Novel synthetic approaches to (Trifluoromethyl)triazoles

Article abstract of DOI:10.1055/s-0029-1218656

New synthetic procedures for the trifluoromethyl-substituted triazoles, 3-(trifluoromethyl)-4H-1,2,4-triazole and 4-(trifluoromethyl)-1H-1,2,3-triazole, have been elaborated. The target compounds were prepared from commercially available trifluoroacethydr

Full text of DOI:10.1055/s-0029-1218656

SHORT PAPER
1075
Novel Synthetic Approaches to (Trifluoromethyl)triazoles
iazole sr iy A. Sibgatulin, Andrii V. Bezdudny, Pavel K. Mykhailiuk,* Nataliia M. Voievoda,a,c
a,b
a,b
a,c
N
D
ovel Synthetic
A
m
pproaches to (Triflu
y
oromethyl)tr
t
a,d
a,b
a,c
Ivan S. Kondratov, Dmitry M. Volochnyuk, Andrey A. Tolmachev
a
Enamine Ltd., Alexandra Matrosova Street 23, 01103 Kiev, Ukraine
Fax +380(44)2351273; E-mail: Pashamk@gmx.de
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, 02660 Kiev-94, Ukraine
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska Street 64, 01033 Kiev, Ukraine
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Murmanska Street 1, 02660 Kiev-94, Ukraine
b
c
d
Received 26 November 2009; revised 8 December 2009
N
N
N
Abstract: New synthetic procedures for the trifluoromethyl-substi-
tuted triazoles, 3-(trifluoromethyl)-4H-1,2,4-triazole and 4-(trifluo-
romethyl)-1H-1,2,3-triazole, have been elaborated. The target
compounds were prepared from commercially available trifluoro-
acethydrazide (one step) and methyl propiolate (three steps), re-
spectively.
N
OH
N
N
N
F
N
N
N
Cl
Cl
Key words: fluorine, triazoles, trifluoromethyl group
F
Fluconazole
Triazolam
N
N
Triazoles are an important class of organic compounds,
playing an important role in modern medicinal chemis-
try.1 Compounds with 1,2,3- and 1,2,4-triazole moieties
are known to possess fungicidal, antimicrobial, anticon-
vulsant, antidepressant, antibacterial, anti-inflammatory,
analgesic and antitumor activities.1 Moreover, many
compounds with the triazole core are market available
N
N
N
,2
O
O
O
,2
Cl
Cl
Terconazole
N
(
Figure 1).
N
O
O
N
OH
N
H
S
The substitution of hydrogen for fluorine in organic com-
pounds is widely used to modify the physical, chemical
and biological characteristics of such compounds. Tak-
ing into account the great potential of triazoles as valuable
building blocks for drug design, fluorinated triazole deriv-
atives are of enormous practical interest; however, al-
N
F
F
N
N
N
3
CO2H
O
N
F
Voriconazole
Tazobactam
though the chemistry of triazoles is quite well Figure 1 Some representative examples of the marketed triazole de-
1
,2
rivatives: Fluconazole (antifungal), Triazolam (sedative), Tercon-
azole (antifungal), Voriconazole (antifungal), Tazobactam (used in
combination with the antibiotic Piperacillin)
elaborated, fluorine-containing triazoles have received
4
much less attention so far. Therefore, in the present work,
we wish to report straightforward, practical procedures for
the multigram preparation of the mono(trifluoromethyl)-
substituted triazoles, 3-(trifluoromethyl)-4H-1,2,4-tri-
azole (1) and 4-(trifluoromethyl)-1H-1,2,3-triazole (2)
failed to reproduce this procedure. A complex mixture
formed each time when we tried to obtain the intermediate
3
. Therefore, we elaborated an alternative procedure for 1.
(
Figure 2), starting from commercially available materi-
Refluxing trifluoroacethydrazide with formamidine ace-
tate in acetic acid for four hours afforded the target com-
als.
Despite the structural simplicity of 3-(trifluoromethyl)- pound 1 in 25% yield after purification by flash column
4
H-1,2,4-triazole (1), there is, to the best of our knowl- chromatography. Despite the relatively poor yield of 25%,
edge, only one synthetic approach to 1 reported in the lit- the given procedure represents an easy and practical meth-
5
erature to date. According to that publication, the target od to obtain 1 in one synthetic step from inexpensive,
compound was obtained in two steps from trifluoro- commercially available materials. Moreover, the reaction
acethydrazide and methyl 2,2,2-trichloroacetimidate, as was easily scaled up for the preparation of 10 grams of 1
shown in Scheme 1; however, despite much effort, we in a single batch.
Another trifluoromethyl-substituted triazole, compound
2
, has also been described in the literature, with three syn-
SYNTHESIS 2010, No. 7, pp 1075–1077
x
x
.
x
x
.2
0
1
0
thetic approaches to 2 known. In 1973, Crossman and co-
workers reported the preparation of milligram quantities
Advanced online publication: 29.01.2010
DOI: 10.1055/s-0029-1218656; Art ID: Z25709SS
Georg Thieme Verlag Stuttgart · New York
©

1
076
D. A. Sibgatulin et al.
SHORT PAPER
CF3
N
g) were prepared in single synthetic runs starting from in-
expensive, commercially available materials.
N
N
N
N
H
CF3
N
H
1
Chemicals were purchased from Aldrich and Enamine Ltd. H, 13C
1
2
1
9
and F NMR spectra were recorded on a Bruker Avance 500 spec-
trometer (at 499.9, 124.9 and 470.3 MHz, respectively). Chemical
Figure 2 3-(Trifluoromethyl)-4H-1,2,4-triazole (1) and 4-(trifluo-
romethyl)-1H-1,2,3-triazole (2)
1
13
shifts are reported in ppm downfield from TMS ( H, C) or CFCl3
1
9
(
F) as internal standard. Mass spectra were recorded on an Agilent
a)
NH
1100 LC/MSD SL instrument by chemical ionization (CI).
Cl3C
0
N
N
N N
OMe
NaOH
3-(Trifluoromethyl)-4H-1,2,4-triazole (1)
CF3CONHNH2
CF3
CF3
CF3
Cl3C
N
H
3
N
H
1
To a stirred soln of trifluoroacethydrazide (40.0 g, 313 mmol) in an-
hyd MeOH (200 mL), formamidine acetate (32.5 g, 313 mmol) was
added. The mixture was stirred at r.t. for 5 h. The solvent was evap-
orated under reduced pressure and AcOH (200 mL) was added to
the residue. The resulting soln was heated at reflux for 4 h. The sol-
vent was evaporated and EtOAc (200 mL) was added. The formed
precipitate was removed by filtration and the mother liquor was
concentrated under reduced pressure. The residue was purified by
%
b)
NH
N
N
NH2⋅AcOH
CF3CONHNH2
25%
N
H
1
flash column chromatography (EtOAc; R = 0.6). The obtained oil
f
Scheme 1 Synthetic approaches to 3-(trifluoromethyl)-4H-1,2,4-
triazole (1): a) original procedure described in the literature (could
not be reproduced); b) proposed approach to 1 (successfully per-
was redissolved in CHCl (200 mL) and decanted from the insoluble
3
5
material. Evaporation of the solvent produced the oil, which was
further purified by flash column chromatography (CHCl –MeOH,
3
formed)
9
:1; R = 0.4) to give 1 (10.7 g, 78 mmol, 25%) as a white solid.
f
Mp 80–81 °C.
of 2 by the reaction of trifluoroacetonitrile with (diazo-
methyl)trimethylsilane. Subsequently, in 2007, Shreeve
and co-workers obtained 2 from 3,3,3-trifluoropropyne
1
H NMR (500 MHz, CDCl ): d = 13.70 (br s, NH), 8.55 (s, CH).
6
3
1
3
2
C NMR (125 MHz, DMSO-d ): d = 152.91 (q, J = 37.7 Hz, C),
6
C,F
1
1
46.32 (s, CH), 120.15 (q, J = 269.0 Hz, CF ).
C,F 3
and trimethylsilyl azide, however, still on a milligram
1
9
7
F NMR (470 MHz, CDCl ): d = –63.05 (s, CF ).
scale. In the same year, Bandera and co-workers pro-
3
3
posed an alternative strategy to 2. Their procedure repre- MS: m/z = 137 [M+].
sents a practical way to obtain 2; however, it commences
8
Methyl 1H-1,2,3-Triazole-4-carboxylate (4)
A mixture of methyl propiolate (39.8 g, 474 mmol) and TMSN3
109.0 g, 948 mmol) in MeCN (500 mL) was heated at reflux for 72
from a rather exotic starting material (C F CH SO Tol)
2
5
2
2
and requires the use of sodium mercury amalgam. There-
(
fore, in order to easily prepare gram quantities of 2, we
h. The reaction mixture was cooled to r.t. and MeOH (200 mL) was
added. The formed suspension was concentrated under reduced
pressure and the obtained residue was recrystallized (MeOH) to
4
turned our attention to the well-elaborated tetrafluoro-l -
9
sulfane technique. The starting compound 4 was readily
prepared from methyl propiolate and trimethylsilyl azide produce 4 (46.3 g, 365 mmol, 77%) as a white solid. Spectroscopic
in 77% yield (Scheme 2). Thereafter, the methyl ester and analytical data were in accordance to those previously report-
1
0
ed.
group in 4 was hydrolyzed under basic conditions to pro-
duce acid 5 in 97% yield. Finally, treatment of acid 5 with
tetrafluoro-l -sulfane in hydrogen fluoride smoothly af-
forded triazole 2 in 64% yield. Using this strategy, a
scaled-up synthesis afforded 30 grams of 2 in one synthet- cooled to r.t. and washed with CH Cl (2 × 100 mL). The aqueous
ic run.
1
H-1,2,3-Triazole-4-carboxylic Acid (5)
4
A soln of methyl ester 4 (46.0 g, 362 mmol) and NaOH (31.9 g, 800
mmol) in H O (500 mL) was heated at reflux for 3 h. The soln was
2
2
2
phase was acidified with aq HCl to pH 2, and then extracted with
EtOAc (2 × 150 mL). The organic extracts were dried (Na SO ) and
concentrated under reduced pressure to produce 5 (39.6 g, 351
2
4
In summary, we have developed simple and efficient pro-
cedures to prepare the mono(trifluoromethyl)-substituted
triazoles 1 and 2. 3-(Trifluoromethyl)-4H-1,2,4-triazole
mmol, 97%) as a white solid.
Mp 260–261 °C.
(
1; 10 g) and 4-(trifluoromethyl)-1H-1,2,3-triazole (2; 30
1
H NMR (500 MHz, DMSO-d ): d = 8.70 (br s, NH), 8.20 (br s,
6
CO2Me
N
CH).
13
TMSN3
7%
NaOH
97%
C NMR (125 MHz, D O): d = 164.35 (s, COOH), 138.15 (s, C),
2
CO2Me
COOH
N
1
31.12 (s, CH).
7
N
H
MS: m/z = 114 [M + 1]+.
4
CF3
4
-(Trifluoromethyl)-1H-1,2,3-triazole (2)
A mixture of acid 5 (39.0 g, 345 mmol), anhyd HF (50 mL) and SF4
46.5 g, 430 mmol) in a 500-mL autoclave was heated at 120 °C (oil
N
N
SF4
4%
N
N
(
6
N
N
H
H
bath temperature) for 16 h. The reaction mixture was cooled to 0 °C
and the autoclave was then opened. The residue was put on a Teflon
plate; after the residual HF had been removed by heating at 30 °C
for 1–2 h (CAUTION! This procedure must be carried out in a fume
5
2
Scheme 2 Synthesis of 4-(trifluoromethyl)-1H-1,2,3-triazole (2)
Synthesis 2010, No. 7, 1075–1077 © Thieme Stuttgart · New York

SHORT PAPER
Novel Synthetic Approaches to (Trifluoromethyl)triazoles
1077
hood!), the product was dissolved in CH Cl (300 mL) to remove all
insoluble materials. The solution was evaporated under vacuum and
the thus-formed tarry residue was purified by double sublimation
(4) (a) Arban, R.; Benedetti, R.; Bonanomi, G.; Capelli, A.-M.;
Castiglioni, E.; Contini, S.; Degiorgis, F.; Di Felice, P.;
Donati, D.; Fazzolari, E.; Gentile, G.; Marchionni, C.;
Marchioro, C.; Messina, F.; Micheli, F.; Oliosi, B.; Pavone,
F.; Pasquarello, A.; Perini, B.; Rinaldi, M.; Sabbatini, F. M.;
Vitulli, G.; Zarantonello, P.; Di Fabio, R.; St-Denis, Y.
ChemMedChem 2007, 2, 528. (b) Hager, C.; Miethchen, R.;
Reinke, H. J. Fluorine Chem. 2000, 104, 135.
2
2
(
20 mmHg, ∼80–90 °C) to give 2 (30.3 g, 221 mmol, 64%) as a
white solid.
Mp 79–80 °C.
1
H NMR (500 MHz, CDCl ): d = 8.95–8.20 (2 × br s, NH + CH).
3
1
3
(c) Stepanova, N. P.; Orlova, N. A.; Galishev, V. A.;
Turbanova, E. S.; Petrov, A. A. Zh. Org. Khim. 1985, 21,
C NMR (125 MHz, CDCl ): d = 137.21 (br s), 124.15 (br s),
3
1
1
21.71 (q, J = 267.7 Hz, CF3).
C,F
979. (d) Stepanova, N. P.; Galishev, V. A.; Turbanova, E. S.;
1
9
F NMR (470 MHz, CDCl ): d = –61.55 (s, CF ).
3
3
Maleev, A. V.; Potehin, K. A.; Kurkutova, E. N.; Struchkov,
Y. T.; Petrov, A. A. Zh. Org. Khim. 1989, 25, 1613.
MS: m/z = 137 [M+].
(
(
(
(
5) Evans, J. J. A.; Holan, G. US 4038405, 1977; Chem. Abstr.
1977, 87, 168041.
References
6) Crossman, J. M.; Haszeldine, R. N.; Tipping, A. E. J. Chem.
Soc., Dalton Trans. 1973, 483.
7) Ye, C.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley,
B.; Shreeve, J. M. Org. Lett. 2007, 9, 3841.
8) Bandera, Y. P.; Kanishchev, O. S.; Timoshenko, V. M.; But,
S. A.; Nesterenko, A. M.; Shermolovich, Y. G. Chem.
Heterocycl. Compd. (Engl. Transl.) 2007, 43, 1138.
9) Dmowski, W. In Houben–Weyl Methods of Organic
Chemistry, Vol. E 10a; Baasner, B.; Hagemann, H.; Tatlow,
J. C., Eds.; Georg Thieme: Stuttgart, 1999, 321.
(
1) Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. Rev. (Engl.
Transl.) 2005, 74, 339.
2) (a) Awad, L. F.; El Ashry, S. H. Carbohydr. Res. 1998, 312,
(
9. (b) Amir, M.; Shikha, K. Eur. J. Med. Chem. 2004, 39,
535. (c) Palaska, E.; Sahin, G.; Kelicen, P.; Durlu, N. T.;
Altinok, G. Farmaco 2002, 57, 101. (d) Holla, B. S.;
Poorjary, K. N.; Rao, B. S.; Shivananda, M. K. Eur. J. Med.
Chem. 2002, 37, 511. (e) Henichart, J. P.; Houssin, R.;
Berier, J. L. J. Heterocycl. Chem. 1986, 23, 1531.
(
(
10) Sternfeld, F.; Carling, R. W.; Jelley, R. A.; Ladduwahetty,
T.; Merchant, K. J.; Moore, K. W.; Reeve, A. J.; Street, L. J.;
O’Connor, D.; Sohal, B.; Atack, J. R.; Cook, S.; Seabrook,
G.; Wafford, K.; Tattersall, F. D.; Collinson, N.; Dawson, G.
R.; Castro, J. L.; MacLeod, A. M. J. Med. Chem. 2004, 47,
(
f) Demirbas, N.; Karaoglu, S. A.; Demirbas, A.; Sancak, K.
Eur. J. Med. Chem. 2004, 39, 793. (g) Demirbas, N.;
Demirbas, A.; Karaoglu, S. A. Russ. J. Bioorg. Chem. (Engl.
Transl.) 2005, 31, 387.
(
3) (a) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
2176.
(
b) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (c) Qiu, X.-L.; Meng, W.-D.; Qing,
F.-L. Tetrahedron 2004, 60, 6711.
Synthesis 2010, No. 7, 1075–1077 © Thieme Stuttgart · New York