AUWERS Flavone synthesis

The Auwers flavone synthesis consists of treatment of dibromo-coumarones 1 with alcoholic alkali to give the flavonols 2. It can also be described as the three-step sequence of 3 — 6. 

In 1908, while working at University of Heidelberg, Auwers and Muller described the transformation of 4-methyl-2-cumaranone (3) to flavanol 6. Thus aldol condensation of 3 with benzaldehyde gave benzylidene derivative 4, which was brominated to give dibromide 5. Subsequent treatment of 5 with alcoholic KOH then furnished 2-methylflavonol 6. In the following years, Auwers published more extensively on the scope and limitations of this reaction.  

There is no published mechanistic study on the Auwers flavone synthesis. The mechanism may involve the nucleophilic addition of oxonium 7, derived from 1, with hydroxide to give 8. Base-promoted ring opening of 8 could provide the putative intermediate 9, which then could undergo an intramolecular Michael addition to form 10. Expulsion of bromide ion from 10 would then give flavonol 2. 

Auwers and others soon discovered that the transformation 3 — 6 did not consistently give flavonols such as 2. For example, alcoholic alkali treatment of dibromide 11 produced 2-benzoyl-benzofuran-3-one 12 instead of the corresponding flavonol. The same observation was made by Robert Robinson in a failed attempt to make datiscetin in 19257 It has reported that when there is a meta (to the coumarone ring oxygen) substituent such as methyl or methoxy, flavonol formation is hindered, whereas methyl, methoxy, and chlorine substituents at the ortho and para positions are conducive to flavonol formation.  

Adopting Auwers original method, Milton and Stephen prepared 2-chloroflavonol 16 from 4-chlorocoumaran-2-one 13 in 3 steps in 70% overall yield. 4-Chloroflavonol was synthesized via the same sequence. The same group also carried out the bromination of 2-benzylidenedihydro-b-naphthafurano-l-one (17) and subsequently treated the dibromide with aqueous potassium hydroxide to give 5,6-benzflavonol 18. However, 

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In summary, the Auwers flavone synthesis has seen only very limited utility in organic synthesis. 

This reaction is closely related to the Baker-Venkataraman Rearrangement and Kostanecki-Robinson Reaction. Regarding the synthesis of flavone derivatives, the Allan-Robinson condensation is also related to the Algar-Flyn-Oyamada (AFO) Reaction and Auwers Synthesis. 

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