Palladium and copper-supported on charcoal: A heterogeneous multi-task catalyst for sequential Sonogashira-Click and Click-Heck reactions

Article abstract of DOI:10.1016/j.jorganchem.2014.01.006

This paper describes the development of one-pot sequential Sonogashira-Click and Click-Heck reactions by using Pd-Cu/C as a heterogeneous multi-task catalyst for the synthesis of heterocyclic structures. Details of the optimization studies and the substrate scope are discussed. These methodologies allow the preparation of functionalized triazoles in simple experimental conditions with inexpensive reagents.

Full text of DOI:10.1016/j.jorganchem.2014.01.006

Journal of Organometallic Chemistry 755 (2014) 78e85
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Palladium and copper-supported on charcoal: A heterogeneous
multi-task catalyst for sequential SonogashiraeClick and ClickeHeck
reactions
,
Cybille Rossy a b, Jérôme Majimel c, Mona Tréguer Delapierre c, Eric Fouquet a,
,
François-Xavier Felpin b
*
a Université de Bordeaux, UMR CNRS 5255, ISM, 351 cours de la Libération, 33405 Talence Cedex, France
b Université de Nantes, UFR Sciences et Techniques, UMR CNRS 6230, CEISAM, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
c Université de Bordeaux, CNRS UPR 9048, 87 Avenue du Dr. Schweitzer, 33608 Pessac Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes the development of one-pot sequential SonogashiraeClick and ClickeHeck re-
actions by using PdeCu/C as a heterogeneous multi-task catalyst for the synthesis of heterocyclic
structures. Details of the optimization studies and the substrate scope are discussed. These methodol-
ogies allow the preparation of functionalized triazoles in simple experimental conditions with inex-
pensive reagents.
Received 23 November 2013
Received in revised form
19 December 2013
Accepted 7 January 2014
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
Sonogashira
Click
Heck
Palladium
Copper
Heterogeneous bimetallic catalyst
1. Introduction
benefits. Multi-task heterogeneous monometallic catalysts are
experimentally easy to use, but the high specificity of the metal
The heterogeneization of metals onto a support constitutes
gained increasing attention these last years in the context of the
development of sustainable organometallic chemistry [1]. Indeed,
immobilized molecular complexes or nanoparticles onto a support
can be recovered from the reaction mixture by a simple filtration,
allowing products and solvents free of metallic residues. Moreover,
the recycling of the recovered catalyst in successive reuses allows
processes interesting from an economical point of view.
Multi-task heterogeneous metallic-based catalysts are a novel
class of catalysts able to be involved in at least two consecutive
reactions having a different mechanism [2]. The heterogeneous
catalytic entity can be monometallic or multimetallic. In the former,
the metal itself is multi-task, while with multimetallic catalysts
each metal may play a specific role. These promising multi-task
catalysts, allowing multiple transformations in the same reaction
vessel, offer significant time-cost, efforts, and waste generation
usually restrains the window of reactions [3]. On the other hand,
multi-task heterogeneous multimetallic catalysts are, in theory,
more convenient and flexible for the cohabitation of two or more
fundamentally different transformations using the specificity of
each metal [4]. However, this approach remains largely unexploited
in synthesis due to a lack of generality and incompatibility issues
between transition metals.
We recently reported PdeCu/C-catalysed Sonogashira alkyny-
lationecyclization sequences for the preparation of indoles and
benzofurans [5]. The good results obtained and the compatibility of
the catalyst with hydrophilic solvents prompted us to investigate
further one-pot sequential transformations.
2. Results and discussions
The preparation of the required PdeCu/C catalyst was adapted
from a procedure previously developed in our laboratory for Pd/C
[6] and PdeAu/C [7] catalysts. Thereby, a solution of Pd(OAc)2,
Cu(OAc)2 and activated charcoal in MeOH stirred under an atmo-
sphere of H2 (1 atm) for 12 h furnished, upon filtration, the required
* Corresponding author.
E-mail address: fx.felpin@univ-nantes.fr (F.-X. Felpin).
0022-328X/$ e see front matter Ó 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2014.01.006

C. Rossy et al. / Journal of Organometallic Chemistry 755 (2014) 78e85
79
PdeCu/C catalyst. The content of impregnated Pd (w5 wt.-%) and
Cu (w3.6 wt.-%) onto charcoal was determined by ICP-MS analysis.
Transmission electron microscopy (TEM) analyses indicated the
formation of small PdeCu nanoparticles along with few larger
colloids onto the support (Fig. 1a). The crystallite mean size ranges
from 4 to 10 nm for the small nanoparticles while the larger colloids
reach 20e30 nm. Complementary Scanning TEM coupled with X-
ray photoelectron spectroscopy highlighted that Cu and Pd species
are mostly homogeneously dispersed onto the charcoal support
which tends to prove that bimetallic alloys can be formed (Fig. 1ce
e). Nevertheless, copper and/or palladium enriched zones can also
be detected meaning that monometallic particles are most
certainly coexisting with the bimetallic ones. This bimetallic Pde
Cu/C catalyst was also characterized by X-ray photoelectron spec-
troscopy. The two large Pd 3d5/2 and Pd 3d3/2 spin-orbit peaks at
respectively 335.7 and 340.9 eV indicated a mixture of Pd0 and Pd2þ
(Fig. 1f). The deconvoluted peaks revealed the presence of 40% Pd0
and 60% Pd2þ at the surface of the support. This result suggests the
formation of PdeO bonds at the surface of the nanoparticles by
rapid oxidation of Pd0 nanoparticles under air. The composition of
copper species was also investigated by XPS (Fig. 1g). The binding
energy of the Cu 2p3/2 peak at 932e935 eV and the satellite
shakeup detected near 938e946 eV are characteristic of Cu2þ
species. However, the shoulder observed on the Cu 2p3/2 spin-orbit
peak also indicated the presence of Cu0/þ1 species. Deconvolution
of Cu 2p3/2 at 932.4 and 934.6 eV revealed the presence of 30% Cu0/
and 70% Cu2þ
.
þ1
We reasoned that aryl acetylenes intermediates, obtained from
a Pd- and Cu-cocatalyzed Sonogashira alkynylation, could be
involved in a subsequent Cu-catalysed [3þ2]-cycloaddition with an
azide, by taking advantage of a multi-task PdeCu/C catalyst.
In order to prove the feasibility of such sequential trans-
formations with our heterogeneous bimetallic catalyst, we initially
studied the PdeCu/C-catalysed Click reaction between benzyl
azide 1 and aryl acetylenes [8]. A rapid survey of experimental
conditions showed that benzyl azide 1 reacted efficiently with
phenylacetylene 2 in water under MW activation with a short re-
action time (10 min) to give the expected triazole 3. The reaction
yield could be even improved with MeOH as solvent, likely due to a
higher solubility of reagents, a crucial point when working with a
heterogeneous catalyst. By contrast, diphenylacetylene 4 did
not react with benzyl azide 1 even under forcing conditions
(Scheme 1). These preliminary results approximately marked out
the substrate scope of the [3þ2]-cycloaddition step and implied
that the Sonogashira alkynylation step would provide terminal
acetylenes.
Fig. 1. a) TEM micrographs of PdeCu/C catalyst; b) HRTEM micrographs of PdeCu/C catalyst; c, d) STEMeEDX elemental maps of Pd and Cu respectively; e) STEM micrographs and
RG-2 colours chemical map of PdeCu/C catalyst; f, g) XPS spectra of Pd3d and Cu2p respectively.

80
C. Rossy et al. / Journal of Organometallic Chemistry 755 (2014) 78e85
TMSA (2 equiv.), a much improved yield for 7 was obtained (70% vs.
47%, entry 7).
With a set of solid optimized experimental conditions, we
evaluated the one-pot sequential SonogashiraeClick reactions
yielding diversely decorated triazoles. Such a strategy has been
recently described with homogeneous metallic complexes and
TBAF as a desilylating agent [9] but heterogeneous catalytic system
has not been reported yet. Results depicted in Scheme 2 indicated
that the Sonogashira step is compatible with both electron-
donating (compounds 8geh) and electron-withdrawing (com-
pounds 8b, 8f) substituents on the iodoaryl. The compatibility of
the sequence with heteroaryls allows structural diversity that could
be of interest for medicinal chemists (compounds 8cee) [10].
Interestingly, the high functional compatibility of our catalytic
system with ketones (8b), alcohols (8g), amines (8e) and halogens
(8e) should be mentioned. On the other hand, the [3þ2]-
cycloaddition step tolerated both benzylic and aliphatic azides
with comparable efficiency (compounds 8feh). Interestingly, by
contrast with literature precedents reported with homogeneous
Scheme 1. [3þ2]-Cycloadditions with PdeCu/C.
We previously described Sonogashira cross-coupling reactions
with our home-made PdeCu/C catalyst in water as solvent. How-
ever, in the present study we observed that the Click-reaction was
preferentially conducted in MeOH as solvent (Scheme 1). Conse-
quently, we reinvestigated the Sonogashira reaction in MeOH
following a short optimization study. Considering that diary-
lacetylenes could not be involved in the [3þ2]-cycloaddition step,
we selected trimethylsilylacetylene 6 (TMSA) as a latent acetylene
substitute that would provide terminal acetylenes upon coupling
with aryl iodides and removing the transient trimethylsilyl pro-
tecting group (Table 1).
Surprisingly, in our preliminary optimization studies we only
isolated diphenylacetylene 4 under both thermal and MW heating
in MeOH suggesting the lost of the TMS under the experimental
conditions (entries 1e2). A similar trend was also observed in water
as solvent with both homogeneous and heterogeneous catalytic
systems, suggesting that the p-acidity of charcoal was not involved
in the TMS cleavage (entries 3e4). Suspecting an effect of the base
on the stability of the TMS protecting group, we evaluated alter-
native amines. While with diisopropylethylamine as
a base
diphenylacetylene 4 was also exclusively formed (entry 5), the use
of Et2NH, under micro-wave heating, gave selectively the cross-
coupled product 7 in short reaction time (20 min), along with
recovered iodobenzene 5 (entry 6). We suspected that the incom-
plete conversion could result of the high volatility of TMSA (bp
53 ꢀC) under the reaction conditions. Indeed, with an excess of
Table 1
Optimization of the Sonogashira coupling with TMSA.
Entry Catalyst
Base
Solvent T (ꢀC) Time
65 20 h
Yield (%)
1a
2
3
4
5
6
7
PdeCu/C
PdeCu/C
PdeCu/C
NH2(CH2)2OH MeOH
NH2(CH2)2OH MeOH 120
NH2(CH2)2OH H2O
eb
20 min eb
80
80
20 h
20 h
eb
eb
Pd(OAc)2, Cu(OAc)2 NH2(CH2)2OH H2O
PdeCu/C
PdeCu/C
PdeCu/C
(iPr)2NEt
Et2NH
Et2NH
MeOH 120
MeOH 120
MeOH 120
20 min eb
20 min 47
20 min 70c
a
Reaction conditions: iodobenzene (0.25 mmol) TMSA (0.3 mmol), base
(0.75 mmol), Ph3P (5 mol%) and catalyst (5 mol% Pd) were stirred in MeOH (1 mL)
under Ar.
b
Diphenylacetylene 4 exclusively formed.
2 equiv. of trimethylsilylacetylene (0.5 mmol) were used.
c
Scheme 2. Scope of the one-pot sequential SonogashiraeClick reactions.

C. Rossy et al. / Journal of Organometallic Chemistry 755 (2014) 78e85
81
Scheme 3. Studies for intramolecular processes e preparation on isoindoline fused with triazoles.
Scheme 4. Evaluation of the reactivity of N3 vs. CeI functions.
systems [7], the use of TBAF as desilylating agents was unnecessary
suggesting that the TMS protecting group was cleaved during the
[3þ2]-cycloaddition step and facilitating the purification step.
Remarkably, the use of MW allows the succession of two different
reactions in only 30 min with an average yield per step in the range
70e87%.
Having demonstrated the potential of our PdeCu/C catalyst for
sequential one-pot SonogashiraeClick reactions through an inter-
molecular process, we studied the opportunity for intramolecular
processes in order to attain structurally intriguing isoindolines
fused with triazoles. The general strategy, depicted in Scheme 3,
can follow two pathways according to the kinetic of reactions
involved in the sequence. In path I, the sequence involves succes-
sive Click and Heck transformations while a tandem Sonogashirae
Click sequence prevails in Path II.
Despite the modest yield obtained for 11, the challenging
intramolecular Heck arylation of triazoles has never been described
under heterogeneous catalysis and examples with homogeneous
catalysts are rare [11]. We further evaluated the one-pot sequential
ClickeHeck reactions (Scheme 5). Such a tandem process, leading
to structurally relevant heterocycles, has been studied by Chowd-
hury et al. [12] under homogeneous catalysis and proved to be
rather difficult. We were surprised to find that under MW heating
irreproducible results and quite low yields were obtained (20e
36%). We attributed these disappointing results to the low stability
of the azide function at 160 ꢀC. This assumption was supported by
the much improved reaction yield obtained under thermal activa-
tion at lower temperatures (120 ꢀC). Although our results cannot be
directly compared with those from Corma et al. [13] using a
MOF-Cu(BTC)e[Pd] catalyst since only conversions were reported,
Initial investigations showed that under the conditions devel-
oped for the Sonogashira coupling [4], the reaction between 2-
iodobenzylazide 9 and phenylacetylene 2 exclusively gave the
[3þ2]-cycloadduct 10 in 86% yield, the carboneiodine bond being
unaffected and the Sonogashira adduct 11 was never detected
(Scheme 4). Interestingly, the optimized conditions with a homo-
geneous catalytic system furnished the [3þ2]-cycloadduct 10 in a
reduced yield (76%), highlighting the high catalytic efficiency of our
heterogeneous bimetallic PdeCu/C catalyst.
Table 2
Optimization of the intramolecular Heck reaction.
This result suggests that the Click reaction, between the azide
and the alkyne, proceed more easily than the concurrent Sonoga-
shira coupling. In order to convert B into the required compound C,
through an intramolecular Heck process, we investigated a series of
experimental conditions (Table 2). With the aim of shortening the
reaction time, we initially privileged MW activations. A short ligand
screening showed that Ph3P was the most efficient and less
expensive ligand for this transformation. Electron-rich biphenyl
phosphines such as X-Phos and Ru-Phos (entries 4e5) as well as
bidentate phosphines such as dppe (entry 3) did not improve the
reaction yield.
Entry
Conditionsa
Ligand
Yield (%)b
1
2
3
4
5
Ethanolamine, H2O, 130 ꢀC, 10 min, MW
Ethanolamine, H2O, 160 ꢀC, 10 min, MW
Ethanolamine, H2O, 160 ꢀC, 10 min, MW
Ethanolamine, H2O, 160 ꢀC, 10 min, MW
Ethanolamine, H2O, 160 ꢀC, 10 min, MW
Ph3P
Ph3P
dppe
X-Phos
Ru-Phos
20
42
28
34
44
a
Reaction conditions: triazole (0.5 mmol), ethanolamine (1.5 mmol), ligand
(5 mol%) and catalyst (5 mol% Pd) were stirred in H2O (3 mL) under Ar.
b
Isolated yield.

82
C. Rossy et al. / Journal of Organometallic Chemistry 755 (2014) 78e85
corrected and determined by using a Stuart Scientific apparatus
(SMP3). Yields refer to isolated material determined to be pure by
NMR spectroscopy and thin layer chromatography (TLC), unless
specified otherwise in the text. Analytical TLC was performed on
Fluka Silica Gel 60 F254. All commercial materials were used
without further purification, unless indicated. Pd(OAc)2 (45.9e
48.4% of metal), Cu(OAc)2 were obtained from Alfa Aesar, methanol
ChromasolvÒ for HPLC > 99.9% and activated charcoal DarcoÒ G-60
(100 mesh) were obtained from SigmaeAldrich.
4.2. Preparation and characterization of PdeCu/C
The PdeCu/C was prepared by following procedure. Pd(OAc)2
(119 mg, 0.5 mmol), Cu(OAc)2 (170 mg, 0.9 mmol) and charcoal (1 g)
were dispersed in MeOH (100 mL). Then, the hydrogen gas was
bubbled through the solution for 5 min to remove the oxygen. The
resulting mixture was stirred for 12 h at 25 ꢀC under H2 (1 atm,
balloon). The catalyst was filtered under Millipore membrane (fil-
ters nylon 0.45 mm, 47 mm), washed with MeOH and dried under
vacuum. The metal loading was determined by ICP analyses: 5 wt.-
% Pd and 3.6 wt.-% Cu. The palladium and copper concentrations
were checked by ICP-MS analysis of the filtrate, on Agilent 7700x.
For the transmission electron microscopy (TEM) investigations, the
powder samples of the catalysts were ultrasonically dispersed in
ethanol and samples of the solution were took and air-dried onto a
300 mesh gold grids covered with a holey carbon film (Electron
Microscopy Sciences). A JEOL 2200FS electron microscope, oper-
ating at 200 kV was used in TEM mode for HRTEM and in STEM
mode for STEM and EDX spectrum imaging. The XPS analysis was
carried out with VG Scientific 220 i-XL ESCALAB spectrometer was
Scheme 5. Preparation on isoindoline fused with triazoles.
a similar trend was observed in our hand. Indeed, they reported
that electron-rich aryl alkynes and aliphatic alkynes gave low
conversion (36% and 25% respectively) while in our hand 43% and
30% isolated yields were respectively obtained.
The recyclability of our home-made 10% PdeCu/C catalyst was
evaluated for one-pot sequential SonogashiraeClick reactions of
compound 8a. Unfortunately, we found that the catalyst was almost
inactive after the second run. ICP-MS analyses of the filtered solu-
tion after the second run showed a marginal leaching of Pd (<0.2%
based on the amount initially introduced) while ca 16% of copper
(based on the initial amount introduced) was detected in the
filtered solution. These results cannot explain the absence of cata-
lytic activity upon recycling. Djakovitch and co-workers suggested
for a similar trend, observed with their PdeCu/NaY catalyst, that
the deactivation likely occurred during the work-up [3f]. They
stated that the use of a flow technology might address this issue
and we are actually exploring this alternative.
used for the surface analysis with a monochromatized AlKa source
(h
n
¼ 1486.6 eV) at 70 W. A pressure of 10ꢁ7 Pa was maintained in
the chamber during analysis. Powders were pressed on copper
tape. The spot size was about 150 mm in diameter. The full spectra
(0e1350 eV) were obtained with a constant pass energy of 150 eV
and high resolution spectra at a constant pass energy of 40 eV. High
resolution spectra were fitted and quantified using the AVANTAGE
software provided by ThermoFisher Scientific.
4.3. Optimization studies
3. Conclusion
4.3.1. 1-Benzyl-4-phenyl-1H-1,2,3-triazole 3
In summary we have described a new heterogeneous multi-task
PdeCu/C catalyst for tandem Sonogashira alkynylatione[3þ2]-
cycloaddition sequences leading to diversely decorated triazoles.
The procedure allows the preparation of useful heterocycles in
hydrophilic solvents with inexpensive ligand and base. These
studies broaden the rare examples of heterogeneous multi-task
bimetallic catalysts working in organic synthesis [1]. Current
studies focus on the extension of this chemistry to flow processes.
In microwave reaction vessel, PdeCu/C catalyst (5 mol% Pd),
phenylacetylene (0.6 mmol), and diethylamine (1.5 mmol) were
suspended in MeOH (3 mL). The microwave reaction vessel was
closed with a Teflon cap, the reaction mixture was flushed with
argon flow for 5 min and benzyl azide (0.5 mmol) was added. Then,
the reaction mixture was stirred 120 ꢀC under microwave irradia-
tions for 10 min. The mixture was cooled at room temperature and
concentrated under reduced pressure. Purification by flash chro-
matography (20% EtOAcepetroleum ether) gave 3 (69 mg, 59%) as a
4. Experimental
white powder. mp 126 ꢀC [lit. [14] 127e129 ꢀC]. IR (KBr)
n 2986,
1607, 1531, 1225 cmꢁ1 1H NMR (CDCl3, 300 MHz)
.
d
5.58 (s, 2H),
4.1. Materials and methods
7.30e7.34 (m, 3H), 7.36e7.43 (m, 5H), 7.66 (s, 1H), 7.80 (dd, 2H,
d 54.4, 119.6, 125.9, 128.2,
128.3, 128.9, 129.3, 130.7, 134.8, 143.8, 148.4. HRMS (FD) calcd for
J ¼ 1.5, 8.5 Hz). 13C NMR (CDCl3, 75 MHz)
1H NMR and 13C NMR were recorded on Brüker DPX-200 FT (1H:
200 MHz, 13C: 50.2 MHz), Brüker Avance 300 FT (1H: 300 MHz, 13C:
75.3 MHz), Brüker DPX-400 FT (1H: 400 MHz, 13C: 100.2 MHz).
Chemical shifts from proton and carbon NMR spectra are reported
in ppm relative to the CDCl3 peak at 7.26 ppm (1H) or 77.0 ppm
C15H13N3 (M) 235.1110, found 235.1106.
4.3.2. Trimethyl(phenylethynyl)silane 7
In microwave reaction vessel, TMSA (71 mL, 0.5 mmol), 10% Pde
Cu/C (5 mol% Pd) and diethylamine (78 mL, 0.75 mmol) were added
(
13C). Coupling constants J are reported in hertz (Hz). The following
abbreviations are used for the multiplicities: s, singlet; d, doublet; t,
triplet; q, quartet; qt, quintet; st, sextet; m, multiplet; br, broad; dd,
doublet of doublet. Infrared (IR) spectra were recorded as neat
samples on NaCl plates or with KBr pellets. Melting points were not
to solution of iodobenzene (51 mg, 0.25 mmol) in MeOH (1.0 mL).
The microwave reaction vessel was closed and the reaction mixture
was flushed with argon flow for 5 min. Then, the reaction mixture
was irradiated with Biotage Initiator for 20 min at 120 ꢀC. The

C. Rossy et al. / Journal of Organometallic Chemistry 755 (2014) 78e85
83
mixture was cooled at room temperature and concentrated under
4.4.4. 1-Azido-6-chlorohexane
Purification by flash chromatography (100% petroleum ether)
gave the titled compound (404 mg, 50%) as colourless oil. IR (neat)
reduced pressure. Purification by flash chromatography (100% pe-
troleum ether) gave 7 (31 mg, 70%) as white powder. 1H NMR
n
(CDCl3, 300 MHz)
d
0.26 (s, 9H), 7.29e7.32 (m, 3H), 7.46e7.49 (m,
2951, 2259 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d 1.35 (m, 4H), 1.55 (m,
2H). 29Si NMR (CDCl3, 59.6 MHz)
d
ꢁ17.75. 13C NMR (CDCl3, 75 MHz)
4H), 1.83 (m, 2H), 3.74 (t, 2H, J ¼ 6.8 Hz). 13C NMR (CDCl3, 75 MHz)
d
0.1, 94.2, 105.3, 123.3, 128.3, 128.6, 132.1. The 1H and 13C NMR data
d 26.1, 26.8, 30.3, 31.4, 44.9, 50.3. HRMS (FD) calcd for C16H12ClN3
corresponds to those reported in literature [15].
(M) 161.6414, found 161.6111.
4.4.5. 2-Iodobenzyl azide 9
4.3.3. 1-(2-Iodobenzyl)-4-phenyl-1H-1,2,3-triazole 10
2-Iodobenzyl alcohol (789 mg, 3.37 mmol) was solubilized in
dry DMF (5 mL) then DBU (1.0 mL, 2.0 mmol) and DPPA (1.4 mL,
2.0 mmol) were added. The reaction mixture was stirred overnight
at room temperature under argon atmosphere. The organic layer
was extracted with EtOAc (6 ꢂ 20 mL). The organic extracts were
collected and concentrated under reduced pressure. Purification by
In microwave reaction vessel, 2-iodobenzylazide 9 (0.5 mmol,
1.0 eq), PPh3 (5 mol%), ethanolamine (1.5 mmol), phenylacetylene
(1 mmol) and PdeCu/C catalyst (5 mol% Pd) were suspended in H2O
(1 mL). The microwave reaction vessel was closed with a Teflon cap
and the reaction mixture was flushed with argon flow for 5 min.
Then, the reaction mixture was stirred 120 ꢀC under microwave
irradiations for 10 min. The mixture was filtered under CeliteÒ pad
and the aqueous layer was extracted with CH2Cl2 (2 ꢂ 10 mL). The
organic extracts were collected, washed with brine (20 mL), dried
on MgSO4, filtered and concentrated under reduced pressure. Pu-
rification by flash chromatography (20% EtOAcepetroleum ether)
gave 10 (155 mg, 86%) as a white powder. mp 115 ꢀC [lit. [11] 115e
flash chromatography (10% EtOAcepetroleum ether) gave
9
.
(803 mg, 92%) as a colourless oil. IR (neat)
n
3057, 2932, 2098 cmꢁ1
1H NMR (CDCl3, 300 MHz)
d 4.46 (s, 2H), 7.07e7.06 (m, 1H), 7.37e
7.39 (m, 2H), 7.88 (d,1H, J ¼ 7.7 Hz). 13C NMR (CDCl3, 75 MHz)
d 59.1,
99.0, 128.7, 129.4, 129.9, 138.1, 139.8. LRMS (GCeMS) 258.96. HRMS
(EI) calcd for C7H6IN3 (M) 258.9606, found 258.9612.
117 ꢀC]. IR (KBr) 3125, 3097, 1529 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
n
4.5. General procedure for tandem reaction Sonogashira/Click
d
5.67 (s, 2H), 7.06 (td, 1H, J ¼ 1.6, 7.7 Hz), 7.14 (dd, 1H, J ¼ 1.4,
7.7 Hz), 7.33 (d, 2H, J ¼ 7.1 Hz), 7.37e7.44 (m, 2H), 7.77 (s, 1H), 7.82e
7.84 (m, 2H), 7.91 (dd, 1H, J ¼ 1.0, 7.9 Hz). 13C NMR (CDCl3, 75 MHz)
In a microwave reaction vessel, the iodide derivative (0.5 mmol,
1.0 eq), PPh3 (5 mol%), diethylamine (1.5 mmol) and PdeCu/C
catalyst (5 mol% Pd) were suspended in MeOH (3 mL). The tube was
sealed with a Teflon cap, the reaction mixture was flushed under an
argon flow for 5 min and then TMSA (1 mmol) was added. Then, the
reaction mixture was stirred 120 ꢀC under microwave irradiations
for 20 min. After completion of the reaction, the azide derivative
(0.6 mmol) was added and the mixture was irradiated again for
10 min at 120 ꢀC. The mixture was cooled to room temperature,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel.
d
58.6, 98.8, 120.0, 125.9, 128.4, 129.0, 129.2, 129.8, 130.6, 137.5,
140.0, 148.3. HRMS (FD) calcd for C15H12IN3 (M) 361.0076, found
361.0093.
4.4. General procedure for the synthesis of azides
Sodium azide (7.5 mmol) was suspended in anhydrous DMF
(10 mL) and the bromide derivative (5 mmol) was added. The re-
action mixture was stirred overnight at 80 ꢀC. Then, the mixture
was cooled at room temperature and quenched with water (20 mL).
The aqueous layer was extracted with Et2O or CH2Cl2 (2 ꢂ 20 mL)
and the organic layer was washed with water (4 ꢂ 25 mL). The
organic extracts were collected, dried on MgSO4, filtered and
concentrated under reduced pressure.
4.5.1. 1-Benzyl-4-phenyl-1H-1,2,3-triazole 8a
Purification by flash chromatography (20% EtOAcepetroleum
ether) gave 3 (69 mg, 59%) as a white powder. mp 126 ꢀC [lit. [14]
127e129 ꢀC]. IR (KBr)
n .
2986, 1607, 1531, 1225 cmꢁ1 1H NMR
(CDCl3, 300 MHz)
d 5.58 (s, 2H), 7.30e7.34 (m, 3H), 7.36e7.43 (m,
4.4.1. Benzyl azide
5H), 7.66 (s, 1H), 7.80 (dd, 2H, J ¼ 1.5, 8.5 Hz). 13C NMR (CDCl3,
Purification by flash chromatography (10% EtOAcepetroleum
ether) gave the titled compound (565 mg, 85%) as a colourless oil. IR
75 MHz)
d 54.4, 119.6, 125.9, 128.2, 128.3, 128.9, 129.3, 130.7, 134.8,
143.8, 148.4. HRMS (FD) calcd for C15H13N3 (M) 235.1110, found
235.1106.
(neat)
d
n .
3032, 2097, 1604, 1496 cmꢁ1 1H NMR (CDCl3, 300 MHz)
4.35 (s, 2H), 7.32e7.44 (m, 5H). 13C NMR (CDCl3, 75 MHz)
d 54.9,
128.33, 128.4, 129.0, 135.5. HRMS (EI) calcd for C7H7N3 (M)
133.0640, found 133.0639.
4.5.2. 1-(4-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl)ethanone 8b
Purification by flash chromatography (20% EtOAcepetroleum
ether) gave 8b (102 mg, 74%) as a yellow powder. mp 160 ꢀC [lit. [16]
160e162 ꢀC]. 1H NMR (CDCl3, 300 MHz)
d 2.65 (s, 3H), 5.62 (s, 2H),
4.4.2. 4-Nitrobenzyl azide
Purification by flash chromatography (20% EtOAcepetroleum
ether) gave the titled compound (757 mg, 86%) as a colourless oil. IR
7.35e7.37 (m, 2H), 7.41e7.45 (m, 3H), 7.75 (s, 1H), 7.92 (d, 2H,
J ¼ 8.5 Hz), 8.01 (d, 2H, J ¼ 8.3 Hz). 13C NMR (CDCl3, 75 MHz)
d 27.1,
(neat)
d
n .
3082, 2857, 2102, 1519 cmꢁ1 1H NMR (CDCl3, 300 MHz)
54.4,120.6, 125.7, 128.5,130.2,129.2, 129.5,134.6,135.3, 136.8,147.2,
197.7. The 1H and 13C NMR data corresponds to that reported in
literature [16].
4.50 (s, 2H), 7.50 (d, 2H, J ¼ 8.7 Hz), 8.25 (d, 2H, J ¼ 8.7 Hz). 13
C
NMR (CDCl3, 75 MHz)
d 53.8, 124.1, 128.7, 142.8, 147.8. HRMS (FD)
calcd for C7H6N4O2 (M) 178.0491, found 178.0492.
4.5.3. 1-(4-Nitrobenzyl)-4-(thiophen-2-yl)-1H-1,2,3-triazole 8c
Purification by flash chromatography (10% EtOAcepetroleum
4.4.3. 2-(2-Azidoethyl)-1,3-dioxolane
Purification by flash chromatography (10% EtOAcepetroleum
ether) gave 8c (74 mg, 52%) as a yellow solid. mp 124 ꢀC. IR (KBr)
n
ether) gave the titled compound (533 mg, 75%) as a colourless oil. IR
3087, 2982, 1538, 1363 cmꢁ1. 1H NMR (CDCl3, 400 MHz)
d 5.68 (s,
(neat)
n
2959, 2887, 2099 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d
1.89e
2H), 7.06e7.09 (m, 1H), 7.31 (dd, 1H, J ¼ 0.9, 5.1 Hz), 7.38 (dd, 1H,
1.95 (m, 2H), 3.39 (t, 2H, J ¼ 6.9 Hz), 3.81e3.90 (m, 2H), 3.92e3.98
J ¼ 1.0, 3.6 Hz), 7.45 (d, 2H, J ¼ 8.6 Hz), 7.65 (s, 1H), 8.25 (d, 2H,
(m, 2H), 4.93 (t, 1H, J ¼ 4.5 Hz). 13C NMR (CDCl3, 75 MHz)
d
33.1,
J ¼ 8.7 Hz). 13C NMR (CDCl3, 100 MHz)
d 53.4, 119.2, 124.5, 124.7,
125.6, 127.9, 128.7, 132.5, 141.7, 144.0, 148.3. HRMS (FD) calcd for
46.6, 65.0, 102.0. HRMS (ESI) calcd for C5H9N3O2Ag (M þ Agþ)
249.9740, found 249.9733.
C13H10N4O2S (M) 286.0525, found 286.0528.

84
C. Rossy et al. / Journal of Organometallic Chemistry 755 (2014) 78e85
4.5.4. 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)pyridine 8d
EtOAc (10 mL) was added. The mixture was filtered under a pad of
CeliteÒ and the aqueous layer was extracted with EtOAc (10 mL).
The organic extract was collected, washed with brine (20 mL), dried
on Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel and
then recrystallized.
Purification by flash chromatography (50% EtOAcepetroleum
ether) gave 8d (73 mg, 62%) as a white solid. mp 103 ꢀC [lit. [9a]
100e102 ꢀC]. IR (KBr)
n .
2993, 2876, 1670, 1588 cmꢁ1 1H NMR
(CDCl3, 300 MHz) d 5.61 (s, 2H), 7.44e7.32 (m, 6H), 7.75 (s, 1H), 8.18
(d,1H, J ¼ 8.0 Hz), 8.58 (s,1H), 8.93 (s,1H). 13C NMR (CDCl3, 75 MHz)
d
54.1, 119.5, 123.4, 126.3, 127.9, 128.8, 129.2, 132.7, 134.1, 144.9,
146.7, 148.9. HRMS (FD) calcd for C14H12N4 (M) 236.2798, found
236.2775.
4.6.1. 3-Phenyl-8H-[1,2,3]triazolo[5,1-a]isoindole 12
Purification by flash chromatography (40% EtOAcepetroleum
ether) and after crystallization from EtOAcepetroleum ether gave
12 (59 mg, 51%) as a pale brown solid. mp 150 ꢀC [lit. [9a] 153e
4.5.5. 5-Chloro-3-(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-
2-amine 8e
155 ꢀC]. IR (KBr)
(CDCl3, 400 MHz)
n .
3065, 2934, 2897, 1655, 1548 cmꢁ1 1H NMR
Purification by flash chromatography (30% EtOAcepetroleum
ether to 60% EtOAcepetroleum ether) gave 8e (50 mg, 76%) as
d
5.45 (s, 2H), 7.30e7.41 (m, 6H), 7.80 (d, 1H,
J ¼ 7.0 Hz), 7.78e7.80 (m, 2H) 13C NMR (CDCl3, 100 MHz)
d 51.8,
yellow powder. mp 188 ꢀC. IR (KBr)
n
3426, 3169, 1636, 1525,
119.9, 125.9, 128.3, 128.8, 129.0, 129.1, 129.2, 129.4, 130.8, 139.8,
139.9, 142.3. HRMS (FD) calcd for C15H11N3 (M) 233.1532, found
233.1533.
1348 cmꢁ1. 1H NMR (Acetone-d6, 400 MHz)
d
5.92 (s, 2H), 6.86 (br,
2H), 7.65 (d, 2H, J ¼ 8.8 Hz), 7.82 (d, 1H, J ¼ 2.5 Hz), 7.90 (d, 1H,
J ¼ 2.5 Hz), 8.24 (d, 2H, J ¼ 8.8 Hz), 8.67 (s, 1H). 13C NMR (Acetone-
d6, 100 MHz)
d 53.9, 110,4, 119.4, 123.6, 124.9, 130.2, 134.9, 139.9,
4.6.2. 3-(4-Methoxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindole 13
Purification by flash chromatography (60% EtOAcepetroleum
ether) and after crystallization from EtOAcepetroleum ether gave
13 (57 mg, 43%) as a pale yellow solid. mp 156 ꢀC [lit. [9a] 154e
143.9, 146.4, 146.7, 147.8, 149.0, 155.8. HRMS (FD) calcd for
C
14H12ClN6O2 (M þ Hþ) 331.0704, found 331.0703.
156 ꢀC]. IR (KBr)
(Acetone-d6, 300 MHz)
7.42 (dd, 1H, J ¼ 1.5, 7.6 Hz), 7.66e7.71 (m, 2H), 7.90e7.95 (m, 3H).
13C NMR (Acetone-d6, 75 MHz)
55.2, 60.5, 116.8, 122.7, 126.3,
n
3058, 2923, 2875, 1661, 1574 cmꢁ1
.
1H NMR
4.5.6. 1-(2-(1,3-Dioxolan-2-yl)ethyl)-4-(2-nitrophenyl)-1H-1,2,3-
triazole 8f
d
3.85 (s, 3H), 5.48(s, 2H), 7.01e7.15 (m, 2H),
Purification by flash chromatography (40% EtOAcepetroleum
ether) gave 8f (94 mg, 65%) as pale yellow oil. IR (neat)
2871, 1667, 1559, 1538, 1373 cmꢁ1 1H NMR (CDCl3, 300 MHz)
2.25e2.32 (m, 2H), 3.80e3.91 (m, 2H), 3.99e4.05 (m, 2H), 4.60
(t, 2H, J ¼ 7.3 Hz), 5.09 (t, 1H, J ¼ 4.1 Hz), 7.37e7.48 (m, 2H), 7.59
(s, 1H), 7.84e7.96 (m, 2H). 13C NMR (CDCl3, 75 MHz)
33.4, 43.1,
n 3091,
d
.
126.9, 128.6, 129.5, 130.6, 131.0, 139.9, 141.0, 145.8, 160.6. HRMS (FD)
calcd for C16H13N3O (M) 263.2837, found 263.2841.
d
d
4.6.3. 3-Pentyl-8H-[1,2,3]triazolo[5,1-a]isoindole 14
66.7, 66.7, 107.9, 125.3, 126.2, 130.6, 131.3, 133.5, 136.7, 146.7,
150.8. HRMS (FD) calcd for C13H14N4O4 (M) 290.1476, found
290.1495.
Purification by flash chromatography (40% EtOAcepetroleum
ether) and after crystallization from petroleum ether gave 14
(34 mg, 30%) as a pale yellow solid. mp 85 ꢀC. IR (KBr)
n
2958, 2910,
2867, 1487 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d
0.91 (t, 3H, J ¼ 6.5 Hz),
4.5.7. 2-(1-(2-(1,3-Dioxolan-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)-4-
(hydroxymethyl)phenol 8g
1.21e1.38 (m, 4H), 1.58e1.64 (m, 2H), 2.54 (t, 2H, J ¼ 7.2 Hz), 5.45 (s,
2H), 7.29 (d, 1H, J ¼ 7.6 Hz), 7.31e7.45 (m, 2H), 7.61 (d, 2H,
Purification by flash chromatography (70% EtOAcepetroleum
J ¼ 7.5 Hz). 13C NMR (CDCl3, 75 MHz)
d 14.1, 22.8, 28.9, 29.2, 31.4,
60.3, 120.7, 124.6, 127.0, 128.6, 128.9, 139.2, 139.2, 139.5, 140.9.
HRMS (FD) calcd for C14H17N3 (M) 227.3952, found 227.3968.
ether) gave 8g (81 mg, 56%) as colourless oil. IR (neat)
n
3345, 3120,
2.25e2.32
2994, 2844,1640,1567 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d
(m, 2H), 3.80e3.91 (m, 2H), 3.96 (br, 1H), 3.99e4.05 (m, 2H), 4.60 (t,
2H, J ¼ 7.3 Hz), 4.67 (s, 2H), 5.09 (t, 1H, J ¼ 4.1 Hz), 5.28 (br, 1H),
6.85e6.96 (m, 2H), 7.62 (s, 1H), 7.79 (s, 1H). 13C NMR (CDCl3,
Acknowledgements
75 MHz) d 33.1, 43.0, 66.7, 66.7, 66.9, 107.9, 117.6, 121.9, 130.4, 135.3,
We gratefully acknowledge the “ Université de Bordeaux”,
the “ Université de Nantes”, the “ Centre National de la Recherche
Scientifique (CNRS)”, and the “ Agence Nationale de la Recherche”
(ANR JCJC 7141) for the financial support to this project. We thank
O. Brugier and C. Douchet (Université Montpellier) for ICP-MS
analyses. F.-X. Felpin is member of the “Institut Universitaire
de France (IUF)”. The authors would like to thank the CREMEM
(Université de Bordeaux) for its electron microscopy facilities.
146.8, 151.2. HRMS (ESI) calcd for C14H17N3O4Na (M þ Naþ)
314.2941, found 314.2955.
4.5.8. 1-(6-Chlorohexyl)-4-(4-methoxyphenyl)-1H-1,2,3-triazole
8h
Purification by flash chromatography (20% EtOAcepetroleum
ether) gave 8h (71 mg, 48%) as pale yellow solid. mp 98 ꢀC. IR (KBr)
n
3120, 2985, 2238, 1671 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d 0.97e
1.29 (m, 2H), 1.31.1.49 (m, 2H), 1.81e2.01 (m, 4H), 3.64 (t, 2H,
J ¼ 6.9 Hz), 3.84 (s, 3H), 4.36 (t, 2H, J ¼ 7.1 Hz), 6.99 (d, 2H,
J ¼ 8.4 Hz), 7.67 (s, 1H), 7.75 (d, 2H, J ¼ 8.3 Hz). 13C NMR (CDCl3,
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