8654
J . Org. Chem. 2001, 66, 8654-8656
to 3-halogen-substituted pyrazoles exists due to prefer-
Con ver gen t Syn th esis of 3-Ar yla ted
1-Hyd r oxyp yr a zoles via 3-Meta la ted
P yr a zole-1-oxid es
ential electrophilic attack at C-4 of 1-substituted pyra-
zoles.7
We now wish to report a convergent preparation of
novel 3-arylated 1-hydroxypyrazoles (5a -g).8 The se-
quence is based on formation of the 2-(4-methoxybenzyl)-
pyrazole-1-oxide (2), which undergoes selective monobro-
mination at C-3 and subsequent bromine-magnesium
exchange, transmetalation with ZnCl2, Negishi-type cross-
coupling, and finally acid-induced deparamethoxybenzyl-
ation.
J ørgen Eskildsen, J esper Kristensen, Per Vedsø,* and
Mikael Begtrup
Department of Medicinal Chemistry, The Royal Danish
School of Pharmacy, Universitetsparken 2, DK-2100
Copenhagen, Denmark
pv@dfh.dk
Traditionally, 2-alkylpyrazole-1-oxides have been pre-
pared by tedious peracid oxidation of the corresponding
1-alkylpyrazoles.9,10 Recently, we described the synthesis
of 2-alkylpyrazole-1-oxides by heating 1 at 60-100 °C
with alkylbromides in CHCl3.11 The elevated tempera-
tures required indicated an SN1-type substitution reac-
tion mechanism. The deparamethoxybenzylation of the
2-PMB-pyrazole-1-oxides 4a -g also indicated a cationic
pathway (vide infra). On this basis, we decided to design
a new reaction for the selective N-alkylation of 1 based
on capture of benzylic cations generated from 4-meth-
oxybenzyl alcohol (PMB-OH) in an acidic environment,
thus avoiding the use of the carcinogenic12 and unstable13
PMB-Br.
Indeed, treatment of 1 and PMB-OH with TFA in
CHCl3 gave the desired 2-PMB-pyrazole-1-oxide in 94%
yield (Scheme 1).
In line with this result, benzhydrol, another carbinol
capable of giving relatively stabilized carbocations, gave
2-benzhydrylpyrazole-1-oxide in 96% yield when sub-
jected to the same conditions.
In contrast to 1-alkoxypyrazoles, 2-alkylpyrazole-1-
oxides are activated toward electrophilic attack at the
C-3 position.9,14 Thus, 2-benzylpyrazole-1-oxide was ex-
clusively brominated at the C-3 position.9 Similarly,
bromine was smoothly introduced at the C-3 position of
2 providing 3 in 94% yield (Scheme 1).
Bromine-magnesium exchange has previously been
shown to be an efficient way of generating aryl and
heteroarylmagnesium species.15 Gratifyingly, 3 was con-
verted to the corresponding magnesium species upon
treatment with isopropylmagnesium chloride (i-PrMgCl)
in THF at -78 °C for 15 min.16
Received J une 27, 2001
Pyrazoles possessing C-aryl substituents appear fre-
quently in molecules of pharmaceutical interest, and a
wide range of biological activities has been reported.1 We
have previously reported the preparation of 4-2 and
5-substituted3 1-benzyloxypyrazoles employing C-4- and
C-5-metalated intermediates generated from 1-benzyl-
oxypyrazole by C-4 iodination and subsequent iodine-
magnesium exchange or by direct C-5 lithiation. These
methods have been extended to the preparation of 4-2 and
5-arylated4 1-benzyloxypyrazoles via transmetalation
with ZnCl2 and Pd(0)-catalyzed cross-coupling. The sub-
stituted 1-benzyloxypyrazoles can be debenzylated by Pd/
C-catalyzed hydrogenolysis or by treatment with aqueous
acid furnishing 4- and 5-substituted 1-hydroxypyrazoles.
While these methodologies smoothly introduce substit-
uents in the 4- and 5-positions, they are incapable of
accessing the 3-position since metalation at the C-3
position of 1-substituted pyrazoles5 is hampered by the
adjacent lone pair effect.6 In addition, no direct approach
(1) (a) Hypocholesterolemic activity: Tanaka, A.; Teresawa, T.;
Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.;
Tanaka, H. J . Med. Chem. 1998, 41, 2390-2410. (b) Cyclooxygenase
2 (COX-2) inhibitors: Penning, T. D.; Talley, J . J .; Bertenshaw, S. R.;
Carter, J . S.; Collins, P. W.; Docter, S.; Graneto, M. J .; Lee, L. F.;
Malecha, J . W.; Miyashiro, J . M.; Rogers, R. S.; Rogier, D. J .; Yu, S.
S.; Anderson, G. D.; Burton, E. G.; Cogburn, J . N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang,
Y. Y.; Isakson, P. C. J . Med. Chem. 1997, 40, 1347-1365. Penning, T.
D.; Kramer, S. W.; Lee, L. F.; Collins, P. W.; Koboldt, C. M.; Seibert,
K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. Bioorg. Med. Chem.
Lett. 1997, 7, 2121-2124. (c) HIV-1 protease inhibitors: Han, Q.;
Chang, C.-H.; Li, R.; Ru, Y.; J adhav, P. K.; Lam, P. Y. S. J . Med. Chem.
1998, 41, 2019-2028. (d) Dopamine D4 receptor ligands: Moore, K.
W.; Bonner, K.; J ones, E. A.; Emms, F.; Leeson, P. D.; Marwood, R.;
Patel, S.; Patel, S.; Rowley, M.; Thomas, S.; Carling, R. W. Bioorg. Med.
Chem. Lett. 1999, 9, 1285-1290. Bourrain, S.; Collins, I.; Neduvelil,
J . G.; Rowley, M.; Leeson, P. D.; Patel, S.; Patel, S.; Emms, F.;
Marwood, R.; Chapman, K. L.; Fletcher, A. E.; Showell, G. A. Bioorg.
Med. Chem. 1998, 6, 1731-1743. (e) Anti-diabetic activity: Soliman,
R.; Faid-Allah, H. M.; El Sadany, S. K. J . Pharm. Sci. 1987, 76, 626-
632. (f) Selective estrogen receptor modifiers: Huang, Y. R.; Katzenel-
lenbogen, J . A. Org. Lett. 2000, 2, 2833-2836; Stauffer, S. R.; Coletta,
C. J .; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J .; Katzenellen-
bogen, B. S.; Katzenellenbogen, J . A. J . Med. Chem. 2000, 43, 4943-
4947. Stauffer, S. R.; Huang, Y.; Coletta, C. J .; Tedesco, R.; Katzenel-
lenbogen, J . A. Bioorg. Med. Chem. 2001, 9, 141-150.
(7) Rodr´ıguez-Franco, M. I.; Dorronsoro, I.; Herna´ndez-Higueras, A.
I.; Antequera, G. Tetrahedron Lett. 2001, 42, 863 and references
therein.
(8) Fitton and Patel have described the preparation of some 3-(2-
hydroxyphenyl)-1-hydroxypyrazoles in 4-30% yield in mixtures with
isoxazoles by refluxing appropriate 1-(2-hydroxyphenyl)-1,3-dioximes
in aqueous NaOH. The presence of the ortho hydroxyl group in the
aryl moiety was crucial for the formation of the 1-hydroxypyrazole.
See: Fitton, A. O.; Rajeshkumar, P. N.; Miller, R. W. J . Chem. Res.,
Miniprint 1986, 4, 1101.
(9) Begtrup, M.; Larsen, P.; Vedsø, P. Acta Chem. Scand. 1992, 46,
972.
(10) Parnell, E. W. Tetrahedron Lett. 1970, 3941.
(2) Felding, J .; Kristensen, J .; Bjerregaard, T.; Sander, L.; Vedsø,
P.; Begtrup, M. J . Org. Chem. 1999, 64, 4196.
(3) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.
(4) Kristensen, J .; Begtrup, M.; Vedsø, P. Synthesis 1998, 1604.
(5) To the best of our knowledge, there is only a single example of
a C-3-metalated pyrazole intermediate, generated by bromine-lithium
exchange of 3-bromo-1-methylpyrazole at -100 °C. See: Pavlik, J . W.;
Kurzweil, E. M. J . Heterocycl. Chem. 1992, 29, 1357.
(6) Takeuchi, Y.; Yeh, H. J . C.; Kirk, L.; Cohen, L. A. J . Org. Chem.
1978, 43, 3565.
(11) Eskildsen, J .; Vedsø, P.; Begtrup, M. Synthesis 2001, 1053.
(12) The very reactive PMB-Br is a carcinogenic alkylating agent
that will polymerize within a few days at room temperature: Ruder,
S. M.; Ronald, R. C. Tetrahedron Lett. 1987, 28, 135.
(13) Caution: We recently experienced a spontaneous and gaseous
HBr-evolving decomposition of PMB-Br stored in a refrigerator.
(14) (a) Ferguson, I. J .; Grimmet, M. R.; Schofield, K. Tetrahedron
Lett. 1972, 27, 2771. (b) Ferguson, I. J .; Schofield, K.; Barnett, J . W.;
Grimmet, M. R. J . Chem. Soc., Perkin Trans. 1 1977, 672.
10.1021/jo015874y CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/01/2001