Synthesis of 4,4-Difluoro-1 H -pyrazole Derivatives

Article abstract of DOI:10.1055/s-0034-1378915

Fluorination of 3,5-diarylpyrazole substrates by Selectfluor^TM in acetonitrile gave 4,4-difluoro-1H-pyrazoles in addition to 4-fluoropyrazole derivatives. The structure of this new class of fluorinated heterocycle was established by X-ray cryst

Full text of DOI:10.1055/s-0034-1378915

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Synthesis of 4,4-Difluoro-1H-pyrazole Derivatives
Jessica R. Breena
Graham Sandford*a
Bhairavi Patelb
SelectfluorTM (2 equiv)
MeCN, MW, 90 °C, 15 min
F
F
Jonathan Frayb
N
HN
N
N
a Department of Chemistry, Durham University, South Road, Durham,
DH1 3LE, UK
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Graham.Sandford@Durham.ac.uk
b Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent,
CT13 9NJ, UK
Received: 22.09.2014
Accepted after revision: 10.10.2014
Published online: 05.11.2014
from appropriately functionalised pyrazole substrates due
to low total yields over several synthetic steps. Potentially,
the most efficient methods for the synthesis of fluoropyra-
zole systems are aromatic substitution processes using
electrophilic fluorinating agents. A few examples of the
preparation of various fluoroaminopyrazole systems from
the reaction of aminopyrazole precursors with NFSI or
SelectfluorTM have been recorded14 whilst several 4-fluoro-
pyrazole derivatives have been prepared by reaction of
SelectfluorTM with a range of N-arylpyrazole substrates.15
As part of a wider research programme concerning the
synthesis of fluoroorganic systems using electrophilic fluo-
rinating agents,16 we were interested in broadening the
scope of ‘late-stage’ fluorination reactions of pyrazole de-
rivatives for applications in the life-sciences industries. In
this paper, we describe electrophilic fluorination reactions
of various pyrazole derivatives with either SelectfluorTM or
fluorine gas which led to the unexpected synthesis of novel
4,4-difluoro-1H-pyrazole systems.
DOI: 10.1055/s-0034-1378915; Art ID: st-2014-d0791-c
Abstract Fluorination of 3,5-diarylpyrazole substrates by SelectfluorTM
in acetonitrile gave 4,4-difluoro-1H-pyrazoles in addition to 4-fluoropyr-
azole derivatives. The structure of this new class of fluorinated hetero-
cycle was established by X-ray crystallography.
Key words organofluorine, fluoroheterocycle, pyrazole, selective fluo-
rination, fluoropyrazole
The importance of fluorine-containing aromatic and
heterocyclic motifs to the pharmaceutical and agrochemi-
cal industries continues to grow1 because approximately 5–
15% of the total number of drugs launched worldwide over
the past 50 years bear fluorinated substituents.2 For exam-
ple, many six-membered fluorinated heteroaromatic deriv-
atives find applications in a wide variety of drugs and plant
protection agents such as Xeloda (anticancer, Roche),
Voriconazole (antifungal, Pfizer), Ancobon (antifungal,
Valeant) and Diclosulam (herbicide, Dow Agroscience).2
Whilst there are many reported examples of the synthe-
sis of commercially important fluorinated six-membered
azaheterocyclic rings, processes for the preparation of relat-
ed fluorinated five-membered ring systems are relatively
rare.3 However, interest in fluoropyrazole derivatives has
increased recently due to their potential use for treating di-
abetes,4 inflammatory disease,5 as gastric acid inhibitors6
and as acaricides.7 Consequently, protocols for the synthesis
of a variety of selectively fluorinated pyrazoles have been
reported using either fluorination or ‘fluorinated building
block’ strategies. Fluorocyclocondensation reactions involv-
ing enamino ketones8 and fluorocyanoketones,9 gold-cata-
lysed aminofluorination of alkynes10 and reaction of
hydrazines with fluoro-β-dicarbonyl substrates11 offer effi-
cient routes to various functional fluoropyrazole deriva-
tives. Adaptation of established fluorination methodology
such as halogen exchange12 or Balz–Schiemann processes13
has had limited success for the synthesis of fluoropyrazoles
Pyrazole substrates 1 were either obtained from com-
mercial suppliers or synthesised by reaction of the appro-
priate diketone derivatives with hydrazine or phenyl
hydrazine by heating to reflux in ethanol following litera-
ture procedures.17
We began our pyrazole fluorination studies by investi-
gating reactions of representative pyrazole systems 1a–c
with either SelectfluorTM or fluorine gas and the results are
collated in Table 1. Reactions involving SelectfluorTM were
carried out by heating the reaction mixture using micro-
wave irradiation (conditions A). Fluorine gas, diluted to a
10% mixture in anhydrous nitrogen was passed at a con-
trolled rate via a mass flow controller into a stirred solution
of the substrate in acetonitrile using equipment discussed
previously (conditions B).16 Monofluorinated pyrazoles 2a–
c were formed in modest yields and could be purified by
column chromatography on silica gel. In contrast, fluorina-
tion of 3,5-dimethyl-1H-pyrazole was inefficient because of
extensive tar formation due to competing fluorination of
the pendant methyl substituents and subsequent product
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 51–54

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J. R. Breen et al.
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degradation. In addition, pyrazole systems bearing two
electron-withdrawing groups (CF3, CO2H, CO2Me), did not
give any observable products upon reaction with either
SelectfluorTM or fluorine gas, reflecting the lower nucleo-
philicity of these substrates, and starting materials were re-
covered in all of these reactions.
material and monofluorinated pyrazole systems. Separation
of monofluoropyrazole products from the corresponding
starting materials proved to be very difficult but could be
achieved in several cases. Yields of the 4,4-difluoro-1H-pyr-
azole products 3a–h were improved upon reaction of the
pyrazole substrates with two equivalents of SelectfluorTM
(Table 2, conditions C).
Table 1 Synthesis of Monofluoropyrazoles 2 using SelectfluorTM or
Fluorine Gas
Table 2 Synthesis of Fluoropyrazole and 1H-Difluoropyrazole Deriva-
tives
R2
R2
F
HN
N
conditions A or B
N
N
R1
Ar
Ar
R1
Ar
Ar
N
R3
N
R3
F
Ar
2d–k
conditions A or C
Pyrazole 1
R1
R2
R3
Conditionsa,b
Fluoropyrazole 2,
N
Ar
N–
yield (%)
N
N
H
1a
1b
1c
Me
CF3
Me
Ph
Ph
Me Ph
H
A
B
2a, 33
2a, 45
1d–k
F
F
H
A
B
2b, 43
2b, 46
3a–h
A
B
2c, 43
2c, 40
Pyrazole 1 Ar
Conditionsa,b Fluoropyrazole Difluoropyra-
2, yield (%)
zole 3, yield (%)
a Conditions A: SelectfluorTM (1 equiv), MW, 15 min, 90 °C.
b Conditions B: 10% F2/N2, MeCN, r.t.
1d
1e
1f
Ph
A
C
2d, 45
2d, 23
3a, 21
3a, 52
4-ClC6H4
A
C
2e, 31c
2e, 15c
3b, 22
3b, 54
Monofluoropyrazole systems 2a–c were identified by
NMR and mass spectrometry techniques. In particular, the
19F NMR spectra of these systems display singlet resonances
at approximately δ = –175 ppm, consistent with reported
spectroscopic data reported for related fluoropyrazole sys-
tems.15 In addition, the structure of 2b was confirmed by
X-ray crystallography (Figure 1).18
4-BrC6H4
A
C
2f, 37c
2f, 19c
3c, 22
3c, 54
1g
1h
1i
4-F3CC6H4
3-F3CC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
A
C
2g, 36c
2g, 20c
3d, 51
3d, 33
A
C
2h, 41c
2h, 24c
3e, 20
3e, 44
A
C
2i, 45
2i, 20
3f, 27
3f, 45
1j
A
C
2j, 31
2j, 24
3g, 24
3g, 43
1k
A
C
2k, 42
2k, 17
3h, 23
3h, 49
a Conditions A: SelectfluorTM (1 equiv), MW, 15 min, 90 °C.
b Conditions C: SelectfluorTM (2 equiv), MW, 15 min, 90 °C.
c Products 2e–h could not be separated from starting materials 1e–h re-
spectively by column chromatography and yields were estimated by 19
NMR in these cases only.
F
In contrast, when 3,5-diarylpyrazoles 1d–k were react-
ed with fluorine gas, many fluorinated products were ob-
served by 19F NMR analysis of the crude product mixture
and no products could be isolated and purified. In these re-
actions, competing fluorination of the aromatic ring sub-
stituents occurs as determined by the observation of many
signals in the aromatic region (δF = –140 to –160 ppm) of
the 19F NMR spectra of the crude product mixture.
Difluorinated products 3a–h were characterized by dis-
tinctive singlet resonances at approximately δ = –115 ppm
in their 19F NMR spectra and the structure of 3f was con-
firmed by X-ray crystallography (Figure 2).18 The difluori-
Figure 1 Molecular structure of 2b
In order to expand the scope of the fluorination reac-
tions we studied reactions of diphenylpyrazole substrates
1d–k which unexpectedly gave mixtures of mono- and di-
fluorinated systems 2d–k and 3a–h even when only one
equivalent of SelectfluorTM was used and these results are
collated in Table 2 (Conditions A). In all reactions, separa-
tion and purification of the difluorinated products 3a–h
were readily achieved because, in general, they eluted from
the silica gel column much more rapidly than the starting
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 51–54

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J. R. Breen et al.
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Br
nated pyrazole systems 3 are a novel class of fluorinated
compounds although the corresponding dichlorinated sys-
tems have been reported and their use in Diels–Alder reac-
tions has been explored.19
Br
SelectfluorTM
(2 equiv)
F
Br
Br
F
MeCN, MW
90 °C, 15 min
HO
HN
HN
N
N
5, 24%
1l
Scheme 2 Hydoxylated pyrazoline 5
In conclusion, a method for the synthesis of unusual
4,4-difluoro-1H-pyrazole systems 321 has been established
using shelf-stable, readily handled SelectfluorTM as the elec-
trophilic fluorinating agent.
Figure 2 Molecular structure of 3f
Initial fluorination of pyrazole derivatives occurs selec-
tively at the 4-position consistent with an electrophilic aro-
matic substitution process (Scheme 1) and further
electrophilic fluorination reaction occurs at the same site to
give a difluorinated salt 4 as an intermediate. Deprotona-
tion on workup gives the observed 4,4-difluoro-1H pyra-
zole product 3.
Acknowledgment
We thank Dr. D. S. Yufit (Durham University) for X-ray crystallograph-
ic structural analysis.
Supporting Information
Supporting information for this article is available online at
+
http://dx.doi.org/10.1055/s-0034-1378915.
S
u
p
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u
p
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R3N
F
+
R33N
F
R2
R2
R2
F
F
H
References and Notes
N
N
R1
R1
N
+
R1
••
N
H
1
N
N
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N
N
H
N
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3
4a
4b
Scheme 1 Fluorination of pyrazole derivatives 2 and 3
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The outcome is consistent with the intermediate carbo-
cation 4b being stabilized by the adjacent phenyl groups (R1
= aryl; Scheme 1) allowing difluorination to proceed as ob-
served for 3,5-diarlpyrazole substrates.
For reaction with dibrominated system 1l, the hydroxy-
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some analogous reactions, 19F NMR analysis indicated the
presence of hydroxylated systems consistent with 5 in
crude product mixtures (Scheme 2). This minor product is
formed by reaction of water with intermediate salt 4 in re-
action workup, consistent with the mechanism shown in
Scheme 1 and related reactions involving other halogenated
4H-pyrazoles.20 The hydroxypyrazoline product 5 could be
identified by the presence of an AB system, with an appro-
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J. R. Breen et al.
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90 °C. The mixture was then extracted with CH2Cl2 (3 × 50 mL)
and washed with NaHCO3 (30 mL) and H2O (30 mL). The com-
bined extracts were dried (MgSO4) and evaporated. Column
chromatography on silica gel using hexane and EtOAc (1:1) as
the eluent, gave 4-fluoro-3,5-diphenyl-1H-pyrazole (0.135 g,
45%) as pale yellow crystals; mp 185–188 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.41–7.47 (m, 2 H, 4-H), 7.48–7.51 (m, 4 H, 3-H),
7.77–7.80 (m, 4 H, 2-H), 10.3 (br s, 1 H, NH). 13C NMR (126 MHz,
CDCl3): δ = 128.2 (Ar), 129.0 (Ar), 129.3 (Ar), 131.1 (d, 2JCF = 15.0
Hz, C-3), 140.0 (d, 1JCF = 226.6 Hz, C-4), 148.7 (Ar). 19F NMR (376
MHz, CDCl3): δ = –174.3 (s). MS: m/z (%, EI+) = 237.9 (100) [M]+,
107.8 (43), 76.9 (40). HRMS: m/z [M + H]+ calcd for C15H12FN2:
239.0983; found: 239.0972. 4,4-Difluoro-3,5-diphenyl-4H-pyr-
azole (3a): obtained as yellow crystals (0.122 g, 21%); mp 105–
107 °C. 1H NMR (400 MHz, CDCl3): δ = 7.44–7.67 (m, 6 H, ArH),
8.06–8.15 (m, 4 H, ArH). 13C NMR (126 MHz, CDCl3): δ = 125.4
(20) Hansen, J.; Kim, Y.; Griswold, L.; Hoelle, G.; Taylor, D.; Vietti, D.
J. Org. Chem. 1980, 45, 76.
1
(Ar), 125.6 (t, JCF = 267.5 Hz, CF2), 128.3 (Ar), 129.5 (Ar), 133.1
(21) Typical Procedure (Conditions A); 4-Fluoro-3,5-diphenyl-1H-
pyrazole (2d) and 4,4-Difluoro-3,5-diphenyl-4H-pyrazole
(3a): 3,5-Diphenyl-1H-pyrazole (0.30 g, 1.36 mmol) and Select-
fluorTM (0.482 g, 1.36 mmol) were dissolved in MeCN (5 mL) and
the mixture was heated by microwave irradiation for 15 min at
(Ar), 162.1 (t, 2JCF = 23.1 Hz, C-2). 19F NMR (376 MHz, CDCl3): δ =
–116.3 (s). MS: m/z (%, EI+) = 256.1 (100) [M]+, 153.0 (45), 103.1
(99), 77.1 (36). HRMS: m/z [M + H]+ calcd for C15H11F2N2:
257.0890; found: 257.0894.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 51–54

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