Synthesis of functionalized 2′,4-diarylbenzophenones based on site-selective Suzuki cross-coupling reactions

Article abstract of DOI:10.1055/s-0029-1217544

The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflates) of 2′,4-dihydroxybenzophenones afforded 2′,4-diarylbenzophenones. The reactions proceeded with very good site selectivity. The first attack occurred at carbon atom C-4. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217544

2154
LETTER
Synthesis of Functionalized 2¢,4-Diarylbenzophenones Based on Site-Selective
Suzuki Cross-Coupling Reactions
S
a
ynthesis of Functiona
u
lized 2
¢
,4-D
i
h
arylbenzoph
a
e
nones mmad Nawaz,a Muhammad Adeel,a Muhammad Farooq Ibad,a Peter Langer*a,b
b
Received 6 April 2009
2¢,4-dihydroxybenzophenones. These reactions proceed
with very good site-selectivity.17 The products, function-
alized 4-arylbenzophenones and 2¢,4-diarylbenzophe-
nones, are not readily available and have only scarcely
been reported in the literature so far.
Abstract: The palladium(0)-catalyzed Suzuki cross-coupling reac-
tion of the bis(triflates) of 2¢,4-dihydroxybenzophenones afforded
2¢,4-diarylbenzophenones. The reactions proceeded with very good
site selectivity. The first attack occurred at carbon atom C-4.
Key Words: benzophenones, cross coupling, palladium, site selec-
tivity, Suzuki reaction
The TMSOTf-mediated reaction of 3-formylchromone
(2) with 1,3-bis(trimethylsilyloxy)buta-1,3-diene (1) af-
forded the 2¢,4-dihydroxybenzophenone 3.12 Its formation
can be explained by a domino ‘addition–retro-Michael–
Mukaiyama–aldol’ reaction (Scheme 1).
4-Arylbenzophenones possess a wide range of pharmaco-
logical properties. This includes, for example, cytotoxic1
and antibacterial activity,2 inhibition of H-progesterone
3
binding,3 inhibition of the interleukin (IL-1) biosynthe-
sis,4 inhibition of the human type-2 steroid 5a-reductase,5
inhibition of COX-1,6 and inhibition of human liver mi-
crosomes.7 2-Benzoylfluorenones and 2-benzoylfluo-
renes, which are structurally related to 4-aryl-
benzophenones, also represent pharmacologically rele-
vant entities.8 The 4-arylbenzophenone core structure is
present, albeit hidden in a polycyclic framework, in vari-
ous naturally occurring anthraquinones and tetracyclins.9
Microtubules represent an important target for anticancer
therapy. The benzophenone phenstatin, 2-hydroxy- and 2-
aminobenzophenones act as antitubulin agents.10,11 We
have reported that 4-(2-hydroxybenzoyl)salicylic acids
show a good in vitro activity in a selectin bioassay.12
Functionalized benzophenones are also widely used as
photosensitizers13 and UV filters.14
Me3SiO
OSiMe3
OMe
O
OH
O
OMe
O
1
i
O
OH
3 (60%)
O
2
+ H2O
– (Me3Si)2O
Me3SiOTf
SiMe3
O
O
O
OMe
Me3SiO
O
O
OH
+
O
SiMe3
–OTf
D
Classic syntheses of benzophenones rely on reactions of
aryllithium or magnesium reagents with aldehydes and
subsequent oxidation and on Friedel–Crafts acyla-
tions.11a,15 For the synthesis of functionalized benzophe-
nones (e.g. containing a hydroxy, halide or ester group),
these methods often give unsatisfactory results, due to
competing side reactions. Therefore, the development of
alternative methods is of considerable interest.16 Recently,
we have reported12 a new approach to 4-(2-hydroxyben-
zoyl)salicylates by domino ‘Michael–retro-Michael–
Mukaiyama–aldol’ reactions of 3-formylchromones with
1,3-bis(silyloxy)-1,3-butadienes. Herein, we report the
synthesis of 2¢,4-diarylbenzophenones based on what are,
to the best of our knowledge, the first palladium(0)-cata-
lyzed Suzuki cross-coupling reactions of bis(triflates) of
A
Me3SiOTf
+SiMe3
O
O
O
O
O
O
Me3SiO
Me3SiOTf
OMe
OMe
OSiMe3
OSiMe3
–OTf
O
SiMe3
C
B
Scheme 1 Synthesis of 3. Reagents and conditions: (i) 1. 2 (1.0
equiv), Me3SiOTf (0.3 equiv), CH2Cl2, 0 °C; 2. 1 (1.1 equiv), 0 °C →
20 °C, 12 h; 3. HCl (10%).
2¢,4-Dihydroxybenzophenone 3 was transformed into the
bis(triflate) 4 in 84% yield (Scheme 2). The Suzuki reac-
tion of 4 with boronic acids 5a–j afforded the novel 2¢,4-
diarylbenzophenones 6a–j in good yields (Scheme 2,
SYNLETT 2009, No. 13, pp 2154–2156
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217544; Art ID: G11809ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

LETTER
Synthesis of Functionalized 2¢,4-Diarylbenzophenones
2155
Table 1). The best yields were obtained when Pd(PPh3)4
(3 mol%) was used as the catalyst, when 2.6 equivalents
of the boronic acid were employed, and when the reaction
was carried out in 1,4-dioxane (reflux, 4 h) using K3PO4
as the base.18,19
OTf
O
OMe
O
(HO)2B
R1
R4
R3
4
R4
R3
i
R2
R1
R2
5f,h–m
7a–g
OMe
O
OH
O
OMe
O
OTf
O
i
i
OH
OTf
B(OH)2
4 (84%)
3
O
OMe
O
R3
5e
R2
ii
R3
R1
O
(HO)2B
R2
R4
R3
R1
OMe
O
R1
5a–j
R2
8a–e
R3
R2
Scheme 3 Synthesis of 7a–g. Reagents and conditions: (i) 4 (1.0
equiv), 5f,h–m (1.3 equiv), K3PO4 (3.0 equiv), Pd(PPh3)4 (3 mol%),
1,4-dioxane, 110 °C, 4 h; (ii) 7a,c,e–g (1.0 equiv), 5e (1.3 equiv),
K3PO4 (3.0 equiv), Pd(PPh3)4 (3 mol%), 1,4-dioxane, 110 °C, 4 h.
6a–j
R1
Scheme 2 Synthesis of 6a–j. Reagents and conditions: (i) 1. 3 (1.0
equiv), pyridine (4.0 equiv), CH2Cl2, –78 °C, 10 min; 2. Tf2O (2.4
equiv), –78 °C → 0 °C, 4 h; (ii) 4 (1.0 equiv), 5a–j (2.6 equiv), K3PO4
(3.0 equiv), Pd(PPh3)4 (3 mol%), 1,4-dioxane, 110 °C, 4 h.
Table 2 Synthesis of 7a–g
5
k
f
7
a
b
c
d
e
f
R1
H
R2
R3
R4
Me
H
Yielda (%) of 7
Me
H
H
78
45
89
78
44
63
43
Table 1 Synthesis of 6a–j
H
Cl
5,6
a
b
c
R1
H
R2
R3
H
Yielda (%) of 6
l
OEt
Br
H
H
H
H
Me
H
87
82
56
77
80
46
65
62
67
50
m
h
i
H
H
H
H
H
OMe
H
OMe
OH
OMe
H
H
Et
H
H
H
d
e
Cl
H
H
H
j
g
H
OMe
OMe
vinyl
Cl
H
a Yields of isolated products.
f
H
H
Table 3 Synthesis of 8a–e
g
h
i
H
Br
H
7
a
f
8
a
b
c
R1
H
H
H
H
H
R2
R3
R4
Me
H
Yielda (%) of 8
OMe
H
OMe
OH
OMe
H
Me
H
H
60
55
65
62
44
H
OH
H
j
OMe
OMe
c
e
g
H
H
a Yields of isolated products.
d
e
OMe
OMe
OMe
OMe
H
The Suzuki reaction of 4 with one equivalent of boronic
acids 5f and 5h–m afforded the 4-arylbenzophenones 7a–
g with very good site-selectivity (Scheme 3, Table 2).18,20
The remaining triflate group of 7a,c,e–g, located at carbon
atom C-2¢, could be further reacted with boronic acid 5e
to give the 2¢,4-diarylbenzophenones 8a–e containing two
different aryl groups (Scheme 3, Table 3). The configura-
tions of all products were studied by spectroscopic meth-
ods. The structures of some derivatives were independently
confirmed by X-ray crystal structure analyses.
OMe
a Yields of isolated products.
The site-selective formation of products 7a–g might be
explained by the fact that the oxidative addition of palla-
dium usually occurs first at the most electron-deficient
carbon atom (Scheme 4).17 Carbon atom C-4 is expected
to be more electron deficient than C-2¢. One electron-
withdrawing benzoyl group is located ortho to C-2¢. In
contrast, both an electron-withdrawing benzoyl group and
Synlett 2009, No. 13, 2154–2156 © Thieme Stuttgart · New York

2156
M. Nawaz et al.
LETTER
(12) Appel, B.; Rotzoll, S.; Kranich, R.; Reinke, H.; Langer, P.
Eur. J. Org. Chem. 2006, 3638.
(13) Cai, X.; Sakamoto, M.; Fujitsuka, M.; Majima, T. Chem.
Eur. J. 2005, 11, 6471; and references cited therein.
(14) Langhals, H.; Fuchs, K. Chem. Unserer Zeit 2004, 38, 98;
and references cited therein.
(15) Buchta, E.; Egger, H. Chem. Ber. 1957, 90, 2760.
(16) For the SmI2-mediated reaction of benzaldehydes with
benzyl halides and subsequent oxidation, see: Shiue, J.-S.;
Lin, M.-H.; Fang, J.-M. J. Org. Chem. 1997, 62, 4643.
(17) For a review of site-selective palladium(0)-catalyzed cross-
coupling reactions, see: Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245.
an electron-withdrawing ester group are located para and
ortho to C-4, respectively. In addition, it might also play
a role that carbon C-2¢ is more sterically hindered than C-4.
carbon C-2'
less electron-deficient
OMe
O
OTf
O
OTf
carbon C-4
more electron-deficient
Scheme 4 Possible explanation for the site-selective formation of
products 7a–g
(18) Typical Procedure for the Synthesis of 6a–j:
A 1,4-dioxane solution (5 mL/mmol of 4) of 5a–j, K3PO4,
Pd(PPh3)4 and 4 was stirred at 110 °C for 4 h. After cooling
to 20 °C, a sat. aq solution of NH4Cl was added, the organic
and the aqueous layer 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.
(19) Methyl 4¢-Methyl-4-(4¢-methylbiphenylcarbonyl)-
biphenyl-2-carboxylate (6a): Starting with 4 (220 mg, 0.4
mmol), K3PO4 (261 mg, 1.2 mmol), Pd(PPh3)4 (3 mol%), p-
tolylboronic acid (144 mg, 1.1 mmol) and 1,4-dioxane (2
mL), 6a was isolated as a highly viscous oil (200 mg, 84%).
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 2.30 (s,
3 H, CH3), 3.56 (s, 3 H, OCH3), 6.95 (d, 2 H, J = 8.0 Hz,
ArH), 7.04–7.21 (m, 6 H, ArH), 7.35–7.53 (m, 5 H, ArH),
7.70 (dd, 1 H, J = 1.9, 8.0 Hz, ArH), 7.98 (d, 1 H, J = 1.9 Hz,
ArH). 13C NMR (62.89 MHz, CDCl3): d = 21.0 (CH3), 21.2
(CH3), 52.1 (OCH3), 126.9 (4 × C, CH), 127.9, 128.8, 128.9
(CH), 129.0 (4 × C, CH), 130.2, 130.6, 131.4, 132.1 (CH),
135.8 (2 × C), 137.1 (C), 137.2 (2 × C), 137.7, 138.3, 141.3,
146.3, 168.4 (C), 197.4 (C=O). IR (KBr): 3080, 3057, 3025
(w), 1724, 1659 (s), 1613 (w), 1595 (m), 1574, 1518 (w),
1438, 1310, 1277 (m), 1231 (s), 1152, 1082, 972 (m), 819,
704 (s), 536 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 420
(100) [M+], 405 (21), 373 (09), 359 (23), 332 (07), 253 (26),
210 (07), 195 (40), 165 (39), 152 (25). HRMS (EI): m/z [M+]
calcd for C29H24O3: 420.17200; found: 420.17153.
(20) Methyl 2¢-Bromo-4-[2-(trifluoromethylsulfonyloxy)-
benzoyl]biphenyl-2-carboxylate (7d): Starting with 4 (150
mg, 0.3 mmol), K3PO4 (171 mg, 0.8 mmol), Pd(PPh3)4 (3
mol%), 2-bromophenylboronic acid (65 mg, 0.3 mmol) and
1,4-dioxane (2 mL), 7d was isolated as a highly viscous oil
(120 mg, 78%). 1H NMR (300 MHz, CDCl3): d = 3.58 (s, 3
H, OCH3), 7.13–7.17 (m, 2 H, ArH), 7.28–7.39 (m, 3 H,
ArH), 7.43–7.48 (m, 1 H, ArH), 7.54–7.62 (m, 3 H, ArH),
7.94 (dd, 1 H, J = 2.1, 8.0 Hz, ArH), 8.36 (d, 1 H, J = 2.1 Hz,
ArH). 13C NMR (75.46 MHz, CDCl3): d = 52.3 (OCH3),
122.7, 127.1, 128.3, 129.2, 129.7, 129.8, 131.3, 131.8,
132.3, 132.9, 133.2 (CH), 134.6, 134.9, 135.0, 136.0, 141.5,
146.7, 146.8, 147.2, 166.2 (C), 191.4 (C=O). 19F NMR (282
MHz, CDCl3): d = –73.29 (CF). IR (KBr): 3053, 2953, 2923
(w), 1728, 1672 (s), 1567 (m), 1482 (w), 1309, 1294 (m),
1241, 1203 (s), 1168 (m), 1087 (s), 948 (m), 887, 769, 592
(s) cm–1. MS (EI, 70 eV): m/z (%) = 544 (100) [M+], 331
(12), 301 (48), 271 (24), 242 (75), 215 (7), 183 (5), 151 (11),
69 (15). HRMS (EI): m/z [M+] calcd for C22H14BrF3O6S:
544.17200; found: 544.171525.
In conclusion, we have reported the synthesis of 2¢,4-di-
arylbenzophenones based on what are, to the best of our
knowledge, the first palladium(0)-catalyzed Suzuki cross-
coupling reactions of bis(triflates) of 2¢,4-dihydroxyben-
zophenones. These reactions proceed with very good site-
selectivity.
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern is gra-
tefully acknowledged.
References and Notes
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Synlett 2009, No. 13, 2154–2156 © Thieme Stuttgart · New York

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