Pyrazole direct lithiation

The ortfe-directed lithiation protocol allows selective functionalization of 3-arylsydnones in the aryl ring, the C4 position of the sydnone ring, or both simultaneously. The method allows access to fused ring structures (Sections 5.03.5.2.4 and 5.03.7.1.1). Reliable routes to otherwise unknown oxadiazolidines have been established (Section 5.03.9.4). Regiospecificity can now be achieved by judicious choice of substituents when propargylic esters react with sydnones to form pyrazoles (Section 5.03.5.2.6). 

No heterocycle containing a C=N bond is as powerful a director as the oxazolines or tetrazoles described above, but their imidazoline analogues 132 direct well if deprotonated to the amidine equivalent 133 of a secondary amide anion (Scheme 61). Pyrazoles 134 also direct lithiation, but need protecting with a bulky Af-substituent to prevent nucleophilic attack by the base (Scheme 62). ... 

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. 

SEM and -THP-protected pyrazole-5-boronates are easily prepared via direct lithiation and undergo cross couplings under standard conditions." Pyrazole-5/3-stannanes (with no M-protection) can be prepared by ring synthesis from alkynyl stannanes. The example shown below, bearing a 4-fluorine, requires iodo-arenes as substrates for cross coupling."" ... 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

It is a significant comment on the relative ease of a-lithiation in six- and five-membered systems that (iV-protected) pyrazoles lithiate at C-5, i.e. at the pyrrole-like a-position, though, again chelation assistance from the iV-protecting group also directs to C-5. ... 

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