Synlett 2015; 26(01): 51-54
DOI: 10.1055/s-0034-1378915
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© Georg Thieme Verlag Stuttgart · New York

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

Jessica R. Breen
a   Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK   Fax: +44(191)3830347   eMail: Graham.Sandford@Durham.ac.uk
,
Graham Sandford*
a   Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK   Fax: +44(191)3830347   eMail: Graham.Sandford@Durham.ac.uk
,
Bhairavi Patel
b   Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
,
Jonathan Fray
b   Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 22. September 2014

Accepted after revision: 10. Oktober 2014

Publikationsdatum:
05. November 2014 (online)

 


Abstract

Fluorination of 3,5-diarylpyrazole substrates by SelectfluorTM 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 crystallography.


The importance of fluorine-containing aromatic and heterocyclic motifs to the pharmaceutical and agrochemical industries continues to grow[1] because approximately 5–15% of the total number of drugs launched worldwide over the past 50 years bear fluorinated substituents.[2] For example, many six-membered fluorinated heteroaromatic derivatives 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 synthesis of commercially important fluorinated six-membered azaheterocyclic rings, processes for the preparation of related fluorinated five-membered ring systems are relatively rare.[3] However, interest in fluoropyrazole derivatives has increased recently due to their potential use for treating diabetes,[4] inflammatory disease,[5] as gastric acid inhibitors[6] 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 involving enamino ketones[8] and fluorocyanoketones,[9] gold-catalysed aminofluorination of alkynes[10] and reaction of hydrazines with fluoro-β-dicarbonyl substrates[11] offer efficient routes to various functional fluoropyrazole derivatives. Adaptation of established fluorination methodology such as halogen exchange[12] or Balz–Schiemann processes[13] has had limited success for the synthesis of fluoropyrazoles from appropriately functionalised pyrazole substrates due to low total yields over several synthetic steps. Potentially, the most efficient methods for the synthesis of fluoropyrazole 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 recorded[14] whilst several 4-fluoropyrazole 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 fluorinating agents,[16] we were interested in broadening the scope of ‘late-stage’ fluorination reactions of pyrazole derivatives 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.

Pyrazole substrates 1 were either obtained from commercial suppliers or synthesised by reaction of the appropriate diketone derivatives with hydrazine or phenyl hydrazine by heating to reflux in ethanol following literature procedures.[17]

We began our pyrazole fluorination studies by investigating reactions of representative pyrazole systems 1ac 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 microwave irradiation (conditions A). Fluorine gas, diluted to a 10% mixture in anhydrous nitrogen was passed at a controlled rate via a mass flow controller into a stirred solution of the substrate in acetonitrile using equipment discussed previously (conditions B).[16] Monofluorinated pyrazoles 2ac were formed in modest yields and could be purified by column chromatography on silica gel. In contrast, fluorination 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 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 nucleo­philicity of these substrates, and starting materials were recovered in all of these reactions.

Table 1 Synthesis of Monofluoropyrazoles 2 using SelectfluorTM or ­Fluorine Gas

Pyrazole 1

R1

R2

R3

Conditionsa,b

Fluoropyrazole 2, yield (%)

1a

Me

Ph

H

A
B

2a, 33
2a, 45

1b

CF3

Ph

H

A
B

2b, 43
2b, 46

1c

Me

Me

Ph

A
B

2c, 43
2c, 40

a Conditions A: SelectfluorTM (1 equiv), MW, 15 min, 90 °C.

b Conditions B: 10% F2/N2, MeCN, r.t.

Monofluoropyrazole systems 2ac 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 systems.[15] In addition, the structure of 2b was confirmed by X-ray crystallography (Figure [1]).[18]

Zoom
Figure 1 Molecular structure of 2b

In order to expand the scope of the fluorination reactions we studied reactions of diphenylpyrazole substrates 1dk which unexpectedly gave mixtures of mono- and difluorinated systems 2dk and 3ah even when only one equivalent of SelectfluorTM was used and these results are collated in Table [2] (Conditions A). In all reactions, separation and purification of the difluorinated products 3ah were readily achieved because, in general, they eluted from the silica gel column much more rapidly than the starting 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-pyrazole products 3ah were improved upon reaction of the pyrazole substrates with two equivalents of SelectfluorTM (Table [2], conditions C).

Table 2 Synthesis of Fluoropyrazole and 1H-Difluoropyrazole Derivatives

Pyrazole 1

Ar

Conditionsa,b

Fluoropyrazole 2, yield (%)

Difluoropyrazole 3, yield (%)

1d

Ph

A
C

2d, 45
2d, 23

3a, 21
3a, 52

1e

4-ClC6H4

A
C

2e, 31c
2e, 15c

3b, 22
3b, 54

1f

4-BrC6H4

A
C

2f, 37c
2f, 19c

3c, 22
3c, 54

1g

4-F3CC6H4

A
C

2g, 36c
2g, 20c

3d, 51
3d, 33

1h

3-F3CC6H4

A
C

2h, 41c
2h, 24c

3e, 20
3e, 44

1i

4-MeOC6H4

A
C

2i, 45
2i, 20

3f, 27
3f, 45

1j

3-MeOC6H4

A
C

2j, 31
2j, 24

3g, 24
3g, 43

1k

2-MeOC6H4

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 2eh could not be separated from starting materials 1eh respectively by column chromatography and yields were estimated by 19F NMR in these cases only.

In contrast, when 3,5-diarylpyrazoles 1dk were reacted with fluorine gas, many fluorinated products were observed by 19F NMR analysis of the crude product mixture and no products could be isolated and purified. In these reactions, competing fluorination of the aromatic ring substituents 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 3ah were characterized by distinctive singlet resonances at approximately δ = –115 ppm in their 19F NMR spectra and the structure of 3f was confirmed by X-ray crystallography (Figure [2]).[18] The difluorinated pyrazole systems 3 are a novel class of fluorinated compounds although the corresponding dichlorinated systems have been reported and their use in Diels–Alder reactions has been explored.[19]

Zoom
Figure 2 Molecular structure of 3f

Initial fluorination of pyrazole derivatives occurs selectively at the 4-position consistent with an electrophilic aromatic substitution process (Scheme [1]) and further electrophilic fluorination reaction occurs at the same site to give a difluorinated salt 4 as an intermediate. Deprotonation on workup gives the observed 4,4-difluoro-1H pyrazole product 3.

Zoom
Scheme 1 Fluorination of pyrazole derivatives 2 and 3

The outcome is consistent with the intermediate carbocation 4b being stabilized by the adjacent phenyl groups (R1 = aryl; Scheme [1]) allowing difluorination to proceed as observed for 3,5-diarlpyrazole substrates.

For reaction with dibrominated system 1l, the hydroxypyrazoline 5 could be isolated albeit in low yield and, in 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 reaction 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 appropriate J AB = 128 Hz coupling constant, in the 19F NMR spectrum.

Zoom
Scheme 2 Hydoxylated pyrazoline 5

In conclusion, a method for the synthesis of unusual 4,4-difluoro-1H-pyrazole systems 3 [21] has been established using shelf-stable, readily handled SelectfluorTM as the electrophilic fluorinating agent.


Acknowledgment

We thank Dr. D. S. Yufit (Durham University) for X-ray crystallographic structural analysis.

Supporting Information



Zoom
Figure 1 Molecular structure of 2b
Zoom
Figure 2 Molecular structure of 3f
Zoom
Scheme 1 Fluorination of pyrazole derivatives 2 and 3
Zoom
Scheme 2 Hydoxylated pyrazoline 5