So you want to make polysubstituted furans: Enolates at Room Temp

As a continuation in theme perhaps made me think of additional reactions where an enolate is used in the formation of a useful or studied heterocycle. Although furans are not at the top of the list as medicinal chemistry frameworks (simply take a look at how CYP enzymes rid themselves of this backbone), they do represent an area of interest on the materials side of things. A recent publication from Mark York (TL 2011) shows an efficient modification of a low temperature batch enolate formation followed the addition of an alpha-bromoketone to form di-/tri-substituted as well as annulated furans in moderate to very good yield without the need for traditional cooling. So in this particular case, a simple solution of a ketone was mixed with LiHMDS at room temp (starting with a flow of 0.76 ml/min and the base at 1.54 ml/min) while flowing through a 10 ml loop…as the enolate is formed it is reacted with an alpha-bromoketone pumped in from a separate line — the mixture is allowed to flow through 2 10 ml loops and quenched at the end of the sequence — so based on the flow the total time for the reaction sequence is about 9 minutes. The scheme (shown: the appropriate substitution which postulated to form from an initial enolate, addition to the haloketone, elimination of LiBr with concurrent epoxide formation and internal attack with the elimination of water) and a section of the table is included to show some of the compounds made (yields were improved moving from low temp to room temperature — indicating that additional work would be of interest in evaluating reactions at higher temperatures than traditionally reported — with flow the kinetics may serve to eliminate a need to cool the reaction as we have done in the past. Happy Reading!

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