Palladium-catalyzed direct arylation of benzoxazoles with unactivated simple arenes

Article abstract of DOI:10.1039/c2cc34238c

Using CuBr₂ as an additive, the Pd-catalyzed intermolecular C-H-C-H cross-coupling between benzoxazoles and unactivated simple arenes has been developed. This protocol provides a straightforward approach for the biological activity of 2-arylbenzoxazole derivatives.

Full text of DOI:10.1039/c2cc34238c

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Palladium-catalyzed direct arylation of benzoxazoles with unactivated
simple arenesw
Ge Wu, Jun Zhou, Min Zhang, Peng Hu and Weiping Su*
Received 13th June 2012, Accepted 14th July 2012
DOI: 10.1039/c2cc34238c
Using CuBr2 as an additive, the Pd-catalyzed intermolecular
C–H–C–H cross-coupling between benzoxazoles and unactivated
simple arenes has been developed. This protocol provides a straight-
forward approach for the biological activity of 2-arylbenzoxazole
derivatives.
Herein, we report that the Pd-catalyzed C–H–C–H cross-coupling
between C–H acidic benzoxazoles and simple arenes can be
achieved by increasing the difference of C–H acidity between
two cross-coupling partners, providing a straightforward and
high-yielding approach to 2-arylbenzoxazoles.9,10
Palladium-catalyzed direct arylation of benzoxazoles with
simple arenes via twofold C–H activation must be addressed
with two inherent difficulties: first, excessive amount of azoles
(relative to Pd catalyst) can strongly ligate the palladium center
via nitrogen atoms,11 which attenuates the electrophilicity of the
palladium center and hence interferes with the C–H activation
of simple arenes; second, 2-arylbenzoxazoles, the products from
this cross-coupling reaction, have a tendency to trap the
palladium catalyst in the cyclopalladated complex form to
block the catalysis process.12 Furthermore, benzoxazole itself
is liable to oxidative homocoupling13a and decomposition under
oxidative conditions.13b
The catalytic C–H–C–H cross-coupling of two different arenes
represents the most efficient approach to the biaryl structures
that are ubiquitous building blocks in natural products, medicinal
compounds and organic materials, and have attracted intense
interest.1 Over the past years, many successful examples of this
class of reactions have been reported, including electron-rich
heteroarene–simple arene,2 electron-rich heteroarene–C–H acidic
heteroarene,3 directing-group-containing arene–simple arene,4 and
C–H acidic arene–simple arene cross-couplings.5 Despite these
encouraging advances, achieving direct cross-coupling of two
different arenes in a general way remains a daunting challenge.
Clearly, such a C–H–C–H cross-coupling strategy will only be
widely accepted and used for biaryl synthesis by synthetic chemists
when a broad spectrum of (hetero) arenes can serve as suitable
substrates with diverse combinations of coupling partners.
We were pleased to find that using K2CO3 as the stoichio-
metric base in conjunction with CuBr2/O2 provided 2-phenyl-
benzoxazole (3a) in 15% yield (Table 1, entry 1). Introducing
the combination of K3PO4 and PivOH into the reaction system
Recently, we have established the Pd-catalyzed direct cross-
coupling of polyfluorobenzenes with simple arenes.5a Inspired
by this result, we continued our efforts to expand the applica-
tion and understanding of the metal-catalyzed cross-coupling
between C–H acidic arenes and simple arenes, of which only a
few examples have been reported to date.5 The obstacles that
impede the realization of this goal stem from the issues
associated with reactivity and selectivity: (1) simple arenes
are minimally reactive toward activation of the C–H bond,6
because they are neither sufficiently electron-rich for the
electrophilic metalation nor electron-poor enough to be active
in the concerted metalation–deprotonation process (CMD)
(usually, the C–H reactivity in the CMD process is parallel
to C–H acidity and therefore to the electron-deficiency of
arenes);7 (2) the small difference in C–H acidity between benzene
and C–H acidic arene tends to lead to undesired homocoupling.8
Table 1 Selected results from the optimization studies for palladium-
catalyzed direct arylation of benzoxazoles with simple benzenea
Entry
Base
Oxidant
Yieldb (%)
1c
2
3
4
5
6
7
8
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CuBr2
Cu(OAc)2
Cu(OTf)2
CuCl2
CuBr2
Ag2CO3
AgOAc
AgF
15
14
27
62
85
None
None
None
65
12
Trace
38
9d
10e
11
12f
CuBr2
CuBr2
—
CuBr2
a
Reaction conditions: benzoxazole 1a (0.2 mmol), benzene (4.0 mL),
Pd(OAc)2 (10 mol %), base (2.0 equiv.), PivOH (3.0 equiv.), oxidant
State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, Fujian 350002, China. E-mail: wpsu@fjirsm.ac.cn;
Fax: +86 591 8377 1575; Tel: +86 591 8377 1575
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc34238c
b
(2 equiv.), O2 (1 atm), DMA (2.0 mL), 120 1C, 24 h. GC yields.
In the absence of PivOH (3 equiv.). Reaction was carried out under
c
d
e
air. Reaction was carried out under nitrogen. CuBr2 (1.0 equiv.).
f
c
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Table 2 Scope of benzoxazoles in palladium-catalyzed oxidative
arylationa,b
Table 3 Scope of simple arenes in palladium-catalyzed oxidative
arylationa,b
a
Reaction conditions: benzoxazole 1 (0.2 mmol), benzene (4.0 ml),
Pd(OAc)2 (10 mol %), CuBr2 (2 equiv.), O2 (1 atm), K3PO4 (2 equiv.),
b
PivOH (3 equiv.), DMA (2 mL), 120 1C, 24 h, Isolated yields are
given. 48 h. Cu(OAc)2 (2 equiv.), PivOH (1.5 equiv.), 130 1C, 48 h.
a
Reaction conditions: 5-methylbenzoxazole 1b (0.2 mmol), arene
(4.0 ml), Pd(OAc)2 (10 mol %), CuBr2 (2 equiv.), O2 (1 atm), K3PO4
c
d
b
(2 equiv.), PivOH (3 equiv.), DMA (2 mL), 120 1C, 48 h. Isolated
yield are given, See ESI for details. CuBr2 (1.8 equiv.), K3PO4
c
d
e
(2.5 equiv.), PivOH (3.75 equiv.). 130 1C. CuBr2 (1.8 equiv.), 140 1C.
gave the satisfactory yield (entry 5). Removal of CuBr2 from
the reaction system completely shuts down the reaction (entry 11),
and reducing the amount of CuBr2 resulted in a decrease in yield
(entry 12). The observations indicate that CuBr2 would work not
only as an oxidant to Pd but also as the crucial accelerator in the
catalytic cycle. CuBr2 may act as a Lewis acid to coordinate to
benzoxazole,14 hence increase C–H acidity of benzoxazole and
prevent the catalyst poisoning caused by coordination of
2-arylbenzoxazole to the palladium center.3a,b The reaction
proceeded smoothly under air rather than O2 atmosphere
(entry 9), and N2 conditions suppressed the catalyst turnover
(entry 10), indicating that O2 played the role of a terminal
oxidant in the oxidation of Pd(0) to Pd(II). The use of Ag2CO3,
AgOAc, AgF instead of a copper oxidant was detrimental to
the reaction. Notably, under the optimized conditions, none of
the homocoupled biphenyl and 2,20-bisbenzoxazole byproducts
were observed.
took place at the C–H bond ortho to the fluoro substituent in
preference to the C–H bond ortho to a larger methyl substituent
(3x). 1,3-Dichlorobenzene provided high selectivity (17 : 1) in
favour of the less hindered C5 position (3z). For 1,2-disubstituted
benzenes, regioselectivity improved as the size of substituents
increased. The reaction of 1,2,3-trisubstituted benzene exclusively
occurred at the less hindered 5-position, which is difficult to
access by traditional organic reactions (3ab) (Table 3).
Next, we sought to test the utility of Pd(II)-catalyzed twofold
C–H activation in the synthesis of known bioactive molecules
(Scheme 1). As a representative example, we elected to target
compound 3ac, the methyl ester version of tafamidis. We were
delighted to find that the direct coupling between benzoxazole
ester 1q and 1,3-dichlorobenzene affords the target product in a
synthetically useful yield.
Under these presently optimal reaction conditions, a broad range
of benzoxazoles was found to undergo efficient direct arylation with
benzene as an arylating reagent in good-to-excellent yields
(Table 2). This reaction is compatible with a variety of functional
groups including electron-donating or electron-neutral methyl, tert-
butyl, methoxy and aryl groups as well as electron-withdrawing
acetyl, ester, nitro, fluoro, chloro, bromo and trifluoromethyl
groups. These easy-to-manipulate functional groups furnish a
versatile handle for further elaboration of products.
To obtain some insight into the reaction mechanism, inter-
molecular kinetic isotope effect (KIE) studies were performed
for both coupling partners (Scheme 2, eqn (1) and (2)). The
competition experiments between 5-methylbenzoxazole and
2-deuterated 5-methylbenzoxazole with benzene show a KIE
of 1.07, suggesting that the cleavage of the C–H bond in
benzoxazoles is not involved in the rate-limiting step. A KIE
of 5.6 for benzene was obtained by comparing the initial reaction
rate of benzene to that of deuterated benzene, indicating that
the cleavage of the C–H bond of simple benzene is an important
An array of mono- and di-substituted benzenes served as suitable
arylating reagents for the direct arylation of benzoxazoles and
afforded the corresponding products in good yield. Some mono-
substituted benzenes gave ortho, meta and para regioisomers with
less ortho isomer than either of the other two isomers (3q and 3s),
but in the cases of 3r and 3aa, no ortho isomer was formed. For
disubstituted benzenes, reactions preferentially occurred at less
hindered positions. For example, the reaction of 4-fluorotoluene
Scheme 1 Expedient synthesis of the precursor to a transthyretin
amyloid fibril inhibitor.
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Chem. Commun.
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concerted metalation–deprotonation mechanism. The observation
that the electron-deficient fluorobenzene is more active than
benzene in the reaction with 5-methylbenzoxazole (see ESIw
for details) is also consistent with the concerted metalation–
deprotonation mechanism. When the reaction was carried out
with CH3CO2D as the acid additive (eqn (3)), no deuterium
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In summary, we have achieved Pd-catalyzed direct cross-
coupling between benzoxazoles and unactivated simple arenes
by using CuBr2 as an additive to avoid catalyst poisoning and
activate benzoxazoles, providing a promising alternative to the
existing methods for the syntheses of 2-arylbenzoxazoles that
are of tremendous importance in medicinal chemistry.
Financial support from the 973 Program (2011CB932404,
2011CBA00501), NSFC (20821061, 20925102), the Key Project
from CAS and NSF of Fujian Province (2009HZ0005) is greatly
appreciated.
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Chem. Commun.