Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazoles via CF 3-directed cyclization of 1-trifluoromethyl-1,3-dicarbonyl compounds with azides

Article abstract of DOI:10.1016/j.tet.2011.10.110

1-Trifluoromethyl-substituted 1,3-dicarbonyl compounds are shown to undergo 100% regioselective cyclization in reactions with alkyl and aryl azides to form 4-acyl-5-trifluoromethyl-1,2,3-triazoles. The reaction represents a general method for the synthesi

Full text of DOI:10.1016/j.tet.2011.10.110

Tetrahedron 68 (2012) 614e618
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazoles via CF3-directed
cyclization of 1-trifluoromethyl-1,3-dicarbonyl compounds with azides
Yury A. Rozin a, Johann Leban b, Wim Dehaen c, Valentine G. Nenajdenko d, Vasiliy M. Muzalevskiy d,
,
Oleg S. Eltsova, Vasiliy A. Bakulev a
*
a Laboratory of Technology for Organic Synthesis, Ural Federal University named after first Russian President B.N. Eltsin, 620002 Ekaterinburg, Russia
b 4sc Am Klopferspitz 19, D-82152 Planegg, Germany
c Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
d Moscow State University, Department of Chemistry, Moscow 119992, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2011
Received in revised form 14 October 2011
Accepted 31 October 2011
Available online 6 November 2011
1-Trifluoromethyl-substituted 1,3-dicarbonyl compounds are shown to undergo 100% regioselective
cyclization in reactions with alkyl and aryl azides to form 4-acyl-5-trifluoromethyl-1,2,3-triazoles. The
reaction represents a general method for the synthesis of otherwise difficulty available 4-acyl-5-
trifluoromethyl-1,2,3-triazoles. The directing role of the trifluoromethyl group is discussed in the light
of stepwise and concerted mechanisms for this reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1-Trifluoromethyl-1,3-dicarbonyl
compounds
Azides
[3þ2] Cycloaddition
4-Acyl-5-trifluoromethyl-1,2,3-triazoles
1. Introduction
derivatives with different substituents including alkyl, aryl,
amino, hydroxy, cyano, various carbonyl functions in positions 4
1,2,3-Triazoles are an important class of compounds with in-
creasing importance in diverse research areas, ranging from me-
dicinal chemistry or crop protection to material sciences.1
Furthermore these substances have been shown to be valuable
amide surrogates in bioactive molecules, because of their physi-
cochemical properties and remarkable metabolic stability.1,2 Al-
though 1,2,3-triazoles are not naturally occurring compounds, the
‘amideetriazole bioequivalence’ was exploited for the de-
velopment of HIV-1 protease inhibitors,3 potential anticancer
agents,1,4 and non-nucleoside reverse transcriptase inhibitors.5 As
a result, triazole forming reactions have recently enjoyed much
attention, particularly those based on the ‘click reaction’ strategy,
which is the copper catalyzed cycloaddition of alkynes and azides.
This reaction has been widely used in bioconjugate chemistry due
to its outstanding chemoselectivity and mild conditions.6
and 5 and alkyl, benzyl, and aryl groups in position 1 of the het-
erocycle. Often, the presence of a cyano or ester group in the active
methylene 1 can afford a single 5-amino or 5-hydroxy triazole
regioisomer (e.g., 3, 4).7 However, only symmetrical 1,3-diketones 1
(R1¼R2¼COR with R¼alkyl or aryl) afford single 4-acyl-1,2,3-
triazoles 2 (Y¼COR) in high yields.7 In the case of nonsymmetrical
diketones, the formation of a mixture of two regioisomers takes
place (Scheme 1).8
X = COR
X = CN
X = COOR (R = H; alkyl)
Y
Y
Y
N
N
N
ZN3
N
N
Z
N
N
R
X
Y
OH
N
NH2
N
Z
Z
2
3
1
4
Base catalyzed reactions of azides with active methylene com-
pounds do also represent a powerful, though less developed, ap-
proach to a variety of monocyclic and bicyclic 1,2,3-triazole
Scheme 1. Reactions of azides with active methylene compounds.
Fluorinated heterocyclic compounds are a very promising class
of organic chemicals widely used in modern pharmacology, me-
dicinal and materials chemistry, agriculture, and other fields.9 On
the other hand, the 5-trifluoromethyl-1,2,3-triazoles moiety is
quite poorly presented in the literature, especially analogs having
* Corresponding author. Tel.: þ73433745483; fax: þ73433754135; e-mail
addresses: vasiliy.bakulev@toslab.com, bakulev@mail.ustu.ru (V.A. Bakulev).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.110

Y.A. Rozin et al. / Tetrahedron 68 (2012) 614e618
615
Table 1
functional groups at the 4-position. Thus, for instance, to the best of
Synthesis of 4-acyl-5-trifluoro-1,2,3-triazoles 7
our knowledge only very few examples of 4-acyl-5-
trifluoromethyl-1,2,3-triazole synthesis has been reported so far.10
Triazole 7
R1
R2
Yield, %
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
r
CH3
CH3
CH3
CH3
CH3
Ph
p-BrC6H4
p-MeOC6H4
CH3
2-Thienyl
Ph
2-Thienyl
p-MeOC6H4
Ph
2-Thienyl
CH3
Ph
63
69
71
66
12
56
77
95
9
83
87
87
92
46
51
48
41
m-ClC6H4
p-NO2C6H4
p-ClC6H4
p-MeOC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
PhCH2
p-ClC6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2CO2Et
2. Results
In order to elaborate a general and convenient method for the
synthesis of 5-fluoroalkylated-1,2,3-triazoles we have studied re-
action of 1-trifluoromethyl-1,3-dicarbonyl compounds 5 with ali-
phatic and aromatic azides 6. We have found that the reaction of
compounds 5 with azides 6 in the presence of various bases, such as
triethylamine, sodium ethoxide, and potassium carbonate pro-
ceeded with 100% regioselectivity. As a result, 4-acyl-5-trifluoro-
1,2,3-triazoles 7 were isolated in good yields as the only isomer. The
protocol of choice includes heating of equimolar amounts of dike-
tone 4 and azide 5 in the presence of triethylamine at 70e80 ꢀC
during 5 h. It should be noted, that the solventless reaction condi-
tions as practiced here, are economically and environmentally
beneficial, while usually proceeding smoothly and faster. The use of
any solvents and other bases lowers the yield of the target products
and results in the formation of tar-like reaction mixtures (Scheme 2).
OEt
carbonyl group to form triazoline AH. Elimination of water to form
the final product, triazole 7, is the last step of both mechanisms.
The effect of increasing of the reaction rate by introduction of
electron-withdrawing substituents on the aryl azides is in agree-
ment with all three mechanisms. In the same way, the reaction rate
is lowered by electron-withdrawing substituents on the nucleo-
philic part (as in hexafluoroacetylacetone). Compounds 7 with
electron rich substituents (entries 7h, 7j, 7l, 7m) gave very good
yields, on the other hand. The monitoring of the reaction mixture
by TLC and 19F NMR spectroscopy did not show any intermediate
products other than triazole 7 and the starting materials.
O
O
CF3
R1
R1
CF3
N
O
O
N
Et3N
N
R2 N3
N
F3C
R1
N
N
70-80 °C
R2
8 not formed
R2
5
6
7
Scheme 2. Reaction of 1-trifluoromethyl-1,3-dicarbonyl compounds 5 with azides 6.
The study of 13C NMR spectra of 1,1,1-trifluoropentane-1,4-dione
in chloroform before and after addition of triethylamine shown,
that the signals of C-5 and C-1 are downfield shifted and signals of
C-2 and C3 are strongly (4e8 ppm) upfield shifted (Scheme 3). It
gave us evidence that first step of the overall process includes
deprotonation of diketones 5 under treatment with triethylamine.
Moreover, the appearance of single set of signals corresponding to
only one enolate formed is in good agreement with extraordinary
regioselectivity of the reaction of CF3-diones with azides.
The reaction has a general character allowing the use of mani-
fold of both azides and 1,3-dicarbonyl compounds. Thus, azides
bearing alkyl, benzyl, and aryl substituents and 1,3-dicarbonyl
compounds with acetyl, benzoyl, and heteroaryl moieties were
successfully involved. To our regret, hexafluoroacetylacetone
(R1¼CF3) did not react with aryl- and alkylazides even at elevated
temperature. One can explain that by the highly specific reactivity
and low nucleophilicity of this polyfluorinated diketone.
The structures of triazoles 7aee were confirmed by a combina-
tion of NMR- and mass-spectroscopic data. Although 1H and 19F
NMR spectra as well as mass-spectra are in accordance with both
isomeric triazoles 7 and 8, 13C NMR broadband spectra prove the
structure of 5-trifluoromethyl 1,2,3-triazole 7. Indeed, we observed
The data of our experiments allow us to make the conclusion
that the trifluoromethyl group directs the reaction of compound 5
with azides to a pathway where the aryl substituted nitrogen atom
of the azides reacts with the trifluoroacetyl rather than the acyl
group. Within the framework of pathways 1 and 2 the observed
regioselectivity can be explained by selective enolization of tri-
fluoromethyl ketone fragment to form enolate with double bond
conjugated to the CF3 group, that is, in agreement with literature
data and our experimental observations.11
In fact, pathways 1 and 2 have more common features than
differences and includes pericyclic reactions: heterocycloaddition
or heteroelectrocyclization12 for the formation of the 1,2,3-triazole
ring. Though the pathway 2 is stepwise, the intermediate B is not
likely to be isolated because of its fast cyclization to triazoline A.
The common thing for both mechanisms is the preferable forma-
tion of a new CeN bond between the N1 azide atom and the carbon-
2 atom of the trifluoroacetyl group. Since the selectivity of the re-
action also depends on the nature of the substituent R1 (see7a) we
propose that depending on the substituents both ways 1 and 2 are
possible. Both pathways 1 and 2 are terminated by elimination of
water from triazoline to form final products 7.
2
a quadruplet at 127 ppm with coupling constant JCF¼42 Hz (C-5)
and
a
singlet corresponding to the carbonyl group at
191.2e191.5 ppm in 13C NMR, that can only fit to structure 7 and
disagree completely with the structure of 4-trifluoromethyl-1,2,3-
triazole 8. Furthermore, in the 13C NMR spectra of triazoles 7neq,
derived from ethyl azidoacetate, a quadruplet at w52 ppm with
coupling constant 4JCF¼2.2e2.9 Hz (CH2) was registered, that addi-
tionally confirmed the choice of the regioisomeric structure 7.
The yields of the prepared triazoles 7 depend mainly on the
nature of substituents R2 (Table 1). Thus the use of azides bearing
electron withdrawing groups, such as 4-nitrophenyl and 4-
chlorophenyl affords the triazoles 7bed,h in high yields. On the
contrary, triazoles 7a,e,f bearing phenyl, p-methoxyphenyl or es-
pecially benzyl groups in position 1 were obtained in lower yields.
The structure of the triazoles formed and the reaction charac-
teristics give some information about the mechanism of the re-
action. One of the possible mechanisms for the cyclizations of
azides with 1,3-dicarbonyl compounds leading to 1,2,3-triazoles is
the concerted [3þ2] Huisgen cycloaddition reaction.7,8 However,
still in earlier studies7a another mechanism was proposed for this
reaction including the formation of triazene type intermediate BH,
followed by nucleophilic addition of the NH fragment to the
On the other hand, the CF3CO group is more electrophilic than
acyl group. However, it has been shown previously that the cycli-
zation of hydrazine derivatives (which are structurally similar to
postulated intermediate triazenes BH) to form pyrazoles proceeds
selectively. Thus, the hydrazine nitrogen attacks the acetyl rather
than the trifluoroacetyl group to give pyrazoles bearing

616
Y.A. Rozin et al. / Tetrahedron 68 (2012) 614e618
O
N
O
O
R1
R1
F3C
O
R2
F3C
R2
N
N
Cycloaddition
N
N
path 1
N
119.5 (+2.3)ppm
R1 = Me: 29.8(+5)ppm
O
O
R1
O
O
R1
R2N3
O
O
F3C
R2
F3C
HO
Et3
N
E1cB
F3C
R1
R1
N
F3C
N
H
path 2
H+
N
N
N
N
N
R2
N
A
N
7
N
R2
B
168.1 (-8) ppm
92.4(-4) ppm
194.6 (+0.4)ppm
Electrocyclization
+H-shift
H+
O
H
N
O
O
R1
F3C
HO
R2
F3C
R1
H
N
2 N
path 3
R
N
BH
N
AH
Nucleophilic addition
O
O
O
O
O
RNHNH2
F3C
F3C
R
F3C
N
H
N
N
OEt
NHR
Scheme 3.
a trifluoroacetyl moiety.13 Therefore the mechanism based on nu-
cleophilic addition step (path 3) can be seen as less likely to occur.
The absence of any detected intermediates in the reaction mixture
by both TLC and 19F NMR spectra also supports this conclusion
because of triazenes have been found to be relatively stable com-
pounds.14 Further elucidation of the reasons of exceptional regio-
selectivity of the reaction between azides and trifluoromethylated
diones could be the subject of careful theoretical study.
column chromatography on silica gel, using dichloromethane as an
eluent.
4.2.1. 1-[1-Phenyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]etha-
none (7a). Yield 0.48 g (63%); viscous oil; Rf (CCl4/CHCl3 2/1 v/v)
0.60; MS-EI, m/z: 255 [M]þ (5), 177 [MꢁC6H5]þ (100); nmax (ATR
ZnSe) 3090 (CHar), 2920 (CH3), 1702 (CO). 1H NMR (DMSO-d6)
d
d
:
:
7.73e7.60 (5H, m, Har), 2.74 (3H, s, CH3); 13C NMR (DMSO-d6)
2
191.2 (C]O), 145.0, 136.8, 131.4, 129.6, 127.4 (q, JCF¼42 Hz, C-5),
126.2, 118.8 (q, 1JCF¼269 Hz, CF3), 28.3 (CH3); 19F NMR (DMSO-d6)
d:
3. Conclusions
ꢁ56.0 (CF3). Requires for C11H8F3N3O: C 51.77; H 3.16; N 16.47.
Found: C 51.61; H 3.14; N 16.55%.
In conclusion, reactions of a variety of alkyl and aryl azides with
1-trifluoromethylated 1,3-dicarbonyl compounds lead 100% regio-
selectively to a single 1,2,3-triazole isomer in good yields. The re-
action represents a general and highly selective method for the
synthesis of otherwise difficulty available 4-acyl-5-trifluoromethyl-
1,2,3-triazoles.
4.2.2. 1-[1-(3-Chlorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl]ethanone (7b). Yield 0.60 g (69%) as white solid; Rf (CCl4/CHCl3 1/
5 v/v) 0.46; mp 57e59 ꢀC; MS-EI, m/z: 289 [M]þ (6), 178
[MꢁC6H4Cl]þ (15); nmax (ATR ZnSe) 3076 (CHar), 3007 (CH), 1703
(CO), 863 (CCl). 1H NMR (DMSO-d6)
d: 7.94 (1H, s, Har), 7.81e7.79
(1H, m, Har), 7.71e7.69 (2H, m, Har), 2.74 (3H, s, CH3); 13C NMR
4. Experimental
4.1. General
(DMSO-d6) d: 191.2 (C]O), 145.3, 136.8, 134.1, 132.0, 131.7, 128.2 (q,
2JCF¼42 Hz, C-5), 127.0, 125.8, 119 (q, 1JCF¼269 Hz, CF3), 28.7 (CH3);
19F NMR (DMSO-d6)
45.62; H 2.44; N 14.51. Found: C 45.57; H 2.41; N 14.59%.
d
: ꢁ55.6 (CF3); Requires for C11H7ClF3N3O: C
The NMR spectra of all substances were recorded on Bruker
WM-400 NMR and Bruker AMX 400 spectrometers (at 400, 376 and
100 MHz for 1H, 19F and 13C NMR spectra, respectively) in DMSO-d6
4.2.3. 1-[1-(4-Nitrophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-
yl]ethanone (7c). Yield 0.64 g (71%) as yellow solid; Rf (CCl4/CHCl3 1/
5 v/v) 0.55; mp 111e113 ꢀC; MS-EI, m/z: 300 [M]þ (9), 178
[MꢁC6H4NO2]þ (43); nmax (ATR ZnSe) 3120 (CHar), 3098 (CHar), 3000
or CDCl3 with TMS as internal standard. d-Values are given in ppm.
Mass-spectra were obtained at 70 eV on a Varian MAT 311A spec-
trometer. IR spectra were obtained with IR 200 spectrometer. Col-
umn and TLC chromatography were performed using silica gel
Merck 60 or Merck 60F254 plates, respectively.
(CH3),1708 (CO),1540 (NO2),1369 (NO2). 1H NMR (DMSO-d6)
d: 8.48
(2H, d, J¼8.8 Hz, Har), 7.98 (2H, d, J¼8.8 Hz, Har), 2.75 (3H, s, CH3); 13
C
NMR (DMSO-d6) d: 191.5 (C]O), 149.5, 145.6, 140.4, 128.5, 125.7 (q,
2JCF¼43 Hz, C-5), 125.4, 119.2 (q, 1JCF¼269 Hz, CF3), 28.7 (CH3); 19F
4.2. 1-[1-Aryl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]
ethanones (7) (general procedure)
NMR (DMSO-d6)
H 2.35; N 18.99. Found: C 43.79; H 2.39; N 18.97%.
d
: ꢁ55.4 (CF3); Requires for C11H7F3N4O3: C 44.01;
A mixture of the corresponding 1,1,1-trifluoro-2,4-pentanedione
5 (3 mmol), appropriate aryl azide 6 (3 mmol), and triethylamine
(1.30 mL, 9 mmol) was heated at 70e80 ꢀC for 5 h. Volatiles were
evaporated in vacuum at 60e70 ꢀC and the residue was purified by
4.2.4. 1-[1-(4-Chlorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-
4-yl]ethanone (7d). Yield 0.57 g (66%) white solid; Rf (CCl4/CHCl3 2/1
v/v) 0.24; mp 56e58 ꢀC; MS-EI, m/z: 289 [M]þ (6), 178 [MꢁC6H4Cl]þ
(12); nmax (ATR ZnSe) 3103 (CHar), 2853 (CH3), 1700 (CO), 835 (CCl).

Y.A. Rozin et al. / Tetrahedron 68 (2012) 614e618
617
1H NMR (DMSO-d6)
(DMSO-d6)
d
: 7.79 (4H, s, Har), 2.77 (3H, s, CH3); 13C NMR
158e160 ꢀC; Rf (CCl4/CHCl3 1/1 v/v) 0.32; MS-EI, m/z: 357 [M]þ (3),
111 [C4H3SCO]þ (100); nmax (ATR ZnSe) 3103 (CHar), 2921 (CH), 2852
d
: 191.5 (C]O), 145.4, 136.7, 134.6, 130.1, 128.7, 128.1 (q,
2JCF¼42.3 Hz, C-5), 119.2 (q, 1JCF¼269 Hz, CF3), 28.7 (CH3); 19F NMR
(CH), 1631 (CO), 832 (C-Cl). 1H NMR (DMSO-d6)
d: 8.35 (1H, dd,
(DMSO-d6)
d
: ꢁ55.6 (CF3); Requires for C11H7ClF3N3O: C 45.62; H
1J¼4.0 Hz, 2J¼1.2 Hz, C4H3S), 8.30 (1H, dd, 1J¼4.8 Hz, 2J¼1.2 Hz,
C4H3S), 7.85 (2H, d, J¼8.8 Hz, C6H5Cl), 7.80 (2H, d, J¼8.8 Hz, C6H5Cl),
2.44; N 14.51. Found: C 45.45; H 2.39; N 14.62%.
7.42 (1H, dd, 1J¼4.0 Hz, 2J¼4.8 Hz, C4H3S); 13C NMR (DMSO-d6)
d:
4.2.5. 1-[1-(4-Methoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3-
triazole-4-yl]ethanone (7e). Yield 0.10 g (12%); viscous oil; Rf (CCl4/
CHCl3 1/1 v/v) 0.32; MS-EI, m/z 285 [M]þ (6); nmax (ATR ZnSe) 3015
176.8 (C]O), 145.0, 142.0, 138.2, 136.6, 134.5, 130.2, 129.6, 129.7,
2
1
128.9 (q, JCF¼35 Hz, C-5), 128.7, 119.6 (q, JCF¼269 Hz, CF3); 19F
NMR (DMSO-d6)
d
: ꢁ55.5 (CF3); Requires for C14H7ClF3N3OS: 47.00;
(CHar), 2838 (MeO), 1670 (CO). 1H NMR (DMSO-d6)
d
: 7.60 (2H, d,
H. 1.97; N 11.75. Found: C 46.85; H 2.07; N 11.94%.
J¼8.8 Hz, Har), 7.17 (2H, d, J¼8.8 Hz, Har), 3.86 (3H, s, COCH3), 2.73
(3H, s, MeO); 13C NMR (DMSO-d6)
d
: 191.6 (C]O), 161.5, 145.3,
4.2.11. [1-(4-Nitrophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl](phenyl)methanone (7k). Yield 0.94 g (87%) yellow solid; Rf (CCl4/
CHCl3 1/1 v/v) 0.45; mp 158e160 ꢀC; MS-EI, m/z: 362 [M]þ (1), 240
[PhCO]þ (67); nmax 3114 (CHar), 3083 (CHar), 1662 (CO), 1524 (NO2),
2
1
128.4, 127.7 (q, JCF¼42.2 Hz, C-5), 127.6, 119.3 (q, JCF¼269.1 Hz,
CF3), 115.0, 56.2 (MeO), 28.7 (Me); 19F NMR (DMSO-d6)
(CF3); Requires for C12H10F3N3O2: C 50.53; H 3.53; N 14.73. Found: C
50.42; H 3.61; N 14.55%.
d
: ꢁ55.7
1348 (NO2). 1H NMR (DMSO-d6)
d
: 8.56 (2H, d, J¼9.0 Hz, H2-3,5),
8.16e8.10 (4H, m, H-aaþH2-2,6), 7.80 (1H, t, J¼7.5 Hz, H-
g), 7.66
4.2.6. [1-(4-Chlorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl](phenyl)ethanone (7f). Yield 0.59 g (56%) white solid; Rf (CCl4/
CHCl3 1/1 v/v) 0.75; mp 106e108 ꢀC; MS-EI, m/z: 351 [M]þ (7), 240
[MꢁC6H4Cl]þ(10); nmax (ATR ZnSe) 3009 (CHar), 1679 (CO), 1597
(2H, t, J¼7.5 Hz, H2-bb0); 13C NMR (DMSO-d6)
d: 185.8 (C]O), 149.5,
145.6, 140.2, 136.0, 135.2, 130.9, 129.6, 128.5, 128.0 (q, 2JCF¼42 Hz, C-
5), 125.5, 119.3 (q, 1JCF¼238 Hz, CF3); 19F NMR (DMSO-d6)
: ꢁ55.4
d
(CF3); Requires for C16H9F3N4O3: C 53.05; H 2.50; N 15.47. Found: C
52.83; H 2.54; N 15.35%.
(C]C), 832 (CeCl). 1H NMR (DMSO-d6)
d
: 8.13 (2H, d, J¼7.5 Hz, H2-
aa0), 7.85 (2H, d, J¼8.8 Hz, C6H4Cl), 7.80e7.78 (3H, m, H-
þC6H4Cl),
g
6.65 (2H, t, J¼7.5 Hz, H2-bb0); 13C NMR (DMSO-d6)
d: 185.5 (C]O),
4.2.12. [1-(4-Nitrophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl](thien-2-yl)methanone (7l). Yield 0.96 g (87%) yellow solid; Rf
(CCl4/CHCl3 1/1 v/v) 0.57; mp 175e176 ꢀC; MS-EI, m/z: 368 [M]þ (2),
111 [C4H3SCO]þ (100); nmax (ATR ZnSe) 3076 (CHar), 3007 (CH), 1703
145.0, 136.3, 135.6, 134.7, 133.9, 130.4, 129.8, 128.9, 128.9 (q,
1
2JCF¼42 Hz, C-5), 128.3, 118.9 (q, JCF¼269 Hz, CF3); 19F NMR
(DMSO-d6)
d
: ꢁ55.6 (CF3); Requires for C16H9ClF3N3O: C 54.64; H
2.58; N 11.95. Found: C 54.50; H 2.64; N 12.03%.
(CO), 1554 (NO2), 1367 (NO2). 1H NMR (DMSO-d6)
d: 8.54 (2H, d,
J¼9.0 Hz, H-
b
), 8.35 (1H, dd, 1J¼4.0 Hz, 2J¼1.2 Hz, H-3), 8.29 (1H, dd,
4.2.7. (4-Bromophenyl)[1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-
1,2,3-triazol-4-yl]methanone (7g). Yield 0.99 g (77%) white solid; Rf
(CCl4/CHCl3 1/1 v/v) 0.63; mp 143e145 ꢀC; MS-EI, m/z: 430 [M]þ
(<1), 91 [p-ClC6H4] (77); nmax (ATR ZnSe) 3101 (CHar), 1660 (CO),
1J¼5.5 Hz, 2J¼1.2 Hz, H-5), 8.10 (2H, d, J¼9.0 Hz, H-
a), 7.40 (2H, dd,
J¼4.0 Hz, J¼5.0 Hz, H-
a d: 176.7 (C]O),149.5,
); 13C NMR (DMSO-d6)
2
145.2, 142.0, 140.3, 138.7, 138.3, 129.7, 129.6 (q, JCF¼42 Hz, C-5),
128.5, 125.5, 119.2 (q, JCF¼269 Hz, CF3); 19F NMR (DMSO-d6)
d:
1
1598 (C]C), 832 (CeCl), 711 (CeBr). 1H NMR (DMSO-d6)
d
: 7.29 (2H,
ꢁ55.3 (CF3); Requires for C14H7F3N4O3S: C 45.66; H 1.92; N 15.21.
d, J¼8.9 Hz, H-
a
), 7.01 (2H, d, J¼8.7 Hz, H2-2,6), 6.95 (2H, d,
Found: C 45.45; H 2.07; N 15.05%.
J¼8.7 Hz, H2-3,5), 6.33 (2H, d, J¼8.9 Hz, H2-bb0); 13C NMR (DMSO-
d6)
d
: 185.5 (C]O), 128.9 (q, 2JCF¼42 Hz, C-5), 119.4 (q, 1JCF¼280 Hz,
4.2.13. (4-Methoxyphenyl)[1-(4-nitrophenyl)-5-(trifluoromethyl)-
1H-1,2,3-triazol-4-yl]methanone (7m). Yield 1.08 g (92%) yellow
solid; Rf (CCl4/CHCl3 2/1 v/v) 0.34; mp 173e175 ꢀC; MS-EI, m/z: 392
[M]þ (10), 135 [MeOPh] (100); nmax (ATR ZnSe) 3114 (CHar), 3088
(CHar), 2844 (MeO), 1660 (CO), 1531 (NO2), 1351 (NO2). 1H NMR
CF3), 145.0, 136.3, 135.6, 134.7, 133.9, 130.4, 129.8, 128.9, 128.3; 19F
NMR (DMSO-d6)
44.63; H 1.87; N 9.76. Found: C 44.75; H 1.97; N 9.87%.
d
: ꢁ55.6 (CF3); Requires for C16H8BrClF3N3O: C
4.2.8. [1-(4-Chlorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl](4-methoxyphenyl) ethanone (7h). Yield 1.09 g (95%) white solid;
Rf (CCl4/CHCl3 1/1 v/v) 0.57; mp 145e147 ꢀC; MS-EI, m/z: 381 [M]þ
(5), 135 [MeOPh] (100); nmax (ATR ZnSe) 3103 (CHar), 2841 (MeO),
(DMSO-d6)
d
: 8.55 (2H, d, J¼9.0 Hz, HB), 8.14e8.10 (4H, m,
2HAþ2Ha), 7.17 (2H, d, J¼9.0 Hz, Hb), 3.91 (3H, s, MeO); 13C NMR
(DMSO-d6) d: 183.6 (C]O), 164.5, 149.0, 145.6, 140.0, 133.0, 128.1,
2
1
127.9 (q, JCF¼42 Hz, C-5), 125.1, 118.9 (q, JCF¼269 Hz, CF3), 114.3,
1660 (CO), 1597 (C]C), 841 (CeCl). 1H NMR (DMSO-d6)
d
: 8.29 (2H,
55.8 (MeO); 19F NMR (DMSO-d6)
d
: ꢁ55.4 (CF3); Requires for
d, J¼8.9 Hz, H-aa0), 7.84 (2H, d, J¼8.9 Hz, H2-2,6), 7.79 (2H, d,
C17H11F3N4O4S: C 52.05; H 2.83; N 14.28. Found: C 51.89; H 3.02; N
14.17%.
J¼8.9 Hz, H2-3,5), 7.17 (2H, d, J¼8.9 Hz, H2-bb0), 3.91 (3H, s, MeO);
13C NMR (DMSO-d6)
d
: 184.2 (C]O), 164.9, 145.8, 136.7, 134.1, 133.5,
2
130.3, 128.9 (q, JCF¼35 Hz, C-5), 128.7, 119.4 (q, 1JCF¼268 Hz, CF3);
4.2.14. Ethyl 2-(4-benzoyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)
acetate (7n). Yield 0.45 g (46%); colorless crystals; mp 71e73 ꢀC; Rf
19F NMR (DMSO-d6)
53.49; H 2.90; N 11.01. Found: C 53.37; H 2.95; N 11.20%.
d
: ꢁ55.6 (CF3); Requires for C17H11ClF3N3O2: C
(CH2Cl2) 0.40; IR (Nujol, cmꢁ1):
n
¼1670 (C]O), 1757 (CO2Et); 1H
NMR (CDCl3)
d
: 8.21 (2H, d, J¼7.6 Hz, Ph), 7.67 (1H, t, J¼7.6 Hz, Ph),
4.2.9. 1-[1-Benzyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]etha-
none (7i). Yield 0.07 g (9%) white solid; Rf (CCl4/CHCl3 1/1 v/v) 0.24;
mp 57e59 ꢀC; MS-EI, m/z: 269 [M]þ (2), 91 [PhCH2] (100). nmax (ATR
ZnSe) 3108 (CHar), 2923 (CH), 2852 (CH), 1705 (CO), 733 (CeCl). 1H
7.54 (2H, t, J¼7.6 Hz, Ph), 5.42 (2H, s, CH2), 4.33 (2H, q, J¼7.1 Hz,
OCH2CH3), 1.38 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR (CDCl3)
d: 184.8
(C]O), 164.9 (CO2Et), 145.8, 135.6, 134.1, 130.7, 128.6, 125.0 (q,
1
J¼42.1 Hz, CeCF3), 119.3 (q, JCF¼270.4 Hz, CF3), 63.1 (OCH2CH3),
NMR (DMSO-d6)
d
: 6.54e6.50 (3H, m, Ph), 6.32 (2H, d, J¼6.8 Hz),
51.9 (q, 4JCF¼2.9 Hz, CH2),14.0 (OCH2CH3); 19F NMR (CDCl3)
: ꢁ58.6
d
5.07 (2H, s, CH2), 1.82 (3H, s, CH3); 13C NMR (DMSO-d6)
d
: 191.5 (C]
(CF3); Anal. Calcd for C14H12F3N3O3: C 51.38; H 3.70; N 12.84.
Found: C 51.52; H 3.79; N 12.75.
O), 146.0, 135.0, 129.4, 128.9, 127.5, 126.6 (q, 2JCF¼42 Hz, C-5), 119.6
(q, 1JCF¼269 Hz, CF3), 54.9 (CH2), 25.5 (CH3); 19F NMR (DMSO-d6)
d:
ꢁ56.5 (CF3); Requires for C12H10N3O: C 53.54; H. 3.74; N 15.61.
4.2.15. Ethyl 2-(4-(thiophene-2-carbonyl)-5-(trifluoromethyl)-1H-
1,2,3-triazol-1-yl)acetate (7o). Yield 0.51 g (51%); colorless crystals;
Found: C 53.37; H 3.95; N 15.20%.
mp 91e92 ꢀC; Rf (CH2Cl2) 0.49; IR (Nujol, cmꢁ1):
n
¼1643 (C]O),
: 8.45 (2H, dd, J¼4.0 Hz, J¼1.1 Hz,
thienyl), 7.80 (1H, dd, J¼4.9 Hz, J¼1.1 Hz, thienyl), 7.22 (1H, dd,
4.2.10. [1-(4-Chlorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl](thien-2-yl)methanone (7j). Yield 0.89 g (83%) white solid; mp
1753 (CO2Et); 1H NMR (CDCl3)
d

618
Y.A. Rozin et al. / Tetrahedron 68 (2012) 614e618
M. O. F.; Pinto, A. V. Eur. J. Med. Chem. 2011, 46, 399e410; (c) Pibiri, I.; Buscemi, S.
Curr. Bioact. Compd. 2010, 6, 208e242; (d) Wang, X.-L.; Wan, K.; Zhou, C. H. Eur.
J. Med. Chem. 2010, 45, 4631e4639; (e) Yan, S.-J.; Liu, Y.-J.; Chen, Y.-L.; Liu, L.;
Lin, J. Bioorg. Med. Chem. Lett. 2010, 20, 5225e5228; (f) Slamova, K.; Marhol, P.;
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Lett. 2010, 20, 4263e4265; (g) Oliva, C. G.; Jagerovic, N.; Goya, P.; Alkorta, I.;
Elguero, J.; Cuberes, R.; Dordal, A. ARKIVOC 2010, 2, 127e147; (h) Ackermann, L.;
Kumar, H. P. Org. Biomol. Chem. 2010, 8, 4503e4513.
2. (a) Tam, A.; Arnold, U.; Matthew, B.; Soellner, M. B.; Raines, R. T. J. Am. Chem.
Soc. 2007, 129, 12670e12671; (b) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev.
2010, 39, 1325e1337.
3. Brik, A.; Muldoon, J.; Lin, Y.-C.; Elder, J. H.; Goodsell, D. S.; Olson, A. J.; Fokin, V.
V.; Sharpless, K. B.; Wong, C.-H. ChemBioChem 2003, 4, 1246e1248.
4. Soltis, M. J.; Yeh, H. J.; Cole, K. A.; Whittaker, N.; Wersto, R. P.; Kohn, E. C. Drug
Metab. Dispos. 1996, 24, 799e806.
5. Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De Clercq, E.; Perno, C.-F. N.;
Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994, 37, 4185e4194.
6. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596e2599; (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004e2021; (c) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev.
2010, 39, 1302e1315; (d) Sokolova, N. V.; Latyshev, G. V.; Lukashev, N. V.; Ne-
najdenko, V. G. Org. Biomol. Chem. 2011, 9, 4921e4926; (e) Nenajdenko, V. G.;
Gulevich, A. V.; Sokolova, N. V.; Mironov, A. V.; Balenkova, E. S. Eur. J. Org. Chem.
2010, 1445e1449.
J¼4.9 Hz, J¼4.0 Hz, thienyl), 5.42 (2H, d, J¼1.3 Hz, CH2), 4.30 (2H, q,
J¼7.1 Hz, OCH2CH3), 1.30 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR
(CDCl3) d: 175.9 (C]O), 164.9 (CO2Et), 145.5, 142.1, 136.9, 136.2,
2
129.9 (q, JCF¼42.1 Hz, CeCF3), 128.6, 119.2 (q, 1JCF¼270.4 Hz, CF3),
63.1 (OCH2CH3), 52.1 (q, 4JCF¼2.2 Hz, CH2), 14.0 (OCH2CH3); 19F NMR
(CDCl3)
d
: ꢁ58.5 (CF3); Anal. Calcd for C12H10F3N3O3S: C 43.24; H
3.02; N 12.61; Found: C 43.44; H 3.10; N 12.51.
4.2.16. Ethyl 2-(4-acetyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)
acetate (7p). Yield 0.41 g (48%); viscous oil; Rf (CH2Cl2) 0.33; IR
(Nujol, cmꢁ1):
n
¼1709 (C]O), 1757 (CO2Et); 1H NMR (CDCl3)
d: 5.37
(2H, d, J¼1.3 Hz, CH2), 4.30 (2H, q, J¼7.1 Hz, OCH2CH3), 2.75 (3H, s,
CH3), 1.29 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR (CDCl3)
d: 190.9 (C]
2
O), 164.9 (CO2Et), 145.8, 128.2 (q, JCF¼43.6 Hz, CeCF3), 119.2 (q,
1JCF¼270.8 Hz, CF3), 63.0 (OCH2CH3), 52.1 (q, 4JCF¼2.9 Hz, CH2), 28.1
(CH3), 13.9 (OCH2CH3); 19F NMR (CDCl3)
d: ꢁ58.8 (CF3); Anal. Calcd
for C9H10F3N3O3: C 40.76; H 3.80; N 15.85. Found: C 40.92; H 3.91; N
15.76.
7. (a) Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. Rev. 2005, 74, 339e379; (b)
Pokhodylo, N. T.; Matiychuk, V. S.; Obushak, M. D. Synth. Commun. 2010, 40,
1932e1938; (c) Stazi, F.; Cancogni, D.; Turco, L.; Westerduin, P.; Bacchi, S. Tet-
rahedron Lett. 2010, 51, 5385e5387; (d) Kamalraj, V. R.; Senthil, S.; Kannan, P. J.
Mol. Struct. 2008, 892, 210e215.
8. (a) Ol’shevskaya, I. A.; Kornilov, M. Y.; Smirnov, M. N. Chem. Heterocycl. Compd.
1990, 8, 938e940; (b) Batog, L. V.; Rozhkov, V. Y.; Strukova, M. I. Mendeleev
Commun. 2002, 12, 159e161.
4.2.17. Ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-
triazole-4-carboxylate (7r). Yield 0.37 g (41%); viscous oil; Rf
(CH2Cl2) 0.24; IR (Nujol, cmꢁ1):
n
¼1750 (CO2Et); 1H NMR (CDCl3)
d:
5.38 (2H, d, J¼1.2 Hz, CH2), 4.47 (2H, q, J¼7.1 Hz, OCH2CH3), 4.29
(2H, q, J¼7.1 Hz, OCH2CH3), 1.43 (3H, t, J¼7.1 Hz, OCH2CH3), 1.29 (3H,
t, J¼7.1 Hz, OCH2CH3); 13C NMR (CDCl3)
d: 164.9 (CO2Et), 158.7
9. (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications;
(CO2Et), 139.6, 129.9 (q, 2JCF¼42.6 Hz, CeCF3), 119.1 (q,
1JCF¼270.8 Hz, CF3), 63.0 (OCH2CH3), 62.3 (OCH2CH3), 52.2 (q,
4JCF¼2.6 Hz, CH2),14.0 (OCH2CH3),13.9 (OCH2CH3); 19F NMR (CDCl3)
€
Wiley-VCH: Weinheim, 2004; 320; (b) Jackel, C.; Koksch, B. Eur. J. Org. Chem.
2005, 4483e4503; (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
ꢀ
ꢀ
Soc. Rev. 2008, 37, 320e330; (d) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine; John Wiley: New York, NY, 2008; (e) Kirk, K. L.
Curr. Top. Med. Chem. 2006, 6, 1447e1456; (f) Kirk, K. L. Org. Process Res. Dev.
2008, 13, 305e321; (g) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27e33; (h)
Ismail, F. M. D.; Drew, M. G. B.; Dascombe, M. J. Chem. Today 2009, 27, 16e20; (i)
d: ꢁ58.2 (CF3); Anal. Calcd for C10H12F3N3O4: C 40.68; H 4.10; N
14.23. Found: C 40.52; H 4.03; N 14.33.
ꢀ
Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horvath, I. T., Eds.;
Acknowledgements
Wiley-VCH: Weinheim, 2004; (j) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308e319;
(k) Gakh, A.; Kirk, K. L. Fluorinated Heterocycles; Oxford University: 2008; (l)
Petrov, V. A. Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Ap-
plications; John Wiley: 2009; (m) Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E.
S. Molecules 1997, 2, 186e232; (n) Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E.
S. Russ. Chem. Rev. 1999, 483e505; (o) Druzhinin, S. V.; Balenkova, E. S.; Ne-
najdenko, V. G. Tetrahedron 2007, 63, 7753e7808; (p) Muzalevskiy, V. M.;
Shastin, A. V.; Balenkova, E. S.; Haufe, G.; Nenajdenko, V. G. Synthesis 2010, 23,
3905e3929; (q) Serdyuk, O.; Butin, A.; Abaev, V. J. Fluorine Chem. 2010, 131,
296e319; (r) Serdyuk, O.; Butin, A.; Abaev, V.; Nenajdenko, V. G. Synthesis 2011,
2505e2529; (s) Nenajdenko, V. G.; Balenkova, E. S. ARKIVOC 2011, i, 246e328.
10. (a) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem.dEur. J. 2011, 17,
3584e3587; (b) Sosnovskikh, V. Y.; Usachev, B. I. Mendeleev Commun. 2002,
75e76.
This project was supported by the Russian Foundation for Basic
Research (grants no. 10-03-00897-a, 11-03-00579-a) and Federal
Special Program (grant P962).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.10.110.
11. (a) Diezi, S.; Ferri, D.; Vargas, A.; Mallat, T.; Baiker, A. J. Am. Chem. Soc. 2006, 128,
4048e4057; (b) Sloop, J. C.; Bumgardner, C. L.; Washington, G.; Loehle, W. D.;
Sankar, S. S.; Lewis, A. B. J. Fluorine Chem. 2006, 127, 780e786.
References and notes
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