Abstract
A simple, inexpensive and efficient one-pot synthesis of piperidine derivatives was achieved in excellent yield via the three-component reaction of substituted aniline, 1,3-dicarbonyl compound and aromatic aldehyde using phenylboronic acid as catalyst.
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).
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.
Entry | Catalysta | Time (h) | Yield (%)b |
---|---|---|---|
1 | ZnCl2 | 20 | 60 |
2 | Sc(OTf)3 | 20 | 58 |
3 | L-proline | 22 | 46 |
4 | Iodine | 20 | 36 |
5 | Phenylboronic acid | 14 | 89 |
aCatalyst 10 mol% used for each reaction. bIsolated yield.
cConditions: 4-Chlorobenzaldehyde (1 mmol), 4-chloroaniline (1 mmol), ethyl acetoacetate (0.5 mmol), acetonitrile (15 mL) at room temperature.
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.
General procedure for the synthesis of functionalized piperidines 4a–l
A mixture of aromatic aldehyde (1 mmol), substituted aniline (1 mmol), 1,3-dicarbonyl compound (0.5 mmol), and a catalytic amount of phenylboronic acid (10 mol%) in acetonitrile (15 mL) was stirred at room temperature for the period of time indicated below. After completion of the reaction, as indicated by thin layer chromatography (petroleum ether/ethyl acetate, 8:2), the mixture was diluted with 50 mL of water and extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4, concentrated, and the residue was subjected to column chromatography to afford the pure product.
Ethyl 4-(4-chlorophenylamino)-1,2,6-tris(4-chlorophenyl)-1,2,5, 6-tetrahydropyridine-3-carboxylate (4a)
White solid; yield 89%; mp 168–169°C; reaction time 14 h; 1H NMR: δ 1.25–1.35 (t, 3H), 2.70–2.85 (d, 2H) 4.15–4.30 (q, 2H) 5.25 (s, 1H), 6.05 (t, 1H), 7.05–7.25 (m, 5H), 7.30–7.50 (m, 8H), 7.75–7.90 (m, 4H), 9.72 (s, 1H); 13C NMR: δ 21.1, 39.6, 57.4, 62.8, 66.3, 106.3, 112.3, 121.5, 124.6, 125.8, 128.2, 131.7, 132.0, 132.2, 132.3, 133.0, 133.9, 134.2, 134.4, 134.8, 135.2, 136.3, 138.7, 139.3, 140.2, 147.5, 149.4, 149.6, 171.3; LC-MS: m/z 614.6692 [M+]. Anal. Calcd for C32H26Cl4N2O2: C, 62.76; H, 4.28; N, 4.57. Found: C, 62.79; H, 4.25; N, 4.59.
Ethyl 2,6-bis(3-chlorophenyl)-1-(4-methoxyphenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4b)
Yellow solid; yield 86%; mp 170–171°C; lit mp 167–170°C (Misra et al., 2009); reaction time 15 h.
Methyl-2,6-bis(4-methylphenyl)-1-(4-methoxyphenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4c)
White solid; yield 89%; mp 224–226°C; lit mp 226–228°C (Misra et al., 2011); reaction time 16 h.
Methyl-1,2,6-tris(4-methoxyphenyl)-4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4d)
White solid; yield 88%; mp 160–161°C; lit mp 158–160°C (Misra et al., 2009); reaction time 14 h.
Methyl (4-chlorophenyl)-4-(4-chlorophenylamino)-2,6-bis(methoxyphenyl)-1,2,5,6-tetra hydropyridine-3-carboxylate (4e)
Yellow solid; yield 90%; mp 194–196°C; lit mp 195°C (Misra et al., 2009); reaction time 14 h.
Methyl 2,6-bis(4-bromophenyl)-1-(4-chlorophenyl)-4-(4-chlorophenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4f)
Yellow solid; yield 80%; mp 163–164°C; lit mp 160–163°C (Misra et al., 2009); reaction time 15 h.
Methyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-1,2,5,6-tetrahydro-2,6-bis(4-nitro phenyl)pyridine-3-carboxylate (4g)
White solid; yield 78%; mp 195–196°C; reaction time 16 h; 1H NMR: δ 2.95 (d, 2H), 4.05 (s, 3H), 4.95 (s, 1H), 5.90 (t, 1H), 6.70–6.85 (m, 4H), 7.08–7.20 (m, 4H), 7.75–8.10 (m, 8H), 10.05 (s, 1H); 13C NMR: δ 32.2, 33.6, 52.5, 55.4, 58.2, 113.5, 117.5, 120.1, 121.6, 122.1, 123.6, 125.1, 126.2, 128.4, 129.3, 129.4, 130.2, 132.8, 141.5, 144.3, 150.1, 153.6, 178.2; LC-MS: m/z 620.7535 [M+]. Anal. Calcd for C34H32Cl2N2O4: C, 67.66; H, 5.34; N, 4.64. Found: C, 67.63; H, 5.37; N, 4.67.
Methyl (4-chlorophenyl)-4-(4-chlorophenylamino)-2,6-bis(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4h)
White solid; yield 77%; mp 178°C; lit mp 176°C (Misra et al., 2009); reaction time 14 h.
Methyl 2,6-bis(3-nitrophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4i)
White solid; yield 80%; mp 178–180°C; lit mp 180°C (Misra et al., 2009); reaction time 15 h.
Methyl 1,2,5,6-tetrahydro-2,6-bis(2-nitrophenyl)-1-phenyl-4-(phenylamino)pyridine-3-carboxylate (4j)
White solid; yield 78%; mp 216°C; lit mp 218–219°C (Misra et al., 2011); reaction time 15 h.
Methyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-tetrahydro-2,6-bis(4-methoxyphenyl)pyridine-3-carboxylate (4k)
Yellow solid; yield 84%; mp 179°C; lit mp 178°C (Misra et al., 2009); reaction time 14 h.
Methyl 4-(p-tolylamino)-2,6-bis(4-cyanophenyl)-1,2,5,6-tetrahydro-1-p-tolylpyridine-3-carboxylate (4l)
White solid; yield 82%; mp 210–212°C; lit mp 214°C (Misra et al., 2011); reaction time 16 h.
Supplementary Information
For detail information about analytical and spectral data please see the Supplementary Information available for this article.
We acknowledge Dr. P.L. More and Dr. W.N. Jadhav, Dnyanopasak College, Parbhani for providing necessary facilities. Financial support for this work by DST-SERC, New Delhi (SR/FT/CS-023/2008) is greatly appreciated.
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