Pyridine—continued nucleophilic substitution

The analgesic Flupirtine 23 is a simple pyridine with three substituents at the 2, 3, and 6 positions. Removal of the amide shows the core 24. The 4-fluorobenzylamine 25 could be added by nucleophilic substitution (easier in pyridines than in benzenes) and we shall delay the choice of the leaving group (X in 26) for the moment. The only amino group we could conceivably add by nitration is the one in the 3-position so we might continue by FGI (reduction) and C—N disconnection 27. 

The supported aqueous phase methodology was applied to the system Pd(OAc)2/5 TPPTS, a catalytic precursor for the Trost-Tsuji reaction. The characterization of the solid by 31P MAS NMR confirms the presence of Pd°(TPPTS)3 as the main surface species. The catalytic properties of the solid were tested for the allylic substitution of E-cinnamylethylcarbonate by different nucleophiles such as ethyl acetoacetate, dimethyl malonate, morpholine, phenol, and 2-mercapto-pyridine. The absence of palladium leaching was demonstrated, and having solved the problem of water leaching from the solid to the organic phase, the SAP-Pd catalyst was successfully recycled several times without loss in its activity. It was used in a continuous flow experiment which... 

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