Ln(OTf)₃- or Cu(OTf)₂-Catalyzed Mannich-Type Reactions of Aldhehydes, Amines and Silyl Enolates in Micellar Systems. Facile Synthesis of β-Amino Ketones and Esters in Water

Abstract

In the presence of a catalytic amount of Ln(OTf) 3 or Cu(OTf) 2 , three-component Mannich-type reactions of aldehydes, amines, and silyl enolates proceeded smoothly in micellar systems to afford the corresponding b-amino ketones or esters in high yields. These reactions were successfully carried out in water without using any organic solvents.Much attention has been focused on organic processes in water without use of harmful organic solvents, which is an environmentally-friendly methodology. 1 Recently, we found that lanthanide triflates are stable Lewis acids in aqueous media that efficiently catalyze reactions of carbonyl and related compounds. 2 In addition, Sc(OTf) 3 -catalyzed aldol reactions of silyl enolates with aldehydes in pure water were found to proceed smoothly with the aid of a small amount of a surfactant such as sodium dodecyl sulfate (SDS). 3 In this micellar system, ketene silyl acetals, which are known to be hydrolyzed easily in the presence of even a small amount of water, reacted with aldehydes to afford the corresponding aldol adducts in high yields. These results indicated that an excellent hydrophobic reaction field would be formed under these conditions, and gave us an idea that Mannich-type reactions of aldehydes, amines, and silyl enolates would also proceed smoothly in such a micellar system.The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of b-amino ketones and esters. 4 Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have improved the process. Some of these materials are, however, unstable and difficult to isolate, and deaminations of the products that occur under the reaction conditions still remain as problems. The direct synthesis of b-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. 5 Our working hypothesis is that aldehydes could react with amines in the hydrophobic micellar system in the presence of a catalytic amount of lanthanide triflate to produce imines, which could react with hydrophobic silyl enolates. 6,7 Milder reaction conditions using lanthanide triflate as a Lewis acid and water as a solvent were expected. First, a model reaction of benzaldehyde, o-methoxyaniline, and 1-phenyl-1-trimethylsiloxyethene was performed in the presence of 0.05 eq. of Sc(OTf) 3 in an aqueous solution of SDS (SDS, 0.2 eq., 35 mM). In a typical procedure, the amine and 1 were combined in the presence of Sc(OTf) 3 in 35 mM SDS, and then the aldehyde was added. 8 The reaction proceeded smoothly at room temperature to afford the corresponding b-amino ketone derivative 2 in 87% yield. It is noted that the dehydration (imine formation) and the coupling reaction between two waterunstable substrates, the imine and the silyl enol ether, occurred successfully in water. 9

Green Lewis acid catalysis in organic synthesis

“…4) [14]. It is noteworthy in these reactions that the intermediate imines were formed in situ from aldehydes and amines even in the presence of water as a solvent.…”

A mild and efficient one-pot three-component synthesis of anti-β-amino-carbonyl compounds catalyzed by NH4OAc and their anticancer activities

“…Recently, the three-component (MCRs) reactions of Mannich and Mannich-type reactions have been catalyzed by lanthanide triflates (Kobayashi et al, 1995(Kobayashi et al, , 1999, bismuth triflates (Gaspard-Iloughmane and Le Roux, 2004), phenylboronic acid (Santosh et al, 2013), zinc tetrafluoroborate (Brindadan et al, 2002), and Cu-nanoparticles (Mazaahir et al, 2009) to get sole diastereomers. Although these methodologies are useful, most of the methods encounter some limitations, such as the requirement of expensive catalysts or longer reaction time, and poor diastereoselectivity.…”

An efficient synthesis of β-aminoketone compounds through three-component Mannich reaction catalyzed by calcium chloride

“…Recent achievements in the efficient construction of these molecules include the development of various catalysts, such as Lewis acid catalysts [17], Bronsted acid catalysts [18,19], and Lewis base catalysts [20], to facilitate Mannich reactions. For example, scandium triflate, copper triflate, scandium tris(dodecyl sulfate), and scandium tris(dodecanesulfonate) [21]. Cl 3 [22], HBF 4 [23], zirconium catalyst [24], ionic liquid [25], and NbCl 5 [26] have also been used to catalyze these reactions and good yields were obtained, but these catalysts are associated with long reaction times, and sterically hindered b-aminoketones could not be obtained.…”