Three Methods and a Mechanism for the Synthesis of Curcuminoids
Pickett, James E.
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Curcumin (I), a yellow food coloring agent, has been synthesized by three new methods, and the mechanism for the synthesis has been studied. In the first process, acetylacetone(V) and boric acid (H3BC3) are dissolved in a polar, aprotic solvent to form a complex (XI). An aromatic aldehyde(VI) 9.nd a catalytic amount of a primary amine are added to form a Schiff base(XV) that condenses with XI at the methyl sites to form the curcuminoid complex(XII). The condensation can be monitored spectrophotometrically. Molecular sieves are present in both steps to consume water and to drive the reactions to completion. This also prevents hydrolysis of the complexes (XI and XVIV) and reversal of the condensation. The amine is neutralized with suIfuric acid, and the boric acid is removed as trimethylborate by co-distillation with methanol to insure a boron-free product. Addition of warm, dilute HC1 to the distillation residue gives a product in 75-82% yields. The second process involves the use of boric anhydride to remove the water in place of the sieves. A 1:3 mixture of boric acid and boric anhydride is suspended in dimethylformamide (DHF), and acetylacetone is added to form complex XI. Aromatic aldehyde (VI) and primary amine are added to form XII. The reaction can be monitored and worked up as in the previous process to give yields of 72-74%. In the third process, water is removed azeotropically and a benzene-tributylborate mixture is used as a solvent. Acetylacetone (V), boric acid, and n-butanol are suspended in benzene and are refluxed with a Dean--Stark trap until water production has ceased. Aromatic aldehyde and primary amine are added and refluxing and moisture trapping are continued. The progress of the condensation can be monitored spectrophotometrically. Sulfuric acid and methanol are added and the boric acid is removed by methanol distillation. A yellow precipitate forms spontaneously which can be collected in 72-78% yields, the mother liquor concentrated, and a second crop of 6-7% collected after recrystallization. Alternatively, dilute HCl may be added after precipitation to collect 80-83% yields in one crop. Thin layer chromatography discloses that the latter product is slightly contaminated with a monocondensation product (XIII).