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Synlett 2010(17): 2565-2570  
DOI: 10.1055/s-0030-1258579
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

New Synthesis of 2,3-Diarylacridin-9(10H)-ones and (E)-2-Phenyl-4-styrylfuro[3,2-c]quinolines

Vera L. M. Silva, Artur M. S. Silva*, José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: artur.silva@ua.pt;
Further Information

Publication History

Received 2 August 2010
Publication Date:
23 September 2010 (online)

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Abstract

A new synthesis of 2,3-diarylacridin-9(10H)-ones and (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines is described. This was accomplished by the Heck reaction of (E)-3-iodo-2-styrylquinolin-4(1H)-ones with styrene, leading to (E,E)-2,3-distyrylquinolin-4(1H)-ones, which when heated at high temperatures, cyclise in two different ways. Electrocyclisation and further in situ oxidation leads to 2,3-diarylacridin-9(10H)-ones and tautomerisation, cyclisation by nucleophilic addition and further in situ oxidation produces (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines.

Key words

(E)-2-styrylquinolin-4(1H)-ones - (E)-3-iodo-2-styryl­quinolin-4(1H)-ones - (E,E)-2,3-distyrylquinolin-4(1H)-ones - 2,3-diaryl­­acridin-9(10H)-ones - (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines - Heck reaction - electrocyclisation

    References

  • 1a Tarus PK. Coombes PH. Crouch NR. Mulholland DA. Moodley B. Phytochemistry  2005,  66:  703 
    Google Scholar
  • 1b Al-Rehaily AJ. Ahmad MS. Muhammad I. Al-Thukair AA. Perzanowski HP. Phytochemistry  2003,  64:  1405 
    Google Scholar
  • 1c Naidoo D. Coombes PH. Mulholland DA. Crouch NR. Van den Bergh AJJ. Phytochemistry  2005,  66:  1724 
    Google Scholar
  • 1d Wansi JD. Wandi J. Meva’a LM. Waffo AFK. Ranjit R. Khan SN. Asma A. Iqbal CM. Lallemand M.-C. Tillequin F. Fomum Tanee Z. Chem. Pharm. Bull.  2006,  54:  292 
    Google Scholar
  • 1e Waffo AFK. Coombes PH. Crouch NR. Mulholland DA. El Amin SMM. Smith PJ. Phytochemistry  2007,  68:  663 
    Google Scholar
  • 1f Kumar S. Raj K. Khare P. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2009,  48:  291 
    Google Scholar
  • 2 Tabarrini O. Cecchetti V. Fravolini A. Nocentini G. Barzi A. Sabatini S. Miao H. Sissi C. J. Med. Chem.  1999,  42:  2136 
    CrossrefGoogle Scholar
  • 3a Basco KL. Mitaku S. Skaltsounis A.-L. Ravelomanantsoa N. Tillequin F. Koch M. Le Bras J. Antimicrob. Agents Chemother.  1994,  38:  1169 
    Google Scholar
  • 3b Winter RW. Kelly JX. Smilkstein MJ. Dodean R. Bagby GC. Rathbun RK. Levin JI. Hinrichs D. Riscoe MK. Exp. Parasitol.  2006,  114:  47 
    Google Scholar
  • 3c Kelly JX. Smilkstein MJ. Cooper RA. Lane KD. Johnson RA. Janowsky A. Dodean RA. Hinrichs DJ. Winter R. Riscoe M. Antimicrob. Agents Chemother.  2007,  51:  4133 
    Google Scholar
  • 4 Demeunynck M. Charmantray F. Martelli A. Curr. Pharm. Design  2001,  7:  1703 
    CrossrefGoogle Scholar
  • 5a Boumendjel A. Macalou S. Ahmed-Belkacem A. Blanc M. Di Pietro A. Bioorg. Med. Chem.  2007,  15:  2892 
    Google Scholar
  • 5b Gopinath VS. Thimmaiah P. Thimmaiah KN. Bioorg. Med. Chem.  2008,  16:  474 
    Google Scholar
  • 5c Bhonde M. Padgaonkar A. Deore V. Yewalkar N. Bhatia D. Rathos M. Joshi K. Vishwakarma RA. Kumar S. Bioorg. Med. Chem. Lett.  2008,  18:  3603 
    Google Scholar
  • 6a Kawaii S. Tomono Y. Katase E. Ogawa K. Yano M. Takemura Y. Ju-ichi M. Ito C. Furukawa H. J. Nat. Prod.  1999,  62:  587 
    Google Scholar
  • 6b Belmont P. Bosson J. Godet T. Tiano M. Anti-Cancer Agents Med. Chem.  2007,  7:  139 
    Google Scholar
  • 7 Zarubaev VV. Slita AV. Krivitskaya VZ. Sirotkin AK. Kovalenko AL. Chatterjee NK. Antiviral Res.  2003,  58:  131 
    CrossrefGoogle Scholar
  • 8 Fujiwara M. Okamoto M. Watanabe M. Machida H. Shigeta S. Konno K. Yokota T. Baba M. Antiviral Res.  1999,  43:  179 
    CrossrefGoogle Scholar
  • 9 Goodell JR. Puig-Basagoiti F. Forshey BM. Shi PY. Ferguson DM. J. Med. Chem.  2006,  49:  2127 
    CrossrefGoogle Scholar
  • 10 Goodell JR. Madhok AA. Hiasa H. Ferguson DM. Bioorg. Med. Chem.  2006,  14:  5467 
    CrossrefGoogle Scholar
  • 11 Tabarrini O. Manfroni G. Fravolini A. Cecchetti V. Sabatini S. De Clercq E. Rozensky J. Canard B. Dutartre H. Paeshuyse J. Neyts J. J. Med. Chem.  2006,  49:  2621 
    CrossrefGoogle Scholar
  • 12a Akanitapichat P. Lowden CT. Bastow KF. Antiviral Res.  2000,  45:  123 
    Google Scholar
  • 12b Akanitapichat P. Bastow KF. Antiviral Res.  2002,  53:  113 
    Google Scholar
  • 13 Bastow KF. Curr. Drug Targets: Infect. Disord.  2004,  4:  323 
    CrossrefGoogle Scholar
  • 14 Bernardino AMR. Castro HC. Frugulhetti ICPP. Loureiro NIV. Azevedo AR. Pinheiro LCS. Souza TML. Giongo V. Passamani F. Magalhães UO. Albuquerque MG. Cabral LM. Rodrigues CR. Bioorg. Med. Chem.  2008,  16:  313 
    CrossrefGoogle Scholar
  • 15a Lowden CT. Bastow KF. Antiviral Res.  2003,  59:  143 
    Google Scholar
  • 15b Lowden CT. Bastow KF. J. Med. Chem.  2003,  46:  5015 
    Google Scholar
  • 16 Stankiewicz-Drogon A. Palchykovska LG. Kostina VG. Alexeeva IV. Shved AD. Boguszewska-Chachulska AM. Bioorg. Med. Chem.  2008,  16:  8846 
    CrossrefGoogle Scholar
  • 17 Basco LK. Mitaku S. Skaltsounis A.-L. Ravelomanantsoa N. Tillequin F. Koch M. Les Bras J. Antimicrob. Agents Chemother.  1994,  38:  1169 
    CrossrefGoogle Scholar
  • 18 Smith JA. West RW. Allen M. J. Fluoresc.  2004,  14:  151 
    CrossrefGoogle Scholar
  • 19 Saito Y. Hanawa K. Bag SS. Motegi K. Saito I. Nucleic Acids Symp. Ser.  2006,  50:  181 
    CrossrefGoogle Scholar
  • 20 Smilkstein M. Sriwilaijaroen N. Kelly JX. Wilairat P. Riscoe M. Antimicrob. Agents Chemother.  2004,  48:  1803 
    CrossrefGoogle Scholar
  • 21 Dadabhoy A. Faulkner S. Sammes PG. J. Chem. Soc., Perkin Trans. 2  2002,  2:  348 
    Google Scholar
  • 22 Nikolov P. Petkova I. Köhler G. Stojanov S. J. Mol. Struct.  1998,  448:  247 
    CrossrefGoogle Scholar
  • 23 Lunardi CN. Tedesco AC. Kurth TL. Brinn IM. Photochem. Photobiol. Sci.  2003,  2:  954 
    CrossrefGoogle Scholar
  • 24 González-Blanco C. Velázquez MM. Costa AMB. Barreleiro P. J. Colloid Interface Sci.  1997,  189:  43 
    CrossrefGoogle Scholar
  • 25 Bretonniere Y. Cann MJ. Parker D. Slater R. Org. Biomol. Chem.  2004,  2:  1624 
    CrossrefGoogle Scholar
  • 26 Wang B. Bouffier L. Demeunynck M. Mailley P. Roget A. Livache T. Dumy P. Bioelectrochemistry  2004,  63:  233 
    CrossrefGoogle Scholar
  • 27 Ferreira ME. de Arias AR. Yaluff G. Bilbao NV. Nakayama H. Torres S. Schinini A. Guy I. Heinzen H. Fournet A. Phytomedicine  2010,  17:  375 
    CrossrefGoogle Scholar
  • 28 Mekouar K. Mouscadet J.-F. Desmaele D. Subra F. Leh H. Savouré D. Auclair C. d’Angelo J. J. Med. Chem.  1998,  41:  2846 
    CrossrefPubMedGoogle Scholar
  • 29 Franck X. Fournet A. Prina E. Mahieux R. Hocquemiller R. Figadere B. Bioorg. Med. Chem.  2004,  14:  3635 
    CrossrefGoogle Scholar
  • 30 Mesa VAM. Molano MPA. Seon B. Figadere B. Robledo SM. Muñoz DL. Sáez VJA. Vitae  2008,  15:  259 ; and references cited therein
    Google Scholar
  • 31 Delmas F. Avellaneda A. Di Giogio C. Robin M. De Clercq E. Timon-David P. Galy JJ. Eur. J. Med. Chem.  2004,  685 
    CrossrefGoogle Scholar
  • 32 Nakamura S. Kozuka M. Bastow KF. Tokuda H. Nishino H. Suzuki M. Tatsuzaki J. Natschke SLM. Kuo S.-C. Lee K.-H. Bioorg. Med. Chem.  2005,  13:  4396 
    CrossrefGoogle Scholar
  • 33 Nishio R. Wessely S. Sugiura M. Kobayashi S. J. Comb. Chem.  2006,  8:  459 
    CrossrefGoogle Scholar
  • 34 Mai HDT. Gaslonde T. Michael S. Tillequin F. Koch M. Bongui J.-B. Elomri A. Seguin E. Pfeiffer B. Renard P. David-Cordonnier M.-H. Laine W. Bailly C. Kraus-Berthier L. Léonce S. Hickman JA. Pierré A. J. Med. Chem.  2003,  46:  3072 
    CrossrefGoogle Scholar
  • 35a Costes N. Le Deit H. Michael S. Tillequim F. Koch M. Pfeiffer B. Renard P. Léonce S. Guilbaud N. Kraus-Berthier L. Pierré A. Atassi G. J. Med. Chem.  2000,  43:  2395 
    Google Scholar
  • 35b Michael S. Gaslonde T. Tillequin F. Eur. J. Med. Chem.  2004,  39:  649 
    Google Scholar
  • 36a Rudas M. Nyerges M. Toke L. Pete B. Groundwater PW. Tetrahedron Lett.  1999,  40:  7003 
    Google Scholar
  • 36b Zhao J. Larock RC. J. Org. Chem.  2007,  72:  583 
    Google Scholar
  • 37 MacNeil SL. Wilson BJ. Snieckus V. Org. Lett.  2006,  8:  1133 
    CrossrefPubMedGoogle Scholar
  • 38a Bhoga U. Mali RS. Adapa SR. Tetrahedron Lett.  2004,  45:  9483 
    Google Scholar
  • 38b Venkataraman S. Barange DK. Pal M. Tetrahedron Lett.  2006,  47:  7317 ; and references cited therein
    Google Scholar
  • 39 Barluenga J. Mendoza A. Rodríguez F. Fañanás FJ. Chem. Eur. J.  2008,  14:  10892 
    CrossrefGoogle Scholar
  • 40 Wall VM. Eisenstadt A. Ager DJ. Laneman SA. Platinum Metals Rev.  1999,  43:  138 
    Google Scholar
  • 43a Plisson C. Chenault J. Heterocycles  1999,  51:  2627 
    Google Scholar
  • 43b Mphalele MJ. Nwamadi MS. Mabeta P. J. Heterocycl. Chem.  2006,  43:  255 
    Google Scholar
  • 43c Almeida AIS. Silva AMS. Cavaleiro JAS. Synlett  2010,  462 
    Google Scholar
  • 49a Wyman GM. Chem. Rev.  1955,  55:  625 
    Google Scholar
  • 49b Yamashita S. Bull. Chem. Soc. Jpn.  1961,  34:  487 
    Google Scholar
41

Optimized Experimental Procedure for the Synthesis of ( E )-3-Iodo-2-styrylquinolin-4(1 H )-ones 2a-c
Na2CO3 (0.064 g, 0.61 mmol) and I2 (0.15 g, 0.61 mmol) were added to a solution of the appropriate (E)-2-styryl-quinolin-4(1H)-one 1a-c (0.40 mmol) in anhyd THF (25 mL). The mixture was stirred, protected from the daylight (to avoid the E/Z isomerisation), at r.t. until complete consumption of the starting material (4-5 h) and then poured into an aq sat. solution of Na2S2O3. The solid obtained was filtered, washed with H2O and crystallised from EtOH. (E)-3-Iodo-2-styrylquinolin-4(1H)-ones 2a-c were obtained as yellow solids (2a, 211.7 mg, 93%; 2b, 201.7 mg, 82%; 2c, 236.2 mg, 95%).

42

Analytical Data for ( E )-3-Iodo-2-styrylquinolin-4(1 H )-one (2a) Mp 194-197 ˚C. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 7.39 (ddd, 1 H, J = 8.0, 6.8, 1.2 Hz, H-6), 7.43 (d, 1 H, J = 16.4 Hz, H-α), 7.45-7.57 (m, 3 H, H-3′,4′,5′), 7.55 (d, 1 H, J = 16.4 Hz, H-β), 7.70-7.76 (m, 3 H, H-7, H-2′,6′), 7.80 (d, 1 H, J = 8.4 Hz, H-8), 8.11 (dd, 1 H, J = 8.0, 1.2 Hz, H-5), 11.97 (s, 1 H, NH) ppm. ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 87.5 (C-3), 118.3 (C-8), 120.8 (C-10), 124.0 (C-6), 125.5 (C-5), 126.4 (C-α), 127.4 (C-2′,6′), 129.2 (C-3′,5′), 129.7 (C-4′), 132.3 (C-7), 135.0 (C-1′), 137.1 (C-β), 139.4 (C-9), 147.6 (C-2), 173.4 (C-4) ppm. MS (ESI+): m/z (%) = 374 (100) [M + H]+, 396 (12) [M + Na]+, 769 (3) [2 M + Na]+. Anal. Calcd (%) for C17H12INO (373.19): C, 54.71; H, 3.24; N, 3.75. Found: C, 55.10; H, 3.17; N, 3.77.

44

Optimized Experimental Procedure for the Heck Reaction of ( E )-3-Iodo-2-styrylquinolin-4(1 H )-one 2a-c with Styrene: Synthesis of ( E , E )-2,3-distyrylquinolin-4(1 H )-ones 4a-c Styrene (138.8 µL, 1.6 mmol) was added to a mixture of the appropriate (E)-3-iodo-2-styrylquinolin-4(1H)-one 2a-c (0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (13.94 mg, 1.2 ¥ 10-² mmol), and Et3N (33.4 µl, 0.24 mmol) in MeCN (6 mL). The mixture was heated at reflux until consumption of the starting material, which was confirmed by TLC (Table  [¹] ). The mixture was then poured into H2O, extracted with CHCl3, and dried over anhyd Na2SO4. The solvent was evaporated and the residue dissolved in CH2Cl2 and purified by TLC using a mixture of EtOAc-light PE (3:2) as eluent. The (E,E)-2,3-distyrylquinolin-4(1H)-ones 4a-c were obtained as yellow solids in good yields (4a, 52.2 mg, 62%; 4b, 55.0 mg, 65%; 4c, 49.3 mg, 58%).

45

Analytical Data of ( E,E )-2,3-Distyrylquinolin-4(1 H )-one (4a) Mp 207-208 ˚C. ¹H NMR (500.13 MHz, DMSO-d 6): δ = 7.24 (t, 1 H, J = 7.6 Hz, H-4′′), 7.32-7.39 (m, 5 H, H-6, H-8, H-2′,6′, H-α′), 7.41 (t, 1 H, J = 7.5 Hz, H-4′), 7.48 (t, 2 H, J = 7.5 Hz, H-3′,5′), 7.52 (d, 1 H, J = 16.4 Hz, H-β), 7.56 (d, 2 H, J = 7.6 Hz, H-2′′,6′′), 7.67 (dt, 1 H, J = 8.0, 1.2 Hz, H-7), 7.70 (d, 1 H, J = 16.4 Hz, H-α), 7.78 (t, 2 H, J = 7.6 Hz, H-3′′,5′′), 7.85 (d, 1 H, J = 16.0 Hz, H-β′), 8.17 (dd, 1 H, J = 8.1, 1.2 Hz, H-5), 11.69 (br s, NH) ppm. ¹³C NMR (125.77 MHz, DMSO-d 6): δ = 115.4 (C-3), 118.6 (C-8), 121.3 (C-α), 122.4 (C-10), 123.1 (C-α′), 124.4 (C-6), 125.2 (C-5), 126.1 (C-2′′,6′′), 127.0 (C-4′′), 127.5 (C-3′′,5′′), 128.7 (C-3′,5′), 129.0 (C-2′,6′), 129.2 (C-4′), 131.0 (C-β′), 131.6 (C-7), 135.7 (C-β,1′), 136.4 (C-1′′), 138.6 (C-9), 145.5 (C-2), 175.9 (C-4). MS (ESI+): m/z (%) = 350 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C25H20NO + H]+: 350.15394; found: 350.15345.

46

Optimized Experimental Procedure for the Synthesis of 2,3-Diarylacridin-9(10 H )-ones 5a-c and ( E )-2-phenyl-4-styrylfuro[3,2- c ]quinolines 7a-c
Iodine (1.82 mg, 7.15 ¥ 10-³ mmol) and PTSA (1.36 mg, 7.15 ¥ 10-² mmol) were added to a solution of the appropriate (E,E)-2,3-distyrylquinolin-4(1H)-one 4a-c (7.15 ¥ 10-² mmol) in 1,2,4-trichlorobenzene (3 mL), and the mixture was refluxed (see Table  [²] for reaction time). After cooling the reaction mixture was purified by column chromatography using light PE as eluent to remove the 1,2,4-trichlorobenzene. Then, the mixture was removed from the column using CH2Cl2 as eluent and was purified by TLC using a mixture of EtOAc-light PE (3:2) as eluent. Two main compounds were isolated in each case: That with the lower R f value corresponded to the 2,3-diarylacridin-9(10H)-ones 5a-c which were isolated as yellow compounds in moderate yields (5a, 9.4 mg, 38%; 5b, 8.7 mg, 35%; 5c, 9.9 mg, 40%); and that with higher R f value corresponded to (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines 7a-c obtained as yellow compounds also in moderate yields (7a, 10.2 mg, 41%; 7b, 10.9 mg, 44%; 7c, 13.9 mg, 56%).

47

Analytical Data of 2,3-Diphenylacridin-9(10 H )-one (5a)
Mp 283-284 ˚C. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 7.15-7.17 (m, 2 H, H-2′,6′), 7.21-7.32 (m, 9 H, H-3′,4′,5′, H-2′′,3′′,4′′,5′′,6′′, H-7), 7.55 (s, 1 H, H-4), 7.58 (d, 1 H, J = 8.0 Hz, H-5), 7.77 (ddd, 1 H, J = 8.0, 7.0, 1.1 Hz, H-6), 8.20 (s, 1 H, H-1), 8.26 (dd, 1 H, J = 8.0, 1.1 Hz, H-8), 11.92 (s, 1 H, NH) ppm. ¹³C NMR (125.77 MHz, DMSO-d 6): δ = 117.5 (C-5), 118.9 (C-4), 119.6 (C-9a), 120.7 (C-7), 121.3 (C-8a), 126.1 (C-4′), 126.6 (C-8), 127.5 (C-4′′), 127.6 (C-1), 128.1 (C-3′′,5′′), 128.2 (C-3′,5′), 129.3 (C-2′,6′), 129.6 (C-2′′,6′′), 133.5 (C-2), 133.6 (C-6), 140.1 and 140.2 (C-1′ and C-1′′), 140.4 (C-4a), 141.0 (C-4b), 145.4 (C-3), 176.5 (C-9). HRMS (ESI+): m/z calcd for [C25H18NO + H]+: 348.1383; found: 348.1384.

48

Analytical Data of ( E )-2-Phenyl-4-styrylfuro[3,2- c ]quinoline (7a) Mp 154-156 ˚C. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 7.41 (t, 1 H, J = 7.0 Hz, H-4′′), 7.48-7.55 (m, 1 H, H-4′), 7.53 (t, 1 H, J = 7.0 Hz, H-3′′,5′′), 7.61 (t, 2 H, J = 7.6 Hz, H-3′,5′), 7.70 (dd, 1 H, J = 7.7, 7.4 Hz, H-8), 7.78 (ddd, 1 H, J = 8.0, 7.7, 1.3 Hz, H-7), 7.89 (d, 1 H, J = 17.4 Hz, H-α), 7.91 (d, 2 H, J = 7.0 Hz, H-2′′,6′′), 8.08 (d, 1 H, J = 17.4 Hz, H-β), 8.11 (d, 2 H, J = 7.6 Hz, H-2′,6′), 8.15 (d, 1 H, J = 8.0 Hz, H-6), 8.25 (s, 1 H, H-3), 8.39 (dd, 1 H, J = 7.4, 1.3 Hz, H-9) ppm. ¹³C NMR (125.77 MHz, DMSO-d 6): δ = 101.6 (C-3), 115.7 (C-9a), 119.8 (C-9), 120.9 (C-3a), 124.7 (C-2′,6′), 125.4 (C-α), 126.8 (C-8), 127.6 (C-2′′,6′′), 128.9, 129.06 and 129.12 (C-3′′,4′′,5′′, C-1′, C-4′, C-7), 129.26 (C-3′,5′), 129.32 (C-6), 135.2 (C-β), 136.2 (C-1′′), 145.0 (C-5a), 150.0 (C-4), 154.9 (C-2), 155.7 (C-9b) ppm. HRMS (ESI+): m/z calcd for [C25H18NO + H]+: 348.1383; found: 348.1378.