Studies Towards the Synthesis of Chrysen-6-ol and Benzo[c]phenanthren-5-ol Derivatives: Usual and Unusual Observations

Khokan Samanta, Gandhi K. Kar, and Achintya K. Sarkar

Department of Chemistry and Biochemistry, Presidency University (formerly Presidency College), Kolkata, India Some interesting observations have been observed in the synthetic studies of chrysen6-ol and benzo[c]phenanthren-5-ol derivatives by intramolecular cyclization of (2phenylnaphthalen-1-yl)acetic acid derivatives (4) and (1-phenylnaphthalen-2-yl)acetic acid derivatives (13) with PPA or triuoroacetic acid (TFA) - triuoroacetic anhydride (TFAA) mixture. Though chrysen-6-ol derivatives were obtained in very good yields (usual observation) under identical condition attempted cyclization of (1phenylnaphthalen-2-yl)-acetic acid derivatives (13) produced no benzo[c]phenanthrene5-ol derivatives (17). On the contrary dimeric intermolecular condensation product (18) (unusual observation) was formed in general in very good to excellent yields. The required precursors (4) were obtained from (2-bromonaphthalen-1-yl)acetonitrile derivative and suitable phenyl boronic acid in two steps although the precursors (13) were prepared from suitable 1-bromo-2-naphthyladehyde and phenyl boronic acid derivatives in six steps. Key Words: benzo[c]phenanthren-5-ol, chrysen-6-ol, dimeric product, polycyclic aromatic hydrocarbon, PPA or TFA-TFAA cyclization, synthesis

Received 8 November 2011; accepted 27 February 2012. Financial help from CSIR and DST acknowledged gratefully. We are thankful to CSIR for providing NET fellowship to one of the authors (KS). Address correspondence to Gandhi K. Kar, Department of Chemistry and Biochemistry, Presidency University (formerly Presidency College), 86/1 College Street, Kolkata 700073, India. E-mail: [email protected]

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INTRODUCTION
The polycyclic aromatic hydrocarbons (PAH) constitute a large class of compounds, many of which are present in the biosphere (1,2). These are grave environmental pollutants and are coming out largely from the power industries, automobile exhaust, and other petrochemical sources (3, 4) due to insufcient combustion of fossil fuels. Many of these PAHs and their oxidative metabolites (58) are suspected carcinogens (Figure 1). These include mainly the PAHs with bay region and their trans dihydrodiol epoxide derivatives (potential proximate carcinogenic (9, 10) metabolite). Some regioisomeric hydroxy and o-quinone derivatives of PAHs are considered as precursors of such carcinogenic metabolites. This unique property of PAH in producing the tumor growth has made these compounds a focal point of considerable synthetic importance. Synthesis of polynuclear phenolic compounds is also a challenging job to chemists. Efcacy of PAH as the base molecules for electronic devices, such as eld-effect transistors (FETs) or light-emitting diodes (LEDs), is also important. Again, a large number of polycyclic aromatic hydrocarbons are used as ligand in the transition metal catalyzed organic synthesis (1114). The structure activity relationship and mechanism of the carcinogenic activities of PAHs are yet to unfold in detail. One of the reasons for the above is the scarcity of proper standard samples. Thus, the development of some efcient

Figure 1: Some carcinogenic polyaromatic hydrocarbons and their oxidative metabolites.

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methods for their synthesis is still an active area of research to synthetic organic chemists. In the last few decades, several synthetic strategies have been reported in the literature for the synthesis of PAHs and derivatives. Among these, the common procedure involves the oxidative photocyclization of stilbene derivatives (1518). Along with other methods, intramolecular Diels-Alder reaction (19), ash vacuum pyrolysis (2023), olen metathesis (24), Friedel-Crafts type cyclization (25), dimerization or trimerization of acetylenes and arynes (26), PtCl2 catalyzed cycloisomerization (27, 28), etc., are used as the key steps for construction of a benzene ring in the synthesis of PAHs.

EXPERIMENTAL
All reactions were carried out using oven-dried glassware. Commercial-grade reagents were used without further purication. Solvents were dried following standard literature procedure prior to use. Tetrakis (triphenylphosphine)palladium(0) and DDQ were purchased from Sigma-Aldrich (USA). Triuoroacetic anhydride was purchased from Alfa Aesar (Lancaster). Arylboronic acids were prepared in the laboratory following standard literature procedure (31). Column chromatography was carried out using Silica gel (60120 mesh or 100200 mesh). TLC was performed on aluminium-backed plates coated with Silica gel 60 with F254 indicator (Merck). Melting points were taken in open capillaries and are uncorrected. The 1H-NMR spectra were recorded on Bruker 500 MHz (at Chemgen Pharma, Kolkata), Bruker 400 MHz (at Chembiotek International, Kolkata), Bruker 400 MHz and 200 MHz (IIT, Kharagpur), Bruker and 300 MHz (IACS, Kolkata) NMR spectrometer, respectively. ESI mass spectra were recorded on a micro mass Q-TOF mass spectrometer (serial no. YA 263) at IACS, Kolkata. IR spectral data was obtained from JASCO FT/IR680 PLUS Spectrometer.

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(2-Phenylnaphthalen-1-yl)acetonitrile (3a). A mixture of (2bromonaphthalen-1-yl)acetonitrile (2) (500 mg, 2.06 mmol), benzene boronic acid (300 mg, 2.47 mmol), Et3 N (1.7 mL, 12.0 mmol), and DMF (3 mL) was degassed by argon for 30 min and then to it the catalyst, Pd(PPh3 )4 (2 mol%) was added. The mixture was then heated with stirring at 100 C under argon atmosphere for 20 h. After cooling to r.t it was poured in cold water and extracted with ether. The ether layer was washed thoroughly with water and dried (anhydrous Na2 SO4 ). Removal of solvent followed by purication of the residue obtained by column chromatography (silica gel: 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 20:1) furnished 330 mg (66%) of 3a as a light yellow oil. IR (KBr) max 2247 cm1; 1H NMR (500 MHz, CDCl3 ) 4.0 (s, 2 H), 7.46 (m, 4 H), 7.54 (t, J = 7.3 Hz, 2 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.70 (t, J = 7.7 Hz, 1 H), 7.91 (d,

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J = 8.4 Hz, 1 H), 7.96 (d, J = 8.1 Hz, 1 H), 8.10 (d, J = 8.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3 ): = 18.8, 118.3, 123.1, 123.4, 126.3, 127.7, 127.9, 128.1, 128.7 (2 C), 128.8, 128.9, 129.3 (2 C), 131.5, 133.0, 140.6, 140.7 ppm.; HRMS (ESI, 70 eV): m/z [M+Na]+ Calcd for C18 H13 NNa: 266.0946; found: 266.0949. (2-Phenylnaphthalen-1-yl)acetic acid (4a). In a 100 mL round-bottom ask attached with a reux condenser, 300 mg (0.81 mmol) of compound 3a, 5 mL 30% KOH, and 25 mL methanol was taken and reuxed with stirring at 110C for 15 h. Excess methanol was removed by distillation and the residue was diluted with ice-water and neutral part was removed by extraction with ether. Aqueous part was acidied with 1:1 HCl under ice cold condition. Solid appeared was ltered through suction. The residue was again dissolved in saturated aqueous NaHCO3 solution and ltered. Filtrate was acidied with conc. HCl in ice cold condition and solid separated was ltered and dried. Recrystallization from pet. ether (6080 C) and ethyl acetate mixture afforded 280 mg (93%) of 4a as a white solid, mp 174176 C. IR (KBr) max : 1693 cm.1 [Compound 4a was characterized as its methyl ester derivative prepared by treating 4a with an ether solution of diazomethane. Spectral data of the methyl ester derivative of 4a: IR (KBr) max 1737 cm1; 1H NMR (200 MHz, CDCl3 ) 3.66 (s, 3 H), 4.01 (s, 2 H), 7.47.63 (m, 8 H), 7.797.89 (m, 3 H); 13C NMR (50 MHz, CDCl3 ): = 35.9, 52.1, 124.0, 125.7, 126.9, 127.3, 127.5, 127.6, 128.2, 128.3 (2 C), 128.7, 129.5 (2 C), 132.6, 133.0, 140.7, 142.0, 172.6 ppm; HRMS (ESI, 70 eV): m/z [M+H]+ Calcd for C19 H17 O2 : 277.1229; found: 277.1237. Chrysen-6-ol (5a): Method A. Cyclization of (2-phenylnaphthalene-1-yl)acetic acid (4a) with PPA. A mixture of compound 4a (100 mg, 0.38 mmol) and 5.0 g PPA was stirred with heating at 100 C for 4 h and then cooled to r.t. The reaction mixture was decomposed with cold water and extracted with dichloromethane. The organic part was washed thoroughly with aqueous NaHCO3 , dried over anhydrous Na2 SO4 , and evaporated to dryness. The crude product was puried by column chromatography [silica gel: 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 10:1] to furnish 40 mg (40%) of 5a as a reddish solid, mp 240242 C (lit (31). mp 248250 C). 1H NMR (500 MHz, CDCl3 ) 5.59 (s, 1 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.75 (t, J = 7.1 Hz, 1 H), 7.87 (d, J = 9 Hz, 1 H), 7.97 (d, J = 7.7 Hz, 1 H), 8.01 (s, 1 H), 8.38 (d, J = 8.1 Hz, 1 H), 8.61 (d, J = 8.4 Hz, 1 H), 8.64 (d, J = 9 Hz, 1 H), 8.78 (d, J = 8 Hz, 1 H); 13C NMR (75 MHz, CDCl3 & DMSO-d6 ): = 101.7, 121.7, 122.5, 122.6, 122.7, 123.1, 123.7, 125.5, 125.6, 125.7, 125.9, 126.8, 128.2, 129.5 (2 C), 152.4 ppm.; MS (ESI-MS positive ion): m/z 245.1

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[M+H]+; HRMS (ESI, 70 eV): m/z [M+H]+ Calcd for C18 H13 O: 245.0966; found: 245.0901. Method B. Cyclization of (2-phenylnaphthalene-1-yl)acetic acid (4a) with TFAA-TFA mixture. To a stirred suspension of 4a (30 mg, 0.12 mmol), in triuoroacetic anhydride (TFAA) (2 mL), 0.6 mL triuoroacetic acid (TFA) was added and stirred at r.t for overnight protecting from moisture. The mixture was then poured into an ice cold saturated NaHCO3 solution and extracted thoroughly with CH2 Cl2 . The organic layer was washed with water and dried (anhyd. Na2 SO4 ). Removal of solvent afforded the crude product which was puried by column chromatography [silica gel/pet. ether (6080 C) & ethyl acetate mixture, 10:1] to furnish 25 mg (83%) of 5a as a reddish solid, mp 240242 C. (2-m-Tolylnaphthalen-1-yl)acetonitrile (3b). 500 mg (2.06 mmol) of (2bromonaphthalen-1-yl)acetonitrile (2) on Suzuki coupling reaction with 310 mg (2.27 mmol) 3-methylbenzene boronic acid under identical condition as used for the preparation of the compound 3a afforded 310 mg (62%) of 3b as colourless oil after purication (column chromatography/silica gel: 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 20:1). IR (KBr) max 2248 cm1; 1H NMR (200 MHz, CDCl3 ) 2.47 (s, 3 H), 4.01 (s, 2 H), 7.227.30 (m, 3 H), 7.387.47 (m, 2 H), 7.557.74 (m, 2 H), 7.88 (t, J = 8.8 Hz, 2 H), 8.09 (dd, J = 0.8 & 8.4 Hz, 1 H,); 13C NMR (50 MHz, CDCl3 ): = 18.8, 21.5, 118.4, 123.1, 123.5, 126.2, 126.4, 127.7, 128.1, 128.6 (2 C), 128.8, 129.0, 130.1, 131.5, 133.1, 138.5, 140.8, 140.9 ppm; HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H16 N: 258.1283; found: 258.1296. (2-m-Tolylnaphthalen-1-yl)acetic acid (4b). 350 mg (1.36 mmol) of (2-mtolylnaphthalen-1-yl)acetonitrile (3b) on hydrolysis with 5 mL 30% KOH in reuxing (15 h) aqueous methanol afforded 315 mg (90%) of the acid (4b) as a white solid, mp 136138 C after usual work up and purication. IR (KBr) max 1707 cm1; 1H NMR (200 MHz, CDCl3 ) 2.38 (s, 3 H), 4.02 (s, 2 H), 7.167.33 (m, 4 H), 7.37 (d, J = 8.4 Hz, 1 H) 7.467.54 (m, 2 H), 7.777.93 (m, 3 H) (carboxylic proton was not observed). HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H17 O2 : 277.1229; found: 277.1239. 9-Methyl-chrysen-6-ol (5b): Method A. Cyclization of (2-m-tolylnaphthalen-1-yl)acetic acid with PPA. 120 mg (0.43 mmol) of (2-m-tolylnaphthalen-1-yl)acetic acid (4b) on cyclization with 6 g of PPA under identical condition as used for the preparation of the compound 5a afforded 43 mg (36%) of 5b as white solid, mp 192194 C after purication (column chromatography/silica gel: 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 15:2). 1 H NMR (300 MHz, CDCl3 ) 2.48 (s, 3 H), 7.437.62 (m, 3 H), 7.73 (d,

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J = 8.6 Hz, 1 H), 7.86 (d, J = 7.7 Hz, 1 H), 7.89 (br s, 1 H), 8.31 (d, J = 8.1 Hz, 1 H), 8.43 (br s, 1 H), 8.56 (d, J = 8.8 Hz, 1 H), 8.58 (d, J = 8.1 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H15 O: 259.1123; found: 259.1128.

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Method B. Cyclization of (2-m-tolylnaphthalen-1-yl)acetic acid (4b) with TFAA-TFA mixture. 30 mg (0.11 mmol) of (2-m-tolylnaphthalen1-yl)-acetic acid (4b) on cyclization with TFAA-TFA mixture under identical condition as used for the preparation of the compound 5a afforded 20 mg (67%) of 5b as white solid, mp 192194 C. (1-Bromonaphthalen-2-yl)methanol (9a). To a stirred solution of the 1bromo-2-naphthaldehyde (8a) (300 mg, 1.19 mmol) in 15 mL ethanol at 510 C, 35 mg (1.0 mmol) of NaBH4 was added pinch by pinch. Stirring was continued at r.t for further 2 h. Excess ethanol was removed by distillation and the reaction mixture was diluted with 3 mL ice water containing 34 drops of dil.HCl and extracted with dichloromethane. The organic layer was washed thoroughly with water and dried (anhyd. Na2 SO4 ). Removal of solvent afforded the crude product which was puried by column chromatography [silica gel/pet. ether (6080 C) & ethyl acetate mixture, 10:1] to furnish 9a as colorless oil. Yield, 282 mg (94%); 1H NMR (500 MHz, CDCl3 ) 2.09 (t, J = 6.5 Hz, 1 H), 4.99 (d, J = 6.5 Hz, 2 H), 7.53 (m, 1 H), 7.597.65 (m, 2 H), 7.84 (dd, J = 3.2 & 8.1 Hz, 2 H), 8.32 (d, J = 8.5 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C11 H10 BrO: 236.9915(100%), 238.9895(95%); found: 236.9936 (100%), 238.9905(95%). 1-Bromo-2-bromomethylnaphthalene (10a). A mixture of compound 9a (300 mg, 1.27 mmol), PBr3 (160 mg, 0.59 mmol) and 5 mL CCl4 was stirred at 60 C for 1 h protecting from moisture. It was then cooled to r.t, poured into crushed ice and extracted with CHCl3 (2 10 mL). The CHCl3 layer was washed with saturated NaHCO3 solution followed by water. Organic layer was separated, dried over anhyd.Na2 SO4 and solvent removed to furnish the bromide 10a as a faint yellow solid mp, 6668 C (crude). It was used directly for the next step without further purication. Yield, 252 mg (82%); 1H NMR (500 MHz, CDCl3 ) 4.87 (m, 2 H), 7.527.56 (m, 2 H), 7.61 (m, 1 H), 7.81 (t, J = 9.2 Hz, 2 H), 8.34 (d, J = 9.0 Hz, 1 H). HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C11 H9 Br2 : 300.9051(100%), 298.9071(50%); found: 300.9062(100%), 298.9084(50%). (1-Bromonaphthalen-2-yl)acetonitrile (11a). In a 50 mL r.b ask tted with anhydrous CaCl2 guard tube, 270 mg (0.9 mmol) of bromide 10a and 2 mL dry DMF was taken. To this 120 mg (1.85 mmol) of potassium cyanide was added and stirred at r.t. for overnight and then 1 h at 50 C. The reaction mixture was then poured into 5 mL ice water and extracted with diethyl ether. Ether part was washed thoroughly with ice-cold brine solution.

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Organic part was collected; dried (anhyd.Na2 SO4 ) and removal of solvent afforded the crude cyanide derivative 11a. It was puried by column chromatography [silica gel/pet. ether (6080 C) and EtOAc, 20:1]. Yield, 150 mg (68%); yellowish oil. IR (KBr) max 2247 cm1; 1H NMR (500 MHz, CDCl3 ) 4.10 (s, 2 H), 7.567.66 (m, 3 H), 7.87 (t, J = 7.5 Hz, 2 H), 8.30 (d, J = 8.5 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C12 H9 BrN: 245.9918(100%), 247.9898(95%); found: 245.9907(100%), 247.9880(95%). (1-Phenylnaphthalen-2-yl)acetonitrile (12a). It was prepared from 360 mg (1.2 mmol) of crude 2-Bromomethyl-1-phenylnaphthalene (16a) under the identical reaction condition and usual work up as used for the preparation of 11a afforded 270 mg (75%) of 12a as a colourless oil after purication (column chromatography/silica gel/ pet. ether (6080 C) and EtOAc, 15:1). IR (KBr) max 2247cm1; 1H NMR (500 MHz, CDCl3 ) 3.64 (s, 2 H), 7.33 (d, J = 7.0 Hz, 2 H), 7.43 (dd, J = 8.5 & 16.2 Hz, 2 H), 7.54 (t, J = 7.0 Hz, 2 H), 7.58 (t, J = 7.2 Hz, 2 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.94 (dd, J = 8.5 & 17.5 Hz, 2 H); 13C NMR (125 MHz, CDCl3 ): = 22.0, 117.8, 124.9, 125.3, 125.8, 126.1, 126.2, 127.5, 127.6, 128.2, 128.5 (2 C), 129.4 (2 C), 132.4, 132.5, 137.2, 138.7; HRMS (ESI, 70 eV): m/z [M+Na]+ Calcd for C18 H13 NNa: 266.0946; found: 266.0946. (1-Phenylnaphthalen-2-yl)acetic acid (13a). 350 mg (1.34 mmol) of nitrile derivative (12a) on hydrolysis with 5 mL 30% KOH in reuxing (15 h) aqueous methanol afforded 332 mg (95%) of the acid (13a) as a white solid, mp, 8788 C after usual work up and purication. Compound 13a was characterized as its methyl ester derivatives prepared by treating 13a with the ether solution of diazomethane. [NMR spectral data of the methyl ester derivative of 13a prepared by treatment of the acid with diazomethane: IR (KBr) max 1741 cm1; 1H NMR (200 MHz, CDCl3 ) 3.6 (s, 2 H), 3.62 (s, 3 H), 7.267.31 (m, 3 H), 7.40 (m, 2 H), 7.47 (dd, J = 3.0 & 5.6 Hz, 4 H), 7.88 (d, J = 8.4 Hz, 2 H); 13C NMR (50 MHz, CDCl3 ): = 39.4, 51.9, 125.6, 126.1, 126.7, 127.5, 127.7, 127.8, 128.4 (2 C), 129.6, 130.3 (2 C), 132.7, 133.0, 138.7, 139.4, 172.3 ppm; HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H17 O2 : 277.1229; found: 277.1240]. 6H -[5,6 ]Bi[benzo[c]phenanthrenylidne]-5 -one (18a): Method A. Cyclization of (1-phenylnaphthalene-2-yl)acetic acid (13a) with PPA. A mixture of compound 13a (130 mg, 0.49 mmol) and 6.0 g PPA was stirred with heating at 100 C for 3 hours and then cooled to r.t. The reaction mixture was decomposed with cold water and extracted with dichloromethane. The organic part was washed thoroughly with aqueous NaHCO3 , dried over anhydrous Na2 SO4 and evaporated to dryness. The crude product was puried by column chromatography [silica gel; 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 10:1]

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to furnish 68 mg (52%) of 18a as a light yellow solid, mp 128130 C. IR (KBr) max 1760 cm1; 1H NMR (500 MHz, CDCl3 ) 4.09 (s, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.44 (d, J = 7.0 Hz, 2 H), 7.48 (d, J = 8.9 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.547.63 (m, 4 H), 7.68 (br s, 2 H), 7.74 (t, J = 9.1 Hz, 3 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.6 Hz, 1 H), 8.00 (d, J = 7.9 Hz, 1 H), 9.05 (d, J = 8.4 Hz, 1 H), 9.12 (d, J = 8.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3 ): = 39.8, 117.9, 121.7, 128.8, 125.9 (2 C), 126.1, 126.2, 126.3, 126.5, 126.6, 126.8, 127.2, 127.7 (2 C), 127.8, 127.9, 128.0, 128.1, 128.2, 128.6, 128.7 (2 C), 129.0, 130.1, 130.5 (3 C), 131.5, 132.9, 133.2, 133.4, 138.8, 139.9, 145.1, 170.2 ppm.; MS (ESI-MS positive ion): m/z 245.0(100%) [M + H]+, 471.1(10%) [M + H]+; HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C36 H23 O: 471.1749; found: 245.0964(100%), 471.0923(10%).

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Method B. Cyclization of (1-phenylnaphthalene-2-yl)acetic acid (13a) with TFAA-TFA mixture. To a stirred suspension of 13a (50 mg, 0.20 mmol), in triuoroacetic anhydride (TFAA) (3 mL), 0.8 mL triuoroacetic acid (TFA) was added and stirred at r.t for overnight protecting from moisture. The mixture was then poured in ice cold saturated NaHCO3 solution and extracted thoroughly with CH2 Cl2 . The organic layer was washed with water and dried (anhyd. Na2 SO4 ). Removal of solvent afforded the crude product which was puried by column chromatography [silica gel; pet. ether (6080 oC) & ethyl acetate mixture, 10:1] to furnish 38 mg (76%) of 18a as a light yellow solid, mp 128130 C. (6-Methoxy-1-phenylnaphthalen-2-yl)acetonitrile (12b). The title compound was prepared from 400 mg (1.2 mmol) of 2-bromomethyl-6-methoxy1-phenylnaphthalene (16b) following the similar reaction condition as used for the preparation of 12a afforded 300 mg (75%) of 12b as a colourless oil after purication (column chromatography/silica gel; pet. ether (6080 oC) and EtOAc, 15:1). IR (KBr) max 2246 cm1; 1H NMR (200 MHz, CDCl3 ) 3.57 (s, 2 H), 3.94 (s, 3 H), 7.04 (dd, J = 2.4 & 9.2 Hz, 1 H), 7.19 (d, J = 2.4 Hz, 1 H), 7.237.34 (m, 3 H), 7.487.59 (m, 4 H), 7.82 (d, J = 7.4 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H16 NO: 274.1232; found: 274.1256. (6-Methoxy-1-phenylnaphthalen-2-yl)acetic acid (13b). 300 mg (1.1 mmol) of nitrile derivative (12b) on hydrolysis with 5 mL 30% KOH in reuxing (15 h) aqueous methanol afforded 276 mg (92%) of the acid (13b) as a white solid, mp 102104 C after usual work up and purication. IR (KBr) max 1702 cm1; 1H NMR (200 MHz, CDCl3 ) 3.53 (s, 2 H), 3.88 (s, 3 H), 6.98 (dd, J = 2.6 & 9.2 Hz, 1 H), 7.13 (d, J = 2.6 Hz, 1 H), 7.23 (m, 3 H), 7.42 (m, 4 H), 7.72 (d, J = 8.4 Hz, 1 H) (carboxylic proton

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was not observed); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H17 O3 : 293.1178; found: 293.1185. 10,10 -Dimethoxy-6H -[5,6 ]bi[benzo[c]phenanthrenylidne]-5 -one (18b): Method A. Cyclization of (6-methoxy-1-phenylnaphthalene-2yl)acetic acid (13b) with PPA. A mixture of compound 13b (120 mg, 0.41 mmol) and 6.0 g PPA was stirred with heating at 100 C for 4 h and then cooled to r.t. After usual work up and purication by column chromatography [silica gel; 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 15:2] furnished 58 mg (48%) of 18b as a reddish solid, mp 142144 C. IR (KBr) max 1757 cm1; 1H NMR (300 MHz, CDCl3 ) 3.86 (s, 3 H), 3.88 (s, 3 H), 3.95 (s, 2 H), 7.097.25 (m, 2 H), 7.267.37 (m, 4 H), 7.39 (br s, 2 H), 7.447.52 (m, 4 H), 7.59 (dd, J = 3.1 & 8.6 Hz, 2 H), 7.75 (m, 2 H), 8.88 (d, J = 8.9 Hz, 1 H), 8.96 (d, J = 8.1 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C38 H27 O3 : 531.1960; found: 275.0984(100%), 531.1978(20%). Method A. Cyclization of (6-methoxy-1-phenylnaphthalene-2yl)acetic acid (13b) with TFAA-TFA mixture. To a stirred suspension of 13b (50 mg, 0.17 mmol), in triuoroacetic anhydride (TFAA) (3 mL), 0.9 mL triuoroacetic acid (TFA) was added and stirred at r.t for overnight protecting from moisture. After usual work up and purication by column chromatography [silica gel/pet. ether (6080 C) & ethyl acetate mixture, 10:1] afforded 44 mg (87%) of 18b as a reddish solid, mp 142144 C. 4-Methyl-1-phenylnaphthalen-2-carbaldehyde (14c. 500 mg (2.01 mmol) of 1-bromo-4-methylnaphthalene-2-carbaldehyde (8c) was subjected to Suzuki reaction with 270 mg (2.2 mmol) benzene boronic acid under the identical reaction condition as used for the preparation of 3a afforded 325 mg (65%) of 14c as a colourless oil after purication (column chromatography/silica gel; pet. ether (6080 C) and EtOAc, 15:1). IR (KBr) max 1666 cm1; 1H NMR (200 MHz, CDCl3 ) 2.78 (s, 3 H), 7.39 (dd, J = 3.0 & 6.5 Hz, 3 H), 7.53 (t, J = 3.0 Hz, 3 H), 7.67 (t, J = 7.7 Hz, 2 H), 7.92 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 9.87 (s, 1 H); 13C NMR (50 MHz, CDCl3 ): = 19.6, 122.3, 124.4, 126.5, 128.2 (3 C), 128.4, 128.7, 130.8, 131.2 (2 C), 132.6, 134.8, 135.4, 135.5, 145.2, 193.0 ppm; HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C18 H15 O: 247.1123; found: 247.1134. (4-Methyl-1-phenylnaphthalen-2-yl)methanol (15c). 300 mg (1.22 mmol) of 14c on NaBH4 reduction under the identical reaction condition as used for the preparation of 9a afforded 285 mg (95%) of 15c as a colourless oil after purication (column chromatography/silica gel; pet. ether (6080 C) and EtOAc, 15:2). IR (KBr) max 3385 cm1; 1H NMR (300 MHz, CDCl3 ) 2.67 (s, 3 H), 4.44 (s, 2 H), 7.13 (s, 1 H), 7.157.33 (m, 3 H), 7.357.44 (m, 5

0.70 4.30 n15

0.70 6.00 n16

0.70 8.20 n17

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1.20 2.00 n18

H), 7.96 (d, J = 8.4 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C18 H17 O: 249.1279; found: 249.1286. 2-Bromomethyl-4-methyl-1-phenylnaphthalene (16c). 250 mg (1.01 mmol) of 15c was subjected to undergo the reaction with PBr3 under the identical reaction condition as used for the preparation of 10a afforded 243 mg (97%) of 16c as a yellowish oil. It was used directly for the next step without further purication due to lower stability of the product. (4-Methyl-1-phenylnaphthalen-2-yl)acetonitrile (12c). The title compound was prepared from 300 mg (0.96 mmol) of 2-bromomethyl-4-methyl1-phenylnaphthalene (16c) following the similar reaction condition as used for the preparation of 12b afforded 216 mg (72%) of 12c as a colorless oil after purication (column chromatography/silica gel/ pet. ether (6080 C) & EtOAc, 15:1). IR (KBr) max 2248 cm1; 1H NMR (500 MHz, CDCl3 ) 2.69 (s, 3 H), 3.46 (s, 2 H), 7.19 (m, 2 H), 7.287.34 (m, 2 H), 7.40 (m, 2 H), 7.427.45 (m, 3 H), 7.94 (d, J = 8.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3 ): = 19.9, 22.8, 118.6, 124.5, 125.3, 126.5, 126.7, 126.8, 127.7, 128.4, 129.3 (2 C), 130.5 (2 C), 132.6, 133.4, 135.6, 137.9, 138.3 ppm; HRMS (ESI, 70 eV): m/z [M + Na]+ Calcd for C19 H15 NNa: 280.1102; found: 280.1102. (4-Methyl-1-phenylnaphthalen-2-yl)acetic acid (13c). 200 mg (0.78 mmol) of nitrile derivative (12c) on hydrolysis with 5 mL 30% KOH in reuxing (15 h) aqueous methanol afforded 190 mg (95%) of the acid (13c) as a white solid, mp 8890 C after usual work up and purication. IR (KBr) max 1706 cm1; 1H NMR (200 MHz, CDCl3 ) 2.74 (s, 3 H), 3.57 (s, 2 H), 7.267.35 (m, 4 H), 7.387.40 (m, 2 H), 7.457.53 (m, 3 H), 7.99 (d, J = 8.4 Hz, 1 H) (carboxylic proton was not observed); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C19 H17 O2 : 277.1229; found: 277.1245. 8,8 -Dimethyl-6H -[5,6 ]bi[benzo[c]phenanthrenylidne]-5 -one (18c): Method A. Cyclization of (4-methyl-1-phenylnaphthalene-2-yl)acetic acid (13c) with PPA. A mixture of compound 13c (100 mg, 0.36 mmol) and 5.0 g PPA was stirred with heating at 100 C for 4 h and then cooled to r.t. After usual work up and purication by column chromatography [silica gel: 100200 mesh/pet. ether (6080 C) & ethyl acetate mixture, 15:2] furnished 42 mg (42%) of 18c as a reddish solid, mp 118120 C. IR (KBr) max 1756 cm1; 1H NMR (200 MHz, CDCl3 ) 2.93 (s, 3 H), 2.96 (s, 3 H), 3.99 (s, 2 H), 7.097.27 (m, 2 H), 7.287.40 (m, 5 H), 7.417.54 (m, 5 H), 7.577.72 (m, 4 H), 8.86 (d, J = 8.8 Hz, 1 H), 8.92 (d, J = 8.2 Hz, 1 H); HRMS (ESI, 70 eV): m/z [M + H]+ Calcd for C38 H27 O: 499.2062; found: 259.1145(100%), 499.2097(10%).

1.20 3.10 n19

1.20 5.30 n20

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0.70 1.50 n21

Method B. Cyclization of (4-methyl-1-phenylnaphthalene-2yl)acetic acid with TFAA-TFA mixture. To a stirred suspension of 13c (30 mg, 0.11 mmol), in triuoroacetic anhydride (2 mL), 0.6 mL triuoroacetic acid was added and stirred at r.t. for overnight protecting from moisture. After usual work up and purication by column chromatography [silica gel; pet. ether (6080 C) & ethyl acetate mixture, 15:2] afforded 20 mg (68%) of 18c as a reddish solid, mp 118120 C.

RESULTS AND DISCUSSIONS

Recently, we have developed a method for the synthesis of tetracyclic furoquinone derivative (29) via furophenanthrenol intermediate. The latter was synthesized by acid catalyzed cyclization of 2-(2 -furyl-1-naphthyl)acetic acid. We now want to explore an acid catalyzed cyclization of the precursors (2phenyl-naphthalen-1-yl)-acetic acid derivatives (4) and (1-phenyl-naphthalen2-yl)-acetic acid derivatives (13) for the synthesis of chrysen-6-ol derivatives and benzo[c]phenanthren-5-ol derivatives, respectively. Intramolecular cyclization of (2-phenylnaphthalen-1-yl)-acetic acid derivatives (4), using polyphosphoric acid (PPA) at 100 C or triuoroacetic anhydride (TFAA) and triuoroacetic acid (TFA) mixture at room temperature, chrysen6-ol derivatives (5) were obtained in moderate to excellent yields in accordance with our expectation (what we call usual observation). Whereas under identical conditions, attempted cyclization of (1-phenylnaphthalen-2-yl)acetic acid derivatives (13) produced no benzo[c]phenanthrene-5-ol derivatives (17). Instead a dimeric intermolecular condensation product (18) was formed in 4287% yields (Scheme 1). We call it an unusual observation (although the results may be explained logically). Herein we report our results. The required arylacetic acid precursors (4), for the synthesis of chrysen6-ol, were efciently obtained in 4 steps starting from 2-bromo-3,4dihydronaphthalen-1-aldehyde (1) (Scheme 2) following an established method developed in our laboratory during the synthesis of tri and tetra cyclic furoquinones simulating BCD/ABCD rings of Tanshinone-I.(29). Suzuki coupling (30) of compound 2 with phenylboronic acid (R H) afforded 3a which on hydrolysis furnished the carboxylic acid (4a) in 93% yield. Following a similar protocol starting from 2 and 3-methylphenylboronic acid, 4b was prepared. The naphthylacetic acid derivative (4a) when treated with PPA at 100C, cyclized to give chrysen-6-ol (31) (5a) in 40% yield. Under identical conditions, cyclization of the naphthylacetic acid derivative (4b) produced 9-methylchrysen-6-ol (5b) (36%) as the only isolable product and formation of no isomeric 7-methyl derivative was noticed. Much better yields (82% for 5a and 67% for 5b) were obtained when the cyclization was carried out with a TFATFAA mixture at room temperature.

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Scheme 1: Synthesis of benzophenanthrenol derivatives.

The same sequence of reactions (as used for the synthesis of 4) were followed to synthesize the precursors (1-phenylnaphthalen-2-yl)acetic acid 13a from 1-bromo-3,4-dihydronaphthalen-2-aldehyde. However, our initial effort to achieve the synthesis of the required precursor (13a) went in vain as the Suzuki reaction of 11a with phenylboronic acid was unsuccessful (Scheme 3).

Scheme 2: Synthesis of chrysen-6-ol derivatives.

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Scheme 3: Synthetic approach for (1-Phenyl-naphthalen-2-yl)-acetic acid derivative.

Scheme 4: Synthesis of (1-Phenylnaphthalen-2-yl)-acetic acid derivatives.

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Scheme 5: Possible mechanistic pathway for formation of 18.

However, we were able to synthesize successfully a series of the required precursor (1-phenylnaphthalen-2-yl)acetic acid derivatives 13(ac) in an alternative route (Scheme 4). Suzuki reaction of compound 8 with phenylboronic acids were carried out to furnish 14 in good yields and then functional group manipulation of CHO to CH2 CN was carried out to synthesize 12. Here, we followed the same protocol as was used in the conversion of compound 1 to compound 2 (Scheme 2). Hydrolysis of compound 12 afforded the corresponding acid (13) in excellent yields. The compounds 15a and 15b were synthesized from 1-tetralone and 6-methoxy-1-tetralone respectively in 4 steps following the standard literature procedure (32). The cyclization of the carboxylic acid 13a with anhydrous HF to produce benzo[c]phenanthrene-5-ol (17) was reported earlier by Newman and Blum (33). Whereas the attempted cyclization of 13(ac) with PPA or by a mixture of TFAA-TFA produced no benzo[c]phnanthrene-5-ol derivatives but the dimeric compounds 18(ac) were isolated in good yields (Scheme 1). This observation was conrmed from the 1 H-NMR, 13C-NMR, IR, and HRMS data. Formation of compound 18 during the cyclization of the compound 13 may be rationalized via in situ aldol condensation of the keto tautomer (17A or 17B) with the enol intermediate (17). The later is in keto-enol tautomeric equilibrium (33) with benzo[c]phenanthrene-5-ol derivative under this reaction condition (Scheme 5). (Due to steric interaction between the two Hs at position 1
Table 1: Comparative yields of cyclization with PPA or TFAA-TFA mixture Yield (%) (with PPA) 40 36 52 48 42 Yield (%) (TFAA-TFA) 82 67 76 87 68

Entry no. 1 2 3 4 5

Arylacetic acid (4 or 13) 4a: R = H 4b: R = CH3 13a: R1 = R2 = H 13b: R1 = OMe, R2 = H, 13c: R1 = H, R2 = Me

Product 5a 5b 18a 18b 18c

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and 12, in the Fjord region, benzo[c]phenanthrene-5-ol possibly isomerizes to the ketonic state under the reaction condition and the strain is relieved partly. In the case of chrysene-6-ol, as there is no Fjord region within the molecule, thus no such dimerization was observed). An improved yield of compound 18 was obtained with TFAA-TFA mixture instead of PPA. The comparative yields are summarized in Table 1.

REFERENCES
1. Grainger, J., W. Huang, Z. Li, S. Edwards, C. Walcott, C. Smith, W. Turner, R. Wang, and D. G. Patterson Jr. Polycyclic Aromatic Hydrocarbon Reference Range Levels in the U.S. Population by Measurement of Urinary Mono-Hydroxy Metabolites. Polycycl. Arom. Comp. 25 (2005): 4765. 2. Jacob, J. The Signicance of Polycyclic Aromatic Hydrocarbons as Environmental Carcinogens: 35 Years Research on PAHA Retrospective. Polycycl. Arom. Comp. 28 (2008): 24272. 3. Watson, M. D., A. Fechtenk otter, and K. Mullen. Big Is BeautifulAromaticity Revised From the Viewpoint of Macromolecular and Supramolecular Benzene Chemistry. Chem. Rev. 101 (2001): 12671300. 4. Harvey, R. G. Advances in the Synthesis of Polycyclic Aromatic Compounds. Curr. Org. Chem. 8 (2004): 30323. 5. Balani, S. K., P. J. van Bladeren, N. Shirai, and D. M. Jerina. Resolution and Absolute Conguration of K-Region Trans Dihydrodiols from Polycyclic Aromatic Hydrocarbons. J. Org. Chem. 51 (1986): 17738. 6. Harvey, R. G. 1991. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogenicity, Cambridge University Press, UK. 7. Harvey, R. G. Polycyclic Aromatic Hydrocarbons (New York: Wiley-VCH, 1997). 8. Murray, R. W., M. Sing, and N. Rath. The Reaction of Dimethyldioxirane with Chrysene: Formation of a Trioxide. Tetrahedron Lett. 37 (1996): 867174. 9. de Visser, S. P. and S. Shaik. A Proton-Shuttle Mechanism Mediated by the Porphyrin in Benzene Hydroxylation by Cytochrome P450 Enzymes. J. Amer. Chem. Soc. 125 (2003): 741324. 10. Rebelo, S. L. H., M. M. Q. Sim oes, M. G. P. M. S. Neves, A. M. S. Silva, and J. A. S. Cavaleiro. An Efcient Approach for Aromatic Epoxidation Using Hydrogen Peroxide and Mn(III) Porphyrins. Chem. Commun. (2004): 6089. 11. Noyori, R. Asymmetric Catalysis in Organic Synthesis (New York: John Wiley & Sons, 1994). 12. Shibasaki, M. and N. Yoshikawa. Lanthanide Complexes in Multifunctional Asymmetric Catalysis. Chem. Rev. 103 (2002): 21872210. 13. Yin, J., M. P. Rainka, X. X. Zhang, and S. L. Buchwald. A Highly Active Suzuki Catalyst for the Synthesis of Sterically Hindered Biaryls: Novel Ligand Coordination. J. Amer. Chem. Soc. 124 (2002): 11623. 14. Terfort, A., H. Gorls, and H. Brunner. The First Helical-Chiral Phosphane Ligands: rac-[5]- and rac-[6]-Heliphos. Synthesis (1997): 7986. 15. Mallory, F. B. and C. W. Mallory. Photocyclization of Stilbenes and Related Molecules. Org. Reac. 30 (1984): 1456.

530

K. Samanta et al.
16. Liu, L., B. Yang, T. J. Katz, and M. K. Poindexter. Improved Methodology for Photocyclization Reactions.J. Org. Chem. 56 (1991): 376975. 17. Hamza, K., R. Abu-Reziq, D. Avnir, and J. Blum. Heck Vinylation of Aryl Iodides by a Silica Sol-Gel Entrapped Pd(II) Catalyst and Its Combination with a Photocyclization Process. Org. Lett. 6 (2004): 9257. 18. Jorgensen, K. and M. Joensen. Photochemical Synthesis of Chrysenols. Polycycl. Arom. Comp. 28 (2008): 36272. 19. Levy, L. A. and V. P. Sashikumar. Synthesis of Chrysene, 5-Substituted Chrysenes, and Chrysene Derivatives via Intramolecular Cycloaddition Reactions. J. Org. Chem. 50 (1985): 17603. 20. Scott, L. T., M. M. Hashemi, D. T. Meyer, and H. B. Warren. Corannulene. A Convenient New Synthesis. J. Amer. Chem. Soc. 113 (1991): 70824. 21. Plater, M. J. Cyclisation of Stilbenes to Phenanthrenes by Flash Vacuum Pyrolysis. Tetrahedron Lett. 35 (1994): 8012. 22. Mehta, G. and H. S. P. Rao. Synthetic Studies Directed Towards Bucky-Balls and Bucky-Bowls. Tetrahedron 54 (1998): 1332570. 23. Sonoda, M., K. Itahashi, and Y. Tobe. Flash Vacuum Pyrolysis of 1,6-Diphenyl1,5-Hexadien-3-Ynes: Tandem Diaryldienyne Cyclization to Form Chrysene. Tetrahedron Lett. 43 (2002): 526972. 24. Bonifacio, M. C., C. R. Robertson, J-Y. Jung, and B. T. King. Polycyclic Aromatic Hydrocarbons by Ring-Closing Metathesis. J. Org. Chem. 70 (2005): 85226. 25. Ichikawa, J., M. Yokota, T. Kudo, and S. Umezaki. Efcient Helicene Synthesis: Friedel-Crafts-Type Cyclization of 1,1-Diuoro-1-Alkenes. Angew. Chem. Int. Ed. 47 (2008): 48703. 26. Pena, D., D. Perez, E. Guitian, and L. Castedo. Synthesis of Hexabenzotriphenylene and Other Srained Polycyclic Aromatic Hydrocarbons by Palladium CatalyzedCatalyzed Cyclotrimerization of Arynes. Org. Lett. 1 (1999): 15557. 27. Furstner, A. and V. Mamane. Flexible Synthesis of Phenanthrenes by a PtCl2Catalyzed Cycloisomerization Reaction. J. Org. Chem. 67 (2002): 62647. 28. Storch, J., J. Cermak, and J. Karban. Synthesis of 1-(2-ethynyl-6-methylphenyl)and 1-(2-ethynyl-6-methoxylphenyl)-Naphthalene and Their Cyclization. Tetrahedron Lett. 48 (2007): 68146. 29. Shaik, F. H. and G. K. Kar. Studies on Polynuclear Furoquinones. Part 1: Synthesis of Tri- and Tetra-Cyclic Furoquinones Simulating BCD/ABCD Ring System of Furoquinone Diterpenoids. Beilstein J. Org. Chem. 5, no. 47 (2009). 30. Samanta, K. G. K. Kar, and A. K. Sarkar. A Generalized Route for the Synthesis of -Furyl-,-Unsaturated Aldehydes Through Suzuki Reactions. Tetrahedron Lett. 49 (2008): 14614. 31. Newman, M. S. A New Synthesis of Chrysene Derivatives. J. Amer. Chem. Soc. 60 (1938): 294751. 32. Moleele, S. S., J. P. Michael, and C. B. de Koning. Methodology for the Synthesis of 1,2- Disubstituted Arylnaphthalenes from -Tetralones. Tetrahedron 62 (2006): 283144. 33. Newman, M. S. and J. Blum. The Synthesis and Ionisation Constants of the Six Hydroxybenzo [c] phenanthrenes. J. Amer. Chem. Soc. 86 (1964): 5037.