Enamine Mannich reaction

Mannich reaction as a part of the enamine (16) is hydrolyzed into its components by the residual water in the paraformaldehyde (126). 

More recently in 2001, Winkler and Kwak reported methodology designed to access the pyrrolidine core of the hetisine alkaloids via a photochemical [2+2], retro-Mannich, Mannich sequence (Scheme 1.3) [26]. In a representative example of the methodology, vinylogous amide 42 was photo-irradiated to give the [2+2] cycloaddition product 43. Heating cyclobutane 43 in ethanol provided enamine 44 via a retro-Mannich reaction. Exposure of enamine 44 to acidic conditions then effected a Mannich reaction, resulting in pyrrolidine 45. 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

Mannich Reactions Expanding the concept of enamine catalysis outside... 

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

The scope of the enamine-catalyzed Mannich reaction can be considerably expanded by the use of preformed imines. These two-component Mannich reactions can be either syn selective [91, 94, 136, 220, 222, 230-233, 245, 248-258] (proline or its simple derivatives as catalysts) or anti selective [220, 259-268]... 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Dixon reported that saturated BINOL 45 sufficiently activates various N-Boc aryl imines toward Mannich reaction with acetophenone-derived enamines to yield P-amrno aryl ketones in good yields and enantioselectivities (Scheme 5.62) [116]. The same group applied a BINOL-derived tetraol catalyst to the addition of meth-yleneaminopyrroHdine to N-Boc aryl imines. Interestingly, appendage of two extra diarymethanol groups to the BINOL scaffold resulted in a marked increase in enantiomeric excess [117]. 

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-... 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

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 mechanism of proline-catalyzed Mannich reactions is depicted in Scheme 5. The ketone or aldehyde donor reacts with proline to give an enamine. Next, the preformed or in-situ-generated imine reacts with the enamine to give, after hydrolysis, the enantiomerically enriched Mannich adduct the catalytic cycle can then be repeated. 

The stereochemical outcome of L-proline catalyzed direct asymmetric Mannich reactions is explained by a Si-facial attack on the imine, which has a trans configuration, by the Si face of the enamine, which has a trans configuration (Fig. 7). 

Scheme 2.1 The enamine catalytic cycle. An enamine derived from an amine- or amino acid-catalyst can react with a variety of electrophiles. The aldehyde and ketone reactants that form enamines and act as nucleophiles are often described as donors . Aldehyde and imine reactants that serve as electrophiles are described as acceptors for aldol and Mannich reactions, respectively. Ketones also serve as acceptors for aldol reactions.

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

By way of Mannich reaction (step 1) and /1-elimination (step 2), the transformations shown in Figures 12.14 and 12.15 demonstrate how an aldol condensation (for the term see Section 13.4.1) can be conducted under acidic conditions as well. Both the enamine reaction in Figure 12.18 and the enol ether reaction in Figure 12.23 illustrate the same thing differently. Many aldol condensations, however, start from carbonyl compounds only and proceed under basic conditions. They follow a totally different mechanism (Section 13.4.1). 

A few other reactions were omitted because they did not fit into the current presentation (nitrile and alkyne chemistry, cyanohydrin formation, reductive amination, Mannich reaction, enol and enamine reactions). 

The Mannich reaction of enaminones was examined intensively. Enamines derived from dimedone are aminoalkylated in the -position in good yield if the nitrogen is unsubstituted or monosubstituted31,34. Primary amines and formaldehyde react with enaminones to yield tetrahydropyrimidines34 (equation 21). A similar reaction is observed for acyclic enaminones. With primary amines and formaldehyde, tetrahydropyrimidines are formed35 (equation 22). 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

Vinylindole 68 was deprotected and the crude product, after purification, was reacted with a large excess of butyric aldehyde in MeCN in the presence of molecular sieves to give 13a and 13b and l,3-ethyl-2,3,4,5-tetrahydro-2-methyl-l,5-methano-l,3-diazocino[l,8- ]indole-6-nitrile 12a and 12b as a mixture of diastereomers (1 2 a-CN, /3-CN) (Equation 5). The formation of these products can be rationalized in terms of a domino process consisting of enamine formation, Michael addition, and Mannich reaction. When TFA was added directly to the reaction mixture, only 13a and 13b were obtained since 12a and 12b in acidic medium rearrange to 13a and 13b (see Section 14.05.2.4 (Equation 3) <1995S592>. 

List " suggested that the proline-catalyzed Mannich reaction proceeds in close analogy to the proline-catalyzed aldol reaction. As detailed in Scheme 6.10, the ketone and proline combine to form an enamine. The aldehyde reacts with a primary amine (usually an aniline derivative) giving an imine. The enamine and imine then combine to produce, after hydrolysis, the Mannich product. 

Houk and Bahmnyar located the TSs for the Mannich reaction of the enamine of acetone and proline with A-ethyUdine-A-phenylamine (Reaction 6.27) at B3LYP/6-31G. They looked only for the TSs that allowed for proton transfer from... 

HCN, 193, 442 de-conjugation, 159 dehydrogenation, 189 enamine formation, 185-186 enolisation, 156 ei seq. epoxidation, 18, 201, 442 formation, 109, 189, 248, 337 hydroboration. So Mannich reaction (aminometh-ylation), 172 methylation, 168-171 methylene addition, 202 oxidation, Baeyer-VUliger, 349, 445... 

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