Domino Inverse Electron Demand Diels-Alder Reactions of Chromones with Ethyl Vinyl Ether

Abstract

E)-Ethyl 3-(4-oxo-4H-chromen-3-yl)acrylate (3), (E)-3-(4-oxo-4Hchromen-3-yl)-2-propenenitrile (12) and their 5-hydroxy-derivatives 11 and 13 undergo alternative, solvent dependent, domino reactions with ethyl vinyl ether. Inverse electron demand Diels-Alder (IEDDA)-elimination-IEDDA generates isomeric tetracycles 15a-d and 16a-d. Instead, IEDDA-elimination-intramolecular elimination reactions provides xanthone 17 or 2-hydroxybenzophenones 18a-d, respectively. In non-polar solvents propenenitriles 12 and 13 experience a third alternative domino sequence: IEDDA-elimination-ene reaction, yielding the highly functionalized tricyclic compounds 21 and 22. 7 9 E-3 50 Z-3 49 8 9 E-11 55 Z-11 40 7 10 E-12 13 Z-12 63 8 10 E-13 30 Z-13 60 * Conditions: toluene, reflux, 2 hSurprisingly, when chromone E-11 was allowed to react with ethyl vinyl ether (14), in a sealed tube at 140 ºC in toluene for 3 days, tetracyclic compounds 15a and 16a were obtained in 56% yield and a 84:16 (15a:16a) ratio along with 5% of xanthone 17 instead of the expected benzophenone 18a (Scheme 2). Scheme 3. Plausible mechanism of the domino reaction of E-11 with vinyl ethyl ether (14). A strong solvent effect directs these alternative reaction paths. Thus, when ethyl vinyl ether, methanol or acetone was used as solvent at 80 °C, only the tetracycles 15a and 16a (path A) and benzophenone 18a (path C) were obtained in variable yields. The xanthone 17 was not detected (path B). In toluene, at the same conditions, compounds 15-17 (path A and B) were obtained in very low yield.15 16 18 E-3 80 3 38 19 11 31 E-12 80 3 10 4 53 22 E-13 80 3 26 --44 4 A comparison between the reactions of chromone E-3 and the 5-hydroxy-derivative E-11 showed that the presence of the hydroxyl group at C-5 causes an increase in the reactivity toward dienophile 14. The amount of unreacted E-3 was about twice as much as unreacted E-11, both recovered under similar reaction conditions. This evidences that the electron withdrawing effect of the intramolecular hydrogen bonding in E-11 increases the reactivity of the diene moiety. When the ethoxycarbonyl substituent was replaced by a cyano group (compounds E-12 and E-13), a J = 7.1 Hz, CO 2 CH 2 J 2 = 7.0 Hz, CH(OCHHCH 3 )CH 3 ), 3.46 (dq, 1H, J 1 = 8.9 Hz, J 2 = 7.0 Hz, CH(OCHHCH 3 )CH 3 ), 3.70 (dd, 1H, J 1 = 9.0 Hz, J 2 = 7.1 Hz, OCHHCH 3 ), 3.74 (dd, 1H, J 1 = 9.0 Hz, J 2 = 7.1 Hz, OCHHCH 3 ), 3.94 (q, 1H, J = 6.4 Hz, CH(OEt)CH 3 ), 4.22 (ddd, 1H, J 1 = 9.0 Hz, J 2 = 7.5 Hz, J 3 = 1.4 Hz, H3), 4.29 (dd, 1H, J 1 = 13.5 Hz, J 2 = 3.8 Hz, H4a), 6.42 (dd, 1H, J 1 = 8.3 Hz, J 2 = 0.8 Hz, H5), 6.54 (dd, 1H, J 1 = 8.3 Hz, J 2 = 0.8 Hz, H7), 7.04 (d, 1H, J = 1.3 Hz, H1), 7.35 (dd, 1H, J 1 = J 2 = 8.3 Hz, H6), 11.37 (s, 1H, OH); 13 C-NMR δ (CDCl 3 ) 14.8 (CH(OCH 2 CH 3 )CH 3 ), 15.3 (OCH 2 CH 3 ), 17.6 (CH(OEt)CH 3 ), 30.7 (C-4), 53.7 (C-9a), 65.8 (CH(OCH 2 CH 3 )CH 3 ), 66.1 (OCH 2