Enamine activation sequence

In 2010, Enders and co-workers developed a quadruple cascade AFC/ Michael/Michael/aldol condensation reaction of indoles, acrolein, and nitroalkenes under the catalysis of diphenylprolinol TMS-ether catalyst (S)-104 following an iminium/enamine/iminium/enamine activation sequence (Scheme 6.42). " The reaction provided a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles 105 bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivity (91 9->95 5 dr and 94->99% ee). 

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

Scheme 42.9 Three

Figure 42.2 Iminium ion-enamine activation sequence compatibility between the nucleophile (Nu) and the electrophile (E) is required.

Scheme 42.20 Changing the fate of a domino process by modulating the concentration of enal 58 (a) double domino reaction by means of an iminium ion-enamine activation sequence (b) quadruple...

Design of Enamine-Iminium Cascades Similar to an enamine-enamine activation sequence, a subsequent iminium process is possible on 6 and 41 (Figure 1.2). 

A new organocatalytic Michael/a-amination sequence based on double enamine activation of aldehydes produces a-hydrazino-aldehydes bearing a quaternary stereocentre in high yield and ee ... 

Chiral secondary amine could be employed to catalyze this cascade process. Kim et al. utilized Jprgensen catalyst 53 successfully to catalyze the cascade [1,5]-HT/ ring closure sequences of o-A -pyrrolidinyl-substituted cinnamaldehydes 51 via sequential iminium and enamine activation, affording chiral tetrahydroquinolines 52 in high enantioselectivities (Scheme 19, a) [98]. Products incorporated with 7- to... 

Jprgensen and coworkers exploited an approach in 2005 by designing a three-component reaction involving iminium/enamine activation (Scheme 2.23). They demonstrated that thiols 84 can initiate the sequence by a thia-Michael addition to... 

Scheme 42.6 A Mannich/aza-Michael tandem reaction under an enamine/iminium ion activation sequence.

Almost simultaneously, MacMillan and colleagues developed a similar MCR based on the iminium ion-enamine activation of enals (Scheme 42.11) [33]. They used the chiral imidazolidinone catalyst 41 to combine the enantioselective conjugate additions of a large number of diverse carbon-based nucleophiles with the a-chlorination of the resulting aldehyde intermediate 42, which proceeds under enamine catalysis [35]. The reaction sequence is accompanied by a high syn-selectivity and excellent enantioselectivities. 

We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode, although an iminium mode might be involved in the following steps. In this regard, several catalytic cascade sequences, including enamine-enamine, enamine-iminium, and enamine cyclization, are discussed here. 

A special but significant case of 6 is that of the a,p-unsaturated ketones 41 (R is a vinyl group). An intramolecular attack on the a,p-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 1.13a). The formation of 42 through an enamine-iminium sequence can also be viewed as a Diels-Alder reaction between intermediate 43 and the electrophile (Scheme 1.13b). 

Enamine-Iminium-Enamine Cascades The enamine-activated process followed by an mtermolecular iminium-mediated process will undergo a new enamine activation step to afford multisubstituted cyclohexanes via an enantine-intinium-enantine sequence. In this way, multicomponent reaction could be designed to produce complex structures from simple reactants. 

The cascade reactions induced by iminium catalysis in the first step are defined as iminium-activated cascade reactions, although almost all of the iminium-initiated cascade reactions are followed by an enamine-mediated process in the subsequent step. Considerable effort has been directed to construction of diverse cyclic structures via the iminium-enamine catalytic sequence. 

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

Later, the same group expanded this chemistry further by developing a cascade Michael addition/cross-benzoin condensation sequence of enolizable aldehydes 43 and activated enones 44 [27]. The reaction proceeded by means of enamine activation of aliphatic aldehydes to induce an asymmetric Michael addition to activated enones followed by an intramolecular cross-benzoin condensation (Scheme 9.30). Compared with their previous work, complex cyclopentanones with complementary substitution patterns were observed. Screening of the reaction parameters revealed that the chiral triazolium catalyst was necessary to ensure a satisfactory stereochemical outcome. Further mechanistic insights indicated that the high diasteroselectivity observed attributed to the secondary amine-induced epimerizing of the a-position of intermediate aldehyde 89. 

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