Introduction

Synthesis of six-membered nitrogen heterocyclic compounds such as piperidine rings is very important because of their pharmacological and biological properties. The piperidines and their analogues exhibit diverse biological activities such as antihypertensive [1], antibacterial [2], anticonvulsant, and anti-inflammatory agents [3], farnesyltransferase inhibitors [4], norepinephrine reuptake inhibitor (CTDP 31, 446) [5], antipsychotic agent (MDL-100907) [6], and antidepressant drug [7]. Furthermore, substituted piperidines have been identified as an important class of therapeutic agents in the treatment of Parkinson’s disease [8–10], prolactinoma [11], schizophrenia [12–14], influenza infection [15, 16], cancer metastasis [17–19], viral infections including AIDS [20, 21], obesity, and diabetes [22–24], and also play key roles in many disease processes [25] (Fig. 1). These extensive investigations have resulted in the development of various synthetic methods for the synthesis of substituted piperidines [25–32].

Fig. 1
figure 1

Pharmaceutically active compounds containing piperidine framework

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Recently, the synthesis of highly functionalized piperidines has been reported using five-component reactions in the presence of InCl3 [33, 34], bromodimethylsulfonium bromide (BDMS) [35], tetrabutylammonium tribromide (TBATB) [36], iodine [37], cerium ammonium nitrate [38], ZrOCl2·8H2O [39], picric acid [40], BF3·SiO2 [41], Bi(NO3)3·5H2O [42], LaCl3·7H2O [43], VCl3 [44], PEG-embedded KBr3 [45], Mg(HSO4)2 [46], Zn(HSO4)2 [47], and NiCl2·6H2O [48] as catalyst. In addition, Misra and co-workers have reported the synthesis of highly functionalized piperidenes catalyzed by l-proline/TFA, and they also reported antimalarial activity of this class of compounds [49]. In view of the immense biological and pharmaceutical significance of these heterocycles, the introduction of an efficient method for the preparation of these compounds is still in demand.

On the other hand, in recent years, organic catalysts have attracted considerable attention in a variety of synthetic reactions as catalyst because of their unique properties, such as the possibility to perform reactions for acid-sensitive substrates and selectivity [50–52]. In this respect, triarylmethyl chlorides get the broad attention of chemists from various fields, including synthesis of important compounds, bulky protective groups for amino and primary hydroxyl functional groups, and organic transformations [51–55]. Triarylmethyl chlorides are inexpensive and can be obtained commercially or easily prepared by the known procedure [56].

As a part of our continuing interest in the development of multi-component reactions for the synthesis of functionalized piperidine [57–60], we report here an efficient and convenient procedure for the synthesis of highly substituted piperidines via a one-pot five-component reaction between aromatic aldehydes, amines and β-ketoesters catalyzed by trityl chloride (TrCl) in methanol at 50 °C (Scheme 1).

Scheme 1
scheme 1

Synthesis of highly substituted piperidines 4

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Results and discussion

Initially, the reaction of 4-methylbenzaldehyde, aniline and methyl acetoacetate in ethanol separately at ambient temperature was examined without any catalyst. This control experiment verified that the reaction did not proceed in the absence of a catalyst (Table 1, entry 1). When the reaction was carried out in the presence of trityl chloride (5 mol%) for 18 h, the corresponding highly substituted piperidine was obtained with 65 % yield. Encouraged by this result, we then focused on optimizing the reaction conditions. As shown in Table 1, the best result was obtained in the presence of 15 mol% of catalyst in methanol at 50 °C (Table 1, entry 10). The lower amounts of catalyst gave a low yield even after a long reaction time, and larger amounts of it did not affect the efficiency of this conversion. Furthermore, the effect of different solvents such as CH3CN and H2O was also investigated, and were found to be ineffective.

Table 1 Optimization of the reaction conditions for the synthesis of highly substituted piperidine form the reaction between 4-methylbenzaldehyde, aniline and methyl acetoacetate
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Therefore, the reactions of a series of substituted benzaldehydes, anilines and methyl- and/or ethyl-acetoacetate were carried out in the presence of 15 mol% of TrCl in methanol at 50 °C to afford the corresponding highly functionalized piperidines. The results are summarized in Table 2. In general, benzaldehydes containing an electron-deficient and/or electron-releasing group reacted efficiently with substituted anilines in the presence of β-ketoesters to give the corresponding piperidines in good to high yields. The low yield obtained in the reaction of benzyl amine, 4-methyl benzaldehyede and methyl acetoacetate is suggested to be because of the higher basicity of aliphatic amine compared to anilines (Table 2, entry 27). In addition, the reaction of propanal, as an aliphatic aldehyde, with aniline and methyl acetoacetate was checked under optimized conditions, but unfortunately did not provide the desired product (Table 2, entry 28).

Table 2 The synthesis of highly substituted piperidine 4
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All known products have been reported previously in the literature and were characterized by comparison of melting point, IR and NMR spectra with authentic samples. The structures of the products were fully characterized by melting points, elemental analyses, IR, 1H and 13C NMR, and mass spectra. For example, the mass spectrum of 4s displayed a molecular ion peak (M+) at m/z = 524, which is consistent with the proposed structure. The 1H NMR spectrum of compound 4s exhibited two singlets at δ 2.36 and 2.38 ppm for methyl groups and two doublets of doublets at 2.66 ppm (J = 15.1, 2.8 Hz) and 2.86 ppm (J = 15.1, 6.0 Hz) for methylene protons of the piperidin ring (H′-, H″-5). The protons of the methoxy group were observed at δ 3.95 ppm as a singlet. One of the methine protons of the piperidine ring (H-6) was observed as a doublet at δ 5.08 (J = 4.0 Hz) ppm and another methine proton (H-2) appeared as a singlet at δ 6.33 ppm. The aromatic protons resonance observed as multiplets at δ 6.25–7.20 ppm. The NH proton was observed at δ 10.17 ppm, which indicating intramolecular hydrogen bond formation with the vicinal carbonyl group. The 13C NMR spectrum of compound 4s showed 24 distinct resonances consistent with the piperidine structure. In the 13C NMR spectrum of this compound, the C-5 carbon was observed at δ 33.6 ppm and C-2 was exhibited at δ 55.4 ppm. The C-6 and C-3 carbons were observed at δ 58.1 and 98.0 ppm, respectively. Also, the methyls and methoxy carbons were exhibited at δ 21.0, 21.1, and 51.0 ppm, respectively. The C-4 and aromatic carbons were observed at δ 113.6–160.7 ppm. In addition, the carbon of the carbonyl group was seen at δ 168.6 ppm. The structure as well as the relative stereochemistry of this class of compounds, for instance 4s, was further elucidated by single crystal X-ray diffraction analysis (Fig. 2). As shown in Fig. 2, the relative anti-configuration of the product was confirmed. It is notable that, in the 1H NMR spectra of the crude products, the corresponding syn-diastereomer was not identified, which confirmed the disatereoselectivity of the present protocol.

Fig. 2
figure 2

ORTEP representation of the X-ray structure of piperidine 4s

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Crystal data and structure refinement for 4s are presented in Table 3. Also, selected bond lengths, bond angles and torsion angles for 4s were extracted from single X-ray crystallographic data and are exhibited in Table 4. It is noteworthy to mention that, on the basis of crystal X-ray analysis data, the piperidine ring adopted a boat conformation with some deviations (Scheme 2).

Table 3 Crystallographic data and structure refinement for compound 4s
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Table 4 Selected bond lengths (Å), bond angles (°) and torsion angles (°) in piperidine structure 4s
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Scheme 2
scheme 2

The boat conformation of piperidine 4

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As reported in the literature [36–38, 41, 42, 57–60], a possible mechanism for the formation of piperidine 4 is shown in Scheme 3. Amine 2 reacts with aromatic aldehyde 1 and β-ketoester 3 in the presence of TrCl to give imine 5 and enamine 6, respectively. The reaction between imine 5 and enamine 6 produces intermediate 7, which reacts with another aldehyde 1 to afford intermediate 8. Then, intermediate 8 is converted to intermediate 9, which immediately undergoes an intramolecular Mannich-type reaction to give intermediate 10. Finally, tautomerization of intermediate 10 gives the desired piperidine 4.

Scheme 3
scheme 3

Proposed reaction mechanism for synthesis of highly substituted piperidines 4

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To show the merit and applicability of TrCl in comparison with the reported catalysts, we compared results of these catalysts for the synthesis of highly functionalized piperidine derivatives 4a and 4i, in Table 5. As shown in Table 5, TrCl can act as an effective and efficient catalyst with respect to reaction times and yield of products.

Table 5 Comparison of TrCl with reported catalysts for the synthesis of highly substituted piperidine derivatives
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Experimental

General procedure for synthesis of highly substituted piperidine 4a–y

First, a solution of aromatic amine (2 mmol) and β-ketoester (1 mmol) in methanol (5 mL) was stirred for 30 min in the presence of TrCl (15 mol%) at ambient temperature. Next, the aromatic aldehyde (2 mmol) was added and the reaction mixture was stirred at 50 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The thick precipitate was filtered off and washed with ethanol (3 × 2 mL) to give the pure product. Physical and spectral data of selected products are represented below.

Methyl 1,2,5,6-tetrahydro-1-phenyl-4-(phenylamino)-2,6-dip-tolylpyridine-3-carboxylate (4a)

White solid. (400 MHz, CDCl3) δ (ppm): 2.25 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.75 (dd, 1H, J = 15.2, 2.4 Hz, H′-5), 2.84 (dd, 1H, J = 15.2, 5.6 Hz, H″-5), 3.93 (s, 3H, OCH3), 5.09 (d, 1H, J = 3.1 Hz, H-6), 6.30 (d, 2H, J = 8.0 Hz, ArH), 6.37 (s, 1H, H-2), 6.48 (d, 2H, J = 8.8 Hz, ArH), 6.60 (t, 1H, J = 7.2 Hz, ArH), 6.99–7.12 (m, 11H, ArH), 7.20 (d, 2H, J = 8.0 Hz, ArH), 10.27 (s, 1H, NH).

Methyl 2,6-bis(4-fluorophenyl)-1,2,5,6-tetrahydro-1-phenyl-4-(phenylamino)pyridine-3-carboxylate (4e)

Withe solid. (400 MHz, CDCl3) δ (ppm): 2.75 (dd, 1H, J = 15.1, 2.0 Hz, H′-5), 2.87 (dd, 1H, J = 15.1, 5.6 Hz, H″-5), 3.95 (s, 3H, OCH3), 5.11 (br s, 1H, H-6), 6.36–6.40 (m, 2H, ArH), 6.41 (s, 1H, H-2), 6.46–6.50 (m, 2H, ArH), 6.65 (t, 1H, J = 7.2 Hz, ArH), 6.90–7.24 (m, 13H, ArH), 10.29 (s, 1H, NH).

Methyl 4-(4-chlorophenylamino)-2,6-bis(4-bromophenyl)-1-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4n)

White solid. (400 MHz, CDCl3) δ (ppm): 2.73 (dd, 1H, J = 15.1, 2.2 Hz, H′-5), 2.85 (dd, 1H, J = 15.2, 5.6 Hz, H″-5), 3.95 (s, 3H, OCH3), 5.13 (br s, 1H, H-6), 6.28 (d, 2H, J = 7.0 Hz, ArH), 6.36 (s, 1H, H-2), 6.45 (d, 2H, J = 6.9 Hz, ArH), 6.99–7.23 (m, 12H, ArH), 10.18 (s, 1H, NH).

Ethyl 4-(p-tolylamino)-1,2,5,6-tetrahydro-2,6-diphenyl-1-p-tolylpyridine-3-carboxylate (4p)

White solid. (400 MHz, CDCl3) δ (ppm): 1.48 (t, 3H, J = 7.0 Hz, OCH2CH 3), 2.19 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.75 (dd, 1H, J = 15.1, 2.4 Hz, H′-5), 2.83 (dd, 1H, J = 15.1, 5.2 Hz, H″-5), 4.33–4.40 (m, 1H, OCHaHb), 4.48–4.55 (m, 1H, OCHaHb), 5.14 (d, 1H, J = 2.8 Hz, H-6), 6.19 (d, 2H, J = 7.8 Hz, ArH), 6.41 (d, 2H, J = 8.0 Hz, ArH), 6.43 (s, 1H, H-2), 6.90–7.17 (m, 7H, ArH), 7.21–7.36 (m, 7H, ArH), 10.24 (s, 1H, NH).

Methyl 4-(4-fluorophenylamino)-1-(4-fluorophenyl)-1,2,5,6-tetrahydro-2,6-dip-tolylpyridine-3-carboxylate (4s)

White solid. mp: 199–201 °C. IR (KBr) ν = 3255 (NH), 1649 (C=O) cm−1. 1H NMR (400 MHz, CDCl3) δ (ppm): 2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.66 (dd, 1H, J = 15.1, 2.8 Hz, H′-5), 2.86 (dd, 1H, J = 15.1, 6.0 Hz, H″-5), 3.95 (s, 3H, OCH3), 5.08 (d, 1H, J = 4.0 Hz, H-6), 6.25–6.28 (m, 2H, ArH), 6.33 (s, 1H, H-2), 6.43–6.48 (m, 2H, ArH), 6.77–6.84 (m, 4H, ArH), 7.05–7.20 (m, 8H, ArH), 10.17 (s, 1H, NH); 13C NMR (100 MHz, CDCl3) δ (ppm): 21.0 (CH3), 21.1 (CH3), 33.6 (C-5), 51.0 (OCH3), 55.4 (C-2), 58.1 (C-6), 98.0 (C-3), 113.6 (d, J = 7.0 Hz), 115.2 (d, J = 22.0 Hz), 115.6 (d, J = 22.0 Hz), 126.4 (d, J = 23.0 Hz), 128.0 (d, J = 8.0 Hz), 129.0, 129.4, 133.9 (d, J = 3.0 Hz), 136.0, 136.9, 139.7, 140.6, 143.5, 155.0 (d, 1 J CF = 233.0 Hz), 156.2 (C-4), 160.7 (d, 1 J CF = 244.0 Hz), 168.6 (C=O). MS (EI, 70 eV) m/z (%): 524 (M+, 16), 465 (6), 433 (100), 414 (8), 401 (18), 310 (61), 296 (51), 278 (22), 212 (66), 115 (23), 95 (41), 59 (14). Anal. Calcd for C33H30F2N2O2: C, 75.55; H, 5.76; N, 5.34. Found: C, 75.82; H, 5.80; N, 5.39.

Crystallographic data (excluding structure factors) for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 864008 for 4s. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk), or via www.ccdc.cam.ac.uk/datarequest/cif.

Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-1,2,5,6-tetrahydro-2,6-dip-tolylpyridine-3-carboxylate (4t)

White solid. mp: 218–220 °C. IR (KBr) ν = 3228 (NH), 1645 (C=O) cm−1. 1H NMR (400 MHz, CDCl3) δ (ppm): 1.49 (t, 3H, J = 6.8 Hz, OCH2CH 3), 2.35 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.73 (d, 1H, J = 14.4 Hz, H′-5), 2. 88 (dd, 1H, J = 15.2, 5.6 Hz, H″-5), 4.31–4.39 (m, 1H, OCHaHb), 4.45–4.51 (m, 1H, OCHaHb), 5.10 (d, 1H, J = 3.2 Hz, H-6), 6.22 (d, 2H, J = 8.0 Hz, ArH), 6.36 (s, 1H, H-2), 6.46 (d, 2H, J = 8.8 Hz, ArH), 7.01–7.21 (m, 12H, ArH), 10.27 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ (ppm): 14.7 (OCH2 CH3), 21.0 (CH3), 21.1 (CH3), 33.5 (C-5), 55.1 (C-2), 58.0 (C-6), 59.8 (OCH2CH3), 98.9 (C-3), 114.0, 121.0, 126.2, 126.4, 126.9, 128.7, 128.9, 129.0, 129.4, 131.2, 136.1, 136.5, 137.0, 139.2, 140.3, 145.6, 155.3 (C-4), 168.1 (C=O). MS (EI, 70 eV) m/z (%): 571 (M+, 2), 570 (4), 479 (22), 439 (20), 299 (21), 228 (39), 105 (32), 91 (63), 77 (31), 55 (100). Anal. Calcd for C34H32Cl2N2O2: C, 61.45; H, 5.64; N, 4.93. Found: C, 61.67; H, 5.75; N, 4.96.

Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-tetrahydro-2,6-dip-tolylpyridine-3-carboxylate (4u)

White solid. mp: 234–236 °C. IR (KBr) ν = 3310 (NH), 1652 (C=O) cm−1. 1H NMR (400 MHz, CDCl3) δ (ppm): 1.49 (t, 3H, J = 6.8 Hz, OCH2CH 3), 2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.74 (d, 1H, J = 15.2 Hz, H′-5), 2.88 (dd, 1H, J = 15.2, 5.6 Hz, H″-5), 4.33-4.39 (m, 1H, OCHaHb), 4.45–4.51 (m, 1H, OCHaHb), 5.09 (d, 1H, J = 3.6 Hz, H-6), 6.17 (d, 2H, J = 8.0 Hz, ArH), 6.35 (s, 1H, H-2), 6.42 (d, 2H, J = 8.8 Hz, ArH), 7.05–7.24 (m, 12H, ArH), 10.26 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ (ppm): 14.7 (OCH2 CH3), 21.0 (CH3), 21.2 (CH3), 33.4 (C-5), 55.0 (C-2), 58.1 (C-6), 59.9 (OCH2CH3), 99.0 (C-3), 108.2, 114.5, 118.9, 126.2, 126.4, 127.2, 129.0, 129.4, 131.5, 131.9, 136.1, 137.0, 139.1, 140.2, 146.0, 155.2 (C-4), 168.1 (C=O); MS (EI, 70 eV) m/z (%): 664 (M+4, 13), 662 (M+2, 25), 660 (M+, 12), 587 (10), 569 (48), 488 (24), 386 (60), 272 (100), 312 (51), 245 (40), 105 (48), 91 (49), 77 (28), 55 (50). Anal. Calcd for C34H32Br2N2O2: C, 61.83; H, 4.88; N, 4.24. Found: C, 61.99; H, 4.93; N, 4.39.

Methyl 1-benzyl-4-(benzylamino)-1,2,5,6-tetrahydro-2,6-dip-tolylpyridine-3-carboxylate (4z)

A mixture of benzyl amine (2 mmol) and methyl acetoacetate (1 mmol) in methanol (5 mL) was stirred for 30 min in the presence of TrCl (15 mol%) at ambient temperature. Next, the 4-methyl benzaldehyde (2 mmol) was added and the reaction mixture was stirred at 50 °C. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to ambient temperate and the solvent was evaporated under reduced pressure. Ethyl acetate (20 mL) was added and washed with H2O and then brine, and dried with anhydrous Na2SO4. The filtrate was concentrated and purified by silica gel column chromatography in ethyl acetate: n-hexane (40:60) as eluent to give the piperidine 4z. Light yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 2.29 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.63 (dd, 1H, J = 17.2, 5.6 Hz, H′-5), 2.74 (dd, 1H, J = 17.2, 11.6 Hz, H″-5), 3.31 (d, 1H, J = 13.5 Hz, NCH aHb), 3.36 (d, 1H, J = 13.5 Hz, NCHa H b), 3.48 (s, 3H, OCH3), 4.05 (dd, 1H, J = 11.6, 5.6 Hz, H-6), 4.56 (dd, 1H, J = 15.6, 6.0 Hz, NHCH aHb), 4.64 (dd, 1H, J = 15.6, 6.2 Hz, NHCHa H b), 4.73 (s, 1H, H-2), 7.08–7.24 (m, 9H, ArH), 7.29–7.38 (m, 9H, ArH), 9.65 (t, 1H, J = 6.0 Hz, NH).

Conclusion

In summary, the use of trityl chloride as an efficient organic catalyst is reported for the synthesis of highly substituted piperidines via a one-pot five-component reaction between aromatic aldehydes, amines and β-ketoesters in methanol at 50 °C in good to high yields. This methodology offered several advantages such as mild reaction conditions, simplicity in operation, diastereoselectivity, and simple and readily available precursors, which make it a useful and attractive process for the synthesis of these important compounds.