Magnetically separable nanoferrite-anchored glutathione: Aqueous homocoupling of arylboronic acids under microwave irradiation

Article abstract of DOI:10.1039/c0gc00083c

A highly active, stable and magnetically separable glutathione-based organocatalyst provided very good to excellent yields to symmetric biaryls in the homocoupling of arylboronic acids under microwave irradiation.

Full text of DOI:10.1039/c0gc00083c

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Luque, Varma and Baruwati
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Magnetically separable nanoferrite-anchored glutathione: aqueous
homocoupling of arylboronic acids under microwave irradiation
a
b
b
Rafael Luque,* Babita Baruwati and Rajender S. Varma*
Received 5th May 2010, Accepted 20th May 2010
DOI: 10.1039/c0gc00083c
A
highly active, stable and magnetically separable
Experimental
glutathione-based organocatalyst provided very good to
excellent yields to symmetric biaryls in the homocoupling
of arylboronic acids under microwave irradiation.
Materials preparation
Materials were synthesized following the protocol previously
12,15
described by our group.
glutathione-based organocatalyst was performed as follows:
Nano-Fe (0.5 g) was dispersed in 15 mL water and 5 mL
A typical preparation of the
Symmetrical biaryl motifs are present in a wide range of natural
products which have interesting properties including antivirals,
1
2
3
3
O
4
polymers and ligands employed in catalysis. This important
family of compounds can be synthesized by a number of organic
protocols including the Suzuki and Sonogashira cross coupling
reactions as well as their homocoupling alternatives. Both
types of reactions have generally been reported to be catalysed
with a variety of supported transition metal and/or transition
metal complexes (mostly palladium) and oxidants under base
of methanol and sonicated for 15 min. Glutathione (reduced
form) (0.4 g) dissolved in 5 mL of water was added to
this solution and again sonicated for 2 h. The glutathione-
functionalized nanomaterial (nano-organocatalyst) was then
isolated by centrifugation, washed with water and methanol,
4,5
4–6
◦
and dried under vacuum at 50 to 60 C.
4,6
conditions in a range of solvents.
Materials characterisation
More recently, Fe has joined the group of catalysts employed
7
for such purposes and reports of iron-catalysed Suzuki and
Sonogashira protocols as well as related C–N and three-
component couplings have recently been described. However,
the effect of impurities of other metals including palladium in
these systems have created the need of further investigations to
MMS X-ray diffractometer with a Cu-Ka source in the 20 to
8
9
◦
-1
80 2q range. The data were collected with a step of 1 min .
10
The phase and crystallinity of the catalyst were determined
by powder X-ray diffraction (XRD) (Fig. 1). All diffraction
planes could be well assigned to the magnetite (JCPDS card no.
11
prevent metal-trace contaminant catalysed processes.
0
0-002-1035) phase of iron oxide without the presence of any
We have recently reported a novel magnetically-separable
glutathione-based organocatalyst that can provide high activ-
ities and selectivites in a variety of base-catalysed processes
including the Knoevenagel and Paal–Knorr reactions. In-
spired by a recent report of the Pd-catalysed homocoupling
detectable amount of impurities from other oxide or hydroxide
phases. Broadening of the XRD peaks clearly indicate the
nanocrystalline nature of the material.
12
6a,13
of arylboronic acids in water
and our previous results that
showed high activities of supported iron oxide nanoparticles
14
in the efficient homocoupling of thiophenols, we envisioned
the potential use of the nanoferrite-glutathione material in
the microwave (MW)-assisted aqueous homocoupling of aryl
boronic acids as alternative to Suzuki catalysed synthesis of
symmetric biaryls (Scheme 1).
Scheme 1 Microwave-assisted heterogeneously catalysed homocou-
pling of boronic acids in water.
Fig. 1 X-Ray diffraction pattern for the as-synthesized catalyst.
TEM micrographs were recorded on a Phillips CM 20 TEM
microscope at an operating voltage of 200 kV. A drop of
as-synthesized nanoparticles was loaded on a carbon-coated
copper grid and then allowed to dry at room temperature
before recording the micrographs. The image depicted in Fig. 2
showed uniform-sized particles with cube like morphology with
an average size range of 10–15 nm, in good agreement with
a
Dpto. Qu ´ı mica Org a´ nica, Universidad de C o´ rdoba, Campus de
Rabanales, Edificio Marie Curie, Ctra Nnal IV, Km 396, E14014,
C o´ rdoba, Spain. E-mail: q62alsor@uco.es; Fax: +34 957212066;
Tel: +34 957211050
b
Sustainable Technology Division, National Risk Management Research
Laboratory, Environmental Protection Agency, 26 West M. L. K. Drive,
MS 443, Cincinnati, Ohio, 45268, USA. E-mail:
Varma.Rajender@epa.gov; Fax: +1 5135697677
1
540 | Green Chem., 2010, 12, 1540–1543
This journal is © The Royal Society of Chemistry 2010

◦
different temperatures ranging from 150 to 170 C were reached
depending on the reaction and/or the catalyst employed. The
identity of the ensuing reaction products were also confirmed by
1
H NMR using a JEOL 400 spectrometer operating at 400.13
MHz. Chemical shifts were calibrated using the internal SiMe
resonance.
4
A typical catalytic test was performed as follows: 1 mmol
phenyl boronic acid was dissolved in 2 mL water after addition of
a few drops of NaOH 0.1 M solution and then 0.05 g catalyst was
added. The resulting mixture was microwaved for 45–60 min at
◦
3
00 W (maximum power output, 120 C maximum temperature
reached) and the contents were subsequently analysed by GC
confirmed by HPLC). The response factors of the main reaction
(
Fig. 2 TEM image of the as-synthesized catalyst.
products were determined with respect to the starting materials
from GC analysis using known compounds in calibration
mixtures of specified compositions. Reagents were used as
purchased from Sigma-Aldrich, Fluka or Avocado.
Isolated yields were obtained from the resulting reaction
mixture via filtration of the crude product through Celite
(solvent removed under reduced pressure) and purification of
the residue (if needed) by flash chromatography on silica gel
(hexane–ethyl acetate) to afford the corresponding products.
the crystallite size (10 ± 0.5 nm) calculated using the Scherrer
equation from the full width at half-maximum (FWHM) of the
major XRD diffraction planes (Fig. 1).
FTIR spectra (not shown) were recorded on a Perkin-Elmer
-
1
SPETRUM 2000 FTIR instrument in the range 400–3700 cm .
-
1
A band observed at 592 cm was due to the vibration of the
Fe–O bond of ferrite. This spectrum also provided evidences
of the strong linkage of thiol groups from glutathione to the
12
nanoferrite as previously reported
Results and discussion
Initial experiments with phenyl boronic acid showed the homo-
coupling reaction proceeded smoothly with almost quantitative
conversion of starting material after 45–60 min reaction under
the optimised conditions (Table 1).
Catalytic experiments
Homocoupling reactions under microwave irradiation condi-
tions were carried out in a Microwave CEM-DISCOVER
reactor with PC control and monitored by sampling aliquots
of reaction mixture that were subsequently analysed by Gas
Chromatography-Mass Spectrometry (GC/GC-MS) using an
Agilent 6890 N GC model equipped with a 7683B series
autosampler fitted with a DB-5 capillary column and an
FID detector. Experiments were conducted on a closed vessel
Interestingly, a glutathione-free ferrite catalyst (Fe
3
4
O )
showed significantly reduced activity under identical reaction
conditions (Table 1, entry 2). This phenomenon seems to be
related to the inherent basicity of the nano-ferrite glutathione
system as compared to the parent ferrite, in good agreement
with previous reports in which an optimum basicity of the
buffer concentration was needed to provide optimised yields
(
pressure controlled) under continuous stirring. The microwave
13
method was generally power controlled. The samples were
microwave-irradiated (300 W, maximum power output) and
of products. However, these authors did not consider any
potential effect of the support in the activity of the systems.
a
Table 1 Optimisation of the activities of nanoferrite materials in the MW-assisted aqueous homocoupling of phenylboronic acid
Entry
Catalyst
Time/min
Conversion (mol%)
Shomocoupling (mol%)
1
2
3
4
5
6
7
8
Blank (no catalyst)
Nano-ferrite
120
60
60
60
60
45
45
45
45
<5
35
48
60
39
94
95
82
67
—
—
>95
>95
>90
>90
>99
>95
>95
>90
—
Nano-ferrite + 0.5 mL NaOH 0.1 M
Nano-ferrite + 1 mL NaOH 0.1 M
Nano-ferrite + 2 mL NaOH 0.1 M
Nano-ferrite glutathione
Nano-ferrite glutathione + 0.5 mL NaOH 0.1 M
Nano-ferrite glutathione + 1 mL NaOH 0.1 M
Nano-ferrite glutathione + 2 mL NaOH 0.1 M
Nano-ferrite glutathione
9
1
b
b
0
1440 (conventional heating)
a
Reaction conditions: 1 mmol phenyl boronic acid, 2 mL water with few drops of NaOH 0.1 M solution (to facilitate dissolution of the boronic acid),
.05 g catalyst, 300 W, 120 C (maximum temperature reached). Conventionally heated reaction, 120 C, 24 h, same conditions as for microwave
◦
b
◦
0
experiments.
This journal is © The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 1540–1543 | 1541

A further addition of NaOH solution to the nanoferrite
material increased yields to some extend but inferior activities
were observed in all cases (Table 1, entries 3–5) compared to
those achieved with the ferrite-glutathione catalyst.
Moreover, the addition of increasing quantities of NaOH
solution has a detrimental effect on the yield of the products for
the nano-ferrite glutathione system, possibly due to the partial
cleavage of glutathione moieties from the catalyst under MW
irradiation conditions. The combination of the transition metal
iron oxide catalyst with the basicity of the amine groups from the
gluthatione moiety is therefore the key asset for the successful
homocoupling of phenyl boronic acid under the investigated
conditions.
Table 2 MW-assisted aqueous homocoupling of substituted aryl-
a
boronic acids using nanoferrite glutathione as catalyst
Time/
min
Conversion
(mol%)
S
homocoupling
(mol%)
Entry
1
Substrate
45
60
60
94
90
87
>99
2
3
>99
>95
MW-assisted reactions were also found to remarkably supe-
rior to the activities of the catalyst under a conventionally heated
system, in which negligible conversion of starting material was
observed after 24 h reaction under identical conditions to those
utilised in the MW protocol (1 mmol boronic acid, 2 mL water
4
5
6
45
45
60
91
89
80
>99
>99
>99
◦
with NaOH 0.1 M, 120 C, 0.05 g catalyst). Selectivities, in
general, were very good for the homocoupling product, although
increasing quantities of deborylated products were obtained at
higher quantities of basic solution used (Table 1). This is a side
reaction of Suzuki/homocoupling reactions involving boronic
16
acids that corroborates earlier observations.
Upon optimisation of reaction conditions, the scope of the
protocol was subsequently extended to a range of substi-
tuted arylboronic acids (Table 2). Results summarized here
demonstrate the methodology was also amenable to a wide
range of substituents regardless of their electron-donating
or withdrawing nature, making this environmentally-friendly
protocol very useful from the viewpoint of simplicity and
versatility (high conversions typically obtained in 45–60 min
under microwave irradiation conditions). Of particular interest
were the selectivities obtained for pyridyl and pyrazole boronic
acids (Table 2, entries 11 and 12). Only small quantities
of homocoupling products were obtained in these reactions,
confirming the previously reported lability of such substrates
7
8
60
45
84
92
>99
>99
9
60
60
70
75
85
16
10
>90
to deborylation phenomena.
The catalyst was also found to be highly stable and reusable
under the investigated reaction conditions, preserving over 90%
of its initial activity after 4 cycles (Fig. 3, left) and easily separable
17
from the final reaction mixture with a simple magnet (Fig. 3,
b
1
1
1
2
60
60
59
67
<40
b
65
a
Reaction conditions: 1 mmol boronic acid, 2 mL water with few drops
of NaOH 0.1 M solution (to facilitate dissolution of the boronic acid),
◦
0
.05 g nano-ferrite glutathione catalyst, 300 W, 120-130 C (maximum
b
temperature reached). The difference in selectivity to 100 corresponds
to the respective deborylation products.
right). These results were in good agreement with previous
reports of the activity of such materials in microwave-assisted
Fig. 3 Reuses of the magnetically separable nanoferrite-glutathione
catalyst in the microwave-assisted homocoupling of phenylboronic acid.
Reaction conditions: 1 mmol phenyl boronic acid, 2 mL water with few
drops of NaOH 0.1 M solution, 0.05 g catalyst, 300 W, 120 C max. temp.
reached (left); catalyst separation using an external magnet (right).
12,17
catalysed processes.
The strong anchoring of the glutathione
◦
to the ferrite support through the thiol group seem to be related
with the observed high reusability of the catalyst.
1
542 | Green Chem., 2010, 12, 1540–1543
This journal is © The Royal Society of Chemistry 2010

Further studies related to the observed deborylation side
reaction as well as the use of iron oxide nanoparticles in related
coupling processes are currently under active investigation in
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Conclusions
6
We have reported the preparation of versatile glutathione-based
nano-organocatalysts nanoparticles that are catalytically active
in the microwave-assisted homocoupling of aryl boronic acids
in water. We envisage these materials to be of utility in other
coupling reactions as well as related base-catalysed processes,
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Green Chem., 2010, 12, 1540–1543 | 1543