A new magnetically recoverable catalyst promoting the synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives via the Hantzsch condensation under solvent-free conditions

Author’s Accepted Manuscript A new magnetically recoverable catalyst promoting the synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives via the Hantzsch condensation under solvent-free conditions Fariba Heidarizadeh www.elsevier.com/locate/jmmm

PII: DOI: Reference:

S0304-8853(16)31297-5 http://dx.doi.org/10.1016/j.jmmm.2016.09.099 MAGMA61880

To appear in: Journal of Magnetism and Magnetic Materials Received date: 30 June 2016 Revised date: 16 September 2016 Accepted date: 21 September 2016 Cite this article as: Fariba Heidarizadeh, A new magnetically recoverable catalyst promoting the synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives via the Hantzsch condensation under solvent-free conditions, Journal of Magnetism and Magnetic Materials, http://dx.doi.org/10.1016/j.jmmm.2016.09.099 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A new magnetically recoverable catalyst promoting the synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives via the Hantzsch condensation under solvent-free conditions fariba heidarizadeh

Abstract In the current study, 1,4-dihydropyridine and polyhydroquinoline derivatives were efficiently synthesized under solvent-less conditions with a magnetic catalyst containing novel acidic ionic liquid functionalized silica modified Fe3O4 nanoparticles through a four component combination of β-ketoester, aldehydes and ammonium acetate (1, 2, 2). Several approaches have been reported for synthesising these derivatives, while each of these approaches have some weaknesses including long time of reaction, excess of volatile organic solvent, low efficiency, costly reagents, complex operation, high temperatures, production of a number of side products, and difficult catalyst recovery. The simple operation, short time of reaction (5– 30 min) and the high efficiency (80–94%) are the special advantages of this technique. The immobilized catalyst exhibited an appropriate thermal stability and excellent recyclability. Different methods such as FT-IR, SEM, EDX, TGA-DTA, and VSM were used to confirm and characterize the catalyst.

Keyworks: Magnetic catalyst; Acidic ionic Liquid; Hantzsch condensation; Heterogenous Catalyst; solvent-free conditions

Introduction The specific features of ionic liquids (ILs) including wide range of liquid temperature, undetectable vapour pressure, excellent thermal stability, and high solubility cause them to be extensively used as an eco-friendly reaction medium or catalysts.1 Excellent catalytic activity

and good selectivity are the usual benefits of the reactions of homogeneous catalytic with ILs . Although, the practical use of this kind of catalysis is restricted with the difficult separation of the catalyst from the product after completion of the reaction, and the use of ILs solvent or catalyst in a large scale, which inescapably produce a large amount of non-eco-friendly waste materials.2 Improving IL-based heterogeneous catalysts is one of the most appropriate solutions for solving these weaknesses.3 The easy separation, recovering, and the appropriate use in an commercial continuous system are the most remarkable benefits of the heterogeneous catalysts compared to homogeneous ones. Ionic liquids were recently immobilized on solids supports and were utilized as supported ionic liquid catalysis (SILC).3 In the current study, the purposes of modification procedure is to transfer the favourite catalytic features of liquids type to a solid one. The supported ionic liquids were synthesized through several approaches,4–8 among them the most consideration was recognized while a covalent linkage to the surface of different solid supports happened through a spacer group. Recently, magnetic nanoparticles (MNPs) have been used as a novel type of catalyst support for ILs as they offer benefits in clean and sustainable chemistry due to their excellent chemical stability, good accessibility, reusability, simple preparation and modification, large surface area, easy separation with an external magnet, relatively low toxicity and reasonable price.9,10 These attractive features have made the MNPs a promising alternative type of catalyst supports. Derivatives of Polyhydroquinoline (PHQ) and 1,4-dihydropyridine (1,4-DHP) have received significant attention due to their various pharmacological and therapeutic features. An important group of calcium channel blockers is quinolines which contains 1,4dihydropyridine nucleus.11 The compounds belonging to this family are applied as vasodilators,

bronchodilators,

antiatherosclerotics,

antitumor,

heptatoprotective,

antidiabetic agents to cure cardiovascular diseases such as hypertension.12, 13

and

Furthermore, the dihydropyridine unit has been widely employed as a hydride source for reductive amination.14 The biological, industrial, and synthetic importance of derivatives of (PHQ) and (1, 4-DHP) is the reason to improve numerous techniques for synthesizing these compounds. Though, all of these techniques have several disadvantages such as long-time reaction, the use of a large amount of volatile organic solvent, low yields of product, costly reagents, hard operation, high temperatures, formation of numerous side products, and difficult recovery process of catalyst.15 Considering abovementioned weaknesses, the present research aimed to find more acceptable procedures based on modified, stable, and retrieval catalysts for replacing the less effective and conventional catalysis protocols. Very recently, we offered the preparation of a novel supported ionic liquid catalyst and its further application for derivatives of 4H-chromene.16 Herein, we suggested a new acidic ionic liquid supported on magnetic nanoparticles with an excellent catalytic activity and selectivity along with easy separation from the reaction media, and we also examined its yield as a catalyst for synthesising derivatives of (PHQ) and (1,4DHP).

Results and Discussion The magnetic nanoparticles immobilize with acidic ionic liquid was verified as a heterogeneous catalyst, which could be applied in the organic synthesis process. The acidic ionic liquid functionalized magnetite nanoparticles prepared according to the procedure shown in (Scheme 1).

Scheme 1. Synthesis of acidic ionic liquid modified silica coated magnetite nanoparticles (AIL-SCMNPs)

A variety of various methods were used to characterize AIL-SCMNPs. FT-IR was used to verify the surface modified magnetite nanoparticles and the synthesized AIL-SCMNPs. Fig. 1 demonstrates the FT-IR spectra relation to the MNPS, SCMNPs and AIL- SCMNPs. The vibrations relating to Fe–O in states of octahedral and tetrahedral were observed as two broad bands around 457-590 cm-1.22,23 The covalent bond between silane and magnetite surface was underlined by the appearance of the band at 1092 cm-1 characteristic for Si–O–Si and Si–OH stretching vibrations. The broad band emerged around 1645 and 3500 cm−1 was attributed to the stretching vibration of SiO-H bond, the HO-H vibration of adsorbed water on the silica surface, and the O-H vibration of carboxylic acid group. The stretching vibrations relating to C=C, C=N were observed at 1566 cm−1 and 1645 cm−1 that they confirm the presence of imidazole ring. The signals appeared at 1660 and 1715 cm−1 regions were attributed to the C=O stretching of carboxylic acid and amid groups.

Fig. 1. FT-IR spectra of Fe3O4 (MNPs), SCMNPs and AIL-SCMNPs

The scanning electron microscopy (SEM) images were utilized to characterize the size and morphology of SCMNPs (Fig. 2a) and AIL-SCMNPs (Fig. 2b) in detail. It can be observed from (Fig. 2a) that SCMNPs micrographs have a mean diameter of nearly 19 nm with an almost spherical shape. The SEM image of functionalized AIL-SCMNPs (Fig. 2b) demonstrated spherical shape particles with a greater average size of 34 nm. As shown in from Fig, 2, coating will increase the size of particles and the magnetic properties of composite NPs also will change (Fig. 3).

Fig. 2. SEM image of SCMNPs (a) and AIL-SCMNPs (b)

A vibrating sample magnetometer (VSM) was applied to examine the magnetic features of AIL-SCMNPs at ambient temperature, (Fig. 3). Compared with the uncoated MNPs, the

saturation magnetization of the AIL-SCMNPs decreased and changed from (59 to 23) emu/g, which was lower than the MNPs and could be attributed to the surface modification and functionalization of the magnetite core. The catalyst could still be expertly separated simply from the solution by applying an external magnetic force, even though the saturation magnetization were decreased.

Fig. 3. VSM magnetization curve of Fe3O4 (a) nanoparticles and AIL-SCMNPs

The ability of AIL-SCMNP as a catalyst was studied in synthesizing asymmetric and symmetric hantzsch reactions for producing derivatives of polyhydroquinoline and 1,4dihydropyridine, respectively. The reaction of benzaldehyde, ethyl acetoacetate and ammonium acetate (1, 2, 2) was selected as a model reaction to optimize the reaction condition in the presence of different amounts of the catalyst in a range of temperatures (Table 1).

After optimizing the conditions, the generality of this procedure was studied on a wide range of aromatic aldehydes, ammonium acetate, and ethyl acetoacetate (1, 2, 2) under a solventless conditions at 60 °C (Scheme 2). Scheme 2. Synthesis of the 1,4-dihydropyridine derivatives. It was observed that the structural variation relating to the aldehyde and substituents on the aromatic ring had no significant impact on this change, as the wanted products were obtained in high to excellent efficiencies with rather short times of reaction (Table 2, entry 1 - 9). These outcomes encouraged us for assessing the preparation process of derivatives of polyhydroquinoline under the same reaction conditions. Therefore, the treatment of different aromatic aldehydes was performed using ethyl acetoacetate, dimedone and ammonium acetate

(1, 1, 1, and 2) under optimal reaction conditions for the synthesis of derivatives of polyhydroquinoline (Scheme 3). Scheme 3. Synthesis of the polyhydroquinoline derivatives The products were acquired with high efficiencies (80-95%). The obtained outcomes are listed in (Table 2, entry 10- 18). One of the most important advantages of the catalysts is its recoverability that makes them suitable for applications in industry. The benzaldehyde, ethyl acetoacetate and ammonium acetate were condensed under solvent-less condition to study the recoverability of the catalyst. After completing the reaction, ethanol was poured to the solution and the nanocatalyst was retrieved with an external magnet, and was washed using water and acetone, and then dried in an oven at 60 °C for 1h prior to test its catalytic activity in the next run (Fig. 4).

Fig. 4. Recyclability of AIL-SCMNPs

Scheme 4 demonstrates a reasonable mechanism for synthesizing polyhydroquinoline derivatives using AIL-SCMNPs as a catalyst). Accordingly, these compounds could be synthesized in several steps. In the first step, an acid-catalyzed Knoevenagel reaction coupling of aldehydes with dimedone’s enol form was occurred (1). In the second step, the activated βketoester (by the acid catalyst) with the liberation of ammonia from NH4OAc gave enamine (2). Thereafter Michael addition between (1) and enamine (2) afforded intermediate (3). When tautomerization (4), intra-molecular cyclization (5) and again tautomerization occurred in succession, the final products were acquired. The mechanism was confirmed by the literatures.29 The proposed mechanism can also be used in the case of 1,4-dihydropyridine derivatives. (Scheme 4)

Scheme 4. Proposed Mechanism for the preparation of (1,4-DHP) derivatives using AILSCMNPs as Catalyst

Experimental

2.1. General All the chemicals and reagents were used as received from the supplier, except for phthalic anhydride which was recrystallized prior to use.17 The chemicals were purchased from Fluka, Merck or Aldrich. The yields refer to the isolated crude products. The NMR spectra were recorded in dimethyl sulfoxide (DMSO) or chloroform (CDCl3) on a Bruker spectrometer at 250 MHz using tetramethylsilane as the internal standard. IR spectra were recorded on a BOMEM MB-Series 1998 FT-IR spectrometer. The purity determination of the products and reaction monitoring were accomplished by TLC on silica gel Polygram SILG/UV 254 plates. The TGA curve of the AIL-SCMNPs was recorded on a BAHR, STA 503 at heating rates of 10 °C min-1. The thermal behaviour was studied by heating 1-10 mg of samples in aluminiumcrimped pans under nitrogen atmosphere, over the temperature range of 25-1300 °C. The particle size, external morphology and elemental analysis of the particles were characterized by energy dispersive X-ray spectroscopy (SEM_/EDS, VEGA\\TESCAN-LMU scanning electron). The magnetic properties of the synthesized AIL-SCMNPs were investigated using vibrating sample magnetometer (VSM) of Meghnatis Daghigh Kavir Company.

Preparation of acidic ionic liquid modified silica coated magnetite nanoparticles (AILSCMNPs) Preparation AIL-SCMNPs involved several steps. First, Fe3O4 and silica coated magnetite nanoparticles (SCMNPs) were synthesized based on the known Common methods.18, 19 Also chloropropyl grafted silica coated nanoparticles (ClpSCMNPs) were prepared according to

the reported method.20 According to the above-mentioned method (2g) of the synthesized SCMNPs was suspended in ethanol (100ml) and then 3-chloropropyltrimethoxysilane (CPTMS) (2ml) was added to this suspension in the next run under dry nitrogen atmosphere. The whole mixture was stirred and refluxed for 12h. After cooling to room temperature, the resulted solid (ClpSCMNPs) were magnetically separated, washed with ethanol several times and then dried in a vacuum. In the second step, to a solution of imidazole (1.9 g, 4 mmol) in 100 mL of dry toluene, sodium hydride (0.668 g, 28 mmol) was added and stirred under a nitrogen atmosphere at room temperature for 2 h to give sodium imidazole.21 Then ClpSCMNPs (2 g) was added and the mixture was refluxed under a nitrogen atmosphere for 24 h. After cooling down to room temperature, the 3-(1-imidazole) propyl-SCMNPs (ImpSCMNPs) were collected by a permanent magnet and washed with ethanol (3 × 20 mL) and dried under vacuum at 80 °C for 8h. The obtained Imp-SCMNPs were suspended in 25 mL of dry DMF and phthalic anhydride that had been already purified (0.592 g, 4 mmol) and a catalytic amount of iodine as a catalyst were added. The mixture was refluxed for 24 h, and then cooled to room temperature. The obtained salt (1) was separated by magnetic decantation and washed with ether (3 × 20 mL) and was dried in vacuum for 8 h. Eventually, AIL-SCMNPs were obtained by protonation of salt (1) with (0.4 ml, 4mmol) hydrochloric acid 37% and diluted with (10 ml) water. The reaction mixtures were stirred for 2 h at room temperature. The obtained AIL-SCMNPs were magnetically separated and washed with water and ethanol several times and then dried in vacuum for 8h at 60 °C.

Typical procedure for the synthesis of 1,4-DHPs A mixture of aryl aldehyde (1 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate (2 mmol) in the presence of AIL-SCMNPs (0.08 g) was prepared and heated at 60 °C. After complete consumption of starting material as judged by TLC (n-hexane–ethyl acetate), hot ethanol was added to the resulting mixture then AIL-SCMNPs separated by an external

magnet. The solvent was evaporated and the crude product was recrystallized from ethanol to give the pure products in (82–94%) yields. The catalyst was recovered, dried and reused to the next run directly. The desired pure products were characterized by comparison of their physical data with those of known 1,4-DHPs. (Table 2, entry 4a): IR (KBr): 3333, 1690, 1649, 1490, 1237, 1120, 717 cm-1. 1H NMR (250 MHz, CDCl3) δ: 7.33-7.12 (m, 5H, CHAr), 5.70 (s, 1H, NH), 5.01 (s, 1H, CH), 4.12 (q, J=7.1, 4H, 2CH2), 2.37 (s, 6H, 2CH3), 1.23 (t, J=7.1, 6H, 2CH3).

13

C NMR (62.5 MHz, CDCl3) δ:

167.3, 145.1, 143.6, 135.3, 128.2, 127.6, 104.0, 59.3, 39.4, 19.2, 14.0.

Typical procedure for the synthesis of PHQ derivatives Aldehyde (1 mmol), dimedone (1 mmol), ammonium acetate (2 mmol), ethyl acetoacetate (1 mmol) and AIL-SCMNPs (0.08 g) were successively charged into a test tube, equipped with a magnetic stirrer. Then the reaction mixture proceeded at 60 °C for about (5-30 min) and a solid product was formed at an appropriate speed. After completion of reaction (monitored by TLC, eluent; n-hexane–ethyl acetate), hot ethanol was added to the resulting mixture then the catalyst by using an external magnet was concentrated on the sidewall of the reaction vessel. The solvent was evaporated and the crude product was recrystallized from ethanol to afford pure crystals in (80–93%) yields. The residual catalyst which could be reused without losing catalytic activity was washed with water and acetone thoroughly and dried under vacuum at 60 °C. The desired pure products were characterized by comparison of their physical data with those of known PHQ derivatives. (Table 2, entry 5a): IR (KBr): 3294, 3060, 2960, 1677, 1612 cm-1. 1H NMR (CDCl3, 250 MHz) δ: 7.77 (s, 1H, NH), 7.34-7.08 (m, 5H, CHAr), 5.09 (s, 1H, CH), 4.11 (q, J=7.1 Hz, 2H, CH2), 2.33 (s, 3H, CH3), 2.22-2.10 (m, 4H, 2CH2), 1.21 (t, J=7.1 Hz, 3H, CH3), 1.04 (s, 3H,

CH3), 0.90 (s, 3H, CH3).

13

C (CDCl3, 63 MHz) δ: 196.1, 167.7, 153.5, 150.2, 147.3, 144.4,

128.0, 126.7, 126.0, 115.5, 111.4, 105.7, 59.8, 50.8, 40.4, 36.6, 32.6, 29.5, 27.0, 19.0, 14.2.

Conclusion In current study, magnetite nanoparticles supported with a new acidic ionic liquid were first synthesized and applied in both symmetric and asymmetric hantzsch reactions for preparing 1, 4-dihydropyridine and polyhydroquinoline derivatives with high efficiencies. The AIL-MNPs both promote the reaction rate and simplify the work-up procedure. Furthermore, the nanomagnetic catalyst could be recovered from solution with an external magnet at once, allowing undemanding recovery and reuse. In addition, the catalyst was reused for five times with no considerable decrease in catalytic activity. Short-time reaction, excellent efficiency of the products, simple operation, and environmental friendly process are other highlights of this new catalyst.

Acknowledgements

We are grateful to financial support from the Research Council of Shahid Chamran University of Ahvaz.

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Table 1. Optimization of reaction conditions

Entry

AIL-SCMNPs

Temperature

Ammonium acetate

Time

Yield

(g)

(°C)

(mmol)

(min)

(%)a

1

0.00

60

2

120

trace

2

0.02

60

2

60

52

3

0.04

60

2

60

70

4

0.06

60

2

40

83

5

0.08

60

2

10

92

6

0.1

60

2

10

92

7

0.08

60

1.5

10

68

8

0.08

80

2

10

93

9

0.08

25

2

120

trace

Table 2. Synthesis of 1,4-Dihydropyridine (entry 1-9) and polyhydroquinoline (entry 10-18) derivatives under Mild and Solvent-free Conditions

Product Time (min) Yield (%)a Melting point (°C) Ref

Entry

R

1

C6H5

4a

10

92

157-159

22

2

4-ClC6H4

4b

15

82

147-150

24

3

4-OHC6H4

4c

30

89

199-201

25

4

4-CH3C6H4

4d

25

92

140-143

26

5

4-NO2C6H4

4e

10

90

131-133

26

6

4-OCH3C6H4

4f

35

88

158-160

22

7

2-ClC6H4

4g

25

86

125-127

24

8

2-Furyl

4h

5

93

160-162

22

9

3-NO2C6H4

4i

15

94

163-165

24

10

C6H5

5a

5

92

202-204

27

11

4-ClC6H4

5b

15

80

245-247

27

12

4-OHC6H4

5c

20

86

234-235

27

13

4-CH3C6H4

5d

15

90

260-263

27

14

4-NO2C6H4

5e

5

93

243-246

27

15

4-OCH3C6H4

5f

30

89

249-251

28

16

2-ClC6H4

5g

20

87

208-211

27

17

2-Furyl

5h

5

92

246-249

27

18

3-NO2C6H4

5i

15

88

176-178

28

Reaction conditions: benzaldehyde (1 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate, solvent free.

a

Yields refer to isolated pure products

Highlights 

A new acidic ionic liquid were first synthesized and applied in both symmetric and asymmetric hantzsch reactions for preparing 1, 4-dihydropyridine and polyhydroquinoline derivatives with high efficiencies.



The reaction was carried out under solvent-less conditions.



The immobilized catalyst exhibited an appropriate thermal stability and excellent recyclability.



The nanomagnetic catalyst could be recovered from solution with an external magnet at once, allowing undemanding recovery and reuse.



The catalyst was reused for five times with no considerable decrease in catalytic activity.