General Synthesis of Ketones from Carboxylic Esters and Carboxamides by Use of Mixed Organolithium‐Magnesium Reagents: Syntheses of Artemisia Ketone

Abstract

The novel reagents formed by combination of Crignard reagents (RMgX) with lithium diisopropylamide (LDA) convert non-enolizable or slowly enolizable carboxylic esters or carboxamides into ketones which are protected from further reaction by their in situ conversion into enolates. These enolates can be trapped with electrophiles such as Me3SiC1 and ally1 bromide. The scope of this Grignard mono-addition is illustrated by two direct syntheses of artemisia ketone (14).Recently, we published a procedure for converting non-enolizable or slowly enolizable carboxylic esters or amides into ketones, using [allyl-MgCI, LDA] as reagent (LDA = lithium diisopropylamide) [ 11. This transformation proceeds via rapid deprotonation of the initially formed ketones by their in situ conversion into enolates (Scheme 1) and was applied to efficient syntheses of a -damascone, B-damascone, and P-damascenone.The general preparative value of this transformation which is the synthetic equivalent of a Grignurd mono-addition [2] has prompted us to extend it to other allylic and non allylic Grignurd reagents (Table). [Methallyl-MgC1, LDA] exhibits a reactivity which is very similar to that of [allyl-MgC1, LDA]: thus, methyl a-cyclogeranate [3] (1; Entry I ) is converted into ketone 7 in excellent yield and high selectivity (ketone us. tertiary alcohol 98:2), whereas normal Grignard reaction in the absence of LDA mainly leads to the diallylic alcohol (selectivity ketone us. tertiary alcohol 21 :79). [Crotyl-MgC1, LDA] (Entry 2) undergoes reaction essentially (9: 1) with allylic transposition. Isomerization with AI,O, [4] affords a mixture of propenyl ketones 9 (57 %).The selectivity for ketone formation strongly depends on the ease of deprotonation of the intermediate ketones. Thus, IPhCH,MgCl, LDA] reacts with cyclohexenyl ester 2 [5] (Entry 3) to afford benzyl ketone 10 with high selectivity (97:3), whereas the reaction of ester 2 with [BuLi, LDA] (Entry 4 ) mainly leads to the tertiary alcohol 12. However,

Synthesis of (+)-Sulcatine G

“…We had thought to convert the ester of the tricycle 13 into the necessary α-hydroxy ketone by oxygenation of an enol ether of the corresponding methyl ketone. As the hindered carbonyl of the ester did not respond to the several modifications of the Tebbe reagent, we turned to the Fehr procedure …”