Enamine cascade reactions

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). 

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]. 

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... 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

Keywords enamine, 1,4-diphenyl-2-buten-l,4-dione, cascade reaction, solid-solid reaction, pyrroles... 

Keywords enamine, dibenzoylethene, cyclization, cascade reaction, waste-free, solid-solid reaction, pyrrole... 

Triethylamine is converted into thienopentathiepin 39 and heptathiocane 40 by the unprecedented cascade reaction with S2CI2 in the presence of DABCO. Oxidation of an A -ethyl group of EtsN by a complex of S2CI2 with l,4-diazabicyclo[2.2.2]octane (DABCO) (X-S-S-Cl) affords an enamine, which reacts with X-S-S-Cl to give a thioamide followed by elimination of X-SH. The condensation of this thioamide with the enamine followed by cyclization and oxidation affords the thiophene 39 (Scheme 9) <20030L1939>. 

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). 

Enders et al. elegantly applied diphenylprolinol silyl ether 6a as a catalyst for triple cascade reactions (Scheme 10.18), wherein 6a played the roles ofboth enamine catalyst and iminium catalyst. It should be noted that the four stereocenters were completely controlled[36].Theproposedcatalyticcycleofthe triplecascade isshownin Scheme 10.2. 

Cascade reactions of substituted 1,2,4-triazines are of great interest as simple ways to a dramatic increase in molecular complexity, from planar 1,2,4-triazine unit into a polycyclic system. Indeed, in this multistep process, the diallylamine and cyclopentanone react first in situ to give the corresponding enamine, which undergoes an inverse electron demand cycloaddition reaction with 1,2,4-triazine to give an intermediate dihydropyridine compound. A spontaneous intramolecular Diels-Alder reaction between the allyl moiety and the dihydropyridine gives the tetracyclic compound (Scheme 99) <2004JA12260>. 

Synthesis of chiral heterocycles by domino organocatalytic processes has also been intensively studied. In particular, various benzo-fused heterocycles, such as chiral chromans, " thiochromanes, hydro-quinolines, dihydropyranes, or thiopyranes were investigated. These organocatalytic sequence were typically initiated by a hetero-Michael addition of a sulfur, oiqrgen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step or an additional cyclisation step follows (Scheme 8.25). 

According to the proposed mechanism (Scheme 6.20), the first step of this cascade reaction is protonation of the substituted pyridine by CPA to generate the pyridinium salt 51. Then, the reduction of 51 by 1,4-hydride transfer from the Hantzsch ester gives the enamine intermediate 52, which isomeri-zes to iminium 53 in the presence of CPA. The subsequent AFC reaction will afford the desired product and release the chiral phosphoric acid. 

Wang, et al. reported an organocatalylic direct inverse electron demand Diels-Alder reaction of ketones 140 with l,2,4,5-tetrazinesl41, Scheme 3.46 [62]. Examination of the results of catalyst screening revealed that L-proline seems to be the best organocatalyst tried in this process. Several steps were involved in the cascade reactions inverse electron demand Diels-Alder reaction of 1,2,4,5-tetrazines 141 with the enamines, derived from ketones and L-proline, followed by a subsequent retro-Diels-Alder process to extrude and elimination to afford pyridazines 142. 

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