Microwave-mediated pyrazole fluorinations using selectfluor

Article abstract of DOI:10.1002/hc.20556

Microwave-mediated electrophilic fluorinations and a new single-pot condensation en route to ring-fluorinated pyrazoles were examined: chemical equation represented The monofluorination by these methods was successful for a variety of pyrazoles, with yields ranging from 13% to 75%. While electrophilic aromatic fluorination of 3-CF₃ pyrazoles proved largely ineffective, development ofa single-pot process overcame this limitation. The microwave-mediated reaction is regioselective; ring fluorination of the heterocycle occurs preferentially over phenyl and alkyl substituents. Alkyl side chain fluorination, when desired, can be modulated by reactant ratios. The single-pot method, which involves acid catalysis by H-TEDA, produces 4-fluoropyrazoles products.

Full text of DOI:10.1002/hc.20556

Heteroatom Chemistry
Volume 20, Number 6, 2009
Microwave-Mediated Pyrazole Fluorinations
R
ꢀ
Using Selectfluor
Joseph C. Sloop1 James L. Jackson,2 and Robert D. Schmidt3
1School of Science and Technology, Georgia Gwinnett College, Lawrenceville, GA 30043
2Department of Chemistry, United States Military Academy, West Point, NY 10996
3Department of Chemistry, North Carolina State University, Raleigh, NC 27695
Received 15 May 2009; revised 30 August 2009
ꢀ
C
4-fluoropyrazoles products.
2009 Wiley Periodicals,
ABSTRACT: Microwave-mediated electrophilic fluo-
rinations and a new single-pot condensation en route
to ring-fluorinated pyrazoles were examined:
Inc. Heteroatom Chem 20:341–345, 2009; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20556
Ar
Ar
N
N
N
N
R
CH3CN
Selectfluor
+
R
R'
μwaves, Δ
R
R'
INTRODUCTION
F
The preparation of fluorinated pyrazoles, impor-
tant precursors to pharmaceuticals and pesticides
[1–4], has been the subject of extensive investigation.
The usual means of introducing fluorine selectively
into aromatic systems have included fluorinated syn-
thons, the Balz–Schiemann process, dilute fluorine
gas mixtures, or nucleophilic aromatic substitution
with fluoride anion [5–13]. In many cases, multiple
steps are required; special glassware is necessary,
and yields are not optimal.
R
,
1. Selectfluor
CH CN,
O
O
Δ
3
R
R'
2. ArNHNH ,
Δ
2
The monofluorination by these methods was suc-
cessful for a variety of pyrazoles, with yields rang-
ing from 13% to 75%. While electrophilic aromatic
fluorination of 3-CF3 pyrazoles proved largely inef-
fective, development of a single-pot process overcame
this limitation. The microwave-mediated reaction is
regioselective; ring fluorination of the heterocycle oc-
curs preferentially over phenyl and alkyl substituents.
Alkyl side chain fluorination, when desired, can be
modulated by reactant ratios. The single-pot method,
which involves acid catalysis by H-TEDA, produces
Over the past decade, expansion of uses for the
F-TEDA family of electrophilic fluorinating reagents
R
R
such as Accufluorꢀ and Selectfluorꢀ has been dra-
matic. Reaction conditions vary widely, with many
processes requiring refluxing conditions to achieve
good yields. While examples of these reagents’ util-
ity in electrophilic heteroaromatic fluorinations of
selected heterocycles such as isoxazoles, pyridines,
and thiazoles are known, the studies concerning
pyrazoles conducted thus far have remained limited
in scope and discussion of substrate reactiv-
ity [14–16]. Furthermore, electrophilic fluorination
of alkyl side chains on heteroaromatic systems
Correspondence to: Joseph C. Sloop; e-mail: jsloop@ggc.edu.
Contract grant sponsor: U.S. Military Academy Faculty
Research Fund.
The views expressed in this academic research paper are those
of the authors and do not necessarily reflect the official policy or
position of the U.S. Government, the Department of Defense, or
R
with Selectfluorꢀ has not been reported in the
any of its agencies.
2009 Wiley Periodicals, Inc.
c
ꢀ
literature.
341

342 Sloop, Jackson and Schmidt
Our efforts were directed toward accomplish-
ing several objectives. First, preparation of a
variety of ring-fluorinated pyrazoles substituted with
electron-withdrawing groups (EWGs) and electron-
donating substituents (EDGs) would provide a more
R1
N
N
R3
R2
R
complete picture of Selectfluorꢀ’s effectiveness as
an electrophilic pyrazole fluorinating agent. In ad-
dition to the reactivity study, a selectivity investi-
FIGURE 1 Fluorination sites observed.
R
gation of the tendency of Selectfluorꢀ to fluorinate
aryl and alkyl functional groups on pyrazolic species
will be reported. Finally, we will take advantage of
the susceptibility of 1,3-diketones to fluorination in
the 2-position by F-TEDA reagents [17] and to exam-
ine the ability of H-TEDA to act as an acid catalyst
in the condensation of in situ generated 2-fluoro-
1,3-diketones with arylhydrazines in a novel one-pot
route to new pyrazole species.
obtained in 1:1 and 2:1 ratios, respectively. This pref-
erence, in accord with previous work, is likely due
to a combination of steric and stereoelectronic ef-
fects in the initial nucleophilic addition of the aryl-
hydrazine to the diketone [5,6].
As expected, reactivity of the pyrazole sys-
tem toward electrophilic aromatic fluorination was
modulated by substituents. Deactivated pyrazoles,
e.g., compounds 2b–2d, 4a, 6a, and 8f, generally
gave lower yields of the ring-fluorinated pyrazoles,
whereas activated pyrazoles (2a, 8a, and 8e) led to
improved yields.
Likewise, substituents affected fluorination re-
gioselectivity. Figure 1 shows the sites of fluorination
observed. In nearly all cases, the ring-fluorinated
pyrazole was the major product. Fluorination of
R1(R1 = 4-CH3OPh) was observed by 19F NMR in
pyrazoles 8a, 8e–f. Attempts to fluorinate the acti-
vated pyrazole 8a under microwave-mediated con-
ditions led to a complex mixture of mono- and di-
fluorinated products after only 2 × 5 min heating
cycles. Consequently, pyrazole 9a was prepared in
75% yield under very mild reaction conditions (room
temperature, 24 h). R1-fluorinated pyrazole deriva-
tives of compounds 8e and 8f accounted for ap-
proximately 5% and 10% of the product mixtures,
respectively. Two additional products were verified
by 19F NMR (δ, CFCl3): fluorination of the anisyl
ring at C-3: s, 1F, −110 ppm; at C-2: s, 1F, −108
ppm Two examples of fluorination at R2 occurred:
(R1 = 4-NO2Ph,R2 = CH3) 4-fluoro-3-fluoromethyl-
5-methyl-1-(4-nitrophenyl)pyrazole (5b) was iso-
RESULTS AND DISCUSSION
Scheme 1 shows the pyrazoles prepared in this work
by electrophilic aromatic fluorination (method A).
Diketones 1a, c–e are available commercially; 1b
and 1f were prepared by literature methods [18].
Fluorinations of pyrazoles via the method A, un-
less otherwise noted, were carried out using 6 × 5
min heating cycles in a standard 1450-W microwave
oven operating at a 10% power level. Microwave-
mediated conditions were chosen for the more than
50-fold reaction time savings when compared to
conventional reflux methods. In addition, a side-
by-side comparison of fluorinations of 2a using the
microwave-mediated process (0.5 h) and standard
reflux conditions (24 h) showed that the microwave
technique afforded a higher product yield: 60% ver-
sus 53%.
Pyrazole regioisomers 2b–d, 4c, 8e, and 8f were
identified by NMR chemical shifts of the pyra-
zolic ring proton H1(δ = 6.7–6.9 ppm) and by 19F
NMR where Rꢁ = CF3 (δ(CF3) ≈ −62 ppm). Ring-
fluorinated pyrazole regioisomers 3a–d, 5a, 5c, 7a,
9a, 9e, and 9f were identified and assigned by 19F
NMR chemical shifts of the pyrazolic ring fluorine
(δ(F) ≈ −171 to −176 ppm) and where Rꢁ = CF3
(δ(CF3) ≈ −62 ppm).
lated in 20% yield, and (R1 = 2,4-NO2Ph,R2
=
CH3) 4-fluoro-3-fluoromethyl-5-methyl-1-(2,4-dini-
trophenyl)pyrazole was identified by 1H and 19F
NMR (10%) but not isolated. It is also of interest
that fluorination at R3 (R3 = Ph, CH3) was not ob-
served; this is undoubtedly a consequence of steric
interference between R3 and F-TEDA. To verify this
preference, pyrazoles 2a and 4a were subjected to
General trends are evident from Scheme 1. In
agreement with previous findings, alkyl-substituted
1,3-diketones gave higher yields of N-arylpyrazoles
than aryl-substituted 1,3-diketones [6]. Arylhy-
drazines substituted with EDGs gave higher yields
of pyrazoles than those substituted with EWGs. The
diketone-hydrazine condensation in the method A
led predominantly to the 3-CH3 or 3-CF3 pyrazole
in all cases except pyrazoles 2c and 8f, for which
both the 3-CF3 and 5-CF3 pyrazole regioisomers were
R
fluorination with 4 equiv of Selectfluorꢀ and pyra-
zoles 3c and 5c were isolated in 58% and 42% yields,
respectively.
Ring-fluorinated pyrazoles produced by the
method B were obtained via in situ fluorination of
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Mediated Pyrazole Fluorinations Using Selectfluor 343
arylhydrazine
Selectfluor
diketone
pyrazole
4-fluoropyrazole
waves,
CH3CN
EtOH, Δ,
cat H 2SO4
(yield)a
(yield)a
C6H5
C6H5
O
O
N
N
N
N
C6H5NHNH2
H3C
CH3
CH3
H3C
CH3
H3C
1a
2a (81%)
F
3a (60%)
O
O
C6H5
C6H5
N
N
N
N
H3C
4-NO2C6H4
4-NO2C6H4
H3C
H3C
4-NO2C6H4
1b
2b (62%)b
F
3b (40%)c
C6H5
C6H5
O
O
N
N
N
N
H3C
CF3
H3C
CF3
H3C
CF3
2c (88%)d
1c
F
3c (40%)(58%)e
O
O
C6H5
C6H5
N
N
N
N
C6H5
CF3
C6H5
CF3
CF3
C6H5
1d
2d (71%)
F
3d (0%)
O
O
4-NO2C6H4
4-NO2C6H4
N
N
4-NO2C6H4NHNH2
N
N
H3C
CH3
CH3
H3C
CH3
H3C
1a
4a (72%)
F
5a (49%)f
NO2C6H4
O
O
4-NO2C6H4
4-
N
N
N
N
H3C
CF3
CF3
H3C
CF3
H3C
1c
4c (78%)b
F
5c (13%)
(42%)e
O
O
2,4-diNO2C6H4
2,4-di
NO2C6H4
H3C
2,4-diNO2C6H3NHNH2
N
N
N
N
H3C
CH3
CH3
CH3
H3C
1a
1a
6a (65%)
F
7a (30%)
CH OC H
O
O
4-CH3OC6H4
4-
3
6
4
N
N
N
N
4-CH3OC6H4NHNH2
H3C
CH3
H3C
CH3
CH3
H3C
8a (85%)
F
9a (20%)f
(75%)g
O
O
CH OC H
CH OC H
4-
4-
3
6
4
3
6
4
N
N
N
N
C6H5
CH3
CH3
C6H5
CH3
C6H5
1e
1f
8e (75%)
F
9e (53%)
O
O
4-
CH3OC6H4
4-CH3OC6H4
N
N
N
N
F3C
4-NO2C6H4
4-NO2C6H4
F3C
4-NO2C6H4
F3C
8f (59%)h
F
9f (0%)f
SCHEME 1 Microwave-mediated pyrazole synthesis. aYield after purification. bRegiosiomeric pyrazole formed in 10% yield.
R
cPyrazole 3b formed exclusively. dRegiosiomeric pyrazole also produced in 1:1 ratio. eYield: 3c from 2a and 4 eq Selectfluorꢀ
;
R
5c from 4a and 4 equiv Selectfluorꢀ. f Multiple fluorinated products produced. g Yield under modified conditions.h Regiosiomeric
pyrazole also produced in 1:2 ratio.
Heteroatom Chemistry DOI 10.1002/hc

344 Sloop, Jackson and Schmidt
1. Selectfluor,CH3CN, reflux
2. arylhydrazine, CH3CN, reflux
diketone
4-fluoropyrazole
(yield)a
C6H5
O
O
C6H5NHNH2
N
N
H3C
CH3
H3C
CH3
1a
1b
F
3a (55%)
C6H5
O
O
N
N
H3C
4-NO2C6H4
H3C
4-NO2C6H4
F
3b (50%)
C6H5
O
O
N
N
H3C
CF3
H3C
CF3
1c
F
3c (60%)
C6H5
O
O
N
N
C6H5
CF3
C6H5
CF3
1d
1c
F
3d (56%)
O
O
4- NO2C6H4
4-NO2C6H4NHNH2
N
N
H3C
CF3
CF3
H3C
F
5c (40%)
O
O
CH OC H
4-
3
6
4
4-CH3OC6H4NHNH2
N
N
H3C
CH3
H3C
CH3
1a
F
9a (70%)
CH OC H
4-
3 6 4
O
O
N
N
C6H5
CH3
C6H5
CH3
1e
1f
F
9e (55%)
O
O
4- CH3OC6H4
N
N
F3C
4-NO2C6H4
4-NO2C6H4
F3C
F
9f (45%)
SCHEME 2 One-pot fluorinated pyrazole synthesis. aYield after purification.
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Mediated Pyrazole Fluorinations Using Selectfluor 345
the diketones (acetonitrile, 70◦C, 24 h). The monoflu-
orinated diketones of 1a, 1c, and 1d were isolated
and identified by 19F NMR to verify the reaction
pathway. The in situ generated diketones then un-
derwent H-TEDA catalyzed condensation with the
arylhydrazines (acetonitrile, 70◦C, 24–40 h) to pro-
vide the 4-fluoropyrazoles are shown in Scheme 2.
The method B led to formation of the 3-CH3,
4-F- and 3-CF3, 4-F-pyrazole isomers, with the sin-
gular exception 3b, which gave the 3-(4-NO2Ph), 4-F-
pyrazole. The trifluoromethyl group regiospecificity
observed in the single-pot process is accounted for
by the preference for the keto form of the in situ gen-
erated 2-fluoro-1,3-diketone formed prior to conden-
sation with arylhydrazines to the pyrazole [5]. Nu-
cleophilic addition by the arylhydrazines occurred
at the most electrophilic site, e.g., the carbonyl ad-
jacent to the –CF3 or 4-NO2Ph group. This strategy
eliminated the likelihood of side reactions; no fluo-
rination of alkyl or aryl groups was observed.
SUPPORTING INFORMATION
Experimental details are available from the corre-
sponding author on request [5,6,18–24].
ACKNOWLEDGMENTS
The authors would like to thank the NCSU NMR fa-
cility for NMR support and the NCSU Mass Spectral
facility for HRMS support.
REFERENCES
[1] Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.;
Swaney, S. M.; Tarpley, W.G.; Yagi, Y.; Romero,
D. L. J Med Chem 2000, 43, 1034.
[2] Guzman-Perez, A.; Wester, R. T.; Allen, M. C.; Brown,
J. A.; Buchholz, A. R.; Cook, E. R.; Day, W. W.;
Hamanaka, E. S.; Kennedy, S. P.; Knight, D. R.;
Kowalczyk, P. J.; Marala, R. B.; Mularski, C. J.;
Novomisle, W. A.; Ruggeri, R. B.; Tracey, W. R.; Hill,
R. J. Bioorg Med Chem Lett 2001, 11(6), 803.
[3] Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter,
J. S.; Collins, P. W.; Docter, S.; Graneto, 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.; Cogburn, J. N.; Gregory, S. A.; Koboldt,
C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhang, Y. Y.; Isakson, P. C. J Med Chem 1997, 40,
1347.
[4] Suschitzky, H. Adv Fluorine Chem 1965, 4, 1.
[5] Bumgardner, C.; Sloop, J. J Fluorine Chem 1992, 56,
141.
[6] Sloop, J.; Bumgardner, C.; Loehle, W. J Fluorine
Chem 2002, 118, 135.
[7] Ishikawa, N. Bull Chem Soc Japan 1981, 59, 3221.
[8] Linderman, R.; Kirollos, K. Tetrahedron Lett 1989,
30(16), 2049.
[9] Norris, T.; Colon-Cruz, R.; Ripin, D. H. B. Org Biomol
Chem 2005, 3, 1844.
CONCLUSION
This study of pyrazole formation provides new in-
sight regarding the effectiveness and selectivity of
the F-TEDA class of reagents in electrophilic aro-
matic fluorinations and how reaction conditions
may be modified to improve yields and regiospeci-
ficity. In addition, the effect that substituents have
on influencing product regioselectivity and reactiv-
ity for this important condensation involving arylhy-
drazines and 1,3-diketones has been outlined.
R
This work shows that Selectfluorꢀ is an effective
[10] Singh, S.; Kumar, D.; Batra, H.; Naithani, R.; Rozas,
I.; Elguero, J. Can J Chem 2000, 78, 1109.
[11] Doyle, M. P.; Bryker, W. J. J Org Chem 1979, 44, 1572.
[12] Katoch-Rouse, R.; Hortu, A. G. J Labelled Compd
Radiopharm 2003, 46(1), 93.
[13] Ichikawa, J.; Kobayashi, M.; Noda, Y.; Yokota, N.;
Amano, K.; Minami, T. J Org Chem 1996, 61(8), 2763.
[14] Stephens, C. E.; Blake, J. A. J Fluorine Chem 2004,
125(12), 1939.
electrophilic-fluorinating agent for pyrazoles, which
are not highly deactivated. Yields are commensu-
rate with those of other multiple-step processes, and
reaction times are dramatically reduced. Overall,
monofluorinated pyrazoles are the major product
unless an activated benzene ring is present. Excep-
tions noted appear to be influenced by a combination
of steric and stereoelectronic effects.
[15] Pace, A.; Buscemi, S.; Vivona, N. Org Prep Proc Int
2007, 39, 1.
R
We have also demonstrated that Selectfluorꢀ
[16] Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem Rev 1996,
96, 1737.
[17] Xiao, J.; Shreeve, J. M. J Fluorine Chem 2004, 126(4),
473.
[18] Reid, J.; Calvin, M. J Am Chem Soc 1950, 72, 2948.
[19] Haddadin, M. J. Tetrahedron 1976, 32(6), 719.
[20] Dilli, S.; Robards, K. J. Chromatogr 1984, 312, 109.
[21] Ried, W.; Muehle, G. Justus Liebigs Ann Chem 1962,
656, 119.
[22] Paul, R.; Tchelitcheff, S. Bull Chim Fr 1958, 11, 4179.
[23] Brady, O. L. J Chem Soc 1931, 756.
[24] Butler, R. N.; Hanniffy, J. N.; Stephens, J. C.; Burke,
L. A. J Org Chem 2008, 73(4), 1354.
provides not only selective fluorination capability,
but its ammonium salt byproduct of that fluori-
nation also catalyzes 4-fluoropyrazole formation in
comparable yields to previous methods. This novel,
single-pot approach is effective irrespective of sub-
stituents on the 1,3-diketone or arylhydrazine. This
process offers a new route for selective incorpora-
tion of fluorine into pyrazolic molecules that is with-
out the use of toxic or unstable fluorinating agents,
specialized reaction conditions, or isolation of
intermediates.
Heteroatom Chemistry DOI 10.1002/hc