Continuous gas/liquid-liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

Article abstract of DOI:10.3762/bjoc.7.120

4-Fluoropyrazole systems may be prepared by a single, sequential telescoped two-step continuous gas/liquid-liquid/liquid flow process from diketone, fluorine gas and hydrazine starting materials.

Full text of DOI:10.3762/bjoc.7.120

Continuous gas/liquid–liquid/liquid flow synthesis
of 4-fluoropyrazole derivatives by
selective direct fluorination
Jessica R. Breen1, Graham Sandford*1, Dmitrii S. Yufit2,
Judith A. K. Howard2, Jonathan Fray3 and Bhairavi Patel3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1048–1054.
1Department of Chemistry, Durham University, South Road, Durham,
DH1 3LE, UK, 2Chemical Crystallography Group, Department of
Chemistry, Durham University, South Road, Durham, DH1 3LE, UK
and 3Pfizer Global Research & Development, Ramsgate Road,
Sandwich, Kent, CT13 9NJ, UK
doi:10.3762/bjoc.7.120
Received: 16 May 2011
Accepted: 04 July 2011
Published: 02 August 2011
Email:
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
Graham Sandford* - Graham.Sandford@durham.ac.uk
* Corresponding author
© 2011 Breen et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
continuous flow reactions; fluorine; fluoropyrazole; gas-liquid flow
reactor; selective direct fluorination
Abstract
4-Fluoropyrazole systems may be prepared by a single, sequential telescoped two-step continuous gas/liquid–liquid/liquid flow
process from diketone, fluorine gas and hydrazine starting materials.
Introduction
Organic systems which bear fluorine atoms are used in an ever interconversion utilising an appropriate nucleophilic or electro-
widening range of applications in the life sciences. Many philic fluorinating agent [6], or syntheses based on the reac-
commercially significant pharmaceutical and agrochemical tions of appropriate fluorine containing building blocks [7]. Of
products [1-3] owe their biological activity to the presence of course, whichever methodology is used for the synthesis of a
fluorinated groups within their structure. Since carbon–fluorine specific fluorinated organic molecule, a carbon–fluorine bond
bonds are rare in naturally occurring organic molecules [4], an must be formed at some stage of the synthetic process, and
efficient, selective and economically viable methodology for the various fluorinating agents have been developed over many
synthesis of fluoroorganic derivatives is required to exploit fully years in attempts to meet synthetic requirements, with varying
the use of fluorinated systems in life science applications. In degrees of success [5].
general, there are two complimentary approaches to the syn-
thesis of fluoroorganic products [5,6], which involve either In an on-going research programme at Durham, aimed at devel-
carbon–fluorine bond formation, requiring functional group oping widely applicable an effective, selective, direct fluorin-
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Beilstein J. Org. Chem. 2011, 7, 1048–1054.
ation methodology, we have been exploring the use of additions of diazo compounds and the direct condensation of
elemental fluorine, a previously underused reagent in organic 1,3-diketones and hydrazines [23].
chemistry, for the synthesis of fluoroorganic systems [8-10].
Methodologies for the preparation of, for example, a range of However, the synthetic methodology for the preparation of the
fluorinated aliphatic [11], carbonyl [12-14], aromatic [15] and corresponding fluoropyrazole derivatives has not been
heterocyclic [16,17] systems have been established and scaled- developed to any great extent despite the potential use of such
up by our industrial collaborators for use in the synthesis of systems in life science applications. Recently, we explored
commercially important pharmaceutical intermediates [18]. As direct fluorination of various pyrazole substrates using
part of our studies, aimed at further control of the direct fluorin- elemental fluorine and, in many cases, obtained low yields of
ation procedures for larger scale manufacturing, we developed the desired fluoropyrazole products due to significant tar forma-
continuous flow microreactor systems that enabled gas/liquid tion [24], while the corresponding fluorination of a limited
fluorination reactions between fluorine and various substrates to number of pyrazole systems by SelectfluorTM has been
occur in very efficient processes [19-21].
described by other researchers [25]. Various building block
strategies that yield fluoropyrazole derivatives from, for
Fluoro-carbonyl derivatives can, in principle, be utilised as example, reactions of appropriate fluorodicarbonyl [26] and
building blocks for the preparation of more complex systems fluorocyano-ketones [27], have also been reported.
such as fluorinated terpenoids, steroids and a range of hetero-
cyclic systems, upon appropriate synthetic elaboration [7], and, Consequently, we aimed to develop an effective, selective
consequently, there is much interest in the development of a continuous flow methodology for the efficient synthesis of
synthetic methodology for the preparation of such useful fluor- fluoropyrazole systems and, in this paper, we demonstrate that
inated intermediates. It has been established that, in both batch fluorination of diketones to corresponding fluorodiketones,
and continuous flow processes, 1,3-dicarbonyl derivatives are followed by sequential cyclization to the appropriate
not equally reactive towards fluorine gas [12] and that the ease fluoropyrazoles upon reaction with a hydrazine derivative, can
of selective direct fluorination depends on the nature and prox- be accomplished in a single, two-step, telescoped, gas/
imity of other functional groups. Substrates that have a high liquid–liquid/liquid continuous flow process. No examples of
initial equilibrium enol concentration in the reaction media that gas/liquid–liquid/liquid processes involving direct fluorination
are used for fluorination reactions, such as formic acid or aceto- as the first stage of a continuous flow procedure have been
nitrile, and/or rapidly convert from the keto to the enol form, reported previously.
will react rapidly and selectively with fluorine to give mono-
fluorinated products in high yield. Conversely, substrates that Results and Discussion
have low enol concentrations at equilibrium and/or slow keto- After some development work, a continuous flow reactor for
enol exchange rates give low yields of the desired monofluorin- sequential gas/liquid–liquid/liquid synthesis of fluoropyrazoles
ated dicarbonyl products [12]. Indeed, for carbonyl systems from fluorine, hydrazine and diketone starting materials was
with low enol equilibrium contents and/or low keto-enol constructed from nickel metal and narrow bore PTFE tubing as
exchange rates, direct fluorination must be carried out in condi- described previously [28,29] (Figure 1).
tions that enhance enol formation by base catalysis, by metal
catalysis or by fluorination of appropriate pre-formed enol Briefly, fluorine gas, diluted to 10% v/v solution in nitrogen
derivatives, such as trimethylsilyl enols or enol acetate deriva- was added via a mass flow controller to the microchannel
tives [13,14].
through Input A, the diketone substrate dissolved in acetonitrile
was added by a syringe pump into the microchannel via Input B
Dicarbonyl systems are, of course, widely used for the construc- and was made to react with fluorine while both these starting
tion of heterocyclic ring systems such a pyrimidine, pyridazine materials passed down the reactor channel in a ‘pipe flow’
and pyrazole derivatives [22,23]. Of relevance to this paper, regime, as observed in previous direct fluorination reactions
pyrazole and its derivatives constitute an important class of using this reactor design. The hydrazine solution was added by
compounds, which exhibit various biological and pharmaceut- a syringe pump, via a T-piece at Input C, into the liquid flow,
ical activities ranging from antitumor to anti-inflammatory, which was carried along the flow reaction channel by the pres-
antipsychotic, antimicrobial, antiviral and antifungal activities. sure of the accompanying nitrogen gas. The crude reaction mix-
Pyrazoles are also useful intermediates for many industrial ture was then passed into a vessel containing water to quench
products and it is, therefore, not surprising that many synthetic the reaction and neutralise any excess HF. Work-up by extrac-
methods have been developed for the preparation of such tion of the crude reaction mixture with dichloromethane, drying
heterocyclic systems, for example, through 1,3-dipolar cyclo- and evaporation of the organic solvent gave a crude product
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Beilstein J. Org. Chem. 2011, 7, 1048–1054.
Figure 1: Sequential gas/liquid–liquid/liquid flow reactor for the synthesis of 4-fluoropyrazole derivatives.
which was further purified by column chromatography or gas mixture was passed into the flow channel at a rate of 18
recrystallisation if required.
mL/min to achieve full conversion of pentane-2,4-dione to the
corresponding 3-fluoropentane-2,4-dione, and subsequent for-
In our initial exploratory reactions, pentane-2,4-dione (1a) was mation of the fluoropyrazole product 4a occurred with no non-
used as the substrate, because this system has a high initial enol fluorinated pyrazole by-product observed. Early investigations
content at equilibrium and rapidly enolises in acetonitrile solu- showed that some of the 3-fluoropentane-2,4-dione remained
tion [12]. By varying the flow rate of fluorine gas we were able unchanged when only 1.2 mmol of the hydrazine was used and,
to achieve reaction conditions that would convert all of the therefore, in subsequent reactions excess hydrazine (1.5 mmol)
diketone substrate to a fluorodiketone in the first stage of the was added to ensure complete conversion of the 3-fluoro-
continuous process. Subsequent separation of fluoropyrazole pentane-2,4-dione to the 4-fluoropyrazole 4a (Table 1).
(4a) from the corresponding non-fluorinated pyrazole, formed
by the coupling of not reacted pentane-2,4-dione and hydrazine, In all reactions, acetonitrile was used as the solvent for the fluo-
was difficult to achieve. Any remaining difluorinated diketone rination stage as this reaction medium has been found to be very
formed by excess fluorination of the substrate was not involved effective for direct fluorination reactions of dicarbonyl systems
in the second cyclization process and remained in aqueous solu- [12]. The hydrazine was added to the continuous flow process
tion in the collection vessel.
dissolved in either acetonitrile, water or ethanol depending on
the solubility of the hydrazine derivative. Water and ethanol are
In initial experiments, 1 mmol of the pentane-2,4-dione (1a) miscible with acetonitrile, thus enabling the cyclisation process
was diluted in 4 mL of acetonitrile, and 1.2 mmol of hydrazine to occur by efficient mixing of the two flow streams within the
hydrate (3a) was also dissolved in 4 mL of solvent (either reactor channel.
acetonitrile, ethanol or water). Both were added concurrently to
the flow reactor at the rate of 2 mL/min into Inputs B and C, Similarly, fluoropyrazole derivatives 4b and 4c were prepared
respectively, using accurate syringe pumps. Excess 10% F2/N2 by reaction of 1a with fluorine and methyl hydrazine 3b and
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Beilstein J. Org. Chem. 2011, 7, 1048–1054.
Table 1: Synthesis of 4-fluoro-3,5-dimethylpyrazole derivatives.
Diketone 1
Hydrazine 3
Solvent
4-Fluoropyrazole 4
Yield
1a
1a
1a
NH2–NH2·H2O, 3a
H2O
EtOH
MeCN
4a, 74%
4a, 66%
4a, 77%
3a
3a
1a
1a
1a
MeNH–NH2, 3b
H2O
EtOH
MeCN
4b, 83%
4b, 73%
4b, 68%
3b
3b
1a
1a
PhNH–NH2, 3c
EtOH
4c, 72%
4c, 67%
3c
MeCN
phenyl hydrazine 3c, respectively, and these results are included Furthermore, the structures of 4a and 4f were confirmed by
in Table 1.
X-ray crystallography (Figure 2). In both cases, the
5-membered rings are planar and the pyrazole hydrogen atoms
With the conditions for gas/liquid–liquid/liquid processes estab- are disordered over two positions. The molecules of both com-
lished from reactions involving pentane-2,4-dione (1a), several pounds in the crystals are linked together in H-bonded cycles.
other fluoropyrazole systems 4d–h were synthesised from a In the case of 4a, the cycles are R33(9) trimers [30], while the
series of related diketone starting materials 1b–f in one presence of bulky t-Bu groups in 4f results in the formation of
continuous flow process from hydrazine 3a and these are R22(6) dimers (Figure 2).
collated in Table 2.
Conclusion
All fluoropyrazole products 4a–h were isolated and purified, 4-Fluoropyrazole derivatives were synthesised by sequential
and then characterised by NMR spectroscopy and mass spectro- direct fluorination of appropriate 1,3-diketones and subsequent
metry techniques; results were compared to literature data cyclisation of the in situ generated fluorodiketone with a
where available. 19F NMR spectra of all 4-fluoropyrazole hydrazine derivative. This represents the first example of a
products show singlets at ~ −175 to −185 ppm, consistent with sequential, continuous flow gas/liquid–liquid/liquid process
literature values.
involving direct fluorination in the first stage of a multi-step,
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Beilstein J. Org. Chem. 2011, 7, 1048–1054.
Table 2: Synthesis of 4-fluoropyrazole derivatives.
Diketone 1
4-Fluoropyrazole 4
Yield
telescoped, continuous flow process. Thus, continuous flow Experimental
methodology was used for successful sequential carbon-fluorine Synthetic procedures for the preparation of all the 4-fluoro-
bond formation and subsequent fluorine-containing building pyrazole compounds described in this paper are given either
block reactions in a single continuous high yielding, efficient below or in Supporting Information File 1. Supporting Informa-
and regioselective process.
tion File 2 contains copies of the NMR spectra.
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Beilstein J. Org. Chem. 2011, 7, 1048–1054.
At the same time, the hydrazine mixture was injected by a
mechanised syringe pump at Input C, into the flow reactor via a
T-piece, at a prescribed flow rate. All flow streams were passed
through the reactor and the product mixture was collected in a
vessel containing water. The collected mixture was then
extracted from DCM (3 × 30 mL) and washed with sodium
bicarbonate (30 mL) and water (30 mL). The combined extracts
were then dried (MgSO4), filtered and the solvent evaporated to
give a solid residue, which was purified by recrystallisation or
column chromatography on silica gel to give the desired
4-fluoropyrazole product.
4-Fluoro-3,5-dimethyl-1H-pyrazole (4a)
Pentane-2,4-dione (1a) (0.10 g, 1.0 mmol) in MeCN (4 mL, 2
mL/h), fluorine (8 mL/min), and hydrazine hydrate (3a, 0.07 g,
1.5 mmol) in ethanol (4 mL, 2 mL/h), after purification by
column chromatography on silica gel with hexane and ethyl
acetate (1:1) as the eluent, gave 4-fluoro-3,5-dimethyl-1H-
pyrazole (4a) (0.075 g, 66%) as pale yellow crystals; mp
107–109 °C (lit. [31]: mp 108–110 °C); 1H NMR (400 MHz,
CDCl3) δ 2.26 (s, 6H, CH3), 8.61 (br s, 1H, NH); 13C NMR
(126 MHz, CDCl3) δ 9.1 (d, 3JCF 2.9 Hz, CH3), 129.6 (br s,
C-3), 143.5 (d, 1JCF 239.8 Hz, C-4); 19F NMR (376 MHz,
CDCl3) δ −183.4 (s); MS (EI+) m/z: 114.1 ([M]+, 100%), 113.0
(82), 41.9 (79); HRMS (m/z): [M + H]+ calcd for C5H7FN2,
115.0672; found, 115.0667.
Supporting Information
Supporting Information File 1
Experimental data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-120-S1.pdf]
Supporting Information File 2
NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-120-S2.pdf]
Figure 2: H-bonded cycles in structures 4a (a) and 4f (b) (only one
disordered pyrazole hydrogen atom is shown in each case).
Acknowledgements
We thank EPSRC (Durham University DTA) and Pfizer R&D
Two step process – general procedure
for funding.
After purging the continuous flow reactor apparatus [29]
(Figure 1) with nitrogen, a 10% mixture of fluorine in nitrogen
(v:v) was passed through the flow reactor via Input A at a
prescribed flow rate that was controlled by a gas mass flow
controller (Brooks Instruments). The flow reactor was cooled
by an external cryostat to 5–10 °C. The diketone solution was
injected by a mechanised syringe pump into the flow reactor
channel at a prescribed flow rate through the substrate Input B.
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