Developments in Pd catalysis: Synthesis of 1H-1,2,3-triazoles from sodium azide and alkenyl bromides

Article abstract of DOI:10.1002/anie.200601045

Another star for the Palladium: The discovery of reactions promoted by the ubiquitous Pd⁰ catalysts is still possible. 1H-1,2,3-Triazoles are directly obtained by reaction of alkenyl bromides and sodium azide in the presence of a Pd⁰-xantphos catalyst (see scheme, xantphos = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, dba = trans,trans- dibenzylideneacetone). (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200601045

Angewandte
Chemie
between organic azides and terminal alkynes to give 1,4-
[
2]
disubstituted 1,2,3-triazoles has represented a definitive
advance in triazole chemistry, and has become a paradigm of a
[
3]
“
click chemistry” reaction. The reaction is effective in the
preparation of a wide variety of triazole-containing mole-
[
4]
cules. However, the reaction has a limitation in that
inorganic azides are not good substrates. Consequently 1H-
[
5]
1
,2,3-triazoles, which also have a wide range of uses, cannot
be prepared directly by using the click chemistry strategy, but
instead require sequences involving deprotection steps and
[
6]
the employment of more elaborated azides. Other routes to
H-1,2,3-triazoles include dipolar cycloadditions between
sodium azide and alkynes with an electron-withdrawing
1
[
7]
substituent, the reaction of sodium azide with nitro-
[
8]
[9]
alkenes, and the rearrangement of propargyl azides.
Over the last few years, we have been interested in Pd-
catalyzed reactions between alkenyl halides and nitrogenated
[
10]
species for the formation of CÀN bonds. During our search
for new coupling partners for such processes, we decided to
explore the potential ability of the azide anion to participate
[
11]
in a Pd-catalyzed cross-coupling reaction. We expected that
the coupling of an azide with alkenyl halides would lead to
vinyl azides. However, vinyl azides were never detected and
instead 1H-1,2,3-triazoles were obtained under the standard
reaction conditions. This unexpected result represents a novel
method for the preparation of 1H-1,2,3-triazoles and a new
Palladium Catalysis
Table 1: Influence of the ligand in the reaction of b-bromostyrene with
sodium azide.
DOI: 10.1002/anie.200601045
[
a]
Developments in Pd Catalysis: Synthesis of 1H-
1
,2,3-Triazoles from Sodium Azide and Alkenyl
Bromides**
Entry
Ligand
Pd [%]
Conv. [%]
JosØ Barluenga,* Carlos ValdØs, Gustavo Beltrµn,
María Escribano, and Fernando Aznar
1
2
3
4
5
6
7
8
9
PPh3
2
2
2
2
2
2
2
2
0
15
0
0
0
0
100
100
0
davephos
johnphos
xphos
1
,2,3-Triazoles are an important class of heterocycles which
binap
display an ample spectrum of biological activities and are
widely employed as pharmaceuticals and agrochemicals.
Moreover, compounds containing 1,2,3-triazoles have found
industrial applications as dyes, corrosion inhibitors, and
dpephos
xantphos
no ligand
no ligand
0
[
1]
photostabilizers. The conventional route to triazoles is the
Huisgen dipolar cycloaddition of alkynes with organic azides.
The development of the copper(I)-catalyzed reaction
[
(
a] Reaction conditions: Alkenyl bromide 1 (1 mmol), sodium azide
3 mmol), 2:1 ligand/Pd, solvent (3 mL), 908C, 12 h. dba=trans,trans-
dibenzylideneacetone, Cy=cyclohexyl.
[*] Prof. J. Barluenga, Dr. C. ValdØs, G. Beltrµn, M. Escribano,
Prof. F. Aznar
Instituto Universitario de Química Organometµlica
“
Enrique Moles”
Unidad Asociada al CSIC
Universidad de Oviedo
Juliµn Clavería 8, 33006 Oviedo (Spain)
Fax: (+34)98-510-3450
E-mail: barluenga@uniovi.es
[**] We acknowledge financial support from the Fundación Ramón
Areces and the DGICYT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 6893 –6896
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6893

Communications
0
reactivity for Pd catalysts. Herein, we report our findings
of triazoles 2 occurred in very high yields for substituted b-
bromostyrenes. The substitution on the aromatic ring had no
influence on the outcome of the reaction, as systems
substituted with neutral (Table 2, entry 1), electron-with-
drawing (entries 3 and 4), or electron-releasing groups
(entries 2 and 9) provided similar results. The reaction
tolerates sensitive functional groups such as methyl esters or
nitriles, ortho substitution in the aromatic ring (Table 2,
entries 5–7), and heteroaromatic rings such as the 2-furan
group (entry 8). The chemoselectivity of the reaction is
noteworthy, as the presence of a halide (bromide or chloride)
on the aromatic ring furnishes the triazole 2 as the sole
reaction product.
regarding this new and intriguing reaction.
In a preliminary set of experiments we studied the
reaction of b-bromostyrene (1a) with sodium azide in dioxane
in the presence of [Pd (dba) ]and a range of supporting
ligands. In most cases, 1a was recovered with no trace of any
reaction product (Table 1). However, when the bidentate
ligand xantphos was employed, no 1a was recovered and
instead the 1H-1,2,3-triazole 2a was obtained in near
quantitative yield.
2
3
The ligand specificity of the reaction is remarkable
indeed. Only the chelating diphosphines xantphos and
dpephos, in which the bite angle is large, promoted the
[
12]
reaction to a considerable extent. Very low conversion was
achieved with triphenylphosphine and no conversion at all
was observed for binap, a bidentate phosphine with a smaller
bite angle, nor for the bulky electron-rich monophosphines,
johnphos, davephos, and xphos, which are usually very active.
Moreover, no conversion at all was observed for control
experiments in the absence of ligand (Table 1, entry 8) and in
the absence of metal and ligand (Table 1, entry 9), thereby
indicating the important role of the catalytic system.
Formation of the triazoles derived from alkyl-substituted
bromoethylenes required a different set of reaction condi-
tions. Thus, when the reaction of 1-bromodecene was carried
out under the same conditions as previously used, we
observed no conversion. By changing the solvent to DMSO,
which enhances the solubility of the inorganic azide, we
observed formation of the triazole with 55% conversion after
24 h. After some experimentation, we determined that the
optimal conditions for this transformation required an
increase in the catalyst loading and reaction temperature (to
1108C) (Table 2, entries 10 and 11). Finally, reaction of 1-
bromo-4-phenyl-1,3-butadiene, as a repre-
The scope of the reaction was examined using the
optimized experimental conditions (Table 2). The formation
sentative bromodiene, proceeded in a very
[
a]
Table 2: Triazoles prepared by the Pd-catalyzed reaction of alkenyl bromides and sodium azide.
short time under the standard reaction
conditions (dioxane, 908C). However, the
alkenyl-substituted triazole suffered partial
[
13]
dimerization, which reduced the overall
yield of the triazole (Table 2, entry 13).
Nevertheless, when the reaction was con-
ducted in DMSO, the dimerization was
inhibited, and gave rise to the correspond-
ing triazole as the sole reaction product
[
b]
[c]
[d]
Entry
Triazole
Pd [%]
Method
t
[h]
Yield [%]
X=H
1
2
2
2
A
A
14
14
93
92
2
a
X=OMe
2
b
3
4
X=CN
2
2
A
A
14
14
89
74
(Table 2, entry 12).
2
c
This novel transformation represents an
X=CO Me
2
unprecedented
Pd-catalyzed
reaction,
2
d
which adds to the already enormous reper-
toire of processes promoted by this transi-
X=Cl
5
6
2
2
A
A
14
14
72
70
2
e
[
14]
X=Br
tion metal.
It is also worth noting the
2
f
differential behavior of Pd and Cu catalysts
in their reactions with sodium azide and
alkenyl halides. While the Cu-catalyzed
7
8
X=Me
2
2
2
A
A
14
14
73
94
g
[
11]
2h
reaction furnishes alkenyl azides,
these
compounds are not even detected in the
reaction with Pd, which provides only 1H-
1,2,3-triazoles.
9
2i
2
A
14
76
A
tentative
reaction
pathway
(
Scheme 1) might involve oxidative addi-
R=n-C H
8
17
0
1
1
0
1
8
B
B
24
20
62
80
tion of the bromoalkene to the Pd complex
I to form alkenylpalladium complex II,
followed by substitution of the bromine by
the azide to provide complex III. Reductive
elimination would furnish the alkenyl azide
IV and release the Pd catalyst. Finally, a
Pd-promoted 1,5-electrocyclization fol-
lowed by tautomerization would furnish
the 1H-1,2,3-triazole V.
2
j
R=CH OBn
10
2
2
k
1
1
2
3
4
2
B
A
20
10
84
[
e]
2l
45
0
[15]
[
a] Reaction conditions: Alkenyl bromide 1 (1 mmol), sodium azide (3 mmol), [Pd (dba) ] (see Table),
2 3
xantphos (2:1, xantphos/Pd), solvent (3 mL). [b] Method A: Dioxane, 908C; Method B: DMSO, 1108C.
c] Reaction times are not optimized. [d] Yields after column chromatography. [e] Complete conversion
of the starting material.
[
6
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Angewandte
Chemie
Scheme 3. Reactions that are not consistent with the mechanism
depicted in Scheme 1.
Scheme 1. Tentative mechanism for the Pd-catalyzed formation of
triazoles from alkenyl bromides and sodium azide.
the triazoles, no reaction ever occurred and the aryl bromide
was always recovered unaltered. From these observations, we
conclude that formation of the vinyl azide through a reductive
elimination process might not be occurring and therefore
discount the mechanism proposed in Scheme 1.
It must be noted that vinyl azides do not undergo
cyclization to 1,2,3-triazoles upon heating; instead 2H-azir-
[
16]
ines and nitriles are formed with evolution of nitrogen. For
this reason, if this mechanistic manifold were operative, the
Pd catalyst should play a role in promoting the electro-
cyclization of the intermediate vinyl azide. In an attempt to
validate this mechanistic hypothesis we carried out several
experimental and computational studies.
After excluding a reaction pathway involving a reductive
elimination step and taking into account that the vinyl-
palladium complex II is in fact an intermediate of the
reaction, the formation of the triazole can be only explained
by a [3+2]cycloaddition (either concerted or stepwise) of the
azide anion with a vinylpalladium complex (Scheme 4). The
dihydrotriazolylpalladium complex VI would then undergo
First of all, we have found evidence that the oxidative
addition step is indeed occurring. The alkenylpalladium
bromide complex II ligated with xantphos was generated
following a procedure reported by Buchwald and co-workers
[
12d,e]
for the analogous aryl bromides,
in which a mixture of
[
Pd (dba) ], xantphos, and b-bromostyrene were stirred in
2
3
benzene at room temperature for 22 h. Treatment of the
resulting solid crude material with sodium azide in dioxane at
9
08C led to the formation of the triazole (Scheme 2). This
observation clearly indicates that II is an intermediate in the
catalytic process and therefore that the oxidative addition
step takes place.
Scheme 4. Proposed mechanism for the Pd-catalyzed formation of
triazoles from alkenyl bromides and sodium azide.
b elimination to release the triazolide VII and the hydrido-
palladium complex VIII. Finally, reductive elimination
releases HBr which protonates the triazolyl anion and
Scheme 2. Evidence for the oxidative addition step.
0
regenerates the Pd complex.
However, we have not found any experimental support
for the reductive elimination/electrocyclization sequence
In summary, we have reported a new methodology for the
Pd-catalyzed synthesis of 1H-triazoles from alkenyl halides
and sodium azide. Importantly, the process represents a
completely new reactivity pattern in the context of Pd
chemistry. Detailed investigations to clarify the mechanism
of this intriguing reaction and further synthetic applications
are underway.
[
17]
(
Scheme 3).
We attempted to transform the preformed
[
16a,b,18]
styryl azide (3)
into triazole 2a by treatment with the
Pd–xantphos catalytic system. Despite extensive experimen-
tation involving different temperatures and reaction condi-
tions, we never detected formation of the triazole, only
decomposition of the vinyl azide.
On the other hand, when 3-bromoanisole (4), a typical
aryl bromide, was subjected to the array of reaction con-
ditions described during the optimization of the synthesis of
Received: March 16, 2006
Revised: August 16, 2006
Published online: September 26, 2006
Angew. Chem. Int. Ed. 2006, 45, 6893 –6896
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6895

Communications
Keywords: amination · azides · heterocycles · palladium
catalysis · triazoles
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reaction.
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[
[
[
2
[
17]DFT calculations (employing the B3LYP functional with the 6-
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linearity of the azide moiety and thus lowers the activation
=
À1
energy of the electrocyclization by nearly 7 kcalmol . However,
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11]Aryl and vinyl azides have been recently prepared by Cu -
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[
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[
[
triazole to the double bond of another alkenyl triazole molecule.
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6
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