Palladium(II)-catalyzed direct intermolecular alkenylation of chromones

Article abstract of DOI:10.1021/ol2018278

A new efficient method for the direct alkenylation of chromones via a palladium(II)-catalyzed C-H functionalization reaction was developed. The use of pivalic acid with Cu(OAc)₃/Ag₂CO₃ provided superior reactivity in the c

Full text of DOI:10.1021/ol2018278

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4466–4469
Palladium(II)-Catalyzed Direct
Intermolecular Alkenylation of
Chromones
Donghee Kim and Sungwoo Hong*
Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon, 305-701, Korea
hongorg@kaist.ac.kr
Received July 7, 2011
ABSTRACT
A new efficient method for the direct alkenylation of chromones via a palladium(II)-catalyzed CÀH functionalization reaction was developed. The
use of pivalic acid with Cu(OAc)3/Ag2CO3 provided superior reactivity in the cross-coupling of chromones with alkene partners. This approach
represents a significant advance over the existing two-step method and afforded various 3-vinylchromone derivatives, which are privileged
structures in many biologically active compounds and versatile synthetic building blocks.
The chromone motif is an important constituent of
natural products,1 and this family of molecules has been
extensively investigated due to their broad range of re-
markable biological activities.2 C-3 vinyl groups on chro-
mones3 are found in many pharmaceutically important
compounds that have antimicrobial, antitumor, antialler-
gic, or anti-inflammatory activities.4 The 3-vinylchromone
scaffolds 2 have proven to be highly useful as versatile
synthetic building blocks for the construction of more
advanced structures, such as xanthones 35 and 2-pyridone
derivatives 4,6 as shown in Scheme 1. Consequently,
vinylchromone derivatives 2 continue to attract the atten-
tion of synthetic chemists.3À7 With the aim of constructing
focused chemical libraries useful for chemical biology re-
search and drug discovery, we were interested in developing
an efficient method for the synthesis of various chromones
bearing a functionalized vinyl unit at the C-3 position.
A general method for introducing C-3 vinyl groups into
preformed chromones is via a Heck coupling reaction
between 3-halochromones and alkene coupling partners.8
This cross-coupling approach outweighs other synthetic
methods due to its flexibility in the synthesis of structurally
diverse 3-vinylchromone derivatives. Despite its flexibility,
the overall coupling requires two discrete activation steps:
(1) (a) Beecher, G. R. J. Nutr. 2003, 133, 3248. (b) Lichtenstein, A. H.
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r
10.1021/ol2018278
Published on Web 07/28/2011
2011 American Chemical Society

species could be accessed in a catalytic one-step fashion,
although the nucleophilic character of enolone systems is
relatively weak compared with that of indole systems. The
resulting intermediate could be further coupled with a
suitable alkene to provide the desired 3-vinylchromone
product. During these efforts, we established an efficient
palladium catalytic protocol for the facile cross-coupling
of chromones with a range of alkenes, and herein we report
the details of this study.
Scheme 1. Strategy for Building a Chromone-Related Chemical
Librarya
To test the feasibility of this process, ourefforts began by
investigating the direct coupling reaction of chromone (1a)
with n-butyl acrylate (5a) in the presence of Pd(OAc)2 as a
catalyst and Cu(OAc)2 as an oxidant under conditions
similar to those employed for the oxidative Heck coupling
of indole.8b Unfortunately, no detectable coupling product
was observed, probably because the innate nucleophilicity
of chromone was insufficient to engage palladation under
these conditions. Thus, a systematic investigation of more
reactive catalytic systems was conducted with testing of
different bases, solvents, oxidants, and temperatures to
establish an optimal combination for the transformation
(Tables 1SÀ3S in the Supporting Information). We found
that the addition of certain bases was crucial, and the
reactions that used 3 equiv of K2CO3 at 120 °C provided a
noticeable product yield (Table 1, entry 2). Reactions
conducted at other temperatures provided lower yields of
the cross-coupled product.
Recent reports have described palladiumÀpivalic acid
combinations that exhibit good reactivity in CÀH activa-
tion reactions by lowering the energy of CÀH bond
cleavage and by acting as partial proton shuttles during
catalysis.11 These observations prompted us to evaluate
the use of various carboxylic acids as sources of a catalytic
carboxylate base to test for beneficial effects on the palla-
dation of chromones. To our delight, the use of acetic acid
as a solvent indeed promoted the reaction with an im-
proved yield (31%) of 3-vinylchromone (Table 1, entry 2).
The use of stronger acids, such as trifluoroacetic acid, did
not positively influence the reaction outcome (entry 3).
Gratifyingly, however, a marked increase in conversion
was observed as the steric encumbrance of the acid in-
creased from acetic acid to pivalic acid, and the use of
pivalic acid with K2CO3 provided superior reactivity to
furnish a 72% yield of the coupled product (entry 6). The
reaction development efforts also focused on the appro-
priate choice of baseÀcarboxylic acid combination. The
use of Ag2CO3 in conjunction with pivalic acid as the
solvent increased the reaction yield, and we successfully
drove the coupling of chromone (1a) with n-butyl acrylate
(5a) to achieve a 94% yield of product (entry 8). The
control reactions performed without an oxidant and the
screening of other base/oxidant combinations further de-
monstrated their critical role in effecting high cross-cou-
pling conversion efficiency. For example, the reaction
a Xanthones 3 and 2-pyridone derivatives 4 can be efficiently pre-
pared from 3-vinylchromones 2 in a one-pot reaction.
(1) formation of 3-halochromone and (2) a palladium(0)-
catalyzed Heck coupling reaction. Therefore, we were
interested in exploring a direct coupling approach that
would allow us to avoid prefunctionalizing the chromones
and that would provide a more efficient process for the C-3
alkenylation of chromones under catalytic conditions. The
direct transition metal-catalyzed functionalization of
CÀH bonds in heterocycles is an exceedingly valuable
process in the context of contemporary organic synthesis.9
In particular, direct arylation and vinylation of hetero-
cycles has found widespread use in synthesis for the
construction of complex frameworks.
Direct olefination of arenes, pyridine N-oxides, and
indoles with alkene units via an oxidative palladium(II)-
catalyzed process appears as a promising alternative to the
conventional procedure.10 In light of the advances in this
area, we envisaged that in the event the nucleophilic attack
of chromone on palladium proceeded, the C3-palladated
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Seki, M.; Hosokawa, S. Chem. Lett. 2007, 36, 10. (f) Patonay, T.; Vasas,
A; Kiss-Szikszai, A.; Silva, A. M. S.; Cavaleiro, J. A. S. Aust. J. Chem.
2010, 63, 1582.
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Org. Lett., Vol. 13, No. 16, 2011
4467

conducted in the presence of only Ag2CO3, which func-
tioned as both a base and an oxidant, gave a lower product
yield (entry 12).
Table 2. Direct Alkenylation of Chromone with Various Alke-
nesa
Table 1. Development of the Direct Alkenylation of Chromonea
oxidant
(equiv)
base
yield
(%)b
entry
solvent
(equiv)
1
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
none
AcOH
none
8
2
AcOH
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
Cs2CO3 (3)
Ag2CO3 (3)
AgOAc (3)
AgO2CF3 (3)
AgOTf (3)
Ag2CO3 (3)
none
31
18
trace
37
72
54
94
25
76
22
74
39
3
TFA
4
PhCO2H
EtCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
5
6
7
8
9
10
11
12
13
Cu(OAc)2 (3)
a Reactions were conducted with chromone (1 equiv), n-butyl acry-
late (2 equiv), Pd(OAc)2 (0.1 equiv), oxidant, and base at 120 °C for 24 h.
b Yields are reported after isolation and purification by flash silica gel
chromatography. TFA = trifluoroacetic acid.
With this optimized protocol in hand, studies of the
coupling reaction were extended to include various func-
tionalized alkenes summarized in Table 2. Reactions in-
volving alkenes conjugated with methyl ester groups 5b led
to a good product yield (Table 2, entry 1). The acrylate
ester bearing a bulky tert-butyl group 5calsoresultedinthe
formation of 2c in high yield (entry 2). The reactions with
methacrylate 5d or lactone 5e efficiently afforded the
corresponding product 2d or 2e, respectively (entries 3
and 4). Alkenes conjugated with a ketone, aldehyde,
amide, or sulfone group were all smoothly alkenylated
on chromone (1a) in good yields (entries 5À8). A synthe-
tically versatile precursor, chromone phosphonate 2j,
could be generated from vinyl phosphonate 5j in 72%
yield (entry 9). Acrylonitrile 5k was also tolerated, and a
49% yield of 2k was provided with 47% recovery of a
starting material (entry 10). The sensitivity of both the rate
and yield of the reaction to the electronic effects could be
seen in the behavior of the alkenes. For example, reaction
of the nonactivated alkene styrene 5l with chromone (1a)
provided only a moderate yield (entry 11).
a Reactions were conducted with chromone (1 equiv), alkene (2 equiv),
Pd(OAc)2 (0.1 equiv), Cu(OAc)2 (3 equiv), and Ag2(OAc)2 (3 equiv) at
120 °C for 24 h. b Yields are reported after isolation and purification by
flash silica gel chromatography. c 47% of a starting material recovered.
isolated in 93% yield with an intact aryl bromo moiety to
provide an opportunity for further functionalization. In
addition, we were pleased to observe that the 2-phenyl-
chromone (flavone) was readily derivatized through this
oxidative alkenylation to afford 3-vinylflavone 2q in 52%
yield. This synthetic route would be useful in providing
access to a set of highly functionalized flavone analogs.
A plausible mechanism for the palladation of chromone
involves initiation by the nucleophilic attack of chromone
on palladium, followed by deprotonation by the pivalate
To explore this coupling reaction further, we next tur-
ned our attention to the scope of chromone substrates
(Figure 1). The 6-nitro, 6-methyl, or 7-methoxychromones
were reacted with n-butyl acrylate (5a) to furnish the
desired products with good yields. Of particular note was
the use of bromochromone: synthetically versatile 2p was
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Org. Lett., Vol. 13, No. 16, 2011

many biologically activecompounds. The beneficial effects
associated with the use of pivalic acid in conjunction with
Cu(OAc)3/Ag2CO3 were clearly observed in the cross-
coupling of chromones with alkene partners. This method
represents an unprecedented example of CÀH functiona-
lization of chromones and a significant advance over the
existing two-step method.
Figure 1. Direct alkenylation of substituted chromones.
ligand to give the palladium(II) intermediate I (Figure 2).
The high reactivity of pivalic acid relative to other car-
boxylic acids may be derived from the increased basicity of
its conjugate base.12 Next, in the presence of an appro-
priate alkene substrate, the C3-palladated species inserts
into the alkene, and reductive elimination provides the
desired coupled product. In the case of the nonactivated
alkene, the rate of insertion into an alkene was relatively
slow, and a lower yield was obtained, presumably because
of competitive oxidative decomposition of the remaining
C3-palladated species. Finally, the oxidation of Pd(0) to
Pd(II) using Cu(OAc)2/Ag2CO3 completes the catalytic
cycle.
Figure 2. Proposed catalytic cycle for the direct alkenylation of
chromone.
Acknowledgment. This research was supported by the
National Research Foundation of Korea (NRF) through
general research grants (NRF-2010-0022179 and 2011-
0016436)
In summary, we developed an efficient method for the
intermolecular alkenylation of chromones via a palladium-
catalyzed CÀH functionalization reaction. This approach
led to the construction of 3-vinylchromone scaffolds,
which are privileged structures and prevalent motifs in
Supporting Information Available.
Experimental
procedures and characterization of all new com-
pounds and biological evaluation data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(12) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64,
6015.
Org. Lett., Vol. 13, No. 16, 2011
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