The Free Internet Journal Paper for Organic Chemistry Archive for Arkivoc 2017, part v, 67-79 Organic Chemistry Synthesis, anti-inflammatory activity of picen-13-ylmethylene derivatives T. Shanmuganathan,*a,b A. A. M. Prince,b N. Dhatchanamoorthy,a K. Parthasarathy,c and M. Venugopald a Orchid Pharma Ltd, R & D Centre, Chennai 600119, India b Ramakrishna Mission Vivekananda College, Department of chemistry, Mylapore, Chennai 600 004, India c Siddha Central Research Institute, Central Council for Research in Siddha, Chennai 600 106, India d Ven Biotech Private Limited, Chennai, India Email: [email protected] Received 03-19-2017 Accepted 05-27-2017 Published on line 07-09-2017 Abstract A series of picene-13-ylmethylene derivatives (11-17) were synthesized by Knoevenagel condensation of active methylene compounds with picene-13-carbaldehyde. Keywords: Photo cyclization, picene-13-carbaldehyde, picene-13-ylmethylene derivatives, anti-inflammatory DOI: https://doi.org/10.24820/ark.5550190.p010.100 Page 67 ©ARKAT USA, Inc Arkivoc 2017, v, 67-79 Shanmuganathan, T. et al. Introduction Picene or benzo[a]chrysene, is well documented for use in material chemistry.1,2 Picene derivatives were found to be present in abundance as pentacyclic triterpenes and triterpenoids which are often bioactive and present a huge therapeutic potential. Many pentacyclic triterpenes namely oleane, oleanolic acid and ursane are reported to possess promising antitumor,3-5 antiviral,6 antidiabetic,7 anti-inflammatory8 activities. Also a derivative of picene, namely octadecahydro-picene-2,3,14,15-tetranone isolated and purified from the root bark of Zizyphus nummularia, reported to possess anti-cancer and anti-inflammatory activities.9,10 Many polycyclic aromatic compounds such as flavone, quercetin, chrysin and pyrimido[4,5-b]quinolines were reported to possess anti-inflammatory or antioxidant properties.11,12 Because of the close structural similarity with the reported polycyclic compounds, we have envisaged to explore the anti-inflammatory activity of picene analogues. Thus, our interest is to conjugate two naphthalene moieties by cyclization which results in the formation of a picene moiety. Substitution at its alpha position with various esters or amides leads to novel picene methylene derivatives in order to evaluate their biological properties. In order to accomplish our objective, we used a Knoevenagel condensation for the synthesis of novel structures incorporating both the picene moiety and several active methylene compounds, namely, ethyl cyanoacetate, malononitrile, cyanoacetamide, diethyl malonate, ethyl acetoacetate, acetylacetone and 5,6 dimethoxy-1- indanone with picene-13-carbaldehyde. The synthesized picen-13-ylmethylene derivatives were characterized by NMR, IR, mass spectra, elemental analysis. The structures were confirmed by single crystal XRD of a selected example. The compounds were evaluated by in vitro biological tests for their anti-inflammatory properties. Results and Discussion In the present work, we synthesized a new series of picen-13-ylmethylene derivatives 11-17 by condensing active methylene groups with picene-13-carbaldehyde as shown in Scheme 1 and 2. The first step in the Scheme 1 was the condensation of 1-naphthaldehyde 1 with 1-naphthyl acetic acid 2 in the presence of triethylamine and acetic anhydride produced 2,3-di(naphthalen-1-yl)acrylic acid 313,14 with 62% yield after recrystallization from ethyl acetate. Table 1. Reaction conditions and yield of 3 for the esterification using an alcohol Reaction Reaction Reaction Product Yield Solvent condition Time conversion % Ethanol Reflux 3 days 60% 50% of compound 4 Mixture of Ethanol and Toluene Reflux 10 hrs 100% 86% of compound 4 Methanol Reflux 3 days 60% 50% of compound 5 Mixture of Methanol and Reflux 10 hrs 100% 87% of compound 5 Toluene Page 68 ©ARKAT USA, Inc Arkivoc 2017, v, 67-79 Shanmuganathan, T. et al. Compound 3 was then converted to the corresponding ester 4 & 5 using ethanol or methanol and a catalytic amount of sulphuric acid. Esterification of compound 3 with ethanol and sulphuric acid under reflux condition over 3 days gave 50% yield of compound 4. As the starting compound 3 was insoluble in 25 volumes of ethanol under reflux condition, we conducted the experiment using toluene as solvent under Dean Stark conditions. Under continuous removal of water, the esterification reaction was completed in 10 hours with 91% yield of compound 4 without further purification. (Table 1) The ester was cyclized to ethyl or methyl picene-13-carboxylate 6 & 715-19 under irradiation with UV light at 365 nm in the presence of iodine. We studied the oxidative cyclisation of compound 4 with several reactants under different reaction conditions and the results are summarized in Table 2. Treatment of compound 4 with aluminium chloride; or a mixture containing aluminium chloride and sodium chloride20 at 140 °C; or aluminium chloride and stannic chloride21 ;or irradiation with 254 nm in the presence of iodine gave no product. Irradiation of compound 4 with 365 nm light without stirring condition gave 30% yield. The previously reported process22 of vanadium trifluoride oxide in trifluoroacetic acid afforded picene-13-carboxylic acid methyl ester 7 with a yield of 47%. In our present study, it was found that 1 mole of iodine and irradiation with light of 365nm in benzene under stirring are necessary to produce compound 6 & 7 in good yield (86% & 87% respectively) without chromatographic purification. Table 2. Mole ratio of reactants, reaction conditions and yield for the oxidative cyclisation of Compound 4 Reaction time Reactant Solvent Temperature (°C) Yield (%) of 6 (hrs.) AlCl3 (5 mol equiv) & Sodium Chloride Neat 140 °C 6 No product (5 mol equiv) AlCl3 (5 mol equiv) Benzene Reflux 6 No product AlCl3 (5 mol equiv) & Stannic Chloride Benzene Reflux 6 No product (2.5 mol equiv) Iodine (1mol equiv); irradiation at 254 25-30°C, without Benzene 12 No product nm stirring Iodine (1mol equiv); irradiation at 254 25-30°C, with Benzene 12 No product nm stirring Iodine (1mol equiv); irradiation at 365 25-30°C, without Benzene 12 30 nm stirring Iodine (1mol equiv); irradiation at 365 25-30 °C, with Benzene 12 8615-19 nm stirring 3122,15 (after Iodine (3mol equiv); irradiation at 500 cyclohexane Not reported Not reported column nm chromatogra phy) Vanadium Trifluoride oxide (4.4 mol Dichloromet 0 °C Not reported 4722 equiv) hane The picene-13-carboxylic acid ethyl ester 6 was hydrolyzed with sodium hydroxide produced picene-13- carboxylic acid 8 in 88% yield. Page 69 ©ARKAT USA, Inc Arkivoc 2017, v, 67-79 Shanmuganathan, T. et al. Reduction of picene-13-carboxylic acid methyl ester with lithium aluminium hydride has been reported for the preparation of compound 9 with a yield of 97%.23 In our study, mild reducing agents like di-isobutyl aluminium hydride [DIBAL (1M in Toluene)] was used to reduce picene-13-carboxylic acid ethyl ester 6 to picen-13-ylmethanol 924 in 90% yield. It was found that the oxidation of compound 9 with manganese dioxide11 in dichloromethane was not completed even under reflux condition. Therefore, we tried pyridinium chlorochromate as an oxidising agent in dichloromethane at 25-30 °C and obtained the compound 1025,26 in 87% yield without further purification. The picene-13-carbaldehyde 10 was condensed with active methylene compounds using piperidine as a base to give the title compounds 11-17.27,28 O O O H O O A c O /T E A E tO H o r M e O H 2 O H + O R H 2 S O 4 1 2 3 4 R = C 2 H 5 5 R = C H 3 O P C C /D C M h v /I 2 D IB A L O R O H O 6 R = C 2 H 5 9 1 0 7 R = C H 3 N a O H O O H 8 Scheme 1. Synthetic route for Picene-13-carboxylic acid (8) and Picene-13-carbaldehyde (10). Page 70 ©ARKAT USA, Inc Arkivoc 2017, v, 67-79 Shanmuganathan, T. et al. O C H 3 N N O C H 3 O C H 3 N H O O 1 7 1 1 1 2 a b g O C H 3 N f C H 3 O c O N H 2 O 1 6 1 0 1 3 e d O O C H 3 O C H O 3 O O O C H 3 H 3 C 1 5 1 4 Scheme 2. Synthetic route for various picen-13-ylmethylene derivatives (11-17) a) ethyl cyanoacetate b) malononitrile c) cyanoacetamide d) diethylmalonate e) ethyl acetoacetate f) acetyl acetone and g) 5,6 dimethoxy-1-indanone. All the synthesized compounds were characterized by 1H NMR, 13C NMR, IR spectroscopy, Mass and elemental analysis. The structure of 11 was confirmed by single crystal X-ray diffractogram (CCDC No. CCDC 1400968). Based on the single crystal structure, the configuration of the compound was confirmed as the E- isomer. The crystal parameters for compound 11 are given in Table 3 and the ORTEP diagram is shown in Figure 1. Page 71 ©ARKAT USA, Inc Arkivoc 2017, v, 67-79 Shanmuganathan, T. et al. Figure 1. ORTEP diagram of Compound 11. Table 3. Crystal data and structure refinement for Compound 11 Empirical formula C28H19NO2 Formula weight 402.1 Temperature 296(2) K Wavelength 0.71073 Å Crystal system, space group Triclinic, P-1 a = 11.4481(11) Å alpha = 108.889(3)° Unit cell dimensions b = 12.8106(11) Å beta = 97.646(3)° c = 15.4300(13) Å gamma = 90.531(3)° Volume 2118.7(3) Å3 Z, Calculated density 2, 1.259 g/cm3 Absorption coefficient 0.079 mm-1 F(000) 840 Crystal size 0.210 x 0.150 x 0.100 mm Theta range for data collection 1.409 to 21.57° Limiting indices -11<=h<=11, -13<=k<=13, -15<=l<=15 Reflections collected / unique 18796 / 4896 [R(int) = 0.0741] Completeness to theta = 21.570 99.90% Absorption correction None Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4896 / 0 / 561 Goodness-of-fit on F^2 1.007 Final R indices [I>2sigma(I)] R1 = 0.0735, wR2 = 0.2161 R indices (all data) R1 = 0.1930, wR2 = 0.3213 Extinction coefficient n/a Largest diff.