Synthesis of N -Substituted 4-Piperidones Clause Samples

Synthesis of N -Substituted 4-Piperidones. ‌ 1). As this dienone is unsubstituted and therefore sterically accessible towards nucleophilc attack, it was envisioned that it would be an ideal double ▇▇▇▇▇▇▇ acceptor for an aza-▇▇▇▇▇▇▇ addition/cyclisation reaction. Facile access to this reactive and unstable 145 ketone was believed possible via the oxidation of commercially available divinylcarbinol 186. [O] RNH2 Figure 2.1: Synthesis of N -substituted 4-piperidones 187 in two steps. Having achieved the preparation of ketone 178, the next step would be the investigation of a double aza-▇▇▇▇▇▇▇ addition involving various aromatic and aliphatic amines. Due to the unstable nature of divinyl ketone 178 it was necessary to achieve an efficient and particularly mild oxidation of divinyl alcohol 186 (Figure 2.2). For this purpose, 2-iodoxybenzoic acid (IBX) was the oxidant of initial choice, as it is known to smoothly and efficiently convert primary and secondary alcohols to the corresponding aldehyde or ketone. 146 OH O Figure 2.2: Oxidation of divinylcarbinol 186. IBX 189 was prepared from 2-iodobenzoic acid 188 following the procedure of Santagostino147 in a yield of 85% (Scheme 2.1). The advantage of this method over other reported preparations148 is the use of less toxic and environmentally benign reagents. HO O I CO2H i O 188 189 O Scheme 2.1: Reaction conditions: i) Oxone, H2O, 70◦C, 3 h. Initial attempts to oxidise divinylcarbinol 186 with IBX were carried out using the procedure of Rao149 (Scheme 2.2). This method involves the oxidation of alcohols at room temperature using IBX in a water/acetone mixture containing β-cyclodextrin as a supramolecular catalyst. OH O Scheme 2.2: Reaction conditions: i) IBX, β-cyclodextrin, H2O/acetone 7.5:1.0, rt, 48 h, 50◦C, 5 h; ii) IBX, DMSO, rt, 18 h. temperature. After heating to 50 ◦C for 5 hours, 1H-NMR analysis of the crude residue revealed that while no product was formed, considerable starting material remained, accompanied by side-products that could not be identified. When the oxidation with IBX was carried out under nitrogen using dimethyl sulfoxide (DMSO) as a solvent, no formation of ketone 178 was observed. Due to the lack of conversion of alcohol 186 to ketone 178 under the IBX-mediated conditions, another oxidant, MnO2, was investigated for this conversion. MnO2 is a mild and widely used oxidant especially for the selective transformation of benzylic and allylic alcohols to the corresponding ketone or aldehyde. 150–152 The oxidising power of MnO2 is ...
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