Ionic Liquid

Send Orders for Reprints to [email protected] Letters in Organic Chemistry, 2016, 13, 000-000

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RESEARCH ARTICLE

Ionic Liquid: An Efficient and Facile Catalyst for the Synthesis of Trisubstituted Imidazole Derivatives via Multi-Component Pathway Using Green Techniques Gopinath D. Shirole1,2 and Sharad N. Shelke2,* 1

Department of Chemistry, A.S.C. College, Rahta, Dist-Ahmednagar (MH) 423107, India; 2Department of Chemistry, S.S.G.M. College, Kopargaon, Dist-Ahmednagar (MH) 423601; India; Affiliated to University of Pune, India Abstract: Background: A green path for the synthesis of 3-aryl-1-phenyl-4-(4,5-diphenyl-1H-imidazol-2-yl)-1Hpyrazole derivatives using [BMIM][BF4] as a catalyst and green methods such as ultrasound and microwave irradiation is discussed in this paper. The titled compounds were obtained by the multi-component condensation of various 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehydes, benzil and ammonium acetate. One pot synthesis, simple reaction conditions and quantitative yields illustrate the utility of this green approach.

ARTICLE HISTORY Received: June 07, 2016 Revised: September 26, 2016 Accepted: October 27, 2016 DOI: 10.2174/15701786146661611141651 13

Methods: Conventional Reflux Condition: A mixture of 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM][BF4] (15 mmol %) was placed in a round bottom flask containing 10 mL of ethanol. The reaction mixture was refluxed for completion. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was poured over crushed ice. Solid imidazole thus obtained was separated by filtration, dried well, and recrystallized by ethanol. Ultrasound Irradiation Method: A mixture of 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM][BF4] (15 mmol %) was placed in a round bottom flask containing 10 mL of ethanol. The round bottom flask was placed in an US bath at 50oC for 80-90 min. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was poured into crushed ice, solid imidazoles thus obtained were separated by filtration, dried well, and recrystallized by ethanol. Microwave Irradiation Method: A 10 mL round bottom flask was charged with 3-aryl-1-phenyl1H-pyrazole-4-carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM] [BF4] (15 mmol %), and placed under MW irradiation at 240 watts for 7-9 min. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was poured over crushed ice, the solid imidazole thus obtained was separated by filtration, dried well, and recrystallized by ethanol. Results: The 3-aryl-1-phenyl-4-(4,5-diphenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives 4a-i (Scheme 1, Table 2) were synthesized by using [BMIM] [BF4] as a catalyst with good yields under reflux in ethanol (68-70%), US irradiation in ethanol (76-80%) and MW irradiation (80-86%) without solvent. All these methods provided good results with IL [BMIM][BF4]. However, the MW and US irradiation methods give good yield in a short period of time with 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 containing a variety of substituents, whereas the conventional reflux condition gives lower yields and takes longer time as compared with MW and US irradiation. The structures of the synthesized compounds have been confirmed on the basis of spectroscopic techniques such as FTIR, HRMS, LCMS, 1H and 13C NMR. Conclusion: In conclusion, we have synthesized differently substituted imidazoles using [BMIM][BF4] as a catalyst under MW and US irradiation via MC condensation strategy. Under the conventional reflux conditions, we get a lower yield in a longer time, while US and MW assisted synthesis gave better results. Comparatively IL [BMIM][BF4] with US and MW irradiation protocol provides several advantages such as improved reaction speed, shorter reaction times, superior yields and a significant contribution towards sustainability.

Keywords: 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehydes, imidazoles, ionic liquid, microwave technique, multicomponent strategy, sonochemistry. INTRODUCTION Green techniques, possessing the capacity of sustainable improvement in synthetic organic chemistry, have attracted *Address correspondence to this author at the Department of Chemistry, S.S.G.M. College, Kopargaon, Dist-Ahmednagar (MH) 423601, India; Tel: +918888199853; E-mail: [email protected] 1570-1786/16 $58.00+.00

great interest. The organic media used in chemical transformations processes are often volatile, highly flammable, and toxic, so incompatible with the plan of the safety of the environment and sustainability [1]. Thus, the search for environmentally friendly reaction routes is still very important. Ionic liquids (ILs) provide an outstanding green strategy for the

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2 Letters in Organic Chemistry, 2016, Vol. 13, No. 9

synthesis of a wide variety of organic molecules and other applications in organic chemistry [2, 3]. The literature survey suggests that ILs are the most successful and alternative reaction media for organic transformations. The relevant interest in such compounds is due to their exclusive chemical and physical properties. The most important property is the non-corrosivity, which decreases the hazard and the loss of solvent to the environment. Many chemical reactions have been carried out on ILs such as trans-esterification [4], oxo-Michael addition [5], epoxidation [6], Prins reaction [7], cyclocondensation reactions [8], and hydroformylation [9] due to high polar character. In the last decades, Ultrasound (US) - assisted reactions have been an important and well established technique in organic synthesis, which proceed via the formation and adiabatic collapse of transient cavitation bubbles. It is used as an environmentally benign technique that is useful tool for achieving the green chemistry goals, helping to minimize the waste formation and reduce energy requirements. It also displays smooth and cleaner reactions by improving yields with homogeneous and heterogeneous processes [10-13]. The microwave (MW) irradiation is also used as an important green tool for organic synthesis in different areas of organic chemistry. Many studies have revealed the relevance of MW technique in minimizing the time, increasing the yield compared to conventional methods. In the MW technique, the reaction mixture is heated from the inside that is the MW energy is transferred directly to the reactants, solvent, and catalyst molecules. Several studies have reported the junction of the MW irradiation and ILs in organic transformations. ILs interact very powerfully in combination with MWs through the ionic conduction path. In particular, in MW-assisted synthesis of heterocyclic compounds, ILs can be used as support [14-22]. Heterocyclic moieties are present in a wide range of many naturally occurring compounds, vitamins, drugs, biomolecules, pigments and biologically active matters [23, 24]. Most of them have a wide range of applications in synthetic pharmaceuticals and industrial chemistry. Imidazole analogues are also a significant group of heterocyclic compounds due to pharmacological activities and significant roles in biochemical transformations. Substituted imidazoles act as fungicidal, antibacterial, anti-inflammatory, antitumor agents, receptor antagonists, inhibitors of mammalian 15LOX, inhibitors of B-Raf kinase herbicides and therapeutic agents [25-31]. Current advances in green chemistry have extended the use of imidazoles as ILs and N-heterocyclic carbenes [32, 33]. The multi-component reactions (MCRs) provide an exceptional standard in synthetic organic chemistry and drug chemistry. Various conventional as well as non conventional methods have been reported for the synthesis of trisubstituted imidazoles by the MCR of the variously substituted benzaldehydes, benzil 2 and ammonium acetate 3 using different catalysts such as ferric (III) nitrate supported on kieselguhr [34], nano-TiCl4.SiO2 [35], InCl3.3H2O [36], chitosan−SO3H [37], p-toluenesulphonic acid (PTSA) [38], etc. J. Banothu et al. [39] and H. B’Bhatt et al. [40] reported methodologies for the condensation of variously substituted

Shirole and Shelke

3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehydes 1, benzil 2, and ammonium acetate 3 employing catalysts such as Brønsted acidic IL (4-sulfobutyl)tris(4-sulfophenyl) phosponium sulphate (1:1) and glacial acetic acid. The starting material 3-aryl-1-phenyl-1H-pyrazole-4carboxaldehydes 1 was obtained by Vilsmeier-Haack formylation reaction of phenyl hydrazone derivative which was obtained from the reaction of appropriate acetophenone with phenylhydrazine in ethanol with a catalytic amount of glacial acetic acid [41, 42]. Literature study revealed that substituted 1,3-diphenyl-1H-pyrazole-4-carboxaldehyde analogues have received important consideration due to their wide range of pharmacophoric as well as biological properties [43-47]. In the present investigation, a series of trisubstituted imidazole derivatives have been synthesized by the condensation of 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehydes |1, Benzil 2, and ammonium acetate 3 in the presence of IL 1-butyl-3-methyl-1H-imidazolium tetrafluoroborate [BMIM][BF4] as a catalyst under conventional heating as well as following green techniques with and without solvent. RESULTS AND DISCUSSION In optimization, we synthesized 4a (Ar = p-tolyl, Scheme 1) in the presence of different catalysts under different conditions. The condensation reaction was carried out between 1-phenyl-3-p-tolyl-1H-pyrazole-4-carboxaldehyde 1a, benzil 2, and ammonium acetate 3 to get 3-(4-methylphenyl)-1phenyl-4-(4,5-diphenyl-1H-imidazol-2-yl)-1H-pyrazole 4a under traditional conditions, US and MW irradiation in the presence of PTSA, IL [BMIM] [BF4], and in the absence of a catalyst. ILs have been in use as solvents and catalysts for a wide variety of reactions, hence we used [BMIM][BF4] to study the scope of the reaction by conventional methods, US and MW irradiation. a) Conventional Method Reflux, 4- 4.5hrs [BMIM] [BF4]/Ethanol

H O O 2

+

Ar N N

O

b)Ultra-sonication (80-90min) [BMIM] [BF4]/Ethanol

1a-i

CH3COONH4 3

N

Ar N N

N H 4a-i

c) MW Irradiation 240watt (7-9min) [BMIM][BF4]/Solvent Free

Scheme (1). Synthesis of 2,4,5-trisubstituted imidazoles 4a-i.

During the optimization of the reaction, it was found that, under conventional as well as green method, [BMIM][BF4] is the best catalyst. The quantity of [BMIM][BF4] required for better results was 150 mmol%. In comparison with conventional methods, the reaction under non-conventional

Ionic Liquid: An Efficient and Facile Catalyst

Table 1.

Letters in Organic Chemistry, 2016, Vol. 13, No. 9

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Optimization of the reaction conditions to synthesize 3-(4-methylphenyl)-1-phenyl-4-(4,5-diphenyl-1H-imidazol-2-yl)-1Hpyrazole 4a under reflux conditions, US and MW irradiation.

Entry

Catalyst / Solvent

Conditions

Reaction Time

Yield

1

No Catalyst / Ethanol

Reflux

10 h

NR

2

No Catalyst / Ethanol

US Irradiation

2h

NR

3

No Catalyst / Solvent Free (SF)

MW Irradiation

20 min

Trace

4

15 mmol % PTSA / Ethanol

Reflux

24 h

30 %

5

15 mmol % PTSA / Ethanol

US Irradiation

2h

30 %

6

15 mmol % PTSA / SF

MW Irradiation

20 min

35 %

7

10 mmol % [BMIM][BF4] / Ethanol

Stirring at RT

10 h

NR

8


Reflux

4h

72 %

9


US Irradiation at RT

1.5 h

Trace

o

10


US Irradiation at 50 C

1.5 h

40 %

11


US Irradiation at RT

1.5 h

10 %

o

12


US Irradiation at 50 C

80 min

80 %

13

10 mmol % [BMIM][BF4] / SF

MW Irradiation at 140 watt

20 min

Trace

14



20 min

Trace

15



20 min

20 %

16



20 min

35 %

17



10 min

60 %

18



7 min

84 %

Reaction Conditions: Benzil 2 (1 mmol), 1-phenyl-3-p-tolyl-1H-pyrazole-4-carboxaldehyde 1a. (1 mmol), ammonium acetate 3 (2 mmol).

methods proceeds in a shorter time with good yield, whereas the US irradiation method takes longer time as compared to MW irradiation. Throughout optimization of the reaction under MW heating, excellent yield was obtained at 240 watt in 7 min (entry 18). The results obtained during the optimization are summarized in Table 1. The targeted 3-aryl-1-phenyl-4-(4,5-diphenyl-1Himidazol-2-yl)-1H-pyrazole derivatives 4a-i (Scheme 1, Table 2) were synthesized by using [BMIM][BF4] as a catalyst with good yields under reflux in ethanol (68-70%), US irradiation in ethanol (76-80%) and MW irradiation (8086%) without solvent. All these methods provided good results with IL. However, the MW and US irradiation methods gave good yield in a short period of time with 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 containing a variety of substituents, whereas the conventional reflux method gives lower yields and takes longer time as compared with MW and US irradiation. Moreover, the US irradiation method takes longer time as compared to MW irradiation for completion of reaction.

was checked by TLC and LCMS. TLC was performed on pre-coated silica gel aluminium plates. IR spectra were recorded on a Perkin-Elmer FTIR spectrophotometer (FTIRSP2 Miracle Accessory ZnSe S2PE). The 1H NMR and 13C NMR spectra were recorded on a Bruker Avance II instrument in DMSO-d6 at 400 and 100 MHz, respectively. General Procedure for the Synthesis Trisubstituted Imidazole Derivatives 4a-i

of

2,4,5-

Under Reflux Conditions A mixture of 3-aryl-1-phenyl-1H-pyrazole-4carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM] [BF4] (15 mmol %) was placed in a round bottom flask containing 10 mL of ethanol. The reaction mixture was refluxed for completion. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was poured over crushed ice. Solid imidazole thus obtained was separated by filtration, dried well, and recrystallized by ethanol.

MATERIALS AND METHODS

Under US Irradiation

Melting points were measured two times in an open capillary and were uncorrected. Mass spectra were recorded on a Finnigan mass spectrometer. The purity of the compound

A mixture of 3-aryl-1-phenyl-1H-pyrazole-4carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM] [BF4]

4 Letters in Organic Chemistry, 2016, Vol. 13, No. 9

Table 2.

Synthesis of 2, 4, 5-trisubstituted imidazole 4a-i using [BMIM][BF4].

Product

4a

Shirole and Shelke

Ar –

Me

4b

Reaction Time in min a

Reflux

b

US

c

Melting Points (oC)

Yield in %

MW SF

a

Reflux

b

US

c

MW SF

Found

Lit. 266-268

240

80

07

72

80

84

262-264

270

85

07

72

80

86

258

260 227-229

4c

F

270

90

09

70

78

82

270

261-263

4d

Cl

240

90

07

72

80

86

290

248-250

4e

Br

270

80

09

70

78

80

288

288-290

4f

O2N

270

90

09

68

78

82

290