General method for dehydration, intramolecular cyclization, and fluorination of trifluoromethyl-1H-pyrazoles using DAST

Article abstract of DOI:10.1016/j.tetlet.2010.05.052

In this study, the versatile diethylaminosulfur trifluoride (DAST), a well-known fluorinating agent, was applied in the dehydration, intramolecular cyclization, and mono-and difluorination reactions of some 5-trifluoromethyl-1H- pyrazoles and 2-pyrazolines employing a general, mild, and efficient methodology. The azole precursors were synthesized from the reactions of acyclic and cyclic trifluoroacetylated enol ethers with hydrazines [NH₂NHR, where R = C₆H₅, C₆F₅, 2-Furanoyl] and showed a differentiated chemical behavior in the presence of DAST.

Full text of DOI:10.1016/j.tetlet.2010.05.052

Tetrahedron Letters 51 (2010) 3759–3761
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General method for dehydration, intramolecular cyclization, and fluorination
of trifluoromethyl-1H-pyrazoles using DAST
*
Helio G. Bonacorso , Liliane M. F. Porte, Gisele R. Paim, Fabio M. Luz, Marcos A. P. Martins, Nilo Zanatta
Núcleo de Química de Heterociclos—NUQUIMHE, Departamento de Química, Universidade Federal de Santa Maria, 97105-900—Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 March 2010
Revised 5 May 2010
Accepted 12 May 2010
Available online 20 May 2010
In this study, the versatile diethylaminosulfur trifluoride (DAST), a well-known fluorinating agent, was
applied in the dehydration, intramolecular cyclization, and mono- and difluorination reactions of some
5-trifluoromethyl-1H-pyrazoles and 2-pyrazolines employing a general, mild, and efficient methodology.
The azole precursors were synthesized from the reactions of acyclic and cyclic trifluoroacetylated enol
ethers with hydrazines [NH2NHR, where R = C6H5, C6F5, 2-Furanoyl] and showed a differentiated chem-
ical behavior in the presence of DAST.
Ó 2010 Elsevier Ltd. All rights reserved.
a
,b-Unsaturated ketones with a trifluoromethyl substituent
of enolethers or acetals to give, in one-step and good yields,
4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones
which proved to be useful building blocks for the regiospecific syn-
thesis of numerous heterocyclic compounds.7
Aminosulfur trifluoride reagents are an important class of
fluorinating agents. Commercially available diethylaminosulfur tri-
fluoride (DAST)8 has been utilized more than the other aminosulfur
trifluorides. DAST reacts with aldehydes and ketones under mild
conditions to give geminal difluorides,9 while organic acids react
with DAST to give acid fluorides.10 Reaction of mono alcohols with
DAST replaces the hydroxy group11 with fluorine while reaction
with diols allows isolation of difluorides, sulfite esters, or cyclic
ethers.12
In this study, a typical methodology for the fluorination of some
5-trifluoromethyl-1H-pyrazoles, derived from acyclic (1a–c) and
cyclic vinyl ketones (4, 5), was employed with the aim of evaluat-
ing the chemical behavior of these azoles in the presence of DAST,
under mild reaction conditions.
Thus, in an effort to synthesize new fluorinated compounds
with promising biological properties, in this paper we describe a
synthetic strategy for dehydration, intramolecular cyclization,
and fluorination of trifluoromethyl-1H-pyrazoles and 2-pyrazo-
lines, using a standard methodology.
represent interesting building blocks for the synthesis of trifluo-
romethyl-containing compounds, especially heterocyclic systems,
for example, pyrazoles, which often show high biological activi-
ties, such as anti-hyperglycemic, analgesic, anti-inflammatory,
anti-pyretic, anti-bacterial, hypoglycemic, and sedative-hypnotic
activities.1
Due to the importance of this class of compounds, since the
1980s we have been developing synthetic routes to obtain strate-
gically substituted pyrazoles that provide possibilities for chemical
derivatizations, leading to a substance, or its structural analogue,
with proven applications.2
Fluorine occupies a unique place among all elements of the
periodic classification due to its high electronegativity and its spe-
cific properties. Thus, organofluorine chemistry is of great impor-
tance, due to this singular nature of the fluorine atom, combined
with the unique physical and chemical properties that fluorine im-
parts to compounds that contain it. The strong electronic contribu-
tion and negligible steric demands of fluorine present interesting
and unusual properties. Indeed, the specific physicochemical prop-
erties of fluorinated organic compounds are of huge interest in a
wide range of applications.3,4 Consequently, organofluorine chem-
istry has been steadily growing and today possesses a distinctive
role in highly diverse technological developments (fluoropolymers,
pharmaceutical and agrochemical products, materials science,
etc.).5,6 Therefore the development of new methods to introduce
fluorine into molecules is of great interest to organic and medicinal
chemists.
While the fluorination reactions using DAST are well known,
few examples of the application of DAST as a dehydration reagent
are found in the literature. Whitehead et al.13 carried out extensive
investigations into the application of aminosulfur trifluorides as re-
agents for the fluorodeoxygenation of organic substrates and de-
scribed reactions with substrates possessing several unprotected
hydroxy groups. However, this reaction needed special conditions,
such as an inert atmosphere, and led to a mixture of dehydrated
and fluorinated products.
One of the better methods to introduce a trifluoromethyl group
into heterocycles is based on the trifluoromethylated building
block approach. This approach relies on the trifluoroacetylation
In an attempt to evaluate the behavior of 4,5-dihydro-1H-pyr-
azoles (2a–c) in the presence of DAST, we carried out reactions
* Corresponding author. Tel.: +55 55 3220 8867; fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.052

3760
H. G. Bonacorso et al. / Tetrahedron Letters 51 (2010) 3759–3761
R2
R2
O
OMe
HO
N
N
i
ii
F3C
N
N
F3C
R2
75-97%
65-75 %
F3C
R1
R1
1a-c
3a-c
2a-c
1-3
a
b
c
R1
R2
2-Furanoyl
C6F5
CH3
C6F5
C6H5
CH2CH(OMe)2
Scheme 1. Reagents and conditions: (i) NH2NHR1, EtOH, reflux, 20 h; (ii) DAST, CH2Cl2, 0–25 °C, 24 h.
HO
H
employing DAST in a 1:2 molar ratio, in dichloromethane as sol-
vent, for 24 h at room temperature. These reactions demonstrated
that only a dehydration reaction occurred (3a–c) and the pres-
ence of the monofluorinated compounds was not observed
(Scheme 1).14,15
2
2
HF2C
2
O
i
ii
N
N
N
F3C
F3C
63 %
71%
F3C
N
N
N
Thus, due to the relative difficulty of this type of dehydration,
the present methodology was simple, mild, and efficient for the
dehydration of these azoles, preventing the elimination of the
N-1 substituent [C(O)–N bond cleavage] as well as, undesirable
reactions on the acetal moiety of the 2-pyrazoline ring 2a, fur-
nishing compounds 3 in good yields (65–75%). Compounds 2a–c
were previously synthesized from the reaction of 4-methoxy-
1,1,1-trifluoroalk-3-en-2-ones (1) with the respective hydrazines
according to the procedure from the literature.9
Ph
11
Ph
14
Ph
15
Scheme 3. Reagents and conditions: (i) PCC, CH2Cl2, reflux, 3 h; (ii) DAST, CH2Cl2,
0–25 °C, 24 h.
only fluorinated products 12 and 13 were obtained (Scheme 2),
also in good yields.14,17 The difference between the electron-with-
drawing effects of phenylhydrazine and pentafluorophenylhydr-
azine allowed the isolation of 4,5-dihydropyrazoles 6, 7 which
reacted with DAST as alkanodiols, leading to the 5,5- and 5,6-gem-
inated heterocycles and not to fluorinated compounds. Previously,
compounds 6, 7, 10, and 11 were obtained from the reactions of
trifluoroacetylated pyran and furan with phenyl- and penta-
fluorophenylhydrazine according to the described procedure.1
Finally, due to the importance of the insertion of a CF2 group
into organic molecules, we carried out an alcohol oxidation reac-
tion of compound 11 using PCC in dichloromethane,18 which
allowed the isolation of aldehyde 14 in 63% yield.19,20 According
to our previous publication,9 after obtaining the carbonyl pyrazole
14, a difluorination step using DAST could be carried out.
Shellhamer et al.12 demonstrated that DAST reacts with dialco-
hols to give difluorides, sulfite esters, or cyclic ethers depending on
the number of carbons separating the alcohol functions, where
semiempirical calculations indicate a preference for cyclic interme-
diates when four or less carbons separate the two hydroxy groups.
Thus, we decided to perform reactions with previously described
4,5-dihydro-1H-pyrazoles (R = C6F5) (6,7) containing four and five
carbon atoms between the two hydroxy substituents, respectively,
being one primary and one tertiary alcohol (Scheme 2).
Surprisingly, when these reactions were carried out, also at a
molar ratio of 1:2 (DAST excess), using dichloromethane as solvent,
for 24 h, the new geminated oxacyclopyrazoles (8, 9) were isolated
in good yields.14,16 The products were isolated as solids by filtra-
tion and purified by a simple washing with cold ethanol.
However, when the dehydrated azoles 10 and 11 were submit-
ted to the same reaction condition as described above for 6 and 7,
Thus, 14 reacted with DAST also in dichloromethane for 24 h at
room temperature14 leading to the desired difluorinated com-
pound 15 in 71% yield (Scheme 3).21
HO
n
HO
i
ii
N
N
74-80 %
O
R = C6F5
60-72 %
O
N
F3C
N
F3C
CF3
C6F5
C6F5
6,7
8,9
+ NH2NHR
n
O
HO
F
n
n
4,5
i
ii
R = C6H5
89-93 %
70-75 %
n
1
2
Compound
4,6,8,10,12
5,7,9,11,13
N
N
F3C
F3C
N
N
C6H5
C6H5
10,11
12,13
Scheme 2. Reagents and conditions: (i) EtOH, reflux, 20 h; (ii) DAST, CH2Cl2, 0–25 °C, 24 h.

H. G. Bonacorso et al. / Tetrahedron Letters 51 (2010) 3759–3761
3761
13. Whitehead, R. C.; Begum, L.; Drew, M. G. B.; Humphreys, J. L.; Lowes, D. J.;
Russi, P. R.; Whitby, H. L. Tetrahedron Lett. 2004, 45, 6249.
In conclusion, this work demonstrated that the employment of
DAST in CH2Cl2 at 0–25 °C for 24 h is a general, mild, and efficient
procedure which can promote dehydration, intramolecular cycliza-
tion, or mono- and difluorination reactions, depending on whether
a hydroxy-alkyl side chain is attached to the C4 of the trifluorom-
ethylated 5-hydroxy-2-pyrazolines and 1H-pyrazoles.
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined on a Reichert
Thermovar apparatus. 1H and 13C NMR spectra were acquired on
a Bruker DPX 200 spectrometer (1H at 200.13 MHz and 13C at
50.32 MHz), 5 mm sample tubes, 298 K, digital resolution
0.01 ppm, in DMSO-d6 for 2a and 2c, and CDCl3 for others, using
TMS as internal reference. The CHN elemental analyses were per-
formed on a Perkin Elmer 2400 CHN elemental analyzer (São Paulo
University—USP/Brazil). Mass spectra were registered in a HP 5973
MSD connected to a HP 6890 GC and interfaced by a Pentium PC.
The GC was equipped with a split–splitless injector, autosampler,
cross-linked HP-5 capillary column (30 m, 0.32 mm of internal
diameter), and He was used as the carrier gas.
14. Synthesis of 5-trifluoromethyl substituted pyrazoles (3a–c, 8, 9, 12, 13, 15).
General procedure: To a stirred solution of 2a–c, 6, 7, 10, 11, or 14 (1 mmol) in
dichloromethane (10 mL) was added dropwise DAST (2 mmol) in
dichloromethane (5 mL) at 0 °C. After addition, the reaction mixture was
stirred at 25 °C for 24 h, and then the reaction was quenched by the slow
addition of aqueous NaHCO3 solution until effervescence was completed. The
dichloromethane layer was separated, dried over anhydrous Na2CO3, and
filtered. The solvent was evaporated under reduced pressure, obtaining the
corresponding compounds 3a–c, 8, 9, 12, 13, or 15, which were purified
following the next procedures.
15. Compounds
3 were obtained as oils (3a–b) or solid (3c). The solid was
recrystallized from diethyl ether. Compounds 3a–b were characterized by 1H
and 13C NMR and GC–MS. Data of 3-(1,1-dimethoxyethyl)-5-trifluoromethyl-
1H-1-(furan-2-oyl) pyrazole (3a): Yield 71%, oil. 1H NMR (400 MHz, CDCl3): d
7.9 (d, 1H, J = 4.0, H-50), 7.7 (s, 1H, H-30), 6.8 (s, 1H, H-4), 6.60–6.68 (m, 1H, H-
40), 4.7 (t, 1H, J = 6.0, H-7), 3.4 (s, 6H, H-7a-b), 3.0 (d, 2H, J = 6.0, H-6). 13C NMR
(CDCl3):
d
153.7 (C@O), 151.3 (C-3), 148.5 (C-20), 144.4 (C-50), 135.2 (q,
2J = 41 Hz, C-5), 124.9 (C-30), 120.5 (q, CF3, J = 269 Hz), 113.9 (C-40), 112.5 (C-4),
102.8 (C-7), 53.4 (C-7a-b), 32.1 (C-6). GC–MS (EI, 70 eV): m/z (%) 287 (20), 149
(12), 95 (93), 75 (100). Anal. Calcd: C, 49.06; H, 4.12; N, 8.80. Found: C, 48.91;
H, 4.22; N, 9.19. Melting points and yields of new compounds 3: Compd. [Mp
(°C), Yield (%)]: 3b [oil, 75]; 3c [76–77, 65].
16. Compounds
8 and 9 were obtained as solids, and after the solvent was
evaporated, the solids were washed with cold ethanol and dried under
vacuum. Compounds 8 and 9 were characterized by 1H and 13C NMR and GC–
MS. Data of 1-(pentafluorophenyl)-6a-(trifluoromethyl)-3a,4,5,6a-tetrahydro-
1H-furo[2,3-c]pyrazole (8): Yield 80%, mp 80–81 °C. 1H NMR (400 MHz, CDCl3):
d 6.8 (s, 1H, H-3), 4.2–4.3 (m, 1H, H-4, J = 8), 3.9–4.1 (m, 2H, H-7), 2.3–2.4 (m,
2H, H-6). 13C NMR (100 MHz, CDCl3): d 148.8, 144.0, 140.0, 134.9 (C6F5), 143.2
(C-3), 125.0 (q, CF3, J = 281), 100.7 (q, 2J = 32, C-5), 70.7 (C-7), 56.0 (C-6), 29.7
(C-4). GC–MS (EI, 70 eV): m/z (%) 346 (M+, 95), 277 (19), 181 (100), 167 (20).
Anal. Calcd: C, 41.63; H, 1.75; N, 8.09. Found: C, 41.61; H, 1.72; N, 8.01. Compd.
9: Yield 74%, mp 75–77 °C.
Acknowledgments
The authors thank the financial support from Conselho Nacional
de Desenvolvimento Científico e Tecnológico–CNPq (Proc. nr.
303.296/2008-9). Fellowships from CAPES and CNPq are also
acknowledged.
17. Compound 12 was obtained as oil and was characterized by 1H and 13C NMR
and GC–MS. Data of 4-(2-fluoroethyl)-5-trifluoromethyl-1H-1-phenylpyrazole
(12): Yield 70%, oil. 1H NMR (400 MHz, CDCl3): d 7.6 (s, 1H, H-3), 7.4 (s, 5H, Ph),
4.6 (td, 2H, H-7, JHF = 47, JHH = 6), 2.9–3.1 (m, 2H, H-6). 13C NMR (100 MHz,
CDCl3): d 147.7 (C-3), 139.4, 129.2, 125.8 (Ph), 127.0 (q, 2J = 38, C-5), 121.0 (q,
CF3, J = 269), 119.5 (C-4), 82.0 (d, C-7, CF, J = 165), 25.0 (d, C-6, J = 19). GC–MS
(EI, 70 eV): m/z (%) 258 (M+, 52), 225 (100), 178 (5), 77 (23). Anal. Calcd: C,
55.82; H, 3.90; N, 10.85. Found: C, 55.64; H, 4.19; N, 10.83. Compd. 13: Yield
75%, oil.
References and notes
1. Zhu, S.; Chu, Q.; Song, L. J. Fluorine Chem. 2001, 107, 107.
2. (a) Milano, J.; Marchesan, S.; Rossato, M. F.; Sauzem, P. D.; Machado, P.; Beck,
P.; Zanatta, N.; Martins, M. A. P.; Mello, C.; Rubin, M. A.; Ferreira, J.; Bonacorso,
H. G. Eur. J. Pharmacol. 2008, 581, 86; (b) Zanatta, N.; Alves, S.; Coelho, H.;
Borchhardt, D. M.; Machado, P.; Flores, K. M.; Silva, F. M.; Spader, T. B.; Santurio,
J. M.; Bonacorso, H. G.; Martins, M. A. P. Bioorg. Med. Chem. 2007, 15, 1947; (c)
Cunico, W.; Cechinel, C. A.; Bonacorso, H. G.; Martins, M. A. P.; Zanatta, N.;
Souza, M.; Freitas, I.; Soares, R.; Kretlli, A. Bioorg. Med. Chem. Lett. 2006, 16, 649;
(d) Obregon, A.; Schetinger, M. R.; Correa, M.; Morsch, V.; Silva, J.; Martins, M.
A. P.; Zanatta, N.; Bonacorso, H. G. Neurochem. Res. 2005, 30, 379.
3. (a) Gro, U.; Rüdiger, S. In Organo-Fluorine Compounds; Baasner, B., Hagemann,
H., Tatlow, J. C., Eds.; Thieme: Stuttgart, 1999; Vol. E10a, Houben- Weyl:
Methods of Organic Chemistry; pp 18–26.; (b) Smart, B. E. J. Fluorine Chem.
2001, 109, 3; (c) Dunitz, J. D. ChemBioChem 2004, 5, 614; (d) Biffinger, J. C.; Kim,
H. W.; DiMagno, S. G. ChemBioChem 2004, 5, 622.
4. (a) Filler, R.; Kobayashi, Y.; Yagulpolskii, L. M. Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications; Elsevier: Amsterdam, 1993;
(b) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles and
Commercial Applications; Plenum Press: New York, 1994; (c) Hiyama, T.
Organofluorine Compounds: Chemistry and Properties; Springer: Berlin, 2000.
Chapter 5, pp 137–182; (d) Becker, A. In Ventory of Industrial Fluoro-
Biochemicals; Eyrolles: Paris, 1996.
5. Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126, 157.
6. Schofield, H. J. Fluorine Chem. 1999, 100, 7.
7. Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753.
8. Hudlicky, M. Org. React. 1987, 35, 513.
9. Bonacorso, H. G.; Porte, L. M. F.; Cechinel, C. A.; Paim, G. R.; Deon, E. D.; Zanatta,
N.; Martins, M. A. P. Tetrahedron Lett. 2009, 50, 1392.
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11. Kermarrec, C.; Madiot, V.; Grée, D.; Meyer, A.; Grée, R. Tetrahedron Lett. 1996,
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12. Shellhamer, D. F.; Anstine, D. T.; Gallego, K. M.; Ganesh, B. R. J. Chem. Soc., Perkin
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Praktikum; Thieme: Stuttgart, 1981.
19. Synthesis of 4-(formylethyl)-5-trifluoromethyl-1H-1-phenylpyrazole (14). General
procedure: To
a solution of 4-(3-hydroxypropyl)-5-trifluoromethyl-1H-1-
phenylpyrazole (11) (2 mmol) in dichloromethane (10 mL) was added PCC
(3.5 mmol) at room temperature. The reaction mixture was stirred at reflux for
3 h, and then the solvent was evaporated. Then, an aqueous NaOH solution
(15 mL) was added and the mixture was extracted with diethyl ether
(2 ꢀ 15 mL). The organic layer was separated, dried over anhydrous Na2CO3,
and filtered. The solvent was evaporated, and compound 14 was obtained as an
oil.
20. Compound 14 was characterized by 1H and 13C NMR and GC–MS. Data of 4-
(formylethyl)-5-trifluoromethyl-1H-1-phenylpyrazole (14): Yield 63%, oil. 1H
NMR (400 MHz, CDCl3): d 9.8 (s, 1H, H-8), 7.5 (s, 1H, H-3), 7.4 (s, 5H, Ph), 3.0 (t,
2H, H-6, J = 7), 2.82 (t, 2H, H-7, J = 7). 13C NMR (100 MHz, CDCl3): d 200.3
(C@O), 140.3 (C-3), 139.4, 129.1, 128.8, 125.1 (Ph), 128.5 (q, 2J = 41, C5), 122.6
(C-4), 120.5 (q, CF3, J = 270), 44.2 (C-7), 16.3 (C-6). GC–MS (EI, 70 eV): m/z (%)
268 (M+, 70), 225 (50), 212 (100), 77 (48). Anal. Calcd: C, 58.21; H, 4.13; N,
10.44. Found: C, 58.47; H, 4.30; N, 10.44.
21. Compound 15 was obtained as oil and was characterized by 1H and 13C NMR
and GC–MS. Data of 4-(1,1-difluoro-3-propyl)-5-trifluoromethyl-1H-1-
phenylpyrazole (15): Yield 71%, oil. 1H NMR (400 MHz, CDCl3): d 7.5 (s, 1H,
H-3), 7.4 (s, 5H, Ph), 5.8 (tt, 1H, H-8, JHF = 56, JHH = 4), 2.84 (t, 2H, H-6, J = 7),
2.1–2.2 (m, 2H, H-7). 13C NMR (100 MHz, CDCl3): d 140.1 (C-3), 139.0, 129.2,
128.1 (Ph), 122.0 (C-4), 127.0 (q, 2J = 39, C-5), 122.0 (q, CF3, J = 270), 116.0 (t,
CF2, C-8, J = 240), 35.0 (t, C-7, J = 20), 16.6 (C-6). GC–MS (EI, 70 eV): m/z (%) 290
(M+, 48), 225 (100), 128 (9), 77 (20). Anal. Calcd: C, 53.80; H, 3.82; N, 9.65.
Found: C, 53.67; H, 3.71; N, 9.58.