Weinreb amides organolithium reagents

When Grignard reagents, organolithium compounds, or complex metal hydrides add to amides, the elimination step is slow at —78 °C, especially when the amine component is -N(Me)OMe (Weinreb amides). When the tetrahedral intermediate is sufficiently long lived, quenching of the reaction mixture with water at —78 °C gives the ketone or aldehyde rather than the alcohol. 

The most popular method these days for the acylation of Grignard or organolithium reagents is the Weinreb amide (also discussed in chapter 8). Acylation of vinyl Grignard with the complex intermediate 60 was part of a synthesis of ( )-fumagillolB 62. 

Formylation. This Weinreb amide is prepared from methyl formate and N,( -dimethylhydroxylamine in the presence of NaOMe. It reacts with Grignard reagents, organolithium compounds, and enolates to furnish aldehydes. 

If, instead, one intends to use the keto group immediately after its introduction, one would rely on a related nucleophilic carbonylation of epoxides [89, 90, 91, 92]. The example given in Scheme 2.51 shows how an initially formed acylmorpholide can be readily converted into a ketone. Acyl-morpholides behave like Weinreb amides in the presence of organolithium reagents, making ketones (in this case a P-hydroxy-ketone) available [93]. 

Polystyrene-bound Weinreb and related amides react with organolithium or Grignard reagents to yield ketones (Table 12.2). Amides have also been used for this purpose, without significant formation of tertiary alcohols. Aldehydes can be prepared on solid phase by reduction of A/,0-dialkylhydroxamates with LiAlH4 (Entry 1, Table... 

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