An Efficient Method For The One-Pot, Four-Component Benzaldehyde Based Synthesis of 3-Methyl-1,4-Diphenyl-7,8-Dihydro-1H-Furo[3,4-E]Pyrazolo[3,4-B]Pyridin-5(4H)-Ones Catalyzed by Alum in Environment-Friendly Media.

INTRODUCTION

Application of multicomponent reactions (MCRs) to the construction of natural product-based libraries would be most beneficial to this area of research. Such processes in which three or more reactants are combined together in a single reaction flask to produce a product. Up to seven starting components have been used, and MCRs have often been shown to produce higher product yields than classical chemistry. Multi-component reactions (MCRs) have emerged as an efficient and powerful tool in modern synthetic organic chemistry due to their valued features such as atom economy, simpler procedures and equipment, time and energy savings, straightforward reaction design, and the opportunity to construct target compounds by the introduction of several diversity elements in a single chemical event. MCRs, leading to interesting heterocyclic scaffolds, are particularly useful for the construction of diverse chemical libraries of ‘drug-like’ molecules_. ^1-8 Tetronic acid (tetrahydrofuran-2,4-dione) is a promising convenient building block and compoundsin which tetronic acid fragment is fused to a heterocyclic systems attract specific attention. A large number of tetronic acid derivatives are widespread in nature found in sponges, lichens, and molds, as well as in higher plants. Many exhibit a wide array of biological properties such as antibiotic, anticoagulant, antiepileptic, antifungal, insecticidal, analgesic and anti-inflammatory activities. Recently, these compounds have also been reported as HIV-1 protease inhibitors. ^9-19 Polyfunctionalized heterocyclic compounds play important roles in the drug discovery process, and analysis of drugs in late development or on the market shows that 68% of them are heterocycles. Therefore, it is not surprising that research in the field of synthesis of polyfunctionalized heterocyclic compounds has received special attention.⁴ Ionic liquids (ILs) have received vast research interests in recent years. They exhibited unique properties such as high ionic conductivity, wide electrochemical window, non-volatility, high thermal stability, nonflammability and miscibility with organic compounds, especially with the heterocyclic compounds as hydrophilicity, hydrophobicity, Lewis acidity, viscosity and density can be altered by the fine-tuning of parameters such as the choice of organic cation, inorganic anion and the length of alkyl chain attached to the organic cation (Fig. 1). ^20-23Because of these useful properties, ILs have been applied in several areas, including catalysis, electrochemistry, separation science for extraction of heavy metal ions, as solvents for green chemistry and materials for optoelectronic applications. ^24-28 Room temperature ionic liquids are increasingly finding a range of laboratory, developmental and technical applications, for example, as media for organic and inorganic chemical synthesis, materials productions, and electrochemical devices²¹. As a part of our research program, which aims to develop new and environmentally friendly methodologies for the preparation of heterocyclic compounds, ²⁹ recently, synthesis of 3-methyl-1,4-diphenyl-7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b]pyridin-5(4H)-ones was reported via three-component reaction, ³⁰  herein, we report a simple and efficient method for the synthesis of these compounds with fused furo, pyrido and pyrazolo rings, through the one-pot four-component reaction in green media, using Alum as a catalyst at short reaction times with excellent yields.

Figure: Chemical structure of the ionic liquids  Click here to View Figure

 

EXPRIMENTAL

General remark

All chemicals were purchased from commercial providers and were used as received.

Physical measurements

The progress of the reaction was monitored by¹H NMR spectra were recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 MHz, Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer, FT-IR on Nicolet 400D and TLC.

Synthesis, Spectral and Analytical Data of Some Representative Compounds.

 A mixture of tetronic acid (1 mmol), 3-aminobut-2-enenitrile (1 mmol) , phenylhydrazine (1 mmol) and Catalyst (0.05 g) in ionic Liquid (0.2 g) was stirred for 5 min  at 70 °C. Then benzaldehyde (1.2 mmol) was added to the mixture and stirred for 15 min at this temperature. After cooling, the water (10 ml) was added to the reaction mixture and filtered. The precipitate washed with water (10 mL) and EtOH (10 mL) to afford the pure product.

6,7-dihydro-4,9-diphenylfuro[3,4-b]quinoline-1,8(3H,4H,5H,9H)-dione (1a): IR(KBr, v,cm^-1): 1737, 1674;¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 1.69-1.89 (m, 2H, CH₂), 2.14-2.23 (m, 2H, CH₂), 2.17-2.28 (m, 2H, CH₂), 4.56-5.02 (m, 2H, CH₂),4.73 (s, 1H, CH), 6.88-7.80 (m, 10H, H-Ar). Anal. Calcd for C₂₃H₁₉NO₃: C, 77.29; H, 5.36; N, 3.92. Found C, 77.37; H, 5.24; N, 3.49.

9-(4-bromophenyl)-4-phenyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4e):IR(KBr, v,cm^-1): 1751, 1667;¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 1.73-1.92 (m, 2H, CH₂), 2.13-2.24 (m, 2H, CH₂), 2.28-2.34 (m, 2H, CH₂), 4.53-4.59 (m, 2H, CH₂),4.89 (s, 1H, CH), 6.88-7.80 (m, 9H, H-Ar). Anal. Calcd for C₂₃H₁₈BrNO₃: C, 63.32; H, 4.16; N, 3.21. Found C, 63.37; H, 4.20; N, 3.16.

9-(4-methoxyphenyl)-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4f):IR(KBr, v,cm^-1): 1756, 1678;¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 1.71-1.86 (m, 2H, CH₂), 2.10-2.23 (m, 2H, CH₂), 2.26-2.33 (m, 2H, CH₂), 2.41 (s, 3H, CH₃), 3.75 (s, 3H, OCH₃), 4.50-4.58 (m, 2H, CH₂), 4.61 (s, 1H, CH), 6.64-7.76 (m, 8H, H-Ar). Anal. Calcd for C₂₅H₂₃NO₄: C, 74.79; H, 5.77; N, 3.49. Found C, 74.74; H, 5.81; N, 3.45.

9-(4-methoxyphenyl)-6,6-dimethyl-4-phenyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4h):IR(KBr, v,cm^-1): 1745, 1689;¹HNMR (300 MHz, DMSO-d₆): δ_H (ppm) 0.84 (s, 3H, CH₃), 0.95 (s, 3H, CH₃),  2.02-2.08 (m, 2H, CH₂), 2.17-2.23 (m, 2H, CH₂), 3.70 (s, 3H, OCH₃), 4.41-4.54 (m, 2H, CH₂),4.68 (s, 1H, CH),  6.85-7.81 (m, 9H, H-Ar). Anal. Calcd for C₂₆H₂₅NO₄: C, 75.16; H, 6.06; N, 3.37. Found C, 75.12; H, 6.11; N, 3.33.

9-(4-bromophenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline 1,8(3H,4H)-dione (4k): IR(KBr, v,cm^-1): 1750, 1683;¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 0.82 (s, 3H, CH₃), 0.91 (s, 3H, CH₃),  2.00-2.05 (m, 2H, CH₂), 2.16-2.20 (m, 2H, CH₂), 2.40 (s, 3H, CH₃), 4.45-4.52 (m, 2H, CH₂), 4.65 (s, 1H, CH), 6.65-7.68 (m, 8H, H-Ar). Anal. Calcd for C₂₆H₂₄BrNO₃: C, 65.28; H, 5.06; N, 2.93. Found C, 65.31; H, 5.10; N, 2.90.

RESULTS AND DISCUSSION

In our first attempt, four-component reaction of benzaldehyde, 1a tetronic acid, 2 3-aminobut-2-enenitrile, 3 and phenylhydrazine, 4 was done in various conditions. Additionally, different types and amounts of catalysts  were considered in order to optimize the reaction conditions. We were pleased to note the formation of 5a in excellent yield (98%). At first, we examined this simple model reaction in the presence of a diverse types of lewis and bronsted acids such as Alum, SSA, SnCl₄, ZnCl₂, SnO₂, p-TSA, CAN, and K-10 as a catalyst. We also tested the reaction in different ionic liquids media such as [Bmim]Br, [Bmim]Cl, [Bmim]CF₃COO, [Bmim]BF₄, and [Bmim]PF₆. It was found that only trace amount of the target compound 5a was obtained in the absence of catalyst. We have found that use of Alum has a unique capability and best promoter to enhance the reaction rate in [Bmim]PF₆ medium (Scheme 1).

 

Scheme1: Standard model reaction. Click here to View Scheme

 

We also evaluated the amount of catalyst needed for this conversion. It was found that using 10 mol % Alum in ionic liquid is adequate to push the reaction forward. There isn’t any increasing in the reaction yield by more amount of the catalyst. However, use of 10 mol % of SSA and p-TSA led to lower yields (60–70%) after 60 min reaction time. The best results were obtained by Alum as catalyst and [Bmim]PF₆ at 70 ºC(Schem 2). The consequences are summarized in Table 1.

 

Schem 2:  synthesis of 3-methyl-1,4-diphenyl-7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b]pyridin-5(4H)-ones Click here to View Scheme

 

Table 1: Model Reaction, Conditions, and Yields

 

Conditions	Catalyst	Time (min)	T.(°C)	Yield(%)
[Bmim]PF6	CAN	20	70	<50
[Bmim]PF6	p-TSA	20	70	66
[Bmim]PF6	SnCl4	20	70	<50
[Bmim]PF6	SSA	20	70	63
[Bmim]PF6	Alum	20	70	98
[Bmim]PF6	ZnCl2	20	70	<50
[Bmim]PF6	SnO2	20	70	<50
[Bmim]BF4	Alum	20	70	88
[Bmim]CF3CO2	Alum	20	70	91
[Bmim]Br	Alum	20	70	70
[Bmim]Cl	Alum	20	70	61

 

After optimizing the conditions, to delineate this approach, particularly in regard to library construction, as shown in Table 2 it was found that this procedure works with a wide variety of benzaldehydes. Corresponding 3-methyl-1,4-diphenyl-7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b]pyridin-5(4H)-ones 5 were synthesized by the one-pot, four-component condensation of benzaldehydes, 1(a-l) tetronic acid, 2 3-aminobut-2-enenitrile, 3 and phenylhydrazine, 4 with excellent yields in the ionic liquid media in the presence of Alum as a catalyst for 20 min at 70 °C . Work-up gave products 5(a-l) 93% to 98% yields. The results are summarized in Table 2. All the products 5(a-l) are Known compounds and were characterized by comparison of their melting point data with authentic samples synthesised by reported procedures³⁰. a.Isolated Yields b.Melting point data in authentic samples synthesised by reported procedures ³⁰. Subsequently, another active carbonyl compounds, indoline-2,3-dione and  acenaphthylene-1,2-dione, were examined as the replacement of aromatic aldehydes in the reaction with tetronic acid,  3-aminobut-2-enenitrile,   and phenylhydrazine,  (Scheme 3).

 

Scheme 3: Replacement of aromatic aldehydes in the reaction with tetronic acid,  3-aminobut-2- enenitrile Click here to View Scheme

 

Table 2: 4,9-diphenyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives5

 

Entry	5	R	Yielda (%)	Mp ºC	Lit.b Mp ºC
1	a	4-CH3C6H4	98	224-225	222-224
2	b	4-BrC6H4	93	240-242	238-240
3	c	4-OHC6H4	98	259-262	358-260
4	d	3,4-OCH2OC6H3	95	270-272	268-270
5	e	4-CH3OC6H4	96	233-235	230-232
6	f	4-ClC6H4	97	222-223	223-224
7	g	4-FC6H4	96	250	249-250
8	h	3-ClC6H4	98	169-172	168-170
9	i	4-NO2C6H4	98	230-231	228-230
10	J	3,4-Cl2C6H3	97	243-244	244-246
11	K	2-ClC6H4	96	259-260	258-260
12	L	2,4-Cl2C6H3	97	257	254-256

 

Scheme 3: Replacement of aromatic aldehydes in the reaction with tetronic acid,  3-aminobut-2- enenitrile

In these reactions 3-methyl-1-phenyl-7,8-dihydrospiro[furo[3,4-e]pyrazolo [3,4-b]pyridine-4,3′-indoline]-2′,5(1H)-dione and 3′-methyl-1′-phenyl-7′,8′-dihydro-2H-spiro[acenaphthylene-1,4′-furo[3,4-e]pyrazolo[3,4-b]pyridine]-2,5′(1′H)-dione were synthesized with excellent yields in the same conditions.

Conclusion

In conclusion, a facile and green one-pot  four component procedure for the syntheses of 3-methyl-1,4-diphenyl-7,8-dihydro-1H-furo[3,4-e]pyrazolo[3,4-b] pyridin-5(4H)-ones in short reaction time is reported. Using readily available starting materials and Alum as a inexpensive and nontoxic catalyst in environmentally friendly reaction media, operational simplicity, excellent   product yields and easy work-up procedures are prominent among the advantages of this new method.

Acknowledgements

We gratefully acknowledge financial support from the Research Council of Islamic Azad University, Omidieh Branch.

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