Stereoelectronic effects in ring closure reactions: the 2′-hydroxychalcone – flavanone equilibrium, and related systems

Abstract

. 68, 1780 (1990).The 2'-hydroxychalcone (2-HOC6H4COCH4HC6H&)-flavanone equilibrium in trifluoroacetic acid (TFA) has been examined. The influence of substituents X on the rate of attainment of equilibrium shows that the 6-endo-trig modeof ring closure by Michael addition is disallowed, by demonstrating a negative p value for the reaction rate when X is varied. Reaction therefore proceeds either on the carbonyl-protonated form, which allows twisting about the 2,3 bond, its double bond character being reduced by resonance, or through direct rate-limiting protonation on the 2,3 double bond. Either pathway permits the allowed 6-exo-trig mode of ring closure to be followed. Alternative mechanisms involving intermolecular Michael addition of trifluoroacetate, followed by intramolecular 6-exo-tet displacement are considered. Such Michael adducts can be detected in the ring closures of 2-crotonyl-4-methylphenol and 4,4-dimethyl-1-(2-hydroxypheny1)-2-penten-1-one in TFA, but they do not appear to lie on the main pathway, because the reactions proceed with equal facility in methanesulphonic acid/chloroform medium, which does not contain a suitable nucleophile for such a mechanism. Further important mechanistic information isgiven by studying the reactions in TFA-d, together with measurements on the (E)-2-methyl-3-0~0-5-aryIpent-4-en-2-01 and 3'-methoxychalcone systems. These isotope effect studies, which yield kH/kD values of about 3, indicate that the proton is in flight during the rate-limiting step, and provide evidence against the mechanism involving a preequilibrium carbonyl protonation, such as in the Nazarov rearrangement of 3'-methoxychalcones, where kH/kD is ca. 0.7. Some results are also reported for ring closure of the 2-aminochalcones in TFA. Key words: 2'-hydroxychalcones, flavanones, 3'methoxychalcones, 3-aryl-6-methoxyindanones, 2'-aminochalcones, 2-aryl-1, 2,3,4-tetrahydroquinolines, Baldwin's rules. On a CtudiC l'tquilibre de la 2'-hydroxychalcone (2-HOC6H4COCH=CHC6H,X)-flavone dans I'acide trifluoroacttique (TFA). L'influence des substituants X sur le temps qu'il faut pour atteindre I'Cquilibre, exprimCe par la valeur nCgative de p sur la vitesse de la rCaction, dCmontre que le mode 6-endo-trig de fermeture du cycle par addition de Michael n'est pas permis. La rCaction se produit donc soit par une attaque sur la forme protonee du carbonyle, qui permet une torsion autour de la liaison 2,3 puisque soncaractere de liaison double est rCduit par resonance, soit par une protonation directe de la double liaison 2,3 qui limite la vitesse. On considbre aussi d'autres mCcanismes impliquant une addition de Michael intramolCculaire de I'ion trifluoroacktate, suivie par des dCplacements 6-exo-tet. On peut dCtecter de tels adduits de Michael dans les cyclisations du 2-crotonyl-4-mCthylph6nol et de la 4,4-dimCthyl-1-(2-hydroxyphCny1)-2-pentkn-I-one dans l'acide TFA; toutefois, ils ne semblent pas faire partie du mecanisme principal puisque les reactions se produisent avec une facilitC similaire dans un milieu comme l'...

Synthesis and Investigation of Flavanone Derivatives as Potential New Anti-Inflammatory Agents

“…A series of 2′-hydroxy chalcones ( 3A–3L ) were synthesized by Claisen–Schmidt condensation from appropriately substituted 2′-hydroxyacetophenones and benzaldehydes. Various experimental conditions, such as acid catalysis [ 19 ], base catalysis [ 20 ], heat treatment [ 21 ], and light activation [ 22 , 23 ], have been reported to achieve the subsequent cyclization to flavanones. Two cyclization procedures were chosen in this work: basic and photochemical activation ( Figure 2 ).…”

Stereoselective Synthesis of Flavonoids: A Brief Overview

“…The 2′-hydroxychalcones can also be building blocks for the synthesis of flavanones (route II, Figure 3 ) and flavones (route III, Figure 3 ). Considering the first class of flavonoids mentioned, they can be obtained through intramolecular cyclisation under acidic [ 36 ] or basic conditions [ 37 ], thermolysis [ 38 ], electrolysis [ 39 ], photolysis [ 40 ], microwave irradiation [ 41 ], a greener catalytic process [ 42 ], and palladium(II) catalysis [ 43 ]. Regarding flavones, these compounds can be synthesised through oxidative cyclisation under several reaction conditions such as classic I 2 -DMSO methodology [ 44 ] or using NH 4 I in a solvent-free environment [ 45 ].…”

Tetrahydronaphthalene as a precursor of new series of chalcones, flavanones, and flavone

“…Other methods are also available for the synthesis of flavanones in a one-pot procedure including condensation between 2-hydroxyacetophenone and benzaldehyde derivatives in the presence of acids 14 or bases, 15,16 Mannich-type reactions, 17 Mitsunobu reactions, 18 Julia-Kocienski olefination, 19 and others. 20 Recently, Chen 18 and co-workers described an environmentally friendly method using tertiary amines as bases in water or ethanol as solvents, directly affording the desired flavanones.…”