LETTER
Synthesis of CF3-Pyrazoles
1405
NC
NC
NC
NC
NC
X
F
CN
CN
CN
9
HO
O
O
O
a
O
F
b
7
10
N
N
N
N
NH
N
8
F3C
F3C
N
N
F3C
N
N
F3C
F3C
OTBS
OH
OH
OH
15
16
17
Scheme 4 Reagents and conditions: a. TBSCl, TEA, DMF, r.t.
72%; b. 9, K2CO3, DMF, 90 °C, 85%.
Figure 1
We also wished to prepare the regioisomer of 10 in an
analogous manner (Scheme 5). However, when the hydra-
zone 11 was treated with the hydrated glyoxal 12,5 none
of the desired product was obtained.
References and Notes
HO OH
H
OH
N
(1) For example, see: (a) Dalinger, I. L.; Vatsadse, I. A.;
O
N
F3C
Shevelev, S. A.; Ivachtchenko, A. V. J. Comb. Chem. 2005,
7, 236. (b) Donohue, B. A.; Michelotti, E. L.; Reader, J. C.;
Reader, V.; Stirling, M.; Tice, C. M. J. Comb. Chem. 2002,
4, 23. (c) Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J.
M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.;
Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang,
L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.;
Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2001, 44, 566.
(2) (a) Iwata, S.; Namekata, J.; Tanaka, K.; Mitsuhashi, K. J.
Heterocycl. Chem. 1991, 28, 1971. (b) Tanaka, K.;
Mitsuhashi, K. Kenkyu Hokoku-Asahi Garasu Kogyo
Gijutsu 1987, 51, 130.
12
a
OH
complex
mixture
OH
11
b
Scheme 5 Reagents and conditions: a. hydroxyethyl hydrazine,
neat, reflux 50%; b. MgSO4, BuOAc, cat. AcOH, reflux.
A possible solution to this problem could be achieved if
the hydroxyethyl group at the 1-position of the pyrazole
10 could be removed, then realkylation and separation of
the regioisomers would provide the desired regioisomer.
A one-pot procedure to remove the hydroxyethyl substit-
uent using PBr3 proved unsuccessful, but a mild, two-
(3) Begtrup, M.; Nytoft, H. P. J. Chem. Soc., Perkin Trans. 1
1985, 81.
6
(4) Smith, L. I.; Rogier, E. R. J. Am. Chem. Soc. 1951, 73, 4047.
(5) Baldwin, J. J.; Hirschmann, R.; Lumma, P. K.; Lumma, W.
C.; Ponticello, G. S.; Sweet, C. S.; Scriabine, A. J. Med.
Chem. 1977, 20, 1024.
(6) Steinborn, D. J. Organomet. Chem. 1979, 182, 313.
(7) Preparation of 10.
step procedure, proceeding via the corresponding cyano-
ethyl derivative was developed (Scheme 6). Mesylation
of the primary alcohol 107 followed by treatment with
sodium cyanide at elevated temperatures resulted in the
formation of the dealkylated compound 13. Realkylation
using THP-protected bromoethanol, followed by separa-
tion of the regioisomers and deprotection furnished the
desired isomer 14 in adequate yield.
Hydroxy pyrazole 8 (0.3 mmol, 105 mg) was dissolved in
DMF (0.5 mL), K2CO3 (0.3 mmol, 42 mg) then aryl fluoride
9 (0.3 mmol, 44 mg) were added and the mixture was heated
to 90 °C for 5 h. The mixture was cooled to r.t., brine was
added, extracted with EtOAc, dried (MgSO4), filtered and
concentrated under reduced pressure. The colourless oil was
purified by FCC (silica gel, 5% MeOH–CH2Cl2) to provide
10 as a white foam (92 mg, 85% yield). 1H NMR (400 MHz,
CDCl3): d = 0.72–0.76 (2 H, m), 0.92–0.97 (2 H, m), 1.40–
1.90 (2 H, m), 4.18 (2 H, t), 4.40 (2 H, t), 7.38 (2 H, s), 7.63
(1 H, s). 19F NMR (376 MHz, CDCl3): d = –62.5 (s). IR
(solid): 3400, 1588, 1298 cm–1. LRMS (CI+): 363 [M + H].
LCMS (CI+): >95%(363)[M + H].
NC
NC
CN
CN
a
b
CF3
10
O
O
NH
N
N
N
F3C
OH
13
14
Preparation of 14.
Scheme 6 Reagents and conditions: a. i) MsCl, TEA, CH2Cl2 ii)
NaCN, DMF, 70 °C, 65%; b. i) NaH, bromoethanol–THP ether,
DMF, separate regioisomers; ii) cat. TsOH·H2O, MeOH, 38%.
Pyrazole 10 (0.64 mmol, 230 mg) was dissolved in CH2Cl2
(5 mL), methane sulfonyl chloride (0.7 mmol, 54 mL) then
Et3N (0.7 mmol, 98 mL) were added and the mixture stirred
at r.t. for 10 min. Then, H2O was added and the mixture was
extracted with CH2Cl2, dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was
dissolved in DMF (5 mL), NaCN (2.2 mmol, 110 mg) was
added and the mixture heated to 75 °C. After 3 h, H2O was
added and the mixture extracted with CH2Cl2, dried
(MgSO4), filtered and concentrated under reduced pressure.
The colourless oil was purified by FCC (silica gel, 4%
MeOH–CH2Cl2) to provide 13 as a white solid (132 mg, 65%
yield). Pyrazole 13 (0.21 mmol, 66 mg) was dissolved in
Similar chemistry was used to prepare the derivatives 15,
16 and 17 shown in Figure 1.
In conclusion, we have developed a concise and efficient
route to trifluoromethyl-substituted 4-aryloxy pyrazoles.
A novel procedure for the removal of an N-hydroxyethyl
group from pyrazoles was also developed.
Synlett 2006, No. 9, 1404–1406 © Thieme Stuttgart · New York