Synthesis of arylated xanthones by site-selective Suzuki-Miyaura reactions of the bis(triflate) of 1,3-dihydroxyxanthone

Article abstract of DOI:10.1016/j.tet.2012.05.046

Arylated xanthones were prepared by site-selective Suzuki-Miyaura reactions of the bis(triflate) of 1,3-dihydroxyxanthone. The first attack occurs at the sterically less encumbered position 3. The site-selectivity is in contrast to the bis(triflate) of 1,

Full text of DOI:10.1016/j.tet.2012.05.046

Tetrahedron 68 (2012) 6298e6304
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Synthesis of arylated xanthones by site-selective SuzukieMiyaura reactions
of the bis(triflate) of 1,3-dihydroxyxanthone
,
b
c
a
a,d,
Omer A. Akrawi a, Hamid H. Mohammed a , Tamas Patonay , Alexander Villinger , Peter Langer
*
ꢀ
a
€
€
Institut fur Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Department of Chemistry, College of Sciences, University of Al-Mustansiriyah, Baghdad, Iraq
c
ꢀ
Department of Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem ter 1, Hungary
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
d
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Arylated xanthones were prepared by site-selective SuzukieMiyaura reactions of the bis(triflate) of 1,3-
dihydroxyxanthone. The first attack occurs at the sterically less encumbered position 3. The site-
selectivity is in contrast to the bis(triflate) of 1,3-dihydroxyanthraquinone.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 20 March 2012
Received in revised form 2 May 2012
Accepted 11 May 2012
Available online 18 May 2012
Keywords:
Palladium
SuzukieMiyaura reaction
Cross-coupling
O-Heterocycles
Xanthones
Regioselectivity
1. Introduction
OH
O
O
OH
O
O
OH
OMe
OH
Xanthones are an important family of oxygenated heterocyclic
compounds that occur in a variety of higher plant families, such as
Gentianaceae,1 Guttiferae,2 and in a few families of fungi and li-
chens (Fig. 1).3 Some xanthone-containing plants, for example,
Cratoxylum cochinchinense (Lour.), have been used as traditional
medicines to treat fever, coughing, diarrhea, itching, ulcers,
and abdominal complaints.4 Lesch and Braese described the xan-
thone moiety as a so-called ‘privileged structure’, since members of
this structural class are able to interact with different types of
drug targets.5 The great interest in synthetic and naturally occur-
ring xanthones is due to their pharmacological properties. They
have been reported to act as antioxidant,6 antiallergic,7 antibacte-
rial,8 antifungal,9 anti-inflammatory,10 antimalarial,11 HIV-1 in-
hibitory,12 antidepressant,13 antidiabetic,14 and antitumor agents.
For example, paeciloxanthone has been reported to exhibit anti-
tumor activity and AChE inhibition.3 5,6-Dimethylxanthone-
4-acetic acid (DMXAA) is a synthetic small molecule that shows
activity as a vascular disrupting agent.15
OH
OMe
OH
OMe
Swertiadecoraxanthone-II
Daphnifolin
OH
OH
O
O
O
O
COOH
Paeciloxanthone
DMXAA
Fig. 1. Xanthone synthetic and natural products.
There are various known synthetic approaches to the xanthone
framework. The classic ones involve the assembly of two benzene
* Corresponding author. E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.046

O.A. Akrawi et al. / Tetrahedron 68 (2012) 6298e6304
6299
rings through a pyran unit.16 The most commonly reported are the
FriedeleCrafts acylation, Fries rearrangement and Ullmann con-
densation.16 The direct formation of the xanthone moiety by re-
action of arynes with substituted benzoates17 or by DielseAlder
reaction18 has also been reported. While the (known) biogenetic
formation of xanthones largely dictates the nature and position of
substituents,19 the development of new synthetic approaches al-
lows to prepare other types of substituted xanthones for biological
screening. The presence of aryl groups located at the xanthone core
has only been reported for a few synthetic derivatives. Arylated
xanthones have been prepared by reaction of 3-(1-alkynyl)chro-
mones with 1,3-dicarbonyl compounds20 or acetonitriles21 or by
condensation of 2-methylchromone with cinnamaldehydes.22
Arylated xanthones have also been synthesized by using transi-
tion metal catalyzed reactions, such as the domino Heck reaction of
3-bromo-2-styryl-chromones and styrenes23e25 or by Suzuki cross-
coupling reactions of brominated xanthones.26 Herein, we report
the synthesis of arylated xanthones by SuzukieMiyaura reactions
of the bis(triflate) of 1,3-dihydroxyxanthone. The reactions proceed
with excellent site-selectivity in favor of position 3.
Table 2
Optimization of the synthesis of 4a,g (all reactions were carried out at 120 ꢀC for 5 h)
Entry
Basea
Solventb
Catalytsc
% (4a)d
% (4g)d
1
2
3
4
5
6
7
8
K3PO4
K3PO4
KF
Dioxane
Toluene
Dioxane
Toluene
Dioxane
Toluene
Dioxane
Toluene
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)2 Cl2]
[Pd(PPh3)2 Cl2]
[Pd(PPh3)2 Cl2]
[Pd(PPh3)2 Cl2]
42
51
57
65
49
60
74
95
25
38
42
47
33
40
58
73
KF
K3PO4
K3PO4
KF
KF
a
K3PO4 (3.0 equiv) or KF (6.6 equiv) per 0.15 mmol of 2.
2 ml per 0.15 mmol of 2.
10 mol % per 0.15 mmol of 2.
b
c
d
Yield of isolated products.
The reaction of bis(triflate) 2 with arylboronic acids 3a,b,dej
(1.1 equiv) afforded the 3-aryl-1-(trifluoromethylsulfonyloxy)xan-
thones 5aei in 72e91% yield (Scheme 3, Table 3). The best yields
were obtained when the reaction was carried out using Pd(PPh3)4
(3 mol %) as the catalyst, K3PO4 (1.5 equiv) as the base, and dioxane
as the solvent. Both electron rich and electron poor as well as
functionalized arylboronic acids could be successfully employed.
While the synthesis of 4aeg was carried out at 120 ꢀC, the synthesis
of 5aei had to be carried out at 80 ꢀC to achieve a good site-
selectivity. Mixtures of mono- and diarylated products were
obtained when the reaction was carried out at 120 ꢀC. The structure
of 5i was independently confirmed by X-ray crystal structure
analysis (Fig. 2).27
The reaction of 1,3-(dihydroxy)xanthone with triflic anhydride
afforded the bis(triflate) 2 in 80% yield (Scheme 1).
O
O
OTf
O
OH
i
OTf
O
OH
1
2 (80%)
Scheme 1. Synthesis of 2. Conditions: i, 1 (1.0 equiv), Tf2O (2.4 equiv), pyridine
(4.0 equiv), CH2Cl2, 20 ꢀC, 12 h.
O
OTf
O
O
OTf
ArB(OH)2
3a,b,d-j
The reaction of bis(triflate) 2 with arylboronic acids 3aeg
(2.4 equiv) afforded the 1,3-diarylxanthones 4aeg in 70e95% yield
(Scheme 2, Table 1). The best yields were obtained when the re-
action was carried out using Pd(PPh3)2Cl2 (10 mol %) as the catalyst,
KF (6.6 equiv) as the base, and toluene as the solvent (Table 2). Both
electron rich and electron poor arylboronic acids could be suc-
cessfully employed.
i
OTf
O
Ar
2
5a-i
Scheme 3. Synthesis of 5aei. Conditions: i,
2 (1.0 equiv), ArB(OH)2 (1.1 equiv),
Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), dioxane, 80 ꢀC, 7 h.
Table 3
Synthesis of 5aei
O
Ar
O
OTf
3
5
Ar
% (5)a
ArB(OH)2
3a-g
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
4-(MeO)C6H4
2-(MeO)C6H4
3,5-Me2C6H3
3-ClC6H4
4-ClC6H4
4-FC6H4
4-tBuC6H4
4-(MeCO)C6H4
4-CF3C6H4
90
77
72
80
85
76
91
83
86
i
O
Ar
O
OTf
4a-g
2
Scheme 2. Synthesis of 4aeg. Conditions: i,
2 (1.0 equiv), ArB(OH)2 (2.4 equiv),
Pd(PPh3)2Cl2 (10 mol %), KF (6.6 equiv), toluene, 120 ꢀC, 5 h.
a
Yields of isolated compounds.
Table 1
Synthesis of 1,3-diarylxanthones 4aeg
3,4
Ar
% (4)a
The one-pot reaction of bis(triflate) 2 with two different aryl-
a
b
c
d
e
f
4-(MeO)C6H4
2-(MeO)C6H4
4-EtC6H4
3,5-Me2C6H3
3-ClC6H4
95
75
90
70
85
81
73
boronic acids (sequential addition) afforded the 1,3-diarylxanthones
6aee in 63e85% yield (Scheme 4, Table 4). The best yields were
obtained when the reaction was carried out using, for the first step,
Pd(PPh3)2Cl2 (3 mol %), KF (3.3 equiv), and toluene (85 ꢀC, 16 h) and,
for the second step, an additional amount of Pd(PPh3)2Cl2 (6 mol %)
(120 ꢀC, 7 h). Both in the first and second stepof the one-pot reaction,
electron poor and rich arylboronic acids could be successfully used.
4-ClC6H4
4-FC6H4
g
a
Yields of isolated compounds.

6300
O.A. Akrawi et al. / Tetrahedron 68 (2012) 6298e6304
sterically hindered than position 1 (Scheme 6). On the other hand,
position 1 is more electron deficient. As mentioned above, we have
earlier observed that SuzukieMiyaura reactions of bis(triflate) 7 of
1,3-dihydroxyanthraquinone proceed with very good site-
selectivity in favor of position 1 (Scheme 5).28 The 1H NMR chem-
ical shifts of the parent compounds, in which the OTf or Br group is
replaced by a hydrogen atom, have been reported to represent
a good tool to predict the electronic character of the atoms and to
predict the regioselectivity of palladium(0) catalyzed cross-coupling
reactions.30 The 1H NMR chemical shifts (in CDCl3) of anthraquinone
are 8.34 ppm (1-H) and 7.80 ppm (3-H), while the values for xan-
thone are 8.32 ppm (1-H) and 7.70 ppm (3-H). The chemical shifts of
the protons 1-H and 3-H of both respective compounds are very
similar. Therefore, the change of the regioselectivity is surprising. It
might be explained by the electron donating effect of the oxygen
atom of the xanthone ring.
Fig. 2. Molecular structure of compound 5i.
Second attack
Sterically more hindered
O
OTf
1) Ar1B(OH)2
Electronically more deficient
O
Ar2
O
O
OTf
2) Ar2B(OH)2
3a-c,f,j,k
O
OTf
First attack
O
Ar1
OTf
Sterically less hindered
i, ii
2
6a-e
2
Scheme 4. Synthesis of 6aee. Conditions: i, 2 (1.0 equiv), Ar1B(OH)2 (1.0 equiv),
Pd(PPh3)2Cl2 (3 mol %), KF (3.3 equiv), toluene, 85 ꢀC, 16 h. ii, Ar2B(OH)2 (1.4 equiv),
Pd(PPh3)2Cl2 (6 mol %), 120 ꢀC, 7 h.
First attack
Sterically more hindered
Electronically more deficient
O
OTf
Table 4
Synthesis of 6aee
OTf
Second attack
O
Sterically less hindered
3
6
Ar1
Ar2
% (6)a
7
c,f
a
b
c
d
e
4-EtC6H4
4-tBuC6H4
4-FC6H4
4-FC6H4
4-CF3C6H4
4-ClC6H4
70
78
81
63
85
h,a
g,b
g,k
j,a
4-(MeO)C6H4
2-(MeO)C6H4
2-MeC6H4
Scheme 6. Possible explanation for the site-selectivity of the Suzuki reactions of 2.
4-(MeO)C6H4
a
Yields of isolated compounds.
2. Experimental section
2.1. Synthesis of 9-oxo-9H-xanthene-1,3-diyl
bis(trifluoromethanesulfonate) (2)
We have earlier reported that the one-pot reaction of the bis(tri-
flate)7 of 1,3-dihydroxyanthraquinonewithtwodifferentarylboronic
acids afforded 1,3-diaryl-anthraquinones, such as derivative
8
To a CH2Cl2 (50 ml) solution of 1,3-dihydroxy-9H-xanthen-9-
one 1 (1.0 g, 4.4 mmol) pyridine (1.42 ml, 17.6 mmol) and Tf2O
(1.8 ml, 10.6 mmol) were added and reaction mixture was stirred at
20 ꢀC under argon atmosphere for 12 h. In the reaction mixture
toluene (20 ml) was added and concentrated in vacuo. Residue was
chromatographed (EtOAc/heptanes) without aqueous work up to
yield 2 as a white solid (1.73 g, 80%), mp: 156 ꢀC. 1H NMR (300 MHz,
(Scheme 5). The first attack occurred at position 1.28
O
Ar1
1) Ar1B(OH)2
2) Ar2B(OH)2
O
OTf
CDCl3):
d
¼7.05 (d, 1H, J¼2.3 Hz, ArH), 7.37e7.45 (m, 2H, ArH), 7.49
i, ii
Ar2
OTf
(d,1H, J¼2.4 Hz, ArH), 7.73 (ddd,1H, J¼1.7, 7.1, 8.6 Hz, ArH), 8.28 (dd,
O
O
7
1H, J¼1.6, 8.1 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
¼ꢁ73.1,
d
Ar1 = 3-ClC6H4
Ar2 = 4-MeC6H4
8 (74%)
ꢁ72.2. 13C NMR (62.9 MHz, CDCl3):
¼111.9, 112.1 (CH), 115.5 (C),
d
117.6 (CH), 118.6 (q, JC,F¼320.9 Hz, CF3), 118.8 (q, JC,F¼320.6 Hz, CF3),
121.8 (C), 125.5, 127.1, 136.1 (CH), 148.6, 151.5, 155.1, 157.5 (C), 173.9
(CO). IR (KBr): v¼3104 (w), 1663 (m), 1611 (s), 1592, 1570, 1471, 1460
(m), 1423 (s), 1353, 1334 (w), 1312 (m), 1280 (w), 1273, 1237 (m),
1202 (s), 1165, 1150 (m), 1135, 1109 (s), 1044, 1020 (m), 991 (s), 922
(w), 884 (s), 855 (w), 842, 810, 799, 768, 758 (m), 722 (w), 712 (m),
697, 684, 682 (w), 614, 592, 585, 570 (m), 545 (w) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼492 ([M]þ, 80), 428 (30), 364 (7), 336 (13), 267
(100). HRMS (EI, 70 eV): calcd for C15H6F6O8S2 [M]þ: 491.94028;
found: 491.94039.
Scheme 5. Synthesis of 8a,b. Conditions: i,
4
(1.0 equiv), Ar1B(OH)2 (1.0 equiv),
Pd(PPh3)4 (3 mol %), K3PO4 (3.0 equiv), dioxane, 60 ꢀC, 30 h; ii, Ar2B(OH)2 (1.2 equiv),
Pd(PPh3)4 (3 mol %), 100 ꢀC, 5 h.
Palladium catalyzed cross-coupling reactions usually proceed by
site-selective attack to the more electron deficient or less sterically
hindered position.29 In case of bis(triflate) 2, the site-selectivity in
favor of position 3 can be explained by the fact that position 3 is less

O.A. Akrawi et al. / Tetrahedron 68 (2012) 6298e6304
6301
2.2. General procedure A for SuzukieMiyaura cross-coupling
reactions to synthesize 4aeg
v¼3055, 3026, 2960, 2867, 2850 (w), 1658 (s), 1614 (w), 1598 (s),
1594 (w), 1574, 1519 (m), 1504 (w), 1467 (s), 1427 (m), 1408 (w),
1386, 1355 (m), 1335 (w), 1308 (s), 1261, 1199, 1186, 1170, 1144, 1121,
1108,1100,1060,1019, 946 (w), 945, 928 (m), 897, 879, 862, 853 (w),
A
toluene solution of 9-oxo-9H-xanthene-1,3-diyl bis(tri-
fluoromethanesulfonate) 2 (0.15 mmol), Pd(PPh3)2Cl2 (10 mol %),
arylboronic acid (2.4 equiv), and KF (6.6 equiv) was heated at 120 ꢀC
for 5 h under argon atmosphere. After cooling to 20 ꢀC, H2O was
added and the reaction mixture was extracted with CH2Cl2
(3ꢂ25 ml) organic layers were dried (Na2SO4), filtered and con-
centrated in vacuo. The residue was purified by column chroma-
tography (EtOAc/heptanes).
818, 756 (s), 727, 699, 670, 624, 606, 591, 582, 553, 532 (w) cmꢁ1
.
GCeMS (EI, 70 eV): m/z (%)¼404 ([M]þ, 47), 403 ([MꢁH]þ, 100), 388
(12), 373 (08). HRMS (EI, 70 eV): calcd for C29H23O2 [MꢁH]þ:
403.16926; found: 403.16953.
2.2.4. 1,3-Bis(3,5-dimethylphenyl)-9H-xanthen-9-one (4d). Starting
with 2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 3,5-
dimethylphenylboronic acid (54 mg, 0.36 mmol), KF (58 mg,
1 mmol), and toluene (2 ml), 4d was isolated as a white solid
(42 mg, 70%), mp: 173e175 ꢀC. Reaction temperature: 120 ꢀC for
2.2.1. 1,3-Bis(4-methoxyphenyl)-9H-xanthen-9-one
(4a). Starting
with 2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 4-
methoxyphenylboronic acid (55 mg, 0.36 mmol), KF (58 mg,
1 mmol), and toluene (2 ml), compound 4a was isolated as a yellow
solid (58 mg, 95%), mp: 196e198 ꢀC. Reaction temperature: 120 ꢀC
5 h. 1H NMR (300 MHz, CDCl3):
d
¼2.31 (br s, 12H, 4CH3), 6.92 (br s,
2H, ArH), 6.99 (br s, 2H, ArH), 7.20e7.25 (m, 3H, ArH), 7.31 (d, 1H,
J¼1.8 Hz, ArH), 7.39 (dd, 1H, J¼0.7, 8.4 Hz, ArH), 7.57e7.63 (m, 2H,
ArH), 8.12 (dd, 1H, J¼1.6, 8.0 Hz, ArH). 13C NMR (62.9 MHz, CDCl3):
for 5 h. 1H NMR (300 MHz, CDCl3):
d
¼3.78, 3.80 (s, 6H, 2OCH3),
6.90e6.95 (m, 4H, ArH), 7.22e7.27 (m, 3H, ArH), 7.29 (d, 1H,
J¼1.9 Hz, ArH), 7.39 (br d, 1H, J¼8.3 Hz, ArH), 7.56e7.59 (m, 4H,
ArH), 8.12 (dd, 1H, J¼1.6, 7.9 Hz, ArH). 13C NMR (62.9 MHz, CDCl3):
d¼21.4, 21.5 (2CH3), 115.1, 117.4 (CH), 118.0, 122.9 (C), 123.7, 125.3,
126.2, 126.3, 127.0, 128.9, 130.4, 134.3 (CH),136.9, 138.6, 138.8, 142.0,
144.8, 146.3, 155.5, 157.5 (C), 176.6 (CO). IR (KBr): v¼3030, 2996,
2914, 2852, 2727 (w), 1665 (s), 1615 (w), 1597, 1555 (s), 1512 (w),
1475 (m), 1462 (s), 1387, 1379, 1359, 1309 (m), 1290, 1265 (w), 1224
(m), 1167, 1151, 1141, 1131, 1106, 1082, 1034, 1018, 966, 946 (w), 841
(s), 808 (w), 792 (m), 758 (s), 731, 709, 702, 684 (w), 674, 656, 643
(m), 625, 608, 589, 554, 545 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼
404 ([M]þ, 53), 403 ([MꢁH]þ, 100), 389 (22). HRMS (EI, 70 eV):
calcd for C29H23O2 [MꢁH]þ: 403.16926; found: 403.16942.
d¼54.2, 54.4 (OCH3), 112.1, 113.3, 113.5, 116.3 (CH), 116.6, 121.9 (C),
122.7, 124.9, 125.9, 127.5, 128.8 (CH), 130.1, 133.2 (C), 133.3 (CH),
143.4, 144.7, 154.5, 156.8, 157.9, 159.4 (C), 175.7 (CO). IR (KBr):
v¼3060, 3044, 2995, 2962, 2917, 2838 (w), 1665, 1598 (s), 1553 (w),
1514 (s), 1474 (w), 1460, 1447 (s), 1430, 1388, 1355 (m), 1325 (w),
1309,1283 (m), 1244,1235 (s), 1189, 1176,1169, 1148,1109, 1099 (w),
1020 (s), 962, 944, 931, 924, 878, 851 (w), 820, 813, 793, 733 (s), 716,
698, 638, 621, 610, 602, 591, 581, 554 (w) cmꢁ1. GCeMS (EI, 70 eV):
m/z (%)¼408 ([M]þ, 39), 407 ([MꢁH]þ, 100), 365 (08), 321 (10), 263
(05). HRMS (EI, 70 eV): calcd for C27H19O4 [MꢁH]þ: 407.12779;
found: 407.12780.
2.2.5. 1,3-Bis(3-chlorophenyl)-9H-xanthen-9-one
(4e). Starting
with 2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 3-
chlorophenylboronic acid (56 mg, 0.36 mmol), KF (58 mg,
1 mmol), and toluene (2 ml), 4e was isolated as a white solid
(53 mg, 85%), mp: 146e148 ꢀC. Reaction temperature: 120 ꢀC for
2.2.2. 1,3-Bis(2-methoxyphenyl)-9H-xanthen-9-one (4b). Starting
with 2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 2-
methoxyphenylboronic acid (55 mg, 0.36 mmol), KF (58 mg,
1 mmol), and toluene (2 ml), 4b was isolated as a yellow solid (46 mg,
75%), mp: 158e160 ꢀC. Reaction temperature: 120 ꢀC for 5 h. 1H NMR
5 h. 1H NMR (300 MHz, CDCl3):
(m, 7H, ArH), 7.38e7.43 (m, 1H, ArH), 7.49e7.52 (m, 1H, ArH),
7.61e7.66 (m, 3H, ArH), 8.11 (dd, 1H, J¼1.3, 8.0 Hz, ArH). 13C NMR
d
¼7.17e7.20 (m, 1H, ArH), 7.24e7.36
(75.5 MHz, CDCl3):
d
¼116.1, 117.5 (CH), 118.3, 122.7 (C), 124.1, 125.6,
(300 MHz, CDCl3):
d
¼3.62, 3.78 (s, 6H, 2OCH3), 6.89e6.99 (m, 4H,
125.9 (CH), 126.9 (2 CH), 127.4, 127.5, 128.5, 128.8, 129.0, 130.4 (CH),
133.6 (C), 134.8 (CH), 135.2, 140.4, 143.3, 143.4, 144.8, 155.5, 157.6,
176.4 (CO). IR (KBr): v¼3054, 2954, 2920, 2850 (w), 1655 (s), 1616
(m), 1601, 1592, 1554 (s), 1515, 1494 (w), 1461 (s), 1414 (w), 1397,
1354 (m), 1338, 1303, 1289 (w), 1227 (m), 1189, 1176, 1169, 1137,
1131, 1081, 1074, 1057, 947 (w), 933 (m), 894, 872 (w), 857 (s), 830,
ArH), 7.16e7.20 (m, 2H, ArH), 7.27e7.32 (m, 3H, ArH), 7.37 (d, 2H,
J¼7.9 Hz, ArH), 7.54e7.60 (m, 1H, ArH), 7.66 (d, 1H, J¼1.6 Hz, ArH),
8.10 (dd, 1H, J¼1.4, 7.9 Hz, ArH). 13C NMR (62.9 MHz, CDCl3):
¼55.6,
d
55.7 (OCH3), 110.3, 111.4, 117.4, 118.3 (CH), 118.8 (C), 120.4, 121.0 (CH),
122.0 (C), 123.5, 126.8, 128.5, 128.7, 129.4, 129.9, 130.9 (CH), 131.5 (C),
134.1 (CH), 139.6, 144.1, 155.6 (C), 156.6 (2C), 157.1 (C), 175.7 (CO). IR
(KBr): v¼3058, 3023, 2997, 2936, 2917, 2836 (w), 1659 (s), 1618 (m),
1605, 1595 (s), 1580, 1554 (w), 1495, 1467, 1461 (s), 1433, 1396, 1356
(m), 1312, 1295, 1270 (w), 1241, 1230 (s), 1181, 1170, 1160, 1147, 1132,
1117, 1097, 1065 (w), 1045 (m), 1020 (s), 947, 931 (m), 885 (w), 870,
840 (m), 810, 791, 772 (w), 752 (s), 728 (m), 697 (w), 674 (m), 647,
622, 599, 572, 553 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼408 ([M]þ,
01), 378 (26), 377 (100), 362 (11), 361 (41). HRMS (EI, 70 eV): calcd
for C27H20O4 [M]þ: 408.13561; found: 408.13574.
806 (w), 779, 752 (s), 728, 676, 668 (m), 650, 624, 585 (w) cmꢁ1
.
GCeMS (EI, 70 eV): m/z (%)¼419 ([MꢁH, 37Cl, 37Cl]þ, 25), 417
([MꢁH, 35Cl, 37Cl]þ, 59), 415 ([MꢁH, 35Cl, 35Cl]þ, 100), 381 (05).
HRMS (EI, 70 eV): calcd for C25H13Cl2O2 [MꢁH, 35Cl, 35Cl]þ:
415.02871; found: 415.02871; calcd for C25H13Cl2O2 [MꢁH, 35Cl,
37Cl]þ: 417.02576; found: 417.02706.
2.2.6. 1,3-Bis(4-chlorophenyl)-9H-xanthen-9-one (4f). Starting with
2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 4-
chlorophenylboronic acid (56 mg, 0.36 mmol), KF (58 mg,
1 mmol), and toluene (2 ml), 4f was isolated as a white solid (51 mg,
81%), mp: 206e208 ꢀC. Reaction temperature: 120 ꢀC for 5 h. 1H
2.2.3. 1,3-Bis(4-ethylphenyl)-9H-xanthen-9-one (4c). Starting with
2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 4-
ethylphenylboronic acid (54 mg, 0.36 mmol), KF (58 mg, 1 mmol),
and toluene (2 ml), 4c was isolated as a white solid (55 mg, 90%),
mp: 123 ꢀC. Reaction temperature: 120 ꢀC for 5 h. 1H NMR
NMR (300 MHz, CDCl3):
d
¼7.21e7.27 (m, 4H, ArH), 7.32e7.40 (m,
5H, ArH), 7.55 (d, 2H, J¼8.5 Hz, ArH), 7.60e7.65 (m, 2H, ArH), 8.10
(dd, 1H, J¼1.4, 7.9 Hz, ArH). 13C NMR (75.5 MHz, CDCl3):
¼115.7,
d
(300 MHz, CDCl3):
d
¼1.18e128 (m, 6H, 2CH3), 2.58e2.73 (m, 4H,
117.5 (CH), 118.1, 122.7 (C), 124.1, 125.8, 126.9, 127.9, 128.6, 129.4,
129.9 (CH), 133.4 (C), 134.7 (CH), 135.3, 137.0, 140.1, 143.6, 145.0,
155.5, 157.7 (C), 176.6 (CO). IR (KBr): v¼3103, 3087, 3069, 3053,
3034, 2952, 2918, 2850 (w), 1661 (s), 1618 (w), 1601 (s), 1547 (w),
1496, 1466 (m), 1420 (w), 1378, 1356 (m), 1340 (s), 1312, 1303 (w),
1296 (m), 1292, 1269 (w), 1108 (m), 964, 956 (w), 945 (m), 929, 907,
892, 872, 855 (w), 821, 809 (s), 759 (w), 750, 732 (m), 719, 704, 641,
2CH2), 7.20e7.25 (m, 7H, ArH), 7.35 (d, 1H, J¼1.8 Hz, ArH), 7.40 (br d,
1H, J¼8.1 Hz, ArH), 7.57 (d, 2H, J¼8.3 Hz, ArH), 7.60e7.64 (m, 2H,
ArH), 8.13 (dd, 1H, J¼1.4, 7.9 Hz, ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼15.3,15.5 (CH3), 28.6, 28.7 (CH2),115.0,117.4 (CH),117.9,122.9 (C),
123.8, 126.2, 127.0, 127.2, 127.3, 128.5, 128.6, 134.4 (CH), 136.2, 139.3,
143.0, 144.7, 145.7, 146.1, 155.6, 157.8 (C), 176.8 (CO). IR (KBr):

6302
O.A. Akrawi et al. / Tetrahedron 68 (2012) 6298e6304
618, 600 (w), 559, 547 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼419
([MꢁH, 37Cl, 37Cl]þ, 18), 417 ([MꢁH, 35Cl, 37Cl]þ, 73), 415 ([MꢁH,
35Cl, 35Cl]þ, 100), 379 (06). HRMS (EI, 70 eV): calcd for C25H13Cl2O2
[MꢁH, 35Cl, 35Cl]þ: 415.02871; found: 415.02852; calcd for
C25H13Cl2O2 [MꢁH, 35Cl, 37Cl]: 417.02576; found: 417.02613.
isolated as a white solid (52 mg, 77%), mp: 145e147 ꢀC. Reaction
temperature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d
¼3.79 (s,
3H, OCH3), 6.89e7.04 (m, 2H, ArH), 7.29e7.40 (m, 5H, ArH),
7.57e7.68 (m, 2H, ArH), 8.29 (dd, 1H, J¼1.4, 7.9 Hz, ArH). 19F NMR
(282.4 MHz, CDCl3):
d
¼ꢁ73.4. 13C NMR (62.9 MHz, CDCl3):
¼55.5
d
(OCH3), 111.6 (CH), 113.8 (C), 117.6 (CH), 118.9 (q, JC,F¼320.8 Hz, CF3),
119.1, 119.4, 121.3 (CH), 122.1 (C), 124.5 (CH), 126.6 (C), 126.9, 130.5,
131.0, 135.2 (CH), 145.6, 146.9, 155.4, 156.5, 156.9 (C), 175.0 (CO). IR
(KBr): v¼3067, 3005, 2950, 2918, 2842 (w), 1659, 1627, 1609 (s),
1581, 1547, 1504 (w), 1471, 1463 (m), 1441 (w), 1422, 1406 (s), 1357
(m), 1334 (w), 1315 (m), 1286, 1271 (w), 1247, 1240 (m), 1225 (w),
1203 (s), 1163 (w), 1140 (s), 1125, 1111 (m), 1064, 1052 (w), 1035 (m),
1015 (s), 958 (w), 890 (s), 870 (m), 852 (w), 814 (s), 800 (w), 784
(m), 757, 750 (s), 721, 701, 682, 661, 634, 626, 606 (w), 592, 575 (s),
544 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼450 ([M]þ, 100), 317
(20), 302 (11), 299 (12), 289 (35), 271 (10), 258 (11). HRMS (EI,
70 eV): calcd for C21H13F3O6S1 [M]þ: 450.03794; found: 450.03826.
2.2.7. 1,3-Bis(4-fluorophenyl)-9H-xanthen-9-one (4g). Starting with
2 (74 mg, 0.15 mmol), Pd(PPh3)2Cl2 (10 mg, 10 mol %), 4-
fluorophenylboronic acid (50 mg, 0.36 mmol), KF (58 mg,
1 mmol), and toluene (2 ml), 4g was isolated as a white solid
(42 mg, 73%), mp: 173e175 ꢀC. Reaction temperature: 120 ꢀC for
5 h. 1H NMR (300 MHz, CDCl3):
d
¼7.02e7.15 (m, 4H, ArH), 7.24e7.31
(m, 4H, ArH), 7.41 (dd, 1H,¼J 0.6, 8.4 Hz, ArH), 7.58e7.65 (m, 4H,
ArH), 8.11 (dd, 1H, J¼1.6, 8.0 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ115.3, ꢁ112.7. 13C NMR (75.5 MHz, CDCl3):
d¼114.6 (d,
JF,C¼21.5 Hz, CH), 115.6 (CH), 116.2 (d, JF,C¼21.5 Hz, CH), 117.5 (CH),
118.0, 122.0 (C), 124.0, 126.1, 126.9 (CH), 129.1 (d, JF,C¼8.3 Hz, CH),
130.1 (d, JF,C¼7.7 Hz, CH), 134.7 (CH), 134.8 (d, JF,C¼3.3 Hz, C), 137.6
(d, JF,C¼3.9 Hz, C), 143.8, 145.2, 155.5, 157.7 (C), 162.0 (d,
JF,C¼245.8 Hz, CF), 163.4 (d, JF,C¼249.3 Hz, CF), 176.7 (CO). IR (KBr):
v¼3060, 2921, 2852 (w), 1658 (s), 1619 (w), 1602, 1594 (s), 1551 (w),
1513, 1506, 1465 (s), 1426 (m), 1404 (w), 1380, 1357 (m), 1338 (w),
1313 (m), 1303 (w), 1222 (s), 1173 (w), 1156, 1145 (m), 1118, 1103,
1065, 1020, 1013, 960 (w), 945, 926 (m), 894, 867, 851 (w), 825 (s),
811, 779 (w), 753 (s), 733, 719, 697, 676, 668, 644, 637, 618, 604, 586,
569 (w), 549 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼384 ([M]þ, 46),
383 ([MꢁH]þ, 100), 367 (04), 325 (04). HRMS (EI, 70 eV): calcd for
C25H13F2O2 [MꢁH]þ: 383.08781; found: 383.08785.
2.3.3. 4-(3-(3,5-Dimethylphenyl)-9-oxo-9H-xanthen-1-yl)phenyl tri-
fluoromethanesulfonate (5c). Starting with 2 (74 mg, 0.15 mmol),
Pd(PPh3)4 (5 mg, 3 mol %), 3,5-dimethylphenylboronic acid (24 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5c was
isolated as a white solid (48 mg, 72%), mp: 210 ꢀC. Reaction tem-
perature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d
¼2.35 (s, 6H,
2CH3), 7.06 (s, 1H, ArH), 7.17 (br s, 2H, ArH), 7.29e7.37 (m, 2H, ArH),
7.42 (dd, 1H, J¼0.6, 8.4 Hz, ArH), 7.65e7.71 (m, 2H, ArH), 8.30 (dd,
1H, J¼1.5, 8.0 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ73.3.13
C
NMR (75.5 MHz, CDCl3):
d¼21.4 (2CH3), 114.0 (C), 116.5, 116.6, 117.6
(CH),118.9 (q, JC,F¼320.7 Hz, CF3),122.2 (C), 124.7,125.0, 127.0,131.4,
135.3 (CH), 137.3, 139.1, 147.8, 148.2, 155.4, 157.9 (C), 174.7 (CO). IR
(KBr): v¼3097, 3067, 3012, 2953, 2920, 2851, 2732, 2664 (w), 1661,
1626, 1610 (s), 1548, 1492 (w), 1464 (m), 1427 (s), 1407 (w), 1395
(m), 1375 (w), 1359 (m), 1310 (w), 1214, 1204, 1187 (s), 1160 (w),
1137 (s), 1110 (m), 1081 (w), 1038, 1016 (m), 957 (w), 914 (m), 901
(w), 843, 834 (s), 798 (w), 716, 749 (s), 722, 689 (w), 666 (m), 656,
631, 609 (w), 594, 572 (s), 547 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z
(%)¼448 ([M]þ,100), 384 (40), 356 (20), 316 (65), 300 (17), 287 (44),
281 (13), 272 (11), 259 (16). HRMS (EI, 70 eV): calcd for
C22H15F3O5S1 [M]þ: 448.05868; found: 448.05883.
2.3. General procedure B for SuzukieMiyaura cross-coupling
reactions to synthesize 5aei
A 1,4-dioxane solution of of 9-oxo-9H-xanthene-1,3-diyl bis(-
trifluoromethanesulfonate) 2 (0.15 mmol), Pd(PPh3)4 (3 mol %),
arylboronic acid (1.1 equiv), and K3PO4 (1.5 equiv) was heated at
80 ꢀC for 7 h under argon atmosphere. After cooling to 20 ꢀC, CH2Cl2
(30 ml) was added and filtered then the filtrate was concentrated in
vacuo. The residue was purified by column chromatography
(EtOAc/heptanes).
2.3.1. 4-(3-(4-Methoxyphenyl)-9-oxo-9H-xanthen-1-yl)phenyl tri-
fluoromethanesulfonate (5a). Starting with 2 (74 mg, 0.15 mmol),
Pd(PPh3)4 (5 mg, 3 mol %), 4-methoxyphenylboronic acid (24 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5a was
isolated as a white solid (61 mg, 90%), mp: 191e193 ꢀC. Reaction
2.3.4. 4-(3-(3-Chlorophenyl)-9-oxo-9H-xanthen-1-yl)phenyl-
trifluoromethanesulfonate (5d). Starting with 2 (74 mg, 0.15 mmol),
Pd(PPh3)4 (5 mg, 3 mol %), 3-chlorophenylboronic acid (25 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5d was
isolated as a white solid (55 mg, 80%), mp: 172 ꢀC. Reaction tem-
temperature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d¼3.79 (s,
perature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d
¼7.24 (d, 1H,
3H, OCH3), 6.95 (d, 2H, J¼8.7 Hz, ArH), 7.26e7.39 (m, 3H, ArH), 7.50
(d, 2H, J¼8.8 Hz, ArH), 7.59 (d, 1H, J¼1.5 Hz, ArH), 7.62e7.67 (m, 1H,
ArH), 8.27 (dd, 1H, J¼1.4, 7.9 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
J¼0.8 Hz, ArH), 7.28e7.34 (m, 1H, ArH), 7.36e7.44 (m, 4H, ArH),
7.50e7.51 (m, 1H, ArH), 7.61e7.69 (m, 2H, ArH), 8.25 (dd, 1H, J¼1.6,
8.0 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ73.3. 13C NMR
d
¼ꢁ73.3. 13C NMR (62.9 MHz, CDCl3):
d
¼55.4 (OCH3), 113.5 (C),
(62.9 MHz, CDCl3):
d
¼114.4 (C), 116.3, 116.7, 117.6 (CH), 118.9 (q,
114.8, 115.5, 115.9, 117.5 (CH), 118.9 (q, JC,F¼320.3 Hz, CF3), 122.1 (C),
124.6, 126.9, 128.4 (CH), 129.4 (C), 135.3 (CH), 147.3, 147.9, 155.3,
157.3, 161.1 (C), 174.7 (CO). IR (KBr): v¼3072, 3012, 2971, 2941, 2912,
2842 (w), 1658, 1628, 1609 (s), 1545 (w), 1519 (s), 1473 (w), 1461,
1406, 1360 (m), 1335 (w), 1315, 1300 (m), 1282, 1270 (w), 1240,1224
(m), 1204 (s), 1179, 1166, 1150 (w), 1137 (s), 1113, 1086, 1066 (w),
1031, 1012 (s), 966 (w), 939 (m), 877, 871, 851 (w), 833, 814, 806,
782, 767, 759 (m), 741, 724, 691, 680, 667, 642 (w), 610 (m), 595 (s),
574, 550, 542 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼450 ([M]þ,
100), 317 (23), 302 (13), 289 (34), 258 (16), 246 (12), HRMS (EI,
70 eV): calcd for C21H13F3O6S1 [M]þ: 450.03794; found: 450.03830.
JC,F¼321.1 Hz, CF3), 122.1 (C), 124.8, 125.4, 126.9, 127.3, 129.7, 130.7
(CH), 135.4 (C), 135.5 (CH), 139.0, 146.1, 147.9, 155.2, 157.3 (C), 175.0
(CO). IR (KBr): v¼3077, 2923, 2851, 2789, 2667 (w), 1665, 1627, 1607
(s), 1572, 1549, 1513 (w), 1502, 1470, 1460 (m), 1407 (w), 1392, 1357
(m), 1335 (w), 1310 (m), 1283, 1245 (w), 1222, 1192 (s), 1166 (m),
1136 (s), 1112, 1105, 1082 (w), 1032, 1012 (s), 995, 960 (w), 947 (m),
902 (s), 881, 862 (w), 823 (s), 800 (w), 785, 759, 721 (m), 694 (w),
678, 662 (m), 637, 631, 606 (w), 590, 572 (s), 548 (w) cmꢁ1. GCeMS
(EI, 70 eV): m/z (%)¼456 ([M, 37Cl]þ, 41), 454 ([M, 35Cl]þ, 100), 392
(21), 390 (62), 364 (11), 362 (29), 295 (11), 293 (39), 286 (28), 267
(16), 265 (43), 258 (26). HRMS (ESI-TOF/MS): calcd for
C20H11ClF3O5S1 [MþH, 35Cl]þ: 454.99623; found: 454.99651, calcd
for C20H11ClF3O5S [MþH, 37Cl]þ: 456.99351; found: 456.99363.
2.3.2. 4-(3-(2-Methoxyphenyl)-9-oxo-9H-xanthen-1-yl)phenyl tri-
fluoromethanesulfonate (5b). Starting with 2 (74 mg, 0.15 mmol),
Pd(PPh3)4 (5 mg, 3 mol %), 2-methoxyphenylboronic acid (24 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5b was
2.3.5. 4-(3-(4-Chlorophenyl)-9-oxo-9H-xanthen-1-yl)phenyl
tri-
fluoromethanesulfonate (5e). Starting with 2 (74 mg, 0.15 mmol),

O.A. Akrawi et al. / Tetrahedron 68 (2012) 6298e6304
6303
Pd(PPh3)4 (5 mg, 3 mol %), 4-chlorophenylboronic acid (25 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5e was
isolated as a white solid (58 mg, 85%), mp: 200e202 ꢀC. Reaction
Pd(PPh3)4 (5 mg, 3 mol %), 4-acetylphenylboronic acid (27 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5h was
isolated as a white solid (58 mg, 83%), mp: 203 ꢀC. Reaction tem-
temperature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d¼7.27 (d,1H,
perature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d¼2.58 (s, 3H,
J¼0.8 Hz, ArH), 7.32e7.37 (m, 1H, ArH), 7.39e7.52 (m, 5H, ArH),
COCH3), 7.31e7.40 (m, 3H, ArH), 7.63e7.69 (m, 4H, ArH), 8.0 (d, 2H,
J¼8.2 Hz, ArH), 8.3 (d, 1H, J¼7.1 Hz, ArH). 19F NMR (282.4 MHz,
7.64e7.71 (m, 2H, ArH), 8.29 (dd, 1H, J¼1.5, 7.9 Hz, ArH). 19F NMR
(282.4 MHz, CDCl3):
d
¼ꢁ73.3. 13C NMR (62.9 MHz, CDCl3):
d¼114.3
CDCl3):
d
¼ꢁ73.3. 13C NMR (62.9 MHz, CDCl3):
¼26.7 (CH3), 114.6
d
(C), 116.4, 116.5, 117.6 (CH), 118.9 (q, JC,F¼320.8 Hz, CF3), 122.1 (C),
124.5, 127.0, 128.5, 129.7, 135.5 (CH), 135.7, 136.2, 146.4, 148.0, 153.3,
157.4 (C), 175.0 (CO). IR (KBr): v¼3110, 3076, 3038 (w), 1666, 1628,
1608 (s),1591,1547,1505 (w),1461 (m),1426 (s),1391,1357,1312 (m),
1285, 1267 (w), 1246 (m), 1221, 1194 (s), 1165 (w), 1091, 1031, 1010
(m), 965 (w), 937 (m), 887 (s), 866 (w), 830, 813, 798 (m), 760 (s), 723
(m), 689, 678 (w), 664 (m), 635, 620 (w), 607 (m), 590, 573 (s), 532
(w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼456 ([M, 37Cl]þ, 46), 454 ([M,
35Cl]þ,100), 392 (18), 390 (61), 364 (09), 362 (30), 322 (20), 295 (13),
293 (35), 286 (23), 267 (12), 265 (33), 258 (38). HRMS (EI, 70 eV):
calcd for C20H10ClF3O5S1 [M, 35Cl]þ: 453.98841; found: 453.98857,
calcd for C20H10ClF3O5S1 [M, 37Cl]þ: 455.98546; found: 455.98437.
(C), 116.5, 117.0, 117.6 (CH), 118.9 (q, JC,F¼321.1 Hz, CF3), 122.1 (C),
124.9, 127.0, 127.5, 129.3, 135.6 (CH), 137.7, 141.4, 146.2, 148.0, 155.2,
157.3 (C), 174.7, 197.2 (CO). IR (KBr): v¼3105, 3076, 3005, 2919, 2850
(w), 1668, 1659, 1628, 1606 (s), 1545, 1519 (w), 1478, 1470 (m), 1422
(s), 1394, 1358 (m), 1337 (w), 1314 (m), 1287 (w), 1267, 1261, 1243
(m), 1208, 1199 (s), 1166, 1155 (w), 1134 (s), 1112, 1075, 1058 (w),
1034, 1012 (s), 961 (w), 938 (m), 887 (s), 863 (w), 834, 816, 802, 758
(s), 742, 720 (w), 665 (m), 623 (w), 609 (m), 595, 586, 573 (s), 550
(w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼462 ([M]þ, 76), 447 (96), 383
(31), 355 (26), 341 (11), 287 (21), 258 (28), 254 (14), 44 (100). HRMS
(EI, 70 eV): calcd for C22H13F3O6S1 [M]þ: 462.03794; found:
462.03783.
2.3.6. 4-(3-(4-Fluorophenyl)-9-oxo-9H-xanthen-1-yl)phenyl
tri-
2.3.9. 4-(9-Oxo-3-(4-(trifluoromethyl)phenyl)-9H-xanthen-1-yl)
phenyl trifluoromethanesulfonate (5i). Starting with 2 (74 mg,
0.15 mmol), Pd(PPh3)4 (5 mg, 3 mol -%), 4-(triflouromethyl)phe-
nylboronic acid (31 mg, 0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and
dioxane (2 ml), 5h was isolated as a white solid (63 mg, 86%), mp:
185e187 ꢀC. Reaction temperature: 80 ꢀC for 7 h. 1H NMR
fluoromethanesulfonate (5f). Starting with 2 (74 mg, 0.15 mmol),
Pd(PPh3)4 (5 mg, 3 mol %), 4-flourophenylboronic acid (23 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5f was
isolated as a white solid (50 mg, 76%), mp: 187 ꢀC. Reaction tem-
perature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d¼7.14 (t, 2H,
J¼8.6 Hz, ArH), 7.26 (d, 1H, J¼0.8 Hz, ArH), 7.31e7.36 (m, 1H, ArH),
7.40 (br d, 1H, J¼8.4 Hz, ArH), 7.52e7.58 (m, 2H, ArH), 7.62 (d, 1H,
J¼1.7 Hz, ArH), 7.67 (ddd, 1H, J¼1.7, 7.0, 8.5 Hz, ArH), 8.28 (dd, 1H,
(300 MHz, CDCl3):
d
¼7.30e7.42 (m, 3H, ArH), 7.66e7.74 (m, 6H,
ArH), 8.28 (dd, 1H, J¼1.4, 7.9 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ73.3, ꢁ62.8. 13C NMR (62.9 MHz, CDCl3):
¼114.7 (C), 116.6,
d
J¼1.6, 7.9 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ111.1, ꢁ73.3.
117.1, 117.6 (CH), 118.8 (q, JC,F¼320.9 Hz, CF3), 122.1 (C), 123.8 (q,
JC,F¼272.4 Hz, CF3), 124.9 (CH),126.4 (q, JC,F¼3.7 Hz, CH),127.0,127.7
(CH), 131.6 (q, JC,F¼32.3 Hz, CeCF3), 135.6 (CH), 140.8, 146.1, 148.1,
155.3, 157.3 (C), 174.6 (CO). IR (KBr): v¼1660 (s), 1631, 1610 (m),
1548, 1524, 1474, 1463 (w), 1424 (s), 1399, 1360 (w), 1322, 1313 (s),
1243 (w), 1219, 1210 (s), 1177, 1156 (w), 1137, 1125, 1110, 1072 (s),
937, 899 (w), 889 (m), 877 (w), 844 (s), 814, 802 (m), 766, 761 (s),
13C NMR (75.5 MHz, CDCl3):
d
¼114.4 (C), 116.4 (2CH), 116.6 (d,
JF,C¼21.7 Hz, CH), 117.6 (CH), 118.9 (q, JC,F¼321.2 Hz, CF3), 122.1 (C),
124.8, 127.0 (CH), 129.1 (d, JF,C¼8.6 Hz, CH), 133.5 (d, JF,C¼3.4 Hz, C),
135.5 (CH), 145.6, 148.0, 155.3, 157.3 (C), 163.8 (d, JF,C¼250.9 Hz, CF),
175.0 (CO). IR (KBr): v¼2922, 2852 (w), 1661, 1626, 1608 (s), 1550
(w), 1512, 1463 (m), 1435 (w), 1423 (s), 1404 (w), 1394, 1361 (m),
1334 (w), 1309 (m), 1286 (w), 1241, 1226 (m), 1216, 1197 (s), 1161,
1151 (w), 1134 (s), 1112, 1061 (w), 1037 (s), 938 (m), 872 (w), 823 (s),
819 (w), 797 (m), 770 (s), 760, 725, 700, 666, 659, 638 (w), 611, 594
(s), 571, 543 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼438 ([M]þ, 100),
374 (52), 346 (29), 305 (20), 277 (56), 249 (43), 220 (38). HRMS (EI,
70 eV): calcd for C20H10F4O5S1 [M]þ: 438.01796; found: 438.01796.
736, 725, 703, 683, 672, 655, 624 (w), 596 (s), 550, 534 (w) cmꢁ1
.
GCeMS (EI, 70 eV): m/z (%)¼488 ([M]þ, 100), 469 (10), 424 (83), 396
(37), 355 (12), 327 (42), 299 (66), 258 (18). HRMS (EI, 70 eV): calcd
for C21H10F6O5S1 [M]þ: 488.01476; found: 488.01455.
2.4. General procedure C for the one-pot synthesis of 1,3-
diarylxanthones 6aee
2.3.7. 4-(3-(4-(tert-Butyl)phenyl)-9-oxo-9H-xanthen-1-yl)phenyl-
trifluoromethanesulfonate (5g). Starting with 2 (74 mg, 0.15 mmol),
Pd(PPh3)4 (5 mg, 3 mol %), 4-tert-butylphenylboronic acid (29 mg,
0.17 mmol), K3PO4 (48 mg, 0.23 mmol), and dioxane (2 ml), 5g was
isolated as a white solid (64 mg, 91%), mp: 150e152 ꢀC. Reaction
A
toluene
solution9-oxo-9H-xanthene-1,3-diyl
bis(tri-
fluoromethanesulfonate) 2 (0.2 mmol), Pd(PPh3)2Cl2 (3 mol %),
Ar1B(OH)2 (1.0 equiv), and KF (3.3 equiv) was heated at 85 ꢀC for
16 h under argon atmosphere. After cooling to 20 ꢀC, Ar2B(OH)2
(1.4 equiv), Pd(PPh3)2Cl2 (6 mol %), and KF (3.3 equiv), were added
reaction mixture was heated at 120 ꢀC for further 7 h. Reaction
mixture was cooled again to 20 ꢀC, H2O was added and the reaction
mixture was extracted with CH2Cl2 (3ꢂ25 ml), organic layers were
dried (Na2SO4), filtered and then concentrated in vacuo. The resi-
due was purified by column chromatography (EtOAc/heptanes).
temperature: 80 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d¼1.31 (s, 9H,
3CH3), 7.29e7.35 (m, 2H, ArH), 7.39 (br d, 1H, J¼8.4 Hz, ArH),
7.46e7.54 (m, 4H, ArH), 7.64e7.70 (m, 2H, ArH), 8.28 (dd, 1H, J¼1.5,
7.9 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ73.3. 13C NMR
(62.9 MHz, CDCl3):
d¼31.2 (3CH3), 34.1, 113.7 (C), 116.1, 116.4, 117.6
(CH), 118.9 (q, JC,F¼320.2 Hz, CF3), 122.1 (C), 124.7, 126.4, 126.9, 127.0
(CH), 134.3 (C), 135.3 (CH), 147.7, 147.9, 153.2, 155.3, 157.3 (C), 174.8
(CO). IR (KBr): v¼3075, 3040, 2965, 2924, 2868 (w),1658,1624,1607
(s), 1545, 1524, 1494 (w), 1462, 1422 (s), 1397, 1359 (m), 1334, 1309,
1285,1268,1242,1230 (w),1209,1186 (s),1166 (m),1137 (s),1111 (m),
1080 (w),1035,1014 (s), 967 (w), 939, 895 (m), 881, 868, 853, 841 (w),
827, 813, 802, 770 (s), 724, 727, 721, 692 (w), 664 (m), 641, 622, 608
(w), 594 (s), 569, 545 (m) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼476
([M]þ, 32), 461 (100), 328 (04), 300 (18), 254 (04). HRMS (ESI-TOF/
MS): calcd for C24H20F3O5S1 [MþH]þ: 477.09781; found: 477.09730.
2.4.1. 1-(4-Chlorophenyl)-3-(4-ethylphenyl)-9H-xanthen-9-one
(6a). Starting with 2 (100 mg, 0.20 mmol), Pd(PPh3)2Cl2 (4 mg,
3 mol %) 4-ethylphenylboronic acid (30 mg, 0.20 mmol), KF (38 mg,
0.66 mmol), toluene (3 ml), and Pd(PPh3)2Cl2 (8 mg, 6 mol %), 4-
chlorophenylboronic acid (44 mg, 0.28 mmol), KF (38 mg,
0.66 mmol), 6a was prepared according to the general procedure C,
as a white solid (57 mg, 70%), mp: 195e197 ꢀC. Reaction tempera-
ture was 85 ꢀC for 16 h and 120 ꢀC for 7 h. 1H NMR (300 MHz,
CDCl3):
d¼1.20 (t, 3H, J¼7.7 Hz, CH3), 2.63 (q, 2H, J¼7.6 Hz, CH2),
2.3.8. 4-(3-(4-Acetylphenyl)-9-oxo-9H-xanthen-1-yl)phenyl
tri-
7.20e7.25 (m, 5H, ArH), 7.28 (d, 1H, J¼1.8 Hz, ArH), 7.32 (d, 2H,
J¼8.4 Hz, ArH), 7.38 (br d, 1H, J¼8.3 Hz, ArH), 7.54 (d, 2H, J¼8.2 Hz,
fluoromethanesulfonate (5h). Starting with 2 (74 mg, 0.15 mmol),

6304
O.A. Akrawi et al. / Tetrahedron 68 (2012) 6298e6304
ArH), 7.58e7.65 (m, 2H, ArH), 8.10 (dd, 1H, J¼1.5, 7.9 Hz, ArH). 13
C
1261, 1251 (s), 1230, 1206, 1176 (w), 1160 (m), 1146 (w), 1107, 1070,
1026, 1013 (s), 970, 956, 926, 888, 853 (w), 836, 830 (s), 801 (m),
758 (s), 736, 728, 704, 681, 670, 565, 624, 611, 601, 589, 578, 556,
530 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼446 ([M]þ, 58), 445
([MꢁH]þ, 100), 402 (20). HRMS (EI, 70 eV): calcd for C27H16F3O3
[MꢁH]þ: 445.10461; found: 445.10501, calcd for. C27H17F3O3 [M]þ:
446.11243; found: 446.11099.
NMR (75.5 MHz, CDCl3):
d
¼14.4 (CH3), 27.8 (CH2), 114.4, 116.4 (CH),
116.7, 121.7 (C), 122.9, 124.8, 125.8, 126.2, 126.6, 127.3, 128.9 (CH),
132.2 (C), 133.5 (CH), 134.8, 139.3, 142.2, 144.4, 145.3, 154.5, 156.6
(C), 175.6 (CO). IR (KBr): v¼3063, 3031, 2960, 2927, 2869, 1956,
1925, 1866 (w), 1660 (s), 1614 (m), 1600 (s), 1574, 1553, 1519, 1488
(w), 1467, 1460 (m), 1426 (w), 1386, 1355, 1311 (m), 1295, 1262 (w),
1230 (m), 1194, 1172, 1146, 1124, 1100 (w), 1014 (m), 996, 965 (w),
944, 929 (m), 874, 861, 852, 835 (w), 825, 816, 764 (s), 730, 705, 697
(w), 671 (m), 640, 623, 603, 590 (w), 552 (m) cmꢁ1. GCeMS (EI,
70 eV): m/z (%)¼412 ([M, 37Cl]þ, 18), 410 ([M, 35Cl]þ, 53), 409
([MꢁH, 35Cl]þ, 100), 394 (20), 373 (08). HRMS (ESI-TOF/MS): calcd
for C27H20ClO2 [MþH, 35Cl]þ: 411.11463; found 411.11476, calcd For
C27H20ClO2 [MþH, 37Cl]þ: 413.11288; found 413.11290.
References and notes
1. Xiao, H.; Yang, L.; Zenai, C.; Guangming, L.; Jinfu, Q. J. Chin. Pharm. Sci. 2001, 10,
172e174.
2. Ee, G. C. L.; Lim, C. K.; Lee, H. L. J. Asian Nat. Prod. Res. 2006, 8, 567e570.
3. Wen, L.; Lin, Y.-C.; She, Z.-G.; Du, D.-S.; Chan, W.-L.; Zheng, Z. H. J. Asian Nat.
Prod. Res. 2008, 10, 133e137.
4. (a) Mahabusarakam, W.; Nuangnaowarat, W.; Taylor, W. C. Phytochemistry
2006, 67, 470e474; (b) Gnerre, C.; Thull, U.; Gailland, P.; Carrupt, P. A.; Testa, B.;
Fernandes, E.; Silva, F.; Pinto, M.; Pinto, M. M. M.; Wolfender, J.-L.; Hostettmann,
K.; Cruciani, G. Helv. Chim. Acta 2001, 84, 552e570.
5. Lesch, B.; Braese, S. Angew. Chem., Int. Ed. 2004, 43, 115e118.
6. (a) Garrity, A. R.; Morton, G. A. R.; Morton, J. C. U.S. Patent 6,730,333, 2004. (b)
2.4.2. 3-(4-(tert-Butyl)phenyl)-1-(4-methoxyphenyl)-9H-xanthen-9-
one (6b). Starting with 2 (100 mg, 0.20 mmol), Pd(PPh3)2Cl2 (4 mg,
3 mol %) 4-tert-butylphenylboronic acid (36 mg, 0.20 mmol), KF
(38 mg, 0.66 mmol), toluene (3 ml), and Pd(PPh3)2Cl2 (8 mg,
6 mol %), 4-methoxyphenylboronic acid (43 mg, 0.28 mmol), KF
(38 mg, 0.66 mmol), 6b was prepared according to the general
procedure C, as a white solid (68 mg, 78%), mp: 225e227 ꢀC. Re-
action temperature was 85 ꢀC for 16 h and 120 ꢀC for 7 h. 1H NMR
ꢀ
€
ꢀ
Selles, A. J. N.; Castro, H. T. V.; Aguero, J.; Gonzalez, J.; Naddeo, F.; De Simone, F.;
Rastrelli, L. J. Agric. Food Chem. 2002, 50, 762e766.
7. (a) Dube, M.; Zunker, K.; Neidhart, S.; Carle, R.; Steinhart, H.; Paschke, A. J. Agric.
Food Chem. 2004, 52, 3938e3945; (b) Pfister, J. R.; Ferraresi, R. W.; Harrison, I.
T.; Rooks, W. H.; Freid, J. H. J. Med. Chem. 1978, 21, 669e672.
8. Rukachaisirikul, V.; Kamkaew, M.; Sukavisit, D.; Taylor, W. C. J. Nat. Prod. 2003,
66, 1531e1535.
(300 MHz, CDCl3):
d
¼1.30 (s, 9H, 3CH3), 3.79 (s, 3H, OCH3), 6.91 (d,
2H, J¼8.8 Hz, ArH), 7.21e7.27 (m, 3H, ArH), 7.33 (d, 1H, J¼1.8 Hz,
ArH), 7.36e7.44 (m, 3H, ArH), 7.55e7.59 (m, 3H, ArH), 7.61 (d, 1H,
J¼1.8 Hz, ArH), 8.12 (dd, 1H, J¼1.5, 7.9 Hz, ArH). 13C NMR (62.9 MHz,
€
9. (a) Abdel-Lateff, A.; Klemke, C.; Konig, G. M.; Wright, A. D. J. Nat. Prod. 2003, 66,
706e708; (b) Fukai, T.; Yonekawa, M.; Hou, A.-J.; Nomura, T.; Sun, H.-D.; Uno, J.
J. Nat. Prod. 2003, 66, 1118e1120; (c) Mackeen, M. M.; Ali, A. M.; Lajis, N. H.;
Kawazu, K.; Hassan, Z.; Amran, M.; Habsah, M.; Mooi, L. Y.; Mohamed, S. M. J.
Ethnopharmacol. 2000, 72, 395e402.
CDCl3):
d
¼31.3 (3CH3), 34.7 (C), 55.2 (OCH3), 113.1, 114.9, 117.3 (CH),
117.9, 122.9 (C), 123.8, 126.1, 126.3, 126.9, 127.1, 129.8 (CH), 134.2 (C),
134.3 (CH), 135.9, 144.4, 145.9, 152.1, 155.1, 157.5, 158.9 (C), 176.8
(CO). IR (KBr): v¼3034, 2953, 2910, 2866, 2838 (w), 1650 (s), 1612
(m),1599 (s),1549 (w),1467 (s),1422,1386 (w),1311,1282 (m),1245
(s), 1173 (m), 1151, 1124, 1104 (w), 1024, 948, 927 (m), 915, 882, 868,
854, 848 (w), 821, 769 (s), 761, 723 (m), 689 (w), 676 (m), 646, 624,
606, 581, 557, 546, 528 (w) cmꢁ1. GCeMS (EI, 70 eV): m/z (%)¼434
([M]þ, 85), 433 ([MꢁH]þ, 100), 419 (17), 417 (08), 390 (07). HRMS
(EI, 70 eV): calcd for C30H25O3 [MꢁH]þ: 433.17982; found:
433.17978; calcd for C30H26O3 [M]þ: 434.18765; found: 434.18620.
10. (a) Park, H. H.; Park, Y.-D.; Han, J.-M.; Im, K.-R.; Lee, B. W.; Jeong, I. Y.; Jeong, T.-
S.; Lee, W. S. Bioorg. Med. Chem. Lett. 2006, 16, 5580e5583; (b) Lin, C. N.; Chung,
M. I.; Liou, S. J.; Lee, T. H.; Wang, J. P. J. Pharm. Pharmacol. 1996, 48, 532e538.
11. (a) Riscoe, M.; Kelly, J. X.; Winter, R. Curr. Med. Chem. 2005, 12, 2539e2549; (b)
Portela, C.; Alfonso, C. M. M.; Pinto, M. M. M.; Ramos, M. J. Bioorg. Med. Chem.
2004, 12, 3313e3321; (c) Dua, V. K.; Ojha, V. P.; Roy, R.; Joshi, B. C.; Valecha, N.;
Devi, C. U.; Batnagar, M. C.; Sharma, V. P.; Subbarao, S. K. J. Ethnopharmacol.
2004, 95, 247e251.
12. Alj, V.; De bruyne, T.; Pieters, A. S. Planta Med. 1998, 64, 97e109.
13. Peres, V.; Nagem, T. J.; De Oliveira, F. F. Phytochemistry 2000, 55, 683e710.
14. Ichikib, H.; Okadab, M.; Ishidac, T.; Tanigawaa, K. Phytomedicine 2001, 8, 85e87.
15. Palmer, B. D.; Henare, K.; Ching, M. J. Med. Chem. 2007, 50, 3759e3764.
16. Casillas, L. K.; Townsend, C. A. J. Org. Chem. 1999, 64, 4050e4059.
17. Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583e588.
18. Dang, A.-T.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233e236.
19. Su, Q.-G.; Liu, Y.; Xi, L.-J. Invest. New Drugs 2011, 29, 1230e1240.
20. Zhao, L.; Xie, F.; Cheng, G.; Hu, Y. Angew. Chem., Int. Ed. 2009, 48, 6520e6523.
21. Liu, Y.; Huang, L.; Xie, F.; Hu, Y. J. Org. Chem. 2010, 75, 6304e6307.
22. Esteves, I. C.; Santos, C. M. M.; Cristela, M. B.; Silva, A. M. S.; Cavaleiro, J. A. S.
Synlett 2011, 1403e1406.
23. Santos, C. M. M.; Cristela, M. B.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett 2005,
3095e3098.
24. Santos, C. M. M.; Cristela, M. B.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett 2007,
3113e3116.
25. Santos, C. M. M.; Cristela, M. B.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem.
2009, 2642e2660.
26. Gardikis, Y.; Tsoungas, P. G.; Cordopatis, P. J. Heterocycl. Chem. 2011, 83,
1077e1091.
27. CCDC-878328 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: (þ44) 1223-336-033; or deposit@
ccdc.cam.ac.uk.
2.4.3. 1-(4-Methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-9H-
xanthen-9-one (6e). Starting with
2 (100 mg, 0.20 mmol),
Pd(PPh3)2Cl2 (4 mg, 3 mol %) 4-(trifluoromethyl)phenylboronic acid
(38 mg, 0.20 mmol), KF (38 mg, 0.66 mmol), toluene (3 ml), and
Pd(PPh3)2Cl2 (8 mg, 6 mol %), 4-methoxylphenylboronic acid
(43 mg, 0.28 mmol), KF (38 mg, 0.66 mmol), 6d was prepared
according to the general procedure C, as a yellow solid (76 mg, 85%),
mp: 195e197 ꢀC. Reaction temperature was 85 ꢀC for 16 h and
120 ꢀC for 7 h. 1H NMR (300 MHz, CDCl3):
d
¼3.81 (s, 3H, OCH3), 6.91
(d, 2H, J¼8.6 Hz, ArH), 7.23e7.28 (m, 3H, ArH), 7.33 (d, 1H, J¼1.9 Hz,
ArH), 7.41 (br d, 1H, J¼8.1 Hz, ArH), 7.60e7.75 (m, 6H, ArH), 8.13 (dd,
1H, J¼1.5, 8.1 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢁ62.6. 13
C
NMR (75.5 MHz, CDCl3):
d
¼54.2 (OCH3), 112.2, 114.6, 116.4 (CH),
117.7, 121.8 (C), 122.9 (CH), 123.0 (q, JC,F¼272.4 Hz, CF3), 125.1 (q,
JC,F¼3.9 Hz, CH), 125.3, 125.9, 126.7, 128.7 (CH), 129.7 (q,
JC,F¼32.5 Hz, CeCF3), 132.7 (C), 133.6 (CH), 141.4, 143.4, 143.9, 154.4,
156.7, 158.0 (C), 175.7 (CO). IR (KBr): v¼3078, 3052, 3031, 2966,
2920, 2828, 2087, 1946, 1923 (w), 1652 (s), 1613 (m), 1599 (s), 1575,
1548 (m), 1513, 1468 (s), 1454, 1446 (m), 1321, 1309 (s), 1292 (m),
28. Akrawi, O. A.; Hussain, M.; Langer, P. Tetrahedron Lett. 2011, 52, 1093e1095.
29. For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
€
(a) Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245e2254; (b)
€
Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P.
Eur. J. Org. Chem. 2006, 3283e3290.
30. Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299e301.