Introduction

Functionalized piperidine rings are found in naturally occurring alkaloids and in anti-tumor and antibiotic drugs [1–6]. Simple derivatives of the substituted piperidine molecule L-pipecolic acid are constituents of plants, fungi, and human physiological fluids [7–9]. In particular, C-2 and C-6-substituted piperidine molecules isolated from extracts of Dendrobates speciosus (a Panamanian poison frog) have a range of activity, for example cytotoxic, antifungal, hemolytic, and anti-HIV [10–12] (Fig. 1). Numerous methods have recently been reported for synthesis of highly substituted piperidines by reaction of aromatic aldehydes, amines, and acetoacetic ester with a variety of catalysts, for example bismuth nitrate [13], molecular iodine [14], bromodimethylsulfonium bromide (BDMS) [15], tetrabutylammonium tribromide (TBATB) [16], InCl3 [17], CAN [18], ZrOCl2.8H2O [19], and picric acid [20]. Although different approaches have been reported, these methods have many limitations, for example use of expensive catalysts, in excessive amounts, at elevated temperatures, long reaction times, hazardous organic solvents and other reagents, and low yields. Hence, the development of novel methods for synthesis of functionalized piperidines is very important, because of their potential biological and pharmaceutical activity.

Fig. 1
figure 1

Substituted piperidine molecules

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Citric acid is a weak organic acid with the formula C6H8O7 (Fig. 2). It is a natural preservative which occurs naturally in citrus fruits and is also used to add an acidic or sour taste to food and drinks. In continuation of our research on green catalysts [21–24], we report herein a green synthesis of highly substituted piperidines in the presence of citric acid as catalyst in MeOH at ambient temperature (Scheme 1).

Fig. 2
figure 2

Structure of citric acid

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Scheme 1
figure 1

Synthesis of piperidines in the presence of citric acid as green catalyst in MeOH at ambient temperature

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Experimental

Melting points and IR spectra were measured on an Electrothermal 9100 apparatus and a Jasco FT-IR-460 plus spectrometer, respectively. 1H NMR spectra were acquired with a Bruker DRX-400 Advance instrument with CDCl3 as solvent. All reagents and solvents were obtained from Merck and Aldrich and used without further purification. TLC was performed on Polygram SILG/UV 254 silica gel plates.

General procedure for synthesis of highly functionalized piperidines

First, a solution of aromatic amine 2 (2 mmol) and β-ketoester 3 (1 mmol) in MeOH (5 mL) was stirred for 20 min in the presence of citric acid (20 mol%) at ambient temperature. Next, the aromatic aldehyde 1 (2 mmol) was added and the reaction mixture was stirred for the appropriate time. After completion of the reaction, as monitored by TLC, the solid obtained was isolated by filtration and washed with MeOH (3 × 2 mL) to give the pure product 4. Physical and spectral data for selected products are reported below.

All of the products are known. Selected spectroscopic data of one known product is given below:

Ethyl 1,2,5,6-tetrahydro-1-(4-methoxyphenyl)-4-(4-methoxyphenylamino)-2,6-diphenylpyridine-3-carboxylate (4e)

White solid; m.p = 179–181 °C; IR (KBr, cm−1) ν = 3295 (NH), 1648 (C=O); 1H NMR (400 MHz, CDCl3): δ = 1.48(t, J = 7.0 Hz, 3H), 2.68 (dd, J = 15.1, 2.4 Hz,1H), 2.83 (dd, J = 15.1, 5.6 Hz, 1H), 3.69 (s,3H), 3.78 (s, 3H), 4.32–4.38 (m, 1H), 4.43–4.49 (m, 1H), 5.09 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 8.8 Hz, 2H), 6.38 (s,1H), 6.48 (d, J = 9.2 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 9.2 Hz, 2H), 7.20–7.37(m, 10H), 10.18 (s, 1H) ppm.

Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-tetrahydro-2,6-diphenylpyridine-3-carboxylate (4h)

White solid; m.p. 245–246 °C; IR (KBr, cm−1) ν = 3248 (NH), 1648 (C=O); 1H NMR (400 MHz, CDCl3) : δ = 1.50(t, J = 6.8 Hz, 3H), 2.74 (d, J = 15.2 Hz,1H), 2. 89 (dd, J = 15.2, 5.6 Hz,1H), 4.35–4.40 (m,1H), 4.46–4.52 (m, 1H), 5.13 (d, J = 4.0 Hz, 1H), 6.14 (d, J = 8.0 Hz, 2H), 6.41 (s, 1H), 6.42 (d, J = 8.0 Hz, 2H), 7.14–7.34 (m, 14H), 10.26 (s, 1H) ppm.

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

White solid; m.p. 169–171 8 °C; IR (KBr, cm−1) ν = 3256 (NH), 1656 (C=O); 1H NMR (400 MHz, CDCl3): δ = 1.49 (t, J = 7.0 Hz, 3H), 2.20 (s, 3H), 2.31 (s, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.78 (dd, J = 15.1, 2.4 Hz,1H), 2.87 (dd, J = 15.1, 5.6 Hz, 1H,), 4.37 (dq, J = 10.4, 7.2 Hz, 1H), 4.48 (dq, J = 10.4, 6.8 Hz, 1H), 5.13 (d, J = 3.6 Hz,1H), 6.23 (d, J = 8.4 Hz, 2H), 6.42 (s, 1H), 6.49 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 10.8 Hz, 2H), 6.93 (d, 2H, J = 7.6 Hz), 7.08–7.29 (m, 8H), 10.26 (s, 1H) ppm.

Ethyl 2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4n)

White solid; m.p. 165–168 °C; IR (KBr, cm−1) ν = 3270 (NH), 1656 (C=O);1H NMR (400 MHz, CDCl3) : δ = 1.50 (t, J = 7.2 Hz, 3H), 2.82 (dd, J = 15.2, 2.4 Hz, 1H), 2.91 (dd,J = 15.2, 5.6 Hz, 1H), 3.82 (s, 3H), 3.83 (s,3H), 4.39 (dq, J = 10.8, 7.2 Hz, 1H), 4.52(dq, J = 10.8, 7.0 Hz, 1H), 5.13 (d, J = 2.8 Hz,1H), 6.40 (d, J = 6.8 Hz, 2H), 6.42 (s, 1H),6.57 (d, J = 8.4 Hz, 2H), 6.65 (t, J = 7.2 Hz, 1H), 6.84–6.88 (m, 4H), 7.09–7.29 (m, 9H),10.35 (s, 1H) ppm.

Results and discussion

In continuation of our work on the synthesis of heterocycles, especially piperidines [25–27], we have used citric acid as an efficient and green catalyst for one-pot, three-component (in situ five-component) synthesis of highly functionalized piperidines in MeOH at ambient temperature (Scheme 1). First, the reaction between benzaldehyde (2 mmol), aniline (2 mmol), and methyl acetoacetate (1 mmol) was chosen as model system. Initially, a control experiment confirmed that the reaction did not proceed in the absence of a catalyst (Entry 1, Table 1). The model reaction was then performed in the presence of different catalysts, PrCl3·6H2O, fumaric acid, salicylic acid, and citric acid, in MeOH (Table 1). Catalyst reactivity in different solvents and amount of catalyst were also investigated (Tables 2, 3).

Table 1 Synthesis of piperidine in the presence of different catalysts
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Table 2 Optimization of the amount of catalyst for synthesis of piperidine
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Table 3 Synthesis of piperidine in the presence of different solvents
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Several reactions between substituted benzaldehydes, anilines, and methyl or ethyl acetoacetate were examined under the optimized conditions; the results are summarized in Table 4. Benzaldehydes with electron-withdrawing and electron-releasing groups reacted efficiently with anilines to give the corresponding piperidines in good to high yields.

Table 4 Synthesis of highly functionalized piperidines in the presence of citric acid as catalyst in MeOH
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On the basis of the literature [13–18], the mechanism proposed for formation of piperidine 4 is illustrated in Scheme 2. First, the β-ketoester 2 and aldehyde 1 react with aniline 3 in the presence of citric acid to give the enamine 5 and imine 6, respectively. Next, reaction between the enamine 5 and imine 6 leads to the intermediate 7 via an intermolecular Mannich-type reaction. The intermediate 7 reacts with aldehyde 1 to generate intermediate 8. Tautomerization of 8 then generates intermediate 9, which immediately undergoes intramolecular Mannich-type reaction to produce intermediate 10. In the final step, tautomerization of the intermediate 10 generates the desired piperidine 4, because of conjugation with the ester group.

Scheme 2
figure 2

Proposed mechanism for synthesis of highly function piperidines in the presence of citric acid as catalyst in MeOH at ambient temperature

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Conclusion

A highly efficient method has been developed for synthesis of highly function piperidines by use of citric acid as catalyst at ambient temperature in MeOH. This procedure has the advantages of high yield, operational simplicity, nonhazardous catalyst, short reaction time, and minimum pollution of the environment.