One-pot synthesis of fluorinated terphenyls by site-selective Suzuki-Miyaura reactions of 1,4-dibromo-2-fluorobenzene

Article abstract of DOI:10.1016/j.tetlet.2010.03.067

The Suzuki-Miyaura reaction of 1,4-dibromo-2-fluorobenzene with two equivalents of arylboronic acids gave fluorinated para-terphenyls. The reaction with 1 equiv of arylboronic acid resulted in site-selective formation of biphenyls. The one-pot reaction of

Full text of DOI:10.1016/j.tetlet.2010.03.067

Tetrahedron Letters 51 (2010) 2810–2812
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Tetrahedron Letters
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One-pot synthesis of fluorinated terphenyls by site-selective
Suzuki–Miyaura reactions of 1,4-dibromo-2-fluorobenzene
a,b
a
a,b
a
a,b,*
Muhammad Sharif , Muhammad Zeeshan , Sebastian Reimann , Alexander Villinger , Peter Langer
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
a r t i c l e i n f o
a b s t r a c t
Article history:
The Suzuki–Miyaura reaction of 1,4-dibromo-2-fluorobenzene with two equivalents of arylboronic acids
gave fluorinated para-terphenyls. The reaction with 1 equiv of arylboronic acid resulted in site-selective
formation of biphenyls. The one-pot reaction of 1,4-dibromo-2-fluorobenzene with two different arylbo-
ronic acids afforded fluorinated para-terphenyls containing two different terminal aryl groups.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 February 2010
Revised 15 March 2010
Accepted 16 March 2010
Available online 20 March 2010
Keywords:
Catalysis
Suzuki–Miyaura reaction
Site-selectivity
Palladium
Organofluorine compounds
Fluorinated arenes and hetarenes have a remarkable record in
medicinal and agricultural chemistry and play an important role
as lead compounds. The solubility, bioavailability and metabolic
of the arylboronic acid, Pd(PPh
Cs CO (2.2 equiv) as the base (1,4-dioxane, 90 °C, 8 h).
The S–M reaction of 1 with arylboronic acids 2a–g (1.0 equiv)
afforded the biaryls 4a–g in good yields and with very good site-
3 4
) (0.03 equiv) as the catalyst and
1
1,12
2
3
1
stability of fluorinated compounds is often enhanced compared
2–4
11,13
to those of non-fluorinated analogues.
Fluorinated arenes and
selectivity (Scheme 2, Table 2).
regioisomers was not observed.
The formation of the opposite
heteroarenes are useful substrates in transition metal-catalyzed
5
6
cross-coupling reactions. Aryl fluorides are used as ligands in cat-
alytic reactions and as organocatalysts.7
In recent years, a number of site-selective palladium(0)-cata-
lyzed cross-coupling reactions of polyhalogenated heterocycles
have been developed. The site-selectivity of these reactions is gen-
erally influenced by electronic and steric parameters.8 For exam-
ple, we have reported site-selective Suzuki–Miyaura (S–M)
reactions of tetrabrominated N-methylpyrrole, thiophene, selen-
ophene and of several other polyhalogenated arenes and hetarenes
Br
Ar
ArB(OH)
F
2
F
2a-f
i
Br
1
Ar
3a-f
9
2 3
Scheme 1. Synthesis of 3a–f. Conditions: (i) 1 (1.0 equiv), 2a–f (2.2 equiv), Cs CO
such as 2,3,5-tribromothiophene and 2,3-dibromoindole. We have
(
2.2 equiv), Pd(PPh
3
)
4
(3 mol %), 1,4-dioxane, 90 °C, 6–8 h.
also developed site-selective S–M reactions of the bis(triflate) of
methyl 2,5-dihydroxybenzoate and of related substrates.10 Herein,
we report the first results of our study related to S–M reactions of
Table 1
Synthesis of 3a–f
1
,4-dibromo-2-fluorobenzene.
The S–M reaction of commercially available 1,4-dibromo-2-
fluorobenzene (1) with 2 equiv of arylboronic acids 2a–f afforded
the fluorinated para-terphenyls 3a–f in moderate to good yields
2
,3
Ar
3a (%)
a
4-(MeO)C
4-tBuC
4-(Vinyl)C
3,4-(MeO)
4-(EtO)C
4-MeC
6
H
4
52
63
45
58
65
60
b
c
d
e
f
6
H
4
(
Scheme 1, Table 1). The best yields were obtained using 2.2 equiv
6
H
4
2
C
6
H
3
6
H
4
6
H
4
*
Corresponding author.
a
Yields of isolated products.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.067

M. Sharif et al. / Tetrahedron Letters 51 (2010) 2810–2812
2811
Br
Br
Table 3
Synthesis of 5a–e
ArB(OH)2
F
F
2
a-g
Ar1
Ar2
5a (%)
2
5
i
h,a
a,i
f,a
f,h
d,j
a
b
c
d
e
4-(Acetyl)C
4-(MeO)C H
6 4
6
H
5
4-(MeO)C
2-(MeO)C
4-(MeO)C
4-(Acetyl)C
2-Thienyl
6
6
6
H
H
H
4
4
60
67
48
42
53
Br
1
Ar
4a-g
4-MeC
4-MeC
6
H
H
4
4
6
4
6
H
5
Scheme 2. Synthesis of 4a–g. Conditions: (i) 1 (1.0 equiv), 2a–g (1.0 equiv), Cs
2
CO
3
3,4-(MeO)
2
C
6
H
3
(
1.5 equiv), Pd(PPh
)
3 4
(3 mol %), 1,4-dioxane, 90 °C, 6–8 h.
a
Yields of isolated products.
Table 2
Synthesis of 4a–g
2,4
Ar
4a (%)
a
4-(MeO)C
4-(tBu)C
4-(Vinyl)C
3,4-(MeO)
4-(EtO)C
4-MeC
4-ClC
6
H
H
6 4
4
60
58
45
67
68
60
60
b
c
d
e
f
6 4
H
2
C
6
H
3
6
H
4
6
H
4
g
6 4
H
a
Yields of isolated products.
Figure 1. Crystal structure of 4b.
1
1
) Ar B(OH)
2
2
a,d,f,h
Ar2
More sterically hindered
Less electron deficient
Br
F
2
Br
Br
2) Ar B(OH)
2
F
F
2
a,h-j
i
Ar1
Less sterically hindered
More electron deficient
Br
1
1
5
a-e
Scheme 4. Possible explanation for the site-selectivity of cross-coupling reactions
of 1.
Scheme 3. One-pot synthesis of 5a–e. Conditions:(1)
1.0 equiv), Cs CO (1.5 equiv), Pd(PPh (3 mol %), 1,4-dioxane, 90 °C, 8 h, 2)
a,h–j (1.2 equiv), Cs CO (1.5 equiv), 100 °C, 6 h.
1 (1.0 equiv), 2a,d,f,h
(
2
2
3
3 4
)
2
3
of material. For all reactions, only one chromatographic purifica-
tion has to be carried out. Inspection of the NMR of the crude prod-
ucts 5a–e (before purification) shows that a small amount of
mono-coupling and double-coupling product (containing two Ar1
groups) is present in most cases. In case of the synthesis of 4a–g,
a small amount of double-coupling product is present in the crude
product mixture.
The one-pot reaction of 1,4-dibromo-2-fluorobenzene with two
different arylboronic acids afforded the unsymmetrical fluorinated
para-terphenyls 5a–e containing two different terminal aryl
groups (Scheme 3, Table 3).1
4,15
Interestingly, the yields of products 5a–e are in the same range
as the yields of 4a–g. This might be explained by the assumption
that the selectivity and the yield are mainly determined by the first
attack of the boronic acid to 1. The second attack during the syn-
thesis of 5a–e only has a small influence on the yield because no
problem of site-selectivity exists. On the other hand, the yield of
products 3a–f (where no problem of site-selectivity exists) is in a
similar range. Therefore, we believe that the chromatographic
purification also has a great influence on the yield, due to some loss
The structures of all products were established by 2D NMR
experiments (NOESY, HMBC). The structures of 4b and 3e were
independently confirmed by X-ray crystal structure analyses (Figs.
1
6
1
and 2).
The site-selective formation of 4a–g and 5a–e can be explained
by steric and electronic reasons. The first attack of palladium(0)-
catalyzed cross-coupling reactions generally occurs at the more
Figure 2. Crystal structure of 3e.

2
812
M. Sharif et al. / Tetrahedron Letters 51 (2010) 2810–2812
electronic deficient and sterically less hindered position.8,17 Posi-
tion 4 of 1,4-dibromo-2-fluorobenzene (1) is sterically less hin-
dered because it is located next to two hydrogen atoms while
position 1 is located next to a fluorine atom (Scheme 4). In addi-
tion, position 4 (located meta to the fluorine atom) is more electron
2 2
Cl . The
aqueous layers were separated and the latter was extracted with CH
combined organic layers were dried (Na SO ), filtered and the filtrate was
concentrated in vacuo. The residue was purified by column chromatography.
2. 1,4-Di(4-tert-butylphenyl)-2-fluorobenzene (3b): Starting with (100 mg,
0.39 mmol), Cs CO (263 mg, 0.81 mmol), Pd(PPh (3 mol %), 4-tert-
2
4
1
1
2
3
3 4
)
butylphenylboronic acid (138 mg, 0.78 mmol) and 1,4-dioxane (4 mL), 3b
1
was isolated as a colourless solid (89 mg, 63%), mp 184–186 °C. H NMR
deficient than position 1 (located ortho to the fluorine atoms), due
(
300 MHz, CDCl
3
): d 1.29 (s, 18H, CH ), 7.30 (dd, J = 12.1, 1.6 Hz, 1H, ArH), 7.36–
3
1
13
to the
p
-donating effect of the fluorine atom. In fact, the H NMR
7.42 (m, 6H, ArH), 7.45–7.50 (m, 4H, ArH). C NMR (75.46 MHz, CDCl
3
): d 31.3
), 34.6 (C), 111.3 (CH), 114.3 (d, J = 23.9 Hz, CH), 122.7 (d, JCF = 3.2 Hz, CH),
25.4 (2CH), 125.9 (2CH), 126.6 (2CH), 127.3 (d, JCF = 13.6 Hz, C), 128.6 (d,
(
CH
3
signals of aromatic protons located ortho to a fluorine atom are
generally shifted to higher field compared to the proton located
in meta position.
In conclusion, we have reported site-selective Suzuki–Miyaura
reactions of 1,4-dibromo-2-fluorobenzene which provide a conve-
nient approach to fluorinated terphenyls and biaryls.
1
J
J
J
3
(
CF = 3.2 Hz, CH), 130.8 (d, JCF = 4.3 Hz, C), 132.6 (d, JCF = 1.4 Hz, CH), 136.7 (d,
CF = 1.9 Hz, C), 141.8 (C), 141.9 (C), 150.8 (d, CF = 19.3 Hz, C), 160.1 (d,
J
19
-1
CF = 247 Hz, C). F NMR (282.4 MHz, CDCl
033 (w), 2950 (m), 2860 (w), 2705 (w), 2163 (w), 1977 (w), 1910 (w), 1741
w), 1616 (w), 1543 (w), 1486 (m), 1428 (w), 1394 (m), 1305 (w), 1261 (m),
1200 (w), 1187 (m), 1122 (w), 1045 (w), 1004 (w), 948 (w), 894 (m), 816 (s),
29 (w), 750 (w), 675 (w), 586 (m), 548 (m). MS (EI, 70 eV): m/z (%) 360 (54)
3
): d À117.97 (CF). IR (ATR, cm ): v
8
+
+
[
M ], 346 (26), 345 (100), 137 (12). HRMS (EI) calcd for
60.22478, found 360.224193.
3. 1-Bromo-4-methoxyphenyl-2-fluorobenzene (4a): Starting with
0.39 mmol), Cs CO (190 mg, 0.50 mmol), Pd(PPh (3 mol %), 4-methoxy
phenylboronic acid (59.3 mg, 0.39 mmol) and 1,4-dioxane (4 mL), 4a was
26 29
C H F [M ]:
Acknowledgements
3
1
1 (100 mg,
We are grateful to Mr. Obaid-ur-Rahman Abid and to Mr. Ras-
heed Ahmad Khera for their help. Financial support by the DAAD
2
3
3 4
)
isolated as a colourless semi solid (66 mg, 60%). 1H NMR (300 MHz, CDCl
): d
.77 (s, 3H, OCH ), 6.90 (td, J = 8.85, 2.18 Hz, 2H, ArH), 7.20–7.27 (m, 3H, ArH),
7.34–7.39 (m, 2H, ArH). C NMR (75.46 MHz, CDCl
3
(
(
scholarships for M.S. and M.Z.) and by the University of Rostock
scholarship of the interdisciplinary faculty of the University of Ro-
3
3
13
3
): d 55.3 (OCH
3
), 114.1 (2CH),
1
1
1
19.6 (d, JCF = 25.9 Hz, H), 120.5 (d, JCF = 9.5 Hz, C), 127.6 (d, JCF = 3.70 Hz, C),
stock for S.R.) is gratefully acknowledged.
28.5 (d, JCF = 12.4 Hz, CH), 129.9 (d, JCF = 2.8 Hz, CH), 131.4 (d, JCF = 4.07 Hz, CH),
31.9 (d, JCF = 2.77 Hz, C), 132.1 (d, JCF = 9.8 Hz, CH), 159.4 (C), 159.5 (d,
19
-1
References and notes
J
CF = 251 Hz, C). F NMR (282.4 MHz, CDCl
3
): d À115.31 (CF). IR (ATR, cm ): v
3
1
1
5
067 (w), 2999 (w), 2922 (w), 2835 (w), 2712 (w), 2550 (w), 2158 (w), 2048 (w),
980 (w), 1891 (w), 1607 (m), 1518 (m), 1477 (s), 1390 (m), 1264 (m), 1247 (s),
178 (s), 1112 (m), 1037 (m), 963 (w), 869 (s), 807 (s), 719 (m), 636 (w), 570 (m),
1
.
(a) Fluorine in Bioorganic Chemistry; Filler, R., Kobayasi, Y., Yagupolskii, L. M.,
Eds.; Elsevier: Amsterdam, 1993; (b) Filler, R. Fluorine Containing Drugs in
Organofluorine Chemicals and their Industrial Application; Pergamon: New York,
+
39 (s). MS (EI, 70 eV): m/z (%) 281 (13) [M ], 280 (100), 267 (30), 265 (31), 239
+
(
29), 158 (15), 157 (35). HRMS (EI) calcd for C13
H
10OBrF [M ]: 281.98731 found
1
979. Chapter 6; (c) Hudlicky, M. Chemistry of Organic Compounds; Ellis
281.987694.
Horwood: Chichester, 1992; (d) Kirsch, P. Modern Fluoroorganic Chemistry;
VCH: Weinheim, 2004; (e) Chambers, R. D. Fluorine in Organic Chemistry;
Blackwell Publishing CRC Press, 2004; (f) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
14. General procedure for the synthesis of 5a–e: The reaction was carried out in a
pressure tube. To a dioxane suspension (4 mL) of 1 (200 mg, 0.79 mmol),
1
Pd(PPh
)
3 4
(3 mol %) and Ar B(OH)
2
(0.79 mmol) was added Cs
2
CO
3
(385 mg,
1.18 mmol), and the resultant solution was degassed by bubbling argon
2
.
Heidelberger, C.; Chaudhuri, K. N.; Danneberg, P.; Mooren, D.; Griesbach, L.;
Duschinsky, R.; Schnitzer, J. R. Nature 1957, 179, 663.
through the solution for 10 min. The mixture was heated at 90 °C under Argon
2
atmosphere for 8 h. The mixture was cooled to 20 °C and Ar B(OH)
0.95 mmol) and Cs CO (385 mg, 1.18 mmol) was added. The reaction
mixtures were heated under Argon atmosphere for 6 h at 100 °C. They were
diluted with water and extracted with CH Cl
(3 Â 50 mL). The combined
organic layers were dried (Na SO ), filtered and the filtrate was concentrated in
2
3
4
.
.
Wong, T. D.; Bymaster, P. F.; Engleman, A. E. Life Sci. 1995, 57, 411.
Roman, L. D.; Walline, C. C.; Rodriguez, J. G.; Barker, L. E. Eur. J. Pharmacol. 2003,
(
2
3
479, 53.
5
6
.
.
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
2
2
2
4
vacuo. The residue was purified by flash chromatography (silica gel, EtOAc/
hexane = 1:4).
(a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126, 3; (b) Dinger, M. B.;
Henderson, W. J. Organomet. Chem. 1998, 560, 233; (c) Liedtke, J.; Loss, S.;
Widauer, C.; Grützmacher, H. Tetrahedron 2000, 56, 143; (d) Schneider, S.;
Tzschucke, C. C.; Bannwarth, W. In Multiphase Homogeneous Catalysis; Cornils,
B., Herrmann, W. A., Horvath, I. T., Leitner, W., Mecking, S., Olivier-Booubigou,
H., Vogt, D., Eds.; Wiley-VCH, 2005; p 346. Chapter 4; (e) Clarke, D.; Ali, M. A.;
Clifford, A. A.; Parratt, A.; Rose, P.; Schwinn, D.; Bannwarth, W.; Rayner, C. M.
Curr. Top. Med. Chem. 2004, 7, 729.
1
5. 4-(4-Acetylphenyl)-1-(4-methoxyphenyl)-2-fluorobenzene (5a): Starting with 1
(
200 mg, 0.79 mmol), Cs
acetylphenylboronic acid (129 mg, 0.79 mmol), 1,4-dioxane (4 mL) and 4-
methoxylphenylboronic acid (144 mg, 0.95 mmol), 5a was isolated as
2 3 3 4
CO (385 mg, 1.18 mmol), Pd(PPh ) (3 mol %), 4-
a
1
colourless solid (151 mg, 60%). Mp 89–90 °C. H NMR (300 MHz, CDCl
3
): d
), 7.25 (dd, J = 7.6, 1.1 Hz, 1H, ArH), 7.30–
.40 (m, 4H, ArH), 7.64 (td, J = 8.53, 2.03 Hz, 2H, ArH), 7.97 (td, J = 8.49, 1.9 Hz,
H, ArH). 13C NMR (75.46 MHz, CDCl
): d 26.6 (CH ), 55.7 (OCH ), 111.2 (CH),
2
7
2
1
1
1
1
(
(
1
(
(
3 3
.57 (s, 3H, CH ), 3.77 (s, 3H, OCH
7
.
(a) Wittkopp, A.; Schreiner, P. R.. In The Chemistry of Diens and Polyenes; John
Wiley & Sons Ltd, 2000; Vol. 2; (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289;
See also: (c) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407; (d) Kleiner,
C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315; (e) Kotke, M.; Schreiner, P. R.
Synthesis 2007, 5, 779; Reviews: (f) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
3
3
3
14.3 (d, JCF = 23.8 Hz, CH), 120.6 (CH), 122.5 (d, JCF = 3.2 Hz, CH), 124.4 (C),
26.1 (d, JCF = 16.3 Hz, C), 127.1 (2CH), 129.0 (2CH), 129.6 (CH), 131.2 (CH),
32.4 (d, JCF = 4.3 Hz, CH), 136.2 (C), 140.8 (d, J = 7.7 Hz, C), 144.3 (C), 156.9 (C),
1
9
60.3 (d, JCF = 249 Hz, C), 197.6 (CO). F NMR (282.4 MHz, CDCl
CF
3
3
): d À113.40
). IR (ATR, cm ): v 054 (w), 2921 (w), 2851 (w), 2335 (w), 2162 (w), 1980
w), 1668 (m), 1601 (w), 1539 (w), 1482 (w), 1393 (w), 1301 (w), 1246 (m),
163 (w), 1078 (w), 1005 (w), 928 (w), 890 (w), 818 (m), 734 (w), 659 (w), 586
8
.
.
-1
(
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.
006, 3283.
(a) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger, A.; Langer, P. Adv. Synth. Catal.
009, 351, 1595; (b) Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P.
2
+
w), 534 (w). MS (EI, 70 eV): m/z (%) 321 (23) [M ], 320 (100), 306 (23), 305
99), 262 (11), 233 (10), 153 (13). HRMS (EI) calcd for C21
9
+
17 2
H O F [M ]:
2
320.12071; found 320.120518.
Tetrahedron Lett. 2008, 49, 1698; (c) Dang, T. T.; Villinger, A.; Langer, P. Adv.
Synth. Catal. 2008, 350, 2109; (d) Tengho Toguem, S.-M.; Villinger, A.; Langer, P.
Synlett 2009, 3311; (e) Farooq, M. I.; Hussain, M.; Obaid-Ur-Rahma, A.; Ali, A.;
Ullah, I.; Zinad, D. S.; Langer, P. Synlett 2010, 411.
1
1
6. CCDC-769080 and 769081 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:
1
0. (a) Nawaz, M.; Farooq, M. I.; Obaid-Ur-Rahman, A.; Khera, R. A.; Villinger, A.;
Langer, P. Synlett 2010, 150; (b) Farooq, M. I.; Obaid-Ur-Rahma, A.; Adeel, M.;
Nawaz, M.; Villinger, A.; Langer, P. Synlett 2010, 195.
(
+44) 1223-336-033; or deposit@ccdc.cam.ac.uk.
7. 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.
1
1. General procedure for Suzuki–Miyaura reactions: A 1,4-dioxane solution (4 mL
per 0.3 mmol of 1) of 1, Cs
2 3 3 4
CO , Pd(PPh ) and arylboronic acid 2 were stirred
at 90 °C for 6 or 8 h. After cooling to room temperature, the organic and the