Regioselective Introduction of Electrophiles in the 4-Position of 1-Hydroxypyrazole via Bromine-Lithium Exchange.
Two protocols for introduction of electrophiles at the 4-position of 1-hydroxypyrazoles have been developed. The first is deprotonation of 4-bromo-1-[(tert-butyldiphenylsilyl)oxy]pyrazole (6) with LDA to produce the 5-lithio derivative in which the silyl group migrates spontaneously from oxygen to C-5 affording 4-bromo-5-(tert-butyldiphenylsilyl)-1-lithoxypyrazole (8). Subsequent treatment with t-BuLi causes bromine-lithium exchange to give 5-tert-butyldiphenylsilyl-4-lithio-1-lithoxypyrazole which is trapped with electrophiles affording 4-substituted 5-(tert-butyldiphenylsilyl)-1-hydroxypyrazoles 9a-e in a one-pot sequence. The second is treatment of 4-bromo-1-hydroxypyrazole (5) with excess LDA and trimethylsilyl chloride to produce 3,5-bis(trimethylsilyl)-4-bromo-1-hydroxypyrazole (12), which upon sequential metalation with n-BuLi and reaction with electrophiles affords 4-substituted 3,5-bis(trimethylsilyl)-1-hydroxypyrazoles 13a-e. The tert-butyldiphenylsilyl group of 9a and the trimethylsilyl groups of 12 can be removed selectively by treatment with tetrabutylammonium fluoride in THF in the presence of trifluoroacetic acid.
Balle
Thomas
T
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and Department of Organic Chemistry, Technical University of Denmark, DK-2800 Lyngby, Denmark.
Vedsø
Per
P
Begtrup
Mikael
M