The first synthesis of furocoumarin dimers

摘要

Mendeleev Communications Electronic Version, Issue 6, 1997 (pp. 213ndash;252) The first synthesis of furocoumarin dimers Valery F. Traven,* Dmitrii V. Kravtchenko and Tatrsquo;yana A. Chibisova D. I. Mendeleev Russian University of Chemical Technology, 125190 Moscow, Russian Federation. Fax: +7 095 200 4204 Self-condensation of 4-methyl-2H-8,9-dihydrofuro2,3-h-1-benzopyran-2,9-diones provides the first example of the synthesis of a furocoumarin dimer. 2H-Furo-1-benzopyran-2-ones (furocoumarins) are widespread natural products. Many of them are useful in the treatment of human skin diseases.1ndash;7 The biological activity of these compounds is based on their ability to react with the pyrimidine bases, particularly with thymine, under UV light. 2H-Furo2,3- g-1-benzopyran-2-ones (psoralens) are bifunctional, since they can crosslink with DNA. 2H-Furo2,3-h-1-benzopyran-2-ones (angelicins) are monofunctional, since they cannot crosslink with DNA due to their angular geometry. However, there are no reports concerning the pharmaceutical properties and photoreactivity of furocoumarin dimers. Moreover, furocoumarin dimers have not yet been synthesized. Whilst developing new ways of synthesising furocoumarin derivatives based on the Fries rearrangement of hydroxy-2H- 1-benzopyran-2-one chloroacetates,8,9 we have undertaken the first synthesis of an angelicin dimer. 4-Methyl-2H-8,9-dihydrofuro2,3-h-1-benzopyran-2,9-diones 1 possess a definite enolate reactivity. For example, compound 1a undergoes croton-type condensations with aldehydes and ketones in acetic acid in the presence of HCl.According to spectral data, the condensation products ndash; 8-benzylideno- 4-methyl-2H-8,9-dihydrofuro2,3-h-1-benzopyran-2,9-diones 2 ndash; have an enone (croton-type) structure (Scheme 1). Intermediate ketols have not been detected among the condensation products. Compounds 1 also undergo self-condensation with dimer formation.dagger; However, neither enone 2e nor intermediate ketol 3 (from compound 1 self-condensation) products have yet been found in the reaction mixtures.Intermediate ketols 3 seem to undergo dehydration with aromatization and furan ring formation. The final products ndash; 9-(4'-methyl- 2'H-8',9'-dihydrofuro2',3'-h-1'-benzopyran-2',9'-dione-8'-yl)- 4-methyl-2H-8,9-dihydrofuro2,3-h-1-benzopyran-2,9-diones 4 ndash; turn out to be more stable when compared with enone condensation products 2e.A small amount of 4a has also been detected among the 7-chloroacetoxy-4-methylcoumarin Fries rearrangement products.9 dagger; Self-condensation of 4-methyldihydrofuro2,3-hcoumarin-9-ones 1 (general procedure). A mixture of compound 1 (4.6 mmol), glacial acetic acid (12 ml) and concentrated HCl (6 ml) was refluxed for 3 h.Product 4 was filtrated off, washed with hot acetone and recrystallized from DMSO. Strong Lewis acids (including AlCl3) are known to catalyse the processes of dehydration and condensation of polycyclic aromatic hydrocarbons and heteroarenes.10 Its content is increased to a maximum of 5 in the reaction mixture under Fries rearrangement temperatures higher than 120 deg;C.According to 1H NMR spectral data, compounds 4 exist in the keto form. However, their enol forms have been isolated as the acetates 5 through acetylation by acetic anhydride in the presence of catalytic amounts of H2SO4. Reduction of the compounds 4 by NaBH4 in dioxanendash; methanol leads to the corresponding alcohols 6, which upon dehydration in H2SO4 gave the 4-methylangelicin 2,3'-bifuran dimers 7 (Scheme 2).The melting points and spectral data of new compounds are listed below.Dagger; Dagger; 1H NMR spectra were recorded on a Varian Gemini-200 spectrometer (USA) at 200 MHz using TMS as internal standard. Chemical shifts are given in ppm. Mass spectra were scanned on a SSQ-710 (Finnigan MAT) spectrometer (USA) at an energy of ionising electrons equal to 70 eV. 2a: mp 286ndash;287 deg;C; 1H NMR (200 MHz, 2H6acetone), d: 2.55 (d, 3H, 4-Me, J3,Me 1.2 Hz), 6.34 (q, 1H, 3-H, JMe,3 1.2 Hz), 6.93 s, 1H, =(Ph)Cndash;H, 7.48 (d, 1H, 6-H, J5,6 8.7 Hz), 7.50 (m, 3H, 3'-H, 4'-H and 5'-H), 8.05 (m, 2H, 2'-H and 6'-H), 8.20 (d, 1H, 5-H, J6,5 8.7 Hz); MS, m/z: 304 (M+, 61), calc.for C19H12O4: 304. 2b: mp 330ndash;331 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 2.44 (d, 3H, 4-Me, J3,Me 0.9 Hz), 3.86 (s, 3H, OMe), 6.35 (q, 1H, 3-H, JMe,3 0.9 Hz), 6.85 (d, 1H, 5'-H, J6',5' 8.5 Hz), 6.90 s, 1H, =(Ph)Cndash;H, 7.48 (d, 1H, 6-H, J5,6 9.0), 7.49 (dd, 1H, 6'-H, J5',6' 8.5 Hz, J2',6' 0.9 Hz), 7.54 (d, 1H, 2'-H, J6',2' 0.9 Hz), 8.09 (d, 1H, 5-H, J6,5 9.0 Hz), 9.94 (s, 1H, OH); MS, m/z: 350 (M+, 100), calc.for C20H14O6: 350. 2c: mp 354ndash;355 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 2.50 (d, 3H, 4-Me, J3,Me 0.9 Hz), 6.38 (q, 1H, 3-H, JMe,3 0.9 Hz), 7.08 s, 1H, =(Ph)Cndash;H, 7.50 (d, 1H, 6-H, J5,6 9.0 Hz), 8.18 (d, 2H, 2'-H, J3',2' 8.5 Hz), 8.23 (d, 1H, 5-H, J6,5 9.0 Hz), 8.30 (d, 2H, 3'-H, J2',3' 8.5 Hz); MS, m/z: 349 (M+, 100), calc.for C19H11NO6: 349. 2d: mp 263ndash;264 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 2.40 (s, 3H, 4'-Me), 2.50 (d, 3H, 4-Me, J3,Me 1.0 Hz), 2.69 s, 3H, =(Ph)Cndash;Me, 6.26 (q, 1H, 3-H, JMe,3 1.0 Hz), 7.20 (d, 1H, 6-H, J5,6 8.5 Hz), 7.30 (d, 2H, 3'-H, J2',3' 8.4 Hz), 7.65 (d, 2H, 2'-H, J3',2' 8.4 Hz), 8.06 (d, 1H, 5-H, J6,5 8.5 Hz); MS, m/z: 332 (M+, 86), calc.for C21H16O4: 332. 4a: mp 310 deg;C (decomp.); 1H NMR (200 MHz, 2H6DMSO), d: 2.42 (d, 3H, 4'-Me, J3',Me' 0.9 Hz), 2.50 (d, 3H, 4-Me, J3,Me 0.9 Hz), 6.10 (q, 1H, 3'-H, JMe',3' 0.9 Hz), 6.27 (s, 1H, 8'-H), 6.30 (q, 1H, 3-H, JMe,3 0.9 Hz), 7.16 (d, 1H, 6'-H, J5',6' 8.9 Hz), 7.64 (d, 1H, 6-H, J5,6 9.0 Hz), 7.74 (d, 1H, 5-H, J6,5 9.0 Hz), 8.10 (d, 1H, 5'-H, J6',5' 8.9 Hz), 8.45 (s, 1H, 8-H); MS, m/z: 414 (M+, 100), calc.for C24H14O7: 414. 4b: mp 275 deg;C (decomp.); 1H NMR (200 MHz, 2H6DMSO), d: 1.15 (t, 3H, Me', JCH2',Me' 7.7 Hz), 1.33 (t, 3H, Me, JCH2,Me 7.6 Hz), 2.42 (d, 3H, 4'-Me, J3',Me' 0.9 Hz), 2.50 (d, 3H, 4-Me, J3,Me 0.9 Hz), 2.71 (q, 2H, CH2', JMe',CH2' 7.7 Hz), 2.94 (q, 2H, CH2, JMe,CH2 7.6 Hz), 6.10 (q, 1H, 3'-H, JMe',3' 0.9 Hz), 6.32 (s, 1H, 8'-H), 6.33 (q, 1H, 3-H, JMe,3 0.9 Hz), 7.57 (s, 1H, 5-H), 7.96 (s, 1H, 5'-H), 8.56 (s, 1H, 8-H); MS, m/z: 470 (M+, 100), calc.for C28H22O7: 470. 5a: mp 313ndash;314 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 2.42 (s, 3H, OAc), 2.52 (2d, 6H, 4-Me and 4'-Me), 6.37 (2q, 2H, 3-H and 3'-H), 7.61 (d, 1H, 6'-H, J5',6' 8.7 Hz), 7.72 (d, 1H, 6-H, J5,6 8.7 Hz), 7.80 (d, 1H, 5-H, J6,5 8.7 Hz), 7.84 (d, 1H, 5'-H, J6',5' 8.7 Hz), 8.54 (s, 1H, 8-H); MS, m/z: 456 (M+, 2), calc.for C26H16O8: 456. 5b: mp 277ndash;278 deg;C (decomp.); 1H NMR (200 MHz, 2H6DMSO), d: 1.35 (2t, 6H, Me and Me'), 2.42 (s, 3H, OAc), 2.52 (2d, 6H, 4-Me and 4'-Me), 2.97 (2q, 4H, CH2 and CH2'), 6.37 (2q, 2H, 3-H and 3'-H), 7.60 (s, 1H, 5-H), 7.66 (s, 1H, 5'-H), 8.60 (s, 1H, 8-H); MS, m/z: 512 (M+, 2), calc.for C30H24O8: 512. O O Me O O R O + O O Me O O R Scheme 1 Reagents and conditions: i, AcOH, HCl, 100 deg;C, 1 h. 1a 2 R R1 2a H H 2b H 4'-OH, 3'-OMe 2c H 4'-NO2 2d Me 4'-Me R1 R1 i 85ndash;90Mendeleev Communications Electronic Version, Issue 6, 1997 (pp. 213ndash;252) This work was generously funded by the Highest Education State Committee of Russian Federation (program lsquo;Fine Organic Synthesisrsquo;). References 1 F. Dallrsquo;Acqua, D. Vedaldi, S. Caffieri, A. Guiotto, P. Rodighiero, F. Baccichetti, F. Carlassare and F. Bordin, J. Med. Chem., 1981, 24, 178. 2 A.Guiotto, P. Rodighiero, P. Manzini, G. Pastorini, F. Bordin, F. Baccichetti, F. Carlassare, D. Vedaldi, F. Dallrsquo;Acqua, M. Tamaro, G. Recchia and M. Cristofolini, J. Med. Chem., 1984, 27, 959. 3 F. Bordin, F. Carlassare, F. Baccichetti, A. Guiotto, P. Rodighiero, D. Vedaldi and F. Dallrsquo;Acqua, Photochem., Photobiol., 1979, 29, 1063. 4 F. Dallrsquo;Acqua, D. Vedaldi, A. Guiotto, P. Rodighiero, F.Carlassare, F. Baccichetti and F. Bordin, J. Med. Chem., 1981, 24, 806. 5 A. Guiotto, P. Rodighiero, G. Pastorini, P. Manzini, F. Bordin, F. Baccichetti, F. Carlassare, D. Vedaldi and F. Dallrsquo;Acqua, Eur. J. Med. Chem.-Chim. Ther., 1981, 16, 489. 6 F. Dallrsquo;Acqua, D. Vedaldi, F. Bordin, F. Baccichetti, F. Carlassare, M. Tamaro, P. Rodighiero, G. Pastorini, A. Guiotto, G. Recchia and M.Cristofolini, J. Med. Chem., 1983, 26, 870. 7 D. Vedaldi, F. Dallrsquo;Acqua, F. Baccichetti, F. Carlassare, F. Bordin, P. Rodighiero, P. Manzini and A. Guiotto, Farmaco., 1991, 46, 1381. 8 V. F. Traven, D. V. Kravtchenko and T. A. Chibisova, Mendeleev Commun., 1995, 21. 9 V. F. Traven, D. V. Kravtchenko, T. A. Chibisova, S. V. Shorshnev, R. Eliason and D. H. Wakefield, Heterocyclic Commun., 1996, 2, 345. 10 H. Wang and L. D. Kispert, J. Chem. Soc., Perkin Trans. 2, 1989, 1463. 6a: mp 283ndash;284 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 2.42 (d, 3H, 4'-Me, J3',Me' 1.0 Hz), 2.52 (d, 3H, 4-Me, J3,Me 1.0 Hz), 5.63 (d, 1H, 9'-OH, J9',9-OH' 7.2 Hz), 5.86 (dd, 1H, 9'-H, J9-OH',9' 7.2 Hz, J8',9' 7.1 Hz), 6.17 (dd, 1H, 8'-H, J9',8' 7.1 Hz, J8,8' 1.2 Hz), 6.21 (q, 1H, 3'-H, JMe',3' 1.0 Hz), 6.39 (q, 1H, 3-H, JMe,3 1.0 Hz), 7.04 (d, 1H, 6'-H, J5',6' 8.7 Hz), 7.63 (d, 1H, 6-H, J5,6 8.8 Hz), 7.74 (d, 1H, 5-H, J6,5 8.8 Hz), 8.77 (d, 1H, 5'-H, J6',5' 8.7 Hz), 8.09 (d, 1H, 8-H, J8',8 1.2 Hz); MS, m/z: 416 (M+, 29), calc.for C24H16O7: 416. 6b: mp 297ndash;298 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 1.27 (t, 3H, Me', JCH2',Me' 7.7 Hz), 1.35 (t, 3H, Me, JCH2,Me 7.6 Hz), 2.44 (d, 3H, 4'-Me, J3',Me' 1.0 Hz), 2.52 (d, 3H, 4-Me, J3,Me 1.0 Hz), 2.73 (q, 2H, CH2', JMe',CH2' 7.7 Hz), 2.96 (q, 2H, CH2, JMe,CH2 7.6 Hz), 5.58 (d, 1H, 9'-OH, J9',9'-OH 7.2 Hz), 5.84 (dd, 1H, 9'-H, J9'-OH,9' 7.2 Hz, J8',9' 7.1 Hz), 6.15 (dd, 1H, 8'-H, J9',8' 7.1 Hz, J8,8' 1.1 Hz), 6.19 (q, 1H, 3'-H, JMe',3' 1.0 Hz), 6.36 (q, 1H, 3-H, JMe,3 1.0 Hz), 7.55 (s, 1H, 5-H), 7.57 (s, 1H, 5'-H), 8.09 (d, 1H, 8-H, J8',8 1.1 Hz); MS, m/z: 472 (M+, 28), calc.for C28H24O7: 472. 7a: mp 319ndash;320 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 2.51 (2d, 6H, 4-Me and 4'-Me), 6.34 (q, 1H, 3'-H, JMe',3' 1.0 Hz), 6.44 (q, 1H, 3-H, JMe,3 1.0 Hz), 7.54 (d, 1H, 6'-H, J5',6' 8.7 Hz), 7.64 (d, 1H, 6-H, J5,6 8.9 Hz), 7.66 (d, 1H, 5-H, J6,5 8.9 Hz), 7.78 (d, 1H, 5'-H, J6',5' 8.7 Hz), 7.91 (s, 1H, 9'-H), 8.65 (s, 1H, 8-H); MS, m/z: 398 (M+, 100), calc. for C24H14O6: 398. 7b: mp 315ndash;316 deg;C; 1H NMR (200 MHz, 2H6DMSO), d: 1.36 (2t, 6H, Me and Me'), 2.51 (2d, 6H, 4-Me and 4'-Me), 2.99 (2q, 4H, CH2 and CH2'), 6.31 (q, 1H, 3'-H, JMe',3' 0.9 Hz), 6.40 (q, 1H, 3-H, JMe,3 0.9 Hz), 7.47 (s, 1H, 5-H), 7.59 (s, 1H, 5'-H), 7.86 (s, 1H, 9'-H), 8.67 (s, 1H, 8-H); MS, m/z: 454 (M+, 100), calc. for C28H22O6: 454. O O O O O Me R HO O Me R O 1 i 85 O O O O O Me R O Me R O O O O O O Me R O Me R O O O O O O Me R O Me R 6 iv 60 iii 65 O O O O O Me R O Me R OAc 3 2e 5 4 7 a R = H b R = Et Scheme 2 Reagents and conditions: i, AcOH, HCl, 100 deg;C, 3 h; ii, Ac2O, H2SO4, 120 deg;C, 1 h; iii, NaBH4, dioxane, MeOH, 20 deg;C, 2 h; iv, 20 H2SO4, EtOH, 80 deg;C, 3 h. ii 75 Received: Moscow, 20th March 1997 Cambridge, 17th July 1997; Com. 7/02263H