Site-selective Suzuki-Miyaura reactions of the bis(triflate) of 1,3-dihydroxythioxanthone

Article abstract of DOI:10.1016/j.tetlet.2011.04.102

The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflate) of 1,3-dihydroxythioxanthone afforded various aryl-substituted thioxanthones. The reactions proceeded with very good site-selectivity in favour of position 3, due to steric reasons.

Full text of DOI:10.1016/j.tetlet.2011.04.102

Tetrahedron Letters 52 (2011) 3451–3454
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Site-selective Suzuki–Miyaura reactions of the bis(triflate)
of 1,3-dihydroxythioxanthone
Dhafer Saber Zinad a, Munawar Hussain a, Omer Adeeb Akrawi a, Alexander Villinger a, Peter Langer a,b,
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflate) of 1,3-dihydroxythioxanth-
one afforded various aryl-substituted thioxanthones. The reactions proceeded with very good site-selec-
tivity in favour of position 3, due to steric reasons.
Received 9 March 2011
Revised 21 April 2011
Accepted 26 April 2011
Available online 6 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Thioxanthones
Palladium
Suzuki–Miyaura reaction
Regioselectivity
Thioxanthones are of considerable pharmacological relevance
and occur in various natural products.1 Thioxanthone derivatives
have been studied extensively owing to their medicinal properties
such as antihistaminic, antiparasitic, neuroleptic, and antitumor
activities.1–9 Lucanthone and hycanthone, a metabolite, represent
derivatives to give 2-phenylmercaptobenzoic acids which are sub-
sequently cyclized by reaction with sulfuric acid,13,18,19 AlCl3,3,6 or
polyphosphoric acid (PPA).5 However, these classical methods have
some disadvantages, such as low yields, long reaction times, use of
large amounts of concentrated sulfuric acid, and lack of regiochem-
ical control in the ring closure step. Moreover, some of these meth-
ods require several synthetic steps, because the starting materials
are not readily available, and are limited to activated benzoic acids
and benzene derivatives containing electron-withdrawing groups.
We have envisaged an alternative approach to substituted thi-
oxanthones based on the functionalization of readily available
hydroxylated thioxanthones by site-selective palladium catalyzed
cross-coupling reactions. In recent years, site-selective palla-
dium(0) catalyzed reactions of polyhalogenated substrates have
gained increasing importance.20 In this context, Suzuki–Miyaura
reactions of bis(triflates) have also been developed.21 Recently,
we have reported site-selective Suzuki–Miyaura reactions of the
bis(triflate) of 1,2- and 1,3-dihydroxyanthraquinone.21g The first
attack occurred at the sterically more hindered position 1 next to
the carbonyl group. This result was explained by the fact that posi-
tion 1 is more electron deficient than positions 2 and 3. In addition,
a catalyst-directive effect of the carbonyl group (by chelation) can
account for the selectivity observed. Because of the pharmacologi-
cal and technical importance of thioxanthones, we were interested
in the question whether site-selective Suzuki–Miyaura (S–M) reac-
tions of the bis(triflate) of 1,3-dihydroxythioxanthone are possible
and by which parameters the selectivity is controlled.
bioactive natural products with thioxanthone core structure.10
A
series of hycanthone derivatives have been recently reported to
display high levels of in vivo activity against murine pancreatic
adenocarcinoma.11–13 Thioxanthone-dioxides are also known to
exhibit significant pharmacological activities, including antitumor,
cytotoxic and monoamine oxidase (MAO) inhibitory activity.14
A
number of plants, such as Cartoxylum cochinchinense (Lour.), con-
tain thioxanthone derived natural products and have been used
as traditional medicines to treat fever, coughing, diarrhoea, itching,
ulcers, and abdominal complaints.15 Thioxanthones are also impor-
tant in the field of material sciences. Various derivatives of thiox-
anthones are used as activators in the photopolymerization of
ethylene-derived unsaturated monomers (particularly acrylate
derivatives).5,16 Moreover, alkyl-, alkoxy- and hydroxy-substituted
thioxanthones are particularly useful as heat and ultraviolet stabi-
lizers of polyolefins.5
Several methods have been used to synthesize thioxanthones.
2–8,15,17
A rather general procedure is based on the condensation
of substituted potassium 2-chlorobenzoates with thiophenols or
on the condensation of substituted thiosalicylic acids with benzene
1,3-Dihydroxythioxanthone (1) was prepared, following
a
⇑
Corresponding author. Fax: +381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
known procedure,22 by AlCl3 mediated reaction of thiosalicylic acid
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.102

3452
D. S. Zinad et al. / Tetrahedron Letters 52 (2011) 3451–3454
with 1,3,5-trihydroxybenzene. The bis(triflate) 2 was prepared by
reaction of 1 with triflic anhydride (Scheme 1).23
O
Ar
O
S
OTf
ArB(OH)2
3a-f
The Suzuki–Miyaura reaction of 2 with arylboronic acids 3a–f
(2.4 equiv) afforded the 1,3-diarylthioxanthones 4a–f (Scheme 2,
Table 1). Good yields were obtained both for reactions of electron
rich and poor arylboronic acids. The best yields were obtained
when the reactions were carried out using Pd(PPh3)4 as the catalyst
and K3PO4 as the base (dioxane, 90 °C, 8 h).24,25
i
S
Ar
OTf
2
4a-f
Scheme 2. Synthesis of 4a–f. Reagents and conditions: (i) 2 (1.0 equiv), 3a–f
(2.4 equiv), Pd(PPh3)4 (10 mol %), K3PO4 (3.0 equiv), 1,4-dioxane, 90 °C, 8 h.
The S–M reaction of 2 with arylboronic acids 3b, c, e, g–i
(1.1 equiv) afforded the 3-aryl-1-(trifluorosulfonyloxy)-thioxant-
hones 5a–f in good yields (Scheme 3, Table 2).24,26 Good yields
were again obtained both for reactions of electron rich and poor
arylboronic acids. It proved to be important to carry out the reac-
tion at 60 instead of 90 °C in order to induce a good site-selectivity
and to avoid double attack. The structure of 5b was independently
confirmed by X-ray crystal structure analysis (Fig. 1).27 The thiox-
anthone moiety is slightly twisted out of plane.
The reaction of 5a, c, e with arylboronic acids 3c, g, j (1.1 equiv)
gave the 1,3-diarylthioxanthones 6a–c, containing two different
aryl groups, in good yields (Table 2).24,28 The structure of 6b was
independently confirmed by X-ray crystal structure analysis
(Fig. 2).27
Products 5a and e were selected for optimization studies (Table
3). Thioxanthone 5a is derived from an electron rich arylboronic
acid, while 5e is derived from an electron poor arylboronic acid.
During the optimization we have found that the best yields were
obtained when the reactions were carried out at 60 °C. Higher tem-
peratures led to the formation of significant amounts of bis-arylat-
ed products. In addition, it proved to be important to use exactly
1.1 equiv of the arylboronic acids. While the use of 1,4-dioxane
as the solvent gave the best results in the case of the synthesis of
1,3-diarylthioxanthones 4, it was observed that employment of
THF was advantageous in the case of monoarylated products 5.
The employment of potassium phosphate gave better yields than
the use of an aqueous solution of potassium carbonate. The use
of Pd(PPh3)4 gave higher yields than the use of [Pd(PPh3)2Cl2].
The one-pot reaction of 2 with two different arylboronic acids,
which were added in a sequential manner, allowed to prepare
1,3-diarylthioxanthone 6d in 75% yield (Scheme 4, Table 4). During
the optimization, it proved to be important to carry out the first
step of the one-pot reaction at 60 °C and the second step at
90 °C. The reaction was carried out by adding one portion of the
catalyst (5 mol %) at the start of the reaction.
In general, the site-selectivity of palladium catalyzed reactions
of poly-halides or -triflates is controlled by steric and electronic
parameters. The first attack usually occurs at the sterically less hin-
dered or electronically more deficient position.29 The S–M reac-
tions of the bis(triflates) of 1,2- and 1,3-dihydroxyanthraquinone
proceed by initial attack at position 1 (next to the carbonyl group)
which can be explained by the fact that position 1 is more electron-
ically deficient than positions 2 and 3. In addition, a chelation of
the catalyst by the carbonyl group might play a role. In contrast,
the S–M reactions of 2 proceed by initial attack at position 3. The
different site-selectivity is surprising. Obviously, the regiodirecting
effect of the carbonyl group of 2 seems to be less pronounced than
Table 1
Synthesis of 4a–f
3,4
Ar
4a (%)
a
b
c
d
e
f
2-(MeO)C6H4
4-EtC6H4
4-tBuC6H4
3,5-Me2C6H3
4-ClC6H4
90
81
86
77
70
75
3-(CF3)C6H4
a
Yields of isolated products.
O
S
OTf
O
OTf
Ar1B(OH)2
3b,c,e,g-i
Ar1
i
OTf
S
2
5a-f
O
Ar2
Ar2B(OH)2
3c,g,j
ii
S
Ar1
6a-c
Scheme 3. Synthesis of 5a–f and of 6a–c. Reagents and conditions: (i) 2 (1.0 equiv),
3b, c, e, g–i (1.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (1.5 equiv), THF, 60 °C, 8 h; (ii)
5a, c, e (1.0 equiv), 3c, g, j (1.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (1.5 equiv), 1,4-
dioxane, 90 °C, 6 h.
Table 2
Synthesis of 5a–f and of 6a–c
5
6
a
Ar1
% (5)a
Ar2
% (6)a
a
b
c
d
e
f
4-(MeO)C6H4
4-EtC6H4
4-tBuC6H4
C6H5
4-ClC6H4
4-FC6H4
88
84
75
71
78
80
4-tBuC6H4
80
b
c
4-(MeO)C6H4
79
71
3,4-(MeO)2C6H3
a
Yields of isolated products.
O
OH
O
S
OTf
i
S
OH
OTf
1
2
Scheme 1. Synthesis of 2. Reagents and conditions: (i) CH2Cl2, 1 (1.0 equiv), Et3N
(4.0 equiv), Tf2O (2.4 equiv), À78 °C ? 20 °C, 8 h.
Figure 1. Crystal structure of 5b.

D. S. Zinad et al. / Tetrahedron Letters 52 (2011) 3451–3454
3453
sterically more hindered
electronically more deficient
O
S
OTf
OTf
sterically less hindered
electronically less deficient
Scheme 5. Possible explanation for the site-selectivity of the reactions of bis(tri-
flate) 2.
Acknowledgments
Financial support by the DAAD (scholarships for D.S.Z. and for
O.A.A.), by the State of Pakistan (HEC scholarship for M.H.) and
by the State of Mecklenburg-Vorpommern (scholarship for M.H.)
is gratefully acknowledged.
Figure 2. Crystal structure of 6b.
References and notes
Table 3
Optimization of the synthesis of 5a and 5e (all reactions were carried out at 60 °C for
8 h)
1. Wentland, M. P.; Perni, R. B.; Hlavac, A. G.; Corbett, T. H.; Coughlin, S. A.; Rake, J.
B. Bioorg. Med. Chem. Lett. 1994, 4, 609.
2. Watanabe, M.; Pate, M.; Tsukazaki, M.; Furukawa, S. Chem. Pharm. Bull. 1989,
37, 36.
3. Showalter, H. D. H.; Angelo, M. M.; Berman, E. M. J. Med. Chem. 1988, 31, 1527.
4. Vacek, L.; Foster, H. M. Chem. Abstr. 1979, 90, 72060a.
5. Archer, S.; Mattoccia, L. P.; Cioli, D.; Seyed-Mozaffari, A.; Zayed, A. H. J. Med.
Chem. 1988, 31, 254.
6. Laidlaw, G. M.; Collins, J. C.; Archer, S.; Rosi, D.; Schulenberg, J. W. J. Org. Chem.
1973, 38, 1743.
7. Foster, B. J.; Wiegand, R. A.; Partricia, S. P.; LoRusso, M.; Rake, J.; Corbett, T. H.
Clin. Cancer Res. 1997, 3, 2047.
8. Horwitz, J. P.; Massova, I.; Wiese, T. E.; Besler, B. H.; Corbett, T. H. J. Med. Chem.
1994, 37, 781.
9. Banerji, A.; Deshpande, A. D.; Prabhu, B. R.; Pradhan, P. J. Nat. Prod. 1994, 57,
396.
Entry
Basea
Solventb
Catalystc
% (5a)d
% (5e)d
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
Dioxane
THF
Dioxane
THF
Dioxane
THF
Dioxane
THF
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)4]
35
41
46
41
55
66
63
88
24
32
37
33
47
50
57
78
[Pd(PPh3)4]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)4]
[Pd(PPh3)4]
a
b
c
1.5 equiv per 0.2 mmol of 2.
5 mL per 0.2 mmol of 2.
5 mol % per 0.2 mmol of 2.
Yields of isolated products.
10. Rosi, D.; Peruzzoti, G.; Dennis, E. W.; Berberian, D. A.; Freele, H.; Tullar, B.;
Archer, S. J. Med. Chem. 1967, 10, 867.
d
11. Perni, R. B.; Wentland, M. P.; Huang, J. I.; Powles, R. G.; Aldous, S.; Klingbeil, K.
M.; Peverly, A. D.; Robinson, R. G.; Corbett, T. H.; Jones, J. L.; Mattes, K. C.; Rake,
J. B.; Coughlin, S. A. J. Med. Chem. 1998, 41, 3645.
12. Kostakis, I.; Pouli, N.; Marakos, P.; Mikros, E.; Skaltsounis, A.; Leonce, S.; Atassi,
G.; Renard, P. Bioorg. Med. Chem. 2001, 9, 2793.
13. Kolokythas, G. M.; Kostakis, I.; Pouli, N.; Marakos, P.; Kletsasb, D.; Pratsinis, B.
Bioorg. Med. Chem. 2003, 11, 4591.
14. Harfenist, M.; Heuser, D. J.; Joyner, C. T.; Batchelor, J. F.; White, H. L. J. Med.
Chem. 1996, 39, 1857.
15. Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583.
O
S
Ar2
1) Ar1B(OH)2
O
S
OTf
2) Ar2B(OH)2
Ar1
i
OTf
2
6d
16. Morita, H.; Mori, S.; Yamaoka, T. Bull. Chem. Soc. Jpn. 1988, 61, 191.
17. Ran, R.; Pittman, U. C. J. Heterocycl. Chem. 1993, 30, 1673.
18. Okabayashi, I.; Fujiwara, H. J. Heterocycl. Chem. 1994, 31, 733.
19. Okabayashi, I.; Fujiwara, H.; Tanaka, C. J. Heterocycl. Chem. 1991, 28, 1977.
20. (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.
Scheme 4. Synthesis of 6d. Reagents and conditions: (i) (1) 2 (1.0 equiv), 3k
(1.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (1.5 equiv), 1,4-dioxane, 60 °C, 6 h; (2) 6g
(1.1 equiv), 90 °C, 6 h.
21. For Suzuki–Miyaura reactions of bis(triflates) of benzene derivatives and other
arenes, see for example: (a) Takeuchi, M.; Tuihiji, T.; Nishimura, J. J. Org. Chem.
1993, 58, 7388; (b) Sugiura, H.; Nigorikawa, Y.; Saiki, Y.; Nakamura, K.;
Yamaguchi, M. J. Am. Chem. Soc. 2004, 126, 14858; (c) Akimoto, K.; Suzuki, H.;
Kondo, Y.; Endo, K.; Akiba, U.; Aoyama, Y.; Hamada, F. Tetrahedron 2007, 63,
6887; (d) Akimoto, K.; Kondo, Y.; Endo, K.; Yamada, M.; Aoyama, Y.; Hamada, F.
Tetrahedron Lett. 2008, 49, 7361; (e) Hosokawa, S.; Fumiyama, H.; Fukuda, H.;
Fukuda, T.; Seki, M.; Tatsuta, K. Tetrahedron Lett. 2007, 48, 7305; (f) Nawaz, M.;
Farooq Ibad, M.; Obaid-Ur-Rahman, A.; Khera, R. A.; Villinger, A.; Langer, P.
Synlett 2010, 150; (g) Mahal, A.; Villinger, A.; Langer, P. Synlett 2010, 1085; (h)
Nawaz, M.; Ibad, M. F.; Abid, O.-U.-R.; Khera, R. A.; Villinger, A.; Langer, P.
Synlett 2010, 150; (i) Abid, O.-U.-R.; Ibad, M. F.; Nawaz, M.; Ali, A.; Sher, M.;
Rama, N. H.; Villinger, A.; Langer, P. Tetrahedron Lett. 2010, 51, 1541; (j) Akrawi,
O. A.; Hussain, M.; Langer, P. Tetrahedron Lett. 2011, 52, 1093.
22. Sharghi, H.; Beni, S. Synthesis 2004, 2900.
Table 4
Synthesis of 6a-d
3
6
d
Ar1
Ar2
% (6)a
k, g
2-MeC6H4
4-(MeO)C6H4
75
a
Yields of isolated products.
in the case of the bis(triflates) of 1,2- and 1,3-dihydroxyanthraqui-
none. Therefore, the sterically less hindered position 3 is attacked
first (Scheme 5).
23. Synthesis of 9-oxo-9H-thioxanthene-1,3-diyl bis(trifluoro-methanesulfonate) (2):
To a solution of 1 (0.34 g, 1.39 mmol) in CH2Cl2 (20 mL) was added Et3N
(0.77 mL, 5.56 mmol), at 20 °C under an argon atmosphere. After stirring for
10 min at À78 °C, Tf2O (0.56 mL, 3.34 mmol) was added. The mixture was
allowed to warm to 20 °C and stirred for further 8 h. The reaction mixture was
filtered and the filtrate was concentrated in vacuo. The residue was
chromatographed without work up (flash silica gel, heptanes–EtOAc) and 2
In conclusion, we have reported an efficient synthesis of arylat-
ed thioxanthones by Suzuki–Miyaura reactions of the bis(triflate)
of 1,3-dihydroxythioxanthone. The reactions proceed with excel-
lent site-selectivity and follow a different pattern than the reac-
tions of the bis(triflates) of 1,2- and 1,3-dihydroxyanthraquinone.
Future studies are directed towards extending the scope of the
methodology (use of nitro-substituted arylboronic acids and het-
erocyclic boronic acids).
was isolated as
a yellow solid (0.57 g, 80%), mp = 149–150 °C (CH2Cl2/
EtOH = 1:1). 1H NMR (300 MHz, CDCl3): d = 7.11 (d, 1H, J = 2.3 Hz, ArH), 7.45–
7.51 (m, 3H, ArH), 7.58–7.65 (m, 1H, ArH), 8.49–8.52 (m, 1H, ArH). 19F NMR

3454
D. S. Zinad et al. / Tetrahedron Letters 52 (2011) 3451–3454
(282.4 MHz, CDCl3): d = À72.26, À73.19. 13C NMR (62.9 MHz, CDCl3): d = 114.7
and THF (5 mL), 5a was isolated as a light yellow solid (82 mg, 88%); mp = 186–
188 °C (CH2Cl2/EtOH = 1:1). 1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3H, OCH3),
6.96 (d, 2H, J = 8.8 Hz, ArH), 7.33 (d, 1H, J = 1.1 Hz, ArH), 7.41–7.58 (m, 5H, ArH),
7.64 (d, 1H, J = 1.7 Hz, ArH), 8.53 (dd, 1H, J = 1.1, 8.2 Hz, ArH). 19F NMR
(282.4 MHz, CDCl3): d = À73.38. 13C NMR (75.5 MHz, CDCl3): d = 55.5 (OCH3),
114.9 (CH), 118.9 (q, JF,C = 321.3 Hz, CF3), 119.1 (CH), 120.3 (C), 123.4, 125.4,
126.9, 128.5 (CH), 129.2 (C), 130.1 (CH), 130.2 (C), 132.6 (CH), 135.3, 141.0, 145.4,
150.4, 161.0 (C), 178.5 (CO). IR (KBr): v = 3082, 3063, 2841, 1651 (w), 1635, 1594
(s), 1558 (w), 1523 (m), 1471, 1460 (w), 1435 (m), 1425 (s), 1404 (w), 1389 (m),
1328, 1317, 1307 (w), 1286, 1256, 1242, 1219 (m), 1191 (s),1135, 1126, 1111(m),
1060 (w), 1030 (m), 1007 (w), 958, 904, 889, 881 (m), 848 (w), 832 (s), 811, 799
(m), 782, 759 (w), 745 (s), 725 (w), 712, 661, 653, 637 (m), 595 (s), 582, 567, 527
(m) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 466 (M+, 100), 334 (13), 305 (44), 262 (17).
HRMS (EI, 70 eV): calcd for C23H13O5F3S2: 466.01510; found: 466.015129.
27. CCDC-821684 (5b) and CCDC-821685 (6b) contain all crystallographic details
of this publication and are 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:
(+44)1223 336 033; or deposit@ccdc.cam.ac.uk.
(CH), 118.6 (q, JF,C = 321.3 Hz, CF3), 118.7 (q, JF,C = 320.9 Hz, CF3), 118.9, 125.4,
127.7 (CH), 129.9 (C), 130.3, 133.3 (CH), 134.3, 142.7, 149.9, 150.8 (C), 177.8
(CO). IR (KBr): v = 3081, 3030, 2958, 2923, 2851, 1728 (w), 1602, 1599, 1590
(m), 1554, 1465 (w), 1426 (s), 1399 (m), 1317, 1295 (w), 1246 (m), 1198 (s),
1150 (m), 1133, 1099 (s), 1080 (m), 1033 (w), 989, 929, 904, 884, 819, 807, 798
(m), 768 (w), 751, 714 (m), 684, 666, 655, 635 (w), 590, 569, 542, 530 (m)
cmÀ1. GC–MS (EI, 70 eV): m/z (%) = 508 (M+, 100), 347 (28), 283 (62), 255 (19).
HR-MS (EI, 70 eV): calcd for C15H6O7S3F6 (M+): 507.91744; found: 507.916890.
24. General procedure for Suzuki–Miyaura reactions: A 1,4-dioxane or THF solution
(4–5 mL), K3PO4 (1.5 equiv per cross-coupling), Pd(PPh3)4 (5 mol % per cross-
coupling) and arylboronic acid 3 (1.10–1.25 equiv per cross-coupling) was
stirred at 65–90 °C for 8–12 h. After cooling to 20 °C, distilled H2O was added.
The organic and the aqueous layers were separated and the latter was
extracted with CH2Cl2. The combined organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The residue was purified by
column chromatography (flash silica gel, heptanes–EtOAc).
25. Synthesis of 1,3-bis(3-(trifluoromethyl)phenyl)-9H-thioxanthen-9-one (4f):
Starting with 2 (101 mg, 0.20 mmol), 3-(trifluoromethyl)phenylboronic acid
3f (86 mg, 0.45 mmol), Pd(PPh3)4 (23 mg, 10 mol %), K3PO4 (127 mg,
0.60 mmol) and 1,4-dioxane (5 mL), 4f was isolated as a light yellow solid
(75 mg, 75%); mp = 167–169 °C (CH2Cl2/EtOH = 1:1). 1H NMR (300 MHz,
CDCl3): d = 7.32–7.38 (m, 2H, ArH), 7.42–7.54 (m, 6H, ArH), 7.56–7.62 (m,
1H, ArH), 7.58–7.59 (m, 1H, ArH), 7.73 (d, 1H, J = 1.9 Hz, ArH), 7.77–7.83 (m,
2H, ArH), 7.73 (dq, 1H, J = 0.5, 8.1 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d = À62.6, À62.3. 13C NMR (62.9 MHz, CDCl3): d = 122.7 (q, JF,C = 3.7 Hz, CH),
122.9 (q, JF,C = 272.5 Hz, CF3), 123.2 (q, JF,C = 272.5 Hz, CF3), 123.2 (q,
JF,C = 3.9 Hz, CH), 123.3 (CH), 123.6 (q, JF,C = 3.9 Hz, CH), 124.4 (CH), 124.5 (q,
JF,C = 3.9 Hz, CH), 125.4 (C), 125.6, 127.2, 128.0, 128.6, 128.7 (CH), 129.5 (q,
JF,C = 32.2 Hz, C-CF3), 129.7 (CH), 130.1 (C), 130.3 (CH), 130.9 (q, JF,C = 32.5 Hz,
C-CF3), 131.2 (CH), 134.7, 138.3, 138.7, 141.2, 142.9, 144.4 (C), 179.3 (CO). IR
(KBr): v = 3270, 3063, 2959, 2852 (w), 1641 (s), 1615 (w), 1588 (s), 1547, 1496,
1486, 1462, 1455 (w), 1435 (m), 1380 (w), 1326, 1304 (s), 1268, 1251, 1226
(m), 1195 (w), 1174 (m), 1154, 1112, 1095, 1069, 1052 (s), 1033, 1000, 961,
928, 897, 887, 871, 859 (m), 797, 755 9 (s), 748 (m), 720, 698 (m), 686, 672, 654
(s), 627, 611, 562, 542 (m) cmÀ1. MS (EI, 70 eV): m/z (%) = 500 (M+, 45), 499
([M-H]+, 100), 356 (19), 277 (07), 240 (08). HR-MS (EI, 70 eV): calcd for
C27H13OSF6 [M-H]+: 499.05858; found: 499.058160.
28. Synthesis of 3-(4-chlorophenyl)-1-(3,4-dimethoxyphenyl)-9H-thioxanthen-9-one
(6c): Starting with 5e (75 mg, 0.16 mmol), 3,4-dimethoxyphenylboronic acid 3j
(31 mg, 0.18 mmol), Pd(PPh3)4 (10 mg, 5 mol %), K3PO4 (37 mg, 0.18 mmol),
and 1,4-dioxane (4 mL), 6c was isolated as
a yellow solid (53 mg, 71%);
mp = 168–170 °C (CH2Cl2/EtOH = 1:1). 1H NMR (300 MHz, CDCl3): d = 3.79 (s,
3H, OCH3), 3.87 (s, 3H, OCH3), 6.76–6.89 (m, 3H, ArH), 7.32–7.39 (m, 4H, ArH),
7.48–7.55 (m, 4H, ArH), 7.02 (d, 1H, J = 1.9 Hz, ArH), 8.24–8.27 (m, 1H, ArH). 13
C
NMR (62.9 MHz, CDCl3): d = 54.8, 54.9 (OCH3), 109.7, 110.7, 119.1, 122.0, 124.3,
125.4, 127.6, 128.1, 128.3, 128.6 (CH), 130.7 (C), 130.9 (CH), 134.0, 134.7,
134.8, 136.1, 138.1, 141.1, 145.5, 147.2, 147.5 (C), 179.8 (CO). IR (KBr):
v = 3052, 2989, 2957, 2925, 2850, 2829, 2247 (w), 1643 (s), 1609 (w), 1589 (m),
1537(w), 1513, 1491, 1469, 1462, 1454, 1434, 1417 (m), 1401, 1372, 1331 (w),
1296 (m), 1281 (w), 1257, 1240, 1216, 1185, 1170, 1153, 1136, 1122, 1102,
1092, 1077, 1056 (m), 1027, 1013 (s), 952, 932 (w), 909, 894, 875, 863 (m), 841
(w), 825 (m), 816 (s), 804, 789, 761 (m), 747, 721 (s), 683, 662, 652, 646, 629,
618, 600, 583, 541 (m) cmÀ1. GC–MS (EI, 70 eV): m/z (%) = 458 (M+, 100), 443
(24), 371 (17), 214 (14). HR-MS (ESI+): calcd for C27H19O3ClS: [M]+: 458.07379;
found: 458.074006.
29. For a simple guide for the prediction of the site-selectivity of palladium(0)
catalyzed cross-coupling reactions based on the 1H NMR chemical shift values,
see: Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.
26. Synthesis of 3-(4-methoxyphenyl)-9-oxo-9H-thioxanthen-1-yl trifluoromethanesul
fonate (5a): Starting with 2 (101 mg, 0.20 mmol), 4-methoxyphenylboronic acid
3g (34 mg, 0.22 mmol), Pd(PPh3)4 (12 mg, 5 mol %), K3PO4 (64 mg, 0.30 mmol)