New synthesis of fluorinated pyrazoles

Article abstract of DOI:10.1021/ol1019713

A new synthesis of fluorinated pyrazoles, a class of compounds with potential in medicinal chemistry, is described. The treatment of benzoylfluoroacetonitrile with hydrazine yielded the expected new 3-amino-4-fluoropyrazole, while the analogous reaction of α-cyano-α, α-difluoroketones with hydrazine in refluxing isopropanol surprisingly gave rise to 3-unsubstituted 4-fluoropyrazoles via an unprecedented mechanism. The isolation of intermediate hydrazine adducts led to a mechanistic rationale for this transformation.

Full text of DOI:10.1021/ol1019713

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4648-4651
New Synthesis of Fluorinated Pyrazoles
Riccardo Surmont,† Guido Verniest,‡ and Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent UniVersity, Coupure Links 653, B-9000 Gent, Belgium
norbert.dekimpe@ugent.be
Received August 19, 2010
ABSTRACT
A new synthesis of fluorinated pyrazoles, a class of compounds with potential in medicinal chemistry, is described. The treatment of
benzoylfluoroacetonitrile with hydrazine yielded the expected new 3-amino-4-fluoropyrazole, while the analogous reaction of r-cyano-r,r-
difluoroketones with hydrazine in refluxing isopropanol surprisingly gave rise to 3-unsubstituted 4-fluoropyrazoles via an unprecedented
mechanism. The isolation of intermediate hydrazine adducts led to a mechanistic rationale for this transformation.
In recent years, interest in chlorinated and brominated
pyrazoles has increased significantly due to their proven
usefulness as intermediates in the preparation of new
pharmaceuticals and agrochemicals.1 In contrast to these
halopyrazoles, research activities concerning fluorinated
pyrazoles are concentrated on perfluoroalkylated pyrazoles,
as illustrated by the development of the blockbuster drug
Celecoxib, which is an anti-inflammatory trifluorometh-
ylpyrazole.2 It is well-known that fluorine substituents in
organic molecules cause significant physicochemical and
biological changes, often resulting in improved bioactivities.3
In contrast to chlorinated and brominated pyrazoles, which
are easily synthesized via direct electrophilic halogenation
of the pyrazole ring, the synthesis of ring fluorinated
pyrazoles has been more problematic and less well studied.4
The selective direct fluorination of pyrazoles remains a
difficult task because of the high reactivity of these com-
pounds toward electrophiles and the high oxidative properties
of electrophilic fluorinating agents. Consequently, the re-
ported yields of the direct ring fluorination of pyrazoles using
F2,5 CF3OF,6 Selectfluor,7 or NFSI8 toward 4-fluoropyrazoles
are rather low and highly substrate dependent. Other synthetic
strategies toward 4-fluoropyrazoles consist of a Balz-
Schiemann process,9 nucleophilic aromatic substitution,10
condensation reactions of fluorinated ꢀ-dicarbonyl com-
(4) (a) Fustero, S.; Simo´n-Fuentes, A.; Sanz-Cervera, J. F. Org. Prep.
Proced. Int. 2009, 41, 253, and references cited therein. (b) Pace, A.;
Buscemi, S.; Vivona, N. Org. Prep. Proced. Int. 2007, 39, 1, and references
cited therein. (c) Hilvo, M.; Salzano, A. M.; Innocenti, A.; Kulomaa, M. S.;
Scozzafava, A.; Scaloni, A.; Parkkila, S.; Supuran, C. T. J. Med. Chem.
2009, 52, 646.
(5) Storer, R.; Ashton, C. J.; Baxter, A. D.; Hann, M. M.; Marr, C. L. P.;
Mason, A. M.; Mo, C.-L.; Myers, P. L.; Noble, S. A.; Penn, C. R.; Weir,
N. G.; Woods, J. M.; Coe, P. L. Nucleosides Nucleotides 1999, 18, 203.
(6) Large, M. S. Eur. Pat. Appl. EP 61318 A2 19820929, 1982; Chem.
Abstr. 1982, 98, 143463.
† Aspirant of the Research Foundation - Flanders (FWO - Vlaanderen,
Belgium).
(7) For examples, see: (a) Skinner, P. J.; Cherrier, M. C.; Webb, P. J.;
Shin, Y.-J.; Gharbaoui, T.; Lindstrom, A.; Hong, V.; Tamura, S. Y.; Dang,
H. T.; Pride, C. C.; Chen, R.; Richman, J. G.; Connolly, D. T.; Semple, G.
Bioorg. Med. Chem. Lett. 2007, 17, 5620. (b) Dressen, D.; Garofalo, A. W.;
Hawkinson, J.; Hom, D.; Jagodzinski, J.; Marugg, J. L.; Neitzel, M. L.;
Pleiss, M. A.; Szoke, B.; Tung, J. S.; Wone, D. W. G.; Wu, J.; Zhang, H.
J. Med. Chem. 2007, 50, 5161. (g) Sloop, J. C.; Jackson, J. L.; Schmidt,
R. D. Heteroat. Chem. 2009, 20, 341.
‡ Postdoctoral Fellow of the Research Foundation - Flanders (FWO -
Vlaanderen, Belgium).
(1) (a) Kim, M.; Sim, C.; Shin, D.; Suh, E.; Cho, K. Crop Prot. 2006,
25, 542. (b) Fustero, S.; Roma´n, R.; Sanz-Cervera, J. F.; Simo´n-Fuentes,
A.; Bueno, J.; Villanova, S. J. Org. Chem. 2008, 73, 8545. (c) Fustero, S.;
Roma´n, R.; Sanz-Cervera, J. F.; Simo´n-Fuentes, A.; Cun˜at, A. C.; Villanova,
S.; Murgui´ıa, M. J. Org. Chem. 2008, 73, 3523. (d) Clemens, L.
Heterocycles 2007, 71, 1467.
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10.1021/ol1019713  2010 American Chemical Society
Published on Web 09/15/2010

pounds,11 or R,ꢀ-unsaturated compounds12 with hydrazines and
cycloaddition reactions of fluoroalkenes with diazocom-
pounds.13 In contrast, synthetic strategies toward fluorinated
amino- or hydroxypyrazoles have not been studied intensively,
although various nonfluorinated amino- and hydroxypyrazoles
are often associated with pronounced bioactivities. Indeed, the
established activities of Zaleplon, Sildenafil, and Allopurinol
have led to a revival of interest in aminopyrazoles.14 Despite
their promising bioactivities, only a few fluorinated 3-amino-
and 3-hydroxypyrazoles have been synthesized.15
In a first synthetic strategy toward 3-amino-4-fluoropy-
razoles, the direct electrophilic fluorination of the com-
mercially available 3-amino-5-methyl-1H-pyrazole 1 was
investigated. In contrast to the efficient direct chlorination,
bromination, and iodination of 3-aminopyrazole 1,16 the
direct fluorination using Selectfluor or xenon(II) fluoride did
not afford the corresponding 4-fluoropyrazole, even when
the free 3-amino group was protected as an aldimine derived
from benzaldehyde. The obtained complex reaction mixtures
confirm the low yields reported in the literature for the direct
fluorination of pyrazoles. Surprisingly, pyrazole 1 was
entirely converted to a mixture of 5-amino-3-methyl-1-
phenylsulfonyl-1H-pyrazole 217 and 3-amino-5-methyl-1-
phenylsulfonyl-1H-pyrazole 3 in a 9:1 ratio upon reaction
with N-fluorobenzenesulfonimide (NFSI) (Scheme 1). This
The most common method to prepare 3-aminopyrazoles
involves the condensation of ꢀ-ketonitriles with hydrazines.19
The corresponding monofluorinated ꢀ-ketonitriles have not
been used before in analogous condensation reactions, which
is probably due to their difficult synthesis.20 Also in our
hands, various strategies to synthesize 7 via electrophilic or
nucleophilic monofluorination failed. Fortunately, a good
synthetic pathway toward benzoylfluoroacetonitrile 7 in gram
quantities was developed by the reaction of the anion of
(diphenylphosphinoyl)fluoroacetonitrile 6, prepared in situ
from fluoroacetonitrile 4 and diphenylphosphinyl chloride
5,21 with benzoyl chloride followed by aqueous workup
(Scheme 2). The synthesis of the desired 3-amino-4-
Scheme 2. Synthesis of 3-Amino- and
3-Hydroxy-4-fluoropyrazoles 9 and 10
Scheme 1. Reaction of Pyrazole 1 with NFSI
fluoropyrazole 9 was subsequently carried out by heating
the obtained benzoylfluoroacetonitrile 7 at reflux temperature
with hydrazine hydrate in isopropanol during 30 min. Despite
reaction can be compared to the sulfonylation of 3-aminopy-
razoles using sulfonyl chlorides.18 Because of the observed
difficulties in the direct fluorination of aminopyrazoles, new
strategies were evaluated to synthesize these interesting
targets.
(14) (a) Elmaati, T. M. A.; El-Taweel, F. M. J. Heterocycl. Chem. 2004,
41, 109. (b) Pochat, F. Tetrahedron Lett. 1979, 32, 2991. (c) Moreno-Manas,
M.; Sebastian, R. M.; Vallribera, A.; Carini, F. Synthesis 1999, 157. (d)
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N. Bioorg. Med. Chem. Lett. 2003, 13, 2985. (e) Teng, M.; Zhu, J.; Johnson,
M. D.; Chen, P.; Kornmann, J.; Chen, E.; Blasina, A.; Register, J.; Anderes,
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Peng, Z.; Kania, R. S. J. Med. Chem. 2007, 50, 5253.
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2003, 46, 93.
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2000; Chem. Abstr. 2000, 134, 17497. (b) Ohata, S.; Kato, K.; Toriyabe,
K.; Ito, Y.; Hamaguchi, R.; Nakano, Y. PCT Int. Appl., WO 2009051245,
2009; Chem. Abstr. 2009, 150, 472709. (c) Kuze, S.; Koboshi, S.; Myaoka,
K. Jpn. Kokai Tokkyo Koho JP 08166663, 1996; Chem. Abstr. 1996, 125,
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1987; Chem. Abstr. 1987, 109, 231008.
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Fluorine Chem. 2002, 118, 135. (b) Katoch-Rouse, R.; Pavlova, O. A.;
Caulder, T.; Hoffman, A. F.; Mukhin, A. G.; Horti, A. G. J. Med. Chem.
2003, 46, 642. (c) Guillou, S.; Bonhomme, F. J.; Janin, Y. Synthesis 2008,
3504.
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Royon, R.; Portella, C. Eur. J. Org. Chem. 2001, 187. (b) Dondy, B.;
Doussot, P.; Portella, C. Tetrahedron Lett. 1994, 35, 409. (c) Chanteau, F.;
Plantier-Royon, R.; Portella, C. Synlett 2004, 512. (d) Ishihara, T.; Okada,
Y.; Kuroboshi, M.; Shinozaki, T.; Ando, T. Chem. Lett. 1988, 819. (e)
Funabiki, K.; Ohtsuki, T.; Ishihara, T.; Yamanaka, H. Chem. Lett. 1995,
239. (f) Zhang, Q.; Lu, L. Tetrahedron Lett. 2000, 41, 8545.
(13) (a) Hanamoto, T.; Koga, Y.; Kawanami, T.; Furuno, H.; Inanaga,
J. Angew. Chem., Int. Ed. 2004, 43, 3582. (b) Hanamoto, T.; Iwamoto, Y.;
Yamada, K.; Anno, R. J. Fluorine Chem. 2007, 128, 1126. (c) Hanamoto,
T.; Koga, Y.; Kido, E.; Kawanami, T.; Furuno, H.; Inanaga, J. Chem.
Commun. 2005, 2041. (d) Hanamoto, T.; Suetake, T.; Koga, Y.; Kawanami,
T.; Furuno, H.; Inanaga, J. Tetrahedron 2007, 63, 5062. (e) Blackwell, G. B.;
Haszeldine, R. N.; Taylor, D. R. J. Chem. Soc., Perkin Trans. 1 1982, 2207.
(16) (a) Blake, A. J.; Clarke, D.; Mares, R. W.; McNab, H. Org. Biomol.
Chem. 2003, 1, 4268. (b) Dziomko, V. M.; Berestevich, B. K. Khim
Geterotsikl. Soedin. 1978, 382. (c) Krasovskiy, A. L.; Hartulyari, A. S.;
Nenajdenko, V. G.; Balenkova, E. S. Synthesis 2002, 2133.
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Mansour, O. A. E. R. Arch. Pharm. 1989, 322, 557.
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Org. Lett., Vol. 12, No. 20, 2010
4649

the high-yielding and rapid condensation reaction toward
3-amino-4-fluoropyrazole 9, this method is rather limited due
to the difficult synthesis of the monofluorinated starting
material 7. However, this procedure proved to be much more
successful for the synthesis of the corresponding hydroxy-
pyrazoles. In contrast to the nonselective fluorination of
ꢀ-ketonitriles, the monofluorination of ꢀ-ketoesters is well
described.22 Ethyl 2-fluoro-3-oxo-3-phenylpropanoate 8 was
treated with hydrazine in isopropanol, affording 4-fluoro-3-
hydroxy-5-phenylpyrazole 10 in 83% yield.
Because of the known and observed difficulties in the
monofluorination of ꢀ-ketonitriles, the synthesis of fluori-
nated pyrazoles from more easily accessible difluorinated
ꢀ-ketonitriles via reaction with hydrazine followed by a
reduction step was evaluated. As a model study, this strategy
was evaluated in the synthesis of fluorinated hydroxypyra-
zoles. Ethyl benzoyldifluoroacetate 11a (R1 ) Ph, R2 ) F)22
was heated with 1 equiv of hydrazine (80% in H2O) in
isopropanol (Scheme 3). A smooth condensation and thermal
11b and 11c were transformed into 4,4-difluoro-1H-pyrazol-
5-one 12c and 4-fluoro-4-methyl-1H-pyrazol-5-one 12d,
respectively. To synthesize the N-substituted fluorinated
pyrazol-5-ones, pyrazol-5-one 12a was treated with NaH and
propyl bromide giving rise to 1-propylpyrazol-5-one 12b in
87% yield. In addition, ethyl benzoyldifluoroacetate 11a was
heated in the presence of substituted hydrazines (MeNHNH2
and PhNHNH2) and a catalytic amount of acetic acid yielding
N-substituted pyrazol-5-ones 12e and 12f.
To accomplish a synthesis of fluorinated pyrazoles, pyra-
zol-5-one 12a was treated with Pd/C under a hydrogen
atmosphere. The hydrogenation resulted in the formation of
4,4-difluoro-5-phenylpyrazolidin-3-one 13, which readily
underwent dehydrofluorination to form the desired 4-fluoro-
3-hydroxypyrazole 10. Unfortunately, N-alkylated pyrazo-
lones 12e and 12f could not be reduced toward the
corresponding fluorinated 5-hydroxypyrazoles using the same
reaction conditions. Because the methodology to synthesize
fluorinated pyrazole 10 from easily accessible R,R-difluoro-
ꢀ-ketoester 11a indeed proved to be a valuable strategy,
efforts were made to convert difluorinated ꢀ-ketonitriles into
3-amino-4-fluoropyrazoles. It was expected that 2,2-difluoro-
3-oxopropanenitrile 14a (R ) Ph) would react with hydrazine
to give the targeted 3-amino-4-fluoropyrazole 9 after treat-
ment with hydrogen over Pd/C. Surprisingly, after heating
nitrile 14a with 1 equiv of hydrazine in isopropanol,
4-fluoropyrazole 18a13d was recovered in 45% yield. It is
remarkable that during the reaction of 14a with hydrazine
one nitrogen atom is lost, probably in the form of ammonia
(NH3).
Scheme 3
.
Synthesis of 4-Fluoropyrazolones 12 and Reduction
Towards 3-Hydroxy-4-fluoropyrazole 10
To investigate the unknown reaction mechanism in more
detail, difluorinated ꢀ-ketonitrile 14a (R ) Ph) was reacted
with 1 equiv of hydroxylamine (50% in H2O) under reflux
conditions in isopropanol. After 2 h, 2,2-difluoro-N′-hydroxy-
3-oxo-3-phenylpropanimidamide 16 was isolated in 80%
yield. This reaction shows that the nitrile function of
difluorinated ꢀ-ketonitrile 14a is the most electrophilic group
for nucleophilic attack of nitrogen nucleophiles such as
hydroxylamine. The stable N′-hydroxyimidamide 16 did not
undergo ring closure to isoxazoline compounds. However,
when compound 16 was further reacted with 1 equiv of
hydrazine in isopropanol at reflux temperature during 15 h,
an equimolar mixture of starting material and 4-fluoro-5-
phenylpyrazole 18a was obtained. When compound 14a was
treated with hydrazine in isopropanol at room temperature,
hydrazonamide 15 was not observed, but its ring closed
product, 3-amino-4,4-difluoro-5-hydroxy-4,5-dihydro-1H-
pyrazole 17 (Scheme 4), was isolated as white crystals in
quantitative yield. The addition of 1 equiv of hydrazine gave
a full conversion toward 4-fluoropyrazole 18a in 83% yield.
These experiments all point to the need for 2 equiv of
hydrazine in the formation of 4-fluoropyrazole 18a.
cyclization afforded the new 4,4-difluoro-1H-pyrazol-5-one
12a. Pyrazol-5-ones are of interest in medicinal chemistry,23
and in contrast to 4,4-dichloropyrazol-5-ones24 and 4,4-
dibromopyrazol-5-ones,25 fluorinated analogues have not
been reported so far. Therefore, also fluorinated ꢀ-ketoesters
(21) van Steenis, J. H.; van den Nieuwendijk, A. M. C. H.; van der
Gen, A. J. Fluorine Chem. 2004, 125, 107.
(22) Xiao, J.-C.; Shreeve, J. M. J. Fluorine Chem. 2005, 126, 475.
(23) Huang, Y.-Y.; Lin, H.-C.; Cheng, K.-M.; Su, W.-N.; Sung, K.-C.;
Lin, T.-P.; Huang, J.-J.; Lin, S.-K.; Wong, F. F. Tetrahedron 2009, 65,
9592.
A possible mechanism can be rationalized by an initial
attack of hydrazine at the carbonyl function of 17, resulting
in compound 19, which can cyclize again by intramolecular
attack of the hydrazinyl substituent at the hydrazonamide
with loss of ammonia to form 5-hydrazonopyrazolidin-3-ol
21. After elimination of water and hydrogen fluoride followed
(24) Kakiuchi, Y.; Sasaki, N.; Satoh-Masuoka, M.; Murofushi, H.;
Murakami-Murofushi, K. Biochem. Biophys. Res. Commun. 2004, 320,
1351.
(25) (a) Sarojbasinidas, A. N.; Mishra, C. R.; Mittra, A. S. J. Indian
Chem. Soc. 1977, 485. (b) Fuminori, K.; Hirohiko, K. Jpn. Kokai Tokkyo
Koho JP 96-227471, 1998; Chem. Abstr. 1998, 128, 235129. (c) Basaif,
S. A.; Hassan, M. A.; Gobouri, A. A. Dyes Pigm. 2007, 72, 387.
4650
Org. Lett., Vol. 12, No. 20, 2010

14c with 1 equiv of hydrazine gave the corresponding 5-(4-
chlorophenyl)- and 5-(4-methylphenyl)-4-fluoropyrazoles
18b and 18c in 42-48% yield. Unfortunately, the synthesis
of 5-alkylated pyrazole derivatives was more problematic.
Difluorinated pivaloyl acetonitrile 14d proved to be unstable
and could not be purified. However, when the crude
compound was reacted with hydrazine, 24% of 4-fluoro-5-
tert-butylpyrazole 18d was isolated. It should be noted that
the analogous reaction of 2-fluoro-2-methyl-3-phenyl-3-
oxopropanenitrile with hydrazine also resulted in the forma-
tion of 4-methyl-5-phenylpyrazole in 50% yield, while
reactions of 2,2-dichloro-3-oxo-3-phenylpropanenitrile with
hydrazine did not give the corresponding chlorinated pyrazole
(Supporting Information, section III).
Scheme 4. Synthesis of 4-Fluoropyrazoles 17
In conclusion, it can be stated that new entries were
developed toward new fluorinated pyrazoles, a class of
compounds with considerable potential as building blocks
in medicinal chemistry. As the direct fluorination of pyrazoles
is problematic, the reactivity of mono- and difluorinated
ꢀ-ketonitriles and ꢀ-ketoesters with hydrazines toward
fluorinated pyrazoles was studied. The monofluorinated
ꢀ-ketonitrile and ꢀ-ketoester reacted with hydrazine affording
the corresponding 3-amino-4-fluoropyrazole for the first time
and the monofluorinated ꢀ-ketoester condensed toward
4-fluoro-3-hydroxypyrazole. The more easily accessible
difluorinated ꢀ-ketoesters reacted with hydrazines toward
new 4,4-difluoropyrazol-5-ones, from which an N-H deriva-
tive was hydrogenated toward 4-fluoro-3-hydroxypyrazole.
Finally, the reaction of difluorinated ꢀ-ketonitriles with
hydrazine unexpectedly gave rise to new 4-fluoropyrazoles
bearing no amino group at C-3, via condensation with
hydrazine followed by a hydrazine-mediated reduction.
by isomerization, the aromatic 5-diazenyl-4-fluoro-1H-pyra-
zole 20 is obtained. Subsequently, 5-diazenyl-1H-pyrazole
20 can eliminate nitrogen gas to form 4-fluoro-5-phenylpyra-
zole 18a. This unexpected reaction pathway thus provides a
new entry toward 4-fluoropyrazoles. Although 2 equiv of
hydrazine is consumed during the reaction of ꢀ-ketonitriles
14 toward pyrazoles 18, it proved impossible to increase the
yields of pyrazoles 18 by using more than 1 equiv of
hydrazine because of the formation of significant amounts
of side products.
Acknowledgment. The authors are indebted to the Re-
search Foundation - Flanders (FWO - Flanders), Ghent
University (GOA, BOF), and Janssen Pharmaceutica (Johnson
& Johnson) for financial support.
Supporting Information Available: General experimental
1
methods and H NMR and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The scope of the reaction was further expanded by varying
the substituent (R) at the 3-position of 2,2-difluoro-3-
oxopropanenitriles 14. The reaction of compounds 14b and
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Org. Lett., Vol. 12, No. 20, 2010
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