Regioselective synthesis of pyrazole triflones based on triflyl alkyne cycloadditions

Article abstract of DOI:10.1021/ol3025154

The regioselective synthesis of pyrazole triflones has been achieved by 1,3-dipolar cycloaddition of triflyl alkynes and hydrazonoyl chloride in the presence of Huenig's base. Pyrazolo[5,1-a]isoquinoline triflones were also regioselectively synthesized for the first time via tandem 1,3-dipolar cycloaddition/oxidative aromatization between triflyl alkynes and C,N-cyclic azomethine imines.

Full text of DOI:10.1021/ol3025154

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regioselective Synthesis of Pyrazole
Triflones Based on Triflyl Alkyne
Cycloadditions
Hiroyuki Kawai, Zhe Yuan, Etsuko Tokunaga, and Norio Shibata*
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
nozshiba@nitech.ac.jp
Received September 12, 2012
ABSTRACT
The regioselective synthesis of pyrazole triflones has been achieved by 1,3-dipolar cycloaddition of triflyl alkynes and hydrazonoyl chloride in the
€
presence of Hunig’s base. Pyrazolo[5,1-a]isoquinoline triflones were also regioselectively synthesized for the first time via tandem 1,3-dipolar
cycloaddition/oxidative aromatization between triflyl alkynes and C,N-cyclic azomethine imines.
The trifluoromethanesulfonyl (triflyl, SO2CF3, Tf) group
is the strongest electron-withdrawing group with high
lipophilicity. The introduction of this functionality into
organic compounds is an effective strategy to alter the fun-
damental character of parent molecules without majorly
changing the molecular complexicity. In this context,
attention has been paid to aryl trifluoromethyl sulfones 1
(aryl triflones, ArSO2CF3) in the development of bioactive
compounds,1 chiral catalysts,2 and functional materials.3
A number of methodologies have been developed for the
synthesis of aryl triflones including oxidation of aryl
trifluoromethyl sulfides,4 trifluoromethylation of aryl sul-
fonyl fluorides or aryl sulfonates,5 thia-Fries rearrangement
of aryl trifluoromethanesulfonates,6 and direct trifluoro-
methanesulfonylation of aromatic compounds.7 Recently,
Taguchi et al. reported a regioselective synthesis of
polysubstituted aryl triflones through a self-promoting
(4) (a) Beaumont, A. J.; Clark, J. H. J. Fluorine Chem. 1991, 52, 295–
300. (b) Chen, Q.-Y.; Duan, J.-X. J. Chem. Soc., Chem. Commun. 1993,
918–919. (c) Su, W. Tetrahedron Lett. 1994, 35, 4955–4958. (d)
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S. K.; Tse, C.; Wang, X.; Wendt, M. D.; Yang, X.; Zhang, H.; Fesik, S. W.;
Rosenberg, S. H.; Elmore, S. W. J. Med. Chem. 2008, 51, 6902–6915. (b)
Brown, B. S.; Keddy, R.; Zheng, G. Z.; Schmidt, R. G.; Koenig, J. R.;
McDonald, H. A.; Bianchi, B. R.; Honore, P.; Jarvis, M. F.; Surowy, C. S.;
Polakowski, J. S.; Marsh, K. C.; Faltynek, C. R.; Lee, C.-H. Bioorg. Med.
Chem. 2008, 16, 8516–8525. (c) Wang, G.; Zhang, H.; Zhou, J.; Ha, C.; Pei,
D.; Ding, K. Synthesis 2008, 2398–2404.
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ꢁ
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r
10.1021/ol3025154
XXXX American Chemical Society

three-component reaction.8 On the other hand, the synth-
esis of heteroaryl triflones has been considerably less
studied. Our research group has recently developed the
synthesis of indole triflones by direct trifluoromethanesul-
fonylation of indoles with the Tf2O/TTBP (2,4,6-tritert-
butylpyridine) system.9 Furthermore, novel heteroaryl
triflones including oxindole, pyrazolone, pyridine, and
quinoline derivatives have been regioselectively synthe-
sized by LDA-mediated thia-Fries rearrangement.10 We
also reported the first practical synthesis of isoxazole
triflones (4-triflyl isoxazoles) by an operationally simple
procedure consisting of the reaction of R-triflyl ketones
and imidoyl chloride.11 As part of our ongoing research
programs directed at the development of efficient methodol-
ogies for the preparation of fluorinated heterocycles,12 we
required pyrazole triflones 2 (4-trifluoromethanesulfonyl
pyrazoles, 4-triflyl pyrazoles) as a key core unit for novel
agrochemicals, in particular, 3,5-diarylpyrazole triflones (R1
and R2 = aromatic group, Figure 1).13
Pyrazoles are a major class of five-membered nitrogen
heterocyclesand are important corecomponentsinnatural
products and valuable molecules in the pharmaceutical
industry.14 Numerous synthetic approaches for the con-
struction of the pyrazole framework have been reported,
for example, a condensation of 1,3-dicarbonyl compounds
with hydrazines,15 1,3-dipolar cycloaddition of diazoalk-
anes or nitrilimines with alkenes or alkynes,16 or the
reaction between hydrazones and activated alkenes such
as nitro olefins.17 However, there are no synthetic methods
for 3,5-diaryl pyrazole triflones, despite their clear poten-
tial usefulness and wide applicability for pharmaceuticals
and agrochemicals. We disclose herein the first practical
and regioselective synthesis of pyrazole 4-triflones 2 by a
1,3-dipolar cycloaddition between readily available mate-
rials, triflyl alkynes 3 and hydrazonoyl chloride 4, in high
yields with a broad scope. Pyrazolo[5,1-a]isoquinoline
triflones 5 were also efficiently synthesized for the first
time via regioselective, tandem 1,3-dipolar cycloaddition/
oxidative aromatization of 3 and C,N-cyclic azomethine
imines 6.
We initiated our investigation with the cyclization of
R-triflyl ketone 7 and hydrazonoyl chloride 4a18 in the
presence of NEt3, according to the modified procedure
based on the synthesis of isoxazole triflones.11 Unfortu-
nately, 15% of desired pyrazole triflone 2a was obtained
(Scheme 1, top). We next attempted the cyclization using
triflyl alkyne 3a19 instead of 7. Gratifyingly, the de-
sired cycloadduct 2a was obtained in 43% regioselec-
tively (Scheme 1, bottom). This preliminary result
encouraged us to further investigate the optimization
Figure 1. Aryl triflones 1, pyrazole triflones 2, and pyrazolo[5,1-
a]isoquinoline triflones 5.
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(13) 3,5-Disubstituted (3,5 = carbon) pyrazole triflones are rare (25
compounds are registered in the SciFinder database), and none of the
examples of 3,5-diarylpyrazole triflones 2 is reported. (a) Jensen-Korte,
U.; Gehring, R.; Schallner, O.; Stetter, J.; Becker, B.; Homeyer, B. 1988,
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B
Org. Lett., Vol. XX, No. XX, XXXX

of the reaction conditions using 3a (Table 1). The
reaction was next attempted using iPr2NEt, yielding
2a in a slightly better yield of 46% (entry 2). The choice
of solvent was found to be important in the conversion
(entries 3;9), and the yield was increased to 92% in MeCN
(entry 9). The structure of 2a was clearly determined after
derivatization to a known 1,3,5-triphenyl-1H-pyrazole by
reductive desulfonylation using LiAlH4 (see Scheme S1 in
Supporting Information, SI).20
of hydrazonoyl chlorides 4 under the same reaction con-
ditions. A series of hydrazonoyl chlorides 4bÀe were nicely
converted to pyrazole triflone 2fÀi in 80%À90% yields,
these being almostindependent ofthefunctionalgroupson
the aromatic ringof 4 suchasmethyl, chloro, and bromo as
well as a sterically demanding naphthyl substrate (entries
6À9). Interestingly, when the reaction was attempted with
imidoyl chloride 8a under the same reaction conditions,
isoxazole triflone 9a was isolated in 82% yield (Scheme 2).
Table 2. Synthesis of Pyrazole Triflones 2a
Scheme 1. Synthesis of 2a Using R-Triflyl Ketone 7 or Triflyl
Alkyne 3a
yield
(%)b
entry
3
R1
4
R2
2
1
2
3
4
3a
3b
3c
3d
Ph
4a
4a
4a
4a
Ph
Ph
Ph
Ph
2a
2b
2c
2d
92
85
80
85
2-MeC6H4
4-MeC6H4
4-n-
C5H11C6H4
3-FC6H4
Ph
5
6
7
8
9
3e
3a
3a
3a
3a
4a
4b
4c
4d
4e
Ph
2e
2f
83
90
81
82
80
4-MeC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
Table 1. Optimization of Bases and Solvents for 1,3-Dipolar
Cycloaddition of 3a and 4aa
Ph
2g
2h
2i
Ph
Ph
a The reaction of 3 with 4 (1.5 equiv) was carried out in the presence
of iPr2NEt (1.5 equiv) in MeCN at rt. b Isolated yield.
entry
base
NEt3
solvent
time (h)
yield (%)b
Scheme 2. Synthesis of Isoxazole Triflone 9a
1
2
3
4
5
6
7
8
MeOH
MeOH
CH2Cl2
CHCl3
toluene
THF
5
4
43
46
63
78
25
15
49
92
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
8
24
24
10
2
DMF
MeCN
3
We next examined the 1,3-dipolar cycloaddition of 3
with C,N-cyclic azomethine imines 621 for the synthesis
of the biologically attractive pyrazolo[5,1-a]isoquinoline
framework.22 Treatment of 3a with 6a in CH2Cl2 at
ambient temperature regioselectively furnished unstable
cycloadduct 10a, which was isolated as pyrazolo[5,1-a]-
isoquinoline triflone 5a in 92% yield after aromatization
a The reaction of 3a with 4a (1.5 equiv) was carried out in the presence
of base (1.5 equiv) at rt. b Isolated yield.
With suitable conditions in hand, the scope of the 1,3-
dipolar cycloaddition was explored with a variety of sub-
strates selected in order to establish the generality of the
process using this strategy, all affording good to excellent
yields (Table 2). A series of triflyl alkynes 3bÀe with a
variety of substituents at their aromatic rings (R1), such
as methyl, pentyl, and fluoro, were nicely converted to
corresponding pyrazole triflones 2bÀe in high yields
(80%À85%) (entries 2À5). We next examined the sub-
strate scope differing in the nature of the aryl substituents
(21) (a) Hashimoto, T.; Maeda, Y.; Omote, M.; Nakatsu, H.;
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Org. Lett., Vol. XX, No. XX, XXXX
C

using DDQ (Scheme 3). The structure of 5a was deter-
mined after derivatization to a known pyrazolo[5,1-a]-
isoquinoline by reductive desulfonylation using Mg/MeOH
(see Scheme S2 in SI).23
Table 3. Synthesis of Pyrazolo[5,1-a]isoquinoline Triflones 5a
Scheme 3. Synthesis of Pyrazolo[5,1-a]isoquinoline Triflones 5a
via 1,3-Dipolar Cycloaddition/Oxidative Aromatization of 3a
with 6a
yield
(%)b
entry
3
R1
6
R3
5
1
2
3
4
3a
3b
3c
3d
Ph
6a
6a
6a
6a
H
5a
5b
5c
5d
92
80
88
98
2-MeC6H4
4-MeC6H4
4-n-
H
H
H
C5H11C6H4
3-FC6H4
cyclopropyl
Ph
5
6
7
8
9
3e
3f
6a
6a
6b
6c
6d
H
5e
5f
90
74
87
98
94
H
3a
3a
3a
5-Me
7-Me
7-Br
5g
5h
5i
Ph
The scope of this tandem regioselective 1,3-dipolar
cycloaddition/oxidative aromatization was investigated
with a range of triflyl alkynes 3 and azomethine imines 6
(Table 3). High to excellent yields were obtained for
all cases up to 98%, with these being almost independent
of the functional groups and the positions of the aro-
matic ring of 3 (entries 2À5). Nonaromatic triflyl alkyne
3f was also a suitable substrate for this transformation
to afford 5f in 74% yield (entry 6). Cyclic azomethine
imines having a methyl or bromo group were also utilized
in this transformation in excellent yields (87%À98%)
(entries 7À9).
Ph
a The reaction of 3 with 6 (1.0 equiv) was carried out in CH2Cl2 at rt.
b Isolated yield.
challenge in this field, and the subject is under active
investigation.
Acknowledgment. This study was financially supported
in part by Grants-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Tech-
nology (Project name: Advanced Molecular Transforma-
tionbyOrganocatalysts) (Projectname: Platformfor Drug
Discovery, Informatics and Structural Life Science). We
are grateful to Central Glass Co., Ltd. for the gift of triflic
anhydride. We also thank the Asahi Glass Foundation.
In summary, we disclose the first practical synthesis of
pyrazole triflones 2 by regioselective 1,3-cycloaddition of
triflyl alkynes 3 and hydrazonoyl chloride 4 in the presence
€
of Hunig’s base. Biologically attractive pyrazolo[5,1-a]-
isoquinoline triflones 5 were also efficiently synthesized for
the first time via regioselective tandem 1,3-dipolarcycload-
dition/oxidative aromatization between triflyl alkynes 3
and C,N-cyclic azomethine imines 6. The direct introduc-
tion of a triflyl group into pyrazoles through CÀH acti-
vation with trifluoromethane sulfonylation is the next
Supporting Information Available. Experimental pro-
cedures, spectra data for all new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(23) Ortega, H.; Ahmed, S.; Alper, H. Synthesis 2007, 3683–3691.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX