A concise synthesis of trifluoromethyl-substituted 4-aryloxy pyrazoles

Article abstract of DOI:10.1055/s-2006-939703

An efficient route to 4-aryloxy pyrazoles bearing a trifluoromethyl group has been developed. A facile removal of the N-hydroxyethyl group has also been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939703

1404
LETTER
A Concise Synthesis of Trifluoromethyl-Substituted 4-Aryloxy Pyrazoles
S
y-Pyrazoles n H. Jones,* Charles Mowbray
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Fax +44(1304)651821; E-mail: Lyn.Jones@pfizer.com
Received 6 February 2006
CN
Abstract: An efficient route to 4-aryloxy pyrazoles bearing a tri-
X
fluoromethyl group has been developed. A facile removal of the N-
CN
X
hydroxyethyl group has also been developed.
R
R
OH
O
Key words: pyrazoles, heterocycles, medicinal chemistry, hydra-
zones, dealkylation
F
2
N
R'
3
N
R'
F3C
N
F3C
N
Scheme 2
The introduction of a trifluoromethyl group into a bio-
logically active template can dramatically modify the po-
tency, physicochemical properties and metabolic profile
of the resulting compounds. As a result, there is consider-
able interest within the pharmaceutical industry to utilise
the properties of the trifluoromethyl group in target de-
sign. In particular, trifluoromethyl-substituted aromatic
and heteroaromatic compounds have recently received
significant attention.1 As part of our work in this area, we
desired a practical and concise route to trifluoromethyl-
containing 4-aryloxy pyrazoles, which would allow us to
prepare related derivatives in a facile manner, particularly
for the reason of generating structure–activity relation-
ships.
droxy pyrazole derivatives have been reported in the
literature previously by Tanaka and co-workers.2 The
method for their preparation utilises an earlier procedure
developed by Begtrup3 relying on the condensation of tri-
fluoroacetaldehyde hydrazones with glyoxals. Tanaka
was then able to convert the 4-hydroxyl group to various
alkyl ethers, esters and carbamates using standard electro-
philes.2a We believed that 4-hydroxy pyrazoles such as 3
would be sufficiently nucleophilic to react with cyano-
substituted aryl fluorides 2.
For our initial target in this series we desired a pyrazole
substituted in the 5-position with a cyclopropyl group
(R = cPr, Scheme 2). The synthesis started with the prep-
aration of the known hydrazone 52b from commercially
available hemiacetal 4 (Scheme 3). Pleasingly, cyclode-
hydration of 5 with known glyoxal 64 provided the desired
hydroxy pyrazole 7 as a single regioisomer, thus high-
lighting the usefulness of this rather underused technique
for the preparation of unsymmetrical pyrazoles.
Our previous attempts to synthesise trifluoromethyl-
substituted pyrazoles using standard chemistry from di-
ketones such as 1 proved unsuccessful (Scheme 1). Al-
though chlorination of trifluoromethyl diketones is well
precedented in the literature, subsequent displacement of
the chloride with phenols is unreported. Unfortunately,
we were never able to isolate the desired aryl ethers, this
two-step process providing only complex mixtures.
O
O
OH
NH
X
OH
X
6
N
a
7
N
b
F3C
OEt
F3C
OH
N
5
F3C
4
a
O
O
R
O
b
OH
R
O
O
R
O
F3C
Scheme 3 Reagents and conditions: a. hydroxyethyl hydrazine,
neat, reflux 66%; b. 6, MgSO4, BuOAc, cat. AcOH, reflux 66%.
1
N
R'
F3C
N
F3C
Scheme 1 Reagents and conditions: a. TMSCl, DMSO, Bu4NBr,
MeCN then ArOH, Cs2CO3; b. R¢NHNH2.
Surprisingly, attempted silylation of the primary alcohol 7
using imidazole as base failed to give the desired silyl
ether, but instead an unidentified adduct had formed with
the imidazole itself, as indicated in the 1H NMR and mass
spectrum. By simply replacing the imidazole with tri-
ethylamine, selective silyl protection proceeded smoothly
to provide 8 (Scheme 4). Arylation of the 4-hydroxy moi-
ety in 8 was effected by treatment with commercially
available aryl fluoride 9, using potassium carbonate as
base, in DMF. Concomitant deprotection of the silyl ether
in situ furnished the target compound 10 in good overall
yield and only four steps.
We supposed that a more successful approach to these
compounds would be to install the 4-aryloxy substituent
following construction of the pyrazole ring, specifically
via the reaction of 4-hydroxy pyrazoles 3 with aryl fluor-
ides 2 (Scheme 2). Moreover, 3-trifluoromethyl-4-hy-
SYNLETT 2006, No. 9, pp 1404–1406
0
1.
0
6.
2
0
0
6
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-939703; Art ID: D03506ST
© Georg Thieme Verlag Stuttgart · New York

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

1406
L. H. Jones, C. Mowbray
LETTER
DMF (4 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.21
mmol, 31 mL) then NaH (0.21 mmol, 8.4 mg of 60% in
mineral oil) were added and after 4 h brine was added,
extracted with EtOAc, dried (MgSO4), filtered, concentrated
under reduced pressure and purified by FCC (silica gel, 10%
EtOAc–toluene) to yield a more polar compound (22 mg)
and a less polar compound (36 mg). The less polar com-
pound was dissolved in MeOH (0.5 mL), TSA monohydrate
(0.008 mmol, 1.5 mg) was added and after 3 h the solvent
was removed under reduced pressure and the residue
purified by FCC (silica gel, 2% MeOH–CH2Cl2) to yield 14
as a colourless oil (29 mg, 38% yield over 2 steps). 1H NMR
(400 MHz, CD3OD): d = 0.78–0.95 (4 H, m), 1.55–1.65 (1
H, m), 3.92 (2 H, t), 4.25 (2 H, t), 7.73 (2 H, s), 7.90 (1 H, s).
19F NMR (376 MHz, CD3OD): d = –60.1 (s). LRMS: (CI+):
363 [M + H]. LCMS (CI+): >95%(363)[M + H].
Data for 15.
1H NMR (400 MHz, CDCl3): d = 2.19 (3 H, s), 2.45 (1 H, t),
4.10 (2 H, m), 4.20 (2 H, m), 6.87 (1 H, d), 6.96 (1 H, s), 7.05
(1 H, d). 19F NMR (376 MHz, CDCl3): d = –62.5 (s), –107.5
(s). LRMS (CI+): 330 [M + H]. LCMS (CI+): >95% (330)
[M + H].
Data for 16.
1H NMR (400 MHz, CDCl3): d = 2.20 (3 H, s), 2.35 (1 H, br
s), 4.13 (2 H, m), 4.25 (2 H, m), 7.40 (2 H, s), 7.62 (1 H, s).
19F NMR (376 MHz, CDCl3): d = –62.3 (s). LRMS (ES–):
335 [M – H]. LCMS (ES–): >95% (335) [M – H].
Data for 17.
1H NMR (400 MHz, CD3OD): d = 2.19 (3 H, s), 7.60 (2 H,
s), 7.87 (1 H, s). 19F NMR (376 MHz, CD3OD): –64.3 (s).
LRMS (ES–): 291 [M – H]. LCMS (ES–): >95% (291)
[M – H].
Synlett 2006, No. 9, 1404–1406 © Thieme Stuttgart · New York