Synthesis of 3,4-diarylbenzophenones by site-selective suzuki-miyaura reactions of 3,4-Bis(trifluoromethylsulfonyloxy)benzophenone

Article abstract of DOI:10.1055/s-0029-1219396

The Suzuki-Miyaura reaction of the bis(triflate) of 3,4- dihydroxybenzophenone with two equivalents of boronic acids gave 3,4-diarylbenzophenones. The reaction with one equivalent of arylboronic acids resulted in site-selective attack onto carbon atom C-4

Full text of DOI:10.1055/s-0029-1219396

LETTER
979
Synthesis of 3,4-Diarylbenzophenones by Site-Selective Suzuki–Miyaura
Reactions of 3,4-Bis(trifluoromethylsulfonyloxy)benzophenone
S
ynthesis of 3,4-Diary
u
lbenzopheno
h
nes ammad Nawaz,a Rasheed Ahmad Khera,a Imran Malik,a Muhammad Farooq Ibad,a Obaid-Ur-Rahman Abid,a
Alexander Villinger,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Received 9 November 2009
3,4-Dihydroxybenzophenone (1) was transformed into its
bis(triflate) 2 in 84% yield (Scheme 1).12
Abstract: The Suzuki–Miyaura reaction of the bis(triflate) of 3,4-
dihydroxybenzophenone with two equivalents of boronic acids
gave 3,4-diarylbenzophenones. The reaction with one equivalent of
arylboronic acids resulted in site-selective attack onto carbon atom
C-4. 3,4-Diarylbenzophenones containing two different aryl groups
were prepared by sequential addition of two different boronic acids.
O
O
OTf
OTf
OH
OH
i
Key words: catalysis, palladium, Suzuki–Miyaura reaction, site-
selectivity, benzophenones
1
2 (84%)
Scheme 1 Synthesis of 2. Reagents and conditions: i, CH2Cl2, 1 (1.0
equiv), –78 °C, pyridine (4.0 equiv), Tf2O (2.4 equiv), –78 to 0 °C, 4 h.
Aryl-substituted benzophenones are of pharmacological
relevance. Biological properties include, for example,
cytotoxic1a and antibacterial activity,1b inhibition of vari-
ous enzymes,2 and activity as selectin antagonists.3 Struc-
turally related benzoylfluorenones are also of
pharmacological interest.4 The 4-arylbenzophenone core
structure occurs in polycyclic frameworks of naturally oc-
curring anthraquinones and tetracyclines.5 2-Hydroxy-
and 2-aminobenzophenones represent antitubulin agents
and are of importance in anticancer therapy.6 Functional-
ized benzophenones are also important as UV-filters (e.g.,
sun screens) and photosensitizers.7
The Suzuki reaction of 2 with boronic acids 3a–i (2.6
equiv) afforded the novel 3,4-diarylbenzophenones 4a–i
in good yields (Scheme 2, Table 1). The best yields were
obtained when Pd(PPh3)4 (6 mol%) was used as the cata-
lyst, when 2.6 equivalents of the boronic acid were em-
ployed, and when the reaction was carried out in 1,4-
dioxane (reflux, 4 h) using K3PO4 as the base.13,14 The
structures of all products were established by spectroscop-
ic methods. The structure of 4c was independently con-
firmed by X-ray crystal-structure analysis (Figure 1).15
Benzophenones are available by reaction of organometal-
lic reagents with aldehydes and subsequent oxidation or
by Friedel–Crafts acylation.6b,8 An alternative strategy re-
lies on the SmI2-mediated reaction of benzaldehydes with
benzylhalides and subsequent oxidation.9 Friedel–Crafts
acylations of highly substituted derivatives do not always
proceed with good regioselectivity. Recently, we reported
the synthesis of 2¢,4-diarylbenzophenones based on site-
selective10 Suzuki–Miyaura cross-coupling reactions of
bis(triflates) of 2¢,4-dihydroxybenzophenones.11 The se-
lectivity can be explained by steric reasons. Herein, we re-
port what are, to the best of our knowledge, the first site-
selective palladium(0)-catalyzed cross-coupling reactions
of the bis(triflate) of 3,4-dihydroxybenzophenone which
represents a commercially available and inexpensive sub-
strate. The site-selectivity can be explained by electronic
reasons. The products reported herein are not readily
available by other methods.
O
R2
OTf
R1
R3
O
OTf
R4
R4
2
i
R2
R1
R1
R3
R3
R2
B(OH)2
4a–i
R4
3a–i
Scheme 2 Synthesis of 4a–i. Reagents and conditions: i, 2 (1.0
equiv), 3a–i (2.6 equiv), K3PO4 (3.0 equiv), Pd(PPh3)4 (6 mol%), 1,4-
dioxane (5 mL per 1 mmol of 2), 110 °C, 4 h.
The Suzuki reaction of 2 with boronic acids 3d and 3j–m
(1.3 equiv), in the presence of Pd(PPh3)4 (3 mol%), pro-
ceeded with very good site selectivity (attack at carbon
atom C-4) to give the benzophenones 5a–e (Scheme 3,
Table 2).13,16 In some cases, a small amount of the biscou-
pled product could be detected in the crude product (by 1H
NMR and GC-MS). The pure monocoupled products were
obtained after chromatographic purification. The reaction
SYNLETT 2010, No. 6, pp 0979–0981
x
x.
x
x.
2
0
1
0
Advanced online publication: 17.02.2010
DOI: 10.1055/s-0029-1219396; Art ID: D31709ST
© Georg Thieme Verlag Stuttgart · New York

980
M. Nawaz et al.
LETTER
Table 1 Synthesis of 4a–i
O
OTf
OTf
4
R1
R2
H
R3
H
R4
H
Yield of 4 (%)a
O
OTf
4a
4b
4c
4d
4e
4f
H
78
69
75
74
67
54
76
58
78
2
R4
R3
H
H
F
H
i
R2
R1
R1
H
Me
H
H
Me
H
R3
B(OH)2
R2
5a–e
OMe
OMe
H
OMe
H
R4
H
H
3d,j–m
(HO)2B
H
OMe
H
H
O
3n
4g
4h
4i
OEt
H
H
H
Me
H
Me
Et
H
R4
R3
H
H
R1
6a–d
a Yields of isolated products.
R2
Scheme 3 Synthesis of 5a–e and 6a–d. Reagents and conditions: i,
2 (1.0 equiv), 3d,j–m (1.3 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3
mol%), 1,4-dioxane, 110 °C, 4 h; ii, 5a,c–e (1.0 equiv), 3n (1.3
equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3 mol%), 1,4-dioxane, 110 °C,
4 h.
Table 2 Synthesis of 5a–e and 6a–d
5
6
R1
R2
R3
R4
H
Yield of 5 Yield of 6
(%)a
(%)a
5a
5b
5c
5d
5e
6a
H
OMe
H
H
68
68
b
OMe
H
H
OMe 72
64
OMe 76
–
6b
6c
6d
H
Me
H
78
64
62
H
OMe OMe
t-Bu
H
H
H
70
Figure 1 ORTEP plot of 4c
a Yields of isolated products.
b Experiment was not carried out.
of 5a–e with (4-vinylphenyl)boronic acid (3n, 1.3 equiv)
gave 2,4-diarylbenzoates 6a–d containing two different
aryl groups. The structures of the products were proved by
2D NMR experiments (NOESY, HMBC).
O
carbon C-3
less electron-deficient
OTf
The oxidative addition of palladium usually occurs first at
the most electron-deficient carbon atom.10 The site-selec-
tive formation of 5a–e can be explained by the fact that
carbon atom C-4 (located para to the keto group) is more
electron deficient than C-3 (located meta to the keto
group). Steric parameters have presumably no effect, due
to the similar steric environment of carbon atoms C-4 and
C-3 (Figure 2).
OTf
carbon C-4
more electron-deficient
Figure 2 Possible explanation for the site-selective formation of
products 5a–e
Acknowledgment
Financial support by the DAAD (scholarships for M.N., O.-u.-R.A.,
F.I., and R.A.K.) is gratefully acknowledged.
In conclusion, we have reported the synthesis of 3,4-di-
arylbenzophenones based on what are, to the best of our
knowledge, the first palladium(0)-catalyzed cross-
coupling reactions of bis(triflates) of 3,4-dihydroxyben-
zophenone. The reactions proceed with very good site se-
lectivity.
References and Notes
(1) Cytotoxic activity: (a) De Souza, A. O.; Santos, R. R.; Melo,
P. S.; Alderete, J. B.; De Conti, R.; Haun, M.; Sato, D. N.;
Duran, N. Pharmazie 2001, 56, 871. Antibacterial activity:
(b) De Souza, A. O.; Alderete, J. B.; Schmidt, F.; Sato,
D. N.; Duran, N. Arzneim. Forsch. 1999, 49, 1025.
Synlett 2010, No. 6, 979–981 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,4-Diarylbenzophenones
981
(2) Inhibition of 3H-progesterone binding: (a) Kumar, S.; Seth,
M.; Bhaduri, A. P.; Agnihotri, A.; Srivastava, A. K. Indian
J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1984, 23,
154. Inhibition of the interleukin (IL-1) biosynthesis:
(b) Batt, D. G.; Goodman, R.; Jones, D. G.; Kerr, J. S.;
Mantegna, L. R. J. Med. Chem. 1993, 36, 1434. Inhibition
of the human type-2 steroid 5a-reductase: (c) Holt, D. A.;
Yamashita, D. S.; Konialian-Beck, A. L.; Luengo, J. I.;
Abell, A. D. J. Med. Chem. 1995, 38, 13. Inhibition of
COX-1: (d) Dannhardt, G.; Fiebich, B. L.;
225 (32), 204 (04), 167 (22), 156 (06), 128 (27), 105 (100),
77 (43), 69 (30), 51 (14). HRMS (EI, 70 eV): m/z calcd for
C15H8F6O7S2 [M+]: 477.96101; found: 477.960958.
(13) General Procedure for the Synthesis of 4a–i, 5a–e, and
6a–d
The reaction was carried out in a pressure tube. To a dioxane
suspension (5 mL) of 2 or 5, Pd(PPh3)4, arylboronic acid, and
K3PO4 were added. The mixture was stirred at 110 °C under
argon atmosphere for the indicated period of time (6–8 h).
The reaction mixture was diluted with H2O and extracted
with CH2Cl2 (3 × 25 mL). The combined organic layers were
dried (Na2SO4), filtered, and the filtrate was concentrated in
vacuo. The residue was purified by flash chromatography
(silica gel, EtOAc–heptanes).
Schweppenhaeuser, J. Eur. J. Med. Chem. 2002, 147.
Inhibition of human liver microsomes: (e) Lenhart, A.;
Reinert, D. J.; Aebi, J. D.; Dehmlow, H.; Morand, O. H.;
Schulz, G. E. J. Med. Chem. 2003, 46, 2083.
(3) Appel, B.; Rotzoll, S.; Kranich, R.; Reinke, H.; Langer, P.
Eur. J. Org. Chem. 2006, 3638.
(4) Guarnieri, A.; Burnelli, S.; Varoli, L.; Busacchi, I.; Barbaro,
A. M. Arch. Pharm. (Weinheim, Ger.) 1981, 314, 703.
(5) Aburaki, S.; Okuyama, S.; Hoshi, H.; Kamachi, H.; Nishio,
M. J. Antibiot. 1993, 46, 1447.
(6) (a) Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.;
Boyd, M. R.; Hamel, E.; Pettit, R. K. J. Med. Chem. 1998,
41, 1688. (b) Liou, J.-P.; Chang, J.-Y.; Chang, C.-W.;
Chang, C.-Y.; Mahindroo, N.; Kuo, F.-M.; Hsieh, H.-P.
J. Med. Chem. 2004, 47, 2897. (c) Liou, J.-P.; Chang,
C.-W.; Song, J. S.; Yang, Y. S.; Yeh, C. F.; Tseng, H. Y.; Lo,
Y. K.; Chang, C.-L.; Chang, C.-M.; Hsieh, H.-P. J. Med.
Chem. 2002, 45, 2556.
(7) (a) Cai, X.; Sakamoto, M.; Fujitsuka, M.; Majima, T. Chem.
Eur. J. 2005, 11, 6471; and references cited therein.
(b) Langhals, H.; Fuchs, K. Chem. Unserer Zeit 2004, 38,
98; and references cited therein.
(14) 3,4-Bis(3,5-dimethylphenyl)benzophenone (4c)
Starting with 2 (220 mg, 0.46 mmol), K3PO4 (292 mg, 1.38
mmol), Pd(PPh3)4 (6 mol%), 3,5-dimethylphenylboronic
acid (180 mg, 1.2 mmol), and 1,4-dioxane (5 mL per mmol
of 2), 4c was isolated as a crystalline solid (134 mg, 75%);
mp 140–142 °C. 1H NMR (250 MHz, CDCl3): d = 2.09 (s,
6 H, 2 CH3), 2.11 (s, 6 H, 2 CH3), 6.67–6.77 (m, 5 H, ArH),
7.38–7.48 (m, 5 H, ArH), 7.68–7.78 (m, 4 H, ArH). 13
C
NMR (75.46 MHz, CDCl3): d = 21.2 (2 CH3), 21.3 (2 CH3),
125.1, 127.5, 127.7, 128.3, 128.6, 128.8, 130.0, 130.4,
132.1, 132.3 (CH), 136.3, 137.1, 137.2, 137.8, 140.4, 140.5,
140.9, 144.9 (C), 196.4 (C=O). IR (KBr): n = 3289, 3013,
2916, 2857, 2732 (w), 1732, (s), 1574 1505 (m), 1495, 1455,
1436, 1386, 1328, 1296 (m), 1250 (s), 1199, 1118, 1067,
1036, 959, 902 (m), 882, 842, 793, 738 (s), 695, 648, 596,
567 (m) cm–1. GC-MS (EI, 70 eV): m/z (%) = 390 (100)
[M+], 313 (29), 270 (13), 239 (7), 148 (4), 105 (22), 77 (11).
HRMS (EI): m/z calcd for C29H26O [M+]: 390.19782; found:
390.197629.
(8) Buchta, E.; Egger, H. Chem. Ber. 1957, 90, 2760.
(9) Shiue, J.-S.; Lin, M.-H.; Fang, J.-M. J. Org. Chem. 1997, 62,
4643.
(15) CCDC-759141 contains all crystallographic details of
this publication and is available free of charge at
(10) For a review of site-selective palladium(0)-catalyzed cross-
coupling reactions, see: Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245.
(11) Nawaz, M.; Adeel, M.; Farooq, M.; Langer, P. Synlett 2009,
2154.
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
(12) 3,4-Bis(trifluoromethylsulfonyloxy)benzophenone (2)
To a CH2Cl2 solution (10 mL/mmol) of 1 (1.0 equiv) was
added pyridine (4.0 equiv) at –78 °C under argon atmo-
sphere. After 10 min, Tf2O (2.4 equiv) was added at
–78 °C. The mixture was allowed to warm to 0 °C during 4
h with stirring. The reaction mixture was filtered, and the
filtrate was concentrated in vacuo. The product was isolated
by rapid column chromatography (flash silica gel, heptanes–
EtOAc). Starting with 1 (214 mg, 1.0 mmol), pyridine (0.32
mL, 4.0 mmol), and Tf2O (0.38 mL, 2.4 mmol), 2 was
isolated as a highly viscous oil (401 mg, 84%). 1H NMR
(300 MHz, CDCl3): d = 7.44–7.60 (m, 5 H, ArH), 7.68–7.74
(m, 2 H, ArH), 7.86 (s, 1 H, ArH). 13C NMR (62.89 MHz,
CDCl3): d = 115.9 (q, JF,C = 320.0 Hz, CF3), 121.1 (q,
JF,C = 321.3 Hz, CF3), 123.6, 125.2, 128.7, 129.9, 130.9,
133.6 (CH), 135.7, 138.7, 140.2, 142.9 (C), 192.6 (C=O). 19F
NMR (282 MHz, CDCl3): d = –73.3, 72.0 (2 CF). IR (KBr):
n = 3061, (w), 1598, 1589, 1580 (m), 1496, 1431, 1414,
1319, 1291 (m), 1265 (s), 1165, 1077, 1028, 989, 976, 932
(m), 887, 787, 757 (s), 680, 595, 572 (m) cm–1. GC-MS (EI,
70 eV): m/z (%) = 478 (74) [M+], 401 (5), 345 (08), 253 (26),
(16) 4-(3,4,5-Trimethoxyphenyl)-3-(trifluorosulfonyloxy)-
benzophenone (5d)
Starting with 2 (220 mg, 0.46 mmol), K3PO4 (146 mg, 0.69
mmol), Pd(PPh3)4 (3 mol%), 3,4,5-trimethoxyphenylboronic
acid (125 mg, 0.59 mmol), and 1,4-dioxane (5mL per mmol
of triflate), 5d was isolated as a viscous oil (173 mg, 76%);
mp 139–140 °C. 1H NMR (300 MHz, CDCl3): d = 3.82 (s, 6
H, 2 OCH3), 3.83 (s, 3 H, OCH3), 6.62 (s, 2 H, ArH), 7.39–
7.47 (m, 3 H, ArH), 7.56 (s, 1 H, ArH), 7.68–7.78 (m, 3 H,
ArH), 7.88 (d, 1 H, J = 6.4 Hz, ArH). 13C NMR (75.47 MHz,
CDCl3): d = 56.2 (2 OCH3), 61.0 (OCH3), 106.8 (CH), 120
(q, JF,C = 320 Hz, CF3), 122.0, 128.5, 130.0, 130.4, 133.1,
133.3 (CH), 135.8, 136.7, 137.7, 138.6, 149.0, 153.3 (C),
194.8 (C=O). 19F NMR (282 MHz, CDCl3): d = –73.8 (CF3).
IR (KBr): n = 3065, 2999, 2936 (w), 1660, 1609 (s),1584,
1514, 1488 (m), 1463, 1418, 1393, 1317, 1291, 1278 (m),
1241 (s), 1170, 1104, 1063, 1001, 978 (m), 889, 831, 790,
745 (s), 675, 630, 598, 569 (m) cm–1. GC-MS (EI, 70 eV):
m/z (%) = 496 (92) [M+], 363 (26), 332 (100), 317 (17), 255
(12), 227 (07), 185 (05), 105 (57), 77 (19). HRMS (EI): m/z
calcd for C23H19F3O7S [M+]: 496.07981; found: 496.079887.
Synlett 2010, No. 6, 979–981 © Thieme Stuttgart · New York