Regioselective Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles from Aryl Azides and Enaminones

Article abstract of DOI:10.1002/ejoc.201900889

A total regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazoles from aryl azides and enaminones is reported. The use of an ionic liquid in the presence of water and trimethylamine is crucial for the progress of the reaction. The process, consisti

Full text of DOI:10.1002/ejoc.201900889

A Journal of
Accepted Article
Title: Regioselective Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles
from Aryl Azides and Enaminones
Authors: Antonio De Nino, Vincenzo Algieri, Matteo Antonio Tallarida,
Paola Constanzo, Manuel Pedron, Tomas Tejero, Pedro
Merino, and Loredana Maiuolo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900889
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10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
Regioselective Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles
from Aryl Azides and Enaminones
Antonio De Nino,*[a] Vincenzo Algieri,[a] Matteo A. Talllarida,[a] Paola Constanzo,[a] Manuel Pedrón,[b]
Tomás Tejero,[c] Pedro Merino*[b] and Loredana Maiuolo*[a]
Dedicated to the memory of Prof. Pierluigi Caramella
Abstract: A total regioselective synthesis of 1,4,5-trisubstituted-1,2,3-
triazoles from aryl azides and enaminones is reported. The use of an
ionic liquid in the presence of water and trimethylamine is crucial for
the progress of the reaction. The process, consisting of a cascade
between enaminones and sulfonylazides to give 1,5-
disubstituted-1,2-3-triazoles in which the carbonyl group is lost.[10]
More recently, Wan and co-workers reported the domino
reactions between NH-based secondary enaminones and tosyl
azide employing t-BuONa as the base promoter to prepare 1,4-
disubstituted-1,2,3-triazoles in which the N-substituent of the
enaminone is conserved and the tosyl group of the azide is lost.[11]
starting with
a
water-promoted 1,3-dipolar cycloaddition (in
agreement with DFT calculations) followed by a base-promoted retro-
aza-Michael reaction, shows a completely different reactivity to
previously reported base-promoted reactions between enaminones
and sulfonyl azides only leading to disubstituted triazoles. Such a
different reactivity, reported herein, allows preparation of trisubstituted
triazoles in a complete regioselective way.
R2
N
R2
N
RuAAC
N
N
CuAAC
N
N
R2 N3
R1
R1
R1
1,5-disubstituted
1,4-disubstituted
O
R1
R2
N
N
tBuOLi
Introduction
N
R2
Ts
N3
Ph
N
toluene, rt
H
R1
1,2,3-Triazoles are significant heterocycles due to their
pharmaceutical properties and biological activities.[1] They are
also widely used in organic synthesis,[2] in the functionalization of
advanced composite materials[3] and for the synthesis of
bioconjugates.[4] Typically, 1,2,3-triazoles are synthesized
through a 1,3 dipolar cycloaddition reaction between an azide and
(Cui, 2013; ref. 10)
1,5-disubstituted
IL, FeCl3, heat
R1
R2 N3
NO2
(our previous work; ref. 15)
R2
N
O
a
terminal alkyne, the so-called AAC (azide-alkyne
tBuONa
N
N
R2
Ts
N3
cycloaaddition) reaction (Scheme 1).[5] Initially, this approach
shows some limitations due to the high temperature required and
the obtention of mixtures of regioisomers. The use of transition
metal catalysts, such as copper (CuAAC) or ruthenium salts
(RuAAC),[6] provides good alternatives to both reactivity and
regiochemistry of the cycloaddition reaction, currently being
considered as a prototype click reaction widely used in several
fields.[7] The eliminative azide–olefin cycloaddition reaction
(EAOC) between azides and alkenes bearing a group suitable to
be eliminated has also been used for preparing disubstituted
1,2,3-triazoles.[8,9] Cui and co-workers reported the cycloaddition
R1
N
H
MeCN, rt
R1
(Wan, 2016; ref. 11)
O
1,4-disubstituted
R2
N
O
R3
IL, H2O
N
N
R2 N3
Ph
R1
N
Et3N, 100ºC
H
R1
R3
(this work)
O
1,4,5-trisubstituted
Scheme 1. Reactivity of 2,3-dihydrothiazoles derived from L-cysteine.
[a]
Prof. A. De Nino, Dr. V: Algieri, M. A. Tallarida, Dr. P. Constanzo,
Dr. L. Maiuolo
I Dipartimento di Chimica e Tecnologie Chimiche, Via P. Bucci, cubo
12C, Università della Calabria, 87036 Rende (CS), Italy.
E-mail:: denino@unical.it; maiuolo@unical.it
https://www.unical.it/portale/strutture/dipartimenti_240/ctc/
M. Pedron, Prof. P. Merino
Instituto de Biocomputación y Física de Sistemas Complejos (BIFI).
Universidad de Zaragoza. 50009 Zaragoza. Spain.
E-mail: pmerino@unizar.es
http://www.pmerino.com
Prof. T. Tejero
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH).
Universidad de Zaragoza-CSIC 50009 Zaragoza, Aragon. Spain
These reactions involve the use of tosyl azides and only give
access to 1,4- or 1,5-disubstituted 1,2,3-triazoles.[12,13] Despite the
great utility of all the above reactions, including the above
mentioned CuAAC and RuAAC click-chemistry reactions, the
regioselective preparation of 1,4,5-trisubstituted-1,2,3-triazoles
still remains a challenge.
Following our interest in solvent-free (or using non-conventional
solvents) 1,3 dipolar cycloaddition reactions,[14] we have recently
developed a synthetic methods for the preparation of substituted
[b]
[c]
1,5-disubstituted-1,2,3-triazoles by using
a highly efficient
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10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
catalytic system (Scheme 1).[15] In this work we present the
regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazoles
through the EAOC reaction between azides and enaminones
using a ionic liquid as a solvent. The different mechanistic
considerations of the reaction have also been studied by DFT
methods.
(Table 1, entry 5). The use of stoichiometric amounts of azide and
base (Table 1, entry 6) or only base (Table 1, entry 7) led to
considerably lower yields even after longer reaction times. By
increasing the amount of azide no better results were found
(Table 1, entry 8). At lower temperature (Table 1, entry 9), the
yield of the product decreased dramatically and when the reaction
was conducted at ambient temperature only traces of 3a were
detected after 3 days (Table 1, entry 10). Upon elimination of
either water (Table 1, entry 11) or trimethylamine (Table 1, entry
12) from the reaction mixture, the reaction does not work.
Similarly, the use of other bases also led to the absence of
reaction (Table 1, entries 13 and 14) even when sodium hydride
was used, demonstrating that deprotonated enaminone is not the
reactive species. The use of other ionic liquids (Table 1, entries
15 and 16) resulted in a good reaction although in lower chemical
yield than with [mpy]OTf, demonstrating the positive effect
exerted in the reaction by the ionic liquid. In fact, for the purpose
of comparison several conditions were tested dioxane or toluene
as a solvent (Table 1, entries 17-20) and in no case was observed
the formation of product, the reagents remaining unaltered after 3
days. These results evidence the necessity of the combined
system IL-water-triethylamine for achieving the reaction.
Moreover, elimination of any of the three elements resulted in no
reaction, the starting materials being recovered unaltered.
Results and Discussion
Synthetic Studies. The Initial attempts of performing the reaction
were carried with enaminone 1a and phenylazide 2a using
catalytic systems previously employed in our laboratory (FeCl3/IL
and Er(OTf)3/IL/H2O)[15] or with other Lewis acids. These systems
might exploit the metal cation chelating capacity of the
enaminones. The selected ionic liquid was 1-methyl pyridinium
trifluoromethanesulfonate, [mpy]OTf, because of its easy one-
step preparation through halide-free direct synthesis by adding
methyl trifluoromethane sulfonate directly to dry pyridine.[16]
Unfortunately, no reaction was observed in any case (Table 1,
entries 1-4). Next, we moved towards exploring the reaction in the
presence of a base. The reaction of enaminone 1a with 2.0 eq of
azide 2a in the presence of 2.0 eq of trimethylamine and 500 µL
of water afforded the triazole 3a in 84% yield after 5 h at 100 ºC
Table 1. 1,3-Dipolar cycloaddition reactions between 1a and 2a-d.a
Ph
N
Ph
O
HN
N
N
Ph
N
N N
+
O
2a
3a
1a
Entry
eq. 2a
Lewis acid (mol%)
Base (eq)
waterb
no
Solvent
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
T (°C)
100
Time (h)
72
Yield (%)
1
2
3
4
2
2
2
2
FeCl3 (20)
-
-
-
-
-
-
-
-
CeCl3 (20)
no
100
72
ZnCl2 (20)
no
100
72
Er(OTf)
yes
100
72
(10)
5
2
1
2
3
2
2
2
2
2
2
2
2
2
2
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Et3N (2.0)
Et3N (1.0)
Et3N (1.0)
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
-
yes
yes
yes
yes
yes
yes
no
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[mpy]OTf
[bmim]Cl
[bmim]BF4
Dioxane
100
100
100
100
60
5
84
6
72
24
5
19
7
41
8
70
9
72
72
72
72
72
72
5
40
10
11
12
13
14
15
16
17
18
19
20
25
traces
100
100
100
100
100
100
100
100
100
100
-
-
yes
yes
no
K2CO3 (1.0)
NaH (1.0)
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
None (2.0)
Et3N (2.0)
Et3N (2.0)
-
-
yes
yes
yes
yes
no
77
75
-
5
72
72
72
72
Dioxane
-
Dioxane
-
yes
Toluene
-
a The reaction was performed in 5 ml of ionic liquid. b 500 µL of water (IL/H2O v/v 5:0.5) were added.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
groups are present in the aromatic ring, In all cases, the reaction
takes place with complete regioselectivity yielding the regioisomer
with the electron-deficient group of the enaminone in position 4
and the alkyl substituent in position 5 as the only product of the
reaction. This is a consequence of the elimination of the aniline to
restore the double bond.
With the optimal reaction conditions in our hands, we studied the
scope of the reaction with enaminones 1a-1c and azides 2a-2g
which were prepared by an adapted procedure from that reported
by Vogel and co-workers.[17] The results are listed in Table 2.The
reaction works fine with both aryl and benzylazides, no
differences being found when electron-deficient or electron-donor
Table 2. Synthesis of 1,4,5-trisubstitued 1,2,3-triazoles 3a-3o.a.
Ph
R3
N
O
HN
Et3N/[mpy]OTf/H2O
100 °C
N
N
R3
N N N
+
R1
R2
O
R2
3a-3p
R1
2a-2g
1a-1d
Entry
R1
Me
Et
R2
R3
Ph
Enaminone
Azide
2a
2a
2b
2a
2b
2c
2c
2d
2d
2e
2e
2f
Product
3a
Time (h)
Yield (%)
84
1
Me
Et
1a
1c
1b
1b
1a
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1d
5
4
6
4
4
4
5
5
6
4
4
4
4
3
4
6
2
Ph
3b
3c
82
3
Ph
Ph
Me
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Bn
82
4
Ph
3d
3e
84
5
Bn
85
6
3-F-Ph
3-F-Ph
3f
85
7
3g
3h
3i
81
8
4-NO2-Ph
4-NO2-Ph
4-Cl-Ph
82
9
84
10
11
12
13
14
15
16
3j
83
4-Cl-Ph
3k
82
4-Me-Ph
4-Me-Ph
4-OMe-Ph
4-OMe-Ph
Ph
3l
85
2f
3m
3n
3o
3p
84
2g
2g
2a
85
81
70
a The reaction was carried out with 2.0 eq of triethylamine, 2.0 eq of enaminone, 500 μL of water in 5 mL of IL.
Mechanistic considerations. The mechanism of the reported
reaction between enaminones and azides to give triazoles have
already been studied (Scheme 2). Cui and co-workers suggested
reactions.[8b] Due to the presence of the carbonyl moiety the last
step (elimination of aniline) can be considered as a retro-aza-
Michael reaction, which is well-known of being favored in a basic
medium.[18] The crucial role of the ionic liquid is suggested to be
the stabilization of transition states perhaps in both cycloaddition
and elimination steps. In fact, the so-called ionic self-assembly
(ISA) structure of ionic liquids might favor the alignment and the
a
typical dipolar cycloaddition between the deprotonated
enaminone and the sulfonyl azides.[10] These authors used t-
BuOLi as a base in anhydrous conditions. In our case, however,
the use of a tertiary amine in the presence of water rules out the
possibility of a cycloaddition of a deprotonated enaminone. In fact,
when our reaction is carried out in anhydrous conditions using
trimethylamine as a base, no reaction was observed. Moreover,
the cycloaddition reported by Cui and co-workers led to the
elimination of the carbonyl moiety furnishing different products
that those observed by us. Consequently, the cycloaddition of an
enolized enaminone can be ruled out, definitively. The approach
reported by Wan and co-workers consisted of a Regitz diazo
transfer mechanism in which the N-substituent of the enaminone
is conserved.[11] Since in our reaction the enaminone amino group
is lost, we can also ruled out the possibility of such a mechanism.
For the obtention of triazoles 3, we suggested a classical 1,3-
dipolar cycloaddition promoted by water, followed by a typical
E1CB elimination of aniline, promoted by trimethylamine. Water
has been demonstrated to be a good promoter for these
dipole/dipolarophile interaction by holding the reagents firmly.
[11b,19]
To verify the possibility of the 1,3-dipolar cycloaddition we carried
out DFT calculations at b3lyp-d3bj/def2svp/cpcm=water level.
This level has demonstrated to perform well for several systems,
particularly because of the introduction of empirical dispersion
correction (for details see SI). The energy values were calculated
at b3lyp-d3bj/def2tzvp/cpcm=water level. Since modelling of ionic
liquids is beyond this study,[20] we considered water as a solvent
to simulate a highly polar medium. We studied the cycloaddition
between 1a and 2a to give triazole 3a (Scheme 3). Two transition
states TS1 and TS2 were found corresponding to the two possible
isomers IN1 and IN2 that can be obtained. The process illustrated
in Scheme 3 was calculated as indicated and in the presence of
a discrete water molecule. We assumed the cycloaddition step as
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10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
the rate-limiting one due to the impossibility of isolating
cycloadducts which is in agreement with a cascade process for
which the transition state corresponding to the second step is
irrelevant.
both isomers. The barriers for the reaction were found to be 20.3
and 24.9 kcal/mol for TS1 and TS2, respectively (Figure 1). When
the same reaction was calculated by placing a water molecule as
an activator, the free energy barriers were 17.5 and 21.3 kcal/mol
for TS1w and TS2w, respectively. These results support the
activation role exerted by water. Despite the polarity of the
medium and the reaction, no stepwise mechanisms were
detected, and it can be concluded that the reaction is a concerted
asynchronous 1,3-dipolar cycloaddition.
O
R3
R4 N3
R2
R1
N
H
a
c
b
1) enolization
2) 1,3-DC
1) enolization
2) nucleophilic
attack
1,3-DC
R2 = phenyl
O
Me
H
Ph
O
N
Ph
R4 = tosyl
Me
N
H
R
1 = phenyl
Me
Me
R3 = H; R4 = tosyl
1a
s-trans-
1a
s-cis-
R2
R2
R3
Ph N3
2a
Ph N3
2a
O
N
N
O
R1
R3
N
R1
EP1
EP2
R4
N
N
N
R4
N
N
III
I
Ph
Ph
N
N
O
N
N
N
N
deacylative
diazo transfer
Regitz
diazo transfer
O
R4
R1
N
Me
Me
H
H
R4 NH2
Me
Me
H
N
N
Ph
Ph
H
O
H
R2
R3
N
O
N
TS1
TS2
N
N
R2
R1
N
R3
N
R1
N
NH
N
R3
R2
O
N
Ph
N
N
N N
Ph
N
N
II
V
IV
retro-Michael
R2 NH2
Me
Ph
Me
Me
Ph
Me
NH
NH
O
O
IN2
IN1
R2
R2
R4
N
N
N
N
N
N
N
N
N
R1
R1
R3
R3
Ph NH2
Ph
O
O
N
(Cui, 2013)
(Wan, 2016)
(this work)
N
N
Scheme 2. Reaction mechanism for the reaction between enaminones and
azides to form triazoles.
Me
Me
O
3a
Scheme 3. Reaction pathways for the formation of 3a from 1a and 2a. EP1 and
EP2 are the corresponding encounter pairs.
Although endo and exo approaches of the azide are, in principle,
possible, the azide adopts a perpendicular orientation with
respect of enaminone independently of the initial orientation.
Indeed, the diastereoselectivity of the dipolar cycloaddition is
originated from the configuration of the dipolarophile (enaminone
1a) that can adopt cisoid (more stable due to the intramolecular
H-bond) and transoid conformations. The equilibrium between s-
cis-1a and s-trans-1a is possible through the corresponding
tautomeric forms.
The s-trans isomer showed to be 6.6 kcal/mol higher in energy
than the s-cis isomer, as expected by the presence of the
intramolecular hydrogen bond in the latter. In any case, in virtue
of the Curtin-Hammett’s principle we calculate the reactivity of
In both the presence and the absence of water, the dipolar
cycloaddition showed to be endergonic (Figure 1, top) thus
explaining the observed lack of reactivity in the absence of
triethylamine and recovering of starting materials. In the presence
of the base, the retro-aza-Michael reaction (elimination of aniline),
is promoted and the stable final 1,4,5-trisubstituted-1,2,3-triazole
is obtained through a cascade process. The transition state
corresponding to the elimination of aniline (TSe1) according to an
E1CB mechanism[21] showed a barrier of 7.1 kcal/mol, confirming
that the cycloadditions step is the rate-limiting one (for details see
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10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
SI). These results are in good agreement with the observed
results although, admittedly, there is an additional favoring effect
exerted by the ionic liquid.
observed in energy can be rationalized on the basis of non-
covalent interactions. The less stable TS2 does not present any
sort of non-covalent interactions. Hydrogen bonds are present in
TS1 and TS2w, and the most stable TS1w presents additional
London interactions.
The origin of the complete regioselectivity is found on the initial
regioselectivity of the 1,3-dipolar cycloaddition that determines
the position of the carbonyl group at C-4 of the triazole. Obviously,
the diastereoselectivity of the cycloaddition (according to
differences in free energy barriers, only the product derived from
TS1 should be observed) is not relevant due to the subsequent
elimination reaction. Furthermore, attempts of detecting in situ
the cycloadduct by NMR before elimination failed, due to the
above-mentioned reversibility of the reaction (endergonic
process).
The possibility of a cycloaddition between the azide and
deprotonated enaminone is ruled out since it is not possible to
have an enolized enaminone in the presence of water. Moreover,
DFT calculations for the reaction between deprotonated 1a and
2a only led to transition structures precursors of intermediates I
(Scheme 2, route a) and III (Scheme 2, route b), no concerted
transition structures leading to deprotonated V being located.
Actually, routes a and b have been initially discarded because the
obtained products are different (see above).
Conclusions
In conclusion, we have developed a new synthetic method to
obtain
1,4,5-trisubstituted-1,2,3-triazoles
with
complete
regioselectivity starting from aryl azides and enaminones. The
reaction is a cascade consisting of a typical Huisgen’s concerted
asynchronous 1,3-dipolar cycloaddition followed by elimination of
aniline through a favored retro-aza-Michael reaction. DFT
calculations further support the activation by water of the
cycloaddition reaction and the cascade process pushed on by the
base-promoted elimination. The experimental observations
revealed the special effects exerted by the ionic liquid in the
reaction, which does not work, under the same conditions, but
using dioxane or toluene as a solvent. The proposed process
provides an easy work procedure, low reaction times, complete
regioselectivity with no formation of by-products and very good
versatility of final trisubstituted triazoles.
Experimental
General Methods. All reagents and commercial ionic liquids were
purchased from Sigma-Aldrich or Alfa Aesar and used without
purification. Reactions were monitored by TLC using silica plates
60-F264 commercially available from Merck (Darmstadt,
Germany). 1H-, 13C- and APT NMR spectra were recorded at 300
and 75 MHz, respectively, in CDCl3 using tetramethylsilane (TMS)
as the internal standard (Bruker ACP 300 MHz). Chemical shifts
are given in parts per million and coupling constants in Hertz. LC-
MS analyses were carried using an Agilent 6540 UHD Accurate-
Mass Q-TOF LC-MS (Agilent, Santa Clara, CA, USA) fitted with a
electrospray ionization source (Dual AJS ESI) operating in
positive ion mode. Chromatographic separation was achieved
using a C18 RP analytical column (Poroshell 120, SB-C18, 50 x
2.1mm, 2.7mm) at 30 °C with an elution gradient from 5% to 95%
of B over 13min, A being H2O (0.1% FA) and B CH3CN (0.1% FA).
Flow rate was 0.4 mL min-1. 1-Methyl pyridinium trifluoromethane
sulfonate ([mpy]OTf) was prepared by halide-free direct synthesis
as reported in reference 15. Enaminones 1a-1c were prepared as
Figure 1. Top: Energy profiles for the formation of triazole 3a from enaminone
1a and phenyl azide 2a. Only the most stable route (TS1, TS1w and TSe1) are
showed. Bottom: Optimized (b3lyp-d3bj/def2svp/cpcm=water) geometries for
the transition structures corresponding to the reaction between 1a and 2a in the
absence (top) and presence (bottom) of water. Relative free energies are given
in kcal/mol and they are referred to the most stable transition structure with
respect to the corresponding reagents.
The geometries of the transition structures is illustrated in Figure
1. For the cycloaddition step, they correspond to typical
asynchronous processes. As mentioned above, the azide is
oriented perpendicular to the dipolarophile. The differences
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10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
reported.[22,23] Azides 2a-2g were prepared through an adapted
Vogel’s procedure.[17] Their characterization was compared with
data reported in literature.[24-27]
120.95 (d), 131.12 (d), 136.54 (d), 137.40, 161.14, 164.45,
194.29. ESI(+)-MS: m/z [M+H]+ calcd for C11H11FN3O 220.0881,
found: 220.0877.
4-Benzoyl-5-methyl-1-(3-fluorophenyl)-1H-1,2,3-triazole (3g)
1H-NMR (CDCl3, 300 MHz): δ (ppm) 2.72 (s, 3H, CH3), 7.27-7.35
(m, 5H, Ar), 7051- 7.66 (m, 3H, Ar), 8.36-8.39 (m, 1H, Ar). 13C-
NMR (CDCl3, 75 MHz): δ (ppm) 10.66, 113.23, 113.27, 121.08,
128.33, 130.63, 131.13, 133.05, 137.31, 139.89, 143.68, 161.17,
164.48, 187.48. ESI(+)-MS: m/z [M+H]+ calcd for C16H13FN3O
282.1037, found: 282.1034.
4-Acetyl-5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (3h)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.70 (s, 3H, CH3), 2.77 (s,
3H, CH3), 7.70-7.79 (m, 2H, Ar), 8.44-8.53 (m, 2H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 10.42, 27.95, 125.18, 125.83, 137.32,
140.08, 144.05, 148.20,194.03. ESI(+)-MS: m/z [M+H]+ calcd for
C11H11N4O3 247.0826, found: 247.0823.
4-Benzoyl-5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (3i)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.77 (s, 3H, CH3), 7.50-7.60
(m, 2H, Ar), 7.61-7.68 (m, 1H, Ar), 7.74-7.84 (m, 2H, Ar), 8.33-
8.41 (m, 2H, Ar), 8.46-8.55 (m, 2H, Ar). 13C NMR (CDCl3, 75
MHz): δ (ppm) 10.82, 125.24, 125.97, 128.39, 130.62, 133.24,
137.12, 139.85, 140.29, 143.87, 148.33, 187.24. ESI(+)-MS: m/z
[M+H]+ calcd for C16H13N4O3 309.0982, found: 309.0979.
4-Acetyl-5-methyl-1-(4-chlorophenyl)-1H-1,2,3-triazole (3j)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.60 (s, 3H, CH3), 2.75 (s,
3H, CH3), 7.39-7.45 (m, 2H, Ar), 7.54-7.61 (m, 2H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 10.12, 27.86, 126.50, 129.99, 133.81,
136.24, 137.37, 143.77, 194.29. ESI(+)-MS: m/z [M+H]+ calcd for
C11H11ClN3O 236.0585, found: 236.0581.
4-Benzoyl-5-methyl-1-(4-chlorophenyl)-1H-1,2,3-triazole (3k)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.68 (s, 3H, CH3), 7.41-7.67
(m, 7H, Ar), 7.61-7.68 (m, 1H, Ar), 8.33-8.42 (m, 2H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm). ESI(+)-MS: m/z [M+H]+ calcd for
C16H13ClN3O 298.0742, found: 298.0738.
4-Acetyl-5-methyl-1-(4-methylphenyl)-1H-1,2,3-triazole (3l).
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.47 (s, 3H, CH3), 2.58 (s,
3H, CH3), 2.75 (s, 3H, CH3), 7.29-7.41 (m, 4H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 10.11, 21.26, 27.82, 125.09, 130.22,
132.85, 137.41, 140.37, 143.62, 194.43. ESI(+)-MS: m/z [M+H]+
calcd for C12H14N3O 216.1131, found: 216.1127.
General Procedure for Synthesis of 1,4,5-Trisubstituted-
1,2,3-Triazoles
In a 10 ml two-necked round bottom flask, equipped with bubble
condenser and magnetic stir bar, a mixture composed by
[mpy]OTf and water 5:0.5 v/v (5 mL and 0.5 μL), freshly distilled
Et3N (2 eq), enaminone 1a-1c (1 eq) and azide 2a–2g (2 eq) were
placed. The reaction was warmed at 100 °C for the appropriate
time. The crude was extracted with dichloromethane (3 x 5 mL),
in which the [mpy]OTf is not soluble, and the combined organic
layer was evaporated under vacuum. The crude product was
purified on a flash silica gel column by using hexane/ethyl acetate
(6:4 v/v) to obtain the desired product (3a–3o). The ionic liquid,
not soluble in organic solvent was reused for successive
reactions. The configuration of regioisomers was attributed by
comparison with literature data.[12a,27]
4-Acetyl-5-methyl-1-phenyl-1H-1,2,3-triazole (3a)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.60 (s, 3H, CH3), 2.76 (s,
3H, CH3), 7.43-7.50 (m, 2H, Ar), 7.55-7.64 (m, 3H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 9.11, 26.82, 124.27, 128.67, 129.05,
134.35, 136.39, 142.67, 193.36. ESI(+)-MS: m/z [M+H]+ calcd for
C11H12N3O 202.0975, found: 202.0971.
5-Ethyl-1-phenyl-4-propionyl-1H-1,2,3-triazole (3b)
1H NMR (CDCl3, 300 MHz): δ (ppm) 1.16 (t, J=7.52 Hz, 3H, CH3),
1.26 (t, J=7.39 Hz, 3H, CH3), 2.99 (q, J=7.52 Hz, 2H, CH2), 3.26
(q, J=7.39 Hz, 2H, CH2), 7.40-7.48 (m, 2H, Ar), 7.55-7.64 (m, 3H,
Ar). 13C NMR (CDCl3, 75 MHz): δ (ppm) 7.89, 12.92, 17.14, 33.31,
125.69, 129.71, 130.21, 135.59, 142.73, 143.05, 197.18. ESI(+)-
MS: m/z [M+H]+ calcd for C13H16N3O 230.1293, found: 230.1285.
4-Benzoyl-1-benzyl-5-methyl-1H-1,2,3-triazole (3c)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.56 (s, 3H, CH3), 5.59 (s,
2H, CH2), 7.18-7.25 (m, 2H, Ar), 7.33-7.42 (m, 3H, Ar), 7.47-7.55
(m, 2H, Ar), 7.56-7.65 (m, 1H, Ar), 8.30-8.38 (m, 2H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 9.64, 51.81, 127.32, 128.23, 128.65,
129.17, 130.62, 132.84, 134.02, 137.42, 139.35, 143.86, 187.58.
ESI(+)-MS: m/z [M+H]+ calcd for C17H16N3O 278.1288, found:
278.1284.
4-Benzoyl-5-methyl-1-(4-methylphenyl)-1H-1,2,3-triazole
(3m)
4-Benzoyl-5-methyl-1-phenyl-1H-1,2,3-triazole (3d)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.69 (s, 3H, CH3), 7.48-7.55
(m, 4H, Ar), 7.55-7.66 (m, 4H, Ar), 8.35-8.43 (m, 2H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm)10.64, 125.44, 128.29, 129.72, 130.09,
130.64, 132.93, 135.49, 137.45, 139.93, 143.55, 187.61.
ESI(+)-MS: m/z [M+H]+ calcd for C16H14N3O 264.1131, found:
264.1128.
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.47 (s, 3H, CH3), 2.66 (s,
3H, CH3), 7.34-7.43 (m, 4H, Ar), 7.48-7.58 (m, 2H, Ar), 7.58-7.66
(m, 1H, Ar), 8.34-8.42 (m, 2H, Ar). 13C NMR (CDCl3, 75 MHz): δ
(ppm) 10.61, 21.29, 125.23, 128.28, 130.25, 130.64, 132.89,
132.96, 137.49, 139.94, 140.39, 143.46, 187.64. ESI(+)-MS: m/z
[M+H]+ calcd for C17H16N3O 278.1288, found: 278.1284.
4-Acetyl-5-methyl-1-(4-methoxyphenyl)-1H-1,2,3-triazole (3n)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.56 (s, 3H, CH3), 2.75 (s,
3H, CH3), 3.89 (s, 3H, CH3), 7.02-7.10 (m, 2H, Ar), 7.32-7.40 (m,
2H, Ar). 13C NMR (CDCl3, 75 MHz): δ (ppm) 10.07, 27.80, 55.68,
114.80, 126.69, 128.16, 137.53, 143.55, 160.72, 194.44. ESI(+)-
MS: m/z [M+H]+ calcd for C12H14N3O2 232.1081, found: 232.1081.
4-Benzoyl-5-methyl-1-(4-methoxyphenyl)-1H-1,2,3-triazole
(3o).
4-Acetyl-1-benzyl-5-methyl-1H-1,2,3-triazole (3e)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.47 (s, 3H, CH3), 2.70 (s,
3H, CH3), 5.52 (s, 2H, CH2), 7.14-7.22 (m, 2H, Ar), 7.31-7.40 (m,
3H, Ar). 13C NMR (CDCl3, 75 MHz): δ (ppm) 9.15, 27.68, 51.70,
127.25, 128.62, 129.14, 133.97, 136.84, 144.03, 194.40. ESI(+)-
MS: m/z [M+H]+ calcd for C12H14N3O 216.1131, found: 216.1129.
4-Acetyl-5-methyl-1-(3-fluorophenyl)-1H-1,2,3-triazole (3f)
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.63 (s, 3H, CH3), 2.76 (s,
3H, CH3), 7.20-7.35 (m, 3H, Ar), 7.53-7.64 (m, 1H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 10.17, 27.89, 113.09 (d), 117.24 (d),
1H NMR (CDCl3, 300 MHz): δ (ppm) 2.65 (s, 3H, CH3), 2.91 (s,
3H, CH3), 7.04-7.14 (m, 2H, Ar), 7.37-7.46 (m, 2H, Ar), 7.49-7.58
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900889
European Journal of Organic Chemistry
FULL PAPER
(m, 2H, Ar), 7.58-7.66 (m, 1H, Ar), 8.34-8.42 (m, 2H, Ar). 13C NMR
(CDCl3, 75 MHz): δ (ppm) 10.58, 55.70, 114.83, 126.82, 128.28,
130.64, 132.89, 137.49, 140.06, 143.39, 148.78, 160.75, 187.66.
ESI(+)-MS: m/z [M+H]+ calcd for C17H16N3O2 294.1237, found:
294.1233.
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(MIUR) for a doctoral grant and the University of Calabria for
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European Journal of Organic Chemistry
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