Mannich-type reaction silicon enolates

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

In Yb(OTf)3-catalyzed Mannich-type reaction of the imine with silicon enolate conducted in SCCO2, the desired product is obtained in only 10 % yield after 3 h due to the low solubility of reactants in scC02 (Scheme 3.11, R1, R2, R3, R4, Rs=Ph, Bn, Me, Me, OMe) [57]. Addition of PEG is found to improve the yield to 72 %. The formation of emulsions can be observed in the presence of PEG. The highest yield (72 %) can be reached at 15 MPa CO2 pressure using PEG400 (MW = 400). This system has been applicable to various substrates including imines derived from aromatic and heterocyclic as well as aliphatic aldehydes and silicon enolates derived from esters, thioesters, and a ketone as depicted in Scheme 3.11. 

It is noteworthy that hydrolysis of the silicon enolate was not a severe problem even in the presence of the Br0sted acid. Akiyama and co-workers also developed Bifisted acid-catalysed Mannich-type reactions in water in the presence of a surfactant [35]. 

Although the reaction system stated above has extended the substrate applicability in Mannich reactions in water, there is still a drawback that the silicon enolates, which are prepared from the corresponding carbonyl compounds usually under anhydrous conditions, have to be used. From atom-economical and practical points of view, it is desirable to develop an efficient system for Mannich-type reactions in which the parent carbonyl compounds are directly used. Along this line, we next investigated three-component Mannich-type reactions in water using ketones, instead of silicon enolates, as nucleophilic components, and found that DBSA was also an effective catalyst [36]. An example is shown in Equation (7), where only 1 mol% DBSA was sufficient to give the desired product. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds. In recent years, various enantioselective Mannich reactions have been developed. Among them, catalytic enantioselective additions of silicon enolates to imines have been elaborated into one of the most powerful and efhcient asymmetric Mannich-type reactions, primarily because sihcon enolates can be prepared regio- and stereoselectively from various carbonyl compounds. ... 

Three-component Mannich-type reactions of aldehydes, amines, and silicon enolates also proceeded smoothly using PS-SO3H in water (Scheme 3.37). In general, ketene silyl acetals are known to be easily hydrolyzed in the presence of water however, such water-labile compounds could be successfully used in this reaction. Moreover, a remarkable effect of the loading levels of the polystyrene-supported sulfonic acid on yields was observed. It was suggested that the hydrophobic environment created by the catalyst might suppress hydrolysis of ketene silyl acetals. 

Kobayashi and coworkers showed that Lewis add surfactant-combined catalysts such as scandium tris(dodecyl sulfate), Sc(03SCi2H25)3, or copper bis(dodecyl sulfate), Cu(03SCi2H25)2, were efficient catalysts for the three-component Mannich-type reaction, with 73-95% yield being obtained in neat water.Neutral salts such as sodium triflate and sodium iodide catalyzed the condensation reaction in water between preformed imines and silicon enolates, or the three-component Mannich-type reaction using aromatic amines, with 49-93% yields and 0-80% diastereoselectivities. Mechanistic studies indicated that both sodium triflate and the Mannich adduct itself cooperatively promote the reaction. 

Finally, Mukaiyama-Mannich-type reactions can also be induced and mediated by proton activation of the imine component, which thereby obtains a sufficient degree of reactivity to be attacked by highly nucleophilic silicon enolates. Thus, Wenzel and Jacobsen have shown that the specific protection by N-aryl substituents with a pendant ortho-hydioxy or ortho-methoxy chelating group is not required, if the acetate-derived sHyl ketene acetals 362 are reacted with simply BOC-protected aryl and hetaryl imines 361. Thus, P-amino esters 364 are obtained in excellent enantiomeric excess, if the reaction is catalyzed by the chiral urea derivative 363 that is assumedto act by activation through hydrogen bonding (Scheme 5.95) [181]. 

In 1998, a new type of Pd(II) binuclear complex was reported which was effective for Mannich reactions of an imine derived from glyoxylate and anisidine with silicon enolates [38,39]. In these reactions, use of solvents including a small amount of water was essential. It was shown that water played an important role in this system water not only activated the Pd(II) complex to generate a cation complex, but also cleaved the N-Pd bond of the intermediate to regenerate the chiral catalyst. This reaction reportedly proceeded via an optically active palladium enolate on the basis of NMR and ESIMS analyses. A unique binuclear palladium-sandwiched enolate was obtained in the reaction of the p-hydroxo palladium complex with the silyl enol ether [(Eq. (9)]. 

---