A convenient route to 1-alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic acids employing a diazo transfer reaction

Article abstract of DOI:10.1002/ejoc.201300030

The reaction of ethyl 3-(alkylamino)-4,4,4-trifluoro-but-2-enoates with mesyl azide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave ethyl 1-alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylates in good yields. Further hydrolysis of the ester group afforded the title compounds on a multigram scale. Copyright

Full text of DOI:10.1002/ejoc.201300030

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FULL PAPER
DOI: 10.1002/ejoc.201300030
A Convenient Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic
Acids Employing a Diazo Transfer Reaction
Rustam T. Iminov,[a] Alexander V. Mashkov,[a] Bohdan A. Chalyk,[b] Pavel K. Mykhailiuk,[a,b]
Anton V. Tverdokhlebov,*[a,b] Andrey A. Tolmachev,[a,b] Yulian M. Volovenko,[a]
Oleg V. Shishkin,[c] and Svetlana V. Shishkina[c]
Keywords: Synthetic methods / Medicinal chemistry / Nitrogen heterocycles / Amines / Azides / Fluorine
The reaction of ethyl 3-(alkylamino)-4,4,4-trifluoro-but-2-
enoates with mesyl azide in the presence of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) gave ethyl 1-alkyl-5-trifluoro-
methyl-1,2,3-triazole-4-carboxylates in good yields. Further
hydrolysis of the ester group afforded the title compounds on
a multigram scale.
Introduction
Hitherto derivatives of 1,2,3-triazole have not been iso-
lated from natural sources. Nevertheless this heterocyclic
core has found numerous applications in medicine[1] and
especially in peptidomimetic chemistry.[1a,1b] In particular,
the 1-alkyl-1,2,3-triazole-4-carboxylic acid scaffold appears
to be very promising, as exemplified by the discovery of at
least two medications based on this structure (see Figure 1).
The first one, named Rufinamide, is already marketed as an
anticonvulsant drug for the treatment of Lennox-Gastaut
syndrome, a severe form of epilepsy. It was developed[2] by
Novartis AG and approved by the FDA in 2008. Recently,
an improved synthesis of Rufinamide, as well as a compre-
hensive overview of its medicinal usage, have been pub-
lished.[3,4] The second compound, known under the names
CAI, L651582, and NSC609974, is an anticancer drug cur-
rently being developed. Namely, its phase II clinical trials
have been completed,[5] and the phase III studies began[6]
in 2008 and are continuing presently.
Fluorine-containing heterocycles are widely recognized
for their biological activities as prospective molecules for
use in the medicinal and agricultural fields.[7] The unique
nature of fluorine substituents[7g] has a profound impact on
the physicochemical properties of substances, and, there-
fore, on their biochemical behavior. In regard to 1,2,3-tri-
azoles, certain 1-alkyl-5-trifluoromethyl derivatives have
been claimed as tachykinin receptor antagonists by Eli
Figure 1. Drugs with 1-alkyl-1,2,3-triazole-4-carboxylic acid scaf-
fold.
Lilly,[8] as herbicides by Syngenta,[9] and as pesticides by
Bayer Cropscience.[10] Notably, all of these patents[8–10] have
been issued during the last decade and are believed to repre-
sent preliminary results in the field. The growing interest in
fluorine-substituted 1,2,3-triazoles is confronted with a lack
of available building blocks and methods for their prepara-
tion. Hence, the elaboration of new, scalable approaches to
fluorinated 1,2,3-triazoles has become an urgent task.
Among them, the 1-alkyl-5-trifluoromethyl-1,2,3-triazole-4-
carboxylic acid scaffold, which combines a motif of known
drugs with the benefits of fluorine substituents, seems to be
the most promising.
Two approaches to the above-mentioned core have been
previously described, and both have utilized azide chemistry
(see Scheme 1). The first one involved a [3+2] cycloaddition
reaction between an azide and 4,4,4-trifluoro-2-butynoic
acid esters 3.[8,11] This approach suffered from insufficient
regioselectivity producing mixtures of isomeric triazoles 4
and 5 with ratios ranging from 1:1 to 3:1 depending on the
nature of substituent R1. The factors affecting the selectiv-
ity were studied both empirically[11a,11b] and by employing
quantum chemical calculations,[11c] but no practical meth-
ods for the preparation of compounds 4 or 5 without the
[a] Kiev National Taras Shevchenko University,
62 Volodimirska St., 01033 Kiev, Ukraine
E-mail: atver@univ.kiev.ua
Homepage: www.enamine.net
[b] Enamine Ltd.,
23 Alexandra Matrosova St., 01103 Kiev, Ukraine
[c] STC, Institute for Single Crystals, NAS of Ukraine,
60 Lenina Ave., 61001 Kharkiv, Ukraine
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300030.
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Scheme 1. Known approaches to 5-trifluoromethyl-1,2,3-triazole-4-carboxylates.
need of tedious chromatographic separations have been de- substituted methyl derivative 10 (64%), the minor product
veloped. 11 (30%) was a result of alkylation at N-3, and a trace
The second approach was based on the reaction of azides amount (6%) of ethyl 1-methyl-5-trifluoromethyl-1,2,3-tri-
with trifluoromethyl-substituted 1,3-dicarbonyls 6 or the azole-4-carboxylate (12) was detected.[9] Thereby, alkylation
enaminones 7 derived from them.[12,13] Initially, the method of 1H-1,2,3-triazoles was unsuitable for the synthesis of the
was developed for enaminones 7.[13a,13b] The reaction was target core. Instead, the reaction occurred predominantly
assumed to proceed through a cycloaddition of the azide at the N-2 atom, obviously because of the strong electron-
with the alkene moiety of 7, followed by an elimination of withdrawing character of both the CF3 and ester groups,
the secondary amine. Later, it was shown that enaminones which decreased the nucleophilicity at the 1- and 3-posi-
7 could be obtained in situ from the appropriate dicarbon- tions.
yls 6 and a secondary amine.[13c] And finally, azides were
found to undergo a straightforward reaction with com-
pounds 6 in the presence of bases such as triethylamine or
Results and Discussion
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). This probably
The aforementioned methods for the preparation of fluo-
occurred through a cycloaddition with the corresponding
rinated 1,2,3-triazoles utilized azides in such a manner that
enols or enolates.[12] In contrast to the approach with al-
all three nitrogen atoms became a part of the triazole ring.
There have been instances, however, in the syntheses of non-
fluorinated 1,2,3-triazoles when only two of the nitrogen
atoms of the azide reagent became a part of heterocyclic
kyne 3, an excellent selectivity was observed, and triazoles
8 were the only isolated products regardless of whether
starting materials 6 or 7 were used.[12,13] However, the reac-
tion required compounds 6 or 7 and the azide to be heated
core (see Scheme 2). Thus, treatment of enaminones 13 (see
Scheme 3) with sulfonyl azides or related azides with strong
electron-withdrawing groups reportedly gave triazoles
18.[15–18] In early works, the reaction was assumed to pro-
ceed through an initial [3+2] cycloaddition to give triazoline
14, followed by a Dimroth rearrangement to give intermedi-
ate 15 that underwent a final aromatization at the expense
of the elimination of sulfonamide (see Scheme 3, path A).[15]
Nevertheless, further investigations[16] revealed that the re-
action depended strongly on the electrophilicity of the az-
ide, the nucleophilicity of substrate 13, and the bulkiness of
the R1 substituent. As a result, the more reliable path B,[16]
which included formation of the triazene intermediate 16
followed by an intramolecular addition of the secondary
amine moiety to the N=N double bond and the elimination
of sulfonamide, was suggested and supported by calcula-
tions.[16a] The latter pathway had received common recogni-
tion, and the method was successfully employed in the syn-
at 70–90 °C at least for several hours[12b] and often for 1–2
days,[13] albeit the yields were good. Furthermore, in some
cases, satisfactory results were only obtained by carrying
out the reaction under solvent-free conditions, since di-
lution with any solvent decreased the rate and yields dra-
matically.[12b,13a,13b] Therefore, the range of suitable azides
was limited to aryl- and benzyl-type derivatives and hence
this method was inapplicable for the synthesis of triazoles
8 with small R1 alkyl substituents because of the volatile
nature of the corresponding alkyl azides. However, in light
of the modern trend of lowering the molecular weight of
drug candidates, these types of building blocks are in the
most demand from a medicinal chemistry perspective, and
simultaneously, they remain the least available. Moreover,
the prolonged heating of bulk amounts of concentrated az-
ides can be an explosion hazard, even in the case of rela-
tively stable aryl and benzyl azides. Therefore, the scal-
ability of the method is also in question.
Furthermore, the alkylation of ethyl 5-trifluoromethyl-
1H-1,2,3-triazole-4-carboxylate (9)[14] with methyl iodide
was examined[9] as a possible route to the corresponding N-
methyl triazoles. This reaction gave a mixture of three iso-
meric triazoles, of which the major component was N-2- Scheme 2. Retrosynthetic approaches to 1,2,3-triazole core.
2
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Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids
Scheme 3. Synthesis of 1,2,3-triazoles through diazo transfer reaction.
thesis of various 1,2,3-triazoles and their fused deriva- philicity of the enamine carbon atom and, thus, hampered
tives.[17] Due to a resemblance of the initial steps of the the reaction. This reasoning is in agreement with the gene-
process to diazo transfer reactions, this approach to the ral trends of the diazo transfer reaction.[16,17] DBU facili-
1,2,3-triazole core is usually referred to by the same tated the reaction of 3-oxo esters with aryl azides,[12a] and
name,[16,17] although some authors have continued to sup- it was suggested to do the same in the present case. How-
port the unusual and unproven claims of path A, even in ever, DBU appeared to invoke vigorous decomposition of
recent publications.[18]
the mesyl azide at temperatures over 0 °C, which was ac-
The main advantage of this diazo transfer approach to companied by a huge amount of gas evolution. After sev-
1,2,3-triazoles is the unequivocal substitution of the prod- eral experiments, –20 °C was determined as the optimal
ucts, which is entirely predefined by the structure of the temperature for the reaction, since at this point formation
starting enaminone. This feature prompted us to employ of the triazoles 21 did occur, but decomposition of the me-
the method for the preparation of 1-alkyl-5-trifluoro- syl azide was negligible, albeit visible. Therefore, a series of
methyl-1,2,3-triazoles (see Scheme 4). Thus, the enamino es- ethyl 1-alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylates
ters 20 were obtained by condensation of appropriate pri- 21 was obtained in 75–85% yield (see Table 1). Usual hy-
mary amines with ethyl 4,4,4-trifluoroacetoacetate (19) ac- drolysis of the ester group with LiOH·H2O furnished acids
cording to previously described procedures.[19] Typically, di-
azo transfer reactions with sulfonyl azides were carried out
in anhydrous acetonitrile in the presence of sodium hy-
dride.[16c,17a,17c,17d] The application of these conditions to
the reaction of compounds 20 with mesyl azide afforded
simultaneously inspiring and discouraging results. Namely,
the desired products 21 were observed and even isolated
from the reaction mixture, but the reaction was very slow,
and conversion was poor. Perhaps, the strong electron-with-
drawing properties of the CF3 group decreased the nucleo-
Table 1. Preparation of compounds 21 and 22.
Scheme 4. Reagents and conditions: (i) RNH2, CHCl3, AcOH, re-
flux; (ii) DBU (3 equiv.), MeSO2–N3 (3 equiv.), –20 °C Ǟ room
temp.; (iii) LiOH, THF/water, room temp., and then aqueous HCl.
For R group assignment, see Table 1.
[a] Starting material. [b] No reaction observed. [c] Obtained from
compound 21i.
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22. Moreover, the procedures were readily scalable, which
allowed for the preparation of up to 20 g of compounds 22
in one run.
Certain important aspects should be emphasized. First,
this method provided the most desired triazoles 22a–22e,
which contained small alkyl substituents at the 1-position,
in good yields. These compounds were basically unavailable
through other known approaches,[8,9,11–13] and, indeed,
their present synthesis has no alternative to date. However,
a tertiary alkyl group could not be introduced in this way
because we were unable to obtain the appropriate triazole
starting from the tert-butyl derivative 20h. This was an ex-
pected limitation of the method because in the course of
previous studies, N-tert-butyl enaminones 13 were found to
be inert towards sulfonyl azides.[17b,17c] Enamino ester 20i,
with additional functionality, was also employed in the re-
action to afford triazole 21i. The latter was converted into
acid 22i and amine 21j, thus offering different opportunities
for further modification. Since primary amines containing
additional functionalities, and therefore the enaminoesters
of type 20 produced from them, are generally more access-
ible than the corresponding azides, the present method op-
ens greater possibilities for further derivatization of tri-
azoles 21 and 22. Furthermore, the diazo transfer reaction
was applied to the synthesis of benzyl- and phenyl-substi-
tuted triazoles 21f and 21g. These derivatives have already
been prepared through previously known approaches,[11–13]
and, therefore in this case, scalability was the only advan-
tage of the present method. However, the synthesis of
benzyl derivative 21f required a modification of the typical
procedure. Upon treatment with organic bases, enamino es-
ter 20f was reported to undergo isomerization to imine 23
(see Figure 2).[20] As the standard procedure required the
slow addition of mesyl azide to a mixture of compound 20
and DBU, it induced the isomerization of derivative 20f
prior to the diazo transfer reaction. To overcome the issue,
the reagents were introduced in the reverse order, that is,
the DBU was added dropwise to a mixture of enamino ester
20f and mesyl azide, which resulted in the smooth forma-
tion of the target triazole 21f.
Figure 3. X-ray crystal structure of compound 22b·H2O with the
atom numbering used in the crystallographic analysis. The tri-
fluoromethyl group is disordered over the two A and B positions
with a population 25:75%, respectively, as a result of the rotation
around the C-2–C-3 bond.
(24)[22] and ethyl 4,4,4-trifluoroacetoacetate. Further treat-
ment with mesyl azide afforded triazole 26. Again, the re-
verse addition procedure was employed because of the
benzylic nature of the N-substituent in compound 25. Hy-
drolysis of ester 26 furnished the corresponding acid 27,
which was smoothly converted into the target derivative 28
by means of a 1,1Ј-carbonyldiimidazole-mediated amide
formation. The 73% overall yield of compound 28 through
the four-step sequence was achieved. The screening of de-
rivative 28 and its comparison with Rufinamide are believed
to be of interest.
Figure 2. The product of base-induced isomerization of compound
20f.
The structure of the prepared compounds 21 and 22 was
initially confirmed by the comparison of derivatives 21f and
21g with the authentic samples obtained through known
methods.[21] Then, to exclude any doubt, an X-ray crystallo-
graphic study was carried out for derivative 22b (see Fig-
ure 3) to prove the structure unambiguously.
To display an advantage of the diazo transfer approach,
it was applied to the synthesis of trifluoromethyl-substi-
tuted Rufinamide analogue 28 (see Scheme 5). Thus, en-
Scheme 5. Reagents and conditions: (i) ethyl 4,4,4-trifluoroace-
toacetate, AcOH, CHCl3; (ii) MeSO2–N3, DBU; (iii) LiOH·H2O,
THF, room temp., and then aqueous HCl; (iv) 1,1Ј-carbonyldiimid-
amino ester 25 was obtained from 2,6-difluorobenzylamine azole (CDI), acetonitrile, and then NH4OH.
4
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Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids
tion of compound 20f (45.9 g, 0.168 mol) in acetonitrile (500 mL)
that was stirring and cooled to –20 °C. DBU (73 mL, 0.486 mol)
was then added dropwise to the mixture at the same temperature.
Conclusions
The present research has resulted in a new approach to 1-
alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic acids 22, The remaining steps were carried out as in the previous procedure
to afford compound 21f as a colorless liquid.
which are essential building blocks for medicinal and agri-
cultural chemistry that were hitherto unavailable. The diazo
transfer reaction has been implemented for the preparation
of fluorine-containing 1,2,3-triazoles and was shown to be
simple, easy to handle, safe, and scalable, thus providing
substantial benefits over previously known meth-
ods.[8,9,11–13] The unequivocal substitution pattern of the
products 21 is the main reaction feature determined a com-
mon successful outcome.
General Procedure for the Preparation of 1-Substituted 5-Trifluoro-
methyl-1,2,3-triazole-4-carboxylic Acids 22a–22g and 22i:
LiOH·H2O (7.7 g, 0.183 mol) was added in one portion to a solu-
tion of the ester 21 (0.122 mol) in THF/water (1:1, 200 mL). The
reaction mixture was stirred until the solid had dissolved and was
then left overnight at room temperature. The solvents were removed
in vacuo, and the residue was dissolved in water (150 mL). The
resulting solution was washed with diethyl ether (1ϫ100 mL). The
aqueous layer was concentrated to half of its volume and then
acidified with 30% hydrochloric acid (25 mL). A precipitate formed
and was filtered and dried to give 22a–22g and 22i as white pow-
ders.
Experimental Section
General Methods: Enamino esters 20a,[19c] 20c,[19e] 20f,[19a,19b] and
20g,[19d] as well as difluorobenzylamine 24[22] and mesyl azide[23]
were prepared according to the described procedures. Other rea-
gents were commercially available. All melting points were mea-
sured in open capillary tubes with a Thiele apparatus. The 1H, 13C,
and 19F NMR spectroscopic data were recorded using [D6]DMSO
Ethyl 1-(Piperidin-4-yl)-5-trifluoromethyl-1,2,3-triazole-4-carboxyl-
ate Hydrochloride (21j·HCl): Trifluoroacetic acid (TFA, 35 mL,
0.46 mol) was added in one portion to a solution of compound 21i
(18.0 g, 0.046 mol) in CH2Cl2 (350 mL), and the mixture was
stirred at room temperature until the evolution of gas had ceased
(12 h). The solvent was removed in vacuo. The residue was dis-
solved in diethyl ether (150 mL), and to this solution was added
anhydrous dioxane (25 mL) saturated with gaseous HCl. The re-
sulting solid precipitate was filtered and dried to yield the hydro-
chloride salt of compound 21j (12.8 g, 85%) as a white powder.
1
and CDCl3 solutions with a Bruker Avance 500 (500 MHz for H
NMR, 125 MHz for 13C NMR, and 470 MHz for 19F NMR) spec-
trometer. Chemical shifts (δ) are given in ppm downfield from an
internal standard of Me4Si (for 1H and 13C NMR) and CFCl3 (for
19F NMR). Coupling contants (J) are reported in Hz. Elemental
analyses were performed at the Microanalytical Department of the
Institute of Organic Chemistry, NAS, Kiev, Ukraine. The purity of
all prepared compounds was determined by LC–MS with an Ag-
ilent 1100 instrument.
Ethyl 3-[(2,6-Difluorobenzyl)amino]-4,4,4-trifluorobut-2-enoate (25):
2,6-Difluorobenzylamine (3.0 g, 20.9 mmol) was added dropwise to
a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (2.8 mL,
19.1 mmol) and acetic acid (1.2 mL, 20.9 mmol) in CHCl3 (15 mL),
while the temperature was kept below 10 °C by external cooling.
After the addition was complete, the mixture was heated at reflux
for 1 d. Upon cooling, the reaction mixture was cautiously added
to a saturated aqueous NaHCO3 solution (20 mL). The organic
layer was separated, washed sequentially with a 5% aqueous
NaHCO3 solution (20 mL) and brine (20 mL), and dried with
Na2SO4. The solvent was evaporated, and the residue was distilled
under reduced pressure to give compound 25 (4.5 g, 69%) as yellow
liquid.
General Procedure for Preparation of Ethyl 3-Amino-4,4,4-trifluoro-
2-butenoates 20b, 20d, 20e, 20h, and 20i: The appropriate primary
amine (0.18 mol) was added dropwise to a stirred solution of ethyl
4,4,4-trifluoroacetoacetate (33.1 g, 0.18 mol) and acetic acid
(10.8 g, 0.18 mol) in CHCl3 (400 mL), while the temperature was
kept below 10 °C by external cooling. After the addition was com-
plete, the mixture was heated at reflux for 1 d. Upon cooling, the
reaction mixture was cautiously added to a saturated aqueous
NaHCO3 solution (600 mL). The organic layer was separated,
washed sequentially with 5% aqueous NaHCO3 (2ϫ200 mL) and
water (2ϫ200 mL), and then dried with Na2SO4. The solvent was
evaporated, and the residue was distilled under reduced pressure to
give compounds 20b, 20d, 20e, 20h, and 20i as yellow liquids.
Ethyl 1-(2,6-Difluorobenzyl)-5-trifluoromethyl-1,2,3-triazole-4-carb-
oxylate (26): Mesyl azide (4.8 g, 0.040 mol) was added in one por-
tion to a solution of enamino ester 25 (4.1 g, 0.013 mol) in acetoni-
trile (150 mL) that was stirring and cooled to –20 °C. DBU
(6.0 mL, 0.040 mol) was then added dropwise to the mixture at the
same temperature. After the addition was complete, the mixture
was warmed slowly (over 1–2 h) to room temperature, and the stir-
ring was continued for 1 d. The solvent was removed in vacuo, and
the residue was dissolved in EtOAc (50 mL). The resulting solution
was washed sequentially with a saturated aqueous NaHSO4 solu-
tion (3ϫ15 mL) and water (2ϫ15 mL), and then dried with
Na2SO4. The organic extract was evaporated, and the residue was
purified by column chromatography (silica gel, hexane/tBuOMe,
9:1) to yield 26 (3.8 g, 86%) as a colorless liquid.
General Procedure for Preparation of 1-Substituted Ethyl 5-Tri-
fluoromethyl-1,2,3-triazole-4-carboxylates 21a–21e, 21g, and 21i:
DBU (73 mL, 0.486 mol) was added in one portion to a solution
of compound 20 (0.168 mol) in acetonitrile (500 mL) that was stir-
ring and cooled to –20 °C. Mesyl azide (58.9 g, 0.486 mol) was then
added dropwise to the mixture at the same temperature. After the
addition was complete, the mixture was warmed slowly (over 1–
2 h) to room temperature, and the stirring was continued for 1 d.
The solvent was removed in vacuo, and the residue was dissolved
in EtOAc (400 mL). The resulting solution was washed sequentially
with a saturated aqueous NaHSO4 solution (5ϫ300 mL) and water
(2ϫ300 mL) and then dried with Na2SO4. The organic extract was
evaporated, and the residue was purified by column chromatog-
raphy (silica gel, hexane/tBuOMe, 9:1) to yield 21a–21e, 21g, and
21i as colorless liquids.
1-(2,6-Difluorobenzyl)-5-trifluoromethyl-1,2,3-triazole-4-carboxylic
Acid (27): LiOH·H2O (0.28 g, 6.7 mmol) was added in one portion
to a solution of ester 26 (1.51 g, 4.5 mmol) in THF/water (1:1,
20 mL). The reaction mixture was stirred until the solid had dis-
solved and was then left overnight at room temperature. The sol-
vents were removed in vacuo, and the residue was dissolved in
water (15 mL). The resulting solution was washed with diethyl
ether (7 mL). The aqueous layer was concentrated to half of its
Ethyl 1-Benzyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylate (21f):
Mesyl azide (58.9 g, 0.486 mol) was added in one portion to a solu-
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[6]
[7]
E. A. Johnson, R. S. Marks, S. J. Mandrekar, S. L. Hillman,
M. D. Hauge, M. D. Bauman, E. J. Wos, D. F. Moore, J. W.
Kugler, H. E. Windschitl, D. L. Graham, A. M. Bernath, T. R.
Fitch, G. S. Soori, J. R. Jett, A. A. Adjei, E. A. Perez, Lung
Cancer 2008, 60, 200–207.
a) D. O’Hagan, J. Fluorine Chem. 2010, 131, 1071–1081; b) K.
Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881–1886;
c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 2008, 37, 320–330; d) W. K. Hagmann, J. Med. Chem.
2008, 51, 4359–4369; e) R. Filler, Y. Kobayashi, L. M. Yagupol-
skii, in: Organofluorine Compounds in Medicinal Chemistry and
Biochemical Applications, Elsevier, Amsterdam, 1993; f) T. Hi-
yama, in: Organofluorine Compounds, Springer-Verlag, Berlin,
2000; g) B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11.
A. K. Amegadzie, K. M. Gardinier, E. J. Hembre, P. A. Hip-
skind, L. N. Jungheim, B. S. Muehl, K. A. Savin, K. J. Trasher,
WO 2005/000821, 2005.
a) J. Black, J. A. Boehmer, E. J. T. Chrystal, A. M. Kozakiew-
icz, A. Plant, WO 2007/071900, 2007; b) J. E. Boehmer,
M. M. W. McLachlan, WO 2007/096576, 2007.
R. Fischer, C. Grondal, E. R. Gesing, H.-J. Wroblowsky, A.
Hense, E.-M. Franken, A. Voerste, U. Goergens, US Patent
275676, 2011.
a) S. J. Coats, J. S. Link, D. Gauthier, D. J. Hlasta, Org. Lett.
2005, 7, 1469–1472; b) J. Wei, J. Chen, J. Xu, L. Cao, H. Deng,
W. Sheng, H. Zhang, W. Cao, J. Fluorine Chem. 2012, 133,
146–154; c) B. Gold, N. E. Shevchenko, N. Bonus, G. B. Dud-
ley, I. V. Alabugin, J. Org. Chem. 2012, 77, 75–89; d) Z. Shan,
M. Peng, H. Fan, Q. Lu, C. Zhao, Y. Chen, Bioorg. Med. Chem.
Lett. 2011, 21, 1731–1735.
a) F. Stazi, D. Cancogni, L. Turco, P. Westerduin, S. Bacchi,
Tetrahedron Lett. 2010, 51, 5385–5387; b) Yu. A. Rozin, J. Le-
ban, W. Dehaen, V. G. Nenajdenko, V. M. Muzalevskiy, O. S.
Eltsov, V. A. Bakulev, Tetrahedron 2012, 68, 614–618.
a) W. Peng, S. Zhu, Synlett 2003, 187–190; b) W. Peng, S. Zhu,
Tetrahedron 2003, 59, 4395–4404; c) L. J. T. Danence, Y. Gao,
M. Li, Y. Huang, J. Wang, Eur. J. Org. Chem. 2011, 17, 3584–
3587.
volume and then acidified with 30% hydrochloric acid (15 mL).
The resulting precipitate was filtered and dried to give compound
27 (1.30 g, 94%) as a white powder.
1-(2,6-Difluorobenzyl)-5-trifluoromethyl-1,2,3-triazole-4-carbox-
amide (F3C-Rufinamide, 28): CDI (0.58 g, 3.6 mmol) was added to
a solution of acid 27 (1.01 g, 3.3 mmol) in acetonitrile (10 mL) that
was stirring and cooled to 0 °C. The reaction mixture was stirred
until the evolution of gas had ceased (≈1 h). A 25% aqueous am-
monia solution (0.61 g, 36.0 mmol) was then added at once, and
the mixture was stirred at room temperature overnight. The solvent
was removed in vacuo, and the residue was triturated with water.
The solid was filtered and recrystallized from ethanol to yield 28
(0.95 g, 95%) as a white powder.
[8]
X-ray Crystal Structure Analysis of Compound 22b: Intensities of
11055 reflections (2843 independent, Rint = 0.023) were measured
with an Xcalibur-3 diffractometer operated in the ω-2θ scan mode,
2θmax = 60°, and using graphite-monochromated Mo-Kα radiation
(λ = 0.71073 Å). Crystal data: C6H6O2N3F3·H2O, Mr = 227.15,
monoclinic, a = 9.808(1) Å, b = 6.3413(6) Å, c = 15.924(2) Å, β =
99.56(1)°, V = 976.6(2) Å3, T = 293 K, space group P21/c, Z = 4,
μ (Mo-Kα) = 0.158 mm–1. The structure was solved by direct
method with the SHELXTL program package.[24] The positions of
the hydrogen atoms were located from electron difference density
maps and refined by the riding model with Uiso = nUeq of the car-
rier atom (n = 1.5 for the methyl group and n = 1.2 for the remain-
der of the hydrogens). Hydrogen atoms participating in hydrogen
bonds (COOH and H2O) were refined isotropically. During the re-
finement, the restraints were placed on the C–F and Csp3–Csp3
bonds lengths (1.34 and 1.54 Å, respectively). Full-matrix least-
squares refinement against F2 with anisotropic approximation for
the non-hydrogen atoms using 2686 reflections was converged to
wR2 = 0.174, R1 = 0.055 [for 1812 reflections with F Ͼ 4σ(F)], S
= 1.025.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
CCDC-913681 (for 22b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
This compound was prepared by means of a cycloaddition be-
tween p-methoxybenzyl azide and ethyl 4,4,4-trifluoro-2-bu-
tynoate followed by cleavage of the p-methoxybenzyl (PMB)
group from the resulting triazoles.[9]
a) R. T. Chakrasali, H. Ila, H. Junjappa, Synthesis 1988, 851–
854; b) M. F. Gordeev, A. V. Komkov, V. S. Bogdanov, A. V.
Dorokhov, Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 1392–1397;
c) Z. T. Huang, M.-X. Wang, J. Org. Chem. 1992, 57, 184–90.
a) R. Augusti, C. Kascheres, J. Org. Chem. 1993, 58, 7079–
7083; b) R. Augusti, C. Kascheres, Tetrahedron 1994, 50, 6723–
6726; c) G. A. Romeiro, L. O. R. Pereira, M. C. B. V. de Souza,
V. F. Ferreira, A. C. Cunha, Tetrahedron Lett. 1997, 38, 5103–
5106.
Supporting Information (see footnote on the first page of this arti-
cle): Characterizations of all new compounds prepared, including
1
m.p. or b.p. values, elemental analyses data, and copies of H, 13C,
and 19F NMR spectra.
Acknowledgments
[17]
a) A. C. Cunha, L. O. R. Pereira, R. O. P. de Souza, M. C. B. V.
de Souza, V. F. Ferreira, Nucleosides Nucleotides 2001, 20,
1555–1569; b) J. O. F. Melo, C. L. Donnici, R. Augusti, M. T. P.
Lopes, A. G. Mikhailovskii, Heterocycl. Commun. 2003, 9,
235–238; c) J. O. F. Melo, P. M. Ratton, R. Augusti, C. L. Don-
nici, Synth. Commun. 2004, 34, 369–376; d) F. C. da Silva,
M. C. B. V. de Souza, I. I. P. Frugulhetti, H. C. Castro, S. L. O.
Souza, T. M. L. de Souza, D. Q. Rodrigues, A. M. T. Souza,
P. A. Abreu, F. Passamani, C. R. Rodrigues, V. F. Ferreira, Eur.
J. Med. Chem. 2009, 44, 373–383; e) S.-J. Yan, Y.-J. Liu, L. Liu,
J. Lin, Bioorg. Med. Chem. Lett. 2010, 20, 5225–5228.
a) J. Gu, W. Xiong, Z. Zhang, S. Zhu, Synthesis 2011, 1717–
1722; b) A. V. Dorokhov, A. V. Komkov, Russ. Chem. Bull.
2004, 53, 676–680.
The authors are grateful to Vladimir A. Lipetskiy for the chroma-
tographic purifications and Ivan I. Vyzir for the preparation of 2,6-
difluorobenzylamine.
[1] For the most recent reviews about 1,2,3-triazole chemistry and
applications, see: a) D. S. Pedersen, A. Abell, Eur. J. Org. Chem.
2011, 2399–2411; b) Y. L. Angell, K. Burgess, Chem. Soc. Rev.
2007, 36, 1674–1689; c) V. P. Krivopalov, O. P. Shkurko, Russ.
Chem. Rev. (Engl. Transl.) 2005, 74, 339–379.
[2] R. Portmann, US Patent 6,156,907, 2000.
[3] W. H. Mudd, E. P. Stevens, Tetrahedron Lett. 2010, 51, 3229–
3231.
[18]
[19]
[4] H. A. Wier, A. Cerna, T.-Y. So, Pediatric Drugs 2011, 13, 97–
106.
a) V. Michaut, F. Metz, J.-M. Paris, J.-C. Plaquevent, J. Fluor-
ine Chem. 2007, 128, 889–895; b) H. Ohkura, D. O. Berbasov,
V. A. Soloshonok, Tetrahedron 2003, 59, 1647–1656; c) R. G.
Hanreich, H.-T. Wu, M. A. Oliver, D. K. Hoglen, US Patent
2003/216594, 2003; d) W. Wan, J. Hou, H. Jiang, Z. Yuan, A.
[5] a) W. M. Stadler, G. Rosner, E. Small, D. Hollis, B. Rini, S. D.
Zaentz, J. Mahoney, M. J. Ratain, J. Clin. Oncol. 2005, 23,
3726–3732; b) J. P. Dutcher, L. Leon, J. Manola, D. M. Fried-
land, B. Roth, G. Wilding, Cancer 2005, 104, 2392–2399.
6
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Pages: 8
Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids
1
Goubin, J. Hao, G. Zhao, Eur. J. Org. Chem. 2010, 1778–1786;
e) A. W. Lutz, S. H. Trotto, J. Heterocycl. Chem. 1972, 9, 513–
522.
[21] The comparison of H, 13C, and 19F NMR spectroscopic data
of compounds 21f and 21g with the reported data[13] revealed
their sameness.
[20] a) V. A. Soloshonok, A. G. Kirilenko, S. V. Galushko, V. P. Ku-
khar, Tetrahedron Lett. 1994, 35, 5063–5064; b) V. Michaut, F.
Metz, J.-M. Paris, J.-C. Plaquevent, J. Fluorine Chem. 2007,
128, 500–506; c) V. A. Soloshonok, V. P. Kukhar, Tetrahedron
1996, 52, 6953–6964; d) V. A. Soloshonok, A. G. Kirilenko,
V. P. Kukhar, G. Resnati, Tetrahedron Lett. 1993, 34, 3621–
3624.
[22] A. M. Roe, R. A. Burton, G. L. Willey, M. W. Baines, A. C.
Rasmussen, J. Med. Chem. 1968, 11, 814–819.
[23] J. H. Boyer, C. H. Mack, N. Goebel, L. R. Morgan, J. Org.
Chem. 1958, 23, 1051–1053.
[24] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
Received: January 9, 2013
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O30030
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Date: 02-04-13 16:59:31
Pages: 8
A. V. Tverdokhlebov et al.
FULL PAPER
Heterocyclic Chemistry
R. T. Iminov, A. V. Mashkov, B. A. Chalyk,
P. K. Mykhailiuk, A. V. Tverdokhlebov,*
A. A. Tolmachev, Y. M. Volovenko,
O. V. Shishkin, S. V. Shishkina ......... 1–8
A Convenient Route to 1-Alkyl-5-trifluoro-
methyl-1,2,3-triazole-4-carboxylic
Employing a Diazo Transfer Reaction
Acids
A multigram-scale synthesis of 1-alkyl-5-
trifluoromethyl-1,2,3-triazole-4-carboxylic
acids has been developed. The triazole ring
formation by means of a diazo transfer re-
action with mesyl azide was the key step.
Keywords: Synthetic methods / Medicinal
chemistry
/
Nitrogen heterocycles
/
Amines / Azides / Fluorine
8
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Eur. J. Org. Chem. 0000, 0–0