Synthesis of N-Benzyl 3,5-Disubstituted Piperidines via Double Michael Addition Strategy (2005)

Recently, Basavaiah and co-workers have reported the facile synthesis of functionalized 1,4-pentadienes from Baylis-Hillman type reaction from cinnamyl bromide derivatives (vide infra, Scheme 1). However, the usefulness of the 1,4-pentadienes has not been studied extensively. We thought that we could prepare 3,5disubstituted piperidine skeleton from these compounds via double Michael addition reaction strategy. 3,5-Disubstituted piperidines are important fundamental backbones for alkaloids, high affinity agonists of human GABA-A receptors, farnesyl-protein transferase inhibitors and continue to be basic moieties in pharmaceutical research. Due to their unique biological properties, the piperidines have been target molecules in organic synthesis. The starting materials 3a-e were synthesized according to the reported methods from the corresponding bromides or acetates 2a-c as shown in Scheme 1. With the 1,4-dienes in our hands, we first tried the reaction of 3a and benzylamine without solvent. As expected, 3,5-disubstituted piperidine 4a was obtained. As shown in Table 1 (entry 1), 4a-cis (28%) and 4a-trans (25%) were isolated. In the reaction, small amount of piperidone derivative 5a was also isolated (16%). The structures of piperidines 4a were easily assigned based on their H NMR spectra. As reported in a similar system, the benzylic protons appear as a singlet for 4a-cis whereas as a typical AB quartet for 4a-trans. However, long reaction time was required to complete the reaction at room temperature (5 days). When we elevated the temperature of the reaction mixture, somewhat complex mixtures were observed on TLC. Thus, we tried the same reaction in CH3CN at refluxing temperature. Long reaction time was required in this case also (entry 2, 60 h) to get similar yields of products. In order to reduce the reaction time we used LiClO4 (2 equiv) in refluxing CH3CN, and we obtained similar results (entry 3, 24 h) in relatively shorter reaction time. Similarly, the corresponding piperidines 4b-e were synthesized in moderate yields from 3b-e and the results are summarized in Table 1. The reaction mechanism for the formation of piperidine 4 and piperidone 5 is depicted in Scheme 2. Intermolecular Michael type addition of benzylamine to 1,4-pentadiene 3 gave the corresponding intermediate I. Intramolecular consecutive Michael type reaction (pathway a) gave the piperidine 4. Piperidone derivative 5 was formed by amide bond formation pathway (pathway b). As mentioned above, the benzylic protons of four cis-isomers (4a, 4c-e) appear as a singlet. The benzylic protons of all trans-isomers appear as AB quartets (∆δ/J = 2.4-5.3). Exceptionally, the benzylic protons of 4b-cis showed a typical AB quartet pattern with a relatively small ∆δ/J value (∆δ/J = 1.6). For the synthesis of 4c, the use of LiClO4 gave unsatisfactory results. Thus, in this case, we used the neat condition (entry 5). In summary, we disclosed the facile synthesis of 3,5disubstituted piperidines from the easily available 1,4pentadienes via double Michael addition reactions. Further studies on the selective formation of one-isomer and the chemical transformations of the synthesized piperidines are underway.