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Article Cite This: ACS Omega 2018, 3, 1850−1855
[2 + 2 + 2] Cyclotrimerization with Propargyl Halides as Copartners: Formal Total Synthesis of the Antitumor Hsp90 Inhibitor AT13387 Sambasivarao Kotha* and Gaddamedi Sreevani Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400 076, India S Supporting Information *
ABSTRACT: Heat shock protein 90 (Hsp90) inhibitors play a remarkable role in cellular growth, and they were shown to exhibit antitumor activity. The Hsp90 inhibitor AT13387 (onalespib) is under clinical trials for the treatment of refractory gastrointestinal stromal tumors. Recently, it was demonstrated that this compound also exhibits inhibition against bladder cancer. Here, we report isoindoline- and isoindolinone-based (halomethyl)benzenes via a [2 + 2 + 2] cyclotrimerization in the presence of catalytic amounts of Mo(CO)6. This strategy has been extended to synthesize the key precursor of the Hsp90 inhibitor, AT13387.
INTRODUCTION Several medicinally important and pharmaceutically active compounds consist of diverse heterocycles, and they are critical components in various biological processes. A great deal of new scientiﬁc insight has been acquired because of the availability of novel heterocyclic compounds.1 Therefore, there is always a pressing need for the development of simple and eﬃcient synthetic methods to heterocycles. Figure 1 shows some of the natural products containing isoindoline1a and isoindolinone1b motifs in their structures. The isoindoline derivative, heat shock protein 90 (Hsp90) inhibitor, AT13387 (1) is currently in clinical trials for the treatment of refractory gastrointestinal stromal tumors.2 Lenalidomide (2) is a modiﬁed phthalimide core used as an anticancer drug against multiple myeloma, approved by FDA in 2004.3 Lactonamycin (3) shows antimicrobial activity against Gram-positive bacteria. Matsumoto and co-workers isolated this compound from a culture broth of Streptomyces rishiriensis MJ773-88K4 in 1996.4a In 2010, Tatsuta group has reported the ﬁrst total synthesis of lactonamycin, where they used a sequential intramolecular conjugate addition of alcohols to the acetylenic ester and stereoselective glycosylation of the tertiary alcohol and Michael−Dieckmann-type cyclization as key steps.4b Stachﬂin (4),5 stachybotrylactam (5),6 memnobotrin A (6),7 erinacerin A (7),8 and hericinone B (8)9 are meroterpenoids, and chilenine (9)10 is an alkaloid containing an isoindolinone unit. Transition-metal-catalyzed [2 + 2 + 2] cycloaddition11 is a useful tool to prepare heterocycles involving eﬃcient atomeconomic routes. These cycloaddition processes enable the formation of several C−C bonds in a single step, and moreover, © 2018 American Chemical Society
a large number of functional groups are tolerated. However, many transition-metal complexes do not tolerate the presence of benzyl halides, as they involve in oxidation insertion and thus decompose; hence, the use of propargyl halides as copartners in [2 + 2 + 2] cycloaddition reactions is not a trivial exercise. Even though, many transition-metal complexes are known to perform [2 + 2 + 2] cycloaddition reactions, very few reports are available with molybdenum-catalyzed cyclotrimerizations in the literature. Mo(CO)6 is a well-known catalyst for alkyne metathesis12a since its discovery by Mortreux and Blanchard in 1974,12b but it is rarely used for [2 + 2 + 2] cycloaddition reactions. In 1995, Mori et al. reported molybdenum-catalyzed alkyne metathesis of alkynes containing hydroxyphenyl groups, where they observed that the monoalkynes containing an ohydroxyphenyl group gave trimerized products.12c Since then only very few reports are available using molybdenum-based catalysts in [2 + 2 + 2] cycloaddition reactions.13 In view of our interest to design polycycles by a [2 + 2 + 2] cyclotrimerization of 1,6-diynes with propargyl halides, we envisioned a simple synthetic route to heterocyclic (halomethyl)benzene derivatives in the presence of catalytic amounts of Mo(CO)6.13g These compounds are diﬃcult to assemble without the involvement of benzyl alcohol derivatives. It is worth mentioning that the conversation of benzyl alcohols to the corresponding bromides (or chlorides) requires the usage of HBr (or HCl) or HBr (or HCl) surrogates, and these Received: December 12, 2017 Accepted: January 22, 2018 Published: February 13, 2018 1850
DOI: 10.1021/acsomega.7b01976 ACS Omega 2018, 3, 1850−1855
Figure 1. Natural products containing isoindoline and isoindolinone core units.
Scheme 1. [2 + 2 + 2] Cyclotrimerization of N-Tosyl-N,N-dipropargylamine 12
with diﬀerent propargyl halides (11a−d) under microwave irradiation (MWI) conditions in the presence of catalytic amounts of Mo(CO)6 in acetonitrile produced the corresponding (halomethyl)benzenes (13a−d) in good yields (Scheme 1). However, in the absence of Mo(CO)6, the reaction did not proceed and the starting material was recovered. Under conventional heating conditions, using propargyl bromide and Mo(CO)6 in acetonitrile, the reaction took longer time and the yield was much less. Because several natural products contain the isoindolinone moiety as a core unit in their structures (e.g., 2−9 in Figure 1), we chose compound 17 as a diyne partner. To prepare this key building block, N-methylamine (14) was treated with methyl propiolate (15) at 0 °C to form N-methyl propiolamide (16), which on further treatment with propargyl bromide (11a) under NaH/tetrahydrofuran (THF) conditions gave the diyne building block 17 (Scheme 2).15 Next, dipropargyl compound 17 was treated with propargyl halides (11a−d) in the presence of Mo(CO)6 under MWI conditions to deliver the (halomethyl)benzene derivatives 18a−d (Scheme 3). Propargyl halide 11a (or 11c) on treatment with unsymmetrical diyne 17 gave 18a (or 18c) as
conditions are incompatible with sensitive functional groups. Here, we chose N-protected dipropargylamine as the diyne partner. There are many reports available where [2 + 2 + 2] cycloaddition reactions involving dipropargylamines are trimerized with a variety of alkyne partners to create isoindoline derivatives. However, no reports are available where dipropargylamines undergo trimerization with propargyl halides via a [2 + 2 + 2] cycloaddition route to deliver heterocyclic targets. This approach to generate (halomethyl)benzene derivatives directly via a [2 + 2 + 2] cycloaddition reaction is not a trivial exercise because many transition metals react with benzyl halides. More interestingly, realization of this methodology allows the preparation of (halomethyl)benzene derivatives of several sensitive substrates (e.g., Meldrum’s acid, peptides, etc.) which are otherwise diﬃcult to prepare by conventional routes.
RESULTS AND DISCUSSION To test the [2 + 2 + 2] cyclotrimerization methodology, we selected N-tosylamide 10, a cheaper and commercially available starting material to produce the key building block 12, which on treatment with propargyl bromide in the presence of Cs2CO3 gave the diyne 12.14 Later, treatment of the diyne 12 1851
DOI: 10.1021/acsomega.7b01976 ACS Omega 2018, 3, 1850−1855
amounts of Mo(CO)6 under MWI conditions for 15 min to deliver the desired product 22 in 55% yield. Further, it was reacted with N-methylpiperazine (23) under K2CO3/acetonitrile conditions at room temperature (rt) for 4 h to produce the N-Boc-piperazinoisoindoline 24 (99%, Scheme 4) whose 1H and 13C NMR spectral data were found to be the same as reported in the literature.2c Our approach to 24 constitutes redox economy where oxidation and reduction steps are eliminated.
Scheme 2. Synthesis of Diyne Derivative 17
Scheme 3. [2 + 2 + 2] Cyclotrimerization of Compound 17 with Propargyl Halides (11a−d)
CONCLUSIONS In summary, we have demonstrated [2 + 2 + 2] cyclotrimerization sequence with propargyl halides to synthesize (halomethyl)benzene derivatives containing isoindoline and isoindolinone moieties in moderate to good yields. In addition, we synthesized the key precursor of isoindoline derivative 24 of AT13387 involving step economy and redox economy and thus achieved a great deal of synthetic economy.17 Because the intermediate 24 has already been converted into AT13387 previously,2c our synthesis of 24 constitutes a formal total synthesis of AT13387.
EXPERIMENTAL SECTION All reactions were performed under an argon or nitrogen atmosphere using a well-dried reaction ﬂask. All commercial products were used as received without further puriﬁcation. All solvents used as reaction media were dried over predried molecular sieves (4 Å) in an oven. Column chromatography was performed with silica gel (100−200 mesh) using a mixture of petroleum ether and EtOAc as an eluent. 1H NMR and 13C NMR spectral data were recorded on 400 and 100 MHz or 500 and 125 MHz spectrometers using tetramethylsilane as an internal standard and chloroform-d as a solvent. Highresolution mass spectroscopy (HRMS) was performed using a Bruker (Maxis Impact) or Micromass Q-ToF spectrometer. The microwave reactor used was Discover SP by CEM Corporation, and all microwave reactions were performed under the standard method, where time and temperature can be monitored manually. Synthesis of Diyne 12.14 To the suspension of 4methylbenzenesulfonamide (10) (2.00 g, 11.7 mmol) in acetone, cesium carbonate (11.4 g, 35 mmol) was added and stirred for 15−20 min at room temperature. To this, propargyl bromide (11a) (4.16 g, 35 mmol) was added, and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo. The residual solid was dissolved in water, and DCM was added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate and ﬁltered. Evaporation
a mixture of inseparable regioisomers (1:1 ratio based on NMR spectra) by column chromatography. Hsp90 is a protein chaperone which controls the cell survival, proliferation, apoptosis, and so forth. It controls many physiological processes such as signal transduction, intracellular transport, and protein degradation. As Hsp90 controls the cellular growth by blocking multiple signaling pathways simultaneously, Hsp90 inhibitors are playing an important role in antitumor activity.16 In 2017, Li and co-workers demonstrated the eﬃcacy of Hsp90 inhibitors against bladder cancer also.16e To this end, we identiﬁed the AT13387 (onalespib) Hsp90 inhibitor as a worthwhile target to test our methodology. In 2012, Barrett group has reported the total synthesis of AT13387 using a novel biomimetic aromatization and Suzuki−Miyaura cross-coupling reaction as key steps.2c Later, in 2014, Liang et al. reported the synthesis of isoindoline derivatives via a [2 + 2 + 2] cycloaddition reaction followed by oxidation and reductive amination with N-methylpiperazine.2d We realized that the [2 + 2 + 2] cyclotrimerization strategy with the propargyl bromide as a cyclotrimerization partner can deliver the bromo derivative 22 directly in a single operation. Therefore, the required diyne 21 was prepared by NH protection of propargylamine (19) with (Boc)2O, followed by propargylation in the presence of propargyl bromide and NaH, as reported in the literature.2d Later, the diyne 21 was treated with propargyl bromide (11a) in the presence of catalytic
Scheme 4. Direct Synthesis of the Key Building Block 24 of AT13387 via [2 + 2 + 2] Cycloaddition
DOI: 10.1021/acsomega.7b01976 ACS Omega 2018, 3, 1850−1855
CDCl3): δ 21.7, 33.1, 53.6, 53.7, 123.2, 123.4, 127.7, 128.8, 130.0, 133.6, 136.6, 137.0, 137.9, 145.0; IR νmax: 670, 1074, 1102, 1154, 1337, 1472, 1497, 1598, 2861, 2917 cm−1; HRMS (ESI, Q-ToF) m/z: calcd for C16H17BrNO2S [M + H]+, 366.0152; found, 366.0150, and other isotopic peak is 368.0146. 5,6-Bis(bromomethyl)-2-tosylisoindoline (13b). Yield = 69%, white ﬂuﬀy solid, mp: 174−176 °C; 1H NMR (400 MHz, CDCl3): δ 2.40 (s, 3H), 4.58 (s, 4H), 4.59 (s, 4H), 7.18 (s, 2H), 7.31 (d, J = 8.16 Hz, 2H), 7.75 (d, J = 8.20 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 29.8, 53.5, 125.4, 127.7, 130.1, 133.5, 136.6, 137.8, 144.1; IR νmax: 610, 1071, 1100, 1151, 1334, 1463, 1492, 1599, 2860, 2922, 2938 cm−1; HRMS (ESI, Q-ToF) m/z: calcd for C17H17Br2NO2S [M + H]+, 457.9425; found, 457.9422 and other isotopic peaks are 459.9434 and 461.9384. 5-(Chloromethyl)-2-tosylisoindoline (13c). Yield = 78%, white ﬂuﬀy solid, mp: 150−152 °C; 1H NMR (500 MHz, CDCl3): δ 2.34 (s, 3H), 4.53 (s, 2H), 4.60 (s, 4H), 7.15 (d, J = 7.80 Hz, 1H), 7.20 (s, 1H), 7.25 (m, 1H), 7.31 (d, J = 8.05 Hz, 2H), 7.76 (d, J = 8.25 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 21.7, 46.0, 53.7, 123.1, 123.1, 127.7, 128.4, 130.0, 133.6, 136.6, 137.0, 137.5, 144.0; IR νmax: 672, 810, 1077, 1104, 1156, 1337, 1449, 1497, 1599, 2865, 2919, 3029 cm−1; HRMS (ESI, Q-ToF) m/z: calcd for C16H16ClNNaO2S [M + Na]+, 344.0482; found, 344.0482 and other isotopic peak is 346.0455. 5,6-Bis(chloromethyl)-2-tosylisoindoline (13d). Yield = 73%, white ﬂuﬀy solid, mp: 162−164 °C; 1H NMR (500 MHz, CDCl3): δ 2.40 (s, 3H), 4.60 (s, 4H), 4.68 (s, 4H), 7.21 (s, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 21.7, 43.1, 53.6, 125.1, 127.7, 130.1, 133.5, 136.3, 137.7, 144.1; IR νmax: 671, 697, 1101, 1117, 1150, 1333, 1465, 1599, 2861, 2925, 2939 cm−1; HRMS (ESI, Q-ToF) m/z: calcd for C17H17Cl2NNaO2S [M + Na]+, 392.0249; found, 392.0242 and other isotopic peaks are 394.0214 and 396.0273. 6-(Bromomethyl)-2-methylisoindolin-1-one (18a). Yield = 51%, white solid, mp: 142−144 °C; 1H NMR (500 MHz, CDCl3): δ 3.19 (d, J = 1.65 Hz, 3H), 4.37 (s, 2H), 4.55 (dd, J1 = 4.0 Hz, J2 = 1.10 Hz, 4H), 7.40−7.57 (m, 2H), 7.78− 7.84 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 29.7, 32.9, 32.9, 52.0, 52.1, 123.3, 123.5, 124.2, 124.2, 129.2, 132.2, 133.2, 133.7, 138.3, 141.2, 141.3, 141.7, 168.2, 168.2; IR νmax: 693, 770, 909, 1049, 1215, 1246, 1277, 1402, 1427, 1489, 1674, 2920 cm−1; HRMS (ESI, Q-ToF) m/z: calcd for C10H11BrNO [M + H]+, 240.0019; found, 240.0012 and other isotopic peak is 241.9992. 5,6-Bis(bromomethyl)-2-methylisoindolin-1-one (18b). Yield = 48%, white solid, 1H NMR (500 MHz, CDCl3): δ = 3.18 (d, J = 3.45 Hz, 3H), 4.37 (d, J = 2.40 Hz, 2H), 4.71 (d, J = 2.50 Hz, 4H), 7.45 (s, 1H), 7.82 (d, J = 3.55 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ = 29.6, 29.6, 29.7, 51.9, 125.6, 126.2, 134.1, 137.1, 140.1, 142.1, 167.6; HRMS (ESI, Q-ToF) m/z: calcd for C11H12Br2NO [M + H]+, 331.9280; found, 331.9281 and other isotopic peaks are 333.9264 and 335.9241. 6-(Chloromethyl)-2-methylisoindolin-1-one (18c). Yield = 56%, white solid, mp: 124−126 °C; 1H NMR (400 MHz, CDCl3): δ 3.19 (s, 3H), 4.37 (s, 2H), 4.65 (s, 2H), 7.42− 7.57 (m, 2H), 7.80−7.84 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 29.7, 45.9, 46.0, 52.1, 52.1, 123.0, 123.2, 123.8, 124.1, 128.7, 131.8, 133.2, 133.7, 138.0, 140.9, 141.2, 141.7, 168.3; IR νmax: 664, 711, 770, 909, 1019, 1052, 1267, 1399, 1422, 1454, 1486, 1675, 2927 cm−1; HRMS (ESI, Q-ToF) m/z:
of the solvent delivered the crude product, which was puriﬁed by silica gel column chromatography (petroleum ether/ethyl acetate 5:1) to obtain diyne 12 (2.8 g, 97%) as a colorless solid. Synthesis of Compound 16.15a To a solution of methylamine (14) (2.0 g, 64.5 mmol) in 5 mL of water, methyl propiolate (15) (6.0 g, 71.0 mmol) was added dropwise at 0 °C for 30 min. The mixture was stirred for 2 h at 0 °C, and then few drops of acetic acid were added. The mixture was stirred for another 10 min and saturated with NaCl, followed by extraction with ethyl acetate (3 × 10 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, and removed by rotary evaporation to give product 16 (3.5 g), which was used for the next step without any further puriﬁcation. Synthesis of Diyne 17.15 To a suspension of NaH (1.13 g, 47 mmol) in dry THF, compound 16 (3.0 g, 36.14 mmol) was added dropwise and stirred for 15−20 min at 0 °C. Next, propargyl bromide (11a) (6.45 g, 54.21 mmol) was added, and the mixture was stirred for 3 h at 0 °C. Water was added to the reaction mixture, followed by extraction with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and ﬁltered. Evaporation of the solvent delivered the crude product, which was puriﬁed by silica gel column chromatography (petroleum ether/ethyl acetate 5:1) to obtain diyne 17 (2.6 g, 60%) as a pale yellow oil. Synthesis of N-Boc-propargylamine (20).2d To a stirred solution of propargylamine (19) (100 mg, 3.63 mmol) in THF was added di-tert-butyl dicarbonate (436.5 mg, 2.0 mmol) at rt. The solution was stirred at the same temperature for 4 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with water and brine, and then dried over anhydrous Na2SO4. After removal of the solvent in vacuo, NBoc-propargylamine (20) (253.64 mg, 90%) was obtained as a yellow solid, which was pure enough and used for the next step without further puriﬁcation. Synthesis of N-Boc-dipropargylamine (21).2d To a stirred solution of N-Boc-propargylamine (20) (200 mg, 1.29 mmol) in anhydrous THF (70 mL) was added 60% NaH (43.35 mg, 1.8 mmol). The suspension was stirred for 0.5 h, and then propargyl bromide (11a) (245.67 mg, 2.06 mmol) was added dropwise. The mixture was stirred at rt for 8 h and then quenched with saturated NH4Cl solution. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were then washed with water and brine and dried over Na2SO4. After the solvent was removed in vacuo, the crude product was subjected to ﬂash column chromatography (eluting with petroleum ether/EtOAc = 120:1) to give 21 as a pale yellow oil (186.77 mg, 75%). General Procedure for [2 + 2 + 2] Cycloaddition under MWI Conditions. To a solution of diyne (50 mg) and propargyl halide (2 equiv) in dry acetonitrile (5 mL), Mo(CO)6 (5 mol %) was added and the reaction mixture was stirred under MWI conditions for 15 min. After the completion of reaction [thin-layer chromatography (TLC) monitoring], the solvent was concentrated at reduced pressure and the crude product was puriﬁed by silica gel column chromatography using ethyl acetate/petroleum ether (10:90) to give the cyclotrimerized product. 5-(Bromomethyl)-2-tosylisoindoline (13a). Yield = 80%, white ﬂuﬀy solid, mp: 176−178 °C; 1H NMR (500 MHz, CDCl3): δ 2.40 (s, 3H), 4.44 (s, 2H), 4.59 (s, 4H), 7.13 (d, J = 7.75 Hz, 1H), 7.20 (s, 1H) 7.25 (d, J = 8.10 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.20 Hz, 2H); 13C NMR (125 MHz, 1853
DOI: 10.1021/acsomega.7b01976 ACS Omega 2018, 3, 1850−1855
ACS Omega calcd for C10H11ClNO [M + H]+, 196.0524; found, 196.0524 and other isotopic peak is 198.0496. 5,6-Bis(chloromethyl)-2-methylisoindolin-1-one (18d). Yield = 50%, white solid, mp: 131−133 °C; 1H NMR (400 MHz, CDCl3): δ 3.18 (s, 3H), 4.37 (s, 2H), 4.80 (d, J = 6.24 Hz, 4H), 7.50 (s, 1H), 7.84 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.7, 43.1, 43.1, 52.0, 125.1, 125.9, 134.0, 136.7, 139.7, 142.1, 167.7; IR νmax: 690, 768, 912, 1027, 1103, 1224, 1262, 1335, 1397, 1418, 1449, 1684, 2927, 3034 cm−1; HRMS (ESI, Q-ToF) m/z: calcd for C11H12Cl2NO [M + H]+, 244.0290; found, 244.0294 and other isotopic peaks are 246.0266 and 248.0298. tert-Butyl 5-(Bromomethyl)isoindoline-2-carboxylate (22). Yield = 55%, white solid, mp: 120−122 °C; 1H NMR (500 MHz, CDCl3): δ 1.51 (s, 9H), 4.50 (s, 2H), 4.64 (d, J = 17.80 Hz, 4H), 7.18−7.30 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 28.7, 33.5, 52.0, 52.3, 80.0, 123.1, 123.3, 123.4, 123.6, 128.5, 137.4, 137.6, 137.9, 138.3, 154.6. HRMS (ESI, QToF) m/z: calcd for C15H18BrNO2 [M + H]+, 312.0594; found, 312.0593 and other isotopic peak is 314.0571. Preparation of Compound 24.2c To the compound 22 in dry MeCN, K2CO3 and N-methylpiperazine 23 were added at rt and continuously stirred for 4 h. After completion of the reaction (TLC monitoring), the reaction mass was quenched with water and extracted with EtOAc. All combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was found to be pure by NMR; hence, it can be used for the next step as it is. Yield = 99%, light brown sticky liquid, 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 2.28 (d, J = 0.08 Hz, 3H), 2.47 (b, 8H), 3.48 (s, 2H), 4.61 (s, 2H), 4.65 (s, 2H), 7.13− 7.22 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 28.7, 46.0, 51.9, 52.0, 52.2, 52.3, 53.0, 55.1, 62.9, 79.8, 122.4, 122.6, 123.4, 123.6, 128.6, 136.0, 136.4, 137.3, 137.58, 137.63, 154.7.
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* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b01976. Copies of 1H and 13C NMR spectra of all new compounds (PDF)
*E-mail: [email protected]
Sambasivarao Kotha: 0000-0002-7173-0233 Notes
The authors declare no competing ﬁnancial interest.
ACKNOWLEDGMENTS We are grateful to the Department of Science and Technology (DST), New Delhi, for the ﬁnancial support (EMR/2015/ 002053). G.S. thanks the CSIR-New Delhi for the award of research fellowship. S.K. thanks the DST for the award of a J. C. Bose fellowship (SR/S2/JCB-33/2010) and Praj industries for Chair Professor (Green Chemistry).
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DOI: 10.1021/acsomega.7b01976 ACS Omega 2018, 3, 1850−1855