Aldehydes ortholithiation

The ortholithiated products 19 and 22 will then react with a wide range of electrophiles the only reported important exceptions are enolisable aldehydes and allylic halides. Products requiring these electrophiles are best made by first transmetallating the organolithium to a Grignard reagent with MgCl2 or copper salts . 

Attachment to a solid support via a secondary amide linkage allows ortholithiations to be carried out in the sohd phase. After a reaction with an aldehyde or ketone, refluxing in toluene returns the amino-substituted polymer 41 (Scheme 21). ... 

To summarize the amides are most suitable for the formation, by ortholithiation, of condensed heterocycles and polycyclic aromatics (in which subsequent rings are formed by intramolecular attack on the amide group). In other cases the removal of the amide group may be problematic, though if carboxylic acids, aldehydes or hydroxymethyl-substituted compounds are required, alternative amide substituents may be used. 

Addition of a lithiated secondary amine to an aldehyde both protects the aldehyde from attack by RLi and turns it into an ortholithiation directing group. The best lithioamines for this purpose are A-lithio-A-methylpiperazine 53, iV-lithio-iV,iV,iV -trimethylethylene-diamine 56 and Al-lithio-Al,0-dimethylhydroxylamine 58 , which optimize the opportunity for coordination of BuLi to the intermediate alkoxide (54) (Scheme 27) . ... 

Ortholithiated oxazoline 62 is best transmetallated to its magnesium analogue before reaction with aldehydes. As with the equivalent amide reaction, treatment with 4.5 M HCl then cyclizes the products to lactones (Scheme 31) °. ... 

Lithium amides (LiTMP) can give good yields of products resulting from ortholithiation of both ketones and lithium carboxylates. Benzophenone 288, for example, with LiTMP gives a good yield of the ortholithiation-dimerisation product 289.103 In general, however, ketones and aldehydes are best lithiated by the method developed by Comins described in section 2.3.2.1.2. 

The total synthesis of veiutamine [53], which has a carbon side chain and a structure similar to makaluvamine D, has also been achieved via route a (Scheme 6). The 6-methoxyindole derivative 9 was converted to the Boc compound 11. Regio-selective ortholithiation at 6-position using the Boc group as a directing group and coupling with an aldehyde followed by intramolecular cyclization afforded the tetracyclic compound 12, which was converted to veiutamine [54]. 

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