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Diastereoselective Synthesis of Symmetrical and Unsymmetrical Tetrahydropyridines Catalyzed by Bi(III) Immobilized on Triazine Dendrimer Stabilized Magnetic Nanoparticles Beheshteh Asadi, Amir Landarani-Isfahani, Iraj Mohammadpoor-Baltork, Shahram Tangestaninejad, Majid Moghadam, Valiollah Mirkhani, and Hadi Amiri Rudbari ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 09 May 2017 Downloaded from http://pubs.acs.org on May 10, 2017

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ACS Combinatorial Science

Diastereoselective Synthesis of Symmetrical and Unsymmetrical Tetrahydropyridines Catalyzed by Bi(III) Immobilized on Triazine Dendrimer Stabilized Magnetic Nanoparticles Beheshteh Asadi,† Amir Landarani-Isfahani,† Iraj Mohammadpoor-Baltork,*,† Shahram Tangestaninejad,† Majid Moghadam,† Valiollah Mirkhani,†and Hadi Amiri Rudbari† † Catalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran. KEYWORDS: Fe3O4 NPs, triazine dendritic polymer, tetrahydropyridine, diastereoselective, multicomponent reactions (MCRs)

ABSTRACT: Unsymmetrical 1,2,5,6-tetrahydropyridine-3-carboxylate were obtained for the first time from a five-component Fe3O4@TDSN-Bi(III)-catalyzed reaction of aryl aldehydes, aryl amines and ethyl acetoacetate. This magnetically separable catalyst enabled the selective incorporation of two different aryl amines or two different aryl aldehydes into the product, and provided excellent yields, short reaction times, mild reaction conditions, satisfactory catalyst recyclability, and low catalyst loading.

INTRODUCTION

ACS Paragon Plus Environment

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The development of efficient and recoverable heterogeneous catalysts has become a prominent goal to enhance the sustainability of chemical synthesis. In the tool box of synthetic chemists, dendrimers have attracted special attention as well-defined polymeric ligands in the fields of nanoscience,1 gene therapy,2 drug delivery,3 and medicinal chemistry.4 Among the potential applications of dendrimers, catalysis is among the most promising,5 since dendrimers can combine the advantages of homogeneous and heterogeneous systems. 1,2,5,6-Tetrahydropyridine (THP), piperidine and their derivatives are attractive targets as components of natural products6 and other biologically active compounds,7 including those with anticonvulsant,8 antibacterial,9 anticancer,10 antihypertensive,11 and antimalarial12 properties. Methods for the synthesis of THP derivatives are therefore of significant interest. One-pot multicomponent reactions (MCRs)13 are remarkably useful for the synthesis of a diverse range of heterocyclic systems, with advantages of selectivity and atom economy.14 A variety of catalysts have been used for the synthesis of THP derivatives from aryl aldehydes, aryl amines and -β-keto ester, including cerium ammonium nitrate (CAN),15 InCl3,16 Bi(NO3)3·5H2O,17 L-proline/TFA,18 BF3·SiO2,19 and molecular iodine.20 However, some of the reported methods suffer from the use of non-reusable catalyst, high catalysts loading, long reaction times, unsatisfactory yields, and high temperatures. We describe here the application of Fe3O4@TDSN-Bi(III) (Figure 1), a catalyst that we have previously described for the synthesis of aminonaphthoquinones,21a quinolines,21b, as an effective and recyclable catalyst for the preparation of penta-substituted THP derivatives via a fivecomponent reaction (Scheme 1). Unique to this system is the selective incorporation of two different aryl amines or two different aryl aldehydes into unsymmetrical products.


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Figure 1. Bi(III) immobilized on triazine dendrimer stabilized magnetic nanoparticles (Fe3O4@TDSNBi(III)) catalyst.

Scheme 1. One-pot five-component synthesis of symmetrical and unsymmetrical THP derivatives catalyzed by Fe3O4@TDSN–Bi(III).

RESULTS AND DISCUSSION The Fe3O4@TDSN-Bi(III) catalyst was prepared according to our previously reported procedure.21a In brief, diethanolamine (DEA) was reacted with cyanuric chloride (CC) in dry


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THF to produce the (DEA)3T, which upon reaction with freshly prepared Fe3O4 at room temperature under intense sonication produced G1. The reaction of G1 with CC was performed for substitution of one of its chlorine atoms under intense sonication at room temperature to give CC2. Then, Fe3O4@TDSN or G2 was prepared by the reaction of CC2 and DEA. Finally, this ligand with hydroxyl groups on its periphery, labeled as G2, was used to form the desired Fe3O4@TDSN-Bi(III) catalyst (Figure 1) by the reaction with bismuth(III) triflate in dry THF. The bismuth content of Fe3O4@TDSN-Bi(III), measured by ICP analysis, was found to be 0.60 mmol per gram.21a To optimize the multicomponent reaction conditions for THP synthesis, we started the investigation by reacting of benzaldehyde 1 {1} (2 mmol), aniline 2 {1} (2 mmol) and ethyl acetoacetate 3 {1} (1 mmol) under conditions (EtOH solvent, room temperature) in which no reaction was observed in the absence of catalyst (Table 1, entry 1). Among nine potential catalysts tested (entries 2-10), Fe3O4@TDSN-Bi(III) appeared to be the best. With this catalyst, EtOH was found to be the best solvent (entries 11-17), giving the desired product in 98% yield within 1 h. Reactivity was dependent on catalyst loading, with 8% catalyst achieving the best result with a 2:2:1 molar ratio of aldehyde, aniline, and ketoester. Table 1. Optimization studies for the synthesis of THP derivative 4a {1, 1, 1}

Entry

Catalyst (mol%)

Solventa

Time (h)

Yield(%)e

1

-

EtOH

10

0


4

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2

p-TSA (8)

EtOH

5

25

3

SSA (8)

EtOH

5

25

4

AlCl3 (8)

EtOH

5

10

5

MnCl2 (8)

EtOH

5

10

6

FeCl3 (8)

EtOH

5

50

7

BiCl3(8)

EtOH

5

35

8

Bi(NO3)3·5H2O (8)

EtOH

5

40

9

Bi(OTf)3 (8)

EtOH

5

70

b

10

Fe3O4@TDSN-Bi(III) (8)

EtOH

1

98

11

Fe3O4@TDSN-Bi(III)b (8)

CH3CN

8

75

b

12


CHCl3

8

55

13


CH2Cl2

8

50

b

14


EtOAc

8

55

15


THF

8

50

b

16


n-hexane

8

20

17


None

4

55

c

18


EtOH

1

70

19

Fe3O4@TDSN-Bi(III)d (10)

EtOH

1

98

a

Reaction was performed using 5 mL of solvent. Containing 133 mg catalyst (8 mol% of Bi(III)). c Containing 83 mg catalyst (5 mol% of Bi(III)). d Containing 166 mg catalyst (10 mol% of Bi(III)). e Isolated yield. b

Using these conditions, the substrate scope was explored with the set of aryl aldehydes and aryl amines shown in Figure 2. The reaction provided 1,2,5,6-tetrahydropyridine-3-carboxylates 4a-s in excellent yields and short reaction times for aldehydes substituted with methyl, methoxy, chloro, bromo and nitro groups and aryl amines substituted with methyl, bromo, and chloro groups at either ortho-, meta- or para-positions of the aromatic ring, as illustrated in Scheme 2. To our delight, 2-naphthaldehyde underwent efficient conversions under this reaction conditions and was successfully transformed into the targeted products in 93-95% yields. Fascinatingly, the yields gained in these transformations are not sensitive to the steric or electronic effects of substituents on the aromatic ring (Scheme 2).


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Figure 2. Diversity of reagents.


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Scheme 2. Fe3O4@TDSN-Bi(III)-catalyzed multicomponent synthesis of 1,2,5,6-tetrahydropyridine-3carboxylates.


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The key finding of this study is that the synthesis of unsymmetrical THP derivatives from the reaction of two different aryl aldehydes with aryl amine and ethyl acetoacetate was achieved for the first time under similar conditions. For example, the use of 2-naphthaldehyde and benzaldehyde with two equivalents of either p-toluidine or p-chloroaniline gave products 5a and 5b exclusively and in high yield (Scheme 3). The source of this selectivity was found to be the initial formation of only one of the two possible imine intermediates, from the more reactive aldehyde. Thus, exposure of a mixture of 2-naphthaldehyde and benzaldehyde (1 mmol each) to p-chloroaniline (1mmol) or p-toluidine (1 mmol) in the presence of Fe3O4@TDSN-Bi(III) gave the benzaldehyde imines 6a and 6c in excellent yields with no formation of 6b or 6d (Scheme 3) as confirmed by 1H NMR spectrometry (See Supporting Information). In each multicomponent reaction, the imine was presumably intercepted by the ketoester enolate to initiate an irreversible reaction cascade to give 5a and 5b, respectively (Scheme 3).


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Scheme 3. Fe3O4@TDSN-Bi(III)-catalyzed multicomponent synthesis of unsymmetrical 1,2,5,6tetrahydropyridine-3-carboxylate.

Similarly, unsymmetrical THP derivative could be prepared for the first time from ethyl acetoacetate and 2-naphthaldehyde with two different aryl amines in the presence of the same catalyst in excellent yield and purity (Scheme 4). These results could be supported by the reaction of ethyl acetoacetate (1 mmol), p-chloroaniline (1 mmol) and p-toluidine (1 mmol) in the presence of Fe3O4@TDSN-Bi(III) in which only β-enaminone 8a is formed from p-toluidine


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(Scheme 4). The structure of 8a, which results in 7a-b product, was further confirmed by 1H NMR spectrometry (See Supporting Information).

Scheme 4. Fe3O4@TDSN-Bi(III)-catalyzed multicomponent synthesis of unsymmetrical 1,2,5,6tetrahydropyridine-3-carboxylate.

The products were identified by melting points, spectral data, and by elemental analysis. Furthermore, the trans stereochemistry of the 2,6-substituents of 4b (Figure 3; CCDC 1501203) was determined by X-ray crystallographic analysis (See Supporting Information, Tables 1 and 2). In addition, absence of any NOE between H-2 and H-6 of tetrahydropyridine indicates that they are trans to each other, which confirmed the disatereoselectivity of the present protocol.


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Figure 3. ORTEP representation of 4b. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. There are two independent molecules in asymmetric unit cell. One molecule is omitted for clarity.

Based on the experimental results and literature,15 a mechanistic pathway for synthesis of unsymmetrical 1,2,5,6-tetrahydropyridine-3-carboxylate 7a-b is described in Scheme 5. First, Fe3O4@TDSN-Bi(III) activates the carbonyl group of ethyl acetoacetate to afford intermediate A. Nucleophilic attack of p-toluidine to A provides the β-enaminone B.

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Subsequently,

activation of aryl aldehyde by the catalyst followed by condensation with amino group of pchloroaniline results in imine C. These results suggest not only that electron-rich anilines make the enamine faster than electron-poor anilines, but also that enamine formation (reaction with βketoester) is faster than aldimine formation (reaction with aromatic aldehyde), and that this determines the product isomer. Then, attack of B to activated imine D via an intermolecular Mannich reaction, leads to the intermediate E. The reaction of E with the second activated aryl aldehyde yields F with elimination of water. Intermediate F tautomerizes to G (due to the stabilization via intramolecular hydrogen bonding) in the presence of the catalyst. Finally, the


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intermediate G undergoes intramolecular Mannich reaction to provide H, which upon tautomerization gives the desired products 7a-b and releases the catalyst for the next catalytic cycle.

Scheme 5. Proposed mechanism for synthesis of unsymmetrical 1,2,5,6-tetrahydropyridine-3carboxylates 7a-b.

In Table 2, the result of condensation of benzaldehyde, p-chloroaniline and ethyl acetoacetate in the presence of Fe3O4@TDSN-Bi(III) is compared with some of those reported with several catalysts. Compared to most of the previously reported methods, our catalyst has remarkably


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improved this multicomponent reaction at room temperature in different terms such as catalyst loading, reaction time, yield, turn-over number (TON) and turn-over frequency (TOF), indicating the efficiency of this method.

Table 2. Comparison of the results of condensation of benzaldehyde, p-chloroaniline and ethyl acetoacetate catalyzed by Fe3O4@TDSN-Bi(III) and reported results with some other catalysts.

Catalyst/conditions

Catalyst loading

Time (h)

Yielda (%)

TONb

TOFc (h-1)

Ref.

LaCl3.7H2O/MeOH, r.t.

10 mol%

4

80

8

2

23

[Hpyro][HSO4]/EtOH, reflux

15 mol%

8

77

5.13

0.641

24

Bi(NO3)3.5H2O/EtOH, r.t.

10 mol%

14

76

7.6

0.543

17

Ph3CCl/MeOH, 50 ◦C

15 mol%

5

84

5.6

1.12

25

CAN/CH3CN, r.t.

15 mol%

35

68

4.53

0.13

15

Citric acid/MeOH, r.t.

20 mol%

6

70

3.5

0.583

26

[Dsbim]Cl/solvent-free, 80 ◦C

10 mol%

32 min

95

9.5

17.81

27

Fe3O4@TDSN-Bi(III)/EtOH, r.t.

8 mol%

1

97

12.12

12.12

Present work

a

Isolated yield. Turn-over number. c Turn-over frequency. b

Due to the superparamagnetic properties with a saturation magnetization value21a (14 emu.g-1) of the Fe3O4@TDSN-Bi(III), this catalyst exhibited excellent reusability. In this work, efficient recovery of the Fe3O4@TDSN-Bi(III) catalyst was examined in the synthesis of 4a. Upon completion of the reaction, the catalyst was easily separated using a permanent magnet. Then the recovered catalyst was washed several times with ethanol, dried and reused for the next run. The


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recovery of the catalyst in the multicomponent reaction of benzaldehyde, aniline and ethyl acetoacetate under identical conditions can be run at least 6 times, without noticeable loss in catalytic activity and product yield (98-96%) (Figure 4). Furthermore, leaching of bismuth species was determined by ICP-OES analysis, and it was observed that only small amounts of bismuth (less than 1%) is leached in the first run. This remarkable reusability of the catalyst proved its robustness.

Figure 4. Recycling experiment of the Fe3O4@TDSN-Bi(III) catalyst in the synthesis of 4a.

CONCLUSION In summary, the Fe3O4@TDSN-Bi(III) catalyst revealed excellent catalytic activity for a onepot five-component reaction of aryl aldehydes, aryl amines, and ethyl acetoacetate through a simple and mild procedure. Specifically, Fe3O4@TDSN-Bi(III) was found to be an efficient heterogeneous catalyst for the synthesis of unsymmetrical THP derivatives from two different aryl aldehydes/aryl amines. Gratifyingly, the catalyst can be recovered magnetically which made the separation of the product easier and reused up to seven times with minimal leaching of bismuth.

EXPERIMENTAL SECTION


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General Information. The chemicals used in this work were purchased from Fluka and Merck chemical companies. Melting points were determined with a Stuart Scientific SMP2 apparatus. FT-IR spectra were recorded on a Nicolet-Impact 400D spectrophotometer. 1H and

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C NMR

(400 and 100 MHz) spectra were recorded on a Bruker Avance 400 MHz spectrometer using CDCl3 as solvent. Elemental analysis was performed on a LECO, CHNS-932 analyzer. Typical Procedure for the Synthesis of Ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6tetrahydropyridine-3-carboxylate 4a {1,1,1} Catalyzed by Fe3O4@TDSN-Bi(III): The Fe3O4@TDSN-Bi(III) catalyst (133 mg, 8 mol% Bi(III)) was added to a mixture of benzaldehyde (2 mmol), aniline (2 mmol), and ethyl acetoacetate (1 mmol), in ethanol (5 mL), and the mixture was stirred at room temperature. On completion of the reaction, as evident from the TLC analysis, (eluent: petroleum ether/EtOAc, 5:1), the catalyst was easily separated using a permanent magnet and washed with EtOH (5 mL). The organic residue was filtered, washed with EtOH for several times and dried under vacuum to provide the pure product 4a {1,1,1} in 98% yield. Mp 169-170 oC. IR (KBr): νmax = 3244, 3065, 2978, 2871, 1652, 1589, 1498, 1372, 1252, 1172, 1069, 750, 696 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3H), 2.69 (dd, 1

J = 15.0 Hz, 2J = 2.4 Hz, 1H), 2.80 (dd, 1J = 15.0 Hz, 2J = 5.7 Hz, 1H), 4.21-4.29 (m, 1H),

4.35-4.43 (m, 1H), 5.06-5.07 (m, 1H), 6.18-6.21 (m, 2H), 6.39 (s, 1H), 6.45 (d, J = 8.2, 2H), 6.53 (t, J = 7.2 Hz, 1H), 6.97-7.04 (m, 5H), 7.08-7.10 (m, 2H), 7.14 (d, J = 7.2, 1H), 7.18-7.22 (m, 5H), 7.21 (d, J = 7.4, 2H), 10.22 (br s, 1H). Anal. Calcd for C32H30N2O2: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.17; H, 6.30; N, 6.01.

ASSOCIATED CONTENT Supporting Information.


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Experimental procedure, NMR copies and data of elemental analysis for all products, and crystallographic data in CIF format for compound 4b {2, 1, 1}. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *Phone: 98 313 7934927. Fax: 98 313 6689732. E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors are grateful to the Research Council of the University of Isfahan for financial support of this work. ABBREVIATIONS NPs, nanoparticles; MCR, multicomponent reaction; THP, tetrahydropyridine; DEA, diethanolamine; CC, cyanuric chloride; (DEA)3T, 2,2',2'',2''',2'''',2'''''-((1,3,5-triazine-2,4,6triyl)tris(azanetriyl))hexaethanol; p-TSA, p-toluenesulfonic acid; SSA, silica sulfuric acid; TLC, thin layer chromatography. REFERENCES (1) (a) Ornelas, C. Brief Timelapse on Dendrimer Chemistry: Advances, Limitations, and Expectations. Macromol. Chem. Phys. 2016, 217, 149-174. (b) Sowinska, M.; Urbanczyk-Lipkowska, Z. Advances in the chemistry of dendrimers. New J. Chem. 2014, 38, 2168-2203.


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For Table of Contents Use Only Diastereoselective Synthesis of Symmetrical and Unsymmetrical Tetrahydropyridines Catalyzed by Bi(III) Immobilized on Triazine Dendrimer Stabilized Magnetic Nanoparticles Beheshteh Asadi,† Amir Landarani-Isfahani,† Iraj Mohammadpoor-Baltork,*,† Shahram Tangestaninejad,† Majid Moghadam,† Valiollah Mirkhani,†and Hadi Amiri Rudbari†

A new method for diastereoselective synthesis of symmetrical and unsymmetrical tetrahydropyridines using Fe3O4@TDSN-Bi(III) as a recoverable and heterogeneous catalyst is reported.


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Diastereoselective Synthesis of Symmetrical and ... - ACS Publications

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