A facile route to isoflavone quinones via the direct cross-coupling of chromones and quinones

Article abstract of DOI:10.1039/c2cc33204c

A straightforward and efficient method for the palladium-catalyzed direct cross-coupling of chromones with various quinones has been developed to rapidly construct isoflavone quinone structural motifs.

Full text of DOI:10.1039/c2cc33204c

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COMMUNICATION
A facile route to isoflavone quinones via the direct cross-coupling of
chromones and quinonesw
Youngtaek Moon and Sungwoo Hong*
Received 4th May 2012, Accepted 24th May 2012
DOI: 10.1039/c2cc33204c
A straightforward and efficient method for the palladium-catalyzed
direct cross-coupling of chromones with various quinones has been
developed to rapidly construct isoflavone quinone structural motifs.
was conducted by testing different solvents, oxidants and
temperatures to establish an optimal combination for achieving
the transformation. To our delight, the replacement of Cu2+ with
Ag+ was crucial, and the reactions that used Ag2CO3 at 100 1C
provided a noticeable product yield (Table 1, entry 2). Reactions
conducted at other temperatures provided lower yields of the
cross-coupled product. Among the palladium sources tested,
Pd(OAc)2 afforded the best catalytic reactivity. The use of
AgOAc with dioxane as the solvent provided a 46% product
yield (entry 5). Introduction of the base K2CO3 negatively
affected the reaction (entry 6). A combination of AgOAc and
acetic acid as an additive promoted the reaction and improved
the yield (52%) (entry 7). On the other hand, stronger acids,
such as trifluoroacetic acid, did not improve the reaction
outcome (entry 9). Pivalic acid provided a superior reactivity,
furnishing a 67% yield of the coupled product (entry 8). The
high reactivity of pivalic acid relative to other carboxylic acids
may be derived from the increased basicity of its conjugate
base.7 Interestingly, variations in the amount of AgOAc present
The family of isoflavone quinones has been extensively investigated
due to its broad range of remarkable biological activities.1
Isoflavone quinone scaffolds are useful and versatile building
blocks and, therefore, provide target systems for synthetic
chemists. Despite significant synthetic efforts, existing methods
for preparing the scaffolds suffer from multiple steps, and
harsh reaction conditions.2 In view of the high synthetic utility
of isoflavone quinone derivatives, the most straightforward
method for synthesizing the compounds would involve a direct
cross-coupling of chromones with quinones via C–H bond
functionalization.3
Although some notable advances in the direct C–H functional-
ization of quinones have been made, C–C bond formation in
quinones often remains a challenge due to the unique electronic
properties of the structures.4 These difficulties have pushed
synthetic strategies toward pre-functionalizing the quinone
substrates5 or investigating other reaction modes, such as
cross-coupling of quinones with organoboron compounds as
coupling partners.6 With these types of reactions, reoxidation
steps are often necessary to revert to the quinone oxidation state.
We were interested in exploring a direct coupling approach
that would allow us to avoid pre-functionalization of the
chromones and quinones, thereby providing a more efficient
process for coupling chromones and quinones under catalytic
conditions. During these investigations, we established an efficient
palladium catalytic protocol for the facile cross-coupling of
chromones with a range of quinones, and herein we report the
details of this study.
Table 1 Development of direct C–C coupling between a benzoquinone
and a chromonea
Entry Oxidant (equiv.) Additive (equiv.) Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (3)
Ag2CO3 (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (3)
AgOAc (2.5)
None
None
None
None
None
K2CO3 (2)
AcOH (2)
PivOH (2)
TFA (2)
PivOH (2)
PivOH (2)
PivOH
PivOH
PivOH
TFA
Dioxane 46
Dioxane Trace
dioxane 52
Dioxane 67
Dioxane 28
Dioxane 77
Dioxane 89
—
20
41
Trace
The feasibility of this process was tested via the direct
coupling of 6-methylchromone (1a) with 1,4-benzoquinone (2a)
in the presence of Pd(OAc)2 and Cu(OAc)2 in pivalic acid.
Unfortunately, no detectable coupling product was observed.
Thus, a systematic investigation of more reactive catalytic systems
9
10c
11c
a
Reactions were conducted with chromone (1 equiv.), benzoquinone
(2 equiv.), Pd(OAc)2 (0.2 equiv.), an oxidant and a base at 100 1C
under N2 for 12–24 h. Yields are reported after isolation and
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/c2cc33204c
b
c
purification by flash silica gel chromatography. Benzoquinone (4 equiv.)
was used. TFA = trifluoroacetic acid.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7191–7193 7191

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influenced the reaction outcomes, and the use of 2.5 equiv. AgOAc
provided the best product yields. An excess of benzoquinone
(4 equiv.) was needed to ensure complete conversion of a
chromone. A combination of these strategies led to the
identification of optimized conditions involving the treatment
of a chromone (1 equiv.) with benzoquinone (4 equiv.) in
the presence of the Pd(OAc)2 catalyst (0.2 equiv.), AgOAc
(2.5 equiv.), and PivOH (2 equiv.) in dioxane at 100 1C (entry 11).
Under the optimized reaction conditions, the direct cross-coupling
of 6-methyl chromone (1a) and 1,4-benzoquinone (2a) proceeded
efficiently to provide the best isolated yield of 89%.
With the optimized protocol in hand, we next investigated
the generality of this transformation by extending it to a
variety of chromone substrates (Table 2). The reaction scope
Table 3 Scope of the quinones with respect to C–C coupling of
chromonesa
Table 2 Direct coupling of various chromones with 1,4-benzoquinonea
a
a
Reactions were conducted with chromone (1 equiv.), benzoquinone
Reactions were conducted with chromone (1 equiv.), quinone (4 equiv.),
(4 equiv.), Pd(OAc)2 (0.2 equiv.) and AgOAc (2.5 equiv.) at 100 1C under
N2 for 12–24 h. Yields are reported after isolation and purification by
flash silica gel chromatography.
Pd(OAc)2 (0.2 equiv.) and AgOAc (2.5 equiv.) at 100 1C under N2 for
12–24 h. Yields are reported after isolation and purification by flash silica
gel chromatography. Ratios were determined by 1H NMR spectroscopy.
c
7192 Chem. Commun., 2012, 48, 7191–7193
This journal is The Royal Society of Chemistry 2012

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with respect to the chromone derivatives was extensive.
Chromones with a broad range of functional groups including,
alkyl, fluoride, bromide, chloride, nitro, methoxy, hydroxy,
triflate, and ester smoothly underwent dehydrogenative
coupling with 1,4-benzoquinone (2a) in moderate to good yields
under the optimal conditions. In some cases, the moderate
yields were attributed to the poor solubility of the products
(e.g., 3c and 3d). The obtained product 3g was reported to
exhibit potent biological activities.2b Of particular note are the
chromones bearing bromo or triflate groups, which yielded the
synthetically versatile 3f and 3i in excellent yields with intact
bromo or triflate moieties, thereby providing an opportunity for
the further formation of C–C or C–heteroatom bonds.
AgOAc were clearly observed in this cross-coupling reaction.
This method represents an unprecedented example of the
direct coupling of chromones with quinones and a significant
advance over existing methods.
This research was supported by the National Research
Foundation of Korea (NRF) through general research grants
(NRF-2010-0022179, 2011-0016436 and 2011-0020322).
Notes and references
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To explore this coupling reaction further, we turned our
attention to the scope of quinone substrates (Table 3). Regio-
chemical issues come into play in the context of unsymmetric
quinones. Reactions involving 1,4-benzoquinone substituted
with a methyl group produced a 1 : 1 mixture of the isomers 3k in
an 81% combined yield. Analogous results were obtained with
the phenyl-, bulky tert-butyl- or long-chain alkyl-substituted
benzoquinones (3m, 3p and 3q). The dependence of the
regioselectivity on the electronic effects could be seen from
the benzoquinone substituent behaviors. For example, a more
electron-rich methoxy substituent on the benzoquinone
donated electron density to the p-system, and this led to the
preferred coupling adduct of the regioisomers 3l in a 3 : 1 ratio.
The chloro or bromo groups had less influence, and the
coupling products 3n and 3o were obtained in a 1.5 : 1 ratio.
A reversal in regioselectivity was observed, albeit small, for the
sterically bulky tert-butyl- and long-chain alkyl-substituted
benzoquinones, probably because bulky groups partially
impede complex formation between the neighboring carbonyl
oxygen and Pd.8 Two other notable variations in the substrate
included 1,4-naphthoquinone and N-methylmaleimide. As a
coupling partner, 1,4-naphthoquinone reacted with similar
efficiencies under the optimal conditions to afford the corres-
ponding products, 3r, 3s and 3t. In a similar manner, the
reaction of N-methylmaleimide afforded the corresponding
product, 3u, in a 52% yield.
C. Navarro, A. Moreno and A. G. Csaky, Org. Lett., 2009, 11, 4938;
´
¨
The catalytic cycle of the coupling reaction can be initiated
by electrophilic palladation at C3 of the chromone. In the
presence of quinone substrates, the C3-palladated species next
inserts into the quinone, and subsequent reductive elimination
provides the desired coupled product.9 Finally, the oxidation
of Pd(0) to Pd(II) using AgOAc completes the catalytic cycle.
In summary, we developed an efficient method for preparing
isoflavone quinones via a palladium-catalyzed direct C–C
coupling reaction. This approach provides facile and affordable
access to isoflavone quinone structural motifs, which are
privileged and prevalent structures in many biologically active
compounds. The beneficial effects associated with the use of
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7191–7193 7193