An efficient one-pot multi-component synthesis of highly functionalized piperidines

Introduction

Functionalized piperidines and their analogs are important heterocycles that are widely distributed in many naturally occurring alkaloids, biologically active synthetic molecules and organic fine chemicals (O’Hagan et al., 2000). In particular, compounds containing piperidine structural patterns show antibacterial, antihypertensive, antimalarial, and anti-inflammatory activities. Many synthetic approaches to such compounds have been developed including imino-Diels-Alder reactions (Takasu et al., 2006), aza-Prins-cyclizations (Murty et al., 2008), intramolecular Michael reactions (Fustero et al., 2007), and intramolecular Mannich reaction of iminium ions (Davis et al., 2001).

Nowadays, one-pot multi-component reactions (MCRs) have received special attention in organic synthesis (Fujioka et al., 2007). However, there are only few reports in the literature on the synthesis of highly functionalized piperidines via MCRs. These methods use catalysts, such as a combination of L-proline and trifluoroacetic acid (TFA) (Misra et al., 2009), ZrOCl₂‧8H₂O (Mishra et al., 2011), bromodimethylsulfonium bromide (BDMS) (Khan et al., 2008), tetrabutylammonium tribromide (TBATB) (Khan et al., 2010a), InCl₃ (Clarke et al., 2007), and iodine (Khan et al., 2010b). The use of expensive and excessive amounts of catalysts are the disadvantages of some of the methods mentioned above. Therefore, there is a need for the development of a facile and eco-friendly synthetic protocol to obtain functionalized piperidines.

Boronic acids are mild Lewis acids which are generally stable and easy to handle, making them important to organic synthesis. Recently, organo-boron compounds have been successfully used as Lewis acid catalysts in organic synthesis. The selected transformations include amidation of carboxylic acids, Diels-Alder cycloadditions and enantioselective allylation reaction (Ishara et al., 2005), synthesis of 3,4-dihydropyrimidinones (Debache et al., 2006), and synthesis of 1,4-dihydropyridines (Debache et al., 2008).

This report describes our further development of MCRs and the use of eco-friendly phenylboronic acid as catalyst (Adude et al., 2012). More specifically, a novel one-pot three-component synthesis of highly substituted piperidines starting from substituted aniline, 1,3-dicarbonyl compound and aromatic aldehyde in the presence of phenylboronic acid as a catalyst at ambient temperature conditions is described (Scheme 1).

Scheme 1

Reagents and conditions: (i) phenylboronic acid, acetonitrile, room temperature.

Results and discussion

The model reaction of 4-chlorobenzaldehyde, 4-chloroaniline, and ethyl acetoacetate was carried out in acetonitrile in the absence and presence of catalyst. The reaction was not completed in 24 h in the absence of phenylboronic acid and only traces of the desired product 4a were observed. The same reaction conducted using 5 mol% of phenylboronic acid as catalyst gave product 4a in 45% yield after 22 h. With a further increase in the amount of catalyst, the optimized conditions were achieved with 10 mol% of phenylboronic. Under the optimized conditions the reaction was completed after 14 h and the yield of 4a was 89%. Interestingly, a further increase in the catalyst concentration to 15 mol% and 20 mol% showed negative effects on the reaction time yield of the product. Using the optimized conditions the reaction was attempted in ethanol, methanol, and chloroform. However, all these solvents were inferior to acetonitrile. Further studies of this reaction were conducted in acetonitrile using other known catalysts including ZnCl₂, Sc(OTf)₃, L-proline and iodine. The use of catalysts ZnCl₂ and Sc(OTf)₃ showed similar results; the yields were 60% and 58%, respectively, after 20 h (Table 1, entries 1 and 2). The yields were lower in the presence of L-proline and iodine (Table 1, entries 3 and 4). As can be seen from entry 5, best results were observed using 10 mol% phenylboronic acid as catalyst.

The protocol was extended to the reactions of other aromatic aldehydes and anilines (Scheme 1). Products 4 were obtained in yields ranging from 78% to 90% regardless of the type of substituents.

Conclusions

The advantages of the present method include high yields of products, simple experimental procedure, and low toxicity of reagents. Both analytical and spectroscopic data of synthesized compounds are in full agreement with the proposed structures of the products.

Experimental

All solvents were used as commercial anhydrous grade without further purification. Merck aluminum sheets 20×20 cm coated with silica gel 60 F₂₅₄ were used for thin layer chromatography to monitor progress of reaction. Column chromatography was carried out with silica gel (80–120 mesh) as the adsorbent, eluting with petroleum ether/ethyl acetate (9:1). Melting points were determined in open capillary tube and are uncorrected. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded in CDCl₃ on a Bruker spectrometer. Mass spectra were taken on a Q-Star pulsar LC-MS instrument.

Supplementary Information

For detail information about analytical and spectral data please see the Supplementary Information available for this article.