A general and regioselective synthesis of 5-trifluoromethyl-pyrazoles

Article abstract of DOI:10.1021/ol3021918

Two synthetic approaches to 4-trifluoromethylsydnones, a novel class of these mesoionic reagents, are reported. These compounds undergo regioselective alkyne cycloaddition reactions, thereby providing a general approach to 5-trifluoromethylpyrazoles. This method has been employed in a short formal synthesis of the herbicide fluazolate.

Full text of DOI:10.1021/ol3021918

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4858–4861
A General and Regioselective Synthesis of
5‑Trifluoromethyl-pyrazoles
Robert S. Foster,† Harald Jakobi,‡ and Joseph P. A. Harrity*,†
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, U.K., and
Bayer CropScience AG, Research À Weed Control Chemistry, 65926 Frankfurt am Main,
Germany
j.harrity@sheffield.ac.uk
Received August 7, 2012
ABSTRACT
Two synthetic approaches to 4-trifluoromethylsydnones, a novel class of these mesoionic reagents, are reported. These compounds undergo
regioselective alkyne cycloaddition reactions, thereby providing a general approach to 5-trifluoromethylpyrazoles. This method has been
employed in a short formal synthesis of the herbicide fluazolate.
Pyrazoles bearing fluorocarbon substituents are becom-
ing increasingly prevalent as synthetic targets and building
blocks within the fine chemicals sector.1 Many examples of
bioactive fluorinated pyrazoles have emerged in recent
years, and among these, the NSAID celecoxib (Celebrex)2
and the herbicide fluazolate3 (Figure 1) are particularly
noteworthy examples.
1,1,1-trifluoromethyl-1,3-diketones, as this approach ex-
ploits the ready availability of trifluoroacetic acid derived
Pyrazoles are most commonly accessed via cyclocon-
densation of a hydrazine with 1,3-diketones or R,β-unsa-
turated carbonyl compounds. However, this approach
often suffers from the formation of regioisomeric mixtures
with respect to substituents incorporated at the pyrazole
3- and 5-positions.4 In the context of trifluoromethylpyra-
zoles, these compounds are typically synthesized using
Figure 1. Bioactive trifluoromethylpyrazoles.
† University of Sheffield.
‡ Bayer CropScience AG.
precursors.5 Such reactions also very often provide mix-
tures, although some regiocontrol can be achieved by
careful choice of solvent.6
(1) (a) Glasnov, T. N.; Groschner, K.; Kappe, C. O. ChemMedChem
2009, 43, 645. (b) Lamberth, C. Heterocycles 2007, 71, 1467.
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Collins, P. W.; Doctor, S.; Greveto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,
G. D.; Burton, E. G.; Gregory, S. A.; Icoboldt, C. M.; Perkus, W. E.;
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´
(3) Maxwell, B. D. J. Labelled Compd. Radiopharm. 2000, 43, 645.
(7) Browne, D. L.; Harrity, J. P. A. Tetrahedron 2010, 66, 553 and
references cited therein.
ꢀ
ꢀ
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(4) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem. Rev. 2011, 111, 6984.
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Shi, F. Org. Lett. 2010, 12, 2234. (c) Delauney, T.; Geux, P.; Es-Sayed,
M.; Vors, J.-P.; Monteiro, N.; Balme, G. Org. Lett. 2010, 12, 3328. (d)
Fang, Y.; Wu, C.; Larock, R. C.; Shi, F. J. Org. Chem. 2011, 76, 8840.
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C. L.; Loehle, W. D. J. Fluorine Chem. 2002, 118, 135.
r
10.1021/ol3021918
Published on Web 08/30/2012
2012 American Chemical Society

The preparation of pyrazoles via cycloaddition of al-
kynes with sydnones represents a convenient approach for
the regioselective synthesis of these azoles.7,8 In this regard,
Meazza reported the synthesis of 3- and 4-trifluoromethyl-
pyrazoles through cycloadditions with trifluoromethyl-
acetylenes,9 complementing traditional approaches to
these motifs. However, elaboration of this chemistry to
provide the analogous 5-trifluoromethylpyrazoles has not
been developed (Scheme 1).
4 h13 consistently delivered the amino acid 4 in 85% yield.
Finally, 4-trifluoromethyl-N-phenylsydnone 5 was pre-
pared from 4 using the standard method of nitrosation
followed by cyclodehydration. This procedure allowed
gram quantities of 5 to be produced in an overall yield
of 33%.
Scheme 2. Synthesis of 4-Trifluoromethylsydnone 5
Scheme 1. Trifluoromethylpyrazoles from Sydnones
The cycloaddition of 4-CF3 substituted sydnone 5 with
alkynes was investigated, and our results are summarized
in Scheme 3. We were pleased to find that the reaction was
Recent studies in our laboratory have endeavored to
develop the scope of sydnone functionalization and alkyne
cycloaddition chemistry, with the goal of establishing this
area as enabling chemistry for pyrazole synthesis.10 We
envisaged that this chemistry could provide a convenient
and general solution to the regiocontrolled synthesis of
5-trifluoromethylpyrazoles. Our studies toward this end
are outlined herein.
Scheme 3. Regioselective Synthesis of 5-Trifluoromethylpyra-
zolesa
We began our investigations by developing a scalable
route to the requisite 4-trifluoromethylsydnone, and our
results are shown in Scheme 2. Condensation of iminophos-
phorane 1 with methyl trifluoromethylpyruvate furnished
imine 2,11 which was reduced to the amino ester 3 using
zinc metal.12 Hydrolysis of 3 proved to be challenging;
saponification provided a complex mixture whereas hy-
drolysis under acid catalysis proved to be capricious.
Ultimately, however, we found that heating the amino
ester 3 at reflux with lithium iodide in ethyl acetate for
(9) Meazza, G.; Zanardi, G.; Piccardi, P. J. Heterocycl. Chem. 1993,
30, 365.
a Values in parentheses refer to A:B selectivities. o-DCB = 1,2-
dichlorobenzene.
(10) (a) Browne, D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A.
Angew. Chem., Int. Ed. 2007, 46, 8656. (b) Browne, D. L.; Taylor, J. B.;
Plant, A.; Harrity, J. P. A. J. Org. Chem. 2009, 74, 396. (c) Browne, D. L.;
Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A. J. Am. Chem.
Soc. 2009, 131, 7762. (d) Foster, R. S.; Huang, J.; Vivat, J. F.; Browne,
D. L.; Harrity, J. P. A. Org. Biomol. Chem. 2009, 7, 4052. (e) Browne,
D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A. J. Org. Chem. 2010, 75,
984. (f) Foster, R. S.; Jakobi, H.; Harrity, J. P. A. Tetrahedron Lett. 2011,
52, 1506.
(11) Soloshonok, V. A.; Gerus, I. I.; Yagupol’skii, Y. L.; Kuhlar,
V. P. Zh. Org. Khim. 1987, 23, 2308.
(12) Soloshonok, V. A.; Yagupol’skii, Y. L. Zh. Org. Khim. 1988, 24,
1638.
(13) (a) Pinhoe Melo, T. M. V. D.; Soares, M. I. L.; Rocha Gonsalives,
quite general, furnishing a selection of N-phenyl-5-trifluoro-
methyl pyrazoles in good yields and with excellent regio-
control. In this respect, the selectivity of formation of 9 is
notable; cycloadditions of 4-Me- and 4-Pri-substituted
sydnones with2-pyridylacetylene proceedwithlower levels
of regiocontrol (<6:1)10f suggesting that the CF3-group
can enhance cycloaddition regioselectivity in some cases.
The reaction was also found to proceed with disubstituted
alkynes, although the products were formed with lower
levels of selectivity in unsymmetrical cases.
~
A. M. d’A.; Paixao, J. A.; Beja, A. M.; Silva, M. R.; da Velga, L. A.; Pessoa,
J. C. J. Org. Chem. 2002, 67, 4045. (b) Pinhoe Melo, T. M. V. D.; Santos,
~
C. I. A.; Rocha Gonsalives, A. M. d’A.; Paixao, J. A.; Beja, A. M.; Silva,
M. R. Tetrahedon Lett. 2003, 44, 8285. (c) Biron, E.; Kessler, H. J. Org.
Chem. 2005, 70, 5183.
Org. Lett., Vol. 14, No. 18, 2012
4859

To improve regioselectivities in the formation of tetra-
substituted pyrazoles, we opted to explore the use of
alkynylboronates, as these typically afford high selectivites
for the 4-borylated isomer.10d,f In the event, the reactions
required heating at 140 °C over a period of 48À72 h
(Scheme 4); however, the corresponding products were
generated in good yield and with useful levels of regiocon-
trol. Notably, the terminal alkyne exhibited the opposite
regiochemical insertion mode, inline with our previous
observations.
Table 1. Trifluoromethylation of 4-Iodo-N-phenylsydnone 17
yield of
conditions
5 (%)
TMSCF3 (5 equiv), CuI (1 equiv), KF (1 equiv),
DMF, air, 100 °C, 24 h
CF3B(OMe)3K (1 equiv), CuI (0.1 equiv), phen. (0.1 equiv),
DMSO, 60 °C, 48 h, sealed tube
CF3CO2Na (1 equiv), CuI (1 equiv),
NMP, 160 °C, 4 h
0
Scheme 4. Synthesis of 5-Trifluoromethylpyrazole Boronic
Estersa
0
0
FSO2CF2CO2Me (5 equiv), CuI (1 equiv),
60
79
DMF, 80 °C, 20 h
FSO2CF2CO2Me (5 equiv), CuI (1 equiv),
DMF, 80 °C, 20 ha
a 5 mmol scale.
fluorosulfonyldifluoroacetate and copper iodide yielded 5,
and optimization of this reaction delivered the product in
consistently high yields.
Finally, we wanted to demonstrate the applicability of
the direct trifluoromethylation and cycloaddition methods
in target synthesis, and we opted to explore the synthesis of
fluazolate. Our synthetic route is outlined in Scheme 5.
Pleasingly, the direct trifluoromethylation could be extended
a Values in parentheses refer to A:B selectivities. o-DCB = 1,2-
dichlorobenzene.
With respect to implementing a general approach to
trifluoromethyl pyrazoles, the route outlined in Scheme 2
has the limitation that the N-substituent is incorporated
early on and carried through a number of steps before
the alkyne cycloaddition reaction. We envisaged that
a more convenient strategy would be to develop a late-
stage trifluoromethylation of sydnones, as this would
provide a simpler means to incorporate a range of
N-substituents.
Scheme 5. Formal Synthesis of Fluazolatea
By analogy to studies highlighting the successful tri-
fluoromethylation of aryl iodides,14 we chose toinvestigate
the trifluoromethylation of 4-iodo-N-phenylsydnone 17.
Our results are summarized in Table 1. Copper-promoted
trifluoromethylations using Ruppert’s reagent are perhaps
the most widely used; however, the reaction gave only the
parent sydnone 18 under a range of conditions. Similarly
Goossen’s15 copper-catalyzed trifluoromethylation using
the potassium salt of Ruppert’s reagent16 did not result
in 4-CF3 sydnone 5, and the transformation also failed
when sodium trifluoromethylacetate was used as the CF3
source. In contrast however, treatment of 17 with methyl
(14) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.; Roy, S.
Tetrahedron 2011, 67, 2161 and references cited therein.
€
(15) Knauber, T.; Arikan, F.; Roschenthaler, G.-V.; Goossen, L. J.
Chem.;Eur. J. 2011, 17, 2689.
(16) Kolomeitsex, A. A.; Kadyrov, A. A.; Szczepkowska-Sztolcman,
J.; Milewska, M.; Koroniak, H.; Bissky, G.; Barten, J. A.;
€
a o-DCB = 1,2-dichlorobenzene.
Roschenthaler, G.-V. Tetrahedron Lett. 2003, 44, 8273.
(17) Harper, B. C.; Mao, M. K. U.S. Patent 5698708, Dec 16, 1997.
4860
Org. Lett., Vol. 14, No. 18, 2012

to N-Me sydnone 19 and delivered the corresponding
CF3-substituted mesoionic reagent 20 in good yield. The
key fluazolate intermediate 21 could be accessed directly by
a regioselective cycloaddition with 1-chloro-4-ethynyl-5-
fluoro-2-methylbenzene in 86% yield. Fluazolate is sube-
quently prepared by bromination of the pyrazole ring
followed by oxidation of the arylmethyl group and ester-
ification of the resulting benzoic acid.17 However, our
strategy also has the flexibility to offer further diversifica-
tion of the 3-aryl moiety by employing alkynylboronates
in the cycloaddition. In the event, pyrazole boronic ester
22 was prepared from sydnone 20 in low yield (44%)
because of the tendency of this compound to undergo rapid
protodeboronation during chromatography. Accordingly,
a telescoped cycloadditionÀcoupling was attempted that
delivered 21 in an acceptable overall yield, thereby
confirming the potential of this approach to generate flua-
zolate analogs.
In conclusion, we have demonstrated that 4-trifluoro-
methylsydnones can be prepared by ring synthesis and ring
functionalization approaches. These compounds function
as valuable precursors to 5-trifluoromethylpyrazoles via
highly regioselective cycloaddition reactions.
Acknowledgment. We are grateful to Bayer CropScience
and the University of Sheffield for financial support.
Supporting Information Available. Full experimental
details for the syntheses reported are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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