most attractive and
ideal from the viewpoint of step economy, since the tedious
preactivation of the two arenes can be obviated (Scheme 1). To
date, a number of successful examples of oxidative cross-cou-
pling, including simple arene/arene3 or heteroarene/hetero-
arene,4 heteroarene/arene,5 directing-group-containing arene/
arene,6 and electron-deficient arene/arene7 or heteroarene,8
have been reported. However, most precedents rely on the
combination of a palladium catalyst and a stoichiometric amount
of a metal oxidant based on Cu or Ag. For the realistic catalyst
loading of precious palladium, further development of new
reaction systems is quite appealing. Herein, we report a cop-
per-mediated intermolecular direct biaryl coupling.9 The reac-
tion proceeds without palladium catalysts and enables an unpre-
cedented coupling between a directing-group-containing arene
and a heteroarene.
to be beneficial in organic synthesis.14 The reaction scope is
summarized in Table 1. Electron-donating as well as electron-
withdrawing groups at the para position on the benzene ring were
compatible under the reaction conditions, although the latter
showed somewhat lower efficiency (3ba-da). Regardless of the
electronic nature of the substituents, a small amount of 1:2 coupling
product 30 was also detected in each case. On the other hand, the
2-naphthyl-substituted pyridine 1e resulted in the selective C-C
bond formation at the less congested position, and the 1:1 coupling
product 3ea was obtained exclusively. The sterically demanding
system 2-(2-methoxyphenyl)pyridine (1f) was also available for use
(3fa). On the contrary, steric hindrance around the pyridine moiety
was detrimental to the reaction; 2-phenylquinoline was converted
to the corresponding product in only 14% GC yield (not shown),
suggesting that the coordination of nitrogen to the copper center
plays a pivotal role in the reaction. Among other heteroarenes
tested, 5-aryloxazoles containing electronically and sterically diverse
functions were found to couple with 2-phenylpyridine very
smoothly under the identical conditions (4aa-ah). In addition,
In a typical experiment, treatment of 2-phenylpyridine (1a)10
with benzoxazole (2a)11 in the presence of Cu(OAc)2 and
PivOH in heated mesitylene for 2 h afforded the corresponding
biaryl 3aa and the 1:2 coupling product 3aa0 in 72% combined
yield (Scheme 2 and footnote a in Table 1).12 The choice of Cu
salts was critical: other divalent copper salts such as CuCl2 and
Cu(OTf)2 completely failed to form 3aa. While the reaction
proceeded even without PivOH, carboxylic acid additives generally
improved the reaction efficiency, with PivOH proving to be optimal.
Although the full conversion required more than a stoichiometric
amount of Cu(OAc)2,13 the copper salt is less expensive and has
relatively low toxicity. Therefore, this palladium-free system appears
Received: December 18, 2010
Published: January 26, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja111401h J. Am. Chem. Soc. 2011, 133, 2160–2162
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Table 1. Copper-Mediated Direct Coupling of 2-Arylazines
with Azolesa
Scheme 3
intramolecular kinetic isotope effect (KIE) was also investigated
by using 2-(2-deuteriophenyl)pyridine (1a-d1). At an early stage
in the reaction, 1a-d1 showed a KIE of 1.6, while a minor H/D
exchange reaction was observed (eq 2).16 Addition of a radical
scavenger, TEMPO or galvinoxyl, had a small effect on the
reaction outcome, which runs counter to the copper-mediated
single-electron-transfer mechanism proposed by Yu (eq 3).10a
These phenomena would be consistent with an electrophilic
metalation pathway.17 However, very little electronic effect of the
substituents para to the site of C-H bond cleavage was observed
(eq 4).18 On the other hand, 2-deuteriobenzoxazole (2a-d1)
underwent rapid H/D scrambling under the standard condi-
tions (eq 5). PivOH rather than AcOH somewhat increased the
rate, which supports the carboxylate-ligand-assisted concerted
metalation-deprotonation19 process of the relatively acidic
azole C-H bond.20
On the basis of the above results, the copper-mediated direct
biaryl coupling could consist of (i) reversible C-H cupration of
the azole involving carboxylate-ligand-promoted proton abstrac-
tion, (ii) C-H metalation of the arylazine, and (iii) productive
reductive elimination. In addition, in view of the necessity of a
stoichiometric amount of Cu(OAc)2, disproportion of Cu(II)
into Cu(III) and Cu(I) might be involved as the fourth elemen-
tary step.21 The above competitive deuterium-labeling experi-
ments are suggestive of rate-determining reductive elimination or
disproportion, but further efforts to clarify the detailed mechan-
ism are essential.
In conclusion, we have developed a palladium-free, copper-
mediated intermolecular direct biaryl coupling of arylazines and
azoles. The process provides a concise access to heteroarene-
containing biaryl structures of substantial utility in the areas of
pharmaceuticals and functional materials. Moreover, the rare-
metal-free approach is quite beneficial from an economical point
of view. The development of catalytic variants and applications to
other arene systems are currently underway.
a A mixture of Cu(OAc)2 (2.5 mmol), PivOH (0.50 mmol), 2-arylazine
(0.50 mmol), and azole (1.0 mmol) in mesitylene (2.0 mL) was stirred at
170 °C for 2 h under N2. b Yield of isolated product. c Readily separable
by chromatographic purification. d Isolated as a mixture of 3 and 30.
the reaction with a highly functionalized imidazole derivative,
caffeine, was possible (4ai).15 As the directing-group-containing
arene, benzoquinoline and 2-phenylpyrimidine also worked well,
furnishing the corresponding biaryls with synthetically useful yields
(5aa-ae and 6aa).
To obtain some mechanistic insights, the following experiments
were performed (Scheme 3). The control experiment with 2-
(pyridin-2-yl)phenyl acetate (7) led to no formation of 3aa,
indicating that the sequential C-H oxidation/C-C bond-forming
reaction would not be operative in the direct coupling (eq 1). The
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’ ASSOCIATED CONTENT
Yoshizumi, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 3072
and references therein.
S
Supporting Information. Experimental details and char-
(12) A small amount (ca. 0.060 mmol) of the product of homo-
coupling of 2a was observed by GC and GC-MS analyses. The
byproduct was readily separated by silica gel column purification. See
the Supporting Information for the detailed optimization studies.
(13) Under catalytic conditions using molecular oxygen as a co-
oxidant, the oxygenation of 1a predominantly occurred (see ref 10a).
Attempts to apply other co-oxidants such as MnO2 and K2S2O8
remained unsuccessful.
(14) Cu(OAc)2 obtained from three commercial sources mediated
the coupling with similar efficiencies. The three sources were Wako
Chemical Co. (>97%), Kanto Chemical Co. (95.0%), and Aldrich
(99.999%). On the other hand, the addition of 10 mol % PdCl2 or
Pd(OAc)2 decreased the yield of 3aa by ca. 10%.
b
acterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.
ac.jp
’ ACKNOWLEDGMENT
(15) The reactions of 1a with benzothiazole, pentafluorobenzene,
and 2-chlorothiophene remained unsuccessful.
(16) The KIE value was calculated by considering the partial H/D
exchange reaction. The intermolecular KIE implies that C-H cleavage
of 2-phenylpyridine would not be involved in the rate-determining step.
See the Supporting Information for details.
(17) For reports of similar KIE values in palladium-catalyzed direct
arylation and alkynylation through electrophilic C-H metalation, see:
(a) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159. (b) Chiong, H. A.; Daugulis, O. Org. Lett.
2007, 9, 1449. (c) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem.
Soc. 2007, 129, 7742.
(18) At this stage, the mechanism of C-H cleavage of phenylazines
is not definitive. Thus, the pathway involving concerted metalation-
deprotonation as well as σ-bond metathesis also could not be excluded.
See: (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 9651.
This work was supported by Grants-in-Aid for Scientific
Research from MEXT and JSPS, Japan.
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