A simple and convenient synthesis of 3-[5-(trifluoromethyl)-1,2,3-triazol- 4-yl]cinnamic acids from 4-aryl-6-(trifluoromethyl)-2H-pyran-2-ones and sodium azide

Article abstract of DOI:10.1016/j.tetlet.2011.09.149

4-Aryl-6-(trifluoromethyl)-2H-pyran-2-ones and ethyl 4-aryl-6- (trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates react with sodium azide to produce highly functionalized CF₃-1,2,3-triazoles: 3-[5-(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acid

Full text of DOI:10.1016/j.tetlet.2011.09.149

Tetrahedron Letters 52 (2011) 6723–6725
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Tetrahedron Letters
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A simple and convenient synthesis of
3-[5-(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acids from 4-aryl-6-(tri-
fluoromethyl)-2H-pyran-2-ones and sodium azide
Boris I. Usachev a, , Sergey A. Usachev a, Gerd-Volker Röschenthaler b, Vyacheslav Ya. Sosnovskikh a
⇑
a Department of Chemistry, Ural Federal University, pr. Lenina 51, Ekaterinburg 620083, Russia
b School of Engineering and Science, Jacobs University Bremen gGmbH, Campus Ring 1, Bremen 28759, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 15 October 2011
4-Aryl-6-(trifluoromethyl)-2H-pyran-2-ones and ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-
3-carboxylates react with sodium azide to produce highly functionalized CF3-1,2,3-triazoles: 3-[5-
(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acids and monoethyl esters of [5-(trifluoromethyl)-1,2,
3-triazol-4-yl]arylmethylidene malonic acids.
Keywords:
Trifluoromethylated 2-pyrones
Sodium azide
Ó 2011 Elsevier Ltd. All rights reserved.
Trifluoromethylated triazoles
Cinnamic acid derivatives
Malonic acid derivatives
1,2,3-Triazoles are an important class of heterocyclic com-
pounds mainly because of their pharmacological properties includ-
ing antiviral,1a antifungal,1b anticoccidiostatic,1c and other types of
biological activities.1d,e
Reactions of 4-aryl-6-CF3-pyrones 1a–d with NaN3 were con-
ducted in DMSO at 120 °C for 0.5–1.5 h (TLC monitoring) to give
3-[5-(trifluoromethyl)-2H-1,2,3-triazol-4-yl]-cinnamic acids (Z)-
2a–d in 48–86% yields (Scheme 1). The structures of CF3-triazoles
2 were confirmed from 1H, 19F, and 13C NMR, IR spectra, elemental
analysis, and X-ray diffraction experiments. In the 1H NMR spectra
(DMSO-d6) of compounds 2 the vinyl proton appeared as a singlet
in the range of d 6.8–7.0. Two broad signals due to the labile pro-
tons (NH and CO2H) at about d 12.7 and 16.0 were observed. In
the 19F NMR spectra (DMSO-d6, C6F6) of products 2 the CF3 group
appeared as a singlet at about d 103.3. In the 13C NMR spectrum
N-Unsubstituted 4-(trifluoromethyl)-1,2,3-triazoles are a small
and poorly explored group of compounds.2,3 It is known that the
cycloaddition of trimethylsilyl azide with 3,3,3-trifluoropropyne
gives 4-(trifluoromethyl)-1,2,3-triazole.2a Alternatively, this
compound can be obtained from trifluoroacetonitrile and (diazom-
ethyl)trimethylsilane,2b from 1,2,3-triazole-4-carboxylic acid and
SF4,2c and from 1,1-dihydroperfluoropropyl sulfones.2d 5-Substi-
tuted 4-(trifluoromethyl)-1,2,3-triazoles can be synthesized from
azides and various dipolarophiles,3a–c by the oxidation of
1,1,1,5,5,5-hexafluoro-4-trifluoromethylpentane-2,3-dione dihy-
drazone,3d and by the cycloaddition of diazomethylene compounds
with trifluoroacetonitrile.3e,f
On the other hand, 2H-pyran-2-ones are a group of biologically
interesting compounds, which exhibit diverse biological properties
including hepatoprotective,4a antitumor,4b and antifungal.4c
Although much attention has been paid to the chemistry of 2-pyr-
ones, mainly due to their use as excellent building blocks for the
preparation of a variety of complex heterocyclic compounds,5 their
reactions with azides have not been described in the literature.
In this Letter, we describe the synthesis of a series of N-unsub-
stituted 4-(trifluoromethyl)-1,2,3-triazoles from 4-aryl-6-(trifluo-
romethyl)-2H-pyran-2-ones6 and sodium azide.
1
of 2a two characteristic quartets at d 121.2 (CF3, JC,F = 268.0 Hz)
2
and 134.3 (C-5, JC,F = 39.0 Hz) were observed confirming the CF3-
triazole structure. It should be noted that compounds 2 were
isolated in isomerically pure forms (no signals due to trace
amounts of E-isomers were found in the NMR spectra). X-ray dif-
fraction analysis of 2c confirmed unambiguously the Z-isomeric
structures of compounds 2 ( Fig. 1). According to the X-ray
Ar
Ar
NaN3, DMSO, 120 oC,
0.5-1.5 h
N
HN
CO2H
CF3
(Z)-2a-d
N
48-86%
F3C
O
1a-d
O
c
d
a
b
4F-C6H4 4Cl-C6H4
Ar Ph
2-naphthyl
⇑
Corresponding author. Tel.: +7 343 261 6824; fax: +7 343 261 5978.
E-mail address: boris.usachev@mail.ru (B.I. Usachev).
Scheme 1. Synthesis of CF3-triazoles 2a–d.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.149

6724
B. I. Usachev et al. / Tetrahedron Letters 52 (2011) 6723–6725
diffraction data, compound 2c exists in the 2H-triazole forms in the
solid state.
Ar
Ar
NaN3, EtOH-H2O, reflux,
4-5 h
CO2Et
CO2H
CO2Et
O
N
A tentative mechanism for the formation of CF3-triazoles 2 can
involve either nucleophilic attack by the azide ion at the CF3 acti-
vated carbon C-6, which is followed by cyclization of the interme-
diate vinyl azide7a into the triazoles, or cycloaddition between the
azide ion and the CF3-pyrones.7b
HN
N
36-86%
F3C
O
CF3
3a-d
(E)-4a-d
+
Ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxyl-
ates 3a–d,6 due to the presence on the pyrone ring of another
activating electron-withdrawing substituent (CO2Et), reacted with
NaN3 under milder conditions (EtOH–H2O, reflux, 4–5 h) leading to
the formation of (E)-2-(ethoxycarbonyl)-3-[5-(trifluoromethyl)-
2H-1,2,3-triazol-4-yl]cinnamic acids (E)-4a–d in 36–86% yields
(Scheme 2). Heating pyrone 1c under reflux in the same medium
for 2 days gave only a 24% yield of triazole 2c. The structures of
CF3-triazoles (E)-4 were confirmed by conventional spectroscopic
methods and elemental analysis. In the 1H NMR spectra the labile
protons of 4 (NH and CO2H), in comparison with those of 2, ap-
peared as broad signals at lower fields in the range d 13.5–13.8
and 16.2–16.3.
Ar
CO2H
CO2Et
N
HN
N
CF3
(Z)-4a,d
c
d
a
b
4F-C6H4 4Cl-C6H4
Ar Ph
2-naphthyl
Scheme 2. Synthesis of CF3-triazoles 4a–d.
Table 1
CF3-triazoles 2a–d and 4a–d produced via Schemes 1 and 28,9
The mechanism of the reaction of 3 with NaN3 is probably sim-
ilar to that proposed above for the formation of 2. However,
according to the NMR spectra, crude compound (E)-4d contained
5% of isomer (Z)-4d, whereas the content of isomer (Z)-4a in crude
triazole (E)-4a reached 23%. Crude compounds 4b,c were obtained
in isomerically pure forms (no signals due to the Z-isomers were
found in the NMR spectra). Isomer (Z)-4a is distinguishable by 1H
NMR spectroscopy due to a small difference between the chemical
shifts of the ethyl protons and the ortho-phenyl protons of (E)-4a
and (Z)-4a. Thus, in the 1H NMR spectrum of 4a the methylene pro-
tons appeared as quartets at d 4.06 (77%) and 4.01 (23%), whereas
the ortho-phenyl protons appeared as doublets of doublets at d
7.13 (77%) and 7.19 (23%). In the 19F NMR spectrum, partially over-
lapping singlets due to the CF3 groups at d 103.6 [(Z)-4a] and 103.7
[(E)-4a] were observed. The use of harsher reaction conditions
(according to Scheme 1: DMSO, 120 °C) for the synthesis of 4
increased the content of side products.
Product
Conditions
Reaction time
Ratio Z:E
Yield (%)
Mp (°C)
2a
2b
2c
2d
4a
4b
4c
4d
A
A
A
A
B
B
B
B
40 min
30 min
1.5 h
1 h
4 h
5 h
100:0
100:0
100:0
100:0
23:77
0:100
0:100
5:95
48
78
86
70
68
82
86
36
72–73
184–186
108–110
187–189
138–139
140–142
181–182
194–197
5 h
4 h
(A) DMSO, NaN3 (1.1 equiv), 120 °C; (B) EtOH–H2O, NaN3 (1.1 equiv), reflux.
of these highly functionalized CF3-triazoles is of interest for the
development of the chemistry of trifluoromethylated and other
RF-bearing 2-pyrones.
A possible reason for the isomerization of (E)-4 into (Z)-4 can be
explained by the push–pull nature of triazoles 4. Electron-donating
aromatic substituents (Ar = Ph, 2-naphthyl) should decrease the
bond order between the methylidene carbons leading to the rota-
tion (isomerization) of (E)-4.
Acknowledgements
The authors thank the Deutsche Forschungsgemeinschaft
(Grant No. RO 362/45-1) and Ural Federal University for financial
support.
The results and conditions used for the synthesis of the 1,2,3-
triazoles 2 and 4 are presented in Table 1.
References and notes
In summary, reactions of 6-CF3-2-pyrones with sodium azide
have been described for the first time. These reactions represent
an efficient approach to 3-[5-(trifluoromethyl)-2H-1,2,3-triazol-4-
yl]cinnamic acids and monoethyl esters of [5-(trifluoromethyl)-
2H-1,2,3-triazol-4-yl]arylmethylidene malonic acids. The synthesis
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Pore, V. S.; Mishra, N. N.; Kumar, A.; Shukla, P. K.; Sharma, A.; Bhat, M. K. Bioorg.
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2. (a) Ye, C.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley, B.; Shreeve, J. M.
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Tolmachev, A. A. Synthesis 2010, 1075; (d) Bandera, Y. P.; Kanishchev, O. S.;
Timoshenko, V. M.; But, S. A.; Nesterenko, A. M.; Shermolovich, Y. G. Chem.
Heterocycl. Compd. 2007, 43, 1138.
3. (a) Sosnovskikh, V. Ya.; Usachev, B. I. Mendeleev Commun. 2002, 75; (b) Black, J.;
Boehmer, J. E.; Chrystal, E. J. T.; Kozakiewicz, A. M.; Plant, A. PCT Int. Appl.
071900, 2007; Chem. Abstr. 2007, 147, 66070.; (c) Greif, D.; Eilitz, U.; Pulst, M.;
Riedel, D.; Wecks, M. J. Fluorine Chem. 1999, 94, 91; (d) Bargamov, G. G.;
Bargamova, M. D. Russ. Chem. Bull. 1998, 47, 192; (e) Fahey, J. L.; Firestone, R. A.;
Christensen, B. G. J. Med. Chem. 1976, 19, 562; (f) Firestone, R. A.; Fahey, J. L.;
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Chem. Lett. 2011, 21, 2341–2344; (c) Parker, S. R.; Cutler, H. G.; Jacyno, J. M.;
Hill, R. A. J. Agric. Food Chem. 1997, 45, 2774–2776.
Figure 1. Molecular structure of 2c (ORTEP diagram).

B. I. Usachev et al. / Tetrahedron Letters 52 (2011) 6723–6725
6725
5. Goel, A.; Ram, V. J. Tetrahedron 2009, 65, 7865–7913.
6. Usachev, B. I.; Obydennov, D. L.; Röschenthaler, G.-V.; Sosnovskikh, V. Ya. Org.
Lett. 2008, 10, 2857.
7. (a) Timoshenko, V. M.; Nikolin, Ya. V.; Chernega, A. N.; Rusanov, E. B.;
Shermolovich, Yu. G. Chem. Heterocycl. Compd. 2001, 37, 470; (b) Peng, W.; Zhu,
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anisotropically, and hydrogen atoms were located and included at their
calculated position. The CCDC deposition number is 829227. Unit cell
parameters: a = 8.1891(7), b = 10.7147(13), c = 16.8085(19),
b = 87.222(8), = 87.372(8). The crystal system is triclinic; space group P1.
9. General procedure; (E)-2-(ethoxycarbonyl)-3-[5-(trifluoromethyl)-2H-1,2,3-
triazol-4-yl]cinnamic acids [(E)-4]. solution of (0.58 mmol) and NaN3
a = 79.363(10),
ꢀ
c
A
3
8. General procedure; [5-(Trifluoromethyl)-2H-1,2,3-triazol-4-yl]cinnamic acids
[(Z)-2]. A solution of 1 (0.73 mmol) and NaN3 (52 mg, 0.80 mmol) in DMSO
(2 mL) was heated at 120 °C for 0.5–1.5 h (see Table 1). The reaction mixture
was cooled to rt and diluted with 7% aqueous HCl (8 mL) and the viscous liquid
residue was separated by decantation. The crude products were crystallized
from toluene or a mixture of toluene and petroleum ether to give (Z)-2 as white
or slightly yellow solids.
(43 mg, 0.64 mmol) in 85% aqueous EtOH (2 mL) was refluxed for 4–5 h (see
Table 1). Then the reaction mixture was cooled to rt and diluted with 7%
aqueous HCl (8 mL) and the viscous liquid residue was separated by
decantation. The crude products were crystallized from toluene or a mixture
of toluene and petroleum ether to give (E)-4 as white or slightly yellow solids.
(E)-2-(Ethoxycarbonyl)-3-[5-(trifluoromethyl)-2H-1,2,3-triazol-4-yl]-40-fluoro-
cinnamic acid [(E)-4b]. Yield 82%, mp 140–142 °C, white solid (toluene). 1H
NMR (400 MHz, DMSO-d6) d 1.02 (t, 3H, Me, J = 7.1 Hz), 4.09 (q, 2H, CH2,
J = 7.1 Hz), 7.15–7.21 (m, 2H, arom.), 7.26 (t, 2H, arom., J = 8.8 Hz), 13.5 (br s,
1H, NH), 16.2 (br s, 1H, CO2H); 19F NMR (376.5 MHz, DMSO-d6, C6F6) d 61.7
(obscured m, 1F, arom.), 103.6 (s, CF3); 13C NMR (100 MHz, DMSO-d6) d 13.4,
61.3, 115.8 (d, JC,F = 22.1 Hz); 120.8 (q, CF3, JC,F = 268.4 Hz), 130.3 (d,
JC,F = 8.8 Hz), 132.3, 132.9, 134.1 (q, C-5, JC,F = 38.2 Hz), 137.8, 161.7, 163.7,
164.0, 164.9. Anal. Calcd for C15H11F4N3O4ꢀ0.5H2O: C, 47.13; H, 3.16; N,
10.99. Found: C, 47.38; H, 2.86; N, 10.87.
5-(Trifluoromethyl)-2H-1,2,3-triazol-4-ylcinnamic acid [(Z)-2a]. Yield 48%, mp
72–73 °C, white solid (toluene-petroleum ether). 1H NMR (400 MHz, DMSO-d6)
d 6.80 (s, 1H, CH), 7.31 (dd, 2H, Ph, J = 7.8, 1.5 Hz), 7.38–7.47 (m, 3H, Ph), 12.7
(br s, 1H, NH), 15.8 (br s, 1H, CO2H); 19F NMR (376.5 MHz, DMSO-d6, C6F6) d
1
103.3 (s, CF3); 13C NMR (100 MHz, DMSO-d6) d 121.2 (q, CF3, JC,F = 268.0 Hz),
2
123.8, 126.8, 129.0, 130.2, 134.3 (q, C-5, JC,F = 39.0 Hz), 136.8, 139.8; 139.9,
165.5. Anal. Calcd for C12H8F3N3O2ꢀH2O: C, 47.85; H, 3.35; N, 13.95. Found: C,
48.05; H, 3.26; N, 13.60. The structure was solved from X-ray data by direct
methods using the SHELXS-97 program and refined by full matrix least-squares
on F2 with the SHELXL-97 program.10 All non-hydrogen atoms were refined
10. Sheldrick, G. M. The SHELX-97 manual–Göttingen (Germany): University of
Göttingen, 1997.