Enol silanes Mannich reaction

As illustrated in Table 10, a wide variety of enolates undergo Mannich reactions with A A -dimethyl-(methylene)iminium salts. They include ester (entries 1), lactone (entries 2-4), a-ethoxycarbonyllactone (entry 5), acyliron (entry 6), aldehyde (entry 7), carboxylic acid (entry 8), and ketone (entries 9-12) enolates. Yields are gener ly comparable to the direct enol silane method except in the case of aldehydes... 

In a comparison study involving Mannich reactions of enol silanes, Holy et al. report that iminium salts (30H32) react at similar rates in DMF, where they are soluble, but in less polar solvents reduced solubility slows the rate and adversely affects the yield. For this reason the more soluble trifluoroace-tate (32) should be used in place of the iodide (30) or chloride (31) when conducting reactions in less polar solvents such as CH2CI2. Iminium salts (30)-(32) must be stored in the absence of moisture, while the iodide (30) should be kept from light. The trifluoroacetate (32) is a liquid and must be distilled to remove traces of TFA, which will adversely affect reactions with enol silanes and enolates. 

Reactions of enol silanes with (V,N-dimethyl(methylene)iminium salts occur under milder conditions than those of simple ketones because an initial enolization step is not required. The reaction is normally performed at room temperature, and aprotic solvents must be used to prevent hydrolysis of the enol silane. Danishefsky and coworkers, in their pioneering investigations of this reaction using TMS enol silanes and iminium iodide (30), have suggested the intermediacy of a silyloxonium salt (57), which loses a proton to give a 2-substituted enol silane (58) as its HI salt (Scheme 11). Subsequent hydrolysis of the enol silane during acid-base work-up affords the Mannich base (59). 

In the corresponding reactions of TBDMS enol silanes (60), Akiba and coworkers have shown that the more stable TBDMS group is able to survive the work-up, affording Mannich bases as their TBDMS enol silane derivatives (62 Scheme 12). Interestingly, acyclic TBDMS enol silanes react with migra-... 

Figure 3 Proposed intramolecular proton abstraction occurring in Mannich reactions of TBDMS enol silanes...

Table 8 highlights some versatile applications of the Mannich reaction of enol silanes, providing Mannich bases that in some cases are very difficult, if not impossible, to obtain using the classical method. Regiocontrol is observed in the preparation of the two Mannich bases of 2-methylcyclohexanone from the corresponding regioisomeric enol silane derivatives (entries 1 and 2)P Aminomethylation of the enol... 

Table 8 Mannich Reactions of Enol Silanes Using jV-Dimethyl(methylene)iminium Salts...

Some comparisons between the yields of the Mannich reaction of enol silanes using in situ methods for preparation of the iminium salt and non in situ methods are shown in Table 9. Higher yields (20-30%) of P-amino ketones using in situ methods are seen in entries 2 and 4 but not in entry 1. Although a clear advantage of the in situ methods is not evident in these limited examples, in situ methods may be preferred from the standpoint of convenience. With aldehyde enol silanes (entry 3), the in situ method of Miyano et al is less practical due to elimination of the amino group, presumably caused by the strongly basic N,/V,/V, N -tetramethyl(methylene)diamine present in solution. 

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. ... 

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