Sequential functionalization of pyrazole 1-oxides via regioselective metalation: synthesis of 3,4,5-trisubstituted 1-hydroxypyrazoles.
A range of 3,5-diarylated and 3,4,5-triarylated 2-(4-methoxybenzyl)pyrazole 1-oxides have been prepared by regioselective deprotonation at C-5 or bromine-magnesium exchange at C-3 or C-4 followed by transmetalation with ZnCl(2) and palladium(0)-catalyzed cross-coupling. Furthermore, the metalated pyrazole 1-oxides could be trapped with electrophiles. The sequential metalation/functionalization of the pyrazole 1-oxides may follow the order C-5, C-3, C-4, or alternatively the order C-3, C-5, C-4. The 4-methoxybenzyl group of the functionalized 2-(4-methoxybenzyl)pyrazole 1-oxides could be removed by treatment with TFA and i-Pr(3)SiH in CH(2)Cl(2), providing the corresponding functionalized 1-hydroxypyrazoles.
Paulson
Anna Sif
AS
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Eskildsen
Jørgen
J
Vedsø
Per
P
Begtrup
Mikael
M
D008274:Magnesium / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D010087:Oxides / Q000138:chemical synthesis*; D010165:Palladium / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis*; D013379:Substrate Specificity; D015032:Zinc / Q000737:chemistry
D008670:Metals; D010087:Oxides; D011720:Pyrazoles; D010165:Palladium; D008274:Magnesium; D015032:Zinc