Synthesis of 3‐Phenyl‐4‐piperidones from Acetophenone by Shapiro and Aza‐Michael Reactions and Their Further Derivatization

Abstract

The Shapiro reaction of acetophenone is the key in a convenient three‐step access to a divinyl ketone which is further transformed by double aza‐Michael reactions with primary amines into N‐substituted 3‐phenyl‐4‐piperidones. In the case of N‐benzyl and N‐allyl derivatives, the piperidine nitrogen atom can be deprotected and further functionalized, for example, by carboxamide, carbamate, or urea formation.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Synthesis of Triazolyl‐Substituted 3‐Aminopiperidines by Huisgen‐1,3‐Dipolar Cycloaddition – New Scaffolds for Combinatorial Chemistry

“…Ring-opening of racemic aziridine with NaN 3 was performed on a 30 g scale under protic conditions (NH 4 Cl, MeOH, H 2 O) and gave azidopiperidine 5 in 93 % yield (Scheme 2). With two carbamate-protective groups, broad signals were observed in NMR spectra at 23°C.…”

“…[2] Progress on the preparation of piperidine derivatives has continuously been reviewed. [3] In the course of our efforts on the preparation of new piperidine building blocks [4] we envisioned 4-triazolyl-substituted aminopiperidines 2 as topological and electronic mimics [5] of compounds 1 with an acylamino-function at the 4-position (Scheme 1). Compounds with scaffold 1 have proved to be inhibitors of factor Xa [6] and antagonists of CC chemokine receptor 2.…”

Development of κ Opioid Receptor Agonists by Focusing on Phenyl Substituents of 4-Dimethylamino-3-phenylpiperidine Derivatives: Structure–Activity Relationship Study of Matrine Type Alkaloids

“…Chemistry 1 H-(400 MHz) and 13 C-NMR (100 MHz) spectra were obtained on a Bruker AVIII-400 instrument, and chemical sifts are reported in ppm on the δ-scale from internal tetramethylsilane. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), septet (sept), multiplet (m) or broad (br), with coupling constants (J) in hertz (Hz).…”

“…Hydrazones 7a-e were prepared by condensation of commercially available 2,4,6-triisopropylbenzenesulfonyl hydrazide 5 and the respective acetophenones 6a-e. Allylic alcohols 8a-e were obtained through the Shapiro reaction with acrolein. 13) Oxidation of 8a-e with MnO 2 yielded the respective dienones, followed by cyclization via a double aza-Michael reaction with benzylamine using microwave irradiation to give piperidones 9a-e. 13) Piperidones 9a-e were converted to oximes 10a-e and subsequently reduced with metal sodium in EtOH to yield the separable diastereomers cis-and trans-11a-d, the 3,4-cis (matrine type) and 3,4-trans configuration compounds (allomatrine type). The relative configuration of these diastereomers were assigned by comparison to literature data and using the coupling constants from the 1 H-NMR spectra.…”

“…trans-1-N-Benzyl-4-N,N-dimethylamino-3-(3-methylphenyl) 26 (1H, m), 7.29-7.30 (4H, m). 13 C-NMR (CDCl 3 ) δ: 21.5, 22.8, 40.4, 46.6, 53.3, 62.1, 62.9, 64.9, 124.9, 127.0, 127.3, 128.2, 128.2, 128.6, 129.1, 137.7, 138.2 Benzyl-4-N,N-dimethylamino-3-(4-fluorophenyl) piperidine (trans-17d) Prepared According to Procedure for the Preparation of cis-17a…”