Synthesis of arylated benzofurans by regioselective Suzuki-Miyaura cross-coupling reactions of 2,3-dibromobenzofurans- and 2,3,5-tribromobenzofurans

Article abstract of DOI:10.1002/jhet.2083

Arylated benzofurans were prepared by regioselective Suzuki-Miyaura cross-coupling reactions of 2,3-dibromobenzofuran. The reactions proceeded with very good site-selectivity in favor of the more electron deficient position 2. The Suzuki-Miyaura reactions

Full text of DOI:10.1002/jhet.2083

Month 2014
Synthesis of Arylated Benzofurans by Regioselective Suzuki–Miyaura
Cross-Coupling Reactions of 2,3-Dibromobenzofurans- and 2,3,5-
Tribromobenzofurans
M. Hussain,a N. Thai Hung,a N. Abbas,a,b R. A. Khera,a,c I. Malik,a,d T. Patonay,e N. Kelzhanova,a,f Z. A. Abilov,f
A. Villinger,a and P. Langera,g
*
aInstitut für Chemie, Universität Rostock, Albert Einstein Street 3a, 18059 Rostock, Germany
bDepartment of Chemistry, University of Gujrat, Gujrat 50700, Pakistan
cDepartment of Chemistry and Biochemistry, University of Agriculture, Faisalabad 38040, Pakistan
dDepartment of Chemistry, COMSATS, Institute of Information Technology, Abbottabad 22060, Khyber Pakhtunkhwa, Pakistan
eDepartment of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1, Hungary
fAl-Farabi Kazakh National University, Al-Farabi ave. 71, 050040 Almaty, Kazakhstan
gLeibniz-Institut für Katalyse an der Universität Rostock e.V, Albert Einstein Street 29a, 18059 Rostock, Germany
*
E-mail: peter.langer@uni-rostock.de
Received May 23, 2013
DOI 10.1002/jhet.2083
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Arylated benzofurans were prepared by regioselective Suzuki–Miyaura cross-coupling reactions of 2,3-
dibromobenzofuran. The reactions proceeded with very good site-selectivity in favor of the more electron
deficient position 2. The Suzuki–Miyaura reactions of 2,3,5-tribromobenzofuran also proceeded in favor
of position 2.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
been studied. The first attack generally occurs at carbon
atom C-2. Site-selective Negishi and Kumada cross-
coupling reactions of 2,3,5-tribromobenzofuran have also
been reported [14]. 3-Substituted benzofurans are difficult
to obtain as the aryl group can rearrange from the 3-
position to the 2-position [15]. Multi-step syntheses of
3-substituted benzofurans in low overall yields have been
reported [16]. Recently, we have reported site-selective
Suzuki–Miyaura reactions of 2,3-dibromobenzofuran [17].
Herein, we report full details of these studies.
The benzofuran scaffold has been identified as a
privileged structure in medicinal chemistry. Benzofuran
derivatives show various biological activities, such as
antifungal and antimicrobial activity. They are also
antagonists of the H3 receptor and of angiotensin II [1].
Synthetic amiodarone represents a potent antiarrhythmic
and antianginal drug [2]. Some 2-pyridinone derivatives
of benzo[b]furans have been identified as selective and
powerful inhibitors of HIV-1 reverse transcriptase.
7-Alkanoylbenzofurans and 7-alkanoyl-2,3-dihydrobenzofurans
occur as natural products. Examples include longicaudatin [3],
flemistrictin E, tovophenone C, vismiaguianone C,
piperaduncin B, and the sessiliflorols A and B [3a,4].
Arylated benzofurans, such as compounds 1–4, also possess
a wide range of pharmacological activities (Figure 1) [5].
Polyhalogenated heterocycles can be site-selectively
functionalized in palladium(0)-catalyzed cross-coupling
reactions by selective activation of a single carbon atom.
The site-selectivity is controlled by electronic and steric
parameters [6]. Recently, we have reported the synthesis
of aryl-substituted thiophenes [7], pyrroles [8],
selenophenes [9], pyrimidines [10], and furans [11] based
on site-selective Suzuki reactions of polyhalogenated
heterocycles. In recent years, site-selective Sonogashira [12],
Negishi [12], and Stille [13] coupling reactions of 2,3-
dibromobenzofuran and 2,6-dibromobenzofuran have
RESULTS AND DISCUSSION
The Suzuki–Miyaura reaction of 2,3-dibromobenzofuran
(5) with various arylboronic acids 6a–n (2.0 equiv.)
afforded 2,3-diarylbenzofurans 7a–n (Scheme 1, Table 1).
High yields were obtained for products derived from both
electron-rich and electron-poor arylboronic acids. The
syntheses of products 7 and 8 were carried out using Pd
(PPh3)4 (5 mol-%) as the catalyst. The employment of Pd
(OAc)2 in the presence of XPhos [18] or SPhos [18] resulted
in a decrease of the yield. All reactions were carried out at
80°C. An aqueous solution of K2CO3 (2M) was used as
the base. The employment of K3PO4 gave equally good re-
sults. 1,4-Dioxane was used as the solvent. In some cases,
we observed the formation of 2-arylbenzofurans, containing
a hydrogen atom located at carbon C-3, as by-products.
© 2014 HeteroCorporation

M. Hussain, N. T. Hung, N. Abbas, R. A. Khera, I. Malik, T. Patonay, N. Kelzhanova,
Z. A. Abilov, A. Villinger, and P. Langer
Vol 000
Figure 1. Arylated benzofurans and 2,3-dihydrobenzofurans and their bioactivities.
Scheme 1. Synthesis of 7a–n. Reagents and conditions: (i) 6a–n (2.0
equiv.), Pd(PPh3)4 (5 mol-%), aq. K2CO3 (2 M), dioxane, 80°C, 8 h.
Table 1
Synthesis of 2,3-diarylbenzofurans 7a–n.
a
6,7
Ar
% (7)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
C6H5
93b
92
81c
86
88
87
78
83
81
73
82
75
85d
79
4-MeC6H4
2-MeC6H4
4-EtC6H4
4-tBuC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
4-(CF3)C6H4
2-(MeO)C6H4
4-(MeO)C6H4
2,5-(MeO)2C6H3
3,5-Me2C6H3
Figure 2. Crystal structure of 7e. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Both electron rich and poor arylboronic acids were
successfully employed. The site-selectivity of the
Suzuki–Miyaura reaction can be explained by the assump-
tion that the oxidative addition of (nucleophilic) Pd(0)
occurs more rapidly at the more electron-deficient carbon
atom C-2. During the optimization, it proved to be
important to carry out the reactions at 70°C instead of
80°C to avoid the formation of products 7. However, in
some cases, the hydrogenated by-products 9b,p,q,r were
isolated. In some cases, the products were formed (tlc
control) but could not be isolated in pure form. Reduction
aYields of isolated products.
bProduct 9a was isolated as by-product (4%); for structures of products 9,
see Scheme 2 and Table 2.
cProduct 9c was isolated as by-product (9%).
dProduct 9m was isolated as by-product (8%).
The structures of 7e, 7h, and 7i were independently
confirmed by X-ray crystal structure analysis (Figures 2–4) [9].
The Suzuki–Miyaura reaction of 5 with 1.0 equiv. of
arylboronic acids 6b,d,g,h,k,n–r afforded the 2-aryl-3-
bromobenzofurans 8a–k in good yields (Scheme 2, Table 2).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Arylated Benzofurans by Regioselective Suzuki–Miyaura Cross-
Coupling Reactions of 2,3-Dibromobenzofurans- and 2,3,5-Tribromobenzofurans
Table 2
Synthesis of 2-aryl-3-bromobenzofuran 8a-k.
a
a
8,9
6
Ar
% (8)
% (9)
a
b
c
d
e
f
g
h
i
b
d
g
h
j
k
o
p
n
q
r
4-MeC6H4
4-EtC6H4
3-ClC6H4
4-ClC6H4
4-(CF3)C6H4
2-(MeO)C6H4
4-(MeO)C6H4
2,6-(MeO)2C6H3
3,5-Me2C6H3
3-PhC6H4
93
86
73
90
79
87
70
89
79
67
63
4
0
0
0
0
0
0
0
0
j
k
23
15
2-Thienyl
aYields of isolated products.
Figure 3. Crystal structure of 7h. [Color figure can be viewed in the on-
line issue, which is available at wileyonlinelibrary.com.]
Figure 5. NOESY and HMBC correlations of compound 8a (single headed
arrow, HMBC; double headed arrow, NOESY). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 3. Synthesis of 10a,b. Reagents and conditions: (i) 1) 6b (1.0
equiv.), Pd(PPh3)4 (5 mol-%), aq. K2CO3 (2 M), dioxane, 70°C, 6 h; 2)
6i,s (1.0 equiv.), 80°C, 6 h.
Table 3
One-pot and two-step syntheses of 2,3-diarybenzofuran 10a,b.
Ar1
Ar2
% (10)
a
10
a
b
4-MeC6H4
4-MeC6H4
3-(MeO)C6H4
4-FC6H4
76
82
Figure 4. Crystal structure of 7i. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
aYields of isolated products.
Scheme 2. Synthesis of 8a–k. Reagents and conditions: (i) 6b,d,g,h,k,n-r
(1.0 equiv.), Pd(PPh3)4 (5 mol-%), aq. K2CO3 (2 M), dioxane, 70°C, 6 h.
The sequential addition of two different arylboronic
acids in a one-pot procedure allowed for the direct synthe-
sis of 2,3-diarylbenzofurans 10a,b containing two different
aryl groups (Scheme 3, Table 3). The yields of the products
were significantly higher when the reactions were carried
out following the one-pot procedure without isolation of
the monoarylated product. The structure of 10b was
previously confirmed by X-ray crystal structure analysis [17].
The Suzuki reaction of 2,3,5-tribromobenzofuran (11)
with 3.0 equivalents of 4-fluorophenylboronic acid (6i) pro-
vided the triarylbenzofuran 12 in 81% yield (Scheme 4).
at C-3 was probably the reason for the fact that products 8j
and 8k could be isolated only in moderate yields.
The structure of compound 8a was unambiguously
established by NOESY and HMBC experiments (Figure 5).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Hussain, N. T. Hung, N. Abbas, R. A. Khera, I. Malik, T. Patonay, N. Kelzhanova,
Z. A. Abilov, A. Villinger, and P. Langer
Vol 000
EXPERIMENTAL
The reaction of 11 with one equivalent of 4-tolylboronic
acid afforded 3,5-dibromo-2-arylbenzofuran 13 in 79%
yield and with very good site-selectivity (Scheme 5).
Attempts to prepare diarylbenzofurans by reaction of 11
with 2.0 equiv. of arylboronic acids resulted in the
formation of complex mixtures under various conditions.
This result suggests that the reactivity of carbon atoms C-3
and C-5 is similar under the reaction conditions studied.
The structure of 13 was confirmed by 2D NMR. The
aromatic protons H-2’/H-6’ resonating at δH 7.96
(d, J = 8.6 Hz) showed clear HMBC correlations with
C-2 resonating at δC 151.8. Furthermore, H-2’/H-6’
did not show HMBC correlation with C-3. No NOESY
correlation was observed with H-4 resonating at δH
7.20. All these facts revealed that the tolyl moiety is
connected with C-2 (Figure 6).
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 equiv-
alent of arylboronic acids resulted in site-selective formation
of 2-aryl-3-bromobenzofurans. 2,3-Diarylbenzofurans con-
taining two different aryl groups were prepared from 2,3-
dibromobenzofuran in a one-pot protocol by sequential
addition of two different boronic acids. Hydrogenated
products were also isolated, which can explain the drop
of yields in specific cases. A 2,3,5-triarylbenzofuran and
a 2-aryl-3,5-dibromobenzofuran were prepared from
2,3,5-tribromobenzofuran.
General procedure for the synthesis of 7a–n, 8a–k, 10a–b,
12, and 13. The reaction was carried out in a pressure tube.
To a dioxane suspension (5 mL) of 5 or 11 (1.0 mmol), Pd
(PPh3)4 (58 mg, 5 mol-%, 0.05 mmol), and the arylboronic acid
(6) (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 × 25 mL). The
combined organic layers were dried (Na2SO4) and filtered, and
the filtrate was concentrated in vacuo. The residue was purified
by flash chromatography (silica gel, EtOAc/heptanes).
2,3-Diphenylbenzofuran (7a). Compound 7a was prepared
from 5 (276 mg 1.0 mmol) and phenylboronic acid (244 mg,
2.0 mmol) as
a
white solid (251 mg, 93%). Reaction
1
temperature: 80°C, mp 84–85°C. H NMR (300 MHz, CDCl3):
δ = 7.13–7.49 (m, 12H, ArH), 7.57–7.60 (m, 2H, ArH). 13C
NMR (62.9 MHz, CDCl3): δ = 111.1 (CH), 117.5 (C), 120.0,
122.9, 134.7, 127.0, 127.6, 128.3, 128.4, 129.0, 129.8 (CH),
130.2, 130.7, 132.9, 150.5, 154.0 (C). IR (KBr): v = 3062, 3027,
2921, 2852, 1602, 1568, 1558, 1498, 1487, 1472 (w), 1455,
1441 (m), 1369, 1340, 1315, 1291 (w), 1255, 1203, 1188,
1110, 1079, 1062, 1022, 1008, 960, 917, 891, 836, 828 (m),
764, 746, 700, 692, 676 (s), 621 (m), 608 (s), 582, 561 (m) cm-
1. GC-MS (EI, 70 eV): m/z (%) = 270 ([M]+, 100), 269 (19), 255
(10), 241 (21), 239 (22), 134 (9), 120 (9). HRMS (EI, 70 eV):
calcd for C20H14O [M]+: 270.10392; found: 270.10393.
2,3-Di-p-tolylbenzofuran (7b). Compound 7b was prepared
from 5 (276 mg, 1.0 mmol) and p-tolylboronic acid (272 mg,
2.0 mmol) as a colorless highly viscous oil (274 mg, 92%).
Reaction temperature: 80°C. 1H NMR (300 MHz, CDCl3):
δ = 2.27 (s, 3H, CH3), 2.36 (s, 3H, CH3), 7.05 (d, 2H,
J = 8.5 Hz, ArH), 7.12–7.26 (m, 4H, ArH), 7.32 (d, 2H,
J = 8.1 Hz, ArH), 7.40–7.51 (m, 4H, ArH). 13C NMR
(75.5 MHz, CDCl3): δ = 21.4 (2CH3), 111.0 (CH), 116.8 (C),
120.0, 122.8, 124.4, 127.0 (CH), 128.0 (C), 129.1, 129.6, 129.7
(CH), 129.9, 130.5, 137.2, 138.3, 150.7, 153.9 (C). IR (KBr):
v = 3025 (w), 2919, 2853 (m), 2731 (w), 1906, 1770, 1611 (w),
1519, 1500 (m), 1451 (s), 1371, 1289 (m), 1255 (s), 1205,
1178, 1109 (m), 1065 (s), 1019, 986 (m), 964 (s), 898, 838 (m),
816 (s), 785, 760 (m), 743, 719 (s), 649, 636 (m), 600 (s), 566
(m) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 298 ([M]+, 100), 268
(9), 255 (9). HRMS (EI, 70 eV): calcd for C22H18O [M]+:
298.13522; found: 298.13549.
Scheme 4. Synthesis of 12. Reagents and conditions: (i) 6i (3.0 equiv.),
Pd(PPh3)4 (5 mol-%), aq. K2CO3 (2 M), dioxane, 90°C, 8 h.
Scheme 5. Synthesis of 13. Reagents and conditions: (i) 6b (1.0 equiv.),
Pd(PPh3)4 (5 mol-%), aq. K2CO3 (2 M), dioxane, 70°C, 4 h.
2,3-Di-o-tolylbenzofuran (7c). Compound 7c was prepared
from 5 (276 mg, 1.0 mmol) and 2-methylphenylboronic acid
(272 mg, 2.0 mmol) as a colorless highly viscous oil (241 mg,
81%). Reaction temperature: 80°C. 1H NMR (300 MHz,
CDCl3): δ = 2.13 (s, 3H, CH3), 2.37 (s, 3H, CH3), 7.12–7.20
(m, 1H, ArH), 7.28–7.49 (m, 10H, ArH), 7.64 (brd, 1H,
J = 8.7Hz, ArH). 13C NMR (75.5 MHz, CDCl3): δ = 20.1, 20.6
(CH3), 111.3 (CH), 118.4 (C), 120.5, 122.8, 124.3, 125.6, 126.0,
127.8, 129.0 (CH), 129.7 (C), 130.5, 130.6, 130.8, 131.0 (CH),
131.9, 137.2, 137.5, 152.6, 154.4 (C). IR (KBr): v = 3058, 3017,
2953, 2923, 2859 (w), 1479 (m), 1450 (s), 1379, 1364, 1294,
1280 (m), 1252 (s), 1207, 1196, 1114, 1066, 1055, 1036, 1008
(m), 961 (s), 945, 928, 899, 835 (m), 761, 743, 723 (s), 683, 666
(m), 616 (s), 590, 576, 549 (m) cmÀ1. GC-MS (EI, 70eV): m/z
(%) = 298 ([M]+, 100), 268 (9), 255 (9). HRMS (EI, 70eV): calcd
for C22H18O [M]+: 298.13522; found: 298.13515.
Figure 6. NOESY and HMBC correlations of compound 13 (single headed
arrow, HMBC; double headed arrow, NOESY). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Arylated Benzofurans by Regioselective Suzuki–Miyaura Cross-
Coupling Reactions of 2,3-Dibromobenzofurans- and 2,3,5-Tribromobenzofurans
2,3-Bis(4-ethylphenyl)benzofuran (7d). Compound 7d was
prepared from 5 (276 mg, 1.0 mmol) and 4-ethylphenylboronic
acid (300 mg, 2.0 mmol) as a colorless highly viscous oil
(280 mg, 86%). Reaction temperature: 80°C. 1H NMR
(250 MHz, CDCl3): δ = 1.30 (t, 3H, J = 7.4 Hz, CH3), 1.38
(t, 3H, J = 7.4 Hz, CH3), 2.69 (q, 2H, J = 7.8 Hz, CH2), 2.81
(q, 2H, J = 7.8 Hz, CH2), 7.19–7.40 (m, 6H, ArH), 7.48–7.69
(m, 6H, ArH). 13C NMR (62.9 MHz, CDCl3): δ = 15.3, 15.4
(CH3), 28.7 (2CH2), 111.0 (CH), 116.9 (C), 120.0 (CH), 120.8
(C), 122.8, 124.4, 127.0, 128.0, 128.3, 129.7 (CH), 130.2,
130.6, 143.5, 144.6, 150.7, 154.0 (C). IR (KBr): v = 3025 (w),
2962 (m), 2929, 2871, 1909, 1667, 1592 (w), 1519, 1499 (m),
1451 (s), 1413, 1372, 1337, 1289, 1256, 1207, 1177, 1109 (m),
1067 (s), 1048, 1018, 1008 (m), 963 (s), 928, 899 (m), 834 (s),
761 (m), 743(s), 691, 660, 647, 633 (m), 603 (s), 582, 557 (m)
cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 326 ([M]+, 100), 311 (34),
148 (9). HRMS (EI, 70 eV): calcd for C24H22O [M]+:
326.16652; found: 326.16642.
130.0, 132.0 (CH), 132.2 (C), 134.9 (CH), 138.3, 149.3, 153.7,
154.0, 154.3, 155.0 (C). IR (KBr) v = 2994, 2976, 2933 (w),
1600, 1451 (s), 1353, 1296, 1145 (m), 1147, 1064 (s), 997, 884
(m), 798, 712 (s), 626, 549 (m) cmÀ1. GC-MS (EI, 70 eV): m/z
(%) = ([M, 2Cl37]+, 03), 340 ([M, Cl37, Cl35]+, 61), 338 ([M]+,
100), 254 (17), 209 (18). HRMS (EI, 70 eV): calcd for
C20H12Cl2O [M]+: 338.02597; found: 338.02545.
2,3-Bis(4-chlorophenyl)benzofuran (7h).
Compound 7h
was prepared from 5 (276 mg, 1.0 mmol) and 4-chlorophenylboronic
acid (312 mg, 2.0 mmol) as a white crystalline solid (281 mg,
83%). Reaction temperature: 80°C, mp 102–103°C. 1H NMR
(300 MHz, CDCl3): δ = 7.15–7.39 (m, 9H, ArH), 7.45–7.51
(m, 3H, ArH). 13C NMR (75.5 MHz, CDCl3): δ = 111.3 (CH),
101.8, 116.8 (C), 119.9, 123.3, 125.2, 128.2, 128.5, 129.2
(CH), 129.8, 133.8, 134.5, 149.7, 154.0 (C), 131.0 (CH). IR
(KBr): v = 3078, 3054, 3037, 2923, 2852 (w), 1581 (m), 1558
(w), 1497, 1484 (m), 1449 (s), 1401, 1373, 1289 (w), 1253,
1201, 1174 (m), 1089, 1066, 1011, 963 (s), 945, 930, 919,
899 (m), 832, 821, 811 (s), 760 (m), 749, 742, 720 (s), 682,
646, 631, 624, 616, 582 (m) cmÀ1. GC-MS (EI, 70 eV):
m/z (%) = ([M, 2Cl37]+, 04), 340 ([M, Cl37, Cl35]+, 64), 338
([M]+, 100), 302 (11), 268 (27), 239 (29), 134 (20), 120 (20),
119 (12). HRMS (EI, 70 eV): calcd for C20H12Cl2O [M]+:
338.02597; found: 338.02559.
2,3-Bis(4-fluorophenyl)benzofuran (7i). Compound 7i was
prepared from 5 (276 mg, 1.0 mmol) and 4-fluorophenylboronic
acid (280 mg, 2.0 mmol) as a white crystalline solid (248 mg,
81%). Reaction temperature: 80°C, mp 80–81°C. 1H NMR
(250 MHz, CDCl3): δ = 6.88–6.95 (m, 2H, ArH), 7.03–7.27 (m,
4H, ArH), 7.31–7.64 (m, 6H, ArH). 19F NMR (282.2 MHz,
CDCl3): δ = À115.3, À113.1. 13C NMR (62.9 MHz, CDCl3):
δ = 111.2 (CH), 115.6 (d, JF,C = 21.2 Hz, CH), 116.2 (d, JF,
C = 21.6 Hz, CH), 119.8, 123.1, 124.9 (CH), 127.7 (d, JF,
C = 3.3 Hz, C), 128.6 (d, JF,C = 3.5 Hz, C), 128.8 (d, JF,
C = 8.2 Hz, CH), 130.1 (C), 131.4 (d, JF,C = 8.0 Hz, CH), 149.8,
153.9 (C), 162.4 (d, JF,C = 247.2 Hz, CF), 162.5 (d, JF,
C = 249.5 Hz, CF). IR (KBr): v = 3067, 3045, 3016, 2925, 2852
(w), 1594, 1582, 1515 (m), 1498, 1450 (s), 1409, 1374, 1338,
1302, 1254 (m), 1223 (s), 1205, 1161, 1155, 1109, 1099, 1088,
1068, 1014, 1009, 965, 934 (m), 836, 821, 814 (s), 802, 794
(m), 749 (s), 720, 686, 665, 627 (m), 598 (s), 580 (m), 564, 536
(s) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 306 ([M]+, 100), 305
(9), 277 (18), 275 (13). HRMS (EI, 70 eV): calcd for
C20H12F2O [M]+: 306.08507; found: 306.08454.
2,3-Bis(4-tert-butylphenyl)benzofuran (7e). Compound 7e
was prepared from
5
(276 mg, 1.0 mmol) and 4-tert-
butylphenylboronic acid (356 mg, 2.0 mmol) as
a
white
crystalline solid (336 mg, 88%). Reaction temperature: 80°C,
mp 121-122°C. 1H NMR (250 MHz, CDCl3): δ = 1.37 (s, 9H,
3CH3), 1.46 (s, 9H, 3CH3), 7.23–7.35(m, 2H, ArH), 7.39 (d,
2H, J = 8.7 Hz, ArH), 7.51–7.60 (m, 6H, ArH), 7.71 (d, 2H,
J = 8.7 Hz, ArH). 13C NMR (62.9 MHz, CDCl3): δ = 31.3, 31.5
(3CH3), 34.7, 34.8 (C), 111.0 (CH), 116.9 (C), 120.1, 122.7,
124.4, 125.4, 125.8, 126.6 (CH), 128.1 (C), 129.4, (CH), 129.9,
130.7, 150.4, 150.5, 151.4, 153.9 (C). IR (KBr): v = 3035 (w),
2960 (m), 2902, 2866, 1589 (w), 1520, 1497, 1472 (m), 1452
(s), 1408, 1393, 1362, 1267 (m), 1257 (s), 1209 (m), 1106 (s),
1064, 1015 (m), 965 (s), 907, 901 (m), 836 (s), 821 (m), 746,
739 (s), 625, 596, 582 (m), 547 (s) cmÀ1. GC-MS (EI, 70 eV):
m/z (%) = 382 ([M]+, 100), 368 (26), 367 (89), 176 (14), 148
(23), 57 (12). HRMS (EI, 70 eV): calcd for C28H30O [M]+:
382.22912; found: 382.22904.
2,3-Bis(2-chlorophenyl)benzofuran (7f).
Compound 7f
was prepared from (276 mg 1.0 mmol) and 2-
5
chlorophenylboronic acid (312 mg, 2.0 mmol) as a white solid
1
(294 mg, 87%). Reaction temperature: 80°C, mp 104–105°C. H
NMR (300 MHz, CDCl3): δ = 7.06–7.19 (m, 6H, ArH),
7.23–7.38 (m, 5H, ArH), 7.48 (dt, J = 0.7, 8.1 Hz, 1H, ArH).
13C NMR (62.9 MHz, CDCl3): δ = 111.5 (CH), 118.1 (C),
121.0, 123.0, 124.9, 126.6, 126.9 (CH), 128.7 (C), 129.2 (CH),
129.9 (C), 130.1, 130.3, 130.4 (CH), 131.4 (C), 132.2, 132.3
(CH), 134.1, 134.3, 150.4, 154.5 (C). IR (KBr): v = 3056, 1631,
1581, 1564, 1537, 1513 (w), 1486, 1448, 1438, 1369, 1295,
1271, 1245, 1204, 1161, 1111, 1088, 1061, 1041, 1030, 1008,
966, 949, 905, 829 (m), 760, 748, 736, 724, 713 (s), 697, 664,
658, 613, 570 (m) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 342
([M, 2Cl37]+, 02), 340 ([M, Cl37, Cl35]+, 63), 338 ([M, 2Cl35]+,
94), 302 (11), 275 (11), 269 (22), 268 (100), 240 (11), 239
(47), 237 (16), 134 (32), 120 (27), 119 (20). HRMS (EI, 70 eV):
calcd for C20H12Cl2O [M]+: 338.02597; found: 338.02554.
2,3-Bis(4-(trifluoromethyl)phenyl)benzofuran (7j). Compound
7j was prepared from
5 (276 mg, 1.0 mmol) and 4-
(trifluoromethyl)phenylboronic acid (380 mg, 2.0 mmol) as a
white crystalline solid (296 mg, 73%). Reaction temperature:
1
80°C, mp 166–168°C. H NMR (300 MHz, CDCl3): δ = 7.07–
7.24 (m, 4H, ArH), 7.24–7.50 (m, 2H, ArH), 7.57-7.81 (m, 4H,
ArH), 8.04–8.24 (m, 2H, ArH). 19F NMR (282.2 MHz, CDCl3):
δ = À62.8, À63.0. 13C NMR (75.5 MHz, CDCl3): δ = 112.2,
112.5, 115.9 (CH), 118.1 (C), 118.2, 120.6 (CH), 121.3(q, JF,
C = 3.7 Hz, CH), 123.9 (q, JF,C = 3.6 Hz, CH), 124.3 (q, JF,
C = 271.5 Hz, CF3), 124.9 (q, JF,C = 272.1 Hz, CF3), 126.8
(CH), 128.2 (q, JF,C = 31.5 Hz, C-CF3), 128.7 (C), 128.8 (q, JF,
C = 32.0 Hz, C-CF3), 130.4, 151.7, 155.3, 158.9 (C). IR (KBr):
v = 3001, 2955 (w), 1672 (w), 1609, 1580 (m), 1460, 1402 (s),
1387, 1250 (w), 1213, 1194 (s), 1110, 1026, 963 (m), 860, 774
(w), 751 (s), 667, 524 (w) cmÀ1. GC-MS (EI, 70 eV): m/z
(%) = 406 ([M]+, 100), 290 (09), 185 (18). HRMS (EI, 70 eV):
calcd for C22H12F6O [M]+: 406.07293; found: 406.07288.
2,3-Bis(3-chlorophenyl)benzofuran (7g).
Compound 7g
was prepared from (276 mg 1.0 mmol) and 2-
5
chlorophenylboronic acid (312 mg, 2.0 mmol) as a white solid
(263 mg, 78%). Reaction temperature: 80°C, mp 76–78°C. 1H
NMR (300 MHz, CDCl3): δ 7.14-7.19 (m, 4H, ArH), 7.24–7.47
(m, 2H, ArH), 7.55–7.75 (m, 4H, ArH), 8.08–8.13 (m, 2H,
ArH). 13C NMR (75.5 MHz, CDCl3): δ 102.4, 111.3 (CH),
121.1 (C), 122.9, 123.1, 124.8, 124.9, 126.9, 128.9, 129.8,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Hussain, N. T. Hung, N. Abbas, R. A. Khera, I. Malik, T. Patonay, N. Kelzhanova,
Z. A. Abilov, A. Villinger, and P. Langer
Vol 000
2,3-Bis(2-methoxyphenyl)benzofuran (7k). Compound 7k
was prepared from (276 mg 1.0 mmol) and 2-
v = 3011, 2913, 2855, 2730, 2142 (w), 1600, 1582 (m), 1566,
1503 (w), 1454, 1377, 1338, 1259, 1234, 1192, 1182, 1169,
1159, 1097, 1054, 1037, 1009 (m), 976, 947 (w), 924, 896 885,
873 (m), 856, 845 (s), 811, 757 (m), 738, 703, 680 (s), 628 (m),
591, 541, 534 (w) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 326
([M]+, 100), 296 (5), 252 (4). HRMS (EI, 70 eV): calcd for
C24H22O [M]+: 326.16652; found: 326.16664.
5
methoxyphenylboronic acid (304 mg, 2.0 mmol) as a white solid
(270 mg, 82%). Reaction temperature: 80°C, mp 78–79°C. 1H
NMR (300 MHz, CDCl3): δ = 3.48 (s, 3H, OCH3), 3.67 (s, 3H,
OCH3), 6.90 (d, 1H, J = 8.3 Hz, ArH), 6.97–7.06 (m, 3H, ArH),
7.26–7.40 (m, 5H, ArH), 7.56–7.64 (m, 3H, ArH). 13C NMR
(75.5 MHz, CDCl3): δ = 55.0, 55.2 (OCH3), 111.0, 111.1, 111.2
(CH), 115.9 (C), 120.4, 120.5 (CH), 120.9 (C), 121.0, 122.4
(CH), 123.0 (C), 124.0, 128.5 (CH), 129.7 (C), 130.1, 130.7,
130.9 (CH), 149.9, 154.5, 157.0, 157.1 (C). IR (KBr): v = 3062,
2998, 2934 (w), 2833 (m), 1600, 1586, 1499, 1486 (m), 1459,
1447, 1433 (s), 1368 (w),1289 (m), 1242 (s), 1203, 1194, 1178,
1161, 1115, 1054, 1041 (m), 1024, 962 (s), 907, 899, 793, 785
(m), 743 (s), 696, 666, 647, 602, 615, 591, 570, 559, 536 (m)
cmÀ1 GC-MS (EI, 70 eV): m/z (%) = 330 ([M]+, 100), 271 (9),
255 (14), 121 (12). HRMS (EI, 70 eV): calcd for C22H18O3
[M]+: 330.12505; found: 330.12479.
Synthesis of 2-aryl-3-bromobenzofurans 8a–k
3-Bromo-2-p-tolylbenzofuran (8a).
Compound 8a was
prepared from 5 (276 mg, 1.0 mmol) and p-tolylboronic acid
(136 mg, 1.0 mmol) as a white solid (266 mg, 93%). Reaction
1
temperature: 70°C, mp 81–82°C. H NMR (300 MHz, CDCl3):
δ = 2.26 (s, 3H, CH3), 7.03–7.26 (m, 4H, ArH), 7.51–7.60 (m,
2H, ArH), 8.10 (d, 2H, J = 8.3 Hz, ArH). 13C NMR (75.5 MHz,
CDCl3): δ = 21.5 (CH3), 93.1 (C), 111.2, 119.8, 123.4, 125.4,
126.7, 129.3 (CH), 129.4, 139.2, 150.6, 153.1 (C). IR (KBr):
v = 3030, 2967, 2917, 2858 (w), 1502 (m), 1450 (s), 1412,
1342, 1325, 1303, 1271, 1252, 1203, 1189, 1175, 1107 (m),
1073 (s), 1018, 1007 (m), 985 (s), 932, 889, 830 (m), 816 (s),
785 (m), 739 (s), 712, 653, 632, 574, 537 (m) cmÀ1. GC-MS
(EI, 70 eV): m/z (%) = 288 ([M, 81Br]+, 99), 286 ([M, 79Br]+,
100), 207 (10), 179 (30), 178 (33), 152 (10), 89 (11), 76 (9),
237 (16), 134 (32), 120 (27), 119 (20). HRMS (EI, 70 eV):
calcd for C15H11Br O [M, 79Br]+: 285.99878; found: 285.99869.
3-Bromo-2-(4-ethylphenyl)benzofuran (8b). Compound 8b
2,3-Bis(4-methoxyphenyl)benzofuran (7l).
Compound 7l
was prepared from (276 mg 1.0 mmol) and 4-
5
methoxyphenylboronic acid (304 mg, 2.0 mmol) as a white solid
1
(247 mg, 75%). Reaction temperature: 80°C, mp 157–158°C. H
NMR (300 MHz, CDCl3): δ = 3.75–3.77 (s, 6H, 2OCH3), 6.91–
6.80 (m, 2H, ArH), 7.17–7.15 (m, 2H, ArH), 7.48–7.38 (m, 4H,
ArH), 7.72 (d, 2H, J = 7.5 Hz, ArH), 8.04 (d, 2H, J = 7.4 Hz,
ArH). 13C NMR (75.5 MHz, CDCl3): = 54.3, 54.4 (CH3O),
111.0, 113.2, 114.1, 114.2 (CH), 114.3 (C), 120.6 (CH), 122.8,
123.7 (C), 126.4 (CH), 127.7 (C), 128.3, 132.5 (CH), 153.7,
155.0, 157.7, 159.0 (C). IR (KBr): v = 3003, 2957, 2912 (w),
1604, 1496, 1451 (s), 1353, 1296 (m), 1243, 1175, 1039 (s),
997, 919, 884 (m), 822, 798, 742 (s), 710, 660 (w), 626, 549
(m) cmÀ1. GCMS (EI, 70 eV): m/z (%) = 330 ([M]+, 100), 315
(21). HRMS (EI, 70 eV): calcd for C22H18O3: [M]+: 330.12505;
found 330.124903.
was prepared from
5
(276 mg 1.0 mmol) and 4-
ethylphenylboronic acid (150 mg, 1.0 mmol) as a white solid
(258 mg, 86%). Reaction temperature: 70°C, mp 89–90°C. 1H
NMR (250 MHz, CDCl3): δ = 1.19 (t, 1H, J = 7.6 Hz, CH3), 2.62
(q, 2H, J = 7.6 Hz, CH2), 7.18-7.28 (m, 4H, ArH), 7.38-7.48 (m,
2H, ArH), 8.00 (d, 2H, J = 8.4 Hz, CH3). 13C NMR (62.9 MHz,
CDCl3): δ = 15.4 (CH3), 28.8 (CH2), 93.1 (C), 111.2, 119.7,
123.4, 125.3, 126.8 (CH), 127.0 (C), 128.1 (CH), 129.7, 145.5,
150.6, 153.1 (C). IR (KBr): v = 3028 (w), 2962, 2927 (m),
2871, 2422, 1907, 1771, 1714, 1666, 1612, 1590 (w), 1502
(m), 1449 (s), 1416, 1345, 1319, 1297, 1272, 1254, 1205, 1185,
1108 (m), 1073 (s), 1049, 1018, 1006 (m), 985 (s), 926, 890
(m), 831, 738 (s), 659, 642, 631, 579, 552 (m) cmÀ1. GC-MS
(EI, 70 eV): m/z (%) = 302 ([M]+, 81Br, 04), 300 ([M, 79Br]+,
05), 298 (100), 255 (11), 178 (9). HRMS (EI, 70 eV): calcd for
C16H13BrO [M, 79B]+: 300.015065; found: 300.015364.
2,3-Bis(2,5-dimethoxyphenyl)benzofuran (7m).
Compound
7m was prepared from (276mg 1.0 mmol) and 2,5-
5
dimethoxyphenylboronic acid (364 mg, 2.0 mmol) as a light
brown solid (331 mg, 85%). Reaction temperature: 80°C, mp
1
79–80°C. H NMR (300 MHz, CDCl3): δ = 3.46 (s, 3H, OCH3),
3.62 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.79 (s, 3H, OCH3),
6.82–6.96 (m, 5H, ArH), 7.18–7.38 (m, 3H, ArH), 7.56–7.63 (m,
2H, ArH). 13C NMR (75.5 MHz, CDCl3): δ = 55.7, 55.8, 55.9
(OCH3), 111.2, 112.3, 112.7, 113.5, 115.6, 115.8 (CH), 115.9
(C), 116.6, 121.0 (CH), 121.3 (C), 122.5 (CH), 123.8 (C), 124.1
(CH), 129.5, 149.8, 151.4, 151.5, 153.4, 153.6, 154.4 (C). IR
(KBr): v = 3057, 2995, 2934, 2903 (w), 2831 (m), 1606, 1581
(w), 1492, 1453 (s), 1421 (m), 1359 (w), 1306, 1293, 1270, 1245
(m), 1216, 1175 (s), 1160 (m), 1042, 1022 (s), 991, 927, 909,
873, 861, 849, 799, 768 (m), 730 (s), 691, 647, 626, 611, 573,
556 (m) cmÀ1. GC-MS (EI, 70eV): m/z (%) = 390 ([M]+, 100),
345 (15), 344 (47), 301 (14), 172 (9). HRMS (EI, 70eV): calcd
for C24H22O5 [M]+: 390.14618; found: 390.14603.
3-Bromo-2-(3-chlorophenyl)benzofuran (8c).
Compound
8c was prepared from (276 mg 1.0 mmol) and 3-
5
chlorophenylboronic acid (156 mg, 1.0 mmol) as a white solid
1
(224 mg, 73%). Reaction temperature: 70°C, mp 200–202°C. H
NMR (300 MHz, CDCl3): δ = 7.30–7.11 (m, 2H, ArH), 7.75–
7.42 (m, 4H, ArH), 8.05-8.04 (m, 2H, ArH). 13C NMR
(75.5 MHz, CDCl3): δ = 99.0 (C), 111.2, 119.7, 123.6, 125.9,
128.9, 130.5, 131.7, 134.2 (CH), 139.8, 149.2, 153.0, 153.5,
152.4 (C). IR (KBr) v = 2987, 2971, 2903 (w), 1601, 1448 (s),
1347, 1277, 1174 (m), 1147, 1064 (s), 990, 891 (m), 798, (s),
666, 524 (m) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 310 ([M,
81Br, 37Cl]+, 12), 308 ([M, 37Cl 79Br or 35Cl81Br]+, 100), 306
([M, 79Br, 35Cl]+, 73), 267 (21). HRMS (EI, 70 eV): calcd for
C14H8BrClO [M, 79Br]+: 305.094416; found: 305.094221.
2,3-Bis(3,5-dimethylphenyl)benzofuran (7n).
Compound
7n was prepared from (276 mg 1.0 mmol) and 3,5-
5
dimethylphenylboronic acid (302 mg, 2.0 mmol) as a white solid
1
(258 mg, 79%). Reaction temperature: 80°C, mp 106–107°C. H
3-Bromo-2-(4-chlorophenyl)benzofuran (8d).
Compound
NMR (250 MHz, CDCl3): δ = 2.18 (s, 6H, 2CH3), 2.27 (s, 6H,
2CH3), 6.85 (s, 1H, ArH), 6.85 (s, 1H, ArH), 6.02 (s, 2H, ArH),
7.11–7.20 (m, 4H, ArH), 7.41–7.47 (m, 2H, ArH). 13C NMR
(62.9 MHz, CDCl3): δ = 21.3, 21.4 (2CH3), 111.0 (CH), 117.5
(C), 120.1, 120.7, 124.4, 124.7, 127.4, 129.2, 130.0 (CH),
130.4, 130.6, 132.7, 167.8, 168.3, 150.6, 153.9 (C). IR (KBr):
8d was prepared from (276 mg, 1.0 mmol) and 4-
5
chlorophenylboronic acid (156 mg, 1.0 mmol) as a white solid
1
(276 mg, 90%). Reaction temperature: 70°C, mp 114–115°C. H
NMR (300 MHz, CDCl3): δ = 7.33–7.60 (m, 6H, ArH), 8.14 (d,
2H, J = 8.9 Hz, ArH). 13C NMR (62.9 MHz, CDCl3): δ = 94.3
(C), 111.3, 120.0, 123.6, 125.9, 127.9 (CH), 128.0 (C), 128.9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Arylated Benzofurans by Regioselective Suzuki–Miyaura Cross-
Coupling Reactions of 2,3-Dibromobenzofurans- and 2,3,5-Tribromobenzofurans
(CH), 134.9, 149.2, 153.1 129.4 (C). IR (KBr) v = 3066 (w),
1889, 1769, 1714, 1594, 1556 (w), 1485, 1474 (m), 1449 (s),
1416, 1403, 1342, 1320, 1300, 1268, 1249, 1201 (m), 1177,
1111 (w), 1093, 1068 (s), 1011 (m), 986 (s), 928, 903, 889 (m),
822 (s), 814 (m), 737, 721 (s), 758, 648, 625, 600, 573 (m)
cmÀ1. GC-MS (EI, 70 eV) m/z (%) = 310 ([M, 81Br, 37Cl]+, 11),
308 ([M, 37Cl 79Br or 35Cl81Br]+, 100), 306 ([M, 79Br, 35Cl]+,
77), 201 (12), 199 (36), 164 (15), 163 (27), 99 (10), 82 (9).
HRMS (EI, 70 eV): calcd for C14H8BrClO [M, 79Br, 35Cl]+:
305.94416; found: 305.94395.
3-Bromo-2-(2,6-dimethoxyphenyl)benzofuran (8h). Compound
8h was prepared from (276 mg, 1.0 mmol) and 2,6-
5
dimethoxyphenylboronic acid (182 mg, 1.0 mmol) as a white
solid (295 mg, 89%). Reaction temperature: 70°C, mp 79–80°
C. 1H NMR (300 MHz, CDCl3): δ = 3.72 (s, 6H, 2OCH3),
6.57 (d, J = 8.5, 2H, ArH), 7.11–7.53 (m, 5H, ArH). 13C
NMR (75.5 MHz, CDCl3): δ = 56.2 (2OCH3), 98.8 (C), 104.0,
111.6, 119.5 (CH), 120.7 (C), 122.9, 124.7 (CH), 128.7 (C),
132.2 (CH), 154.3, 159.2, 159.7 (C). IR (KBr): v = 3056,
3003, 2961, 2936, 2837 (w), 1619, 1587 (m), 1473 (s), 1448
(m), 1431 (s), 1297 (m), 1247 (s), 1202, 1134 (m), 1106 (s),
1050, 1031, 1012, 986, 919, 906 890, 820, 781, 748 (m),
728 (s), 693, 637, 591, 556 (m) cmÀ1. GC-MS (EI, 70 eV):
m/z (%) = 334 ([M, 81Br]+, 98), 332 ([M, 79Br]+, 100), 238
(29), 237 (16), 223 (78), 165 (9), 152 (11), 147 (42), 139
(16), 131 (20). HRMS (EI, 70 eV): calcd for C16H13BrO3
[M, 79Br]+: 332.00426; found: 332.00332.
3-Bromo-2-(4-(trifluoromethyl)phenyl)benzofuran
(8e).
Compound 8e was prepared from 5 (276 mg, 1.0 mmol) and
4-(trifluoromethyl)phenylboronic acid (190 mg, 1.0 mmol) as
a white solid (269 mg, 79%). Reaction temperature: 70°C, mp
140-142°C. 1H NMR (300 MHz, CDCl3): δ = 6.90–6.91 (m,
1H, ArH), 7.03–7.07 (m, 2H, ArH), 7.16–7.18 (m, 3H, ArH),
7.84–7.90 (m, 2H, ArH). 19F NMR (282.2 MHz, CDCl3): δ
À62.3. 13C NMR (75.5 MHz, CDCl3): δ = 91.7 (C), 112.5
(CH), 115.8 (C), 116.2, 124.3 (CH), 124.3 (q, JF,C = 272.9 Hz,
CF3), 125.9 (CH), 126.0 (q, JF,C = 3.8 Hz, CH), 128.37 (q, JF,
C = 32.3.0Hz, C-CF3), 128.5 (CH), 153.8, 154.3, 158.6 (C). IR
(KBr) v = 3077, 2921, 2850 (w), 1609, 1580 (m), 1482, 1452 (s),
1392, 1255 (w), 1213 (s), 1154, 1108, 1048, 963 (m), 862, 790
(w), 749 (s), 667, 550 (w) cmÀ1. GC-MS (EI, 70eV): m/z
(%) = 341 ([M, 81Br]+, 99), 339 ([M, 79Br]+, 100), 227 (34), 213
(10), 132 (10), 123 (41), 95 (20). HRMS (EI, 70 eV): calcd for
C15H8BrF3O [M, 79Br]+: 339.97106; found: 339.97133.
3-Bromo-2-(3,5-dimethylphenyl)benzofuran (8i). Compound 8i
was prepared from
5
(276 mg, 1.0 mmol) and 3,5-
dimethylphenylboronic acid (150 mg, 1.0 mmol) as a white
solid (237 mg, 79%). Reaction temperature: 70°C, mp 95–96°
C. 1H NMR (250 MHz, CDCl3): δ = 2.45 (s, 6H, 2CH3), 7.08
(s, 1H, ArH), 7.31–7.41 (m, 2H, ArH), 7.51–7.60 (m, 2H,
ArH), 7.82 (s, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
δ = 21.5 (2CH3), 93.6 (C), 111.2, 119.8, 123.4, 124.6, 125.4
(CH), 129.4, 129.7 (C), 130.9 (CH), 138.2, 150.7, 153.1 (C).
IR (KBr): v = 3063, 3037, 2947 (w), 2916 (m), 2855, 2724,
1925, 1888, 1767, 1740 (w), 1602, 1558 (m), 1451 (s), 1419,
1371, 1343, 1319, 1302, 1263, 1229, 1190, 1176, 1148, 1115,
1099 (m), 1019 (s), 1006, 980, 949, 926, 894, 872, 862 (m),
848 (s), 755 (m), 740, 692 (s), 662, 639, 592, 539, 531 (m)
cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 302 ([M, 81Br]+, 99), 300
([M, 79Br]+, 100), 193 (17), 178 (19). HRMS (EI, 70 eV): calcd
for C16H13BrO [M, 79Br]+: 300.01443; found: 300.01422.
3-Bromo-2-(2-methoxyphenyl)benzofuran (8f). Compound
8f was prepared from
5 (276 mg, 1.0 mmol) and 2-
methoxyphenylboronic acid (152 mg, 1.0 mmol) as white solid
(263 mg, 87%). Reaction temperature: 70°C, mp 86–87°C. 1H
NMR (300 MHz, CDCl3): δ = 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 (75.5 MHz, CDCl3):
δ = 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, 3037, 3003, 2959, 2934,
2835 (w), 1610, 1586 (m), 1485 (s), 1461 (m), 1446, 1433 (s),
1313, 1296 (m), 1255, 1243 (s), 1200, 1180, 1162, 1120, 1107,
1073 (m), 1057, 1043, 1023, 984 (s), 932, 891, 827, 781 (m),
739 (s), 667, 636, 588, 554 (m) cmÀ1. GC-MS (EI, 70 eV): m/z
(%) = 304 ([M, 81Br]+, 84), 302 ([M, 79Br]+, 86), 223 (22), 209
(28), 208 (100), 167 (12), 165 (24), 152 (30), 151 (17). HRMS
(EI, 70 eV): calcd for C15H11BrO2 [M, 79Br]+: 301.99369;
found: 301.99370.
2-(3-Phenylphenyl)-3-bromobenzofuran (8j).
Compound
8j was prepared from (276 mg, 1.0 mmol) and 3-
5
phenylphenylboronic acid (198 mg, 1.0 mmol) as a white solid
(233 mg, 67%). Reaction temperature: 70°C, mp 78–79°C. 1H
NMR (300 MHz, CDCl3): δ = 7.22–7.62 (m, 11H, ArH), 8.08
(dt, 1H, J = 1.5, 7.7 Hz, ArH), 8.33 (t, 1H, J = 1.4 Hz, ArH). 13C
NMR (75.5 MHz, CDCl3): δ = 94.16 (C), 111.3, 120.0, 123.6,
125.5, 125.6, 125.7, 127.3, 127.7, 127.8, 128.9, 129.1 (CH),
129.6, 130.0, 140.7, 141.7, 150.3, 153.2 (C). IR (KBr):
v = 3053, 3031 (m), 2918, 2849, 2790, 2682, 2351, 1953, 1894,
1811, 1705, 1674 (w), 1593, 1573, 1472 (m), 1453 (s), 1401,
1341, 1299, 1265, 1198, 1173, 1113 (m), 1071 (s), 1051, 1024,
1007 (m), 988 (s), 893, 843, 810 (m), 757, 741, 690, 671 (s),
640, 613, 577, 569 (m) cmÀ1. GC-MS (EI, 70 eV): m/z
(%) = 350 ([M, 81Br]+, 99), 348 ([M, 79Br]+, 100), 241 (21), 239
(36), 119 (10). HRMS (EI, 70 eV): calcd for C20H13BrO [M,
79Br]+: 348.01443; found: 348.01420.
3-Bromo-2-(thiophen-2-yl)benzofuran (8k). Compound 8k
was prepared from 5 (276 mg, 1.0 mmol) and thien-2-ylboronic
acid (128 mg, 1.0 mmol) as a white solid (175 mg, 63%).
Reaction temperature: 70°C, mp 194–195°C. 1H NMR
(250 MHz, CDCl3): δ = 6.98–7.02 (m, 1H, ArH), 7.08–7.21 (m,
2H, ArH), 7.27–7.37 (m, 3H, ArH), 7.69 (dd, 1H, J = 0.8,
3.7 Hz, ArH). 13C NMR (75.5 MHz, CDCl3): δ = 93.0 (C),
111.2, 119.6, 123.7, 125.6, 126.6, 127.0, 127.7 (CH), 129.3,
131.3, 147.5, 153.1 (C). IR (KBr): v = 3097, 3071, 3034, 3016,
1932, 1895, 1779, 1667, 1551 (w), 1586 (m), 1494, 1471 (w),
1448 (s), 1420, 1362, 1341, 1303, 1270, 1254, 1223, 1206,
3-Bromo-2-(4-methoxy phenyl)benzofuran (8g). Compound
8g was prepared from
5
(276 mg, 1.0 mmol) and 4-
methoxyphenylboronic acid (152 mg, 1.0 mmol) as a colorless
viscous oil (212 mg, 70%). Reaction temperature: 70°C. 1H NMR
(300MHz, CDCl3): δ 3.80 (s, 3H, OCH3), 6.94 (d, 2H,
J = 7.5 Hz, ArH), 7.22–7.24 (m, 1H, ArH), 7.26–7.28 (m, 1H,
ArH), 7.31–7.33 (m, 1H, ArH), 7.39–7.47 (m, 1H, ArH), 8.04 (d,
2H, J = 7.5 Hz, ArH). 13C NMR (75.5MHz, CDCl3): δ = 55.4
(OCH3), 99.0 (C), 111.1, 114.2 (CH), 119.6 (C), 122.2 (CH),
123.4 (C), 125.1, 126.8, 128.3 (CH), 150.5, 153.0, 160.2 (C). IR
(KBr): v = 2998, 2946, 2929 (w), 1607 (m), 1500 (s), 1449, 1439,
1306, 1273 (m), 1247, 1175 (s), 1070, 983 (m), 927, 889 (w),
828, 739 (s), 633, 548 (m) cmÀ1. GC-MS (EI, 70eV): m/z
(%) = 304 ([M, 81Br]+, 99), 302 ([M, 79Br]+, 100), 207 (39), 134
(08). HRMS (EI, 70eV): calcd for C15H11BrO2: (M+, [81Br]):
303.99369; found 303.991943, calcd for (M+, [79Br]): 301.99369;
found 301. 993881.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Hussain, N. T. Hung, N. Abbas, R. A. Khera, I. Malik, T. Patonay, N. Kelzhanova,
Z. A. Abilov, A. Villinger, and P. Langer
Vol 000
1194, 1171, 1148, 1082 (m), 1064, 1031 (s), 1004, 970, 887, 877,
2-(Biphenyl-3-yl)benzofuran (9q).
Compound 9q was
848, 824, 791 (m), 741, 694 (s), 657, 634, 574, 547 (m) cmÀ1
.
obtained as a by-product of 8j (62 mg, 23%). 1H NMR
(300 MHz, CDCl3): δ = 7.01 (s, 1H, ArH), 7.13–7.61
(m, 11H, ArH), 7.77 (dt, J = 1.6, 7.5 Hz, 1H, ArH), 8.02
(t, J = 1.7 Hz, 1H, ArH). 13C NMR (75.5 MHz, CDCl3):
δ = 101.6, 111.2, 121.0, 123.0, 123.7, 123.8, 124.4, 127.2,
127.4, 127.6, 128.9 (CH), 129.2 (C), 129.3 (CH) 131.0,
140.9, 141.9, 155.0, 155.9 (C). IR (KBr): v = 3119, 3053,
3026 (w), 1598, 1556, 1471, 1453, 1421 (m), 1391 (w),
1347, 1305, 1253, 1200, 1167 (m), 1144, 1107, 1095, 1074,
1056 (w), 1036 (m), 1018, 1004, 967 (w), 925, 892, 882,
820, 809 (m), 795, 760, 748, 740, 693, 675 (s), 617, 609,
578, 560, 537 (m) cmÀ1. GC-MS (EI, 70 eV): m/z (%) = 270
([M]+, 100), 241 (9), 239 (14), 135 (10). HRMS (EI, 70 eV):
calcd for C20H14O [M]+: 270.10392; found: 270.10402.
GC-MS (EI, 70 eV): m/z (%) = 280 ([M, 81Br]+, 100), 278
([M, 79Br]+, 98), 171 (59), 139 (9), 127 (14), 85 (18). HRMS
(EI, 70 eV): calcd for C12H7BrOS [M, 79Br]+: 277.93955;
found: 277.93989.
2-Phenylbenzofuran (9a). Compound 9a was obtained as a
by-product of 7a (8 mg, 4%). 1H NMR (300 MHz, CDCl3):
δ = 6.95 (d, J = 0.8 Hz, 1H, ArH), 7.12–7.31 (m, 3H, ArH),
7.35–7.53 (m, 4H, ArH), 7.78–7.81 (m, 2H, ArH). 13C NMR
(75.5 MHz, CDCl3): δ = 101.3, 111.2, 120.9, 122.9, 124.3,
125.0 (CH), 127.5 (C), 128.6, 128.8 (CH), 130.5, 154.9, 154.9
(C). GC-MS (EI, 70 eV): m/z (%) = 194 ([M]+, 100), 176 (08).
HRMS (EI, 70 eV): calcd for C14H10O [M]+: 194.07361;
found: 194.07321.
2-p-Tolylbenzofuran (9b). Compound 9b was obtained as a
by-product of 8b (9 mg, 4%). 1H NMR (300 MHz, CDCl3):
δ = 2.32 (s, 3H, CH3), 7.11–7.21 (m, 5H, ArH), 7.41–7.50 (m,
2H, ArH), 7.66–7.70 (m, 2H, ArH). 13C NMR (75.5 MHz,
CDCl3): δ = 20.8 (CH3), 100.0, 110.5, 120.1, 122.2, 123.4,
124.3 (CH), 127.2, 128.7 (C), 128.9 (CH), 138.0, 154.2,
155.6 (C). IR (KBr): v = 3060, 2953, 2928, 2865, 1923, 1847,
1809, 1771, 1667, 1604, 1575 (w), 1488, 1473 (m), 1449 (s),
1379, 1356, 1311, 1285 (w), 1254 (s), 11207, 1170, 1119,
1107 (m), 1054, 1034 (w), 1017 (s), 920, 885, 803 (m), 760,
744, 737, 718 (s), 662, 614, 572, 555, 530 (m) cmÀ1. GC-MS
(EI, 70 eV): m/z (%) = 208 ([M]+, 100), 207 (74), 189 (16),
179 (18), 178 (27), 165 (12), 115 (10), 89 (14). HRMS (EI,
70 eV): calcd for C15H12O [M]+: 208.08827; found:
208.088577.
2-o-Tolylbenzofuran (9c). Compound 9c was obtained as a
by-product of 7c (19 mg, 9%). 1H NMR (250 MHz, CDCl3):
δ = 2.61 (s, 3H, CH3), 6.92 (s, 1H, ArH), 7.23–7.37 (m, 5H,
ArH), 7.53–7.65 (m, 2H, ArH), 7.85–7.89 (m, 1H, ArH).
13C NMR (62.9 MHz, CDCl3): δ = 21.9 (CH3), 105.1, 111.1,
120.9, 122.8, 124.2, 126.1, 128.2, 128.5 (CH), 129.2, 129.9
(C), 131.3 (CH), 135.8, 154.4, 155.7 (C). IR (KBr):
v = 3060, 2953, 2928, 2865, 1923, 1847, 1809, 1771, 1667,
1604, 1575 (w), 1488, 1473 (m), 1449 (s), 1379, 1356,
1311, 1285 (w), 1254 (s), 11207, 1170, 1119, 1107 (m),
1054, 1034 (w), 1017 (s), 920, 885, 803 (m), 760, 744, 737,
718 (s), 662, 614, 572, 555, 530 (m) cmÀ1. GC-MS (EI,
70 eV): m/z (%) = 208 ([M]+, 100), 189 (16), 178 (27), 165
(12), 115 (10), 89 (14). HRMS (EI, 70 eV): calcd for
C15H12O [M]+: 208.08827; found: 208.08861.
2-(Thiophen-2-yl)benzofuran (9r).
Compound 9r was
obtained as a by-product of 8k (30 mg, 15%). 1H NMR
(250 MHz, CDCl3): δ = 6.88 (d, J = 0.8 Hz, 1H, ArH), 7.12 (dd,
J = 3.7, 5.1 Hz, 1H, ArH), 7.20–7.36 (m, 3H, ArH), 7.49–7.58
(m, 3H, ArH). 13C NMR (75.5 MHz, CDCl3): δ = 101.1, 111.1,
120.8, 123.1, 124.3, 124.6, 125.8, 127.9 (CH), 129.1, 133.3,
151.3, 154.6 (C). GC-MS (EI, 70 eV): m/z (%) = 200 ([M]+,
100), 185 (18). HRMS (EI, 70 eV): calcd for C12H8OS [M]+:
200.02959; found: 200.02977.
Procedure for the synthesis of 10a,b.
carried out in a pressure tube. To a dioxane suspension (10 mL)
of (546 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 5 mol %,
The reaction was
5
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 and 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 × 25 mL). The
combined organic layers were dried (Na2SO4) and filtered,
and the filtrate was concentrated in vacuo. The residue was
purified by flash chromatography (silica gel, EtOAc/heptanes).
Products 10a (238 mg, 76%) and 10b (248 mg, 82%) were
isolated as colorless oils.
3-(3-Methoxyphenyl)-2-p-tolylbenzofuran (10a). mp 73–74°C.
1H NMR (300 MHz, CDCl3): δ = 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 (75.5 MHz, CDCl3): δ = 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), 1607, 1592, 1574, 1512, 1484 (m), 1451 (s), 1427, 1369,
1314, 1282 (m), 1246, 1234 (s), 1205, 1184, 1156, 1064 (m),
1042 (s), 1019, 1009, 987, 876, 838 (m), 819 (s), 779 (m), 742,
701 (s), 618, 610, 587, 563, 537 (m) cmÀ1. GC-MS (EI,
70 eV): m/z (%) = 314 ([M]+, 100), 271 (9), 255 (14), 121 (12).
HRMS (EI, 70 eV): calcd for C22H18O2 [M]+: 314.13068;
found: 314.12999.
3-(4-Fluorophenyl)-2-p-tolylbenzofuran (10b). mp 103–104°C.
1H NMR (300 MHz, CDCl3): δ = 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). 19F NMR (282.2 MHz,
CDCl3): δ = À114.35. 13C NMR (62.9 MHz, CDCl3): δ = 21.4
(CH3), 111.1 (CH), 115.8 (C), 116.1 (d, JF,C = 21.0 Hz, CH),
119.6, 123.0, 124.6, 127.0 (CH), 127.7 (C), 128.9 (d, JF,
2-(2,5-Dimethoxyphenyl)benzofuran (9m). Compound 9m
was obtained as a by-product of 7m (20 mg, 8%). 1H NMR
(250 MHz, CDCl3): δ = 3.80 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 6.77–6.88 (m, 2H, ArH), 7.10–7.25 (m, 2H, ArH),
7.30 (d, J = 0.8 Hz, 1H, ArH), 7.42–7.56 (m, 3H, ArH). 13C
NMR (62.9 MHz, CDCl3): δ = 54.9 (OCH3), 55.0 (OCH3),
105.6, 109.8, 110.9, 111.4, 113.8 (CH), 118.9 (C), 120.1,
121.7, 123.2 (CH), 127.5, 150.0, 150.1 152.7, 152.8 (C). IR
(KBr): v = 3060, 2996, 2946, 2931, 2904, 2831, 2495, 2349,
2068, 1613, 1584 (w), 1567 (m), 1500, 1453 (s), 1438 (m),
1347, 1322 (w), 1301 (m), 1273, 1259, 1242 (m), 1219,
1197 (s), 1180, 1160, 1132, 1122, 1108 (m), 1045, 1024 (s),
940, 868 (m), 809, 733 (s), 695, 666, 614, 540 (m) cmÀ1
.
GC-MS (EI, 70 eV): m/z (%) = 254 ([M]+, 100), 240 (16),
239 (96), 211 (16), 196 (13), 168 (18), 142 (14), 127 (9).
HRMS (EI, 70 eV): calcd for C16H14O3 [M]+: 254.09429;
found: 254.09411.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Arylated Benzofurans by Regioselective Suzuki–Miyaura Cross-
Coupling Reactions of 2,3-Dibromobenzofurans- and 2,3,5-Tribromobenzofurans
REFERENCES AND NOTES
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 (C), 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]+, 100), 286 (10), 259 (9), 257 (10). HRMS (EI,
70 eV): calcd for C21H15FO [M]+: 302.11014; found: 302.11031.
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[4] Tovophenone C: (a) Seo, E.-K.; Wall, M. E.; Wani, M. C.;
Navarro, H.; Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D.
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M. C.; Wall, M. E.; Navarro, H.; Mukherjee, R.; Farnsworth, N. R.;
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[6] Review: Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005,
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2,3,5-Tris(4-fluorophenyl)benzofuran (12).
Compound 12
was prepared from 11 (177 mg, 0.5 mmol) and 4-
fluorophenylboronic acid (210 mg, 1.5 mmol), according to the
procedure given for the synthesis of products 7, as a colorless
1
highly viscous oil (162 mg, 81%). Reaction temperature: 90°C. H
NMR (300 MHz, CDCl3): δ =6.42–6.67 (m, 6H, ArH), 6.86–7.06
(m, 9H, ArH). 19F NMR (282.2 MHz, CDCl3): δ =À116.8,
À114.3, À112.3. 13C NMR (62.9 MHz, CDCl3): δ = 111.2 (CH),
115.6 (d, JF,C = 21.2 Hz, CH), 115.4 (d, JF,C = 21.1 Hz, CH), 116.2
(d, JF,C = 21.6 Hz, CH), 119.8, 123.1, 124.9 (CH), 127.6, 127.7 (d,
JF,C = 3.3 Hz, C), 128.6 (d, JF,C = 3.5 Hz, C), 128.8 (d, JF,C =8.2Hz,
CH), 130.1, 130.2 (C), 130.4 (d, JF,C = 8.3 Hz, CH), 131.4 (d, JF,
C = 8.0 Hz, CH), 149.8, 153.9 (C), 1162.3 (d, JF,C = 247.0 Hz, CF),
1162.4 (d, JF,C = 247.2 Hz, CF), 1162.5 (d, JF,C = 249.5 Hz, CF). IR
(KBr): v= 3067, 3045, 3016, 2925, 2852 (w), 1594, 1582, 1515
(m), 1498, 1450 (s), 1409, 1374, 1338, 1302, 1254 (m), 1223 (s),
1205, 1161, 1155, 1589, 1099, 1088, 1068, 1014, 1009, 965, 934
(m), 836, 821, 814 (s), 802, 794 (m), 749 (s), 720, 686, 665, 627
(m), 598 (s), 580 (m), 564, 536 (s) cmÀ1. GC-MS (EI, 70 eV): m/z
(%) = 400 ([M]+, 100), 371 (7), 275 (8). HRMS (EI, 70 eV): calcd
for C26H15F3O [M]+: 400.10695; found: 400.10681.
3,5-Dibromo-2-p-tolylbenzofuran (13). Compound 13 was
prepared from 11 (177 mg, 0.5 mmol), p-tolylboronic acid (68 mg,
0.5 mmol), according to the procedure given for the synthesis of
products 7, as a white solid (144 mg, 79%). Reaction temperature:
1
70°C, mp 114–115°C. H NMR (250 MHz, CDCl3): δ = 2.43 (s,
3H, CH3), 7.16–7.37 (m, 4H, ArH), 7.58–7.70 (m, 1H, ArH),
7.91–7.98 (m, 2H, ArH). 13C NMR (62.9 MHz, CDCl3): δ = 21.5
(CH3), 92.0 (C), 112.7 (CH), 116.3 (C) 122.5 (CH), 123.8, 126.2
(C), 126.8, 128.2, 129.4 (CH), 131.6, 139.7, 151.8 (C). IR (KBr):
v = 3086, 3027, 2917, 2853, 2723, 1907, 1855, 1714, 1608, 1575
(w), 1500, 1461 (m), 1450, 1435 (s), 1409, 1390, 1325, 1298,
1257, 1203, 1191, 1186, 1133, 1112 (m), 1071 (s), 1050, 1017
(m), 986 (s), 902 (m), 858 (s), 833 (m), 813, 794 (s), 735, 710,
683 (m), 655 (s), 640, 593, 580, 551, 532 (m) cmÀ1. GC-MS (EI,
70eV): m/z (%)= 368 ([M, 81Br, 81Br ]+, 49), 366 ([M, 81Br,
79Br]+, 100), 364 ([M, 79Br, 79Br]+, 52), 259 (13), 257 (14), 177
(10), 176 (12). HRMS (EI, 70eV): calcd for C15H10OBr [M, 79Br,
79Br]+: 363.90929; found: 363.90898.
Acknowledgments. Financial support by the State of Pakistan
(HEC scholarships for M.H., N.A., and I.M.), by the DAAD
(scholarships for I.M. and N.T.H.), by the State of Vietnam
(MOET scholarship for N.T.H.), and by the State of
Mecklenburg-Vorpommern (scholarships for M.H., R.A.K., and
I.M.) is gratefully acknowledged. The work was supported
by the European Union (EFRE program) and by the
TÁMOP-4.2.1/B-09/KONV-2010-007 project. The project is
implemented through the New Hungary Development Plan,
co-financed by the European Social Fund and the European
Regional Development Fund.
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[19] CCDC- 956111-956113 contain all crystallographic details of
this publication and is available free of charge at http://www.ccdc.cam.
ac.uk/conts/retrieving.html
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet