CC BY-NC-ND 4.0 · SynOpen 2021; 05(02): 100-103
DOI: 10.1055/a-1469-6721
letter
Virtual Collection in Honor of Prof. Issa Yavari

Clean One-Pot Multicomponent Synthesis of Pyrans Using a Green and Magnetically Recyclable Heterogeneous Nanocatalyst

,
Ali Maleki
The authors gratefully acknowledge the partial support from the Research Council of the Iran University of Science and Technology.
 


Dedicated to Prof. Issa Yavari

Abstract

Copper ferrite (CuFe2O4) magnetic nanoparticles (MNPs) were synthesized via thermal decomposition and applied as a reusable and green catalyst in the synthesis of functionalized 4H-pyran derivatives using malononitrile, an aromatic aldehyde, and a β-ketoester in ethanol at room temperature. The nanoparticles were characterized by FT-IR, EDX, SEM, TGA, and DTG analysis. The catalyst was recovered from the reaction mixture by applying an external magnet and decanting the mixture. Recycled catalyst was reused for several times without significant loss in its activity. Running the one-pot three-component reaction at room temperature, using a green solvent under environmentally friendly reaction conditions, ease of catalyst recovery and recyclability, no need for column chromatography and good to excellent yields are advantages of this protocol.


#

In attempts to mitigate the greenhouse effect and environmental pollution, chemical and pharmaceutical companies look to environmentally friendly protocols to reduce environmental pollution using so-called green and sustainable chemistry.[1] Multicomponent reactions (MCRs), in which one-pot reactions involving more than two reactants to produce a single product, represent one of the important strategies in green chemistry.[2] These reactions produce multifunctionalized products using fewer steps compared to classical synthesis approaches.[3] Strecker reported first MCR in 1850 for the synthesis of α-amino cyanides,[4] and nowadays MCRs have been applied to the synthesis of a wide range of complex molecules.[5] [6] [7] [8] In this context, catalysts play a major role; in particular nanocatalysts provide a large surface-to-volume ratio, which increases their activity further.[9–11] However, because of their nanoscale size, separating them from the reaction mixture by conventional methods is not efficient, but use of magnetic nanoparticles (MNPs) can overcome this issue.[12,13] These particles can be synthesized in various forms such as metal nanoparticles, iron oxides, and ferrites.[14] Copper ferrite (CuFe2O4) is one member of the ferrite family that has been widely applied as a catalyst in organic transformations.[15] [16] [17]

2-Amino-3-cyano-4H-pyrans are important heterocyclic scaffolds considering their varied biological activities and pharmaceutical properties such as antitumor (Figure [1], I, II),[18] antibacterial (Figure [1], III, IV), antiviral, antiallergic, spasmolytic, anticoagulant, antianaphylactic,[5] [19] [20] and antioxidant (Figure [1], VVII) activities.[21] They have also been applied to treatment of neurodegenerative disorders including Alzheimer’s disease (Figure [1], VIII, IX),[22] [23] amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease.[24] Additionally, they can be found in cosmetic products.[25] Some examples of biologically active 4H-pyrans are shown in Scheme [1]. 4H-Pyrans are also components of some plant-derived natural products.[26] In addition, 4H-pyrans can be efficiently applied as precursors to produce different classes of heterocycles.[27] Many examples of 4H-pyran synthesis using different catalyst systems have been reported in the literature, including potassium phthalimide-N-oxyl,[28] baker’s yeast,[5] MgO,[19] Mg/La,[20] SiO2,[24] SnCl2/ nano SiO2,[29] ionic liquids such as [2-aemim][PF6];[30] and catalyst-free conditions have also been disclosed.[31]

Zoom Image
Figure 1 The structures of some biologically active molecules with 4H-pyran cores
Zoom Image
Scheme 1 Synthesis of 2-amino-3-cyano-4H-pyrans

In continuation of our interest in the design, discovery, and application of new catalysts in organic syntheses via MCRs to develop green procedures,[7] we present herein an environmentally friendly synthesis of 4H-pyrans 4 via a green one-pot three-component reaction of an aldehyde 1, malononitrile 2, and methyl/ethyl acetoacetate 3 using CuFe2O4 magnetic nanoparticles as an efficient and green catalyst under mild reaction conditions in good to excellent yields (Scheme [1]).To the best of our knowledge, this is the first time that copper ferrite magnetic nanoparticles have been applied as catalyst for the synthesis of this class of heterocycles.

The CuFe2O4 nanoparticles were prepared by thermal decomposition of copper(II) nitrate and iron(III) nitrate by a published method[16] [32] and characterized by FT-IR spectroscopy (Figure S11), EDX analysis (Figure S12), SEM analysis (Figure S13), and TGA/DTG analysis (Figure S15). To optimize conditions, the three-component reaction of 3-nitrobenzaldehyde (0.5 mmol), malononitrile (0.5 mmol), ethyl acetoacetate (0.5 mmol), and CuFe2O4 was run in various solvents at room temperature, as the model reaction for pyran derivative synthesis. Initially, the amount of CuFe2O4 catalyst was optimized. Best results were obtained with 20 mol% of the catalyst. No further increase in yield was observed with additional amounts of catalyst. Next, the role of the solvent was reconsidered with the best yield being obtained in ethanol[33] (Table [1]). Following the optimization efforts, a range of reactions was run under optimized conditions, and the desired products were obtained in good to excellent yields (Table [2]). Known compounds were identified by comparison of their physical data (melting points) with those of authentic samples. In addition, 1HNMR and IR analyses were carried out. These data are provided in the Supporting Information.

Table 1 Optimization of Reaction Conditions in the Synthesis of 5-Ethoxycarbonyl-2-amino-4-(3-nitrophenyl)-3-cyano-6-methyl-4H-pyran (4e)a

Entry

Catalyst (mol%)

Solvent

Time (h)b

Yield (%)c

1d

EtOH

6

53

2

EtOH

3

trace

3e

EtOH

3

70

4f

EtOH

2

75

5

1

EtOH

3

10

6

5

EtOH

3

59

7

10

EtOH

3

59

8

20

EtOH

3

86

9

20

EtOH

2

86

10f

20

EtOH

0.75

85

11

20

10

23

12

20

H2O

20

12

13

20

MeCN

4

25

a Room temperature unless otherwise temperature is mentioned.

b Reactions were followed by TLC.

c Isolated yields.

d Optimization studies of this entry are omitted, and just highest yield in the shortest time is noted.

e This reaction was run at 40 °C.

f This reaction was run at 60 °C.

Table 2 Synthesis of 2-Amino-4-aryl-3-cyano-6-methyl-4H-pyran Derivatives 4at a

Entry

R1

R2

Product

Time (h)

Yield (%)b

mp (°C)

Found

Reported

1

H

Et

4a

3

77

189–193

189–191[29]

2

2-NO2

Et

4b

3

73

178–179

176–178[24]

3

2-Cl

Et

4c

3.5

79

190–192

191–193[34]

4

3-OH

Et

4d

3

83

168–171

162–164[29]

5

3-NO2

Et

4e

2

86

187–188

181–183[29]

6

4-OH

Et

4f

3

75

196–198

192–193[35]

7

4-NO2

Et

4g

2

78

179–181

180–182[29]

8

4-Cl

Et

4h

2

73

174–176

174–176[24]

9

4-Br

Et

4i

3.5

70

176–177

176–178[35]

10

4-Me

Et

4j

3

79

139–140

158[36]

11

4-OMe

Et

4k

2

72

133–136

138–140[35]

12

2-NO2

Me

4l

4

70

187–189

181[37]

13

2-Cl

Me

4m

3

75

151–153

148–150[38]

14

3-OH

Me

4n

3.5

70

136–139c

15

3-NO2

Me

4o

3

84

210–212

212–213[38]

16

4-OH

Me

4p

4

65

163–165

160–162[38]

17

4-NO2

Me

4q

3

70

155–157

165[37]

18

4-Cl

Me

4r

3

79

171–173

172–173[39]

19

4-Me

Me

4s

3

71

165–167

164–165[38]

20

4-OMe

Me

4t

3

76

141–143

138–140[38]

a Reaction conditions: aldehyde (1 mmol), malononitrile (1 mmol), ethyl/methylacetoacetate (1 mmol), catalyst (20 mol%), ethanol (5 mL), room temperature.

b Isolated yield.

c The products were characterized by 1H NMR and IR spectroscopy.

To investigate the catalyst reusability, the catalyst was recovered and washed with distilled water and ethanol, and the model reaction was run again in the presence of recycled catalyst. The results shown in Figure [2] indicate that very slight decreases in yields were observed after 3 cycles and after the 5th cycle, catalyst activity was still satisfying.

Zoom Image
Figure 2 Catalyst recyclability for model reaction (4e)

In order to demonstrate the advantages of this methodology, some other methods for the synthesis of 4H-pyran (4e) were compared with the present protocol. Some of the methods need an external source of energy such as heating or ultrasonic radiation. In some cases, the catalysts are expensive or may not be recyclable. Typical results are gathered in Table [3].

Table 3 Comparison of the Present Work with other Methods for the Synthesis of Pyran 4e

Entry

Catalyst

Solvent/conditions

Temp (°C)

Time (min)

Yield (%)

1

MgO

water/grinding/two steps

r.t.

25

92[19]

2

Mg/La

MeOH/reflux

65

60

86[20]

3

SiO2

EtOH

r.t.

120

86[24]

5

SnCl2/SiO2

EtOH/reflux

reflux

30

93[29]

6

CuFe2O4

EtOH

r.t.

120

86a

a This work.

In summary, we have represented clean, efficient, one-pot methodology for the synthesis of highly functionalized 4H-pyrans using CuFe2O4 magnetic nanoparticles as a reusable and green nanocatalyst. Reactions are run at room temperature in ethanol providing a green synthesis of 4H-pyran heterocycles. Short reaction times, nontoxic catalyst, ease of catalyst separation by using an external magnet, catalyst recyclability, no need for heating, good to excellent yields, and mild conditions are advantages of the reported protocol. Moreover, the high tolerance of this procedure towards various functional groups, easy and simple work-up procedure, exceptionally high yields of the desired products, and scalability are the added advantages.


#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

  • References and Notes

    • 1a Anastas PT, Warner JC. Green Chemistry: Theory and Practice. Oxford University Press; New York: 1998
    • 1b Tundo P, Anastas P, Black DS, Breen J, Collins T, Memoli S, Miyamoto J, Polyakoff M, Tumas W. Pure Appl. Chem. 2000; 72: 1207
  • 2 Dömling A. Chem. Rev. 2006; 106: 17
  • 3 Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
  • 4 Strecker A. Eur. J. Org. Chem. 1850; 75: 27
  • 5 Pratap UR, Jawale DV, Netankar PD, Mane RA. Tetrahedron Lett. 2011; 52: 5817
  • 6 Baral ER, Sharma K, Akhtar MS, Lee YR. Org. Biomol. Chem. 2016; 14: 10285
  • 7 Maleki A, Azizi M, Emdadi Z. Green Chem. Lett. Rev. 2018; 114: 573
  • 8 Eslami M, Dekamin MG, Motlagh L, Maleki A. Green Chem. Lett. Rev. 2018; 11: 36
  • 9 Maleki A, Ghassemi M, Firouzi-Haji R. Pure Appl. Chem. 2018; 90: 387
  • 10 Hajipour AR, Tadayoni NS, Khorsandi Z. Appl. Organomet. Chem. 2016; 30: 590
  • 11 Safari J, Zarnegar Z. New J. Chem. 2014; 38: 358
  • 12 Doustkhah E, Rostamnia S. J. Colloid Interface Sci. 2016; 478: 280
  • 13 Rostamnia S, Doustkhah E. J. Magn. Magn. Mater. 2015; 386: 111
  • 14 Wang D, Astruc D. Chem. Rev. 2014; 114: 6949
  • 15 Gholinejad M, Karimi B, Mansouri F. J. Mol. Catal. A: Chem. 2014; 386: 20
  • 16 Dandia A, Jain AK, Sharma S. RSC Adv. 2013; 3: 2924
  • 17 Maleki A, Firouzi-Haji A, Farahani P. Org. Chem. Res. 2018; 4: 86
  • 18 Wang DC, Xie YM, Fan C, Yao S, Song H. Chin. Chem. Lett. 2014; 25: 1011
  • 19 Kumar D, Reddy VB, Sharad S, Dube U, Kapur S. Eur. J. Med. Chem. 2009; 44: 3805
  • 20 Babu NS, Pasha N, Rao KT. V, Prasad PS. S, Lingaiah N. Tetrahedron Lett. 2008; 49: 2730
  • 21 Shanthi G, Perumal PT, Rao U, Sehgal PK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2009; 48: 1319
  • 22 Marco-Contelles J, León R, Ríos CD. L, García AG, López MG, Villarroya M. Bioorg. Med. Chem. 2006; 14: 8176
  • 23 Khoobi M, Ghanoni F, Nadri H, Moradi A, Pirali HamedaniM, Homayouni MoghadamF, Emami S, Vosooghi M, Zadmard R, Foroumadi A, Shafiee A. Eur. J. Med. Chem. 2015; 89: 296
  • 24 Banerjee S, Horn A, Khatri H, Sereda G. Tetrahedron Lett. 2011; 52: 1878
  • 25 Kim DH, Hwang JS. S, Baek HS, Kim KJ. J, Lee BG, Chang I, Kang HH, Lee OS. Chem. Pharm. Bull. 2003; 51: 113
  • 26 Wickel SM, Citron CA, Dickschat JS. Eur. J. Org. Chem. 2013; 2906
  • 27 Das P, Dutta A, Bhaumik A, Mukhopadhyay C. Green Chem. 2014; 16: 1426
  • 28 Dekamin MG, Eslami M, Maleki A. Tetrahedron 2013; 69: 1074
  • 29 Safaei-Ghomi J, Teymuri R, Shahbazi-Alavi H, Ziarati A. Chin. Chem. Lett. 2013; 24: 921
  • 30 Peng Y, Song G. Catal. Commun. 2007; 8: 111
  • 31 Survase DN, Chavan HV, Dongare SB, Helavi VB. Synth. Commun. 2016; 46: 1665
  • 32 Preparation of Copper Ferrite NanoparticlesFe(NO3)3·9H2O (3.34 g, 8.2 mmol) and Cu(NO3)2·3H2O (1.0 g, 4.1 mmol) were dissolved in distilled water (75 mL), then NaOH (3.0 g, 75 mmol) dissolved in distilled water (15 mL) was added at room temperature over 10 min, during which time a reddish-black precipitate was formed. Then the reaction mixture was warmed to 90 °C with stirring under ultrasonic irradiation for 2 h and then cooled to room temperature. The magnetic particles so formed were separated by an external magnet then washed with distilled water (3 × 30 mL) and kept in an oven at 80 °C overnight. The powder was further grounded in a mortar, heated at 700 °C for 5 h, and then cooled to room temperature.
  • 33 A mixture of aryl aldehyde (1 mmol), malononitrile (1 mmol), methyl/ethyl acetoacetate (1 mmol), and CuFe2O4 (20 mol%) was stirred in ethanol (5 mL) at room temperature until completion of the reaction as indicated by TLC. After completion of the reaction, the catalyst was removed from the reaction mixture via an external magnet and the product allowed to precipitate. The solid product was filtered and recrystallized from ethanol. All the products are known compounds that were identified by comparison of their physical data (melting points) with those authentic samples.
  • 34 Amirnejad M, Naimi-Jamal MR, Tourani H, Ghafuri H. Monatsh. Chem. 2013; 144: 1219
  • 35 Ramesh R, Lalitha A. Res. Chem. Intermed. 2015; 41: 8009
  • 36 Bhattacharyya P, Pradhan K, Paul S, Das AR. Tetrahedron Lett. 2012; 53: 4687
  • 37 Molla A, Hossain E, Hussain S. RSC Adv. 2013; 3: 21517
  • 38 Kalla RM. N, Kim MR, Kim I. Tetrahedron Lett. 2015; 56: 717
  • 39 Yi F, Peng Y, Song G. Tetrahedron Lett. 2005; 46: 3931

Corresponding Author

Ali Maleki
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology
Tehran 16846-13114
Iran   

Publication History

Received: 14 February 2021

Accepted after revision: 25 March 2021

Publication Date:
30 March 2021 (online)

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  • References and Notes

    • 1a Anastas PT, Warner JC. Green Chemistry: Theory and Practice. Oxford University Press; New York: 1998
    • 1b Tundo P, Anastas P, Black DS, Breen J, Collins T, Memoli S, Miyamoto J, Polyakoff M, Tumas W. Pure Appl. Chem. 2000; 72: 1207
  • 2 Dömling A. Chem. Rev. 2006; 106: 17
  • 3 Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
  • 4 Strecker A. Eur. J. Org. Chem. 1850; 75: 27
  • 5 Pratap UR, Jawale DV, Netankar PD, Mane RA. Tetrahedron Lett. 2011; 52: 5817
  • 6 Baral ER, Sharma K, Akhtar MS, Lee YR. Org. Biomol. Chem. 2016; 14: 10285
  • 7 Maleki A, Azizi M, Emdadi Z. Green Chem. Lett. Rev. 2018; 114: 573
  • 8 Eslami M, Dekamin MG, Motlagh L, Maleki A. Green Chem. Lett. Rev. 2018; 11: 36
  • 9 Maleki A, Ghassemi M, Firouzi-Haji R. Pure Appl. Chem. 2018; 90: 387
  • 10 Hajipour AR, Tadayoni NS, Khorsandi Z. Appl. Organomet. Chem. 2016; 30: 590
  • 11 Safari J, Zarnegar Z. New J. Chem. 2014; 38: 358
  • 12 Doustkhah E, Rostamnia S. J. Colloid Interface Sci. 2016; 478: 280
  • 13 Rostamnia S, Doustkhah E. J. Magn. Magn. Mater. 2015; 386: 111
  • 14 Wang D, Astruc D. Chem. Rev. 2014; 114: 6949
  • 15 Gholinejad M, Karimi B, Mansouri F. J. Mol. Catal. A: Chem. 2014; 386: 20
  • 16 Dandia A, Jain AK, Sharma S. RSC Adv. 2013; 3: 2924
  • 17 Maleki A, Firouzi-Haji A, Farahani P. Org. Chem. Res. 2018; 4: 86
  • 18 Wang DC, Xie YM, Fan C, Yao S, Song H. Chin. Chem. Lett. 2014; 25: 1011
  • 19 Kumar D, Reddy VB, Sharad S, Dube U, Kapur S. Eur. J. Med. Chem. 2009; 44: 3805
  • 20 Babu NS, Pasha N, Rao KT. V, Prasad PS. S, Lingaiah N. Tetrahedron Lett. 2008; 49: 2730
  • 21 Shanthi G, Perumal PT, Rao U, Sehgal PK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2009; 48: 1319
  • 22 Marco-Contelles J, León R, Ríos CD. L, García AG, López MG, Villarroya M. Bioorg. Med. Chem. 2006; 14: 8176
  • 23 Khoobi M, Ghanoni F, Nadri H, Moradi A, Pirali HamedaniM, Homayouni MoghadamF, Emami S, Vosooghi M, Zadmard R, Foroumadi A, Shafiee A. Eur. J. Med. Chem. 2015; 89: 296
  • 24 Banerjee S, Horn A, Khatri H, Sereda G. Tetrahedron Lett. 2011; 52: 1878
  • 25 Kim DH, Hwang JS. S, Baek HS, Kim KJ. J, Lee BG, Chang I, Kang HH, Lee OS. Chem. Pharm. Bull. 2003; 51: 113
  • 26 Wickel SM, Citron CA, Dickschat JS. Eur. J. Org. Chem. 2013; 2906
  • 27 Das P, Dutta A, Bhaumik A, Mukhopadhyay C. Green Chem. 2014; 16: 1426
  • 28 Dekamin MG, Eslami M, Maleki A. Tetrahedron 2013; 69: 1074
  • 29 Safaei-Ghomi J, Teymuri R, Shahbazi-Alavi H, Ziarati A. Chin. Chem. Lett. 2013; 24: 921
  • 30 Peng Y, Song G. Catal. Commun. 2007; 8: 111
  • 31 Survase DN, Chavan HV, Dongare SB, Helavi VB. Synth. Commun. 2016; 46: 1665
  • 32 Preparation of Copper Ferrite NanoparticlesFe(NO3)3·9H2O (3.34 g, 8.2 mmol) and Cu(NO3)2·3H2O (1.0 g, 4.1 mmol) were dissolved in distilled water (75 mL), then NaOH (3.0 g, 75 mmol) dissolved in distilled water (15 mL) was added at room temperature over 10 min, during which time a reddish-black precipitate was formed. Then the reaction mixture was warmed to 90 °C with stirring under ultrasonic irradiation for 2 h and then cooled to room temperature. The magnetic particles so formed were separated by an external magnet then washed with distilled water (3 × 30 mL) and kept in an oven at 80 °C overnight. The powder was further grounded in a mortar, heated at 700 °C for 5 h, and then cooled to room temperature.
  • 33 A mixture of aryl aldehyde (1 mmol), malononitrile (1 mmol), methyl/ethyl acetoacetate (1 mmol), and CuFe2O4 (20 mol%) was stirred in ethanol (5 mL) at room temperature until completion of the reaction as indicated by TLC. After completion of the reaction, the catalyst was removed from the reaction mixture via an external magnet and the product allowed to precipitate. The solid product was filtered and recrystallized from ethanol. All the products are known compounds that were identified by comparison of their physical data (melting points) with those authentic samples.
  • 34 Amirnejad M, Naimi-Jamal MR, Tourani H, Ghafuri H. Monatsh. Chem. 2013; 144: 1219
  • 35 Ramesh R, Lalitha A. Res. Chem. Intermed. 2015; 41: 8009
  • 36 Bhattacharyya P, Pradhan K, Paul S, Das AR. Tetrahedron Lett. 2012; 53: 4687
  • 37 Molla A, Hossain E, Hussain S. RSC Adv. 2013; 3: 21517
  • 38 Kalla RM. N, Kim MR, Kim I. Tetrahedron Lett. 2015; 56: 717
  • 39 Yi F, Peng Y, Song G. Tetrahedron Lett. 2005; 46: 3931

Zoom Image
Figure 1 The structures of some biologically active molecules with 4H-pyran cores
Zoom Image
Scheme 1 Synthesis of 2-amino-3-cyano-4H-pyrans
Zoom Image
Figure 2 Catalyst recyclability for model reaction (4e)