Mannich three-component catalyzed

Quite recently, not only Lewis adds, but also Bronsted adds were found to be effedive catalysts for the three-component Mannich-type reactions in water with the aid of a surfadant. For example, Akiyama and co-workers1301 have reported that a combination of HBF4 and SDS is effedive for the readions of aldehydes, amines, and silyl enolates. We have found that dodecylbenzenesulfonic add (DBSA), a Bronsted add with a surfadant moiety, also catalyzes the reactions in water.1311 Furthermore, DBSA can be used for the dired Mannich-type reactions of aldehydes, amines, and ketones, without using silyl enolates as nucleophilic components (Eq. 8).1321... 

In parallel to the bismuth(III)-catalyzed three-component allylation reaction, we have reported the corresponding three-component bismuth(III)-catalyzed Mannich-type reaction. A major merit of the three-component reaction is indeed that many unique structures can be afforded rapidly when three or more reactants are combined in a single step to afford new compounds. The development of an efficient bismuth-catalyzed Mannich-type three-component reaction that combines an aldehyde, an amine, and a silyl enolate to give compounds with a (3-amino carbonyl core... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Scheme 9.2. (R)-LaLi3tris(binaphthoxide)-catalyzed enantioselective three-component Mannich reaction.

List and coworkers discovered the first efficient catalytic asymmetric three-component Mannich reaction. In this proline-catalyzed Mannich reaction between ketones, aldehydes, and amines (typically p-anisidine, 6), Mannich products are formed in up to >99% ee and up to 96% yield (Scheme 9.3) [4],... 

The proline-catalyzed three-component Mannich reaction is proposed to proceed through the reaction of enamine a, formed by the reaction of the ketone with pro-... 

The required aldehyde precursor 186 was obtained by a Sn(II)-catalyzed asymmetric aldol reaction [90]. It was then mixed in one pot with o-methoxy aniline 187 and enol ether 188 to afford the key /7-amino ketone 189 in a 2 1 diastereomeric ratio through a Mannich-type three-component reaction. This reaction was performed in an aqueous medium and the use of a surfactant such as dodecyl sulfate (DS) was essential. The diastereomeric mixture 189 was treated with HF and the... 

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

The reaction can be regarded as a regiospecific asymmetric synthesis of 3-amino-l-ols. Proline also catalyzes the first one-pot three-component direct catalytic enantioseledive Mannich readions with two unmodified aldehydes and anilines (Eq. 11) [39, 40],... 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

S)-Proline also catalyzed Mannich reactions in a three-component (donor aldehyde, 4-methoxyaniline, arylaldehyde) protocol - that is, without preformation of imine (Table 2.14) [71b, 82]. (For experimental details see Chapter 14.2.2). This three-component format also afforded the syn-Mannich products in good yields with high diastereoselectivity and enantioselectivities when slow addition of donor aldehyde and/or formation of the imine prior to addition of donor aldehyde was used at a lower reaction temperature, such —20 °C. Reactivity of benzaldehyde and of N-PMP-imine of benzaldehyde as acceptors was compared in the... 

Table 2.14 (S)-Proline-catalyzed three-component Mannich reactions of aldehyde donors [71b, 82].

S)-proline-catalyzed reaction using propionaldehyde as donor and the results showed that the imine reactivity was approximately sevenfold higher than that of the aldehyde [83]. Under basic conditions, it is generally accepted that nucleophilic addition to an aldehyde is typically faster than addition to an aldimine, but nucleophilic addition to an aldimine is faster than addition to an aldehyde when protonation of the imine nitrogen occurs [83]. In the (S)-proline-catalyzed three-component Mannich reactions in the absence of arylaldehyde, self-Mannich products were obtained with moderate to high diastereo- and enantioselectivities (Scheme 2.19) [71b, 82]. 

S)-Proline also catalyzed Mannich reactions of ketone donors in a three-component (donor ketone, 4-methoxyaniline, aryaldehyde) protocol, as shown in Table 2.16 [84b, 90, 91]. In these three component reactions, the C-C bond formation occurred at both a-positions of unsymmetrical alkyl ketones (entry 3), and the ratio of the regioisomers depended on the reactant ketones and aldehydes. When the reaction was performed using a ketone donor possessing an a-hydroxy or methoxy group, C-C bond formation occurred exclusively at the oxy-substituted a-carbon (entries 5-7) the major diastereomer was again the syn-product. The enantioselectivities of (S)-proline-catalyzed three-component... 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

List B, Pojarliev P, Biller TW, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

Although the authors used a pre-formed imine, there are several examples known of proline catalyzed one-pot three component Mannich reactions. However, if aromatic aldehydes are used in this one-pot procedure, the obtained Mannich products had to be reduced (by NaBH4> to the corresponding alcohols to avoid epimerization [38, 39]. 

L-Proline catalyzes the aldol reaction. This approach has been applied to the synthesis of carbohydrate derivatives as illustrated by the glucose derivative 7 (Fig. 11) (237). The three-component Mannich reaction can be used to prepare p-amino and p-amino a-hydroxy carbonyl compounds in a single step (Fig. 12) (233). As with other types of catalysts, organocatalysts can be immobilized to aid recovery (253). 

The Hf(OTf)4-catalyzed Mannich-type reaction of imine with enol silyl ethers has been used as a means of access to 8-amino carbonyl compounds (Eq. 21) [23] this also was extended to a three-component reaction (Eq. 22). 

In the solid phase, Sc(OTf)3 also effectively catalyzed Mannich-type three-component reactions of aldehydes, amines, and PSSEEs to afford polymer-supported /3-amino thioesters (Eq. 22). Reductive cleavage from the supports gave the amino alcohols in good to high yields [85b]. /3-Amino acid and /3-lactam libraries are also constructed according by this method (Eq. 23). 

List, B., Pojarliev, P., Biller, W. T., Martin, H. J. The Proline-Catalyzed Direct Asymmetric Three-Component Mannich Reaction Scope, Optimization, and Application to the Highly Enantioselective Synthesis of 1,2-Amino Alcohols. J. Am. Chem. Soc. 2002,124, 827-833. 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

Gong K, Dong F, Wang HL, Liu ZL (2007) Basic functionalized ionic liquid catalyzed one-pot Mannich-type reaction three component synthesis of P-amino carbonyl compounds. Monatsh fur Chemie 138 1195-1198... 

A variety of propargylamines can be prepared by three-component Mannich condensation of acetylenes, aldehydes, and secondary amines (Scheme 7.19) [66, 67). These reactions were performed using CuCl to activate the acetylene component. Reaction times varied from 3-36 h. Silver iodide has recently been used to catalyze the reaction [68]. 

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