Regioselective Introduction of Electrophiles in the 4-Position of 1-Hydroxypyrazole via Bromine−Lithium Exchange

Abstract

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.

Metalated Heterocycles and Their Applications in Synthetic Organic Chemistry

“…107b Moreover, different electrophiles have been introduced in the 4-position of N-substituted pyrazoles via bromine-lithium exchange. 108 The lithiation of isoxazoles 109 and isothiazoles 110a at C-3 by deprotonation leads to ring-opening reactions, direct lithiation to the next more acidic C-4position being possible if a substituent is already at C-3.…”

“…N -Substituted pyrazoles can be directly lithiated at C-3 using alkyllithiums,107a a recent example being the deprotonation of N -benzyloxypyrazole ( 54 ) and the further reaction of the lithiated intermediate 55 with diethyl N -Boc-iminomalonate (Boc = tert -butoxycarbonyl) as an electrophilic glycine equivalent for the subsequent synthesis of N -hydroxypyrazole glycine derivatives such as compound 56 (Scheme ) 107b. Moreover, different electrophiles have been introduced in the 4-position of N -substituted pyrazoles via bromine−lithium exchange 15 …”

“…An example of the former methodology is the synthesis of the 4-silylpyrazole 275 from bromopyrazole 274 , which can be used in ipso -substitution reactions using, for example, chlorosulfonyl isocyanate to give the cyanopyrazole 276 (Scheme ) . In addition, 1-hydroxypyrazoles have been silylated at C-5 via the usual lithiation−silylation sequence, thus allowing further metalation at C-4, whereas other silylpyrazoles have been recently obtained from silylated β-enaminones or from lithiated (trimethylsilyl)diazomethane . Moreover, 3,5-disubstituted isoxazoles and isothiazoles can be silylated at C-3 after lithiation with different alkyllithiums …”

Phthaloyl Dichloride–DMF Mediated Synthesis of Benzothiazole‐based 4‐Formylpyrazole Derivatives: Studies on Their Antimicrobial and Antioxidant Activities

“…Several methods have been reported for the synthesis of pyrazole‐4‐carbaldehydes. These includes, via Grignard intermediates , oxidation of the corresponding alcohols , bromine–lithium exchange or direct ortho‐lithiation followed by treatment with dimethylformamide (DMF) , treatment of hydrazones with cyanuric chloride/DMF , and with Vilsmeier–Haack (VH) reagent .…”

One‐Step Synthesis of Symmetrically Substituted 2,6‐Bis(pyrazol‐1‐yl)pyridine Systems

“…[42][43][44][45] Such reactions proceed with low selectivity, due to competing deprotonation at C-5 [42] or isomerization of the 4-lithiopyrazole to the corresponding 5-lithiopyrazole. [46] This problem can be circumvented through the introduction of a second protecting group at C-5, [47] but the overall multi-step synthesis makes such an option not very attractive, in our opinion. Here we describe a one-pot reaction that allows functionalization of the Pz 2 Py backbone in the 4-and 4Љ-positions by direct H(4)-pyrazole halogen (iodine or bromine) exchange.…”