Chemoselective Suzuki-Miyaura cross-coupling reactions of 6-bromo-3-(trifluoromethylsulfonyloxy)flavone

Article abstract of DOI:10.1055/s-0032-1318479

Arylated flavones were prepared by Suzuki-Miyaura reactions of 6-bromo-3-(trifluoro-sulfonyloxy)flavone. The reactions proceeded with very good chemoselectivity in favor of position 3. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318479

860▌
LETTER
lCetther emoselective Suzuki–Miyaura Cross-Coupling Reactions of 6-Bromo-
3-(trifluoromethylsulfonyloxy)flavone
Cross-Coupling Reactions of 6-Bromo-3-(trifluoromethylsulfonyloxy)flavone
Omer A. Akrawi,a Tamás Patonay,b Krisztina Kónya,b Peter Langer*a,c
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
c
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Received: 14.01.2013; Accepted after revision: 26.02.2013
vone.33 Herein, we report a convenient approach to
Abstract: Arylated flavones were prepared by Suzuki–Miyaura re-
arylated flavones by what are, to the best of our knowl-
actions of 6-bromo-3-(trifluoro-sulfonyloxy)flavone. The reactions
edge, the first Suzuki–Miyaura cross-coupling reactions
of 6-bromo-3-(trifluorosulfonyloxy)flavone. Surprising-
ly, the reactions proceed with very good chemoselectivity
in favor of position 3.
proceeded with very good chemoselectivity in favor of position 3.
Key words: catalysis, flavones, heterocycles, palladium, cross-
coupling reactions
OH
O
O
Flavones (2-arylchromones) constitute an important class
of oxygen heterocycles which are widespread in various
plants and agricultural products, including vegetables,
seeds, nuts, and fruits.1–4 Examples include apigenin and
genistein which are found in Apium graveolens and Soya
hispida, respectively (Figure 1).5 Flavonoids received
considerable attention in recent years because of their po-
tential beneficial effects on human health. Flavonoids
have been reported to exhibit various pharmacological ac-
tivities, including vasodilating,6 antiviral,7 antioxidative,8
antimicrobial,9 DNA cleaving,10 antiinflammatory,11 anti-
mutagenic,12 antiallergic,13 anticancer,14 antiarthritic,15
analgesic,16 antidiabetic,17 antiulcer,18 antianginous,19 an-
tiosteoporotic,20 antihepatotoxic,21 antidiarrhoeal,22 anti-
fungal,23 and various enzyme-inhibitory effects.24
OH
OH
O
HO
HO
O
OH
apigenin
genistein
(antiinflammatory)
(protein tyrosin kinase inhibitor)
OMe
O
O
OH
O
O
O
OH
OH
OH
HO
O
Various synthetic protocols have been developed for the
synthesis of flavones and isoflavones. Traditionally, fla-
vones have been prepared by Baker–Venkataraman rear-
rangement,25 by oxidative cyclization of 2-
hydroxychalcones,26 or by regioselective cyclization of
ortho-alkynoylphenols.27 Flavones have also been pre-
pared by intramolecular Wittig reactions.28 The easiest
synthesis of 3-hydroxyflavones is the so-called Algar–
Flynn–Ozamada reaction, that is, oxidative cyclization of
2-hydroxychalcones by alkaline hydrogenperoxide.29
semiglabrin
(antifungal)
quercetin
(antidiabetic)
Figure 1 Some pharmacologically active flavone natural products
The reaction of 6-bromo-3-hydroxyflavone34 (1) with tri-
flic anhydride afforded triflate 2 in good yield (Scheme
1).36
O
O
Flavones and isoflavones are available by transition-met-
al-catalyzed cross-coupling reactions, such as the cycliza-
tion of 2-halophenols with terminal acetylenes and carbon
monoxide30 or by Suzuki–Miyaura cross-coupling reac-
tions of halogenated chromones.31 Flavones have been
prepared by oxidative addition of arylboronic acids to
chromones.32 We have recently reported the synthesis of
arylated flavones by regioselective Suzuki–Miyaura reac-
tions of the bis(triflates) of 5,7- and 7,8-dihydroxyfla-
Br
OH
Br
OTf
i
O
O
1
2 (95%)
Scheme 1 Synthesis of 2. Reagents and conditions: (i) 1 (1.0 equiv),
Tf2O (2.0 equiv), pyridine (5.0 equiv), CH2Cl2, 0–20 °C, 18 h.
The Suzuki–Miyaura reaction of 2 with arylboronic acids
3a–f (2.3 equiv) afforded the 3,6-diarylflavones 4a–g
(Scheme 2, Table 1).37,38 The best yields were obtained
when Pd(PPh3)4 (6 mol%) and K3PO4 (3.0 equiv) were
used as catalyst and base, respectively. The reactions were
SYNLETT 2013, 24, 0860–0864
Advanced online publication: 08.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318479; Art ID: ST-2013-D0046-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reactions of 6-Bromo-3-(trifluoromethylsulfonyloxy)flavone
861
carried out in dioxane (90 °C, 12 h). The highest yields
were obtained for products 4a,b, which are derived from
electron-rich (highly nucleophilic) arylboronic acids 3a,b.
The yield dropped when the more sterically hindered or-
tho-substituted arylboronic acid 3c was employed. The
use of electron-poor arylboronic acids (products 4e,f) also
worked well, although the yields were slightly lower as
compared to 4a,b.
Table 2 Synthesis of 5a–g
3
5
Ar
Yield of 5 (%)a
a
b
c
e
f
a
b
c
d
e
f
4-MeOC6H4
4-EtOC6H4
2-MeOC6H4
4-ClC6H4
82
90
71
68
85
90
78
O
O
3-FC6H4
Br
OTf
Ar
Ar
ArB(OH)2
g
h
4-FC6H4
3a–g
O
O
i
g
4-F3CC6H4
2
4a–g
a Yields of isolated compounds.
Scheme 2 Synthesis of 4a–g. Reagents and conditions: (i) 2 (1.0
equiv), ArB(OH)2 (2.3 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (3.0
equiv), dioxane, 90 °C, 12 h.
The one-pot Suzuki–Miyaura reaction of 2 with two dif-
ferent arylboronic acids (sequential addition) afforded the
3,6-diarylflavones 6a–d (Scheme 4, Table 3).41,42 During
the optimization, it proved again to be important to carry
out the first step of the one-pot reaction at 65 °C. A rela-
tively long reaction time (36 h) was again necessary in or-
der to induce a complete conversion.
Table 1 Synthesis of 4a–g
3, 4
Ar
Yield of 4 (%)a
a
b
c
d
e
f
4-MeOC6H4
4-EtOC6H4
2-MeOC6H4
4-MeC6H4
4-ClC6H4
3-FC6H4
90
95
78
85
75
83
73
O
O
Br
OTf
1) Ar1B(OH)2 Ar2
2) Ar2B(OH)2
Ar1
i,ii
O
O
2
6a–d
Scheme 4 Synthesis of 6a–d. Reagents and conditions: (i) 2 (1.0
equiv), Ar1B(OH)2 (1.0 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (1.5
equiv), toluene–MeOH (4:1), 65 °C, 36 h; (ii) Ar2B(OH)2 (1.3 equiv),
K3PO4 (1.5 equiv), Pd(PPh3)4 (6 mol%), 105 °C, 12 h.
g
4-FC6H4
a Yields of isolated compounds.
The Suzuki–Miyaura reaction of 2 with 1.1 equivalents of
arylboronic acids 3a–c,e–h gave the 3-aryl-6-bromofla-
vones 5a–g (Scheme 3, Table 2).39,40 The reactions pro-
ceeded with very good chemoselectivity in favor of
position 3. During the optimization, it proved to be impor-
tant to carry out the reaction at 65 °C instead of 90 °C.
Higher temperatures result in the formation of consider-
able amounts of diarylated products. The use of a 9:1 mix-
ture of toluene and MeOH proved to be important, as the
use of dioxane resulted in the formation of mixtures. A
relatively long reaction time (24 h) was necessary in order
to achieve a complete conversion.
Table 3 Synthesis of 6a–d
3, 4
6
Ar1
Ar2
Yield of 6 (%)a
b,g
g,b
b,k
g,e
a
b
c
4-EtOC6H4
4-FC6H4
4-FC6H4
76
84
91
70
4-EtOC6H4
3-MeC6H4
4-ClC6H4
4-EtOC6H4
4-FC6H4
d
a Yields of isolated compounds.
It is noteworthy that 2,3-diarylflavones have been report-
ed recently to comprise a new class of selective COX-2 in-
hibitors.43
O
O
O
Br
OTf
Br
Ar
ArB(OH)2
3a–c,e–h
In general, Pd-catalyzed cross-coupling reactions of poly-
halogenated substrates or of bis(triflates) proceed more
rapidly at the sterically less hindered and more electron-
deficient position.44 In case of Suzuki–Miyaura reactions,
bromides usually react faster than triflates, due to the for-
mation of a stable boron–bromide bond.45 Surprisingly,
the Suzuki–Miyaura reactions of 2 proceeded by che-
moselective attack onto the triflate group. We have report-
i
O
5a–g
2
Scheme 3 Synthesis of 5a–g. Reagents and conditions: (i) 2 (1.0
equiv), ArB(OH)2 (1.1 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (1.5
equiv), toluene–MeOH (9:1), 65 °C, 24 h.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 860–864

862
O. A. Akrawi et al.
LETTER
L.; Piro, O. E.; Castellano, E. E.; Vidal, A.; Azqueta, A.;
ed earlier that the Suzuki–Miyaura reaction of 6-bromo-4-
(trifluoromethylsulfonyloxy)coumarin also proceeded at
the triflate group first.46 However, in that case, position 4
is highly electron deficient, while position 3 of the current
substrate 2 is less electron deficient, due to the electron-
donating effect of the flavones’ oxygen atom. In case of
the current substrate 2, the higher reactivity of position 3,
which is more sterically hindered than position 6, might
be explained by a catalyst directing effect of the neighbor-
ing carbonyl group.
Monge, A.; Lopez-Cerain, A.; Sagrera, G.; Seoane, G.;
Cerecetto, H.; Gonzalez, M. Bioorg. Med. Chem. 2007, 15,
3356. (e) Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins,
D. B.; Hunt, J. T.; Xiao, H. Y.; Lu, S.; Qian, L.; Han, W. C.;
Shan, W.; Mitt, T.; Cai, Z. W.; Poss, M. A.; Zhu, H.; Sack,
J. S.; Tokarski, J. S.; Chang, C. Y.; Pavletich, N.; Kamath,
A.; Humphreys, W. G.; Marathe, P.; Bursuker, I.; Kellar, K.
A.; Roongta, U.; Batorsky, R.; Mulheron, J. G.; Bol, D.;
Fairchilds, C. R.; Lee, F. Y.; Webster, K. R. J. Med. Chem.
2002, 45, 3905.
(15) Kim, H. K.; Son, K. H.; Chang, H. W.; Kang, S. S.; Kim, H.
P. Planta Med. 1999, 65, 465.
(16) Soike, H.; Leng-Peschlow, E. Planta Med. 1987, 53, 37.
(17) Havsteen, B. Biochem. Pharmacol. 1983, 32, 141.
(18) Beil, W.; Birkholz, C.; Sewing, K. F. Arzneim. Forsch. 1995,
45, 697.
(19) Goitsegen, A. Proceedings of the 2nd International Meeting
on Medicinal and Aromatic Plants; 1981, 117.
(20) Eaton-Evans, J. Br. J. Biomed. Sci. 1994, 51, 358.
(21) Vijayaraghavan, R.; Sugendran, K.; Pant, S. C.; Husain, K.;
Malhotra, R. C. Toxicology 1991, 69, 34.
Acknowledgment
Financial support by the DAAD (scholarships for O.A.A.) and by
the State of Mecklenburg-Vorpommern is gratefully acknow-
ledged. The project is implemented through the New Hungary De-
velopment Plan, co-financed by the European Social Fund and the
European Regional Development Fund. The project was also fun-
ded by the EFRE program of the EU.
(22) Dicarlo, G.; Autore, G.; Izzo, A. A.; Maiolino, P.; Mascolo,
N.; Viola, P.; Diurno, M. V.; Capasso, F. J. Pharm.
Pharmacol. 1993, 45, 1054.
(23) Ammar, N. M.; El-Diwany, A. I. J. Islamic Acad. Sci. 1988,
1, 72.
(24) Polkowski, K.; Mazurek, A. P. Acta Pol. Pharm. Drug Res.
2000, 57, 135.
(25) (a) Baker, W. J. Chem. Soc. 1933, 1381. (b) Mahal, H. S.;
Venkataraman, K. J. Chem. Soc. 1934, 1767.
(26) (a) Zhiyun, D.; Kun, Z.; Huifen, N.; Huaqiang, Z.; Jian, W.
Org. Biomol. Chem. 2011, 9, 6930. (b) Hemanth, K. K.;
Paramasivan, P. T. Tetrahedron 2007, 63, 9531. (c) Patonay,
T.; Cavaleiro, J. A. S.; Lévai, A.; Silva, A. M. S. Heterocycl.
Commun. 1997, 3, 223.
References and Notes
(1) (a) The Handbook of Natural Flavonoids; Harborne, J. B.;
Baxter, H., Eds.; 1999, Vol. 2: 8, 79. (b) Aherne, S. A.;
O’Brien, N. M. Nutrition 2002, 18, 75. (c) Middleton, E. Jr.;
Kandaswami, C.; Theoharides, T. C. Pharmacol. Rev. 2000,
52, 673. (d) Middleton, E.; Kandaswami, C. In The
Flavanoids: Advance in Research since 1986; Harborne, J.
B., Ed.; Chapman and Hall: London, 1994, 619. (e) Wong,
E.; Harborne, J. B.; Mabry, T. J.; Mabry, H. In The
Flavanoids; Harborne, J. B.; Mabry, T. J.; Mabry, H., Eds.;
Chapman and Hall: London, 1975, 184.
(2) Malikov, V. M.; Yuldashev, M. P. Chem. Nat. Compd. 2002,
38, 358.
(27) Yoshida, M.; Fujino, Y.; Do, T. Org. Lett. 2011, 13, 4526.
(28) Das, J.; Ghosh, S. Tetrahedron Lett. 2011, 52, 7189.
(29) (a) Algar, J.; Flynn, J. P. Proc. Roy. Irish Acad. 1934, 42B,
1. (b) Oyamada, T. J. Chem. Soc. Jpn. 1934, 55, 1256.
(c) Smith, M. A.; Neumann, R. M.; Webb, R. A. J.
Heterocycl. Chem. 1968, 5, 425. (d) Montana, M. P.;
Pappano, N.; Giordano, S. O.; Molina, P.; Debattista, N. B.;
Garcia, N. A. Pharmazie 2007, 62, 72.
(30) Yang, Q.; Alper, H. J. Org. Chem. 2010, 75, 948.
(31) Rao, M. L. N.; Venkatesh, V.; Jadhav, D. N. Synlett 2009,
2597.
(32) Kim, D.; Ham, K.; Hong, S. Org. Biomol. Chem. 2012, 10,
7305.
(3) Huck, C. W.; Huber, C. G.; Ongania, K. H.; Bonn, G. K. J.
Chromatogr. A 2000, 453.
(4) Nagao, T.; Abe, F.; Kinjo, J.; Okabe, H. Biol. Pharm. Bull.
2002, 7, 875.
(5) Carlo, G. Di.; Mascolo, N.; Izzo, A. A.; Capasso, F. Life Sci.
1999, 65, 337.
(6) Perez-Vizcaino, F.; Ibarra, M.; Cogolludo, A. L.; Duarte, J.;
Zaragoza-Arnaez, F.; Moreno, L.; Lopez-Lopez, G.;
Tamargo, J. J. Pharmacol. Exp. Ther. 2002, 301, 66.
(7) (a) Sanchez, I.; Gomez-Garibay, F.; Taboada, J.; Ruiz, B. H.
Phytother. Res. 2000, 14, 89. (b) Bae, E. A.; Han, M. J.; Lee,
M.; Kim, D. H. Biol. Pharm. Bull. 2000, 23, 1122.
(8) (a) Grassmann, J.; Hippeli, S.; Elstner, E. F. Plant. Physiol.
Biochem. 2002, 40, 471. (b) Miura, S.; Watanabe, J.; Sano,
M.; Tomita, T.; Osawa, T.; Hara, Y.; Tomita, I. Biol. Pharm.
Bull. 1995, 18, 1.
(33) Eleya, N.; Malik, I.; Reimann, S.; Wittler, K.; Hein, M.;
Patonay, T.; Villinger, A.; Ludwig, R.; Langer, P. Eur. J.
Org. Chem. 2012, 1639.
(34) 6-Bromo-3-hydroxyflavone (1) was prepared by the reaction
of the corresponding 2′-hydroxychalcone with ethanolic
alkaline hydrogenperoxide solution,29 the product was
obtained after recrystallization (EtOH) in 56% yield; mp
189–191 °C, lit.35a; mp 180–181 °C, lit.35a; mp 183–184 °C.
(35) (a) Chang, C. T.; Chen, F. C.; Chen, T. S.; Hsu, K. K.; Hung,
M. J. Chem. Soc. 1961, 3414. (b) Hasan, A.; Rasheed, L.;
Malik, A. Asian J. Chem. 2007, 19, 937.
(9) (a) Xu, H. X.; Lee, S. F. Phytother. Res. 2001, 15, 39.
(b) Hamiltonmiller, J. M. T. Antimicrob. Agents Chemother.
1995, 39, 2375.
(10) Jain, A.; Martin, M. C.; Parveen, N.; Khan, N. U.; Parish, J.
H.; Hadi, S. M. Phytother Res. 1999, 13, 609.
(11) Landolfi, R.; Mower, R. L.; Steiner, M. Biochem.
Pharmacol. 1984, 32, 1525.
(12) Yamada, J.; Tomita, Y. Biosci. Biotech. Biochem. 1994, 58,
2197.
(13) Matsuo, N.; Yamada, K.; Yamashita, K.; Shoji, K.; Mori,
M.; Sugano, M. In Vitro Cell Dev. Biol. 1996, 32, 340.
(14) (a) Han, C. Cancer Lett. 1997, 114, 153. (b) Birt, D. F.;
Hendrich, S.; Wang, W. Pharmacol. Therap. 2001, 90, 157.
(c) Cushman, M.; Nagarathnam, D. J. Nat. Prod. 1991, 54,
1656. (d) Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M.
(36) Synthesis of 6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl
Trifluoromethanesulfonate (2)
Tf2O (0.53 mL, 3.20 mmol) was added at 0 °C to a solution
of 1 (0.5 g, 1.58 mmol) and pyridine (0.64 mL, 7.88 mmol)
in CH2Cl2 (15 mL). The reaction mixture was stirred at r.t.
under argon atmosphere for 18 h. To the reaction mixture
was added toluene (10 mL), and the solution was
Synlett 2013, 24, 860–864
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reactions of 6-Bromo-3-(trifluoromethylsulfonyloxy)flavone
863
concentrated in vacuo. The residue was purified by
chromatography (EtOAc–heptanes) without aqueous
and concentrated in vacuo. The residue was purified by
column chromatography (EtOAc–heptanes).
workup to yield 2 as a white solid (0.674 g, 95%); mp 160–
162 °C. 1H NMR (300 MHz, CDCl3): δ = 7.42 (d, 1 H,
J = 8.9 Hz, ArH), 7.48–7.60 (m, 3 H, ArH), 7.77–7.81 (m, 3
H, ArH), 8.35 (d, 1 H, J = 2.5 Hz, ArH). 19F NMR (282.4
MHz, CDCl3): δ = –73.7. 13C NMR (62.9 MHz, CDCl3):
δ = 118.20 (q, JC,F = 320.9, CF3), 119.7 (C), 120.2 (CH),
124.8, 128.1 (C), 128.2 (2 CH), 129.0, 132.7 (CH), 133.8
(C), 137.8 (CH), 154.2, 159.2 (C), 170.0 (CO). IR (KBr):
ν = 3083, 3070, 2928 (w), 1651, 1620 (s), 1604, 1538, 1496,
1461, 1451 (m), 1425 (s), 1367 (m), 1335, 1321, 1292, 1269,
1250, 1232 (w), 1212, 1201, 1170, 1139, 1120 (s), 1078,
1060, 1033 (w), 990 (m), 975, 932, 912, 894 (w), 856, 827,
804 (s), 784 (w), 767, 764 (s), 711 (m), 693, 678, 661 (s), 646
(m), 619 (s), 571, 559, 545, 529 (m) cm–1. GC–MS (EI, 70
eV): m/z (%) = 450 (13) [M, 81Br]+, 448 (13) [M, 79Br]+, 319
(12), 318 (59), 317 (35), 316 (59), 315 (53), 290 (19), 289
(100), 287 (95), 261 (17), 259 (12). HRMS (EI, 70 eV): m/z
calcd for C16H8BrF3O5S [M, 79Br]+: 447.92224; found:
447.92265; m/z calcd. for C16H8BrF3O5S [M, 81Br]+:
449.92020; found: 449.92043.
(40) 6-Bromo-3-(4-methoxyphenyl)-2-phenyl-4H-chromen-4-
one (5a)
Starting with 2 (50 mg, 0.11 mmol), 5a was prepared as a
white solid (37 mg, 82%), mp 237–238 °C. Reaction
temperature: 65 °C for 24 h. 1H NMR (300 MHz, CDCl3):
δ = 3.73 (s, 3 H, OCH3), 6.77 (d, 2 H, J = 8.9 Hz, ArH), 7.06
(d, 2 H, J = 8.9 Hz, ArH), 7.19–7.37 (m, 6 H, ArH), 7.70 (dd,
1 H, J = 8.9, 2.5 Hz, ArH), 8.33 (d, 1 H, J = 2.5 Hz, ArH).
13C NMR (62.9 MHz, CDCl3): δ = 55.2 (OCH3), 113.9 (CH),
118.3 (C), 119.9 (CH), 122.6, 124.4, 124.8 (C), 128.2, 128.9,
129.5, 130.1, 132.3 (CH), 133.1 (C), 136.5 (CH), 154.8,
159.1, 161.4 (C), 176.3 (CO). IR (KBr): ν = 3081, 3059,
3015, 2928, 2850, 2832 (w), 1635, 1604 (s), 1574, 1563 (w),
1556 (s), 1510 (w), 1466, 1455, 1444 (m), 1426, 1361 (s),
1288, 1270 (m), 1232, 1219, 1177 (s), 1146, 1121, 1107,
1061, 1048 (w), 1027, 1000 (s), 976, 960 (w), 928 (m), 906,
896, 841 (w), 824, 815 (s), 794 (w), 777 (s), 728 (w), 701,
696, 676, 666, 653, 648 (m), 640, 619, 610, 551 (w), 540,
530 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 408 (67) [M,
81Br]+, 407 (100) [M – H, 81Br]+, 406 (69) [M, 79Br]+, 405
(84) [M – H, 79Br]+, 364 (5), 362 (5), 327 (7), 283 (6), 255
(6), 226 (5), 208 (22). HRMS (ESI-TOF/MS): m/z calcd. for
C22H16BrO3 [M + H, 79Br]+: 407.02773; found: 407.0270;
m/z calcd for C22H16BrO3 [M + H, 81Br]+: 409.02597; found:
409.02509.
(37) General Procedure for the Synthesis of 4a–g
A 1,4-dioxane solution of 2 (0.11 mmol), arylboronic acid
(2.3 equiv), K3PO4 (3.0 equiv), and Pd(PPh3)4 (6 mol%) was
heated at 90 °C for 12 h under argon atmosphere. After
cooling to 20 °C, H2O was added, and the reaction mixture
was extracted with CH2Cl2 (3 × 25 mL). Organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (EtOAc–
heptanes).
(41) General Procedure for the One-Pot Synthesis of 6a–d
A toluene–MeOH (9:1) solution of 2 (0.17 mmol),
Ar1B(OH)2 (1.0 equiv), K3PO4 (1.5 equiv), and Pd(PPh3)4 (3
mol%) was heated at 65 °C for 36 h under argon atmosphere.
After cooling to 20 °C, Ar2B(OH)2 (1.3 equiv), Pd(PPh3)4 (6
mol%), and MeOH (0.2 mL) were added, and the reaction
mixture was heated at 105 °C for further 12 h. The reaction
mixture was cooled again to 20 °C, H2O was added, and the
reaction mixture was extracted with CH2Cl2 (3 × 25
mL).The combined organic layers were dried over Na2SO4,
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (EtOAc–
heptanes).
(38) 3,6-Bis(4-methoxyphenyl)-2-phenyl-4H-chromen-4-one
(4a)
Starting with 2 (50 mg, 0.11 mmol), (4-
methoxyphenyl)boronic acid (39 mg, 0.26 mmol), K3PO4
(70 mg, 0.33 mmol), and Pd(PPh3)4 (8 mg, 6 mol%), 4a was
prepared as a white solid (48 mg, 90%); mp 181–183 °C.
Reaction temperature: 90 °C for 12 h. 1H NMR (250 MHz,
CDCl3): δ = 3.73 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 6.77
(d, 2 H, J = 8.8 Hz, ArH), 6.94 (d, 2 H, J = 8.8 Hz, ArH),
7.08 (d, 2 H, J = 8.8 Hz, ArH), 7.18–7.28 (m, 3 H, ArH),
7.34–7.38 (m, 2 H, ArH), 7.49 (d, 1 H, J = 8.7 Hz, ArH),
7.55 (d, 2 H, J = 8.8 Hz, ArH), 7.82 (dd, 1 H, J = 8.8, 2.4 Hz,
ArH), 8.37 (d, 1 H, J = 2.3 Hz, ArH). 13C NMR (75.5 MHz,
CDCl3): δ = 55.2, 55.4, (OCH3), 113.9, 114.4, 118.4, (CH),
122.4 (C), 123.0 (CH), 123.6 125.0 (C), 128.1, 128.3, 129.6,
129.9 (CH), 132.1 (C), 132.2, 132.4 (CH), 133.5, 137.8,
155.1, 159.0, 159.5, 161.2 (C), 177.7 (CO). IR (KBr):
ν = 3060, 3035, 2954, 2929, 2834 (w), 1633, 1605 (s), 1580,
1563 (m), 1557 (s), 1538 (w), 1511 (m), 1494 (w), 1479,
1446, 1439, 1410 (s), 1291, 1282, 1268 (m), 1244, 1229,
1179 (s), 1149, 1122, 1106, 1079, 1055 (w), 1031, 1018 (m),
1005, 973 (w), 928 (m), 916, 905, 848 (w), 835 (m), 813 (s),
797, 770 (m), 732, 709 (w), 689 (m), 673, 661, 652, 639,
624, 584, 579, 563 (w), 585, 539 (m) cm–1. GC–MS (EI, 70
eV): m/z (%) = 434 (76) [M]+, 433 (100) [M – H]+, 418 (4),
390 (6), 311 (24), 226 (4). HRMS (EI, 70 eV): m/z calcd for
C29H22O4 [M]+: 434.15126; found: 434.14966; m/z calcd for
C29H21O4 [M – H]+: 433.14344; found: 433.14334.
(39) General Procedure for the One-Pot Synthesis of 5a–g
A toluene–MeOH (9:1) solution of 2 (0.11 mmol),
(42) 3-(4-Ethoxyphenyl)-2-phenyl-6-(m-tolyl)-4H-chromen-
4-one (6c)
Starting with 2 (75 mg, 0.17 mmol), (4-
ethoxyphenyl)boronic acid as Ar1B(OH)2 (29 mg, 0.17
mmol), K3PO4 (53 mg, 0.26 mmol), Pd(PPh3)4 (6 mg, 3
mol%), and (3-methylphenyl)boronic acid as Ar2B(OH)2 (30
mg, 0.22 mmol), 6c was prepared as a light yellow highly
viscous oil (66 mg, 91%). Reaction temperature: 65 °C for
36 h, then 105 °C for 12 h. 1H NMR (300 MHz, CDCl3):
δ = 1.33 (t, 3 H, J = 7.0 Hz, CH3), 2.36 (s, 3 H, CH3), 3.95
(q, 2 H, J = 7.0 Hz, OCH2), 6.75 (d, 2 H, J = 8.8 Hz, ArH),
7.07 (d, 2 H, J = 8.8 Hz, ArH), 7.11–7.31 (m, 5 H, ArH),
7.34–7.43 (m, 4 H, ArH), 7.50 (d, 1 H, J = 8.7 Hz, ArH),
7.84 (dd, 1 H, J = 8.7, 2.3 Hz, ArH), 8.41 (d, 1 H, J = 2.3 Hz,
ArH). 13C NMR (75.5 MHz, CDCl3): δ = 14.9, 21.6 (CH3),
63.4 (OCH2), 114.4, 118.4 (CH), 122.5, 123.6 (C), 124.1,
124.3 (CH), 124.8 (C), 128.0, 128.1, 128.5, 128.9, 129.6,
129.9, 132.4, 132.6 (CH), 133.5, 138.3, 138.7, 139.5, 155.4,
158.5, 161.2 (C), 177.7 (CO). IR (KBr): ν = 3055, 3034,
2975, 2922, 2871 (w), 1636, 1606 (s), 1558 (m), 1510 (s),
1494 (w), 1474 (s), 1444 (m), 1405, 1393 (w), 1361 (s),
1285, 1270 (w), 1224, 1174 (s), 1143, 1114, 1094, 1076 (w),
1041, 1029 (m), 1012, 1000, 933, 919, 845 (w), 825, 782,
769, 729, 718, 692 (s), 665 (w), 643, 631 (m), 597, 564, 531
(w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 432 (79) [M]+, 431
(100) [M – H]+, 403 (18), 375 (5), 222 (10). HRMS (EI, 70
arylboronic acid (1.1 equiv), K3PO4 (1.5 equiv), and
Pd(PPh3)4 (3 mol%) was heated at 65 °C for 24 h under
argon atmosphere. After cooling to 20 °C, H2O was added,
and the reaction mixture was extracted with CH2Cl2 (3 × 25
mL). The organic layers were dried over Na2SO4, filtered,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 860–864

864
O. A. Akrawi et al.
LETTER
eV): m/z calcd for C30H24O3 [M]+: 432.17200; found:
432.17124.
(45) (a) Kamikawa, T.; Hayashi, T. Tetrahedron Lett. 1997, 38,
7087. (b) Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem.
Soc. 2000, 122, 4020. (c) Roy, A. H.; Hartwig, J. F.
Organometallics 2004, 23, 194. (d) Espinet, P.; Echavarren,
A. M. Angew. Chem. Int. Ed. 2004, 43, 4704. (e) Espino, G.;
Kurbangalieva, A.; Brown, J. M. Chem. Commun. 2007,
1742; and references cited therein.
(43) Joo, Y. H.; Kim, J. K. Kang S.-H.; Noh, M.-S.; Ha, J.-Y.;
Choi, J. K.; Lim, K. M.; Lee, C. H.; Chung, S. Bioorg. Med.
Chem. 2003, 13, 413.
(44) For reviews of site-selective palladium(0)-catalyzed cross-
coupling reactions, see: (a) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Schnürch, M.; Flasik, R.;
Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur.
J. Org. Chem. 2006, 3283. (c) Wang, R.; Manabe, K.
Synthesis 2009, 1405.
(46) Akrawi, O. A.; Nagy, G. Z.; Patonay, T.; Villinger, A.;
Langer, P. Tetrahedron Lett. 2012, 53, 3206.
Synlett 2013, 24, 860–864
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