One-pot synthesis of CF3-substituted pyrazolines/pyrazoles from electron-deficient alkenes/alkynes and CF3CHN2 generated in situ: Optimized synthesis of tris(trifluoromethyl)pyrazole

Article abstract of DOI:10.1002/ejoc.201301852

The [3+2] cycloaddition of CF₃CHN₂, generated in situ, with electron-deficient alkenes/alkynes affords CF₃-substituted pyrazolines/pyrazoles in quantitative yields. The one-pot three-component reaction between CF₃

Full text of DOI:10.1002/ejoc.201301852

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FULL PAPER
DOI: 10.1002/ejoc.201301852
One-Pot Synthesis of CF -Substituted Pyrazolines/Pyrazoles from Electron-
3
Deficient Alkenes/Alkynes and CF CHN Generated in situ: Optimized
3
2
Synthesis of Tris(trifluoromethyl)pyrazole
[a]
[b]
[c]
Evgeniy Y. Slobodyanyuk, Olexiy S. Artamonov, Oleg V. Shishkin, and
Pavel K. Mykhailiuk*[
a,d]
Keywords: Synthetic methods / Nitrogen heterocycles / Fluorine / Multicomponent reactions / Cycloaddition
The [3+2] cycloaddition of CF
electron-deficient alkenes/alkynes affords CF
pyrazolines/pyrazoles in quantitative yields. The one-pot
3
CHN
2
, generated in situ, with
-substituted
three-component reaction between CF
NaNO , and the substrate proceeds at room temperature in
dichloromethane/water.
3 2 2
CH NH ·HCl,
3
2
Introduction
In 1968, Atherton and Fields prepared CF -substituted
3
Pyrazolines play an important role in drug discovery and pyrazolines by [3+2] cycloaddition between CF CHN and
3
2
[
8]
organic synthesis: they exhibit a broad spectrum of bio- alkenes. The transformation, however, was technically
[
1,2]
logical activities (Figure 1),
and serve as precursors to challenging, because it required (i) generation of the
[
3]
[4]
[5]
[9,10]
cyclopropanes, pyrazoles, and diamines. Considering toxic, potentially explosive gas CF CHN2
from
3
[6,7]
that more than 45 drugs contain the CF group,
CF3- CF CH NH ·HCl and NaNO and (ii) purification of the
3
3
2
2
2
substituted pyrazolines look to be promising molecules for reagent by two vacuum distillations at –80 and –196 °C.[
11]
medicinal chemists.
Therefore, this method has had very little practical applica-
Figure 1. Bioactive pyrazolines.[1,2]
tion so far.[12,13] In this context, we have developed a safe,
[
[
[
[
a] Organic Chemistry Department, Taras Shevchenko National
University of Kyiv,
Volodymyrska 64, Kyiv 01601, Ukraine
b] Institute of Organic Chemistry, National Academy of Sciences
of Ukraine,
Murmanska 5, Kyiv 02660, Ukraine
c] STC, Institute for Single Crystals, National Academy of Science
of Ukraine,
Lenina ave. 60, Kharkiv 61001, Ukraine
d] Enamine Ltd.,
one-pot procedure to prepare CF -substituted pyrazolines
3
without isolation of the dangerous CF CHN .
3
2
Results and Discussion
Reaction with Alkenes
Matrosova Street 23, Kyiv 01103, Ukraine
E-mail: Pavel.Mykhailiuk@gmail.com
Pavel.Mykhailiuk@enamine.net
www.enamine.net
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301852.
Optimization of the Reaction
In 2012, we synthesized pyrazoline 1a (Scheme 1).[12c] In
that approach, we first generated CF CHN2 from
3
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P. K. Mykhailiuk et al.
FULL PAPER
Scheme 1. Previous synthesis of pyrazoline 1a.[12c]
CF CH NH ·HCl and NaNO in water (generating flask), Table 1. Reaction scope.[a]
3
2
2
2
and blew it off by argon through magnesium sulfate (drying
flasks) into a solution of maleimide 1 in dichloromethane
(reaction flask). Unfortunately, the risks associated with
gaseous CF CHN prevented the large-scale synthesis (see
3
2
the Supporting Information[ ).
14]
Recently, Carreira and Morandi used CF CHN gener-
3
2
ated in situ in catalytic reactions.[ Inspired by this work,
15]
we explored the [3+2] cycloaddition of CF CHN , gener-
3
2
ated in situ, with alkene 1. In the experimental setup,
[
18]
CF CH NH ·HCl (3.0 equiv.) was added to a solution of
3
2
2
NaNO (3.0 equiv.) in dichloromethane/water at 0 °C under
2
air. The reaction mixture was stirred for 1 h, during which
the organic layer became yellow, and maleimide
1
(1.0 equiv.) was added. After 24 h at room temperature,
evaporation of dichloromethane under vacuum afforded the
pure product 1a in 95% yield. The presence of water had
no influence on the reaction. Because maleimide 1 reacts
with neither NaNO nor CF CH NH ·HCl, we then simply
2
3
2
2
mixed all reagents at once in dichloromethane/water (see
the Supporting Information) and, after stirring the suspen-
sion at 0 °C for 1 h and at room temp. for 24 h, again ob-
tained the pure product. The reaction also worked well on [a] Isolated yield. [b] Reaction time: 2 weeks; 12 equiv. of
3 2
CF CHN . [c] Reaction time: 4 weeks.
a large scale, and we easily synthesized 75 g of product 1a
in a single run (Scheme 2).
Scheme 2. Optimized one-pot synthesis of pyrazoline 1a.
Scope of the Reaction
We then investigated the steric requirements of the reac-
Given the simplicity of the developed reaction, we then tion. Diverse di- and trisubstituted alkenes (1 and 7–20),
studied its scope. First, we investigated various monosubsti- with at least one strong EWG (–COR, –NO ), were exam-
2
tuted alkenes 2–6 (Table 1). Substrates 2 and 3, with strong ined (Table 2, Figure 2). The 1,1-disubstituted alkenes
electron-withdrawing groups (EWGs), reacted completely smoothly gave the corresponding pyrazolines, irrespective
with CF CHN generated in situ; however, substrates with of the nature of the second substituent, EWG (7) or EDG
3
2
either a weak EWG (4), or electron-donating groups (8). The 1,2-disubstituted alkenes behaved differently: alk-
EDGs) (5 and 6) did not. Because the reaction conversion enes with a second EWG (1 and 9–12) reacted completely,
(
for alkene 4 was only 15%, we increased the reaction time alkenes with an EDG (13 and 14) required longer reaction
to two weeks and used 12 equiv. of CF CHN to obtain times, whereas those with strong EDGs (15 and 16) did not
3
2
the pure product 4a. These results suggest that CF CHN2 react. For reasons that are not yet clear, the five-membered
3
generated in situ reacts only with electron-deficient alkenes. substrates 17 and 18 did not react either. Trisubstituted alk-
2
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3
Synthesis of CF -Substituted Pyrazolines/Pyrazoles
3 2
Figure 2. Alkenes that are inert to CF CHN generated in situ (Table 2).
enes 19 and even 20 – with three EWGs – also remained Regioselectivity
unchanged. These data show that CF CHN generated in
situ reacts only with mono- and disubstituted alkenes.
3
2
The [3+2] cycloaddition of CF CHN , generated in situ,
3
2
with alkenes leads to pyrazolines with the CF and EWG
3
substituents at the 3- and 5-positions (Tables 1 and 2). We
observed no corresponding 3,4-disubstituted isomers.
Table 2. Reaction scope.[a]
1
2
Δ -/Δ -Pyrazoline Isomerism
Monosubstituted alkenes formed the thermodynamically
2
more stable Δ -pyrazolines with the conjugated N=C and
the CϵN (2b)/S=O (3b) bonds. Alkene 4, with no such
1
groups, afforded Δ -pyrazoline 4a. The 1,1-disubstituted
1
2
alkenes gave the Δ -pyrazolines 7a, 8a [Δ -isomers (b) are
2
not possible]. The 1,2-disubstituted substrates afforded Δ -
pyrazolines 9b–14b, except for 1a and 9a. Presumably, the
putative bicyclic alkenes 1b and 9b are strained according
to Bredt’s rule.
Diastereoselectivity
Monosubstituted (4) and symmetric 1,2-cis-disubstituted
1
(
1 and 9) alkenes afforded the pure trans-Δ -pyrazolines (1a,
4a and 9a), whereas 1,1-disubstituted substrates (7 and 8)
gave trans/cis mixtures.
Reaction with Alkynes
Having developed the reaction of CF CHN with alk-
3
2
enes, we next investigated its application with alkynes. First,
we examined the monosubstituted alkynes (Table 3) and
found that those with EWGs (21–23) gave the correspond-
ing pyrazoles 21a–23a in quantitative yield; while alkynes
with EDGs (24 and 25) remained intact. Similar to alkenes,
the regioselective reaction gave only 3,5-disubstituted iso-
mers.
In the next step, we studied the disubstituted alkynes
with one EWG (–CO R or –CF ) and various substituents.
2
3
We found that alkynes with a second strong EWG (26 and
7) reacted completely, whereas alkynes with a second EDG
28) reacted slowly. The reaction of 28 reached only 72%
2
(
conversion and afforded only one regioisomer. The crystal-
line product was obtained by purification of the starting
liquid material by washing with hexane. Unexpectedly, in-
[
a] Isolated yield. [b] Mixture of trans/cis isomers, 9:1 (7a) and 1:1
(
8a). Reaction time 2 weeks. [c] Formed as ca. 10% cis isomer. verted regioselectivity was observed for 28b with an EWG
1
[
d] Formed as ca. 10% Δ -pyrazoline. [e] Reaction time 48 h.
[16]
group at the 4-position of the pyrazole core. Presumably,
the steric clash between the bulky CF and SiMe groups
3
3
The structures of compounds 2b, 4a, 9a, 10b, and 14b forced the reaction to take the inverted pathway.[17]
were confirmed by X-ray crystallographic analysis (Fig-
The structure of pyrazoles 21a and 26a was proven by
ure 3).
X-ray crystallographic analysis (Figure 4).
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Figure 3. X-ray crystal structures of 2b, 4a, 9a, 10b, 14b. Color code: C grey, N blue, O red, F green. Atom ellipsoids are shown at a
30% probability level.
These results suggest that the reaction between
CF CHN generated in situ and alkenes/alkynes belongs to
3
2
type I [3+2] cycloadditions:[
17b]
the EWG of the substrate
Table 3. Reaction scope.
Figure 4. X-ray crystal structures of compounds 21a and 26a.
Color code: C grey, N blue, O red, F green. Atom ellipsoids are
shown at a 30% probability level.
accelerates the reaction, whereas EDGs decelerate. The
properties and reactivity of CF CHN2 generated in situ
3
[
8b]
closely resemble those of the individual reagent.
Practical Application
Having developed a useful method to construct the CF3-
substituted pyrazolines/pyrazoles, we also wanted to briefly
demonstrate its high synthetic potential.
1
Isomerization of Δ -Pyrazolines
2
Medicinal chemists extensively exploit Δ -pyrazolines as
building blocks to synthesize bioactive compounds (Fig-
1
2
ure 1). Δ -Pyrazolines, in turn, isomerize to the Δ isomers
[
2a,18]
under acidic conditions.
an arbitrary Δ -pyrazoline 1a with a catalytic amount of
In this respect, treatment of
1
acetic acid in dichloromethane quantitatively afforded the
2
pure Δ isomer 1c (Scheme 3).
1
2
Scheme 3. Acidic isomerization of Δ -pyrazoline 1a to Δ -pyraz-
oline 1c.
[a] Isolated yield. [b] Reaction conversion.
4
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3
Synthesis of CF -Substituted Pyrazolines/Pyrazoles
Preparation of CF -Substituted Pyrazolecarboxylic Acids
sized for the first time in 1968 by reaction between two
3
gases, CF CHN and bis(trifluoromethyl)acetylene (27), at
3
2
CF -substituted pyrazolecarboxylic acid 29 is a useful
3
[
6]
building block in medicinal projects (Figure 5).[
19]
–80 °C in a sealed tube (Scheme 5). Given the inconve-
nience of this approach, recently Gerus and colleagues de-
veloped an alternative strategy to generate pyrazole 27a
In this
context, we synthesized acid 29 through a one-step acidic
hydrolysis of the ester group in pyrazole 21a (Scheme 4).
We also prepared its homologue 31 by oxidation of pyrazo-
line 13b with bromine (to give pyrazole 30), followed by
acidic hydrolysis of the ester group.
from diketone 32 by employing SF /HF in the last synthesis
4
[
21]
step.
Herein, we have elaborated a convenient, one-step pro-
cedure to obtain pyrazole 27a from CF CHN generated in
3
2
One-Pot Synthesis of Tris(trifluoromethyl)pyrazole
situ. First, a solution of 27 in dichloromethane was pre-
pared at –30 °C and added to a solution of CF CHN gen-
Recently, Diaz and colleagues synthesized complexes of
3
2
erated in situ in water/dichloromethane. After 24 h at room
temperature, the standard workup afforded the pure prod-
uct in 80% yield. This attractive one-step synthesis of 27a
can be performed in a laboratory on a routine basis without
any special equipment.
tris(trifluoromethyl)pyrazole 27a with Ag and CO (C H )
2
4
to study their catalytic activity in the reaction between
ethyldiazoacetate and alkanes.[20] Pyrazole 27a was synthe-
Conclusions
We have elaborated the reaction between CF CHN gen-
3
2
erated in situ and alkenes/alkynes to construct CF -substi-
3
tuted pyrazolines/pyrazoles. The reaction belongs to type I
[
3+2] cycloadditions. At room temperature, CF CHN gen-
3 2
erated in situ smoothly reacts with mono- and disubstituted
alkenes/alkynes with at least one strong EWG. The syn-
thetic protocol is practical, the reaction proceeds in air, at
room temperature, without any catalysts, and in common
solvents such as H O/CH Cl . Moreover, the reaction gives
2
2
2
Scheme 4. Synthesis of acids 29 and 31.
products in excellent yields without purification. Given the
Figure 5. Bioactive derivatives of CF
3
-substituted pyrazolecarboxylic acid 29 (grey).[18]
Scheme 5. Syntheses of pyrazole 27a.
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1
simplicity of the developed procedure, we believe that it will solid; m.p. 137–139 °C. H NMR (500 MHz, CDCl
.08–2.21 (m, 2 H, CH ), 5.74–5.79 (m, 1 H, CHCF
(m, 1 H, NCHN), 7.79–7.82 (m, 2 H, Pht), 7.89–7.82 (m, 2 H, Pht)
3
4
; Me Si): δ =
2
2
3
), 6.86–6.90
find wide application in both agrochemistry and medicinal
[
22,23]
chemistry.
1
3
ppm. C NMR (125 MHz, CDCl
3
; Me
s, NCHN), 90.6 (q, JC,F = 28.0 Hz, CHCF
79.0 Hz, CF ), 124.8 (s, 2CH of phthalimide), 131.4 (s, 2C of
phthalimide), 134.8 (s, 2CH of phthalimide), 166.4 (s, CO) ppm.
4 2
Si): δ = 20.9 (s, CH ), 89.5
2
1
(
2
3
), 123.7 (q, JC,F =
3
Experimental Section
1
9
3
F NMR (375 MHz, CDCl
3 3
; CFCl ): δ = –71.7 (d, JF,H = 7.0 Hz,
General: Solvents were purified according to standard procedures.
All reactions were performed in air. CH
CF ) ppm. MS: m/z = 283 [M]. Crystals of the compound suitable
for X-ray crystallographic analysis were obtained by slow concen-
3
2
2
Cl was distilled from
CaH (to remove the residual HCl). All the other starting materials
2
1
19 13
31
tration of a solution of 4a in CDCl3.
were provided by Enamine Ltd. H, F, C, and P NMR spectra
were recorded with a Bruker Avance 500 spectrometer at 499.9,
Ethyl 3-(3-Nitropyridin-2-yl)-5-(trifluoromethyl)-4,5-dihydro-3H-
470.3, 124.9, and 202.4 MHz, respectively. Chemical shifts are re-
1
pyrazole-3-carboxylate (7a): Obtained in the form of Δ -pyrazoline
1
13
ported in ppm downfield from TMS ( H, C), OPA (85% phos-
as a 90:10 mixture of isomers. Yield: 200 mg (98%); yellowish oil
31
19
6 6
phoric acid) ( P) or C F ( F) as internal standards. Mass spectra
1
that solidified upon standing; m.p. 67–68 °C. H NMR (500 MHz,
were recorded with an Agilent 1100 LCMSD SL instrument by
chemical ionization (CI, LC-MS).
3
CDCl
COCH
COCH ), 5.13 (m, 1 H, CHCF ), 7.58 (dd, J
3
; Me
4
Si): δ (major isomer) = 1.27 (t, JH,H = 7.1 Hz, 3 H,
3
2
CH
3
), 2.72 (d, JH,H = 9.1 Hz, 2 H, CH
2
), 4.29 (m, 2 H,
= 4.5 Hz, 1 H,
3
Typical Procedure. 5-Benzyl-3-(trifluoromethyl)-3a,6a-dihydropyr-
2
3
H,H
3
rolo[3,4-c]pyrazole-4,6(3H,5H)-dione (1a): Alkene
.27 mol) was dissolved in CH Cl (400 mL), and a solution of
NaNO (27.9 g, 0.40 mol) in water (200 mL) was added at room
temp. The suspension was cooled to 0 °C, and CF CH NH ·HCl
54.2 g, 0.40 mol) was added in small portions while stirring. The
1
(50.0 g,
CH of pyridine), 8.46 (d, J
= 4.5 Hz, 1 H, CH of pyridine),
H,H
8.73 (d, JH,H = 4.5 Hz, 1 H, CH of pyridine) ppm. 13C NMR
3
0
2
2
2
(125 MHz, CDCl ; Me Si): δ (major isomer) = 13.7 (s, CH ), 28.4
3
4
3
3
3
2
2
(s, CH ), 63.3 (s, CH CH ), 90.5 (q, J
103.6 (s, CCOOEt), 123.1 (q, J
2
2
3
C,F
= 29.3 Hz, CHCF ),
3
1
(
C,F 3
= 280.0 Hz, CF ), 124.6 (s, CH
reaction mixture was vigorously stirred for 1 h, then the cooling
bath was removed, and stirring was continued for another 12 h.
The organic layer was separated, washed once with brine, dried
of pyridine), 133.8 (c, CH of pyridine), 144.4 (s, C of pyridine),
1
9
149.3 (s, CNO ), 152.5 (s, CH of pyridine), 166.0 (s, CO) ppm.
2
F
NMR (375 MHz, CDCl ; CFCl ): δ (major isomer) = –71.2 (d,
3
3
3
with Na
2
SO
4
, and concentrated under reduced pressure to give the
3
JF,H = 8.0 Hz, CF ) ppm. MS: m/z = 305 [M – 28].
1
title product 1a (76.2 g, 0.26 mol, 95%) in the form of Δ -pyrazol-
ine as single stereoisomer. An analytical sample of the product was
obtained by crystallization of the material (hexane/EtOAc, 4:1) to
give the pure product as a white solid. M.p. 108–109 °C. Analytical
characteristics of that material are identical to those reported pre-
Methyl 3-(2-Methoxy-2-oxoethyl)-5-(trifluoromethyl)-4,5-dihydro-
1
3
H-pyrazole-3-carboxylate (8a): Obtained in the form of Δ -pyrazo-
1
line as a 50:50 mixture of isomers. Yield: 5.0 g (94%); clear oil. H
NMR (500 MHz, CDCl ; Me Si): δ = 1.57 (m, 0.46 H, CHH of
pyrazoline cycle), 2.12 (m, 0.51 H, CHH of pyrazoline cycle), 2.24
m, 0.51 H, CHH of pyrazoline cycle), 2.73 (overlap, 0.91 H, CHH
3
4
[
12c]
viously.
(
5
-(Trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carbonitrile
(2b):
2
of pyrazoline cycle, CHHCOOMe), 2.90 [d, JH,H = 17.6 Hz, 0.52
2
Obtained as Δ -pyrazoline as a white solid. Yield: 2.0 g (97%); m.p.
2
H , C H H C O O M e ] , 3 . 2 7 ( d ,
CHHCOOMe), 3.63 (s, 1.49 H, COOCH
OCH ), 3.73 (s, 1.40 H, COOCH ), 3.77–3.81 (overlap, 1.98 H,
COOCH , CHHCOOMe), 5.19–5.29 (m, 0.5 H, CF CH), 5.30–
CH) ppm. C NMR (125 MHz, CDCl
Si): δ (diastereoisomers A and B) = 37.7 (s, CH of pyrazoline
COOMe), 51.9 (s, CH COOCH of A), 51.0
J
H , H = 1 7 . 2 H z, 0. 52 H,
1
2
91–92 °C. H NMR (500 MHz, CDCl
3
; Me
4
Si): δ = 3.12 [dd, JH,H
3
), 3.68 (s, 1.42 H, CO-
3
2
3
=
=
17.9, JH,H = 7.9 Hz, 1 H, CHH, ], 3.24 [dd, JH,H = 17.9, JH,H
3
3
12.6 Hz, 1 H, CHH], 4.44–4.52 (m, 1 H, CHCF
3
), 6.69 (s, 1 H,
Si): δ = 34.2 (s, CH ),
), 113.1 (s, CH), 120.5–127.2 (q,
), 123.4 (s, CN) ppm. 19F NMR (375 MHz,
): δ = –78.0 (d, 3JF,H = 7.0 Hz) ppm. MS: m/z = 163
M]. Crystals of the compound suitable for X-ray crystallographic
3
3
13
NH) ppm. C NMR (125 MHz, CDCl
3
; Me
4
2
13
5
Me
.36 (m, 0.5 H, CF
3
3
;
2
6
J
0.8 (q, JC,F = 32.0 Hz, CHCF
3
4
2
1
C,F = 280.0 Hz, CF
3
cycle), 39.4 (s, CH
s, CH COOCH of B), 53.3 (s, COOCH
CHCF of A,B), 98.4 [s, C(COOMe)CH
C(COOMe)CH
2
2
3
CDCl ; CFCl
[
3
3
(
2
3
3
), 90.4–91.3 (m, overlap
COOMe of A], 98.0 [s,
3
2
1
analysis were obtained by slow concentration of a solution of 2a
in diethyl ether.
2
COOMe of B] 123.5 (q, JC,F = 279.0 Hz, CF
3
of
COOMe
2
COOMe of B), 169.4 (s, COOMe of A), 169.6
1
A), 123.6 (q, JC,F = 279.0 Hz, CF
of A), 168.3 (s, CH
(s, COOMe of B) ppm. F NMR (375 MHz, CDCl ; CFCl ): δ =
3 2
of B), 167.4 (s, CH
5
(
-(Trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-sulfonyl
Fluoride
3b): Obtained in the stable form of Δ -pyrazoline as a yellow oil
1
9
2
3
3
3
3
–
72.3 (d, JF,H = 8.0 Hz, CF
3 3
of A), –71.8 (d, JF,H = 8.0 Hz, CF
with 94% purity (according to LC-MS analysis). Yield: 2.0 g
1
2
of B) ppm. MS: m/z = 268.
(
1
92%). H NMR (500 MHz, CDCl
3
; Me
4
Si): δ = 3.33 (dd, JH,H
=
=
3
2
3
7.6, JH,H = 8.1 Hz, 1 H, CHH), 3.47 (dd, JH,H = 17.6, JH,H
5
4
-Phenyl-3-(trifluoromethyl)-3a,6a-dihydropyrrolo[3,4-c]pyrazole-
,6(3H,5H)-dione (9a): Obtained in the form of Δ -pyrazoline as
8
.1 Hz, 1 H, CHH), 4.71 (m, 1 H, CHCF
3
), 7.25 (s, 1 H, NH) ppm.
Si): δ = 31.8 (s, CH ), 62.7 (q,
), 123.5 (q, JC,F = 280.0 Hz, CF ), 140.2
C,F = 38.0 Hz, C=N) ppm. F NMR (375 MHz, CDCl
1
13
C NMR (125 MHz, CDCl
2JC,F = 32.0 Hz, CHCF
d, 2
CFCl
3
; Me
4
2
one stereoisomer. Yield: 2.0 g (96%); white solid; m.p. 166–168 °C.
1
3
3
1
3
3 4
H NMR (500 MHz, CDCl ; Me Si): δ = 3.53 (dd, JH,H = 3.0,
19
(
J
3
;
3
J
3
H,H = 7.3 Hz, 1 H, CHCHCO), 5.81 (m, 1 H, CHCF ), 6.03 (dd,
3
3
): δ = –78.2 (d, JF,H = 6.0 Hz, CF
3
) ppm. MS: m/z = 220
3JH,H = 7.8, JH,H = 2.4 Hz, 1 H, NCHCO), 7.23 (m, 2 H, Ph),
4
[M].
13
7
.47 (m, 3 H, Ph) ppm. C NMR (125 MHz, CDCl
3
; Me
C,F = 29.0 Hz, CHCF ), 94.8 (s,
NCHCO), 122.3 (q, JC,F = 280.0 Hz, CF ), 126.1 (s, 2CH of
phenyl), 129.4 (s, overlap of 3 CH of phenyl), 130.4 (s, C of phenyl),
4
Si): δ =
2
2
1
-[(5-Trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl]-1H-isoindole-
,3(2H)-dione (4a): The reaction was performed as described in the
38.8 (s, CHCO), 92.9 (q,
J
3
1
3
typical procedure. CF
equiv. then 4 equiv. after 3 d, then 4 equiv. after 6 d); the reaction
time was 14 d. The crude material was crystallized (Et O/hexane,
:1) to afford the Δ -pyrazoline 4a. Yield: 280 mg (80%); white
3 2 2
CH NH ·HCl (2.0 g, 12 equiv. in total;
1
9
4
3
166.4 (s, CO), 171.6 (s, CO) ppm. F NMR (375 MHz, CDCl ;
CFCl
3
2
3 3
): δ = –72.0 (d, JF,H = 8.0 Hz, CF ) ppm. MS: m/z = 283
1
9
6
[M]. Crystals of the compound suitable for X-ray crystallographic
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31852
/KAP1
Date: 04-03-14 16:37:24
Pages: 10
3
Synthesis of CF -Substituted Pyrazolines/Pyrazoles
analysis were obtained by slow concentration of a solution of 9a
in THF.
H, CH
one), 2.72–2.76 (m, 1 H, CH of cyclohexanone), 3.41–3.47 (m, 1
H, CHCHCF ), 4.25–4.30 (m, 1 H, CHCF ), 6.55 (s, 1 H, NH)
ppm. C NMR (125 MHz, CDCl ; Me Si): δ = 23.2 (s, CH ), 28.5
(s, CH CH), 40.7 (s, CH CO), 46.5 (s, CHC=N), 70.1 (q, JC,F
2
of cyclohexanone), 2.42–2.49 (m, 1 H, CH of cyclohexan-
3
3
Dimethyl 5-(Trifluoromethyl)-4,5-dihydro-1H-pyrazole-3,4-dicarb-
1
3
2
3
4
2
oxylate (10b): Obtained in the form of Δ -pyrazoline as a single
2
1
2
2
=
isomer. Yield: 2.5 g (97%); white solid; m.p. 90–91 °C. H NMR
1
3
1.0 Hz, CHCF
3
), 124.6 (q, JC,F = 277.0 Hz, CF
3
), 150.4 (s, C=N),
(
(
4
(
500 MHz, CDCl
s, 3 H, N=CCOOCH
.63–4.71 (m, 1 H, CHCF
125 MHz, CDCl ; Me
3
; Me
4 3
Si): δ = 3.78 (s, 3 H, CHCOOCH ), 3.82
193.2 (s, CO) ppm. 19F NMR (375 MHz, CDCl
3
3
3
; CFCl ): δ = –82.4
3
), 4.20 (d, JH,H = 7.8 Hz, 1 H, CHCOOMe),
3
13
(d, JF,H = 5.0 Hz, CF
3
) ppm. MS: m/z = 207 [M + 1]. Crystals
3
), 7.02 (s, 1 H, NH) ppm. C NMR
S i): δ = 5 0. 1 ( q, 3
of the compound suitable for X-ray crystallographic analysis were
obtained by slow concentration of a solution of 14b in THF.
3
4
J
C , F = 3 Hz,
), 65.5
C,F = 279.0 Hz, CF
CHCOOCH
3
), 52.2 (s, CHCOOCH
3 3
), 53.0 (s, N=CCOOCH
2
), 123.2 (q, 1
(q,
JC,F = 32.0 Hz, CHCF
3
J
3
), Methyl 5-(Trifluoromethyl)-1H-pyrazol-3-carboxylate (21a): Yield:
1
1
38.5 (s, N=C), 160.8 (s, CHCOOMe), 168.6 (s, N=CCOOMe)
2.0 g (99%); white solid; m.p. 125–126 °C. H NMR (500 MHz,
19
3
ppm. F NMR (375 MHz, CDCl
.0 Hz, CF ) ppm. MS: m/z = 255 [M + 1]. Crystals of the com-
pound suitable for X-ray crystallographic analysis were obtained
by slow concentration of a solution of 10b in CH Cl
3
; CFCl
3
): δ = –87.5 (d, JF,H
=
CDCl
3
; Me
4
Si): δ = 3.99 (s, 3 H, COOCH
ppm. C NMR (125 MHz, CDCl ; Me Si): δ = 52.8 (s, COOCH
107.4 (s, CH), 120.5 (q, JC,F = 269.0 Hz, CF ), 135.2 (s, C=N),
), 159.1 (s, CO) ppm. 19F NMR
): δ = –62.9 (s, CF ) ppm. MS: m/z = 195
3
), 7.10 (s, 1 H, NH)
1
3
7
3
3
4
3
),
1
3
2
2
2
.
144.2 (q, JC,F = 37.0 Hz, CCF
375 MHz, CDCl ; CFCl
[M + 1].
3
(
3
3
3
Diethyl 5-(Trifluoromethyl)-4,5-dihydro-1H-pyrazole-3,4-dicarb-
2
oxylate (11b): Obtained in the form of Δ -pyrazoline as a 92:8 mix-
1
ture of isomers. Yield: 2.3 g (98%); clear oil. H NMR (500 MHz,
2-Phenyl-1-[5-(trifluoromethyl)-1H-pyrazol-3-yl]ethanone (22a):
1
CDCl
signals of CH
two CH CH and CHCOOEt), 4.57–4.65 (m, 1 H, CHCF
s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl
; Me Si): δ (major (125 MHz, CDCl
isomer) = 13.4 (s, CCOOCH CH ), 13.6 (s, N=CCOOCH CH ), pyrazole), 120.1 (q, JC,F = 268.0 Hz, CF
0.4 (s, CHCOOEt), 61.2 (s, CCOOCH CH ), 62.0 (s, phenyl), 128.6 (s, m-CH of phenyl), 129.0 (s, o-CH of phenyl), 132.1
), 65.5 (q, JC,F = 32.0 Hz, CHCF
), 138.7 (s, C=N), 160.4 (s, CHCOOEt), 168.3 CCF
3
; Me
4
Si): δ (major isomer) = 1.18–1.25 (m, 6 H, overlap two Yield: 180 mg (99 %); yellowish solid; m.p. 74–75 °C. H NMR
CH ), 4.09–4.24 (m, 5 H, overlap three signals of (500 MHz, CDCl ; Me Si): δ = 4.17 (s, 2 H, CH Ph), 7.05 (s, 1 H,
), 7.25 CH of pyrazole), 7.27–7.38 (m, 5 H, CH of phenyl) ppm. C NMR
; Me Si): δ = 46.2 (s, CH Ph), 106.7 (s, CH of
), 127.3 (s, p-CH of
2
3
3
4
2
13
2
3
3
(
3
4
3
4
2
1
2
3
2
3
3
5
2
3
2
2
N=CCOOCH
2
CH
3
3
), 123.4 (q,
(s, C of phenyl), 141.0 (s, CCOCH
2
Ph), 143.3 (q, JC,F = 39.0 Hz,
), 188.0 (s, CO) ppm. F NMR (375 MHz, CDCl ; CFCl ):
): δ δ = –61.5 (s, CF ) ppm. MS: m/z = 255 [M + 1].
3
) ppm. MS: m/z =
1
19
J
C,F = 279.0 Hz, CF
3
3
3
3
1
9
(
(
2
s, N=CCOOEt) ppm. F NMR (375 MHz, CDCl
major isomer) = –87.5 (d, JF,H = 7.0 Hz, CF
83 [M + 1].
3
; CFCl
3
3
3
3
-(Diphenylphosphoryl)-5-(trifluoromethyl)-1H-pyrazole (23a):
1
Yield: 200 mg (99%). White solid; sublimation at ca. 220 °C. H
NMR (500 MHz, CDCl ; Me Si): δ = 6.48 (s, 1 H, CH of pyrazole),
7.44–7.61 (m, 10 H, CH of phenyls) ppm. C NMR (125 MHz,
Ethyl 4,5-Bis(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxyl-
3
4
2
13
ate (12b): Obtained in the form of Δ -pyrazoline as a 91:9 mixture
1
2
of isomers. Yield: 5.0 g (91%); white solid; m.p. 66–68 °C. H NMR
CDCl
3 4
; Me Si): δ = 110.6 (d, JC,P = 17.0 Hz, CH of pyrazole),
3
1
3
(
1
4
500 MHz, CDCl
3
; Me
4
Si): δ = 1.32 (t, JH,H = 7.1 Hz, 0.36 H),
120.7 (q, JC,F = 269.0 Hz, CF ), 128.4 (d, JC,P = 13.0 Hz, m-CH
3
3
1
.37 (t, JH,H = 7.1 Hz, 2.64 H), 4.15–4.22 (m, 1 H, CHCF
.40 (m, 2 H, CH CH ), 4.53–4.60 [m, 0.91 H, CH(CF )NH], 4.89
3
), 4.30– of phenyls), 129.8 (d, JC,P = 113.0 Hz, C of phenyls), 131.2 (d,
2
4
2
3
3
J(C,F) = 11.0 Hz, o-CH of phenyls], 132.5 (d, JC,F = 2.0 Hz, p-
1
[
m, 0.8 H, CH(CF
3
)NH], 6.47 (s, 0.08 H, NH), 6.87 (s, 0.81 H, CH of phenyls], 135.7 (d, JC,F = 117.0 Hz, CPOPh
2
), 142.3–143.3
; CFCl ): δ = –60.8
) ppm. P NMR (202.4 MHz, CDCl ; OPA): δ = 19.8
) ppm. MS: m/z = 337 [M + 1].
13
) ppm. 19F NMR (375 MHz, CDCl
NH) ppm. C NMR (125 MHz, CDCl
A and B) = 13.4 (s, CH of A), 13.7 (s, CH
overlap CHCF of A,B), 61.7 (s, CH ), 61.7–62.7 [m, overlap
CH(CF )NH of A,B], 122.7 (q, JC,F = 281.0 Hz, CF of A), 123.2
q, JC,F = 280.0 Hz, CF of B), 134.9 (s, C=N), 159.8 (s, C=O)
3
; Me
4
Si): δ (diastereomer (m, CCF
of B), 49.1–50.1 (m, (s, CF
(pseudo t, JP,H = 12.1 Hz, PPh
2
3
3
3
3
1
3
3
3
3
3
3
2
1
3
3
Dimethyl 5-(Trifluoromethyl)-1H-pyrazole-3,4-dicarboxylate (26a):
1
(
3
1
Yield: 500 mg (96 %); yellowish solid; m.p. 65–66 °C. H NMR
19
3
ppm. F NMR (375 MHz, CDCl
3
; CFCl
), –91.5 (d, JF,H = 7.0 Hz, NHCHCF
m/z = 279 [M + 1].
3
): δ = –82.3 (d, JF,H
=
(
(
500 MHz, CDCl
s, 3 H, N=CCOOCH
Si): δ = 53.0 (s, C=CCOOCH
3
; Me
4
Si): δ = 3.94 (s, 3 H, C=CCOOCH
3
), 3.97
) ppm. C NMR (125 MHz, CDCl
), 53.3 (s, N=CCOOCH ), 115.0
), 119.9 (q, JC,F = 270.0 Hz, CF ), 134.9 (s,
C), 158.2 (s,
3
7
.0 Hz, CHCF
3
3
) ppm. MS:
13
3
3
;
Me
(s, C=CCOOCH
N=CCOOMe), 141.8 (q,
4
3
3
1
Methyl 4-Methyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-
3
3
2
2
carboxylate (13b): Obtained in the form of Δ -pyrazoline as a 90:10
JC,F = 39.0 Hz, CF
3
1
19
mixture of isomers and ca. 10% of Δ -pyrazoline. The product pu- C=CCOOMe), 161.6 (s, N=CCOOMe) ppm. F NMR (375 MHz,
rity was ca. 90%. This material was used directly in the synthesis of
3 3 3
CDCl ; CFCl ): δ = –62.3 (s, CF ) ppm. MS: m/z = 253 [M + 1].
Crystals of the compound suitable for X-ray crystallographic analy-
sis were obtained by slow concentration of a solution of 26a in
1
pyrazole 30. Yield: 75 g (85%); colorless oil. H NMR (500 MHz,
3
CDCl
CHCH
H, CHCF
CDCl ; Me Si): δ = 17.5 (s, CHCH
COOCH ), 68.3 (q,
80.0 Hz, CF ), 145.6 (s, C=N), 161.9 (s, COOMe) ppm. MS: m/z
211 [M + 1].
3
; Me
), 3.51 (m, 1 H, CHCH
), 6.53 (s, 1 H, NH) ppm. 13C NMR (125 MHz,
), 40.4 (s, CHCH ), 52.2 (s,
C,F = 31.0 Hz, CHCF ), 124.4 (q,
4
Si): δ (major isomer) = 1.39 (d, JH,H = 7.0 Hz, 3 H,
3
3
), 3.85 (s, 3 H, COOCH
3
), 3.97 (m, CH
,4,5-Tris(trifluoromethyl)-1H-pyrazole (27a): A solution of bis(tri-
fluoromethyl)acetylene (27) in CH Cl was prepared at –30 °C
Flask 1). An aliquot of a solution of 27 (1.0 g, 6.2 mmol) in
CH Cl (ca. 50 mL) was added to a previously generated solution
Flask 2) of CF CHN (obtained from 1.3 g of CF CH NH ·HCl,
2 2
Cl .
1
3
3
3
4
3
3
2
2
1
1
3
J
3
C,F
J =
(
2
=
3
2
2
(
3
2
3
2
2
3
-(Trifluoromethyl)-2,3,3a,4,5,6-hexahydro-7H-indazol-7-one (14b):
CF CH NH ·HCl (4.5 g, 3 equiv.) was used; the reaction time was
8 h. Yield: 1.1 g (90%); white solid; m.p. 168–170 °C. H NMR
500 MHz, CDCl ; Me Si): δ = 1.66–1.74 (m, 1 H, CH of cyclohex-
anone), 1.91–1.99 (m, 1 H, CH of cyclohexanone), 2.17–2.30 (m, 2
1.5 equiv.) in dichloromethane at –10 °C. The reaction mixture was
allowed to warm slowly to room temp. for 12 h. The organic layer
was separated, washed with brine, dried with sodium sulfate, and
concentrated under vacuum to give pyrazole 27a (1.3 g, 4.9 mmol,
80% yield) as a white solid (CAUTION: The product is very vola-
3
2
2
1
4
(
3
4
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31852
/KAP1
Date: 04-03-14 16:37:24
Pages: 10
P. K. Mykhailiuk et al.
FULL PAPER
tile!). An analytical sample was obtained by low-temperature
recrystallization from pentane. Analytical characteristics of that
material are identical to those reported previously.[
Acknowledgments
17]
The authors are grateful to Prof. Andrei Tolmachev for financial
support of the work; to Dr. Andrii Kysil, Rustam Iminov, Bohdan
Chalyc, Sergii Yasik for starting alkenes; and to Dr. Sci. Dmytro
Volochnyuk and Prof. Igor V. Komarov for support.
1
(
-[3-(Trifluoromethyl)-5-(trimethylsilyl)-1H-pyrazol-4-yl]ethanone
28b): The crude material was crystallized from hexane to afford
the pure product 28b. Yield: 140 mg. (65%); white solid; m.p. 120–
1
1
3 4
21 °C (subl.). H NMR (500 MHz, CDCl ; Me Si): δ = 0.39 [s, 9
H, Si(CH
CDCl ; Me
270.0 Hz, CF
), 151.3 (s, CCO), 192.6 (s, CO) ppm. 1 F NMR (375 MHz,
CCF
CDCl ; CFCl ): δ = –58.1 (s,CF ) ppm. MS: m/z = 251 [M + 1].
3
)
3
], 2.57 (s, 3 H, COCH
3
) ppm. 13C NMR (125 MHz,
[1] For reviews on bioactive pyrazolines, see: a) S. Kumar, S. Bawa,
S. Drabu, R. Kumar, H. Gupta, Recent Pat. Antiinfect. Drug
Discov. 2009, 4, 154; b) M. A. Rahman, A. A. Siddiqui, Int. J.
Pharm. Sci. Drug Res. 2010, 2, 165; c) X.-H. Liu, B.-F. Ruan,
J. Li, F.-H. Chen, B.-A. Song, H.-L. Zhu, P. S. Bhadury, J.
Zhao, Mini-Rev. Med. Chem. 2011, 11, 771; d) M. R. Shaaban,
A. S. Mayhoub, A. M. Farag, Expert Opin. Ther. Pat. 2012, 22,
1
3
4
Si): δ = –2.6 [s, Si(CH
3
)
3
], 29.2 (s, CH
3
2
), 120.8 (q, JC,F
=
3
), 127.1 (s, CTMS), 141.0 (q, JC,F = 36.0 Hz,
9
3
3
3
3
5
2
2
-(Trifluoromethyl)-1H-pyrazole-3-carboxylic Acid (29): Pyrazole
1a (1.0 g, 5.15 mmol) was suspended in dioxane/water (2:1,
0 mL), and aq. 20% HCl (5 mL) was added. The reaction mixture
2
53; e) A. Ganesh, Int. J. Pharma Bio Sci. 2013, 4, 727; f) A.
Marella, M. R. Ali, M. T. Alam, R. Saha, O. Tanwar, M.
Akhter, M. Shaquiquzzaman, M. Mumtaz Alam, Mini-Rev.
Med. Chem. 2013, 13, 921.
was heated at reflux overnight; then the solvent was evaporated
under vacuum, and the formed solid residue was crystallized from
[2] a) X. Zhang, X. Li, G. F. Allan, T. Sbriscia, O. Linton, S. G.
Lundeen, Z. Sui, J. Med. Chem. 2007, 50, 3857; b) M. Shahar-
yar, M. M. Abdullah, M. A. Bakht, J. Majeed, Eur. J. Med.
Chem. 2010, 45, 114; c) X. H. Liu, P. C. Lv, B. Li, H. L. Zhu,
B. A. Song, Aust. J. Chem. 2008, 61, 223; d) L. S. Bai, Y. Wang,
X. H. Liu, H. L. Zhu, B. A. Song, Chin. Chem. Lett. 2009, 20,
2
-propanol to obtain the pure product 29. Yield: 0.862 g
1
(
(
4.79 mmol, 93 %); white solid; m.p. 167–169 °C. H NMR
500 MHz, CDCl ; Me Si): δ = 2.31 (s, 3 H, CH ), 4.72 (br. s, 2 H,
; Me Si): δ = 106.7
), 136.4 (s, C=N), 141.3 (q,
), 159.4 (s, COOH) ppm. 19F NMR
): δ = –70.7 (s, CF ) ppm. MS: m/z = 180
3
4
3
13
NH, COOH) ppm. C NMR (125 MHz, CDCl
3
4
1
(
s, CH), 121.0 (q, JC,F = 268.0 Hz, CF
3
J
4
27; e) M. V. R. Reddy, V. K. Billa, V. R. Pallela, M. R. Malli-
2
C,F = 38.3 Hz, CCF
375 MHz, CDCl ; CFCl
M].
3
reddigari, R. Boominathan, J. L. Gabriel, E. P. Reddy, Bioorg.
Med. Chem. 2008, 16, 3907.
(
3
3
3
[
[3] In The Chemistry of The Cyclopropyl Group (Ed.: Z. Rappo-
port), Wiley-VCH, Weinheim, 1987.
[
[
4] a) A. P. Molchanov, A. V. Stepakov, R. R. Kostikov, Russ. J.
Org. Chem. 2001, 37, 128; b) V. Padmavathi, C. P. Kumari,
B. C. Venkatesh, A. Padmaja, Eur. J. Med. Chem. 2011, 46,
Methyl 4-Methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate
30): In a reactor equipped with a dropping funnel and a thermo-
meter, pyrazoline 27a (75.0 g, 0.36 mol) was dissolved in Et
700 mL). The solution was cooled to 0 °C followed by slow drop-
wise addition of bromine (22.3 mL, 0.43 mol). The reaction mixture
was stirred at room temp. for 24 h; then the solvent was evaporated
(
2
O
5
317; c) A. Muralikrishna, B. C. Venkatesh, V. Padmavathi, A.
Padmaja, P. Kondaiah, N. S. Krishna, Eur. J. Med. Chem. 2012,
4, 605.
(
5
5] a) R. Chenevert, F. Jacques, Tetrahedron: Asymmetry 2006, 11,
1017; b) E. A. Yatsynich, D. V. Petrov, V. A. Dokichev, Y. V.
Tomilov, Russ. J. Org. Chem. 2005, 41, 1187; c) K. V. Yakovlev,
D. V. Petrov, V. A. Dokichev, Y. V. Tomilov, Russ. J. Org. Chem.
under vacuum. The solid residue was dissolved in CH
2
Cl
2
(500 mL), and this solution was washed twice with a saturated solu-
3
tion of NaHCO (150 mL) and brine. The organic phase was dried
with sodium sulfate, filtered, and the solvents were evaporated un-
der vacuum to obtain the crude product. Crystallization from hex-
2011, 47, 168.
[
[
6] D. S. Wishart, C. Knox, A. C. Guo, D. Cheng, S. Shrivastaya,
D. Tzur, B. Gautam, M. Hassanali, Nucleic Acids Res. 2008,
ane gave pure pyrazole 30. Yield: 68.9 g (0.33 mmol, 92%); white
36 database issue, D.901 (http://www.drugbank.ca).
1
solid; m.p. 77–78 °C. H NMR (500 MHz, CDCl
3
; Me
) ppm. 13C NMR (125 MHz,
), 52.4 (s, COOCH ), 120.1 (s,
), 132.3 (s, CCOOMe),
4
Si): δ = 2.42
7] For selected reviews, see: a) K. L. Kirk, Org. Process Res. Dev.
(
s, 3 H, CH
CDCl ; Me
CCH
42.7 (q, 2JC,F = 37.0 Hz, CCF
NMR (375 MHz, CDCl ; CFCl ): δ = –62.4 (s, CF
209 [M + 1].
3
), 3.99 (s, 3 H, COOCH
3
2
008, 12, 305; b) R. Filler, R. Saha, Future Med. Chem. 2009,
3
4
Si): δ = 8.1 (s, CCH
3
3
1
, 777; c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
1
3
), 121.2 (q, JC,F = 269.0 Hz, CF
), 159.6 (s, COOMe) ppm.
3
Chem. Soc. Rev. 2008, 37, 320; d) W. K. Hagmann, J. Med.
Chem. 2008, 51, 4359; e) H.-J. Bohm, D. Banner, S. Bendels,
M. Kansy, B. Kuhn, K. Muller, U. Obst-Sander, M. Stahl,
ChemBioChem 2004, 5, 637.
19
1
3
F
3
3
3
) ppm. MS: m/z
=
[
[
8] a) J. H. Atherton, R. Fields, J. Chem. Soc. C 1968, 1507; b) R.
Fields, J. P. Tomlinson, J. Fluorine Chem. 1979, 13, 147.
9] Prudent Practices for Handling Hazardous Chemicals in
Laboratories (Ed.: H. O. House), National Academy Press,
Washington D.C., 1981, pp. 57–68.
4
-Methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic Acid (31):
Pyrazole 30 (67.0 g, 0.32 mol) was suspended in dioxane/water (2:1,
00 mL), and aq. 20% HCl (100 mL) was added. The reaction mix-
3
ture was heated at reflux overnight; then the solvent was evaporated
under vacuum, and the formed solid residue was crystallized from
[
[
10] H. Gilman, R. G. Jones, J. Am. Chem. Soc. 1943, 65, 1458.
11] J. H. Atherton, R. Fields, J. Chem. Soc. C 1967, 1450.
2
9
-propanol to obtain the pure product 31. Yield: 58.3 g (0.3 mol,
[12] a) R. Fields, J. P. Tomlinson, J. Fluorine Chem. 1979, 13, 147;
b) O. S. Artamonov, P. K. Mykhailiuk, N. M. Voievoda, D. M.
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4 %); white solid; m.p. Ͼ250 °C (dec.). 1H NMR (500 MHz,
CDCl
3
; Me
4
Si): δ = 2.30 (s, 3 H, CH
; Me Si): δ = 7.9 (s, CH
), 121.8 (q, JC,F = 268.0 Hz, CF ), 133.0 (s, CCOOH), 140.2
3
), 14.34 (s, 1 H, COOH) ppm.
13
C NMR (125 MHz, CDCl
3
4
3
), 118.3 (s,
1
CCH
3
3
[
13] Preparation of trifluoromethyldiazomethane in situ and its re-
action with alkenes was previously briefly mentioned, see: F.
Jin, Y. Xu, Y. Ma, Tetrahedron Lett. 1992, 33, 6161. The au-
thors, however, used unique starting material that was not com-
mercially available, and did not provide experimental details.
2
19
(
q, JC,F = 36.0 Hz, CCF
3
), 160.1 (s, COOH) ppm. F NMR
) ppm. MS: m/z = 195
(375 MHz, CDCl ; CFCl ): δ = –58.4 (s, CF
3
3
3
[M + 1].
Supporting Information (see footnote on the first page of this arti-
[14] The Supporting Information includes a photograph of the sys-
cle): Copies of NMR spectra for all new compounds.
tem used to initially synthesize pyrazoline 1a.
8
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Job/Unit: O31852
/KAP1
Date: 04-03-14 16:37:24
Pages: 10
3
Synthesis of CF -Substituted Pyrazolines/Pyrazoles
[
15] a) B. Morandi, E. M. Carreira, Angew. Chem. 2010, 122, 950;
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2
[20]
N. B. Jayaratna, I. I. Gerus, R. V. Mironets, P. K. Mykhailiuk,
M. Yousufuddin, H. V. R. Dias, Inorg. Chem. 2013, 52, 1691.
Morandi, E. M. Carreira, Org. Lett. 2011, 13, 5984; e) S. A.
Künzi, B. Morandi, E. M. Carreira, Org. Lett. 2012, 14, 1900.
16] In the 13C NMR spectrum the methyl group is observed as a
[
21] I. I. Gerus, R. X. Mironetz, I. S. Kondratov, A. V. Bezdudny,
Y. V. Dmytriv, O. V. Shishkin, V. S. Starova, O. A. Zaporozhets,
A. A. Tolmachev, P. K. Mykhailiuk, J. Org. Chem. 2012, 77,
[
[
5
quartet ( JC,F = 6.3 Hz).
17] For a discussion of steric effects in [3+2] cycloadditions, see: a)
R. Huisgen, Angew. Chem. 1963, 75, 742; Angew. Chem. Int.
Ed. Engl. 1963, 2, 633; b) G. Maas, Diazoalkanes in Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products (Eds.: A. Padwa, W. H.
Pearson), Wiley, New York, 2002, p. 539.
4
7.
22] During the preparation of this manuscript a publication on
the Ag-catalyzed addition of CF CHN to terminal alkynes
[
3
2
appeared, see: F. Li, J. Nie, L. Sun, Y. Zheng, J.-A. Ma, Angew.
Chem. Int. Ed. 2013, 52, 6255.
23] CCDC-950992 (2b), -972780 (4a), -951420 (9a), -972779
[
[
18] See, for example: a) C. H. Yang, H.-J. Shen, R.-H. Wang, J.-C.
Wang, J. Chin. Chem. Soc. 2002, 49, 95; b) P. Schiess, H.
Stalder, Tetrahedron Lett. 1980, 21, 1413.
(
10b), -951421 (14b), -972781 (21a), and -951422 (26a) contain
the supplementary crystallographic 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.
[
19] a) J. G. Varnes, D. A. Wacker, D. J. P. Pinto, M. J. Orwat, J. P.
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Received: December 17, 2013
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O31852
/KAP1
Date: 04-03-14 16:37:24
Pages: 10
P. K. Mykhailiuk et al.
FULL PAPER
Fluorinated Heterocycles
E. Y. Slobodyanyuk, O. S. Artamonov,
O. V. Shishkin,
P. K. Mykhailiuk* ........................... 1–10
One-Pot Synthesis of CF
azolines/Pyrazoles from Electron-Deficient
Alkenes/Alkynes and CF CHN Generated
in situ: Optimized Synthesis of Tris(tri-
fluoromethyl)pyrazole
3
-Substituted Pyr-
Three-component
reaction
between
tuted pyrazolines/pyrazoles at room tem-
perature in excellent yields.
CF CH NH ·HCl, NaNO
3
2
2
2
and electron-
3
2
3
deficient alkenes/alkynes gives CF -substi-
Keywords: Synthetic methods / Nitrogen
heterocycles / Fluorine / Multicomponent
reactions / Cycloaddition
10
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