Domino Reactions Initiated by the Michael Reaction

Coumarin derivatives are probably one of the most common skeletons found in natural products. Owing to their extensive array of biological 

The nucleophilic 1,4-addition of stabilized carbon nucleophiles to electron-poor olefins, generally a,fS-unsaturated carbonyl compounds, is known as Michael addition, although it was first reported by Komnenos [14] in 1883. Michael-type reactions can be considered as one of the most powerful and reliable tools for the stereo-controlled formation of carbon-carbon and carbon-heteroatom bonds [15], as has been demonstrated by the huge number of examples in which it has been applied as a key strategic transformation in total synthesis. As a consequence, in recent years, many different organocatalytic versions of this important transformation 

A large number of enantioselective domino Michael/intramolecular heterocyclization reactions have been successfully developed in the last years, using three 

It was based on an enantioselective domino Michael/hemiketalization reaction of ethyl 4,4,4-trifluoroacetoacetate and other trifluoromethyl-substituted nucleophiles with p,y-unsaturated a-ketoesters catalyzed by a chiral quinine-derived thiourea. 

Another asymmetric domino Michael/alkylation methodology was independently developed by Xie et al. [149] and Rueping et al. [150] for the synthesis of a range of chiral 2,3-dihydrofurans from reaction of a-bromonitroalkenes with 1,3-dicarbonyl compounds. In both cases, the catalysts were chiral bifunctional thioureas (30mol%) associated to a base, such as diisopropylethylamine (DIPEA) or tetramethylethylenediamine (TMEDA). For example, the reaction of bicyclic 1,3-dicarbonyl compounds, such as 4-hydroxyl(thio)coumarins, led to the corresponding tricyclic 2,3-dihydrofurans in yields of 89-98%, general 

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Other Domino Reactions Initiated by the Michael Reaction... 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

The following example completes the section of threefold anionic domino processes initiated by a SN-type reaction. As discussed earlier in Section 2.2, the reaction of a five-membered cyclic phosphonium ylide with enones, a, 3-unsaturated esters, and a, 3-unsaturated thioesters provides cycloheptene or hydroazulene derivatives in a domino Michael/intramolecular Wittig reaction. This sequence... 

Tsuchii et al. reported a very interesting four-component domino process where an alkyne, two olefins and diphenyl diselenide sequentially react to form a highly functionalized cyclopentane derivative, after a linear addition sequence and 5-exo-trig cyclization [136]. This reaction can be seen as an interrupted polymerization process initiated by the addition of selenyl radical to an electron-deficient alkyne in the presence of a large excess of a Michael acceptor. The identity of each reaction partner is important for the outcome of the reaction. For instance, use of (PhS)2 instead of (PhSe)2 leads to the polymerization product rather than to the cyclization one, while (PhTe)2 did... 

Chiral cyclohexene derivatives were also constructed by an asymmetric four-component quadruple domino reaction initiated by oxa-Michael addition of alcohols to acrolein. The other two components were another equivalent of acrolein and a nitroalkene. Enders has shown that cyclohexene derivatives can also be assembled by a domino reaction of y-nitroketones and enals. Domino Michael/aldol condensation of 5-oxoalkanals and a,p-unsaturated aldehydes afforded densely functionalised cyclohexenes. Combination of unsaturated aldehydes with unsaturated p-ketoesters resulted in the formation of chiral cyclohexene derivatives via a Michael/ Morita-Baylis-Hillman sequence (Scheme 8.21). ... 

Later, Sasai et al. [204] developed another example of domino reaction initiated by the aza-Morita-Bayhs-HiUman reaction followed successively by an aza-Michael reaction, an aldol reaction, and a dehydration. This novel process, induced by a chiral acid-base organocatalyst (20mol%), involved acrolein and various N-tosylarylimines as the substrates, leading to the corresponding highly functionahzed tetrahydropyridines in moderate yields (40-60%) and good enantioselectivities of 80-88% ee. Attempts to extend the scope of the reaction to other activated alkenes such as methylvinylketone failed. 

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). 

In a transition-metal-free approach to indolo[2,3-d]quinolizines, our group has shown that the four-component reaction between tryptamines, a,p-unsaturated aldehydes, p-dicarbonyl compounds, and ethanol in the presence of cerium(IV) ammonium nitrate as a Lewis acid catalyst gives direct access to indolo[2,3-a]quinolizines 93 (Scheme 3.29) [72], On the basis of previous work on related multicomponent reactions [73], this domino transformation was proposed to comprise the initial formation of a p-enaminone by reaction between the primary amine and dicarbonyl components, its Michael addition to the unsaturated aldehyde, a hemiaminalization reaction, and a final Pictet-Spengler reaction initiated by the formation of a vinylo-gous acyliminium species. This method could also be extended to the preparation of benzo[fl]quinolizines. 

Besides the Michael addition-initiated domino reactions presented here, a multitude of other anionic domino reactions exist. Many of these take advantage of an incipient SN-type reaction (for a discussion, see above). In addition to the presented SN/Michael transformations [97, 98, 100], a SN/retro-Dieckmann condensation was described by Rodriguez and coworkers, which can be used for the construction of substituted cycloheptanes as well as octanes [123]. Various twofold SN-type domino... 

The final group of threefold anionic domino processes described here includes transformations with an initiating elimination step which is either followed by two Michael additions or by substitutions. Thus, reaction of protected nitro alcohol 2-... 

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