Pyrazoles, 1-substituted, lithiation

Synthesis of 3(5)-Substituted Pyrazoles via oi-Lithiation of N-Protected Derivatives... 

In a manner analogous to that seen with N-substituted pyrazoles (Section II,D), isothiazole undergoes lithiation at the 5-position, adjacent to the 5p -heteroatom, and reaction with electrophiles then leads to a variety of 5-substituted derivatives (Scheme 74) [64JCS446 72AHC(14)1 84JMC1245]. 

The lithiated and magnesiated 2-substituted pyrazole 1-oxides undergo metal-metal exchange by treatment with zinc chloride (2001JOC8654, 2002JOC3904) (see Scheme 43,49 and 50). 

N-Unsubstituted pyrazole is readily converted into 3(5)-substituted derivatives in a one-pot sequence, using formaldehyde both for N-protection and to mediate the lithiation at the 5-position the transient N-(hy droxymethy 1) unit is readily removed during work-up. Direct lithiation of 1-substituted pyrazoles provides an efficient entry to 1,5-disubstituted pyrazoles. 

The C-5-lithiation of pyrazoles requires the absence of the A-hydrogen removable iV-protecting groups that have been used include phenylsulfonyl," trimethylsilylethoxymethyl, hydroxymethyl," methylsulfo-nyl," dimethylaminosulfonyl," tetrahydropyran-2-yl, and pyrrolidin-l-ylmethyl. Lithiation of 1-benzyloxypyrazole" or 3-benzyloxyisothiazole" takes place at C-5 and of 1-substituted pyrazole IV-oxides at C-3. °... 

The reactions of 5-lithiated isothiazoles and of 5-lithiated-l-substituted pyrazoles allow the introduction of substituents at that position by reaction with a range of electrophiles three examples are shown... 

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