Iminium salts synthesis, Mannich reaction

The reaction of enamines with iminium salts provides an alternative route to Mannich bases which are an attractive class of compounds, since they have found many applications (synthesis of drugs, pesticides, synthetic building blocks, etc.). This methodology has several basic advantages compared to the classic aminomethylation procedure15-18-24 ... 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of y -amino ketones and esters [46]. 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 /5-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view [47, 48]. 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 and a surfactant to produce imines, which could react with hydrophobic silyl enolates [49]. 

Considerable rate enhancements have been observed when water is used as solvent compared with alcoholic or hydrocarbon media for Mannich reactions, i.e. condensations of ketones with secondary amines in the presence of formaldehyde [65]. Allylsilanes [66] and allylstannanes [67] in aqueous media were used in organic synthesis under Mannich-like conditions. More recently, Kobayashi reported the catalysis of the reaction of vinyl ethers with iminium salts by ytterbium triflate in tetrahydrofuran-water mixtures [68]. 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of /3-amino ketones. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have been developed [18]. These materials however, are often hy-... 

A(, -Dimethyl(methylene)iminium salts have been the most widely used class of preformed iminium salts, mainly due to their applications in the synthesis of a,p-unsaturated carbonyl compounds, normally accomplished by subjecting the /V, -dimethyl Mannich base to quatemarization followed by base-induced elimination. Table 3 outlines various counterion forms of /V, -dimethyl(methylene)iminium salts that have been used in Mannich reactions as well as their synthetic precursors. The crystalline iodide (30), known also as Eschenmoser s salt , has seen the most widespread use and is prepared by thermal fragmentation of (iodomethyl)trimethylammonium iodide or, more conveniently, by a variant of the... 

Imines are more versatile than preformed iminium salts in reactions with active methylene compounds because the product, a secondary Mannich base, has an additional site on the nitrogen for further elaboration (equation 11). Imine condensation reactions are also superior to the classical method for the synthesis of secondary Mannich bases because cross-condensation reactions do not occur, due to the absence of free aldehyde in solution. The major side reactions occurring in imine condensation reactions are abstraction of enolizable ot-protons and self-condensation reactions of enolizable imines at elevated temperature. 

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