Alkynylation of aryl halides with perfluoro-tagged palladium nanoparticles immobilized on silica gel under aerobic, copper- and phosphine-free conditions in water

Article abstract of DOI:10.1039/b903233a

The utilization of perfluoro-tagged palladium nanoparticles immobilized on fluorous silica gel through fluorous-fluorous interactions (Pd _np-A/FSG) or linked to silica gel by covalent bonds (Pd _np-B) in the alkynylation of terminal a

Full text of DOI:10.1039/b903233a

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Alkynylation of aryl halides with perfluoro-tagged palladium nanoparticles
immobilized on silica gel under aerobic, copper- and phosphine-free
conditions in water†‡
Roberta Bernini,a Sandro Cacchi,*b Giancarlo Fabrizi,b Giovanni Forte,c Francesco Petrucci,c
Alessandro Prastaro,a Sandra Niembro,d Alexandr Shafird and Adelina Vallriberad
Received 17th February 2009, Accepted 6th April 2009
First published as an Advance Article on the web 16th April 2009
DOI: 10.1039/b903233a
The utilization of perfluoro-tagged palladium nanoparticles
immobilized on fluorous silica gel through fluorous–fluorous
interactions (Pdnp-A/FSG) or linked to silica gel by cova-
lent bonds (Pdnp-B) in the alkynylation of terminal alkynes
with aryl halides under aerobic, copper- and phosphine-free
conditions in water, and their recovery and re-utilization, is
described.
readily available and some limits to their use in large scale
applications still remain.
To avoid these drawbacks, and consequently to provide access
to alkynylation reactions under aerobic conditions, copper- and
phosphine-free procedures have been developed. This approach
is exceedingly convenient in industrial applications as well as in
cases when the reactions are carried out in multiple vessels for
library generation. Particularly attractive would be a combination
of copper- and phosphine-free conditions with the use of a solid-
supported palladium catalyst.7 This approach could provide two
additional advantages: it could facilitate the recovery and reuse of
palladium and could also reduce the palladium contamination of
the isolated product, a significant problem for the pharmaceutical
industry.8 As to the solvent, the use of water as the reaction
medium is very attractive in organic synthesis due to safety,
economical, and environmental reasons.9 In addition, water has
a high dielectric constant and density so that when reactions
involving water insoluble substrates are carried out in water they
often benefit from the hydrophobic effect.10
There are only a few reports of alkynylation reactions of
aryl halides in the presence of immobilized palladium catalysts
under copper- and phosphine-free conditions in water11 or using
water as co-solvent.12 None of them, however, involve palladium
nanoparticles.
In this context, on the basis of the positive results we obtained
with air-stable perfluoro-tagged palladium nanoparticles sup-
ported on fluorous silica gel (Pdnp-A/FSG) in the Heck reaction
in terms both of yields and recovery and re-utilization of the
catalyst system,13 we became interested in investigating their use in
the reaction of terminal alkynes with aryl halides under aerobic,
copper- and phosphine-free conditions in water (Scheme 1).
The palladium-catalyzed cross-coupling of terminal alkynes with
aryl and vinyl halides or triflates is one of the most powerful
tools for the formation of C–C bonds. The reaction, developed
independently by Sonogashira,1 Heck,2 and Cassar3 in 1975, has
found a large number of applications ranging from the preparation
of fine chemicals to the synthesis of biologically active substances.
Under Sonogashira conditions (copper salts are used as co-
catalysts) the reaction can be carried out using milder conditions
than those typical of Heck and Cassar protocols and this can
explain the enormous success of the Pd/Cu co-catalyzed cross-
coupling chemistry.4
Nevertheless, since its discovery a great deal of work has been
done to modify the original protocol so as to include an even wider
range of reactants as well as to limit some of the major drawbacks
of the process: the presence of copper salts and phosphines.
Indeed, copper salts can induce Glaser-type homocoupling5 of
terminal alkynes when copper acetylide intermediates are exposed
to oxidative agents or air. In addition, the utilization of two metals
hinders the recovery and re-utilization of the expensive palladium
catalysts (its recovery would be the best way to overcome cost
related problems). Phosphines, which are frequently used in this
reaction, are often air-sensitive. As to this point, interesting results
have been achieved by enhancing the catalyst efficacy employing
more efficient phosphines.6 However, these phosphines are not
aDipartimento A.B.A.C., Universita’ della Tuscia e Consorzio Universitario
“La Chimica per l’Ambiente”, Via S. Camillo De Lellis, 01100 Viterbo,
Italy
bDipartimento di Chimica e Tecnologie del Farmaco, Universita` degli Studi
“La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy. E-mail: sandro.
cacchi@uniroma1.it; Fax: +39 (06) 4991 2780; Tel: +39 (06) 4991 2795
cIstituto Superiore di Sanita`, Viale Regina Elena 299, 00161 Rome, Italy
dDepartment of Chemistry, Universitat Auto`noma de Barcelona, Cerdanyola
08193, Spain
† Dedicated to Professor Josep Font Cierco (Universitat Auto`noma de
Barcelona) on the occasion of his 70th birthday.
Scheme 1 Alkynylation of aryl halides under aerobic, copper- and
phosphine-free conditions in water.
‡ Electronic supplementary information (ESI) available: A complete
description of experimental details and product characterization. See DOI:
10.1039/b903233a
The air-stable immobilized pre-catalyst was prepared by adsorb-
ing palladium nanoparticles stabilized by the perfluoro-tagged
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Table 1 The influence of bases on the reaction of phenylacetylene with
3-(trifluoromethyl)iodobenzene catalyzed by Pdnp-A/FSGa in water
runs that could be performed without a significant loss of activity
(Fig. 1).
Sector field inductively coupled plasma mass spectrometry (SF-
ICP-MS) analysis indicated the level of palladium to be in the
range of only 0.05–0.08 ppm in water. However, a high level of
palladium (39–240 ppm) was found in the crude product. Most
probably, the main cause of this result is the relative weakness
of fluorous–fluorous interactions, responsible for binding Pdnp-
A to the FSG, in the alkynylation reaction (no such effect was
observed in the Heck reaction13). Accordingly, 19F NMR analysis
of the crude mixture derived from the reaction of phenylacetylene
with m-(trifluoromethyl)iodobenzene after filtration revealed the
presence of significant amounts of A, corresponding to an original
nanoparticle support loss of about 50% per run.
Consequently, we decided to investigate the use of palladium
nanoparticles stabilized by a perfluorinated compound covalently
bound to silica gel. This precatalyst system (Pdnp-B), containing
3.47% of palladium in the form of nanoparticles with an average
particle size of 3.9 0.9 nm, was prepared by the sol-gel process
described previously15 (Scheme 2).
Entry
Base
Yield % of 3ab
1
2
3
4
5
6
K2CO3
KOAc
Et2NH
Et3N
piperidine
pyrrolidine
50
50
89
91
95
99
a Reactions were carried out using 1 mmol of 3-(trifluoromethyl)iodoben-
zene, 1 mmol of phenylacetylene, 2 mmol of base at 100 ◦C for 5 h in the
presence of 0.1 mol % of Pdnp-A/FSG in 2 mL of water. b Yields are given
for isolated products.
heterocyclic derivative A (Pdnp-A) onto commercially available
fluorous silica gel (FSG).13,14
Using the reaction of 3-(trifluoromethyl)iodobenzene with
phenylacetylene as a probe for evaluating the reaction conditions,
we observed that the corresponding coupled product could be
isolated in moderate yields after 5 h at 100 ◦C in H2O using
0.1 mol% Pdnp-A/FSG with K2CO3 or KOAc as the base under
aerobic conditions (Table 1, entries 1 and 2). No homocoupling
derivative was observed. We then explored the effect of nitrogen
bases and found that an almost quantitative yield could be
obtained with pyrrolidine (Table 1, entry 6).
Although the coupled product was isolated in excellent yield un-
der the best conditions found (0.1 mol% Pdnp-A/FSG, pyrrolidine,
H2O, 100 ◦C, 5 h), recycling studies revealed a limited capacity for
Pdnp-A/FSG to be reused. Indeed, a significant loss of activity was
observed in the third run (Fig. 1). Increasing the catalyst loading
to 0.5 mol% resulted only in a slight increase of the number of
Scheme 2 Synthesis of Pdnp-B.
The catalytic activity and stability of Pdnp-B was tested using
our model system in water with a variety of bases (K2CO3,
KOAc, pyrrolidine, piperidine, Et2NH, and Et3N). After some
experimentation, we found that 3a could be isolated in 95% yield
using 0.5 mol% of Pdnp-B and 2 equiv. of pyrrolidine at 100 ◦C
for 1 h. Recycling studies were then performed which showed
that this supported catalyst system allowed for a number of cycles
largely higher than with Pdnp-A/FSG (Fig. 1). The recovery of the
supported palladium involves centrifugation and decanting the
solution in the presence of air, without any particular precautions.
The Ostwald ripening process16 was not observed upon recycling.
The recovered material after 11 runs was examined by TEM and
showed nanoparticles of about 3.2 nm of diameter (Fig. 2).
A variety of terminal alkynes and aryl halides were then
subjected to the optimized conditions using both Pdnp-A/FSG
(procedure A) and Pdnp-B (procedure B). Our preparative results
are summarized in Table 2. Acetylenes bearing electron-rich and
electron-poor aryl groups, as well as alkyl substituents, give
coupling products in excellent yields when reacted with aryl
iodides which in turn can accommodate electron-withdrawing
and electron-donating substituents. Ortho substituents in the aryl
halide are also tolerated (Table 2, entries 9 and 10). With aryl
bromides, longer reaction times are required and similar or lower
Fig. 1 Recycling studies for the reaction of 3-(trifluoromethyl)iodoben-
zene with phenylacetylene catalyzed by Pdnp-A/FSG or Pdnp-B.
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Table 2 The reaction of terminal alkynes 1 with aryl iodides and bromides 2 in the presence of Pdnp-A/FSG or Pdnp-Ba
Entry
Terminal Alkyne 1 R
ArX 2
Proc.
Time (h)
Yield% of 3b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Ph
3-CF3C6H4-I
3-CF3-C6H4-I
3-CF3-C6H4-I
4-EtO2C-C6H4-I
4-NO2-C6H4-I
4-MeO-C6H4-I
4-CN-C6H4-I
4-CN-C6H4-I
2-Me-C6H4-I
2-Me-C6H4-I
3-CF3-C6H4-I
3-CF3-C6H4-I
4-CN-C6H4-I
4-CN-C6H4-I
4-MeO-C6H4-I
4-MeO-C6H4-I
4-CN-C6H4-I
4-MeO-C6H4-I
4-MeO-C6H4-I
4-MeCO-C6H4-I
A
A
B
A
A
B
A
B
A
B
A
B
A
B
A
B
B
A
B
B
3
3
1
5
5
12
5
7
29
9
2
2
4
2
3
24
24
48
24
14
3a
3a
3a
3b
3c
3d
3e
3e
3f
95
95c
95
95
93
90
85
95
80
90
89
99
90
99
85
87
89
83
90
92
4-MeO-C6H4
3f
4-CN-C6H4
4-MeCO-C6H4
4-CN-C6H4
3g
3g
3h
3h
3e
3e
3i
3j
3k
3l
HOCH2
HO(Me)2C
HOMe(Ph)C
21
22
23
Ph
4-MeCO-C6H4-Br
3-CF3-C6H4-Br
4-MeO-C6H4-Br
A
B
B
44
9
48
3m
3a
3d
50
91
65
a Reactions were carried out under aerobic conditions using 1 mmol of aryl halide, 1 mmol of terminal alkyne, 2 mmol of pyrrolidine at 100 ◦C in 2 mL
of H2O with 0.1 mol % of Pdnp-A/FSG (procedure A) or 0.5 mol% of Pdnp-B (procedure B). b Yields are given for isolated products. c In the presence of
0.5 mol% of Pdnp-A/FSG.
can be carried out in the presence of air without any particular
precautions) and re-utilization.
Notes and references
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entry 6 with entry 23).
In conclusion, we have demonstrated that perfluoro-tagged
palladium nanoparticles immobilized on fluorous silica gel by
fluorous-fluorous interactions (Pdnp-A/FSG) or linked to silica
gel by covalent bonds (Pdnp-B) can be successfully used in the
alkynylation of aryl halides under aerobic, copper- and phosphine-
free conditions in water. Both catalyst systems allow for the
isolation of coupled products in high to excellent yields. However,
the use of Pdnp-B gives the best results in term of recovery (which
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