Approaches for the introduction of fluorinated substituents into [1,2,3]Triazolo[1,5-a]pyridines

Article abstract of DOI:10.1016/j.jfluchem.2014.05.001

[1,2,3]Triazolo[1,5-a]pyridines functionalization with a trifluoromethyl group has been achieved for the first time using different synthetic strategies. Furthermore, these scaffolds have been employed as starting material in the synthesis of new 2,6-disubstituted pyridines containing the trifluoromethyl group, compounds that are not available using other methodologies. A fluorine-mediated triazolopyridine dimerisation is described, improving the previously known synthetic method. Preliminary studies focused on exploring triazolopyridines reactivity with electrophilic fluorine have revealed a new approach for the obtainment of imidazopyridines.

Full text of DOI:10.1016/j.jfluchem.2014.05.001

Accepted Manuscript
Title: Approaches for the introduction of fluorinated
substituents into [1,2,3]Triazolo[1,5-a]pyridines
Author: Leonardo Chiassai Rosa Adam Marcela
´
´
Drechslerova Rafael Ballesteros Belen Abarca
PII:
S0022-1139(14)00119-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.05.001
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9-5-2014
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Please cite this article as: L. Chiassai, R. Adam, M. Drechslerova, R.
Ballesteros, B. Abarca, Approaches for the introduction of fluorinated substituents
into [1,2,3]Triazolo[1,5-a]pyridines, Journal of Fluorine Chemistry (2014),
http://dx.doi.org/10.1016/j.jfluchem.2014.05.001
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Approaches for the introduction of fluorinated substituents into
[1,2,3]Triazolo[1,5-a]pyridines
Leonardo Chiassai, Rosa Adam, Marcela Drechslerová, Rafael Ballesteros,* Belén Abarca,*
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia, Avd. Vte. Andrés Estelles s/n, 46100, Burjassot
(Valencia), Spain.
E-mail: Rafael. Ballesteros@uv.es, Belen.Abarca@uv.es. Tel. 34963543054, 34963544933
ABSTRACT
[1,2,3]Triazolo[1,5-a]pyridines functionalisation with a trifluoromethyl group has been achieved for the first time using
different synthetic strategies. Furthermore, these scaffolds have been employed as starting material in the synthesis of new
2,6-disubstituted pyridines containing the trifluoromethyl group, compounds that are not available using other
methodologies. A fluorine-mediated triazolopyridine dimerisation is described, improving the previously known synthetic
method. Preliminary studies focused on exploring triazolopyridines reactivity with electrophilic fluorine have revealed a
new approach for the obtainment of imidazopyridines.
1. Introduction
The insertion of a fluorine atom, or a fluorinated radical, in heterocyclic compounds may modify their
biological, optical or electronic properties. Agriculture and medicine are the two most important areas of
application for ring fluorinated heterocycles, although their use in other fields is becoming increasingly important
[1,2]. Fluorescent probes are also an area of application that should be highlighted [3].
Introduction of a fluorine (or fluorine-bearing fragment) into an already formed heterocyclic moiety is a widely
used synthetic methodology. Several approaches are routinely used to accomplish this transformation. Reactions
with electrophilic fluorine derivatives, by electrophilic replacement of an H atom (including an addition-
elimination pathway), or by trapping lithium derivatives, are the most commonly used methods. Another approach
for the preparation of fluorinated heterocycles is the synthesis from fluorinated building blocks [1,4].
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[1,2,3]Triazolo[1,5-a]pyridines 1 are small but versatile heterocyclic compounds, with an interesting chemistry
widely studied by our group [5]. These compounds are easily obtained from 2-acyl and formyl pyridines (Scheme
1). The application of triazolopyridines as potential drugs (antichagasic and leishmanicide agents [6a], or DNA
interacting agents [6b]), and as fluorescent sensors [7], is currently being explored by our group with promising
results. So far, there is no reported example of triazolopyridine fluorinated derivatives. Given the far-reaching
applicability of these heterocycles, we considered the obtention of fluorinated triazolopyridines an important
challenge, as well as the study of their behaviour towards fluorinating reagents. Herein, we report our results of a
project aimed at the introduction of fluorine, or fluorine-bearing fragments into triazolopyridines.
R
1) NH2NH2, MeOH
2) MnO2, CHCl3
R
N
O
N
N
N
1a R=H, b R=CH3, c R=Ph, d R=2-Py
Scheme 1. Synthesis of [1,2,3]triazolo[1,5-a]pyridines
2. Result and discussion
The first triazolopyridine fluorination approach explored was based on the trapping of a 7-lithium
triazolopyridine with a fluorinating agent. Reaction of 7-lithium-3-methyltriazolopyridine 2b (obtained by
regio-selective lithiation of 1b in THF at -40ºC) [5], with N-fluorobenzene sulphonimide (NFSI) as
electrophile, was performed. Under these conditions the interesting dimer 4b was obtained in excellent yields
(88%), and no fluorinated products were detected (Scheme 2).
The formation of the dimer 4b in this reaction can be explained by a mechanism involving an initial
formation of 7-fluorotriazolopyridine, which could undergo a nucleophilic substitution with another molecule
of 2b (Scheme 2). Nucleophilic substitution reactions in 7-position of triazolopyridines have been widely
studied [8]. It cannot be ruled out that the formation of the dimer is proceeded by a radical process (NFSI
inducing oxidation of the lithic derivative 2b), although according to the literature the nucleophilic
substitution reaction between a 2,6-difluoropyridine and 2-lithiummethylpyridine requires heating [9].
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CH3
N
CH3
N
1) n-BuLi,THF.
-40ºC
N
N
4b
(88%)
N
N
N
2) NFSI, THF
N
N
1b
n-BuLi,THF.
-40ºC
H3C
2b
CH3
CH3
NFSI, THF
N
N
N
N
N
N
Li
F
2b
3b
Scheme 2. Reactivity of the lithium derivative 2b with NFSI
Triazolopyridine dimers have been described in the literature; however these compounds were obtained in
much lower yields and with large amount of side products [10]. Under the conditions described above, dimer
4b is obtained almost pure and in excellent yield, therefore the BuLi/electrophilic fluorine (NFSI)
methodology constitutes an interesting alternative for the obtainment of triazolopyridine dimers.
The lithiation/trapping methodology was also employed in an attempt of functionalising triazolopyridines
with the trifluoromethylcarbonyl moiety. Regioselective lithiation of 1a-c and subsequent treatment with ethyl
trifluoroacetate yielded, instead of the initially expected ketones 5a-c, gem-diols 6 in moderate to good yields
(Scheme 3). It should be highlighted that in the 6a-c 13C spectra, hydrate carbons appear at 91-97ppm as a
quadruplet with a coupling constant of 33 Hz.
R
N
N
N
H2O
OH
OH
R
R
1) n-BuLi,Tol.
-40ºC
F3C
N
N
6a-c
(36-86%)
N
N
O
N
N
2) CF3COOEt
3) HCl,H2O
CH3OH
R
F3C
5a-c
1a-c
N
N
R= H, Me, Ph, 2-Py
N
OH
OCH3
7a-c
F3C
Scheme 3. Equilibrium of the trifluoromethyl ketones and gem-diols
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The gem-diols formation can be easily explained by the addition of water to the previously formed ketone.
Salvador and Saucier [11], studied this reaction on compounds similar to triazolopyridine, and described
stable gem-diols. In that study, the authors concluded that the electronic effect of the trifluoromethyl group
was not the only cause of this unusual stability, but also the stabilisation effect of the H-bond formation
between the acidic OH groups of the diols, and their basic N atoms, was relevant.
HRMS (ESI QTOF) analysis of compounds 6a-c in methanol solution afforded the molecular ions
corresponding to [MH+MeOH]+ (M corresponds to the molecular weight of 5a-c). These results can be
explained by a dehydratation process of compounds 6 under thermal conditions, to form compounds 5, which
may react with the solvent forming 7a-c. (Scheme 3).
In 7-substituted-3-(2-pyridyl)-triazolopyridines a ring-chain isomerization is present [12a].The triazole ring
can migrate from one pyridine to the other by means of an open form. Previous studies indicated that the
observed equilibrium rates of the two possible isomers could be explained by the electronic effect of the
substituent in position 7 [12b,c]. In the case of reaction of 1d under the conditions related above, the electron-
withdrawing effect of trifluoromethyl gem-diol group justifies that 9d appears as the major product; however
an accurate analysis of the NMR spectra revealed the presence of a small amount of 6d. (Scheme 4).
N
N
N
N
N
N
N
N
N
N
N
N
OH
OH
6d
OH
OH
OH
F3C
F3C
F3C
OH
9d
8d
open f or m
Scheme 4. Rearrangement of the 3-(2-pyridyl)-triazolopyridine derivatives
7-Substituted-[1,2,3]triazolo[1,5-a]pyridines are considered important precursors of 2,6-disubstituted
pyridines, since these compounds react with different electrophiles resulting in the triazole ring opening with
lose of nitrogen, affording 2,6-functionalized pyridines [13]. Pyridines fluorination is a topic of great
relevance given a large number of drugs with this heterocyclic structure [1]. Therefore, we decided to study
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the reaction of compounds 6a-c and 9d with acetic acid aiming at the obtention of new fluorinated pyridines
(Scheme 5).
R
R
R
AcOH
N
OAc
OAc
N
N
N
O
N
OH
OH
6a-c
OH
OH
F3C
F3C
F3C
10a-c
(42-64%)
11c
N
N
N
N
N
N
AcOH
N
N
H
OH
OH
OH
OH
F3C
9d
F3C
Scheme 5. Triazole ring opening reactions of triazolopyridines
Compounds 6a-c reacted with acetic acid affording 2,6-disubstituted pyridines 10a-c bearing a CF3 moiety,
which are not available by other methods. Surprisingly, in the case of compound 10c (R = Ph), 11c is also
observed in NMR. Treatment of compound 9d with acetic acid, under the same conditions, did not afford the
corresponding 2,6-disubstituted pyridine. The lack of reactivity of 9d can be explained by the protonation of
the pyridine nitrogen affording a species stabilised by H-bond formation (Scheme 5 bottom). This particular
stability towards acids had also been observed in similar systems [14].
The reactivity of triazolopyridines towards different electrophiles has been extensively reported in the
literature [5,13,15,16]. These kind of reactions yield either 3-substituted triazolopyridines or 2-substituted
pyridines, depending on the electrophile. However, an electrophilic fluorine has, so far, never been employed
to activate triazolopyridines. In this context, we focused on studying the reactivity with electrophilic fluorine
reagents (NFSI and Selectfluor) [17].
Triazolopyridine reactions with NFSI and Selectfluor under various conditions were performed. Reaction
with triazolopyridine 1a and NFSI did not afford the fluorination product 1e, and complex mixtures were
found (Scheme 6). In the case of Selectfluor, when reactions of triazolopyridine 1a were performed in THF,
toluene, or DMF similar results were observed; however, when acetonitrile was used as solvent, surprisingly
1-methylimidazo[1,5-a]pyridine 12a was formed in moderate yield (30%) (Scheme 6).
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Due to the great interest of synthesizing imidazo[1,5-a]pyridines from the easily accessible
triazolopyridines, we decided to assay this reaction with other triazolopyridines. Triazolopyridine 1c, under
similar conditions, gave 3-phenyl-1-methylimidazo[1,5-a]pyridine 12c in small yield (6%). A small amount
of 2-benzoylpyridine 13c was also isolated in this reaction. In the case of triazolopyridine 1d, a complex
mixture was observed, and only the 2-dipyridyl ketone 13d was identified in very low yield (3%). Another
interesting result was obtained with 3-methyltriazolopyridine 1b, since the imidazopyridine 14 was isolated
after chromatographic purification using methanol as eluent (Scheme 6, bottom).
R
R
F
R
R = H
NFSI
Selectfluor
O
N
+
N
N
N
N
N
N
CH3CN, reflux
N
N
CH3
12a R=H,
12c R=Ph
1a,c,d
1e
13c R= Ph
13d 2-Py
O
CH3
CH3
N
Selectfluor
N
N
N
CH3CN, reflux
N
CH3
14
1b
Scheme 6. Synthesis of the imidazo[1,5-a]pyridines
To explain the formation of compounds 12a,c and 14 a plausible mechanism, based on the widely studied
mechanism of the triazolopyridine ring opening reaction with acids [13], may be proposed. The 3-position of
the triazolopyridine may undergo an electrophilic fluorination in the presence of Selectfluor to form
intermediate 15, which may be in equilibrium with the open diazo form 16. The diazo intermediate is able to
lose nitrogen forming fluorocarbocation 17. This kind of carbocations are known to be highly stabilized [18].
Intermediate 17 could react with acetonitrile forming 18, which can cyclize in a 5-endo-dig process to form a
pyridinium cation 19. The latter intermediate finally converts into imidazopyridine 12, probably due to the
nucleophilic attack of the tertiary bicyclic amine derived from Selectfluor on Fluorine. In the case of R= CH3,
the base promoted elimination of HF by the bicyclic amine competes effectively to give methyleneimidazo-
pyridine intermediate 20, which undergoes a nucleophilic attack by methanol to give the corresponding
methoxymethyl substituted imidazopyridine 14 (Scheme 7). Reaction of carbocation 17 with water would
explain the formation of ketones 13, due to an addition-elimination process.
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R
R
R
F
F
Selectfluor
N2
N
N
N
N
CH3CN, reflux
N
N
N
16
1a-d
15
R
R
R
F
F
F
CH3CN
N
N
N
N
N
N2
17
CH3
18
CH3
19
R= CH3
H2O
R
R = Py or Ph
CH2OCH3
R
MeOH
O
N
N
N
N
N
N
N
CH3
CH3
CH3
12a,c
14
13c,d
20
Scheme 7. Proposed mechanism for the obtention of imidazo[1,5-a]pyridines 12a,c and 14.
Triazolopyridines reactions with Selectfluor in acetonitrile constitute a new procedure to access
imidazo[1,5-a]pyridines, compounds which represent an interesting scaffold of pharmacological active drugs
[19,20].
With the aim of obtaining larger structural diversity of fluorine functionalised triazolopyridines, a synthetic
strategy based on the use of fluorinated building blocks was employed. Unknown 3-trifluoromethyl
triazolopyridine 21 in 24% yield was prepared from 2-trifluoromethylcarbonylpyridine 22, by reaction of this
compound with tosylhydrazine, followed by NaOH treatment [21]. In this reaction 2,2,2-trifluoro-1-(pyridin-
2-yl)-ethanol 23 was also obtained [22]. The formation of this alcohol can be explained by the decomposition
of the diazo intermediate, in equilibrium with the corresponding triazolopyridine, to give a carbene that is
able to react with water [12a]. The standard triazolopyridines synthesis procedure, with hydrazine and further
oxidation with MnO2 in chloroform [23], also afforded the trifluoromethyltriazolopyridine 21, but in lower
yield. This compound was subjected to the lithiation/trapping methodology using ethyltrifluoroacetate as
electrophile. This route afforded the gem-diol 25 in moderate yield (36%), by the reaction of the first formed
ketone 24 with water (Scheme 8).
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CF3
N
CF3
OH
CF3 1) TsNHNH2, EtOH
2) NaOH
O
+
N
N
N
N
23
21
22
1) n-BuLi,Tol.
-40ºC
2) CF3COOEt
3) HCl,H2O
CF3
CF3
H2O
N
N
N
O
N
N
N
OH
OH
25 (36%)
F3C
F3C
24
Scheme 8. Synthesis of trifluoromethyltriazolpyridines 21, and 25
3. Conclusions
The lithiation/trapping methodology enabled us to achieve a straightforward trifluoromethyldihydroxy-
methyl functionalisation of triazolopyridines. Furthermore, this methodology allows the obtention of new 2,6-
disubstituted pyridines containing the trifluoromethyl group with good yields. This reaction constitutes a new
example of the great utility of triazolopyridines as pyridine precursors and opens an interesting strategy in the
field of pyridines fluorination. The lithiation/trapping methodology applied to achieve the direct introduction
of fluorine into the triazolopyridine ring has resulted in the synthesis of dimer 4 in high yields.
The direct reaction of triazolopyridines with Selectfluor in acetonitrile led to imidazopyridines 12. This
reaction constitutes a new route for the obtainment of these pharmacologically relevant heterocycles, and we
are currently working to improve the applicability of this methodology.
New 3-trifluoromethyltriazolopyridine 21 and 3-trifluoromethyl-7-(2-trifluoro-1,1-dihydroxyethyl)-
triazolopyridine 25 were obtained in moderate yields from previously fluorinated building blocks.
4. Experimental
4.1 General methods
Commercial starting materials were purchased and used as such, provided that adequate checks (melting
ranges, refractive indices, and gas chromatography) had confirmed the claimed purity. When known
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compounds had to be prepared according to the procedures in the literature, pertinent references are given. Air
sensitive materials were stored in Schlenk tubes, being handled under argon atmosphere, using appropriate
glassware. Tetrahydrofuran was dried by distillation from sodium after the characteristic blue colour of
sodium diphenyl ketyl (benzophenone-sodium “radical-anion”) had been found to persist. Ethereal or other
organic extracts were dried by washing with brine and then by storage over sodium sulphate. Melting points
were determined on a Kofler heated stage and are uncorrected. NMR spectra were recorded on a Bruker
AC300MHz in CDCl3 or DMSO-d6 as solvent. Chemical shifts are reported in δ units, parts per million (ppm)
and were measured relative to the signals for residual chloroform (7.27 ppm). HRMS Electron Impact (EI)
Quadrupole time of flight (QqTOF) 5600 system (Applied Biosystems-MDS Sciex). Mode positive.
Conditions: Gas1 35 psi, GS2: 35, CUR: 25, temperature: 450ºC, ion spray voltage: 5500 V. Collision energy
(CE): 25-35 V. IR spectra were recorded using a Thermo-scientific Nicolet FT IR iS10 ATR. Column
chromatography was carried out on a column packed with silica-gel 60N spherical neutral size 63-210 μm.
Chromatotron was used in several cases. [1,2,3]Triazolo[1,5-a]pyridine 1a [24], 3-methyl-[1,2,3]Triazolo[1,5-
a]pyridine 1b [21], 3-phenyl-[1,2,3]triazolo[1,5-a]pyridine 1c [21], 3-(2-pyridyl)-[1,2,3]triazolo[1,5-a]
pyridine 1d [23] were prepared as described elsewhere.
4.2 Reaction between the 7-lithium-3-methyl-[1,2,3]triazolo[1,5-a]pyridine 2b and N-fluorobenzene
sulphonimide (NFSI). Synthesis of 3,3'-dimethyl-7,7'-bi[1,2,3]triazolo[1,5-a]pyridine 4b.
At -40°C, butyllithium (1.4 mL, 2.25 mmol, 1 eq) in hexane (1.4 M) was added dropwise to a stirred
solution of 3-methyl-[1,2,3]triazolo[1,5-a]pyridine 1b (0.3 g, 2.25 mmol 1 eq) in THF (50 mL). A dark red
colour developed. Lithiated triazolopyridine was poured, using a double-needle, over a solution of N-
fluorobenzenesulfonimide (NFSI) (0.71g, 2.23mmol, 1 eq) in THF (10mL). The mixture was left at -40 ºC
(1h) and allowed to reach room temperature, a saturated aqueous solution of ammonium chloride (20 mL) was
added, followed by extraction with dichloromethane (3 x 20 mL). The combined organic layers were dried
over sodium sulphate, filtered, and evaporated. A solid was obtained by treatment with ethyl acetate,
identified as 3,3'-dimethyl-7,7'-bi[1,2,3]triazolo[1,5-a]pyridine 4b (0.29g, 88%, mp 239-240 ºC, lit.[10] 238-
240 ºC ethyl acetate/hexane.
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4.3 General procedure for lithiation of [1,2,3]triazolo[1,5-a]pyridines (1a-d) and reaction with ethyl
trifluoracetate.
To a solution of the corresponding [1,2,3]triazolo[1,5-a]pyridine 1a-d in anhydrous toluene at -40 ºC, a
solution of n-butyllithium in hexane (1,6 M) (10% excess) was added dropwise whilst being stirred for twenty
minutes. A deep red colour developed. The mixture kept at -40 ºC, and a solution of ethyl trifluoroacetate (1.1
eq) in dry toluene (10 mL) was dropped in twenty minutes, producing a colour change to yellow. The mixture
remained at -40 ºC (2h) and left at room temperature overnight. Then, it was treated with hydrochloric acid
and ice. The organic layer was separated and the aqueous layer extracted several times with ethyl acetate. The
combined extracts were washed twice with a saturated solution of NaHCO3 and then with water. After drying
over anhydrous Na2SO4 and evaporation of the organic solvents, a residue was obtained. Precipitation with
ethyl acetate gave yellow solids, compounds 6a-c and 9d. In some cases the filtrate was evaporated to dryness
and the residue purified by chromatotron with hexane/ethyl acetate as eluent, to obtain an additional amount
of compounds.
4.3.1. 2,2,2-Trifluoro-1-([1,2,3]triazolo[1,5-a]pyridin-7-yl)-ethane-1,1-diol 6a. Yellow solid: (1,6 g, 40%);
mp 124 ºC (dec.); IR (ATR) (cm-1) 3311, 3114, 3097, 1385, 1254, 1160, 1021, 733. 1H NMR (300 MHz,
MeOD-d4) δ= 8.27 (s, 1H), 8.07 (dd, J = 8.8, 1.3 Hz, 1H), 7.60 (dd, J = 7.0, 1.3 Hz, 1H), 7.49 (dd, J = 8.8, 7.0
Hz, 1H), 4.9(sbr,2H). 13C NMR (75 MHz, MeOD-d4) δ 136.99 (C), 132.86 (C), 126.82 (CH), 126.62(CH)
123.91 (C, q, J = 288.3 Hz), 121.38 (CH), 120.74 (CH), 97.53 (C, q, J= 33.5Hz). 19F NMR (282 MHz,
MeOD-d4) δ = -85.72. MS (EI): m/z (%) = 248(6.3), 216(100), 188(3). HRMS (ESI-TOF) m/z Calcd. for
C9H9F3N3O2 [MH+MeOH]+ 248.0641, found 248.0638.
4.3.2. 2,2,2-Trifluoro-1-(3-methyl-[1,2,3]triazolo[1,5-a]pyridin-7-yl)-ethane-1,1-diol 6b. Yellow solid: (626
1
mg, 86%); mp 131 ºC (dec.); IR (ATR) (cm-1) 3272, 3095, 3072, 2936, 2850, 1404, 1263, 1177, 741. H
NMR (300 MHz, MeOD-d4) δ= 7.95 (dd, J = 8.8, 1.3 Hz, 1H), 7.52 (dd, J = 7.0, 1.3 Hz, 1H), 7.41 (dd, J =
8.8, 7.0 Hz, 1H), 4.91 (sbr, 2H), 2.62 (s, 3H). 13C NMR (75 MHz, MeOD-d4) δ=135.69 (C), 134.52 (C), 132.35
(C), 125.26 (CH), 123.75 (C, q, J = 288.5 Hz), 120.79 (CH), 120.47 (CH), 97.46 (C, q, J = 33.8 Hz), 9.98
(CH3). 19F NMR (282 MHz, MeOD-d4) δ = -80.31. MS (EI): m/z (%) = 262(6), 230(100). HRMS (ESI-TOF)
m/z Calcd. for C10H11F3N3O2 [MH+MeOH]+ 262.0798, found 262.0799.
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4.3.3. 2,2,2-Trifluoro-1-(3-phenyl-[1,2,3]triazolo[1,5-a]pyridin-7-yl)ethane-1,1-diol 6c. Bright yellow solid:
(1,9 g, 55,5%); mp 173 ºC (dec.); IR (ATR) (cm-1): 3283, 3114, 3078, 2865, 1415, 1400, 1271, 1179, 1093,
794, 733, 699. 1H NMR (300 MHz, MeOD-d4) δ= 8.29 (dd, J = 8.8, 1.3 Hz, 1H), 7.97-7.93 (m, 2H), 7.64 (dd,
J = 7.0, 1.3 Hz, 1H), 7.59-7.51 (m, 3H), 7.43 (dd, J = 8.8, 7.0 Hz, 1H), 4.92 (sbr, 2H). 13C NMR (75 MHz,
MeOD-d4) δ 139.12 (C), 133.40 (C), 133.16 (C), 131.95 (C), 130.22 (CH), 129.48 (CH),128.12 (CH), 127.19
(CH), 123.93 (C, q, J = 288.2 Hz), 122.02 (CH), 121.01 (CH), 96.25 (C, q, J = 33.0 Hz). 19F NMR (282 MHz,
MeOD-d4) δ = -85.54. MS (EI): m/z (%) = 324(12), 292(100), 264(70), 167(62), 166(25). HRMS (ESI-TOF)
m/z Calcd. for C15H13F3N3O2 [MH+MeOH]+ 324.0954, found 324.0959.
4.3.4. 2,2,2-Trifluoro-1-[6-([1,2,3]triazolo[1,5-a]pyridin-3-yl) pyridin-2-yl]ethane-1,1-diol 9d. Yellow solid:
(1,84g, 72%); mp 142-144 ºC; IR (ATR) (cm-1): 3419, 3228, 1599, 1529, 1268, 1177, 1146, 1068, 949, 816,
738. 1H NMR (300 MHz, MeOD-d4) δ= 8.97 (dd, , J = 7.0, 1.1 Hz, 1H), 8.76 (dd, , J = 8.9, 1.1 Hz, 1H), 8.31
(d, J = 7.9 Hz, 1H), 8.03 (dd, J = 7.9, 7.9, Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.57 (ddd, J= 6.7, 7.0, 1.0Hz,
1H), 7.26 (ddd, J= 8.9, 7.0, 1.0Hz, 1H), 4.92 (sbr, 2H). Some signals also appear assignable to 6d: 8.74 (dd, J
= 8.9, 1.2 Hz, 1H), 8.29 (dd, J = 7.9, 1.0 Hz, 1H), 8.01 (dd, J = 7.9, 7.9, Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H). 13C
NMR (75 MHz, MeOD-d4) δ 154.53 (C), 152.18 (C), 139.15 (CH), 136.49 (C), 132.40 (C), 128.69 (CH),
126.73 (CH), 123.12 (C, q, J=287.0Hz), 122.83(CH), 121.76 (CH), 121.64 (CH), 117.99 (CH), 92.00 (C, q,
J= 33.0Hz). Besides are some small signals assignable to 6d: 138.88, 128.49, 126.68, 122.38, 121.85, 120.99,
117.90. 19F NMR (282 MHz, MeOD-d4) δ = -83.87. MS /EI): m/z (%) = 279(8.6), 265(100), 239(24.6),
195(22), 168(42), 167(37). HRMS (ESI-TOF) m/z Calcd. for C14H12F3N4O2 [MH+MeOH]+ 325.0907, found
325.0902.
4.4. General procedure for triazole ring opening of 2,2,2-trifluoro-([1,2,3]triazolo[1,5-a]pyridin-7-yl)-
ethane-1,1-dioles (6a-c).
A solution of the corresponding 2,2,2-trifluoro-1-([1,2,3] triazolo[1,5-a]pyridin-7-yl)ethane-1,1-diol 6a-c
(1mmol) in acetic acid (2ml) was heated to reflux for 10h. The acetic acid was evaporated and the residue
neutralised with NaHCO3/water and extracted with dichloromethane. The organic layer was dried over
Na2SO4, filtered and evaporated. The residue was purified by chromatotron with hexane/ethyl acetate as
eluent to obtain 10a-c.
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4.4.1 [6-(2,2,2-Trifluoro-1,1-dihydroxyethyl)-pyridin-2-yl]methyl acetate 10a. White solid: (170 mg, 64%);
mp 79-81 ºC; IR (ATR) (cm-1): 3341, 2949, 2911, 1736, 1376, 1225, 1171, 796. 1H NMR (300 MHz, CDCl3)
δ= 7.83 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 5.42 (s, 2H), 5.19 (s, 2H), 2.11
(s, 3H). 13C NMR (75 MHz, CDCl3) δ= 170.81 (C), 154.20 (C), 152.43 (C), 139.09 (CH), 123.26 (CH),
122.80 (C, q, J= 287.4Hz), 121.63 (CH), 91.96 (C, q, J= 33.3Hz), 66.04 (CH2), 20.94 (CH3). 19F NMR (282
MHz, MeOD-d4) δ = -84.57. MS (EI): m/z (%) = 266(2.5), 224(21), 206(100), 188(28). HRMS (ESI-TOF)
m/z Calcd. for C11H13F3NO4 [MH+MeOH]+ 280.0791, found 280.0781.
4.4.2. 1-[6-(2,2,2-Trifluoro-1,1-dihydroxyethyl)-pyridin-2-yl]ethyl acetate 10b. White solid: (60 mg, 42%);
mp 86-88 ºC; IR (ATR) (cm-1): 3334, 3314, 1701, 1374, 1254, 1171, 1146, 1077, 946, 799, 752. 1H NMR
(300 MHz, CDCl3) δ = 7.80 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 5.86 (q, J =
6.7 Hz, 1H), 5.67 (s,1H), 2.05 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ= 170.62 (C),
158.55 (C), 152.31 (C), 139.09 (CH), 122.81 (C, q, J = 287.3Hz), 121.96 (CH), 121.40 (CH), 91.96 (C, q,
J=33.1Hz), 72.39 (CH2), 21.19 (CH3), 20.56 (CH). 19F NMR (282 MHz, MeOD-d4) δ = -84.57. MS (EI): m/z
(%) = 276(1), 216(80), 202(100). HRMS (ESI-TOF) m/z Calcd. for C12H15F3NO4 [MH+MeOH]+ 294.0948,
found 294.0949.
4.4.3. Phenyl-[6-(2,2,2-trifluoro-1,1-dihydroxyethyl)-pyridin-2-yl]methyl acetate 10c. White solid: (162 mg,
62 %); mp 89-91 ºC; IR (ATR) (cm-1): 3369, 3222, 1735, 1374, 1238, 1182, 1053, 694. 1H NMR (300MHz,
CDCl3) Major product 10c δ= 7.88 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H),
7.44-7.35 (m, 2H), 7.30-7.10 (m, 2H), 6.83-6.69(m,1H) 6.77 (s, 1H), 5.61 (s, 2H), 2.10 (s, 3H). Minor product
11c δ = 7.98 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.55(sbr, 1H), 7.51(sbr, 1H),
7.50-7.47 (m, 2H), 7.38-7.28 (m, 3H), 6.79 (s, 1H), 2.18 (s, 3H). 13C NMR (75 MHz, CDCl3) Major product
δ= 170.26 (C), 159.62 (C), 157.29 (C), 147.78 (C), 139.09 (CH), 138.10 (CH), 128.75 (CH), 127.38 (CH),
126.04 (CH), 123.73 (CH), 116.76 (C, q, J = 289.5 Hz), 91.87 (C, q, J = 33.3 Hz), 77.33 (CH), 20.93 (CH3).
Minor product: 13C NMR (75 MHz, CDCl3) δ = 180.56 (C, q, J= 34Hz), 170.04 (C), 157.80 (C) 152.51 (C),
150.97 (C), 139.24 (CH), 138.20 (CH), 128.64 (CH), 127.25 (CH), 127.07 (CH), 122.79 (C, q, J = 285.7Hz),
77.04 (CH), 21.03 (CH3). 19F NMR (282 MHz, CDCl3) Major product δ= -72.18, Minor product -84.47, MS
(EI): m/z (%) = 296(62), 264(100). HRMS (ESI-TOF) m/z Calcd. for C17H17F3NO4 [MH+MeOH]+ 356.1104,
found 356.1104.
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4.5. Reaction between triazolopyridines 1a-d with Selectfluor®. Synthesis of imidazo[1,5-a]pyridines 12
and 14. General Procedure
A solution of [1,2,3]triazolo[1,5-a]pyridine 1a-d (1eq.), and Selectfluor® (1,1 molar equivalent) in
acetonitrile (10ml.) was refluxed and controlled by TLC. When no starting material was present, the solvent
was evaporated and the crude mixture was purified using column chromatography.
4.5.1. 1-Methylimidazol[1,5-a]pyridine 12a. White solid: (30%yield). mp 55 °C, lit 55ºC [25]. 1H NMR (300
MHz, CDCl3): δ = 7.71 (ddd , J = 7.6, 1.2, 1.0 Hz, 1H), 7.44 (ddd, J = 9.2, 1.2, 1.3Hz, 1H), 7.39 (d, J = 1 Hz,
1H), 6.73 (ddd, J = 9.2, 6.4, 1.0 Hz, 1H), 6.64 (ddd, J = 7.6, 6.4, 1.3 Hz, 1H), 2.71 (s, 3H). 13C NMR (75
MHz, CDCl3): δ = 134.80 (C), 130.32 (C), 120.79 (CH), 118.82 (CH), 118.68 (CH), 116.83 (CH), 113.31
(CH), 12.28 (CH3). MS (EI): m/z(%) = 133(8.6), 131(24.7), 118(28.1), 117(13.6), 116(8.6), 106(100.0),
104(12.4). HRMS for C8H8N2: Calcd. [M+H+] 133.0766; found 133.0762
1
4.5.2. 3-(Methoxymethyl)-1-methylimidazol[1,5-a]pyridine 14. Oil. (16 % yield). H NMR (300 MHz,
CDCl3): δ = 7.62 (ddd, J = 7.1, 1.1, 1.1 Hz, 1H), 7.47 (ddd, J = 9.2, 1.2, 1.1 Hz, 1H), 6.67 (ddd, J = 9.2, 6.4,
1.1 Hz, 1H), 6.54 (ddd, J = 7.1, 6.4, 1.1 Hz 1H), 4.69 (s, 2H), 3.41 (s, 3H), 2.62 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ = 134.47 (C), 128.59 (C), 126.90 (C), 120.77 (CH), 117.96 (C), 117.89 (CH), 112.45 (CH),
67.47(CH2), 58.05 (CH3), 12.58 (CH3). MS (EI): m/z(%) = 145(100), 104(40). HRMS for C10H13N2O: Calcd.
[M+H+] 177.1022; found 177.1022.
4.5.3 3-Phenyl-1-methylimidazol[1,5-a]pyridine 12c. Oil [20b]. (6% yield). 1H NMR (300 MHz, CDCl3): δ =
7.86 (m, 2H), 7.78 (ddd, J = 9.3, 1.2, 1.1 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.44 (m, 2H), 7.26 (m, 1H), 6.74
(ddd, J = 9.3, 6.4, 0.9 Hz, 1H), 6.59 (m, 1H), 2.71 (s, 3H)..13C NMR (75 MHz, CDCl3): δ = 137.2 (C), 133.5
(C), 131.12 (C), 128.97 (CH), 128.31 (C), 126.77 (CH), 126.68 (CH), 121.15 (CH), 119.40 (CH), 119.23
(CH), 113.41 (CH), 12.36 (CH3). MS (EI): m/z (%) = 209(3.7), 194(2.5), 168(56.8), 167(100), 166(7),
139(2.5). HRMS for C14H13N2: Calcd. [M+H+] 209.1079; found 209.1063. We are isolated also the 2-
pyridylphenyl ketone 13c (12%).
4.6. Preparation of 3-trifluoromethyl-[1,2,3]triazolo[1,5-a]pyridine 21
To a solution of 2-trifluoromethylcarbonylpyridine 22 (prepared as described [11]) in ethanol 96%, 1,1 eq.
of tosylhydrazine (1.1eq) and an aqueous solution of NaOH (1,1 eq. 36%) were added. The mixture was
13
Page 13 of 18

refluxed for 8h and then the solvent removed. The 2,2,2-trifluoro-1-(pyridin-2-yl)ethanol 23 [22] was the first
compound isolated in purification by chromatotron using hexan/ethyl acetate as eluent, then 3-
trifluoromethyl-[1,2,3]triazolo[1,5-a]pyridine 21 was eluted. Yellow solid: (26 mg, 24%); mp 54-55 ºC
1
(AcOEt.); H NMR (300 MHz, CDCl3) δ = 8.75 (ddd, J = 7.1, 1.0, 1.0 Hz, 1H), 7.81 (ddd, J = 9.0, 1.1, 1.1
Hz, 1H), 7.43 (ddd, J = 9.0, 6.8, 1.0 Hz, 1H), 7.09 (ddd, J = 7.1, 6.8, 1.1 Hz, 1H). 13C NMR (75 MHz, CDCl3)
δ = 131.96 (C), 128.43 (CH), 128.06 (C), 125.92 (CH), 121.52 (C, q, J = 267.4 Hz), 117.35 (CH), 116.42
(CH). 19F NMR (282 MHz, CDCl3) δ = -59.94 (s). MS (EI): m/z (%) = 188(1), 140(56), 120(75), 113(100),
100(35). HRMS (ESI-TOF) m/z Calcd. for C7H5F3N3 [M+H+] 188.0430, found 188.0428.
4.7. Synthesis of 2,2,2-trifluoro-1-[3-(trifluoromethyl)-[1,2,3]triazolo[1,5-a]pyridin-7-yl]ethane-1,1-diol
25.
To a solution of 3-trifluoromethyl-[1,2,3]triazolo[1,5-a]pyridine 21 in anhydrous toluene at -40 ºC, a
solution of n-butyllithium in hexane (1,6 M) (10% excess) was added dropwise whilst being stirred for twenty
minutes. A deep red colour developed. The mixture kept at -40 ºC, and a solution of ethyl trifluoroacetate (1.1
eq) in dry toluene (10 mL) was dropped in twenty minutes, producing a colour change to yellow. The mixture
was left at -40 ºC (2h) and left at room temperature overnight. Then it was treated with hydrochloric acid in
ice. The organic layer was separated and the aqueous layer extracted several times with ethyl acetate. The
combined extracts were washed twice with a saturated solution of NaHCO3 and then with water. After drying
over anhydrous Na2SO4 and evaporation of the organic solvents, a residue was obtained. Precipitation with
ethyl acetate gave a solid identified as 2,2,2-Trifluoro-1-[3-(trifluoromethyl)- [1,2,3]triazolo[1,5-a]pyridin-7-
yl]ethane-1,1-diol 25. White solid: (40mg, 36%); mp 81-83 ºC; IR (ATR) (cm-1): 3439, 3134, 1646, 1549,
1457, 1360, 1272, 1176, 1117, 1056, 999, 900, 797, 742, 681. 1H NMR (300 MHz, MeOD-d4) δ = 8.11 (dd, J
= 7.1 Hz, 1H), 7.76 (sbr, 1H), 7.76 (d, J= 7.1Hz 1H), 7.72 (d, J = 7.1 Hz, 1H), 4.85 (sbr, 1H). 13C NMR (75
MHz MeOD-d4) δ = 134.82 (C), 134.38 (C), 131.00 (CH), 130.12 (CH), 123.76 (C, q, J = 288.5 Hz), 122.94
(C, q, J = 266.5 Hz), 121.72 (CH), 119.87 (CH), 97.35 (C, d, J = 35 Hz). 19F NMR (282 MHz, MeOD-d4) δ =
-61.54, -83.49. MS (EI): m/z (%) = 284(100), 236(19), 186 (50), 158(52). HRMS (ESI-TOF) m/z Calcd for
C10H7F6N3O2 [MH+MeOH]+ 316.0515, found 316.0519.
14
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Acknowledgments
We are grateful to the Ministerio de Ciencia e Innovación (Spain) (Project CONSOLIDER-INGENIO
SUPRAMED CSD 2010-00065), to Generalitat Valenciana (Valencia, Spain) (project PROMETEO
2011/008) for their financial support, and to the SCSIE for carrying out the HRMS spectra. R. A. would like
to thank Generalitat Valenciana for a doctoral fellowship.
References and notes
[1] Edited by A. A. Gakh,; K. L. Kirt, Fluorinated Heterocycles, American Chemical Society, 2009.
[2] W. K. Hagmann, J. Med. Chem. 51 (2008) 4359-4369.
[3] R. Uchiyama, T. Santa, N. Okiyama, T. Fukushima, K. Imai, Biomed. Chromattogr.15 (2001) 295-
318.
[4] R. Ruzziconi, F. Buonerba, J. Fluorine Chem. 152 (2013) 12-28.
[5] a) G. Jones, B. Abarca Adv. Heterocycl. Chem.100 (2010) 195-252. b) B. Abarca, J. Enz. Inh. Med.
Chem. 17 (2002) 359-367. c) G. Jones, Adv. Heterocycl. Chem. 83 (2002) 1-70. d) G. Jones, R. D.
Sliskovic, Adv. Heterocycl. Chem. 34 (1983) 79-143.
[6] a) B. Abarca, R. Adam, R. Ballesteros, P. Bilbao, M. A. Dea-Ayuela, E. González-Rosende, M.
Lapier, J. D. Maya, C. Olea-Azar, b) R. Adam, G. Alzuet, R. Ballesteros, B. Abarca, P. Bilbao, M.
A. Dea-Ayuela, E. González-Rosende, XXIInd International Symposium on Medicinal Chemistry.
ISMC 2012. Berlin, (Germany).
[7] R. Ballesteros-Garrido, B. Abarca, R. Ballesteros, C. Ramirez de Arellano, F. R. Leroux, F.
Colobert, E. Garcia-España, New J. Chem. 33 (2009) 2102-2106.
[8] B. Abarca, R. Ballesteros, G. Jones, F. Mojarrad, Tetrahedron Lett. 27 (1986) 3543-3546.
[9] G. Dyker, O. Muth, Eur. J. Org. Chem. (2004) 4319-4322
[10] G. Jones, M. A. Pitman, E. Lunt, D. J. Lythgoe, B. Abarca, R. Ballesteros, M. Elmasnaouy,
Tetrahedron 53 (1997) 8257-8268.
[11] R. L. Salvador, M. Saucier, Tetrahedron 27 (1971) 1221-1226.
[12] a) B. Abarca, R. Ballesteros, M. Chadlaoui, Tetrahedron 60 (2004) 5785-5792. b) B. Abarca, I.
Alkorta, R. Ballesteros, F. Blanco, M. Chadlaoui, J. Elguero, F. Mojarrad, Org. Biomol. Chem. 3
15
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(2005) 3905-3910. c) R. Ballesteros-Garrido, E. Delgado-Pinar, B. Abarca, R. Ballesteros, F. R.
Leroux, F. Colobert, R. J. Zaragoza, E. Garcia-España, Tetrahedron 68 (2012) 3701-3707.
[13] a) G. Jones, D. R. Sliskovic, Tetrahedron Lett. 21 (1980) 4529-4530. b) G. Jones, D. J. Mouat, D. J.
Tonkinson, J. Chem. Soc. Perkin Trans. 1 (1985) 2719-2723.
[14] B. Abarca, R. Ballesteros, R. Ballesteros-Garrido, F. Colobert, F. R. Leroux, Tetrahedron 63 (2007)
10479-10485.
[15] L. S. Davies, G. Jones, J. Chem. Soc. (C) (1970) 688-693.
[16] E. Fahr, N. Markert, N. Pelz, T. Erlenmaier, Ann. Chim. (1973) 2088.
[17] G. S. Lal, G. P. Pez, R. G. Syvret, Chem.Rev. 96 (1996) 1737-1755.
[18] K. Fuchibe, Y. Mayumi, N. Zhao, S. Watanabe, M. Yokota, J. Ichikawa, Angew. Chem. Int. Ed. 52
(2013) 7825-7828 and references cited herein.
[19] Imidazo[1,5-a]pyridines have been synthesized from triazolopyridines through the formation of a
rhodium pyridyl carbene: S. Chuprakov, F. W. Hwang, V. Gevorgyan, Angew. Chem. Int. Ed. 46
(2007) 4757-4759.
[20] a) V. S. Arvapalli, G. Chen, S. Kosarev, M. E. Tan, D. Xie, L. Yet, Tetrahedron Lett. 51 (2010) 284-
286. b) J. M. Crawforth, M. Paoletti, Tetrahedron Lett. 50 (2009) 4916-4918.
[21] J. H. Boyer, N. Goebel, J. Org. Chem. 25 (1960) 304-305.
[22] C. Francese, M. Tordeux, C. Wakselman, J. Chem. Soc. Chem. Commun. (1987) 642-643.
[23] B. Abarca, R. Ballesteros, M. Elmasnaouy, Tetrahedron 54 (1998) 15287-15292.
[24] D. J. Bower, G. R. Ramage, J. Chem. Soc. (1957) 4506. Note that it is now commercially available
(ASM Research Chemicals)
[25] D. J. Bower, G. R. Ramage, J. Chem. Soc. (1955) 2834-2837.
16
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Graphical Abstract
Approaches for the introduction of fluorinated substituents into
[1,2,3]triazolo[1,5-a]pyridines
Leonardo Chiassai, Rosa Adam, Marcela Drechslerová, Rafael Ballesteros,* Belén Abarca.*
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia,
Burjassot (Valencia), Spain.
Several approaches aimed at the fluorination of [1,2,3]triazolo[1,5-a]pyridines have been
explored. Novel trifluoromethyl substituted pyridines have been synthesized from
triazolopyridines. Fluorination attempts have yielded two new synthetic routes for the
obtention of triazolopyridines dimers and imidazo[1,5-a]pyridines.
R
R
1) CF3
Introduction
N
OAc
1) lithiation
N
N
N
O
N
N
F+
2) triazolo
ring opening
N
N
2) [
]
N
N
F
3C
R= H, Me,Ph,2-Py, CF3
[F+]
R
N
N
CH3
17
Page 17 of 18

‐
‐
‐
‐
‐
Highlights
Novel trifluoromethyl triazolopyridines have been synthesized.
Trifluoromethylated pyridines have been obtained from triazolopyridines.
A fluorine mediated triazolopyridine dimerization was found.
Imidazo[1,5‐a]pyridines have been synthesized from triazolopyridines by reaction of this
heterocycles with Selectfluor.
18
Page 18 of 18