DOI: 10.1002/ajoc.
201200036
Regioselective Cross-Dehydrogenative Coupling of Chromones and Non-
Activated Arenes
Minsik Min, Hyeonjeong Choe, and Sungwoo Hong*[a]
Flavones, also known as 2-phenylchromones, are abun-
dant in numerous naturally occurring products[1] and have
been shown to have a variety of biological activities.[2] As
a consequence, synthetic approaches to flavone skeletons
through efficient bond formation have been extensively in-
vestigated, and a number of classical synthetic approaches
to this family of compounds have been developed.[3–5] De-
spite these advances, most methods suffer from drawbacks
that include multiple steps, harsh reaction conditions, or the
use of toxic CO gas.
In recent years, impressive progress has been made
toward enhancing the efficiency of the twofold direct C H
bond functionalization of (hetero)arenes by using transi-
tion-metal catalysts.[6] Although notable improvements in
the oxidative homocoupling and intramolecular arylation
have been made,[7] intermolecular cross-dehydrogenative
couplings of heteroaromatic compounds with non-activated
arenes by regioselective C H bond functionalizations have
been achieved in only a few instances.[8] This approach is
also limited by modest substrate scope, and such reactions
remain a significant challenge in organic synthesis because
of the difficulties in controlling site-selective C H activa-
tion.[9] A breakthrough in the cross-dehydrogenative aryla-
tion of indoles with simple arenes was accomplished by
Fagnou and co-workers.[8d] One of the most notable aspects
of this cross-coupling reaction is that the reaction site on
the indole is influenced by the choice of oxidant between
CuACHTUNGRE(OAc)2 and AgOAc.
In terms of high synthetic efficiency, the most straightfor-
ward method for synthesizing flavones or 2-arylchromone
derivatives would involve the oxidative cross-coupling of
chromones with simple arenes by a double C H bond func-
tionalization. The selective functionalizations at the C3 po-
sition of chromones or the a position of enaminones could
be achieved by taking advantage of their innate nucleophil-
ic characteristics.[10] Despite recent advances, the substrate
scope of dehydrogenative coupling reactions is limited to
electron-deficient perfluoroarenes[10a] or alkenes.[10b] More
[a] M. Min, H. Choe, Prof. Dr. S. Hong
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, 305-701 (Korea)
Fax: (+ 82) 42-350-2810
E-mail: hongorg@kaist.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ajoc.201200036.
Asian J. Org. Chem. 2012, 1, 47 – 50  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
importantly, cross-coupling reactions with simple arenes at
the C2 position of chromones have not been reported to
date. Herein, we present the first example of a regiocon-
trolled C H functionalization of chromones at the C2 posi-
tion, which enables facile oxidative cross-coupling reactions
with non-activated arene compounds (Figure 1). Further-
more, we validate the use of this method for the synthesis
of various 2-arylchromone derivatives.
Figure 1. Selectivity controlled oxidative cross-coupling of chromones.
In light of precedents with indole derivatives,[8, 11] we en-
visioned that the initial electrophilic palladation at the C3
position of chromone could migrate to the C2 position, de-
pending on the reaction conditions. To test the feasibility of
this process, we began with an investigation of the direct
coupling reaction of chromone (1) with benzene as model
substrates in the presence of PdACHTUNGRE(TFA)2 (TFA = trifluoroace-
tate) as a catalyst[12] (Table 1). 3-Phenylchromone (3) was
only obtained in the presence of Ag2CO3 and iPr2S in diox-
ane,[13] although the yield of the product was only 14 %
(Table 1, entry 1). Negligible activity was obtained when
iPr2S was replaced with a base (Table 1, entry 2). To our de-
light, the site of reaction on the chromone switched to the
C2 position in the presence of a carboxylic acid (Table 1,
entry 1 versus entry 3). Encouraged by this preliminary
result, an intensive screening of the reaction media was
conducted, and it was determined that pivalic acid (PivOH)
is the optimal solvent in terms of reaction efficiency and
regioselectivity. The use of AgOAc in conjunction with
CsOPiv afforded a better yield of product than the use of
AgOAc alone. A systematic investigation of more reactive
catalytic systems was conducted by testing various oxidants
and temperatures, which led to the establishment of opti-
mized conditions: chromone (1 equiv) is treated with ben-
zene (30 equiv) and the PdACHTUNGRE(TFA)2 catalyst (0.2 equiv),
AgOAc (3 equiv), and CsOPiv (3 equiv) in PivOH at
47
 COMMUNICATION
Table 1. Optimization of the dehydrogenative coupling conditions.[a] Table 2. Direct C2-arylation of the chromone with various arenes.[a]

Entry Arene Product Yield [%][b]

Entry Oxidant Additive Solvent Yield 2:3[c]
2 + 3 [%][b]
1 Ag2CO3 iPr2S dioxane 14 > 1:99
2 AgOAc CsOPiv dioxane trace – 1 2a 80
3 AgOAc CsOPiv AcOH 36 91:9
4 AgOAc - PivOH 66 86:14
5 AgOAc CsOPiv PivOH/ 76 90:10
dioxane
6 AgOAc CsOPiv PivOH 84 95:5 77
2 2b
7 AgF CsOPiv PivOH 57 94:6 ACHTUNGRE(m/p=2:1)
8 Oxone CsOPiv PivOH 51 94:6
9 Ag2O CsOPiv PivOH 64 93:7
10 AgOAc CuACHTUNGRE(OAc)2 PivOH 54 82:18
[a] Reactions were conducted with chromone, benzene (30 equiv),
PdACHTUNGRE(TFA)2 (0.2 equiv), oxidant (3 equiv), and additive (3 equiv) in sol- 3 2c 72
vent at 100 8C for 12 h. [b] Yields are reported after isolation and purifi-
cation by chromatography on a silica gel column. [c] Ratio was deter-
mined by 1H NMR spectroscopy.

4 2d 74
100 8C (Table 1, entry 6). Under these reaction conditions,
arylation at the C2 position of the chromone was efficiently
achieved with the best isolated yield and excellent selectivi-
ty (C2/C3 greater than 95:5). We also investigated the influ-
ence of CuACHTUNGRE(OAc)2 on the reaction sites, as previously tested 71
5 2e
(o/m/p=1:5:2.8)
in coupling reactions with indole derivatives.[8e] However,
the use of either CuACHTUNGRE(OAc)2 (Table S3 in the Supporting In-
formation) or CuACHTUNGRE(OAc)2/AgOAc (Table 1, entry 10) gave
lower yields of the product with a preference for 2.
With the optimized conditions in hand, studies of the 6 2f 68
coupling reaction were extended to include a range of
useful substituted arenes, as summarized in Table 2. Grati-
fyingly, we observed that the C2-functionalization process
works well with various types of arenes, which include ben- 90
7 2g
zene substrates with methyl, fluoro, chloro, nitro, or me- ACHTUNGRE(m/p=2:1)
thoxy groups. The reaction with toluene produced a 2:1
mixture of the meta/para isomers in a 77 % combined yield
(Table 2, entry 2). None of the ortho-substituted product
was obtained, probably as a result of the steric effect of
8 2h 91
methyl group. Analogous results were obtained with the
chloro- and methoxy-substituted benzenes. Chlorobenzene
reacted to give a 2:1 ratio of the meta/para isomers
(Table 2, entry 7), and anisole reacted to give a 1.8:1 mix-
ture of the meta/para isomers (Table 2, entry 12). Fluoro-
benzene reacted to provide a mixture of ortho, meta, and 9 2i 81
para isomers, probably as a consequence of the rather small
steric effect of the fluoro group (Table 2, entry 5). In the
case of nitrobenzene, the acidity of the C H bond seems to
play to an important role in the selectivity of the reaction,
as a 69 % yield of 2 k was obtained and 25 % of the starting 10 2j 70
chromone was recovered (Table 2, entry 11). The coupling
reaction of chromone with ortho-, meta-, or para-disubsti-
tuted benzenes was also efficient, and occurred at the more

48 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 47 – 50
Cross-Dehydrogenative Coupling of Chromones

Table 2. (Continued)
Entry Arene Product Yield [%][b]

11 2k 69

48
12[c] 2l
(m/p=1.8:1)

13 2 m 54

14 2n 66

[a] Reactions were conducted with chromone, arene (30 equiv),

PdACHTUNGRE(TFA)2 (0.2 equiv), oxidant (3 equiv), and additive (3 equiv) in
PivOH at 100 8C for 12 h. [b] Yields are reported after isolation and pu-
rification by chromatography on a silica gel column. [c] Reaction was
conducted at 120 8C for 24 h.

sterically accessible C H bond of the benzene ring to pro-

vide only one regioisomer. Furthermore, a trisubstituted
benzene reacted with chromone to give 2 h in excellent
yield (Table 2, entry 8). Both the rate and yield of the reac-
tion were sensitive to the electronic effects of the arenes,
which is an important parameter for tuning the arene reac-
tivity. For example, a more electron-rich methoxy group on
the phenyl ring retarded the reaction, and a prolonged re-
action time (24 h) and elevated temperature (120 8C) were
required to obtain a moderate yield (Table 2, entry 12).
To further test the scope of this method, a range of chro-
mone substrates were investigated, as illustrated in
Scheme 1. Chromone derivatives substituted with a range
of functional groups, for example, alkyl, fluoro, bromo,
chloro, nitro, methoxy, hydroxy, ether, triflate, and ester)
smoothly underwent dehydrogenative coupling with excel-
lent regioselectivity in moderate to good yields. Substitu-
tion with an electron-donating or an electron-withdrawing
group on the chromone minimally affected the reactivity.
Of particular note are chromones substituted with bromo
or triflate groups: the synthetically versatile products 2 s
and 2 v were isolated in good yields with intact bromo or
triflate moieties, which provides an opportunity for further
formation of C C or C heteroatom bonds. A naturally oc-
curring flavone, chrysin (2 w) was also readily obtained
from the reaction of 5,7-dihydroxylchromone and benzene
and, thus, provides a new strategy for the facile synthesis of
this family of compounds that have good anticancer activi-
ties.[14]
Scheme 1. Products of direct C2-arylation of various chromones with
benzene. Reactions were conducted with chromone, arene (30 equiv),
PdACHTUNGRE(TFA)2 (0.2 equiv), oxidant (3 equiv), and additive (3 equiv) in
PivOH at 100 8C for 12 h. Yields are reported after isolation and purifi-
cation by chromatography on a silica gel column.
In summary, we have developed an efficient method for
the oxidative cross-coupling of chromones and non-activat-
ed arenes by a palladium-catalyzed twofold C H function-
alization. This protocol offers an unprecedented direct
route to the C2-selective arylation of chromones with the
simple arene partners under mild conditions. The substrate
scope is broad and permits the construction of various fla-
vones, which are prominent structural motifs in many bio-
logically active compounds. The beneficial effects that are
associated with the use of PivOH in conjunction with
AgOAc/CsOPiv were clearly demonstrated in the cross-
coupling of the chromones. Additional studies on the mech-
anism of the reaction and further synthetic applications of
this method are currently underway.

Asian J. Org. Chem. 2012, 1, 47 – 50  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org 49

COMMUNICATION
Experimental Section
Example procedure: A mixture of chromone (0.1 mmol), benzene
(0.4 mL), PdACHTUNGRE(TFA)2 (0.2 equiv), AgOAc (0.3 mmol), and CsOPiv
(0.3 mmol) were combined in PivOH (0.7 mL). The test tube was sealed
with a Teflon-lined cap and the reaction mixture was stirred in an oil
bath maintained at 100 8C for 12 h. The reaction mixture was cooled to
room temperature, and then diluted with CH2Cl2 and NaHCO3. After
stirring for 10 min, the mixture was washed sequentially with aqueous
NaHCO3 and NH4Cl. The combined organic layers were dried over
MgSO4. The filtrate was concentrated in vacuo and the residue was puri-
fied by chromatography on a silica gel column to give 2-phenyl-4H-chro-
men-4-one (2 a) in 80 % yield.
Acknowledgements
This research was supported by the National Research Foundation of
Korea (NRF) through general research grants (NRF-2010-0022179,
2011-0016436). M.M. is the recipient of a Global Ph.D. Fellowship
(NRF-2011-0007511).
Keywords: arenes · C H functionalization · chromones ·
flavones · regioselectivity
[1] a) P.-G. Pietta, J. Nat. Prod. 2000, 63, 1035; b) M. M. Abou-Zaid,
D. A. Lombardo, G. C. Kite, R. J. Grayer, N. C. Veitch, Phytochem-
istry 2001, 58, 167.
[2] a) B. Kosmider, R. Osiecka, Drug Dev. Res. 2004, 63, 200; b) L.
Costantino, G. Rastelli, M. C. Gamberini, J. A. Vinson, P. Bose, A.
Iannone, M. Staffieri, L. Antolini, A. D. Corso, U. Mura, A. Albasi-
ni, J. Med. Chem. 1999, 42, 1881; c) D. C. Rowley, M. S. T. Hansen,
D. Rhodes, C. A. Sotrier, H. Ni, J. A. McCammon, F. D. Bushmanb,
W. Fenicala, Bioorg. Med. Chem. 2002, 10, 3619; d) N. R. Guz, F. R.
Stermitz, J. B. Johnson, T. D. Beeson, S. Willen, J. F. Hsiang, K.
Lewis, J. Med. Chem. 2001, 44, 261; e) J. H. Wu, X. H. Wang, Y. H.
Yic, K. H. Leeb, Bioorg. Med. Chem. Lett. 2003, 13, 1813; f) R.
Cermak, Expert Opin. Drug Metab. Toxicol. 2008, 4, 17.
[3] For selected reports, see: a) W. Baker, J. Chem. Soc. 1933, 1381;
b) H. S. Mahal, K. Venkataraman, J. Chem. Soc. 1934, 1767; c) K.
Dekermendjian, P. Kahnberg, M.-R. Witt, O. Sterner, M. Nielsen,
T. Liljefors, J. Med. Chem. 1999, 42, 4343; d) L. W. McGarry, M. R.
Detty, J. Org. Chem. 1990, 55, 4349; e) D. E. Zembower, H. Zhang,
J. Org. Chem. 1998, 63, 9300; f) K. Hemanth Kumar, P. T. Perumal,
Tetrahedron 2007, 63, 9531; g) N. Yao, A. Song, X. Wang, S. Dixon,
K. S. Lam, J. Comb. Chem. 2007, 9, 668.
[4] a) P. G. Ciattini, E. Morera, G. Ortar, S. S. Rossi, Tetrahedron 1991,
47, 6449; b) B. Liang, M. Huang, Z. You, Z. Xiong, K. Lu, R. Fathi,
J. Chen, Z. Yang, J. Org. Chem. 2005, 70, 6097; c) H. Miao, Z.
Yang, Org. Lett. 2000, 2, 1765; d) E. Awuah, A. Capretta, Org. Lett.
2009, 11, 3210; e) Q. Yang, H. Alper, J. Org. Chem. 2010, 75, 948.
[5] Recently, oxidative Heck-type coupling reactions of chromones
with arylboronic acids were reported, see: M. Khoobi, M. Alipour,
S. Zarei, F. Jafarpour, A. Shafiee, Chem. Commun. 2012, 48, 2985.
[6] For recent reviews on this topic, see; a) S.-H. Cho, J. Y. Kim, J.
Kwak, S. Chang, Chem. Soc. Rev. 2011, 40, 5068; b) K. Hirano, M.
50 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Sungwoo Hong et al.
Miura, Synlett 2011, 294; c) L. Ackermann, R. Vicente, A. R.
Kapdi, Angew. Chem. 2009, 121, 9976; Angew. Chem. Int. Ed. 2009,
48, 9792; d) F. Bellina, R. Rossi, Tetrahedron 2009, 65, 10269;
e) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173;
f) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174;
g) L.-C. Campeau, K. Fagnou, Chem. Soc. Rev. 2007, 36, 1058;
h) C.-J. Li, Acc. Chem. Res. 2009, 42, 335.
[7] For selected reports, see: a) T. Truong, J. Alvarado, L. D. Tran, O.
Daugulis, Org. Lett. 2010, 12, 1200; b) D. Monguchi, A. Yamamura,
T. Fujiwara, T. Somete, A. Mori, Tetrahedron Lett. 2010, 51, 850;
c) Y. Li, W.-H. Wang, S.-D. Yang, B.-J. Li, C. Feng, Z.-J. Shi, Chem.
Commun. 2010, 46, 4553; d) Z. Liang, J. Zhao, Y. Zhang, J. Org.
Chem. 2010, 75, 170; e) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc.
2009, 131, 17052; f) J.-B. Xia, X.-Q. Wang, S.-L. You, J. Org. Chem.
2009, 74, 456; g) M. Takahashi, K. Masui, H. Sekiguchi, N. Kobaya-
shi, A. Mori, M. Funahashi, N. Tamaoki, J. Am. Chem. Soc. 2006,
128, 10930; h) K. Masui, H. Ikegami, A. Mori, J. Am. Chem. Soc.
2004, 126, 5074; i) D. G. Pintori, M. F. Greaney, J. Am. Chem. Soc.
2011, 133, 1209; j) L. Ackermann, R. Vicente, A. Althammer, Org.
Lett. 2008, 10, 2299; k) W. Yu, Y. Du, K. Zhao, Org. Lett. 2009, 11,
2417; l) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew.
Chem. 2009, 121, 8222; Angew. Chem. Int. Ed. 2009, 48, 8078; m) B.
Ligault, D. Lee, M. P. Huestis, D. R. Stuart, K. Fagnou, J. Org.
Chem. 2008, 73, 5022.
[8] For selected reports, see: a) S. Potavathri, K. C. Pereira, S. I. Gorel-
sky, A. Pike, A. P. LeBris, B. DeBoef, J. Am. Chem. Soc. 2010, 132,
14676; b) B.-J. Li, S.-L. Tian, Z. Fang, Z.-J. Shi, Angew. Chem. 2008,
120, 1131; Angew. Chem. Int. Ed. 2008, 47, 1115; c) D. R. Stuart, K.
Fagnou, Science 2007, 316, 1172; d) D. R. Stuart, E. Villemure, K.
Fagnou, J. Am. Chem. Soc. 2007, 129, 12072.
[9] For selected reports, see: a) M. Kitahara, N. Umeda, K. Hirano, T.
Satoh, M. Miura, J. Am. Chem. Soc. 2011, 133, 2160; b) C.-Y. He, S.
Fan, X. Zhang, J. Am. Chem. Soc. 2010, 132, 12850; c) P. Xi, F.
Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu, J. You, J. Am. Chem.
Soc. 2010, 132, 1822; d) K. L. Hull, M. S. Sanford, J. Am. Chem.
Soc. 2009, 131, 9651.
[10] For examples of the direct C-H functionalization of chromones and
enaminones, see: a) F. Chen, Z. Feng, C.-Y. He, H.-Y. Wang, Y.-L.
Guo, X. Zhang, Org. Lett. 2012, 14, 1176; b) D. Kim, S. Hong, Org.
Lett. 2011, 13, 4466; c) Y.-Y. Yu, M. J. Niphakis, G. I. Georg, Org.
Lett. 2011, 13, 5932; d) L. Bi, G. I. Georg, Org. Lett. 2011, 13, 5413;
e) D. Cheng, T. Gallagher, Org. Lett. 2009, 11, 2639; f) H. Geo,
M. J. Niphakis, G. I. Georg, J. Am. Chem. Soc. 2008, 130, 3708.
[11] a) Q. Liu, G. Li, H. Yi, P. Wu, J. Liu, A. Lei, Chem. Eur. J. 2011,
17, 2353; b) X. Mu, S. Chen, X. Zhen, G. Liu, Chem. Eur. J. 2011,
17, 6039; c) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J.
Gaunt, Angew. Chem. 2005, 117, 3185; Angew. Chem. Int. Ed. 2005,
44, 3125.
[12] In general, the activity of PdACHTUNGRE(TFA)2 was comparable or slightly
lower than that of PdACHTUNGRE(OAc)2.
[13] The reaction was conducted with chromone, benzene (30 equiv),
PdACHTUNGRE(OAc)2 (0.1 equiv), Ag2CO3 (1 equiv), and iPr2S (5 equiv) at
140 8C for 10 h.
[14] a) T. Phan, X.-M. Yu, M. Kunnimalaiyaan, H. Chen, J. Surg. Res.
2011, 170, 84; b) B. Y. Khoo, S. L. Chua, P. Balaram, Int. J. Mol.
Sci. 2010, 11, 2188.
Received: May 21, 2012
Published online: July 2, 2012
Asian J. Org. Chem. 2012, 1, 47 – 50