A facile route to flavone and neoflavone backbones via a regioselective palladium catalyzed oxidative Heck reaction

Article abstract of DOI:10.1039/c2cc18150a

A straightforward and atom-economical base-free palladium-catalyzed regioselective direct arylation of coumarins and chromenones is devised. This protocol is compatible with a wide variety of electron-donating and -withdrawing substituents and allows construction of various biologically important flavone and neoflavone backbones.

Full text of DOI:10.1039/c2cc18150a

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COMMUNICATION
A facile route to flavone and neoflavone backbones via a regioselective
palladium catalyzed oxidative Heck reactionw
Mehdi Khoobi,a Masoumeh Alipour,b Samaneh Zarei,b Farnaz Jafarpour*b and
Abbas Shafiee*a
Received 30th December 2011, Accepted 20th January 2012
DOI: 10.1039/c2cc18150a
A straightforward and atom-economical base-free palladium-
catalyzed regioselective direct arylation of coumarins and
chromenones is devised. This protocol is compatible with a wide
variety of electron-donating and -withdrawing substituents and
allows construction of various biologically important flavone and
neoflavone backbones.
bromo,12 triflate,13 tosylate,14 phosphonate15 and carbonate16
derivatives of coumarins with organoboron, -tin, -zinc,
-bismuth and -indium organometallic reagents has been
developed. An alternative procedure includes cross-coupling
reaction of aryl halides and 4-coumarinylzinc bromide, prepared
from bromocoumarin.17
Despite significant progress in this area, synthesis of
4-arylcoumarins via direct-arylation of unactivated coumarins
remains an unsolved problem. Although transition-metal
catalyzed installment of aryl groups on the pyranone ring is wider
in scope than older procedures, however, its application requires the
prior selective functionalization of the C-4 position of the coumarin
with a halogen or hydroxyl group which is not always trivial. Direct
functionalization of the desired scaffold through regioselective
C–H bond activation provides an efficient cost-effective and
atom-economical entry to these compounds as it eliminates the
need for introducing protecting groups and reactive function-
alities prior to C–C formation. One might therefore expect
that the development of general, atom-economical and regio-
selective arylation methods merits further consideration.
On the other hand, organoboron-mediated Heck-type reaction
is one of the most attractive metal-catalyzed reactions which
constitute a useful synthetic C–C bond-forming method. The
commercial availability of boron reagents, broad functional
group tolerance, low toxicity and general applicability of the
reaction contributed to its increasing importance in academic
and industrial research.18
Chromenone derivatives such as flavones (2-aryl-4H-4-
chromenones) and neoflavones (4-arylcoumarins) have attracted
considerable attention as a result of their interesting biological and
pharmacological activities and their presence in a variety of natural
products. Depending on the substitution pattern of neoflavones,
their antiprotozoal,1 anticancer,2–4 anti-HIV,5 antimalarial,6,7
antibacterial,8 and cytotoxic properties9 have been recognized.
Moreover several polyoxygenated 4-arylcoumarins have been
evaluated as neoflavonoid analogues of combretastatin A-4, an
anti-tubulin agent that targets the colchicine site.2 Furthermore,
2-aryl-4H-4-chromenones are very interesting structural scaffolds
with various biological and pharmaceutical activities and have
been assigned as privileged structures in drug development.10
Hence several methods for the construction of these privileged
motifs have been pursued during the past years.
Construction of 4-arylcoumarins is based on two conventional
strategies. First is the reactions in which benzopyranone rings
are closed via Pechmann, Perkin, Ponndorf, Houben-Hoesch
reactions11a and very recently catalytic hydroarylation of alkynes
as the key synthetic steps,11b,c and second is the reactions in
which coumarin frameworks activated at the 4-position are
arylated via transition-metal catalyzed cross-coupling reactions.
Compared with classical procedures, transition-metal mediated
cross-couplings result in various types of coumarin derivatives in
a divergent manner which is a highly promising tool for drug
discovery and development. In this regard, several research
groups are focused on the use of transition metals in the synthesis
of 4-arylated coumarins, and metal catalyzed coupling of
As part of our continuing efforts in metal-catalyzed C–H
bond functionalization of heterocycles,19 herein, we set out to
explore a cost-effective and atom-economical regioselective direct
arylation of chromenones via palladium-catalyzed oxidative boron
Heck-type reaction. This protocol should give economically viable
and environmentally attractive access to C2 and C4 arylated
chromenones.
To begin, coumarin 1a was chosen as the test substrate in
the oxidative Heck reaction with phenylboronic acid. The
feasibility of the reaction was tested by treating the substrates
under various reaction conditions (Table 1). Due to previous
reports which suggested a base-assisted b-elimination process
for the Heck type reaction with cyclic systems,18b we initiated
an investigation of base-mediated reaction. In this regard,
coumarin was treated with phenylboronic acid under oxygen-
promoted Pd(II)-catalyzed coupling reaction in the presence of
a Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, 14176, Tehran, Iran. E-mail: ashafiee@ams.ac.ir
b School of Chemistry, College of Science, University of Tehran,
P.O. Box 14155-6455, Tehran, Iran.
E-mail: jafarpur@khayam.ut.ac.ir
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c2cc18150a
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2985–2987 2985

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Table 2 Scope of the regioselective arylation of coumarinsa
Table 1 Screening of reaction conditions for the intermolecular
oxidative Heck-reaction of coumarin and phenylboronic acida
Yieldb (%)
Entry
R1
R2
Product
Yieldb (%)
3a
4
Entry Catalyst
Ligand
Base
Solvent
1
2
3
4
5
6
7
8
H 1a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
4-CH3 2b
4-CH2CH3 2c
4-CH2CH3 2c
4-CH3 2b
4-CH2CH3 2c
4-CH3 2b
4-Br 2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
85
88
72
68
71
74
73
76
68
77
84
82
80
68
0
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
—
Na2CO3 DMF
Na2CO3 DMF
K2CO3 DMF
KOAc DMF
K2HPO4 DMF
0
0
5
5
5
62
40
15
85
94
80
85
90
90
30
20
70
10
15
0
6-CH3 1b
6-NO2 1c
7-OH 1d
7-OCH3 1e
7-OCH2CH3 1f
H 1a
phen
phen
phen
phen
bpy
dmap
dmphen
phen
phen
phen
phen
phen
phen
—
—
—
—
—
—
—
—
—
—
—
DMF
DMF
DMF
DMF
Dioxane 68
ACN
Toluene
DMF
DMF
DMF
DMF
H 1a
9
6-NO2 1c
6-NO2 1c
6-CH3 1b
7-Cl 1g
6-CH3 1b
7-OH 1d
H 1a
9
10
11
12
13
14
15
10
11
12
13
14
15
16c
14
0
35
78
35
5
0
10
20
25
15
4-CH2CH3 2c
3-NO2 2e
Pd(acac)2
Pd(dppf)2Cl2 phen
Pd(dba)2 phen
a
All reactions were run under the following conditions: coumarin
1 (2 equiv.), arylboronic acid 2 (0.1 mmol), Pd(OAc)2 (10 mol%),
1,10-phenanthroline (20 mol%), O2 (balloon pressure) in DMF (0.4 M)
a
All reactions were run under the following conditions: coumarin
1a (2 equiv.), phenylboronic acid 2a (0.1 mmol), Pd catalyst (10 mol%),
ligand (20 mol%), O2 (balloon pressure) in the corresponding solvent
b
were heated in a sealed tube at 100 1C for 24 h. Isolated yields.
b
(0.4 M) were heated in a sealed tube at 100 1C for 24 h. Isolated yields.
30% of 3-arylated derivative 5 was also formed.
c
5 and low amounts of biphenyl 4 were obtained (entry 16).
A screening of oxidants such as Na2S2O8, BQ and Cu(OAc)2
was also conducted, but provided no improvements (see ESIw).
Using the optimized conditions, various electron-rich and
electron-poor coumarins were tested in their reaction with
phenylboronic acid (Table 2, entries 1–6). The results indicated
that the scope of the reaction was quite broad given that alkyl,
alkoxy, nitro, halo and hydroxyl substituents were tolerated.
The desired products were obtained in high yields and the
reactions were highly regioselective, with no 3-arylated coumarin
detected. The highest yield was obtained with methylcoumarin 1b
but also methoxy, ethoxy and nitro substituted coumarins
resulted in the corresponding 4-arylcoumarins in yields exceeding
70%. Furthermore, the tolerance of an unprotected hydroxyl
group on coumarin was noteworthy. Hydroxycoumarin 1d
reacted with phenylboronic acid to afford the desired product
with no requirement of hydroxyl protection. This feature is
ubiquitous in hydroxycoumarin based biologically active
products, which eliminates the requirement of protection and
deprotection of hydroxyl groups. Furthermore, we studied the
scope and limitations of the oxidative Heck arylation of coumarins
with various aryl boronic acids. The cross-coupling reaction of
alkyl substituted arylboronic acids and coumarins with various
electron releasing and withdrawing groups also proceeded
smoothly under the same optimized reaction conditions to give
the corresponding 4-arylcoumarins in moderate to high yields
(entries 7–14). However, 3-nitrophenylboronic acid did not react
under the optimized reaction conditions (entry 15). Furthermore,
both halo-substituted partners were tolerated under the reaction
conditions. 7-Chloro coumarin 1g arylated at the C-4 position in
82% yield and the 7-arylated adduct was not observed at
all (entry 12). 4-Bromophenylboronic acid 2d also showed
Pd(OAc)2 (10 mol%), Na2CO3 (2 equiv.) in DMF at 100 1C
for 24 h. However we found that the reaction was not
successful with Na2CO3 as the base, and 4, the boronic acid
homo-coupled product, was obtained solely (entry 1). Addition of
a ligand and screening of the bases also did not give any
satisfactory results (entries 2–5). The results revealed that inorganic
bases were incompatible with the proposed system. On the basis of
these results, we screened the reaction conditions to determine
optimal base-free conditions. In this regard some nitrogen ligands
which are supposed to work as not only a palladium ligand but
also a base participating in the b-elimination step were screened.
We were pleased to see that in the presence of 20 mol% of
bipyridine, 4-phenylcoumarin 3a was obtained in 62% yield
accompanied with 30% of the homo-coupling product 4
(entry 6). While N,N-dimethyl-4-aminopyridine and 2,9-dimethyl-
1,10-phenanthroline resulted in only moderate to low yields of the
desired product and large amounts of biphenyl (entries 7 and 8),
in the presence of phenanthroline as a ligand, the desired
4-arylcoumarin was constructed in 85% yield (entry 9). The
3-arylated product was not detected at all and the reaction
proceeded with minimal biphenyl formation. A screening of
solvents was then performed. Replacing DMF with other
solvents such as 1,4-dioxane and acetonitrile resulted in lower
yields (entries 10 and 11). In toluene, the reaction did not
proceed at all (entry 12). Subsequently, we sought optimal
conditions by screening various palladium sources. While with
PdCl2 and Pd(dppf)2Cl2 the conversions were unsatisfactorily
low (entries 13 and 15), Pd(acac)2 provided 3a in 78% yield
(entry 14). With Pd(dba)2 as the catalyst, only traces of the
desired product 3a along with 30% of 3-arylated coumarin
c
2986 Chem. Commun., 2012, 48, 2985–2987
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Table 3 Scope of the regioselective arylation of chromenonesa
We acknowledge the financial support of the Iran National
Science Foundation (INSF) and the University of Tehran.
Notes and references
1 J.-T. Pierson, A. Dumetre, S. Hutter, F. Delmas, M. Laget,
J.-P. Finet, N. Azas and S. Combes, Eur. J. Med. Chem., 2010,
45, 864.
2 C. Bailly, C. Bal, P. Barbier, S. Combes, J.-P. Finet,
M.-P. Hildebrand, V. Peyrot and N. Wattez, J. Med. Chem.,
2003, 46, 5437.
Entry R1
R2, R3
Product Yieldb (%)
1
2
3
4
5
6
7
8
9
10
H 6a
H, H 2a
4-OCH3, H 2f
2-OCH3, 4-OCH3 2g 7c
4-CH2CH3, H 2c
4-CH3, H 2b
4-Br, H 2d
7a
7b
86
80
88
92
90
85
91
81
77
0
3 C. Rappl, P. Barbier, V. Bourgarel-Rey, C. Gregoire, R. Gilli,
M. Carre, S. Combes, J.-P. Finet and V. Peyrot, Biochemistry,
2006, 45, 9210.
4 C. Billard, F. Menasria, C. Quiney, A. M. Faussat, J.-P. Finet,
S. Combes and J. P. Kolb, Exp. Hematol., 2008, 36, 1625.
5 A. D. Patil, A. J. Freyer, D. S. Eggleston, R. C. Haltiwanger,
M. F. Bean, P. B. Taylor, M. J. Caranfa, A. L. Breen,
H. R. Bartus, R. K. Johnson, R. P. Hertzberg and
J. W. Westley, J. Med. Chem., 1993, 36, 4131.
6 I. Kohler, K. Jenett-Siems, F. P. Mockenhaupt, K. Siems,
´
J. Jakupovic, J. C. Gonzalez, M. A. Hernandez, R. A. Ibarra,
W. G. Berendsohn, U. Bienzle and E. Eich, Planta Med., 2001,
67, 89.
7 R. Argotte-Ramos, G. Ramırez-Avila, M. C. Rodriguez-Gutierrez,
´
H 6a
H 6a
H 6a
H 6a
H 6a
7d
7e
7f
7-OCH3 6b 2-OCH3, 4-OCH3 2g 7g
7-OCH3 6b H, H 2a
7-OCH3 6b 4-CH2CH3, H 2c
7h
7i
7j
H 6a
3-NO2, H 2e
a
b
All reactions were run under the optimized conditions. Isolated yields.
compatibility with the reaction conditions and resulted in
the halogenated coumarin 3m, a good partner for further
functionalizations, in high yield (80%, entry 13).
M. Ovilla-Munoz, H. Lanz-Mendoza, M. H. Rodriguez,
M. Gonzalez-Cortazar and L. Alvarez, J. Nat. Prod., 2006,
69, 1442.
Motivated by these results, we next sought to expand the
scope of our system to regioselective arylation of a more
challenging substrate such as 4H-chromen-4-one. Like cyclo-
hexenone, chromenone is a typical example of a substrate
where mixtures are commonly noticed.
8 L. Verotta, E. Lovaglio, G. Vidari, P. V. Finzi, M. G. Neri,
A. Raimondi, S. Parapini, D. Taramelli, A. Riva and
E. Bombardelli, Phytochemistry, 2004, 65, 2867.
9 S.-F. Wu, F.-R. Chang, S.-Y. Wang, T.-L. Hwang, C.-L. Lee,
S.-L. Chen, C.-C. Wu and Y.-C. Wu, J. Nat. Prod., 2011, 74, 989.
10 J. Zhao, Y. Zhao and H. Fu, Angew. Chem., Int. Ed., 2011,
50, 3769.
We were pleased to see that under our optimized reaction
conditions, the reaction of chromenone 6a and phenylboronic
acid 2a proceeded with high regioselectivity to afford the
desired C-2 arylated adduct 7a in 86% yield (Table 3, entry 1).
Furthermore, methoxy substituted arylboronic acids 2f and 2g
provided the desired products 7b and 7c in 80% and 88% yields,
respectively (entries 2 and 3). 4-Alkyl substituted arylboronic
acids 2c and 2b also reacted with high efficiency and selectivity,
resulting in the desired products 7d and 7e in 92% and 90%
yields, respectively (entries 4 and 5). 40-Brominated flavone 7f
was also obtained in high yield (entry 6).
11 (a) M. M. Garazd, Ya. L. Garazd and V. P. Khilya, Chem. Nat.
Compd., 2005, 41, 245; (b) S. Kutubi, T. Hashimoto and
T. Kitamura, Synthesis, 2011, 1283; (c) Y. Yamamoto and
N. Kirai, Org. Lett., 2008, 10, 5513.
12 (a) L. Zhang, T. Meng, R. Fan and J. Wu, J. Org. Chem., 2007,
72, 7279; (b) M. L. N. Rao, V. Venkatesh and D. N. Jadhav, Eur.
J. Org. Chem., 2010, 3945.
13 For selected recent examples see: (a) S. Oh, H. J. Jang, S. K. Ko,
Y. Ko and S. B. Park, J. Comb. Chem., 2010, 12, 548;
(b) S. Combes, J.-T. Pierson, J.-P. Finet, P. Barbier,
S. Douillard, V. Bourgarel-Rey, V. Peyrot, A. McLeer-Florin,
J. Boutonnat and A. Yu. Fedorov, J. Med. Chem., 2011, 54, 3153.
14 For selected recent examples see: (a) J.-i. Kuroda, K. Inamoto,
K. Hiroya and T. Doi, Eur. J. Org. Chem., 2009, 2251; (b) Y. Luo
and J. Wu, Tetrahedron Lett., 2009, 50, 2103; (c) W. Gao, Y. Luo,
Q. Ding, Y. Peng and J. Wu, Tetrahedron Lett., 2010, 51, 136;
(d) P. Y. Wong, W. K. Chow, K. H. Chung, C. M. So, C. P. Lau
and F. Y. Kwong, Chem. Commun., 2011, 47, 8328; (e) C.-H. Xing,
J.-R. Lee, Z.-Y. Tang, J. R. Zheng and Q.-S. Hu, Adv. Synth.
Catal., 2011, 353, 2051.
Next it was desirable to extend the scope of this regioselective
arylation reaction to construct methoxy flavones as a superior
cancer chemopreventive flavonoid subclass with high hepatic
metabolic stability.20 In this regard, 7-methoxy chromenone 6b
was reacted with 2,4-dimethoxyphenylboronic acid 2g and the
result was gratifying (91% yield, entry 7). Also the cross-coupling
of 6b with unsubstituted and alkyl substituted arylboronic acids
proceeded successfully, affording the desired products 7h and 7i
in 81% and 77% yields, respectively (entries 8 and 9). The
reaction of chromenone with nitro substituted boronic acid
was not successful (entry 10).
15 J. Wu and Z. Yang, J. Org. Chem., 2001, 66, 7875.
16 L. Xu, B.-J. Li, Z.-H. Wu, X.-Y. Lu, B.-T. Guan, B.-Q. Wang and
K.-Q. Zhao, Org. Lett., 2010, 12, 884.
17 R. D. Rieke and S.-H. Kim, Tetrahedron Lett., 2011, 52, 3094.
18 For some selected examples see: (a) K. Yoshida and T. Hayashi, in
Boronic Acids, ed. D. G. Hall, Wiley-VCH, Weinheim, 2005;
(b) K. S. Yoo, C. H. Yoon and K. W. Jung, J. Am. Chem. Soc.,
2006, 128, 16384; (c) S. L. Buchwald and R. Martin, Acc. Chem.
Res., 2008, 41, 1461; (d) S. Wurtz and F. Glorius, Acc. Chem. Res.,
2008, 41, 1523; (e) J. H. Delcamp, A. P. Brucks and M. C. White,
J. Am. Chem. Soc., 2008, 130, 11270; (f) J. Ruan, X. Li, O. Saidi
and J. Xiao, J. Am. Chem. Soc., 2008, 130, 2424;
(g) G. A. Molander and B. Canturk, Angew. Chem., Int. Ed.,
2009, 48, 9240; (h) M. Tobisu and N. Chatani, Angew. Chem., Int.
Ed., 2009, 48, 3565.
In summary, we have developed a versatile, regioselective
and atom economical arylation of chromenones. This protocol
provides a straightforward route to biologically interesting
flavone or neoflavone backbones. It takes advantages of the
regioselective heteroarene functionalization precluding its
prefunctionalization, the no base requirements and the
compatibility with a wide range of substituents including
OH and halo functionalities. Investigation on broadening
the scope of the reaction toward the synthesis of biological
active targets is currently underway.
19 (a) F. Jafarpour and P. T. Ashtiani, J. Org. Chem., 2009, 74, 1364;
(b) F. Jafarpour, S. Rahiminejadan and H. Hazrati, J. Org. Chem.,
2010, 75, 3109; (c) F. Jafarpour and H. Hazrati, Adv. Synth. Catal.,
2010, 352, 363.
20 T. Walle, Mol. Pharmaceutics, 2007, 4, 826.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2985–2987 2987