Document Type : Original Article

Authors

1 Department of Chemistry, Dr. Rafiq Zakariya College For Women, Aurangabad (MS) India- 431001.

2 Department of Chemistry, Ramkrishna ParamhansaMahavidyalaya, Osmanabad (MS) India- 431501.

3 Department of Chemistry, Badrinarayan Barwale Mahavidyalaya, Jalna (MS) India- 431213.

4 Department of Chemistry, Maulana Azad College of Arts Science and Commerce, Aurangabad, (MS) India- 431001.

Abstract

An efficient and simple one-pot synthetic protocol has been developed for the first time to synthesize the series of Ethyl-6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylates. This was achieved by the cyclocondensation of aromatic aldehydes, malononitrile, and ethylacetoacetate in the presence of the catalytic amount of Maglumine as a readily available, reusable, and biodegradable catalyst. This technique is very promising asit provides mild reaction conditions, an environmentally benign greener approach, easy workup process, high yield, less reaction time, low cost, and recycled up to five catalytic cycles without substantial loss of catalytic activity or product yield.

Graphical Abstract

Meglumine Catalysed Green Synthesis of Ethyl-6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate Derivatives

Keywords

Main Subjects

 

Introduction

One of the most important challenges in organic synthesis is to design easy synthetic pathways for commonly used organic molecules using easily available reagents. Single-step, one-pot, and three-component condensation reactions are now widely used for the synthesis of various heterocyclic compounds in synthetic organic chemistry.As compared to multistep techniques, one-pot protocols are more efficientasitoffers higher yield in shorter reaction time with easy workup processes. 4H-pyranare oxygen-containing heterocyclic moiety, with several biological properties including antibacterial,[1],[2] anticancer,[3]antiviral,[4]antitumor,[5]antifungal, antioxidant[6], [7], and antimicrobial activities[8]as well as shows anti-corrosion properties[9].Asillustrated in Figure 1, the pyran scaffold acts as asignificant structural motif in various bioactive compounds such as beta-lapachone,alpha- apachone,zanamivir,laninamivir. Correspondingly, derivatives of 4H-pyrans have been found as highly bioactive compounds because of their biodegradable abilities. They are alsofound in cosmetics, dyes, pigments,and agrochemicals[10].Consequently,the organic community has been encouraged to discover an excellent method for the synthesis of 4H-pyran.


A review of the literature indicates that 4H-pyran could be synthesized by several different protocols, which includethe two-step approachas well as the one-pot three-component system.Mostly, 4H-pyrans are synthesized by a one-pot cyclocondensationreaction in betweenan aromatic aldehyde, malononitrile, and ethylacetoacetatein presence of a basic catalyst.This synthetic approachwas involved in presence of various catalysts such as BaFe12O19@IM,[11]PPh3,[12]Potassium fluoride,[13]Mg/La mixed oxide,[14] tetramethylguanidine-[bmim][BF4],[15]potassium phthalimide,[16]molecular sieve-supported zinc,[17]BNFe3O4,[18]Silica Supported V2O5,[19]thiourea dioxide[20]and Baker’s yeast.[21]However, these above-mentioned protocols have one or more disadvantages, and the majority of therequired heating conditions and provide moderate yields even after a considerable reaction time. This clearly indicates that there is still scope for improvement in terms of developing an effective and environmentally friendly protocol for the synthesis of 4H-pyrans.

Hence, we have planned to synthesize Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylateby using Meglumine as a catalyst.The presence of hydroxyl groups and an amino group from the Meglumine tends to activate the nucleophilicas well as electrophilic centers, which helps in hydrogen bonding and electron donation. Meglumine shows fantastic properties such as low toxicity, biodegradability, physiological inertness, reusability, low cost, and non-corrosion nature. Because of the above findings and our ongoing efforts [22-25] to develop environment-friendly synthetic methods for various reactions, herein, we present Meglumine as a biodegradable catalyst for one-pot synthesis of ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylatebyreactingaromatic aldehydes, malononitrile,andethylacetoacetatein Ethanol: Water at room temperature.

Figure 2.Structure of Meglumine Catalyst

Results and Discussion

The synthesis of Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylatederivativeswas achieved by reacting substituted aromatic benzaldehydes(1a-l) with malononitrile(2) and ethylacetoacetate(3)in ethanol:water in the presence of Meglumine as a catalyst. The product was obtained after stirring the reaction mixture for30-35 minutes at room temperature. Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylatederivatives(4a-l) were obtainedwith high purity and better toexcellent yields, as shown in Scheme 1.

The structures of all the newly synthesized Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylates(4a-l) are depicted in Figure 3.Optimization of the reaction parameters was performed bymodel reaction of benzaldehyde(1a), malononitrile (2), and ethylacetoacetate (3) as shown below.

Figure 3. Structures of the synthesized Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate derivatives (4a-l)


Scheme 2. Model reaction for Synthesis of 4H-pyran

Firstly, we have considered solvent parameters and observed reactions in different solvents like water, methanol, PEG-400, and ethanol as protic solvents as well as DCM, DMF, and acetonitrile as aprotic solvents. We observed that the solvent has an important role in the progress of the reaction. The reaction with ethanol:water gave the corresponding product in good yields, whereas the findings with other solvents such as DCM, DMF, and acetonitrile, yielded the product 4a in fewer quantities, neither PEG-400 nor water were particularly given good results.Further,it has beendecided the impressive and ideal solvent for this conversion was aqueous ethanol (water:ethanol, 9:1, v/v).

 

Table 1.Screening of reaction conditions with respect to solvent and catalyst loading 4aa

Entry

Solvent

Catalyst(mol%)

Yieldb(%)

 

1

Water

10% Meglumine

N R

2

Methanol

10% Meglumine

74

 

3

Ethanol

10% Meglumine

79

 

4

PEG-400

10% Meglumine

58

 

5

DCM

10% Meglumine

26

 

6

DMF

10% Meglumine

29

 

7

Acetonitrile

10% Meglumine

31

 

8

Ethanol:Water(1:1)

10% Meglumine

79

 

9

Ethanol:Water(9:1)

5% Meglumine

90

 

10

Ethanol:Water(9:1)

10% Meglumine

96

 

11

Ethanol:Water(9:1)

15% Meglumine

93

 

12

Ethanol:Water(9:1)

No catalyst

09

 

aReactionconditions:Benzaldehyde (1mmol), Malononitrile (1mmol), Ethylacetoacetate(1mmol), 10mol% Meglumine in 5 mL ethanol:water, at room temperature for 30-35 min.bIsolated yields, NR: No Reaction

However, in the model reaction, the influence of catalyst loading was also investigated. The results revealed that a catalyst concentration of 10mol% was a great choice for this process. Increasing the catalyst concentration 10 to 15mol% resulted in a low effect on yield and not be further increased.When the reaction was conducted with reducing amounts of catalyst, the yield of 4a could not be further increased.Under optimized conditions when the standard reaction was performed in absence of Megluminethere was less conversion of reactants to products after stirring at room temperature(Table 1, entry 12).

This result motivates us to investigate the methods for synthesis of Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylates from substituted benzaldehydes,malononitrile, and ethylacetoacetate using a 10mol%Meglumine catalyst and ethanol:water as a solvent in an optimized reaction condition.

The recyclability of the meglumine catalyst was further examined for the standard reaction of benzaldehyde (1a), malononitrile (2), and ethylacetoacetate(3) in ethanol:water solvent at room temperature for 30-35 minutes. The results are shown in Figure 4.

Figure 4.The recyclability of Megluminea in the synthesis of 4H-pyran


After the completion of the reaction, the catalyst was recovered andthe filtrate was dried. The recovered catalyst was reused after drying for the next run. The catalyst was reused for four runs, and the target compounds were formed in yields (96% to 94%) in their corresponding reaction periods in each and every reaction.

The plausible mechanism for the synthesis of Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate(4a)as shown in Scheme 3, involves the proton abstraction of the active methylene group of malononitrile by the Meglumineindicated as A, later it reacts with benzaldehyde involves the dehydration resulting in the formation of B, which on the attack of active methylene group of ethylacetoacetateto form C, after that abstraction of hydrogen by Meglumine from C and D to form desired product E.

Conclusion

Finally, by utilizing Meglumine as a green and recyclable catalyst, we designed a mild, rapid, and environmentally sustainable synthesis process for Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (4a-l) from aromatic benzaldehyde, malononitrile, and ethylacetoacetate.Simple reaction conditions, no side reactions, and high yield product formation are all essential features of the technique. For the synthesis of Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate, the current technique is an alternative to traditional methods. The catalyst was retrieved several times without losing catalytic activity, resulting in a cost-effective method.

Experimental

General experimental procedure for the synthesis of ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate

In a dry and clean 50mL round bottom flask, a mixture of substituted benzaldehyde (1 mmol), malononitrile (1mmol), and ethylacetoacetate(1mmol) was stirred in 5 mL ethanol:water as a solvent along with Meglumine(10 mole%) as a catalyst at room temperature for 30-35 min. The progress of the reaction was monitored by thin-layer chromatography. After the completion of the reaction, the reaction mixture was poured oncrushed ice, which was then filtered. The crude product was crystallized using ethanol to yield pure 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate.The melting points of the products are in good agreement with those described in the literature[26-32].

Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (4a)

The compound (4a) was synthesized with Megluminecatalyzed reaction in betweenbenzaldehyde(1a),malononitrile(2)andethylacetoacetate(3) aswhite solid; yield 96%; Mp 190-192oC; 1H NMR (300 MHz, CDCl3)δ (ppm):1.00-1.03 (t, 3H, CH3-CH2-), 2.31 (s, 3H, CH3), 3.92-3.99 (m, 2H, CH2-CH3), 4.37 (s, 1H, pyran-H), 4.40 (s, 2H, NH2), 7.12-7.24 (m, 5H, Ar-H).;13C NMR (75 MHz, CDCl3)δ (ppm) :12.86, 17.37, 37.74, 59.65, 76.00, 106.98, 117.80, 126.17, 126.49, 127.56, 142.73, 155.76, 156.39, 164.84.; LCMS (ESI+) calcd. for C16H16N2O3(M+H)+: 285.12; found 285.14.

Ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (4c)

The compound (4c) was synthesized with Megluminecatalyzed reaction in between4-chlorobenzaldehyde(1c),malononitrile(2)andethylacetoacetate(3) as light yellow solid; yield 94%; mp 138-139oC;1H-NMR (300 MHz, CDCl3)δ (ppm) :1.03-1.05(t, 3H,CH3-CH2-), 2.30 (s, 3H,CH3), 3.96-4.00 (q, 2H,CH2-CH3), 4.36 (s, 1H,pyran-H), 4.49 (s, 2H,NH2), 7.06-7.08 (d, 2H, Ar-H), 7.19-7.20 (d, 2H, Ar-H).; 13C NMR (75 MHz, CDCl3) δ (ppm) :12.77, 17.30, 37.16, 59.62, 75.88, 106.46, 117.52, 127.59, 127.76, 131.80, 141.24, 155.90, 156.37, 164.49.; LCMS (ESI+) calcd. for C16H15ClN2O3(M+H)+: 319.08; found 319.09.

Ethyl 6-amino-5-cyano-2-methyl-4-(2-nitrophenyl)-4H-pyran-3-carboxylate (4f)

The compound (4f) was synthesized with Meglumine catalyzed reaction in between2-nitrobenzaldehyde(1f), malononitrile(2)andethylacetoacetate(3) as yellowish solid; yield 94%;Mp 178-179oC; 1H NMR (300 MHz, CDCl3)δ (ppm) :0.88-0.91 (t, 3H, CH3-CH2-), 2.31 (s, 3H,CH3), 3.85-3.87 (q, 2H, CH2-CH3), 4.56 (s, 2H, NH2), 5.16 (s, 1H, pyran-H), 7.17–7.72 (m, 4H, Ar-H ).; 13C NMR (75 MHz, CDCl3)δ (ppm):12.51, 17.30, 31.83, 59.79, 75.61, 106.15, 117.00, 122.91, 126.76, 129.46, 132.08, 137.95, 147.95, 156.91, 157.09, 163.89;LCMS (ESI+) calcd. for C16H15N3O5(M+H)+: 330.31; found 330.35.

Supporting Information

Full experimental detail, LCMS, 1H, and 13C NMR spectra. This material can be found via the “Supplementary Content” section of this article’s webpage.

Acknowledgments

The author G.B.P. is very much thankful to the Council for Scientific and Industrial Research (CSIR), New Delhi, for theaward senior research fellowship. File No. 08/613(0005)/2018-EMR-I

Conflict of Interest

The authors declare no conflict of interest.

  Orcid:

Ganesh Baburao Pund

https://orcid.org/0000-0003-1560-6171

Sambhaji Tukaram Dhumal

https://orcid.org/0000-0003-3018-6179

Madhav Janardan Hebade

https://orcid.org/0000-0003-0008-8834

Mazahar Farooqui

https://orcid.org/0000-0003-2236-6639

Bhagwansing Shivsing Dobhal

https://orcid.org/0000-0002-9469-3869

 

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