2
L. Maiuolo et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Preparation of 1,5-dsubstituted 1,2,3-triazoles 3a-3n.a
Entry
R
R1
Product
Yield (%)
1
2
3
4
5
6
7
8
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
90
94
91
88
81
85
90
91
90
92
86
81
80
85
4-Me
4-MeO
2-NO2
2-Cl
3-Cl
4-Cl
Scheme 1. Generic reaction to synthesize 1,5-disubstituted 1,2,3-triazole.
H
we proposed a method to synthesize triazoles by the FeCl3/Ionic
Liquid catalytic system, in which we clarified in detail the role of
the catalyst through theoretical calculations [30].
9
4-Me
4-MeO
2-NO2
2-Cl
3-Cl
4-Cl
10
11
12
13
14
Herein, we report a new synthetic method for 1,5 disubstituted
1,2,3-triazoles formation obtained by [3 + 2] cycloaddition of
azides with electron-deficient dipolarophiles catalyzed by the
highly recyclable Er(OTf)3/[mpy]OTf/H2O system (Scheme 1).
In addition to the development of an eco-compatible process of
synthesis of substituted triazoles, the ulterior aim of this work is
the attempt to explain the probable role of the ionic liquid and
the water in proposed method. For this reason, we selected only
metal triflate salts as Lewis acid catalyst in order to have a unique
anion present in the reaction media, reducing the number of
variables.
Initially, we commenced the reaction with (E)-nitrostyrene 1a
(R = H) and phenylazide 2a (R’ = Ph) as model substrates (Table 1).
Based on our previous experience [19,31], we decided to
explore solely 1-methyl pyridinium trifluoromethanesulfonate
[mpy]OTf as ionic liquid also for its easy one-step preparation
through halide-free direct synthesis, by adding directly methyltri-
fluoromethanesulfonate to dry pyridine. Also, as stated above, tri-
flate salts were only employed to avoid the simultaneous presence
of different counteranions in the reaction system. Without any cat-
alyst, a mixture of 1,4- and 1,5-disubstituted triazoles were
observed in very low yield after a long reaction time (entry 1,
Table 1). Exploring between a number of triflate salts (entry 2–7,
Table 1) we found that the Er(OTf)3 was the most effective, carry-
ing out the desired product in very high yield (entry 7, Table 1).
Halving the amount of reagent 2a only a 55% of 3a was obtained
(entry 8, Table 1), whereas, when the catalyst was decreased to
5 mol% (entry 9, Table 1) the yield of final product was lower than
that obtained using 10 mol% of catalyst. Ulterior experiments were
a
Reaction conditions: 2.0 eq. of 2a or 2b, 500 ml of water, 5 ml of ionic liquid (IL/
H2O v/v 5:0.5).
Using our optimized experimental conditions, we investigated
the reaction of various arylnitroolefins 1a-1n and phenylazide 2a
or benzylazide 2b (Table 2).
It is to note that nitroolefins bearing electron-withdrawing and
electron-donors substituents were used as starting materials with-
out observing considerable variations in the reaction path. Further-
more, in all cases, it is good to highlight that the intermediate
triazoline has never been isolated because it spontaneously evolves
to the corresponding triazole by loss of HNO2. General synthetic
procedure and characterization data are collected in Supplemen-
tary material.
At this point, we propose a possible reaction mechanism for the
reaction of 1a with 2a as illustrated in Scheme 2.
The first step of the reaction may be represented by the coordi-
nation of erbium(III) triflate to nitroolefin compound 1a to form an
activated intermediate with
a chair conformation stabilized
through hydrogen bonds with water and electrostatic interactions
with the cation and the anion of ionic liquid. Generally, the
accepted mechanism of cycloaddition 1,3-dipolar is of the con-
certed nature, providing for the alignment of the dipole and the
dipolarophile on two parallel planes with an highly ordered system
and a low degree of entropy. The ionic liquids may have a so-called
ionic self-assembly (ISA) structure due to noncovalent electrostatic
interactions as the primary driving force and hydrophobic interac-
conducted both with
a reduced reaction temperature (60 °C
instead of 100 °C, entry 10, Table 1) and in absence of water (entry
11, Table 1, observing low yields in both cases.
tions and
p–p interactions like secondary driving forces. [32] The
ionic liquids may give clusters that act as a support of dipole and
dipolarophile, confining them in two parallel planes. The 1,3 dipo-
lar cycloaddition transition state involves the stacking of reagents
[33]. Therefore, the combination of cations and anions of IL highly
organized in hierarchical superstructures might held firmly the
reagents, favoring their alignment and improving the HOMO-
dipole/LUMO-dipolarophile interaction. Then, the trapped reagents
lead to the formation of a triazoline substrate that evolves to the
1,5-disubstituted 1,2,3-triazole 3a via a step of elimination of
HNO2.
The catalytic system [mpy]OTf/Er(TfO)3 has been analyzed with
respect recovery and re-use in the reaction between (E)-nitrostyr-
ene 1a and benzylazide 2a and the results are shown in Table 3.
The results demonstrate that the [mpy]OTf/H2O/Er(OTf)3 sys-
tem remains active until six cycles without loss of efficiency, which
combines with the other advantages of the method that we have
proposed: high yields and regioselectivity, the using of low catalyst
amount, simple procedure of work and of the catalytic system
recycling.
Table 1
Optimization of reaction conditions for preparing 1,5 disubstituted 1,2,3-triazoles.a
Entry
Catalyst
IL
Time (h)
Yield (%)
Product
1
2
3
4
5
6
none
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
48
3
3
3
3
3
3
3
6
3
3
18
20
34
29
13
82
91
55
78
36
12
3ab
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
AgOTf (10%)
Zn(OTf)2 (10%)
Cu(OTf)2 (10%)
Sc(OTf)3 (10%)
Ce(OTf)3 (10%)
Er(OTf)3 (10%)
Er(OTf)3 (10%)
Er(OTf)3 (5%)
Er(OTf)3 (10%)
Er(OTf)3 (10%)
7
8c
9
10d
11e
a
Reaction conditions: 2.0 eq. of 2a, 500 ml of water, 5 ml of ionic liquid (IL/H2O v/
v 5:0.5), T = 100 °C.
b
A mixture of 1,4- and 1,5-disubstituted 1,2,3-triazoles was observed.
1.0 eq. of 2a was used.
T = 60 °C.
In absence of water.
General recycling procedure is reported in Supplementary
material.
c
d
e
Please cite this article as: L. Maiuolo, B. Russo, V. Algieri et al., Regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles by 1,3-dipolar cycloaddition:
Maiuolo, Loredana
