General and efficient route for the synthesis of 3,4-disubstituted coumarins via Pd-catalyzed site-selective cross-coupling reactions

Article abstract of DOI:10.1021/jo071117+

(Chemical Equation Presented) Palladium-catalyzed site-selective cross-coupling reactions of 3-bromo-4-trifloxycoumarin or 3-bromo-4- tosyloxycoumarin provide an efficient and facile route for the synthesis of 3,4-disubstituted coumarins, which include 3,

Full text of DOI:10.1021/jo071117+

General and Efficient Route for the Synthesis of 3,4-Disubstituted
Coumarins via Pd-Catalyzed Site-Selective Cross-Coupling
Reactions
Liang Zhang,† Tianhao Meng,† Renhua Fan,† and Jie Wu*,†,‡
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai, 200433, People’s Republic of China, State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, People’s Republic of China
jie_wu@fudan.edu.cn
ReceiVed June 4, 2007
Palladium-catalyzed site-selective cross-coupling reactions of 3-bromo-4-trifloxycoumarin or 3-bromo-
4-tosyloxycoumarin provide an efficient and facile route for the synthesis of 3,4-disubstituted coumarins,
which include 3,4-diarylcoumarins, 3-amino-4-arylcoumarins, and 3-aryl-4-aminocoumarins. The order
of reactivity of the (pseudo)halide substituents in the coumarins was found to be 4-OTf > 3-Br > 4-OTs.
Introduction
marin-derived antibiotic used as a competitive inhibitor of the
bacterial ATP binding gyrase B subunit, blocking the negative
supercoiling of relaxed DNA.2a,d Lamellarin is utilized as a
selective inhibitor of HIV-1 integrase.2i Recently, we also
discovered that 4-substituted coumarins showed good anti-HCV
activity.3 The discovery of promising lead antivirus compounds
and their moderate activity warranted the development of
efficient and rapid syntheses and evaluations of analogous
structures in the search for better inhibitors. Thus, we initiated
The prominence of coumarin in natural products and biologi-
cally active molecules1 has promoted considerable efforts toward
their synthesis. As a “privileged” scaffold, coumarins show
interesting biological properties, especially for their anti-HIV
and antibiotic activities.2 For example, Novobiocin is a cou-
† Fudan University.
‡ Chinese Academy of Sciences.
(1) For selected examples, see: (a) Murakami, A.; Gao, G.; Omura, M.;
Yano, M.; Ito, C.; Furukawa, H.; Takahashi, D.; Koshimizu, K.; Ohigashi,
H. Bioorg. Med. Chem. Lett. 2000, 10, 59. (b) Maier, W.; Schmidt, J.; Nimtz,
M.; Wray, V.; Strack, D. Phytochemistry 2000, 54, 473. (c) Garcia-Argaez,
A. N.; Ramirez, Apan, T. O.; Delgado, H. P.; Velazquez, G.; Martinez-
Vazquez, M. Planta Med. 2000, 66, 279. (d) Zhou, P.; Takaishi, Y.; Duan,
H.; Chen, B.; Honda, G.; Itoh, M.; Takeda, Y.; Kodzhimatov, O. K.; Lee,
K-H. Phytochemistry 2000, 53, 689. (e) Khalmuradov, M. A.; Said-
khodzhaev, A. I. Chem. Nat. Compd. 1999, 35, 364. (f) Kamalam, M.;
Jegadeesan, M. Indian Drugs 1999, 36, 484. (g) Tan, R. X.; Lu, H.;
Wolfender, J. L.; Yu, T. T.; Zheng, W. F.; Yang, L.; Gafner, S.;
Hostettmann, K. Planta Med. 1999, 65, 64. (h) Vlietinck, A. J.; De Bruyne,
T.; Apers, S.; Pieters, L. A. Planta Med. 1998, 64, 97. (i) Bal-Tembe, S.;
Joshi, D. D.; Lakdawala, A. D. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1996, 35B, 518. (j) Silvan, A. M.; Abad, M. J.; Bermejo, P.;
Villar, A.; Sollhuber, M. J. Nat. Prod. 1996, 59, 1183. (k) Yang, Y. M.;
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Tomizawa, J. I. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474, 4478. (b)
Murray, R. D. H.; Me´ndez, J.; Brown, S. A. The Natural Coumarins:
Occurrence, Chemistry, and Biochemistry; Wiley: New York, 1982. (c)
Ali, J. A.; Jackson, A. P.; Howells, A. J.; Maxwell, A. Biochemistry 1993,
32, 2717. (d) Pereira, N. A.; Pereira, B. M. R.; Celia, do Nascimento, M.;
Parente, J. P.; Mors, W. B. Planta Med. 1994, 60, 99. (e) Vlietinck, A. J.;
De Bruyne, T.; Apers, S.; Pieters, L. A. Planta Med. 1998, 64, 97. (f)
Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa, H.;
Takahashi, D.; Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett. 2000,
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Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001,
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10.1021/jo071117+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/18/2007
J. Org. Chem. 2007, 72, 7279-7286
7279

Zhang et al.
of a variety of 3,4-disubstituted coumarins by using the
palladium-catalyzed coupling of o-iodophenols with internal
alkynes and carbon monoxide. When a series of phenylalky-
lacetylenes was employed in the reaction, mixtures of regioi-
somers were obtained in all cases with modest regioselectivity.7j
Thus, it is of great interest to develop general protocols for the
synthesis of 3,4-disubstituted coumarins under mild reaction
conditions.
FIGURE 1. Diversified coumarins.
Transition-metal-catalyzed cross-coupling reactions with mul-
tifunctional substrates which proceed stepwise and display site-
selectivity are particularly attractive for synthetic chemists.
Diversified structures, often containing bioactive scaffolds, could
be generated via successive introduction of various substituents
in specific positions of the molecular skeleton. A number of
compounds bearing two or more leaving groups, especially
dihaloheteroarenes, have proven to be suitable partners for this
kind of transformation.8 Inspired by the recent advances of site-
selective transition-metal-catalyzed dicoupling reactions,8k we
conceived that the synthesis of differentially 3,4-disubstituted
coumarins could be achieved via Pd-catalyzed regioselective
cross-coupling reactions. The key step in our program is
installing R1 and R2 groups to the C-4 and C-3 positions of the
coumarin scaffold. By attaching leaving groups of different
reactivities to the electronically different C-3 and C-4 positions,
two substituents were expected to be successively installed into
the coumarin moiety. This controllable site-selectivity comes
from the chemoselectivity. We envisioned this strategy should
be particularly useful for the facile and concise synthesis of
diversified coumarin derivatives. Herein, we describe our efforts
for palladium-catalyzed site-selective dicouplings of 3-bromo-
4-trifloxycoumarins or 3-bromo-4-tosyloxycoumarins for the
synthesis of differentially 3,4-disubstituted coumarins.
a program to develop efficient methods for the synthesis of
diversified coumarin molecules (Figure 1), with the hope of
finding more active hits or leads for our particular biological
assays.
Although there are classical methods, such as the Perkin and
Pechman reactions,4 for the synthesis of a wide variety of
substituted coumarins, these methods often require the use of
strong acids and high temperatures. The scope of these
transformations is therefore somewhat limited. Recent research
has centered on the use of palladium-catalyzed C-C bond
formation leading to the 3- or 4-substituted coumarins,5 and the
number of transition-metal-catalyzed approaches for accessing
coumarins is increasing.6 However, most of these approaches
are focused on monosubstituted coumarins. Only limited ap-
plications of transition-metal-catalyzed reactions for the syn-
thesis of 3,4-disubstituted coumarins have been reported;
however, these impose restrictions upon substituent diversity
and also suffer from regioselectivity problems.7 For example,
Larock7i,j reported a novel synthetic method for the synthesis
(4) For selected examples, see: (a) von Pechmann, H.; Duisberg, C.
Chem. Ber. 1884, 17, 929. (b) Johnson, J. R. Org. React. 1942, 1, 210. (c)
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1942, 1, 1. (f) Narasimhan, N. S.; Mali, R. S.; Barve, M. V. Synthesis 1979,
906. (g) Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A. Tetrahedron Lett. 1998,
39, 2391. (h) Cartwright, G. A.; McNab, W. J. Chem. Res. (S) 1997, 296.
(i) Alexander, V. M.; Bhat, R. P.; Samant, S. D. Tetrahedron Lett. 2005,
46, 6957 and references cited therein. (j) Sengh, V.; Sengh, J.; Kaur, K. P.;
Kad, G. L. J. Chem. Res. (S) 1997, 58. (k) Frere, S.; Thiery, V.; Besson, T.
Tetrahedron Lett. 2001, 42, 2791. (l) John, E. V. O.; Israelstam, S. S. J.
Org. Chem. 1961, 26, 240. (m) Hoefnagel, A. J.; Gennewagh, E. A.;
Downing, R. S.; Bekkum, H. V. J. Chem. Soc., Chem. Commun. 1995,
225. (n) Wu, J.; Diao, T.-N.; Sun, W.; Li, Y. Synth. Commun. 2006, 36,
2949. (o) Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R.
Tetrahedron Lett. 2005, 46, 6119.
(5) For examples, see: (a) Tang, Z. Y.; Hu, Q.-S. AdV. Synth. Catal.
2004, 346, 1635. (b) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66,
3642. (c) Lei, J.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2004, 2364. (d) Wu, J.;
Wang, L.; Fathi, R.; Yang, Z. Tetrahedron Lett. 2002, 43, 4395. (e) Schio,
L.; Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41, 1543. (f) Yao,
M.-L.; Deng, M.-Z. Heterocycl. Chem. 2000, 11, 380. (g) Wu, J.; Yang, Z.
J. Org. Chem. 2001, 66, 7875.
(6) (a) Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669 and references cited
therein. (b) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.; Kitamura,
T.; Fujiwara, Y. Science 2000, 287, 1992. (c) Fu¨rstner, A.; Mamane, V. J.
Org. Chem. 2002, 67, 6264. (d) Pastine, S. J.; Youn, S. W.; Sames, D.
Org. Lett. 2003, 5, 1055. (e) Youn, S. W.; Pastine, S. J.; Sames, D. Org.
Lett. 2004, 6, 581.
(7) (a) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C. -H. Angew. Chem.,
Int. Ed. 2001, 40, 1286. (b) Yoneda, E.; Sugioka, T.; Hirao, K.; Zhang,
S.-W.; Takahashi, S. J. Chem. Soc., Perkin Trans. 1 1998, 477. (c) Van, T.
N.; Debenedetti, S.; De Kimpe, N. Tetrahedron Lett. 2003, 44, 4199. (d)
Catellani, M.; Chuisoli, G. P.; Fagnola, M. C.; Solari, G. Tetrahedron Lett.
1994, 35, 5919. (e) Catellani, M.; Chiusoli, G. P.; Fagnola, M. C.; Solari,
G. Tetrahedron Lett. 1994, 35, 5923. (f) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 1996, 118, 6305. (g) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.;
Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992. (h) Jia, C.; Piao, D.;
Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000, 65, 7516. (i) Kadnikov, D.
V.; Larock, R. C. Org. Lett. 2000, 2, 3643. (j) Kadnikov, D. V.; Larock, R.
C. J. Org. Chem. 2003, 68, 9423. (k) Kitamura, T.; Yamamoto, K.; Kotani,
M.; Oyamada, J.; Jia, C.; Fujiwara, Y. Bull. Chem. Soc. Jpn. 2003, 76,
1889. (l) An, Z.; Catellani, M.; Chiusoli, G. P. Gazz. Chim. Ital. 1990,
120, 383. (m) Park, K. H.; Jung, G., II; Chung, Y. K. Synlett 2004, 2541.
Results and Discussion
Our strategy is based on the decoration of the readily available
coumarin core structure using site-selective cross-coupling
reactions. The key compound in our overall synthetic route was
identified as 4-hydroxycoumain. It is well-known that 4-hy-
droxycoumarins are useful intermediates for many industrial
products and several methods for their preparation have been
reported.9 Prompted by the recent advances of halogenation of
1,3-dicarbonyl compounds,10 we envisioned that 3-bromo-4-
(8) (a) Review on site-selective cross-coupling reactions of multiple
halogenated heterocycles, see: Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron
2005, 61, 2245. Selected examples: (b) Zezschwitz, P.; Petry, F.; Meijere,
A. Chem. Eur. J. 2001, 7, 4035. (c) Voigt, K.; Zezschwitz, P.; Rosauer,
K.; Lansky, A.; Adams, A.; Reiser, O.; Meijere, A. Eur. J. Org. Chem.
1998, 1521. (d) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537. (e)
Duan, X.-F.; Li, X.-H.; Li, F.-Y.; Huang, C.-H. Synthesis 2004, 2614. (f)
Kaswasaki, I.; Yamashita, M.; Ohta, S. J. Chem. Soc., Chem. Commun.
1994, 2085. (g) Bellina, F.; Anselmi, A.; Martina, F.; Rossi, R. Eur. J.
Org. Chem. 2003, 2290. (h) Bellina, F.; Falchi, E.; Rossi, R. Tetrahedron
2003, 59, 9091. (i) Christoforou, I. C.; Koutentis, P. A. Org. Biomol. Chem.
2007, 5, 1381. (j) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Org.
Lett. 2006, 8, 5389. (k) Conreaux, D.; Bossharth, E.; Monteiro, N.;
Desbordes, P.; Vors, J.; Balme, G. Org. Lett. 2007, 9, 271. (l) Pereira, R.;
Furst, A.; Iglesias, B.; Germain, P.; Gronemeyerb, H.; Lera, A. R. Org.
Biomol. Chem. 2006, 4, 4514. (m) Araujo-Junior, J. X.; Schmitt, M.;
Benderittera, P.; Bourguignon, J. Tetrahedron Lett. 2006, 47, 6125. (n) Dang,
T. T.; Rasool, N.; Dang, T. T.; Reinkea, H.; Langer, P. Tetrahedron Lett.
2007, 48, 845.
(9) Selected examples: (a) Jung, J.-C.; Jung, Y.-J.; Park, O.-S. Synth.
Commun. 2001, 31, 1195. (b) Kalinin, A. V.; Da, S.; Alcides, J. M.; Lopes,
C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4995. (c)
Mizuno, T.; Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda,
N. Synthesis 1988, 257.
7280 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of 3,4-Disubstituted Coumarins
SCHEME 1. Synthesis of 3-Bromo-4-trifloxycoumarin 2a or 3-Bromo-4-tosyloxycoumarin 3a from 4-Hydroxycoumarin
TABLE 1. Monocoupling of 2a with 4-Methoxyphenylboronic
Acida
SCHEME 2. Synthesis of 3-Bromo-4-arylcoumarin 4
entry
catalyst
base
yield (%)b
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
K2HPO4‚3H2O
K2HPO4‚3H2O
K2HPO4‚3H2O
K2HPO4‚3H2O
KF‚2H2O
72
70c
68d
75
30
40
85
98
38
63
K3PO4
Na2CO3
NaHCO3
K2CO3
CsOAc
10
a Reaction conditions: substrate (0.30 mmol), arylboronic acid (1.1
equiv), [Pd] (5 mol %), methanol (2.0 mL), base (3.0 equiv), rt, 15 min.
b Isolated yield. c With 10 mol % of PCy3. d At 0 °C, 3 h.
yield), although combined with a small amount of bis-arylated
product as a slight excess of the boronic acid was needed to
ensure complete conversion of starting material 2a (Table 1,
entry 1). This result established that the coupling reaction
proceeds essentially at C-4 rather than at C-3. The yield of 4a
could not be improved by the addition of a phosphine ligand or
changing reaction temperature (Table 1, entries 2 and 3). To
our delight, excellent yield was obtained when Pd(PhCN)2Cl2-
was employed as a catalyst and NaHCO3 was used as a base
(Table 1, entry 8, 98% yield).
To demonstrate the generality of this strategy, the method
was applied to other arylboronic acids. Remarkably, both
electron-rich and electron-poor arylboronic acids are suitable
partners in this process, affording the corresponding monosub-
stituted products in good to excellent yields (Scheme 2).
To further diversify the monocoupled coumarins, we then
explored the reactivity of the remaining bromide atom at the
C-3 position. After screening, Pd(OAc)2 was found to be the
best catalyst, and K2HPO4‚3H2O was the choice of base. The
corresponding disubstituted products were afforded in good to
excellent yields by using tricyclohexylphosphine as the ligand
at 60 °C (Table 2). It was found that electron-withdrawing as
well as electron-donating substituents attached on arylboronic
acids are tolerated under these conditions. The success of this
method opens a new access to unsymmetrically bis-arylated
coumarins.
Symmetrically 3,4-diarylated coumarins can also be directly
generated under suitable conditions. For example, by increasing
the amount of arylboronic acid to 3.0 equiv compared to
substrate, reaction of 3-bromo-4-trifloxycoumarin 2a with
4-methoxyphenylboronic acid leads to the corresponding
symmetrically 3,4-diarylated coumarin 5a in 81% yield. This
hydroxycoumarin could be generated by treatment of 4-hy-
droxycoumarin with NBS/Mg(ClO4)2. Further treatment with
Tf2O or TsCl in the presence of base afforded the 3-bromo-4-
trifloxycoumarin 2a or 3-bromo-4-tosyloxycoumarin 3a, re-
spectively (Scheme 1).
Among transition-metal-catalyzed cross-coupling reactions,
the Suzuki-Miyaura coupling is probably most widely used in
both the laboratory and industry, due to the great functional
group tolerance of this transformation and the innocuous nature
of boronic acids, which are generally nontoxic and thermally,
air, and moisture stable.11 Thus, initial studies were carried out
for the palladium-catalyzed reaction of 3-bromo-4-trifloxycou-
marin 2a with 4-methoxyphenylboronic acid (Table 1). The
reactivity of the vinyl trifloxy group is favored over vinyl
bromide in cross-coupling reactions,12 and we reasoned that the
electron-withdrawing property of the ester group in compound
2a may also facilitate the oxidative addition step of the C-4
trifloxy group. As expected, we observed the formation of the
4-arylcoumarin 4a as the only monocoupled product (72%
(10) Yang, D.; Yan, Y.-L.; Lui, B. J. Org. Chem. 2002, 67, 7429.
(11) For recent reviews, see: (a) Miyaura, N. Top. Curr. Chem. 2002,
219, 11. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Littke, A.
F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(12) For selected examples, see: (a) De Meijere, A.; Diederich, F. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; John Wiley & Sons:
Weinheim, Germany, 2004. (b) Lesuisse, D.; Albert, E.; Bouchoux, F.;
Cerede, E.; Lefrancois, J.; Levif, M.; Tessier, S.; Trica, B.; Teutscha. G.
Bioorg. Med. Chem. Lett. 2001, 1709. (c) Echavarren, A. M.; Stille, J. K.
J. Am. Chem. Soc. 1987, 109, 5478. (d) Chan, D. C. M.; Fu, H.; Forsch, R.
A.; Queener, S. F.; Rosowsky, A. J. Med. Chem. 2005, 48, 4420. (e)
Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 8146. (f) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest,
R. L. J. Org. Chem. 2003, 68, 7379. (g) Wu, X.; Nilsson, P.; Larhed, M.
J. Org. Chem. 2005, 70, 346.
J. Org. Chem, Vol. 72, No. 19, 2007 7281

Zhang et al.
TABLE 2. Cross-Coupling Reaction of 4 with Arylboronic Acidsa
position. Tosylate was also selected because 3-bromo-4-tosy-
loxycoumarin 3a could be easily accessed as described previ-
ously, and has the additional benefit of being more stable than
3-bromo-4-trifloxycoumarin 2a.
To explore the possibility of C-3/C-4 selectivity, we again
choose arylboronic acid as the reaction partner (screening results
are shown in Table 3). Treatment of 3-bromo-4-tosyloxycou-
marin 3a with 2-methoxyphenylboronic acid under modified
conditions from Scheme 2 did afford the desired C-3 mono-
coupled product 7a in 9% yield (Table 3, entry 4). Encouraged
by this result, reaction conditions were systematically investi-
gated. It was noted that Pd(0) catalysts and phosphine ligand-
containing palladium complexes improved the yield of 7a
dramatically (Table 3, entries 1-6). In conjunction with Pd-
(PPh3)4, NaHCO3 was the best base after screening (Table 3,
entry 14). Sterically hindered electron-rich phosphine ligands
were found to be somewhat beneficial to this transformation
(Table 3, entries 15-24), and 62% yield of product 7a was
generated when P(2,6-dimethoxyphenyl)3 was utilized as the
ligand (Table 3, entry 22). The THF/H2O cosolvent remained
the one of choice. Meanwhile, it was found that water was
crucial to the reaction with only a trace amount of product was
detected in the absence of water. Increasing the amount of
2-methoxyphenylboronic acid (1.5 equiv) reduced 7a yield
(47%) as the excess boronic acid facilitated the generation of
disubstituted product (result not shown in Table 3).
entry
substrate 4
R2
product 5
yield (%)b
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4c
4c
4e
4f
4-MeOC6H4
4-CF3OC6H4
4-MeC6H4
C6H5
4-NO2C6H4
4-MeO2CC6H4
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
98
96
92
83
46
68
94
96
81
83
10
5j
a Reaction conditions: substrate (0.30 mmol), arylboronic acid (1.5
equiv), Pd(OAc)2 (5 mol %), PCy3 (10 mol %), K2HPO4‚3H2O (3.0 equiv),
methanol (2.0 mL), 60 °C, 0.5-1.0 h. b Isolated yield.
SCHEME 3. Synthesis of 3,4-Diarylcoumarin 5 or 6
The optimized conditions showed that the coupling reaction
proceeded essentially at the C-3 position. Thus, reverse site-
selectivity was displayed by replacing the trifloxy group with a
tosyloxy group at the C-4 position of the coumarin scaffold.
Selectivity of C-3 to C-4 substitution would be helpful at this
point. Modulation of site-selectivity based on this strategy is
of great significance since more complexity can now be
introduced. The generality of this new protocol was thus further
investigated (Table 4). As shown, in most of cases, different
substituted arylboronic acids furnished the corresponding
3-monoarylated products in moderate to good yields. Better
results were observed when arylboronic acids bearing electron-
donation groups were utilized. For instance, compound 3a
reacted with 4-methoxyphenylboronic acid, leading to the
desired product 7e in 75% yield (Table 4, entry 5), while 24%
yield of product 7f was afforded when 4-(methoxycarbonyl)-
phenylboronic acid was employed in the reaction (Table 4, entry
6). These conditions also proved to be useful for fluoro-
substituted coumarin derivative 3b as well (entries 7 and 8).
As the remaining tosyloxy group at the C-4 position of
compounds 7 is in principle coupling with another arylboronic
acid, the 3-monoarylated coumarins could be further elaborated
to unsymmetrically diarylated coumarin derivatives. To our
delight, this protocol proceeded successfully under the conditions
shown in Table 2, although a slightly longer reaction time was
needed (Table 5). The reactions of various arylboronic acids
with different 3-monoarylated coumarins occurred smoothly,
leading to the corresponding 3,4-disubstituted coumarins in
excellent yields. For example, 4-(trifluoromethoxy)phenylbo-
protocol proved to be very useful for a range of arylbor-
onic acids, affording the desired products in good yields
(Scheme 3).
Toward the goal of a diversified library of coumarins,
different consecutive transformations were expected to furnish
coumarin derivatives of more molecular complexity. However,
in some cases initial functionalization at C-3 of the coumarin
nucleus is required. That means a C-3/C-4 reaction order. Such
a reverse site-selectivity in favor of the less electron-deficient
position may be expected if a newly introduced leaving group
deactivates the usual preference for C-4 regioselectivity. Con-
sidering the inert reactivity of tosylate over bromide in Suzuki-
Miyaura cross-coupling reactions,13,14 we hypothesized that a
tosyloxy group at the C-4 position of the coumarin core would
decrease the reactivity of this more electron-deficient position,
and that the site-selectivity may even be redirected to the C-3
(14) For examples, see: (a) Santana, L.; Uriarte, E.; Gonzalez-Diaz, H.;
Zagotto, G.; Soto-Otero, R.; Mendez-Alvarez, E. J. Med. Chem. 2006, 49,
1149. (b) Rivkin, A.; Adams, B. Tetrahedron Lett. 2006, 47, 2395. (c)
Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron Lett. 2006,
47, 3755 and references cited therein. (d) Gellert, M.; O’Dea, M. H.; Itoh,
T.; Tomizawa, J. I. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474. (e) Pereira,
N. A.; Pereira, B. M. R.; Celia do Nascimento, M.; Parente, J. P.; Mors,
W. B. Planta Med. 1994, 60, 99. (f) Levine, C.; Hiasa, H.; Marians, K. J.
Biochim. Biophys. Acta 1998, 29.
(13) For examples, see: (a) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc.
2004, 126, 3058. (b) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 11818.
7282 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of 3,4-Disubstituted Coumarins
TABLE 3. Conditions Screened for Monocoupling of 3-Bromo-4-tosyloxycoumarin 3a with 2-Methoxyphenylboronic Acida
a Reaction conditions: substrate (0.30 mmol), arylboronic acid (1.1 equiv), [Pd] catalyst (5 mol %), ligand (10 mol %), solvent (2.0 mL), base (4.0 equiv,
1.0 M in H2O), 60 °C, 24 h. b Isolated yield.
J. Org. Chem, Vol. 72, No. 19, 2007 7283

Zhang et al.
TABLE 4. Monocoupling of 3-Bromo-4-tosyloxycoumarin 3 with Arylboronic Acida
entry
substrate
R1
product
yield (%)b
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3b
2-MeOC6H4
4-CF3OC6H4
4-MeC6H4
7a
7b
7c
7d
7e
7f
62
70
42
54
75
24
48
32
C6H5
4-MeOC6H4
4-MeO2CC6H4
4-MeOC6H4
2-MeOC6H4
7g
7h
a Reaction conditions: substrate (0.30 mmol), arylboronic acid (1.1 equiv), Pd(PPh3)4 (5 mol %), P(2,6-dimethoxyphenyl)3 (10 mol %), THF (2.0 mL),
NaHCO3 (4.0 equiv, 1.0 M in H2O), 60 °C, 24 h. b Isolated yield.
TABLE 5. Second Monocoupling of Compound 7 with
Arylboronic Acidsa
SCHEME 4. Synthesis of 3,4-Diarylcoumarin 5 or 6
entry
substrate
R2
product
yield (%)b
1
2
3
4
5
6
7
7e
7e
7e
7e
7e
7c
7c
4-MeOC6H4
4-CF3OC6H4
4-MeC6H4
C6H5
4-MeO2CC6H4
4-MeC6H4
4-MeOC6H4
5a
5k
5l
5f
5j
92
99
93
94
74
92
93
6a
5c
a Reaction conditions: substrate (0.30 mmol), arylboronic acid
(1.5 equiv), Pd(OAc)2 (5 mol %), PCy3 (10 mol %), K2HPO4‚3H2O (3.0
equiv., methanol (2.0 mL), 60 °C, 1-5 h. b Isolated yield.
ronic acid coupled with compound 7e gave the product 5g in
almost quantitative yield (Table 5, entry 2). Reaction of
compound 7e with 4-(methoxycarbonyl)phenylboronic acid also
gave the corresponding product 5j in 74% yield (Table 5,
entry 5).
SCHEME 5. One-Pot Synthesis of Bis-Arylated Coumarins
Similarly, symmetrically 3,4-diarylated coumarins 5 or 6
could be generated under the conditions shown in Scheme 3,
from the reactions of 3-bromo-4-tosyloxycoumarin 3a with
arylboronic acid (3.0 equiv). Again, excellent yields were
observed for this kind of transformation when arylboronic acids
bearing electron-donation groups were used (Scheme 4). Inferior
results was displayed in the presence of 4-(methoxycarbonyl)-
phenylboronic acid (56% yield).
We also tried the one-pot synthesis of the 3,4-disubstituted
coumarins from 3-bromo-4-trifloxycoumarin 2a or 3-bromo-4-
tosyloxycoumarin 3a (Scheme 5). For example, reaction of
3-bromo-4-trifloxycoumarin 2a with 4-methoxyphenylboronic
acid and 4-(trifluoromethoxy)phenylboronic acid subsequently
afforded the desire product 5b in 16% yield (Scheme 5, eq 1).
However, only a trace amount of product 5c was detected when
3-bromo-4-tosyloxycoumarin 3a was utilized as the substrate
(Scheme 5, eq 2).
Hartwig amination of bromine derivative 4c with p-anisidine
in the presence of Pd2(dba)3 and Xantphos provided the
corresponding 3-amino-4-aryl coumarin 8 in 74% yield (Scheme
6, eq 1). While the 3-aminocoumarin core is a ubiquitous subunit
in many natural products with remarkable biological activities,14
the 4-aminocoumarin scaffold is extensively incorporated in
Armed with this encouraging strategy of tunable site-selective
dicouplings, we briefly explored the synthetic application of
this work for diversified coumarins. For example, Buchwald-
7284 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of 3,4-Disubstituted Coumarins
SCHEME 6. Synthesis of 3-Amino-4-arylcoumarin or
3-Aryl-4-aminocoumarin
m/z 385 (M+). Anal. Calcd for C16H8BrF3O3: C, 49.90; H, 2.09.
Found: C, 50.05; H, 2.10.
General Procedure for the Pd-Catalyzed Cross-Coupling of
Compound 4 with Arylboronic Acids (Table 2). K2HPO4‚3H2O
(0.90 mmol, 3.0 equiv) was added to a mixture of compound 4
(0.30 mmol), arylboronic acid (1.5 equiv), Pd(OAc)2 (5 mol %),
and PCy3 (10 mol %) in methanol (2.0 mL). The reaction mixture
was stirred at 60 °C for a period of time. After completion of the
reaction as indicated by TLC, the mixture was cooled to room
temperature and purified directly by flash column chromatography
on silica gel to afford the corresponding product 5. Selected
examples: 4-(4-Methoxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-
2H-chromen-2-one (5b): 96% yield. 1H NMR (400 MHz, CDCl3)
δ (ppm) 3.80 (s, 3H), 6.83 (d, J ) 8.7 Hz, 2H), 7.00-7.05 (m,
4H), 7.14-7.22 (m, 3H), 7.29 (d, J ) 8.3 Hz, 1H), 7.40 (d, J )
8.2 Hz, 1H), 7.52 (t, J ) 7.8 Hz, 1H). 13C NMR (100 MHz) δ
(ppm) 161.2, 159.8, 153.4, 152.2, 148.5, 132.9, 132.4, 131.8, 130.9,
128.0, 126.2, 125.5, 124.3, 121.7, 120.6, 120.2, 119.2, 116.9, 116.6,
114.0, 55.3. MS m/z 413 (M+ + 1). Anal. Calcd for C23H15F3O4:
C, 66.99; H, 3.67. Found: C, 66.72; H, 3.52. 4-(4-Methoxyphenyl)-
3-phenyl-2H-chromen-2-one (5d):16d 83% yield. 1H NMR (400
MHz, CDCl3) δ (ppm) 3.78 (s, 3H), 6.81 (d, J ) 8.7 Hz, 2H), 7.02
(d, J ) 8.2 Hz, 2H), 7.11-7.21 (m, 6H), 7.28 (dd, J ) 8.3, 1.4
Hz, 1H), 7.40 (d, J ) 8.2 Hz, 1H), 7.50 (t, J ) 8.3 Hz, 1H). 13C
NMR (100 MHz) δ (ppm) 161.5, 159.5, 153.3, 151.5, 134.2, 131.5,
130.9, 130.7, 127.9 (5), 127.9 (1), 127.6, 127.0, 126.6, 124.2, 120.8,
116.9, 113.8, 55.3.
fluorescent brighteners.15 4-Amino-3-aryl coumarin 9 was
generated by consecutive Suzuki-Miyaura reaction/nucleophilic
substitution of 3-aryl-4-tosyloxy coumarin 7e (Scheme 6, eq
2). These promising results displayed the potential of this
strategy for numerous synthetic applications to diversified
coumarins.
In summary, on the basis of different selectivities of 3-bromo-
4-trifloxycoumarins and 3-bromo-4-tosyloxycoumarins in Su-
zuki-Miyaura cross-couplings, we have developed a tunable
strategy that allows Pd-catalyzed dicoupling reactions to proceed
in reversible sequences. This new protocol tremendously
facilitates the concise synthesis of diversified 3,4-diarylated
coumarins, especially unsymmetrically 3,4-diarylated ones.
Since both monocoupled intermediates from 3-bromo-4-tri-
floxycoumarins and 3-bromo-4-tosyloxycoumarins can be fur-
ther elaborated by many other transformations, this work now
opens the door for numerous synthetic applications to diversified
coumarins. Efforts toward this goal and screening for biological
activity of these small molecules are being undertaken in our
laboratory.
General Procedure for the Pd-Catalyzed Cross-Coupling of
2a with Arylboronic Acids (Scheme 3). A mixture of compound
2a (0.30 mmol), arylboronic acid (3.0 equiv), Pd(OAc)2 (5 mol
%), PCy3 (10 mol %), and K2HPO4‚3H2O (3.0 equiv) in methanol
(2.0 mL) was stirred at 60 °C for a period of time. After completion
of the reaction as indicated by TLC, the mixture was cooled to
room temperature and purified directly by flash column chroma-
tography on silica gel to afford the corresponding product. Selected
examples: 3,4-Diphenyl-2H-chromen-2-one (5g):16c 83% yield. 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.11-7.22 (m, 9H), 7.20-
7.32 (m, 3H), 7.42 (d, J ) 8.3 Hz, 1H), 7.51-7.55 (m, 1H). 13C
NMR (100 MHz) δ (ppm) 161.3, 153.2, 151.6, 134.5, 133.9, 131.4,
130.5, 129.4, 128.3 (3), 128.2 (5), 127.8, 127.7, 127.6, 127.0, 124.1,
120.5, 116.8. 3,4-Di(4-(methoxycarbonyl)phenyl)-2H-chromen-2-
1
one (6c): 81% yield. H NMR (400 MHz, CDCl3) δ (ppm) 3.85
Experiment Section
(s, 3H), 3.89 (s, 3H), 7.11-7.21 (m, 6H), 7.42 (d, J ) 7.8 Hz,
1H), 7.53-7.58 (m, 1H), 7.83 (d, J ) 8.7 Hz, 2H), 7.96 (d, J )
8.7 Hz, 2H). 13C NMR (100 MHz) δ (ppm) 166.6, 166.3, 160.6,
153.4, 151.3, 138.8, 138.4, 132.2, 130.7, 130.5, 129.8, 129.6, 129.5,
129.2, 127.6, 126.4, 124.6, 119.8, 117.1,52.4, 52.2. MS m/z 415
(M+ + 1). Anal. Calcd for C25H18O6: C, 72.46; H, 4.38. Found:
C, 72.51; H, 4.00.
General Procedure for the Pd-Catalyzed Monocoupling of
2a with Arylboronic Acids (Scheme 2). Under nitrogen atmo-
sphere, a mixture of compound 2a (0.30 mmol), arylboronic acid
(1.1 equiv), Pd(PhCN)2Cl2 (5 mol %), and NaHCO3 (3.0 equiv) in
methanol (2.0 mL) was stirred at room temperature for a period of
time. After completion of the reaction as indicated by TLC, the
reaction mixture was purified directly by flash column chroma-
tography on silica gel to afford the corresponding product 4.
Selected examples: 3-Bromo-4-(4-methoxyphenyl)-2H-chromen-
2-one (4a): 98% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.91
(s, 3H), 7.07 (d, J ) 8.8 Hz, 2H), 7.15-7.27 (m, 4H), 7.39 (d, J
) 8.0 Hz, 1H), 7.54-7.58 (m, 1H). 13C NMR (100 MHz) δ (ppm)
160.3, 157.4, 154.5, 152.4, 131.9, 129.8, 127.7, 127.3, 124.6, 120.5,
116.8, 114.2, 112.8, 55.4. MS m/z 331 (M+). Anal. Calcd for C16H11-
BrO3: C, 58.03; H, 3.35. Found: C, 58.05; H, 3.15. 3-Bromo-4-
(4-(trifluoromethoxy)phenyl)-2H-chromen-2-one (4d): 96% yield.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.03 (d, J ) 7.8 Hz, 1H),
7.21 (t, J ) 7.6 Hz, 1H), 7.34-7.43 (m, 5H), 7.58 (t, J ) 7.8 Hz,
1H). 19F NMR (376 MHz) δ (ppm) -57.6. 13C NMR (100 MHz)
δ (ppm) 157.2, 153.4, 152.5, 149.9, 133.7, 132.4, 130.1, 127.4,
125.0, 124.4, 121.8, 121.4, 120.1, 119.2, 117.1, 116.7, 113.2. MS
General Procedure for the Pd-Catalyzed Monocoupling of
Compound 3 with Arylboronic Acids (Table 4). NaHCO3 (4.0
equiv, 1.0 M in H2O) was added to a mixture of compound 3 (0.30
mmol), arylboronic acid (1.1 equiv), Pd(PPh3)4 (5 mol %), and
P(2,6-dimethoxyphenyl)3 (10 mol %) in THF (2.0 mL) at 60 °C.
After completion of the reaction as indicated by TLC, the mixture
was cooled to room temperatureand extracted with EtOAc (3 × 2
mL). The organic phase was concentrated under reduced pressure.
Purification by flash column chromatography on silica gel afforded
the corresponding product 7. Selected examples: 2-Oxo-3-(4-
(trifluoromethoxy)phenyl)-2H-chromen-4-yl 4-methylbenzene-
1
sulfonate (7b): 70% yield. H NMR (400 MHz, CDCl3) δ (ppm)
2.40 (s, 3H), 6.99 (d, J ) 8.2 Hz, 2H), 7.08 (d, J ) 8.2 Hz, 2H),
(16) (a) Chatterjea, J. N.; Prasad Gupta, S. N.; Prasad, N. Chem. Ber.
1966, 99, 2699. (b) Rossi, R.; Bellina, F.; Carpita, A.; Mazzarella, F.
Tetrahedron 1996, 52, 4095. (c) Kadnikov, D. V.; Larock, R. C. J. Org.
Chem. 2003, 68, 9423. (d) Reed, M. A.; Chang, M. T.; Snieckus, V. Org.
Lett. 2004, 6, 2297. (e) Sabitha, G.; Reddy, G. J; Rao, A. V. S. Synth.
Commun. 1988, 18, 639.
(15) (a) Chavan, A. P. J. Chem. Res. 2006, 3, 179. (b) Rana, B. J.; Desai,
K. R. J. Inst. Chem. (India) 1996, 68, 85. (c) Zhao, D.; Li, Z.; Xiu, J. Chin.
J. Chem. Eng. 2000, 8, 366. (d) Sivakumar, K.; Xie, F.; Cash, B. M.; Long,
S.; Barnhill, H. N.; Wang, Q. Org. Lett. 2004, 6, 4603.
J. Org. Chem, Vol. 72, No. 19, 2007 7285

Zhang et al.
7.27-7.33 (m, 4H), 7.39-7.43 (m, 2H), 7.64 (t, J ) 7.8 Hz, 1H),
8.01 (d, J ) 8.2 Hz, 1H). 13C NMR (100 MHz) δ (ppm) 161.2,
154.2, 152.5, 149.2, 146.1, 133.0, 132.6, 132.2, 129.7, 128.4, 128.0,
127.7, 125.5, 124.8, 121.6, 120.0, 119.6, 119.1, 117.1, 116.5, 21.5.
MS m/z 477 (M+ + 1). Anal. Calcd for C23H15F3O6S: C, 57.98;
H, 3.17. Found: C, 57.88; H, 2.93. 2-Oxo-3-p-tolyl-2H-chromen-
for C23H18O4: C, 77.08; H, 5.06. Found: C, 76.83; H, 5.01. 3,4-
Di-4-tolyl-2H-chromen-2-one (6a): 88% yield. 1H NMR (400 MHz,
CDCl3): δ (ppm) 2.26, (s, 3H), 2.36, (s, 3H), 6.99-7.03 (m, 6H),
7.11-7.19 (m, 3H), 7.22 (dd, J ) 7.8, 1.4, 1H), 7.40 (d, J ) 8.2,
1H), 7.48-7.52 (m, 1H). 13C NMR (100 MHz): δ (ppm) 161.5,
153.1, 151.3, 138.1, 137.3, 131.6, 131.2, 131.0, 130.4, 129.3, 129.0,
128.5, 127.8, 126.9, 124.0, 120.8, 116.7, 21.2 (9), 21.2 (5). MS:
m/z 327 (M+ +1). Anal. Calcd for C23H18O2: C, 84.64; H, 5.56.
Found: C, 84.37; H, 5.70.
1
4-yl 4-methylbenzenesulfonate (7c): 42% yield. H NMR (400
MHz, CDCl3) δ (ppm) 2.32 (s, 3H), 2.40 (s, 3H), 6.95 (d, J ) 7.8
Hz, 2H), 7.20 (d, J ) 8.2 Hz, 2H), 7.11 (d, J ) 7.3 Hz, 2H), 7.27-
7.40 (m, 4H), 7.60 (t, J ) 7.8 Hz, 1H), 7.98 (d, J ) 8.2 Hz, 1H).
13C NMR (100 MHz) δ (ppm) 161.6, 153.6, 152.3, 145.3, 138.6,
133.0, 132.5, 130.4, 129.5, 128.6, 127.8, 126.9, 125.3, 124.7, 121.1,
117.4, 116.4, 21.7, 21.4. MS m/z 407 (M+ + 1). Anal. Calcd for
C23H18O5S: C, 67.97; H, 4.46. Found: C, 67.66; H, 4.43.
Pd-Catalyzed Buchwald-Hartwig Amination of Compound
4c with p-Anisidine (Scheme 6, eq 1). 3-(4-Methoxypheny-
lamino)-4-phenyl-2H-chromen-2-one (8): A mixture of compound
4c (0.15 mmol), p-anisidine (1.2 equiv), Pd2(dba)3 (2.5 mol %),
Xantphos (5 mol %), and K2CO3 (2.0 equiv) in toluene (1.0 mL)
was stirred at 80 °C for 12 h. After completion of the reaction as
indicated by TLC, the mixture was cooled to room temperature
and purified directly by flash column chromatography on silica gel
General Procedure for the Pd-Catalyzed Cross-Coupling of
Compound 7 with Arylboronic Acids (Table 5). A mixture of
compound 7 (0.30 mmol), arylboronic acid (1.5 equiv), Pd(OAc)2
(5 mol %), PCy3 (10 mol %), and K2HPO4‚3H2O (3.0 equiv) in
methanol (2.0 mL) was stirred at 60 °C for a period of time. After
completion of the reaction as indicated by TLC, the mixture was
cooled to room temperature and purified directly by flash column
chromatography on silica gel to afford the corresponding product.
Selected examples: 3-(4-Methoxyphenyl)-4-phenyl-2H-chromen-
1
to afford the corresponding product in 74% yield. H NMR (400
MHz, CDCl3) δ (ppm) 3.68 (s, 3H), 6.19 (s, 1H), 6.49 (d, J ) 8.7
Hz, 2H), 6.59 (d, J ) 9.2 Hz, 2H), 7.11-7.25 (m, 7H), 7.31-7.39
(m, 2H). 13C NMR (100 MHz) δ (ppm) 160.4, 155.7, 149.4, 134.3,
133.4, 129.6, 128.6, 128.2, 128.0, 127.8, 127.4, 125.1, 124.5, 123.4,
121.9, 116.5, 113.7, 55.6. MS m/z 344 (M+ + 1). Anal. Calcd for
C22H17NO3: C, 76.95; H, 4.99; N, 4.08. Found: C, 76.57; H, 4.97;
N, 3.91.
Nucleophilic Substitution of Compound 7e with p-Anisidine
(Scheme 6, eq 2). 3-(4-Methoxyphenyl)-4-(4-methoxypheny-
lamino)-2H-chromen-2-one (9): A mixture of compound 7e (0.15
mmol), p-anisidine (1.2 equiv), and K2CO3 (2.0 equiv) in ethanol
(1.0 mL) was stirred at 60 °C for 3 h. After completion of the
reaction as indicated by TLC, the mixture was cooled to room
temperature and purified directly by flash column chromatography
on silica gel to afford the corresponding product in 60% yield. 1H
NMR (400 MHz, CDCl3) δ (ppm) 3.78 (s, 3H), 3.81 (s, 3H), 6.17
(s, 1H), 6.78 (d, J ) 8.7 Hz, 2H), 6.90-7.00 (m, 5H), 7.25-7.43
(m, 5H). 13C NMR (100 MHz) δ (ppm) 162.2, 159.7, 157.1, 153.6,
149.5, 135.3, 131.7, 131.2, 126.3, 124.4, 123.0, 117.4, 115.4, 115.0,
114.8, 109.9, 55.6, 55.4. MS m/z 374 (M+ + 1). Anal. Calcd for
C23H19NO4: C, 73.98; H, 5.13; N, 3.75. Found: C, 73.64; H, 5.35;
N, 3.86.
1
2-one (5f):16e 94% yield. H NMR (400 MHz, CDCl3) δ (ppm)
3.72, (s, 3H), 6.70 (d, J ) 9.2 Hz, 2H), 7.05-7.21 (m, 6H), 7.30-
7.33 (m, 3H), 7.40 (d, J ) 8.2 Hz, 1H), 7.49-7.51 (m, 1H). 13C
NMR (100 MHz) δ (ppm) 161.5, 158.9, 153.1, 151.0, 134.7, 131.9,
131.2, 129.4, 128.4, 128.3, 127.7, 126.6, 126.0, 124.1, 120.6, 116.7,
113.3, 55.1. 3-(4-Methoxyphenyl)-4-(4-(trifluoromethoxy)phenyl)-
2H-chromen-2-one (5g): 99% yield. 1H NMR (400 MHz, CDCl3):
δ (ppm) 3.74 (s, 3H), 6.71 (d, J ) 8.2, 2H), 7.01 (d, J ) 9.2, 2H),
7.14-7.22 (m, 6H), 7.41 (d, J ) 8.7, 1H), 7.51-7.55 (m, 1H). 13
C
NMR (100 MHz): δ (ppm) 161.3, 159.2, 153.2, 149.6, 149.1, 133.4,
131.9, 131.6, 131.2, 127.4, 127.2, 125.7, 124.4, 121.7, 120.9, 120.3,
119.2, 117.0, 116.6, 113.5, 55.2. MS: m/z 413 (M+ +1). Anal.
Calcd for C23H15F3O4: C, 66.99; H, 3.67. Found: C, 66.98; H,
3.64.
General Procedure for the Pd-Catalyzed Cross-Coupling of
Compound 3a with Arylboronic Acids (Scheme 4). A mixture
of compound 3a (0.30 mmol), arylboronic acid (3.0 equiv), Pd-
(OAc)2 (5 mol %), PCy3 (10 mol %), and K2HPO4‚3H2O (3.0 equiv)
in methanol (2.0 mL) was stirred at 60 °C for a period of time.
After completion of the reaction as indicated by TLC, the mixture
was cooled to room temperature and purified directly by flash
column chromatography on silica gel to afford the corresponding
product. Selected examples: 3,4-Bis(4-methoxyphenyl)-2H-chromen-
2-one (5a): 99% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.74
(s, 3H), 3.80 (s, 3H), 6.72 (d, J ) 8.7 Hz, 2H), 6.83 (d, J ) 8.7
Hz, 2H), 7.03-7.07 (m, 4H), 7.17 (t, J ) 7.6 Hz, 1H), 7.27 (dd, J
) 8.2, 1.4 Hz, 1H), 7.39 (d, J ) 8.2 Hz, 1H), 7.50 (t, J ) 7.8 Hz,
1H). 13C NMR (100 MHz) δ (ppm) 161.6, 159.4, 158.8, 153.1,
150.9, 131.9, 131.1, 130.9, 127.7, 126.8, 126.5, 126.3, 124.0, 120.9,
116.7, 113.8, 113.3, 55.2, 55.2. MS m/z 359 (M+ + 1). Anal. Calcd
Acknowledgment. Financial support from National Natural
Science Foundation of China (20502004) and the Science &
Technology Commission of Shanghai Municipality (05ZR14013)
is gratefully acknowledged. We also thank Dr. Jason Wong for
polishing the English.
Supporting Information Available: Experimental procedures,
characterization data, and copies of 1H and 13C NMR spectra of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO071117+
7286 J. Org. Chem., Vol. 72, No. 19, 2007