Iminium-enamine cascade

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Melchiorre and co-workers [55] demonstrated the efficiency of the TEA salt of 9-amino-(9-deoxy)-epi-hydroquinine 21 in promoting an iminium/enamine cascade sequence including a sulfa-Michael followed by an amination reaction (Figure 14.6). The reaction of a,(3-disubstituted enals with t-butyl or benzyl mercaptan and di-t-butoxycarbonyl azodicarboxylate enabled the formation, in excellent levels of enantioselectivity, of valuable precursors of a-amino acids containing two contiguous stereocenters, one of which is quaternary (Scheme 14.19). The diastereomeric ratio of products was also satisfactory. 

Albertshofer, K., Anderson, K. E., Barbas 111, C. R (2012). Assembly of spirooxindole derivatives via organocatalytic iminium-enamine cascade reactions. Organic Letters, 14, 5968-5971. 

For a merged metal catalyzed (cross-metathesis) and organocatalyzed (iminium/ enamine) cascade reaction see Reference [111]. 

The rapid development of organocatalysis impels chemists to discover new synthetic methodologies. Many important transformations that could only be realized by transition metal catalysis can now be achieved via organocatalysis. In 2010, Kim and coworkers reported a novel C-H bond functionalization reaction via a tandem 1,5-hydride transfer/ring closure sequence. Based on the iminium-enamine cascade activation of catalyst 33, the fused tetrahydroquino-Unes 35 could be synthesized from substrates 34 with good stereoselectivity. This is the first example of an organocatalytic intramolecular redox reaction (Scheme 36.10) [16]. 

Design of enamine-iminium cascades Examples of [4-1-2] reactions with enamine-activated dienes Inverse-electron-demand [4-1-2] reactions with enamine-activated dienophiles Enamine-iminium-enamine cascades... 

Design of iminium-enamine cascade reactions Iminium-activated Diels-Alder reactions Iminium-activated sequential [4h-2] reactions Iminium-activated [3-h2] reactions Iminium-activated sequential [3-1-2] reactions Iminium-activated [2h-1] reactions... 

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. 

In each of the tandem iminium ion/enamine cascade processes described above, the enamine is trapped in an intramolecular fashion. The ability to perform the trapping seQuence in an intermolecular manner would allow for the one—pot introduction of three points of diversity. IVIacNlillan has realised this goal and described a series of secondary amine catalysed conjugate addition—enamine trapping sequences with oc P Unsaturated aldehydes using tryptophan derived imidazolidinone 115 to give the products in near perfect enantiomeric excess (Scheme 47) [178]. 

Alternatively, a cascade Michael/aldol process has also been devised for the preparation of cyclopentenes also using this iminium/enamine manifold. In this reaction, a malonate reagent containing a functionalized side chain incorporating a formyl group at the appropriate position has been used as the nucleophile initiating the cascade process (Scheme 7.20). The reaction started with the Michael addition of the malonate to the a,(3-unsaturated aldehyde... 

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). 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

SCHEME 231 Proposed cascade iminium-enamine activation. 

On the wave of such impressive results, other notable research groups addressed their efforts to the development of alternative and complementary triple cascade procedures. For instance, amazing contributes have been published, over the years, by Melchiorre et al. that successfully suggested a practical synthesis of several spirocyclic oxindoles and then-analogues [72]. Exploiting the enamine-iminium-enamine activation mode of aminocatalysis, the organocatalytic triple cascade process disclosed by the Spanish group provided the stereoselective construction of all-carbon quaternary... 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

SCHEME 6.12 Cascade reaction through iminium-enamine catalysis. 

Tu et al. reported a Macmillan s catalyst 172-catalyzed asymmetric a-alkylation of tetrahydrofuran 170 containing an a,p-unsaturated aldehyde, via which chiral spiroether 171 could be prepared (Scheme 64) [129]. The sequential [l,5]-hydride transfer/cyclization was facilitated via cascade iminium/enamine activation. The presence of strong acid was indispensable to ensure sufficient electrophilicity of the iminium intermediate. Theoretically, substrate 170 reacts with 172 to give iminium intermediate I. Owing to the steric interaction of the bulky ferf-butyl group, the E enamine II is formed preferentially upon [1,5]-HT, which exists in two possible conformers III and IV. Because of dipole repulsion between the cyclic-oxocarbe-nium and enamine moieties in conformer III, IV is the more favored conformer, which undergoes intramolecular C-C bond formation to afford the final product 171. 

The previously discussed enamine/iminium activation cascade can also be reversed to give ricciocarpin A, as shown by List and coworkers in 2009 [8]. This interesting natural product shows some remarkable activity against a water snail species that acts as an intermediate host for the Schistosoma mansoni parasite, which is the most widespread trematode (flatworm) to infect humans and causes up to 200,000 deaths each year. 

Along similar lines, a DFT computational study on a double Michael cascade reaction, as shown in Scheme 17.12, has been reported by Chen and coworkers [47]. They proposed an iminium-enamine catalytic cycle wherein the stereochemistry is controlled by the catalyst backbone, which participates in C-H O hydrogen bonding interaction with the substrates. 

Enamine-intramolecular aldol cascades Iminium-initiated cascade reactions... 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

SCHEME U3 Four-component cascade reactions through iminium-enamine-iminium-enamine sequential activation. 

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 conventional Diels-Alder reactions, consecutive [4-1-2] reactions have been subjected to extensive investigation through the iminium-enamine catalytic sequence. Wang, Rios, and others simultaneously described enantioselective cascade sulfa-, oxa-, and aza-Michael/aldol/dehydration reactions promoted by chiral secondary amines. An initial strategy for a one-pot synthesis of chiral thiochromenes with good to high enantioselectivities was reported (Schemes 1.46 and 1.47) [71]. 

Iminium-enamine cycle-specific cascade catalysis... 

One main advantage of aminocatalysts is their ability to promote several activation modes (iminium-enamine) or their high compatibility with other systems allowing for their applications in cascades reactions. 

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