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Synlett 2008(20): 3193-3197  
DOI: 10.1055/s-0028-1087372
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A New Synthesis of Benzo[b]acridones

Raquel S. G. R. Seixas, Artur M. S. Silva*, Diana C. G. A. Pinto, 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 4 September 2008
Publication Date:
26 November 2008 (online)

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Abstract

A novel and efficient route for the synthesis of new benzo[b]acridones has been described. It involves the Diels-Alder reaction of N-substituted-4-quinolone-3-carbaldehyde with ortho-benzoquinodimethanes giving benzo[b]-1,6,6a,12a-tetrahydroacridones, which are the result of a cycloaddition reaction followed by an in situ deformylation. The oxidation of these tetrahydroacridones in dimethyl sulfoxide using a catalytic amount of iodine gives the new benzo[b]acridone derivatives. It was demonstrated that the ­cycloaddition reaction is only efficient if an electron-withdrawing N-protecting group is present.

Key words

4-quinolone-3-carbaldehydes - benzo[b]acridones - Diels-Alder reactions - oxidation - N-protecting groups.

    References and Notes

  • 1 Michael JP. Nat. Prod. Rep.  2008,  25:  166 
    CrossrefPubMedGoogle Scholar
  • 2a Ahua KM. Ioset J.-R. Ransijn A. Mauël J. Mavi S. Hostettmann K. Phytochemistry  2004,  65:  963 
    Google Scholar
  • 2b Meepagala KA. Schrader KK. Wedge DE. Duke SO. Phytochemistry  2005,  66:  2689 
    Google Scholar
  • 3a Delmas F. Avellaneda A. Di Giogio C. Robin M.
    De Clercq     E. Timon-David P. Galy JJ. Eur. J. Med. Chem.  2004,  685 
    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
  • 4a Kawaii S. Tomono Y. Katase E. Ogawa K. Yano M. Takemura Y. Juichi M. Ito C. Furukawa H. Leukemia Res.  1999,  23:  263 
    Google Scholar
  • 4b Itoigawa M. Ito C. Wu T.-S. Enjo F. Tokuda H. Nishino H. Furukawa H. Cancer Lett.  2003,  193:  133 
    Google Scholar
  • 4c Harrison RJ. Reszka AP. Haider SM. Romagnoli B. Morrell J. Read MA. Gowan SM. Incles CM. Kelland LR. Neidle S. Bioorg. Med. Chem. Lett.  2004,  14:  5845 
    Google Scholar
  • 5a Tabarrini O. Cecchetti V. Fravolini A. Nocentini G. Barzi A. Sabatini S. Miao H. Sissi C. J. Med. Chem.  1999,  42:  2136 
    Google Scholar
  • 5b 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 
    Google Scholar
  • 5c Boumendjel A. Macalou S. Ahmed-Belkacem A. Blanc M. Di Pietro A. Bioorg. Med. Chem.  2007,  15:  2892 
    Google Scholar
  • 5d Gopinath VS. Thimmaiah P. Thimmaiah KN. Bioorg. Med. Chem.  2008,  16:  474 
    Google Scholar
  • 6a Yamamoto N. Furukawa H. Ito Y. Yoshida S. Maeno K. Nishiyama Y. Antiviral Res.  1989,  12:  21 
    Google Scholar
  • 6b Fujiwara M. Okamoto M. Okamoto M. Watanabe M. Machida H. Shigeta S. Konno K. Yokota T. Baba M. Antiviral Res.  1999,  43:  189 
    Google Scholar
  • 6c Tabarrini O. Manfroni G. Fravolini A. Cecchetti V. Sabatini S.
    De Clercq     E. Rozenski J. Canard B. Dutartre H. Paeshuyse J. Neyts J. J. Med. Chem.  2006,  49:  2621 
    Google Scholar
  • 7a Goodell JR. Madhok AA. Hiasa H. Ferguson DM. Bioorg. Med. Chem.  2006,  14:  5467 
    Google Scholar
  • 7b Bernardino AMR. Castro HC. Frugulhetti ICPP. Loureiro NIV. Azevedo AR. Pinheiro LCS. Souza PML. Giongo V. Passamani F. Magalhães UO. Alburquerque MG. Cabral LM. Rodrigues CR. Bioorg. Med. Chem.  2008,  16:  313 
    Google Scholar
  • 8 Lowden CT. Bastow KF. Antiviral Res.  2003,  59:  143 
    CrossrefGoogle Scholar
  • 9a Smith JA, and West RM. inventors; WO  099424.  ; PCT/GB2002/002509
  • 9b Taki M, and Masahiko S. inventors; WO  132335.  ; PCT/JP2006/311561
  • 9c Blázquez MT. Muñiz FM. Sáez S. Simón LM. Alonso A. Raposo C. Lithgow A. Alcázar V. Morán JR. Heterocycles  2006,  69:  73 
    Google Scholar
  • 9d García-Garrido SE. Caltagirone C. Light ME. Gale PA. Chem. Commun.  2007,  1450 
    Google Scholar
  • 10a Costes N. Le Deit H. Michel S. Tillequin 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
  • 10b Tillequin F. In Natural Products in the New Millenium: Prospects and Industrial Applications   Rauter AP. Palma FB. Justino J. Araújo ME. Santos SP. Kluwer; Dordrecht: 2002.  p.311-328  
    Google Scholar
  • 10c Michel S. Gaslonde T. Tillequin F. Eur. J. Med. Chem.  2004,  649 
    Google Scholar
  • 11 Nguyen TM. Sittisombut C. Boutefnouchet S. Lallemand M.-C. Michel S. Koch M. Tillequin F. Mazinghien R. Lansiaux A. David-Cordonnier M.-H. Pfeiffer B. Kraus-Berthier L. Léonce S. Pierré A. J. Med. Chem.  2006,  49:  3383 
    CrossrefGoogle Scholar
  • 12 Koch M. Bull. Acad. Nat. Med.  2007,  191:  83 
    Google Scholar
  • 13 Mai HDT. Gaslonde T. Michel 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
  • 14a Hughes GK. Lahey FN. Price JR. Webb LJ. Nature (London)  1948,  162 
    Google Scholar
  • 14b Tillequin F. Michel S. Skaltsounis A.-L. In Alkaloids: Chemical and Biological Perspectives   Vol. 12:  Pelletier SW. Pergamon; Oxford: 1998.  p.1-102  
    Google Scholar
  • 15 Nishio R. Wessely S. Sugiura M. Kobayashi S. J. Comb. Chem.  2006,  8:  459 
    CrossrefGoogle Scholar
  • 16a Rudas M. Nyerges M. Toke L. Pete B. Groundwater PW. Tetrahedron Lett.  1999,  40:  7003 
    Google Scholar
  • 16b Zhao J. Larock RC. J. Org. Chem.  2007,  72:  583 
    Google Scholar
  • 17 MacNeil SL. Wilson BJ. Snieckus V. Org. Lett.  2006,  8:  1133 
    CrossrefPubMedGoogle Scholar
  • 18 1-Methyl-4-quinolone-3-carbaldehyde(1) was prepared by a Vilsmeier reaction of 2′-aminoacetophenone, followed by acidic hydrolysis of the resultant 4-chloroquinoline-3-carbaldehyde to form 4-quinolone-3-carbaldehyde (8), which was then N-methylated to avoid undesirable side reactions of the amino group. The following procedure was used: Coelho A. El-Maatougui A. Ravina E. Cavaleiro JAS. Silva AMS. Synlett  2006,  3324 
    Article in Thieme ConnectGoogle Scholar
  • 19 Cava MP. Deana AA. J. Am. Chem. Soc.  1959,  81:  4266 
    CrossrefGoogle Scholar
  • This type of deformylation reaction has been previously reported for similar compounds, see:
  • 23a Cremins PJ. Saengchantara ST. Wallace TW. Tetrahedron  1987,  43:  3075 
    Google Scholar
  • 23b Sandulache A. Silva AMS. Cavaleiro JAS. Tetrahedron  2002,  58:  105 
    Google Scholar
  • 26 4,7-Dimethoxy-1,3-dihydrobenzo[c]thiophene 2,2-dioxides 2b,c were prepared according to the following literature procedure: Sandulache A. Silva AMS. Cavaleiro JAS. Monatsh. Chem.  2003,  134:  551 
    CrossrefGoogle Scholar
  • A reagent system used by our group in the cyclodehydro-genation of 2′-hydroxychalcones and dehydrogenation of tetrahydroxanthones, see:
  • 27a Silva AMS. Pinto D. Tavares HR. Cavaleiro JAS. Jimeno ML. Elguero J. Eur. J. Org. Chem.  1998,  2031 
    Google Scholar
  • 27b Barros A. Silva AMS. Magn. Reson. Chem.  2006,  44:  1122 
    Google Scholar
  • 27c Barros A. Silva AMS. Monatsh. Chem.  2006,  137:  1505 
    Google Scholar
20

Optimized Experimental Procedure
A mixture of 1-methyl-4-quinolone-3-carbaldehyde (1, 121.7 mg, 0.65 mmol) and 1,3-dihydrobenzo[c]thiophene 2,2-dioxide (2a) in 1,2,4-trichlorobenzene (TCB, 6 mL) was refluxed under a variety of reaction conditions (see Table  [¹] ). After cooling to r.t., the reaction mixture was purified by silica gel column chromatography; the TCB solvent was removed using light PE as eluent, and then the cycloadducts were eluted with a mixture of light PE-EtOAc (4:1). The solvent was evaporated to dryness and the mixture of diastereomers was separated by preparative thin-layer chromatography using a mixture of light PE-EtOAc (9:1). The 7-methylbenzo[b]-1,6,6a,12a-tetrahydroacridones 4 and 5 and the benzo[b]acridone(6) were obtained as yellow compounds.

21

Physical Data for cis -7-Methylbenzo[ b ]-1,6,6a,12a-tetrahydroacridone (4) ¹H NMR (300.1 MHz, CDCl3): δ = 2.80-3.02 (m, 3 H, 1 × H-1, 2 × H-6), 3.11 (s, 3 H, NCH3), 3.31-3.36 (m, 1 H, H-12a), 3.81 (dd, 1 H, J = 1.6, 17.3 Hz, H-1), 3.95 (dt, 1 H, J = 5.5, 11.0 Hz, H-6a), 6.69 (d, 1 H, J = 8.6 Hz, H-8), 6.71 (ddd, 1 H, J = 0.9, 7.3, 7.6 Hz, H-10), 6.96 (d, 1 H, J = 7.4 Hz, H-5), 7.06 (dt, 1 H, J = 1.5, 7.4 Hz, H-4), 7.13 (dt, 1 H, J = 1.3, 7.4 Hz, H-3), 7.20 (d, 1 H, J = 7.4 Hz, H-2), 7.41 (ddd, 1 H, J = 1.7, 7.3, 8.6 Hz, H-9), 7.86 (dd, 1 H, J = 1.7, 7.6 Hz, H-11). ¹³C NMR (75.47 MHz, CDCl3): δ = 26.1 and 26.6 (C-1 and C-6), 37.6 (NCH3), 45.1 (C-12a), 60.4 (C-6a), 113.1 (C-8), 116.6 (C-10), 118.8 (C-11a), 125.8 (C-4), 126.4 (C-3), 127.9 (C-11), 129.1 and 129.2 (C-2 and C-5), 133.0 (C-5a), 133.8 (C-1a), 135.6 (C-9), 150.0 (C-7a), 194.1 (C-12). ESI+-MS: m/z (%) = 264 (100) [M + H]+, 286 (93) [M + Na]+, 302 (8) [M + K]+, 549 (47) [2 M + Na]+. HRMS (EI, 70 eV): m/z calcd for C18H17NO: 263.1310; found: 263.1309.

22

Physical Data for trans -7-Methylbenzo[ b ]-1,6,6a,12a-tetrahydroacridone (5) ¹H NMR (300.1 MHz, CDCl3): δ = 2.80-2.90 (m, 1 H,
H-12a), 2.91-3.01 (m, 1 H, H-1), 3.07 (s, 3 H, NCH3), 3.11-3.16 (m, 1 H, H-6), 3.49-3.56 (m, 2 H, H-1, H-6), 3.57-3.63 (m, 1 H, H-6a), 6.81 (ddd, 1 H, J = 0.9, 7.3, 7.6 Hz, H-10), 6.90 (d, 1 H, J = 8.7 Hz, H-8), 7.18-7.25 (m, 4 H, H-2 to
H-5), 7.46 (ddd, 1 H, J = 1.8, 7.3, 8.7 Hz, H-9), 7.96 (dd, 1 H, J = 1.8, 7.6 Hz, H-11). ¹³C NMR (75.47 MHz, CDCl3): δ = 29.1 (C-1), 34.1 (NCH3), 36.6 (C-6), 46.8 (C-12a), 59.0 (C-6a), 113.9 (C-8), 117.5 (C-10), 119.6 (C-11a), 126.2 and 126.6 (C-3 and C-4), 127.9 (C-1), 128.9 and 129.0 (C-2 and C-5), 132.9 (C-5a), 134.4 (C-1a), 135.7 (C-9), 152.7 (C-7a), 194.6 (C-12). ESI+-MS: m/z (%) = 264 (100) [M + H]+, 286 (25) [M + Na]+, 549 (19) [2 M + Na]+. HRMS (EI, 70 eV): m/z calcd for C18H17NO: 263.1310; found: 263.1312.

24

Physical Data for 7-Methylbenzo[ b ]acridone (6)
¹H NMR (300.1 MHz, CDCl3): δ = 3.95 (s, 1 H, NCH3), 7.26 (ddd, 1 H, J = 0.8, 6.8, 7.9 Hz, H-10), 7.43 (ddd, 1 H, J = 1.2, 6.7, 8.1 Hz, H-3), 7.50 (d, 1 H, J = 8.6 Hz, H-8), 7.57 (ddd, 1 H, J = 1.3, 6.7, 8.2 Hz, H-4), 7.74 (ddd, 1 H, J = 1.7, 6.8, 8.6 Hz, H-9), 7.81 (s, 1 H, H-6), 7.90 (d, 1 H, J = 8.2 Hz,
H-5), 8.05 (d, 1 H, J = 8.1 Hz, H-2), 8.57 (dd, 1 H, J = 1.7, 7.9 Hz, H-11), 9.13 (s, 1 H, H-1). ¹³C NMR (75.47 MHz, CDCl3): δ = 33.8 (NCH3), 110.5 (C-6), 114.4 (C-8), 120.5 (C-10), 121.3 (C11a), 122.6 (C-12a), 124.5 (C-3), 126.9
(C-5), 127.9 (C-1a), 128.0 (C-11), 128.7 (C-4), 129.0 (C-1), 129.5 (C-2), 134.4 (C-9), 136.4 (C-5a), 139.7 (C-6a), 143.6 (C-7a), 179.4 (C-12). ESI+-MS: m/z (%) = 260 (100) [M + H]+, 282 (33) [M + Na]+, 541 (54) [2 M + Na]+. HRMS (EI, 70 eV): m/z calcd for C18H13NO: 259.0997; found: 259.0999.

25

Although the cycloaddition reactions were carried out under nitrogen to avoid moisture, the reaction medium was not deoxygenated, the residual oxygen presumably being the oxidant.

28

Optimized Experimental Procedure Iodine (4%) was added to a solution of the appropriate
7-ethoxycarbonylbenzo[b]-1,6,6a,12a-tetrahydroacridones 10a-c (0.16 mmol) in DMSO (3 mL). The solution was heated at 170-180 ˚C or at reflux, for 50 min. After cooling to r.t., the reaction mixture was poured onto ice (10 g) and H2O (10 mL), a small amount of Na2S2O3 was added to eliminate the remaining traces of iodine, and the reaction mixture was stirred for some minutes. The yellow solid obtained was filtered off, washed with H2O (2 × 20 mL), dissolved in EtOAc (20 mL), and washed with H2O (2 × 20 mL). The solvent was evaporated to dryness and the residue was purified by silica gel column with a mixture of light PE-EtOAc (4:1 to 2:1). The 7-ethoxycarbonylbenzo[b]acridones 12a-c were obtained as yellow solids and the benzo[b]acridones 13a-c were obtained as orange solids. When the reactions were carried out 170-180 ˚C; the results were as follows: 12a, 37%; 13a, 49%; 12b, 25%; 13b, 37%; 12c, 25%; 13c, 45%. When the reactions were carried in refluxing DMSO, the yields were: 12a, 2%; 13a, 59%; 12b, 2%; 13b, 59%; 12c, 4%; 13c, 82%.

29

Physical Data for 7-Ethoxycarbonylbenzo[ b ]-acridone (12a) Mp 118-120 ˚C. ¹H NMR (300.1 MHz, CDCl3): δ = 1.42 (t, 3 H, J = 7.1 Hz, NCO2CH2CH 3), 4.47 (q, 2 H, J = 7.1 Hz, NCO2CH 2CH3), 7.39 (ddd, 1 H, J = 1.1, 7.4, 7.7 Hz, H-10), 7.52 (ddd, 1 H, J = 1.2, 6.8, 8.1 Hz, H-3), 7.62 (ddd, 1 H, J = 1.3, 6.8, 8.2 Hz, H-4), 7.66 (ddd, 1 H, J = 1.7, 7.4, 8.4 Hz, H-9), 7.86 (d, 1 H, J = 8.4 Hz, H-8), 7.92 (d, 1 H, J = 8.2 Hz, H-5), 8.04 (d, 1 H, J = 8.1 Hz, H-2), 8.31 (dd, 1 H, J = 1.7, 7.7 Hz, H-11), 8.37 (s, 1 H, H-6), 8.85 (s, 1 H, H-1). ¹³C NMR (75.47 MHz, CDCl3): δ = 14.1 (NCO2CH2 CH3), 64.2 (NCO2 CH2CH3), 119.8 (C-6), 122.6 (C-8), 124.6
(C-10), 125.4 (C-12a), 125.8 (C-11a), 126.1 (C-3), 126.8
(C-11), 127.7 (C-5), 128.0 (C-1), 128.9 (C-4), 129.5 (C-2), 129.9 (C-1a), 133.0 (C-9), 135.2 (C-5a), 135.9 (C-6a), 140.8 (C-7a), 153.8 (NCO2CH2CH3), 181.0 (C-12). ESI+-MS: m/z (%) = 318 (75) [M + H]+, 340 (31) [M + Na]+, 356 (11)
[M + K]+, 657 (100) [2 M + Na]+, 974 (30) [3 M + Na]+. HRMS (EI, 70 eV): m/z calcd for C20H15NO3: 317.1052; found: 317.1053.

30

Physical Data for Benzo[ b ]acridone (13a) Mp >300 ˚C. ¹H NMR (300.1 MHz, CDCl3): δ = 7.22 (ddd, 1 H, J = 0.8, 6.9, 8.0 Hz, H-10), 7.44 (ddd, 1 H, J = 0.9, 7.1, 7.9 Hz, H-3), 7.55 (d, 1 H, J = 8.4 Hz, H-8), 7.60 (ddd, 1 H, J = 1.1, 7.1, 8.2 Hz, H-4), 7.76 (ddd, 1 H, J = 1.5, 6.9, 8.4 Hz, H-9), 7.96 (s, 1 H, H-6), 8.01 (d, 1 H, J = 8.2 Hz, H-5), 8.17 (d, 1 H, J = 7.9 Hz, H-2), 8.26 (dd, 1 H, J = 1.5, 8.0 Hz, H-11), 8.94 (s, 1 H, H-1), 11.75 (s, 1 H, NH). ¹³C NMR (75.47 MHz, CDCl3): δ = 112.0 (C-6), 117.0 (C-8), 118.9 (C-11a), 120.2 (C-10), 121.2 (C-12a), 124.1 (C-3), 126.4
(C-11), 126.5 (C-5), 127.3 (C-1), 127.7 (C-1a), 128.5 (C-4), 129.7 (C-2), 134.3 (C-9), 135.9 (C-5a), 137.9 (C-6a), 142.1 (C-7a), 178.2 (C-12). ESI+-MS: m/z (%) = 246 (100) [M + H]+. HRMS (EI, 70 eV): m/z calcd for C17H11NO: 245.0841; found: 245.0842.