Synthesis of isomerically pure 3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acid derivatives via the reaction of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide

Article abstract of DOI:10.1016/j.tet.2014.09.093

Treatment of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide in DMSO afforded the corresponding (Z)-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in good yields. Similarly, 4-aryl-3-carbethoxy-6-trifluoromethyl-2-pyrones smoothly reacted wit

Full text of DOI:10.1016/j.tet.2014.09.093

Tetrahedron xxx (2014) 1e9
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Tetrahedron
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Synthesis of isomerically pure 3-(5-trifluoromethyl-1,2,3-triazol-4-
yl)cinnamic acid derivatives via the reaction of 4-aryl-6-
trifluoromethyl-2-pyrones with sodium azide
*
Sergey A. Usachev, Boris I. Usachev, Oleg S. Eltsov, Vyacheslav Y. Sosnovskikh
Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2014
Received in revised form 19 September 2014
Accepted 29 September 2014
Available online xxx
Treatment of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide in DMSO afforded the corre-
sponding (Z)-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in good yields. Similarly, 4-aryl-3-
carbethoxy-6-trifluoromethyl-2-pyrones smoothly reacted with sodium azide in acetonitrile to pro-
duce (E)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in high yields, whereas
their reactions in ethanol, accompanied by a configurational change, gave the thermodynamically more
stable (Z)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids.
Keywords:
Pyrones
Ó 2014 Elsevier Ltd. All rights reserved.
Sodium azide
Cinnamic acids
1,2,3-Triazoles
Geometric isomers
Trifluoromethylated heterocycles
1. Introduction
prepared by the [3þ2] cycloaddition reactions of organic azides to
CF3-containing acetylenes4 and by the reaction of azides with
Vicinal triazoles are an important class of heterocyclic com-
pounds1 mainly because of their pharmacological properties in-
cluding antiviral,2a antifungal,2b anticoccidial,2c antimicrobial,2d
and other types of biological activities.2e,f Trifluoromethyl-
substituted vicinal triazoles have also drawn considerable atten-
tion because they often show unique biological and physiological
activities.3 Since inorganic azides are not good reagents in the
Huisgen 1,3-dipolar cycloaddition, most of the developed methods
for the preparation of CF3-triazoles lead to N-substituted 1,2,3-
trifluoromethyl-substituted b-diketones and b-ketoesters or b-
alkoxyenones and enaminones derived from them.5 The latter re-
action was assumed to proceed through a cycloaddition of the azide
with the alkene moiety of carbonyl compounds, followed by the
elimination of water, alcohol or secondary amine.
However, N-unsubstituted 4-trifluoromethyl-1,2,3-triazoles III
and IV are a small and poorly explored group of compounds,
probably owing to the limited number of methods available for
their preparation. The parent 4-CF3-1,2,3-triazole III has been
synthesized by the cycloaddition of trimethylsilyl azide with 3,3,3-
trifluoropropyne.6a Alternatively, this compound can be obtained
from the reactions of trifluoroacetonitrile with (diazomethyl)tri-
methylsilane,6b 1,2,3-triazole-4-carboxylic acid with SF4,6c and 1,1-
dihydroperfluoropropyl sulfone with trimethylsilyl azide.6d N-
Unsubstituted 4-CF3-5-R-1,2,3-triazoles IV can be synthesized from
triazoles
I
and II (Fig. 1). These compounds are primarily
CF3
R
CF3 CF3
R
CF3
R'
R
N
N
N
N
N
N
N
N
N
N
N
H
N
H
R'
2-(trifluoromethyl)chromones7a and
b-chloro-b-perfluoroalkyl
substituted acroleins7b with sodium azide, by the oxidation of
1,1,1,5,5,5-hexafluoro-4-(trifluoromethyl)pentane-2,3-dione dihy-
drazone,7c by the N-debenzylation of the corresponding 1,2,3-
triazole derivative,3e and by the cycloaddition of 3-
diazomethylcephem with trifluoroacetonitrile.7d Apart from these
approaches towards the synthesis of triazoles IV, a simple pro-
cedure for the preparation of CF3-triazoles bearing a cinnamic acid
I
II
III
IV
Fig. 1. Vicinal CF3-triazoles IeIV.
* Corresponding author. Fax: þ7 343 261 59 78; e-mail addresses: vy.sosnov-
skikh@urfu.ru, sosn1951@mail.ru (V.Y. Sosnovskikh).
http://dx.doi.org/10.1016/j.tet.2014.09.093
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
Table 1
moiety at the 5-position from 4-aryl-6-trifluoromethyl-2-pyrones
and sodium azide has been developed by us recently.8 This re-
Optimization of the model reaction with 2-pyrone 1b
Entry
Solvent
NaN3, equiv.
Temp, ꢀC
Time, h
Yield, %
action is the first example of conversion of the a-pyrone system to
1,2,3-triazoles and deserves further investigations in order to ex-
pand the scope of its possible applications.
1
2
3
4
5
6
7
8
EtOH/AcOH (1:1)
EtOH
Dioxane
Diglyme
MeCN
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1.5
1.5
1.1
1.1
2.0
1.1
1.1
3.0
3.0
3.0
3.0
1.5
1.5
1.1
Reflux
Reflux
Reflux
130
Reflux
120
100
rt
50
70
72
8
12
12
8
0.25
1.5
50
21
2.5
1
24
24
NRa
Mixture
NR
69
Within the framework of our project on the synthetic exploi-
tation of the ring-opening of 2-pyrones, incorporating the phar-
maceutically relevant trifluoromethyl group at the 6-position,3 we
now report on the use of readily available 4-aryl-6-trifluoromethyl-
2-pyrones and 4-aryl-3-carbethoxy-6-trifluoromethyl-2-pyrones9
as valuable building blocks for the construction of novel de-
rivatives of cinnamic acid bearing a trifluoromethylated triazole
ring. Moreover, in this paper we describe the preparation of (Z)-
and (E)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)
cinnamic acids in isomerically pure forms in various solvents.
75
84
41
65
90
88
87
86
9
10
11
12
13
14
100
100
120
120
1
0.5
0.5
DMSO
a
NR¼no reaction.
2. Results and discussion
EtOH and EtOH/AcOH, no conversion at all was observed for other
solvents except for diglyme, in which a complex mixture was ob-
tained. Only DMF and DMSO promoted the [3þ2] cycloaddition of
sodium azide with 1b to a large extent (entries 6e14). The elevated
temperatures (100e120 ꢀC, entries 6, 7, 11e14) were most suitable
for the formation of 2b in the presence of an excess of NaN3. At both
3.0 and 1.1 equiv of NaN3, almost the same product yields were
observed (entries 11e14) and the amount of azide was reduced to
improve overall reaction efficiency. The use of harsher reaction
conditions for the synthesis increased the content of side products.
These experiments suggested that dissolving both NaN3 and the
substrate in the reaction medium was important for improving the
reaction.
Although much attention has been paid to the chemistry of a-
pyrones, mainly due to their use as excellent substrates for the
preparation of a variety of complex heterocyclic compounds,10 their
reactions with azides have not been described in the literature.
However, it is known that the activation of 2-pyrones by the in-
troduction of the electron-withdrawing CF3 group at the 6-position
makes this heterocyclic system more electrophilic and enables
a diverse range of productive chemistry, with or without ring-
opening. Although several papers have appeared regarding the
preparation of 6-CF3-2-pyrones in the recent literature, the syn-
thetic utility of these compounds has not been extensively ex-
plored.9 From this point of view, we envisaged that the reaction of
4-aryl-6-trifluoromethyl-2-pyrones 1aed and ethyl 4-aryl-6-(tri-
fluoromethyl)-2-oxo-2H-pyran-3-carboxylates 4aed, prepared
from commercial 1-aryl-4,4,4-trifluorobutane-1,3-diones, PCl5 and
sodium diethyl malonate,9a,b with sodium azide would produce the
corresponding cinnamic acid derivatives bearing the N-unsub-
stituted triazole ring.
Thus, the optimum reaction conditions were 1.1 equiv of NaN3 in
DMSO at 120 ꢀC for 0.5 h. Under these conditions, 2-pyrones 1aed
gave the corresponding b-(triazolyl)cinnamic acids 2aed in good
yields (58e86%) and complete Z-stereoselectivity. The products
were isolated as colourless solids following an aqueous hydrochloric
acid work-up and recrystallization from toluene. Conversion of acids
2aed to the esters 3aed was effected with 96% H2SO4 in ethanol for
2.5 h in excellent yields (Scheme 1). Thus, the reactions of 2-pyrones
1 with sodium azide lead to the successful synthesis of b-(1,2,3-
triazol-4-yl)cinnamic acids containing a CF3 group in the triazole
ring, a previously unknown group of cinnamic acid derivatives.
In our initial studies, we optimized the reaction conditions by
using 4-(4-chlorophenyl)-6-trifluoromethyl-2-pyrone (1b); the
progress of the reaction was monitored by TLC, and the results are
summarized in Table 1. As observed from Table 1 (entries 1e5), such
solvents as ethanol, acetic acid, dioxane, diglyme and acetonitrile
Scheme 1. Synthesis of triazoles 2 and 3. Reagents and conditions: (i) NaN3, DMSO, 120 ꢀC, 0.5e1 h; (ii) concd H2SO4, ethanol, reflux, 2.5 h.
cannot be used for the reaction with NaN3 due to low rate and
unfavourable equilibrium of the addition of azide anion to the
pyrone double bond. While very low conversion was achieved in
The structures of CF3-triazoles 2 and 3 were confirmed from 1H,
19F, and 13C NMR, IR spectra, elemental analysis, and X-ray dif-
fraction studies. In the 1H NMR spectra of compounds 2aed in
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S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
3
DMSO-d6 the vinyl proton appeared as a singlet in the range of
carboxylic functionalities appear as a suitable class of building
blocks useful for the synthesis of biologically active compounds.
Previously, a mixture of (E)- and (Z)-benzylidene malonic acid
monoethyl esters was prepared from ethyl potassium malonate and
benzaldehyde.11 Some limitation in the use of monoethyl malonate
is apparent because the decarboxylation often occurs spontane-
ously during the reaction. Recently reported synthesis of arylidene
malonates with two different geminal carboxylate functions rely on
the Knoevenagel condensation of ethyl tert-butyl malonate with
different aromatic aldehydes12 and dialkyl malonates with benz-
aldehydes followed by a controlled saponification of the resulting
dialkyl arylidene malonates with 1 equiv of alkali.13
Interestingly, we found a remarkable solvent effect in alkene
stereochemistry, when acetonitrile was used as solvent for the re-
action of sodium azide with 2-pyrones 4aed. We investigated the
transformation of pyrone 4b in acetonitrile under various condi-
tions and found that it reacts smoothly with sodium azide (2 equiv)
at reflux for 3.5 h (Table 3). In contrast to the above conditions in
ethanol, when acetonitrile was employed the stereoselectivity ob-
tained was the opposite and the (E)-5b isomer was the only product
(Scheme 3). The reaction was carried out by simply pouring a sub-
strate solution directly over excess, dry NaN3, and stirring the two-
phase system vigorously at reflux temperature for 3.5 h. The so-
dium salt of acid (E)-5b, which is virtually insoluble in acetonitrile,
was filtered, washed with dry acetonitrile and acidified with an
aqueous HCl to give analytically pure product (E)-5b (no signals due
to the Z-isomer were found in the 1H NMR spectra).
d
6.8e7.0 ppm; two broad signals due to the labile protons at about
d
12.7 (CO2H) and 16.0 ppm (NH) were observed. In the 19F NMR
spectra of these products the CF3 group appeared as a singlet at
d
ꢁ59.6 ppm. In the 13C NMR spectra of 2a,b two characteristic
1
quartets at
d
121.2 (CF3, JC,F¼268.0 Hz) and 134.3 (C-5,
2JC,F¼38.0 Hz) were observed confirming the CF3-triazole structure.
It should be noted that compounds 2aed were isolated in an iso-
merically pure form and their Z-geometry was supported un-
ambiguously by X-ray diffraction analysis of 2b. According to this
they exist in the 2H-triazole form in the solid state; the benzene
moiety has a more planar conformation (dihedral angle 27ꢀ) and
the triazole moiety is twisted against the double bond plane (di-
hedral angle 90ꢀ).8
Ethyl 4-aryl-6-trifluoromethyl-2-oxo-2H-pyran-3-carboxylates
4aed due to the presence on the pyrone ring of another activat-
ing electron-withdrawing substituent (CO2Et), reacted with NaN3
under milder conditions leading to the formation of cinnamic
acid derivatives 5aed. To optimize the reaction conditions, we in-
vestigated
the
preparation
of
(Z)-3-(4-chlorophenyl)-2-
ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)acrylic acid
(5b) from pyrone 4b as a model compound (the progress of the
reaction was monitored by TLC, eluentdethyl acetate/hexane (1:2);
configuration discussion see below). Among the different solvents
(DMSO, DMF, EtOH) tested, ethanol appeared to give the best re-
sults; the rate and yield are substantially increased at reflux tem-
perature (Table 2, entries
3 and 4). Large amounts of the
unidentified side products were observed in DMSO and DMF, which
accounted for the reduced yields (entries 1 and 2).
Table 3
Optimization of the model reaction with 2-pyrone 4b in acetonitrile
Entry
NaN3, equiv
Time, h
Yield of (E)-5b, %
Table 2
1
2
3
4
5
6
7
8
1.1
1.1
1.1
1.1
1.1
2
20 min
2
3.5
4.5
16
3.5
4
3.5
46
77
80
70
52
89
83
79
Optimization of the model reaction with 2-pyrone 4b
Entry
Solvent
NaN3, equiv
Temp, ꢀC
Time, h
Yield, %
1
2
3
4
DMSO
DMF
EtOH
EtOH
1.1
1.1
1.5
1.1
80
80
25
Reflux
0.5
0.33
25
27
20
53
79
2
3
4.5
The optimum conditions for the transformation of pyrone 4b
into triazole 5b were applied for the preparation of triazoles 5a,
5c and 5d (1.1 equiv of NaN3, 90% EtOH, reflux, 4.5e5.5 h). Com-
pounds 5aed were obtained as a mixture of isomeric alkenes (Z)-
5aed and (E)-5aed in 67e81% yield (Scheme 2). Their ratio was
easily determined by 1H NMR analysis; in all cases examined, the
dominant product was the Z-isomer (75e96%). Only the major Z-
isomer of 5 could be isolated in a pure form by recrystallization of
the mixture from toluene in 58e63% yield. These monoesters ow-
ing to the various possible transformations of the different
With optimized reaction conditions established, the substrate
scope was studied (all reactions were run using at least a 2-fold
excess of sodium azide). The electronic nature of the aryl sub-
stituents in pyrones 4 has no significant effect on the yield of the
reaction. With 2-pyrones 4aee bearing neutral, moderately
electron-rich, or electron-poor aryl substituents, the reactions were
found to be highly stereoselective affording (E)-triazoles 5aee in
excellent yield (79e91%). However, in the case of derivative 4f, with
a 2-thienyl group as aryl substituent, a 70:30 mixture of Z- and E-
isomers 5f, was obtained in 50% yield. Clearly the electron-
withdrawing CF3 group enhances the electrophilicity of the sub-
strate and encourages conjugate addition at the initial stage. At the
same time, the reaction of pyrone 4g bearing the (CF2)2H group
with sodium azide in acetonitrile at reflux gives the corresponding
alkene (E)-5g in only 30% yield, indicating the importance of the
steric accessibility at the 6-position of the pyrone ring (Scheme 3).
Thus, from these results, the reaction seems to be an interesting
synthetic method, which allows to prepare the thermodynamically
less stable derivatives of cinnamic acid (E)-5 from a given 2-pyrone
due to a low solubility of this geometric isomer in acetonitrile. It
should be noted that the less reactive pyrones 1 did not react with
NaN3 under these conditions.
It was also found that monoesters 5 are convenient precursors of
diesters 6 because of their ability to undergo easy esterification.
Thus, when alkenes (E)-5 were refluxed in ethanol with addition of
concd H2SO4 for 5 h, the desired compounds 6a,b,d were isolated in
Scheme 2. Synthesis of triazoles (Z)-5. Reagents and conditions: (i) NaN3, 90% ethanol,
reflux, 5 h.
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4
S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
Scheme 3. Synthesis of triazoles (E)-5, 6 and 7. Reagents and conditions: (i) NaN3, MeCN, reflux, 3.5 h; (ii) 5 M HCl, w20 ꢀC; (iii) concd H2SO4, ethanol, reflux, 5 h; (iv) 1 N NaOH,
w20 ꢀC, overnight.
high yields. On the other hand, treatment of (E)-5 with an aqueous
1 N NaOH solution at room temperature gave diacids 7aed, novel
methylidene malonic acid derivatives, in nearly quantitative yields
(Scheme 3).
the CO2Et protons resonated downfield and the ortho aromatic
protons resonated upfield in comparison to Z-isomer (Fig. 2).
Monoesters 5 can be regarded as representatives of polarized
alkenes with a highly electrophilic b-C atom, which allows them to
The stereochemistry of the tetrasubstituted alkenes 5 merits
some comment. To establish the geometry of alkenes 5, we carried
out a 2D NOESY experiment for (E)-5b, prepared in MeCN, which
demonstrates the spatial proximity of CO2Et group to aromatic
protons. In this case, a strong one cross-peak for CH2O with H-2, H-
6 (Ar) and two cross-peaks for Me with H-2, H-6, and H-3, H-5 (Ar)
show that these protons are sited close to each other, thus estab-
lishing the trans configuration of the CO2Et group and triazolyl
moiety relative to the double bond. Note that none of these cross-
peaks were found in the NOESY spectrum of alkene (Z)-5b, all in
accord with such configuration assignment. Because of the similar
shielding effects of the ester and carboxylic acid groups as well as
the aryl and triazolyl moieties the geometric isomers 5 are distin-
guishable by 1H NMR spectroscopy due to only a small difference
between the chemical shifts of the CH2O group and the ortho-aryl
protons. In the 1H NMR spectra of (E)- and (Z)-alkenes 5aed the
react in solution with sodium azide. This is confirmed by the data
on the isomerization of pure Z-5b and E-5b in the presence of
1 equiv of sodium azide. Thus, the sodium salt of Z-isomer 5b was
found to isomerize in refluxing acetonitrile in the presence of
NaN3 for 4 h to give a 9:1 mixture of E- and Z-isomers, re-
spectively. When E-isomer 5b as sodium salt was treated with
NaN3 in refluxing 90% ethanol for 5 h a 1:1 mixture of E- and Z-
isomers 5b was obtained. It should be noted that when the neutral
form or sodium salt was used in the absence of NaN3 or in the
presence of NaOAc the isomerization process occurs only to a very
small degree (2e3%). The proportions of E- and Z-isomers were
determined by integration of the CO2Et protons in the 1H NMR
spectra.
Based on these results and in accord with the previously re-
ported mechanism,14 a plausible pathway leading to compounds 5
via intermediates AeC is outlined in Scheme 4. The first stage of the
reaction most likely involves Michael addition of azide ion on the C-
methylene protons appeared as quartets at
4.01e4.05 ppm, whereas the ortho-aryl protons appeared at
7.13e7.20 and 7.20e7.29 ppm, respectively. Thus, in the E-isomer
d 4.05e4.10 and
6 atom. Subsequent cyclization of an incipient b-azido a-carbanion
d
A would lead to intermediate B. Ring-opening in B affords insoluble
in acetonitrile sodium salts (E)-50, which can be separated and after
acidification results in the formation of E-isomers 5. Soluble in
ethanol salts (E)-50 through an additioneelimination process of
azide anion can yield the thermodynamically more stable (due to
steric reasons) sodium salts (Z)-50 leading to Z-isomers 5 after ad-
dition of hydrochloric acid. Thus, the control of the double bond
geometry was realized. This result may imply that the stereo-
chemistry of alkenes 5 is controlled by solubility of salts 50 in or-
ganic solvents and in a less degree steric effects. Thus, starting from
2-pyrones 4 the two methods yield isomeric products and are thus
complimentary. It should be noted that ethyl 6-methyl-2-oxo-4-
phenyl-2H-pyran-3-carboxylate and dehydroacetic acid as
Cl
Cl
4.10 ppm
7.20 ppm
7.15 ppm
OCH2CH3
F3C
N
F3C
1.03 ppm
CO2H
O
N
4.01 ppm
N
N
CO2H
N
N
H
O
OCH2CH3
H
0.98 ppm
(Z)-5b
(E)-5b
Fig. 2. Diagnostic 1H NMR signals (DMSO-d6) of compounds (Z)- and (E)-5b.
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S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
5
representatives of non-fluorinated
a
-pyrones did not form the
Finally, we investigated the reactivity of 2-(trifluoromethyl)
chromones 11aed towards sodium azide as an entry into tri-
fluoromethylated salicyloyltriazoles. Previously, we reported that
2-CF3-chromones 11a,b having electron-withdrawing substituents
react with sodium azide in AcOH/EtOH (1:1) at 80 ꢀC for 4e10 h to
produce 5-salicyloyl-4-trifluoromethyl-1,2,3-triazoles 12a,b, while
chromones 11c,d with electron-donating groups on the benzene
ring did not give the corresponding triazoles 12c,d after longer
reaction time. The latter were prepared from the more reactive in
acidic medium but less accessible chromone-4-imines.7a It was felt
that the direct formation of triazoles 12c,d by treatment of 11c,d
with NaN3 in DMSO might be possible. Indeed, we found that at
120 ꢀC for 0.5 h not only the expected 12a,b but also the target
compounds 12c,d can be obtained in excellent yields (Scheme 6). In
the case of unsubstituted chromone and 2-methylchromone, this
reaction failed presumably due to a low electrophilicity of the C-2
atom. These facts, along with the similar results obtained in the
corresponding triazoles even in DMSO at 120 ꢀC.
series of a- and g-pyrones, suggest an important electronic effect of
the CF3 group in pyrones and chromones on the course of the an-
nulation reaction with sodium azide.
Scheme 4. Possible mechanism for the formation of products 5.
Next, we were interested in the reactivity of g-pyrones, carrying
the CF3 group on the 6-position.15 We envisaged that 6-(tri-
fluoromethyl)comanic acid 8 could be converted into previously
unknown tricarbonyl derivative 9 by its reaction with sodium azide.
In fact, we found that when 4-pyrone 8 was heated in DMSO with
NaN3 at 120 ꢀC for 3.5 h, the desired product 9 was obtained, albeit
in only 13% yield, and presumably arises via ring-opening of the
initially formed fused intermediate. The 1H NMR spectrum of 9 in
DMSO showed two sets of signals, which were consistent with the
enol and keto forms with the former predominating (94%). A sim-
ilar reaction, when performed in 90% ethanol at reflux for 40 h,
provided 4-acetyl-5-(trifluoromethyl)-1,2,3-triazole (10) in 42%
yield as the product of a ketonic cleavage (Scheme 5). Note that 6-
(trifluoromethyl)comanic acid ethyl ester did not give positive re-
sults under the above experimental conditions. In this case, the
reaction in DMSO gave a complex multicomponent mixture, from
which no individual compounds could be isolated; in ethanol only
triazole 10 was obtained in a low yield. Thus, the differences in
behaviour between the derivatives of 6-CF3-2-pyrones and those of
6-CF3-4-pyrones are remarkable. This reaction did not work for
comanic and 6-methylcomanic acids.
Scheme 6. Synthesis of compounds 12aed.
3. Conclusion
In conclusion, we have shown that the reaction of sodium azide
with
a- and g-pyrones and chromones, activated by the tri-
fluoromethyl group provides a convenient and short approach to
the synthesis of a variety of cinnamic acid derivatives bearing the
triazole ring. Both (E)- and (Z)-2-ethoxycarbonyl-3-(5-
trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids could be ob-
tained by varying the nature of the solvent. The products obtained
constitute an important structural subunit of a variety of bi-
ologically active compounds and could be serve as useful substrates
in the construction of more complex heterocyclic systems.
4. Experimental
4.1. General
NMR spectra were recorded on Bruker DRX-400 and Bruker
Avance II spectrometers (1Hd400 MHz, 19Fd376 MHz and
13Cd100 MHz) in DMSO-d6 and CDCl3 with TMS, CFCl3 and C6F6
(
d
¼ꢁ162.9 ppm) as internal standards. IR spectra were recorded on
a PerkineElmer Spectrum BX-II and Nicolet 6700 instruments (KBr
pellets, FTIR mode, ZnSe crystal). Elemental analyses were per-
formed at the Microanalysis Services of the Institute of Organic
Synthesis, Ural Branch, Russian Academy of Sciences. All solvents
Scheme 5. Synthesis of compounds 9 and 10 (aDMSO, 120 ꢀC, 3.5 h; b90% EtOH, reflux,
40 h).
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6
S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
used were dried and distilled per standard procedures. Melting
points were determined on a Stuart SMP30 apparatus. The starting
4-aryl-6-(trifluoromethyl)-2H-pyran-2-ones 1 and ethyl 4-aryl-2-
oxo-(6-trifluoromethyl)-2H-pyran-3-carboxylates 4,9a,b as well as
6-(trifluoromethyl)comanic acid15c were prepared according to
described procedures.
135.5e137.4 (br s), 137.6e141.6 (br s, 2C), 165.6. Anal. Calcd for
16H10F3N3O2$0.5H2O: C, 56.15; H, 3.24; N, 12.28. Found: C, 56.08;
H, 2.97; N, 12.40.
C
4.3. General procedure for the synthesis of compounds 3aed
A solution of b-(1,2,3-triazol-4-yl)acrylic acid 2 (1.2 mmol) and
4.2. General procedure for the synthesis of compounds 2aed
0.5 mL 96% H2SO4 in 3 mL of ethanol was refluxed for 2.5 h. The
reaction mixture was then diluted with water and the product was
filtered and recrystallized from heptane to give esters 3aed as
colourless solids.
A
solution of 4-aryl-6-(trifluoromethyl)-2H-pyran-2-one 1
(0.72 mmol) and NaN3 (52 mg, 0.79 mmol) in 2 mL of DMSO was
heated at 120 ꢀC until completion of the reaction (TLC, ethyl ace-
tate/hexane, 1:2). The reaction mixture was then cooled to w20 ꢀC
and acidified with an aqueous 5 M HCl solution. The viscous liquid
product was separated by decantation and crystallized from tolu-
ene to give triazoles (Z)-2aed as colourless (2aec) or slightly
brown (2d) solids.
4.3.1. (Z)-Ethyl 3-phenyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)ac-
rylate (3a). Yield 85%, mp 147e150 ꢀC. IR (ATR): 3211, 1701, 1631,
1521, 1454, 1370, 1347, 1292, 1242, 1193, 1136, 1069, 1024, 990 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.20 (t, J¼7.1 Hz, 3H, Me), 4.13 (q, J¼7.1 Hz,
2H, CH2O), 6.68 (s, 1H, ]CH), 7.29 (d, J¼7.1 Hz, 2H, Ph), 7.33e7.43 (m,
3H, Ph), 12.40e12.80 (br s, 1H, NH); 19F NMR (376 MHz, CDCl3)
4.2.1. (Z)-3-Phenyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)acrylic
acid (2a). Yield 58% (40 min), mp 72e73 ꢀC (hydrate), 126e128 ꢀC
(anhydrous). IR (ATR): 1710, 1697, 1637, 1525, 1300, 1199, 1160, 1132,
d
ꢁ60.6 (s, CF3); 13C NMR (101 MHz, CDCl3)
d 14.0, 61.3, 120.8 (q,
1JC,F¼269.1 Hz, CF3), 122.8, 127.4, 129.0, 130.6, 136.8 (q, 2JC,F¼39.1 Hz),
137.2, 141.2, 143.0, 165.7. Anal. Calcd for C14H12F3N3O2: C, 54.02; H,
3.89; N, 13.50. Found: C, 54.13; H, 3.63; N, 13.71.
1072 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 6.80 (s, 1H, ]CH), 7.31
(dd, J¼7.8, 1.5 Hz, 2H, Ph), 7.38e7.47 (m, 3H, Ph), 11.80e13.70 (br s,
1H, OH), 15.50e16.50 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
4.3.2. (Z)-Ethyl 3-(4-chlorophenyl)-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylate (3b). Yield 92%, mp 113e114 ꢀC. IR (ATR):
3225,1694,1628,1589,1518,1492,1448,1370,1342,1293,1237,1192,
d
ꢁ59.6 (s, CF3); 13C NMR (101 MHz, DMSO-d6)
d 121.2 (q,
1JC,F¼268.0 Hz, CF3), 123.8, 126.8, 129.0, 130.2, 134.3 (q,
2JC,F¼39.0 Hz), 136.8, 138.5e141.0 (br s, 2C), 165.5. Anal. Calcd for
1155, 1129, 1094, 1070, 1027, 1011, 991 cmꢁ1 1H NMR (400 MHz,
;
C
12H8F3N3O2$H2O: C, 47.85; H, 3.35; N, 13.95. Found: C, 48.05; H,
CDCl3)
d
1.21 (t, J¼7.1 Hz, 3H, Me), 4.13 (q, J¼7.1 Hz, 2H, CH2O), 6.66
3.26; N, 13.60.
(s, 1H, ]CH), 7.23 (d, J¼8.7 Hz, 2H, Ar), 7.34 (d, J¼8.7 Hz, 2H, Ar); 1H
NMR (400 MHz, DMSO-d6)
d
1.07 (t, J¼7.1 Hz, 3H, Me), 4.01 (q,
4.2.2. (Z)-3-(4-Chlorophenyl)-3-(5-trifluoromethyl-1,2,3-triazol-4-
yl)acrylic acid (2b). Yield 86% (30 min), mp 108e110 ꢀC (hydrate),
184e186 ꢀC (anhydrous). IR (ATR): 1705, 1692, 1626, 1585, 1526,
J¼7.1 Hz, 2H, CH2O), 6.92 (br s, 1H, ]CH), 7.38 (d, J¼8.7 Hz, 2H, Ar),
7.49 (d, J¼8.4 Hz, 2H, Ar), 16.10e16.30 (br s, 1H, NH); 19F NMR
(376 MHz, CDCl3)
d
ꢁ60.6 (s, CF3); 19F NMR (376 MHz, DMSO-d6)
1491, 1297, 1194, 1160, 1133, 1095, 1070 cmꢁ1
;
1H NMR (400 MHz,
d
ꢁ59.3 (br s, CF3), ꢁ59.4 (br s, CF3). Anal. Calcd for C14H11ClF3N3O2:
DMSO-d6)
d
6.83 (s, 1H, ]CH), 7.34 (d, J¼8.7 Hz, 2H, Ar), 7.48 (d,
C, 48.64; H, 3.21; N, 12.15. Found: C, 48.65; H, 3.11; N, 12.16.
J¼8.7 Hz, 2H, Ar), 12.30e13.20 (br s, 1H, OH), 15.70e16.50 (br s, 1H,
NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ59.6 (s, CF3); 13C NMR
4.3.3. (Z)-Ethyl 3-(4-fluorophenyl)-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylate (3c). Yield 85%, mp 119e121 ꢀC. IR (ATR):
3206, 1698, 1631, 1600, 1508, 1452, 1371, 1346, 1292, 1279, 1248,
1
(101 MHz, DMSO-d6)
d
121.2 (q, JC,F¼268.0 Hz, CF3), 124.6, 128.7,
2
129.1, 134.4 (q, JC,F¼37.7 Hz), 135.0, 135.7, 138.0e139.4 (br s, 2C),
165.5. Anal. Calcd for C12H7ClF3N3O2$H2O: C, 42.94; H, 2.70; N,
12.52. Found: C, 43.12; H, 2.68; N, 12.56.
1176, 1137, 1069, 1025, 991 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.21
(t, J¼7.1 Hz, 3H, Me), 4.13 (q, J¼7.1 Hz, 2H, CH2O), 6.62 (s, 1H, ]CH),
7.05 (t, J¼8.6 Hz, 2H, Ar), 7.28 (dd, J¼8.9, 5.2 Hz, 2H, Ar),
4.2.3. (Z)-3-(4-Fluorophenyl)-3-(5-trifluoromethyl-1,2,3-triazol-4-
yl)acrylic acid (2c). Yield 78% (30 min), mp 184e186 ꢀC. IR (ATR):
1716, 1685, 1635, 1605, 1579, 1509, 1433, 1396, 1336, 1274, 1228,
1205, 1169, 1159, 1132, 1081, 1024 cmꢁ1; 1H NMR (400 MHz, DMSO-
10.00e13.50 (br s, 1H, NH); 19F NMR (376 MHz, CDCl3)
d
ꢁ109.7 (br
s, F), ꢁ60.6 (s, CF3). Anal. Calcd for C14H11F4N3O2: C, 51.07; H, 3.37;
N, 12.76. Found: C, 50.97; H, 3.12; N, 12.73.
d6)
5.4 Hz, 2H, Ar), 12.00e13.30 (br s, 1H, OH), 15.50e16.50 (br s, 1H,
NH); 19F NMR (376 MHz, DMSO-d6)
ꢁ111.1 (br s, F), ꢁ59.6 (s, CF3);
13C NMR (126 MHz, DMSO-d6)
d
6.79 (s, 1H, ]CH), 7.25 (t, J¼8.3 Hz, 2H, Ar), 7.37 (dd, J¼8.3,
4.3.4. (Z)-Ethyl 3-(2-naphthyl)-3-(5-trifluoromethyl-1,2,3-triazol-4-
yl)acrylate (3d). Yield 89%, mp 155e157 ꢀC. IR (ATR): 3191, 1688,
1620, 1514, 1447, 1371, 1290, 1203, 1181, 1157, 1126, 1067, 1027,
d
2
d
116.0 (d, JC,F¼21.9 Hz, C-3, C-5),
990 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.21 (t, J¼7.1 Hz, 3H, Me), 4.14
121.2 (q, 1JC,F¼268.1 Hz, CF3), 123.9, 129.3 (d, 3JC,F¼8.4 Hz, C-2, C-6),
133.3, 133.5e135.4 (br s), 136.6e140.6 (br s, 2C), 163.1 (d,
1JC,F¼248.8 Hz, C-4), 165.5. Anal. Calcd for C12H7F4N3O2: C, 47.85; H,
2.34; N, 13.95. Found: C, 47.46; H, 2.38; N, 13.75.
(q, J¼7.1 Hz, 2H, CH2O), 6.81 (s,1H, ]CH), 7.46e7.56 (m, 3H, H-3, H-6,
H-7), 7.58 (s, 1H, H-1), 7.76 (d, J¼7.8 Hz, 1H, H-5/8), 7.83 (d, J¼7.6 Hz,
1H, H-8/5), 7.84 (d, J¼8.7 Hz, 1H, H-4), 11.70e13.10 (br s, 1H, NH); 19
F
NMR (376 MHz, CDCl3)
d
d
ꢁ60.6 (s, CF3); 13C NMR (101 MHz, CDCl3)
1
14.0, 61.4, 120.8 (q, JC,F¼269.1 Hz, CF3), 122.7, 123.5, 127.0, 127.7,
4.2.4. (Z)-3-(2-Naphthyl)-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)
acrylic acid (2d). Yield 64% (1 h), mp 187e189 ꢀC (toluene/petro-
leum ether 2:1, bp 40e70 ꢀC). IR (ATR): 1705,1683,1653,1624,1585,
1576, 1558, 1540, 1521, 1507, 1490, 1473, 1457, 1437, 1411, 1327, 1303,
127.8, 128.4, 128.9, 129.0, 133.0, 134.2, 134.3, 136.9 (q, 2JC,F¼39.1 Hz),
141.1, 142.9, 165.9. Anal. Calcd for C18H14F3N3O2: C, 59.83; H, 3.91; N,
11.63. Found: C, 59.87; H, 3.73; N, 11.63.
1285, 1237, 1211, 1184, 1165, 1138, 1118, 1074, 1012, 988 cmꢁ1
;
1H
4.4. General procedure for the synthesis of compounds (Z)-
5aed
NMR (400 MHz, DMSO-d6)
d 6.97 (s,1H, ]CH), 7.50e7.62 (m, 2H, H-
6, H-7), 7.66 (d, J¼8.9 Hz, 1H, H-3), 7.69 (s, 1H, H-1), 7.90e8.00 (m,
3H, H-4, H-5, H-8), 11.90e13.90 (br s, 1H, OH), 15.50e16.50 (br s, 1H,
A solution of ethyl 4-aryl-2-oxo-(6-trifluoromethyl)-2H-pyran-
3-carboxylate 4 (0.6 mmol) and NaN3 (43 mg, 0.66 mmol) in 2 mL of
90% ethanol was refluxed for 4.5e5.5 h (TLC, ethyl acetate/hexane,
1:2). The reaction mixture was then acidified with an aqueous 5 M
NH); 19F NMR (471 MHz, DMSO-d6)
d
ꢁ59.6 (s, CF3); 13C NMR
(126 MHz, DMSO-d6)
d
121.2 (q, 1JC,F¼268.0 Hz, CF3), 123.5, 124.2,
126.9, 127.4, 127.5, 127.6, 128.70, 128.74, 132.6, 133.4, 134.2,
Please cite this article in press as: Usachev, S. A.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.093

S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
7
HCl solution and the product formed was crystallized from toluene
to give pure Z-triazoles 5aed as colourless solids. The mother liquor
was then diluted with light petroleum (bp 40e70 ꢀC) affording
a mixture of Z- and E-isomers.
give the product (E)-5 as a colourless oil, which solidified eventu-
ally as a colourless solid.
4.5.1. (E)-2-Ethoxycarbonyl-3-phenyl-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylic acid (E-5a). Yield 80% (4 h), mp 143e145 ꢀC. IR
(ATR): 1727, 1702, 1638, 1448, 1409, 1290, 1263, 1223, 1141, 1099,
4.4.1. (Z)-2-Ethoxycarbonyl-3-phenyl-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylic acid (Z-5a). Overall yield 74%: 61% as a pure Z-
isomer, mp 202e203 ꢀC, and 13% as a mixture of E- and Z-isomers
(85:15). IR (ATR): 1728, 1702, 1640, 1516, 1446, 1410, 1369, 1291,
1066 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
1.03 (t, J¼7.1 Hz, 3H,
Me), 4.06 (q, J¼7.1 Hz, 2H, CH2O), 7.13 (dd, J¼7.9, 1.6 Hz, 2H, Ph),
7.30e7.44 (m, 3H, Ph), 12.00e14.00 (br s, 1H, OH), 15.60e16.10 (br s,
1263, 1223, 1144, 1100, 1068 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ59.2 (s, CF3); 13C NMR
1
d
1.05 (t, J¼7.1 Hz, 3H, Me), 4.02 (q, J¼7.1 Hz, 2H, CH2O), 7.20 (dd,
(101 MHz, DMSO-d6)
d
13.5, 61.4, 120.9 (q, JC,F¼268.3 Hz, CF3),
J¼7.6, 1.7 Hz, 2H, Ph), 7.33e7.42 (m, 3H, Ph), 12.40e14.10 (br s, 1H,
127.9, 128.7, 130.0, 132.3, 134.1 (q, 2JC,F¼38.4 Hz), 136.6, 139.0, 164.2,
165.1. Anal. Calcd for C15H12F3N3O4: C, 50.71; H, 3.40; N, 11.83.
Found: C, 50.65; H, 3.35; N, 11.79. Sodium (E)-2-ethoxycarbonyl-3-
phenyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)acrylate (E-50a): 1H
OH), 15.50e16.30 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ59.3 (s, CF3); 13C NMR (101 MHz, DMSO-d6)
d 13.4, 61.1, 120.8 (q,
1JC,F¼268.4 Hz, CF3), 128.0, 128.6, 129.9, 132.2, 134.2 (q,
2JC,F¼41.4 Hz), 136.4, 138.2, 163.3, 165.8. Anal. Calcd for
NMR (500 MHz, DMSO-d6)
d
0.91 (t, J¼7.1 Hz, 3H, Me), 3.87 (q,
C
15H12F3N3O4: C, 50.71; H, 3.40; N, 11.83. Found: C, 50.70; H, 3.27;
J¼7.1 Hz, 2H, CH2O), 7.00 (dd, J¼7.5, 1.9 Hz, 2H, Ph), 7.18e7.24 (m,
N, 11.87.
3H, Ph); 13C NMR (101 MHz, DMSO-d6)
d 13.7, 59.7, 123.8 (q,
1JC,F¼267.1 Hz, CF3), 127.4, 127.5, 128.2, 131.9 (q, JC,F¼34.4 Hz),
2
4.4.2. (Z)-3-(4-Chlorophenyl)-2-ethoxycarbonyl-3-(5-trifluoromethyl-
1,2,3-triazol-4-yl)acrylic acid (Z-5b). Overall yield 79%: 45% a pure Z-
isomer, mp 185e187 ꢀC, and 34% as a mixture of E- and Z-isomers
(59:41). IR (ATR): 3202,1733,1697,1637, 1591,1484, 1444,1400,1374,
1321, 1298, 1280, 1237, 1204, 1170, 1140, 1117, 1089, 1078, 1022,
133.7, 136.9, 140.8, 141.5, 168.0, 168.3.
4.5.2. (E)-3-(4-Chlorophenyl)-2-ethoxycarbonyl-3-(5-trifluoromethyl-
1,2,3-triazol-4-yl)acrylic acid (E-5b). Yield 89% (3.5 h), mp
167e168 ꢀC. IR (ATR): 3207, 3006, 2932, 1704, 1631, 1591, 1493, 1438,
1402, 1368, 1315, 1278, 1227, 1187, 1169, 1151, 1105, 1093, 1074, 1009,
1010 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
0.98 (t, J¼7.1 Hz, 3H, Me),
4.01 (q, J¼7.1 Hz, 2H, CH2O), 7.20 (d, J¼8.5 Hz, 2H, Ar), 7.50 (d,
J¼8.5 Hz, 2H, Ar), 13.40e14.20 (br s, 1H, OH), 16.00e16.60 (br s, 1H,
992 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
1.03 (t, J¼7.1 Hz, 3H, Me),
4.10 (q, J¼7.1 Hz, 2H, CH2O), 7.15 (d, J¼8.6 Hz, 2H, Ar), 7.50 (d,
NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ59.2 (s, CF3). Anal. Calcd for
J¼8.6 Hz, 2H, Ar), 13.00e14.30 (br s, 1H, OH), 15.90e16.70 (br s, 1H,
C15H11ClF3N3O4$0.33H2O: C, 45.53; H, 2.97; N,10.62. Found: C, 45.38;
NH); 19F NMR (376 MHz, DMSO-d6þCCl4)
d
ꢁ59.2 (s, CF3); 13C NMR
H, 2.75; N, 10.51.
(101 MHz, DMSO-d6þCCl4)
d
13.4, 61.1, 120.6 (q, 1JC,F¼268.5 Hz, CF3),
128.4, 129.4, 132.6, 134.7, 132.9e136.6 (br s), 135.3, 136.4e139.8 (br s,
2C), 140.3e143.8 (br s, 2C), 163.7, 164.5. Anal. Calcd for
4.4.3. (Z)-2-Ethoxycarbonyl-3-(4-fluorophenyl)-3-(5-trifluoromethyl-
1,2,3-triazol-4-yl)acrylic acid (Z-5c). Overall yield 81%: 62% as a pure
Z-isomer, mp 201e202 ꢀC, and 19% as a mixture of E- and Z-isomers
(57:43). IR (ATR): 1724, 1715, 1604, 1579, 1510, 1478, 1369, 1325, 1300,
C15H11ClF3N3O4: C, 46.23; H, 2.84; N, 10.78. Found: C, 45.97; H, 2.52;
N, 10.74. Sodium (E)-3-(4-chlorophenyl)-2-ethoxycarbonyl-3-(5-
trifluoromethyl-1,2,3-triazol-4-yl)acrylate (E-50b): IR (ATR): 1689,
1250, 1226, 1206, 1165, 1148, 1102, 1074, 1019 cmꢁ1
;
1H NMR
0.98 (t, J¼7.1 Hz, 3H, Me), 4.01 (q, J¼7.1 Hz,
2H, CH2O), 7.22e7.30 (m, 4H, Ar), 12.90e14.40 (br s, 1H, OH),
1605, 1577, 1487, 1398, 1386, 1327, 1288 cmꢁ1 1H NMR (400 MHz,
;
(400 MHz, DMSO-d6)
d
DMSO-d6)
d
0.96 (t, J¼7.1 Hz, 3H, Me), 3.93 (q, J¼7.1 Hz, 2H, CH2O),
7.01 (d, J¼8.5 Hz, 2H, Ar), 7.33 (d, J¼8.5 Hz, 2H, Ar).
15.60e16.80 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ110.8
(br s, F), ꢁ59.0 (s, CF3); 13C NMR (126 MHz, DMSO-d6)
d
13.4, 61.2,
4.5.3. (E)-2-Ethoxycarbonyl-3-(4-fluorophenyl)-3-(5-trifluoromethyl-
1,2,3-triazol-4-yl)acrylic acid (E-5c). Yield 81% (2.5 h), mp
156e157 ꢀC. IR (ATR): 3191, 1703, 1685, 1603, 1506, 1451, 1391, 1375,
115.8 (d, 2JC,F¼22.1 Hz, C-3, C-5), 120.8 (q, 1JC,F¼268.5 Hz, CF3), 130.5
(d, 3JC,F¼8.9 Hz, C-2, C-6), 132.3, 132.8, 134.3 (q, 2JC,F¼38.5 Hz), 137.2,
1
162.8 (d, JC,F¼248.5 Hz, C-4), 163.3, 165.7. Anal. Calcd for
1281 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
1.02 (t, J¼7.1 Hz, 3H, Me),
C15H11F4N3O4: C, 48.27; H, 2.97; N, 11.26. Found: C, 48.01; H, 2.93; N,
4.09 (q, J¼7.1 Hz, 2H, CH2O), 7.18 (dd, J¼8.7, 5.4 Hz, 2H, Ar), 7.26 (t,
J¼8.8 Hz, 2H, Ar), 12.90e14.10 (br s, 1H, OH), 15.90e16.50 (br s, 1H,
11.48.
NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ111.2 (br s, F), ꢁ59.3 (s, CF3);
4.4.4. (Z)-2-Ethoxycarbonyl-3-(2-naphthyl)-3-(5-trifluoromethyl-
1,2,3-triazol-4-yl)acrylic acid (Z-5d). Overall yield 67%: 58% as
a pure Z-isomer, mp 194e197 ꢀC, and 9% (crystallized from CHCl3/
CCl4) as a mixture of E- and Z-isomers (27:73). IR (ATR): 1707, 1578,
1476, 1370, 1299, 1260, 1233, 1152, 1102, 1075, 1018 cmꢁ1; 1H NMR
13C NMR (126 MHz, DMSO-d6)
d
13.4, 61.3,115.8 (d, 2JC,F¼22.1 Hz, C-3,
C-5), 120.8 (q, 1JC,F¼268.4 Hz, CF3), 130.3 (d, JC,F¼8.8 Hz, C-2, C-6),
3
2
132.3, 132.9, 134.1 (q, JC,F¼38.1 Hz), 137.8, 139.4e142.0 (br s), 162.7
(d, 1JC,F¼248.3 Hz, C-4), 164.0, 164.9. Anal. Calcd for
C15H11F4N3O4$0.5H2O: C, 47.13; H, 3.16; N, 10.99. Found: C, 47.38; H,
(400 MHz, DMSO-d6)
d
1.07 (t, J¼7.1 Hz, 3H, Me), 4.05 (q, J¼7.1 Hz,
2.86; N, 10.87. Sodium (E)-2-ethoxycarbonyl-3-(4-fluorophenyl)-3-(5-
trifluoromethyl-1,2,3-triazol-4-yl)acrylate NMR
(E-50c): 1H
(400 MHz, DMSO-d6)
0.94 (t, J¼7.1 Hz, 3H, Me), 3.88 (q, J¼7.1 Hz,
2H, CH2O), 6.96e7.06 (m, 4H, Ar); 19F NMR (376 MHz, DMSO-d6)
ꢁ55.0 (s, CF3), ꢁ116.3 (m, F).
2H, CH2O), 7.29 (d, J¼8.3 Hz, 1H, H-3), 7.47e7.57 (m, 2H, H-6, H-7),
7.72 (s, 1H, H-1), 7.82e7.92 (m, 3H, H-4, H-5, H-8), 12.30e14.30 (br
s, 1H, OH), 15.70e16.70 (br s, 1H, NH). Anal. Calcd for C19H14F3N3O4:
C, 56.30; H, 3.48; N, 10.37. Found: C, 56.22; H, 3.53; N, 10.40.
d
d
4.5. General procedure for the synthesis of compounds (E)-
5aeg
4.5.4. (E)-2-Ethoxycarbonyl-3-(2-naphthyl)-3-(5-trifluoromethyl-
1,2,3-triazol-4-yl)acrylic acid (E-5d). Yield 79% (4 h), mp
148e149 ꢀC. IR (ATR): 3193, 1702,1683, 1515, 1446, 1387, 1373,1296,
A solution of ethyl 4-aryl-2-oxo-(6-trifluoromethyl)-2H-pyran-
3-carboxylate 4 (0.3 mmol) and NaN3 (39 mg, 0.6 mmol) in 2 mL of
dry acetonitrile was refluxed with a drying tube until completion of
the reaction (TLC, ethyl acetate/hexane, 1:2). The precipitate
formed (sodium salt) was filtered, washed with a small amount of
dry acetonitrile and acidified with an aqueous 5 M HCl solution to
1281, 1222, 1169, 1149, 1097, 1070, 994 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6)
d
0.98 (t, J¼7.1 Hz, 3H, Me), 4.05 (q, J¼7.1 Hz, 2H, CH2O),
7.20 (dd, J¼8.5, 1.7 Hz, 1H, H-3), 7.48e7.57 (m, 2H, H-6, H-7), 7.68 (s,
1H, H-1), 7.83e7.89 (m, 3H, H-4, H-5, H-8), 11.00e14.00 (br s, 1H,
OH), 15.70e16.20 (br s, 1H, NH). Anal. Calcd for C19H14F3N3O4: C,
56.30; H, 3.48; N, 10.37. Found: C, 56.14; H, 3.44; N, 10.38. Sodium
Please cite this article in press as: Usachev, S. A.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.093

8
S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
(E)-2-ethoxycarbonyl-3-(2-naphthyl)-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylate (E-50d): 1H NMR (400 MHz, DMSO-d6)
0.86 (t,
1324, 1294, 1253, 1143, 1090, 1071, 1013, 990 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
d
1.12 (t, J¼7.1 Hz, 3H, Me), 1.14 (t, J¼7.1 Hz, 3H,
J¼7.1 Hz, 3H, Me), 3.85 (q, J¼7.1 Hz, 2H, CH2O), 7.12 (dd, J¼8.5,
1.6 Hz, 1H, H-3), 7.42e7.46 (m, 2H, H-6, H-7), 7.49 (s, 1H, H-1), 7.71
(d, J¼8.6 Hz, 1H, H-4), 7.73e7.77 (m, 1H, H-5/8), 7.80e7.84 (m, 1H,
Me), 4.14 (q, J¼7.1 Hz, 2H, CH2O), 4.17 (q, J¼7.1 Hz, 2H, CH2O), 7.17
(d, J¼8.6 Hz, 2H, Ar), 7.32 (d, J¼8.6 Hz, 2H, Ar), 7.80e11.20 (br s, 1H,
NH); 19F NMR (471 MHz, CDCl3)
d
ꢁ61.4 (s, CF3); 13C NMR (126 MHz,
H-8/5); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ55.0 (s, CF3).
CDCl3)
d
13.7, 13.8, 62.3, 62.4, 120.5 (q, 1JC,F¼269.2 Hz, CF3), 129.0,
129.8, 131.9, 135.1, 136.5, 136.7 (q, 2JC,F¼39.4 Hz), 140.8, 142.6, 163.8,
165.1. Anal. Calcd for C17H15ClF3N3O4: C, 48.87; H, 3.62; N, 10.06.
Found: C, 48.70; H, 3.62; N, 9.99.
4.5.5. (E)-2-Ethoxycarbonyl-3-p-tolyl-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylic acid (E-5e). Yield 91% (6 h), mp 199e201 ꢀC. IR
(ATR): 3241, 1717, 1673, 1623, 1605, 1526, 1508, 1450, 1408, 1374,
1314, 1300, 1245, 1223 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.04 (t,
4.6.3. Diethyl
(2-naphthyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)
J¼7.1 Hz, 3H, Me), 2.31 (s, 3H, Me), 4.09 (q, J¼7.1 Hz, 2H, CH2O), 7.01
(d, J¼8.0 Hz, 2H, Ar), 7.21 (d, J¼8.0 Hz, 2H, Ar),12.90e13.90 (br s,1H,
OH), 15.90e16.60 (br s, 1H, NH). Anal. Calcd for C16H14F3N3O4: C,
52.04; H, 3.82; N, 11.38. Found: C, 51.80; H, 3.96; N, 11.34.
methylenemalonate (6d). Yield 83%, light yellow viscous liquid. IR
(ATR): 3205, 2986, 2938, 1712, 1597, 1516, 1469, 1446, 1371, 1293,
1237, 1138, 1089, 1066, 1004, 988 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.00 (t, J¼7.1 Hz, 3H, Me), 1.14 (t, J¼7.1 Hz, 3H, Me), 4.12 (q,
J¼7.1 Hz, 2H, CH2O), 4.14 (q, J¼7.1 Hz, 2H, CH2O), 7.28 (dd, J¼8.6,
1.8 Hz, 1H, H-3), 7.46e7.55 (m, 2H, H-6, H-7), 7.73 (d, J¼1.1 Hz, 1H,
4.5.6. 2-Ethoxycarbonyl-3-(2-thienyl)-3-(5-trifluoromethyl-1,2,3-
triazol-4-yl)acrylic acid (5f). Yield 50% (5 h, Z/E¼70:30), pale yellow
H-1), 7.75e7.83 (m, 3H, H-4, H-5, H-8), 8.10e11.50 (br s,1H, NH); 19
F
solid, mp 204e207 ꢀC. 1H NMR (400 MHz, CDCl3)
d
(Z): 1.22 (t,
NMR (471 MHz, CDCl3)
d
d
ꢁ61.4 (s, CF3); 13C NMR (126 MHz, CDCl3)
1
J¼7.1 Hz, 3H, Me), 4.27 (q, J¼7.1 Hz, 2H, CH2O), 6.98 (dd, J¼3.8,
1.1 Hz, 1H, H-3), 7.13 (dd, J¼5.1, 3.8 Hz, 1H, H-4), 7.85 (dd, J¼5.1,
1.1 Hz, 1H, H-5), 13.00e14.00 (br s, 1H, OH), 15.90e16.40 (br s, 1H,
NH); (E): 0.98 (t, J¼7.1 Hz, 3H, Me), 3.98 (q, J¼7.1 Hz, 2H, CH2O), 7.12
(dd, J¼3.8, 1.1 Hz, 1H, H-3), 7.14 (dd, J¼5.1, 3.8 Hz, 1H, H-4), 7.85 (dd,
J¼5.1, 1.1 Hz, 1H, H-5), 13.00e14.00 (br s, 1H, OH), 15.90e16.40 (br s,
13.7, 13.8, 62.1, 62.2, 120.6 (q, JC,F¼269.2 Hz, CF3), 125.2, 127.0,
127.6, 127.9, 128.5, 128.6, 128.7, 131.7, 132.9, 133.9, 134.1, 136.8 (q,
2JC,F¼39.3 Hz), 141.9, 142.7, 163.9, 165.5. Anal. Calcd for
C
21H18F3N3O4$0.25H2O: C, 57.60; H, 4.26; N, 9.60. Found: C, 57.48;
H, 4.07; N, 9.58.
1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
(Z): ꢁ59.59 (s, CF3); (E):
4.7. General procedure for the synthesis of compounds 7aed
ꢁ59.64 (s, CF3). Anal. Calcd for C13H10F3N3O4S$0.5H2O: C, 42.17; H,
2.99; N, 11.35. Found: C, 42.29; H, 2.84; N, 11.34.
A solution of acid 5 (0.3 mmol) in 2 mL of an aqueous 1 N NaOH
was allowed to stand during overnight at room temperature. The
reaction mixture was then diluted with 1 mL of concd HCl to give
the target product 8 as a colourless solid.
4.5.7. (E)-3-(4-Bromophenyl)-2-ethoxycarbonyl-3-(5-(1,1,2,2-
tetrafluoroethyl)-1,2,3-triazol-4-yl)acrylic acid (E-5g). Yield 30%
(5 h), mp 159e161 ꢀC. IR (ATR): 3318, 1698, 1631, 1586, 1487, 1411,
1393, 1370, 1302, 1266, 1227, 1211, 1183, 1143, 1106, 1091, 1074, 1011,
4.7.1. Phenyl(5-trifluoromethyl-1,2,3-triazol-4-yl)methylenemalonic
acid (7a). Yield 92%, mp 214e216 ꢀC (with decarboxylation). IR
(ATR): 3398, 1716, 1687, 1645, 1586, 1497, 1447, 1410, 1320, 1273,
990 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
4.08 (q, J¼7.1 Hz, 2H, CH2O), 6.72 (t, JH,F¼52.2 Hz, 1H, CF2H), 7.05
(d, J¼8.3 Hz, 2H, Ar), 7.61 (d, J¼8.3 Hz, 2H, Ar), 12.90e13.90 (s, 1H,
OH), 15.80e16.40 (s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
1.03 (t, J¼7.1 Hz, 3H, Me),
2
1247, 1228, 1210, 1165, 1141, 1103, 1069, 1017 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6) d 7.19 (m, 2H, Ph), 7.31e7.50 (m, 3H, Ph), 13.38
d
ꢁ137.0 (s, CF2), ꢁ111.3 (s, CF2H). Anal. Calcd for C16H12BrF4N3O4: C,
(br s, 2H, OH), 16.08 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
41.22; H, 2.59; N, 9.01. Found: C, 40.92; H, 2.51; N, 8.84.
d
ꢁ58.9 (s, CF3); 13C NMR (101 MHz, DMSO-d6)
d 120.9 (q,
1JC,F¼268.3 Hz, CF3), 127.9, 128.6, 129.7, 132.7e135.1 (br s), 133.6,
135.7e138.5 (br s), 136.7, 141.7e144.7 (br s), 164.5, 166.4. Anal.
Calcd for C13H8F3N3O4$0.5H2O: C, 46.44; H, 2.70; N, 12.50. Found: C,
46.56; H, 2.84; N, 12.44.
4.6. General procedure for the synthesis of compounds 6aed
A solution of corresponding (E)-3-aryl-2-(ethoxycarbonyl)-3-(5-
trifluoromethyl-1,2,3-triazol-4-yl)acrylic acid (Z)-5 (0.3 mmol) and
0.3 mL 96% H2SO4 in2 mLofethanol wasrefluxed for 5 h. Thereaction
mixture was then diluted with water and the product was extracted
with CHCl3 (3ꢂ2 mL). The extract was dried with Na2SO4, filtered and
then evaporated. The resulting diester was purified by flash-
chromatography on silica gel using CHCl3/EtOH gradient system.
4.7.2. (4-Chlorophenyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)methyl-
enemalonic acid (7b). Yield 97%, mp 203e204 ꢀC (with de-
carboxylation). IR (ATR): 3404, 1715, 1689, 1648, 1589, 1493, 1405,
1325, 1279, 1228, 1210, 1170, 1146, 1104, 1092, 1071, 1018 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6)
d
7.19 (d, J¼8.5 Hz, 2H, Ar), 7.38 (d,
J¼8.4 Hz, 2H, Ar), 13.18 (br s, 2H, 2OH), 15.87 (s, 1H, NH); 19F NMR
4.6.1. Diethyl
phenyl(5-trifluoromethyl-1,2,3-triazol-4-yl)methyl-
(376 MHz, DMSO-d6þCCl4)
d
ꢁ59.1 (s, CF3); 13C NMR (101 MHz,
enemalonate (6a). Yield 90%, colourless viscous liquid. IR (ATR):
DMSO-d6þCCl4)
d
120.7 (q, 1JC,F¼268.6 Hz, CF3), 128.4, 129.6, 134.0,
3213, 2987, 2941, 1729, 1626, 1517, 1494, 1446, 1393, 1372, 1327,
134.5, 132.8e137.9 (br s, 2C), 135.6, 140.3e144.2 (br s, 3C), 164.2,
166.0. Anal. Calcd for C13H7ClF3N3O4$0.5H2O: C, 42.12; H, 2.18; N,
11.34. Found: C, 42.04; H, 2.09; N, 11.24.
1294, 1251, 1221, 1198, 1162, 1141, 1095, 1071, 1004, 989 cmꢁ1 1H
;
NMR (500 MHz, CDCl3)
d
1.05 (t, J¼7.1 Hz, 3H, Me), 1.14 (t, J¼7.1 Hz,
3H, Me), 4.129 (q, J¼7.1 Hz, 2H, CH2O), 4.132 (q, J¼7.1 Hz, 2H, CH2O),
7.19e7.25 (m, 2H, Ph), 7.31e7.40 (m, 3H, Ph); 19F NMR (376 MHz,
4.7.3. (4-Fluorophenyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)methyl-
enemalonic acid (7c). Yield 92%, mp 216e217 ꢀC (with de-
carboxylation). IR (ATR): 3406, 1714, 1684, 1645, 1604, 1584, 1511,
1405, 1324, 1276, 1243, 1228, 1210, 1164, 1140, 1101, 1070,
CDCl3)
d
ꢁ60.2 (s, CF3); 13C NMR (101 MHz, CDCl3)
d 13.7, 13.8, 62.1,
62.2, 120.5 (q, 1JC,F¼269.3 Hz, CF3), 128.4, 128.7, 130.2, 131.5, 136.6
2
(q, JC,F¼39.2 Hz), 136.7, 142.0, 142.6, 163.9, 165.4. Anal. Calcd for
C
17H16F3N3O4$0.66H2O: C, 51.64; H, 4.42; N, 10.63. Found: C, 51.53;
1017 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.18e7.31 (m, 4H, Ar), 13.46
H, 4.22; N, 10.39.
(br s, 2H, 2OH), 16.13 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d
ꢁ111.3 (br s, F), ꢁ59.0 (s, CF3); 13C NMR (126 MHz, DMSO-d6)
2
1
4.6.2. Diethyl (4-chlorophenyl)(5-trifluoromethyl-1,2,3-triazol-4-yl)
methylenemalonate (6b). Yield 91%, colourless viscous liquid. IR
(ATR): 3212, 2987, 2941, 1729, 1593, 1517, 1491, 1447, 1400, 1372,
d
115.8 (d, JC,F¼21.7 Hz, C-3, C-5); 120.9 (q, JC,F¼268.2 Hz, CF3),
3
130.4 (d, JC,F¼8.8 Hz, C-2, C-6), 133.0e135.5 (br s), 133.2, 133.8,
135.6e136.2 (br s), 142.2e144.4 (br s), 162.7 (d, 1JC,F¼247.9 Hz, C-4),
Please cite this article in press as: Usachev, S. A.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.093

S.A. Usachev et al. / Tetrahedron xxx (2014) 1e9
9
164.5, 166.4. Anal. Calcd for C13H7F4N3O4$0.25H2O: C, 44.65; H,
Supplementary data
2.16; N, 12.02. Found: C, 44.68; H, 2.35; N, 11.92.
2D NOESY experiments for (E)-5b and (Z)-5b; copies of 1H, 19F,
and 13C NMR spectra. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2014.09.093.
4.7.4. (Naphthalen-2-yl)(5-trifluoromethyl-1,2,3-triazol-4-yl)meth-
ylenemalonic acid (7d). Yield 95%, mp 205e207 ꢀC (with de-
carboxylation). IR (ATR): 3401, 1724, 1684, 1576, 1505, 1428, 1394,
1325, 1292, 1274, 1252, 1234, 1186, 1164, 1127, 1103, 1070,
1021 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
7.28 (dd, J¼8.6, 1.7 Hz,
1H, H-3), 7.45e7.60 (m, 2H, H-6, H-7), 7.72 (s, 1H, H-1), 7.82e7.91
References and notes
(m, 3H, H-4, H-5, H-8), 13.13 (br s, 2H, 2OH), 15.90 (s, 1H, NH); 19F
ꢁ59.1 (s, CF3); 13C NMR
1. (a) Benson, F. R.; Savell, W. L. Chem. Rev. 1950, 46, 1e68; (b) Fan, W.-Q.;
Katritzky, A. R. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford, UK, 1996; Vol. 4, pp 1e126.
2. (a) Zhou, L.; Amer, A.; Korn, M.; Burda, R.; Balzarini, J.; De Clercq, E.; Kern, E. R.;
Torrence, P. F. Antiviral Chem. Chemother. 2005, 16, 375e383; (b) Aher, N. G.;
Pore, V. S.; Mishra, N. N.; Kumar, A.; Shukla, P. K.; Sharma, A.; Bhat, M. K. Bioorg.
Med. Chem. Lett. 2009, 19, 759e763; (c) Bochis, R. J.; Chabala, J. C.; Harris, E.;
Peterson, L. H.; Barash, L.; Beattie, T.; Brown, J. E.; Graham, D. W.; Waksmunski,
F. S. J. Med. Chem. 1991, 34, 2843e2852; (d) El-Sayed, W. A.; Abdel-Rahman, A.
A.-H. Z. Naturforsch. 2010, 65b, 57e66; (e) Kim, D.-K.; Kim, J.; Park, H.-J. Bioorg.
Med. Chem. Lett. 2004, 14, 2401e2405; (f) Hlasta, D. J.; Ackerman, J. H. J. Org.
Chem. 1994, 59, 6184e6189.
NMR (376 MHz, DMSO-d6þCCl4)
d
(101 MHz, DMSO-d6þCCl4)
d
120.7 (q, 1JC,F¼268.3 Hz), 125.0, 126.4,
126.9, 127.4, 127.6, 127.8, 128.2, 132.2, 132.9, 133.4e135.3 (br s),
133.8, 134.4, 136.4e138.6 (br s), 142.0e143.8 (br s), 164.3, 166.3.
Anal. Calcd for C17H10F3N3O4$H2O: C, 51.65; H, 3.06; N, 10.63.
Found: C, 51.76; H, 3.24; N, 10.63.
4.8. Compounds 9 and 10
3. (a) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071e1081; (b) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320e330; (c) Orga-
nofluorine Compounds in Medicinal Chemistry and Biomedical Applications; Filler,
R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, The Netherlands,
1993; (d) Hiyama, T. Organofluorine Compounds: Chemistry and Applications;
Springer: Berlin, Germany, 2000; (e) Black, J.; Boehmer, J. E.; Chrystal, E. J. T.;
Kozakiewicz, A. M.; Plant, A. WO 2007/071900, 2007; Chem. Abstr. 2007,147, 66070.
4. (a) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J. Org. Lett. 2005, 7, 1469e1472;
(b) Wei, J.; Chen, J.; Xu, J.; Cao, L.; Deng, H.; Sheng, W.; Zhang, H.; Cao, W. J.
Fluorine Chem. 2012, 133, 146e154; (c) Meazza, G.; Zanardi, G. J. Fluorine Chem.
1991, 55, 199e206; (d) Kobayashi, Y.; Yamashita, T.; Takahashi, K.; Kuroda, H.;
Kumadaki, I. Chem. Pharm. Bull. 1984, 32, 4402e4409; (e) Xiong, Z.; Qiu, X.-L.;
Huang, Y.; Qing, F.-L. J. Fluorine Chem. 2011, 132, 166e174; (f) Zhang, C.-T.;
Zhang, X.; Qing, F.-L. Tetrahedron Lett. 2008, 49, 3927e3930; (g) Fu, D.; Zhang, J.;
Cao, S. J. Fluorine Chem. 2013, 156, 170e176.
4.8.1. 2,4-Dioxo-4-(5-trifluoromethyl-1,2,3-triazol-4-yl)butanoic
acid (9). To a solution of 6-(trifluoromethyl)comanic acid 8 (0.1 g,
0.48 mmol) in DMSO (1 mL), NaHCO3 (40 mg, 0.48 mmol) was
added. After completion of CO2 evolution, NaN3 (34 mg, 0.52 mmol)
was added and the reaction mixture was heated at 120 ꢀC for 3.5 h,
then cooled to room temperature and acidified with an aqueous
5 M HCl solution to give the product 9 as a colourless solid. Yield
0.016 g (13%), mp 192e194 ꢀC. 1H NMR (400 MHz, DMSO-d6)
(s, 2H, CH2, keto), 7.11 (s, 1H, ]CH, enol), 11.7e14.7 (br s, OH),
15.6e16.6 (br s, 1H, NH); 19F NMR (376 MHz, DMSO-d6)
d 4.45
d
ꢁ60.8 (s,
CF3, keto), ꢁ60.3 (s, CF3, enol). We were unable to isolate this
compound in an analytically pure state.
5. (a) Stazi, F.; Cancogni, D.; Turco, L.; Westerduin, P.; Bacchi, S. Tetrahedron Lett.
2010, 51, 5385e5387; (b) Rozin, Y. A.; Leban, J.; Dehaen, W.; Nenajdenko, V. G.;
Muzalevskiy, V. M.; Eltsov, O. S.; Bakulev, V. A. Tetrahedron 2012, 68, 614e618;
(c) Bonacorso, H. G.; Moraes, M. C.; Wiethan, C. W.; Luz, F. M.; Meyer, A. R.;
Zanatta, N.; Martins, M. A. P. J. Fluorine Chem. 2013, 156, 112e119; (d) Peng, W.;
Zhu, S. Tetrahedron 2003, 59, 4395e4404; (e) Zhang, J.; Jin, G.; Xiao, S.; Wu, J.;
Cao, S. Tetrahedron 2013, 69, 2352e2356; (f) Seus, N.; Gonc¸ alves, L. C.; Deobald,
4.8.2. 1-(5-Trifluoromethyl-1,2,3-triazol-4-yl)ethanone (10). To a so-
lution of 6-(trifluoromethyl)comanic acid 8 (0.1 g, 0.48 mmol) in 90%
ethanol (1.5 mL), NaHCO3 (40 mg, 0.48 mmol) was added. After
completion of CO2 evolution, NaN3 (63 mg, 0.97 mmol) was added
and the reaction mixture was refluxed for 40 h, then cooled to room
temperature and saturated with gaseous HCl. The solvent was then
evaporated and the product was separated by hot extraction with
toluene. The most amount of toluene was then evaporated to give
the product 10 as a colourless solid. Yield 0.036 g (42%), mp
125e127 ꢀC. The product contains a small amountof toluene (ca. 3%),
which is difficult to remove because of its sublimation at elevated
temperatures. It can be recrystallized for elemental analysis with
a high loss from a small amount of water. IR (ATR): 3124, 3009, 2926,
2871, 2828, 2748,1684,1516,1445,1366,1330,1309,1193,1157,1047,
~
A. M.; Savegnago, L.; Alves, D.; Paixao, M. W. Tetrahedron 2012, 68,
10456e10463; (g) Iminov, R. T.; Mashkov, A. V.; Chalyk, B. A.; Mykhailiuk, P. K.;
Tverdokhlebov, A. V.; Tolmachev, A. A.; Volovenko, Y. M.; Shishkin, O. V.;
Shishkina, S. V. Eur. J. Org. Chem. 2013, 2891e2897; (h) Danence, L. J. T.; Gao, Y.;
Li, M.; Huang, Y.; Wang, J. Chem.dEur. J. 2011, 17, 3584e3587; (i) Peng, W.; Zhu,
S. Synlett 2003, 187e190; (j) Peng, W.; Zhu, S. J. Fluorine Chem. 2002, 116, 81e86.
6. (a) Ye, C.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley, B.; Shreeve, J. M. Org.
Lett. 2007, 9, 3841e3844; (b) Crossman, J. M.; Haszeldine, R. N.; Tipping, A. E. J.
Chem. Soc., Dalton Trans. 1973, 483e486; (c) Sibgatulin, D. A.; Bezdudny, A. V.;
Mykhailiuk, P. K.; Voievoda, N. M.; Kondratov, I. S.; Volochnyuk, D. M.; Tol-
machev, A. A. Synthesis 2010, 1075e1077; (d) Bandera, Y. P.; Kanishchev, O. S.;
Timoshenko, V. M.; But, S. A.; Nesterenko, A. M.; Shermolovich, Y. G. Chem.
Heterocycl. Compd. 2007, 43, 1138e1147.
986, 962, 859 cmꢁ1; 1H NMR (500 MHz, DMSO-d6)
d 2.61 (s, 3H, Me),
7. (a) Sosnovskikh, V. Y.; Usachev, B. I. Mendeleev Commun. 2002, 12, 75e76; (b)
Greif, D.; Eilitz, U.; Pulst, M.; Riedel, D.; Wecks, M. J. Fluorine Chem. 1999, 94,
91e103; (c) Bargamov, G. G.; Bargamova, M. D. Russ. Chem. Bull.1998, 47,192e193;
(d) Fahey, J. L.; Firestone, R. A.; Christensen, B. G. J. Med. Chem.1976, 19, 562e565.
15.5e17.5 (br s, 1H, NH); 19F NMR (471 MHz, DMSO-d6)
d
ꢁ60.5 (s,
CF3); 13C NMR (101 MHz, DMSO-d6)
d
30.0, 120.6 (q, 1JC,F¼268.8 Hz,
CF3),136.1 (q, 2JC,F¼39.7 Hz),142.9,190.8. Anal. Calcd for C5H4F3N3O:
€
8. Usachev, B. I.; Usachev, S. A.; Roschenthaler, G.-V.; Sosnovskikh, V. Y. Tetrahe-
dron Lett. 2011, 52, 6723e6725.
9. (a) Usachev, B. I.; Obydennov, D. L.; Roschenthaler, G.-V.; Sosnovskikh, V. Y. Org.
C, 33.53; H, 2.25; N, 23.46. Found: C, 33.78; H, 2.25; N, 23.32.
€
Lett. 2008, 10, 2857e2859; (b) Usachev, S. A.; Usachev, B. I.; Sosnovskikh, V. Y.
Tetrahedron 2014, 70, 60e66; (c) Yeh, P.-P.; Daniels, D. S. B.; Cordes, D. B.;
Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2014, 16, 964e967.
4.9. General procedure for the synthesis of compounds 12aed
10. (a) Ram, V. J.; Srivastava, P. Curr. Org. Chem. 2001, 5, 571e599; (b) Goel, A.; Ram,
V. J. Tetrahedron 2009, 65, 7865e7913.
11. Nabeya, A.; Culp, F. B.; Moore, J. A. J. Org. Chem. 1970, 35, 2015e2021.
12. Bartoli, G.; Beleggia, R.; Giuli, S.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.;
Paoletti, M. Tetrahedron Lett. 2006, 47, 6501e6504.
A solution of chromone 11 (0.25 mmol) and NaN3 (18 mg,
0.28 mmol) in DMSO (1 mL) was heated at 120 ꢀC for 30 min. The
reaction mixture was then cooled to room temperature and acidi-
fied with an aqueous HCl solution (1:1) to give the product 12 as
yellow solid in an excellent yield (Scheme 6). All properties of 4-
salicyloyl-5-trifluoromethyl-1,2,3-triazoles 12 were in good agree-
ment with the literature data.7a
13. Nigmatov, A. G.; Kornilova, I. N.; Serebryakov, E. P. Russ. Chem. Bull. 1996, 45,
144e152.
14. (a) Dong, Z.; Hellmund, K. A.; Pyne, S. G. Aust. J. Chem. 1993, 46, 1431e1436; (b)
Timoshenko, V. M.; Nikolin, Y. V.; Chernega, A. N.; Rusanov, E. B.; Shermolovich, Y.
G. Chem. Heterocycl. Compd. 2001, 37, 470e476; (c) Wang, T.; Hu, X.-C.; Huang, X.-
J.; Li, X.-S.; Xie, J.-W. J. Braz. Chem. Soc. 2012, 23, 1119e1123; (d) Augustine, J. K.;
Boodappa, C.; Venkatachaliah, S. Org. Biomol. Chem. 2014, 12, 2280e2288; (e)
Ponpandian, T.; Muthusubramanian, S. Tetrahedron Lett. 2012, 53, 59e63.
15. (a) Usachev, B. I.; Obydennov, D. L.; Sosnovskikh, V. Y. J. Fluorine Chem. 2012,
135, 278e284; (b) Usachev, B. I.; Obydennov, D. L.; Kodess, M. I.; Sosnovskikh,
V. Y. Tetrahedron Lett. 2009, 50, 4446e4448; (c) Usachev, B. I.; Bizenkov, I. A.;
Sosnovskikh, V. Y. Russ. Chem. Bull., Int. Ed. 2007, 56, 558e559.
Acknowledgements
This work was financially supported by the Russian Science
Foundation (Grant 14-13-00388) and by the Ural Federal University
(Program of Support of Young Scientists).
Please cite this article in press as: Usachev, S. A.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.093