M.S. Ermolenko et al. / Tetrahedron 69 (2013) 257e263
263
4.6. Preparation of 17 and 18
(br). HRMS: calcd for
261.0393.
C
11H8ClF3N2þH: 261.0406; found:
In a 60 mL round-bottomed thick glass tube fitted with
a
PTFE-faced screw cap, the corresponding iodopyrazole
(0.65 mmol) was degassed with a slow stream of argon for
10 min. 0.5 solution of benzylzinc bromide in THF
Acknowledgements
A
M
This work was supported by the Medicen initiative (Chemical
Library Project; grants of the Region Ile de France n I 06-222/R and
I 09-1739/R, which included a fellowship for S.G.). Dr. Daniel Larzul,
Institut Pasteur is acknowledged for his unfailing support as well as
Dr. Emile Bisagni for his interest.
ꢀ
(1.96 mmol) was added, followed by a pre-milled 1:2 mixture
palladium(II) acetate/XPhos (0.032 mmol). The tube was sealed
and heated at 85 ꢀC for 5 h using an oil bath. After cooling to
room temperature, the reaction mixture was diluted in ethyl
acetate, washed with a 0.25 M solution of potassium-sodium
tartrate twice. The organic phase was dried over sodium sulfate
and concentrated to dryness. The resulting residue was further
purified as described below.
ꢀ
References and notes
1. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Pyrazoles as Drugs: Facts and
Fantasies InAttanasi, O. A., Spinelli, D., Eds.; Targets in Heterocyclic Systems; Italian
Society of Chemistry: Roma, 2002; Vol. 6, pp 52e98.
4.6.1. 3-Ethoxy-4-benzyl-5-(trifluoromethyl)-1H-pyrazole
(17). Obtained as a white powder in 51% yield after a chromatog-
raphy over neutral alumina (1.5% water; dichloromethane/ethanol
from 99:1 to 95:5) followed by a second chromatography over silica
gel (dichloromethane); mp 72 ꢀC. 1H NMR (CDCl3): 1.38 (t, 3H,
J¼7.0 Hz); 3.83 (s, 2H); 4.26 (q, 2H, J¼7 Hz); 7.25 (m, 5H). 13C NMR
(CDCl3): 14.7; 27.1; 65.3; 105.6; 120.2 (q, J¼269 Hz); 126.1; 128.3;
131.1 (q, J¼38 Hz); 139.5; 161.2. HRMS: calcd for C13H13F3N2OþH:
271.1058; found: 271.1002.
2. Lamberth, C. Heterocycles 2007, 71, 1467e1502.
3. Elguero, J. Pyrazoles In Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Shinkai, I., Eds.;
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and 817e932.
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4.6.2. 4-Benzyl-3-(trifluoromethyl)-1H-pyrazole (18). Obtained as
an oil in 64% yield after a chromatography over silica gel (cyclo-
hexane/dichloromethane from 1:1 to 0:1). 1H NMR (CDCl3): 4.04 (s,
2H); 7.30 (m, 3H); 7.39 (m, 2H); 7.43 (s, H), 13.77 (br s, 1H). 13C NMR
(CDCl3): 29.3; 119.5; 122.1 (q, J¼266 Hz); 126.5; 128.5; 128.6; 130.2;
139.5; 139.7 (q, J¼36 Hz). HRMS: calcd for C11H9F3N2þH: 227.0796;
found: 227.0750.
16. Harris, L. J.; Levett, P. C. Patent EP 1176142.
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carboxylate (21)
In a glass tube sealable with a Teflon-coated joint, compound
12 (0.6 g, 1.79 mmol) was degassed with a slow stream of argon for
10 min. A 0.5 M solution of benzylzinc bromide in THF (10.6 mL,
5.38 mmol) was added, followed by [1,10-bis(diphenylphosphino)
ferrocene] dichloropalladium complexed with dichloromethane
(0.072 g; 0.09 mmol). This mixture was sealed and heated at
120 ꢀC for 60 min in an oil bath. After cooling to room tempera-
ture, the reaction mixture was diluted in ethyl acetate, washed
with a 0.25 M solution of potassium-sodium tartrate twice. The
organic phase was dried over sodium sulfate and concentrated to
dryness and the residue was purified by a chromatography over
silica gel (dichloromethane) to yield compound 21 (0.32 g, 65%),
after drying this fraction under a high vacuum to remove some
benzyl alcohol, as an off-white powder; mp 104 ꢀC. 1H NMR
(CDCl3): 1.39 (t, 3H, J¼7.0 Hz); 4.37 (q, 2H, J¼7.0 Hz); 4.40 (s, 2H);
7.38 (m, 5H). 13C NMR (CDCl3): 13.9; 31.7; 60.9; 109.1; 120.5 (q,
J¼269 Hz); 127.4; 128.8; 129.0; 135.6; 142.7 (q, J¼37 Hz); 149.3;
161.8. HRMS: calcd for C14H16F3N2O2þH: 299.1007; found:
299.0996.
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4.8. 5-Benzyl-4-chloro-3-(trifluoromethyl)-1H-pyrazole (22)
By using the procedure described for the preparation of 21,
compound 22 was obtained in 69% yield as an off-white powder;
mp 107 ꢀC. 1H NMR (CDCl3): 4.05 (s, 2H); 7.23e7.38 (m, 5H);
9.99 (br s, 1H). 13C NMR (CDCl3): 30.0; 107.1; 120.5 (q,
J¼269 Hz); 127.5; 128.6; 129.1; 135.2; 139.2 (q, J¼37 Hz); 141.6
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