Michael reactions, 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]. 

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]. 

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. 

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

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). 

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

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],... 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

It should be noted that several domino reactions exist where the Michael/SN-type... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

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... 

Scheme 2.70. Asymetric domino Knoevenagel/Michael addition reaction.

Scheme 2.217. Domino Michael/MPV reaction of the oc, 3-unsaturated ketones.

Combinatorial solid-phase synthetic methodologies have been used extensively in drug development [8]. A new solid-phase synthesis of 2-imidazolidones has been discovered by Goff, based on a domino aminoacylation/Michael addition reaction [9]. Thus, when immobilized amine 10-26 (HMPB-BHA resin) was treated with phenylisocyanate in the presence of triethylamine, a smooth formation of 2-imida-zolidone took place. Acid-catalyzed removal from solid phase provided 10-27 in good yield (Scheme 10.6). 

An impressive example for the successful use of domino reactions for the synthesis of pharmacological lead structures was described by Paulsen et al1241 Recently, the difluoro compound 57 has been identified as highly potent inhibitor of the cholesterin-ester-transferprotein (CETP), which is responsible for a transfer of cholesterin from high-density lipoprotein (HDL) to low-density lipoprotein (LDL). This clearly results in an increase of LDL and a decrease of HDL which raise the risk of coronary heart desea-ses. The core structure of 57 is now accessible efficiently by a combination of a Mukaiyama-MichaeL... 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Scheme 41 Divergent domino Michael/aldol reaction...

Lieby-Muller F, Simon C, Constantieux T, Rodriguez J (2006) Current developments in Michael addition-based multicomponent domino reactions involving 1,3-dicarbonyls and derivatives. QSAR Comb Sci 25 432 38... 

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