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This journal is©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017 New J. Chem., 2017, 41, 7203--7219 | 7203

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41, 7203

Cu(II)-grafted SBA-15 functionalizedS-methylisothiourea aminated epibromohydrin(SBA-15/E-SMTU-CuII): a novel and efficientheterogeneous mesoporous catalyst†

R. Jahanshahi and B. Akhlaghinia *

Cu(II)-grafted SBA-15 functionalized S-methylisothiourea aminated epibromohydrin (SBA-15/E-SMTU-CuII) as

a novel and efficient, heterogeneous mesoporous catalyst was synthesized and characterized by different

techniques, such as FT-IR, BET, small-angle XRD, FE-SEM, TEM, TGA, ICP-OES and CHNS analysis. The

as-synthesized catalyst revealed a superior catalytic activity towards the one-pot synthesis of tetrahydropyridine

derivatives through the pseudo five-component reactions of aromatic aldehydes, aromatic amines and ethyl/

methyl acetoacetate, in ethanol at room temperature. Importantly, the synthesized mesoporous catalyst can be

recovered and reused at least ten times without any appreciable loss in its catalytic reactivity. Moreover, a TEM

image of the recovered catalyst after ten consecutive runs clearly proved the advantageous durability and

stability of the presented catalyst under the applied reaction condition.

1. Introduction

Nowadays, organic transformations would be greener, moreeconomic and more sustainable if purposive heterogeneouscatalytic systems were devised. Among the various heterogeneouscatalysts, mesoporous silica materials have attracted a great deal ofattention in this regard. SBA-15, as a mesoporous silica with 2Dchannels and higher stability compared to MCM-types, is anexcellent candidate for various types of catalytic cases.1,2 This isdue to the unique features of SBA-15, including its large surfacearea, high hydrothermal stability, regular channels with uniformand tunable pore size, and intrinsic stability and flexibility for awide variety of surface functionalizations.1,2 Based on these dis-tinctive attributes, SBA-15 silicates are considered as promisingmesoporous materials for a large number of applications, suchas environmental remediation, drug delivery processes, energystorage, photoluminescence developments, immobilization ofenzymes, proton conductivity and most importantly, utilizationas a support for the heterogenization of catalysts.2,3 In thisregard, for the development of green protocols in catalytic fields,the ingenious design of efficient heterogeneous catalytic systemsbased on mesoporous silica has been accomplished by theimmobilization of organic groups containing acidic or basic

functionalities or metal supported species.4,5 With such modifica-tions, organic–inorganic hybrid heterogeneous catalysts based onmesoporous silica would be fabricated.

Hybrid mesochannels could provide a convenient masstransfer during organic processes, as they facilitate the effectiveapproach of reactants to the catalytic active sites, as well asdriving away the products into the bulk solution of the reactionto improve the reusability of the catalyst.6–9

In recent years, the development of organic transformationsbased on multi-component reactions (MCRs) has gained eminenceas an attractive topic for assembling complex molecules withsignificant pharmaceutical features using simple and readilyavailable starting materials in a one-pot process.10 Among thereported MCRs, synthesis of tetrahydropyridine derivatives hasreceived a great deal of attention owing to their interestingbiological and pharmacological properties, such as anti-bacterial,11 anti-malarial,12 anti-hypertensive,13 anti-inflammatory14

and anti-convulsant effects.14 They are also well-known as veryimportant precursors for the total synthesis of natural productslike Reserpine, Catharanthine and Lepadin B.15 The firstreported synthesis of functionalized piperidines was performedin 1943, via multicomponent reactions between amines, aldehydesand 1,3-dicarbonyl compounds.16 Recently, a variety of catalysts,17

such as Bi(NO3)3.5H2O,18 p-toluenesulfonic acid,19 bromodimethyl-sulfonium bromide,20 nano ZrP2O7,21 thiourea oxide,22 sulfamicacid,23 CAN,24 and tetrabutylammonium tribromide (TBATB),25 hasbeen reported for the synthesis of tetrahydropyridine derivatives.However, most of these catalytic approaches have witnessed one ormore of the following drawbacks: harsh reaction conditions, high

Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad,

Mashhad 9177948974, Iran. E-mail: [email protected]; Fax: +98-51-3879-5457;

Tel: +98-51-3880-5527

† Electronic supplementary information (ESI) available: General information,spectral data of organic compounds. See DOI: 10.1039/c7nj00849j

Received 14th March 2017,Accepted 15th June 2017

DOI: 10.1039/c7nj00849j

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catalyst loadings, expensiveness or non-recyclability of the catalysts,high temperatures, long reaction times, unsatisfactory yields of theproducts and use of hazardous solvents. So, considering theimportance of these compounds, the introduction of a milder,faster and more eco-benign route accompanied with higher yieldsof the desired products is still needed.

Encouraged by these successful achievements and aiming todevelop a stable and highly active porous heterogeneous acidiccatalyst, herein we are able to report a simple, green andefficient methodology for the synthesis of tetrahydropyridinederivatives via a one-pot, pseudo five-component reactionbetween various aromatic aldehydes, aromatic amines andb-ketoesters in the presence of catalytic amounts of SBA-15/E-SMTU-CuII as a novel heterogeneous mesoporous catalyst, inethanol at ambient temperature (see Scheme 2).

2. Experimental2.1. Materials and instruments

All chemical reagents and solvents were purchased from Merck andSigma-Aldrich chemical companies and were used as received with-out further purification. Mesoporous silica (SBA-15) was prepared bythe previously reported method in the literature.26

The purity determinations of the products and the progressof the reactions were accomplished by TLC on silica gel poly-gram STL G/UV 254 plates. The melting points of the productswere determined with an Electrothermal Type 9100 meltingpoint apparatus. The FT-IR spectra were recorded on pressedKBr pellets using an AVATAR 370 FT-IR spectrometer (ThermaNicolet spectrometer, USA) at room temperature in the rangebetween 4000 and 400 cm�1 with a resolution of 4 cm�1. TheNMR spectra were recorded on an NMR Bruker Avance spectro-meter at 300 MHz in CDCl3 as solvent in the presence oftetramethylsilane as the internal standard and the couplingconstants ( J values) are given in Hz. Elemental analyses wereperformed using a Thermo Finnigan Flash EA 1112 Seriesinstrument (furnace: 900 1C, oven: 65 1C, flow carrier: 140 mL min�1,flow reference: 100 mL min�1). Mass spectra were recorded witha CH7A Varianmat Bremen instrument at 70 eV electron impactionization, in m/z (rel%). The BET surface area and pore sizedistribution were measured on a Belsorp-mini II system at–196 1C using N2 as the adsorbate. Thermogravimetric analysis(TGA) was carried out using a Shimadzu ThermogravimetricAnalyzer (TG-50) in the temperature range of 25–900 1C at aheating rate of 10 1C min�1, under air atmosphere. Transmis-sion electron microscopy (TEM) was performed with a Leo 912AB microscope (Zeiss, Germany) with an accelerating voltage of120 kV. Inductively coupled plasma optical emission spectro-scopy (ICP-OES) was carried out on a 76004555 SPECTRO ARCOSICP-OES analyzer. FE-SEM images were recorded using a TESCAN,Model: MIRA3 scanning electron microscope operating at anacceleration voltage of 30.0 kV and resolution of about 200 and500 nm (manufactured in the Czech Republic). The crystallinestructure of the catalyst was analyzed by small-angle XRD using aPANalytical Company X’Pert PRO MPD diffractometer operated at

40 kV and 40 mA, utilizing Cu Ka radiation (l = 0.154 nm) (at a stepsize of 0.0201 and step time of 2 s). All yields refer to isolatedproducts after purification by recrystallization.

2.2. Preparation of mesoporous silica (SBA-15) (I)

Pluronic P123 triblock copolymer surfactant (4.0 g) was dis-solved as a template in double distilled H2O (30 mL) and 2 MHCl solution (80.5 mL). To this solution, TEOS (tetraethylorthosilicate) (40.8 mmol, 8.5 g) was added and the reactionmixture was stirred for 8 h at 40 1C. Thereupon, the resultingmixture was transferred into a Teflon-lined stainless steelautoclave and kept at 100 1C for 20 h without stirring. Aftercooling to room temperature, the obtained product was filtered,washed with distilled H2O and dried overnight at 65 1C. Finally,the as-synthesized sample was calcined at 550 1C for 6 h toremove the copolymer template.

2.3. Preparation of epibromohydrin functionalizedmesoporous silica (SBA-15/E) (II)

SBA-15 (I) (1.5 g) was incorporated with pure epibromohydrin(10 mL) at 60 1C with vigorous stirring. After 24 h the resultingsuspension was cooled to room temperature and centrifuged.Thereafter, the obtained white precipitate was washed withethanol (4� 10 mL) until the additional amount of epibromohydrinhad been removed and then dried at 40 1C under vacuum for 10 h.

2.4. Preparation of SBA-15 functionalized S-methylisothioureaaminated epibromohydrin (SBA-15/E-SMTU) (III)

The obtained SBA-15/E (II) (1 g) was dispersed in ethanol(50 mL) for 30 min, and then S-methylisothiourea hemisulfatesalt (2.5 mmol, 0.347 g) and potassium carbonate (2.5 mmol,0.345 g) were added to the reaction mixture and refluxed for28 h. Subsequently, the resulting SBA-15/E-SMTU nanoparticleswere collected by centrifuge, washed with ethanol (3 � 15 mL)and dried at ambient temperature for 16 h.

2.5. Preparation of Cu(II)-grafted SBA-15 functionalizedS-methylisothiourea aminated epibromohydrin(SBA-15/E-SMTU-CuII) (IV)

To a solution of Cu(OAc)2�H2O (0.3 mmol, 0.055 g) in absoluteEtOH (5 mL), SBA-15/E-SMTU (III) (0.5 g) was added at roomtemperature. The reaction mixture was stirred under argonatmosphere for 4 h. Afterward, the resulting suspension wascentrifuged and the blue precipitate (SBA-15/E-SMTU-CuII) (IV)was washed with ethanol (4 � 5 mL), before being dried undervacuum at ambient temperature overnight.

2.6. Typical procedure for the synthesis of ethyl1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4a)

SBA-15/E-SMTU-CuII (0.015 g, 1 mol%) was added to a solutionof aniline (2 mmol, 0.186 g) and ethyl acetoacetate (1 mmol,0.130 g) in ethanol (5 mL) and the resulting mixture was stirredat room temperature for 5 min. Then, benzaldehyde (2 mmol,0.212 g) was added and vigorous stirring continued untilcompletion of the reaction. The progress of the reaction was

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monitored by TLC (n-hexane : EtOAc, 7 : 3; Rf = 0.73). Uponcompletion of the reaction, hot ethanol was added to thereaction mixture and the solid was filtered off and thoroughlywashed with hot ethanol. The residue was dissolved in chloro-form and then filtered to recover the heterogeneous meso-porous catalyst. The filtrate was evaporated and the resultingcrude product was recrystallized from ethanol to afford thepure 4a product (0.46 g, 98%).

2.7. Spectral data

Ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4a). (0.46 g, 98%); white solid; mp 170–171 1C(from EtOH) (lit.,27 169–171 1C); MS, m/z 474 (M+, 18%), 476(13, M + 2), 397 (30, M � C6H5

�), 271 (24, M � C12H13NO22�),

203 (37, M � C20H17N2�), 77 (19, M � C26H25N2O2�), 28 (100,

M � C30H26N2O2�).

Ethyl 2,6-bis(4-nitrophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4b). (0.50 g, 89%); pale yellowsolid; mp 246–248 1C (from EtOH) (lit.,28 247–249 1C); FT-IR(KBr): nmax/cm�1 3235, 3043, 2973, 2851, 1656, 1592, 1502, 1344,1254, 1069; 1H NMR: dH (300 MHz; CDCl3; Me4Si) 1.52 (3H, t, J =7.2 Hz, CH2CH3), 2.92 (2H, br d, J = 3.9 Hz, 5-H0, 5-H00), 4.35–4.46(1H, m, OCHaHb), 4.47–4.58 (1H, m, OCHaHb), 5.31 (1H, br s,6-H), 6.43–6.48 (4H, m, Ph), 6.52 (1H, s, 2-H), 6.73 (1H, t, J =7.2 Hz, Ph), 7.11–7.23 (5H, m, Ph), 7.29-7.35 (1H, m, Ph), 7.56(2H, d, J = 8.7 Hz, Ph), 8.18 (5H, t, J = 8.4 Hz, Ph), 10.37 (1H, br s,NH); 13C NMR: dC (75 MHz; CDCl3; Me4Si) 14.84, 33.63, 55.23,57.37, 60.30, 96.91, 112.95, 117.68, 123.81, 123.97, 125.46,126.38, 127.37, 127.40, 129.24, 129.39, 137.21, 145.82, 146.81,147.32, 149.80, 151.71, 155.35, 167.64; MS, m/z 564 (M+, 28%), 565(34, M + 1), 491 (13, M � C3H5O2

�), 441 (97, M � C6H5NO2�), 334

(72), 223 (75), 77 (56, M� C26H23N4O6�), 28 (90, M� C30H24N4O6

�).Ethyl 2,6-bis(4-cyanophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-

tetrahydropyridine-3-carboxylate (4c). (0.50 g, 97%); whitesolid; mp 191–192 1C (from EtOH) (lit.,29 190–193 1C); MS,m/z 525 (M+, 20%), 527 (9, M + 2), 422 (95, M � C7H4N�),204 (82, M � C22H14N3

2�), 93 (90, M � C28H21N3O2�), 77

(94, M � C28H23N4O2�), 29 (93, M � C32H23N4O2

�).Ethyl 2,6-bis(4-fluorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-

tetrahydropyridine-3-carboxylate (4d). (0.49 g, 96%); white solid;mp 202–203 1C (from EtOH) (lit.,30 203–204 1C), 1H NMR: dH(300 MHz; CDCl3; Me4Si) 1.38 (3H, t, J = 7.2 Hz, CH2CH3), 2.67(1H, dd, J = 2.7, 2.7 Hz, 5-H0), 2.76 (1H, dd, J = 5.1, 5.4 Hz, 5-H00),4.19-4.30 (1H, m, OCHaHb), 4.32-4.43 (1H, m, OCHaHb), 5.03(1H, br s, 6-H), 6.30 (1H, s, 2-H), 6.33 (1H, s, Ph), 6.40 (2H, d,J = 8.4 Hz, Ph), 6.56 (1H, t, J = 7.2 Hz, Ph), 6.88 (4H, t, J = 7.9 Hz,Ph), 6.98–7.22 (10 H, m, Ph), 10.23 (1H, br s, NH); 13C NMR: dC(75 MHz; CDCl3; Me4Si) 14.80, 33.80, 54.62, 57.34, 59.82, 98.05,113.01, 114.87, 115.15, 115.32, 115.60, 116.58, 125.65, 125.86,127.84, 127.95, 128.06, 128.16, 129.00, 137.75, 138.08, 139.50,146.63, 155.89, 159.89, 160.35, 163.12, 163.59, 168.06; MS, m/z510 (M+, 75%), 512 (95, M + 2), 437 (28, M� C3H5O2

�), 415 (100, M�C6H4F�), 307 (95, M� C12H13NO2

2�), 77 (96, M� C26H23F2N2O2�), 28

(94, M � C30H24F2N2O2�).

Ethyl 2,6-bis(4-chlorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4e). (0.50 g, 93%);

white solid; 200–201 1C (from EtOH) (lit.,31 199–201 1C); FT-IR(KBr): nmax/cm�1 3235, 3056, 2982, 2876, 1651, 1595, 1500,1368, 1254, 1091, 1011; 1H NMR: dH (300 MHz; CDCl3; Me4Si)1.49 (3H, t, J = 7.2 Hz, CH2CH3), 2.78 (1H, br d, J = 13.2 Hz,5-H0), 2.87 (1H, dd, J = 5.1, 5.1 Hz, 5-H00), 4.27-4.39 (1H, m,OCHaHb), 4.41–4.54 (1H, m, OCHaHb), 5.13 (1H, br s, 6-H), 6.40(1H, s, 2-H), 6.44 (2H, d, J = 7.2 Hz, Ph), 6.49 (2H, d, J = 8.4 Hz,Ph), 6.73 (1H, t, J = 7.2 Hz, Ph), 7.08–7.20 (7H, m, Ph), 7.26–7.29(6 H, m, Ph), 10.33 (1H, br s, NH); 13C NMR: dC (75 MHz; CDCl3;Me4Si) 14.82, 33.71, 54.70, 57.38, 59.89, 97.77, 112.96, 116.74,125.69, 125.96, 127.78, 128.03, 128.41, 128.79, 129.02, 129.07,132.12, 132.86, 137.66, 140.93, 142.45, 146.49, 155.83, 167.99;MS, m/z 542 (M+, 2%), 540 (14, M – 2), 465 (25, M � C6H5

�),252 (86), 166 (90), 77 (90, M � C26H23Cl2N2O2

�), 28 (100,M � C30H24Cl2N2O2

�).Ethyl 1-phenyl-4-(phenylamino)-2,6-di-p-tolyl-1,2,5,6-tetra-

hydropyridine-3-carboxylate (4f). (0.46 g, 93%); white solid;mp 229–230 1C (from EtOH) (lit.,31 227–230 1C); 1H NMR: dH(300 MHz; CDCl3; Me4Si) 1.38 (3H, t, J = 7.2 Hz, CH2CH3), 2.24(3H, s, CH3), 2.25 (3H, s, CH3), 2.68 (1H, dd, J = 2.7, 2.7 Hz,5-H0), 2.79 (1H, dd, J = 5.4, 5.4 Hz, 5-H00), 4.18–4.29 (1H, m,OCHaHb), 4.32–4.42 (1H, m, OCHaHb), 5.03 (1H, br s, 6-H),6.21–6.23 (4H, m, Ph), 6.33 (1H, s, 2-H), 6.45 (2H, d, J = 8.4 Hz,Ph), 6.51 (2H, t, J = 7.2 Hz, Ph), 6.95–7.16 (10 H, m, Ph), 10.21(1H, br s, NH); 13C NMR: dC (75 MHz; CDCl3; Me4Si) 14.83,21.04, 21.14, 33.67, 54.89, 57.96, 59.64, 98.38, 112.91, 115.96,125.53, 125.75, 126.33, 126.56, 128.79, 128.86, 128.93, 129.27,135.75, 136.60, 138.01, 139.71, 141.06, 147.09, 156.08, 168.28;MS, m/z 502 (M+, 9%), 504 (38, M + 2), 429 (9, M � C3H5O2

�),411 (100, M � C7H7

�), 71 (26, M � C31H31N2�), 28 (100,

M � C32H30N2O2�).

Ethyl 1-phenyl-4-(phenylamino)-2,6-di(thiophen-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4g). (0.45 g, 94%); white solid;mp 204–205 1C (from EtOH) (lit.,32 205–206 1C); MS, m/z 487 (M+,4%), 410 (55, M � C6H4

�), 335 (100), 187 (54, M � C17H17NO2S2�),110 (88), 77 (98, M� C22H21N2O2S2

�), 29 (98, M� C26H21N2O2S2�).

Ethyl 1-(4-nitrophenyl)-4-((4-nitrophenyl)amino)-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (4h). (0.51 g, 92%); paleyellow solid; mp, 251–252 1C (from EtOH) (lit.,33 250–252 1C);1H NMR: dH (300 MHz; CDCl3; Me4Si) 1.51 (3H, t, J = 7.2 Hz,CH2CH3), 2.72 (1H, dd, J = 5.7, 5.7 Hz, 5-H0), 2.97 (1H, dd, J = 10.2,10.5 Hz, 5-H00), 4.34–4.45 (1H, m, OCHaHb), 4.47–4.57 (1H, m,OCHaHb), 5.29 (1H, br s, 6-H), 6.42-6.46 (4H, m, Ph), 6.51 (1H, s,2-H), 6.73 (2H, t, J = 7.2 Hz, Ph), 7.10–7.33 (8 H, m, Ph), 7.55 (2H,d, J = 8.4 Hz, Ph), 8.18 (2H, t, J = 9 Hz, Ph), 10.35 (1H, br s, NH);13C NMR: dC (75 MHz; CDCl3; Me4Si) 14.81, 33.62, 55.25, 57.38,60.27, 96.94, 112.96, 117.72, 123.78, 123.94, 125.46, 126.37,127.33, 127.37, 129.22, 129.38, 137.20, 145.81, 146.84, 147.34,149.75, 151.66, 155.28, 167.60; MS, m/z 564 (M+, 84%), 566(70, M + 2), 519 (13, M – NO2

4�), 473 (41, M – 2NO2), 442(100, M � C6H4NO2

�), 269 (83), 45 (12, M � C32H29N3O4).Ethyl 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-diphenyl-

1,2,5,6-tetrahydropyridine-3-carboxylate (4i). (0.51 g, 95%); whitesolid; mp 201–203 1C (from EtOH) (lit.,28 202–204 1C); FT-IR(KBr): nmax/cm�1; 3370, 3051, 2983, 2896, 1708, 1603, 1493, 1397,1245, 1072, 1008; 1H NMR: dH (300 MHz; CDCl3; Me4Si) 1.35

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(3H, t, J = 7.2 Hz, CH2CH3), 2.67 (1H, dd, J = 2.7, 2.7 Hz, 5-H0),2.80 (1H, dd, J = 5.1, 5.4 Hz, 5-H00), 4.15-4.26 (1H, m, OCHaHb),4.29–4.40 (1H, m, OCHaHb), 4.98 (1H, br s, 6-H), 6.32 (1H, s,2-H), 6.47–6.62 (4H, m, Ph), 6.92–6.95 (4H, m, Ph), 7.06–7.23(10 H, m, Ph), 10.27 (1H, br s, NH); 13C NMR: dC (75 MHz;CDCl3; Me4Si) 13.73, 33.49, 55.27, 59.48, 60.32, 97.25, 126.525,127.00, 127.03, 127.52, 128.31, 129.17, 129.98, 131.43, 138.50,139.00, 139.36, 141.24, 143.07, 145.50, 155.41, 159.93, 168.15;MS, m/z 543 (M+, 20%), 545 (12, M + 2), 465 (77, M � C6H5

�), 322(46), 110 (36, M � C26H25ClN2O2

�), 28 (100, M � C30H24Cl2N2O2�).

Ethyl 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-bis(4-cyanophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4j). (0.56 g,95%); pale yellow solid; mp 219–220 1C (from EtOH) (lit.,29 222–224 1C); MS, m/z 593 (M+, 11%), 595 (20, M + 2), 596 (16, M + 3), 520(6, M � C3H4O2

�), 493 (68), 348 (100), 238 (95, M � C22H13ClN32�),

111 (38, M � C28H22ClN4O2�), 29 (33, M � C32H21Cl2N4O2

�).Ethyl 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-bis(4-

fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4k). (0.53 g,93%); white solid; mp 206–207 1C (from EtOH) (lit.,33 208–209 1C);1H NMR: dH (300 MHz; CDCl3; Me4Si), 1.48 (3H, t, J = 7.2 Hz,CH2CH3), 2.71 (1H, dd, J = 2.1, 2.1 Hz, 5-H0), 2.85 (1H, dd, J = 5.4,5.4 Hz, 5-H00), 4.30–4.40 (1H, m, OCHaHb), 4.43–4.54 (1H, m,OCHaHb), 5.10 (1H, br s, 6-H), 6.32 (2H, d, J = 2.7 Hz, Ph), 6.34(1H, s, 2-H), 6.41 (2H, d, J = 9 Hz, Ph), 6.97–7.06 (6 H, m, Ph), 7.09-7.15 (4H, m, Ph), 7.23–7.29 (2H, m, Ph), 10.29 (1H, br s, NH); 13CNMR: dC (75 MHz; CDCl3; Me4Si); 14.77, 33.67, 54.79, 57.41, 60.06,98.51, 114.13, 115.06, 115.34, 115.55, 115.83, 121.73, 126.83, 127.78,127.89, 127.96, 128.06, 128.85, 129.17, 131.56, 136.26, 137.53,138.76, 145.14, 155.23, 167.97; MS, m/z 580 (M+, 38%), 581(35, M + 1), 582 (26, M + 2), 583 (24, M + 3), 471 (30, M –[2F + 2Cl]), 341 (52, M � C12H12ClNO2

2�), 232 (68, M � C19H18-ClFNO2

2�), 111 (38, M � C26H22ClF2N2O2�), 29 (88, M � C30H21-

Cl2F2N2O2�).

Ethyl 1,2,6-tris(4-chlorophenyl)-4-((4-chlorophenyl)amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4l). (0.58 g, 95%);white solid; 212–213 1C (from EtOH) (lit.,34 214–215 1C); FT-IR(KBr): nmax/cm�1 3231, 3063, 2979, 2871, 1653, 1601, 1494,1369, 1256, 1090, 1012; 1H NMR: dH (300 MHz; CDCl3; Me4Si)1.38 (3H, t, J = 7.2 Hz, CH2CH3), 2.60 (1H, dd, J = 2.4, 2.7 Hz,5-H0), 2.74 (1H, dd, J = 5.7, 5.4 Hz, 5-H00), 4.19–4.30 (1H, m,OCHaHb), 4.33–4.43 (1H, m, OCHaHb), 4.98 (1H, br s, 6-H), 6.22(2H, d, J = 6.6 Hz, Ph), 6.26 (2H, d, J = 3.9 Hz, Ph), 6.30 (1H, s,2-H), 6.92–6.97 (4H, m, Ph), 7.03–7.06 (2H, m, Ph), 7.11–7.19(6 H, m, Ph), 10.17 (1H, br s, NH); 13C NMR: dC (75 MHz; CDCl3;Me4Si); 14.79, 33.59, 54.88, 57.45, 60.14, 98.24, 114.09, 121.86,126.87, 127. 69, 127.90, 128.57, 128.91, 128.97, 129.21, 131.63,132.42, 133.22, 136.18, 140.37, 141.69, 145.02, 155.16, 167.89;MS, m/z 613 (M+, 27%), 615 (18, M + 2), 358 (54, M �C13H12Cl2N�), 248 (14, M � C19H18Cl2NO2

2�), 111 (14, M �C26H22Cl3N2O2

�), 29 (98, M � C30H21Cl4N2O2�).

Ethyl 1-(4-bromophenyl)-4-((4-bromophenyl)amino)-2,6-di(thio-phen-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4m). (0.59 g,93%); white solid; mp 204–205 1C (from EtOH); FT-IR (KBr):nmax/cm�1 3246, 3084, 2924, 2855, 1651, 1607, 1491, 1369, 1261,1065; 1H NMR: dH (300 MHz; CDCl3; Me4Si) 1.49 (3H, t, J = 7.2 Hz,CH2CH3), 2.88 (1H, br d, J = 15 Hz, 5-H0), 3.14 (1H, dd, J = 5.1,

5.1 Hz, 5-H00), 4.31–4.39 (1H, m, OCHaHb), 4.43–4.51 (1H, m,OCHaHb), 5.39 (1H, br s, 6-H), 6.40 (1H, s, 2-H), 6.44 (1H, d, J =8.1 Hz, Ph), 6.65 (2H, d, J = 8.7 Hz, Ph), 6.86–6.95 (4H, m, Ph), 7.17(2H, d, J = 4.8 Hz, Ph), 7.23 (2H, d, J = 8.7 Hz, Ph), 7.29 (1H, s, Ph),7.34 (2H, d, J = 8.1 Hz, Ph), 10.45 (1H, br s, NH); dC (75 MHz;CDCl3; Me4Si) 14.733, 34.15, 52.56, 53.77, 60.08, 98.14, 109.50,114.92, 118.05, 119.12, 123.84, 124.14, 124.47, 124.57, 124.90,125.34, 126.55, 126.67, 126.82, 127.07, 127.20, 131.50, 131.63,132.20, 132.44, 137.05, 145.08, 146.57, 148.22, 155.20, 167.58;MS, m/z 645 (M+, 23%), 647 (19, M + 2), 475 (27, M – 2[C4H3S�]),473 (37, M� C6H4BrN�), 347 (89, M� C13H13BrNS3�), 154 (90, M�C22H20BrN2O2S2

�), 29 (90, M � C26H19Br2N2O2S2�); elemental

analysis: found: C, 52.22; H, 3.79; H, 4.37. Calc. for C28H24Br2-N2O2S2: C, 52.19; H, 3.75; N, 4.35%.

Methyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydro-pyridine-3-carboxylate (4n). (0.44 g, 97%); white solid; mp198–199 1C (from EtOH) (lit.,35 200–202 1C); MS, m/z 460 (M+,7%), 461 (38, M + 1), 181 (100, M � C18H17NO2

2�), 92 (70, M �C25H22NO2

�), 77 (85, M � C25H23N2O2�), 57 (43, M �

C29H27N2�).

Methyl 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (4o). (0.50 g, 96%); whitesolid; mp 200–201 1C (from EtOH) (lit.,27 202–204 1C); FT-IR (KBr):nmax/cm�1 3258, 3084, 3023, 2949, 2872, 1651, 1600, 1492, 1318, 1254,1077; 1H NMR: dH (300 MHz; CDCl3; Me4Si), 2.74 (1H, dd, J = 1.8, 1.8Hz, 5-H0), 2.91 (1H, dd, J = 5.7, 5.7 Hz, 5-H00), 3.99 (3H, s, OCH3), 5.16(1H, br s, 6-H), 6.20 (1H, s, 2-H), 6.22 (1H, s, Ph), 6.44 (1H, s, Ph), 6.47(1H, s, Ph), 6.50 (1H, s, Ph), 7.02 (1H, s, Ph), 7.05 (1H, s, Ph), 7.09 (1H,s, Ph), 7.11 (1H, s, Ph), 7.19–7.22 (2H, m, Ph), 7.25–7.33 (8 H, m, Ph),10.26 (1H, br s, NH); 13C NMR: dC (75 MHz; CDCl3; Me4Si) 33.50,51.26, 55.28, 58.33, 98.43, 114.03, 121.25, 126.32, 126.53, 126.64,127.13, 127.52, 128.43, 128.76, 128.87, 129.07, 131.49, 136.35,142.25, 143.15, 145.48, 155.64, 168.50; MS, m/z 529 (M+, 57%), 531(38, M + 2), 451 (98, M� C6H5

�), 417 (27, M� C6H4Cl�), 214 (94), 77(61, M � C25H21Cl2N2O2

�), 59 (100, M � C29H23Cl2N2�).

Methyl 2,6-diphenyl-1-(p-tolyl)-4-(p-tolylamino)-1,2,5,6-tetrahydro-pyridine-3-carboxylate (4p). (0.46 g, 96%); white solid; mp 218–219 1C(from EtOH) (lit.,27 218–220 1C); MS, m/z 488 (M+, 37%), 489(22, M + 1), 461 (23, M � C2H4

2�), 285 (17, M � C12H13NO22�),

203 (14, M � C21H19N2�), 28 (87, M � C31H29N2O23�).

Methyl 1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-2,6-diphenyl-1,2,5,6 tetrahydropyridine-3-carboxylate (4q).(0.50 g, 97%); white solid; mp 220–221 1C (from EtOH) (Lit.36

220–222 1C); MS, m/z 520 (M+, 15%), 522 (10, M + 2), 301 (35,M � C12H13NO3

2�), 219 (15, M � C21H19NO2�), 205 (20, M �C22H21NO2�), 69 (95, M � C29H27N2O3

3�), 32 (100, M �C32H28N2O3

�).

3. Results and discussion3.1. Synthesis and characterization of SBA-15/E-SMTU-CuII

Following our interest in designing new efficient and environ-mentally benign heterogeneous catalysts for organic transforma-tions,37 in the present study, SBA-15/E-SMTU-CuII was initiallysynthesized according to the pathway shown in Scheme 1.

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Then, the newly synthesized catalyst was fully characterizedby means of different techniques, such as Fourier transforminfrared spectroscopy (FT-IR), thermogravimetric analysis(TGA), transmission electron microscopy (TEM), small-angleX-ray diffraction (small-angle XRD), field emission scanningelectron microscopy (FE-SEM), Brunauer, Emmett and Teller(BET) surface area analysis, inductively coupled plasma opticalemission spectroscopy (ICP-OES) and elemental analysis(CHNS). The results obtained from these techniques confirmedthe successful preparation of the new mesoporous catalyst.

Fig. 1 illustrates the FT-IR spectra of SBA-15, SBA-15/E, SBA-15/E-SMTU and SBA-15/E-SMTU-CuII. Typical bands at 464, 804and 1087 cm�1 are correlated to bending, symmetric andasymmetric vibrations of Si–O–Si, respectively.37a A distinctiveband at 1635 cm�1, in addition to the broad absorption bandcentered at ca. 3428 cm�1, are respectively assigned to thebending and stretching modes of the surface attached hydroxylgroups with regard to Si–OH moieties and the adsorbed watermolecules.38 The existence of the epoxy groups grafted to theSBA-15 framework was confirmed by the methylene C–Hstretching and bending vibration bands at 2879–2956 and1425 cm�1, respectively (Fig. 1b).39 Furthermore, the appear-ance of four new bands at 619, 1427, 1546 and 1660 cm�1, wellconfirmed the ring opening of the epoxy group with S-methylisothiourea (Fig. 1c). Likewise, the diminution in inten-sity of the weak bands at around the 850–950 and 1635 cm�1

regions in the modified SBA-15 against the parent SBA-15

clearly documented the successful surface functionalizationof the silicate1c (see dotted areas in Fig. 1).

Importantly, in the FT-IR spectrum of SBA-15/E-SMTU(Fig. 1c), the appearance of a new band at 1660 cm�1 whichis assigned to the CQN vibrations could authenticate theexistence of the anchored S-methylisothiourea groups.40 Fasci-natingly, the characteristic absorption band related to the CQNstretching vibration experienced a strong shift to a lower

Scheme 1 An overview of the synthesis of SBA-15/E-SMTU-CuII.

Fig. 1 FT-IR spectra of (a) SBA-15; (b) SBA-15/E; (c) SBA-15/E-SMTU; (d)SBA-15/E-SMTU-CuII and (e) 10th recovered SBA-15/E-SMTU-CuII.

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frequency upon CuII coordination, which can be attributed tothe formation of a strong copper complex on the surface of thefunctionalized SBA-15.40

Fig. 2 shows the N2 adsorption–desorption isotherms andthe corresponding BJH pore-size distribution curves of the SBA-15 and SBA-15/E-SMTU-CuII. As can be seen in Fig. 2(a and c), atypical type IV isotherm with a H1 hysteresis loop was present forboth the intact SBA-15 and SBA-15/E-SMTU-CuII, which is character-istic of mesoporous materials with uniform cylindrical pores.41

Table 1 illustrates the respective average surface areas, pore volumesand mean pore diameters of both SBA-15 and SBA-15/E-SMTU-CuII.The BET surface area, pore volume and pore diameter of the intactSBA-15 were 737.09, 1.219, and 6.615, respectively which werediminished after the modification process. These results verify thesuccessful functionalization of the SBA-15 structure. In addition, theBJH calculations demonstrated a uniform pore-size distribution witha high-intensity peak, which proves the high regularity of themesostructure (Fig. 2b and d).

Small-angle XRD was performed to gain further insight intothe structural features of the catalyst. As is illustrated in Fig. 3,diffraction peaks below 21, which are related to (100), (110) and(200) reflections, can be readily recognized from the XRDpatterns of SBA-15, SBA-15/E-SMTU-CuII and also the 10th recov-ered SBA-15/E-SMTU-CuII. These indicated diffraction peaks

clearly suggested a two-dimensional hexagonal structure42 forthe intact SBA-15, final designed catalyst and 10th recovered one.

Field emission scanning electron microscopy (FE-SEM) analysiswas also performed to study the morphology of the as-synthesizedcatalyst (Fig. 4a and b). As is clearly evident, FE-SEM images of SBA-15/E-SMTU-CuII revealed a uniform rod-like morphology.

Transmission electron microscopy (TEM) images of SBA-15/E-SMTU-CuII also indicated that the newly synthesized catalysthas an ordered hexagonally mesoporous structure with anaverage pore size of about 4.5 nm, along with a superbregularity in the channel framework (Fig. 4c).

These observations are also in very good agreement with thedata obtained from the small-angle XRD and nitrogen adsorp-tion–desorption analyses. Accordingly, it can be concluded thatthe regularity of the mesoscopic channels was well retainedafter the modification procedure, which further highlights thestability of the catalyst during the functionalization process.

TGA was carried out to investigate the thermal stability ofboth fresh and 10th recovered SBA-15/E-SMTU-CuII catalysts(Fig. 5). The results exhibited two weight losses in differenttemperature ranges. As is evident from Fig. 5a, TGA thermo-gram of the fresh catalyst demonstrated a significant weightloss of about 1.8% at temperatures below 120 1C which could beattributed to the removal of the physically adsorbed water andmost probably ethanol. Also, the main weight loss (18.5%)between 120 and 550 1C could be assigned to the eliminationof organic functional groups incorporated in the mesoporouscatalyst framework.

Based on the TGA thermogram of the fresh catalyst, theamount of organic motif supported on SBA-15 was estimated tobe 0.63 mmol g�1. These results were also in good agreementwith the obtained elemental analysis data (N = 1.75% and C =4.05%) and ICP-OES of the fresh catalyst. The ICP-OES analysisof the fresh catalyst indicated that 0.67 mmol of copper wasanchored on 1.00 g of the catalyst.

3.2. Catalytic synthesis of tetrahydropyridine derivatives

After successful preparation and full characterization of theSBA-15/E-SMTU-CuII, its catalytic activity was evaluated for thegreen, one-pot, pseudo five-component synthesis of tetrahydro-pyridine derivatives by conducting the reaction of various

Fig. 2 Nitrogen adsorption–desorption isotherms (a and c) and pore sizedistribution isotherms (b and d) of SBA-15 and SBA-15/E-SMTU-CuII.

Table 1 Specific surface area (SBET), pore volume and mean pore dia-meter of SBA-15 and SBA-15/E-SMTU-CuII

SampleSBET

(m2 g�1)Pore volume(cm3 g�1)

Mean porediameter (nm)

SBA-15 737 1.2 6.6SBA-15/E-SMTU-CuII 319 0.5 4.5

Fig. 3 Small-angle XRD patterns of (a) SBA-15, (b) fresh SBA-15/E-SMTU-CuII and (c) 10th recovered SBA-15/E-SMTU-CuII.

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aromatic aldehydes (2.0 mmol), aromatic amines (2.0 mmol)and ethyl/methyl acetoacetate (1.0 mmol), at room temperature(Scheme 2).

Initially, in order to optimize the reaction conditions, thesynthesis of compound 4a was investigated as a model reaction(Table 2). At the beginning, the reaction of benzaldehyde(2.0 mmol), aniline (2.0 mmol) and ethyl acetoacetate(1.0 mmol) was studied under solvent-free conditions, as wellas with different solvents to assess the solvent effect on thereaction rate (Table 2, entries 3–13). In this context, althoughthe reaction temperature range varied from ambient to thereflux temperature of the tested solvent, the best result wasobtained when EtOH at room temperature (in the presence of0.015 g of SBA-15/E-SMTU-CuII) was used as the reactionmedium (Table 2, entry 6). Consequently, the efficiency of themesoporous catalyst was considerably affected by the selectedsolvent. As can be seen from the data summarized in Table 2,by diminishing the amount of catalyst, the product yield wassignificantly decreased (Table 2, entries 3 and 4). This evidentlyestablished that the reaction was strongly affected by the

Fig. 4 FE-SEM images of SBA-15/E-SMTU-CuII (a and b); TEM images of the fresh SBA-15/E-SMTU-CuII (c) and TEM images of SBA-15/E-SMTU-CuII

after 10 runs (d).

Fig. 5 TGA thermograms of the fresh SBA-15/E-SMTU-CuII (a) and 10thrun recycled SBA-15/E-SMTU-CuII (b).

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amount of catalyst. As observed, a blank experiment in theabsence of any catalyst in solvent-free conditions, either atroom temperature or 100 1C, afforded no desired product evenafter a prolonged reaction time (Table 2, entries 1 and 2). Toshow the crucial effect of SBA-15/E-SMTU-CuII on the reactionprogress, in the next experiment, the catalytic performances ofSBA-15, SBA-15/E and SBA-15/E-SMTU were also checked underthe same reaction conditions (Table 2, entries 14–16). In thisregard, the product yields were trace amounts, even after a longreaction time. In addition, by keeping the other conditions thesame, the effect of using Cu(OAc)2 as catalyst was also investi-gated. Nevertheless, the result was far from satisfactory in thiscontext (Table 2, entry 17). Despite Cu(OAc)2 being homogenousin nature and being expected to have more activity, the catalyticactivity of the SBA-15/E-SMTU-CuII mesoporous catalyst wasextremely higher. The reason may be deduced from the fact thatthe mesoporous SBA-15/E-SMTU-CuII catalyst acts as a smartnanoreactor, which could increase the impressive collisions ofthe reactants within the catalyst structure, leading to an improve-ment in the product yields. These findings confirm the key roleof SBA-15/E-SMTU-CuII in the catalytic process of this reaction.

To explore the scope and limitations of this reaction, varioussubstituted aromatic aldehydes, aromatic amines and methylor ethyl acetoacetate were examined under the optimizedconditions and the results are summarized in Table 3. Aromaticaldehydes with electron-withdrawing as well as electron-releasing groups reacted with an almost equal efficiency witheither electron-poor or electron-rich anilines to furnish thecorresponding piperidines in good to excellent yields. It is worthmentioning that even heteroaromatic aldehydes such asthiophen-2-carbaldehyde also afforded the respective productsin high yields, at room temperature (Table 3, entries 7 and 13).These observations further proved the outstanding capability ofthe SBA-15/E-SMTU-CuII mesoporous catalyst in catalyzing theone-pot, pseudo five-component reaction of a broad range ofaromatic aldehydes with aromatic amines and b-ketoesters.

All of the synthesized products were known compounds,except compound 4m, and their structures were confirmed bycomparison of their melting points and mass spectrometry withthose of authentic compounds. The selected compounds werefurther identified by FT-IR, 1H NMR and 13C NMR spectro-scopy, which were in a good agreement with the data reportedin the literature (see ESI†). The novel synthesized compound(4m) was also characterized by using an elemental analysistechnique. FT-IR spectra of the purified products exhibited anabsorption band at around 1592–1657 cm�1, which obviouslyconfirms the conjugation of carbonyl and olefinic groups.Furthermore, the 1H NMR spectra displayed two close multipletsat around 4.15–4.58 ppm relating to the methylene protons of acarbethoxy group. Also, the proton attached to C-2 of the piperidinering was visualized as a sharp singlet at around 6.30–6.52 ppm or itmight come into view along with a number of aromatic protonsmultiplets ranging from 6.20 to 6.51 ppm. In addition, the onlyexchangeable secondary amine proton (NH) devoted to C-4appeared as a broad singlet at about 10.21–10.35 ppm. Likewise,the 13C NMR spectra disclosed the requisite number of distinctresonances in agreement with the proposed product structure. Inaddition, mass spectra of all the prepared products showed mole-cular ion peaks at their respective m/z.

On the other hand, comparing the physical and spectro-scopic data of known compounds (4a–q) with those of authen-tic compounds evidently proved the anti-configuration of thecorresponding tetrahydropyridine derivatives.18,24,29,43 For amore detailed study, the structure of a selected compound (4l)was scrutinized according to an extensive 1H NMR experimentinvolving the NOESY technique. As can be observed in Fig. 6, theabsence of any cross-peak between H2 and H6 on the six-memberedring of the evaluated tetrahydropyridine clearly indicated the lack ofspatial vicinity and interaction between H2 and H6 and conse-quently offered a certain anti-configuration for the respectiveproduct. Nevertheless, weak interactions between H6 and aromatichydrogens are visualized in the NOESY 1H NMR spectrum of theproduct (see the magnified red cycle in Fig. 6).44

By analogy with previous reports in the literature,17b,19,21,24,25,43a,44

as well as our investigations, a conceivable mechanism for thesynthesis of tetrahydropyridine derivatives under the catalytic per-formance of SBA-15/E-SMTU-CuII is proposed in Scheme 3. Based on

Scheme 2 Synthesis of tetrahydropyridine derivatives in the presence ofSBA-15/E-SMTU-CuII at room temperature.

Table 2 One-pot, pseudo five-component synthesis of ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4a)under different reaction conditions

Entry Catalyst (g) Solvent Time (min) Temp. (1C) Isolated yield (%)

1 — — 100 r.t. N.R.2 — — 100 100 N.R.3 0.009 — 20 r.t. 504 0.010 — 20 r.t. 755 0.015 — 20 r.t. 856 0.015a EtOH 20 r.t. 987 0.015 EtOH 20 50 988 0.015 EtOH 15 Reflux 989 0.015 MeOH 30 Reflux 9810 0.015 H2O 40 Reflux 4711 0.015 CH3CN 80 Reflux 8312 0.015 CHCl3 80 Reflux 5913 0.015 Toluene 80 Reflux 6814 0.015b EtOH 60 r.t. Trace15 0.015c EtOH 60 r.t. Trace16 0.015d EtOH 60 r.t. Trace17 1 (mol%)e EtOH 60 r.t. 15

a 0.015 g of the catalyst is equal to 1 mol% of copper. b Reaction wasperformed in the presence of SBA-15 as catalyst. c Reaction was per-formed in the presence of SBA-15/E as catalyst. d Reaction was per-formed in the presence of SBA-15/E-SMTU as catalyst. e Reaction wasperformed in the presence of Cu(OAc)2 as catalyst.

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Table 3 Pseudo five-component synthesis of tetrahydropyridines (4a–q) under the catalytic pathway of SBA-15/E-SMTU-CuIIa

Entry R1 R2 R3 Product Time (min) Yieldb (%)

1 C6H5 C6H5 Et 20 98

2 4-NO2C6H4 C6H5 Et 45 89

3 4-CNC6H4 C6H5 Et 20 97

4 4-FC6H4 C6H5 Et 20 96

5 4-ClC6H4 C6H5 Et 20 93

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Table 3 (continued )


6 4-CH3C6H4 C6H5 Et 35 93

7 C4H3S C6H5 Et 25 94

8 C6H5 4-NO2C6H4 Et 30 92

9 C6H5 4-ClC6H4 Et 25 95

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10 4-CNC6H4 4-ClC6H4 Et 25 95

11 4-FC6H4 4-ClC6H4 Et 25 93

12 4-ClC6H4 4-ClC6H4 Et 30 95

13 C4H3S 4-BrC6H4 Et 25 93

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the presented mechanism, initially, the carbonyl groups ofb-ketoester and aromatic aldehyde were activated by the SBA-

15/E-SMTU-CuII catalyst, which made them susceptible to thenucleophilic attack of aniline. Thereafter, the activated b-ketoester



14 C6H5 C6H5 Me 15 97

15 C6H5 4-ClC6H4 Me 25 96

16 C6H5 4-CH3C6H4 Me 20 96

17 C6H5 4-OCH3C6H4 Me 15 97

a Reaction conditions: aromatic aldehydes (2 mmol), aromatic amines (2 mmol), ethyl/methyl acetoacetate (1 mmol), SBA-15/E-SMTU-CuII

(1 mol%), in ethanol (5 ml) at room temperature. b Isolated yield.

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and aromatic aldehyde were separately condensed with aniline togive b-enaminone (I) and imine (II), respectively. Subsequently, anintermolecular Mannich reaction occurred between b-enaminone(I) and imine (II) to generate intermediate III. Intermediate III wasreacted with another molecule of aldehyde to give intermediate IVthrough the elimination of one H2O molecule. Finally, tauto-merization of IV led to the formation of intermediate V, whichinstantaneously underwent an intramolecular Mannich reaction tooffer the product VI. Next, upon tautomerization, VI was convertedto the more stable form of the desired tetrahydropyridine (VII).Further investigations to elucidate the details of the mechanismand scope of this reaction are ongoing.

In continuation of our study, a hot filtration test was alsoperformed. For this purpose, the reaction of benzaldehyde,aniline and ethyl acetoacetate was selected as a model reactionand evaluated under the optimal conditions. Then, precisely10 minutes after the start of the reaction (before completeconsumption of all the substrates), the catalyst was separatedfrom the reaction mixture by filtration. In this step, only

45% conversion was achieved. Afterwards, the reaction waspermitted to continue at room temperature for a further 3 h.That there was no considerable reaction progress in this regardwell suggested that no leaching of copper occurred during thereaction. However, the negative hot filtration test should not beused to attribute the actual catalytic activity to heterogeneityalone. This is due to the fact that in many circumstances,leached and soluble metal species can be redeposited back onthe insoluble support, during the hot filtration stage. In thiscontext, the catalytic pathway would proceed through a ‘‘release–capture’’ mechanism.45 By the way, since the reactions presentedin the current study were conducted under ambient temperatureand by considering the fact that the release of true active speciesfrom the support under ambient temperature is difficult to someextent, we have speculated that the respective mesoporouscatalyst most likely operated in a heterogeneous manner.

The measured copper content of the freshly prepared SBA-15/E-SMTU-CuII based on ICP-OES analysis was estimated to be0.67 mmol of Cu per 1.00 g of the catalyst, whereas ICP-OES

Fig. 6 H–H NOESY spectrum of ethyl 1,2,6-tris(4-chlorophenyl)-4-((4-chlorophenyl)amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4l).

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analysis of the 10th reused catalyst showed that the recoveredmesoporous catalyst contains 0.64 mmol of Cu per 1.00 g of thecatalyst. This means that the amount of copper leached fromthe surface of the mesoporous catalyst is negligible.

The reusability of the catalyst is a very significant factor,particularly for commercial and industrial applications. Alongthese lines, we devised a set of experiments to study the recycl-ability of the SBA-15/E-SMTU-CuII catalyst in the model reactionunder the optimized conditions. It can be seen that the aforemen-tioned catalytic system is extremely reusable under the investigatedreaction conditions since almost no significant deactivation of themesoporous catalyst occurred after several recovery processes(Fig. 7). However, the lower observed efficiency for the regeneratedmesoporous catalyst after 10 cycles might be principally due to thepartial saturation of mesochannels containing catalytic active sitesduring the reaction process.

To gain a deeper insight into the structural stability of SBA-15/E-SMTU-CuII after 10 runs, the recovered catalyst was alsocharacterized by FT-IR, small-angle XRD, TEM and TGAtechniques.

It is noteworthy that the FT-IR spectrum of the 10th recov-ered catalyst (Fig. 1e) revealed the complete preservation of theshape, position and relative intensity of the characteristicabsorption bands. These results clearly proved that no sub-stantial changes occurred in the chemical structure of thefunctional groups and the hydrogen bonding network of themesoporous catalyst.

Scheme 3 A plausible reaction mechanism for the synthesis of tetrahydropyridine derivatives in the presence of SBA-15/E-SMTU-CuII.

Fig. 7 Recyclability study of SBA-15/E-SMTU-CuII for the model reaction.

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In the small-angle XRD patterns of SBA-15, fresh SBA-15/E-SMTU-CuII and 10th recovered SBA-15/E-SMTU-CuII, thepresence of three well-resolved peaks below 21, indexed as(100), (110) and (200) reflections, clearly confirmed the two-dimensional hexagonal symmetry (P6mm) of these materials(Fig. 3).2c,d,42 However, an overall attenuation in the intensity ofthese 3 peaks (especially the intensity of the (100) reflection)was noticed after the modification process (Fig. 3b). This mightbe caused by the effect of pore-filling of functional groups thatcan reduce the scattering contrast between the framework ofthe SBA-15 support and the filled pores with the organicmoieties, which would be accompanied by the fractional lossof the ordered silica structure due to the incorporation oforganic motifs.2c,d,46 More importantly, the small-angle XRDpattern of SBA-15/E-SMTU-CuII after ten runs showed no con-siderable broadening or shifting of peaks when compared withthe small-angle XRD pattern of the fresh catalyst (Fig. 3c). Thepersistence of the (100), (110) and (200) reflections not onlyproved the structural stability and existence of a long rangeordering to the mesochanels, but also the survival of theundisturbed pore wall thickness, even after several cycles.47

Interestingly, the TEM image of the recycled catalyst exhibitedthe preservation of well-ordered arrays of SBA-15/E-SMTU-CuII,even after 10 runs of the reaction (Fig. 4d).

Furthermore, the TGA thermogram of the 10th recoveredcatalyst revealed an almost similar decomposition pattern tothat of the fresh catalyst (Fig. 5b). While the fresh SBA-15/E-SMTU-CuII revealed 18.5% loss of the grafted organic motif inthe main step, this percentage loss was calculated to be 17.4%for the recycled catalyst. Accordingly, the amount of the graftedorganic motif decreased from 0.63 mmol to 0.60 mmol after10 cycles, which might be ascribed to the small amount ofleaching of organic motif from the support surface, afterconsecutive runs. However, the amount of leaching was verynegligible even after ten successive cycles.

These data are in a reasonable agreement with each otherand strongly confirm the admirable structural and mechanicalstability of the presented catalyst in this protocol.

To further elucidate the superiority of the presented metho-dology over some previously reported procedures for the one-pot

pseudo-five component synthesis of ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4a),the catalytic efficiency of SBA-15/E-SMTU-CuII was comparedwith some hitherto reported catalytic systems in the literature(Table 4). Although each of these approaches has their ownmerits, they often suffer from one or more of the followingdrawbacks: using hazardous solvents, strict reaction condi-tions, non-reusable catalysts, large amounts of catalysts, higherreaction temperatures, longer reaction times and lower yieldsof the products. However, as can be seen in Table 4, theseproblems were eliminated by using the introduced catalyticsystem in the respective study, which significantly confirmsthe privileged performance of SBA-15/E-SMTU-CuII in such atransformation.

4. Conclusion

In summary, we have successfully synthesized SBA-15/E-SMTU-CuII as a novel, efficient, heterogeneous mesoporous catalystand then characterized it by different techniques such as FT-IR,BET, small-angle XRD, FE-SEM, TEM, TGA, ICP-OES and CHNSanalysis. The catalytic efficiency of this new catalytic system wasinvestigated for the preparation of a wide range of tetrahydro-pyridine derivatives through the pseudo five-component reac-tions of aromatic aldehydes, aromatic amines, and ethyl/methylacetoacetate, in ethanol at room temperature. Surprisingly, theperformance of the present methodology surpasses that ofmany other approaches reported in the literature, especiallyin terms of the operational simplicity of the reaction, mildnessof the reaction conditions, using lower amounts of the catalyst,attaining high yields of products within shorter reaction timesand the generality of the synthetic route. More importantly, thedeveloped protocol not only involves the preparation of highlydiastereoselective pharmaceutically imperative tetrahydro-pyridine derivatives, but also its association with high atomefficiency and the superb reusability of the catalyst, as well asthe simple purification of the products (without the use ofcolumn chromatography), make it more suitable and a pre-ferred methodology over most existing procedures.

Table 4 Comparison the catalytic efficiency of SBA-15/E-SMTU-CuII with the previously reported catalytic systems in the one-pot pseudo-fivecomponent synthesis of 4a

Entry Catalyst (mol%) Reaction conditions Time (h) Yield (%) Ref.

1 Nano ZrP2O7, (5) EtOH, ultrasonic irradiation 1 93 212 CAN, (15) MeCN, r.t. 23 80 243 ([K+PEG]Br3

�),a (10) EtOH, r.t. 8 80 484 — AcOH, r.t. 3 84 495 BDMS,b (10) MeCN, r.t. 6 76 206 FeCl3.6H2O (0.3 mmol) EtOH, r.t. 7 75 507 Sulfamic acid, (15) EtOH, reflux 5 78 238 ZrOCl2.8H2O, (20) EtOH, reflux 3.5 83 519 L-Proline nitrate, (10) MeOH, r.t. 8 80 5210 ZrCl4, (10) EtOH, r.t. 9 87 43a11 [TMG]ClO4,c (20) Solvent-free, 100 1C 52 min 87 43c12 Bi(OTf)3, (10) EtOH, reflux 7 66 5313 SBA-15/E-SMTU-CuII, (1) EtOH, r.t. 20 min 98 Present study

a PEG-embedded potassium tribromide. b Bromodimethylsulfonium bromide. c 1,1,3,3-Tetramethylguanidinium perchlorate.

NJC Paper


Acknowledgements

The authors gratefully acknowledge the partial support of thisstudy by Ferdowsi University of Mashhad Research Council(Grant no. p/3/39490).

Notes and references

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