A highly efficient and recyclable Fe3O4 magnetic nanoparticle immobilized palladium catalyst for the direct C-2 arylation of indoles with arylboronic acids

Article abstract of DOI:10.1039/c4cy00040d

A highly efficient Fe₃O₄ magnetic nanoparticle (MNP) immobilized palladium catalyst was prepared and applied to the direct C-2 arylation of indoles with arylboronic acids. The reactions generated the corresponding cross-coupling products in good yields. In addition, the supported catalyst with low loading (2.0 mol%) showed high stability and could be recovered and reused 8 times without significant loss of activity. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4cy00040d

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Abstract
A highly efficient and recyclable Fe3O4 magnetic nanoparticles
immobilized palladium catalyst for the direct C-2 arylation of indoles
with arylboronic acids
Lei Zhang,a Pinhua Li,a Can Liu,a Jin Yang,a Min Wang,a and Lei Wang*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient and reusable Fe3O4ꢀnanoparticlesꢀimmobilizedꢀpalladium catalyst was
prepared and applied in the direct Cꢀ2 arylation of indoles with arylboronic acids.
10
15 a Department of Chemistry, Huaibei Normal University, Huaibei,
Anhui 235000, P R China; E-mail: leiwang@chnu.edu.cn
Tel.: +86-561-380-2069; fax: +86-561-309-0518
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
20 Shanghai 200032, P R China
† Electronic Supplementary Information (ESI) available: [details
of any supplementary information available should be included
here]. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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Cite this: DOI: 10.1039/c0xx00000x
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Paper
A highly efficient and recyclable Fe3O4 magnetic nanoparticles immobilized
palladium catalyst for the direct C-2 arylation of indoles with arylboronic acids
Lei Zhang,a Pinhua Li,a Can Liu,a Jin Yang,a Min Wanga and Lei Wang*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
concise approach to 2ꢀarylated indoles,5 and significant
achievements which have been accomplished are based on Pdꢀ
catalyzed direct Cꢀ2 arylation of indoles with a variety of
50 coupling partners, such as aryl halides,2h,6 hypervalent iodine
arylating agents,7 organoboranes,8 organosilanes9 and sodium
sulfinates.10 Although homogeneous palladium catalysts exhibit
excellent activity, homogeneous catalysis suffers from the high
expense, and it is worth noting that large amounts of palladium
55 catalysts were used, which attendant brings a series of problems,
such as catalyst separation and recycling, heavy metal
contamination of the product purification, economic concern in
largeꢀscale syntheses could not be ignored. The supported
catalysts have become extremely powerful tools in the
A highly efficient Fe3O4 magnetic nanoparticles (MNPs)
immobilized palladium catalyst was prepared and applied in
the direct C-2 arylation of indoles with arylboronic acids. The
reactions generated the corresponding cross-coupling
10 products in good yields. In addition, the supported catalyst
with low loading (2.0 mol%) showed high stability, which
could be recovered and reused for 8 times without significant
loss of its activity.
Introduction
15 The indoles are one of the most important nitrogenꢀcontaining
organic molecules, which are widely presented in natural 60 development of modern methods for chemical synthesis, due to
products, materials, and bioactive compounds, such as antibiotics
and anticancers.1 Over the past decades, Cꢀ2 arylation of indoles
received considerable attention due to Cꢀ2 arylated indoles are
20 important building blocks for the natural products and
the increasing environmental concerns, and exploring
environmentally friendly supported catalysts is becoming more
and more important because they are fits for green methodologies
and they have more advantages, such as the easier separation,
pharmaceuticals.2 For the synthesis of these compounds and their 65 recovery, reuse of the catalyst and the removal conveniently of
further functionalization, remarkable progress has been made by
a numbers of organic chemists.3 In 2005, a one–pot synthesis of
indoles from oꢀhaloanilines and alkenyl halides was reported by
25 Barluenga,3a and a Pdꢀcatalyzed tandem C–N/C–C coupling of
the expensive and/or toxic heavy metal complexes from the
reaction medium.11
More recently, magnetite Fe3O4 nanoparticles have been
emerged widely for various areas, such as biotechnology, medical
gemꢀdihalovinyl with arylboronic acids for the synthesis of 2ꢀ 70 applications, environmental remediation.12 Application of
arylated indoles was developed by Lautens.3b Then, a Auꢀ
catalyzed crossꢀcouplingꢀcyclization reaction of terminal alkynes
with 2ꢀiodoaniline to form Cꢀ2 arylated indoles in excellent
30 yields was described by our group,3c and a Pdꢀcatalyzed synthesis
functionalized magnetic nanoparticles (MNPs) has been
extensively explored in organic synthesis,13 which have been
considered as excellent and ideal supports with significant
industrial potential for immobilization because the magnetic
of 2ꢀarylindoles from ammonia and bromophenylacetylenes was 75 nanoparticles supported catalysts are readily available, chemically
report by Stradiotto.3d Recently, transitionꢀmetalꢀcatalyzed C–H
bond activation has contributed greatly to the construction of C–
C bonds in organic synthesis.4 Most importantly, the direct Cꢀ2
35 arylation of indoles has recently attracted significantly attention.
stable and can be prepared by simple methods.14 Furthermore,
these MNPs can be easily separated from the reaction medium by
an external permanent magnet, which achieves simple separation
of the catalysts without filtration. Recently, RosarioꢀAmorin and
Palladiumꢀcatalyzed
crossꢀcoupling
reactions
between 80 Heuzé have developed an efficient magnetic nanoparticle–
functionalized indoles and activated arenes are an efficient and
supported metallodendritic Pdꢀcatalyzed Suzuki C–C coupling
reactions.15 After that, Pericàs and his coꢀworkers reported
MacMillanꢀtype organocatalysts used “click” strategy for the
asymmetric FriedelꢀCrafts alkylation of Nꢀsubstituted pyrroles
85 with α,βꢀunsaturated aldehydes.16 Meanwhile, Varma et al. have
prepared Fe3O4ꢀdopamineꢀPd/Ru/Ni catalyst successfully and
used in a variety of organic transformations.17 Recently, we have
developed a series of Fe3O4 magnetic nanoparticles immobilized
catalysts and used in the organic transformations.18 Following the
90 research of our group, we focused our attention on developing
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui
235000, P R China; Eꢀmail: leiwang@chnu.edu.cn
40 Tel.: +86ꢀ561ꢀ380ꢀ2069; fax: +86ꢀ561ꢀ309ꢀ0518
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
P R China
† Electronic Supplementary Information (ESI) available: [details of any
45 supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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new MNPs supported palladium catalysts and their application in 40 was carried out by the ‘‘click’’ reaction of phenylacetylene with
the organic reactions. Triazoles has been gained much attention
for catalyst immobilization as a high stable linker and a chelator,
and researchers have successively explored many their metal
catalysts, such as Pd,19 Au20 and V.21 Recently reports have been
the azide functionalized magnetic coreꢀshell nanoparticles in the
presence of copper sulfate and sodium ascorbate in aqueous
methanol solution for 24 h to form the triazole loaded magnetic
nanoparticles, with a loading of 0.27 mmol of triazole per gram,
5
shown that 1,4ꢀsubstituted 1,2,3ꢀtriazole could be used as a 45 which was quantified by CHN microanalysis on the basis of
potentially monoꢀdentate ligand coordinating to Pd(II).22 Inspired
by its attractive features, herein we attempt to apply “click”
chemistry concept, forming 1,2,3ꢀtriazole as a monoꢀdentate
nitrogen content determination. The supported Pd catalyst was
obtained by dissolving Pd(OAc)2 in THF and treating it with the
above triazoleꢀfunctionalized SiO2@Fe3O4, with a loading of
0.166 mmol of palladium per gram determined via inductively
10 ligand to coordinate with PdII and providing 1,2,3ꢀtriazoleꢀPdII
complex immobilized on the Fe3O4 magnetic nanoparticles 50 coupled plasma atomic emission spectrometry (ICPꢀAES). XRD
(MNPs). The results indicated that the MNPsꢀ1,2,3ꢀtriazoleꢀPd
catalyst exhibits high catalytic activity for the direct Cꢀ2 arylation
of indoles with arylboronic acids (Scheme 1). More importantly,
15 the supported catalyst could be recovered and reused well for 8
times without significant loss of its catalytic activity.
measurements of the supported palladium catalysts exhibited
diffraction peaks corresponding to the typical spinel maghemite
structure and the diffraction peak of the layered amorphous silica
was not obvious. There were also no peaks characteristic for
55 palladium(0) nanoparticles observed, proving that the good
dispersion of the palladium sites on the magnetic nanoparticles
(Figure 3). However, there will be aggregated in some extent
after several cycles (Figure 2, a vs b).
N3
a)
b)
O
O
b)
Fe3O4
Fe3O4
Fe3O4
SiO2
Si
OMe
MNP-1
SiO2
OMe
c)
O
O
Ph
Fe3O4
SiO2
Si
N
MNP-2
N
N
d)
SiO2@Fe3O4 triazole Pd
R2
R2
(2.0 mol% Pd)
H
B(OH)2
+
R3
R3
CH3OH, K2S2O8
H2SO4, r.t.,10 h
N
R1
N
R1
R1= H, Me, Et
60
Scheme
1 Preparation of magnetic nanoparticlesꢀsupported
20 palladium catalyst and its application in Cꢀ2 arylation of indoles.
Figure 1 The size of SiO2@Fe3O4–triazole–Pd particles and their
Reaction
conditions:
a)
Si(OEt)4,
EtOH;
b)
(4ꢀ
distribution
(azidomethyl)phenethyl)trimethoxysilane, toluene; c) phenylacetylene,
CuSO4, NaAsc, tertꢀbutanol/H2O; d) Pd(OAc)2, THF.
65
25 Results and discussion
The magnetic nanoparticles supported palladium catalyst was
synthesized according to the procedure in Scheme 1. The silicaꢀ
coated Fe3O4 (SiO2@Fe3O4) was prepared according to the
literature,23 the prepared Fe3O4 nanoparticles, with an average
30 diameter of 140 nm (Figure 1), were coated with a thin layer of
silica using a solꢀgel process to give silicaꢀcoated Fe3O4. TEM
images of the SiO2@Fe3O4 indicated the coreꢀshell structure of
the particles, and the silica coating, which has a uniform
thickness of 20 nm (Figure 2). The azide could be anchored easily
35 onto the surface of the SiO2@Fe3O4 by using (4ꢀ
(azidomethyl)phenethyl)trimethoxysilane at reflux temperature in
toluene for 24 h, with a loading of 0.206 mmol of azide per gram,
which was quantified via CHN microanalysis based on the carbon
content determination. Immobilization of the triazole moieties
70
Figure 2 TEM images of the catalysts: (a) SiO2@Fe3O4–
triazole–Pd catalyst; (b) recycled SiO2@Fe3O4–triazole–Pd
catalyst
75
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Table 1 Optimization of the crossꢀcoupling between Nꢀmethyl
indole and (4ꢀmethoxyphenyl)boronic acida
Yield
[%]b
Entry
Solvent
Oxidant
Additive
1
2
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
C2H5OH
TBHP
TBPB
O2
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
42
39
3
56
4
K2S2O8
PhI(OAc)2
BQ
68
5
trace
NR
NR
NR
NR
49
6
Figure 3 XRD determinations of the supported catalysts
7
DDQ
8
(NH4)2S2O8
—
In order to evaluate the catalytic activity of obtained
catalyst, a direct arylation of 1ꢀmethylindole (1a) with 4ꢀ
methoxyphenylboronic acid (2a) was chosen as model reaction
for our investigation, and the results were listed in Table 1.
Initially, the influence of oxidant on the model reaction was
explored using the MNPsꢀimmobilized palladium catalyst
9
5
10
K2S2O8
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1,4ꢀdioxane
DMSO
DMF
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
H2SO4
17
NR
NR
NR
NR
NR
NR
81
10 (SiO2@Fe3O4ꢀtriazoleꢀPd, containing 2.0 mol% Pd) in CH3OH
with CH3CO2H (0.5 equiv) as additive at room temperature
(Table 1, entries 1–8).7 Among the tested oxidants, K2S2O8
exhibited the highest activity and 68% of desired product 3a was
obtained. O2, TBHP, and TBPB were subsequently inferior, and
15 3a was isolated in 39–56% yields. However, BQ, DDQ,
PhI(OAc)2 and (NH4)2S2O8 were found to be ineffective for this
reaction. No desired product was formed in the absence of
oxidant (Table 1, entry 9). Then the influence of the solvents on
the reaction was examined, and a significant solvent effect was
20 observed. Good yield was obtained with CH3OH (Table 1, entry
1). C2H5OH and 1,4ꢀdioxane was found to be inferior (Table 1,
entries 10 and 11). No desired product 3a was observed when the
reaction was performed in DMSO, DMF, CH3CN, CH2Cl2, THF,
or toluene (Table 1, entries 12–17). The additive was also
25 investigated and the results clearly indicated that 0.50 equiv of
H2SO4 was the best one and gave the product 3a in 81% yield
(Table 1, entry 18). CF3CO2H, CF3SO3H and PivOH shut down
the reaction completely (Table 1, entries 19–21). Other organic
acids, such as PhCO2H, oꢀNO2PhCO2H, or pꢀNO2PhCO2H were
30 less effective (Table 1, entries 22–24). In the absence of any
additive, only 30% yield of 3a was obtained (Table 1, entry 25).
The loading of the catalyst was also examined. As shown in
Table 1, it was found that catalyst loading affected the reaction
obviously. The use of 0.50 mol% Pd catalyst only gave 3a in 20%
35 yield. Increasing the amount of catalyst loading up to 1.0 mol%,
57% yield of 3a was obtained. However, the yields of 3a were
not improved significantly upon increasing the amount of catalyst
loading up to 3.0 mol%. Thus, 2.0 mol% of catalyst was the best
choice (Table 1, entry 26). During further investigation of the
40 reaction time, the model reaction was found to be completed in
10 h at room temperature (Table 1, entry 27).
CH3CN
CH2Cl2
THF
Toluene
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CF3CO2H
CF3SO3H
PivOH
NR
NR
NR
42
PhCO2H
oꢀNO2PhCO2H
pꢀNO2PhCO2H
—
55
53
30
20c
57d
81e
43f
26
27
CH3OH
CH3OH
K2S2O8
K2S2O8
H2SO4
H2SO4
79g
81h
a
45
Reaction conditions: 1ꢀmethylindole (1a, 0.50 mmol), 4ꢀ
methoxyphenylboronic acid (2a, 1.0 mmol), oxidant (1.0 mmol),
additive (0.25 mmol), SiO2@Fe3O4–triazoleꢀPd catalyst (60 mg,
containing Pd 0.01 mmol, 2.0 mol%), in solvent (2.0 mL) at room
temperature and stirred for 12 h. Isolated yields. c 0.5 mol% of
b
50 SiO2@Fe3O4–Pd catalyst was used. d 1.0 mol% of SiO2@Fe3O4–
e
triazoleꢀPd catalyst was used. 3.0 mol% of SiO2@Fe3O4–
triazoleꢀPd catalyst was used. for 4 h. g for 8 h. h for 16 h. BQ =
f
1,4ꢀbenzoquinone; DDQ
benzoquinone; TBHP = tertꢀbutyl hydroperoxide; TBPB = tertꢀ
55 butyl peroxybenzoate; PivOH = pivalic acid.
=
2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀ
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We next examined the versatility of this protocol, the
subsequently displaced by arylboronic acid to generate an arylꢀ
SiO2@Fe3O4–triazoleꢀPd catalyzed Cꢀ2 arylation of a variety of 60 palladium complex, ArꢀPd(II)ꢀAr’. Then, a reductive elimination
substituted indoles with different aryl boronic acids were
investigated under the optimized reaction conditions and the
results were summarized in Scheme 2. As shown in Scheme 2,
good yields of the corresponding products were obtained in the
reaction of 1ꢀmethylindole with different arylboronic acids in the
most cases. The reaction of 1ꢀmethylindole (1a) with
phenylboronic acid generated the corresponding product 1ꢀ
of the formed ArꢀPd(II)ꢀAr’ affords the coupling product and
Pd(0) species, which is oxidized by K2S2O8 to regenerate Pd(II),
completing the catalytic cycle.
5
65
10 methylꢀ2ꢀphenylindole (3b) in 75% yield. It is worth noting that
the substituted aryl boronic acids with both electronꢀrich and
electronꢀpoor groups, such as CH3, CH3O, tꢀBu, biphenyl, F and
Cl groups at the paraꢀ or metaꢀpositions on the benzene rings
tolerated the reaction with 1a under the present reaction
15 conditions, and generated the corresponding products in good to
excellent yields (Scheme 2, 3a, 3c–e, and 3g–3i, 66-82% yields).
The steric effect was observed when arylboronic acid with paraꢀ,
metaꢀ, or orthoꢀmethoxy on the benzene ring was used as one of
the substrate to react with 1a (Scheme 2, 3a and 3e, vs 3f). It
20 should be noted that the reaction of 1ꢀmethylindole with
naphthalenꢀ2ꢀylboronic acid underwent direct Cꢀ2 arylation to
generate the corresponding product 3j in 60% yield (Scheme 2,
3j).
Finally, the substitution effect in the indole moiety was
25 investigated under the standard reaction conditions. Indoles,
which containing electronꢀdonating groups, such as MeO or Me
on the phenyl rings reacted smoothly with arylboronic acids and
generated the corresponding direct Cꢀ2 arylation of indoles
products (Scheme 2, 3k, 3r, 3s). However, the product yields of
30 the reactions of indoles containing electronꢀwithdrawing groups,
for instance, CN, F and CO2Me on the phenyl rings with
arylboronic acids were slightly lower (Scheme 2, 3r and 3s vs 3t–
3v). In the case of the free NꢀH indole, it was found that it
slightly less reactive than 1ꢀmethyl indole, giving the
35 corresponding products in good yields (Scheme 2, 3a vs 3o; 3b vs
3n; 3e vs 3p; 3h vs 3q; 3k vs 3r; 3l vs 3t). When 1ꢀethyl indole
was used instead of 1ꢀmethyl indole to react with phenylboronic
acid under the recommended reaction conditions, 61% of 3m was
isolated (Scheme 2). However, when 1ꢀ(nꢀbutyl)indole or 1ꢀ
40 pivaloyl indole reacted with phenylboronic acid, no
corresponding product was obtained, probably due to the steric
hindrance.
In addition, the recovery and reuse of the developed magnetic
nanoparticles supported palladium catalyst was examined, 4ꢀ
45 methoxyphenylboronic acid and 1ꢀmethylindole were chosen as
model substrates. After the reaction carried out under the
optimized reaction conditions, the catalyst was washed with
diethyl ether, ethanol and water respectively, dried in air and
reused for the next reaction. It was found that the supported
50 catalyst could be recycled and reused for 8 consecutive trials
without significant loss of its catalytic activity (Table 2).
Moreover, palladium leaching in SiO2@Fe3O4ꢀtriazoleꢀPd
catalyst was determined. ICP analysis of the reaction solution
indicated that Pd contents were less than 0.20 ppm.
Scheme 2 Fe3O4 magnetic nanoparticles immobilized palladium
catalyzed Cꢀ2 arylation of indoles with arylboronic acids.
Reaction conditions: indole (0.50 mmol), arylboronic acid (1.0 mmol),
K2S2O8 (1.0 mmol), H2SO4 (0.25 mmol), SiO2@Fe3O4–triazoleꢀPd
catalyst (60 mg, containing Pd 0.01 mmol, 2.0 mol%), CH3OH (2.0
mL), room temperature, 12 h; isolated yields of the products.
70
55
According to the literature7,8a,8c,8d,24 and our observation, the
possible reaction mechanism is via a Pd(0)/Pd(II) process.
Initially, the Pd (II) catalyst reacts with C–H of indole in the Cꢀ2
position to form an ArꢀPd(II)ꢀOAc intermediate, which is
75
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Table 2 Recycling SiO2@Fe3O4–triazoleꢀPd catalyst for the
direct Cꢀ2 arylation of 1ꢀmethyl indole with (4ꢀ
methoxyphenyl)boronic acida
40 ethylene glycol stirring for 1.0 h. Then 12.0 g of sodium acetate
were added to the solution. After stirring for 1.0 h, the resultant
solution was transferred into
a Teflonꢀlined stainlessꢀsteel
autoclave (200 mL). The autoclave was sealed and heated at 200
oC for 10 h, then cooled to room temperature. The magnetic
45 microspheres were separated by using an external magnet,
washed with ethanol and diethylether each for three times and
dried under vacuum.
Run
1
Yield (%)b
Run
5
Yield (%)b
81
81
80
79
79
78
77
76
2.2 Synthesis of the silica-coated magnetic nanoparticles
50 (SiO2@Fe3O4)
2
6
3
7
Generally, the magnetite particles (0.18 g) were treated with HCl
aqueous solution (5.0 mL, 2.0 mol/L) under ultrasound for 3 min.
And 2.0 mL of NH3·H2O were added to a mixture of deionized
water (15.0 mL) and ethanol (85.0 mL), the mixture was then
55 sonicated for approximately 0.50 h. To this well dispersed
magnetic nanoparticles solution, followed 1.0 g of Si(OEt)4 was
slowly added, the solution was stirred for 12 h at room
temperature. Finally, the product was washed with deionized
water until the solution was neutral, then washed with ethanol
60 and diethylether each for three times and dried under vacuum.
4
8
a
Reaction conditions: 1ꢀmethylindole (1a, 0.50 mmol), 4ꢀ
methoxyphenylboronic acid (2a, 1.0 mmol), K2S2O8 (1.0 mmol), H2SO4
(0.25 mmol), SiO2@Fe3O4–triazoleꢀPd catalyst (60 mg, containing Pd
0.01 mmol, 2.0 mol%), in CH3OH (2.0 mL) at room temperature and
stirred for 12 h. b Isolated yields.
5
Conclusions
2.3 Synthesis of azide-functionalized SiO2@Fe3O4
In summary, we have successfully applied a recyclable MNPs–
triazole–Pd catalyst in the direct Cꢀ2 arylation of indoles
reactions. A variety of substituted indoles reacted with different
aryl boronic acids in the presence of 2.0 mol% supported
10 palladium catalyst, affording the corresponding products in good
yields. It is important to note that the supported catalyst could be
recovered and reused at least 8 times without significant loss of
its activity. The operationally simple procedure for the catalyst
preparation and recovery of the catalyst make it an ideal catalytic
15 system for the direct Cꢀ2 arylation of indoles reaction.
(4ꢀ(Azidomethyl)phenethyl)trimethoxysilane19a
(0.494
g)
dissolved in dry toluene (10.0 mL), were added to a suspension of
65 SiO2@Fe3O4 (2.0 g) in dry toluene (45.0 mL). Then the mixture
was shaking for 24 h at 100 °C. The product was separated by
using an external magnet, washed with toluene and CH2Cl2 three
times to remove the unꢀimmobilized species and dried under
vacuum.
70
2.4
Synthesis
of
triazole-functionalized
magnetic
nanoparticles (SiO2@Fe3O4)
Azideꢀfunctionalized SiO2@Fe3O4 (1.0 g) was dispersed in the
MeOH/H2O (80 mL, v/v = 1/1). Then phenylacetylene (0.122 g,
75 1.2 mmol), CuSO4•5H2O (0.013 g, 0.05 mmol), sodium ascorbate
(0.033 g, 0.17 mmol) were added to the mixed solution. The
reaction mixture was stirred at 60 °C for 24 h in air. Then the
product (SiO2@Fe3O4ꢀtriazole) was separated by using an
external magnet and washed with methanol, deionized water,
80 ethanol, ether each of three times to remove excess components.
Finally, the product was dried under vacuum at 60 °C.
Experimental Section
1. General Remarks
The chemicals were purchased from commercial suppliers
(Aldrich, USA and Shanghai Chemical Company, China) and
20 were used without purification prior to use. All H NMR and 13C
1
NMR spectra were recorded at 400 MHz and 100 MHz by a
Bruker 400 MHz FTꢀNMR spectrometer, respectively. Chemical
shift are given as δ value with reference to tetramethylsilane
(TMS) as internal standard. The CHN analysis was performed on
25 a Vario El III elementar. The Pd content was determined by a
JarrellꢀAsh 1100 ICP analysis. Transmission electron micrograph
(TEM) images were obtained at JEOLꢀ2010 transmission
electronic microscopy. Xꢀray diffraction (XRD) measurements
were carried out at room temperature using a Bruker D8 Advance
30 Xꢀray powder diffractmeter. Xꢀray photoelectron spectroscopy
(XPS) measurements were performed on a PerkinꢀElmer PHI
5000C ESCA system. Products were purified by flash
chromatography on 200–300 mesh silica gel, SiO2.
2.5 Synthesis of SiO2@Fe3O4-Pd
Palladium acetate (11.2 mg, 0.05 mmol) and THF (8.0 mL) were
85 added to a sealable reaction tube. The solution was shaking at
room temperature for 10 min, and then 1.0 g of the above
triazoleꢀfunctionalized magnetic nanoparticles (SiO2@Fe3O4ꢀ
triazole) was added. The mixture was shaking at room
temperature for 5 h, then the catalyst was magnetically separated
90 using external magnate, and the solid was washed with THF three
times, and dried under vacuum at 50 °C for 3 h.
35 2. Preparation of the magnetic nanoparticles supported
palladium catalyst
2.1 Synthesis of the magnetic nanoparticles (Fe3O4)
The magnetic microspheres were synthesized according to the
literature.23 FeCl3·6H2O (5.4 g) was dissolved in 120 mL of
2.6 Preparation of the TEM samples
First a small amount of the catalyst was dispersed in ethanol,
95 ultrasonic dispersed about 15 minutes, allowing large particles
precipitated for 3ꢀ5 minutes. Then take 3 drops of superficial
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1
liquid on the copper grid. At last the sample dried at room
temperature then observed by TEM.
White solid. m.p. 97.4–99.5 °C (lit.7 m.p. 96–98 °C). H NMR
(400 MHz, CDCl3): δ 7.71 (1H, d, J = 7.8 Hz), 7.46 (2H, d, J =
7.9 Hz), 7.42 (1H, d, J = 8.1 Hz), 7.36–7.29 (3H, m), 7.24–7.20
50 (1H, m), 6.62 (1H, s), 3.80 (3H, s), 2.50 (3H, s); 13C NMR (100
MHz, CDCl3): δ 141.6, 138.3, 137.7, 129.9, 129.2, 129.1, 128.0,
121.5, 120.3, 119.8, 109.5, 101.3, 31.1, 21.2. HRMS (ESI)
([M+H]+) Calcd. for C16H16N: 222.1283, Found: 222.1282.
2.7 Preparation of the XRD samples
5
The catalyst sample was placed in a mortar grinding for about 20
minutes. Then the sample powder was sprinkled on the glass slide
as evenly as possible. After that the sample was dispersed evenly
with ethanol, the sample dried at room temperature.
10 3. General procedure for the direct C-2 arylation of indoles
1ꢀMethylindole (0.5 mmol), 4ꢀmethoxyphenylboronic acid (1.0
mmol), K2S2O8 (1.0 mmol) and SiO2@Fe3O4–Pd catalyst (60 mg,
containing Pd 0.01 mmol) were added to a reaction tube.
Anhydrous CH3OH (4.0 mL) was added, then H2SO4 (0.25
15 mmol) was added to the mixture. The resulting solution was then
stirring for 10 h at room temperature. After the catalyst separated
by magnetic, the catalyst was washed with diethyl ether, alcohol,
water, diethyl ether each of three times, and used directly for the
next run. The organic phase was evaporated under the reduced
20 pressure and the product was purified by column chromatography
on silica gel.
55
3d: 2-(4-(tert-Butyl)phenyl)-1-methyl-1H-indole
White solid. m.p. 114.3–115.5 °C (lit.25 m.p. 115–116 °C).1H
NMR (400 MHz, CDCl3): δ 7.65 (1H, d, J = 7.8 Hz), 7.53–7.46
(4H, m), 7.38 (1H, d, J = 8.2 Hz), 7.28–7.26 (1H, m), 7.17–7.14
60 (1H, m), 6.57 (1H, s), 3.78 (3H, s), 1.41 (9H, s); 13C NMR (100
MHz, CDCl3): δ 150.9, 141.7, 138.3, 129.9, 129.1, 128.0, 125.4,
121.5, 120.0, 119.8, 109.5, 101.4, 34.7, 31.3. HRMS (ESI)
([M+H]+) Calcd. for C19H22N: 264.1752, Found: 264.1749.
65
3a: 2-(4-Methoxy-phenyl)-1-methyl-1H-indole
25 White solid. m.p. 117.2–119.5 °C (lit.7 m.p. 117–120 °C). 1H
NMR (400 MHz, CDCl3): δ 7.67 (1H, d, J = 7.8 Hz), 7.48 (2H, d,
J = 8.5 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.30–7.27 (1H, m), 7.20–
7.17 (1H, m), 7.05 (2H, d, J = 8.5 Hz), 6.55 (1H, s), 3.91 (3H, s),
3.76 (3H, s); 13C NMR (100 MHz, CDCl3): δ 159.5, 141.4, 138.2,
30 130.6, 128.0, 125.3, 121.4,120.2, 119.7, 114.0, 109.5, 101.0,
55.3, 31.0. HRMS (ESI) ([M+H]+) Calcd. for C16H16NO:
238.1232, Found: 238.1230.
3e: 2-(3-Methoxyphenyl)-1-methyl-1H-indole
Colorless oil.8a 1H NMR (400 MHz, CDCl3): δ 7.70 (1H, d, J =
7.8 Hz), 7.46–7.41 (2H, m), 7.33–7.30 (1H, m), 7.23–7.20 (1H,
70 m), 7.17–7.12 (2H, m), 6.64 (1H, s), 3.92 (3H, s), 3.81 (3H, s);
13C NMR (100 MHz, CDCl3): δ 159.5, 141.4, 138.4, 134.2,
129.5, 127.9, 121.8, 121.7, 120.5, 119.9, 115.1, 113.4, 109.6,
101.7, 55.3, 31.1. HRMS (ESI) ([M+H]+) Calcd. for C16H16NO:
238.1232, Found: 238.1234.
75
N
Me
35 3b: 1–Methyl–2–phenyl–1H–indole
White solid. m.p. 101.2–102.5 °C (lit.7 m.p. 99–102 °C). 1H NMR
(400 MHz, CDCl3): δ 7.70 (1H, d, J = 7.8 Hz), 7.59–7.57 (2H,
m), 7.54–7.51 (2H, m), 7.48–7.41 (2H, m), 7.34–7.30 (1H, m),
7.23–7.20 (1H, m), 6.64 (1H, s), 3.80 (3H, s); 13C NMR (100
40 MHz, CDCl3): δ 141.5, 138.3, 132.8, 129.4, 128.5, 128.0, 127.9,
127.8, 121.6, 120.5, 119.8, 109.6, 101.6, 31.1. HRMS (ESI)
([M+H]+) Calcd. for C15H14N: 208.1126, Found: 208.1130.
3f: 2-(2-Methoxyphenyl)-1-methyl-1H-indole
Colorless oil.26 1H NMR (400 MHz, CDCl3): δ 7.74 (1H, d, J =
7.8 Hz), 7.54–7.44 (3H, m), 7.36–7.32 (1H, m), 7.25–7.21 (1H,
80 m), 7.17–7.13 (1H, m), 7.09 (1H, d, J = 8.3 Hz), 6.61 (1H, s),
3.89 (3H, s), 3.68 (3H, s); 13C NMR (100 MHz, CDCl3): δ 157.5,
138.5, 137.6, 132.5, 130.0, 127.9, 122.0, 121.2, 120.6, 120.4,
119.3, 110.8, 109.3, 101.7, 55.4, 30.6. HRMS (ESI) ([M+H]+)
Calcd. for C16H16NO: 238.1232, Found: 238.1235.
85
F
N
45
Me
3c: 1-Methyl-2-p-tolyl-1H-indole
3g: 2-(4-Fluorophenyl)-1-methyl-1H-indole
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White solid. m.p. 119.7–121.3 °C (lit.7 m.p. 119–122 °C). 1H
NMR (400 MHz, CDCl3): δ 7.68 (1H, d, J = 7.8 Hz), 7.52–7.49
(2H, m), 7.40 (1H, d, J = 8.2 Hz), 7.32–7.29 (1H, m), 7.23–7.18
3k: 5-Methoxy-1-methyl-2-phenyl-1H-indole8a
White solid. m.p. 126.7–129.2 °C. 1H NMR (400 MHz, CDCl3): δ
7.57–7.50 (4H, m), 7.46–7.43 (1H, m), 7.31 (1H, d, J = 8.8 Hz),
(3H, m), 6.58 (1H, s), 3.75 (3H, s); 13C NMR (100 MHz, CDCl3): 45 7.17–7.16 (1H, m), 6.99–6.96 (1H, m), 6.56 (1H, s), 3.99 (3H, s),
5
δ 162.6 (d, J = 246.2 Hz), 140.4, 138.3, 131.1 (d, J = 8.0 Hz),
128.9 (d, J = 3.4 Hz), 127.9, 121.8, 120.5, 120.0, 115.5 (d, J =
21.5 Hz), 109.6, 101.7, 31.0. HRMS (ESI) ([M+H]+) Calcd. for
C15H13FN: 226.1032, Found: 226.1029.
3.76 (3H, s); 13C NMR (100 MHz, CDCl3): δ 154.3, 142.1, 133.8,
132.9, 129.2, 128.4, 128.2, 127.7, 111.9, 110.3, 102.2, 101.3,
55.9, 31.2. HRMS (ESI) ([M+H]+) Calcd. for C16H16NO:
238.1232, Found: 238.1236.
50
10
3h: 2-(4-Chlorophenyl)-1-methyl-1H-indole
White solid. m.p. 115.1–117.2 °C (lit.7 m.p. 115–118 °C). 1H
NMR (400 MHz, CDCl3): δ 7.67 (1H, d, J = 7.8 Hz), 7.48 (4H,
s), 7.39 (1H, d, J = 8.2 Hz), 7.32–7.28 (1H, m), 7.21–7.17 (1H,
3l: 1-Methyl-2-phenyl-1H-indole-5-carbonitrile8b
White solid. m.p. 118.9–120.5 °C. 1H NMR (400 MHz, CDCl3): δ
7.98 (1H, s), 7.52–7.47 (6H, m), 7.42–7.40 (1H, m), 6.63 (1H, s),
15 m), 6.60 (1H, s), 3.76 (3H, s); 13C NMR (100 MHz, CDCl3): δ
140.2, 138.5, 134.0, 131.3, 130.5, 128.7, 127.9, 121.9, 120.5,
120.0, 109.6, 102.0, 31.1. HRMS (ESI) ([M+H]+) Calcd. for
C15H1335ClN: 242.0737, Found: 242.0741.
55 3.79 (3H, s); 13C NMR (100 MHz, CDCl3): δ 143.9, 139.7, 131.6,
129.4, 128.7, 128.6, 127.7, 125.9, 124.6, 120.9, 110.4, 102.8,
102.3, 31.4. HRMS (ESI) ([M+H]+) Calcd. for C16H13N2:
233.1079, Found: 233.1076.
60
N
20
3i: 2-([1,1'-Biphenyl]-4-yl)-1-methyl-1H-indole
White solid. m.p. 153.7–155.3 °C. 1H NMR (400 MHz, CDCl3): δ
7.73–7.67 (5H, m), 7.62–7.60 (2H, m), 7.51–7.48 (2H, m), 7.41–
7.39 (2H, m), 7.30–7.26 (2H, m), 7.19–7.15 (1H, m), 6.64 (1H,
25 s), 3.82 (3H, s); 13C NMR (100 MHz, CDCl3): δ 141.2, 140.7,
140.6, 138.5, 131.8, 129.7, 128.9, 128.0, 127.5, 127.2, 127.1,
121.7, 120.5, 119.9, 109.6, 101.8, 31.3. HRMS (ESI) ([M+H]+)
Calcd. for C21H18N: 284.1439, Found: 284.1436.
3m: 1-Ethyl-2-phenyl-1H-indole28
White solid. m.p. 85.6–87.0 °C. H NMR (400 MHz, CDCl3): δ
1
7.67 (1H, d, J = 7.8 Hz), 7.55–7.43 (6H, m), 7.29–7.25 (1H, m),
65 7.19–7.15 (1H, m), 6.56 (1H, s), 4.23 (2H, q, J = 7.2 Hz), 1.36
(3H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 141.1, 137.0,
133.2, 129.4, 128.5, 128.3, 127.9, 121.5, 120.6, 119.7, 109.9,
102.0, 38.7, 15.4. HRMS (ESI) ([M+H]+) Calcd. for C16H16N:
222.1283, Found: 222.1288.
70
30
3j: 1-Methyl-2-(naphthalen-2-yl)-1H-indole
White solid. m.p. 151.0–152.4 °C (lit.27 m.p. 152–153 °C). 1H
NMR (400 MHz, CDCl3): δ 8.01–7.93 (4H, m), 7.72–7.67 (2H,
3n: 2-Phenyl-1H-indole
White solid. m.p. 186.5–187.6 °C (lit.7 m.p. 188–189 °C). 1H
m), 7.58–7.56 (2H, m), 7.43 (1H, d, J = 8.2 Hz), 7.34–7.30 (1H, 75 NMR (400 MHz, CDCl3): δ 8.37 (1H, br, s), 7.69–7.64 (3H, m),
35 m), 7.23–7.19 (1H, m), 6.71 (1H, s), 3.84 (3H, s); 13C NMR (100
MHz, CDCl3): δ 141.6, 138.6, 133.3, 132.8, 130.3, 128.3, 128.1,
128.0, 127.8, 127.2, 126.5, 126.4, 121.8, 120.5, 120.0, 109.6,
102.2, 31.3. HRMS (ESI) ([M+H]+) Calcd. for C19H16N:
258.1283, Found: 258.1281.
7.48–7.41 (3H, m), 7.36–7.32 (1H, m), 7.23–7.19 (1H, m), 7.15–
7.12 (1H, m), 6.85 (1H, s); 13C NMR (100 MHz, CDCl3): δ
137.9, 136.9, 132.4, 129.3, 129.0, 127.7, 125.2, 122.4, 120.7,
120.3, 110.9, 100.0. HRMS (ESI) ([M+H]+) Calcd. for C14H12N:
80 194.0970, Found: 194.0971.
40
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3o: 2-(4-Methoxyphenyl)-1H-indole
White solid. m.p. 226.6–228.4 °C (lit.29 m.p. 228–229 °C). 1H 45 NMR (400 MHz, CDCl3): δ 8.35 (1H, br, s), 7.76–7.74 (2H, m),
White solid. m.p. 116.2–117.9 °C (lit.30 m.p. 116–117 °C). 1H
NMR (400 MHz, CDCl3): δ 8.26 (1H, br, s), 7.62–7.60 (3H, m),
7.40 (1H, d, J = 7.8 Hz), 7.20–7.10 (2H, m), 6.99 (2H, d, J = 8.2
Hz), 6.73 (1H, s), 3.87 (3H, s); 13C NMR (100 MHz, CDCl3): δ
159.4, 138.0, 136.7, 129.5, 126.5, 125.3, 121.9, 120.4, 120.2,
7.57 (1H, d, J = 7.8 Hz), 7.52–7.48 (2H, m), 7.41–7.37 (1H, m),
7.16–7.07 (2H, m), 6.91 (1H, s), 2.61 (3H, s); 13C NMR (100
MHz, CDCl3): δ 137.6, 136.4, 132.5, 128.9, 128.8, 127.5, 125.1,
122.9, 120.4, 120.0, 118.3, 100.5, 20.9. HRMS (ESI) ([M+H]+)
5
114.5, 110.7, 98.9, 55.4. HRMS (ESI) ([M+H]+) Calcd. for 50 Calcd. for C15H14N: 208.1126, Found: 208.1127.
C15H14NO: 224.1075, Found: 224.1074.
3t: 2-Phenyl-1H-indole-5-carbonitrile
10
White solid. m.p. 193.6–195.7 °C (lit.31 m.p. 194–196 °C). 1H
3p: 2-(3-Methoxyphenyl)-1H-indole
55 NMR (400 MHz, CDCl3): δ 8.80 (1H, br, s), 7.98 (1H, s), 7.70–
7.69 (2H, m), 7.51–7.38 (5H, m), 8.89 (1H, s); 13C NMR (100
MHz, CDCl3): δ 140.3, 138.5, 131.3, 129.2, 129.0, 128.6, 126.0,
125.4, 125.2, 120.7, 111.8, 103.4, 100.2. HRMS (ESI) ([M+H]+)
Calcd. for C15H11N2: 219.0922, Found: 219.0921.
60
White solid. m.p. 137.2–148.5 °C (lit.29 m.p. 136–137 °C). 1H
NMR (400 MHz, CDCl3): δ 8.36 (1H, br, s), 7.66 (1H, d, J = 7.8
Hz), 7.42–7.36 (2H, m), 7.28–7.27 (1H, m), 7.23–7.21 (2H, m),
15 7.18–7.14 (1H, m), 6.92–6.90 (1H, m), 6.86 (1H, s), 3.90 (3H, s);
13C NMR (100 MHz, CDCl3): δ 160.1, 137.7, 136.8, 133.8,
130.0, 129.2, 122.4, 120.7, 120.2, 117.7, 113.1, 111.0, 110.9,
100.2, 55.3. HRMS (ESI) ([M+H]+) Calcd. for C15H14NO:
224.1075, Found: 224.1078.
20
3u: 6-Fluoro-2-phenyl-1H-indole
White solid. m.p. 179.5–180.3 °C (lit.32 m.p. 180–181 °C). 1H
65 NMR (400 MHz, CDCl3): δ 8.33 (1H, br, s), 7.65–7.64 (2H, m),
7.56 (1H, s), 7.46 (2H, s), 7.36–7.35 (1H, m), 7.11–7.08 (1H, m),
6.94–6.90 (1H, m), 6.81 (1H, s); 13C NMR (100 MHz, CDCl3): δ
160.1 (d, J = 236.7 Hz), 138.4 (d, J = 3.8 Hz), 136.8 (d, J = 12.4
Hz), 132.1, 129.1, 127.7, 125.8, 125.0, 121.3 (d, J = 10.0 Hz),
70 109.0 (d, J = 24.3 Hz), 99.9, 97.3 (d, J = 26.1 Hz). HRMS (ESI)
([M+H]+) Calcd. for C14H11FN: 212.0876, Found: 212.0879.
3q: 2-(4-Chlorophenyl)-1H-indole
White solid. m.p. 201.3–202.6 °C (lit.29 m.p. 203–205 °C). 1H
NMR (400 MHz, CDCl3): δ 8.27 (1H, br, s), 7.65 (1H, d, J = 7.8
25 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.43–7.40 (3H, m), 7.25–7.21 (1H,
m), 7.17–7.13 (1H, m), 6.83 (1H, s); 13C NMR (100 MHz,
CDCl3): δ 136.9, 136.7, 133.4, 130.9, 129.2, 129.1, 126.3, 122.7,
120.7, 120.5, 110.9, 100.5. HRMS (ESI) ([M+H]+) Calcd. for
C14H1135ClN: 228.0580, Found: 228.0582.
30
75 3v: Methyl 2-phenyl-1H-indole-4-carboxylate26
3r: 5-Methoxy-2-phenyl-1H-indole
White solid. m.p. 208.7–210.1 °C. 1H NMR (400 MHz, CDCl3): δ
8.90 (1H, br, s), 7.94 (1H, d, J = 7.5 Hz), 7.74–7.72 (2H, m),
7.60–7.58 (1H, m), 7.52 (1H, s), 7.45–7.42 (2H, m), 7.37–7.33
(1H, m), 7.24–7.20 (1H, m), 4.04 (3H, s); 13C NMR (100 MHz,
80 CDCl3): δ 168.4, 140.1, 137.7, 131.9, 129.0, 128.9, 128.2, 125.5,
123.8, 121.3, 121.2, 115.8, 101.1, 51.8. HRMS (ESI) ([M+H]+)
Calcd. for C16H14NO2: 252.1025, Found: 252.1024.
White solid. m.p. 168.7–170.0 °C (lit.7 m.p. 166–169 °C). 1H
35 NMR (400 MHz, CDCl3): δ 8.26 (1H, br, s), 7.67–7.65 (2H, m),
7.47–7.43 (2H, m), 7.35–7.29 (2H, m), 7.11 (1H, s), 6.89–6.86
(1H, m), 6.77 (1H, s), 3.88 (3H, s); 13C NMR (100 MHz, CDCl3):
δ 154.6, 138.6, 132.5, 132.1, 129.8, 129.0, 127.6, 125.1, 112.6,
111.6, 102.4, 99.9, 55.9. HRMS (ESI) ([M+H]+) Calcd. for
40 C15H14NO: 224.1075, Found: 224.1077.
Acknowledgements
85 Financial supports from the National Natural Science Foundation
of China (Nos. 21172092, 20972057, and 21002039), the Natural
Science Foundation of Anhui (No. 090416223), the Key Project
3s: 7-Methyl-2-phenyl-1H-indole
8
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of Science and Technology of the Department of Education, 55 7. N. R. Deprez, D. Kalyani, A. Krause and M. S. Sanford, J. Am.
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