Ketene silyl acetals Mannich reaction

Examples of the Bronsted-acid catalysts and hydrogen-bond catalysts are shown in Figure 2.1. We have recently reported the Mannich-type reaction of ketene silyl acetals with aldimines derived from aromatic aldehyde catalyzed by chiral phosphoric acid 7 (Figure 2.2, Scheme 2.6) [12]. The corresponding [5-amino esters were obtained with high syn-diastereoselectivities and excellent enantioselectivities. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

In another study by Dondoni et al. [17] the synthesis of C-glycosyl-/ -aminoesters as single diastereomers is achieved via a Mannich-type three-component reaction of /Minked C-galactosyl or C-ribosyl formaldehyde, p-methoxybenzyl amine and ketene silyl acetals using catalytic amounts of InCfi (Scheme 9.8). 

Another type of organocatalyst, which is suitable for the Mannich reaction with ketene silyl acetals, is a chiral binaphthyl phosphoric acid [38c]. Very recently, it has been reported that high enantioselectivity of up to 96% ee can be obtained with this type of catalyst [38c]. 

Diastereoselective Mannich-type reactions between ketene silyl acetals and chiral sulfinimines using simple metal-free Lewis bases such as tetraalkylammonium car-boxylates have been reported. The sulfinimine can even be generated in situ (from aldehyde and a chiral sulfonamide), using cesium carbonate, followed by addition of ketene silyl acetal at -78 °C, and as little as 1 mol% of catalyst.32... 

Several procedures for a one-pot Mannich-type reaction in water to give (3-amino carbonyl compounds catalyzed by either Lewis acid or Bronsted acid with or without addition of surfactants have been developed. The reactions are high yielding however, the diastereoselectivities are moderate. The HBF4-catalyzed reaction between aldimines and ketene silyl acetals in a water/SDS mixture provides high stereoselectivity with very good yields (Scheme 5.19). 

Scheme 3.3 Mukaiyama type Mannich reaction of imines with ketene silyl acetals.

Wenzel and Jacobsen reported the thiourea 15b-catalyzed Mannich-type reaction of a ketene silyl acetal with an N-Boc-aldimine, furnishing (3-amino esters with excellent enantioselectivities (Equation 10.30) [59]. Subsequently, Jacobsen and co-workers reported the hydrophosphonylation of dialkyl phosphites with aldimines to yield a-amino phosphonates [60]. 

In the addition of indole toiV-benzoyl aldimines, 3 also can be put to use. The catalyst IF is for promoting reaction between ketene silyl acetals and A-(o-hydroxyphenyl)aldimines, ° and the 3,3 -dimesityl analogue for vinylogous Mannich reaction. The imines are suitably activated as shown below. 

Mannich reaction. Reaction between ketene silyl acetals and aldimines occurs in the presence of sulfated zirconia in MeCN at room temperature. The reusable solid catalyst is easily recovered. 

Mannich-type Reactions. The reactions of imines with ketene silyl acetals proceed smoothly in the presence of Sc(OTf)3 to afford the corresponding /3-amino ester derivative in moderate yield (eq 6). Sc(OTf)3 shows higher activity than Yb(OTf>3 does in this case. The catalyst can be recovered after the reaction is complete and reused. A Mannich-type reaction of IV-(/3-aminoalkyl)benzotriazoles with sUyl enolates has also been developed. Mannich-type reactions of polymer-supported sUyl enol ethers with imines or of polymer-supported a-iminoaceta-tes with silyl enolates are also catalyzed by Sc(OTf)3. 

Sc(OTf)3-catalyzed Mannich-type reactions ofhydrazones with ketene silyl acetals also proceeded readily to give the corresponding P-N-benzoylhydrazinocarbonyl compounds (Scheme 12.4) [7,8]. When o-glyceraldehyde-derivedbenzoylhydrazone was used, five-membered lactone was obtained in high yield with a single isomer after treatment with an acid. 

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. 

Mannich-type Reactions. Reactions of imines with ketene silyl acetals proceed smoothly in the presence of 5 mol % Y(OTf)3 to give the corresponding /3-amino ester in high yield (eq 2). Yb(OTf)3 and Sc(OTf)3 were both found to be more active for this reaction. 

Chiral BBA (30) has been shown to be effective as a Bronsted acid catalyst for Mannich-type reaction of ketene silyl acetals and aldimines and good enantioselectivity was observed (up to 77% ee) using 3.5 or 10mol% of chiral BBA (30) (Scheme 1.35). 

Ketimines and aldimines proved to be good substrates [73]. Based on the structure modification, nuclear magnetic resonance (NMR) study, kinetic study, and computational study, they proposed a double hydrogen bond structure between the acidic N-H protons and the imine lone pair to activate the electrophile toward the attack by the cyanide ion (Figure 2.15) [74]. The catalyst system is applicable to the Mannich-type reaction of N-Boc-aldimine with ketene silyl acetals to give corresponding P-amino esters in 86-98% ee (Scheme 2.25) [75]. Hydrophospho-nylation of aldimines with bis(2-nitrobenzyl)phosphite by means of (4d) furnished a-amino phosphonates in good enantioselectivity (Scheme 2.26) [76]. 

Ishihara and Yamamoto designed a Bronsted acid assisted chiral Bronsted acid catalyst (40), bearing a bis (trifly l)methyl group (Figure 2.31) [152]. The enantios-elective Mannich-type reaction of ketene silyl acetals with aldimines catalyzed by (40) in the presence of stoichiometric achiral proton source gave (S)-P-amino esters in high yields with good enantiomeric excesses. 

We have synthesized a TADDOL-based phosphoric acid diester (47), which catalyzed the Mannich-type reaction of ketene silyl acetal with aldimines to give p-amino esters with high enantioselectivity. (Scheme 2.104) [180]. 

Entry 6 is analogous to a silyl ketene acetal rearrangement. The reactant in this case is an imide. Entry 7 is an example of PdCl2-catalyzed imidate rearrangement. Entry 8 is an example of an azonia-Cope rearrangement, with the monocylic intermediate then undergoing an intramolecular Mannich condensation. (See Section 2.2.1 for a discussion of the Mannich reaction). Entry 9 shows a thioimidate rearrangement. 

Related catalytic enantioseiective processes Representative examples of other catalytic asymmetric Mannich additions are depicted in Scheme 6.31. In 1997, Tomioka demonstrated a Li-catalyzed synthesis of functionalized p-lactams that proceeds through a catalytic enantioseiective Mannich reaction (promoted by 103) [95], and a year later Lectka and his team published a series of reports concerning additions of silyl ketene acetals... 

Interestingly, fundamentally different stereoinduction mechanisms have been proposed for the activation of a number of related imine substrates, studies that resulted in the development of simple and highly effective new catalytic systems (27) for the addition of silyl ketene acetals to Al-Boc-protected aldimines (Mannich reaction) (Scheme 11.12c). ... 

The Akiyama group tested various BINOL phosphates 3 as catalysts for the indirect Mannich reaction of aldimines 8 derived from 2-aminophenol with silyl ketene acetals 9 (Scheme 4). All of these Brpnsted acids furnished P-amino ester 10a in (nearly) quantitative yields. Both the reaction rates (4-46 h) and the enantioselectivities (27-87% ee) were strongly dependent on the nature of the substituents at the 3,3 -positions. 

Scheme 5 Mannich reaction of silyl ketene acetals...

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

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