Cross-dehydrogenative coupling reaction using copper oxide impregnated on magnetite in deep eutectic solvents

Article abstract of DOI:10.1039/c5gc01745a

The synthesis of different tetrahydroisoquinolines using choline chlorideethylene glycol as a deep eutectic solvent (DES) and copper(ii) oxide impregnated on magnetite as a catalyst has been accomplished successfully. The copper catalyst amount is the low

Full text of DOI:10.1039/c5gc01745a

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Cross-Dehydrogenative Coupling Reaction using Copper Oxide
Impregnated on Magnetite in Deep Eutectic Solvents
Xavier Marset, Juana M. Pérez, and Diego J. Ramón*
Received 00th January 20xx,
Accepted 00th January 20xx
The synthesis of different tetrahydroisoquinolines using choline chloride:ethylene glycol as deep eutectic solvent (DES) and
copper(II) oxide impregnated on magnetite as catalyst has been accomplished succesfully. The copper catalyst amount is
the lowest loading ever reported. The presence of DES showed to be essential since the reaction in absence of this
medium did not proceed. A direct proportional relationship was found between conductivity of DES medium and yield
obtained. The DES and the catalyst could be reused up to ten times without a detrimental effect on the yield of the
reaction, with the aerobic conditions making the protocol highly sustainable, where the only waste is water.
DOI: 10.1039/x0xx00000x
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strategic place. To be qualified as a green medium, the
components of this solvent have to meet different criteria such
as availability, non-toxicity, biodegradability, recyclability,
Introduction
Tetrahydroisoquinolines are widely present in Nature.1 The
synthesis of these compounds has been payed attention in
industrial and academic research due to their biological and
pharmaceutical properties, such as anticancer2 and
anticonvulsant activities,3 enzymes inhibitors,4 ligands
receptors5 and therapeutic agents.6
inflammability, renewability and low price, among others. DES
(Deep Eutectic Solvent) is an environmentally benign
alternative to hazardous (organic) solvents and, in many cases,
might replace them. DESs are liquid systems formed from a
eutectic mixture of a solid Lewis or Brønsted acids and bases
which can contain a variety of anionic and/or cationic
species.19 These two components are capable of self-
association, often through a strong bond interaction, to form
an eutectic mixture with a melting or phase transition point
lower than that of each individual component.20 The
properties of a solvent, such as conductivity, viscosity, vapour
pressure and thermal stability can be fine-tuned by the
appropriate choosing of the mixture components, with the
large-scale preparation being feasible. Besides these
interesting advantages, the application of DES in Organic
Synthesis is in its childhood,21 with the related metal-catalysed
process being nearly unknown.22 Only, very recently, the
superparamagnetic CuFeO2 has been used as catalyst for the
The C-C bond formation via C-H activation7 is one of the most
challenging reactions in organic synthesis. Various strategies
for transition-metal-catalysed C-H bond activation have been
of significant interest, as they are environmentally friendly
processes, since no functionalization step needed. The C(sp3)-
H bond activation at α-position of a nitrogen has been broadly
used in different transformations. The key step, in this
transformation, is the generation of an iminium intermediate
assisted by the lone pair of nitrogen atom, via a single-electron
transfer (SET) mechanism.8
For this purpose an important number of different methods
have been developed, with metal-catalysed protocols being
well stablished. Different catalysts derived from vanadium,9
iron,10 copper,11 ruthenium,12 rhodium,13 palladium,14
antimonium,15 iridium16 or gold,17 among others have been
recently introduced. In all cases, the protocols needed a highly
reactive oxidizing agent such as peroxides or high oxygen
pressure. Moreover, the lack of recyclability, and the high
catalyst loading (5-20 mol%) made these protocols
unsustainable for large chemicals production. The metal-free
version using organic radical promoters, recently published,
has similar drawbacks.18
multicomponent synthesis of Imidazo[1,2-
citric acid medium.23
a]pyridines in DMU-
Here, we introduced
a recyclable copper-impregnated
magnetite catalyst for the C-H activation in choline
chloride:ethylene glycol as medium using bio-renewable air as
the only oxidizing agent.
Results and discussion
To start with this study, 2-(4-fluorophenyl)-1,2,3,4-
tetrahydroisoquinoline (1a) and phenylacetylene (2a) using
copper impregnated on magnetite as catalyst was selected as
the model reaction for the optimization of the conditions
(Table 1).
Within the framework of green chemistry, solvents occupy a
*Instituto de Síntesis Orgánica (ISO), and Departamento de Química Orgánica,
Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain.
Electronic Supplementary Information (ESI) available: [TEM images,
characterization data, 1H-NMR and 13C-NMR]. See DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the reaction conditions.a
Entry
1
Catalyst (mol%)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (0.91)
CuO-Fe3O4 (0.37)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (1.82)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (3.64)
CuO-Fe3O4 (3.64)
DES (molar ratio)
T (ºC)
50
50
50
50
50
50
50
50
50
50
50
RT
100
50
50
50
53
50
3a (%)b
4a (%)b
ChCl:urea (1:2)
55
50
59
83
60
10
83
56
95
75
92
57e
38
42
49
32
17
40
29
13
11
2
2
AcChCl:urea (1:2)
3
ChCl:glycerol (1:2)
4
ChCl:ethylene glycol (1:2)
Ph3P+MeBr–:glycerol (1:2)
ChCl:resorcinol (1:1)
5
11
21
3
6
7
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
ChCl:ethylene glycol (1:2)
Ethylene glycol
8
21
3
9
10c
11d
12
13
14f
15g
16h
17i
18
2
2
0
0
0
9
6
0
9
b
1
a Reaction carried out using compounds 1a (0.5 mmol) and 2a (1 mmol) in 1mL of DES. Conversion determined by H-NMR. c Reaction
carried out using compounds 1a (0.5 mmol) and 2a (0.5 mmol) in 1mL of DES. d Reaction carried out using 1a (0.5 mmol) and 2a (2.5
mmol) in 1mL of DES. e 99% of conversion after 7 days of reaction. f Reaction carried out in Argon atmosphere. g Reaction carried out using
visible LED light irradiation. h Reaction carried out under microwave irradiation during 10h at 80W. I Reaction carried out under ultrasound
bath during 8h.
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Initially, the reaction was performed using different DESs
(entries 1-6), obtaining the best result with the mixture choline
chloride (ChCl):ethylene glycol (1:2) (entry 4), with the only by-
product observed being the corresponding lactam 4a. Then,
the amount of catalyst was evaluated obtaining similar results
when loading was decreased (entry 7). However, a further
decrease of catalyst loading down to 0.37 mol% (entry 8) led
to lower yield. Increasing the amount of copper to 3.64 mol%
(entry 9) the yield could be improved. It should be pointed out
that even this high amount of copper catalyst is one of the
lowest metal catalyst loading reported so far in the literature.
The addition of only one equivalent of alkyne led to the
decrease of the reaction yield (entry 10), and the addition of
an excess of alkyne did not improve it (entry 11). The study of
the temperature of reaction was carried out obtaining, after
seven days of reaction at room temperature, a full conversion
of the starting material (entry 12). Increasing the temperature
up to 100 ºC decreased the yield (entry 13). The reaction was
carried out under argon atmosphere (entry 14) obtaining a
very low yield, highlighting the capital role of oxygen in the air
as final oxidizing agent. To finish with the optimization of the
reaction conditions, the reaction was tested using LED
irradiation (photoredox conditions), microwave irradiation and
an ultrasound bath (entries 15-17), but the yield was not
improved. Finally, the reaction was repeated in ethylene glycol
obtaining a modest result (entry 18).
ChCl:(CH2OH)2
(1:2)
90
80
70
60
50
40
30
20
10
0
ChCl:glycerol (1:2)
Ph3PMeBr:glycerol
(1:2)
ChCl:urea
(1:2)
Yield (%) = 4,0·Conductivity + 52,6
R2 = 0,9915
H2O
0
2
4
6
8
Conductivity (mS/cm)
Figure 2.Relationship between solvent conductivity and yield.
We also found an interesting correlation between the DES
conductivity and the yield of the desired product (Figure 2), in
such a way that a higher conductivity affords a better yield.
Since an iminium intermediate is generated on the reaction
media, a better conductivity means an easier movement of
ions that could explain the increase in the yield. Nevertheless,
yields and conductivities of VOC solvents or water did not fit in
this plot. It should be pointed out that the reaction using
ChCl:1,2-propanodiol:water (1:1:1, conductivity 12.09mS/cm)
or ChCl:glycerol:water (1:2:1, conductivity 13.78mS/cm) gave
the product 3a in 46 and 53% yield respectively. Although
these two mixtures have higher conductivity than previous DES
used, the presence of water change the direct proportion
between yield and conductivity probably due to the high
nucleophilic character of water.
To prove the essential role of DES [ChCl:(CH2OH)2], other VOC
solvents were tested as reaction medium (Figure 1). In all cases
a mixture of products 3a and 4a were obtained in a ratio close
to 1:1, highlighting the role of DES for minimizing the lactam
formation. It should be pointed out that when the reaction
was performed in 1,4-dioxane as solvent the main product was
Once the optimal conditions were determined, the reaction
was repeated with a variety of catalysts prepared by the
simple impregnation protocol24 (Table 2). The reaction without
catalyst gave a poor yield (entry 2). Then, the activity of the
support was evaluated using magnetite as the unique catalyst.
Nanoparticles or microparticles of magnetite (entries 3 and 4)
were used with the results showing the inactivity of the
support, reaching a low conversion of product and biggest
amount of compound 4a, as the only by-product detected by
CG-MS. Once the activity of magnetite was tested, different
metal oxides impregnated on magnetite (entries 5-17) were
evaluated as catalyst, observing that none of them gave better
results than the copper catalyst (entry 1). After that, different
copper salts were tested (entries 18-20), obtaining from
moderate to good results, but poorer results than the one
obtained by the heterogeneous copper oxide impregnated on
magnetite.
4a.
100
50
3a
4a
0
Figure 1.Obtained yield in different solvents.
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Table 2. Optimization of the catalyst.a
Entry
1
Catalyst (mol%)
CuO-Fe3O4 (3.64)
-
3a (%)b
Entry
12
Catalyst (mol%)
3a (%)b
33 (47)
33 (7)
13 (4)
35 (28)
78 (2)
37 (8)
88 (5)
46 (10)
80 (6)
51 (9)
95 (3)
6 (20)
0 (34)
15 (48)
4 (31)
30 (30)
8 (28)
0 (45)
46 (7)
13 (0)
5 (21)
IrO2-Fe3O4 (0.26)
2
13
PtO/PtO2-Fe3O4 (1.08)
Au2O3-Fe3O4 (0.28)
PdO/Cu-Fe3O4 (3.05/1.79)
NiO/Cu-Fe3O4 (1.82/1.76)
WO3-Fe3O4 (1.13)
CuCl2 (8.5)
3
Nano-Fe3O4 (259.15)
Micro-Fe3O4 (259.15)
CoO-Fe3O4 (2.83)
NiO-Fe3O4 (2.06)
Ru2O3-Fe3O4 (2.64)
Rh2O3-Fe3O4 (0.84)
PdO-Fe3O4 (2.43)
Ag2O-Fe3O4 (2.5)
OsO2-Fe3O4 (1.03)
14
4
15
5
16
6
17
7
18
8
18
CuO (4.04)
9
20
Cu(OAc)2 (3.64)
10
11
21
CuO (3.64) + Fe3O4 (255.26)
1
a Reaction carried out using compounds 1a (0.5 mmol) and 2a (1 mmol) in 1mL of DES. b Yield determined by H-NMR, yield of oxidised
compound 4a in brackets.
After that, the addition of a mixture of CuO and Fe3O4, was up to 10 times without any decrease in the yield. When just the
evaluated (entry 21), obtaining a decrease in the conversion catalyst was recovered, by magnetic decantation, and fresh solvent
compared to the impregnated catalyst, what seems to be related was used, the obtained yield showed an important decrease,
with a synergic effect between the metal oxide and support in the pointing out the sharp decrease of the catalyst after 4 reaction
catalyst.
cycles. In fact, the ICP-MS analysis of crude reaction solution
In order to establish the reusability of the catalyst and DES, the showed the leaching of a small amount of copper (14.2 ppm; 3.6 %
reaction with nitromethane (see Table 5, entry 1) was repeated of the initial amount) and iron (0.30 ppm; 0.001% of initial amount),
under standard conditions (Figure 3). When the reaction was values completely different from the reported solubility of these
completed, the mixture was extracted with cyclopentyl methyl metal oxides (3.68 ppm for CuO and 10.85 ppm for Fe3O4).26 The
ether, recently reported as a potential green alternative solvent.25 higher solubility in DES of copper species could seem to show that
All organic compounds were removed and the mixture of DES and the heterogeneous catalyst is only a reservoir of highly active
catalyst, lower phase in the decantation, was reused under the copper clusters. To try to understand more this effect, the standard
same reaction conditions. This catalytic mixture could be recycled reaction was performed as usual (Table 2, entry 1) and, after 36 h,
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only the catalyst was removed by magnetic decantation, with the
yield of 3a being estimated in 40% by CG-MS. The mixture was
heated again during 36 h, and after usual work up the yield of
compound 3a increased up to 65%, with the oxidised by-product 4a
reaching 25%. At the end of the first cycle, the catalyst was
removed, by magnetic decantation, as well as the organics by
cyclopentyl methyl ether extraction (yield of compound 3a 93%).
Then, the used DES medium was employed alone in other cycle
(without catalyst) and the final product 3a was obtained in 52%
(29% for by-product 4a). These two experiments showed that there
was a partial leaching of active species, capable to perform the
oxidative step. However, and due to the great amount of by-
product, these leached species seemed to be less effective to
catalyze the final nucleophilic addition.
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DOI: 10.1039/C5GC01745A
Before reaction
10000
8000
6000
4000
2000
0
Fit
Cu 2p3/2
CuO 2p3/2
928
933
938
943
948
Binding energy (eV)
In order to study the effect of the reaction conditions on the copper
heterogeneous catalyst, the nanosize distribution of the copper
nanoparticles were measured after one reaction cycle. A uniform
size distribution was found, 60% of nanoparticles have an average
size between 2-4 nm. In the fresh catalyst 63% of them have a size
average between 2-6 nm, showing a small overall decrease on the
particle size with the reaction cycles which is in concordance with a
partial solubilization-readsorption of copper species.
3450
2950
2450
1950
1450
950
After reaction
Fit
Cu2O 2p3/2
CuO 2p3/2
Cu(OH)2 2p3/2
CuO 2p3/2 sat.
CuO 2p3/2 sat.
450
-50
926
931
936 941
Binding energy (eV)
946
CuO-Fe3O4
CuO-Fe3O4 + DES
100
Figure 5. XPS of fresh and recycled copper catalyst.
The XPS and Auger Electron Spectroscopy (AES, see supporting
information) studies of catalyst showed the transformation of the
initial Cu(0) onto the corresponding copper(I) oxide and Cu(OH)2 in
the recycled catalyst (Figure 5) with CuO being the main species in
both cases. These changes in particle size as well as the initial
oxidation state seemed not to affect the activity of the catalyst,
since it could be reused ten times without losing its activity.
Once the best conditions were established, the scope of the
reaction was evaluated. First of all, different pro-electrophiles were
tested by modifying the nitrogen substituent at the
tetrahydroisoquinoline ring (Table 3). The reaction was carried out
with different N-substituted substrates. When the substituent was
an aryl group, bearing both, electron-withdrawing or electron-
donating groups (entries 1, 3), the results were excellent. In the
case of phenyl derivatives, the yield was moderate. On the other
hand, when the reaction was carried out with the free amine or
with a strong electron-withdrawing group such as tosyl, the
reaction did not take place at all (entries 4-5), recovering the
starting material unchanged.
50
0
1
2
3
4
5
6
7
8
9
10
Cycle
Figure 3. Recycling of the CuO-Fe3O4 catalyst and CuO-Fe3O4+DES.
80
Recycled catalyst
60
Initial catalyst
40
20
0
Having studied the scope for pro-electrophiles, we tested a variety
of alkynes as pro-nucleophiles (Table 4). Once again, the reaction
took place obtaining from moderate to good yields when the alkyne
had an electron-rich (entry 1) or electron-poor (entries 2-5) aryl
substituent ones. Not only aryl substituents were tested, but also
olefinic and aliphatic ones (entries 6-9) and the reaction still worked
smoothly. It has to be pointed out that, in the case of using a
dialkyne, the reaction was selective in such a way that only one of
the two alkynes reacted (entry 8).
Particles size (nm)
Figure 4. Particle size distribution of fresh and recycled catalyst.
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After the study of alkynes, as pro-nucleophiles, was completed, we
Table 3. Scope of the reaction with different pro-electrophiles.a
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decided to check other type reagents (TableD5O),I:s1u0c.h10a3s9/nCit5rGoCa0lk1a74n5eAs
(entry 1), heterocycles (entry 2), phosphonates (entry 3), sylil enol
ethers (entry 4), ketones (entries 5-6) and fluoroborates (entry 7),
proving that this methodology can be applied to a wide range of
substrates with very different properties and obtaining similar
results. It should be noted that both, silyl enol ether and ketone
(entries 4 and 5) afford the same product 3r but with different
diastereomeric ratio. Only starting material alongside with a small
amount of by-product 4a were detected from the crude of the
reaction, when moderate or low yield of product was obtained.
Entry
R
Product
3a
Yield (%)b
1
2
3
4
5
4-FC6H4
94
63
90
0/0c
0
Experimental
General
Ph
3b
XPS analyses were carried out on a VG-MicrotechMutilab. XRD
analyses were obtained on a BRUKER D-8 ADVANCE diffractometer
with Göebel mirror, with a high temperature chamber (up to
900ºC), with a X-ray generator KRISTALLOFLEX K 760-80F (3KW, 20-
60KV and 5-80mA).
4-MeOC6H4
3c
Ts
3d
H
3e
Table 5. Scope of the reaction with different pro-nucleophiles.a
a Reaction carried out using compounds 1a (0.5 mmol) and 2a (1
mmol) in 1mL of DES. Isolated yield after distillation. Yield
obtained after 7 days of reaction at room temperature.
b
c
Table 4. Scope of the reaction using different alkynes.a
Entry
Nu-H
Product
3o
Yield (%)b
95/15c
84
1
2
MeNO2
3p
Entry
R’
Product
3f
Yield (%)b
3
3q
45
1
2
3
4
5
6
7
8
9
4-MeOC6H4
4-BrC6H4
4-CF3C6H4
3-ClC6H4
2-BrC6H4
1-C6H9
57
61
68
58
64
37
83
71
65
3g
4
5
6
3r
3r
50d
38e
3h
3i
3j
3k
3s
3t
24
51
C6H11
3l
3m
3n
7
HC≡CC5H10
c
THPOCH2
a
Reaction carried out using compounds 1a (0.5 mmol) and 4 (1
a Reaction carried out using compounds 1a (0.5 mmol) and 2a (1
mmol) in 1mL of DES. b Isolated yield after distillation. c Yield after 7
b
c
days at rt. Mixture of isomers syn:anti (1:1.25).e Mixture of
d
mmol) in 1mL of DES. Isolated yield after distillation. THPO
stands for 2-(tetrahydro-2H-pyran-2-yl)oxy.
isomers syn:anti (1.4:1).
6 | J. Name., 2012, 00, 1-3
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TEM images were obtained on a JEOL, model JEM-2010 equipped combined organic phases were washed with brine aVniedwdArrtiieclde Oonvliener
with an X-ray detector OXFORD INCA Energy TEM 100 for sodium sulphate. The solvent was removeDdOaI:n1d0.1t0h3e9/rCe5sGidCu0e17w45aAs
microanalysis (EDS). XRF analyses were obtained on a PHILIPS purified by column chromatography on silica gel using hexane/ethyl
MAGIX PRO (PW2400) X-ray spectrometer equipped with a rhodium acetate (20:1) as an eluent.
X-ray tube and a beryllium window. BET isotherms were carried out Procedure
for
the
preparation
of
2-tosyl-1,2,3,4-
on a AUTOSORB-6 (Quantachrome), using N2. Melting points were tetrahydroisoquinoline (1d).28 To
a
mixture of 1,2,3,4-
obtained with a Reichert Thermovar apparatus. NMR spectra were tetrahydroisoquinoline (0.2663 g, 2 mmol) and pyridine (0.5 mL), p-
1
recorded on a Bruker AC-300 (300 MHz for H and 75 MHz for 13C) toluenesulfonyl chloride (0.46 g, 2.4 mmol) in dry dichloromethane
1
using CDCl3 as a solvent and TMS as internal standard for H and (5 mL) was added slowly and stirred at room temperature for 1 h.
13C; chemical shifts are given in δ (parts per million) and coupling The reaction mixture was then washed with aqueous 1N HCl (10
constants (J) in Hertz. FT-IR spectra were obtained on a JASCO mL) and extracted with diethyl ether (2 x 10 mL). The combined
4100LE (Pike Miracle ATR) spectrophotometer. Mass spectra (EI) organic phases were washed with water (10 mL), brine solution (10
were obtained at 70 eV on a Himazdu QP-5000 spectrometer, giving mL) and dried over anhydrous sodium sulphate. The filtered
fragment ions in m/z with relative intensities (%) in parentheses. solution was concentrated and was purified by column
The chromatographic analyses (GLC) were determined with a chromatography to yield 2-tosyl-1,2,3,4-tetrahydroisoquinoline 1d.
Hewlett Packard HP-5890 instrument equipped with a flame General procedures for the synthesis of compounds 3. To a stirred
ionization detector and 12 m HP-1 capillary column (0.2 mm diam, solution of the corresponding tetrahydroisoquinoline 1 (0.5 mmol)
0.33 mm film thickness, OV-1 stationary phase), using nitrogen (2 and catalyst (100 mg) in 1 mL of DES were added and the
mL/min) as a carrier gas, Tinjector = 275 ºC, Tdetector = 300ºC, Tcolumn
=
corresponding nucleophiles 2 (1 mmol). The resulting mixture was
60ºC (3 min) and 60-270 ºC (15 ºC/min), P = 40 kPa. Thin layer stirred at 50 ºC during 3 days until the end of the reaction. The
chromatography (TLC) was carried out on Schleicher&Schuell mixture was quenched with water and extracted with AcOEt (3 x 5
F1400/LS 254 plates coated with a 0.2 mm layer of silica gel; mL). The organic phases were dried over MgSO4, followed by
detection by UV254 light. Column chromatography was performed evaporation under reduced pressure to remove the solvent. The
using silica gel 60 of 40-63 mesh. All reagents were commercially product was usually purified by chromatography on silica gel
available (Acros, Aldrich, Fluorochem) and were used as received. (hexane/ethyl acetate) and/or distillation to give the corresponding
The ICP-MS analyses were carried out on a Thermo Elemental product 3. Physical and spectroscopic data, as well as literature for
VGPQ-ExCell spectrometer. The Elemental Analysis was performed known compounds, are given below.
on an Elemental MicroanalyzerThermoFinningan Flash 1112 Series.
Procedure for catalyst recycling. Reaction was performed according
to the general procedure. After 3 days, the mixture was extracted
with cyclopentyl methyl ether, dissolving all organic compounds, in
such a way that the mixture of DES and catalyst remained in the
reaction vessel. To the remaining mixture, nitromethane (or
phenylacetylene) and compound 1a were added, carrying out the
reaction again under the same reaction conditions.
Synthetic procedures
General procedure for the preparation of CuO-Fe3O4 catalyst. To a
stirred solution of CuCl2 (1 mmol, 130 mg) in deionized water (120
mL) was added commercially available Fe3O4 (4 g, 17 mmol, powder
< 5 µm, BET area: 9.86 m2/g). After 10 minutes at room
temperature, the mixture was slowly basified with NaOH (1M) until
pH around 13. The mixture was stirred in air during one day at room
temperature. After that, the catalyst was filtered and washed
several times with deionized water (3 × 10 mL). The solid was dried
at 100ºC during 24 h in a standard glassware oven, obtaining
thereafter the expected catalyst.
On the other hand, in order to recycle only the catalyst, we added
water to the reaction mixture, dissolving the DES and decanting the
solution with the aid of a magnet, the catalyst remained in the
reaction vessel. Then, fresh DES, nitromethane and compound 1a
were added to the vessel, carrying out the new reaction under
standard conditions.
General procedure for the preparation of DES. A mixture of
hydrogen-bond donor and hydrogen-bond acceptor, with the
previously specified molar ratio, were added in a round bottom
flask under inert atmosphere. The mixture was stirred during 60
minutes in a range value of T between 65-80 ºC, obtaining the
corresponding DES.
Conclusions
In conclusion, we have demonstrated that the appropiate
mixture of DES and copper (II) oxide impregnated on
magnetite is a good catalytic system to perform the cross-
General
procedure
for
the
N-arylation
of
tetrahydroisoquinolines.27 Copper(I) iodide (200 mg, 1.0 mmol) and
potassium phosphate (4.25 g, 20.0 mmol) were placed into a 50 mL
two-neck flask. The flask was evacuated and back filled with argon.
2-Propanol (10.0 mL), ethylene glycol (1.11 mL), 1,2,3,4-
tetrahydroisoquinoline (2.0 mL, 15 mmol) and the corresponding
iodoaryl (10.0 mmol) were added successively by syringe at room
temperature. The reaction mixture was heated at 90 °C for 24 h and
then allowed to cool to room temperature. Diethyl ether (20 mL)
and water (20 mL) were then added to the reaction mixture. The
organic layer was extracted with diethyl ether (2 × 20 mL). The
dehydrogenative
coupling
reaction
between
tetrahydroisoquinolines with
a
broad range of pro-
nucleophiles in a highly selective way. The little amount of
copper catalyst used is the lowest copper catalyst loading ever
published. A direct proportional relationship between yield
and conductivity was found in absence of water. The highly
recyclability of the mixture (solvent + catalyst), as well as the
use of cyclopentyl methyl ether for the work up drives this
protocol to the Green Chemistry topic. Moreover, the protocol
uses only the oxygen present in air, showing the high activity
of catalytic system and providing the first example of a
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ARTICLE
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Zhang, T. F. Jamison, C. R. J. Stephenson, Ang. Chem. Int. Ed.
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This work was supported by the Spanish Ministerio de
Economía y Competitividad (MICINN; CTQ2011-24151) and
University of Alicante. J.M.P. thanks the MICINN (FPI program)
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26 A. P. Abbot, G. Capper, D. L. Davies, K. J. McKenzie, S. U. Obi,
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