Aldehyde reaction with organometallics

When artemisinin 9a was treated with 2-lithiothiazole followed by in situ O-acetylation, the thiazole carbonyl adduct 161 was formed chemoselectively in good yield (Scheme 22) the same reaction with PhLi produced a mixture of uncharacterized products. When this acetyl adduct 161 was exposed to TMSOTf, the corresponding elimination product 162 was formed, which was converted in three steps without purification of intermediates into aldehyde 163. This was reacted with high chemoselectivity in reactions with organometallics ( -BuLi, PhMgBr) and with phosphonium ylides in a Wittig procedure <1999T3625>. 

The use of acyl chlorides in Friedel-Craft acylations of benzene rings, as well as their reactions with organometallics and reductions to aldehydes, has been discussed in Section 15.2. 

An extension of the Erlenmeyer synthesis is the condensation of acylamino acids with triethyl orthoformate which leads to the ethoxymethylene derivatives (297). These can be hydrolyzed to the corresponding enols, which in turn can be converted into chloromethylene compounds, e.g. (298). The lability of the chlorine atom in this compound (see arrows) can be put to good account reaction with organometallic compounds or with benzene and its derivatives under Friedel-Crafts conditions yields unsaturated lactones (298 aryl or heteroaryl in place of Cl). The method is especially valuable in cases where the aldehyde is not readily available. 

Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, partial reduction to aldehydes, and reaction with organometallic reagents to yield ketones. 

Aldehyde 50 is an excellent chiral intermediate in reactions with organometallics. Addition at —78 °C of vinylmagnesium bromide to 50, that has been precomplexed with magnesium bromide etherate, affords the chelation-controlled product 51 with remarkably high diaster-eofacial selectivity (155 1). It is imperative that methylene chloride be used as the solvent in order to achieve this level of selectivity. In fact, if commercial vinylmagnesium bromide in THF is to be employed, the THF must be removed and replaced with methylene chloride [13] or else selectivity drops to 40 1. An analogous reaction of 50 with allyl tri- -butylstannane at — 23 °C furnishes chelation-controlled product 52 with 49 1 stereoselectivity. 

The oxidation of alcohols to aldehydes and ketones by chromium(VI) reagents opens up important synthetic possibilities based on further reactions with organometallic reagents. 

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