Mannich aldehyde donors

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

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. 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

Mannich-Type Reactions of Aldehyde Donors with Glyoxylate Imines... 

Table 2.10 (S)-Proline-catalyzed Mannich-type reactions of aldehyde donors and /N/-PMP-protected glyoxylate imine [71 a,b].

Table 2.12 ont/ -Mannich-type reactions of aldehyde donors and N-PMP-protected glyoxylate imine catalyzed by (3/ ,5/ )-5-methyl-3-pyrrolidine-carboxylic acid (13) [73]. 

The (S)-proline-catalyzed Mannich reactions of aldehyde donors and N-PMP-protected imines of fluorinated aldehyde, such as CF3CHO, C2F5CHO, and PI1CF2CHO, were also used for the expedient synthesis of fluorinated aminoalco-hols [81]. 

Three-Component Mannich Reactions using Aldehyde Donors... 

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

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

In 2003, the groups headed by Hayashi [80], Barbas [81], and Cordova [82] simultaneously extended the scope of this asymmetric MCR using aldehyde donors in the presence of chiral pyrrolidine-based catalysts for the so-called enantioselective cross-Mannich reaction (Scheme 16.39). This efficient combination of two different aldehydes has led to a highly stereoselective synthesis of 3-amino aldehydes and y-amino alcohols. Recently, chiral ionic liquids have been efficiently used as catalysts for similar asymmetric Mannich reactions [83]. 

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 easiest way to perform a Mannich reaction is to use an excess of the ketone donor and an aldehyde-amine pair to form the required imine in situ. This three-component Mannich protocol is, however, mostly restricted to aromatic amines (Scheme 24). 

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) ... 

This protocol complements Akiyama s method which provides P-amino carbonyl compounds as i yn-diastereomers [14], It tolerated aromatic, heteroaromatic, and aliphatic aldehydes. Cyclic ketones, acetone, as well as acetophenone derivatives could be employed. The use of aromatic ketones as Mannich donors was up to that time unprecedented in asymmetric organocatalysis. Rueping et al. independently expanded the scope of the asymmetric Brpnsted acid-catalyzed Mannich reaction of acetophenone [45]. 

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

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.

S)-Proline has been used to catalyze Mannich-type reactions of enolizable carbonyl donors. Reactions of unmodified aldehydes and N-p-methoxyphenyl (PMP)-protected glyoxylate imine in the presence of a catalytic amount of (S)-proline at room temperature afforded enantiomerically enriched / -aminoaldehydes, as... 

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... 

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... 

Enders and co-workers [162] have reported a protocol for the synthesis of aminopentoses and aminohexoses based on the use of 2,2-dimethyl-l,3-dioxan-5-one (25) as the ketone donor in a three-component Mannich reaction with several aldehydes and p-anisidine in the presence of L-proline or (fert-butyl)dimethylsilyloxy-L-proline as organocatalysts. 

The three-component Mannich reactions with various donor aldehydes have been studied also by Hayashi and co-workers [164], giving rise, after reduction, to several aminopolyols with high i yw-diastereo and enantioselectivities. 

Complexes of a variety of binaphtholate derivatives of general formulas Zr(OR)2(OC10H5R)2, Zr[(OC 10H5R)2]2L2 (R = H, Br, Cl L = donor),470 and Zr(0 Bu )2(0 Ph BrC, 0H, )2509 have been prepared. The chirality of these binaphthol derivatives has prompted applications as catalysts for enantioselective organic transformations. These included alkylation of aldehydes,510 Mannich-type reactions,511-513 allylation of imines,514-517 aza-Diels-Alder reactions,509 518 asymmetric prop-2-ynylation,519 aldol reactions,520,521 and alkene polymerization.508,522,523... 

The Morita-Baylis-Hillman reaction and its aza-variant - the reaction of an electron-deficient alkene with an aldehyde (MBH) or an imine (aza-MBH) - provide a convenient route to highly functionalized allylic alcohols and amines. This reaction is catalyzed by simple amines or phosphines, which can react as a Michael donor with an electron-deficient alkene, generating an enolate intermediate. This intermediate in turn undergoes the aldol or Mannich reaction with electrophilic C=0 or C=N bonds, respectively, to deliver allylic alcohols and amines. 

As the intermediate enamine reacts faster with imines than aldehydes, a one-pot three component coupling of the donor ketone, aldehyde and amine is possible. List and coworkers have achieved high ees in this reaction utilising L-proline (7.66) and some aliphatic aldehydes and aromatic aldehydes such as (7.136) in combination with p-anisidene (7.137). This catalyst system is also effective for the coupling of a-hydroxyketones. Use of the tetrazole-substituted proline (7.80) allows the reaction to be performed in dichloromethane rather than DMSO and high ees in the Mannich reaction between aliphatic ketones and imines derived from ethyl glyoxalate have been obtained imder these reaction conditions. 

Chiral amines can react with so-called Mannich donors such as ketones or aldehydes. The resulting chiral enamines wiU then attack a Mannich acceptor, usually a prochiral aldimine, thereby introducing one or two chiral centers in the Mannich product. This usually is a P-aminoaldehyde or P-aminoketone, optionally substituted at the a-position. Inspired by their work on proline-catalyzed asymmetric aldol reactions [1], the List group envisioned that the related Mannich reactions might also be carried out with a catalytic amount of an enantiomerically pure chiral amine. This led in 2000 to the first direct catalytic asymmetric organocatalyzed Mannich reaction, catalyzed by L-proline (1, Scheme 5.1) [2],... 

List also reported on the synthesis of iV-Boc protected aldimines employing proline as the catalyst, and found that acetone could be used as Mannich donor (73% yield, ee >98%) [20]. The latter gronp nicely exemplified the viability of using Boc-protected aldimines 23a-e in Mannich reactions with aldehydes 2b, 2d, 2f to prepare a series of p-aminoaldehydes 25a-g in high yield and excellent selectivities (Scheme 5.14) [21], An important difference with the A-aryl-protected imines 10 is that due to the more difficult formation of A-acylated imines, preformation of the imines is required and that three-component Mannich reactions are not possible. 

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