Domino Michael/Mannich reactions

Scheme 2.38 Domino Michael/Mannich reaction of imino esters with nitroalkenes catalysed by an in situ generated imidazoline-aminophenol nickel catalyst.

Scheme 4.1 Domino Michael/Mannich reaction of imino esters with nitroalkenes.

As additional examples, we can first note the use of silylated serine or threonine for the addition of 2-phenylpropanal to vinylsulfone, giving the corresponding adduct in good yields (85-90%) but low ee (44-45%). As a second example, an aza-Michael reaction has been described with the ethyl methyl imidazolium salt of glycine as a catalyst. As a last example, the interest in tert-leucine can be noticed as it could act as a cocatalyst with a pyrrolidine bearing a thiopyridine. The ion-pair catalyst catalysed the domino oxa-Michael-Mannich reaction of salicylic aldehydes with cyclohex-2-enones. ... 

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

Scheme 2.6 Domino oxa-Michael-Mannich reaction catalysed by a combination of a chiral pyrrolidine and n-tert-leucine.

Scheme 2.22 Three-component domino Michael-Mannich-cyclisation reaction catalysed by a combination of chiral diphenylprolinol triethylsilyl ether and a chiral thiourea.

With regard to asymmetric aldol reactions, it has been shown that prolinamine catalysts such as 22 can also work well for intramolecular aldol [126-128], Henry (nitroaldol) [129], Mannich [130, 131], and domino-Michael-aldol reactions [132] as valuable asymmetric transformations. 

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>. 

In contrast to aldol reactions, the major diastereoisomer formed in the Mannich reaction has syn configuration, because the orientation of the imine is opposite to that of the carbonyl in the transition state (figure C in Scheme 6.5). Carter et al. reported an organocatalysed domino Mannich-aza-Michael reaction for accessing nitrogen-containing [2.2.2]-bicyclic scaffolds promoted by 15e, in a highly enantioselective and diastereoselective manner (eqn. (3) in Scheme 6.5). 

The aza-Morita-Baylis-HiUman reaction is known to be a useful and atom-economical C-C bond-forming reaction of electron-deficient alkenes with imines usually catalyzed by Lewis bases [202]. It formally involves a sequence of reactions including a Michael addition, a Mannich reaction, a proton transfer, and a retro-Michael reaction ( -elimination). Although there are many reports in the field of the enantioselective aza-Morita-Baylis-Hilhnan reaction, only rare examples of asymmetric domino reactions initiated by this reaction have been reported. In 2010, Sasai et al. [203] developed the first organocatalyzed asymmetric domino aza-Morita-Baylis-Hillman/aza-Michael reaction of a,p-unsaturated carbonyl compounds with N-tosylimines, allowing an easy access to chiral cis-1,3-disubstituted isoindolines as single diastereomers. The process was induced by a Hg-BINOL-derived catalyst and provided these products in high yields and enantioselectivities, as shown in Scheme 10.18. 

In addition, a four-component domino Michael/nitro-Mannich/lactamization reaction was recently developed by Dixon et al. [286]. It occurred between a... 

A great deal of attention has been given to asymmetric Mannich reactions, some of which can be applied to the preparation of bridged piperidine systems. Among them, we will mention Carter s preparation of compound 130 from diaryl imines and 2-cyclohexenone in the presence of a modified proline catalyst via an asymmetric Mannich-Michael domino sequence (Scheme 3.39) [88]. 

The zinc chloride-mediated reaction of galactosyl imine 338 (R = Pr) with Danishefsky s diene 345 followed by acid treatment led to the diastereoselective formation of cyclic enaminone 346 in a domino Mannich-Michael sequence. The pure diastereomer 346, isolated in 81% yield, was converted into (5)-coniine, again under recovery of the reusable tetra-pivaloyl galactose 341 (Scheme 4.76) [170b, 173]. Later, the use of polymer-bound galactosyl imines for Mannich reactions and other transformations was reported [174]. 

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

Scheme 10.17 Synthesis of pyrrolidines through domino Mannich/aza-Michael reaction.

In parallel, Akiyama used the same type of catalysts for highly enantioselective indirect Mannich-type reactions [8]. His group also disclosed that these chiral phosphoric acid derivatives can catalyse the aza-Diels-Alder reaction with high stereoselectivity [75]. In addition, chiral-phosphoric acids can mediate similar transformations as the proline-catalyzed domino Mannich/aza-Michael reactions with high enantioselectivity [76]. 

One of the first examples of an enamine-catalyzed cascade reaction for the synthesis of a complex alkaloid was reported by Itoh et al. (179). Reaction of the dihydrocarboline 194 with enone 195 in the presence of (5)-12 (7 days) gave the tetracycle 196 as a single diastereomer and in excellent enantiopurity (99%). This reaction can be described best as an enamine-catalyzed Mannich-Michael domino addition. Further manipulations then gave access to the indole alkaloid ent-dihydrocorynantheol (197) in an elegant and facile manner. As depicted in... 

With regard to aldol chemistry, Mannich or domino-Mannich-Michael reactions can also be promoted by N-arylsulfonyl-substituted prolinamide catalysts such as 17 with high levels of enantioselectivity [82, 83). 

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