Synthesis of trifluoromethyl-substituted di- and terphenyls by site-selective suzuki-miyaura reactions of 1,4-dibromo-2-trifluoromethyl-benzene

Article abstract of DOI:10.1055/s-0030-1260956

The Suzuki-Miyaura reaction of 1,4-dibromo-2-(trifluoromethyl)benzene provides a convenient route for the synthesis of various trifluoromethylated di- and terphenyls. The reactions proceed with excellent site selectivity in favor of the 4-position due to

Full text of DOI:10.1055/s-0030-1260956

LETTER
1895
Synthesis of Trifluoromethyl-Substituted Di- and Terphenyls by Site-Selective
Suzuki–Miyaura Reactions of 1,4-Dibromo-2-trifluoromethyl-benzene
S
ynthesi
h
s
of
T
rifluoro
s
m
ethyl-
S
a
ubstituted
D
n
i- and
T
erphenylsUllah,a Muhammad Nawaz, 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
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Received 25 March 2011
ArB(OH)2
2a–o
Ar
CF3
Br
Br
CF3
Br
Abstract: The Suzuki–Miyaura reaction of 1,4-dibromo-2-(trifluo-
romethyl)benzene provides a convenient route for the synthesis of
various trifluoromethylated di- and terphenyls. The reactions pro-
ceed with excellent site selectivity in favor of the 4-position due to
steric and electronic reasons.
i
1
3a–o
Scheme 1 Synthesis of 3a–o. Reagents and conditions: i, 2a–o (1.0
equiv), Pd(PPh3)4 (5 mol%), K2CO3 (H2O, 2 M), dioxane, 70 °C, 8 h.
Key words: catalysis, palladium, Suzuki–Miyaura reaction, site se-
lectivity, organofluorine compounds
results in this field: the Suzuki–Miyaura reaction of 1,4-
dibromo-2-(trifluoromethyl)benzene with various arylbo-
ronic acids allowing for a convenient synthesis of various
CF3-substituted di- and terphenyls which are not readily
available by other methods.
Trifluoromethyl-substituted arenes and heterocycles are
of considerable importance in agricultural and medicinal
chemistry.1 On the one hand, the CF3 group has a strong
electron-withdrawing effect; whilst on the other hand, it
has a similar size to a CH3 group. Trifluoromethyl-substi-
tuted molecules show a high lipophilicity and, thus, excel-
lent bioavailability. In addition, the CF3 group is
chemically and biologically stable which is an important
feature to avoid undesired metabolic transformations. The
CF3 group also plays an important role in the field of ca-
talysis. This includes new substrates, fluorous reaction
media, fluorinated ligands,2,3 and fluorinated organocata-
lysts.4 Trifluoromethyl-substituted arenes and heteroare-
nes have been prepared by reaction of aryl halides with 2,3
The Suzuki–Miyaura reaction of commercially available
1,4-dibromo-2-trifluoromethylbenzene (1) with arylbo-
ronic acids 2a–o (1.0 equiv) afforded the 4-aryl-1-bromo-
2-trifluoromethylbenzenes 3a–o in 79–94% yields
(Scheme 1, Table 1). All reactions proceeded with very
good site selectivity in favor of position 4. Very good
Table 1 Synthesis of 3a–o
Ar
Yield of 3 (%)a
trifluoromethylcopper.5 This strategy is limited by the un-
a
Ph
82
87
84
86
84
87
88
83
80
79
92
87
94
83
82
stable nature of the reagents and its failure for problematic
substrates. Trifluoromethyl-substituted arenes have also
been prepared by using CF3-containing building blocks in
cyclization reactions. Examples include cyclocondensa-
tions of enamines, Diels–Alder reactions, and formal
[3+3] cyclizations.6
b
c
d
e
f
2-MeC6H4
2-ClC6H4
3-ClC6H4
3-vinylC6H4
4-EtC6H4
An alternative strategy relies on transition-metal cross-
coupling reactions of trifluoromethyl-substituted sub-
strates. In recent years, site-selective palladium(0)-cata-
lyzed cross-coupling reactions of polyhalogenated arenes
and heteroarenes have been studied. It has been shown for
various nonfluorinated substrates that such reactions pro-
vide a valuable tool for the rapid assembly of highly sub-
stituted arenes and heteroarenes.7,8 Recently, we have
reported the first examples of site-selective cross-cou-
pling reactions of fluorinated substrates, such as 1,2-di-
bromo-3,5-difluorobenzene.9 Site-selective reactions of
CF3-substituted substrates have, to the best of our knowl-
edge, not been reported to date. Herein, we report our first
g
h
i
4-t-BuC6H4
4-ClC6H4
4-FC6H4
j
2-naphthyl
2,5-(MeO)2C6H3
2,6-(MeO)2C6H3
3,4-(MeO)2C6H3
3,5-Me2C6H3
2,3,4-(MeO)3C6H2
k
l
m
n
o
SYNLETT 2011, No. 13, pp 1895–1899
x
x
.x
x
.2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260956; Art ID: D09511ST
© Georg Thieme Verlag Stuttgart · New York
a Yields of isolated products.

1896
I. Ullah et al.
LETTER
Table 2 Optimization of the Synthesis of 3g and 3ma
Entry
1
solvent
dioxane
THF
base
Temp (°C)
Time (h)
Yield of 3m (%)
Yield of 3g (%)
b
b
b
b
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
Cs2CO3 (3 equiv)
K3PO4 (3 equiv)
K3PO4 (3 equiv)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
60
60
70
70
70
70
70
90
90
80
75
70
70
8
8
8
8
8
8
8
8
6
6
6
3
8
–
–
–
–
b
2
–
b
3
DME
–
4
dioxane
dioxane
toluene
toluene
toluene
dioxane
dioxane
THF
traces
traces
traces
traces
traces
traces
traces
traces
traces
traces
5
6
7
8
c
c
9
–
–
c
c
10
11
12
13
–
–
d
d
–
–
dioxane
dioxane
87
94
82
88
a Pd(PPh3)4 was used as the catalyst in all reactions.
b No conversion.
c Inseparable mixture of mono- and diarylated products.
d Inseparable mixture, mainly diarylated product.
Table 3 Synthesis of 1,4-Diarylbenzenes 4a–m
yields were obtained for products derived from both elec-
tron-rich and electron-poor arylboronic acids.
2
a
b
p
q
r
4
a
b
c
d
e
f
Ar
Yield of 4 (%)a
The best yields were obtained using exactly 1.0 equivalent
of the arylboronic acid, Pd(PPh3)4 (5 mol%) as the cata-
lyst, and K2CO3 (2 M aq solution) as the base (1,4-diox-
ane, 70 °C, 8 h; Table 2).10,11 The employment of other
solvents or bases resulted in the formation of only trace
amounts of product or no conversion at all. Increase in re-
action temperature resulted in the formation of mixtures
due to the formation of significant amounts of terphenyls.
The length of reaction time had only a small effect on the
yields.
Ph
84
85
86
82
89
85
87
93
87
79
95
87
91
2-MeC6H4
3-MeC6H4
3-F3CC6H4
3-MeOC6H4
4-MeC6H4
s
f
g
h
i
4-EtC6H4
The Suzuki–Miyaura reaction of 1 with 2.5 equivalents of
various arylboronic acids 2 afforded the 2,5-diaryl-1-tri-
fluoromethylbenzene derivatives 4a–m in good yields
(Scheme 2, Table 3).10,12 The reactions had to be carried
out at 90 °C instead of 70 °C to ensure a complete conver-
sion. Very good yields were again obtained for products
derived from both electron-rich and electron-poor arylbo-
ronic acids.
t
4-MeOC6H4
2,3-(MeO)2C6H3
2,5-(MeO)2C6H3
3,4-(MeO)2C6H3
3,5-Me2C6H3
2,3,4-(MeO)3C6H2
u
k
m
n
o
j
k
i
m
Br
CF3
Br
ArB(OH)2
Ar
CF3
Ar
2
a Yields of isolated products
i
1
4a–m
Bromobiaryls 3 also easily undergo Suzuki–Miyaura re-
actions. The reaction of 3f,j,m with arylboronic acids af-
forded terphenyls 5a–d in high yields (Scheme 3,
Table 4).10,13 A one-pot synthesis of 5a–d starting with 1
also proved to be possible (sequential addition of the two
Scheme 2 Synthesis of 1,4-diarylbenzenes 4a–m. Reagents and
conditions: i, 2 (2.5 equiv), Pd(PPh3)4 (5 mol%), K2CO3 (H2O, 2 M),
dioxane, 90 °C, 8 h.
Synlett 2011, No. 13, 1895–1899 © Thieme Stuttgart · New York

LETTER
Synthesis of Trifluoromethyl-Substituted Di- and Terphenyls
1897
different boronic acids). However, the yields proved to be The first attack of palladium(0)-catalyzed cross-coupling
lower compared to the stepwise procedure. Therefore, this reactions generally occurs at the more electron-deficient
strategy was not further studied.
and sterically less hindered position.7,15 From the elec-
tronic viewpoint, position C-1 is expected to be slightly
more electron deficient than C-4. On the other hand, car-
bon atom C-4 is sterically less hindered than carbon C-1,
due to its location meta to the CF3 group (Figure 3).
Therefore, initial attack C-4 can be explained by steric ef-
fects.
Ar1
CF3
Ar2
Ar1
CF3
Br
Ar2B(OH)2
i
5a–d
3f,j,m
Scheme 3 Synthesis of 5a–d. Reagents and conditions: i, 2i,m,n
(1.0 equiv), Pd(PPh3)4 (5 mol%), K2CO3 (H2O, 2 M), dioxane, 80 °C,
8 h.
less sterically hindered
slightly less electron-deficient
Br
Table 4 Synthesis of 5a–d
CF3
5
3
2
Ar1
Ar2
Yield of 5
Br
(%)a
more sterically hindered
slightly more electron-deficient
a
b
c
f
m
m
i
4-EtC6H4
2-Naph
3,4-(MeO)2C6H3 88
3,4-(MeO)2C6H3 85
Figure 3 Possible explanation for the site selectivity of cross-cou-
pling reactions of 1
j
m
m
3,4-(MeO)2C6H3 4-FC6H4
80
86
In conclusion, we have reported site-selective Suzuki–
Miyaura reactions of 1,4-dibromo-2-trifluoromethyl-ben-
zene. These reactions provide a convenient and site-selec-
tive approach to trifluoromethyl-substituted di- and
terphenyls which are not readily available by other meth-
ods.
d
n
3,4-(MeO)2C6H3 3,5-Me2C6H3
a Yields of isolated products.
The structures of 3j and 4i were independently confirmed
by X-ray crystal-structure analyses (Figure 1 and
Figure 2).14
Acknowledgment
Financial support by the DAAD (scholarship for I.U.) is gratefully
acknowledged.
References and Notes
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Synlett 2011, No. 13, 1895–1899 © Thieme Stuttgart · New York

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LETTER
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(10) Typical Procedure for Suzuki–Miyaura Reactions
The reaction was carried out in a pressure tube. To a dioxane
suspension (5 mL) of 1, Pd(PPh3)4 (3–5 mol%), and of the
arylboronic acid 2a–o was added an aq solution of K2CO3 (2
M, 1–2 mL). The mixture was heated at 70 °C (3a–o) or
90 °C (4a–o) under argon for 8 h. The solution was cooled to
20 °C, poured into H2O and CH2Cl2 (5 mL each), and the
organic and the aqueous layers were separated. The latter
was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were washed with H2O (3 × 10 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by chromatography (flash silica gel, heptanes–
EtOAc).
(3) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
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1992, 48, 6555.
(6) (a) Ding, W.; Pu, J.; Zhang, C. Synthesis 1992, 635.
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Balenkova, E. S. Russ. Chem. Rev. 1999, 68, 437.
(11) 4-Bromo-4¢-tert-butyl-3-(trifluoromethyl)biphenyl (3g)
Starting with 1 (150 mg, 0.5 mmol) and 2g (90 mg, 0.5
mmol), 3g was isolated as a colorless viscous oil (158 mg,
88%). 1H NMR (300 MHz, 298 K, CDCl3): d = 1.28 [s, 9 H,
(CH3)3], 7.42 (s, 4 H, HAr), 7.50 (dd, J = 2.1, 8.3 Hz, 1 H,
HAr), 7.67 (d, J = 8.2 Hz, 1 H, HAr), 7.80 (d, J = 2.1 Hz, 1 H,
HAr). 19F NMR (282 MHz, 298 K, CDCl3): d = –62.61. 13
NMR (75 MHz, 298 K, CDCl3): d = 31.2 [(CH3)3], 34.6
C
[C(CH3)3], 118.3 (JC–F = 1.9 Hz, CAr), 123.0 (JC–F = 272 Hz,
CF3), 126.1, 126.3 (JC–F = 5.4 Hz), 126.6 (CHAr), 130.4
(JC–F = 31.7 Hz, CAr), 131.1, 135.2 (CHAr), 135.7, 140.6,
151.6 (CAr). IR (neat): 3034, 2961, 2868, 1601 (w), 1473,
1418 (m), 1325 (s), 1251, 1172 (m), 1129, 1100 (s), 1021
(m), 962 (w), 902 (m), 818 (s), 743, 697, 659 (m), 603 (w),
566 (m) cm–1. GC-MS (EI, 70 eV): m/z (%) = 358 (28) [M+,
81Br], 344 (18), 343 (98), 342 (19), 341 (100), 315 (20), 313
(20), 262 (10), 233 (7), 222 (8), 165 (7), 157 (8), 156 (9).
HRMS (EI): m/z calcd for C17H1681BrF3 [M]+: 358.036150;
found: 358.036852.
(j) Billard, T. Chem. Eur. J. 2006, 12, 974. (k) Druzhinin,
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Chem. 1996, 78, 59. (n) Abubakar, A. B.; Booth, B. L.;
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56, 359. (o) Barlow, M. G.; Suliman, N. N. E.; Tipping, A.
E. J. Fluorine Chem. 1995, 70, 59. (p) Volochnyuk, D. M.;
Kostyuk, A. N.; Sibgatulin, D. A.; Chernega, A. N.; Pinchuk,
A. M.; Tolmachev, A. A. Tetrahedron 2004, 60, 2361.
(q) Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.;
Chernega, A. N. Tetrahedron 2005, 61, 2839. (r) Mamat,
C.; Pundt, T.; Schmidt, A.; Langer, P. Tetrahedron Lett.
2006, 47, 2183. (s) Mamat, C.; Pundt, T.; Dang, T. H. T.;
Klassen, R.; Reinke, H.; Köckerling, M.; Langer, P. Eur. J.
Org. Chem. 2008, 492. (t) For a review, see: Bunescu, A.;
Reimann, S.; Lubbe, M.; Spannenberg, A.; Langer, P.
(12) 2-Trifluoromethyl-1,4-bis(4-methoxyphenyl)benzene
(4h)
Starting with 1 (150 mg, 0.5 mmol) and 2t (190 mg, 1.25
mmol), 4h was isolated as a viscous oil (167 mg, 93%). 1H
NMR (300 MHz, 298 K, CDCl3): d = 3.77, 3.78 (s, 6 H, 2
OCH3), 6.86 (d, J = 8.7 Hz, 2 H, HAr), 6.93 (d, J = 8.7 Hz, 2
H, HAr), 7.18–7.27 (m, 3 H, HAr), 7.48 (d, J = 8.8 Hz, 2 H,
HAr), 7.62 (dd, J = 8.8, 1.6 Hz, 1 H, HAr), 7.82 (d, J = 1.6 Hz,
1 H, HAr). 19F NMR (282 MHz, 298 K, CDCl3): d = –56.83.
Synlett 2011, No. 13, 1895–1899 © Thieme Stuttgart · New York

LETTER
Synthesis of Trifluoromethyl-Substituted Di- and Terphenyls
1899
13C NMR (75 MHz, 298 K, CDCl3): d = 55.2, 55.4 (OCH3),
113.3, 114.5, 124.2 (JC–F = 4.5 Hz) (CHAr) 124.3 (JC–F = 275
(CHAr), 127.1, 127.3 (CAr), 127.7, 128.3 (CHAr), 128.5
(JC–F = 29.7 Hz, CAr), 128.8, 129.9 (CHAr), 132.1 (CAr), 132.9
(CHAr), 133.6, 136.7, 140.0, 140.2, 148.2, 148.7 (CAr). IR
(neat): 3052, 2954, 2834, 1602 (w), 1495, 1462, 1407 (m),
1369 (w), 1314 (m), 1244, 1217, 1164, 1118 (s), 1071 (m),
1022 (s), 952, 886, 857 (m), 811, 748 (s), 719, 644, 607, 553
(m) cm–1. GC-MS (EI, 70 eV): m/z (%) 409 (27) [M + 1], 408
(100) [M+], 393 (13), 365 (32), 350 (29), 326 (23), 325 (47),
322 (30), 305 (14), 297 (16), 296 (44), 253 (14), 252 (39),
204 (59), 163 (52), 162 (36). HRMS (EI): m/z calcd for
C25H19O2F3 [M]+: 408.133170; found: 408.133547.
(14) CCDC-822983 (3j) and CCDC-822984 (4i) contain 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: +44 (1223)336033; or
Hz, CF3), 128.1, 129.2, 130.1 (JC–F = 1.4 Hz, CHAr), 130.8
(JC–F = 30.9 Hz, CAr), 132.0 (CHAr), 132.8, 139.2, 139.3,
139.8 (JC–F = 1.9 Hz), 159.1, 159.7 (CAr). IR (neat): 3028,
2922 (w), 1605, 1475 (m), 1395 (w), 1321, 1270, 1241, 1165
(m), 1118 (s), 1074, 1050, 1032 (m), 972 (w), 895, 839 (m),
778, 705 (s), 663, 607 (m) cm–1. GC-MS (EI, 70 eV): m/z
(%) = 359 (22) [M + 1], 358 (100) [M+], 344 (12), 243 (32),
315 (14), 300(14), 271 (17), 251 (41), 207 (15), 202 (22),
179 (49), 157 (28). HRMS (EI): m/z calcd for C21H17O2F3
[M]+: m/z = 358.117520; found: 358.116620.
(13) 1-(3¢,4¢-Dimethoxy)-phenyl-4-naphthyl-2-
trifluoromethyl-benzene (5b)
Starting with 3j (88 mg, 0.25 mmol) and 2m (45 mg, 0.25
mmol), 5b was obtained as a yellowish crystalline solid (87
mg, 85%). 1H NMR (300 MHz, 298 K, CDCl3): d = 3.81,
3.84 (s, 6 H, 2 OCH3), 6.82–6.86 (m, 3 H, HAr), 7.36–7.45
(m, 3 H, HAr), 7.67 (dd, J = 8.5, 1.8 Hz, 1 H, HAr), 7.77–7.87
(m, 4 H, HAr), 8.00 (s, 2 H, HAr). 19F NMR (282 MHz, 298K,
CDCl3): d = –56.72. 13C NMR (75 MHz, 298K, CDCl3):
d = 55.9, 56.0 (OCH3), 110.4, 112.6, 121.4 (CHAr), 122.8
(JC–F = 275.2 Hz, CF3), 125.0, 125.1, 126.0, 126.4, 126.6
deposit@ccdc.cam.ac.uk.
(15) 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.
Synlett 2011, No. 13, 1895–1899 © Thieme Stuttgart · New York