Site-selective Suzuki cross-coupling reactions of 2,3-dibromobenzofuran

Article abstract of DOI:10.1016/j.tetlet.2010.02.141

The Suzuki-Miyaura reaction of 2,3-dibromobenzofuran with two equivalents of boronic acids gave 2,3-diarylbenzofurans. The reaction with one equivalent of arylboronic acids resulted in site-selective formation of 2-aryl-3-bromobenzofurans. 2,3-Diarylbenzofurans containing two different aryl groups were prepared from 2,3-dibromobenzofuran in a one-pot protocol by sequential addition of two different boronic acids.

Full text of DOI:10.1016/j.tetlet.2010.02.141

Tetrahedron Letters 51 (2010) 2420–2422
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Site-selective Suzuki cross-coupling reactions of 2,3-dibromobenzofuran
Nguyen Thai Hung a, Munawar Hussain a, Imran Malik 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 Suzuki–Miyaura reaction of 2,3-dibromobenzofuran with two equivalents of boronic acids gave 2,3-
diarylbenzofurans. The reaction with one equivalent of arylboronic acids resulted in site-selective forma-
tion of 2-aryl-3-bromobenzofurans. 2,3-Diarylbenzofurans containing two different aryl groups were
prepared from 2,3-dibromobenzofuran in a one-pot protocol by sequential addition of two different boro-
nic acids.
Received 7 January 2010
Revised 18 February 2010
Accepted 22 February 2010
Available online 26 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Palladium
Suzuki–Miyaura reaction
Site-selectivity
Benzofuran
Benzofurans are pharmacologically important heterocycles.1
For example, synthetic amiodarone represents a potent antiarryth-
mic and antianginal drug.2 7-Alkanoylbenzofurans and 7-alkanoyl-
2,3-dihydrobenzofurans occur in various natural products, such as
longicaudatin,3 flemistrictin E, tovophenone C, vismiaguianone C,
piperaduncin B and sessiliflorols A and B.4
lbenzofurans 3a–h (Scheme 1, Table 1).13 High yields were ob-
tained for products derived from both electron-rich and electron-
poor boronic acids.
The Suzuki–Miyaura reaction of 1 with 1.0 equiv of arylboronic
acids 2c,e,g–i afforded the 2-aryl-3-bromobenzofurans 4a–e in
very good yields (Scheme 2, Table 2).13,14 The reactions proceeded
with very good site-selectivity.
In all the reactions, the best yields were obtained when
Pd(PPh3)4 (5 mol %) was used as the catalyst. The use of Pd(OAc)2
in the presence of XPhos15 or SPhos15 proved to be less successful
in terms of yield. All the reactions were carried out at 70–80 °C. For
the mono-coupling it proved to be important to carry out the reac-
tion at 70 °C. An aqueous solution of K2CO3 (2 M) was used as the
base. The employment of K3PO4 gave equally good results. 1,4-
Dioxane was used throughout as the organic solvent.
The sequential addition of two different arylboronic acids al-
lowed the direct synthesis of 2,3-diarylbenzofurans 5a,b contain-
ing two different aryl groups (Scheme 3, Table 3).16,17 The yields
of the products were significantly higher when the reactions were
carried out in a one-pot procedure without isolation of the mono-
coupling product.
In recent years, it has been shown that polyhalogenated hetero-
cycles can be site-selectively functionalized in palladium(0)-cata-
lyzed cross-coupling reactions by selective activation of a single
halogen atom. The site-selectivity is controlled by electronic and
steric parameters.5 Recently, we have reported the synthesis of
aryl-substituted thiophenes,6 pyrroles7 and selenophenes8 based
on site-selective Suzuki reactions of tetrabrominated thiophene,
N-methylpyrrole and selenophene, respectively. 2,3-Dibromoben-
zofuran and 2,6-dibromobenzofuran represent interesting starting
materialswhich have beenused in site-selective Sonogashira,9 Negi-
shi9 and Stille10 coupling reactions. Site-selective Negishi and
Kumada cross-coupling reactions of 2,3,5-tribromobenzofuran have
also been reported.11 Recently, we have reported Heck reactions of
2,3-dibromobenzofuran.12 Herein, we report what are, to the best
of our knowledge, the first Suzuki–Miyaura reactions of 2,3-dib-
romobenzofuran. These reactions proceed with excellent site-selec-
tivity. We also have developed a one-potprotocol for the synthesisof
unsymmetrical 2,3-diarylbenzofurans in one step.
Ar
ArB(OH)2
2a-h
Br
The Suzuki–Miyaura reaction of 2,3-dibromobenzofuran (1)
with various arylboronic acids (2.0 equiv) afforded the 2,3-diary-
Ar
Br
O
3a-h
O
i
1
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Scheme 1. Synthesis of 3a–h. Conditions: (i) 2a–h (2.0 equiv), Pd(PPh3)4 (5 mol %),
aq K2CO3 (2 M), dioxane, 80 °C, 8 h.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.141

N. T. Hung et al. / Tetrahedron Letters 51 (2010) 2420–2422
2421
Table 1
Synthesis of 2,3-diarylbenzofurans 3a–h
2,3
Ar
% (3)a
a
b
c
d
e
f
4-MeC6H4
2-MeC6H4
4-EtC6H4
4-tBuC6H4
4-ClC6H4
4-FC6H4
2-(MeO)C6H4
3,5-Me2C6H3
92
81
86
88
83
81
82
79
g
h
a
Yields of isolated products.
Br
ArB(OH)2
2c,e,g-i
Br
Ar
O
4a-e
Br
O
i
1
Figure 1. Crystal structure of 5b.
Scheme 2. Synthesis of 4a–e. Conditions: (i) 2c,e,g–i (1.0 equiv), Pd(PPh3)4
(5 mol %), aq K2CO3 (2 M), dioxane, 70 °C, 6 h.
Table 2
more electron-rich
Synthesis of 2-aryl-3-bromobenzofuran 4a–e
2
2
4
Ar
% (4)a
Br
c
e
g
h
i
a
b
c
d
e
4-EtC6H4
4-ClC6H4
2-(MeO)C6H4
3,5-Me2C6H3
2,3-(MeO)2C6H3
86
90
87
79
82
Br
O
1
less electron rich
Figure 2. Possible explanation for the site-selectivity of the Suzuki–Miyaura
reactions of 1.
a
Yields of isolated products.
In conclusion, 2,3-diarylbenzofurans were prepared by Suzuki–
Miyaura reactions of 2,3-dibromobenzofuran with two equivalents
of boronic acids. The reaction with one equivalent of arylboronic
acids resulted in site-selective formation of 2-aryl-3-bromoben-
zofurans. 2,3-Diarylbenzofurans containing two different aryl
groups were prepared from 2,3-dibromobenzofuran in a one-pot
protocol by sequential addition of two different boronic acids.
1) Ar1B(OH)2
Ar2
Br
2) Ar2B(OH)2
Ar1
Br
O
5a,b
O
i
1
Scheme 3. Synthesis of 5a,b. Conditions: (i) (1) 2a (1.0 equiv), Pd(PPh3)4 (5 mol %),
aq K2CO3 (2 M), dioxane, 70 °C, 6 h; (2) 2f,j (1.0 equiv), 80 °C, 6 h.
Acknowledgements
Table 3
Financial support by the State of Pakistan (HEC scholarships for
M.H. and I.M.), the DAAD (scholarships for I.M. and N.T.H.), the
State of Vietnam (MOET scholarship for N.T.H.) and the State of
Mecklenburg-Vorpommern (scholarship for M.H.) is gratefully
acknowledged.
Synthesis of unsymmetrical 2,3-diarybenzofuran 5a,b
5
Ar1
Ar2
% (5)a
a
b
4-MeC6H4
4-MeC6H4
3-(MeO)C6H4
4-FC6H4
76
79
a
Yields of isolated products.
References and notes
1. For a review, see: (a) Butin, A. V.; Gutnow, A. V.; Abaev, V. T.; Krapivin, G. D.
Molecules 1999, 4, 52; see also: (b) Fuerst, D. E.; Stoltz, B. M.; Wood, J. L. Org.
Lett. 2000, 22, 3521; (c) Schneider, B. Phytochemistry 2003, 64, 459; (d)
Katritzky, A. R.; Kirichenkok, K.; Ji, Y.; Steel, P. J.; Karelson, M. ARKIVOC 2003, vi,
49; (e) Miyata, O.; Takeda, N.; Morikami, Y.; Naito, T. Org. Biomol. Chem. 2003, 1,
254; (f) Xie, X.; Chen, B.; Lu, J.; Han, J.; She, X.; Pan, X. Tetrahedron Lett. 2004, 45,
6235; (g) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43,
6144; (h) Hagiwara, H.; Sato, K.; Nishino, D.; Hoshi, T.; Suzuki, T.; Ando, M. J.
Chem. Soc., Perkin Trans. 1 2001, 2946.
2. For reviews, see: (a) Matyus, P.; Varga, I.; Rettegi, T.; Simay, A.; Kallay, N.;
Karolyhazy, L.; Kocsis, A.; Varro, A.; Penzes, I.; Papp, J. G. Curr. Med. Chem. 2004,
1, 61; (b) Wong, H. N. C.; Pei, Yu; Yick, C. Y. Pure Appl. Chem. 1999, 71, 1041; see
also: (c) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106, 4218; (d)
Wendt, B.; Ha, H. R.; Hesse, M. Helv. Chim. Acta 2002, 85, 2990; (e) Carlsson, B.;
Singh, B. N.; Temciuc, M.; Nilsson, S.; Li, Y. L.; Mellin, C.; Malm, J. J. Med. Chem.
2002, 45, 623. and references cited therein; (f) Kwiecien, H.; Baumann, E. J.
Heterocycl. Chem. 1997, 1587.
The structures of all the products 3, 4 and 5 were established by
spectroscopic methods. The structure of 5b was independently
confirmed by X-ray crystal structure analysis (Fig. 1).18
The first attack of palladium(0)-catalyzed cross-coupling reac-
tions generally occurs at the less electron-rich position.5 A simple
guide for the prediction of the site-selectivity of palladium(0)-cat-
alyzed cross-coupling reactions of polyhalogenated molecules is
based on the 1H NMR chemical shift values of those analogues in
which the halide atom is replaced by a hydrogen atom.19 In fact,
the 1H NMR signal of proton 2-H of benzofuran (7.52 ppm) appears
at much lower field than the signal of proton 3-H (6.66 ppm).
Position 2 of dibromobenzofuran is much less electron-rich than
position 3 (Fig. 2). This is further supported by preliminary semi-
empirical calculations and HMO calculations.20
3. Longicaudatin: (a) Joshi, A. S.; Li, X.-C.; Nimrod, A. C.; ElSohly, H. N.; Walker, L.
A.; Clark, A. M. Planta Med. 2001, 67, 186; for related natural products, see: (b)

2422
N. T. Hung et al. / Tetrahedron Letters 51 (2010) 2420–2422
Sigstad, E.; Catalan, C. A. N.; Diaz, J. G.; Herz, W. Phytochemistry 1993, 33, 165;
(c) Drewes, S. E.; Hudson, N. A.; Bates, R. B. J. Chem. Soc., Perkin Trans. 1 1987,
2809.
1200, 1180, 1162, 1120, 1107, 1073 (m), 1056, 1043, 1023, 984 (s), 932 (w),
737 (s), 667, 636, 588, 577, 534, 541 (m) cmÀ1. GC–MS (EI, 70 eV): m/z
(%) = 302 ([M]+, 85), 259 (02), 223 (22), 208 (100), 165 (24), 152 (30). HRMS (EI,
70 eV): calcd for C15H11BrO2 [M]+: 301.99369; found: 301.99370.
4. Tovophenone C: (a) Seo, E.-K.; Wall, M. E.; Wani, M. C.; Navarro, H.; Mukherjee,
R.; Farnsworth, N. R.; Kinghorn, A. D. Phytochemistry 1999, 52, 669;
vismiaguianone C: (b) Seo, E.-K.; Wani, M. C.; Wall, M. E.; Navarro, H.;
Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D. Phytochemistry 2000, 55, 35;
piperaduncin B: (c) Joshi, A. S.; Li, X.-C.; Nimrod, A. C.; ElSohly, H. N.; Walker, L.
A.; Clark, A. M. Planta Med. 2001, 67, 186; see also: (d) Bohlmann, F.; Zdero, C.
Chem. Ber. 1976, 109, 1436; sessiliflorol A: (e) Chan, J. A.; Shultis, E. A.; Carr, S.
A.; DeBrosse, C. W.; Eggleston, D. S. J. Org. Chem. 1989, 54, 2098; sessiliflorol B:
(f) Marston, A.; Zagorski, M. G.; Hostettmann, K. Helv. Chim. Acta 1988, 71,
1210; (g) Drewes, S. E.; Hudson, N. A.; Bates, R. B.; Linz, G. S. Tetrahedron Lett.
1984, 25, 105; flemistrictin E: (h) Subrahmanyam, K.; Rao, J. M.; Vemuri, V. S.
S.; Babu, S. S.; Roy, C. P.; Rao, K. V. J. Indian J. Chem., Sect B 1982, 21, 895.
5. For reviews, see: (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.
6. Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger, A.; Langer, P. Adv. Synth. Catal.
2009, 351, 1595.
7. Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P. Tetrahedron Lett. 2008,
49, 1698.
8. Dang, T. T.; Villinger, A.; Langer, P. Adv. Synth. Catal. 2008, 350, 2109.
9. (a) Bach, T.; Bartels, M. Synlett 2001, 1284; (b) Bach, T.; Bartels, M. Synthesis
2003, 925.
10. Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968.
11. Bach, T.; Bartels, M. Tetrahedron Lett. 2002, 43, 9125.
12. Hussain, M.; Hung, N. T.; Langer, P. Tetrahedron Lett. 2009, 50, 3929.
13. General procedure for the synthesis of 3a–h and 4a–e: The reaction was carried
out in a pressure tube. To a dioxane suspension (5 mL) of 1 (274 mg, 1.0 mmol),
Pd(PPh3)4 (58 mg, 5 mol %, 0.05 mmol) and the arylboronic acid (1.0 mmol per
coupling) was added an aqueous solution of K2CO3 (2 M, 1 mL). The mixture
was heated at the indicated temperature (70–80 °C) under an argon
atmosphere for the indicated period of time (6–8 h). The reaction mixture
was diluted with water and extracted with CH2Cl2 (3 Â 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).
15. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358. and references
cited therein.
16. Procedure for the synthesis of 5a,b: The reaction was carried out in a pressure
tube. To a dioxane suspension (10 mL) of 1 (348 mg, 2.0 mmol), Pd(PPh3)4
(116 mg, 5 mol %, 0.10 mmol) and Ar1B(OH)2 (2.0 mmol) was added an
aqueous solution of K2CO3 (2 M, 2 mL). The mixture was heated at 70 °C
under an argon atmosphere for 6 h. The mixture was cooled to 20 °C, divided
into two equal portions and Ar2B(OH)2 (1.0 mmol) was added to each portion.
The reaction mixtures were heated under Argon atmosphere for 6 h at 80 °C.
Each reaction mixture was diluted with water and extracted with CH2Cl2
(3 Â 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). Products 5a (238 mg, 76%) and
5b (248 mg, 79%) were isolated as colourless oils. 3-(3-Methoxyphenyl)-2-(p-
tolyl)benzofuran (5a): 1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3H, CH3), 3.69 (s,
3H, OCH3), 6.82–6.86 (m, 1H, ArH), 6.95–7.12 (m, 4H), ArH), 7.14–7.25 (m, 3H,
ArH), 7.39–7.50 (m, 4H, ArH). 13C NMR (75 MHz, CDCl3): d = 21.4 (CH3), 55.3
(OCH3), 111.1, 113.4, 115.1 (CH), 116.7 (C), 120.0, 122.3, 122.9, 124.5, 127.0
(CH), 127.8 (C), 129.2, 130.0 (CH), 130.3, 134.4, 138.5, 150.9, 153.9, 160.1 (C). IR
(KBr): v = 3031, 2997, 2917, 2832 (w), 1606, 1591, 1574, 1511, 1484 (m), 1451
(s), 1426, 1369, 1314, 1282 (m), 1246, 1234 (s), 1205, 1183, 1156, 1065, 1042
(m), 818, 742, 701 (s), 617, 610, 587, 562, 537 (w) cmÀ1. GC–MS (EI, 70 eV): m/z
(%) = 314 ([M]+, 56), 283 (38), 268 (100), 207 (10), 156 (11), 125 (43). HRMS (EI,
70 eV): calcd for C22H18O2 [M]+: 314.13068; found: 314.13059.
17. 3-(4Fluorophenyl)-2-p-tolylbenzofuran (5b): 1H NMR (300 MHz, CDCl3): d = 2.41
(s, 3H, CH3), 7.17–7.31 (m, 5H, ArH), 7.35–7.40 (m, 1H, ArH), 7.50–7.54 (m, 3H,
ArH), 7.57–7.61 (m, 3H, ArH). 13C NMR (62.9 MHz, CDCl3): d = 21.4 (CH3), 111.1
(CH), 115.8 (C), 116.1 (d, JF,C = 21.0 Hz), 119.6, 123.0, 124.6, 127.0 (CH), 127.7,
128.9 (d, JF,C = 3.3 Hz) (C), 129.2 (CH), 130.2 (C), 131.4 (d, JF,C = 8.1 Hz) (CH),
136.6, 151.1, 153.9, 162.3 (d, JF,C = 246.7 Hz) (C). IR (KBr): v = 3066, 3036 2918,
2853, 2790, 1613, 1601, 1557 (w), 1515, 1495 (m), 1452 (s), 1432, 1371, 1337,
1292 (3), 1254, 1230, 1216, 1205, 1196, 1182, 1156, 1091, 1066 (s), 1037, 1020,
1008, 964, 930, 897 (m), 842, 817, 811, 744 (s), 718, 716, 663, 598, 564 (m)
cmÀ1. GC–MS (EI, 70 eV): m/z (%) = 302 ([M]+, 16), 283 (42), 261 (100), 188 (07),
200 (20), 148 (33). HRMS (EI, 70 eV): calcd for C21H15FO [M]+: 302.11069;
found: 302.11099.
18. CCDC-764171 contains 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)1223-336-033; or deposit@
ccdc.cam.ac.uk.
14. 3-Bromo-2-(2-methoxyphenyl)benzofuran (4c). Compound 4c was prepared
from
1.0 mmol) as
1
(274 mg, 1.0 mmol) and 2-methoxyphenylboronic acid (152 mg,
colourless highly viscous oil (262 mg, 87%). Reaction
a
temperature: 70 °C. 1H NMR (300 MHz, CDCl3): d = 3.77 (s, 3H, OCH3), 6.91–
7.00 (m, 2H, ArH), 7.19–7.24 (m, 2H, ArH), 7.24–7.28 (m, 2H, ArH), 7.31–7.33
(m, 2H, ArH). 13C NMR (75 MHz, CDCl3): d = 55.7 (OCH3), 96.7 (C), 111.5, 111.6
(CH), 118.3 (C), 119.8, 120.5, 123.3, 125.2 (CH), 129.0 (C), 131.4, 131.7 (CH),
150.5, 153.9, 157.7 (C). IR (KBr): v = 3062, 3000, 2958, 2933, 2834 (w), 1610,
1586 (m), 1484, 1461, 1446, 1433 (s), 1342, 1313, 1296 (w), 1255, 1243 (s),
19. Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.
20. For HMO calculations, see: Hermann, R. B. Int. J. Quant. Chem. 1968, 2, 165.