Full Paper
Figure 4. Crystallographic structures of 4-NO2-NH-pyrazole·0.5H2O 20d (left)
and N-THP-4-NO2-pyrazole 22c (right). Ellipsoids set at 50% probability.[16]
Scheme 3. Dehydration/debenzylamination of pyrazolines 14, 15, and 17.
[a] 19F NMR yield with PhF as internal standard. [b] Yield of isolated product.
[c] N-H pyrazole 5a isolated instead of 15c.
use of fluorinated ketimines, activated FARs and hydrazines.
These pyrazoles are highly valuable building blocks for agro-
chemical ingredients showing a novel mode of action. A new
FAR has been employed to introduce a novel fluoroalkyl
moiety (CHFOCF3), prepared by hydroamination of trifluoro-
methyl trifluorovinyl ether and in situ activation. The opposite
reactivity of vinamidinium and vinamide species was found to
be of great value to tune the regioselectivity of hydrazine addi-
tion. We demonstrated the feasibility of further functionaliza-
tion of the 4-position of such building blocks to introduce vari-
ous functional groups for later coupling reactions. We expect
these studies to provide facile access to bis-fluorinated pyra-
zoles and to have a significant impact on agrochemistry, me-
dicinal chemistry and related fields.
Scheme 4. Introduction of various functional groups into the 4-position of
bis(CHF2) pyrazole 5a. i) aq. NaOCl, AcOH, RT, 18 h. 82%; ii) cat. Fe, Br2,
1008C, 1 h, 90%; iii) I2, CF3COOAg, CH2Cl2, À158C!RT, 4 h, 98%; iv) HNO3,
H2SO4, 1158C, 15 min, microwave, 99%; v) 20c, MeI, Et3N, CH2Cl2, RT, 52%;
vi) 20d, MeI, Et3N, CH2Cl2, RT, 18 h, 99%; vii) 21b, cat. Pd/C, H2, EtOH, RT, 1 h,
86%; viii) 20b, 3,4-dihydropyran (DHP), cat. TsOH, CH2Cl2, 508C, 18 h, 95%;
ix) 20c, DHP, cat. TsOH, CH2Cl2, RT, 18 h, 89%; x) 20d, DHP, cat. TsOH, CH2Cl2,
RT, 18 h, 45%; xi) 22c, cat. Pd/C, H2, EtOH, 508C, 18 h, 86%; xii) 1) 22b,
iPrMgCl·LiCl solution in THF, À308C, 1 h; 2) iPrOB(pin), À308C!RT, 1 h, 99%;
xiii) 1) 22b, iPrMgCl·LiCl solution in THF, À308C, 1 h; 2) DMF, À308C!RT,
1 h; 3) conc. HCl, EtOH, RT, 72 h, 54%; xiv) 1) 22b, iPrMgCl·LiCl solution in
THF, À308C, 1 h; 2) Dry CO2(s), À308C!RT, 1 h. 3) 1m HCl, 60%, then rapidly
3) cat. conc. HCl, MeOH, RT, 1 h, 39%; xv) 22d, 2m HCl in Et2O, RT, 30 min,
46%; xvi) 23a, aq. KHF2, MeOH, RT, 30 min, 99%.
Experimental Section
General procedure for the preparation of bis(fluoroalkyl)vin-
amides 3 and 4: A solution of fluorinated ketimine 2 (1 equiv,
1.64 mmol) in dry MeCN (2 mL) was added to a solution of activat-
ed FAR 1a–d (1.2 equiv, 1.95 mmol) in dry MeCN (2 mL). The mix-
ture was stirred at the given temperature (20–508C) for 15–60 min.
The mixture was diluted with CH2Cl2 (10 mL) and hydrolyzed with
1m HCl (10 mL) with vigorous stirring for 1 h. If the purity of the
crude product was not sufficient, flash chromatography or distilla-
tion under reduced pressure was performed.
General procedure for the preparation of bis(fluoroalkyl)pyra-
zoles 5–12: A solution of fluorinated ketimine 2 (1.64 mmol) in dry
MeCN (2 mL) was added to a solution of activated FAR 1a–d
(1.2 equiv, 1.95 mmol) in dry MeCN (2 mL). The mixture was stirred
at the given temperature (20–508C) for 15–60 min. Hydrazine hy-
drate (1.51 equiv, 123 mg, 0.12 mL, 2.47 mmol) or methylhydrazine
(1.51 equiv, 123 mg, 0.12 mL, 2.47 mmol) was added by syringe at
the given temperature (20–508C), rapidly followed by conc. H2SO4
(0.56 equiv, 0.05 mL, 0.91 mmol). The mixture was stirred at the
given temperature for 1–18 h.
a 2-tetrahydropyranyl (THP) group. Interestingly, 4-NO2-pyra-
zole 20d was crystalline as the hydrate, but amorphous after
chromatography, and N-THP-4-NO2-pyrazole 22c was also crys-
talline (Figure 4). N-Methyl pyrazoles 21a–c were accessed by
methylation reactions. The use of the turbo Grignard reagent
was found to be the most efficient route to compounds 23a–
d starting from THP-iodo-pyrazole 22b. The conversion of the
pinacol boronic ester 23a to the potassium trifluoroborate
23b was quantitatively achieved under the described condi-
tions.[15] Despite numerous efforts, it was not possible to intro-
duce fluorine in the 4-position between two fluoroalkyl groups
by using electrophilic fluorinating reagents such as Selectfluor,
N-fluorodibenzene sulfonimide and 1-fluoropyridinium triflate,
starting from THP-iodo-pyrazole 22b. Instead, fluorination of
the THP group was observed, mainly in the 6-position.
Preparation of N-alkyl/aryl 3,5-bis(fluoroalkyl) pyrazoles 13a–f:
Method A: Corresponding vinamidinium intermediates were treat-
ed with corresponding hydrazines, and cyclization/aromatization
was carried out under classical heating conditions (20–508C, 1–
18 h). Reaction mixtures were concentrated in vacuo and purified
by flash chromatography.
Method B: Vinamide 3a (500 mg, 1.91 mmol) was treated with the
corresponding hydrazine (1.5 equiv, 2.87 mmol) and conc. H2SO4
(2.1 equiv, 0.22 mL, 4.0 mmol) in toluene (8 mL). The mixture was
heated for 0.5–2 h at 120–1408C under microwave irradiation in
a sealed vial. Crude materials were purified by flash chromatogra-
phy.
Conclusion
We have developed an elegant method to access 3,5-bis(fluo-
roalkyl)pyrazoles with tuneable regioselectivity, based on the
Chem. Eur. J. 2016, 22, 11239 – 11244
11243
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim