The Preparation Of Phenol-Formadehyde-Piperazine Mannich Bases And Their Application As Ligands In Cu-catalyzed Ullmann Type Coupling

The product of the three-component Mannich reaction, the condensation of a CH-activated compound with a primary or secondary amine and a nonenolizable aldehyde, is often referred to as Mannich base. Variations of each component of the Mannich reaction led to the synthesis of a series of Mannich bases. Many Mannich bases are useful intermediates for the synthesis of drugs and other fine chemicals. Mannich bases containing nitrogen or oxygen functional groups are also useful as ligands in metal catalyzed organic reactions. In this dissertation, several phenol-formadehyde-piperazine type Mannich bases were synthesized. It was found that use of the Mannich bases as ligands in the Ullmann type coupling of iodobenzene with imidazole in water led to remarkable increase of the yield of the coupling product.Mannich reaction of 4-methoxyphenol, formaldehyde and piperazine in methanol gave 1,4-bis(2-hydroxy-5-methoxybenzyl)piperazine. Effects of parameters on the reaction were studied. Best yield (71%) was obtained when the reaction was carred out at 62℃for 14 hours with ratios of n(4-methoxyphenol):n(piperazine):n(formaldehyde)= 1:0.505:1.5. The reaction was operated in a one-pot two-step manner. To 20 mL of methanol was added 25 mmol of piperazine and 75 mmol of 40% aqueous formaldehyde solution and the solution was stirred at 62℃for 2 hours. To the solution 50 mmol of 4-methoxyphenol in 30 mL of methanol was then added at 62℃and the resultant mixture was stirred at 62℃for another 12 hours. The precipitate was filtered and washed with methanol. After drying the desired product was obtained. The scope of the reaction was tested with other phenols including 2,4-and 2,6-di-t-butylphenol,4-nitrophenol,4-t-butylphenol,4-chlorophenol and 4-acetylphenol. It was found that phenols with electron donating group or groups gave better yield than phenols with with electron withdrawing group or groups. The mechanism of the reaction was discussed.Mannich reaction of 4-methoxyphenol with formaldehyde and piperazine in water gave 1,4-bis(2-hydroxy-5-methoxybenzyl)piperazine in 96% yield, much higher than the yield of the same reaction carried in methanol. However, lipophilic phenols including 4-t-butylphenol, 2,4-and 2,6-di-t-butylphenol cannot react with formaldehyde and piperazine in water because their insolubility in water.The phenol-formadehyde-piperazine type Mannich bases contain amino and hydroxyl groups and may be used as multidentate ligands in metal catalyzed organic reactions. It was found that in the presence of 20 mol% of 1,4-bis(2-hydroxy-5-methoxybenzyl)piperazine the yield of the cuprous catalyzed Ullmann reaction of iodobenzene with imidazole in water was increased from 52% to 96%.