Synthesis of polysubstituted 1,4-dihydropyridines via three-component reaction

Tetrahedron 69 (2013) 738e743

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Synthesis of polysubstituted 1,4-dihydropyridines via three-component reaction Saeed Balalaie a, *, Leila Baoosi a, Fatemeh Tahoori a, Frank Rominger b, Hamid Reza Bijanzadeh a a b

Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran €t Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany Organisch-Chemisches Institut der Universita

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 May 2012 Received in revised form 16 October 2012 Accepted 29 October 2012 Available online 21 November 2012

An efficient one-pot synthesis of novel N-substituted 1,4-dihydropyridine derivatives via a threecomponent reaction of primary amines, dialkyl acetylenedicarboxylates, and methyl (arylmethylidene) pyruvates has been reported. The reaction is performed using ZnCl2 (40 mol %) in dichloroethane in good to high yields through a domino Michael/cyclization sequence. Notably, the ready availability of the starting materials, high bond-forming efficiency, good to high yields and the high level of practicability of the reaction and work up make this approach an attractive complementary method for access to Nsubstituted 1,4-dihydropyridines. Ó 2012 Elsevier Ltd. All rights reserved.

Dedicated to Professor Issa Yavari on the occasion of his 65th birthday

Keywords: N-Substituted 1,4-dihydropyridines Methyl (arylmethylidene) pyruvate Enaminone Zinc chloride Dialkyl acetylenedicarboxylate Domino Michael/cyclization

1. Introduction The design and efficient synthesis of bioactive compounds is one of the main objectives of organic and medicinal chemistry. In recent years, multicomponent reactions have become important tools in the preparation of structurally diverse chemical libraries of drug-like polyfunctional compounds.1 However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions with high efficiency and selectivity.2 Development of more efficient synthetic methods in order to assemble diverse molecules with minimal by-products, in a highly efficient and atom-economical manner attracted a great deal of attention from chemists around the world.2 To this day 4-aryl-1,4-dihydropyridine-3,5-dicarboxylic esters of the nifedipine type (1) are one of the most widely used and studied medications among calcium-channel blockers.3 Furthermore, they are also used as cognition enhancers, neuroprotectants, and platelet antiaggregatory agents.4 Additionally a number of 1,4-DHP calcium antagonists have been introduced as potential drugs for the treatment of congestive heart failure.5 For example, 2 is suitable in treatment of multidrug resistance,6 SNAP5089

* Corresponding author. Fax: þ98 21 22853650; e-mail address: balalaie@ kntu.ac.ir (S. Balalaie). 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.10.082

3 could reduce hyperplasia,7 and DHPs 4, and 5 have antimicrobial activity8 and antitubercular activity,9 respectively (Fig. 1). It is shown that the existence of ester groups in the structure of DHP and their positions has an important role in its antihypertensive activity.3def So far, many protocols for the synthesis of DHPs have been reported.10 As a part of our current studies on the development of new routes in heterocyclic synthesis via novel one-pot MCRs,11 we report here for the first time a novel threecomponent reaction of methyl (arylmethylidene) pyruvates 6, primary amines 7, and dialkyl acetylenedicarboxylates 8 in the presence of zinc chloride (40 mol %) for the synthesis of polyfunctionalized 1,4-dihydropyridines (Scheme 1). 2. Results and discussion Recently, we have focused our research and development efforts on the preparation of new compound libraries containing biologically active heterocyclic skeletons. In this way, methyl (arylmethylidene) pyruvates (6) have been used as suitable starting materials. They play an important role as an attractive starting material for the following reasons: (a) they have higher reactivities in comparison to usual b,g-unsaturated a-ketones; (b) they contain active functional groups, which can be used for further synthesis; and (c) their preparation is easy, i.e., they can be synthesized

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3

2

4 5 Fig. 1. Bioactive compounds with dihydropyridine core structure.

Scheme 1. Synthesis of N-substituted 1,4-dihydropyridines via three-component reaction in the presence of ZnCl2.

according to the known procedure by reaction of aromatic aldehydes and pyruvic acid in an aqueous MeOH solution of KOH.12 Typically, the addition of amines to dialkyl acetylenedicarboxylate has been extensively studied and the desired DMAD-primary amine adducts (enaminone) as a mixture of E and Z isomers have been used as efficient starting materials for the synthesis of heterocyclic skeletons.13 We began our investigation with methyl (phenylmethylidene) pyruvate 6a, which was synthesized according to the reported procedure.12 The reaction of 6a with benzylamine and dimethyl acetylenedicarboxylate was selected as the model reaction. Heating of the mixture in toluene for 72 h did not provide our goal and a mixture of E and Z of enaminones was obtained. After this failure, we tried various Lewis acids, such as ZrO2, ZrCl4, CuI, but the desired product was not formed. We only got satisfactory results with ZnCl2 and FeCl3. The best result was obtained with ZnCl2. According to this result, ZnCl2 was selected as the best Lewis acid for the synthesis of desired N-substituted 1,4-dihydropyridine 9a. Then the amount of this Lewis acid was examined in the model reaction. The reaction was checked without the presence of ZnCl2 and FeCl3 as Lewis acids, and we did not get any product. In the presence of 20, 30, and 40% of ZnCl2, the yield of 9a was obtained 38, 47, and 61%, respectively. This confirmed the important role of ZnCl2 in this reaction. The optimum reaction condition used of 40% ZnCl2 and boiling toluene as reaction medium (Table 1). The amount of reactants was further optimized and, finally, the best ratio of 6a, 7a, and 8a (1.3:1.3:1) was selected. In an attempt to investigate the range of solvents compatible with this reaction, methyl (phenylmethylidene) pyruvate 6a and enaminone from reaction of benzylamine and dimethyl acetylenedicarboxylate in the

Table 1 The effect of the amount of different Lewis acids on the synthesis of N-substituted 1,4-dihydropyridine 9a Lewis acid

(mol %)

Yielda [%]

CuI ZrO2 ZrCl4 CuBr2 Zn(OAc)2 FeCl3 ZnCl2 ZnCl2 ZnCl2

20 20 20 20 20 20 20 30 40

d d d 30 d 50 38 47 61

a

Yield of isolated product.

presence of 40% ZnCl2 were chosen for a model system, and this reaction was performed in various solvents. A change in the solvent to trifluoroethanol, ethanol, acetonitrile, toluene, 1,4-dioxane, THF, and dichloroethane gave the desired N-substituted 1,4-dihydropyridine 9a in 8e68% yield. The results summarized in Table 2. The best yield for reaction model was obtained in dichloroethane. After finding suitable conditions, the three-component reaction of methyl (arylmethylidene) pyruvates, dialkyl acetylenedicarboxylates, and also different primary amines for the synthesis of 1,4dihydropyridines 9aen were studied. The results summarized in Table 3. The scope of the reaction with regard to a substitution pattern in primary amines was investigated. Some aniline derivatives were used as primary amines and the best result was obtained with 4-methoxyaniline (9e, 84%). Our investigation showed that the existence of substituents on the aromatic ring in

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Table 2 Solvent effect on the synthesis of N-substituted 1,4-dihydropyridines 9a via threecomponent tandem cyclization reaction Solvent

Yield [%]a

Trifluoroethanol Ethanol Acetonitrile Dichloroethane Toluene 1,4-Dioxane THF

8 10 32 68 50 44 20

a

Yield of isolated product.

Table 3 Synthesis of N-substituted 1,4-dihydropyridines 9aen via three-component reaction in the presence of ZnCl2 (40%) Entry

Product

R1

R2

Ar

Yield [%]a

1 2 3 4 5 6 7 8 9 10 11 12 13 14

9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 9l 9m 9n

PhCH2 PhCH2 C6H5 Allyl p-CH3OeC6H4 p-BreC6H4 PhCH2 C6H5 p-CH3OeC6H4 p-BreC6H4 PhCH2 C6H5 p-CH3OeC6H4 p-BreC6H4

Me Et Me Me Me Me Me Me Me Me Me Me Me Me

p-CH3C6H4 p-CH3C6H4 p-CH3C6H4 p-CH3C6H4 p-CH3C6H4 p-CH3C6H4 p-CH3OC6H4 p-CH3OC6H4 p-CH3OC6H4 p-CH3OC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4

68 52 71 42 84 61 61 52 76 59 74 77 87 67

Reaction conditions: 1.3 mmol 8, 1.3 mmol primary amine, 1 mmol methyl (arylidene) pyruvate, 20 mL dichloroethane, 8e12 h. a Yield of isolated product.

amine and methyl (arylmethylidene) pyruvates had a minor effect on the reaction times of the products 9aen. The structures of the products 9aen were deduced from their HR-mass spectrometry and NMR spectroscopic data. The distinguished peak in the 1H NMR spectra of the products was indicated by a signal at d 4.46e4.69 ppm for the H-4 of 1,4-DHP proton, as a doublet in 1H NMR and in 13C NMR a signal at 37.9e38.7 ppm for C-4. Meanwhile, the structure of the products was confirmed according to the X-ray crystallographic data.14 Fig. 2 shows the ORTEP structure of the compound 9g. The possible mechanism of this conversion is shown in Scheme 2. This conversion involves the initial reaction of primary amines with

dimethyl acetylenedicarboxylate to form the desired enaminone (A), then methyl (arylmethylidene) pyruvate could be activated by ZnCl2 and undergo the nucleophilic addition. The subsequent cyclization of intermediate B followed by the nucleophilic addition of the amine group leads to intermediate C. On the basis of the established chemistry of Zn(II) chemistry, it is reasonable to assume that zinc(II) chloride has an essential role in the addition of enaminone to methyl (arylmethylidene) pyruvate via coordination with oxygen lone pairs.15 Meanwhile, the presence of Zn(II) chloride could facilitate two steps of reaction mechanism and also formation of 1,4-dihydropyridine moiety. Meanwhile, Zn(II) has an essential role for the dehydration process to obtain the final product 4aen. The reaction could proceed via a domino Michael addition/cyclization reaction sequence. 3. Conclusion In conclusion, an efficient approach for the one-pot synthesis of N-substituted 1,4-dihydropyridines by ZnCl2 has been developed. Easy work-up, synthesis of polyfunctional compounds, which are ready for further reactions, and an easily available and less expensive Lewis acid, good to high yields are advantages of the present method. 4. Experimental section 4.1. General Commercially available materials were used without further purification. Melting points were determined on an Electrothermal 9100 apparatus and were uncorrected. IR spectra were obtained on an ABB FT-IR FTLA 2000 spectrometer. 1H NMR and 13C NMR spectra were run on Bruker DRX-500 AVANCE spectrometer at 500 MHz and 300 MHz for 1H NMR, and 125 MHz and 75 MHz for 13 C NMR. CDCl3 was used as solvent. HRMS was recorded on MassESI-POS (Apex Qe-FT-ICR instrument) spectrometer. 4.2. General procedure for the synthesis of N-substituted-1,4dihydropyridines 9aen A solution of primary amine (1.3 mmol) and dialkyl acetylenedicarboxylate (1.3 mmol) was stirred vigorously at room temperature for 10 min then methyl (arylmethylide) pyruvates (1 mmol) and ZnCl2 (40%, 54 mg) in dichloroethane (20 mL) was added and the mixture was heated under reflux for 8e12 h. The progress of reaction was monitored by TLC (eluent hexane/ethyl acetate 3:1). The solvent was removed under reduced pressure, and produced an oil, which was purified by prep TLC plates (2020 cm) (Eluent hexane/ethyl acetate 3:1). Further purification was done by recrystallization in mixture of methanol/water (9:1). 4.2.1. Trimethyl 1-benzyl-4-p-tolyl-1,4-dihydropyridine-2,3,6-tricarboxylate (9a). Yield (0.274 g, 63%) as a yellow solid; mp 165.6e166.8  C; Rf (33% EtOAc/Hexane) 0.42; nmax (KBr) 1725 cm1; dH (500 MHz, CDCl3) 2.28 (3H, s, CH3), 3.59 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.46 (1H, d, J 15.6 Hz, NeCH), 4.48 (1H, d, J 6.6 Hz, CH), 5.08 (1H, d, J 15.6 Hz, NeCH), 6.05 (1H, d, J 6.6 Hz, ] CH), 6.84 (1H, d, J 7.9 Hz, Ar), 6.96 (1H, d, J 7.9 Hz, Ar), 7.24e7.33 (5H, m, Ar); dC (125 MHz, CDCl3) 21.0, 38.4, 51.6, 52.0, 52.3, 53.0, 103.2, 122.3, 127.8, 128.1, 128.6, 128.7, 129.1, 130.5, 136.3, 136.4, 141.1, 145.8, 163.4, 165.6, 166.6; HRMS (ESI): [MþH]þ found 436.1756. C25H26NO6 requires 436.1756, [MþNa]þ found 458.1574. C25H25NNaO6 requires 458.1574, [MþK]þ found 474.1314. C25H25KNO6 requires 474.1314.

Fig. 2. ORTEP structure of compound 9g.

4.2.2. 2,3-Diethyl 6-methyl 1-benzyl-4-p-tolyl-1,4-dihydropyridine2,3,6-tricarboxylate (9b). Yield (0.241 g, 52%) as an oil; Rf (33%

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Scheme 2. Proposed mechanism for the synthesis N-substituted 1,4-dihydropyridines.

EtOAc/Hexane) 0.42; nmax (KBr) 1730 cm1; dH (500 MHz, CDCl3) 1.15 (3H, t, J 7.1 Hz, CH3), 1.35 (3H, t, J 7.1 Hz, CH3), 2.28 (3H, s, CH3), 3.71 (3H, s, OCH3), 4.04 (2H, q, J 7.1 Hz, CH2), 4.29e4.44 (2H, m, CH2), 4.50 (1H, d, J 15.6 Hz, NeCH), 4.51 (1H, d, J 6.5 Hz, CH), 5.10 (1H, d, J 15.6 Hz, NeCH), 6.04 (1H, d, J 6.5 Hz, ]CH), 6.84 (1H, d, J 8.0 Hz, Ar), 6.95 (1H, d, J 8.0 Hz, Ar), 7.27e7.34 (5H, m, Ar); dC (125 MHz, CDCl3) 13.9, 14.0, 21.0, 38.6, 51.7, 52.3, 60.4, 62.2, 103.3, 122.2, 128.0, 128.6, 128.7, 129.0, 130.5, 136.3, 136.5, 141.3, 145.6, 163.5, 165.1, 166.1; HRMS (ESI): [MþH]þ found 464.2063. C27H30NO6 requires 464.2064, [MþNa]þ found 486.1883. C27H29NNaO6 requires 486.1884. 4.2.3. Trimethyl 1-phenyl-4-p-tolyl-1,4-dihydropyridine-2,3,6-tricarboxylate (9c). Yield (0.300 g, 71%) as a yellow solid; mp 149.8e150.9  C; Rf (33% EtOAc/Hexane) 0.44; nmax (KBr) 1725 cm1; dH (500 MHz, CDCl3) 2.35 (3H, s, CH3), 3.46 (3H, s, OCH3), 3.52 (3H, s, OCH3), 3.56 (3H, s, OCH3), 4.66 (1H, d, J 6.0 Hz, CH), 6.11 (1H, d, J 6.0 Hz, ]CH), 7.3 (9H, m, Ar); dC (125 MHz, CDCl3) 21.1, 38.7, 51.6, 52.0, 52.4, 101.9, 119.8, 127.6, 128.3, 128.4, 128.9, 129.6, 131.3, 136.7, 141.0, 142.2, 145.6, 162.8, 164.6, 166.6; HRMS (ESI): [MþH]þ found 422.1596. C24H23NNaO6 requires 422.1596, [MþNa]þ found 444.1414. C24H23NNaO6 requires 444.1415. 4.2.4. Trimethyl 1-allyl-4-p-tolyl-1,4-dihydropyridine-2,3,6-tricarboxylate (9d). Yield (0.162 g, 42%) as an oil; Rf (33% EtOAc/ Hexane) 0.33; nmax (KBr) 1735 cm1; dH (500 MHz, CDCl3) 2.32 (3H, s, CH3), 3.57 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.96e4.03 (1H, m, NeCH2), 4.39 (1H, dd, J 16.5, 7.5 Hz, NeCH2), 4.53 (1H, d, J 6.4 Hz, CH), 5.14 (1H, d, J 17.0 Hz, ]CH), 5.17 (1H, d, J 10.0 Hz, ]CH), 5.83e5.88 (1H, m, ]CH), 6.15 (1H, d, J 6.4 Hz, ]CH), 7.13 (2H, d, J 8.05 Hz, Ar), 7.17 (2H, d, J 8.05 Hz, Ar); dC (125 MHz, CDCl3) 21.0, 38.4, 51.0, 51.6, 52.3, 52.8, 102.4, 118.9, 121.7, 127.6, 129.4, 130.5, 133.7, 136.6, 141.6, 145.8, 163.3, 165.4, 166.6; HRMS (ESI): [MþH]þ found 386.4100. C21H24NO6 requires 386.4100. 4.2.5. Trimethyl 1-(4-methoxyphenyl)-4-p-tolyl-1,4-dihydropyridine-2,3,6-tricarboxylate (9e). Yield (0.380 g, 84%) as an orange solid; mp146.4e147.5  C; Rf (33% EtOAc/Hexane) 0.42; nmax (KBr) 1735 cm1; dH (500 MHz, CDCl3) 2.36 (3H, s, CH3), 3.49 (3H, s, OCH3), 3.54 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.65 (1H, d, J 6.0 Hz, CH), 6.05 (1H, d, J 6.0 Hz, ]CH), 6.84 (2H, d, J 8.9 Hz, Ar), 7.19 (2H, d, J 7.9 Hz, Ar), 7.21 (2H, d, J 8.9 Hz, Ar), 7.28 (2H, d, J 7.9 Hz, Ar); dC (125 MHz, CDCl3) 21.1, 38.6, 51.6, 51.1, 52.4, 55.3, 101.6, 113.8, 119.2, 127.6, 129.6, 130.0, 131.5, 133.4, 136.7, 142.3, 146.0, 159.2, 162.9, 164.6, 166.6; HRMS (ESI): [MþH]þ found

452.1702. C25H26NO7 requires 452.1702, [MþNa]þ found 474.1520. C25H26NO7 requires 474.1520, [MþK]þ found 490.1260. C25H25KNO7 requires 490.1260. 4.2.6. Trimethyl 1-(4-bromophenyl)-4-p-tolyl-1,4-dihydropyridine2,3,6-tricarboxylate (9f). Yield (0.305 g, 61%) as a yellow solid; mp 164.5e165.8  C; Rf (33% EtOAc/Hexane) 0.45; nmax (KBr) 1724.96 cm1; dH (500 MHz, CDCl3) 2.36 (3H, s, CH3), 3.50 (3H, s, OCH3), 3.57 (6H, s, OCH3), 4.65 (1H, d, J 6.0 Hz, CH), 6.16 (1H, d, J 6.0 Hz, ]CH), 7.16 (2H, d, J 8.0 Hz, Ar), 7.19 (2H, d, J 8.0 Hz, Ar), 7.25 (2H, d, J 8.5 Hz, Ar), 7.47 (2H, d, J 8.5 Hz, Ar); dC (125 MHz, CDCl3) 21.1, 38.6, 51.7, 52.1, 52.6, 102.6, 120.6, 122.3, 127.5, 129.6, 130.2, 130.8, 132.1, 136.9, 140.15, 141.8, 145.2, 162.6, 164.5, 166.4; HRMS (ESI): [MþH]þ found 500.0700. C24 H23 79 BrNO6 requires 500.0699, [MþNa]þ found 522.0518. C24 H22 79 BrNNaO6 requires 522.0517. 4.2.7. Trimethyl 1-benzyl-4-(4-methoxyphenyl)-1,4-dihydropyridine2,3,6-tricarboxylate (9g). Yield (0.275 g, 61%) as a yellow crystalline; mp 173.5e174.5  C; Rf (33% EtOAc/Hexane) 0.55; nmax (KBr) 1740 cm1; dH (500 MHz, CDCl3) 3.60 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.44 (1H, d, J 15.5 Hz, NeCH), 4.46 (1H, d, J 6.6 Hz, CH), 5.10 (1H, d, J 15.5 Hz, NeCH), 6.06 (1H, d, J 6.6 Hz, ]CH), 6.67 (2H, d, J 8.4 Hz, Ar), 6.84 (2H, d, J 8.4 Hz, Ar), 7.24e7.32 (5H, m, Ar); dC (125 MHz, CDCl3) 37.9, 51.63, 52.0, 52.4, 53.0, 55.2, 103.4, 113.8, 122.36, 128.0, 128.7, 128.7, 129.0, 130.5, 136.3, 136.4, 145.6, 158.5, 163.4, 165.6, 166.6; HRMS (ESI): [MþH]þ found 452.1704. C25H26NO7 requires 452.1705. Yellow crystal (polyhedron), dimensions 0.200.180.17 mm3, A, crystal system triclinic, space group P1, Z¼2, a¼9.634(2)  b¼10.353(2)  A, c¼12.449(3)  A, a¼92.670(5) , b¼103.161(5) , g¼112.601(4) , V¼1103.8(4)  A3, r¼1.358 g/cm3, T¼200(2) K,  A, 0.3 omega-scans Thetamax¼28.39 , radiation Mo Ka, l¼0.71073  with CCD area detector, covering a whole sphere in reciprocal space, 11,762 reflections measured, 5427 unique (R(int)¼0.0472), 3724 observed (I>2s(I)), intensities were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using SADABS14a based on the Laue symmetry of the reciprocal space, m¼0.10 mm1, Tmin¼0.98, Tmax¼0.98, structure solved by direct methods and refined against F2 with a Full-matrix leastsquares algorithm using the SHELXTL (Version 2008/4) software package,14b 298 parameters refined, hydrogen atoms were treated using appropriate riding models, goodness of fit 0.96 for observed reflections, final residual values R1(F)¼0.057, wR(F2)¼0.146 for observed reflections, residual electron density 0.27e0.39 e  A3. CCDC 883084 contains the supplementary crystallographic data for

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this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. 4.2.8. Trimethyl4-(4-methoxyphenyl)-1-phenyl-1,4-dihydropyridine2,3,6-tricarboxylate (9h). Yield (0.227 g, 52%) as a yellow solid; mp 134.4e135.1  C; Rf (33% EtOAc/Hexane) 0.49; nmax (KBr) 1740 cm1; dH (500 MHz, CDCl3) 3.47 (3H, s, OCH3), 3.51 (3H, s, OCH3), 3.57 (3H, s, OCH3), 3.82 (3H, s, OCH3), 4.65 (1H, d, J 6.0 Hz, CH), 6.10 (1H, d, J 6.0 Hz, ]CH), 6.92 (2H, d, J 7.0 Hz, Ar), 7.27e7.37 (7H, m, Ar); dC (125 MHz, CDCl3) 38.2, 51.6, 52.0, 52.4, 55.3, 102.0, 114.3, 119.7, 128.3, 128.4, 128.8, 128.9, 131.2, 137.5, 141.1, 145.4, 158.7, 162.9, 164.6, 166.6; HRMS (ESI): [MþH]þ found 438.1546. C24H24NO7 requires 438.1546, [MþNa]þ found 460.1366. C24H23NNaO7 requires 460.1366, [MþK]þ found 476.1105. C24H23KNO7 requires 476.1105. 4.2.9. Trimethyl 1,4-bis(4-methoxyphenyl)-1,4-dihydropyridine-2,3,6tricarboxylate (9i). Yield (0.355 g, 76%) as a light-red solid; mp 117.4e118.4  C; Rf (33% EtOAc/Hexane) 0.45; nmax (KBr) 1735, 1704 cm1; dH (300 MHz, CDCl3) 3.49 (3H, s, OCH3), 3.53 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.63 (1H, d, J 6.0 Hz, CH), 6.04 (1H, d, J 6.0 Hz, ]CH), 6.84 (2H, d, J 8.8 Hz, Ar), 6.92 (2H, d, J 8.5 Hz, Ar), 7.21 (2H, d, J 8.8 Hz, Ar), 7.30 (2H, d, J 8.5 Hz, Ar); dC (75 MHz, CDCl3) 38.1, 51.6, 52.0, 52.4, 55.2, 55.3, 101.7, 113.8, 114.2, 119.2, 128.8, 129.9, 131.3, 133.3, 137.6, 145.8, 158.7, 159.2, 162.9, 164.6, 166.7; HRMS (ESI): [MþH]þ found 468.1657. C25H26NO8 requires 468.1658, [MþNa]þ found 490.1474. C25H25NNaO8 requires 490.1475, [MþK]þ found 506.1215. C25H25KNO8 requires 506.1215. 4.2.10. Trimethyl1-(4-bromophenyl)-4-(4-methoxyphenyl)-1,4dihydropyridine-2,3,6-tricarboxylate (9j). Yield (0.304 g, 59%) as a yellow solid; mp 145.6e146.7  C; Rf (33% EtOAc/Hexane) 0.62; nmax (KBr) 1776, 1730 cm1; dH (300 MHz, CDCl3) 3.51 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.57 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.63 (1H, d, J 6.0 Hz, CH), 6.15 (1H, d, J 6.0 Hz, ]CH), 6.91 (2H, d, J 8.7 Hz, Ar), 7.16 (2H, d, J 8.7 Hz, Ar), 7.28 (2H, d, J 8.9 Hz, Ar), 7.48 (2H, d, J 8.9 Hz, Ar); dC (75 MHz, CDCl3) 38.1, 51.8, 52.2, 52.6, 55.7, 102.6, 109.6, 114.3, 120.5, 122.3, 128.7, 130.1, 130.7, 132.1, 137.0, 140.1, 158.8, 162.6, 164.5, 166.5; HRMS (ESI): [MþNa]þ found 538.0476. C24 H22 79 BrNNaO7 requires 538.0476, [MþK]þ found 554.0217. C24 H22 79 BrKNO7 requires 554.0218. 4.2.11. Trimethyl 1-benzyl-4-(4-chlorophenyl)-1,4-dihydropyridine2,3,6-tricarboxylate (9k). Yield (0.337 g, 74%) as a yellow crystalline; mp 217.3e218.5  C; Rf (33% EtOAc/Hexane) 0.31; nmax (KBr) 1730, 1694 cm1; dH (500 MHz, CDCl3) 3.60 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.93 (3H, s, OCH3), 4.42 (1H, d, J 15.5 Hz, NeCH2), 4.49 (1H, d, J 6.6 Hz, CH), 5.11 (1H, d, J 15.5 Hz, NeCH2), 6.03 (1H, d, J 6.6 Hz, ] CH), 6.83 (2H, d, J 8.4 Hz, Ar), 7.08 (2H, d, J 8.4 Hz, Ar), 7.21e7.33 (5H, m, Ar); dC (125 MHz, CDCl3) 38.2, 51.7, 52.0, 52.5, 53.1, 102.9, 121.6, 128.3, 128.5, 128.7, 128.8, 129.2, 131.0, 132.6, 136.2, 142.3, 146.0, 163.2, 165.4, 166.3; HRMS (ESI): [MþH]þ found 456.1213. C24 H23 35 ClNO6 requires 456.1214, [MþH]þ found 458.1184. C24 H23 37 ClNO6 requires 458.1185, [MþNa]þ found 478.1030. C24 H22 35 ClNNaO6 requires 478.1031, [MþNa]þ found 480.1003. C24 H22 37 ClNNaO6 requires 480.1003, [MþK]þ found 494.0771. C24 H22 35 ClNKO6 requires 494.0772, [MþK]þ found 496.0744. C24 H22 37 ClNKO6 requires 496.0745. 4.2.12. Trimethyl 4-(4-chlorophenyl)-1-phenyl-1,4-dihydropyridine2,3,6-tricarboxylate (9l). Yield (0.339 g, 77%) as a yellow solid; mp 149.6e150.7  C; Rf (33% EtOAc/Hexane) 0.22; nmax (KBr) 1735 cm1; dH (500 MHz, CDCl3) 3.47 (3H, s, OCH3), 3.52 (3H, s, OCH3), 3.56 (3H, s, OCH3), 4.69 (1H, d, J 6.0 Hz, CH), 6.05 (1H, d, J 6.0 Hz, ]CH), 7.25e7.38 (9H, m, Ar); dC (125 MHz, CDCl3) 38.6, 51.8, 52.1, 52.5, 101.3, 118.8, 128.4, 128.5, 128.9, 129.0, 131.7, 132.9, 140.7, 143.6,

145.8, 162.7, 164.4, 166.3; HRMS (ESI): [MþH]þ found C23 H21 35 ClNO6 requires 442.1053, [MþH]þ found C23 H21 37 ClNO6 requires 444.1024, [MþNa]þ found C23 H20 35 ClNNaO6 requires 464.0872, [MþNa]þ found C23 H20 37 ClNNaO6 requires 466.0843, [MþK]þ found C23 H20 35 ClKNO6 requires 480.0611, [MþK]þ found C23 H20 37 ClKNO6 requires 482.0584.

442.1053. 444.1024. 464.0872. 466.0843. 480.0611. 482.0584.

4.2.13. Trimethyl4-(4-chlorophenyl)-1-(4-methoxyphenyl)-1,4dihydropyridine-2,3,6-tricarboxylate (9m). Yield (0.410 g, 87%) as a yellow crystalline; mp 164.4e165.4  C; Rf (33% EtOAc/Hexane) 0.52; nmax (KBr) 1740 cm1; dH (300 MHz, CDCl3) 3.50 (3H, s, OCH3), 3.54 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.68 (1H, d, J 5.8 Hz, CH), 6.00 (1H, d, J 5.8 Hz, ]CH), 6.84 (2H, d, J 8.8 Hz, Ar), 7.19 (2H, d, J 8.8 Hz, Ar), 7.26e7.37 (4H, m, Ar); dC (75 MHz, CDCl3) 38.5, 51.7, 52.2, 52.5, 55.4, 100.3, 113.9, 118.1, 128.1, 129.9, 132.9, 133.0, 143.7, 146.2, 159.3, 162.7, 164.4, 166.4; HRMS (ESI): [MþH]þ found 472.1161. C24 H23 35 ClNO7 requires 472.1161, [MþNa]þ found 494.0977. C24 H22 35 ClNNaO7 requires 494.0977, [MþNa]þ found 496.0949. C24 H22 37 ClNNaO7 requires 496.0949, [MþK]þ found 510.0717 C24 H22 35 ClKNO7 requires 510.0718, [MþK]þ found 512.0691. C24 H22 37 ClKNO7 requires 512.0691. 4.2.14. Trimethyl 1-(4-bromophenyl)-4-(4-chlorophenyl)-1,4dihydropyridine-2,3,6-tricarboxylate (9n). Yield (0.350 g, 67%) as a yellow crystalline; mp 188.4e189.3  C; Rf (33% EtOAc/Hexane) 0.51; nmax (KBr) 1730, 1709 cm1; dH (500 MHz, CDCl3) 3.52 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.57 (3H, s, OCH3), 4.68 (1H, d, J 6.0 Hz, CH), 6.09 (1H, d, J 6.0 Hz, ]CH), 7.14 (2H, d, J 8.7 Hz, Ar), 7.29 (2H, d, J 8.4 Hz, Ar), 7.35 (2H, d, J 8.4 Hz, Ar), 7.48 (2H, d, J 8.7 Hz, Ar); dC (125 MHz, CDCl3) 38.5, 51.8, 52.2, 52.7,102.0,119.4,122.5,129.0,129.1,130.2,131.3,132.2, 133.1, 139.8, 143.2, 145.4, 162.4, 164.2, 166.1; HRMS (ESI): [MþH]þ found 520.0158. C23 H20 79 Br35 ClNO6 requires 520.0158, [MþNa]þ found 541.9974. C23 H19 79 Br35 ClNaNO6 requires 541.9974, [MþK]þ found 557.9715. C23 H19 79 Br35 ClKNO6 requires 557.9715. Acknowledgements S.B. gratefully acknowledges Alexander von Humboldt foundation for research fellowship. We are also thanking Ministry of Health and medicinal education (Iran) and also presidential office deputy of science and technology for financial support. Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2012.10.082. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006; (b) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; (c) Tietze, L. F.; Hauner, F. In Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart, J. F., Eds.; Wiley-VCH: Weinheim, €mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 2000; pp 39e64; (d) Do €mling, A. Chem. Rev. 2006, 106, 17e89; (f) Isambert, N.; 3168e3210; (e) Do Lavilla, R. Chem.dEur. J. 2008, 14, 8444e8454. 2. (a) Arndtsen, B. A. Chem.dEur. J. 2009, 15, 302e313; (b) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300e1308; (c) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234e6246. 3. (a) Bocker, H.; Guengerich, F. P. J. Med. Chem. 1986, 28, 1596e1603; (b) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269e289; (c) Goldman, S.; Stoltefuss, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1559e1578; (d) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed. Engl. 1981, 20, 762e769; (e) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291e324; (f) Bossert, F.; Meyer, H.; Vater, W. U.S. Patent 3,943,140, 1976. 4. (a) Vo, D.; Matowe, W. C.; Ramesh, M.; Iqbal, N.; Wolowyk, M. W.; Howlett, S. E.; Knaus, E. E. J. Med. Chem. 1995, 38, 2851e2859; (b) Gaudio, A. C.; Korolkovas,

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