Mannich bases, preparation reaction with enolates

Enolizable A -trimethylsilylaldimines can be generated in situ by the addition of organolithium reagents to bis(trimethylsilyl)formamide. These undergo addition reactions with enolates to form 3-lactams. Phosphonium salts used in catalytic amounts promote the reaction between aryl aldimines and silylketene acetals to form 3-amino esters. Mannich bases with N-2-hydroxyethyl-N-methyl substitution are prepared by the reaction of the iminium salt synthon, 3-methyl-1,3-oxazolidine, with enol silanes in the presence of chloromethylsilanes. ... 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

A method of synthesis which has been used generally in this series employed a Fischer reaction at an early stage to form the tetrahydrocarbazolone nucleus [59] (Scheme 7.2). We devised a second route employing the Fischer method in which the key intermediate was the cyclohexenone (22) (Scheme 7.3). This was readily prepared by treating the enolate of the methyl enol ether (21) with dimethyl(methylene)ammonium iodide [60] to form the Mannich base which was then condensed with 2-methylimidazole to give (22). 

Diaslereoselective Mannich reaction. Mannich bases can be prepared by addition of a lithium dialkylamide to a nonenolizable aldehyde to form a lithium alkoxide. Trans-metallation provides a trichlorotitanium alkoxide, which reacts with a lithium enolate to form a Mannich base. 

Trimethylsilyl enol ethers continue to be useful synthons for various aldol typeis,lb and Michael1 18 reactions. Their utility in part is due to their ease of regiospecific preparation, ease of cleavage and high reactivity. Danishefsky and coworkers have shown that silyl enol ethers react with dimethyl(methylene)ammonium iodide yielding Mannich bases.19 Otherwise inaccessible Mannich bases are accessible via the series below. 

A new -arylethylamine synthesis by aryl aldehyde homologation has also been developed. A procedure has been found for the specific ortho alkylation of aromatic amines.A review of the use of quaternary ammonium compounds in organic synthesis has recently appeared. Mannich bases may be prepared regiospeclfically using the reaction of enol borates with dimethyl (methylene)-ammonium iodide. A very complete review of... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Based on Mannich-type reactions of N-acryliminoacetates with silyl enol ethers, a new method for the preparation of N-acylated amino acid derivatives via nucleophilic addition to N-acrylimino ester has been developed using a polymer-supported amine and scandium catalysts (Scheme 12.5) [9]. Ethyl N-benzoyl-2-bromoglycine was used as a substrate. It could be readily converted to reactive N-acrylimino ester in situ by treatment with a base. Immobilizations of the amine and the scandium species into polymeric supports prevented loss of activity of the catalyst. The method is simple and provides a convenient method for the preparation of N-acrylated amino acid derivatives. 

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