Microwave-promoted heck and suzuki coupling reactions of new 3-(5-bromobenzofuranyl)pyrazole in aqueous media

Article abstract of DOI:10.24820/ark.5550190.p010.609

Suzuki-Miyaura and Mizoroki-Heck cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole with various arylboronic acids and terminal olefins, respectively, were investigated using a benzothiazole-oxime palladium(II) complex, under both thermal and microwave-irradiation conditions, in an open vessel, using aqueous solvent. The benzothiazole-oxime-based Pd(II) complex was found to be an efficient, and highly active pre-catalyst for the cross-coupling reactions, and for the preparation of new C-C cross-coupled compounds of potential biological interest which are difficult to obtain using other synthetic routes.

Full text of DOI:10.24820/ark.5550190.p010.609

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Arkivoc 2018, part v, 0-0
Microwave-promoted Heck and Suzuki coupling reactions of new 3-(5-
bromobenzofuranyl)pyrazole in aqueous media
Kamal M. Dawood,* Ahmed F. Darweesh, Mohamed R. Shaaban, and Ahmad M. Farag
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
E-mail: dr_dawood@yahoo.com
Received 05-01-2018
Accepted 07-09-2018
Published on line 08-04-2018
Abstract
Suzuki-Miyaura and Mizoroki-Heck cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole with
various arylboronic acids and terminal olefins, respectively, were investigated using a benzothiazole-oxime
palladium(II) complex, under both thermal and microwave-irradiation conditions, in an open vessel, using
aqueous solvent. The benzothiazole-oxime-based Pd(II) complex was found to be an efficient, and highly active
pre-catalyst for the cross-coupling reactions, and for the preparation of new C-C cross-coupled compounds of
potential biological interest which are difficult to obtain using other synthetic routes.
Ar
Br
O
NH
O
N
O
Me
and
EWG
NH
O
N
Keywords: Benzofurans, pyrazoles, palladium catalysis, microwave, C-C cross couplings.
DOI: https://doi.org/10.24820/ark.5550190.p010.609
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Introduction
The palladium-catalyzed Suzuki–Miyaura cross-coupling reaction represents one of the most widely used
processes for arylation of aromatic and heteroaromatic compounds.1–6 In addition, palladium-catalyzed Heck
reactions of aryl halides with alkenes are one of the most powerful tools in organic synthesis for the construction
of carbon–carbon bonds.7–10 Interestingly, growing research work is focused on the use of microwave-irradiation
methodology as a heating source because it markedly assists in achieving rapid incorporation of organic
synthesis into diverse industrial applications.11–14 Furthermore, organic reactions that proceed well in aqueous
media have several advantages over those that take place in organic solvents.15–17
The benzofuran moiety constitutes the core of several pharmaceutically-active natural products, such as
Cicerfuran, Conocarpan, Ailanthoidol, Amiodarone and Bufuralol.18–22 The synthetic benzofuran derivatives are
23–26
reported to be effective drugs which have huge medicinal applications.
Pyrazolylbenzofuran derivatives,
for example, have proven to have potent cytotoxic,27 antimicrobial,28–30 antioxidant31 and insecticidal32
activities.
In continuation of our research work on the use of palladium(II) complexes under microwave irradiation for
Suzuki–Miyaura, Heck–Mizoroki, and Sonogashira cross-coupling reactions,33–44 we report, herein, the use of
the benzothiazole-oxime palladium(II) complex (4) as a pre-catalyst for the Suzuki–Miyaura and Heck–Mizoroki
cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) under thermal heating and microwave
irradiation in aqueous media.
Results and Discussion
1-(5-Bromobenzofuran-2-yl)ethanone (1) was first prepared following a procedure reported in the literature.45
Treatment of 1 with dimethylformamide-dimethylacetal (DMF-DMA) in dry xylene at reflux temperature
afforded (E)-1-(5-bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-1-one (2).46 The enaminone derivative 2
was then reacted with hydrazine hydrate in refluxing ethanol to give 3-(5-bromobenzofuran-2-yl)-1H-pyrazole
(3) as shown in Scheme 1.46 The structures of the new 5-bromobenzofuran derivatives (2) and (3) were
confirmed from their elemental analyses and spectroscopic data (IR, MS, 1H and 13C NMR). The E-configuration
of structure 2 was established based on the coupling constant J of 12.6 Hz.
Scheme 1. Synthesis of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3).
Suzuki cross-coupling of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with arylboronic acids (5a-f) under
thermal heating and microwave irradiation
The catalytic activity of the Pd(II)-complex (4) (0.25 mol%) in the Suzuki-Miyaura cross-coupling reaction of a
novel candidate, 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3), with arylboronic acids (5a-f) has been examined
(Scheme 2).
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Scheme 2. Suzuki cross-coupling of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with arylboronic acids (5a-f)
under thermal and µw conditions.
First, the catalytic condition [water/tetrabutylammonium bromide (TBAB)/KOH] was applied for the
coupling of the 5-bromobenzofuran derivative (3) with phenylboronic acid (5a). No reaction was observed,
however, after 15 min of microwave irradiation (µw) or 6 h of thermal heating (entry 1, Table 1). Repeating the
same reaction in DMF instead of water using Et3N and TBAB under µw irradiation for 20 min gave 3-(5-
phenylbenzofuran-2-yl)-1H-pyrazole (6) in 70% isolated yield (entry 2, Table 1). Next, the solvent mixture of
water-DMF (1:1, v/v) was applied using KOH and TBAB under thermal heating for 6 h as well as under µw
irradiation for 20 min. Under these conditions, full conversions were observed (based on TLC) with 90% and 88%
isolated yields, respectively, to 3-(5-phenylbenzofuran-2-yl)-1H-pyrazole (6) (entry 3, Table 1).
The above reaction conditions were applied for further Suzuki-Miyaura cross-coupling reactions of the
bromide (3) with aryl and heteroarylboronic acids (5b-f). The reaction-components molar ratios, in all cases,
were: 1 mmol of bromide, 1.2 mmol of the arylboronic acids, 0.6 mmol TBAB, 2 mmoles of KOH and 0.25 mol%
of the complex (4) in a water-DMF mixture (1:1, v/v) (3 mL). The arylboronic acids were coupled, accordingly,
with the bromide (3) under thermal heating as well as microwave irradiation to give the corresponding arylated
benzofuran products (7-11) in very good isolated yields (Table 1). The only exception was the coupling of
bromide (3) with 2-thienylboronic acid (5f), in which the reaction did not proceed at all when water-
DMF/TBAB/KOH was used (entry 8, Table 1). Therefore, KOH was replaced with cesium carbonate, a more
reactive base. Using Cs2CO3 and 0.5 mol% of Pd-pre-catalyst (4), reasonable yields were obtained after 30 min
of µw irradiation (53%), and after 14 h of thermal heating (42%), respectively (entry 9, Table 1).
Although, the microwave irradiation reaction times were generally ~ 20-25 min, the corresponding coupled
products (6-10) were isolated mostly in high yields (~ 73-88%) as shown in Table 1. A rationale for the long
reaction time required to accomplish C-C cross-coupling of bromide (3) might be due to the presence of two π-
electron-excessive heterocycles (pyrazole and furan) in 3. Therefore, even though the 3-(5-bromobenzofuran-
2-yl)-1H-pyrazole (3) is considered to be a deactivated bromide, the full conversion of 3 in water-DMF using 0.25
mol% of the pre-catalyst (4) reflects the high catalytic activity of this catalyst. The structures of the cross-coupled
products were confirmed by spectral data (1H and 13C NMR, MS and IR) and elemental analyses, as reported in
the experimental section.
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Table 1. Results of Suzuki cross-coupling of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with arylboronic acids
(5a-f) under thermal and µw conditions
Thermal heatinga,b
µw heatinga,b
Entry
Product
Solvent
Time (h)
Yield%
Time (min) Yield%
1
2
3
H2O/ KOH
DMF/ TEA
H2O-DMF/ KOH
6
-
6
0
-
90
15
20
20
0
70
88
6
7
8
9
4
H2O-DMF/ KOH
8
80
25
84
5
6
H2O-DMF/ KOH
H2O-DMF/ KOH
8
6
72
95
25
20
80
87
7
H2O-DMF/ KOH
8
70c
25
73c
10
8
9
H2O-DMF/ KOH
H2O-DMF/Cs2CO3
6
14
0
42c
20
30
0
53c
11
aConditions. Bromide: 1 mmol; arylboronic acid: 1.2 mmol; TBAB: 0.6 mmol; base: 2 mmol; water or DMF: 3 mL,
water-DMF: 3 mL (1:1, v/v), Pd-complex: 0.25 mol%, microwave heating (250 Watt) at 160 ºC and at reflux for
b
c
thermal heating. The values of yield% refer to the isolated yields. The starting substrate (3) was detected by
TLC.
Heck cross-coupling of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with olefins (12a-d)
The potential of the Pd-complex (4) towards Heck cross-coupling of the olefins (12a-d) with 3-(5-
bromobenzofuran-2-yl)-1H-pyrazole (3) under both microwave and thermal heating was studied (Scheme 3).
Scheme 3. Heck cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with olefins 12a-d
under thermal and µw conditions.
In all cases, full conversions into the corresponding disubstituted olefins (13-16) were confirmed by high
isolated yields (Table 2). Styrene (12a) was easily coupled with the 5-bromobenzofuran (3) in the presence of
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0.25 mol% of the Pd-complex (4) using DMF/Et3N/TBAB as the catalytic system, to afford the 5-styrylbenzofuran
derivative (13) in excellent yield (entry 1, Table 2) after 8 hours of thermal heating or 20 min of microwave
irradiation. In a similar trend, 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) cross-coupled with acrylonitrile, ethyl
acrylate, and n-butyl acrylate, respectively, under similar catalytic conditions, resulting in full conversions into
the corresponding pyrazolyl benzofuranyl acrylates (14-16) under both thermal and microwave heating
conditions.
Table 2. Results of Heck cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with olefins
(12a-d) under thermal and µw conditions
Olefins
Thermal heatinga,b µw heatinga,b
Entry
Product
No.
R
Yield%
Yield%
1
2
12a
12b
Ph
CN
13
14
84
87
79
82
3
4
12c
CO2Et
15
16
94
91
90
85
12d CO2Bun
aConditions. Bromide: 1 mmol; olefin: 1.5 mmol; TBAB: 0.6 mmol; Et3N: 3 mmol; DMF: 3 mL, Pd-complex: 0.25
mol%, microwave heating (250 Watt) at 160 ºC for 20 min, and thermal heating at 130 ºC for 8 h. bThe values of
yield% refer to the isolated yields.
In all cases, the cross-coupling reaction was highly regio- and stereoselective, yielding only the E-isomer of
1
the disubstituted olefins 13-16, as substantiated by the GC, GC-MS and H NMR-spectra of the crude reaction
mixtures. The structures of the new products were confirmed from their elemental and spectral analyses. The
trans-configuration of the products was estimated from spectral data, in which the butyl acrylate derivative (16)
showed, for example, two characteristic doublets at δ 6.62 and 7.76 ppm with coupling constant J value 15.9
Hz, respectively, in its 1H NMR spectrum.
Conclusions
In conclusion, the benzothiazole-oxime-based Palladium(II) complex (4) was found to be an efficient and highly
active pre-catalyst for Suzuki-Miyaura and Heck-Mizoroki cross-coupling reactions of deactivated 3-(5-
bromobenzofuran-2-yl)-1H-pyrazole (3) in aqueous medium, under thermal heating and microwave-irradiation
conditions, for the preparation of new C-C cross-coupled products which are of potential biological and
therapeutic interest and are difficult to obtain by other synthetic routes.
Experimental Section
General. Melting points were determined in open glass capillaries with a Gallenkamp apparatus. The infrared
spectra were recorded in potassium bromide disks on a Pye Unicam SP 3-300 and Shimaduz FTIR 8101 PC
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infrared spectrophotometer. NMR spectra were recorded using a Varian Mercury VXR-300 NMR spectrometer
at 300 MHz (1H NMR) and at 75 MHz (13C NMR) using DMSO-d6 as solvent. Capillary GC analyses were performed
with a Shimadzu GC-14A or GC-14B, a Shimadzu C-R6A Integrator, and a HP 5 column (25 m length, 0.25 mm
i.d., 0.25 μm film) or recorded with an Agilent GC 6890N. Mass spectra (EI) were obtained at 70 eV using a type
Shimadzu GCMQP 1000 EX Spectrometer. Analytical thin-layer chromatography (TLC) was performed using pre-
coated silica gel 60778 plates (Fluka), and the spots were visualized with UV light at 254 nm. Fluka silica gel
60741 (70-230 mesh) was used for flash column chromatography. Microwave experiments were carried out
using a CEM Discover LabmateTM Microwave (300 W with ChemDriverTM Software). The palladium complex (4)
was prepared following our procedure previously reported in the literature.38
Synthesis of (E)-1-(5-bromobenzofuran-2-yl)-3-(dimethylamino)-prop-2-en-1-one (2). A mixture of 1-(5-
bromobenzofuran-2-yl)ethanone (1) (4.78 g, 20 mmol) and dimethyl formamide-dimethylacetal (DMF-DMA)
(2.66 ml, 20 mmol ) was taken up in dried xylene (20 ml). The mixture was refluxed for 8 h, then left to cool to
room temperature. The reddish-brown precipitated product was filtered off, washed with petroleum ether
o
(60/80 C), and dried. Recrystallization of the precipitate from benzene afforded 5.17 g of (E)-1-(5-
o
bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-1-one (2) (88% yield ), mp 148-150 C; IR (KBr)  3434,
3100, 2915, 1638, 1566, 1539, 1353, 1109 cm-1; 1H NMR (300 MHz, DMSO-d6) δH 2.94 (s, 3H, CH3), 3.18 (s, 3H,
CH3), 5.81 (d, 1H, J 12.6 Hz, CH olefinic), 7.48 (s, 1H, CH aromatic), 7.54 (d, 1H, J 8.7 Hz, CH aromatic), 7.64 (d,
1H, J 8.7 Hz, CH aromatic), 7.81 (d, 1H, J 12.6 Hz, CH olefinic), 7.93 (s, 1H, CH aromatic); 13C NMR (75 MHz,
DMSO-d6) δ 37.2, 44.6, 90.9, 107.8, 113.8, 115.5, 124.7, 128.9, 129.7, 153.0, 154.1, 156.5, 175.4; MS m/z (%)
294 (24.2, M+), 276 (18.7), 167 (25.3), 98 (58.2), 88 (40.7), 70 (57.1), 55 (100). Anal. Calcd for C13H12BrNO2: C,
53.08; H, 4.11; N, 4.76. Found: C, 53.10; H, 4.07; N, 4.69%.
Synthesis of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3). Hydrazine hydrate (2 ml) was added to a stirred
solution of the 3-(dimethylamino)prop-2-en-1-one (2) (2.94, 10 mmol) in acetic acid (30 ml). Stirring was
continued overnight at room temperature and the solid product obtained was filtered off, washed with ethanol,
dried and recrystallized from DMF to afford 2.23 g (85% yield) of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3)
o
1
as yellow crystals; mp. 204-206 C; IR (KBr)  3511, 3126, 2913, 1536, 1412, 1044 cm-1; H NMR (300 MHz,
DMSO-d6) δ 6.76 (d, 1H, J = 2.1 Hz, CH aromatic), 7.14 (s, 1H, CH aromatic), 7.41 (d, 1H, J 8.7 Hz, CH aromatic),
7.59 (d, 1H, J 8.7 Hz, CH aromatic), 7.84 (s, 1H, CH aromatic), 7.88 (s, 1H, CH aromatic), 13.25 (s, 1H, NH); 13C
NMR (75 MHz, DMSO-d6) δ 100.8, 103.2, 112.9, 115.3, 120.7, 123.3, 126.6, 130.0, 130.8, 131.8, 152.6; MS m/z
(%) 263 (100, M+), 184 (24.7), 156 (31.2), 128 (37.7), 101 (58.4), 75 (76.6), 62 (87). Anal. Calcd for C11H7BrN2O:
C, 50.22; H, 2.68; N, 10.65. Found: C, 50.26; H, 2.61; N, 10.62%.
Suzuki cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with arylboronic acids in
water-DMF under thermal heating. General procedure. A mixture of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole
(3) (263 mg, 1 mmol), and the appropriate arylboronic acids (5a-f) (1.2 mmol), tetrabutylammonium bromide
(TBAB) (194 mg, 0.6 mmol), palladium complex (4) (1.14 mg, 0.25 mol %), KOH (112 mg, 2 mmol), and water-
DMF (1:1) (3 mL) was stirred at 100 °C in an open reation vessel for ~ 4-10 hr (monitored by TLC) as listed in
Table 1. The products were extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over
anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was then
subjected to separation with flash column chromatography, using petroleum-distilled n-hexane/EtOAc (5:1) as
an eluent, to give the corresponding pure products 6-11.
Suzuki cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with arylboronic acids in
water-DMF using microwave irradiation. General procedure. A mixture of the above components and solvent
were mixed thoroughly in a process glass vial. The vial was capped properly, and the mixture was heated under
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microwave-irradiating conditions at 160 °C and 250 Watts for the appropriate reaction times as shown in Table
1. After the reaction was almost complete (by TLC), the products were extracted with EtOAc (3 x 20 mL). The
combined organic extracts were dried over anhydrous MgSO4, filtered off, and the solvent was evaporated under
reduced pressure. The residue was then subjected to separation with flash column chromatography, as
described above, to give the corresponding pure cross-coupled products 6-11.
3-(5-Phenylbenzofuran-2-yl)-1H-pyrazole (6). White crystals; mp 84-86 ºC; Rf 0.47 (hexane:ethyl acetate, 5:1);
IR (KBr)  3375, 3139, 3036, 2922, 1600, 1442, 1256, 1072 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 6.76 (d, 1H, J
5.7 Hz, CH aromatic), 7.15 (s, 1H, CH aromatic), 7.26-7.47 (m, 3H, CH aromatic), 7.60 (d, 2H, J 7.8 Hz, CH
aromatic), 7.69 (d, 1H, J 8.4 Hz, CH aromatic), 7.78 (d, 1H, J 8.1 Hz, CH aromatic), 7.88 (d, 1H, J 5.4 Hz, CH
aromatic), 7.98 (s, 1H, CH aromatic), 13.81 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 101.1, 102.9, 110.9, 111.2,
120.8, 123.0, 123.3, 124.0, 126.8, 127.2, 128.5, 128.8, 129.9, 133.9, 153.8; MS m/z (%) 260 (5.9, M+), 184 (100),
155 (33.1), 128 (40.7), 102 (55.9), 63 (74.6), 50 (83.1). Anal. Calcd for C17H12N2O: C, 78.44; H, 4.65; N, 10.76.
Found: C, 78.55; H, 4.58; N, 10.69%.
3-(5-(p-Tolyl)benzofuran-2-yl)-1H-pyrazole (7). White crystals; mp 108-110 ºC; Rf 0.44 (hexane:ethyl acetate,
5:1); IR (KBr)  3356, 3139, 2921, 2846, 1614, 1442, 1348 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H, CH3),
6.75 (d, 1H, J 6.9 Hz, CH aromatic), 7.13 (d, 2H, J 7.5 Hz, CH aromatic), 7.26 (d, 2H, J 7.5 Hz, CH aromatic), 7.58
(d, 1H, J 8.1 Hz, CH aromatic), 7.61 (s, 1H, CH aromatic), 7.69 (d, 1H, J 7.8 Hz, CH aromatic), 7.87 (d, 1H, J 6.9 Hz,
CH aromatic), 7.88 (s, 1H, CH aromatic), 13.19 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 21.0, 101.1, 102.9,
110.9, 111.1, 112.9, 120.8, 123.0, 124.0, 126.6, 127.9, 129.4, 129.8, 134.1, 139.2, 153.8; MS m/z (%) 274 (100,
M+), 245 (10.6), 184 (16.8), 155 (23.5), 88 (15.1), 63 (23.5), 51 (18.4). Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14;
N, 10.21. Found: C, 78.72; H, 5.22; N, 10.17%.
3-(5-(4-Methoxyphenyl)benzofuran-2-yl)-1H-pyrazole (8). Yellow crystals; mp 104-106 ºC; Rf
0.36
(hexane:ethyl acetate 5:1); IR (KBr) 3353, 3139, 2929, 2836, 1602, 1442, 1245, 1168 cm-1; 1H NMR (300 MHz,
DMSO-d6) δ 3.75 (s, 3H, OCH3), 6.75 (d, 1H, J 6.3 Hz, CH aromatic), 6.88 (d, 2H, J 8.7 Hz, CH aromatic), 7.02 (d,
2H, J 9 Hz, CH aromatic), 7.59 (s, 1H, CH aromatic),7.61 (d, 1H, J 8.4 Hz, CH aromatic), 7.74 (d, 1H, J 8.4 Hz, CH
aromatic), 7.81 (s, 1H, CH aromatic), 7.86 (d, 1H, J 6.3 Hz, CH aromatic), 13.19 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ 55.1, 101.2, 102.9, 110.9, 111.1, 112.9, 114.2, 120.7, 120.9, 123.0, 124.1, 127.9, 128.5, 129.8, 135.7,
153.8; MS m/z (%) 290 (100, M+), 275 (41.5), 247 (16.5), 189 (16.0), 145 (22.9), 87 (15.4), 55 (18.6). Anal. Calcd
for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.33; H, 4.81; N, 9.58%.
3-(5-(4-Chlorophenyl)benzofuran-2-yl)-1H-pyrazole (9). White powder; mp 78-80 ºC; Rf 0.4 (hexane:ethyl
acetate, 5:1); IR (KBr)  3379, 3141, 2925, 2844, 1590, 1442, 1257 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 6.75 (d,
1H, J 8.7 Hz, CH aromatic), 7.39 (d, 2H, J 8.1 Hz, CH aromatic), 7.51 (d, 1H, J 8.4 Hz, CH aromatic), 7.58 (s, 1H, CH
aromatic), 7.72 (d, 1H, J 8.7 Hz, CH aromatic), 7.79 (d, 2H, J 8.1 Hz, CH aromatic), 7.86 (d, 1H, J 8.7 Hz, CH
aromatic), 8.13 (s, 1H, CH aromatic), 13.22 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 102.9, 110.9, 111.3, 112.9,
120.7, 120.9, 123.0, 123.3, 127.3, 128.6, 128.7, 129.9, 135.8, 136.1, 153.8; MS m/z (%) 296 (33.3, M++2), 295
(37.4, M++1), 294 (100, M+), 202 (29.3), 150 (12.2), 133 (24.4), 56 (15.4). Anal. Calcd for C17H11ClN2O: C, 69.28;
H, 3.76; N, 9.50. Found: C, 69.31; H, 3.77; N, 9.45%.
3-(5-(3,4-Methylenedioxophenyl)benzofuran-2-yl)-1H-pyrazole (10). Buff powder; mp 114-116 ºC; Rf 0.39
(hexane:ethyl acetate, 5:1); IR (KBr)  3427, 3139, 2921, 2845, 2361, 1437 cm-1; 1H NMR (300 MHz, DMSO-d6) 
6.06 (s, 2H, OCH2), 6.75 (d, 1H, J 6.6 Hz, CH aromatic), 6.88 (d, 1H, J 7.8 Hz, CH aromatic), 6.99 (d, 1H, J 7.8 Hz,
CH aromatic), 7.16 (s, 1H, CH aromatic), 7.27 (s, 1H, CH aromatic), 7.60 (d, 1H, J 9 Hz, CH aromatic), 7.64 (d, 1H,
J 8.7 Hz, CH aromatic), 7.84 (d, 1H, J 6.6 Hz, CH aromatic), 7.85 (s, 1H, CH aromatic), 13.29 (s, 1H, NH); 13C NMR
(75 MHz, DMSO-d6) δ 101.1, 101.4, 102.9, 103.2, 107.3, 108.5, 110.9, 112.9, 115.4, 120.9, 123.0, 123.3, 124.1,
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126.6, 128.4, 130.8, 152.6, 153.8; MS m/z (%) 304 (100, M+), 264 (27.2), 184 (32.9), 128 (34.7), 92 (26.0), 51
(42.8). Anal. Calcd for C18H12N2O3: C, 71.05; H, 3.97; N, 9.21. Found: C, 70.92; H, 3.88; N, 9.15%.
3-(5-(Thien-3-yl)benzofuran-2-yl)-1H-pyrazole (11). Yellowish-white powder; mp 180-182 ºC; Rf 0.41
(hexane:ethyl acetate, 5:1); IR (KBr)  3439, 3135, 2916, 2361, 1436, 1044 cm-1; 1H NMR (300 MHz, DMSO-d6)
δ 6.76 (d, 1H, J 6.3 Hz, CH aromatic), 7.15 (s, 1H, CH aromatic), 7.22-7.44 (m, 2H, CH aromatic), 7.54 (s, 1H, CH
aromatic), 7.59 (d, 1H, J 8.7 Hz, CH aromatic), 7.62 (d, 1H, J 9 Hz, CH aromatic), 7.86 (d, 1H, J 6.3 Hz, CH aromatic),
7.88 (s, 1H, CH aromatic), 13.25 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 100.7, 103.2, 110.9, 111.2, 112.9,
115.4, 120.2, 120.9, 123.3, 126.4, 126.6, 126.8, 129.9, 130.8, 152.6; MS m/z (%) 266 (16.2, M+), 184 (17.6), 155
(25.7), 127 (46.3), 98 (27.9), 74 (66.9), 63 (88.2), 50 (100). Anal. Calcd for C15H10N2OS: C, 67.65; H, 3.78; N, 10.52;
S, 12.04. Found: C, 67.59; H, 3.82; N, 10.46; S, 11.97%.
Mizoroki-Heck cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with olefins in DMF
under thermal heating. A mixture of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) (263 mg, 1 mmol) and the
appropriate olefin 12a-d (1.5 mmol), TBAB (0.6 mmol), complex (4) (0.25 mol%), and TEA (303 mg, 3 mmol) in
DMF (3 mL) was stirred at 130 °C in an open reaction vessel for 8h. After the reaction was almost complete (by
TLC), the reaction mixture was left to cool to room temperature. The reaction mixture was then extracted three
times with EtOAc (3 x 20 mL), and the organic fractions were combined, dried over MgSO4, filtered, and the
solvent was removed under vacuum. The residue was then subjected to purification via flash column
chromatography with petroleum n-hexane/EtOAc (6:1) as eluent to give the corresponding pure products 13-
16.
Mizoroki-Heck cross-coupling reactions of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) with olefins in DMF
under microwave heating. A mixture of 3-(5-bromobenzofuran-2-yl)-1H-pyrazole (3) (263 mg, 1 mmol) and the
appropriate olefin 12a-d (1.5 mmol), TBAB (0.6 mmol), complex (4) (0.25 mol%), and TEA (303 mg, 3 mmol) in
DMF (3 mL) was mixed in a process glass vial. The vial was capped properly, and the mixture was heated under
microwave-irradiating conditions at 160 °C and 250 Watt for 20 min. After the reaction was almost complete
(by TLC), the reaction mixture was left to cool to room temperature. The reaction mixture was then extracted
three times with EtOAc (3 x 20 mL), the organic fractions were combined, dried over MgSO4, filtered and the
solvent removed under vacuum. The residue was then subjected to purification via flash column
chromatography with petroleum n-hexane/EtOAc (6:1) as eluent to give the corresponding pure products 13-
16.
(E)-3-(5-β-Styrylbenzofuran-2-yl)-1H-pyrazole (13). Pale yellow powder; mp 196-198 ºC; Rf 0.20 (hexane:ethyl
acetate, 6:1); IR (KBr)  3376, 3140, 3021, 2917, 1448, 1254 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 6.76 (d, 1H, J
2.1 Hz, CH aromatic), 7.18 (s, 1H, CH aromatic), 7.24 (d, 1H, J 16.2 Hz, CH, olefinic), 7.28-7.38 (m, 3H, CH
aromatic), 7.38 (d, 1H, J 15.9 Hz, CH, olefinic), 7.56-7.62 (m, 4H, CH aromatic), 7.86 (s, 2H, CH aromatic), 13.24
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 101.4, 103.0, 111.1, 118.7, 120.8, 120.9, 123.1, 126.2, 127.3, 127.4,
127.8, 128.2, 128.6, 129.0, 132.5, 137.1, 153.6; MS m/z (%) 286 (100, M+), 257 (14.6), 227 (17.4), 189 (30.6), 163
(17.4), 129 (17.4), 95 (37.5), 63 (25.0). Anal. Calcd for C19H14N2O: C, 79.70; H, 4.93; N, 9.78. Found: C, 79.76; H,
4.85; N, 9.68%.
(E)-3-(2-(1H-Pyrazol-3-yl)benzofuran-5-yl)acrylonitrile (14). Buff powder; mp 154-156 ºC; Rf 0.24 (hexane:ethyl
acetate, 6:1); IR (KBr)  3273, 3141, 3043, 2935, 2842, 2211, 1619, 1450, 1268 cm-1; 1H NMR (300 MHz, DMSO-
d6) δ 6.44 (d, 1H, J 16.5 Hz, CH, olefinic), 6.77 (s, 1H, CH aromatic), 7.20 (s, 1H, CH aromatic), 7.62 (d, 1H, J 9 Hz,
CH aromatic), 7.68 (d, 1H, J 8.4 Hz, CH aromatic), 7.75 (d, 1H, J 16.8 Hz, CH olefinic), 7.89 (s, 1H, CH aromatic),
7.93 (s, 1H, CH aromatic), 13.24 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 95.2, 101.2, 103.1, 111.6, 118.9,
120.7, 120.8, 120.9, 121.6, 123.8, 129.2, 129.9, 150.8, 155.2; MS m/z (%) 235 (100, M+), 179 (19.1), 151 (19.1),
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128 (31.9), 76 (57.4), 62 (44.7), 50 (29.8). Anal. Calcd for C14H9N3O: C, 71.48; H, 3.86; N, 17.86. Found: C, 71.41;
H, 3.80; N, 17.83%.
(E)-Ethyl 3-(2-(1H-pyrazol-3-yl)benzofuran-5-yl)acrylate (15). White crystals; mp 180-182 ºC; Rf 0.14
(hexane:ethyl acetate 7:1); IR (KBr)  3238, 3115, 3062, 2986, 1682, 1367, 1294, 1237, 1038 cm-1; 1H NMR (300
MHz, DMSO-d6) δ 1.27 (t, 3H, CH3CH2-, J 7.2 Hz), 4.20 (q, 2H, CH3CH2-, J 7.2 Hz), 6.62 (d, 1H, J 16.2 Hz, CH
olefinic), 6.77 (s, 1H, CH aromatic), 7.17 (s, 1H, CH aromatic), 7.64 (d, 1H, J 8.4 Hz, CH aromatic), 7.69 (d, 1H, J 9
Hz, CH aromatic), 7.76 (d, 1H, J 15.9 Hz, CH, olefinic), 7.88 (s, 1H, CH aromatic), 8.00 (s, 1H, CH aromatic), 13.22
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 59.8, 101.2, 103.1, 111.5, 116.8, 121.4, 124.5, 129.1, 129.4,
129.9, 141.9, 144.7, 152.5, 154.9, 166.2; MS m/z (%) 282 (100, M+), 237 (61.2), 210 (26.0), 152 (15.3), 77 (18.0),
63 (27.3). Anal. Calcd for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 68.11; H, 4.95; N, 9.89%.
(E)-Butyl 3-(2-(1H-pyrazol-3-yl)benzofuran-5-yl)acrylate (16). White powder; mp 146-148 ºC; Rf 0.26
(hexane:ethyl acetate 6:1); IR (KBr)  3423, 3142, 3043, 2954, 2864, 1709, 1631, 1447, 1260, 1170 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 0.92 (t, 3H, J 7.5 Hz, CH3CH2CH2CH2), 1.35-1.43 (m, 2H, CH3CH2CH2CH2), 1.59-1.66 (m, 2H,
CH3CH2CH2CH2), 4.16 (t, 2H, J 6.6 Hz, CH3CH2CH2CH2), 6.62 (d, 1H, J 15.9 Hz, CH, olefinic), 6.77 (d, 1H, J = 2.1 Hz,
CH aromatic), 7.18 (s, 1H, CH aromatic), 7.64 (d, 1H, J 8.7 Hz, CH aromatic), 7.70 (d, 1H, J 9 Hz, CH aromatic),
7.76 (d, 1H, J 15.9 Hz, CH olefinic), 7.88 (s, 1H, CH aromatic), 8.00 (s, 1H, CH aromatic), 13.24 (s, 1H, NH); 13C
NMR (75 MHz, DMSO-d6) δ 13.5, 18.6, 30.2, 63.5, 101.2, 103.1, 111.4, 116.8, 121.5, 124.5, 129.2, 129.4, 130.0,
141.9, 144.7, 152.5, 154.9, 166.3; MS m/z (%) 310 (89.5, M+), 254 (100), 237 (75.3), 210 (26.0), 154 (14.2), 105
(25.3), 63 (31.8). Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.54; H, 5.77; N, 8.93%.
Supplementary Materials
Copies of 1H and 13C spectra for compounds 2, 3, 6-11, and 13-16 associated with this article can be found in the
online version of the text.
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