Process for the preparation of flavone derivatives
The invention relates to a process for the preparation of flavone derivatives in which a 2-hydroxyacetophenone compound is metallated using a lithium compound at low temperatures and subsequently reacted with a keto compound, and where the ratio of the molar equivalents of lithium compound to the 2-hydroxyacetophenone compound functional groups to be metallated is from 1 to 1.2. The resultant β-diketone compound is subsequently cyclized with warming in an acidic medium.
1. A process for preparing a compound of the formula:
comprising metallating a compound of the formula:
wherein R 1 –R 4 , are, independently, hydrogen or a group of hydroxyl, alkyl, alkenyl, ether, ester, aryl, O-glycosyl, alkoxy, alkenoxy, aryloxy, halogen, nitro or amino, and/or any two adjacent R 1 –R 4 may combine to form a ring system, and R is hydrogen, an alkoxy group or an optionally substituted phenyl group, with an inorganic lithium compound, and
subsequently reacting the metallated compound with a keto compound of the formula:
wherein R 6 –R 10 are, independently, hydrogen or a group of hydroxyl, alkyl, alkenyl, ether, ester, aryl, O-glycosyl, alkoxy, alkenoxy, aryloxy, halogen, nitro or amino, and/or any two adjacent R 6 –R 10 may combine to form a ring system, and R 5 is a halide, alkoxy or ester group, wherein the ratio of molar equivalents of the lithium compound to the functional groups to be metallated on the 2-hydroxyacetophenone compound is 1–1.2.
2. A process according to claim 1 , wherein the ratio of the molar equivalents of lithium compound to the 2-hydroxyacetophenone compound functional groups to be metallated is about 1.
3. A process according to claim 1 , wherein the metallation is conducted in an ethereal solvent.
4. A process according to claim 1 , wherein the hydroxyl groups of the 2-hydroxyacetophenone compound are unprotected.
5. A process according to claim 1 , wherein the inorganic lithium compound is LiNH 2 , LiCN, LiC(NO 3 ) 3 , LiC(CN) 3 , LiClO 4 , Li 2 O, LiOH or Li 2 CO 3 .
6. A process according to claim 1 , wherein the inorganic lithium compound is LiOH.
7. A process according to claim 1 , wherein the keto compound is isophthaloyl chloride or 9-fluorenone-4-carbonyl chloride.
8. A process according to claim 1 , wherein the 2-hydroxy-acetophenone compound is 2,4-dihydroxyacetophenone, 2,5-dihydroxyacetophenone, 2,6-dihydroxyacetophenone, or 2,4,6-trihydroxyacetophenone.
9. A process according to claim 1 , wherein the keto compound is 4-methoxybenzoyl chloride, 3,4-dimethoxybenzoyl chloride, isophthaloyl chloride, 9-fluorene-4-carbonyl chloride, piperonylbenzoyl chloride, 4-chlorobenzoyl chloride, or 4-nitrobenzoyl chloride.
10. A process for preparing a compound of the formula:
comprising metallating a compound of the formula:
wherein R 1 –R 4 , are, independently, hydrogen or a group of hydroxyl, alkyl, alkenyl, ether, ester, aryl, O-glycosyl, alkoxy, alkenoxy, aryloxy, halogen, nitro or amino, and/or any two adjacent R 1 –R 4 may combine to form a ring system, and R is hydrogen, an alkoxy group or an optionally substituted phenyl group, with an inorganic lithium compound, and
subsequently reacting the metallated compound with a compound of the formula:
wherein R 6 –R 10 are, independently, hydrogen or a group of hydroxyl, alkyl, alkenyl, ether, ester, aryl, O-glycosyl, alkoxy, alkenoxy, aryloxy, halogen, nitro or amino, and/or any two adjacent R 6 –R 10 may combine to form a ring system, and R 5 is a halide, alkoxy or ester group.