Asymmetric Synthesis of (S)‐Mirtazapine: Unexpected Racemization through an Aromatic ipso‐Attack Mechanism
An asymmetric synthesis of (S)-mirtazapine has been achieved from the synthesis of the racemate by using (S)-1-methyl-3-phenylpiperazine as the starting material. Unfortunately, significant racemization was encountered in the final step, which involved an electrophilic aromatic ring closure of a alcohol by concentrated sulfuric acid. A significantly higher ee was observed when polyphosphoric acid (PPA) was used instead. A remarkable correlation between the amount of PPA used and the ee of the product was revealed, namely, an increase in the ee upon decreasing the amount of PPA. This trend was paralleled by the formation of an increasing amount of a side-product upon lowering the amount of PPA. The racemization and formation of a side-product can be explained by an ipso-attack mechanism during the electrophilic aromatic ring-closure reaction. This mechanism was supported by a mechanistic study using a deuterium-labeled substrate.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)