Target molecule aromatic

The Diels-Alder reaction with triple bond dienophiles gives access to cyclo-hexa-1,4-diene derivatives. Further reaction of a reactive intermediate thus produced or a subsequent oxidation step can then lead to a six-membered ring aromatic target molecule. 

This reaction scheme involves two substitutions of fluorine moieties at the aromatic ring by amines, yielding the final product for pharmaceutical applications [83, 118]. In total, five synthesis steps are actually required to obtain the target molecule. 

To achieve excellent thermal control, to use short residence times and to have no back-mixing were the main drivers for an industrial investigation of the methylation of an aromatic. The target molecule yielded thereby, a precursor for a crop-protection product, is temperature sensitive [127]. Accordingly, cryo-processing has to be applied to avoid decomposition when the reaction is conventionally performed. A driver for micro reactor processing would be to enable room-temperature processing or, at least, to increase the reaction temperature closer to ambient... 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

Nucleophilic substitutions with [ F]fluoride have been largely developed both in aromatic (SNAr) and aliphatic (generally SN2) series. Nucleophilic additions remain rare. F-Nucleophilic radiofluorinations usually do not require any carrier and thus enable the synthesis of products with high specific radioactivity. The SN can be performed either directly on a suitable and generally complex precursor of the target molecule or indirectly via a small labelled precursor. Both approaches present drawbacks the first one generally leads to poor yields and the second requires multistep synthesis and more sophisticated automation processes. 

---