Secondary amides directed lithiation

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

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). ... 

The usual directing groups such as secondary amides will also successfully direct lateral lithiation at the 2-methyl group of a pyrrole (Scheme 226/° . 

Secondary amides may direct ortho lithiation, but they must first be deprotonated. This makes them somewhat weaker ortho directors than tertiary amides, but they may still serve the purpose quite well. For example, the lithiation and addition of benzamide (12) to aldehyde (13) was us in a synthesis of 11-deoxycaiminomycinone (Scheme 8). More recently, it has been shown that the amide monoanion may be obtained by addition of a phenylsodium to an isocyanate. ... 

The co-operative effect of 1,3-interrelated directing groups is a powerful strategy in synthesis. This allows the otherwise difficult preparation of 1,2,3-trisubstituted aromatic compounds. Hence the lithiation of the aromatic compound 129 is directed by both the methoxy and secondary amide groups (1.118). Two equivalents of the... 

Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using Bu Li produces the vinyl-lithium species (355) which condenses with aliphatic aldehydes to give... 

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