Carbonylative sonogashira coupling in the synthesis of ynones: A study of boomerang phenomena

Article abstract of DOI:10.1002/adsc.201300357

The behaviour of several organophosphino-palladium complexes immobilized on mesoporous silica during the palladium-catalyzed synthesis of propynone by carbonylative Sonogashira coupling was studied, particularly concerning leaching/redeposition phenomena. The results demonstrated that this cross-coupling reaction is catalyzed by soluble species. Furthermore, it is shown that the palladium leaching is not initiated by the oxidative addition step but rather by palladium-decoordination from grafted ligand. Despite this decoordination, catalyst performance after recycling is adequate. Additionally, several parameters linked either to catalyst preparation or reaction procedures were shown to reduce leaching allowing one to achieve metal contamination levels close to the recommendation of the European Agency for the Evaluation of Medicinal Products. Interestingly, this heterogeneous palladium-catalyzed procedure is fully selective toward the formation of ynones, allowing the preparation of various target compounds. Copyright

Full text of DOI:10.1002/adsc.201300357

FULL PAPERS
DOI: 10.1002/adsc.201300357
Carbonylative Sonogashira Coupling in the Synthesis of Ynones:
A Study of “Boomerang” Phenomena
Marie Genelot,a,b Vꢀronique Dufaud,b,c,* and Laurent Djakovitcha,*
a
Universitꢀ de Lyon, CNRS, UMR 5256, IRCELYON, Institut de recherches sur la catalyse et l’environnement de Lyon, 2
avenue Albert Einstein, F-69626 Villeurbanne, France
Fax : (+33)-4-7244-5399; phone: (+33)-4-7244-5381; e-mail: Laurent.Djakovitch@ircelyon.univ-lyon1.fr
Universitꢀ de Lyon, CNRS, UMR 5182, Laboratoire de Chimie, Ecole Normale Supꢀrieure de Lyon, 46 Allꢀe d’Italie,
b
F-69364 Lyon Cedex 07, France
Present address: Universitꢀ de Lyon, Laboratoire de Chimie, Catalyse, Polymꢁre, Procꢀdꢀs (C2P2), 43 Bd du 11
c
novembre 1918, 69616 Villeurbanne cedex, France
Fax : (+33)-4-7243 1795; phone: (+33)-4-7243-1792; e-mail: veronique.dufaud@univ-lyon1.fr
Received: April 26, 2013; Revised: July 4, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300357.
Abstract: The behaviour of several organophosphi- ration or reaction procedures were shown to reduce
no-palladium complexes immobilized on mesoporous leaching allowing one to achieve metal contamina-
silica during the palladium-catalyzed synthesis of tion levels close to the recommendation of the Euro-
propynone by carbonylative Sonogashira coupling pean Agency for the Evaluation of Medicinal Prod-
was studied, particularly concerning leaching/redepo- ucts. Interestingly, this heterogeneous palladium-cat-
sition phenomena. The results demonstrated that this alyzed procedure is fully selective toward the forma-
cross-coupling reaction is catalyzed by soluble spe- tion of ynones, allowing the preparation of various
cies. Furthermore, it is shown that the palladium target compounds.
leaching is not initiated by the oxidative addition
step but rather by palladium-decoordination from Keywords: boomerang phenomena; carbonylative
grafted ligand. Despite this decoordination, catalyst Sonogashira cross-coupling; leaching/redeposition
performance after recycling is adequate. Additional- phenomena; mesoporous silica; SBA-15 and SBA-3
ly, several parameters linked either to catalyst prepa- palladium catalysts; ynones
Introduction
erally concern the bases that are often linked to sol-
vent modifications. Thus, although triethylamine re-
Ynones represent attractive structures due to their mains the most commonly used, inorganic and water-
numerous biological properties.[1] Additionally, they compatible bases such as potassium carbonate[14] and
are also widely used as key intermediates for the syn- ammonia[15] have also been employed. In addition, re-
thesis of natural compounds,[2] pharmaceuticals,[3,4] or action times have been decreased by microwave heat-
more generally, various heterocycles.[5–8] Among the ing,[16] temperature and pressure have been lowered[12]
different pathways described for their synthesis, the and microflow reactors[17] have also been developed
carbonylative
Sonogashira
cross-coupling
has to work at atmospheric pressure of carbon monoxide,
emerged as a powerful tool to access this class of to name just a few examples. The most investigated
compounds. Indeed, this reaction allows for the one- aspect is the modification of the catalytic system
step formation of ynones starting from three simple either by the adjustment of the metal catalyst (palla-
(available) reagents: an aryl or alkyl halide, a terminal dium, copper,[18] or a combination of both[14,19]) or the
alkyne and carbon monoxide. During the last three use of different ligands,[10,16,20] the choice being gener-
decades, numerous modifications of the original work ally dictated by the reactivity of the targeted sub-
of Tanaka[9] have been made. The solvent has been strates.[15] Heterogeneous catalysts have also been de-
the object of studies oriented toward greener process- veloped using either commercially available Pd/C[21]
es by, for example, using of ionic liquid[10,11] to enable or custom catalysts such as magnetically separable
[22]
recycling of the catalytic system, or the use of greener Pd/Fe3O4
or Pd complexes grafted onto MCM-41
solvents such as water.[12,13] Other improvements gen- silica[23]
.
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In the course of our studies toward the Pd-cata-
lyzed multi-step synthesis of 4-quinolones from iodo-
ACHTUNGTRENNUNGanilines and alkynes under a carbon monoxide atmos-
phere,[24–27] various heterogeneous Pd catalysts pre-
pared by grafting onto SBA-15 type silica were evalu-
ated. In this approach, ynones represent key inter-
mediates; therefore developing Pd catalysts based on
mesoporous supports particularly retained our atten-
tion. Ynones can also either be active compounds or
useful intermediates to access biologically active mol-
ecules, thus metallic contamination of the product is
of particular concern. Indeed, the European specifica-
tions regarding metal contamination in medically rele-
vant products are quite low as only 1 ppm of palladi-
um are recommended for a parenteral administration
of the active molecule.[28] It should be easier to reach
such a low palladium contamination limit using solid,
heterogeneous catalysts rather than homogeneous
ones (ease of separation, recovery and recycling).
Given that the metal contamination issue is gener-
Figure 1. Targeted Pd hybrid catalysts.
ally related to leaching of active metal species from tronic and steric properties, namely Alkyl-PPh2 and
the support, we were surprised to find only sporadic Alkyl-PCy2. A third Pd complex bearing a bidendate
reports dealing with this point for the carbonylative phosphine ligand, namely Alkyl-NACTHNUTRGNE(UNG CH2PPh2)2 was
Sonogashira coupling while it has been intensively also selected. These complexes were then immobi-
studied for other Pd-catalyzed couplings such as So- lized by grafting onto SBA-15 silica following proce-
nogashira,[29–31] Suzuki[32–48] or Heck[32,37,39,41,49–71] reac- dures previously reported elsewhere[72] and the result-
tions.
ing hybrid materials are denoted in this study as
(PPh2)2/SBA-15, Pd(PCy2)2/SBA-15 and Pd(PNP)/
Thus, we decided to undertake studies on the syn- Pd
G
N
ACHTUNGTRENNUNG
thesis of ynones using various heterogeneous Pd cata- SBA-15, respectively (Figure 1, top). Additionally, in
lysts, focusing our attention on leaching and redeposi- order to evaluate what effect the spatial location of
tion of Pd species from and to the support (the so- Pd sites in the solid has on leaching, one of these Pd
called “boomerang effect”). Different parameters in- complexes bearing Alkyl-PPh2 as ligand was encapsu-
fluencing those phenomena were evaluated in order lated within the silica framework using a synthesis
to reduce the final palladium contamination. Herein, adapted from a procedure described by Dufaud et al.
we describe the results of these studies enhanced by and which leads to SBA-3 mesostructured silicas.[73]
kinetic experiments, comparing different types of het- Typically, siloxanes containing Pd complex, PdCl2
erogeneous Pd catalysts to a homogeneous Pd com-
plex in the carbonylative Sonogashira coupling.
CAHUTNGTRENNU{G PPh2ACHTUNGTREN[NUNG CH2CH2Si(OR)3]}2, was co-hydrolyzed and pol-
ycondensed with TEOS (tetraethyl orthosilicate) in
the presence of CTAB (cetyltrimethylammonium bro-
mide) used as structure directing agent (SDA) in
a mixture of water, HCl and acetonitrile (see Experi-
mental Section). The synthesis was carried out at low
temperature (258C) and short reaction time (4 h) to
preserve the integrity of the molecular precursor. The
Results and Discussion
Preparation of Palladium Catalysts
Four heterogeneous Pd catalysts based on SBA type resulting solid was then silylated with TMSCl in tolu-
silica materials were prepared and evaluated in ene prior to SDA removal in order to maintain the
this study. The results were compared to those mesostructuration of the material named as
obtained with a homogeneous Pd catalyst, namely Pd
[PdCl2A(dppp)] (with dppp=diphenylphosphinopro- All solid materials were fully characterized using
pane), which, according to previous results,[24] was molecular and bulk analytical and spectroscopic tech-
found to be very selective for this transformation. niques. The results obtained for the three grafted de-
In order to investigate the influence of the structur- rived solids, Pd(PPh2)2/SBA-15, Pd(PCy2)2/SBA-15
(PNP)/SBA-15, were in full agreement with
ACHTUGNRTEN(NUGN PPh2)2@SBA-3 (Figure 1, bottom).
N
CHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
al features of the Pd complex toward leaching, we and PdACHTUNGTRENNUNG
choose three Pd complexes differing by the nature of previously reported characterizations.[72] We have
the phosphine ligands and the degree of linkage to summarized in Table 1 only the main textural and
the solid surface. These include two complexes with physical characteristics for comparison with
monodentate phosphine ligands varying by the elec- PdACHTNUTRGNEUNG(PPh2)2@SBA-3. The XRD pattern of the latter ex-
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Carbonylative Sonogashira Coupling in the Synthesis of Ynones
Table 1. Physical and textural properties of palladium containing hybrid silica materials.
[a]
[e]
Catalyst
Pd [%wt] d100 [ꢃ] a0[b] [ꢃ] Wall thickness[c] [ꢃ] Vp[d] [cm3gꢀ1] Dp [ꢃ] SBET [m2gꢀ1] CBET
Pd
Pd
Pd
U
35
96
100
41
111
115
18
56
53
0.58
0.66
0.80
23
54
63
1009
601
458
15
181
102
[a]
[b]
[c]
[d]
[e]
dACHTUNGTRENNUNG(100) spacing.
p
a0 =2dACHTUNGTRENNUNG(100)/ 3, hexagonal lattice parameter calculated from XRD.
Calculated by a0ꢀpore size.
Total pore volume at P/P0 =0.980.
Pore size from desorption branch applying the BJH pore analysis except for PdACTHUNTRGNE(UNG PPh2)2@SBA-3 where the adsorption
branch was used.
Figure 3. Nitrogen adsorption/desorption isotherm and pore
size distribution (insert; from adsorption branch applying
the BJH pore analysis) of PdACHTNUTRGEN(UNG PPh2)2@SBA-3.
Figure 2. XRD pattern of palladium containing SBA-3 silica
embedded into the silica walls.
hibited three well-resolved peaks at 2q values be-
tween 2–58 that can be indexed as (100), (110) and <20 ꢃ and 0.50 cm3 gꢀ1, see Table S1 in the Support-
(200) diffractions which is typical for a well ordered ing Information) in agreement with inclusion of the
2D hexagonal mesostructure (Figure 2). The d
ACHTUNGTRENNUNG
spacing was found to be ca. 36 ꢃ which corresponds
AHCTUNGTRENNUNG
to a unit cell parameter of 41 ꢃ. The presence of Pd and 0.16 wt% P (P/Pd ~1.8) suggesting that
higher order reflections indicates that the preparation the
method allowed for the synthesis of a long-range PdCl
integrity
of
the
molecular
was
precursor
maintained
{PPh2A[CH2CH2Si(OR)3]}2
G
structural ordered Pd
ACHTUNGTREN(NNUG PPh2)2@SBA-3 hybrid material. throughout the synthesis with on average two phos-
No strong modification in the unit cell parameters phorus atoms per palladium centre.
was observed between the hybrid (41 ꢃ) compared to
The 29Si CP-MAS NMR spectrum (Supporting In-
the parent SBA-3 (38 ꢃ) attesting that the Pd com- formation, Figure S1) displayed discernable peaks in
plex is effectively inserted in the walls rather than in two different spectral regions. One region ranging
the pores.
Nitrogen
from ꢀ80 to ꢀ120 ppm characteristic of Q-type [Qn =
showed a type IV isotherm, characteristic of mesopo- ceous bulk material with Q2, Q3 and Q4 at, respective-
rous solids, with a relatively smooth capillary conden- ly, ꢀ89, ꢀ100 and ꢀ109 ppm. A single resonance at
sation step appearing at relative pressure of P/P0 =0.3 14 ppm typical of M-type [R3Si(O-)] silicates was at-
(Figure 3 left) which indicates the presence of regular tributed to the trimethylsilyl capped silanol groups. T-
adsorption-desorption
measurement Si-(OSi)n-(OH)4ꢀn] silicates originating from the sili-
pores in the sample. This was also confirmed by type [Tm =RSi
ACHTUNTRGENUNG(OSi)m-(OH)3ꢀm] silicates, that is the sil-
a narrow pore diameter distribution in the micro/mes- icon atoms attached to the phosphine through the
opore range (Figure 3 right). High BET surface area alkyl chain, expected in the ꢀ40 to ꢀ70 ppm spectral
(1009 m2 gꢀ1) was obtained with average pore diame- region, were not discernable likely due to the low Pd
ters and pore volumes of respectively 23 ꢃ and and phosphorous contents in the solid.
0.58 cm3 gꢀ1. These values are close to those obtained
Solid-state MAS 31P NMR spectroscopy proved to
for metal-free SBA-3 (i.e., respectivel,y 1024 m2 gꢀ1, be a useful technique to elucidate the structural integ-
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rity and coordination mode of the phosphine linkers
at the palladium centre in PdACHTNUGRTNEUNG
(PPh2)2@SBA-3. The 31P
MAS NMR spectrum (Supporting Information, Fig-
ure S2) exhibits a relatively broad signal centred at
21 ppm attributed to the trans-isomer of the Pd pre-
cursor; however, one cannot exclude the presence of
the corresponding cis-isomer (d=30 ppm) for which
the relative intensity should be rather low due to the
ꢀ
low Pd loading. The Pd P bond seemed unaffected:
no signal corresponding to free phosphine ligands
(d=9 ppm) was detected.
Comparing
the
textural
properties
of
Pd(PPh2)2@SBA-3 to those of the other Pd catalysts
ACHTUNGTRENNUNG
prepared by simple grafting onto SBA-15 type silica
(Table 1), we observed that this material is in the
lower range of mesoporous solids, near to that of mi-
croporous materials; the structure appears to be more
contracted with smaller pore sizes (23 ꢃ versus ca.
54–63 ꢃ) and thinner walls (18 ꢃ versus ca. 53–63 ꢃ)
than those based on SBA-15 with however a higher
specific surface area attributed to the inclusion of the
Figure 4. Kinetic curves for the different Pd hybrid materials
and comparison to the homogeneous [PdCl2ACHTNUTRGNEUNG(dppp)]. Condi-
tions: iodoaniline (6 mmol), phenylacetylene (1.2 equiv.),
[Pd] (0.1 mol%), triethylamine (2.5 equiv.), anisole (10 mL),
5 bar CO, 808C.
All hybrid materials were evaluated for the synthe-
Pd complex inside the walls rather than held at the sis of 1-(2-aminophenyl)-3-phenylprop-2-yn-1-one
surface of the pores. Moreover, the CBET coefficient from 2-iodoaniline, phenylacetylene and carbon mon-
indicates a hydrophilic surface in the case of SBA-15 oxide through kinetic experiments (Figure 4). A full
based materials with an average value of 131 and a hy- selectivity toward the expected ynone was observed
drophobic surface for the Pd
(CBET =15) which is a direct consequence of the silyla- pared to those issued from the reaction using the ho-
tion of the remaining silanol groups on the surface of mogeneous [PdCl2A(dppp)] complex, which was found
ACHTUNGTREN(NNUG PPh2)2@SBA-3 hybrid for all the catalytic materials. The results were com-
CTHUNGTRENNUNG
this latter material. These variations can affect the to be very selective in this transformation according
“boomerang effect” and can provide important infor- to our previous studies.[24]
mation concerning deactivation processes.
All catalysts proved to be effective in this coupling
giving generally high conversions and selectivities
toward the expected ynone. The highest reaction rates
(vmax), as measured at the maximum of the slope, de-
livered values for the hybrid materials in the same
range or higher than that obtained with the homoge-
Evaluation of Catalytic Efficiency of the Different
Materials
In the field of our studies related to the synthesis of neous complex (Table 2, entry 1). Among the evaluat-
4-quinolones from 2-iodoanilines, terminal alkynes ed hybrid materials, Pd(PNP)/SBA-15 showed the
and carbon monoxide, we demonstrated that ynones highest rate (1.2 mmolhꢀ1) that is 3 times higher than
were intermediately formed before cyclization to de- that of [PdCl2A
(dppp)] (0.4 mmolhꢀ1).
liver the target compound (Scheme 1). In these stud- On the basis of these results, no clear influence of
ies, we also demonstrated that ynones were produced the structure of the support was observed
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
through a Pd-catalyzed cross-coupling, whereas cycli- PdACTHNURGTENN(UG PPh2)2@SBA-3 and PdAHCTUNGTRNE(NUGN PPh2)2/SBA-15 showing
zation occurred under amine catalysis.[24,25] Thus, de- nearly the same tendency. Thus, the palladium con-
creasing the Pd leaching during the formation of the tamination in the crude product was determined, in
ynone intermediate should reduce the Pd contamina- a first approach, for two of the hybrid materials,
tion in the final target compound.
namely PdACTHUNGERTNNU(G PCy2)2/SBA-15 and PdACHTUNGTNER(NUNG PNP)/SBA-15
which exhibited the highest reaction rates (Figure 4).
This determination measured by ICP-AES was found
to be, respectively, 1.4 ppm and 10 ppm. In both cases,
these values are lower than that achieved when using
the homogeneous catalyst (47 ppm). As this Pd con-
tamination finds generally its origin in the leaching of
metal species from the solid catalysts during reaction,
we undertook a systematic study of this leaching pro-
cess using the well-known hot-filtration technique
(see below) to determine whether the reaction occurs
Scheme 1. Synthetic strategy for the formation of 4-quino-
lone: palladium-catalyzed carbonylative Sonogashira cou-
pling and subsequent cyclization of the obtained ynone.
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Carbonylative Sonogashira Coupling in the Synthesis of Ynones
Table 2. Reaction rates, activities and leaching ratios for the different Pd catalysts.
Entry 1
Entry 2
Leaching
ppm
Entry 3
%
Entry 4
vmax [mmolhꢀ1]
Amax [mol/minmolꢀ1
]
Pd
Catalyst
Homogeneous
In the pores
G
E
0.4
0.6
0.5
1.2
0.4
47
3
4
22
10
100
6
7
47
20
2
52
37
15
11
In the walls
via a true heterogeneous process or through a dissolu- evolution followed by GC. The results were compared
tion-redeposition process.
to that of a standard catalytic run in the presence of
the solid material. As shown in Figure 5, all hybrid
materials exhibited a more or less pronounced leach-
ing phenomenon. Comparing the kinetics obtained
with or without the heterogeneous catalyst clearly in-
dicates that the coupling reaction was mainly cata-
Hot-Filtration Test and Determination of Pd Content
in Solution
Estimation of the leaching rate was performed by two lyzed by dissolved Pd species, the participation of het-
complementary determinations. In a first set of ex- erogeneous palladium being minor.
periments, hot-filtration tests were performed for all
materials. Typically, a standard catalytic run was ini- of the support or that of the immobilized Pd-complex.
tially started and after 2–4 h of reaction, which corre- For Pd(PCy2)2/SBA-15 and Pd(PPh2)2/SBA-15, an im-
Two trends were observed regardless of the nature
A
ACHTUNGTRENNUNG
sponds to 15–30% conversion, the reaction mixture portant decrease in the reaction rate was observed
was filtered through a hot syringe filter (PTFE, after the removal of the solid material, although fur-
0.45 mm) to afford a clear filtrate. The clear filtrate ther conversion is observed. Thus we cannot exclude
was then treated as a standard catalytic run and its the possibility of the contribution of the solid material
Figure 5. Comparison between hot filtration tests (solid line) and “standard” kinetic runs (dotted line) or [a] Pd
ACHTUNGTRENNUNG(PCy2)2/
SBA-15, [b] Pd(PPh2)2/SBA-15, [c] Pd(PNP)/SBA-15 and [d] Pd(PPh2)2@SBA-3. The hot-filtration is symbolized by the
A
R
ACHTUNGTRENNUNG
double-headed arrow.
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to the catalytic reaction rate for these two materials,
but this is very likely as a Pd reservoir rather than
a true heterogeneous catalyst. For Pd
ACHTUNGTREN(NUNG PNP)/SBA-15
and Pd(PPh2)2@SBA-3, the situation was quite differ-
ACHTUNGTRENNUNG
ent since no significant changes in the reaction rates
were observed after removal of the solid material
which suggests that the reaction proceeds only
through dissolved species.
In order to gain a deeper understanding in those
two different behaviours, we measured the (dissolved)
palladium content in the clear filtrates by ICP-AES
(Table 2, entry 2). The leaching ratio was then calcu-
lated referring to the initial palladium loading at the
beginning of the reaction run (Table 2, entry 3).
It clearly appears that the two materials for which
the hot filtration has an important impact on the reac-
Figure 6. Correlation between lixiviation and activity.
tion rate are those for which the leaching ratio is the Parameters Influencing Pd Leaching from Pd
lowest, namely Pd(PPh2)2/SBA-15 and Pd(PCy2)2/ SBA-15
SBA-15 with, respectively, 7% and 6%. This corre-
ACHTUNGTRNE(NUNG PNP)/
N
ACHTUNGTRENNUNG
lates with the proposed role of the solid material as In order to identify parameters influencing this leach-
a Pd reservoir, the leached species having a tendency ing phenomenon a study was undertaken using
to deactivate with time. Note that this deactivation PdACTHUNTGRNEUNG(PNP)/SBA-15 as this hybrid material showed the
phenomenon is not counterbalanced either by a high highest leaching ratio (47%) in reaction among those
Pd concentration, or by a continuous dissolution of evaluated. The catalyst was suspended in solvent
active Pd species in solution or a stabilization of the under an Ar or CO atmosphere and heated at 808C
soluble species through the ligand or the support as for 1 h. The suspension was then “hot-filtered” at
would be the case in homogeneous catalysis or when 808C. In a parallel experiment, the suspension was
heterogeneous solid is present. This situation con- cooled to room temperature prior to filtration. The
trasts severely with PdACHTNUGTRENNUG(PPh2)2@SBA-3 and PdACHTUTGNREN(NUGN PNP)/ palladium amounts in the filtrates were measured by
SBA-15 for which significant amounts of leached Pd ICP-AES. From the hot-filtration tests the leaching
species were measured (10 ppm and 22 ppm, respec- ratio can be determined referring to the initial
tively). Thus, whatever the deactivation process of amount of Pd introduced. From the cooled-filtration
these dissolved Pd species, the deactivation will have tests, determination of palladium in solution allows
dramatic effects in the former cases due to the low Pd one to calculate the redeposition ratio by comparing
concentration in solution whereas it is somewhat the Pd concentrations in “hot” and “cooled” solu-
counterbalanced for the latter regarding the higher tions.
leaching ratio.
The results reported in Table 3 indicate, firstly, that
From those leached palladium amounts, activities the leaching ratio is not strongly influenced by the
can also be estimated by dividing the maximum reac- presence of reagents (Table 3, entries 1 and 2). Thus,
tion rate by the concentration of dissolved palladium the oxidative addition is not the triggering factor of
(Table 2, entry 4). As expected from a direct conse- the leaching phenomenon as dissolution of palladium
quence of the low leaching ratios, Pd
and Pd(PCy2)2/SBA-15 showed the best activities, ed when using catalysts based on immobilized molec-
with 37 mol/minmolꢀ1 and 52 mol/minmolꢀ1Pd, re- ular complexes as the initial “activation” step is most
ACHTUNGTREN(NNUG PPh2)2/SBA-15 occurred without reactants. This result is to be expect-
ACHTUNGTRENNUNG
Pd
spectively, the poorer activity (2 mol/minmolꢀ1
)
probably the molecular transformation of the Pd com-
being catalyst plex to allow oxidative addition (according to the gen-
[PdCl2ACHTUNGTRENNUNG(dppp)]. Figure 6 illustrates the dependence be- erally accepted mechanism using homogenous soluble
Pd
that
of
the
homogeneous
G
tween the measured Pd content in solution and the Pd species in cross-coupling reactions); that contrasts
resulting determined catalyst activity (that is closely with situations in which heterogeneous catalysts bear-
related to dissolved palladium) which correlates well ing immobilized palladium particles are used.
with the postulate of De Vries based on the use of ho-
The role of working atmosphere is not so trivial.
meopathic Pd loading[74,75] and a deactivation process Apparently, working under CO or an inert atmos-
through aggregation of dissolved Pd species resulting phere of Ar did not influence the leaching ratio
in the formation of inactive palladium particles.[76,77] (Table 3, entry 2 vs. 3) despite the ability of carbon
Thus, the highest Pd concentration in solution did not monoxide to coordinate Pd species, thus, providing
result in the highest measured catalyst activity.
a stabilization of leached species in solution. Our re-
sults are in accordance with those reported by Davies
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Carbonylative Sonogashira Coupling in the Synthesis of Ynones
Table 3. Influence of different parameters on leaching and redeposition for PdACHTNUGTRENNUNG
Entry Atmosphere Solvent
Silica
[Pd] in hot
Leaching
solution [ppm] ratio [%][b] solution [ppm]
1[d]
2
CO (5 bar)
CO (5 bar)
Ar (PA)
Ar (PA)
Ar (PA)
Ar (PA)
Ar (PA)
Ar (PA)
Ar (PA)
Ar (PA)
Ar (PA)
anisole/NEt3
anisole
anisole
–
–
–
–
22
29
28
2
25
8
12
34
38
29
22
47
48
47
3
42
13
20
57
64
48
37
10
13
24
2
25
8
54
55
14
0
0
0
33
0
0
41
9
3[e]
4
toluene
anisole/NEt3
anisole
[f]
5
6
7
8
–
silylated[g]
anisole[h]
NMP
–
–
–
–
–
8
34
38
17
20
9
DMF
10[i]
11
DMF:H2O 1:1[i]
NEt3
[a]
Conditions: 8 mg PdACTHNUTRGNEUNG
(PNP)/SBA-15 (3.10ꢀ3 mmol Pd), solvent 5 mL, 808C, 1 h.
Referring to the initial amount of palladium introduced.
Represents redeposition of leached Pd.
Values issued from Table 2 obtained in reaction (i.e., in presence of the reactants).
The 31P NMR spectroscopy was performed on the material after experiment.
In the proportions used in reaction: 5 mL of anisole and 1.1 mL of NEt3.
Preparation described in the Supporting Information.
92 mg of “blank” SBA-15 silica was added.
A hydrophilic filter was used (Milliporeꢄ HVLP type, 0.45 mm).
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
et al. who demonstrated through a three-phase test
As often demonstrated in the literature, the solvent
that carbon monoxide was not required to initiate the also may drastically influence the degree of leaching,
leaching of Pd to generate active species in palladi- less polar solvents leading, in general, to strongly de-
um-catalyzed carbonylative coupling.[32] However, the creased leaching ratio while polar solvents seem to
atmosphere plays a role in the redeposition process favour metal extraction from the solid. Thus, except
(see discussion below).
for the case where the surface of the catalyst was pas-
By contrast, the hydrophilic/hydrophobic nature of sivated, all polar solvents (i.e., anisole, DMF, DMF/
the surface of the solid catalyst proved to have a sig- H2O, NMP, NEt3) afford important palladium dissolu-
nificant influence on the stability of supported Pd spe- tion in the bulk solution, an observation in full agree-
cies against leaching. Indeed, when the surface of the ment with almost all reports concerning Pd-catalyzed
material was silylated with a hydrophobic trimethyl- cross-coupling reactions that are generally carried out
silyl group (see the Supporting Information for this in such media. These conclusions are strongly sup-
procedure), the leaching ratio could be decreased ported by the results observed when using a less polar
from 47% to 13% (Table 3, entry 6 vs. 3). Such an ob- solvent such as toluene in which only a leaching ratio
servation has been previously reported for a copper of 3% (vs. 40–65%) is observed (Table 3, entry 3).
catalyst grafted on SBA-15 silica and used in epoxida- This tendency can find an explanation by the possible
tion reactions,[78] or Ti-MCM-41 catalyst applied in stabilization of small Pd-clusters in solution when
oxidative desulfurization[79] and epoxidation.[80] Un- using polar solvents, like anisole or triethylamine.[83] If
fortunately, from these results, it seems that the sur- the solvent plays apparently a role on the leaching
face hydrophobization also prevents redeposition of ratio, it also plays a role on the redeposition. Thus,
leached species as was already observed in some poly- higher redeposition (41%) is observed when using the
meric materials bearing Pd complexes and used in mixture DMF/H2O. This result can be compared with
cross-coupling reactions.[81,82] These results are in that observed under CO atmosphere (55% redeposi-
agreement with what was observed during the catalyt- tion). In both cases reducing conditions are achieved
ic run while using PdACHTNUGRTNEUNG(PPh2)2@SBA-3 catalyst whose either due to CO as reducing agent of Pd(II) species,
surface had been silylated with TMSCl prior to sur- or to the DMF/H2O mixture that was previously de-
factant removal (Table 2) when considering the longer scribed to have reducing properties of metallic spe-
reaction time for the latter and the reduced redeposi- cies, according to the following Eqs. (1) and (2):
tion capacity. All together, these results suggest that
such hydrophobic hybrid materials would act as Pd
reservoirs but with probably lower recycling capacity
due to the very limited redeposition process.
Adv. Synth. Catal. 0000, 000, 0 – 0
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Marie Genelot et al.
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The difference observed between DMF (no redepo- Palladium would thus be leached as Pd(II) species as
sition) and DMF/H2O mixture (41% redeposition) PdCl2Sn before being reduced in solution to give
lies to the fact that reducing conditions are only a Pd(0)Sn species that enters in the catalytic cycle. Re-
achieved in the presence of water (Table 3, entry 10 duction can be done by CO combined with traces of
vs. 9). According to Kçhler’s reports,[42,59] reducing water [see Eq. (1)] or by the formation of alkyne
conditions help considerably to recover the dissolved dimers [Eq. (3)]:
palladium species by precipitation/stabilization at the
solid surface.
An interesting way to reduce the leaching ratio was
found by adding to the Pd catalyst additional blank
SBA-15. Thus, working with a mixture of Pd
SBA-15 and SBA-15 (1:10) allowed us to reduce the
ACHTUNGTRNE(NUNG PNP)/
Some directions aiming at reducing the overall
overall leaching ratio by a factor 2.4, that is closely re- leaching point out the control of the surface philicity
lated to the higher redeposition process (33% vs. to reduce leaching as well as the reduction of Pd load-
14%) provided by the higher availability of silica sur- ing in order to maximize available silica surface for
face (Table 3, entry 7 vs. 3). The corollary of this ob- the redeposition process, the latter being favoured
servation is that a decrease in the Pd loading in the under reducing conditions.
hybrid material will probably result in a higher rede-
position possibility, hence reducing the overall leach-
ing ratio.
While the leaching of palladium in solution from
Characterization of the Catalysts after Reaction
supported Pd particles is generally related to the ini- While we demonstrated that the presence of reactants
tial oxidative addition of reagents, that from immobi- was not necessary to initiate leaching of Pd species in
lized molecular Pd complexes can have several ori- solution, we were, however, interested to investigate
gins: the cleavage of the link between the surface and how it can influence leaching and redeposition rates
the complex, the pure loss of palladium through de- and to some extent recycling efficiency. Therefore,
coordination or the degradation of the ligand leading various analyses [i.e.: elemental analysis (P, Pd),
to the loss of some palladium. In order to answer this small- and wide-angle XRD and MAS 31P NMR]
question, we examined both the solution and the solid were performed on the catalytic solids after a single
catalyst after a standard catalytic run using 31P NMR run and are displayed in the Supporting Information.
spectroscopy. No phosphorus signal was detected in Three catalysts were evaluated, namely Pd
the 31P NMR spectrum of the solution thus ruling out SBA-15, Pd
(PCy2)2/SBA-15 and Pd(Ph2)2@SBA-3.
any phosphine degradation (at the silicon or at the or- For all catalysts, small angle XRD patterns (Sup-
ACHTUNGTRENNUNG(PNP)/
N
ACHTUNGTRENNUNG
ganic spacer) and subsequent extraction. This conclu- porting Information, Figures S6, S10 and S13) showed
sion was further supported by solid state 31P NMR of long-range mesoscopic ordering, indicating that the
the material (Supporting Information, Figure S3) that mesostructure remained intact during the course of
showed a broad signal corresponding to the Pd-coor- the reaction. However, depending on the catalysts,
dinated phosphine (+10 ppm). No signals related to other analyses showed differences.
free phosphine (ꢀ28 ppm) could be detected on
For PdACTHGUNRETNNU(G PCy2)2/SBA-15, the P/Pd ratio determined
31P NMR; however, we cannot fully exclude the for- by elemental analysis on the fresh and the used cata-
mation of phosphine oxide (+28 ppm) following the lyst (Supporting Information, Table S3) did not
loss of coordinated palladium that could be expected change significantly after reaction. This result is in ac-
regarding the leaching ratio and the relatively low Pd cordance with the low leaching ratio observed for this
redeposition. Thus, from these analyses we can con- catalyst (6%, Table 2). MAS 31P NMR (Supporting In-
clude that the main route toward leaching under our formation, Figure S9 vs. S8) showed, however, two
reaction conditions is related to the decoordination of broad signals that could be attributed to initially com-
Pd from the original immobilized complex.
plexed phosphine and phosphine oxide. Thus, consid-
In summary, we have demonstrated in this study ering that palladium is not coordinated to phosphine
that the leaching of palladium from hybrid material oxide, we can determine a leaching ratio from
bearing immobilized Pd complexes could be caused 31P NMR of 11% which is close to that calculated
by other phenomenon than the oxidative addition from the hot-filtration experiment. These results point
since neither carbon monoxide nor the base or the re- out that elemental analysis alone cannot be used to
agents were required to initiate the solubilization of rule out a possible leaching of the metal during reac-
the metal. Palladium decoordination from the grafted tion, particularly when the leaching rate is low, due to
complexes, very probably triggered by temperature the precision limits of this analysis. The presence of
and favoured by the stabilizing nature of polar sol- phosphine oxide, in combination with the stable P/Pd
vent, is more likely responsible for the metal leaching. ratio, could indicate that palladium could be redepos-
8
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Carbonylative Sonogashira Coupling in the Synthesis of Ynones
ited on the support, probably as very small Pd parti-
The above results are in accordance with a Pd rede-
cles, since no signal attested the formation of Pd par- position as small particles on the silica surface stabi-
ticles in wide angle XRD (Supporting Information, lized by remaining silanol groups, an effect favoured
Figure S11).
For Pd(PPh2)2@SBA-3, an increase of the P/Pd
ratio (Supporting Information, Table S4) was ob-
by the high specific area of the SBA-15 silicas.
ACHTUNGTRENNUNG
served after reaction indicating a loss of Pd of ca. Recycling
30% which is in agreement with the leaching ratio
measured during reaction (20%, Table 2). For this cat- Even though heterogeneous catalysts are generally
alyst, due to the low Pd complex loading, the intensity not reused in industrial pharmaceutical syntheses be-
of the signals obtained in MAS 31P NMR were too cause of the risk of cross contaminations, we decided
low to determine the existence of leaching in the pres- to perform recycling studies with two of the evaluated
ence of decoordinated or oxidized phosphines.
hybrid materials, namely, Pd
ACHTUNGTREN(NGNU PNP)/SBA-15 and
Pd(PNP)/SBA-15 showed a very different behav- PdCAHTUNGTRENNUNG
N
(PPh2)2/SBA-15, which differ by their leaching ex-
iour in the presence of reagents (i.e., iodoaniline, phe- tents, respectively, of 47% and 7%. Figure 7 clearly
nylacetylene) compared to what was observed in evidences that both materials could be reused without
leaching/redeposition experiments realized in sole sol- any regeneration or reactivation. Unfortunately, ex-
vent (Table 3). While we demonstrated through 31P perimental difficulties in recovering the Pd
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
performed after a reaction run clearly indicates a deg- up to four times without noticeable deactivation
radation of the ligand with a single broad signal cen- which was only observed during the fifth run with
tered at ꢀ4 ppm that could not be attributed to Pd- a drop in the Vmax to 0.32 mmolhꢀ1 leading to a limited
coordinated phosphine (expected at +7–11 ppm), conversion of 39% in 24 h (Table 4). For this catalyst,
phosphine oxide (ibid +28 ppm) or free phosphine a TON of over 6000 was determined demonstrating
(ibid ꢀ28 ppm). Additionally, the decrease of the its high efficiency. The loss of activity observed upon
P/Pd ratio (Supporting Information, Table S2) indi- recycling can be due to limitations in the Pd redeposi-
cates a loss of phosphorus that is connected to a rela- tion as observed in our tests and/or mass loss of cata-
tively good Pd-redeposition (54%, Table 3, entry 1) as lytic material upon such successive recovery series.
attested by wide angle XRD performed on the mate-
rial after reaction that showed a small peak at 2q=
408 attributed to metallic Pd particles (Supporting In- Preparation of Other Ynones
formation, Figure S7). This confirms the role played
by CO: given that a high leaching ratio is observed, This optimized methodology was then applied to the
Pd redeposits on the non-silylated support as large synthesis of several ynones. In all reactions, the selec-
particles, a phenomenon which is favoured by the re- tivity reached using heterogeneous catalysts was
ducing CO atmosphere. To date, the best explanation higher than that observed with homogeneous catalytic
for the lack of stability of the (PNP)-ligand under the systems[24] as full selectivity toward the expected
reaction conditions lies in the basic conditions used to ynone was achieved. Indeed, on the contrary to the
perform the catalytic run leading to degradation of previously described homogeneously catalyzed reac-
the (PCH2NCH2P) linkages once the Pd atom is de- tions, no cyclization of the ynones towards indoxyl –
coordinated.
as activated by phosphines – was observed. As is
Figure 7. Kinetic curves of the different runs for the recycling of [a] PdACHTUNTRGENN(UG PNP)/SBA-15 and [b] PdAHCTUNGTREN(NGUN PPh2)2/SBA-15 in the pres-
ence of an added amount of “blank” SBA-15.
Adv. Synth. Catal. 0000, 000, 0 – 0
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Marie Genelot et al.
FULL PAPERS
Table 4. Maximum reaction rates along the successive runs
cies, agreeing with literature reports; (ii) all the mate-
rials evaluated undergo Pd leaching at a more or less
important level; (iii) when engaging immobilized Pd
complexes, the leaching of Pd is not initiated through
an oxidative addition step but rather by Pd decoordi-
nation from ligand probably favoured by temperature
and solvent polarity.
The detailed study of the boomerang effect allowed
us to identify some of the parameters that enable a de-
crease of the leaching (also through a better redeposi-
tion): (i) low grafting ratio; (ii) hydrophobic state of
the surface; (iii) low polarity of the solvent; (iv) re-
ducing conditions (either through the atmosphere or
the solvent).
for the recycling of Pd
15.
ACHUTGTNRNE(GUN PNP)/SBA-15 and PdACHTUGNTREN(NNGU PPh2)2/SBA-
Catalyst
Cycle vmax
[mmolhꢀ1]
Conv. at 24 h
[%]
Pd(PNP)/SBA-15
G
1
2
1
2
3
4
5
0.57
94
92
87
83
82
75
39
0.45
0.53
0.48
0.53
0.53
0.32
Pd (PPh2)2/SBA-
15
likely in homogeneous systems, no product resulting
Despite leaching of metallic species from the sup-
from simple Sonogashira coupling (i.e., non-carbony- port, the use of heterogeneous catalysts still remains
lated product) was detected. Thus, using Pd(PNP)/ interesting regarding the metal contamination issue of
AHCTUNGTRENNUNG
SBA-15 as catalyst various ynones were obtained with the final compounds compared to homogeneous cata-
isolated yields ranging from 58% to 81% (Table 5, see lysts since the contamination in the crude product was
Supporting Information for more details).
found in the best cases to be very close to the recom-
mendation level of 10 ppm for oral intake of the Eu-
ropean Agency for the Evaluation of Medicinal Prod-
ucts. As a result, several ynones were prepared thanks
to this heterogeneous catalytic system achieving full
Conclusions
The synthesis of propynone by heterogeneously palla- selectivity toward desired compounds.
dium-catalyzed carbonylative Sonogashira coupling
was studied, focusing on the behaviour of the catalytic
materials in reaction especially toward “boomerang”
Experimental Section
(i.e., leaching/redeposition) phenomena. Several orga-
nophosphino-palladium complexes grafted on SBA-15
silica or incorporated within the walls of SBA-3 silica
were evaluated. The mains results of these studies
are: (i) the cross-coupling reaction of 2-iodonaline
with phenylacetylene under a CO atmosphere leading
Synthesis of Heterogeneous Pd Catalysts
PdACHTUNGTNERN(UNG PPh2)2/SBA-15, PdACHTUNTRGE(NGNUN PNP)/SBA-15 and PdACHTNUGTERN(NUGN PCy2)2/SBA-
15 were prepared by post-synthesis grafting of the corre-
sponding molecular precursors onto SBA-15 silica as de-
to the formation of ynones is catalysed by soluble spe- scribed elsewhere[72]
.
Table 5. Synthesis of ynones.[a]
Product
Yield
64%
Product
Yield
81%
75%
58%
70%
[a]
Conditions: 2-iodoaniline (3 mmol), alkyne (1.2 equiv.), Pd
(20 bar), 808C, 10 h.
ACHTUNGTREN(NNUG PNP)/SBA-15 (0.1 mol%), NEt3 (2.5 equiv.), anisole, (5 mL), CO
10
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Carbonylative Sonogashira Coupling in the Synthesis of Ynones
Leaching and redeposition experiments: PdACTHNURTGNEU(GN PNP)/SBA-15
Preparation of PdACHTUNTRGNEUNG(PPh2)2@SBA-3
was suspended in a solvent under an Ar or CO atmosphere
and heated at 808C for 1 hour. The suspension was then
“hot filtrated” through a syringe PTFE, 0.45 mm filter or
a hydrophilic Milliporeꢄ HVLP type, 0.45 mm filter (in the
case of the DMF/H2O mixture) preheated with warm sol-
vent. The palladium content in the filtrate was measured by
ICP-AES. The leaching ratio was determined by comparison
of the Pd amount in the hot filtrate and the initial Pd
amount introduced in the material.
In parallel experiments, the suspension was first cooled
down to room temperature and then filtrated. The palladi-
um content in solution was also measured by ICP-AES. The
redeposition ratio was calculated by comparison with the
leaching ratio.
Recycling experiments: For these experiments, prior to its
use, the catalyst was “diluted” by addition of an amount of
non-functionalized SBA-15 silica (877 m2 gꢀ1) in order to
reach a weight of 100 mg of material in the reaction mixture
facilitating its separation. This was done with the aim of
having a sufficient amount of material to isolate the solid by
filtration after each run. Thus, after a first catalytic cycle,
the mixture of catalyst and “blank” SBA-15 silica was sepa-
rated by filtration, washed with DCM, MeOH and Et2O and
dried under vacuum. It was then reused in the next cycle
without further reactivation steps. The same stoichiometry
as during the first cycle was used but the amounts of reac-
tants and solvent were adjusted according to the collected
amount of recovered solid.
This hybrid material was obtained in a three-step reaction
sequence. Typically, CTAB (4.65 g) was suspended in water
(118 g) and solubilized by addition of concentrated HCl
(58 mL, 37% HCl). A portion of acetonitrile (6.6 g) was
added and the solution was stirred for 15–30 min. TEOS
(15.62 g) was then added dropwise (over 10 min). The super-
natant of
a suspension of PdCl2ACHTNURTGNENG[U PPh2ACHUTGNTNERNUG(CH2)3SiACHUTGNTRENNGU(OEt)3]2
(349 mg) in acetonitrile (6.6 g) was then slowly added to the
gel which was then stirred at room temperature for 4 h and
filtered on sintered glass. The solid was washed with HCl
(1M) then with water and dried under air overnight then
under vacuum at 608C for 2 days. The material was then sta-
bilized by silylation as follows: the material was suspended
in toluene and TMSCl (21 mL) was added. The suspension
was heated at 508C for 3 h then filtered, washed thoroughly
with toluene and dried under vacuum overnight. The surfac-
tant was then removed by extraction with warm ethanol (1 h
at 508C, 3 successive extractions) and the material was dried
under vacuum at 608C overnight. The molecular state of the
resulting hybrid material was characterized by multi-nuclear
NMR spectroscopy (31P and 29Si NMR). The quantitative de-
termination was assessed by elemental and thermogravimet-
ric analyses and the textural and physical properties by ni-
trogen sorption measurements and powder X-ray diffraction
at small angles (see Table S1 in Supporting Information for
comparison with parent SBA-3 silica). 29Si CP-MAS NMR:
d=14, ꢀ89.5, ꢀ100, ꢀ109; 31P MAS NMR: d=21; ICP-AES
analysis: 0.31wt% Pd, 0.16 wt% P.
Catalytic Tests
Kinetic experiments: A mixture of 2-iodoaniline (6 mmol),
alkyne (1.2 equiv.), [Pd] (0.1 mol%) and triethylamine
(2.5 equiv.) in solvent (10 mL) was placed in a stainless auto-
clave which was purged twice at 20 bar with Ar and once
with CO. The autoclave was charged with 5 bar CO and the
mixture was stirred at 808C. For kinetic follow-up, the con-
version was measured by regular GC sampling referring to
an external standard (biphenyl) calibrated to the corre-
sponding pure compound (experimental error ꢁ5%). To
obtain pure ynone, after completion of the reaction, the au-
toclave was depressurized and purged twice at 20 bar with
Ar. The reaction medium was taken up with CH2Cl2
(20 mL) and filtered on sintered glass. The filtrate was
washed with NaHCO3 (2ꢅ20 mL) then with brine (1ꢅ
20 mL). The organic layer was dried over MgSO4 and
Acknowledgements
The authors gratefully acknowledge the National Agency of
Research (No. ANR-07-BLAN-0167-01/02) for funding.
M.G. thanks ANR for a fellowship. CNRS and Universitꢀ
Claude Bernard de Lyon 1 are kindly thanked for financial
support. The authors kindly acknowledge the scientific serv-
ices of IRCELYON for analyses and helpful discussions (C.
Lorentz for Solid-Sate NMR, F. Bosselet and G. Bergeret for
XRD, P. Mascunan and N. Cristin for ICP-AES analyses).
The authors warmly thank G. Niccolai for proof reading our
manuscript.
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FULL PAPERS
14 Carbonylative Sonogashira Coupling in the Synthesis of
Ynones: A Study of “Boomerang” Phenomena
Adv. Synth. Catal. 2013, 355, 1 – 14
Marie Genelot, Vꢀronique Dufaud,* Laurent Djakovitch*
14
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These are not the final page numbers!