Enamine-Intramolecular Addition Cascades

SCHEME 137 Catalytic asymmetric Michael-Henry cascade. 

A similar strategy was extended to the reaction of pentane-l,5-dial with aldehydes [55a], imine [55b], and alkylidene malonate [55c], 

It also proved feasible to replace pentane-l,5-dial with alkenal 105 [56] or 2-(5-oxopentylidene) malonates [57] for a-aminoxylation/aza-Michael reactions based on a similar strategy. The a-aminoxylation of alkenal 105 with nitrosobenzene 

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Enamine-Intramolecular Addition Cascades Hayashi et al. envisioned that an enamine generated from one carbonyl of pentane-1,5-dial with catalyst 34 reacted with a nitroalkene in a Michael addition, followed by an intramolecular Henry reaction with the other aldehyde, would provide substituted nitrocyclohexan-ecarbaldehyde 104 (Scheme 1.37) [54],... 

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]. 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

Taylor and Raw recently designed a tethered imine-enamine cascade sequence that converts 1,2,4-triazenes into substituted pyridines. In the presence of molecular sieves, A-methylethylenediamine (147) underwent condensation with excess cyclic ketone 148 (n — 1-4) to give imine-enamine 150 (04CC508). The enamine portion of the molecule then participated in an inverse-demand Diels-Alder cycloaddition reaction with 149 to provide intermediate 151. Cycloreversion of 151 with loss of N2 then gave 152 in which the tertiary amino group underwent addition to the adjacent imine functionality to afford zwiterionic 153. Finally, an intramolecular Cope elimination produced 154 in 74-100% yield. Several other triazines were also shown to participate in this novel cascade (Scheme 27). 

A similar cascade reaction was reported by Melchiorre and co-workers [69] in 2008. Initially, this triple cascade reaction between an enolizable aldehyde, 2-cyanoacrylate, and enal consists of the aldehyde addition to a 2-cyanoacrylate derivative (108), promoted by a diphenylprolinol derivative (VII). Next, the resulting adduct reacts with enal via a Michael addition promoted by the same catalyst. Finally, an intramolecular aldol reaction takes place between the formed enamine and the aldehyde, leading to the cyclohexane 109. It should be noticed that the use of an acid as a co-catalyst is cmcial to obtain high levels of stereoselectivity. 

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). 

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

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]. 

In terms of enamine and iminium ion catalysis, an intramolecular cascade conjugate addition/Mannich reaction was shown to be effectively catalyzed by 36 [108]. The reaction involves the construction of a tetracycUc structure from the indoyl methyl enone shown in Scheme 6.53. The highest enantioselectivities were obtained with addition of nitrobenzoic acid and with ethyl acetate as the solvent... 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

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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