Michael domino

Spirocyclohexene compounds bearing 1,3-thiazohdinediones were prepared through a double Michael domino reaction of 1,3-thiazolidinedione, malonon-itrile, and aromatic aldehydes and organic amines [104]. Later, in the field of preparing the spirocyclohexene scaffold, a single carbon quaternary stereocenter of a l, 3-spiro-2 -oxocyclohexan-3,4-dihydrocoumarin 202 was constmcted through a domino Michael/acetalization sequence. Following treatment of 2-oxocyclohexanecarbaldehyde 200 with the Takemoto catalyst 3 in the presence of the phenol 201, the reaction was completed in under 30 min (Scheme 7.41) [105]. 

SCHEME 16.32. Functionalized pyrrolidine synthesis aza-Michael/Michael domino sequence. 

One of the first examples of an enamine-catalyzed cascade reaction for the synthesis of a complex alkaloid was reported by Itoh et al. (179). Reaction of the dihydrocarboline 194 with enone 195 in the presence of (5)-12 (7 days) gave the tetracycle 196 as a single diastereomer and in excellent enantiopurity (99%). This reaction can be described best as an enamine-catalyzed Mannich-Michael domino addition. Further manipulations then gave access to the indole alkaloid ent-dihydrocorynantheol (197) in an elegant and facile manner. As depicted in... 

Building on this chemistry, the same authors developed a novel four-component reaction of p-hydroxybenzaldehyde derivatives, benzylamine derivatives, fumaric acid monoethyl ester and isonitriles in water under microwave irradiation to give natural product-like 5,5,6-fused azaspiro tricycle systems 16 as the main products [11]. This transformation can be assmned to proceed through addition of a final aza-Michael step to the previously developed Ugi/Michael domino sequence, and generates six contiguous bonds and fonr stereogenic centres, including one... 

A very short synthesis of rac-incarviditone and rac-incarvilleatone was reported in 2012 by Lawrence and co-workers [147], who first prepared on a multigram scale rengyolone in three steps from tyrosol via a DIB-mediated hydroxylative dearomatization into the para-quinol 287 and an oxa-Michael addition. The resulting (zh)-rengyolone was then biomimetically dimerized under mildly basic conditions simply using a catalytic amount of potassium carbonate to furnish ( )-incarviditone in 19% yield via a homochiral oxa-Michael/Michael domino reaction, and ( )-incarvilleatone in 23% yield via a heterochiral oxa-Michael/ Michael/aldol domino reaction (Fig. 70) [147]. 

In a similar way, spirooxindole tetrahydroquinolines (301) were prepared in 94% ee and >25 1 dr via the aza-Michael-Michael domino addition of tosylamide (299) to oxindoles (300), catalysed by the quinine-derived squaramide (283c).2 ... 

A great deal of attention has been given to asymmetric Mannich reactions, some of which can be applied to the preparation of bridged piperidine systems. Among them, we will mention Carter s preparation of compound 130 from diaryl imines and 2-cyclohexenone in the presence of a modified proline catalyst via an asymmetric Mannich-Michael domino sequence (Scheme 3.39) [88]. 

Another procedure relies on a domino Michael-O-alkylation reaction sequence to yield a variety of dihydrofurans. Combination of cyclohexanedione (30) with vinyl bromide 50 in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provides dihydrofuran 51 in 83% yield. Numerous 1,3-dicarbonyls and vinyl bromides are amenable to this methodology, and thus a wide range of products like 51 are available via this strategy. 

On the other hand, many reactions are known where in a first intermolecular step a functionality is introduced which than can undergo an intramolecular reaction. A nice example is the reaction of dienone 0-34 with methyl acrylate in the presence of diethylaluminum chloride to give the bridged compound 0-35 (Scheme 0-11). The first step is an intermolecular Michael addition, which is followed by an intramolecular Michael addition. This domino process is the key step of the total synthesis of valeriananoid A, as described by Hagiwara and coworkers [21]. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

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... 

Scheme 2.1. Twofold anionic domino reaction initiated by a Michael addition.

Domino Michael/aldol addition processes unquestionably represent the largest group of domino transformations. Numerous synthetic applications - for example, in natural product synthesis as well as for the preparation of other bioactive compounds - have been reported. Thus, the procedure is rather flexible and allows the use of many different substrates [12]. In this process it is possible, in theory, to establish up to two new C-C-bonds and three new stereogenic centers in a single step. For example, Collin s group developed a three-component approach. 

Scheme 2.7. Domino Mukaiyama/Michael/aldol reactions catalyzed by Sml2(THF)2.

Feringa s group has demonstrated that cyclopentene-3,5-dione monoacetals as 2-47 can also be successfully applied as substrates in an asymmetric three-component domino Michael/aldol reaction with dialkyl zinc reagents 2-48 and aromatic aldehydes 2-49 [17]. In the presence of 2 mol% of the in-sitw-generated enantiomeri-cally pure catalyst Cu(OTf)2/phosphoramidite 2-54, the cyclopentanone derivatives 2-51 were formed nearly exclusively in good yields and with high ee-values (Scheme 2.11). 

The selectivity of the aldol addition can be rationalized in terms of a Zimmer -man-Traxler transition-state model with TS-2-50 having the lowest energy and leading to dr-values of >95 5 for 2-51 and 2-52 [18]. The chiral copper complex, responsible for the enantioselective 1,4-addition of the dialkyl zinc derivative in the first anionic transformation, seems to have no influence on the aldol addition. To facilitate the ee-determination of the domino Michael/aldol products and to show that 2-51 and 2-52 are l -epimers, the mixture of the two compounds was oxidized to the corresponding diketones 2-53. 

Another group of natural products, namely the biologically active lignans of the aryltetralin series - for example, isopodophyllotoxone (2-59), picropodophyllone (2-60), and podophyllotoxin (2-61) (Scheme 2.13) [19] - have also been synthesized using a domino Michael/aldol process. 

Scheme 2.16. Intermolecular domino Michael/aldol process initiated by the addition of...

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]. 

An unusual two-component domino Michael/aldol process was described by Tomioka and coworkers in which the initiating step is the formation of an a-lithiated vinyl-phosphine oxide [28] or vinyl phosphate [29]. 

Besides this unique above-described process, there a numerous examples of inter- and intramolecular domino Michael/aldol processes in which the sequence is initiated by the addition of a metalorganic compound to an enone moiety. The Kamimura group [30] synthesized several five- to seven-membered thio- and hy-... 

Scheme 2.18. Diastereoselective AIEt2l-mediated domino Michael/aldol process.

Scheme 2.21. Domino Michael/aldol reactions of 7-keto-2-enimides 2-93.

The group of Terashima [35] developed an asymmetric domino Michael/aldol process using the chinchona alkaloid (-)-cinchonidine (2-103), to prepare an intermediate for the synthesis of the natural product (-)-huperzine A (2-102) [36] (Scheme 2.22). 

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Scheme 2.23. Domino Michael/aldol reaction of a,(5-unsaturated ketones with (3-ketoesters.

Alkenones were used by Rao and coworkers [40] to prepare cyclohexane derivatives which, for example, can be transformed into substituted arenes in a single step. Another interesting intermolecular Michael/intramolecular aldol reaction sequence for the construction of the highly substituted 2-hydroxybicy-clo[3.2.1]octan-8-one framework has been described by Rodriguez group [41]. This process can be extended to a three- and even a fourfold domino reaction [41a, 42, 43],... 

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