Synthetic Route to 4,4a‐ and 3,4‐Dihydroxanthones through [4+2] Cycloaddition and Base‐Assisted Sigmatropic Rearrangement

Abstract

The [4+2] cycloaddition of chromone‐fused dienes with enamines was found to be an efficient method for the synthesis of 4,4a‐ and 3,4‐dihydroxanthone derivatives. Either product type could be obtained by choosing the proper conditions [reaction time and addition of La(NO3)3 as a Lewis acid]. Calculations using density functional theory and Møller–Plesset perturbation theory showed that the isomerization of 4,4a‐dihydroxanthones to 3,4‐dihydroxanthones occurred through a base‐assisted sigmatropic rearrangement. The described reaction provides a convenient route to a natural‐product‐inspired group of 4,4a‐dihydroxanthones with cytotoxic activity.

Design, Synthesis, and Antiproliferative Activity of Benzopyran-4-One-Isoxazole Hybrid Compounds

“…(E)-3-(6-Methoxy-4-oxo-4H-1-benzopyran-3-yl)acrylic acid ( 4c ). Yield = 81%; R f = 0.72 [ethyl acetate]; IR (neat) ν max : 3696, 3679, 3655, 3634, 3346, 3064, 2970, 2866, 2844, 2362, 2342, 2165, 2074, 2050, 1695, 1646, 1611, 1564, 1547, 1484, 1454, 1436, 1421, 1395, 1374, 1343, 1320, 1296, 1212, 1197, 1159, 1055, 1031, 1014, 941, 867, 830, 791, 726, 678 and 610 cm −1 ; UV/vis (MeOH) λ: 245 nm; 1 H NMR (400 MHz, DMSO): δ 12.37 (s, 1H, -COOH), 8.83 (s, 1H, H-2), 7.65 (d, J = 9.1 Hz, 1H, H-8), 7.47–7.40 (m, 3H, H-2′, H-7 and H-5), 7.10 (d, J = 15.9 Hz, 1H, H-1′), 3.86 (s, 3H, -OCH 3 ); 13 C NMR (101 MHz, DMSO): δ 174.96 (C-4 C=O), 167.81 (C-3′ C=O), 159.51 (C-2), 156.97 (C-6), 149.86 (C-8a), 136.02 (C-2′), 124.24 (C-4a), 123.53 (C-3), 121.11 (C-7), 120.14 (C-8), 117.31 (C-1′), 105.22 (C-5), 55.79 (OCH 3 ); HRMS (ESI-TOF) ( m / z ) C 13 H 10 O 5 calculated, 247.061, found 247.215 [M + H] + ; calculated, 269.043, found, 269.211 [M + Na] + ; and calculated, 285.017, found, 285.195 [M + K] + [ 48 ].…”

“…After 30 min, the solvent was evaporated in vacuum and the resulting precipitate was recrystallized from acetone to afford 4a-d. (E)-3-(4-Oxo-4H-1-benzopyran-3-yl)acrylic acid (4a). Yield = 74%; R f = 0.69 [ethyl acetate]; IR (neat) ν max : 3364,2955,2919,2848,2666,2367,2343,1659,1611,1562,1547,1464,1425,1410,1360,1323,1300,1249,1015,987,858,784,760,710,684, 657 and 614 cm −1 ; UV/vis (MeOH) λ: 289, 266 nm; 1 H NMR (400 MHz, DMSO): δ 12.34 (brs, 1H, -COOH), 8.87 (s, 1H, H-2), 8.13 (dd, J = 8.0, 1.5 Hz, 1H, H-5), 7.84 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H, H-7), 7.70 (dd, J = 8.4, 0.6 Hz, 1H, H-8), 7.54 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H, H-6), 7.43 (d, J = 15.9 Hz, 1H, H-1 ), 7.12 (d, J = 15.9 Hz, 1H, H-2 ); 13 [48]. (E)-3-(7-Methoxy-4-oxo-4H-1-benzopyran-3-yl)acrylic acid (4d).…”

Synthesis and Reactivity of Electron-Deficient 3-Vinylchromones

“…In another report, 74 [4+2] cycloaddition between chromonylacrylic acids 2a and enamines from isobutyric aldehyde and pyrrolidine or piperidine led to the preparation of 4,4a-dihydroxanthones 134 in 43-81% yields (Scheme 55). Further study of this reaction using the example of a more active enamine with a pyrrolidine fragment showed that, if the reaction is carried out with the addition of La(NO 3 ) 3 as a Lewis acid for 0.5-5 h, 4,4a-dihydroxanthones 134 are formed.…”

Конструирование Конденсированных Гетероциклических Систем На Основе Реакции Электронодефицитных 3-Винилхромонов С Цианацетамидом

“…3-Винилхромоны 1, содержащие в винильном фрагменте электроноакцепторную группу (EWG), зарекомендовали себя как многоцелевые структурные блоки для построения на их основе конденсированных гетероциклических систем [1,2]. В частности, наличие в их структуре нескольких электрофильных центров с резко отличающейся реакционной способностью позволило создать эффективный метод синтеза хромено [4,3-d]пиримидинов [2].…”