untitled European Journal of Chemistry 7 (2) (2016) 192‐194 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2016 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.7.2.192‐194.1389 European Journal of Chemistry Journal webpage: www.eurjchem.com Synthesis and characterization of tetralones as intermediates for podophyllotoxin analogues Kanakapura Narayanaramakrishna Padmavathi, Yeriyuru Basavaiah Basavaraju * and Basavaiah Umesha Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India * Corresponding author at: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India. Tel.: +91.948.0441804. Fax: +91.821.2421263. E‐mail address: basavaraju_yb@yahoo.co.in (Y.B. Basavaraju). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.7.2.192‐194.1389 Received: 27 December 2015 Received in revised form: 04 April 2016 Accepted: 09 April 2016 Published online: 30 June 2016 Printed: 30 June 2016 Podophyllotoxin has captured the attention of chemists all over the world for its biological activity. It was isolated from many plants of Podophyllum species such as Podophyllum emodi, Podophyllum peltatum and others. It mainly exhibits anticancer, antimitotic, antimalarial, anti‐aids and other activities. Its use is restricted due to its toxicity and unfavourable solubility. It was aimed to synthesize some new heterocyclic analogues of podophyllotoxin by changing the substituents by changing lactone ring with pyrazoline ring and substituents in ring C with hydrogen and methoxy group. Chalcones were prepared by Claisen‐Schmidt reaction of 1,3‐methylene dioxyacetophenone with benzaldehyde and p‐anisaldehyde. The reaction of chalcone with trimethylsulphoxonium iodide in presence of sodium hydride gave cyclopropyl ketone. Intramolecular cyclization reaction of cyclopropyl ketone gave tetralone intermediates of podophyllotoxin. They are obtained in good yields. The structure of all the products was confirmed by spectral data. KEYWORDS Synthesis Chalcones Tetralones Acetophenone Podophyllotoxin Cyclopropyl ketones Cite this: Eur. J. Chem. 2016, 7(2), 192‐194 1. Introduction Plants of genus podophyllum are rich sources of aryl tetralin type lignans. Podophyllotoxin is a cytotoxin lignan found in Berberidaceae plants such as Podophyllum peltatum Linnaeus, Podophyllum emodi Wall and Podophyllum pleianthum [1,2]. Extensive chemical investigation of podophyl‐ lum species revealed the presence of a number of compounds like podophyllotoxin, quercetin, 4‐demethyl podophyllotoxin, podophyllotoxin glucoside, 4‐demethyl podophyllotoxin glucoside, kempferol, picropodophyllin, deoxy podophyllo‐ toxin, 4‐demethyl deoxy podophyllotoxin, isopicropodophyllin, α‐peltatin, β‐peltatin. The lignan podophyllotoxin is highly valued as precursor for clinical use compounds. Extracts of podophyllum species have been used for diverse cultures since ancient times as antidotes against poisons and toxic, cathartic, purgative, antihelminthic and vesicant [3]. Podophyllotoxin is effective in the treatment of genital warts in children and against Molluscum contagiosum which is generally a self limiting benign skin disease that affects mostly children, young adults and HIV patients. In the modern system of medicine, the plant extracts has been successfully used for treatment of various disorders such as monocytoid leukemia, hodgkins lymphoma, bacterial and viral infections, veneral warts, rheumatoid arthralgia, associated with numbness of the limbs and pyogenic infection of skin tissues, AIDS associated with kaposis sarcoma and different cancers of brain, lungs and bladder. Antitumor activity is the outstanding property of podophyllotoxin [4]. Some of the derivatives and analogues of podophyllotoxin showed good anticancer activity. In view of these, it was decided to synthesize new tetralone intermediates of podophyllotoxin by chalcone route. The tetralones were synthesized by modifying lactone ring with pyrazoline ring and change the substituent in ring C with hydrogen and methoxy group to study structure activity relationship (Figure 1). 2. Experimental 2.1. Materials and methods All the required reagents and chemicals were purchased from Merck. They were used without further purification. Melting points were taken in open capillary tubes and are uncorrected. Padmavathi et al. / European Journal of Chemistry 7 (2) (2016) 192‐194 193 Figure 1. Podophyllotoxin. O O O I 1 O O O II O O CHO R1 R2 R3 R3 III R1 R2 2 O O O R3 R1 R2 IV O O O R2 R3R1 (5a,b) 6&7 1 2 3 1 2 3 1 2 34 56 7 8 + a. R1 = R2 = R3 = H b. R1 = R3 = H; R2 = OCH3 Reagents and conditions: I: Ac2O, fused ZnCl2, stirred at room temperature (29 oC) for 4 hours. II: NaOH, H2O, C2H5OH stirred at room temperature (29 oC) for 10 hours. III: NaH, dry benzene, trimethyl sulphoxonium iodide, stirred for 5 hr and further at 50-60 oC for 1 hour. IV: Anhydrous SnCl4, Ac2O, dry CH2Cl2. stirred at room temperature for 5 hours. (3a,b) (4a,b) Scheme 1 Thin layer chromatography (TLC) is performed with Merck pre‐coated silica gel plates (60F254) with iodine as a developing agent. IR spectra in KBr were recorded on Perkin‐ Elmer model 683 spectrometers. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded using tetramethyl silane (TMS) as an internal reference on Bruker spectrometer. Elemental analyses were performed on a Perkin‐Elmer 2400. Mass spectra were obtained by Hitachi RMU‐61 spectro‐ photometer. 2.2. Synthesis 2.2.1. General procedure for the synthesis of 1‐(benzo[d] [1,3]dioxol‐6‐yl)ethanone (2) 1,3‐Benzodioxole (10 g) in acetic anhydride (30 mL) containing fused zinc chloride (12 g) as catalyst was stirred at room temperature for 4 h. After the usual work up, thick brown solid product was obtained in 85% yield (9 g). The purity of the compound was checked by TLC in different solvent mixture (Scheme 1). 1‐(Benzo[d][1, 3]dioxol‐6‐yl) ethanone (2): Color: Dark brown solid. Yield: 85%. M.p.: 95‐97 °C. FT‐IR (KBr, , cm‐1): 2917 (C‐H), 1661 (C=O), 1603 (Ar, C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.52 (s, 3H, CH3), 6.02 (s, 2H,‐O‐CH2‐O‐), 6.84 (d, 1H, J = 3 Hz, Ar‐H), 7.24 (s, 1H, Ar‐H), 7.42 (d, 1H, J = 3 Hz, Ar‐H). 2.2.2. General procedure for the synthesis of chalcones (4a, 4b) Substituted benzaldehydes (3.5 mL) and substituted acetophenone (5 g) were stirred in water (25 mL) and ethanol (15 mL) mixture in the presence of sodium hydroxide (2 g) at room temperature for 6 h. The reaction mixture was kept overnight in an ice bath. The precipitated products were filtered and recrystallized from methanol (Scheme 1). 1‐(Benzo[d][1,3] dioxol‐6‐yl)‐3‐phenylprop‐2‐en‐1‐one (4a): Color: Light yellow solid. Yield: 80%. M.p.: 194‐196 °C. FT‐IR (KBr, , cm‐1): 1653 (C=O), 1590 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 6.04 (s, 2H, ‐O‐CH2‐O), 6.87 (d, 1H, J = 3 Hz, α‐ C‐H), 7.76 (d, 1H, J = 3 Hz, β‐C‐H), 7.39‐7.65 (m, 8H, Ar‐H). MS (EI, m/z): 253, 231, 215, 198, 167, 149, 97, 58. Anal. calcd. or C16H12O3: C, 76.18; H, 4.79. Found: C, 76.75; H, 4.83%. 1‐(Benzo[d][1, 3] dioxol‐6‐yl)‐3‐(4 methoxyl phenyl) prop‐2‐ en‐1‐one (4b): Color: Light yellow solid. Yield: 80%. M.p.: 241‐ 243 °C. FT‐IR (KBr, , cm‐1): 1646 (C=O), 1603 (C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 3.82 (s, 3H, OCH3), 6.02 (s, 2H, ‐ OCH2O‐), 6.85‐7.24 (m, 4H, Ar‐H, α‐C‐H), 7.32‐7.82 (m, 5H, Ar‐ H). MS (EI, m/z): 283, 211, 144, 99. Anal. calcd. for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.34; H, 4.96%. 194 Padmavathi et al. / European Journal of Chemistry 7 (2) (2016) 192‐194 2.2.3. General procedure for the synthesis of cyclopropyl ketones (5a,b) To the stirred suspensions of sodium hydride (0.9 g) in dry benzene (20 mL) the trimethy sulphoxonium iodide (7 g) was added. The reaction mixture was stirred for 20 minutes at 30 °C. Chalcone (8 g) in dry benzene (15 mL) was added dropwise to the above solution. The reaction mass was stirred at 28‐29 °C for 6 hours and raised the temperature to 50‐60 °C for 1 hour. The completion of the reaction was confirmed by thin layer chromatography and the cooled reaction mixture was poured into 5% hydrochloric acid solution (30 mL). The precipitated gummy residue was extracted into chloroform. The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. They were recrystallized from methanol (Scheme 1). Benzo[d][1, 3]dioxol‐5‐yl (2‐phenylcyclopropyl)methanone (5a): Color: Light yellow solid. Yield: 75 %. M.p.: 226‐228 °C. FT‐IR (KBr, , cm‐1): 1653 (C=O), 1604 (C‐C of cyclopropyl), 1590 (Ar, C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 6.01 (s, 2H, O‐CH2‐O), 1.48‐1.86 (t, 2H, J = 4 Hz, C2‐H), 2.64 (m, 1H, C1‐H), 2.79 (m, 1H, C3‐H), 6.81 (d, 1H, Ar‐H), 7.15‐7.61 (m, 7H, Ar‐H). MS (EI, m/z): 267 (M+1), 167, 149. Anal. calcd. for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.7; H, 5.26%. Benzo[d][1, 3]dioxol‐5‐yl (2‐(4‐methoxyphenyl)cyclopropyl) methanone (5b): Color: Light yellow solid. Yield: 81 %. M.p.: 276‐279 °C. FT‐IR (KBr, , cm‐1): 1647 (C=O), 1603 (C‐C of cyclopropyl), 1580 (C=C, Ar). 1H NMR (400 MHz, CDCl3, δ, ppm): 3.74 (s, 3H, OCH3), 1.41‐1.80 (t, 2H, J = 4 Hz,C2‐H), 2.59 (m, 1H, C3‐H), 2.69 (m, 1H, C1‐H). MS (EI, m/z (%)): 283 (M+1). Anal. calcd. for C18H16O4: C, 72.96; H, 5.44. Found: C, 72.99; H, 5.42%. 2.2.4. General procedure for the synthesis of tetralones (6, 7) Acetic anhydride (0.94 mL) and anhydrous stannic chloride (1 mL) were added to the cyclopropyl ketones (3 g) were dissolved in dry dichloromethane (20 mL) solution. The resultant reaction mixture was stirred at 28‐29 °C for 6 hrs. The completion of reaction was known by thin layer chromatography. The reaction mixture was poured into 5% hydrochloric acid solution (40 mL), the product was extracted into chloroform. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum using a rotary evaporator to give brown residue. The product was purified by column chromatography using silica gel (60‐ 120 mesh) as adsorbent and benzene as eluent. The benzene solution was concentrated to a small volume (20 mL) to give products in good yields. They were recrystallized from methanol (Scheme 1). 8‐Phenyl‐7, 8‐dihydronaphtho[2, 3‐d][1, 3]dioxol‐5(6H)‐one (6): Color: Dark brown gummy solid. Yield: 68%. M.p.: 256‐ 258 °C. FT‐IR (KBr, , cm‐1): 2922 (C‐H), 1608 (C=C), 1677 (C=O). 1H NMR (400 MHz, CDCl3, δ, ppm): 2.62‐2.68 (tt, 2H, C2‐ H), 1.25‐1.40 (m, 2H, C3‐H), 3.16 (t, 1H, C4‐H), 5.97 (s, 2H, O‐ CH2‐O‐), 6.58 (s, 1H, Ar‐H), 6.90‐7.53 (m, 6H, Ar‐H). MS (EI, m/z (%)): 267 (M+1). Anal. calcd. for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.93; H, 5.26%. 8‐(4‐Methoxyphenyl)‐7,8‐dihydronaphtho[2, 3‐d][1,3]dioxol‐ 5(6H)‐one (7): Color: Dark brown gummy solid. Yield: 60 %. M.p.: 273‐275 °C. FT‐IR (KBr, , cm‐1): 1673 (C=O), 2922 (C‐H), 1607 (Ar, C=C). 1H NMR (400 MHz, CDCl3, δ, ppm): 3.78 (s, 3H, OCH3), 5.84 (s, 2H, O‐CH2‐O‐), 2.53 (tt, 2H, C2‐H), 1.24 (m, 2H, C3‐H), 3.16 (m, 1H, C4‐H), 6.40 (s, 1H, Ar‐H), 6.84 (d, 2H, Ar‐H), 7.01‐7.52 (m, 3H, Ar‐H). MS (EI, m/z): 297 (M+1). Anal. calcd. for C18H16O4: C, 72.96; H, 5.44. Found: C, 72.93; H, 5.46%. 3. Results and discussion 1‐(Benzo[d][1,3]dioxol‐6‐yl) ethanone (2) was prepared in excellent yield by Friedel‐Crafts acylation reaction of 1,3‐ benzodioxole with acetic anhydride in presence of fused zinc chloride (Scheme 1). The structure of compound 2 was confirmed by FT‐IR and 1H NMR spectra. The chalcones (4a, 5b) were prepared in good yields by the Claisen‐Schmidt condensation of 1‐(benzo[d][1,3]dioxol‐6‐yl) ethanone (2) with benzaldehydes (3a,b) separately in the presence of sodium hydroxide in ethanol‐water mixture [5,6]. The cyclo‐ propyl ketones (5a,b) were prepared in high yields by the reaction of chalcones (4a,b) with trimethyl sulphoxonium iodide in presence of sodium hydride in dry benzene [7‐9]. The tetralones (6 and 7) were prepared in good yields by the intramolecular cyclization of cyclopropyl ketones (5a,b) in presence of anhydrous stannic chloride and acetic anhydride in dry dichloromethane [10,11]. The structure of all the synthesized compounds was confirmed by FT‐IR, 1H NMR, Mass spectra and elemental analysis. The 1H NMR spectrum of compound 6 showed distinct singlets at δ 6.58 and 7.53 ppm assignable to aromatic C5‐H and C8‐H, respectively. The tetralone protons showed absorption peaks at δ 2.62‐2.68 ppm (tt, 2H, C2‐H), 1.25‐1.40 ppm (m, 2H, C3‐H), 3.16 ppm (t, 1H, C4‐H). IR spectrum of the carbonyl group stretching frequency of compound 6 appeared at 1677 cm‐1. 4. Conclusion In summary, a convenient synthesis of tetralones as intermediates for podophyllotoxin analogues has been developed. We have used environmental friendly chemicals and conditions. The chalcone method gave good yields of tetralones. They are very useful for the synthesis of analogues of podophyllotoxin. Acknowledgement One of the authors is grateful to University Grant Commission (UGC) for providing Rajiv Gandhi National Fellowship (RGNF) for financial assistance and thankful to the University of Mysore, Mysore for providing necessary facility and spectral data. References [1]. Podwyssotzki, V. Arch. Exp. Pathol. Pharmakol. 1880, 13, 29‐52. [2]. Smissmann, E. S.; Murray, R. J.; McChesneyet, J. D. J. Med. Chem. 1976, 19, 148‐153. [3]. Ward, R. S. Synthesis 1992, 8, 719‐730. [4]. Nencki, M.; Sieber, N. J. Prakt. Chem. 1881, 23, 147‐156. [5]. Lokanatha Rai, K. M.; Anjanamurthy, C.; Radhakrishna, P. M. Synth. Commun. 1990, 20, 1273‐1277. [6]. Furniss, B. S.; Hannaford, A. 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