Michael/aldol addition domino reactions

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]. 

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). 

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... 

Using diarylprolinol ether 55 in conjunction with an additional base, a domino Michael/aldol/intramolecular Sj 2 process has been developed that led to highly functionalised epoxy cyclohexanones 110, with excellent control of three of the chiral centres generated (Scheme 42) [169]. Despite the apparent complexity, these reactions proceed at room temperature in less than 24 h and the products contain significant potential for a host of further transformations. 

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). ... 

Recently, there has been considerable progress in the synthesis of nitrogen-containing heterocycles based on (ox)indole skeleton. Oxindole derivatives serve as useful reaction partners in various domino transformations. Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral intermediates, which were further combined with diverse activated olefins or imines to afford spirocyclic oxindoles with high molecular complexity (Scheme 8.27). Spiro-oxindole derivatives were also assembled by a Michael/Michael/aldol cascade of oxindole and two equivalents of enal. " ... 

Catalytic, enantioselective Michael reactions of cyclopentenones have attracted particular attention in recent years. Ben L. Feringa, Albert S. C. Chan, Andreas Pfaltz and Amir H. Hoveyda described various hgand systems for stereoselective addition of organo-zinc reagents to cyclopentenones. With the aid of a phos-phoramidite derived from BINOL, Feringa developed an enantioselective, catalytic domino-Michael/aldol reaction for the preparation of (+)-PGEi methyl ester. [223]... 

In expanding the number Michael/aldol domino processes, chiral N-sulfinimines 27 could be subjected to a magnesium thiolate in the presence of an acrylate 26 to undergo an asymmetric thio-Michael/nucleophilic addition reaction (Scheme 7.4)... 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

The inexpensive and readily available diisopropylamine was used in the iminium-ion-forming process for domino Michael addition/aldol condensation reaction to N-hydroxypyrrole 232 (Scheme 7.49). When a variety of different functional groups at R3 of the a,P-unsaturated aldehydes 231 were tried (phenylethyl, benzoxypropyl, and 2-(tert-butoxycarbonylamino)ethyl), the process was efficient in forming the highly substituted hydroxypyrroles 232. However, aromatic groups in this position were unsuccessful. The regioselectivity of the domino reaction in water and methods for the later synthesis of liT-pyrrole were also reported [116]. 

When a vinylogous aldol reaction occurs, an a,P-unsaturated carbonyl compound is generated, which may react in a subsequent intramolecular Michael addition. In 2005, the group of Erase [20] introduced a domino reaction of several salicylaldehy-des and senecioaldehydes to produce tricyclic hemiacetals 39 (Scheme 8.12). Only one stereoisomer was formed in the presence of sodium carbonate with various salicylaldehydes. y-Deprotonation of senecioaldehyde followed by a vinylogous aldol... 

Organometallic reagents are well known for 1,4-additions and can hence be utilized to catalyze domino Michael/aldol reactions. Based on a methodology published by Noyori et al. [24], the group of Feringa estabhshed a catalytic enantios-elective protocol for the synthesis of (—)-prostaglandin Ej methyl ester [25]. There,... 

An intramolecular domino Michael/aldol reaction starting from the chiral Cope products 58 was developed by the group of Schneider [27], After 1,4-addition of... 

The access toward tetrahydrothiophenes via domino thia-Michael/aldol reactions has been well studied recently [29]. Jorgensen et al. [29d] introduced an organocat-alytic approach toward optically active and highly substituted tetrahydrothiophenes by the treatment of a,fi-unsaturated aldehydes with 2-mercapto ketones. The corresponding products were obtained as single diastereomers in moderate yields and very good enantioselectivities (Table 8.8). Depending on the additive, they... 

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