A Bio-degradable and Recyclable Phase Transfer Catalyst for

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Microwave Assisted Synthesis of Highly Substituted Dicoumarols. Anant R. Kapdi,*a .... To a microwaveable vial was added 4-hydroxycoumarin. (2.0 mmol) and ...

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International Journal of Green Chemistry and Bioprocess Universal Research Publications. All rights reserved

ISSN 2277-7199 Original Article Tween-80: A Bio-degradable and Recyclable Phase Transfer Catalyst for Microwave Assisted Synthesis of Highly Substituted Dicoumarols Anant R. Kapdi,*a Chetna Jain,a Tejas Padte,b Unmesh Shevde,b Suhas Pednekarb, Christian Fischerc and Carola Schulzkec a Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh road, Matunga, Mumbai-400019, India. Fax: 00-91-22-3361-1020; Tel: 00-91-22-3361-2609; E-mail: [email protected], [email protected] b Department of Chemistry, Ramnarain Ruia College, L. Nappo road, Matunga, Mumbai-400019, India. c Institut fur Biochemie, Ernst-Moritz-Arndt Universität Greifswald, Felix-Hausdorff-Straße 4, D-17487 Greifswald, Germany. Received XXXX 2013; accepted YYYY 2013 Abstract A highly efficient, practical and green protocol for the Tween-80 (1) facilitated synthesis of highly substituted dicoumarols using microwave irradiations in water as solvent has been presented. Several diversely substituted analogs have been obtained in competitive reaction time using this protocol. Recycling studies have also been performed with the PTC retaining its activity over 4 recycles. A stability study for Tween-80 suggests the solution to be stable for several days (upto 15 days). © 2013 Universal Research Publications. All rights reserved Keywords: Tween-80, Phase Transfer Catalyst, Microwave Assisted Synthesis, Dicoumarols, Green Chemistry 1. Introduction For several years Dicoumarols have been used effectively as an anticoagulant however, with the development of more active analog warfarin sodium its application has slowly diminished. An important advancement was reported recently about the synthesis of lanthanum based transitionmetal complexes with dicoumarols which have shown potent cytotoxic activity and could exhibit promising catalytic properties [1]. Given the commercial importance of dicoumarols which have consistently shown a variety of other pharmacological activities such as insecticidal, anthelmintic, hypnotic, antifungal, phytoalexin, HIV proteases inhibition, antimicrobial and antioxidant etc [2-6], several synthetic protocols have been reported in the last decades. Early reports suggested the use of bronsted bases such as DBU diazabicyclo[5.4.0]undec-7-ene) [7] for obtaining good amounts of the desired dicoumarols. The use of catalysts such as manganous chloride [8], sulphated TiO2 [9], Phosphotungstic acid [10] as well as SO3H-functionalized Ionic liquid [11] under relatively mild conditions have also shown encouraging results that are comparable to the ones obtained without catalyst in solvents such as ethanol and acetic acid. Although, these protocols have shown good reactivity, they suffer from increased reaction times, formation of

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hazardous side products and tedious work-up procedures. To make things simpler we envisaged developing an efficient and environmentally benign protocol for the synthesis of highly substituted dicoumarols and related compounds using microwave irradiations in water as solvent; using a biodegradable and readily available phase transfer catalyst Tween-80 (1).[12] The advantages of such a procedure will be the drastic reduction in the reaction times in comparison to other methods, while the employment of water as the reaction solvent makes the overall process environmentally benign and synthetically more attractive. Recyclable ability of 1 (Fig. 1) has also been tested and was shown to be active upto 4 recycles. Figure 1: Tween-80 1 as Phase Transfer catalyst.

Figure 1: Tween-80 1 as Phase Transfer catalyst. 2. Materials and methods Aryl aldehydes and other chemicals were obtained from commercial sources, and were used without further purification. Yields refer to isolated compounds, estimated to be >95 % pure as determined by 1H-NMR. Flash

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chromatography: silica gel 60 (70-230 mesh). NMR data (1H, 13C) were recorded on Bruker 300 spectrometers. IR spectra were recorded on a Perkin-Elmer spectrophotometer 16F PC FT-IR, using Nujol mulls between polyethylene sheets. LC-MS analyses were performed on an Agilent VL mass-spectrometer. Elemental analysis was performed using a Carlo-Erba EA 1108. CEM Discover mono-mode Microwave Reactor used as the microwave source. X-ray structural analysis: Diffraction data were collected at low temperature (-103.0 °C) using a STOE-IPDS 2T diffractometer with graphite-monochromated molybdenum Kα radiation, λ = 0.71073 Å. The structures were solved by direct methods (SHELXS-97) and refined by full-matrix least-squares techniques (SHELXL-97). All non-hydrogenatoms were refined with anisotropic displacement parameters. The hydrogen atoms were refined isotropically on calculated positions using a riding model with their U iso values constrained to 1.5 Ueq of their pivot atoms for terminal sp3 carbon atoms and 1.2 times for all other carbon atoms. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre with deposition numbers CCDC XX. Copies of the data can be obtained free of charge by contacting the CCDC via e-mail: [email protected] (Also see Supporting information for more details). 2. 2.1. Representative procedure for synthesis of substituted dicoumarols: To a microwaveable vial was added 4-hydroxycoumarin (2.0 mmol) and aryl aldehyde (1.0 mmol). To this was added Millipore water (5.0 mL) as the reaction solvent alongwith Tween-80 (1) (1.0 mol%, 0.01 mmol) as the phase transfer catalyst. The vial was then placed in a CEM Discover mono-mode Microwave reactor for the specified amount of time. The vial was then removed from the reactor and allowed to cool to room temperature. The solid obtained was then filtered on buchner funnel and washed thoroughly with water (3 x 10 mL). The crude product thus obtained was purified using column chromatography furnishing the pure product in most cases as white solid. 3,3’-(Phenylmethylene)bis-(4-hydroxy-2H-chromen-2one) (4) [17]. White crystalline solid: mp = 230-232 oC; IR (KBr): μmax/cm-1 3085 (OH), 2943 (C-H) 1660, 1610 (CO) 1312; 1H NMR (DMSO-d6, 300 MHz): 6.38 (1H, s, CH), 7.10–7.25 (5H, m, Ar-H), 7.28-7.42 (4H, m, Ar-H), 7.54-7.63 (2H, m, Ar-H), 7.88-7.96 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 109.4, 121.2, 123.0, 129.0, 129.1, 130.8, 131.9, 133.3, 137.2, 144.9, 157.4, 170.1, 170.4; LC-MS: 413.0. 3,3’-(4-Nitrophenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (6) [10]. White crystalline solid: mp = 250–251 oC; IR (KBr): μmax/cm-1: 3082 (OH), 2926 (C-H) 1654, 1617 (CO), 1542 (NO), 1347 (NO); 1H NMR (DMSO-d6, 300 MHz): 6.35 (1H, s, CH), 7.21-7.42 (6H, m, Ar-H), 7.51-7.57 (2H, m, Ar-H), 7.76-7.84 (2H, m, Ar-H), 8.04-8.14 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 104.9, 114.0, 116.5, 118.1, 124.3, 128.2, 131.6, 132.5, 152.6, 157.8, 165.3; LC-MS: 459.2. 3,3’-(2,6-Dichlorophenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (8) [10]. White crystalline solid: mp =

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301–302 oC; IR (KBr): μmax/cm_1 3330 (OH), 1723, 1672 (CO) 1244, 785, 758 (C-Cl); 1H NMR (DMSO-d6, 300 MHz): 5.73 (1H, s, CH), 7.23–7.79 (11H, m, Ar-H), 8.028.09 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 113.9, 115.8, 116.5, 116.6, 117.0, 123.1, 124.5, 125.0, 126.3, 129.6, 132.7, 133.2, 133.3, 151.7, 152.4, 152.8, 160.6, 161.3, 161.9; LC-MS: 462.9. 3,3’-(6-Methoxynaphthylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (10). White crystalline solid: mp = 250– 251 oC; IR (KBr): μmax/cm-1 3060 (OH), 1669, 1603 (CO), 1220; 1H NMR (DMSO-d6, 300 MHz): 3.92 (3H, s, OCH3), 6.58 (1H, s, CH), 7.02-7.06 (1H, m, Ar-H), 7.17-7.33 (6H, m, Ar-H), 7.54-7.69 (5H, m, Ar-H), 7.79-7.82 (2H, m, ArH); 13C NMR (DMSO-d6, 75 MHz): 55.6, 104.8, 106.1, 116.5, 118.4, 118.7, 124.3, 124.4, 124.8, 126.9, 127.0, 128.9, 129.6, 132.4, 133.2, 135.5, 152.7, 157.3, 165.3, 165.7; LC-MS: 493.0; Anal. calc. For C30H20O7: C, 73.17; H, 4.09. Found: C, 73.13; H, 4.12%. 3,3’-(4-Methoxyphenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (12) [10]. White crystalline solid: mp = 250–251 oC; IR (KBr): μmax/cm-1: 3074 (OH), 1672, 1604 (CO), 1244 (Carbon Bonded to Oxygen), 1048 (C-O); 1H NMR (DMSO-d6, 300 MHz): 3.65 (3H, s, OCH3), 6.31 (1H, s, CH), 6.79-6.83 (2H, m, Ar-H), 7.08-7.09 (2H, m, Ar-H), 7.31-7.33 (4H, m, Ar-H), 7.57-7.61 (2H, m, Ar-H), 7.90-7.93 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 55.4, 104.9, 114.0, 116.5, 118.1, 124.3, 128.2, 131.6, 132.5, 152.6, 157.8, 165.3; LC-MS: 459.2. 3,3’-(3,4,5-Trimethoxyphenylmethylene)bis-(4-hydroxy2H-chromen-2-one) (14). [9] White crystalline solid: mp = 238-239 oC; IR (KBr): μmax/cm-1: 3004 (OH) 2956 (C-H) 1660, 1602 (CO), 1348, 1042 (C-O); 1H NMR (DMSO-d6, 300 MHz): 3.61 (6H, s, OCH3), 3.65 (3H, s, OCH3), 6.31 (1H, s, CH), 6.45 (2H, s, Ar-H), 7.29-7.37 (4H, m, Ar-H), 7.56-7.62 (2H, m, Ar-H), 7.90-7.93 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 55.9, 59.9, 104.2, 115.9, 117.9, 123.7, 123.9, 135.8, 135.9, 152.2, 152.3, 164.7, 165.3; LC-MS: 502.2. 3,3’-(2-Chlorophenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (16) [17]. White crystalline solid: mp = 218-220 oC; IR (KBr): μmax/cm-1: 3079 (OH), 1670, 1615 (CO), 769 (C-Cl); 1H NMR (DMSO-d6, 300 MHz): 6.13 (1H, s, CH), 7.15–7.25 (8H, m, Ar-H), 7.37-7.41 (2H, m, Ar-H), 7.59-7.61 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 104.4, 116.4, 118.4, 123.9, 124.1, 126.8, 128.0, 129.7, 130.6, 132.0, 133.3, 139.5, 152.8, 163.9, 165.2; LCMS: 446.8. 3,3’-(3-Ethoxy-4-hydroxyphenylmethylene)bis-(4hydroxy-2H-chromen-2-one) (18). White crystalline solid: mp = 232-233 oC; IR (KBr): μmax/cm-1 3387(OH), 3076 (C-H), 1664, 1615 (CO), 1265, 1045 (C-O); 1H NMR (DMSO-d6, 300 MHz): 1.24 (3H , J = 7.6 Hz, t, CH3), 3.84 (2H, J = 7.4 Hz, q, OCH2), 6.15 (1H, s, CH), 6.51-6.72 (3H, m, Ar-H), 7.21-7.39 (4H, m, Ar-H), 7.45–7.58 (2H, m, Ar-H), 7.79-7.91 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 15.1, 64.4, 104.3, 113.9, 115.5, 115.9, 119.9, 120.3, 123.4, 124.5, 131.2, 133.3, 145.0, 146.4, 152.9, 165.1, 167.9; LC-MS: 472.1; Anal. calc. For C27H20O8: C, 68.64; H, 4.27. Found: C, 68.59; H, 4.23%.

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3,3’-(3-Bromophenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (20) [11]. White crystalline solid: mp = 222-223 oC; IR (KBr): μmax/cm-1: 3080 (OH), 1672, 1614 (CO), 1570, 761 (C-Br); 1H NMR (DMSO-d6, 300 MHz): 6.35 (1H, s, CH), 7.15–7.43 (8H, m, Ar-H), 7.60-7.62 (2H, m, Ar-H), 8.02-8.04 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 104.0, 116.4, 118.7, 122.0, 124.1, 126.5, 128.9, 129.8,130.6,132.3,144.3,152.8,165.0,166.2; LC-MS: 490.8. 3,3’-(4-Phenylphenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (22) [18]. White crystalline solid: mp = 227-229 oC; IR (KBr): μmax/cm-1: 3077, 3027 (OH), 2947 (C-H), 1668, 1605 (CO); 1H NMR (DMSO-d6, 300 MHz): 6.35 (1H, s, CH), 7.15–7.72 (15H, m, Ar-H), 7.79-7.87 (2H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 104.3, 116.2, 119.3, 123.9, 124.5, 126.7, 126.9, 127.5, 127.8, 129.3, 132.0, 137.7, 140.7, 141.0, 152.8, 165.2, 166.9; LCMS: 488.1. 3,3’-(2-Nitrophenylmethylene)bis-(4-hydroxy-2Hchromen-2-one) (24) [10]. White crystalline solid: mp = 104-105 oC; IR (KBr): μmax/cm-1: 3082 (OH), 2926 (C-H) 1654, 1617 (CO), 1575 (NO), 1347 (NO); 1H NMR (DMSO-d6, 300 MHz): 6.54 (1H, s, CH), 7.37–8.41 (12H, m, Ar-H); 13C NMR (DMSO-d6, 75 MHz): 103.8, 116.4, 118.4, 123.9, 124.3, 124.5, 127.5, 130.3, 132.1, 135.2, 149.9, 152.8, 163.7, 165.8; LC-MS: 459.1. Dicoumarol of Terephthaldehyde (26):[10] White crystalline solid: mp = 238-239 oC; IR (KBr): μmax/cm-1 3089 (OH), 2948 (C-H), 1662, 1609 (CO) 1312; 1H NMR (DMSO-d6, 300 MHz): 6.39 (2H, s, CH), 6.93-6.97 (4H, m,

Ar-H), 7.24-7.41 (8H, m, Ar-H), 7.52-7.63 (4H, m, Ar-H), 7.85-7.92 (4H, m, Ar-H), 10.62-11.07 (4H, br, OH); 13C NMR (DMSO-d6, 75 MHz): 104.7, 116.4, 118.1, 123.9, 127.9, 132.4, 138.6, 152.0, 164.9; LC-MS: 738.3. 3. Results and Discussion Hitherto, dicoumarols have been synthesized via several methods which suffer from drawbacks such as tedious work-up, possible formation of hazardous by-products and use of toxic chemicals which make all these protocols synthetically less attractive. Besides these problems the time required in achieving good yields of the product is in most cases not practical. We therefore envisaged developing a protocol which could address all these problems and allow the process to be synthetically more viable. Our initial studies were focussed on the application of microwave radiation as an efficient and faster way for the synthesis of dicoumarols. Microwave radiations have been used effectively in the past for the enhancement of reactivity [13] as well as in certain cases resulting in the formation of a different product which under normal conditions was not possible [14]. Given the importance of incorporating greener solvents [15] or catalytic activation of substrates into the synthetic procedures for sustainable development we first screened a variety of solvents. Under microwave irradiation (carried out at 120 oC in a CEM Discover mono-mode microwave reactor for 15 min) the reaction of 4-hydroxycoumarin (2) with benzaldehyde (3) was performed using different solvents (Table 1).

Table 1: Dicoumarol synthesis in different solvents using phase transfer catalyst a

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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Solvent Methanol Ethanol Ethyl Acetate Chloroform Dimethyl formamide Dimethyl sulfoxide Deep Eutectic solvent Water Water Water Water Water Water Water Water

PTC Sodium lauryl sulphate Cetostearyl alcohol Cetrimide CTAB Sorbitane Monopalmitate TBAOH Tween-80 (1)

Time (min) 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15

Yield %b 15 18 5 10 14 22 27 -c -c 87 87 -d -d 89

2 mmol of coumarin, 1 mmol benzaldehyde, μw, 120 oC, 5 mL of solvent, 20 mol% PTC for 15 mins; from an average of two runs; c multiple spots were observed; d No product was obtained. Organic protic polar solvents such as MeOH, EtOH (Entries 1 and 2 respectively, Table 1) gave decent yields of the dicoumarol. Lower yields were obtained for solvents such as ethyl acetate and chloroform (Entries 3 and 4 respectively, Table 1). Aprotic polar solvents such as DMF and DMSO (Entries 5 and 6 respectively, Table 1) showed similar trend as ethyl acetate suggesting the importance of hydrogen bonding interactions (induced by polar protic

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b

Isolated yields

solvents) having a facilitating effect on the synthesis of dicoumarols. In order to make the protocol environmentally benign and synthetically viable, green solvents such as Deep Eutectic solvent [16] (Urea + Choline chloride) and water (Entries 7 and 8 respectively, Table 1) were also employed and to our surprise gave comparatively better yields of the desired product. Water being the better of the two giving 27% of the dicoumarol product.

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Although the results obtained were encouraging, we envisaged the employment of a possible phase transfer catalyst (PTC) that could help us improve the viability of the overall process by efficient solubilization of the starting materials. Several commercially available PTCs were employed. Sodium lauryl sulphate (SDS) (Entry 9, Table 1) when employed as the PTC for the synthesis of dicoumarol we were able to obtain the desired product in good yields however on isolation, the material showed several spots rendering the process less feasible. Similar observations were made even in the case of cetostearyl alcohol (Entry 10, Table 1). However, cetrimide or cetyl trimethyl ammonium bromide (CTAB) when used as PTC showed improved yields and purity of the final product. Finally, a biodegradable and readily available phase transfer catalyst Tween-80 (1) (Entry 15, Table 1) which has been used in biological studies as a surfactant was employed and to our surprise furnished the product in excellent yields with very high purity. This could be related to the better solubility of the substrates in water leading to better reactivity towards dicoumarol formation. Table 2: Effect of temperature on reactivitya

Entry Temp °C Time (min) Yield %b 1 100 15 65 2 120 15 89 3 140 9 (15) 85 (97) 4 160 3.5 (15) 70 (-)c a 2 mmol of coumarin, 1 mmol benzaldehyde, μw, 5 mL of H2O, 20 mol% Tween-80 (1); b Isolated yield; c When left for 15 mins showed complete decomposition. Based on these results we further investigated the effect of temperature on the developed protocol using Tween-80 (1) as the PTC in water as solvent under microwave radiations. Initially at lower temperature of 100 oC (Entry 1, Table 2) led to a drastic reduction in the product formation. However, an increase in the reaction temperature to 140 oC (Entry 3, Table 2) brought about a marked improvement in the yields enabling the reduction in the reaction time to 9 mins from 15 mins (see Table 1). Interestingly when the temperature was increased further to 160 oC (Entry 4, Table 2) it was still possible to obtain good yields of the dicoumarol 4 in much lower reaction time (3.5 mins) but any longer led to decomposition of the product. Next we turned our attention towards understanding the effect of catalyst concentration on the catalytic efficiency of the PTC of choice Tween-80 (1). Catalyst loading experiments were performed to determine the overall reactivity of the catalyst by varying its concentration in the reaction. Initial studies were performed at a relatively high concentration of Tween-80 (20 mol%). At a lower concentration of the catalyst (10 mol%) similar product yield was obtained. Encouraged by this result we further reduced the catalyst loading to from 5 to 1 mol%. It was

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observed that even at 1.0 mol% very good yields of the product were observed. Any further reduction led to decrease in the product formation. Table 3: Effect of catalyst loading on reactivitya

Concentration Time (min) Yield %b (X Mol %) 1 20 9 85 2 10 9 85 3 5 9 92 4 2.5 9 91 5 1 9 94 a 2 mmol of coumarin, 1 mmol benzaldehyde, μw, 5 mL of H2O, X mol% Tween-80 (1), 140 oC, 9 min; b Isolated yield Entry

With the optimized conditions in hand, we probed Tween80 (1) as a biodegradable phase transfer catalyst in water as a solvent under microwave irradiations for the greener and efficient synthesis of highly substituted dicoumarols. Less sterically demanding benzaldehydes when employed as one of the coupling partners led to the formation of the respective dicoumarols in excellent yields (Entries 1-2, Table 4). Sterically more demanding benzaldehydes such as 2,6-dichloro (7) also gave good yields of the product. Substituted naphthalene aldehyde (9) which also imparts lot of steric hindrance furnished excellent yield of the dicoumarol product (Entry 3, Table 4). Ethyl vanillin (17) when used as the coupling partner furnished the dicoumarol in very good yields (Entries 8 & 9, Table 4). Similar observations were made for several other substituted benzaldehydes suggesting the high efficiency of the developed protocol. The use of terephthaldehyde (23) as the coupling partner led to the formation of tetra coumarin containing molecule in excellent yields. In most cases the product formed could be isolated by simple filtration and no further purification steps are required. It thus represents a practical approach for the greener and efficient synthesis of dicoumarols. It was also possible to obtain single crystal X-ray structure for one of the synthesized dicoumarol 10. Although the crystal showed slightly weak diffraction which led to long exposure time however it confirms the structure of the dicoumarol to be one expected (Figure 2).

Figure 2: ORTEP representation of compound 10 with atomic labelling. Thermal ellipsoids are drawn at 50% probability (CCDC 946340).

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Table 4: Scope studies for the synthesis of highly substituted dicoumarols in water using microwave irradiation and Tween-80 1 as PTC.a

Next we turned our attention to understanding the recyclable capacity of the phase transfer catalyst Tween-80 (1). Recyclability of a catalyst is an important aspect for developing environmentally benign and synthetically efficient protocol for the synthesis of biologically relevant molecules. Our initial recyclability studies were focussed on the formation of dicoumarol using benzaldehyde (3) as the coupling partner (Figure 3). It was possible to recycle the catalyst efficiently without loss of activity upto 4 recycles. However, a slight reduction in yield was observed at the 5th recycle suggesting loss of activity for Tween-80. The recyclability studies were then repeated for two other aldehydes 7 and 9 which showed similar recyclable ability for 4 recycles.

Figure 3: Recyclability studies of Tween-80 (1) The biodegradable nature of Tween-80 (1) is an important aspect that allows the catalyst to be used as a green alternative for most other commercially available catalysts. In the earlier section we have seen the efficiency of Tween80 as a catalyst for the synthesis of highly substituted dicoumarols under microwave irradiations. Excellent

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recyclable property of the catalyst has also been explored, but an important factor for deciding its applicability is the stability studies. After the reaction of different aryl aldehydes (3, 7 and 9) with 4-hydroxycoumarin (2) in the presence of Tween-80 as the catalyst in water as the solvent, the product was filtered off and the solution was kept on shelf and reused for the reactions for several days (Scheme 2). It was found that over a period of 15 days the stability of the solution reduced drastically with lowering of reactivity observed over the period the experiments.

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7.

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9. Figure 4: Stability studies of Tween-80 (1) as PTC over 15 days period 4. Conclusion In this manuscript we have put forth a greener protocol for the synthesis of highly substituted dicoumarols using a cheap, biodegradable phase transfer catalyst Tween-80 (1) under microwave radiations in water as the solvent. Several substituted dicoumarols could be synthesized in good to excellent yields. Recyclability of the phase transfer catalyst was also tested with the reactivity remaining intact for 4 recycles. 5. Acknowledgements The authors also would like to thank Dr. P. S. Ramanathan Advanced Instrumentation Centre (PSRAIC), Ramnarain Ruia College for extending their facilities with respect to Infrared analysis. 6. References and notes 1. J. L. Mohler, L. G. Gomella, E. D. Crawford, L. M. Glode, C. D. Zippe, W. R. Fair, M. E. Marshall, Phase II evaluation of coumarin (1,2-benzopyrone) in metastatic prostatic carcinoma, The Prostate 20 (1992) 123-131. 2. B. Musicki, A. M. Periers, P. Laurin, D. Ferroud, Y. Benedetti, S. Lachaud, F. Chatreaux, J. L. Haesslein, A. IItis, C. Pierre, Improved antibacterial activities of coumarin antibiotics bearing 5′,5′-dialkylnoviose: biological activity of RU79115, Bioorg. Med. Chem. Lett. 10 (2000) 1695-1699. 3. M. E. Marshall, J. L. Mohler, K. Edmonds, B. Williams, K. Bulter, M. Ryles, L. Weiss, D. Urban, A. Beuschen, M. Markiewicz, G. J. Cloud, An updated review of the clinical development of coumarin (1,2benzopyrone) and 7-hydroxycoumarin, J. Cancer Res. Clin. Oncol. 120 (1994) S39-S42. 4. A. Maucher, E. J. von Angerer, Antitumour activity of coumarin and 7-hydroxycoumarin against 7, 12dimethylbenz[a]anthracene-induced rat mammary

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Source of support: Nil; Conflict of interest: None declared

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