Impregnated Copper(II) Oxide on Magnetite as Catalyst for the Synthesis of Benzo[b]furans from 2-Hydroxyarylcarbonyl Derivatives and Alkynes

Article abstract of DOI:10.1002/ejoc.201600671

The coupling-allenylation-cyclization reaction sequence of o-hydroxybenzaldehydes with alkynes in the presence of 4-methylbenzenesulfonohydrazide was carried out in ethanol as a nontoxic biorenewable solvent and in the presence of impregnated copper(II) oxide on magnetite as a heterogeneous catalyst. The catalyst can be easily removed from the reaction medium by a simple magnetic decantation, and the reaction can be performed with a very low copper loading. The in situ reduction of the starting copper(II) oxide nanoparticles into copper(0) sheets made the recyclability of catalyst impossible. The versatility of the reaction was shown by employing different o-hydroxyacetophenones to give 2,3-disubstituted benzo[b]furans. The reaction can be carried out on a gram scale without any complications.

Full text of DOI:10.1002/ejoc.201600671

DOI: 10.1002/ejoc.201600671
Full Paper
Heterogeneous Catalysis
Impregnated Copper(II) Oxide on Magnetite as Catalyst for the
Synthesis of Benzo[b]furans from 2-Hydroxyarylcarbonyl
Derivatives and Alkynes
Juana M. Pérez[a] and Diego J. Ramón*[a]
Abstract: The coupling-allenylation-cyclization reaction se- tion can be performed with a very low copper loading. The in
quence of o-hydroxybenzaldehydes with alkynes in the pres- situ reduction of the starting copper(II) oxide nanoparticles into
ence of 4-methylbenzenesulfonohydrazide was carried out in copper(0) sheets made the recyclability of catalyst impossible.
ethanol as a nontoxic biorenewable solvent and in the presence The versatility of the reaction was shown by employing differ-
of impregnated copper(II) oxide on magnetite as a heterogene- ent o-hydroxyacetophenones to give 2,3-disubstituted benzo-
ous catalyst. The catalyst can be easily removed from the reac- [b]furans. The reaction can be carried out on a gram scale with-
tion medium by a simple magnetic decantation, and the reac- out any complications.
Introduction
and using terminal alkynes, acetonitrile as the solvent, and CuBr
(10 mol-%) as the homogeneous catalyst.[8] Herein, we report
the first example of the use of the heterogeneous catalyst CuO-
Fe3O4 for the coupling-allenylation-cyclization of o-hydroxy-
benzaldehydes with terminal alkynes to yield benzo[b]furan de-
Heterocycles are important structural motifs that are found in a
wide range of natural substrates, compounds of pharmaceutical
interest, and commodity chemicals. More specifically, the
benzo[b]furan[1] core is present in a large number of natural
products that have attracted a great deal of interest because
of their biological properties, such as anticancer, antimicrobial,
antiviral, and anti-inflammatory activities, as well as their poten-
tial applications as pharmacological agents.[2] These benzo[b]-
furan-containing compounds are important intermediates in
the syntheses of a variety of useful and new heterocyclic sys-
tems that are otherwise difficult to prepare.[3] The synthesis of
these heterocyclic compounds has attracted an enormous
amount of attention from organic chemists, and various syn-
thetic approaches have been developed.[4] The most common
route, however, is a cyclization reaction that proceeds through
a distinct mechanism that begins with phenols.[5] An alternative
involves the formation of a C–C bond by a Sonogashira-type
process using 2-iodophenol derivatives and a subsequent cycli-
zation to give the corresponding benzo[b]furan.[6] It has also
been demonstrated that the addition of ortho-hydroxy-substi-
tuted arylalkynes to N-tosylhydrazones[7] catalyzed by copper
salts (CuBr, 10 mol-%) in acetonitrile can directly give the corre-
sponding benzo[b]furans. An alternative route has been de-
signed, which avoids the high cost of ortho-functionalized aryl-
alkynes, by starting from the corresponding N-tosylhydrazone
[9]
rivatives.
Results and Discussion
The coupling of 2-hydroxybenzaldehyde (1a) with phenylacet-
ylene (2a) by using impregnated copper(II) oxide on magnetite
in the presence of 4-methylbenzenesulfonohydrazide was se-
lected as a model to optimize the reaction conditions (Table 1).
Initially, the reaction was examined in different solvents
(Table 1, Entries 1–8) and in the absence of one (Table 1, En-
try 9), but a good yield was only obtained when EtOH was
used. Some organic and inorganic bases were then examined
(Table 1, Entries 10–18), and trace amounts and moderate yields
of the product were obtained by using organic bases and some
inorganic hydroxide salts, respectively. The reaction failed in the
absence of base (Table 1, Entry 19). Furthermore, a decrease in
the temperature of the reaction mixture gave lower yields
(Table 1, Entries 20 and 21). Employing only 1 equiv. of base
afforded a decrease in the reaction yield (Table 1, Entry 22).
Moderate results were obtained by using 3 equiv. of the termi-
nal alkyne (Table 1, Entry 23) or different amounts of solvent
(Table 1, Entries 24 and 25).
Having established the optimal reaction conditions (Table 1,
Entry 8), we examined the effects of various catalysts that were
prepared by a simple impregnation protocol (Table 2).[10] When
the reaction was performed without a catalyst (Table 2, Entry 1)
or only with the support of the catalyst (Table 2, Entries 2 and
3), trace amounts of the product resulted. The use of different
supported metal catalysts (Table 2, Entries 4–16) gave trace
[a] Instituto de Síntesis Orgánica (ISO), and Departamento de Química
Orgánica, Facultad de Ciencias, Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
E-mail: djramon@ua.es
http://personal.ua.es/en/djramon/research-group-of-diego-j-ramon.html
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600671.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Optimization of the catalyst.[a]
Entry
Solvent
Base
T [°C]
Yield [%][b]
Entry
Catalyst [mol-%]
Yield [%][b]
1
2
3
4
5
6
7
8
THF[c]
toluene
CH3CN
1,4-dioxane
DMF[c]
H2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOAc
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
26
0
0
3
0
0
0
91
0
0
3
0
0
56
43
58
34
0
1
2
3
4
5
6
7
8
–
5
4
4
4
3
91
4
4
32
0
3
nano-Fe3O4 (162)
micro-Fe3O4 (162)
CoO-Fe3O4 (3.54)
NiO-Fe3O4 (2.58)
CuO-Fe3O4 (2.4)
Ru2O3-Fe3O4 (3.3)
Rh2O3-Fe3O4 (1.05)
PdO-Fe3O4 (3.04)
AgO2/Ag-Fe3O4 (3.13)
OsO2-Fe3O4 (1.28)
PtO/PtO2-Fe3O4 (1.34)
Au2O3/Au-Fe3O4 (0.35)
PdO/Cu-Fe3O4 (3.82/2.24)
NiO/Cu-Fe3O4 (2.28/2.20)
WO3-Fe3O4 (1.41)
CuO-Fe3O4 (1.2)
CuO-Fe3O4 (0.5)
CuO (2.4)
DMSO[c]
EtOH
–
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
23[e]
24[f]
25[g]
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
MeONa
Et3N
4
4
6
2
DABCO[c]
KOH
NaOH
CsOH·H2O
tBuOK
K2CO3
2
56
44
46
43
46
36
49
61
9
–
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
28
37
35
63
58
44
Cu(OAc)2 (2.4)
CuBr2 (2.4)
Cu2O (2.4)
CuCN (2.4)
CuBr (2.4)
Cu powder (2.4)
r.t.
100
100
100
100
[a] Reagents and conditions: 1a (0.4 mmol), 2a (0.5 mmol), base (1.2 mmol)
in the corresponding solvent (2 mL); Ts = para-tolylsulfonyl. [b] Yield was
calculated by GC analysis using tridecane as an internal standard. [c] THF =
tetrahydrofuran, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide,
DABCO = 1,4-diazabicyclo[2.2.2]octane. [d] Reaction was carried out by using
1a (0.4 mmol), 2a (0.5 mmol), and base (0.4 mmol) in the corresponding
solvent (2 mL). [e] Reaction was carried out by using 1a (0.4 mmol), 2a
(1.2 mmol), and base (1.2 mmol) in the corresponding solvent (2 mL). [f] Re-
action was carried out by using 1a (0.4 mmol), 2a (0.5 mmol), and base
(1.2 mmol) in the corresponding solvent (1 mL). [g] Reaction was carried out
by using 1a (0.4 mmol), 2a (0.5 mmol), and base (1.2 mmol) in the corre-
sponding solvent (6 mL).
[a] Reaction was carried out by using 1a (0.4 mmol) and 2a (0.5 mmol).
[b] Yield was calculated by GC analysis using tridecane as an internal stan-
dard.
spectroscopic analysis of the copper catalyst both before and
after the reaction occurred (Figure 1). These results show that
the catalyst was formed by a 4:1 mixture of CuII/Cu0 nanoparti-
cles prior to the reaction, whereas only Cu0 was detected in the
catalyst after the reaction.
Transmission electron microscopy (TEM) images were ana-
amounts of the product in some cases. The reaction took place lyzed before and after the completion of the reaction. Prior to
with moderate results when a palladium catalyst was used. Hav- the reaction, 73 % of the copper oxide nanoparticles had an
ing established that impregnated copper(II) oxide on magnetite average size between 2 and 6 nm. Upon completion of the
best catalyzed this reaction (Table 2, Entry 6), we then investi- reaction, the nanostructure particles were not observed but
gated different loadings (Table 2, Entries 17 and 18). A decrease transformed into a homogeneous sheet of copper(0) that cov-
in the metal loading, however, only afforded moderate results. ered the magnetite surface (Figure 2).
When a variety of copper(I) and copper(II) salts were used, mod-
erates yields were obtained (Table 2, Entries 19–25), which con-
firmed the higher activity of the supported catalyst.
The analysis of the reaction mixture by inductively coupled
plasma–mass spectrometry (ICP–MS) showed the presence of
copper (20.5 % of the initial amount) as well as a low amount
Once the optimal reaction conditions were obtained, we of iron (0.03 % of the initial amount). With these results in hand,
faced the challenge of recycling. When the catalyst was recov- we speculate that the heterogeneous CuO-Fe3O4 catalyst could
ered from the reaction mixture by using a magnet, washing serve as a reservoir of copper. When the copper is added to the
with ethanol, and reemploying under the same reaction condi- reaction mixture,[11] it catalyzes the reaction and then is re-
tions, only a trace amount (12 %) of the expected product 3a duced by ethanol to give the Cu0 sheet. In fact, using Cu0 pow-
was obtained (see Figure 3). Studies were carried out to explain der (Table 2, Entry 25) afforded the same result as that obtained
this phenomenon. First, we performed X-ray photoelectron by using the recycled catalyst.
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A hot filtration experiment was performed to confirm that
the nanoparticles of copper had leached into the homogene-
ous solution upon completion of the standard reaction. The
catalyst was removed, and the same reaction was attempted
with 1-ethynyl-4-methoxybenzene. After 6 h, the reaction was
quenched, and only a trace amount of the corresponding prod-
1
uct 3j was observed by H NMR analysis along with the recov-
ered starting alkyne.
Because of the inability of the catalyst to be reused, various
reoxidation strategies were investigated. One method to oxidize
the Cu0 sheet involves bubbling O2 through the solution over
four hours in THF as the solvent. However, only a yield of 22 %
was obtained when the reaction was repeated. Another method
involved the addition of tBuOOH in decane to the catalyst,
which was previously washed with ethanol to remove the crude
product of the reaction. The mixture was then heated at 70 °C
overnight. In this case, better results were obtained than those
of the aforementioned protocol, but this catalyst recycling strat-
egy did not sufficiently give good results (Figure 3).
Figure 1. (a) X-ray photoelectron spectroscopic (XPS) of copper catalyst before
reaction. (b) XPS of copper catalyst after reaction.
Figure 3. Catalyst recycling by different methods.
The hypothesized mechanism for the formation of the final
product is similar to that previously introduced[8] (Scheme 1).
2-Hydroxybenzaldehyde first undergoes a reaction with 4-
methylbenzenesulfonohydrazine to give the corresponding
hydrazone, which in turn is treated with base (Cs2CO3) to form
the 2-(diazomethyl)phenol derivative. At the same time, phen-
ylacetylene undergoes a reaction with the base and catalyst to
give
copper
phen-
ylacetylide. Although the hot filtration test indicates that the
reaction is heterogeneous, the large amount of leached copper
could indicate a possible homogeneous pathway. The two spe-
cies that were formed could then undergo a dediazotization
reaction to give a copper carbene intermediate that through a
migratory insertion forms a [1-(2-hydroxyphenyl)-3-phenylprop-
2-yn-1-yl]copper intermediate. The subsequent protonation of
this intermediate gives the corresponding allene, which finally
cyclizes to generate the corresponding benzo[b]furan.
To determine if the mechanism proceeded through the for-
mation of the N-tosylhydrazone, the reaction was performed
with previously prepared 4-methylbenzenesulfonohydrazine. In
this case, product 3a was obtained in the same yield as that
obtained under the standard reaction conditions. Moreover,
when only 30 mol-% of TsNHNH2 was used in the reaction, only
a 29 % conversion into product 3a was achieved. These results
Figure 2. (a) Particle size distribution of copper on the catalyst before the
reaction. (b) TEM image of copper catalyst before the reaction. (c) TEM image
of copper catalyst after the reaction.
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Table 3. Scope of the reaction.[a]
Entry
R1
R2
R3
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
91 (58)[c]
71
75
70
82
90
92
67
67
68
54
39
70
90
17
69
tBu
Br
H
H
H
H
H
H
H
H
H
H
H
H
tBu
tBu
OMe
H
H
H
H
H
H
H
H
H
H
H
H
tBu
2-BrC6H4
3-ClC6H4
4-BrC6H4
4-CF3C6H4
2-MeC6H4
3-MeC6H4
4-MeOC6H4
CH3(CH2)4
C6H11
9
10
11
12
13
14
15
16
Cl(CH2)3
CH2OC5H10
3-(CH≡ C)C6H4
4-BrC6H4
O
[a] Reaction was carried out by using 1a (0.4 mmol) and 2a (0.5 mmol).
[b] Isolated yield after column chromatography. [c] Reaction was carried out
by using 1a (8 mmol) and 2a (10 mmol).
The same reaction could be carried out with o-hydroxy-
benzophenones 4a and 4b. Good yields of the corresponding
substituted benzo[b]furans were obtained in both cases, which
demonstrates the versatility of the reaction (Scheme 2).
Scheme 1. Proposed mechanism for the synthesis of benzo[b]furans.
indicate that the formation of hydrazine is fundamental to the
reaction pathway.
Scheme 2. Reaction with o-hydroxyacetophenones.
The optimized reaction conditions were then applied to
other substrates (Table 3). Different substituted o-hydroxybenz-
aldehydes afforded good product yields (Table 3, Entries 2 and
3). Various arylalkynes that have electron-withdrawing substitu-
ents at different positions of the aromatic ring were then exam-
ined and found to give good results (Table 3, Entries 4–7).
Slightly lower yields were obtained when the reaction was per-
formed with arylalkynes that contain electron-donating groups
on the aromatic ring (Table 3, Entries 8–10). Some aliphatic alk-
ynes were then examined in the reaction (Table 3, Entries 11–
14) and found to give moderate to good yields. The reaction
proceeded selectively by using a diyne to give benzofuran 3o
in a low yield (Table 3, Entry 15). To complete the study of the
reaction scope, a combination of the substituted o-hydroxy-
benzaldehyde and a substituted alkyne were used to obtain
compound 3p in a good yield (Table 3, Entry 16). The scale of
the reaction could be increased 20-fold, and a good yield was
still obtained (Table 3, Entry 1, footnote c).
Conclusions
In summary, we have demonstrated that impregnated cop-
per(II) oxide on magnetite is an inexpensive and versatile cata-
lyst for the coupling-allenylation-cyclization reaction of o-
hydroxybenzaldehydes (or ketones) and alkynes in ethanol as a
nontoxic and biorenewable solvent and in the presence of 4-
methylbenzenesulfonohydrazide. The magnetic properties of
the catalyst allow for its easy separation from the reaction me-
dium. The high activity of the heterogeneous copper catalyst
enables a very low copper loading. This new approach is gen-
eral for the construction of benzofuran ring systems that are
substituted at the 2- and 3-positions.
Experimental Section
General Methods: XPS analyses were carried out on a VG-Micro-
tech Mutilab. TEM images were obtained on a JEOL model JEM-
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2010 that was equipped with an X-ray detector OXFORD INCA En-
ergy TEM 100 for microanalysis energy dispersive spectroscopy
(EDS). X-ray fluorescence (XRF) analyses were obtained on a PHILIPS
MAGIX PRO (PW2400) X-ray spectrometer that was equipped with
a rhodium X-ray tube and a beryllium window. Brunauer, Emmett,
and Teller (BET) isotherms were carried out on a AUTOSORB-6
(Quantachrome) by using N2. Melting points were obtained with a
Reichert Thermovar apparatus. The NMR spectroscopic data were
2-Benzylbenzofuran (3a):[8] Colorless oil; tR = 14.2 min. Rf = 0.6
(hexane/ethyl acetate, 4:1). 1H NMR (300 MHz, CDCl3): δ = 7.40–7.45
(m, 1 H, ArH), 7.35–7.40 (m, 1 H, ArH), 7.15–7.30 (m, 7 H, ArH), 6.33
(s, 1 H, CH), 4.06 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
157.8, 154.9, 137.2, 128.9 (2 C), 128.8, 128.6 (2 C), 126.7, 123.4, 122.5,
120.4, 110.9, 103.3, 35.0 ppm. IR [attenuated total reflectance (ATR)]:
ν = 3029, 1454, 1252, 952 cm–1. MS (EI): m/z (%) = 208 (88) [M]+,
˜
207 (100) [M – 1]+, 178 (22), 131 (36), 77 (8).
1
recorded with a Bruker AC-300 (300 MHz for H NMR and 75 MHz
2-Benzyl-5,7-di-tert-butylbenzofuran (3b): Colorless oil; tR
=
for 13C NMR). CDCl3 was used as the solvent, and TMS was em-
ployed as an internal standard for the 1H and 13C NMR spectra.
Chemical shifts are given in δ (parts per million), and the coupling
constants (J) are reported in Hertz. FTIR spectra were obtained on
a JASCO 4100LE (Pike Miracle ATR) spectrophotometer. Mass spectra
(EI) were obtained at 70 eV on a Himazdu QP-5000 spectrometer,
and the fragment ions were reported in m/z with the relative inten-
sities (%) in parentheses. The gas–liquid chromatographic analyses
(GLC) were determined with a Hewlett Packard HP-5890 instrument
that was equipped with a flame ionization detector and 12 m HP-
1 capillary column (0.2 mm diameter, 0.33 mm film thickness, OV-1
stationary phase). Nitrogen (2 mL min–1) was used as the carrier gas
[Tinjector = 275 °C, Tdetector = 300 °C, Tcolumn = 60 °C (3 min) and 60–
270 °C (15 °C min–1), P = 40 kPa]. Thin-layer chromatography was
carried out on Schleicher & Schuell F1400/LS 254 plates that were
coated with a 0.2 mm layer of silica gel, and the developed plates
were visualized by UV254 light and staining with phosphomolybdic
acid [phosphomolybdic acid (25 g), Ce(SO4)2·4H2O (10 g), concen-
trated H2SO4 (60 mL), and H2O (940 mL)]. Column chromatography
was performed with silica gel 60 (40–63 mesh). All reagents were
commercially available (Acros, Aldrich, and Fluorochem) and used
as received. The ICP–MS analyses were carried out on a Thermo
Elemental VGPQ-ExCell spectrometer. The elemental analysis was
performed on an elemental microanalyzer Thermo Finningan Flash
1112 Series.
17.0 min. Rf = 0.7 (hexane/ethyl acetate, 4:1). 1H NMR (300 MHz,
CDCl3): δ = 7.31 (d, J = 1.9 Hz, 1 H, ArH), 7.20–7.30 (m, 5 H, ArH),
7.17 (d, J = 1.9 Hz, 1 H, ArH), 6.31 (s, 1 H, CH), 4.10 (s, 2 H, CH2),
1.47 (s, 9 H, 3 CH3), 1.35 (s, 9 H, 3 CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.8, 151.3, 145.2, 137.7, 133.4, 128.8 (3 C), 128.4 (2 C),
126.5, 118.0, 114.5, 103.1, 35.1, 34.8, 34.4, 31.9 (3 C), 29.9 (3 C) ppm.
IR (ATR): ν = 2955, 2905, 1603, 1479, 1242, 1030 cm–1. MS (EI): m/z
˜
(%) = 321 (11) [M + 1]+, 320 (49) [M]+, 306 (31), 305 (100), 153 (9), 91
(17), 57 (12). HRMS: calcd. for C23H28O 320.21402; found 320.2137.
2-Benzyl-5-bromo-7-methoxybenzofuran (3c): Yellow solid; m.p.
52–54 °C (hexane); tR = 17.6 min. Rf = 0.7 (hexane/ethyl acetate,
4:1). 1H NMR (300 MHz, CDCl3): δ = 7.20–7.35 (m, 5 H, ArH), 7.18 (d,
J = 1.7 Hz, 1 H, ArH), 6.83 (d, J = 1.7 Hz, 1 H, ArH), 6.24 (t, J =
0.94 Hz, 1 H, CH), 4.09 (s, 2 H, CH2), 3.95 (s, 3 H, OMe) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.3, 145.2, 142.9, 136.7, 131.6, 128.9 (2
C), 128.6 (2 C), 126.8, 115.6 (2 C), 109.3, 103.2, 56.2, 34.8 ppm. IR
(ATR): ν = 1597, 1472, 1207 cm–1. MS (EI): m/z (%) = 319 (17) [M +
˜
3]+, 318 (96) [M + 2]+, 317 (57) [M + 1]+, 316 (100) [M]+, 315 (21),
281 (19), 241 (10), 237 (19), 222 (16), 209 (11), 208 (19), 207 (41),
206 (91), 194 (19), 181 (37), 166 (19), 165 (64), 89 (14), 82 (12), 78
(44). HRMS: calcd for C16H13BrO2 316.0099; found 316.0109.
2-(2-Bromobenzyl)benzofuran (3d): Pale yellow oil; tR = 16.0 min.
1
Rf = 0.6 (hexane/ethyl acetate, 4:1). H NMR (300 MHz, CDCl3): δ =
7.55–7.60 (m, 1 H, ArH), 7.45–7.50 (m, 1 H, ArH), 7.40–7.45 (m, 1 H,
ArH), 7.10–7.30 (m, 5 H, ArH), 6.38 (s, 1 H, CH), 4.24 (s, 2 H, CH2) ppm.
13C NMR (75 MHz, CDCl3): δ = 156.0, 154.9, 136.8, 132.9, 130.9, 128.7,
128.5, 127.6, 124.6, 123.5, 122.6, 120.5, 110.9, 104.0, 35.2 ppm. IR
General Procedure for the Preparation of the Catalysts: Com-
mercially available Fe3O4 (<5 μm, BET area: 9.86 m2 g–1; 4 g,
17 mmol) was added to a stirred solution of the appropriate metal
chloride MCln [1 mmol; or a mixture of M1Cln (1 mmol) and M2Cln′
(1 mmol) for a bimetallic species] in deionized H2O (120 mL). In the
cases of the Pd and Cu–Pd catalysts, a large excess amount of KCl
(1 g, 13 mmol) was also added to the initial solution to increase the
solubility of the PdCl2. After 10 min at r.t., the mixture was slowly
(ATR): ν = 1601, 1585, 1453, 1251, 1025 cm–1. MS (EI): m/z (%) = 289
˜
(15) [M + 3]+, 288 (98) [M + 2]+, 287 (54) [M + 1]+, 286 (100) [M]+,
285 (39) [M – 1]+, 208 (11), 207 (63), 206 (17), 105 (41), 178 (73),
177 (16), 176 (24), 152 (16), 151 (12), 131 (82), 89 (33), 88 (11), 77
(14), 76 (26), 63 (12). HRMS: calcd. for C15H11BrO 285.9993; found
285.9985.
basified by the addition of NaOH (1
M aqueous solution) to a pH ≈
13. The mixture was then stirred at r.t. for 1 d under air. The catalyst
was isolated by filtration, washed with deionized H2O (3 × 10 mL),
and dried for 24 h at 100 °C in a standard glassware oven.
2-(3-Chlorobenzyl)benzofuran (3e):[7] Pale yellow oil; tR
=
15.5 min. Rf = 0.6 (hexane/ethyl acetate, 4:1). 1H NMR (300 MHz,
CDCl3): δ = 7.45–7.50 (m, 1 H, ArH), 7.35–7.40 (m, 1 H, ArH), 7.29
(br. s, 1 H, ArH), 7.15–7.25 (m, 5 H, ArH), 6.40 (s, 1 H, CH), 4.06 (s, 2
H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.7, 155.0, 139.2,
134.4, 129.8, 129.0, 128.6, 127.0 (2 C), 123.6, 122.6, 120.5, 110.9,
General Procedure for the Preparation of the Product 3: To a
stirred solution of the corresponding aldehyde 1 (0.4 mmol) in EtOH
(2 mL) was added 4-methylbenzenesulfonohydrazide (74 mg,
0.4 mmol), and the reaction was stirred at 100 °C for 1 h. After that
time, Cs2CO3 (390 mg, 1.2 mmol), tridecane (73.7 mg, 0.4 mmol as
an internal standard), and CuO-Fe3O4 (50 mg, 2.4 mol-%) were
added to the reaction mixture followed by the addition of the corre-
sponding terminal alkyne 2 (0.5 mmol). The resulting mixture was
103.7, 34.6 ppm. IR (ATR): ν = 1596, 1585, 1574, 1453, 1252,
˜
1008 cm–1. MS (EI): m/z (%) = 244 (34) [M + 2]+, 243 (37) [M + 1]+,
242 (100) [M]+, 241 (69) [M – 1]+, 208 (10), 207 (77), 205 (13), 179
(22), 178 (44), 131 (67), 77 (13), 76 (14).
stirred at 100 °C for 5 h. The catalyst was removed by magnetic 2-(4-Bromobenzyl)benzofuran (3f):[12] White solid; m.p. 47–49 °C
decantation, and the solvent was evaporated under reduce pres- (hexane); tR = 16.2 min. Rf = 0.7 (hexane/ethyl acetate, 4:1). 1H NMR
sure. The resulting mixture was partitioned between deionized wa-
ter and AcOEt, and this solution was extracted with AcOEt (3 ×
5 mL). The combined organic phases were dried with MgSO4 and
concentrated under reduced pressure to remove the solvent. The
(300 MHz, CDCl3): δ = 7.40–7.50 (m, 4 H, ArH), 7.10–7.20 (m, 4 H,
ArH), 6.36 (dd, J = 1.1, 0.9 Hz, 1 H, CH), 4.03 (s, 2 H, CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 156.9, 154.9, 136.2, 131.7 (2 C), 130.6 (2
C), 128.6, 123.6, 122.6, 120.7, 120.5, 110.9, 103.6, 34.4 ppm. IR (ATR):
crude product was usually purified by column chromatography on ν = 1599, 1584, 1488, 1452, 1250, 1010 cm–1. MS (EI): m/z (%) = 289
˜
silica gel (hexane/ethyl acetate) to give the corresponding product
3.
(19) [M + 3]+, 288 (78) [M + 2]+, 287 (69) [M + 1]+, 286 (75) [M]+,
285 (66) [M – 1]+, 208 (19), 207 (100), 205 (24), 179 (25), 178 (56),
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177 (16), 176 (14), 152 (14), 151 (11), 131 (52), 103 (12), 102 (13), 89
(25), 77 (17), 76 (32), 63 (12).
7.45–7.50 (m, 1 H, ArH), 7.40–7.45 (m, 1 H, ArH), 7.15–7.25 (m, 2 H,
ArH), 6.40 (s, 1 H, CH), 3.58 (t, J = 6.2 Hz, 2 H, CH2), 2.81 (t, J =
7.1 Hz, 2 H, CH2), 1.85–1.95 (m, 4 H, 2 CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.6, 154.6, 128.8, 123.2, 122.5, 120.2, 110.7, 102.2, 44.6,
2-(4-Trifluoromethyl)benzylbenzofuran (3g):[8] Pale yellow oil;
tR = 14.0 min. Rf = 0.6 (hexane/ethyl acetate, 4:1). 1H NMR (300 MHz,
CDCl3): δ = 7.58 (d, J = 7.8 Hz, 2 H, ArH), 7.45–7.50 (m, 1 H, ArH),
7.40–7.45 (m, 3 H, ArH), 7.15–7.25 (m, 2 H, ArH), 6.41 (s, 1 H, CH),
4.16 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.4, 155.0,
141.3, 129.2 (2 C), 129.2 (q, J = 32.3 Hz), 128.1, 126.0 (q, J =
272.4 Hz), 125.5 (q, J = 3.8 Hz, 2 C), 123.7, 122.7, 120.5, 110.9, 103.8,
31.9, 27.7, 25.0 ppm. IR (ATR): ν = 2922, 2853, 1603, 1584, 1455,
˜
1252, 948 cm–1. MS (EI): m/z (%) = 208 (18) [M]+, 132 (15), 131 (100),
77 (10).
2-[2-(Tetrahydro-2H-pyran-2-yl)oxy]ethylbenzofuran (3n): Color-
1
less oil; tR = 15.0 min. Rf = 0.5 (hexane/ethyl acetate, 4:1). H NMR
34.8 ppm. IR (ATR): ν = 1454, 1322, 1252 cm–1. MS (EI): m/z (%) =
˜
(300 MHz, CDCl3): δ = 7.45–7.50 (m, 1 H, ArH), 7.35–7.40 (m, 1 H,
ArH), 7.15–7.25 (m, 2 H, ArH), 6.47 (d, J = 0.9 Hz, 1 H, CH), 4.60–4.65
(m, 1 H, CH), 4.09 (dt, J = 9.8, 6.8 Hz, 1 H, CH), 3.75–3.85 (m, 2 H,
CH2), 3.45–3.55 (m, 1 H, CH), 3.08 (td, J = 6.8, 0.8 Hz, 2 H, CH2CH2O),
1.45–1.85 (m, 6 H, 3 CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.4,
154.6, 128.9, 123.2, 122.4, 120.3, 110.7, 103.0, 98.8, 65.0, 62.2, 30.6,
277 (16) [M + 1]+, 276 (100) [M]+, 275 (84) [M – 1]+, 207 (59), 179
(11), 178 (26), 131 (57).
2-(2-Methylbenzyl)benzofuran (3h):[7] Pale yellow oil; tR
=
14.8 min. Rf = 0.6 (hexane/ethyl acetate, 4:1). 1H NMR (300 MHz,
CDCl3): δ = 7.42 (ddd, J = 8.2, 1.8, 0.7 Hz, 2 H, ArH), 7.10–7.25 (m, 6
H, ArH), 6.23 (d, J = 0.9 Hz, 1 H, CH), 4.09 (s, 2 H, CH2), 2.34 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.5, 154.9, 136.6, 135.4,
130.4, 129.8, 128.8, 127.1, 126.2, 123.3, 122.5, 120.3, 110.9, 103.2,
29.3, 25.4, 19.4 ppm. IR (ATR): ν = 2941, 2871, 1602, 1587, 1455,
˜
1252, 1030 cm–1. MS (EI): m/z (%) = 246 (1) [M]+, 162 (28), 145 (813),
144 (50), 132 (16), 131 (100), 85 (26), 77 (14), 55 (12). HRMS: calcd.
for C15H18O3 246.1256; found 246.1264.
32.7, 19.4 ppm. IR (ATR): ν = 1599, 1585, 1454, 1253, 1008 cm–1. MS
˜
(EI): m/z (%) = 223 (18) [M + 1]+ 222 (100) [M]+, 221 (31) [M – 1]+,
207 (37), 178 (23), 131 (27), 116 (11), 115 (10), 110 (10), 107 (48),
104 (22), 77 (11).
2-(3-Ethylbenzyl)benzofuran (3o): Pale yellow oil; tR = 15.4 min.
1
Rf = 0.7 (hexane/ethyl acetate, 4:1). H NMR (300 MHz, CDCl3): δ =
7.35–7.50 (m, 4 H, ArH), 7.25–7.30 (m, 2 H, ArH), 7.15–7.20 (m, 2 H,
ArH), 6.39 (d, J = 0.9 Hz, 1 H, CH), 4.08 (s, 2 H, CH2), 3.06 (s, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.0, 155.0, 144.9, 137.5,
132.5, 130.6, 129.5, 128.6, 123.6, 122.6, 120.5, 110.9, 103.6, 83.5, 77.3,
2-(3-Methylbenzyl)benzofuran (3i):[8] Colorless oil; tR = 14.7 min.
1
Rf = 0.7 (hexane/ethyl acetate, 4:1). H NMR (300 MHz, CDCl3): δ =
7.45–7.50 (m, 1 H, ArH), 7.40–7.45 (m, 1 H, ArH), 7.15–7.25 (m, 3 H,
ArH), 7.05–7.10 (m, 3 H, ArH), 6.37 (s, 1 H, CH), 4.06 (s, 2 H, CH2),
2.33 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.9, 154.9,
138.2, 137.1, 129.6, 128.8, 128.5, 127.5, 125.9, 123.3, 122.5, 120.4,
34.7 ppm. IR (ATR): ν = 3291, 1599, 1584, 1454, 1251, 1008 cm–1
.
˜
MS (EI): m/z (%) = 233 (18) [M + 1]+, 232 (100) [M]+, 231 (87) [M –
1]+, 203 (14), 202 (31), 131 (36), 101 (11). HRMS: calcd. for C17H12
232.0888; found 232.0886.
O
110.9, 103.3, 34.9, 21.4 ppm. IR (ATR): ν = 3065, 3026, 1601, 1586,
˜
1454, 1251, 954 cm–1. MS (EI): m/z (%) = 222 (100) [M]+, 221 (81) [M
2-(4-Bromobenzyl)-5,7-di-tert-butylbenzofuran (3p): White solid;
m.p. 104–106 °C (hexane); tR = 15.0 min. Rf = 0.8 (hexane/ethyl
acetate, 4:1). 1H NMR (300 MHz, CDCl3): δ = 7.40–7.45 (m, 2 H, ArH),
7.32 (d, J = 1.9 Hz, 1 H, ArH), 7.15–7.20 (m, 3 H, ArH), 6.32 (s, 1 H,
CH), 4.05 (s, 2 H, CH2), 1.46 (s, 9 H, 3 CH3), 1.35 (s, 9 H, 3 CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.9, 151.4, 145.4, 136.7, 133.5, 131.5
(2 C), 130.5 (2 C), 126.7, 120.4, 118.2, 114.6, 103.4, 34.8, 34.5, 34.4,
– 1]+, 207 (54), 179 (11), 178 (25), 131 (34).
2-(4-Methoxybenzyl)benzofuran (3j):[8] Colorless oil; tR
=
15.9 min. Rf = 0.5 (hexane/ethyl acetate, 4:1). 1H NMR (300 MHz,
CDCl3): δ = 7.45–7.50 (m, 1 H, ArH), 7.35–7.40 (m, 1 H, ArH), 7.15–
7.25 (m, 4 H, ArH), 6.85–6.90 (m, 2 H, ArH), 6.34 (dd, J = 1.9, 0.9 Hz,
1 H, CH), 4.04 (s, 2 H, CH2), 3.79 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.5, 158.3, 154.9, 129.9 (2 C), 129.3, 128.8,
123.3, 122.5, 120.4, 114.0 (2 C), 110.9, 103.1, 55.3, 34.1 ppm. IR (ATR):
31.9 (3 C), 29.9 (3 C) ppm. IR (ATR): ν = 2959, 2950, 1607,
˜
1478 cm–1. MS (EI): m/z (%) = 401 (39) [M + 2]+, 400 (10) [M + 1]+,
399 (39) [M]+, 386 (22), 385 (99), 384 (24), 383 (100), 281 (10), 227
(12), 207 (28), 169 (16), 152 (10), 138 (56), 57 (46). HRMS: calcd. for
C23H27BrO 398.1245; found 398.1251.
ν = 1612, 1584, 1509, 1245 cm–1. MS (EI): m/z (%) = 238 (59) [M]+,
˜
237 (56) [M – 1]+, 207 (100), 131 (13).
2-Hexylbenzofuran (3k):[6c] Colorless oil; tR = 12.6 min. Rf = 0.9
(hexane/ethyl acetate, 4:1). 1H NMR (300 MHz, CDCl3): δ = 7.35–
7.40, 7.45–7.50 (2 m; 1 H and 1 H, respectively; 2 CH), 7.10–7.20 (m,
2 H, 2 CH), 6.34 (s, 1 H, OCCH), 2.74 (t, J = 7.5 Hz, 2 H, CH2), 1.73
(quin, J = 7.5 Hz, 2 H, CH2), 1.25–1.40 (m, 6 H, 3 CH2), 0.89 (t, J =
7.14 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.8, 154.7,
129.1, 123.0, 122.4, 120.2, 110.7, 101.8, 31.6, 28.9, 28.5, 27.7, 22.6,
General Procedure for the Preparation of the Products 5: To a
stirred solution of the corresponding acetophenone 4 (0.4 mmol) in
EtOH (2 mL) was added 4-methylbenzenesulfonohydrazide (74 mg,
0.4 mmol), and the resulting mixture was stirred at 100 °C for 1 h.
After that time, Cs2CO3 (390 mg, 1.2 mmol) and CuO-Fe3O4 (50 mg,
2.4 mol-%) were added followed by the corresponding terminal alk-
yne 2 (0.5 mmol). The resulting mixture was stirred at 100 °C for
5 h. The catalyst was removed by magnetic decantation, and the
solvent was evaporated under reduced pressure. The resulting mix-
ture was partitioned between deionized water and AcOEt, and the
solution was extracted with AcOEt (3 × 5 mL). The organic phases
were dried with MgSO4 and concentrated under reduced pressure
to remove the solvent. The crude product was usually purified by
chromatography on silica gel (hexane/ethyl acetate) to give the cor-
responding product 5.
14.1 ppm. IR (ATR): ν = 1600, 1587, 1252, 1009, 738 cm–1. MS (EI):
˜
m/z (%) = 202 (24) [M]+, 132 (29), 131 (100), 95 (13), 77 (13).
2-(Cyclohexylmethyl)benzofuran (3l): Colorless oil; tR = 13.9 min.
1
Rf = 0.7 (hexane/ethyl acetate, 4:1). H NMR (300 MHz, CDCl3): δ =
7.35–7.50 (m, 2 H, ArH), 7.10–7.20 (m, 2 H, ArH), 6.35 (s, 1 H, CH),
2.63 (d, J = 6.8 Hz, 2 H, CH2), 1.60–1.80 (m, 6 H, 3 CH2), 1.10–1.30
(m, 3 H, CH2, CH), 0.90–1.05 (m, 2 H, CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.5, 154.7, 129.0, 122.9, 122.3, 120.1, 110.7, 102.8, 37.0,
36.3, 33.2 (2 C), 26.4, 26.2 (2 C) ppm. IR (ATR): ν = 2921, 2850, 1601,
˜
1586, 1453, 1253, 1008 cm–1. MS (EI): m/z (%) = 214 (50) [M]+, 133
2-Benzyl-3-methylbenzofuran (5a):[14] Colorless oil; tR = 14.4 min.
(12), 132 (90), 131 (100), 83 (10), 77 (10). HRMS: calcd. for C15H18
214.1357; found 214.1351.
O
1
Rf = 0.7 (hexane/ethyl acetate, 4:1). H NMR (300 MHz, CDCl3): δ =
7.45–7.50 (m, 1 H, ArH), 7.20–7.40 (m, 8 H, ArH), 4.09 (s, 2 H, CH2),
2-(4-Chlorobutyl)benzofuran (3m):[13] Colorless oil; tR = 13.2 min.
2.23 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.0, 152.1,
1
Rf = 0.7 (hexane/ethyl acetate, 4:1). H NMR (300 MHz, CDCl3): δ = 138.0, 130.2, 128.6 (2 C), 128.5 (2 C), 126.5, 123.4, 122.0, 118.9, 110.8,
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32.6, 8.0 ppm. IR (ATR): ν = 1494, 1454, 1088, 744 cm–1. MS (EI): m/z
E. J. Thomas), Georg Thieme Verlag, Stuttgart, Germany, 2002, vol. 10,
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Goggiamani, Org. Biomol. Chem. 2011, 9, 641–652.
˜
(%) = 223 (19) [M + 1]+, 222 (94) [M]+, 221 (49) [M – 1]+, 208 (23),
207 (100), 178 (20), 145 (48), 131 (10), 115 (19).
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2-Benzyl-5-bromo-3-methylbenzofuran (5b): Colorless oil; tR
=
16.5 min. Rf = 0.7 (hexane/ethyl acetate, 4:1). 1H NMR (300 MHz,
CDCl3): δ = 7.56 (d, J = 1.9 Hz, 1 H, ArH), 7.25–7.30 (m, 3 H, ArH),
7.20–7.25 (m, 4 H, ArH), 4.07 (s, 2 H, CH2), 2.18 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 153.6, 152.8, 137.5, 132.3, 128.6 (2
C), 128.4 (2 C), 126.6, 126.2, 121.7, 115.2, 112.2, 110.5, 32.6, 7.9 pm.
IR (ATR): ν = 1602, 1494, 1445, 1262, 1089, 799 cm–1. MS (EI): m/z
˜
(%) = 302 (72) [M + 2]+, 301 (38) [M+ + 1], 300 (80) [M+], 299 (28)
[M+ – 1], 287 (85), 285 (100), 281 (33), 225 (37), 223 (27), 207 (99),
205 (27), 193 (29), 191 (18), 115 (28), 110 (18), 103 (27), 89 (21), 88
(16), 78 (17), 74 (17), 73 (16), 63 (19), 61 (23). HRMS: calcd. for
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C
16H13BrO 300.0150; found 300.0143.
Acknowledgments
This work was supported by the Spanish Ministerio de Educa-
ción y Ciencia (MEC), the Ministerio de Ciencia e Innovación
(MICINN) (grant numbers CTQ2011-24151 and CTQ2015-66624-
P) and the University of Alicante. J. M. P. thanks the Spanish
Ministerio de Economía y Competitividad (MINECO) for her fel-
lowship.
Keywords: Heterogeneous catalysis · Nanoparticles ·
Oxygen heterocycles · Alkynes · Copper
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[11] For an example of recyclable impregnated cobalt oxide on magnetite
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Received: June 1, 2016
Published Online: ■
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Full Paper
Heterogeneous Catalysis
The direct and efficient transformation
of o-hydroxybenzaldehydes into the
corresponding benzo[b]furans by us-
ing alkynes and copper oxide impreg-
nated on magnetite as a heterogene-
ous catalyst has been introduced. The
versatility of this approach was dem-
onstrated by preparing various 2,3-
disubstituted benzofuran derivatives.
J. M. Pérez, D. J. Ramón* ................. 1–8
Impregnated Copper(II) Oxide on
Magnetite as Catalyst for the Syn-
thesis of Benzo[b]furans from 2-
Hydroxyarylcarbonyl
and Alkynes
Derivatives
DOI: 10.1002/ejoc.201600671
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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