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Original article
12 (
8
); 3254-3262
doi:
10.1016/j.arabjc.2015.08.027

Aqua mediated multicomponent reaction under phase transfer catalysis: A novel and green approach to access fused pyrazoles

, , ,
 Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India

⁎Corresponding author. dr.irsiddiqui@gmail.com (I.R. Siddiqui)

Received: , Accepted: ,
© The Author(s) 2015
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

An environmentally benign multicomponent strategy for the synthesis of fused pyrazole derivatives has been developed. The present strategy provides a rapid access to construct a diversity-oriented library of fused pyrazoles by using three simple and readily available substrates viz. aromatic aldehyde, tetronic acid and aryl hydrazine as amine source. Further, the employment of molecular iodine, phase transfer catalyst and water altogether served as a “green attribute” to the present protocol.

Keywords

Phase transfer catalysis
Aqueous medium
One-pot
Molecular iodine
Environmentally benign
1

1 Introduction

In the mainstream of current interest, the greening of chemical processes has become a major contention in the modern chemical industry. In the combination of multicomponent reactions (MCRs) and water, a green solvent has emerged as a new research strategy which enables simultaneous growth of both MCRs and green solvents towards an ideal organic synthesis. Designing organic reactions in aqueous media has an inherent flexibility for creating molecular complexity and diversity coupled with minimization of time, labour, cost and waste production (Tejedor and Garcia-Tellado, 2007; Ugi, 2001; Lie’by-Muller et al., 2006; Evdokimov et al., 2007; Weber, 2002; Hulme and Gore, 2001). A particular reaction with negative activation volume is reported to occur faster in water than in organic solvents (Kljin and Engberts, 2005; Narayan et al., 2005; Kanizsai et al., 2007). MCRs are suggested to have a negative activation of volume (Pirrung and Das Sarma, 2004; Hailes, 2007). Therefore, the design of new MCRs accompanied with eco-advantageous strategies has been paid great heed, especially in the areas of drug discovery, organic synthesis and material science due to its remarkable art of depreciating the likelihood of side reactions.

N-containing heterocycles are especially considered “privileged” structure for the synthesis and development of new drugs (Sheldon, 1997; Dabholkar and Ansari, 2010). Pyrazoles and their derivatives have occupied a unique place in the field of medicinal chemistry as they exhibit vital pharmaceutical and biological activities (Lamberth, 2007) and are also widely used in coordination and material chemistry (Olguin and Brooker, 2011; Viciano-Chumillas et al., 2010; Klingele et al., 2009; Dias and Lovely, 2008; Kumar and Singh, 2004). They exhibit pharmaceutical activities such as herbicidal (Volk et al., 2002), human complement component (C1S) inhibitors (Subasinghe et al., 2004) and cholecystokinin 1 (CCK1) receptor antagonist (Liang et al., 2007). It is worth mentioning that a good number of pyrazoles have also been reported to have anti-inflammatory (Nugent et al., 1993) and antiprotozoal (Hantoon and Minnesssota, 2001) (Zhang et al., 2007) activities which render them valuable active ingredients of medicine and plant protecting agents (Abunanda et al., 2008), photo-receptors, ultraviolet stabilizers and energetic materials (Cavero et al., 2007; Catalan et al., 1992; Ye et al., 2007) (see Fig. 1).

Representatives of compounds containing pyrazole moiety.
Figure 1
Representatives of compounds containing pyrazole moiety.

The design and synthesis of new pyrazole derivatives has been a subject of consistent interest. As they do not exist in nature probably, due to the difficulty in the construction of N—N bond by living organisms, their availability depends on synthetic methods (Aggarwal et al., 2011). Much work has been directed towards the design and synthesis of complex pyrazoles (Schenone et al., 2008; Manetti et al., 2008; Huang et al., 2009; Varano et al., 2005) giving particular relevance to the functionalization of the scaffold in different regions, and to the synthesis of ring-fused structures. Indeed, the preparation of pyrazole-fused ring derivatives seems to be very important and challenging from the synthetic point of view. The most important methods for preparing this class of heterocycles are the reaction between hydrazines with β-difunctional compounds (Kost and Grandberg, 1996) and 1, 3 dipolar cycloadditions of diazo compound on triple bonds (Padwa, 1984). The former process came out to be the best method owing to the easy availability of 1, 3 diketones. Moreover, the carbonyl group of diketone can be easily replaced by an acetal, a hemiacetal, a chlorovinyl group, dihalides etc. (Arora and Jain, 2013; Peruncheralathan et al., 2005; Kumar et al., 2009; Surmont et al., 2011; Wang et al., 2011; Beveridge et al., 2010; Verma et al., 2010; Polshettiwar and Varma, 2010; Liu et al., 2008; Heller and Natarajan, 2006; Armstrong et al., 2005; Wang and Qin, 2004; Huang and Katzenellenbogen, 2000; Palacios et al., 1999). The latter method is second in importance due to the need to prepare and handle toxic and potentially explosive diazo compounds. The synthesis of fused pyrazoles has earlier been reported (Li et al., 2013; Attanasi et al., 2013; Chandanshive et al., 2012) but most of them suffered from several drawbacks from green chemistry point of view such as poor yield, long reaction time, need of high temperature, use of volatile organic solvents as reaction media, metal halides as catalyst and tedious synthetic procedures.

In a project aiming at the developments of protocols for the preparation of pyrazole-fused architectures, we have successfully accomplished the synthesis of 2,3-diphenyl-2H-furo[3,4-c]pyrazol-4(6H)-one making use of a holistic approach that considers not only the reaction step but also the economics and environmental outcome of the product generated. This relatively green approach has been rendered even greener by our efforts in solvent selection which has been the cornerstone of our so-called Aqueous Protocol. In recent years, iodine has emerged as an effective Lewis acid catalyst in several combinatorial syntheses and has been viewed as an eco-friendly catalyst, affording lower reaction time, excellent yield and easier work-up (Phukan, 2004; Jiang et al., 2010; Zengand and Cai, 2010a,b; Sharma et al., 2011; Prajapati et al., 2011). Moreover, phase transfer catalyst is an effective tool for synthesis of organic chemicals from two immiscible reactants (Yadav, 2004). It provides higher isolated yield due to higher selectivity achieved by taking advantage of the great flexibility in designing the micro-environment of the reaction (Freedman, 1986; Selvaraj and Rajendran, 2013). Hence, PTC presents itself as an invaluable agent for organic synthesis from two or more immiscible reactants and all its scope and applications are the subjects of current research (see Scheme 1).

One pot synthesis of fused pyrazole.
Scheme 1
One pot synthesis of fused pyrazole.

2

2 Results and discussion

2.1

2.1 Effect of catalysts

The experiment initiated with the intention of optimizing the reaction conditions for the synthesis of 2, 3-diphenyl-2H-furo[3,4-c]pyrazol-4(6H)-one. Green reaction conditions were set up to study the reaction and in our initial endeavour we carried out the synthesis in water in the absence of catalyst at 60 °C. The reaction did not proceed to completion even after 14 h (Table 1- entry 1). Then, the reaction was checked in the presence of several Lewis acid catalysts and simultaneously their efficiency was examined using the same amount (10 mol%) among which iodine proved to be the best Lewis acid catalyst, yielding 68% of the product in 5 h (Table 1- entry 7).

Table 1 Influence of various Lewis-acid catalysts on the synthesis of compound 4.a
Entry Solvent Catalyst (10 mol%) Time (h) Yieldb (%)
1 Water None 14 –
2 Water AlCl3 11 45
3 Water HgCl2 9 55
4 Water LiBr 8 50
5 Water FeCl3 8 54
6 Water TMSCl 12 40
7 Water Iodine 5 68
a Reaction conditions: benzaldehyde 1 (1.0 mmol), tetronic acid 2 (1.0 mmol), phenyl hydrazine 3 (1 mmol).
b Isolated yields after purification.

2.2

2.2 Effect of solvent and catalyst amount

Subsequently, to assess the effect of solvent as well as the amount of catalyst on the reaction time and yield of the product, we attempted the above model reaction using variable amounts of iodine in various solvents such as polar protic, polar aprotic and non-polar solvents. It was inferred that the reaction proceeded smoothly in terms of yield and time in polar protic solvent as compared to polar aprotic ones. This result while, increasing the amount of iodine catalyst from 5 to 10 mol% brought an increment in the yield from 60% to 68% (Table 2- entries 8–9). Further increase in the amount of iodine from 10 to 20 mol% did not display any change in the yield (Table 2- entries 9–11). Moreover, iodine is non-toxic and may be used in water as well as organic solvents (Ganguly and Chandra, 2014) and the fact that water is best known to accelerate and enhance reaction rate (Zhang et al., 2008; Li and Chan, 1997; Grieco, 1997) brings us to the conclusion that iodine and water synergy acted as best reaction system to bring out the transformation.

Table 2 Assessment of effect of catalyst amount in different solvents.a
Entry Solvent Catalyst (mol%) Time (h) Yieldb (%)
1 1,4-dioxane Iodine (10) 10 45
2 Ethanol Iodine (10) 14 58
3 t- Butanol Iodine (10) 13 56
4 Acetonitrile Iodine (10) 13 50
5 THF Iodine (10) 15 52
6 DMF Iodine (10) 14 55
7 Toluene Iodine (10) 10 55
8 Water Iodine (5) 8 60
9 Water Iodine (10) 5 68
10 Water Iodine (15) 5 68
11 Water Iodine (20) 5 68
a Reaction conditions: benzaldehyde 1 (1.0 mmol), tetronic acid 2 (1.0 mmol), phenyl hydrazine 3 (1 mmol).
b Isolated yields after purification.

2.2.1

2.2.1 Effect of various phase transfer catalysts

The scope of this methodology was further broadened by exploring the influence of various phase transfer catalysts (PTCs) over the time and product yield. We began to optimize the reaction conditions using different phase transfer catalysts in aqueous medium. It was observed that the addition of phase transfer catalyst (PTC) to the reaction system led to dramatically increased yields. This result is due to the increased solubility of aromatic aldehyde in water which was previously slightly soluble and hence low yield (60–68%) was obtained prior to the use of phase transfer catalyst (PTC) (Table 2- entries 8–11). Importantly, employment of PTC facilitates the transference of benzaldehyde from organic phase to aqueous phase. Comparison among PTCs with different anions revealed that (n-Bu)4NBr served its purpose to the best, consuming just 5 h and yielding 86% of the product (Table 3- entry 1) which was appreciably a high jump in yield when compared to the reaction stirred without phase transfer catalyst (Table 2- entry 9).

Table 3 Influence of various phase transfer catalysts.a
Entry PTC Solvent Time (h) Yieldb (%)
1 (n-Bu)4NBr Water 5 86
2 (n-Bu)4NCl Water 10 82
3 (n-Bu)4NI Water 10 78
4 (n-Bu)4NOH Water 12 75
5 (n-Bu)4NPF4 Water 11 74
6 DC18C6 Water 14 70
7 (n-Bu)4NHSO4 Water 10 72
a Reaction conditions: benzaldehyde 1 (1 mmol), tetronic acid 2 (1 mmol), phenyl hydrazine 3 (1 mmol).
b Isolated yields after purification.

The mechanism shown in Scheme 2 is based on the concept of a stabilized interaction between the cation and the face of the aromatic ring (Dougherty and Stauffer, 1990; Dougherty, 1996; Ma and Dougherty, 1997; Zacharias and Dougherty, 2002) that plays an important role in nature, particularly in synthetic systems (Anslyn and Dougherty, 2004; Dougherty and Ma, 1997). The transfer of benzaldehyde from aqueous phase to organic phase is facilitated by the binding between the aromatic π system and quaternary nitrogenous cation through van der Waals contact (Tsuzuki et al., 2001). This promotes the reaction between reagents with opposite solubility preferences (Fiamegos et al., 2006). This leads to increased product yield.

Proposed mechanism for the phase transfer catalysis involving cation-π interaction.
Scheme 2
Proposed mechanism for the phase transfer catalysis involving cation-π interaction.

2.2.2

2.2.2 Effect of catalyst amount

Encouraged by the high output of the product (86%), we began to explore the effect of different amounts of phase transfer catalysts on the reaction time and yield of the product. It was found that increasing the amount of (n-Bu)4NBr from 5 to 10 mol% enhanced the yield from 78% to 82% (Table 4- entries 1–2). The yield showed an increment from 82% to 86% when the amount of catalyst was increased from 10% to 15% (Table 4- entries 2–3). Also, it was found that further increase in the amount from 15% to 25% did not change the yield (Table 4- entries 3–5). Hence, it can be concluded from the above optimizations that the optimum conditions to access the fused pyrazole are iodine 10 mol%, and PTC 15 mol% using water as a green solvent.

Table 4 Assessment of effect of catalyst amount.a
Entry PTC (mol%) Time (h) Yieldb (%)
1 (n-Bu)4NBr (5) 9 78
2 (n-Bu)4NBr (10) 5 82
3 (n-Bu)4NBr (15) 5 86
4 (n-Bu)4NBr (20) 5 86
5 (n-Bu)4NBr (25) 5 86
a Reaction conditions: benzaldehyde 1 (1 mmol), tetronic acid 2 (1 mmol), phenyl hydrazine 3 (1 mmol).
b Isolated yields after purification.

Having established the optimal conditions, the scope of the one-pot reaction was probed using a range of variants of aldehydes and hydrazines at 60 °C, using 10 mol% of iodine and 15 mol% of phase transfer catalyst. The results are shown in Table 5. It is noteworthy that the electron withdrawing groups in benzaldehydes favoured high yield as it facilitated the reaction of enol form of tetronic acid with aldehyde (Table 5- entry 1). Notably, aliphatic aldehydes did not show good response to our reaction strategy, thereby yielding 60–68% of the product (Table 5- entries 7–8). Moreover, in benzaldehydes electronic effects were prominent rather than steric effects contrary to hydrazines in which the increase in bulky group revealed much influence on reaction yield, thereby showing less yield (Table 5- entries 5–6). Also, the electron releasing groups in hydrazines facilitate the reaction thereby increasing the product yield (Table 5- entry 1).

Table 5 Scope of the reaction using variants of reactants 1 and 3.a
Entry Hydrazine Aldehyde Product Time (h) Yieldb (%)
1 5 86
2 6 84
3 6 78
4 7 78
5 9 53
6 9 58
7 7 68
8 10 60
9 9 60
10 8 73
11 8 70

b 

a Reaction conditions: Aldehyde 1 (a–k) (1 mmol), tetronic acid 2 (1 mmol), hydrazine 3 (a–k) (1 mmol).
b Isolated yields after purification.

On the basis of all our experimental results, we have proposed the plausible mechanism for the formation of DPFP (Scheme 3). The strategy involves the initiation of reaction by iodine which binds with the carbonyl oxygen of the benzaldehyde 1 to form a reactive species. The resulting reactive species on nucleophilic addition by active methylene group of tetronic acid gave an intermediate A which on nucleophilic addition of phenyl hydrazine 3 chemoselectively on the keto group gives rise to complex B. The complex B on dehydration yielded compound C having activated C⚌C. Finally intermolecular Michael addition followed by oxidative cyclization and aromatization leads to the formation of pyrazole ring, the target compound.

Proposed mechanism for the synthesis of DPFP.
Scheme 3
Proposed mechanism for the synthesis of DPFP.

3

3 Experimental

3.1

3.1 Methods and Apparatus

The starting materials aldehydes, hydrazines and tetronic acid were purchased from Aldrich and Alfa Aesar and were used without purification. 1H and 13C NMR spectra were recorded on a Bruker Avance II (400 MHz) FT spectrometer at 400 and 100 MHz, respectively, with CDCl3 as solvent. Chemical shifts are reported in parts per million relative to TMS as internal reference. Mass (EI) spectra were recorded on JEOL D-300 mass spectrometer. Elemental analysis was performed on an Elementar vario EL.

3.2

3.2 General procedure for the synthesis of compound 4

In a suspension of benzaldehyde (1.0 mmol), tetronic acid (1.0 mmol) and phenyl hydrazine (1.0 mmol) in water (5 ml), iodine (10 mol%) was added followed by the addition of phase transfer catalyst (15 mol%) and the reaction mixture was stirred at 60 °C for 4–5 h. After completion of the reaction, as indicated by TLC, the reaction mixture was cooled to room temperature and ethyl acetate was added. After phase separation the aqueous phase was extracted three times with ethyl acetate and the organic layer was dried over sodium sulphate and concentrated in vacuum to give mostly analytical pure product. The crude product was purified by column chromatography (ethyl acetate and hexane, 3:1, v/v).

3.3

3.3 Spectral data of synthesized compounds

3.3.1

3.3.1 4a: 2-(4-methoxyphenyl)-3-(4-nitrophenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Dark brown viscous liquid (86%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.03 (d, J = 14.8 Hz, 1H), 3.75 (s, 3H, OCH3), 4.67 (d, J = 14.8 Hz, 1H), 6.82 (d, J = 7. 3 Hz, 2 H), 7.46 (d, J = 7.5 Hz, 2 H), 8.01(d, J = 7. 1 Hz, 2 H), 8.31(d, J = 7.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3/TMS, δ ppm) δ = 56.0, 65.0, 107.0, 114.7, 119.8, 124.0, 127.6, 132.2, 142.5, 146.3, 148.3, 153.0, 160.0, 165.2; EI-MS: (m/z): 352.0 (M+), Anal. calcd. For C18H13N3O5: C, 61.54; H, 3.73; N, 11.96. Found: C, 61.22; H, 3.75; N, 11.84.

3.3.2

3.3.2 4b: 2-(4-bromophenyl)-3-(4-nitrophenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Dark brown viscous liquid (84%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.02 (d, J = 14.7 Hz, 1H), 4.66 (d, J = 14. 7 Hz, 1H), 7.48 (d, J = 8.64 Hz, 2 H), 7.57 (d, J = 8.62 Hz, 2 H); 8.01 (d, J = 7. 1 Hz, 2 H); 8.31(d, J = 7.9 Hz, 2 H); 13C NMR (100 MHz,CDCl3/TMS, δ ppm) δ = 64.3, 107.4, 120.5, 121.3, 124.1, 126.8, 132.0, 138.6, 142.0, 146.2, 148.3, 153.1, 167.4; EI-MS: (m/z): 399.01(M+), Anal. calcd. For C17H10 Br N3O4: C, 51.01; H, 2.53; N,10.51. Found: C, 51.2; H, 2.55; N, 10.50.

3.3.3

3.3.3 4c: 2-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Dark Brown viscous liquid (78%);(EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.04 (d, J = 14. 9 Hz, 1H), 4.68 (d, J = 14. 9 Hz, 1H), 7.32–7.48 (m, 3 H), 7.44 (s, 1H), 7.46 (d, J = 8.68 Hz, 2 H), 7.74 (s, 1H), 8.01 (d, J = 8.71 Hz, 2 H); 13C NMR (100 MHz,CDCl3/TMS, δ ppm) δ = 65.1, 107.3, 115.7, 119.46,125. 8, 127. 4, 129. 2, 129.76, 129.78, 133.5, 135.1, 135.4, 138.1, 139.5, 146.1, 153.2, 167.2; EI-MS: (m/z): 392.01(M+), Anal. calcd. For C17H9 Cl3N2O2: C, 54.75; H, 3.07; N,7.0. Found: C, 54.73; H, 3.05; N, 7.05.

3.3.4

3.3.4 4d: 2-benzyl-3-(thiophen-3-yl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Light brown viscous liquid (78%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm,) δ = 3.04 (d, J = 14.9 Hz, 1H), 4.67 (d, J = 14. 9 Hz, 1H), 5.44 (s, 2 H), 7.01 (d, J = 5.3 Hz, 1 H), 7.21–7.31 (m, 5 H), 7.70 (d, J = 5.3 Hz, 1H); 13C NMR (100 MHz,CDCl3/TMS, δ ppm) δ = 54.6, 65.1, 106.05, 121.76, 124.32, 125.0, 128.1, 128.32, 129.21, 133.02, 137.5, 142.2, 150.05, 167.01; EI-MS: (m/z): 296.76 (M+), Anal. calcd. For C16H12 N2O2S: C, 64.83; H, 4.07; N, 9.43 Found: C, 64.82; H, 4.05; N, 9.42.

3.3.5

3.3.5 4e: 3-(pyridin-3-yl)-2-(2,4,6-trimethoxyphenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Light brown viscous liquid (53%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.03 (d, J = 14.8 Hz, 1H), 3.71 (s, 9 H, OCH3), 4.67 (d, J = 14.8 Hz, 1H), 6.12 (s, 2 H), 7. 54–8.68 (m, 3 H), 9.22 (s, 1H); 13C NMR (100 MHz, CDCl3/TMS, δ ppm) δ: = 56.03, 65.2, 92.58, 103.17, 108.05, 123.76, 129.05, 133.36, 134.21, 148.13, 149.37, 152.03, 154.20, 161.42, 167.25; EI-MS: (m/z): 367.10(M+), Anal. calcd. For C19H17 N3O5: C, 62.18; H, 4.70; N, 11.45 Found: C, 62.10; (H, 4.76; N, 11.40.

3.3.6

3.3.6 4f: 3-(naphthalen-1-yl)-2-(3-(trifluoromethyl)phenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Brownish black viscous liquid (58%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.02 (d, J = 14.7 Hz, 1H), 4.66 (d, J = 14. 7 Hz, 1H), 7.36–7.61 (m, 3 H), 7.52–8.52 (m, 7 H), 7.92 (s, 1 H); 13C NMR100 MHz,CDCl3/TMS, δ ppm) δ = 65.03, 107.05, 115.57, 119.32, 122.0, 122.76, 124.41, 125.78, 126.3, 128.0, 128.01, 129.05, 131.6, 132.0, 134.0, 136.1, 140.05, 146.2, 153.06, 167.0; EI-MS: (m/z): 394.34 (M+), Anal. calcd. For C22H13F3 N2O2: C, 67.02; H, 4.01; N, 7.14; Found: C, 67.04; H, 4.05; N, 7.15.

3.3.7

3.3.7 4g: 3-isopropyl-2-phenyl-2H-furo[3,4-c]pyrazol-4(6H)-one

Light brown viscous liquid (68%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 1.26 (d, 6H), 1.05 (d, J = 6.9 Hz, 6H), 2.58 (septet, J = 6.9 Hz, 1 H), 3.03 (d, J = 14.8 Hz, 1H), 4.67 (d, J = 14. 8 Hz, 1H), 44–7.60 (m, 5 H, Ar-H); 13C NMR (100 MHz,CDCl3/TMS, δ ppm) δ = 18.55, 24.41, 65.2, 109.1, 118.76, 126.04, 129.07, 139.5, 140.03, 154.2, 167.09. EI-MS: (m/z): 242.13 (M+), Anal. calcd. For C14H14 N2O2: C, 69.40; H, 5.85; N, 11.54; Found: C, 69.44; H, 5.80; N, 11.55.

3.3.8

3.3.8 4h: 3-tert-butyl-2-isopropyl-2H-furo[3,4-c]pyrazol-4(6H)-one

Light brown viscous liquid (60%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 1.05 (d, J = 6.9 Hz, 6H), 1.32 (s, 9H), 2.58 (septet, J = 6.9 Hz, 1 H), 3.03 (d, J = 14.8 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H); 13C NMR (100 MHz, CDCl3/TMS, δ ppm) δ = 19.76, 23.92, 31.51, 46.12, 65.03, 106.11, 144.02, 152.04, 167.08. EIMS: (m/z): 222.13 (M+), Anal. calcd. For C12H18N2O2: C, 64.80; H, 8.15; N, 12.55; Found: C, 64.89; H, 8.10; N, 12.61.

3.3.9

3.3.9 4i: 2-tert-butyl-3-(4-hydroxyphenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Light brown viscous liquid (60%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 1.70 (s, 9H), 3.04 (d, J = 14.9 Hz, 1H), 4.68 (d, J = 14. 9 Hz, 1H), 5.03 (s,—OH), 6.80–7.30 (m, 4H); 13C NMR (100 MHz, CDCl3/TMS, δ ppm) δ: 26.78, 48.0, 64.96, 104.89, 116.0, 128.37, 129.05, 150.11, 151.05, 157.2, 167.21. EIMS: (m/z): 271.17(M+), Anal. calcd. For C15H16N2O3: C, 66.15; H, 5.93; N, 10.30; Found: C, 66.20; H, 5.90; N, 10.32.

3.3.10

3.3.10 4j: 2,3-bis(4-fluorophenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Dark Brown viscous liquid (73%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.04 (d, J = 14.9 Hz, 1H), 4.68 (d, J = 14.9 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2 H), 7. 30 (d, J = 8.7 Hz, 2 H), 7.58 (d, J = 7. 1 Hz, 2 H), 8. 11(d, J = 7.8 Hz, 2 H); 13C NMR (100 MHz,CDCl3/TMS, δ ppm) δ = 65.54, 107.01, 116.1, 116.2, 120.3, 128.52, 132.0, 135.5, 146.12, 153.45, 159.5, 162.2, 167.2. EIMS: (m/z): 312.00 (M+), Anal. calcd. For C17H10F2 N2O2: C, 65.30; H, 3.20; N, 8.95; Found: C, 65.35; H, 5.3.26; N, 9.01.

3.3.11

3.3.11 4k: 2-(4-methoxyphenyl)-3-(2,4,6-trimethoxyphenyl)-2H-furo[3,4-c]pyrazol-4(6H)-one

Dark brown viscous liquid (70%); (EtoAc: Hexane = 3:1); 1H NMR (400 MHz, CDCl3/TMS, δ ppm) δ = 3.03 (d, J = 14.8 Hz, 1H), 3.75 (s, 12H, OCH3), 4.67 (d, J = 14. 8 Hz, 1H), 6.14 (s, 2 H), 6.92 (d, J = 7.5 Hz, 2 H), 7.46 (d, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3/TMS, δ ppm) δ = 55.76, 56. 20, 64.98, 92.38, 100.15, 107.10, 114.64, 119.82, 132.45, 146.02, 153.36, 159.53, 162.52, 164.23, 167.01; EI-MS: (m/z): 382.15 (M+), Anal. calcd. For C21H20N2O6: C, 62.86; H, 4.73; N, 7.30; Found: C, 62.85; H, 4.75; N, 7.32.

4

4 Conclusion

Conclusively, we have developed a novel, metal free and atom-economical method for the synthesis of fully decorated DPFP and its analogues by one-pot multicomponent reaction. Notably, this protocol offers flexibility in tuning the molecular complexity and diversity in a cascade fashion. The reactions proceeded at a reasonable time and pure product was obtained. This work will not only lead to practical synthetic methods but also assure the expansion of the versatility of clean organic reactions in water. Operational simplicity, reusability of phase transfer catalyst (PTC), high conversions and cleaner reaction profiles are outstanding features of this protocol.

Acknowledgements

We gratefully acknowledge the financial support from the Council of Scientific and Industrial Research and University Grant Commission. Authors gratefully acknowledge the SAIF, Punjab University, Chandigarh, for providing all the spectroscopic data.

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