Filling the gap: Chemistry of 3,5-bis(trifluoromethyl)-1H-pyrazoles

Article abstract of DOI:10.1016/j.jfluchem.2012.04.003

Pyrazoles represent important building blocks for the preparation of bioactive compounds and a large variety of materials, due to their rich coordination chemistry. Unusual and interesting properties may be imparted to molecules embodying highly fluorinated pyrazoles, but to date only few examples of polyfluorinated pyrazoles have been described. In this work we report an improved preparation of 3,5-bis(trifluoromethyl)-1H-pyrazole, the subsequent transformation into hitherto unknown 4-functionalized (F, Cl, Br, I, NO ₂, NH₂) derivatives and the evaluation of selected chemical and physical properties of these compounds.

Full text of DOI:10.1016/j.jfluchem.2012.04.003

Journal of Fluorine Chemistry 139 (2012) 53–57
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Filling the gap: Chemistry of 3,5-bis(trifluoromethyl)-1H-pyrazoles
b
a
c
Angelo Maspero a, , Giovanni B. Giovenzana , Damiano Monticelli , Silvia Tagliapietra ,
*
Giovanni Palmisano a, Andrea Penoni a
a
`
Dipartimento di Scienza e Alta Tecnologia, Universita degli Studi dell’Insubria, Via Valleggio 11, I-22100 Como, Italy
b
c
`
Dipartimento di Scienze del Farmaco, Universita degli Studi del Piemonte Orientale ‘‘A. Avogadro’’, Largo Donegani 2/3, I-28100 Novara, Italy
`
Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Via Giuria 9, I-10125 Torino, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
Pyrazoles represent important building blocks for the preparation of bioactive compounds and a large
variety of materials, due to their rich coordination chemistry. Unusual and interesting properties may be
imparted to molecules embodying highly fluorinated pyrazoles, but to date only few examples of
polyfluorinated pyrazoles have been described. In this work we report an improved preparation of 3,5-
bis(trifluoromethyl)-1H-pyrazole, the subsequent transformation into hitherto unknown 4-functional-
ized (F, Cl, Br, I, NO2, NH2) derivatives and the evaluation of selected chemical and physical properties of
these compounds.
Received 10 February 2012
Received in revised form 2 April 2012
Accepted 3 April 2012
Available online 11 April 2012
Keywords:
Pyrazoles
ß 2012 Elsevier B.V. All rights reserved.
Electrophilic aromatic substitution
Heterocycles
1. Introduction
detailed reports of synthesis of highly fluorinated pyrazoles that
might provide potential leads in the formation of F-MOFs. Our
It is well known that the presence of a C–F bond (as alkyl/aryl-F
or CF3, SCF3 and OCF3 functional groups) in an organic framework
can dramatically modify the physicochemical profile including, i.a.,
increased chemical and metabolic stability (by blocking oxidative
metabolism), enhanced lipophilicity, conformational changes, low
dielectric constant, changes in hydrogen bonding ability (i.e., a
good hydrogen-bond acceptor) [1]. In this context, the CF3 group
represents one of the most powerful electron-withdrawing groups
abiding interest in pyrazolates as ligands in coordination and
organometallic chemistry [5] prompted to optimize the access to
3,5-bis(trifluoromethyl)-1H-pyrazole 2 and to develop methodol-
ogy for further elaboration to its derivatives 3–8, thereby filling
this gap [6]. Within this context, papers by Trofimenko [7] and
Elguero [8] are today recognized as the seminal works, both
theoretical and experimental, to the chemistry of pyrazoles.
as documented by the various Hammett
s values [sm, 0.42;sp,
2. Results and discussion
0.54; sm+ 0.52; sp+, 0.61;
s
I, 0.38; R 0.18] [2]. The electronic effect
s
of CF3 combined to its relatively small steric effect makes this
group an interesting structural motif for the design of pharma-
ceuticals, agrochemicals and functional materials (e.g., polymers
and liquid crystals). In particular, the last years have witnessed a
blooming of research interest on the preparation, characterization
and optimization of porous functional materials based on metal
ions linked by organic spacers (as carboxylate, pyrazolate or
triazolate ligands) in 3D-networks [i.e., metal organic frameworks
(MOFs)] with the aim of obtaining outperforming adsorbents for
environmentally relevant gases [3]. As anticipated, it has been
shown that fluorinated MOFs (F-MOFs) wherein hydrogen atoms
are substituted by fluorine atoms leads to enhanced thermal
stability and low surface tension [4]. While fluorinated carbox-
ylates has been well-documented, the literature contains no
The primary problem affecting any methods targeting 3,5-
bis(trifluoromethyl)-1H-pyrazole 2 in large supply is poor recovery
due to volatility loss (i.e., vapour pressure 626.6 Pa @ STP
conditions). Preparation of 3 was achieved through adaptation
of the procedure of Venanzi [9] and based on a two-step
cyclocondensation of the appropriate
b-dicarbonyl compound
with hydrazine. In the event, this involved the addition of neat
hydrazine hydrate to a 1 M solution of hexafluoroacetylacetone
(hfacac) 1a in EtOH at 5 8C, followed by refluxing for 8 h and
subsequent removal of the solvent at 40 8C. The unusual stability of
the intermediate half-aminals (i.e., hydroxypyrazolines and
dihydroxypyrazolidines) [10] represents the major kinetic bottle-
neck [11], thereby limiting the performance of such approach en
route to 2 (Scheme 1). This was readily overcome by acid treatment
(98% H2SO4, 0 8C followed by quenching in ice, our procedure). In
spite of extraordinary volatility [12], this route gave the required 2
in reproducible yield ranging from 79% to 88% and could be readily
scaled up to produce quantities of 2 in excess of 20 g. Also, it must
* Corresponding author. Tel.: +39 0 31 2386472; fax: +39 0 31 2386449.
E-mail address: angelo.maspero@uninsubria.it (A. Maspero).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.04.003

54
A. Maspero et al. / Journal of Fluorine Chemistry 139 (2012) 53–57
X
O
O
1) N2H4.H2O, EtOH, Rfx, 8h
2) H2SO4 conc., 0°C, 15' (1a)
F3C
CF3
F3C
CF3
1) N2H4.H2O, EtOH, 70°C, 4h
2) H2SO4 conc., r.t., 4h (1b)
N
NH
X
(88%)
(77%)
1a X = H
1b X = F
2
3
X = H
X = F
Scheme 1.
be noted that meticulous adherence to experimental details by
Venanzi (i.e., thermal dehydration at 180 8C) is essential in order to
obtain maximum yields, but in our hands this procedure led to 2 in
erratic yields (30–60%).
DMF even after prolonged treatment at room temperature under
ultrasound irradiation and in the presence of catalysts. Instead,
prolonged heating (at 80 8C) of 2 with NCS alone in DMF led to 55%
conversion (checked by GC–MS), topping after 22 h. Compound 4
was difficult to purify due to either detrimental presence of DMF
during workup or retention of succinimide in the crude product,
thus resulting in yields of less than 30% [16].
Furthermore, aprotic conditions (anhydrous hydrazine, Hu¨nig’s
˚
base, 3 A molecular sieves in refluxing toluene) were employed
throughout to avoid half-aminal formation leading to 2 in 40%
(unoptimized) yield; however, the difficulty in handling of
anhydrous N2H4 have curtailed the utility of this method.
With an easy access to an ample supply of 2 [13], our attention
was next focused on the reactivity towards electrophilic species
although it was expected that the presence of two CF3 groups
would deeply impact the electronic and steric properties of
pyrazole ring. For the sake of comparison, trifluoromethyl benzene
undergoes nitration 40,000ꢀ more slowly than benzene [14]!
Accordingly, 2 is required to withstand harsh conditions but care
must be exercised in view of the well-known propensity of CF3
group located on (hetero)aromatic ring systems to undergo
hydrolysis to CO2H functionality by action of strong protic acids
and high temperatures [15].
The first efforts towards the functionalization of 2 (Scheme 2)
were devoted to halogenation reactions. The presence of an halogen
atom more significantly would allow for further elaboration either
by Pd-catalyzed Suzuki-Miyaura and Sonogashira cross-coupling or
nucleophilic substitution to give more diversified derivatives.
Different conditions were explored in order to achieve an
efficient chlorination of the pyrazole ring of compound 2. Initial
attempts relied on N-chloroimides [N-chlorosuccimide (NCS), N-
chlorobenzotriazole (NCBt), trichloroisocyanuric acid (TCIA)] as
chlorine carrier but 2 was left practically unchanged in EtOAc or
Recourse to superelectrophilic reagents, which proved to be
particularly conducive to clean halogenation of deactivated
substrates was made. However, exposure of 2 to NCS in 98%
H2SO4 at 120 8C for 6 h resulted in low conversion (20%) whereas
changing to CF3SO3H (triflic acid) (80 8C, 6 h) brought to extensive
decomposition of NCS and no chlorinated pyrazoles were observed
at all. The successful conversion of 2–4 was realized by making use
of a different chlorine carrier in the presence of a Brønsted acid.
After additional experimentation, we found that when 2 was
subjected to trichoroisocyanuric acid (TCIA) in CF3SO3H [17] at
120 8C for 4 h, the required 4 was finally obtained. Separation of 4
from byproducts was simpler, thereby allowing to reach an
isolated yield of 63%. Multigram quantities (3–6 g) of 4 were
routinely prepared using these reaction conditions. Interestingly,
the reaction proceeded cleanly in triflic acid (i.e., a superacidic
Brønsted acid with H0 – 14.1 vs. 11.9 for 100% H2SO4) [18].
Regardless the reaction conditions, the use of TCIA in 98% H2SO4 or
in FSO3H (H0 – 15.1) gave a mixture of 4 and 3,5-bis(trifluor-
omethyl)-4-pyrazolesulfonic acid or messy results. Although triflic
acid is 10 times weaker than fluorosulfonic acid it avoids
sulfonation or oxidation as side reactions.
N-Bromosuccinimide (NBS) was at first selected as brominating
agents. Indeed, heating 2 with NBS in DMF at 130 8C for 16 h
Br
Cl
F3C
CF3
F3C
CF3
N
NH
N
NH
KBrO3
H2SO4/H2O
150°C 12h
TCIA, CF3SO3H
120°C, 4h
5
4
(63%)
(78%)
F3C
CF3
NIS
CF3SO3H
90°C, 6h
N
NH
HNO3/H2SO4
115°C, 2h
2
I
NH2
NO2
H2 (8 Atm)
Pd/C
F3C
CF3
F3C
CF3
F3C
CF3
N
NH
N NH
8
(86%)
N
NH
EtOH/HCl
6
7
(69%)
(58%)
Scheme 2.

A. Maspero et al. / Journal of Fluorine Chemistry 139 (2012) 53–57
55
provided a clean bromination to 5 as observed by GC–MS.
Nevertheless, the same problems previously observed in the
removal of succinimide from the chloro pyrazole spoiled the
workup procedure, reducing once more the isolated yields to 43%.
Reaction of 2 with other brominating agents (e.g., N,N0-dibromo-
5,5-dimethylhydantoin, benzyltrimethylammonium tribromide,
dibromoisocyanuric acid) in the presence of a Brønsted acid (triflic
acid, 98% H2SO4) failed to provide 5 in satisfactory yields while we
were able to obtain 5 (78% isolated yield) employing KBrO3 in 98%
H2SO4 at 150 8C for 12 h [19].
Iodination usually requires stronger activating conditions in
order to generate a reactive electrophilic iodonium species. A
thorough examination of literature procedures for iodination of
deactivated (hetero)aromatic systems indicated that superelec-
trophilic iodine (I) salts (by productive merger of iodine carrier and
protic acids) would represent the method of choice. The first
attempts were performed with molecular iodine in 20% oleum (H0
– 13.41) at 160 8C for 10 h in a sealed vessel but this route was
clearly disfavored by the low yield of 6 (32%) due to the anticipated
competitive sulfonation and/or hydrolysis of 2. After several
variations in reaction conditions, exposure to N-iodosuccinimide
in triflic acid at 90 8C for 6 h led to 5 in a satisfying 69% yield
avoiding the formation of byproducts [20]. This different behaviour
may be most explained by the different solubilities of the reaction
products. Whereas 6 precipitates directly by aqueous work-up, the
corresponding halo derivatives issuing from chlorination and
bromination are likely to be more soluble in the aqueous reaction
mixture.
With 4 in hand, we proceeded to investigate nucleophilic
displacement of chlorine by fluoride [HalEx (halogen exchange)
or Finkelstein reaction] [21] to produce the perfluorinated
pyrazole 3. However, despite examining a range of fluoride
sources (CsF, spray dried KF, NaF), solvents (MeCN, DMF, DMSO,
sulfolane), reaction times, temperatures and additives (e.g.,
cetyltrimethylammonium bromide, tetraphenylphosphonium
bromide, Kryptofix1 222), we were unable to effect clean
reaction of chloro derivative 4. The preparation of 3 was then
achieved relying on the commercial availability of 1,1,1,3,5,5,5-
heptafluoro-2,4-pentanedione 1b [22]. The same conditions
employed in the preparation of the 4-unsubstituted pyrazole 2
were applied leading to the isolation of the heptafluoropyrazole
3 in 77% yield.
Additional experiments were projected towards the introduc-
tion of nitrogen-containing functional groups. Initial efforts
towards the nitration of 2 using KNO3 and 98% sulfuric acid failed
giving only recovered starting material. Accordingly, it is stated
authoritatively by Elguero et al. [23] that 3,5-bis(trifluoromethyl)-
1H-pyrazole 2 cannot be nitrated at the 4-position. However, in our
hands, use of 98% H2SO4 – fuming HNO3 in 2:1 molar ratio (at
115 8C) gave complete consumption of the starting material after
18 h and the desired product 7 [24] was obtained in an isolated
yield of 58%. The presence of a nitro group in 7 provided the
opportunity for further elaboration. Thus, a variety of reagents and
conditions for the reduction of the nitro group were screened [e.g.,
H2 (101 kPa), 10% Pd/C in EtOH; SnCl2ꢁ2H2O in EtOH; N2H4 or
HCO2NH4 in the presence of Pd/C; Na2S2O4, K2CO3 in CH2Cl2 under
PTC conditions] but all these conditions led to intractable mixtures.
For the majority of reductions, notable side-reactions were the
formation of azo- and azoxy derivatives (checked by ESI-MS)
arising from incomplete reduction and/or oxidation process. Lastly,
conversion of the nitro derivative 7–8 was best carried out by
catalytic hydrogenation (at 810 kPa) in a 4:1 EtOH–12 N HCl
mixture over 10% Pd/C at ambient temperature for 18 h delivering
the desired amino compound 8 in 86% yield. This compound
rapidly turned purple on standing in air and was kept at ꢂ15 8C
under nitrogen.
The synthesized 3,5-bis(trifluoromethyl)-1H-pyrazoles 3–8
were fully characterized by IR, UV, pKa (pzH/pzꢂ), 1H, 13C, 19F
NMR, GC–MS and elemental analysis confirming their structure
and purity.
3. Conclusion
An optimized protocol for the preparation of 3,5-bis(trifluor-
omethyl)-1H-pyrazole 2 was developed. Contrary to the original
assumptions and after a fine tuning of experimental conditions, the
electrophilic substitution of 2 was successfully achieved. The
obtained 4-substituted derivatives 3–8 appear to be valuable
synthetic intermediates for preparation of heterocyclic com-
pounds of pharmaceutical interest, thereby expanding the already
burgeoning arsenal of polyfluorinated pyrazoles. Furthermore,
these new compounds pave the route to designing and tailoring
more complex structures that can be used to suit a well-defined
molecular function.
4. Experimental
4.1. General techniques
Chemicals were used as received (Sigma Aldrich). Infrared
spectra (nujol) were recorded on a Shimadzu Prestige-21 FTIR
instrument. Elemental analyses were carried out on a Perkin Elmer
CHN Analyzer 2400 Series. Melting points were determined on a
Stuart Scientific SMP3 melting point apparatus. Unless stated
otherwise 1H and 13C NMR spectra were recorded on Bruker
Avance 400 spectrometers in DMSO-d6 using TMS as an internal
standard. Unless stated otherwise 19F NMR spectra were recorded
on a Jeol Eclipse ECP300 (282.3 MHz) in CDCl3 and referenced to
CFCl3 using an external standard of BF3ꢁOEt2
(
d
= ꢂ153.0 ppm).
GC–MS analyses (retention times tR are reported) and mass spectra
were determined with a Thermo Quest GC with a Agilent DB-5MS
capillary column (30 m, 0.25 mm) equipped with a Ultra Trace MS
mass selective detector under the following conditions: 5 min @
50 8C, 50–150 8C @ 58/min, 150–280 8C @ 15 8C/min, 15 min @
280 8C; helium gas flow 1 mL/min. Elemental analyses were
performed in-house at the Dipartimento di Scienza
e Alta
Tecnologia with a Perkin Elmer 2400 Series II Elemental Analyzer.
In general, samples prepared for CHN analyses were dried in
vacuum (1600 Pa) over P4O10 for 18 h at ambient temperature. The
pKa (pzH/pzꢂ) were determined at 20 8C in aqueous 0.1 M KNO3 by
neutralization titrations with 0.02 M NaOH using a pHmeter model
GLP 21 (Crison Strumenti Spa, Italy) and a glass electrode model 50
11 T (Crison Strumenti Spa, Italy) embodying a temperature
sensor. Repetitive measurements (n = 3) suggested that the
method precision is ꢃ0.02 expressed as standard deviation. Spectra
(EtOH) in the ultraviolet region (190–350 nm range) were measured
by a Beckman DU-640 spectrophotometer (Beckman, USA). Thermo-
gravimetric and differential (TGA-TDA) analysis was performed with
a NETZSCH STA 409 thermobalance. Pressure reactions were carried
out in autoclave. Yields refer to isolated compounds estimated to be
>95% pure as determined by capillary GC analysis.
4.2. Preparation of pyrazoles 2–8
4.2.1. 3,5-Bis(trifluoromethyl)-1H-pyrazole (2)
A 250-mL three-necked round-bottomed flask, equipped with a
magnetic stitrring bar, thermometer, water condenser and
dropping funnel was loaded with hexafluoroacetylacetone 1a
(29.4 g, 20 mL; 141 mmol) and EtOH (100 mL). The flask was
cooled to 5 8C with an ice bath. Hydrazine monohydrate (7.0 g,
6.8 mL; 140 mmol) was added over 20 min, while keeping the
reaction temperature below 8 8C. After addition was complete, the

56
A. Maspero et al. / Journal of Fluorine Chemistry 139 (2012) 53–57
mixture was brought to reflux for 8 h. After cooling to room
temperature, the reaction mixture was evaporated on a rotary
evaporator while keeping the bath temperature below 40 8C to
leave a yellow syrup. This was dissolved in 98% H2SO4 (10 mL)
under ice cooling and vigorous stirring. After 15 min the reaction
mixture was cautiously poured onto ice (300 g) and the light
yellow solid was collected, washed with ice-cold water (50 mL) to
afford the title compound 2 (25.13 g; 88%) as a colourless solid
Na2SO3 solution. The white product was collected by filtration,
washed with ice-cold water (3 ꢀ 5 mL) and dried under vacuum at
room temperature for 4 h to afford the title compound 6 (530 mg;
32%).
Method B. N-Iodosuccinimide (NIS) (2.25 g; 5 mmol) was
dissolved in triflic acid (10 mL) at 0 8C kept under stirring for
5 min (during which time a blue colour developed). Pyrazole 2
(1.02 g; 5 mmol) was then slowly added over 5 min. The mixture
was warmed to 90 8C for 6 h, cooled to 0 8C and the deep blue
solution was cautiously poured into ice (100 g). A white precipitate
formed, which was collected by filtration, washed with ice-cold
water (3 ꢀ 10 mL) and dried under vacuum for 4 h to leave the title
compound 5 (1.14 g, 69%).
with a distinctive odor. 1H NMR (DMSO-d6/CDCl3, 2:1):
d
= 5.70
(brs, 1H, NH), 7.40 (s, 1H, H-4). 13C NMR:
d
= 138.1 (q, 2JC–F = 39 Hz,
C-3/C-5), 120.5 (q, JC–F = 267 Hz, CF3), 105.2 (s, C-4). 19F NMR
1
(DMSO-d6/CDCl3, 2:1):
d
= ꢂ62.5 (s). IR: 3160 (s) 1510, 1595 (s)
1150 (s) cmꢂ1. GC MS (tR 6.78 min). Anal. Calcd for C5H2F6N2: C,
29.43; N, 13.73. Found: C, 29.44; N, 13.76. pKa 7.10 [Ref. [25] 7.5].
Mp 81 8C [Ref. [25] 83–84 8C]. The sample purity of 2 was
determined to be >98% by DSC (scan rate, 2.5 8C/min; mp 85.2 8C).
13C NMR (DMSO-d6):
d
= 141.5 (q, 2JC–F = 38 Hz, C-3/C-5), 119.2
= ꢂ61.8 (s). IR:
1
(q, JC–F = 269 Hz, CF3), 55.7 (s, C-4). 19F NMR:
d
3166(s), 1569 (w), 1310 (s), 1192 (vs), 1156 (vs), 997 (s) cmꢂ1. UV
(EtOH): lmax ) = 232 nm (3.04). GC MS: (tR 18.84 min). Anal.
(
e
4.2.2. 4-Chloro-3,5-bis(trifluoromethyl)-1H-pyrazole (4)
Calcd for C5HF6IN2: C, 18.20; N, 8.49. Found: C, 18.22; N, 8.58. pKa
Trichloroisocyanuric acid (TCIA) (2.32 g, 10 mmol) was added
portionwise over 10 min to triflic acid (6 mL) chilled to 0 8C.
Pyrazole 2 (2.04 g, 10 mmol) was added and allowed to warm to
room temperature as it stirred for 5 min. The reaction temperature
was brought to 120 8C and stirred for further 5 h, while following
the conversion by GLC. The colourless mixture was cooled at 0 8C,
poured into water/ice (10 mL), extracted with CH2Cl2 (4 ꢀ 20 mL)
and dried over Na2SO4. Evaporation of the solvent afforded the title
6.09. Mp 126 8C.
4.2.5. 4-Fluoro-3,5-bis(trifluoromethyl)-1H-pyrazole (3)
Hydrazine monohydrate (0.5 mL, 10.4 mmol) was slowly added
to a solution of 1,1,1,3,5,5,5-heptafluoroaceylacetone 1b (1.0 mL,
6.95 mmol) in EtOH (8 mL) at room temperature. The solution was
then heated to 70 8C for 4 h. The solvent was removed by vacuum
at 20 8C and to the yellow oil 98% H2SO4 (1 mL) was cautiously
added under ice cooling and stirring. After 15 min the reaction
mixture was cautiously poured onto ice (20 g), the solid was
collected, washed with ice-cold water (5 mL) to afford the title
compound 3 (1.04 g; 77%) as a colourless glass.
compound 4 (1.50 g; 63%) as an off- white solid. 13C NMR:
(q, 2JC–F = 39 Hz, C-3/C-5), 119.4 (q, 1JC–F = 268 Hz, CF3), 109.5 (s, C-
4). 19F NMR:
= –61.8 (s). IR: 3198 (s), 1577 (w), 1326 (s), 1273 (s),
1212 (vs), 1164 (vs), 973 (s) cmꢂ1
UV (EtOH): lmax
(log ) = 224 nm (3.25). GC MS: (tR 13.15 min). Anal. Calcd for
d = 135.7
d
.
e
13C NMR (CD2Cl2):
d
= 118.8 (qd; 1JC–F = 267 Hz, 3JC–F 3 Hz; CF3),
2
2
1
C5HClF6N2: C, 25.18; N, 11.74. Found: C, 25.15; N, 11.71. pKa 5.49.
125.4 (qd; JC–F = 42 Hz, JC–F 13 Hz; C-3/C-5), 142.1 (s, JC–
Mp 89 8C.
F = 265 Hz, C-4). 19F NMR:
d
= ꢂ60.4 (s,6F), ꢂ166.6 (s, 1F). GC
MS: (tR 8.42 min). Anal. Calcd for C5HF7N2: C, 27.04; N, 12.61.
Found: C, 27.09; N, 12.53. pKa 6.85. Mp 51 8C (DSC).
4.2.3. 4-Bromo-3,5-bis(trifluoromethyl)-1H-pyrazole (5)
Method A. Pyrazole 2 (2.04 g, 10 mmol) was dissolved in DMF
(5 mL) and under stirring N-bromosuccinimide (NBS) (2.31 g,
13 mmol) was added at room temperature. The solution was
warmed at 130 8C for 15 h, cooled to room temperature, and water
(200 mL) was added, the mixture was then extracted with ethyl
acetate (4 ꢀ 30 mL). The organic layers were washed with water,
brine and dried over Na2SO4. The solvent was removed by vacuum
at 40 8C and a colourless product was obtained. This was purified
by sublimation under vacuum (1.33 Pa @ 80 8C) to give the title
compound 5 (1.21 g; 43%).
Method B. A mixture of KBrO3 (1.67 g, 10 mmol), pyrazole 2
(2.04 g; 10 mmol) and 98% H2SO4 (d 1.84 g/mL) (13 mL) was
heated in 25-mL stainless steel Teflon-lined autoclave at 150 8C for
12 h. The mixture was allowed to cool to room temperature and
poured slowly onto ice (100 g). The off-white product was
collected by filtration, washed with ice-cold water (2 ꢀ 10 mL)
and dried under vacuum at room temperature for 4 h to give the
title compound (2.20 g; 78%).
4.2.6. 4-Nitro-3,5-bis(trifluoromethyl)-1H-pyrazole (7)
Fuming HNO3 (d 1.50 g/mL, 3.5 mL) was added over 10 min to
the ice-cooled solution of pyrazole 2 (2.04 g, 10 mmol) in 98%
H2SO4 (d 1.80 g/mL, 8.1 mL). The solution was then transferred into
a 25-mL stainless steel Teflon-lined autoclave, sealed and heated at
115 8C for 12 h. On cooling to 0 8C, the brown solution was
cautiously poured into ice (100 g) and kept at 0 8C for 30 min. The
white solid was then filtered off, washed with ice-cold water
(2 ꢀ 10 mL) and dried under vacuum at room temperature for 4 h
to give the title compound 7 (1.44 g; 58%).
13C NMR (DMSO-d6/CDCl3, 2:1):
C-5), 130.2 (s, C-4), 119.2 (q, 1JC–F = 268 Hz, CF3), 55.7 (s, C-4). 19
NMR:
= ꢂ61.8(s). IR: 3239 (s), 1553 (s), 1513 (s), 1264 (s), 1224
(s), 1200 (vs), 1155 (vs), 1131 (vs), 973 (vs) cmꢂ1. UV (EtOH): lmax
(log ) = 225 nm (3.11). GC MS: (tR 20.50 min). Anal. Calcd for
d
= 134.9 (q, 2JC–F = 39 Hz, C-3/
F
d
e
C5HF6N3O2: C, 24.11; N, 16.87. Found: C, 24.08; N, 17.02. pKa 3.39.
Rf (silica) = 0.10 (EtOAc-hexane, 4:1). Mp 80 8C.
2
1
13C NMR:
F = 269 Hz, CF3), 92.6 (s, C-4). 19F NMR:
1577 (s), 1395 (s), 1321 (s), 1261 (vs), 1200 (vs), 1141 (vs), 981 (s)
cmꢂ1. UV (EtOH): lmax
) = 225 nm (3.20). GC MS: (tR 15.38 min).
d
= 138.1 (q, JC–F = 38 Hz, C-3/C-5), 119.2 (q, JC–
= ꢂ62.1 (s). IR: 3174(s),
d
4.2.7. 4-Amino-3,5-bis(trifluoromethyl)-1H-pyrazole (8)
Into a 50-mL glass-lined autoclave were charged 4-nitro-3,5-
bis(trifluoromethyl)-1H-pyrazole 7 (3.60 g, 14.5 mmol), 10% Pd/C
(0.5 g) and 4:1 (v/v) EtOH–12 N HCl mixture (20 mL). The reactor
was pressurized to 810 kPa with hydrogen and stirred at room
temperature for 18 h. After venting, the mixture was filtered
through a Celite1 pad, rinsing the filter cake well with EtOH
(2 ꢀ 15 mL). The volatiles were removed on the rotary evaporator
to leave the title compound 8 (2.72 g; 86%) as a light yellow solid
which was stored at ꢂ15 8C under nitrogen.
(e
Anal. Calcd for C5HBrF6N2: C, 21.22; N, 9.90. Found: C, 21.26; N,
9.83. pKa 6.02. Mp 109 8C.
4.2.4. 4-Iodio-3,5-bis(trifluoromethyl)-1H-pyrazole (6)
Method A. A mixture of pyrazole 2 (1.02 g; 5 mmol), iodine
(0.622 g, 2.58 mmol) and fuming H2SO4 (20% free SO3 basis)
(8.5 mL) was heated in a 25-mL stainless steel Teflon-lined
autoclave at 160 8C for 10 h. The mixture was cooled to 0 8C and
the excess of iodine was destroyed by the addition of a 0.1 M
13C NMR (DMSO-d6/CDCl3, 2:1):
d
= 124.2 (q, 2JC–F = 39 Hz, C-3/
1
C-5), 128.4 (s, C-4), 120.6 (q, JC–F = 266 Hz, CF3). 19F NMR:

A. Maspero et al. / Journal of Fluorine Chemistry 139 (2012) 53–57
57
[5] (a) V. Colombo, S. Galli, H.J. Choi, G.D. Han, A. Maspero, G. Palmisano, N. Mas-
ciocchi, J.R. Long, Chemical Science 2 (2011) 1311–1319;
(b) E. Quartapelle Procopio, F. Linares, C. Montoro, V. Colombo, A. Maspero, E.
Barea, J.A.R. Navarro, Angewandte Chemie International Edition 49 (2010) 7308–
7311;
d
= ꢂ61.2 (s). IR: 3429 (w), 3399 (w), 3152 (s), 1604 (s), 1336 (s),
1307 (s), 1292 (s), 1145 (vs), 978 (s) cmꢂ1. UV (EtOH): lmax
(log ) = 250 nm (3.20). GC MS: (tR 12.89 min). Anal. Calcd for
e
C5H3F6N3: C, 27.41; N, 19.18. Found: C, 27.29; N, 19.11. pKa 8.13. Rf
(silica) = 0.72 (EtOAc-hexane, 4:1). Mp 131 8C.
(c) N. Masciocchi, S. Galli, V. Colombo, A. Maspero, G. Palmisano, B. Seyyedi, C.
Lamberti, S. Bordiga, Journal of the American Chemical Society 132 (2010) 7902–
7904.
[6] For recent contribution in the synthesis of trifluoromethyl pyrazole derivatives,
see: I.G. Gerus, R.X. Mironetz, I.S. Kondratov, A.I. Bezdudny, Y.V. Dmytriv, O.V.
Shishkin, V.S. Starova, O.A. Zaporezhets, A.A. Tolmachev, P.V. Mykhailiuk, Journal
of Organic Chemistry, 77 (2012) 47–56.
Acknowledgements
The present work was generously supported by Ministero
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`
dell’Istruzione, dell’Universita e della Ricerca (PRIN 2008) (prot
2008M3Y5WX) (Ottimizzazione della sintesi di molecole eterocicliche
e carbocicliche mediante l’uso di procedure non convenzionali). The
reviewers’ comments contributed to a significant improvement of
the manuscript.
For other preparations of 2, see:
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Appendix A. Supplementary data
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compound (MVOC) exerting a vapour pressure @ STP conditions in the 266.6 Pa to
10.66 kPa range..
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2012.
04.003.
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