Regioselective palladium-catalyzed direct cross-coupling of coumarins with simple arenes

Article abstract of DOI:10.1039/c2cc34551j

An efficient method for the C4-regiocontrolled C-H functionalization of coumarins to enable facile oxidative cross-couplings with simple arene components is disclosed.

Full text of DOI:10.1039/c2cc34551j

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COMMUNICATION
Regioselective palladium-catalyzed direct cross-coupling of coumarins
with simple arenesw
Minsik Min and Sungwoo Hong*
Received 25th June 2012, Accepted 9th August 2012
DOI: 10.1039/c2cc34551j
An efficient method for the C4-regiocontrolled C–H functional-
ization of coumarins to enable facile oxidative cross-couplings
with simple arene components is disclosed.
Transition metal-catalyzed direct functionalization of C–H
bonds has emerged as a straightforward and environmentally
friendly synthetic tool.1 In recent years, notable progress has
been made toward enhancing the efficiency of the twofold direct
C–H bond activation of (hetero)arenes.2 The regioselective
dehydrogenative arylation of indoles and pyrroles with simple
arenes has been pioneered by several groups.3 However, the
oxidative double C–H bond functionalization approach is often
limited by a modest substrate scope and the difficulties associated
with controlling the site-selective C–H bond activation.4
Coumarins constitute a major class of naturally occurring
compounds and privileged medicinal scaffolds that exhibit a broad
range of biological activities.5 Coumarins are also one of the most
important classes of fluorophores, and they have been extensively
investigated as powerful tools in complex biological systems.6 The
general methods for installing aryl groups and olefins have been
developed based on transition metal-catalyzed cross-coupling
reactions of 3- or 4-bromocoumarins with coupling substrates,
such as organometallic reagents and alkenes.7,8 Recently, an
efficient synthetic route to 4-arylcoumarins (neoflavones) via
palladium-catalyzed oxidative Heck coupling of coumarins
and arylboronic acids was disclosed (Scheme 1A).9
Scheme 1 Regioselective direct 4-arylation of coumarins.
in the coumarin scaffold in the presence of electronically or
sterically similar C–H bonds is crucial for realizing the utility
of this approach.10 Herein, we present the first example of the
regiocontrolled C–H functionalization of coumarins to enable
the catalytic cross-coupling of unactivated arenes with coumarins
at the C4 position.
The nature of the substituents on the coumarin core has
profound effects on the fluorescence, and the addition of
electron-donating groups such as OMe and NEt2 at position
7 on the coumarin core triggers a bathochromic shift with
stronger charge transfer character.7d,11 Therefore, we initially
focused on the cross-coupling of 7-methoxycoumarin (1a) and
benzene as test substrates to optimize the reaction conditions,
as summarized in Table 1. Negligible activity was observed
when 7-methoxycoumarin reacted with benzene under neat
conditions (Table 1, entry 1). Low yields of the coupling
products were obtained, except under conditions employing
pivalic acid as the solvent. Recent reports have described
palladium–pivalic acid combinations that exhibit good reactivity
in C–H activation reactions by lowering the energy of C–H bond
cleavage and by acting as partial proton shuttles during catalysis.12
The use of Cu(OAc)2 (entry 5) or the addition of 3-nitropyridine
(entry 7) provided lower product yields with preference for the
4-aryl coumarin product 2a.3d No coupling product was observed
without the presence of an oxidant, and the oxidant’s properties
were critical to the coupling efficiency. The use of AgOPiv in
conjunction with CsOPiv dramatically improved the catalytic
efficiency, and the reactions were reasonably selective for the
In spite of the important contributions, a direct catalytic
method for constructing these scaffolds via twofold oxidative
C–H bond activation has not yet been reported. Driven by the
need for a more efficient synthetic route to the coumarin
derivatives, we were particularly interested in exploring a
direct coupling approach that would avoid pre-functionalizing
both the coumarin unit and the coupling partners prior to the
coupling reaction (Scheme 1B). We envisioned that the initial
electrophilic palladation of coumarin could proceed given the
innate nucleophilic, albeit weak, characteristics of the coumarin
core. The ability to selectively functionalize a single C–H bond
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon, 305-701, Korea.
E-mail: hongorg@kaist.ac.kr; Fax: +82 42-350-2810;
Tel: +82 42-350-2811
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc34551j
c
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Chem. Commun., 2012, 48, 9613–9615 9613

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Table 2 Direct C4-arylation of the coumarins with various arenesa
Table 1 Optimization of the dehydrogenative coupling conditionsa
Entry Catalyst
Oxidant
Additive Solvent Yieldb (%) (2/3)c
1
2
3
4
Pd(OAc)2 AgOAc
Pd(OAc)2 AgOAc
Pd(OAc)2 AgOPiv
Cs2CO3 Benzene Trace
Cs2CO3 AcOH
PivOH 17 (88 : 12)
CsOPiv PivOH Trace
Pd(OAc)2 Cu(OAc)2 CsOPiv PivOH 7 (87 : 13)
14 (86 : 14)
—
Pd(OAc)2
—
5
6
Pd(OAc)2 AgOAc
Pd(OAc)2 AgOAc
Pd(OPiv)2 AgOAc
Pd(OPiv)2 Ag2CO3
Pd(OPiv)2 AgOPiv
Cs2CO3 PivOH 53 (84 : 16)
Cs2CO3 PivOH 35 (87 : 13)
CsOPiv PivOH 89 (86 : 14)
CsOPiv PivOH 84 (88 : 11)
CsOPiv PivOH 91 (91 : 9)
7d
8
9
10
a
Reactions were conducted with coumarin, benzene (30 equiv.), Pd
(0.2 equiv.), oxidant (3 equiv.), and additive (3 equiv.) in PivOH at
b
100 1C under N2 for 6–12 h. Yields are reported after isolation
and purification by flash silica gel chromatography. Ratio was
c
1
d
determined by H NMR spectroscopy. 0.2 equiv. of 3-nitropyridine
was added.
4-arylcoumarin 2a. An excess of benzene (30 equiv.) was
needed to ensure complete conversion of 7-methoxycoumarin.
Among the Pd species screened, Pd(OPiv)2 (0.2 equiv.) was
most effective in promoting coupling in the presence of
AgOPiv (3 equiv.), and CsOPiv (3 equiv.) in pivalic acid at
100 1C (entry 10). The reaction conditions promoted the efficient
C4 arylation of the coumarin with the best isolated yield and
good selectivity (2a/3a, 91 : 9 in a 91% combined yield). This
approach allows for the direct installation of aryl groups at the
C-4 position, providing efficient access to the 4-arylcoumarin
derivatives.
With the optimized conditions in hand, we next investigated
the substrate scope of both the coumarin and the arene
substrate, as summarized in Table 2. To our delight, we
observed that the C4-functionalization process was amenable
to a variety of arene types, including benzene substrates
bearing methyl, fluoro, chloro, trifluoromethyl or nitro
groups, with good C4 regioselectivity.13 The coupling reaction
of the coumarin with di- or tri-substituted benzenes was also
efficient, and occurred at the more sterically accessible C–H
bond of the benzene to provide only one regiomeric product.14
In the case of the nitro group, the C–H bond acidity parameter
seems to play an important role in selectivity of nitrobenzene,
and a 52% yield of one regiomeric product 2k was obtained.15
In addition, a relatively broad range of functional groups (e.g.,
alkyl, bromo, chloro, methoxy, dimethoxy, hydroxy, triflate,
and diethylamino groups) on the coumarin core were compatible
with the dehydrogenative coupling conditions and provided
moderate to good yields. Substitution with an electron-donating
OMe group at the 7-position enhanced the reaction efficiency
(2a vs. 2k). An amino group at the 7-position gave only
moderate yield of desired product 2r, most likely because the
partially protonated amino group reduced the electron-donating
properties under the reaction conditions. Expanding the scope
from the phenyl to the naphthyl system was also possible, leading
to the formation of 2j. Notably, a coumarin bearing bromo or
triflate substituents resulted in the isolation of the synthetically
a
Reactions were conducted with coumarin, benzene (30 equiv.),
Pd(OPiv)2 (0.2 equiv.), AgOPiv (3 equiv.), and CsOPiv (3 equiv.) in
PivOH at 100 1C under N2 for 6–12 h. Yields are reported after
isolation and purification by flash silica gel chromatography.
b
Naphthalene (10 equiv.) was used.
versatile 2n and 2o with intact bromo or triflate moieties under
the reaction conditions, providing an opportunity for further
formation of the C–C or C–heteroatom bonds.
c
9614 Chem. Commun., 2012, 48, 9613–9615
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We also preliminarily investigated the possibility of whether
this catalytic system could be effective towards the alkenylation of
coumarins and observed that coumarin 1a reacted with alkene
(3 equiv.) under slightly altered reaction conditions (eqn (1)).16
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ð1Þ
In summary, we developed an efficient method for the
oxidative cross-coupling of the coumarins and unactivated
arenes via a palladium-catalyzed twofold C–H functionalization.
This approach offers an unprecedented direct route to the
C4-selective arylation of coumarins with simple arene partners
under mild conditions. The substrate scope was broad, permitting
the construction of a variety of 4-arylcoumarins (neoflavones),
which are prominent structural motifs in many biologically
active compounds. Detailed mechanistic studies and synthetic
applications are now underway.
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This research was supported by National Research Foundation
of Korea (NRF) through general research grants (NRF-2010-
0022179, 2011-0016436, 2011-0020322). M. Min is the recipient of
a Global PhD Fellowship (NRF-2011-0007511).
Notes and references
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13 In all cases, an appreciable amount of the C3 products (3–8%) was
formed.
14 Ratio was determined by H NMR spectroscopy.
1
15 The reaction with toluene produced a 2 : 1 mixture of the inseparable
meta/para isomers in a 77% combined yield.
16 Unoptimized conditions.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9613–9615 9615