1 Introduction

As an important aspect of synthetic organic chemistry, multi-component organic reactions (MCRs) are among the most prosperity reaction classes. 1,3-Dicarbonyl compounds are one of the most multifaceted reagents to be used in MCRs because of the high reactivity of enaminones in both keto and enol forms, which are very advantageous to construct useful bioactive heterocycles [1, 2]. MCRs offer a highly valuable synthetic protocol for the construction of highly complex molecules with minimum number of synthetic steps. Wu et al. [3] has described the synthesis of naphthyridine derivatives in which thirteen bonds were cleaved and twelve new bonds were constructed through one-pot cascade reaction, while only two molecules of H2O were removed. In most of the situations a single product was obtained from three or more different, willingly available starting materials in an illustrious synthetic manner through MCRs [4]. The beneficial effects of these MCRs over the conventional synthesis are shorter reaction time, eco friendliness, cost effectiveness, high atom economy, inexpensive purification and no necessity for protection and deprotection process [5, 6]. Recently, Lewis acids catalyzed Michael addition of Schiff base to enaminones has attracted great attention of synthetic chemists [7, 8].

Poly functionalized piperidines are widely distributed in naturally occurring monocyclic and bicyclic alkaloids and synthetic drugs [9]. A variety of structural features surrounded the naturally occurring and synthetically prepared piperidines, among them many exhibit significant biological properties including anti-HIV, anticancer, antimycobacterial, antimicrobial, antimalarial, antiinflammatory, antiinsecticidal and they are potent inhibitors for many biological systems [10–14]. Much considerable efforts have been focused on the synthetic methods and some of the synthetic routes have been recommended for the synthesis of highly substituted piperidines essentially intramolecular Mannich reaction [15], cyclohydrocarboxylation [16], aziridine ring expansion [17], radical cyclization [18], domino reaction [19], Diels–Alder reaction [20], imino Diels–Alder reaction [21] and domino imino-aldol-aza-Michael addition [22]. Recently one-pot synthesis of these scaffolds has been achieved by employing InCl3 [23], bromodimethylsulfonium bromide [24], l-proline/TFA [25], tetrabutylammonium tribromide [26], molecular I2 [27], CAN [28], ZrOCl2·8H2O [29], picric acid [30], thiourea dioxide (TUD) [31], BF3-SiO2 [32], VCl3 [33] and Bi(NO3)3·5H2O [34] as efficient catalysts. The above deliberated methods have some disadvantages such as the use of expensive and excess amount of catalysts. Efficacious new approaches for the preparation of chemically and biologically active complex molecules are of great significance with simple mechanism and good selectivity.

Nowadays lanthanides including lanthanum [35], cerium [36], samarium [37] and ytterbium [38] have been employed as efficient catalysts for a wide variety of synthetic reactions. Jun Lu et al. [39] has described an efficient one-pot synthesis of 3,4-dihydropyrimidinones using lanthanum chloride heptahydrate as catalyst from an aldehyde, β-keto ester and urea or thiourea in ethanol. In continuation of this, here we report the one-pot efficient synthesis of highly functionalized piperidines using 10 mol% of LaCl3·7H2O as a catalyst in a three-component intramolecular aza Diels–Alder reaction.

2 Result and Discussion

For the initial optimization of the reaction conditions and the identification of the suitable solvent and effective reaction conditions, ethyl acetoacetate, benzaldehyde, aniline and 10 mol% of catalyst was selected as prototype. Among the chosen solvents MeOH was the best for the synthesis of tetrahydropyridines showed in Table 1. Although acetonitrile, chloroform and dichloromethane allowed the reaction at a faster rate, the yield was less than that obtained using MeOH as solvent. THF and ethyl acetate gave low yields and no desired product was obtained with water.

Table 1 Initial solvent effect studies for synthesis of tetrahydropyridines with 10 mol% catalyst
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By screening a wide range of catalysts, we found out that the product 5a could be obtained in good yields ranging from 20 to 83 % in different mole ratios of LaCl3·7H2O (1, 2, 5, 10 and 15 mol%) and the results are summarized in Table 2. Better yields were obtained up to 83 % by carrying out the reaction using 10 mol% of LaCl3·7H2O in MeOH as solvent. The reaction takes place efficiently in an open air system and it does not require any special apparatus like Schlenk system. When the reaction was carried out at reflux conditions, there was no significant change in yields and time (Entry 16, Table 2). Primary screening studies of a variety of catalysts also revealed that lanthanum oxide and silica chloride also act as catalyst. La2O3 (10 mol%) and silica chloride (10 mol%) were employed as catalysts for the three-component reaction but moderate yields were obtained. Lower yields were obtained with the use of NH4OAc and ammonium molybdate.

Table 2 Screening of catalysts for the one-pot synthesis of tetrahydropyridines
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A wide range of aromatic aldehydes and amines were subjected to react with 1,3-dicarbonyl compounds in the presence of catalytic amount of LaCl3·7H2O and the results are summarized in Table 3. A variety of aromatic aldehydes possessing electron withdrawing and electron donating groups at different positions on the aromatic ring, were allowed to react with ethyl acetoacetate under standard conditions affording substituted piperidine with good yields. Nitro group (at 3 and 4 positions) containing aldehyde gave moderate yields with both ethyl acetoacetate and methyl acetoacetate due to stable imine formation. Likewise a variety of aromatic anilines possessing electron withdrawing and electron donating groups, were allowed to react with ethyl acetoacetate and aromatic aldehydes under standard conditions and results are summarized in Table 3. Similarly for getting piperidine moiety, we treated ethyl acetoacetate and aniline with different aliphatic aldehydes including formaldehyde, acetaldehyde, and propanaldehyde under same reaction conditions. However, no desired compounds were formed in the reaction. This is due to the electron releasing nature of alkyl groups in aliphatic aldehydes. The reaction is shown in Scheme 1.

Table 3 LaCl3·7H2O (10 mol%) catalyzed one-pot synthesis of highly functionalized piperidines
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Scheme 1
scheme 1

Reaction of 1,3-dicarbonyl compound, aniline with various aldehydes in the presence of LaCl3·7H2O

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All the synthesized products were characterized by FTIR, H1 NMR, C13 NMR and mass spectral analyses. The structures of 4a and 5a were determined by single crystal X-ray diffraction analysis shown in Fig. 1 and it can be concluded that the ring exists in trans form. The H1 NMR spectral analyses of compounds 4a–4j and 5a–5m reveal that N–H peak comes around 10.250–10.350 ppm with the exception of 4b which comes around 9.80 ppm. Proton present at the stereogenic center C-2 (denoted by asterisk in Scheme 2) position comes at around 6.35–6.55 ppm. Proton present at the stereogenic center is shifted towards the deshielding region, when the electron donating groups are present at para position on aromatic aldehyde ring. This is further confirmed by H1 NMR spectra of compounds 5g–j. In compound 5g and 5h stereogenic proton comes next to two aromatic protons but in the case of 5i and 5j stereogenic proton comes first followed by aromatic proton.

Fig. 1
figure 1

Crystal structures of 4a and 5a

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Scheme 2
scheme 2

Three-component one-pot reaction leading to poly substituted piperidines

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The possible reaction mechanism for this three-component reaction is described in Scheme 3. LaCl3·7H2O is Lewis acid, which serves as an acid catalyst for the construction of β-enaminone (6) formed by the reaction of ethyl acetoacetate with aniline and imine (7) which is formed in the reaction of benzaldehyde with aniline (Step 1). Benzaldehyde which is retained in the reaction mixture undergoes Knoevenagel condensation with β-enaminone leading to the formation of intermediate 8 and reactive form 8a (Step 2). Due to the diene core present in intermediate 8a, it proceeds towards an intramolecular aza Diels–Alder reaction with imine (serves as dienophile) which affords the expected piperidine (Step 3). Intermediates 6 and 7 had earlier been isolated from similar reaction.

Scheme 3
scheme 3

The possible mechanism for three-component one-pot reaction leading to poly substituted piperidine

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3 Experimental Section

3.1 General Procedure for the preparation of Methyl 1,2,5,6-Tetrahydro-1,2,6-triphenyl-4-(phenylamino) pyridine-3-carboxylate (4a)

A mixture of β-keto ester (1 mmol), aniline (2 mmol) and LaCl3·7H2O (0.1 mmol) in 5 ml methanol was stirred at room temperature for 15 min followed by the addition of aldehyde (2 mmol) and stirring was continued for an appropriate time. The completion of the reaction was monitored by TLC. The solid product formed in reaction mixture was filtered, washed with methanol and recrystallized using ethanol and tetrahedrofuran (1:1 ratio). If the product was in gel form, it was purified by silica gel column chromatography using hexane and ethyl acetate as eluant.

White yellow solid; melting point: 192–194 °C: IR (KBr): 3250, 3024, 2949, 2867, 1815, 1661, 1606, 1504, 1449, 1375, 1321, 1245, 1183, 1070, 978, 920, 748, 646 cm−1: H1NMR (400 MHz, CDCl3)™ ppm: 2.78–2.74 (d, J = 14.8 Hz, 1H), 2.89–2.84 (dd, J = 30.4, 5.6 Hz, 1H), 3.93 (s, 3H), 5.15(s, 1H), 6.29–6.26 (d, J = 7.6 Hz, 2H), 6.45 (s, 1H), 6.53–6.51 (d, J = 8.4 Hz, 2H), 6.61–6.58 (t, J = 7.2 Hz, 1H), 7.33–7.03 (m, 15H), 10.25 (br s, 1H, NH); C13NMR (100 MHz, CDCl3)™ ppm: 33.6, 51.0, 55.1, 58.2, 97.9, 112.9, 116.2, 125.8, 125.9, 126.4, 126.4, 126.6, 127.2, 128.3, 128.7, 128.9, 128.9, 137.8, 142.7, 143.9, 146.9, 156.3, 168.6;

4 Conclusion

In conclusion, we have developed a one-pot three-component intramolecular aza Diels–Alder reaction of aldehydes, aniline and 1,3-dicarbonyl compounds in the presence of 10 mol% of LaCl3·7H2O in MeOH as an efficient catalyst. The main feature of this strategy includes easy work up, mild reaction conditions, good yields and high atom economy. The current methodology is attractive for the preparation of a wide variety of biologically active highly functionalized piperidines.