Aminoesters and amino acids are valuable synthetic scaffolds for both medicinal and synthetic organic chemists. A bioreducible linear poly(β-amino ester) as a safe and effective siRNA delivery vehicle have been designed to condense siRNA into nanoparticles and efficiently release it upon entering the cytoplasm ^[1]. A library of end-modified poly(β-amino ester)s have been reported as gene delivery vehicles. These polymers will provide promising candidates for the systemic treatment of cancer ^[2]. A series of the β-aminoester class of factor Xa (fXa) inhibitors has been expanded with excellent in vivo anticoagulant activity ^[3]. Therefore,looking for efficient and concise methods for the synthesis of β-amino ester has commanded vast attention. Synthesis of bioactive compounds should be facile,rapid,highly flexible,and practical in organic synthesis. Multicomponent reactions have been successfully employed to generate molecular complexity starting from simple substrates. Hence,synthetic organic chemists have increasingly focused on the use of MCRs to synthesize a broad range of products ^{[4, 5, 6, 7, 8, 9, 10, 11, 12]}. The possibility of accomplishing multicomponent reactions under mild conditions with a heterogeneous catalyst could improve their significant advantages from cost-effectiveness and ecological points of view. The improvement of a catalytic system utilizing inexpensive and commercially available catalysts has been a challenge in organic syntheses. Nanoparticles have undergone extensive examination in the past years. Recently, nanoparticle catalysts have emerged as an alternative method for the development of many considerable organic reactions. Nanocatalysts decrease reaction times and they can be easily recovered from the reaction mixture by standard techniques (filtration, centrifugation) and recycle without losing their activity ^{[13, 14, 15, 16, 17, 18, 19, 20]}. In comparison with conventional supports like solid-phase,nanoparticular matrixes have a higher catalyst loading capacity owing to their very large surface area. Among various solid supports,nano silica gel is one of the extensively used surface material supports for different chemical transformations in organic chemistry ^{[21, 22]}. Recently,silica-supported ferric chloride has been used as an efficient heterogeneous catalyst for the synthesis 1,4- dihydropyridines ^[23],xanthenes ^[24],1,2-dihydro-1-arylnaphtho[ 1,2-e]^{[1, 3]}oxazine-3-ones ^[25]. Recently,the synthesis of cyclic β-aminoesters via the three-component coupling of primary amines,β-ketoesters,and chalcones has been reported using MCRs in the presence of cerium(IV) ammonium nitrate (CAN) as catalyst ^[26]. Herein,we report that FeCl₃/SiO₂ nanoparticles acts as an efficient heterogeneous catalyst for the direct synthesis of 4,6-disubstituted 2-alkylaminocyclohexene-1-carboxylic esters by the three-component reaction between primary amines,ethyl acetoacetate and chalcones in ethanol as solvent (Scheme 1).

Scheme 1

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Scheme 1.Synthesis of 2-aminocyclohex-1-ene-1-carboxylic esters from of primary amines, ethyl acetoacetate and chalcones using FeCl3/SiO2 NPs.

All reagents were purchased from Merck and Aldrich and used without further purification. Melting points were measured on an Electrothermal 9200 apparatus. The IR spectra were recorded on an FT-IR Magna 550 apparatus using KBr discs. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance DRX-400 instrument using TMS as the internal standard and CDCl₃ as solvent. The elemental analyses (C,H,N) were obtained from a Carlo ERBA Model EA 1108 analyzer. Microscopic morphology of products was examined by SEM (LEO 1455VP).

Nano silica gel (25 g) and FeCl₃·6H₂O (2 g) (8% of the weight of nano-SiO₂) were vigorously stirred under solvent-free conditions at room temperature for 24 h to achieve a homogeneous adsorption. A yellowish powder was obtained. This powder was heated for 1 h at 100 ℃ to give a brownish powder (‘active’ FeCl₃- SiO₂ reagent).

A solution of amine (3.9 mmol) and ethyl acetoacetate (3 mmol) in ethanol (4 mL) and FeCl₃/SiO₂ nanoparticles (0.6 mol%) as catalyst was stirred for 15 min at room temperature. Chalcone (3.3 mmol) was then added to the stirred solution and the stirring was continued for the time periods specified. After completion of the reaction,as indicated by TLC,the mixture was dissolved in CH₂Cl₂ (20 mL),was filtered and the heterogeneous catalyst was recovered,washed with water,brine,dried (anhydrous Na₂SO₄),and the solvent was evaporated under reduced pressure. Pure products were obtained by column chromatography on neutral alumina,eluting with a n-hexane-ethyl acetate mixture (90:10,v/v). The structures of the products were fully established on the basis of their ¹H NMR,¹³C NMR and FT-IR spectra.

Ethyl 2-(butylamino)-4-hydroxy-4,6-diphenylcyclohex-1-enecarboxylate (4a): mp 97-100 ℃. IR (KBr,cm^-1): υ_max 3445.6, 3269.5,3019.7,1628.5,1594.5,1449.0,¹H NMR (CDCl₃,400 MHz): δ 0.88 (t,3H,J = 6.9 Hz),1.06 (t,3H,J = 7.2 Hz),1.09 (m,2H),1.27 (m,2H),2.28 (dd,1H,J = 14.0,12.0 Hz),2.39 (dd,1H,J = 14.0, 6.9 Hz),2.49 (m,1H),2.80 (m,1H),3.13 (dd,1H,J = 12,6.9 Hz),3.61 (m,2H),4.08 (q,2H,OCH₂),6.59 (bs,1H,NH),7.50 (bs,1H,OH), 7.24-7.55 (m,10H,CH_Ar). ¹³C NMR (CDCl₃,100 MHz): δ 14.1,14.4, 20.6,32.9,39.9,41.7,42.9,46.2,58.9,72.3,91.6,124.9,125.7, 127.1,127.8,128.5,128.8,146.9,150.1,157.9,170.9. Anal. Calcd. for C₂₅H₃₁NO₃: C,76.30; H,7.94; N,3.56. Found: C,76.41; H,7.85; N,3.61.

Ethyl 2-(butylamino)-4-(4-chlorophenyl)-4-hydroxy-6-phenylcyclohex- 1-enecarboxylate (4b): mp 118-119 ℃. IR (KBr, cm^-1): υ_max 3431.1,3276.8,3024.6,2932.1,1625.1,1592.5, 1452.1,1095.1. ¹H NMR (CDCl₃,400 MHz): δ 0.80 (t,3H, J = 7.1 Hz),1.01 (t,3H,J = 7.2 Hz),1.08 (m,2H),1.30 (m,2H), 2.27 (dd,1H,J = 13.7,11.0 Hz),2.38 (dd,1H,J = 13.7,6.8 Hz),2.46 (m,1H),2.75 (m,1H),3.12 (dd,1H,J = 11.0,6.8 Hz),3.53 (m,2H), 4.08 (q,2H,OCH₂),6.59 (bs,1H,NH),7.50 (brs,1H,OH),7.24-7.55 (m,9H,CH_Ar). ¹³C NMR (CDCl₃,100 MHz): δ 14.1,14.3,20.7,32.8, 39.9,41.5,42.9,45.9,59.1,71.9,91.6,125.7,126.7,127.1,128.6, 128.9,133.6,145.6,149.7,157.6,170.8. Anal. Calcd. for C₂₅H₃₀ClNO₃: C,70.16; H,7.07; N,3.27. Found: C,70.11; H, 6.96; N,3.31.

Ethyl 2-amino-4-hydroxy-4,6-diphenylcyclohex-1-enecarboxylate (4c): mp 140-141 ℃. IR (KBr,cm^-1): υ_max 3473.1,3329.5, 2983.2,2924.5,1655.3,1609.6,1532.1,1360.3,1065.8,¹H NMR (CDCl₃,400 MHz): δ 0.9 (t,3H,J = 7.2 Hz),2.00 (dd,1H,J = 13.7, 11.2 Hz),2.27-2.35 (m,2H),2.41 (m,1H),3.01 (m,1H),3.73-4.00 (m,2H),6.20 (bs,2H),7.12-7.48 (m,10H),7.50 (bs,1H,OH),¹³C NMR (CDCl₃,100 MHz): δ 14.1,39.9,45.4,46.7,59.4,72.6,94.9, 124.9,125.8,127.4,127.9,128.6,128.8,146.5,149.2,154.7, 170.2. Anal. Calcd. for C₂₁H₂₃NO₃: C,74.75; H,6.87; N,4.15. Found: C,74.62; H,6.82; N,4.11.

Ethyl 2-amino-4-(4-chlorophenyl)-4-hydroxy-6-phenylcyclohex- 1-enecarboxylate (4d): mp 146-147 ℃. IR (KBr,cm^-1): υ_max 3489.5,3446.2,3310.3,2981.5,2945.6,1664.4,1612.3,1542.0, 1492.5,1366.8,1065.7; ¹H NMR (CDCl₃,400 MHz): δ 0.82 (t,3H, J = 7.2 Hz),1.97 (dd,1H,J = 13.7,11.2 Hz),2.25-2.41 (m,3H),2.99 (m,1H),3.75-4.00 (m,2H),6.20 (bs,2H),7.13-7.45 (m,9H),7.50 (bs,1H,OH); ¹³C NMR (CDCl₃,100 MHz): δ 14.1,39.9,45.2,46.6, 59.3,72.4,94.8,125.9,126.6,127.3,128.6,128.9,133.6,145.2, 148.9,154.5,170.2. Anal. Calcd. for C₂₁H₂₂ClNO₃: C,67.83; H,5.96; N,3.77. Found: C,67.71; H,5.91; N,3.82.

Ethyl 2-amino-6-(4-fluorophenyl)-4-hydroxy-4-phenylcyclohex- 1-enecarboxylate (4e): mp 168-171 ℃. IR (KBr,cm^-1): υ_max 3485.5,3447.2,3310.3,1628.5,1594.5,1449.0,¹H NMR (CDCl₃, 400 MHz): δ 0.9 (t,3H,J = 7.2 Hz),2.21(m,1H),2.36(m,2H),2.43(m, 1H),3.11(m,1H),3.75-4.00 (q,2H,J = 7.2 Hz),6.22 (bs,2H),6.93 (bs, 1H,OH),7.21-7.87 (m,9H); ¹³CNMR (CDCl₃,100 MHz): δ 14.2,39.9, 45.6,46.8,59.6,72.8,94.9,124.9,125.9,127.5,127.9,128.7,128.9, 146.5,149.4,154.9,170.3. Anal. Calcd. for C₂₁H₂₂FNO₃: C,70.97; H, 6.24; N,3.94; Found: C,70.91; H,6.15; N,3.89.

Ethyl 2-(butylamino)-6-(4-fluorophenyl)-4-hydroxy-4-phenylcyclohex- 1-enecarboxylate (4f): mp 126-129 ℃. IR (KBr, cm^-1): υ_max 3430.0,3276.5,3022.4,2931.1,1623.2,1593.5, 1094.2; ¹H NMR (CDCl₃,400 MHz): δ 0.69 (t,3H,J = 7.0 Hz),1.01 (t,3H,J = 7.2 Hz),1.09 (m,2H),1.43 (m,2H),2.30 (dd,1H,J = 13.7, 11.0 Hz),2.38 (dd,1H,J = 13.7,6.8 Hz),2.46 (m,1H),2.77 (m,1H), 3.12 (dd,1H,J = 11.0,6.8 Hz),3.20 (m,2H),4.04 (q,2H,J = 7.0 Hz, OCH₂),6.59 (bs,1H,NH),7.40 (bs,1H,OH),7.24-7.49 (m,9 H, CH_Ar). ¹³C NMR (CDCl₃,100 MHz): δ 14.0,14.2,20.5,32.6,39.9, 41.4,42.9,45.9,59.2,71.9,91.8,125.8,126.6,127.1,128.5,128.7, 133.6,145.5,149.5,157.4,170.5. Anal. Calcd. for C₂₅H₃₀FNO₃: C, 72.97; H,7.35; N,3.40; Found: C,72.89; H,7.29; N,3.31.

The recovered catalyst from the experiment was washed by acetone (3 × 6 mL). Then,it was dried in an oven at 100 ℃ and used in the synthesis of 2-aminocyclohex-1-ene-1-carboxylic esters. Then the catalyst was recycled for five times.

In this article,we report a simple,mild and effective procedure for the one-pot synthesis of 2-aminocyclohex-1-ene-1-carboxylic esters using FeCl₃/nano-SiO₂ as a recyclable catalyst. This catalyst is safe,easy to handle and environmentally favorable. Initially,we carried out the MCR between butyl amine,ethyl acetoacetate and chalcone at room temperature as a model reaction in the presence of different catalysts. We tested several catalysts for this multicomponent synthesis. The model reaction was carried out in the presence of various catalysts such as FeCl₃,nano SiO₂,and FeCl₃/ SiO₂ nanoparticles. When the reaction was carried out using FeCl₃, nano SiO₂,and FeCl₃/SiO₂ as the catalyst,the product could be obtained in moderate to good yield. From the results,it is obvious that FeCl₃/SiO₂ NPs is the best catalyst among those examined which are reported in Table 1. When 0.3,0.6,and 0.9 mol% of FeCl₃/ SiO₂ nanoparticles were used,the yields were 73%,78% and 78%, respectively. Therefore,performing the reaction with a higher catalyst loading (0.9 mol%) had no noteworthy effect on yield. Nano silica supported ferric chloride is an effective catalyst in terms of reaction times and yields of product,because of the supported nano-SiO₂ increase contact surface of materials. The SEM image of FeCl₃/nano-SiO₂ is shown Fig. 1. The SEM image shows particles with diameters in the range of nanometers. As shown in Fig. 1 the particle size of the FeCl₃-SiO₂ (np) has been found to be 45-50 nm. The reaction works well for different chalcone and primary amines (Table 2). The mechanism of these domino reactions is proposed in Scheme 2. Also,in the present reaction FeCl₃-SiO₂ NPs may play as Lewis solid acids. In this mechanism the FeCl₃-SiO₂ NPs act as Lewis solid acid and activate the C=O group for better reaction with nucleophiles. The mechanism has been supported by literature ^{[17, 18, 19]}. The increased surface area due to small particle size increased reactivity. The reaction proceeded with complete selectivity in favor of the diastereoisomer having a cis-arrangement for the aryl substituents at C-4 and C-6,with both substituents placed in an equatorial position ^[20]. The ¹H NMR spectra in DMSO-d₆ showed diastereotopic protons around δ 2.25-3.50. These diastereotopic protons give different signals,couple the protons on C-3 with each other and the protons on C-5 with C-6 (with different coupling constants),and couple with each other.

Table 1

Table 1 Optimization of reaction condition using different catalysts using FeCl3/SiO2 NPs (0.6 mol%).a

Table 1 Optimization of reaction condition using different catalysts using FeCl3/SiO2 NPs (0.6 mol%).a

Fig. 1

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Fig. 1.SEM images of FeCl3 nano-SiO2.

Table 2

Table 2 Synthesis of 2-aminocyclohex-1-ene-1-carboxylic esters at room temperature in ethanol.

Table 2 Synthesis of 2-aminocyclohex-1-ene-1-carboxylic esters at room temperature in ethanol.

Scheme 2

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Scheme 2.Proposed reaction pathway for the synthesis of 2-aminocyclohex-1-ene-1-carboxylic esters using FeCl3/SiO2 NPs.

Wealso investigatedrecycling of the FeCl₃-SiO₂NPs as catalyst in ethanol. The results showed that FeCl₃-SiO₂ NPs can be recycled several times without noticeable loss of catalytic activity (yields 75%-78%) (Fig. 2). The leaching of the Fe from the FeCl₃/SiO₂ NPs nanoparticleswas investigated. After completion of the reaction,the supernatant was collected and tested for Fe by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The leaching of Fe in five continuous runs was found to be ≤0.6 ppm. We believe that, this is also the possible reason for the extreme stability of the FeCl₃/ SiO₂ NPs nano-particles presented herein.

Fig. 2

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Fig. 2.Recycling of FeCl3 nano-SiO2 catalyst for the preparation of 4a.

In conclusion,we have developed a straightforward and efficient approach to synthesis of 2-aminocyclohex-1-ene-1- carboxylic esters by an easy one-pot three-component reaction of primary amines,ethyl acetoacetate and chalcones in ethanol using FeCl₃-SiO₂ NPs. The present methodology offers several advantages,such as good yields,room temperature,recyclable catalyst with a very easy operation and little catalyst loading.

The authors acknowledge a reviewer who provided helpful insights. The authors are grateful to Islamic Azad University,Qom Branch.