Silica-immobilized NHC-gold(I) complexes: Versatile catalysts for the functionalization of alkynes under batch and continuous flow conditions

Article abstract of DOI:10.1021/acscatal.7b02142

Immobilized sterically demanding NHC-Au(I) complexes silica-[(IPr_R)Au]Cl and silica-[(IAdPr_R)Au]Cl are synthesized and characterized. These complexes are suitable catalysts in typical homogeneous Au(I)-catalyzed alkyne reactions such

Full text of DOI:10.1021/acscatal.7b02142

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Article
Silica Immobilized NHC-Gold(I) Complexes: Versatile Catalysts for the
Functionalization of Alkynes under Batch and Continuous Flow Conditions
Jeymy T. Sarmiento, Samuel Suarez-Pantiga, Andrea Olmos, Teresa Varea, and Gregorio Asensio
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02142 • Publication Date (Web): 11 Sep 2017
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Silica Immobilized NHCꢀGold(I) Complexes:
Versatile Catalysts for the Functionalization of
Alkynes under Batch and Continuous Flow
Conditions
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Jeymy T. Sarmiento, Samuel Suárez-Pantiga,† ,§ Andrea Olmos, ‡ §
,
Teresa Varea* and Gregorio Asensio*
Departamento de Química Orgánica, Universidad de Valencia,
Avda. Vicente Andrés Estellés s/n 46100ꢀBurjasot, Valencia, Spain
KEYWORDS: Gold catalysis, Immobilized catalyst, Flow Chemistry, Alkyne, NHC ligand
ABSTRACT: Immobilized sterically demanding NHCꢀAu(I) complexes Silicaꢀ[(IPrR)Au]Cl and
Silicaꢀ[(IAdPrR)Au]Cl are synthesized and characterized. These complexes are suitable catalysts
in typical homogeneous Au(I) catalyzed alkyne reactions such as the hydration, hydroamination,
hydroarylation or cycloisomerization. The results obtained with the immobilized catalysts in
reactions in batch are comparable to those obtained with their homogeneous counterparts with
the advantage of easily recovered and recycled in successive reactions. Their catalytic activity
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decreases when reused in batch reactions probably due to crushing associated with magnetic
stirring. In contrast, these immobilized catalysts are very effective when used under continuous
flow conditions in which the same cartridge can be used to catalyze successively different types
of reaction for a long period without noticeable loss of activity.
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INTRODUCTION
Gold is a transition metal that is not considered toxic. For example, in the European Union its
presence is permitted in food1 and its concentration in drugs is not limited by law, unlike what
happens with other metals used in catalysis.2 This is a good reason to develop catalysts based on
this metal to be applied to the synthesis of organic compounds of interest in foods or medicine.
In the last decades, homogeneous catalysis with gold (I) complexes has played a very prominent
role in the transformations of organic substrates involving unsaturated carbonꢀcarbon bonds.3 In
these complexes, the carbenes derived from nitrogenous heterocycles (NHC) represent a very
interesting alternative to the traditional phosphines as organic ligands, standing out for its good σ
donor properties and its great chemical stability against humidity or heat.4 Of these, carbenes
obtained from imidazolium or imidazolinium salts with two groups derived from sterically
congested anilines are among the most commonly used today in organometallic catalysis because
of their stability and versatility, as well as their facile synthesis.5 In particular, the soꢀcalled IPr,
derived from the N, N'ꢀbisꢀ(2,6ꢀdiisopropylphenyl)imidazolium cation, forms part of some
commercially available gold (I) complexes which have proved their versatility as catalysts in a
great variety of transformations.
On the other hand, the immobilization of homogeneous catalysts by the covalent attachment of
the ligand on a solid support has been a widely explored research area in the last years in the
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search of advantages, such as an easy recovery and subsequent reuse of the catalyst or the lower
metal contamination of the final products.6 These alleged advantages have recently been
questioned in particular for immobilized palladium and rhodium catalysts.7 The catalysis with
immobilized metals has been directed in most cases to the use of immobilized Pd in crossꢀ
coupling or Heck processes and, in the case of other metals, to their use to catalyze
hydrogenation reactions. Continuous flow metal catalysis seems to be a methodology suitable to
be used with gold better than with other metals since the oxidation state of gold remains
unchanged throughout the processes unlike what happens for instance with palladium or
rhodium, a change associated to leaching phenomena.8 The development of immobilized
catalysts that combine the performance of homogeneous NHCꢀAu(I) catalysts and, on the other
hand, could be used under continuousꢀflow conditions, is an attractive idea for their possible use
in synthetic processes at multigram scale.
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RESULTS AND DISCUSSION
Silica has been the carrier most used to date in the preparation of immobilized NHCꢀ
complexes of Au(I)9 and other metals.10 The imidazolium nucleus is usually anchored to the
support at the nitrogen through an alkyl or benzyl linker. Porous organic polymers with Au(I)ꢀIPr
(AuꢀNHC@POPs) have been synthesized by Li et al.11 showing superior catalytic activity in
batch in alkyne hydration reactions. With the aim of generating a supported catalyst with an
activity similar to that of their homogeneous (IPr)AuCl (1a) and (IAdPr)AuCl (1b) counterparts
the silica immobilized complexes 2a and 2b (Chart 1) were synthesized. It is to be noted that
unlike other silica immobilized Au(I)ꢀNHC complexes described so far, complexes 2a and 2b,
as important differential characteristic, have the 2,6ꢀdiisopropylꢀ4ꢀalkylphenyl moieties linked to
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silica at the para position of the aromatic ring and consequently the metal environment of 2a is
identical to that of the sterically demanding IPr ligand and related ligands,12 which have been
widely used in homogeneous catalysis with many metal complexes in a variety of processes. A
bulky 2ꢀadamantyl group was substituted for one of the 2,6ꢀdiisopropylꢀ4ꢀalkylphenyl group in
the mixed IAdPr ligand used for the preparation of complex 2b.
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Chart 1. Silica immobilized catalysts 2a and 2b.
As shown in Scheme 1, two different methodologies were used for the preparation of the
necessary symmetrical and unsymmetrical imidazolium salts used as carbene precursors.10a
Symmetrical 1,3ꢀbisꢀ(4ꢀallylꢀ2,6ꢀdiisopropylphenyl)imidazolium chloride (3)13 was synthesized
by reacting N,N’ꢀbisꢀ(4ꢀallylꢀ2,6ꢀdiisopropylphenyl)ethaneꢀ1,2ꢀdiimine (4),14 obtained by
condensation of glyoxal and two equivalents of 4ꢀallylꢀ2,6ꢀdiisopropylaniline (5),15 with
formaldehyde (for experimental details see SI).
1,3ꢀ(adamantꢀ1ꢀyl)ꢀ(4ꢀallylꢀ2,6ꢀ
diisopropylphenyl) imidazolium chloride (6) was synthesized by a multicomponent reaction from
amine 5, 1ꢀadamantylamine (7), glyoxal and an aqueous solution of formaldehyde in acetic acid
following the procedure described by Baslé and Mauduit16 for other unsymmetrical unsaturated
imidazolium salts (for experimental details see SI). Catalytic hydrosilylation of the terminal
double bonds of 3 and 6 using catalytic PtCl4 and trichlorosilane followed by ethanolysis with
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ethanol/triethyl amine afforded the corresponding triethoxysily substituted imidazolium salts 8
and 10 (Scheme 1).
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N
N
N
iii)
N
N
N
i)
Cl
ii)
Cl
Au
Cl
9
R
R
H
R
H
R
3
8
N
N
N
N
N
N
iii)
i)
ii)
Cl
Au
Cl
H
Cl
R
R
H
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11
10
R = CH2CH2CH2Si(OEt)3
i) HSiCl3,PtCl4,CH2Cl2, 60 °C, 24h; ii) Et3N,EtOH; iii) K2CO3/Au(DMS)Cl, Acetone, 60 °C
Scheme 1. Preparation of silylated gold complexes 9 and 11.
To obtain the corresponding supported complexes we tested two alternative strategies that
differ in the order in which the formation of the gold complex and the anchoring process is
carried out. First, imidazolium salts 8 or 10 were anchored on silica and then treated with
Au(DMS)Cl/K2CO3 but complexes 2a or 2b could not be obtained. The use of Au(THT)Cl/
KOtBu was also inefficient.
By contrast, gold complexes 2a and 2b were readily synthesized when the processes of
grafting and complexation were performed in the reverse order. Accordingly, silylated NHCꢀAu
complexes 9 (64% yield) and 11 (90% yield) were respectively obtained following the improved
general protocols reported by Nolan and Gimeno17 by treatment of 8 or 10 respectively with
Au(DMS)Cl and K2CO3 in acetone.
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The immobilized catalysts 2a and 2b (designated as Silicaꢀ[(IPrR)Au]Cl and Silicaꢀ
[(IAdPrR)Au]Cl respectively) were obtained by grafting the silylated gold complex 9 or 11 on
activated silica in toluene under reflux using a DeanꢀStark apparatus. The gold loading found per
gram of silica immobilized complex, determined by atomic absorption spectrometry, was 12,37
mg (0,063 mmol) and 9,85 mg (0,05 mmol) in solids 2a and 2b respectively (for experimental
details see SI). Gold loading reached under the reported conditions was within the range of other
immobilized catalysts10a and was found to be adequate in the essayed reactions. For this reason
optimization of the silica support or grafting conditions was not performed.
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Characterization of hybrid silica materials 2a and 2b.
Hybrid silica materials 2a and 2b were analyzed by 13C and 29Si CPꢀMAS NMR
spectrometry, 13C CPꢀMAS spectra are displayed in Figures 1 and 2. Spectra of silylated gold
complexes 9 and 11 in solution are shown for comparison. Good accordance between the
chemical shift values of the precursor gold carbene complexes and the resulting hybrid materials
can be observed in both cases. Complete disappearance of the signals at δ = 57,7 and 18,6 ppm
corresponding to the triethoxy groups occurs during the grafting reactions as expected.
In the 29Si CPꢀMAS spectra new signals can be observed between ꢀ56 and ꢀ68 δ ppm
corresponding to T2 and T3 silicon atoms as well as a decrease of the Q2 signal demonstrating the
covalent bonding of the ligand to the silica surface (Figure 3).
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Figure 1. a) 13C NMR spectrum of complex 9 in CDCl3 solution; b) 13C CPꢀMAS NMR
spectrum of hybrid material Silicaꢀ[(IPrR)Au]Cl (2a).
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Figure 2. a) 13C NMR spectrum of complex 11 in CDCl3 solution; b) 13C CPꢀMAS NMR
spectrum of hybrid material Silicaꢀ[(IAdPrR)Au]Cl (2b).
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Figure 3. Si CPꢀMAS spectra of: a) activated silica; b) hybrid silica material 2a and c) hybrid
silica material 2b.
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SEM images of the hybrid materials were also acquired. Figure 4a shows the typical laminar
morphology of silica particles before grafting. A significant reduction of particle size due to
sintering during stirring in the grafting reaction is observed in the silica immobilized complexes
2a and 2b (Figures 4b and 4c).
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a)
b)
c)
Figure 4. SEM images of a) activated silica before grafting; b) hybrid silica material 2a; c)
hybrid silica material 2b.
Four typical gold catalyzed nucleophilic addition reactions to alkynes (Scheme 2) were
selected to test the catalytic activity of the hybrid materials compared to that of their homologous
complexes (IPr)AuCl (1a) and (IAdPr)AuCl (1b) under homogeneous conditions. AgSbF6 was
used in all the cases to obtain the corresponding cationic Au(I) catalysts (see supporting
information).
The hydration of alkynes with gold catalysts18 is perhaps one of the most studied reactions in
the chemistry of this metal, due to its great potential in sustainable chemical transformations. It
implies only water as the reagent and a low catalyst loading. Phenylacetylene (12) was selected
as the substrate to test the activity of the immobilized catalysts in this transformation. Different
reaction conditions have been described for the Au(I)ꢀcatalyzed hydration of alkynes in
homogeneous phase. Long reaction times (c.a.20 h) were required to achieve complete
conversion into the corresponding ketone when the water addition to the alkyne was carried out
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using a 2:1 methanol/water mixture as the solvent at 65 C and 0.5 mol% loading of the silica
supported catalysts.19 Hydration reactions catalyzed by 2a proceeded slightly faster than those
carried out using 2b as the catalyst. A similar result was obtained when 1,4ꢀdioxane was
substituted for methanol as the solvent. However complete conversion of the alkyne was
achieved in only 2 h in 2:1 dioxane/water solution with the same catalyst load when the
temperature was raised to 120 oC (Table 1, entries 1 and 2).
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Table 1. Hydration of 12 catalyzed by silica immobilized NHC gold complexes 2a and 2b
Time,[b] yield %
Entry Cycle Catalyst[a]
1h
77 >99
57 >99
2h
3h
4h
5h
20h
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2
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
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3
4
5
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73
57
>99
97
70
87
80
>99
87
80
80
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73
>99
>99
>99
>99
>99
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8
9
10
[a] AgSbF6 was used in all the cases to obtain the corresponding cationic Au(I) catalysts. [b] The
first conversion was monitored in each case at the time required to achieve full conversion in the
previous cycle.
Reactions were monitored by gas chromatography using benzaldehyde as the standard.
Although both silica supported catalysts were efficient to promote the expected transformation
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and could be recovered by filtration, the reactions performed at 65 C seem to be too slow to
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allow the design of neither practical recycling process nor their use under continuous flow
conditions.
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Then, we examined the possibility of reusing 2a or 2b to catalyze the hydration of 12 in 2:1
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o
dioxane/water solution at 120 C. Five successive reaction cycles were essayed by recovering
each time the catalyst by filtration after the complete conversion of the alkyne had been achieved
prior to the catalyst reuse in the next cycle (see Table 1).
The catalyzed intramolecular hydroamidation of 1ꢀ(oꢀakynylaryl)ureas with 5 mol% of
o
(IPr)AuCl (1a) in DMF at 60 C leads to indoles in 1 h.20 The immobilized catalysts Silicaꢀ
[(IPr)Au]Cl (2a) and Silicaꢀ[(IAdPr)Au]Cl (2b) activated with AgSbF6 were found to be fairly
active in this transformation.
The reaction conditions were optimized using ethanol as the solvent at room temperature and a
catalyst load of 1 mol% percent. Complete conversion was observed to take place after 2 or 2.5 h
respectively and both catalysts could be recovered by filtration. Reaction times were slightly
longer using immobilized catalysts instead of their homogeneous analogous 1a and 1b under the
optimized conditions (Table 2, entries 1ꢀ4).
Five successive reaction cycles were essayed by recovering each time the catalyst by filtration
after the complete conversion of the alkyne had been achieved for reuse in the next cycle (see
Table 2).
We then selected the cycloisomerization reaction of enynes to continue testing the activity and
selectivity of the silica immobilized catalysts 2a and 2b. This reaction has found numerous
applications both in the synthesis of carbocyclic and heterocyclic structures as well. Besides its
practical interest, the reaction offers different alternatives from the mechanistic point of view
with and without skeletal rearrangement and, consequently, several reaction paths can be
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followed along the cyclization processes. Goldꢀcatalyzed homogeneous cycloisomerization
reaction with catalysts containing a variety of phosphine and NHC ligands have been extensively
studied and reviewed.21
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Table 2. Cyclization of 1ꢀ(oꢀakynylaryl)urea 14 catalyzed by silica immobilized gold NHC
complexes 2a and 2b.
Time,[b] conversion %
Entry Cycle Catalyst[a]
1 h
>99
70
56
67
2 h
3 h
4 h
5 h
6 h
1a
1b
2a
2b
2a
2b
2a
2b
2a
2b
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2b
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1
1
1
1
2
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5
100
>99
85
>99
84
75
78
>99
83
>99
83
78
50
30
>99
90[c]
70[d]
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50
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12
64[d]
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[a]AgSbF6 was used in all the cases to obtain the corresponding cationic Au(I) catalysts. [b]The
first conversion was monitored in each case at the time required to achieve full conversion in the
[c]
[d]
previous cycle.
Complete conversion was attained after 10 h.
Complete conversion was
observed after 18 h.
Interestingly, Yu et al. reported22 the use of two recyclable polystyreneꢀsupported gold
catalysts in the cycloisomerization of 1,6ꢀenyne 16 to give tetrahydropyridine 17 and alcohol 18
with a 6 mol% catalyst load. Then, the product selectivity of these PSꢀimmobilized gold catalysts
resembles to that of homogeneous phosphine complexes.23 Different results were obtained from
this substrate using 2a or 2b depending on whether the reactions were performed under strictly
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anhydrous conditions or water was not completely excluded. In our preliminary experiments
carried out in wet CH2Cl2, the cycloisomerization of 16 catalyzed by 1 mol% 2a led to a 4:1
mixture of the 5ꢀexo-dig hydroxicyclization alcohol 18 and the tetrahydropyridine 17 resulting
from a 6ꢀendo-dig cyclization of the enyne precursor. Complete conversion was reached in
methylene dichloride at room temperature in only 15 min. The cycloisomerization of 16 with 5
mol% of silver activated 1a and 1b in a 6:1 mixture CH2Cl2:H2O at room temperature was
essayed for comparison leading to a 4:1 mixture of 18 and 17 with complete conversion of the
substrate in 5 h and 4h, respectively. Accordingly, silicaꢀimmobilized 2a and 2b behave under
these conditions as their homogeneous counterparts as expected being even more active in this
transformation. In a new series of experiments 2a and 2b were carefully dried under vacuum in a
desiccator using P2O5 as drying agent and cycloisomerization reactions were carried out at room
temperature in previously dried CH2Cl2 under Ar atmosphere (see SI for details). Complete
conversion of 16 into a 4:1 mixture of dienes 19 and 17 respectively took place now in 15 min
with a catalyst load of 1 mol% (Scheme 2).
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Scheme 2. Cycloisomerization of enyne 16 catalyzed by silica immobilized gold NHC
complexes 2a and 2b.
The catalysts were readily recovered by filtration under inert atmosphere after completion of
each cycle for subsequent reuse. Five cycles were run in dry CH2Cl2 as the solvent with the
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catalysts recovered leading in all the cases to an 4:1 mixture of 19 and 17. The progress over
time of the conversion of 16 into the products was monitored for each cycle by GC (see Table 3).
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Table 3. Progress over time of the conversion of 16 into an 4:1 mixture of 19 + 17 in dry CH2Cl2
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at r.t.
Time,[b] conversion %
Entry
Cycle
Catalyst[a]
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[a] AgSbF6 was used in all the cases to obtain the corresponding cationic Au(I) catalysts. [b] The
first conversion was monitored in each case at the time required to achieve full conversion in the
previous cycle.
Gold complexes catalyze the intermolecular hydroarylation of alkynes.24 In an intramolecular
version of this reaction, aryl propargyl ethers under homogeneous conditions with low catalyst
loadings (1 mol%) were shown to provide a mild an easy entry to 2Hꢀchromenes, coumarins and
benzofurans, their formal 6ꢀendo-dig or 5ꢀexo-dig cyclization products. In the syntheses
reported,25 Au(I) complexes containing phosphine ligands were used to obtain 2Hꢀchromenes
and benzofurans in a variable ratio depending on the substitution pattern at the aryl ether
precursor. Only the 2Hꢀchromene is obtained from (propꢀ2ꢀynꢀ1ꢀyloxy)benzene (20)25b,c and this
reaction was selected to test the catalytic activity of silica supported complexes 2a and 2b.
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Unfortunately, no reports were found for comparison on the hydroarylation of 20 using NHCꢀ
Au(I) complexes. For this reason, first of all we essayed this reaction under homogeneous
conditions with 1 mol% of the silver activated complexes (IPr)AuCl (1a) and (IAdPr)AuCl (1b)
as the catalyst, in CH2Cl2 solution at room temperature. The reaction was very selective giving in
both cases a 95:5 mixture of 2Hꢀchromene 21 and benzofurane 22 (Scheme 3). Interestingly, the
hydroarylation reaction with the complex 1b was faster and complete conversion was achieved
in just 7 minutes while 1a required 15 min under these conditions (Table 4, entries 1 and 2).
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Scheme 3. Hydroarylation of arylalkyne 20 catalyzed by activated gold NHC complexes.
The cyclization of 20 catalyzed with silver activated immobilized 2a (1 mol%) or 2b (1 mol%)
was somewhat slower than that under homogeneous conditions with the analogue catalyst and it
took place in dry CH2Cl2 at room temperature with complete conversion of 20 in 30 min (Table
4, entries 3 and 4). The exo/endo selectivity in the cyclization was slightly lower for 2a giving in
this case an 88:12 mixture of 21 and 22 while 2b showed the same selectivity as that found with
the homogeneous catalysts (Scheme 3).
The reactions become progressively slower, to a lesser or greater extent depending on the
nature of the substrate, when using recycled catalysts in all the cases, what at first could be
attributed to catalyst leaching or poisoning.26 Then, the loss of activity was investigated, and the
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metal content in the filtrate resulting from recovery and washing the catalyst for reuse was
quantified by ICP. It was found to be <1% of the initial gold content of the catalyst in any case.
This allows ruling out leaching to justify the progressive deactivation of the silica supported
catalysts along the successive reaction cycles. It should also be noted that color changes
associated with the presence of gold nanoparticles were never observed.
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Table 4. Progress over time of the conversion of 20 into the mixture 21 + 22 in dry CH2Cl2 at r.t
Time min,[b] Conversion %
entry Cycle Catalyst[a]
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[a] AgSbF6 was used in all the cases to obtain the corresponding cationic Au(I) catalysts. [b] The
first conversion was monitored in each case at the time required to achieve full conversion in the
previous cycle. [c] Orbital shaker. [d] Complete conversion was attained after 10 h.
In the protocol followed to recover the catalysts all operations were performed under inert
atmosphere and the same dry solvent in which the reactions were carried out was used in each
case to wash the solid removing the reaction produc and other subsrtances that coud poison the
catalyst. Sonication of 2b in dry CH2Cl2 at 25 oC for 10 m under Ar atmosphere was essayed as
an alternative efficient method to refresh27 the catalyst after the third cycle in the hydroarilation
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reaction. Unfortunately, the nature of the catalyst resulted altered under sonication and the color
changed from pale brown to violet. This new solid was essayed as catalyst to resume the
hydroarylation reaction requiring 24 h to reach only a 89% conversion. Since all the reactions
were carried out with magnetic stirring, we hypothesized that the solid support could be crushed
during the stirring time modifying its structure. This mechanical effect obviously increases the
surface of the silica suppot but does not affect the charge of Au(I), the actual catalyst, in the
solid nor promote the dissociation of the metal complex.
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To test this hypothesis the hydroarylation of 20 was carried out again with 2b using now an
orbital shaker. The catalyst was recovered by filtration following the same protocol as described
above. In this way all cycles were faster than the corresponding cycle carried out with magnetic
stirring (see Table 4 entries 6, 9, 12 and 15). SEM images of the catalysts after being used in
several cycles in selected reactions were acquired for comparison. Indeed, a severe reduction of
the particle size could be observed in 2a and 2b after several cycles of magnetically stirred
reactions as expected (compare Figures 5a and 5b with Figures 4b and 4c, respectively). By
contrast, the particle size of 2b did not decrease when the reactions were carried out using an
orbital shaker as observed in Figure 5c.
This clearly points to crushing of the solid as responsible, at least in part,27 of the progressive
loss of activity observed in 2b in the successive cycles essayed under batch reactions. Aimed by
this idea we decided to test the performance of 2b under flow conditions since in this way any
stirring or manipulation of the catalyst is avoided. The hydroarylation reaction of 20 was first
selected for the flow experiments provided that this transformation is quite fast at room
temperature under batch conditions as shown above although the catalytic activity of 2b
decreases along the successive cycles.
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a)
b)
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c)
d)
Figure 5. SEM images of a) hybrid silica material 2a after 12 cycles of hydration reaction; b)
hybrid silica material 2b after 4 cycles of hydroarylation reaction; c) hybrid silica material 2b
after 4 cycles of catalysis using an orbital shaker; d) hybrid silica material 2b after all the
experiments carried out under continuous flow conditions.
The flow reactions were carried out using a HꢀCube Pro (ThalesNano) instrument equipped
with a micro HPLC pump which allows to control a 0,3ꢀ3 mL/min flow rate with increasing
intervals of 0,01 mL/min. The cartridge containing the catalyst was charged with previously
activated 2b (98 mg, 0,0049 mmol Au). Alumina and Celite were placed at both ends of the
cartridge to prevent any eventual removal of catalyst by the solvent to complete a total solid
charge of 120 mg. Different concentrations of 20 in dry CH2Cl2 and flow rate were essayed to
optimize the flow conditions. Optimal conditions to reach complete conversion of the substrate
were achieved by using a 0,05 M solution of 20 in dry CH2Cl2 and a 0,5 mL/min flow rate.
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Separate samples were collected during 40 min with 4 min intervals each one corresponding to
the transformation of 0,1 mmol of substrate. The activity of 2b remained unaltered in the
cartridge along the complete flow experiment and hence complete conversion of 1 mmol of 20
into a 95:5 mixture of 2Hꢀchromene 21 and benzofurane 22 was attained in 40 min. This
conversion rate would correspond to a productivity of 306 mmolproduct.mmolAuꢀ1.hꢀ1.
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In a second experiment a new cartridge was packed as described above to further explore the
lifeꢀtime of 1b under flow conditions in this transformation. The same concentration of 20 in
CH2Cl2 and flow rate were also used but in this case the progress of the reaction was followed by
GC with 1 h intervals. (see Figure 6). After 12 h, 18 mmol of the mixture of hydroarylation
products were obtained with complete conversion of the substrate in this time. However, in the
sample analyzed after 13 h the activity of the catalyst had diminished and the conversion was
only 86%. The apparent loss of activity of 2b could be reverted by washing the cartridge with 45
mL of dry CH2Cl2 at a 1 mL/min flow rate. Afterwards, the flow reaction was continued by using
the same cartridge and now 4 mmol of 20 were synthesized in 160 min with complete conversion
of the alkyne 20. At this point of the transformation, the TON value was 4753 and the
experiment was discontinued. These results show that silica supported gold catalyst 2b is suitable
to perform hydroarylation reactions under flow conditions without loss of activity, maintaining a
productivity value of 300 hꢀ1 approximately.
To further assure the suitability of 2b to be used under flow conditions we decided to reuse this
same cartridge to carry out a different transformation. The above cartridge was washed with
CH2Cl2 for 30 minutes at a flow rate of 1 mL/min and then tested to catalyze the
cycloisomerization reaction. Enyne 16 (1 mmol) was dissolved in 20 mL of a 6:1 CH2Cl2/water
mixture and passed through the recycled cartridge at 1 mL/min flow rate (see Figure 6).
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Complete conversion of the substrate into a 4:1 mixture of compounds 18 and 17 was attained in
20 min. Then, the productivity for this transformation was at least 612 hꢀ1, twice the observed
value in the hydroarylation reaction. At this point the flow experiment was discontinued. The
supported solid was then removed from the cartridge and SEM images of the hybrid material
were acquired as above described confirming that its structure remains practically unchanged
during the hydroarylation and cycloisomerization experiments performed under flow conditions
as expected (see Figure 5d).
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Figure 6. Hydroarylation and cycloisomerization carried out sequentially under continuous flow
conditions catalyzed by 2b. Productivities in mmolproduct.mmolAuꢀ1.hꢀ1 are shown in brackets.
CONCLUSIONS
Strongly hindered symmetrical or unsymmetrical NHC ligands derived from two amines of
wellꢀdifferentiated basicity are readily synthesized by condensation reactions from conventional
products. Both types of ligand can be easily anchored on silica when they possess one or two
unsaturated chains in the para position of the aromatic amine from which they derive by
hydrosilylation with subsequent grafting. The preparation of the corresponding immobilized
Au(I) complexes requires forming the metal complex prior to the grafting. The immobilized
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complexes have been shown to be excellent catalysts that replicate and sometimes even exceed
the activity of their homologues in homogeneous phase in the typical reactions involving the
activation of the alkynes tested. The immobilized catalysts studied are easily recovered by simple
filtration and can be reused in batch reactions in successive cycles, keeping constant its metal
content demonstrating that they do not undergo leaching processes. However, a loss of catalytic
activity occurs after several cycles associate to degradation of the original surface of the solids
by crushing induced by magnetic stirring. The degradation of the catalysts occurs more slowly
by using an orbital shaker in the reactions. These immobilized catalysts have been shown to be
particularly suitable in reactions under continuous flow conditions which take advantage of the
fact that the metal complex is bound to the surface of the solid support by a strong covalent
bond. In addition, the surface of the catalysts does not undergo mechanical degradation due to
the absence of stirring. The immobilized gold complexes have shown to be highly stable against
leaching compared to those derived from other transition metals most likely because the
oxidation state of gold remains constant throughout the catalytic process. Excellent productivities
were attained using activated Silicaꢀ[(IAdPrR)Au]Cl (2b) as the catalyst under continuous flow
conditions.
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■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
Experimental part including general information, procedures for the synthesis of
unsymmetrical gold(I) complex 1b and immobilized gold (I) complexes 2a and 2b, general
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procedures for catalytic reactions in batch and recycling procedure, experimental procedure for
the reactions under flow conditions, characterization data for new compounds and cold
complexes and NMR spectra.
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■ AUTHOR INFORMATION
Corresponding Author
*Email: gregorio.asensio@uv.es
*Email: maria.t.varea@uv.es
Present address
†Departamento de Química, Universidad de Burgos, Pza. Misael Bañuelos s/n 09001ꢀBurgos,
Spain
‡Laboratorio de Catálisis Homogénea, CIQSOꢀCentro de Investigación en Química Sostenible,
Universidad de Huelva, 21007ꢀHuelva, Spain
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript. §These authors contributed equally.
Funding Sources
Support for this work was provided by the Ministerio de Economía y Competitividad (MINECO)
and European Community Founds (FEDER) (CTQ2014ꢀ52769ꢀC3ꢀ2ꢀR).
Notes
The authors declare no competing financial interest
.
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■ ACKNOWLEDGMENTS
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J. T. S. thanks MINECO for FPI and A. O. for Juan de la Cierva fellowships. We acknowledge
the SCSIE (Universidad de Valencia) for access to instrumental facilities. We thank Prof.
Manuel Hernández Córdoba (Universidad de Murcia, Spain) for atomic absorption gold
measurements and Prof. Jesús de la Rosa (Centro de Investigación en Química Sostenible,
Universidad de Huelva, Spain) for ICPꢀMS spectra.
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■ REFERENCES
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We acknowledge our referees for suggesting sonication essays in order to restore the
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Silica Immobilized NHC-Gold(I) Complexes: Versatile Catalysts for the functionalization of
alkynes under batch and continuous flow conditions.
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