Tandem 1,4-addition-aldol condensation

Fusion of SIX membered nngs by reactnn of cyclanones with vinyl ketones (base or acd catalyzed), a tandem Michael addition aldol condensation... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

Fig. 12.13. An acid-catalyzed Michael addition. Unlike base-catalyzed Michael additions, which are also known (Section 13.6.1), a Michael addition occurring under acidic conditions cannot be followed by the formation of a six-mem-bered ring through aldol addition, aldol condensation or— starting from other reactants than the ones shown here— acylation. Under basic conditions, however, the corresponding tandem reactions are quite common (see Section 13.6.2).

Besides the very low stereosdectivities, a major problem encountered with this substrate is the low chemical yield (due to subsequent reaction between the resulting zinc enolate and the starting material) and the hi volatility of the product. Using TADDOL-phosphoramidite 27 in a tandem lj4-addition-aldol condensation to cydopentenone we were only able to obtain an ee of 37%, but the enantiosele-ctLvity was raised to 62% in the presence of wet powdered molecular sieves (4 A) [52]. This beneficial effect of water and molecular sieves in some catalytic 1,4-additions has been observed in other cases recently [52, 59]. Important to note is that the yidds in the tandem version are dramatically increased, presumably due to in situ trapping of the reactive enolate (vide infra). Pfaltz et al. reported a 72% ee in the addition of Et Zn to 44 when using BINOL-oxazoline phosphite ligand 22 [47]. 

Tandem Michael addition/aldol condensation of l-(2-oxopropyl)pyridinium chloride (112) or l-(3-ethoxycarbonyl-2-oxopropyl)pyridinium bromide (113) with chalcones 111 forms diketones 114 or 115, respectively, which under condensation afford cyclohexanones that aromatize by the elimination of pyridinium chloride or bromide, respectively, to give 3,5-disubstituted phenols 116 and 4,6-disubstituted ethyl 2-hydroxybenzoates 117, respectively (equation 104) . This approach has been extended to solid-phase synthesis in order to prepare a phenol library (equation 105) . ... 

An alternative tandem Michael addition/aldol condensation for the synthesis of 3,5-diaryl-substituted phenols 121 employs, instead of 1-(2-oxopropyl)pyridinium chloride (112), l-(benzotriazol-l-yl)propan-2-one (119) in the presence of excess of NaOH in refluxing ethanol (equation 106) ". Under these conditions, several types of 3,5-diaryl-substituted phenols 121 have been obtained in 52-94% yield. The reaction proceeds by Michael addition of the enolate of 119 to the a,/3-unsaturated ketone 118 to afford intermediate 120, which then undergoes an intramolecular aldol condensation with elimination of benzotriazole. 

Note Michael addition-aldol condensation with cyclization is an example of a tandem reaction, discovered by Nobel Prize laureate R. Robinson and named the Robinson annulation [26]. Tandem reactions are two or more reactions that occur in a defined order without the isolation of intermediates [27]. Robinson annulation affords mono-, bi- and tricyclic derivatives of cyclohexanone, important intermediates in many syntheses of natural products, in particular steroids. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

Tandem aldol addition/allyImetal addition Protected 1,3-diols can be prepared by the aldol condensation of the enol borate of an aldehyde with another aldehyde. These products can react with an ally lie Grignard reagent to provide homoallylic 1,3-diols. 

Further transformations of the intermediate alkenyloxydialkylboranes (46), as shown in Scheme 10, include aqueous hydrolysis to the homologated aldehydes or ketones 30 electrophilic additions to afford the corresponding a-dialkylaminomethyl aldehydes and ketones (47),31 and a-halogenated (48)32 or a-arylselenylated aldehydes or ketones (49) 33 transmetallation-alkylation to afford a-substituted aldehydes or ketones (50) 34 and aldol condensations with aldehydes (51).35 These reagents offer the equivalent of the tandem 1,4-conjugate addition-electrophile-trapping protocol. A prototypical prosta-... 

Fig. 13.71. Tandem reaction I, consisting of a Michael addition and an aldol condensation Robinson annulation reaction for the synthesis of six-membered rings that are condensed to an existing ring.

Fig. 13.72. Tandem reaction II, consisting of Michael addition and aldol condensation.

A tandem aldol condensation-radical cyclization sequence has been developed for the preparation of functionalized bicyclo[3.3.0]octane systems [116]. Conjugate addition of Me2AlSePh to dimethylcyclopentanone (118) followed by trapping of the resulting enolate with aldehyde gave predominantly the trans, erythro aldol 119 this then underwent radical cyclization with BusSnH and catalytic AIBN yielding the bicyclic ketol 120 stereospecifically (Sch. 80). 

Enones have most often been prepared by oxidation of vinyl carbinols [89, 90]. They have also been prepared by addition of vinyl Uthium to a carboxyhc acid, and by aldol condensation [91,92]. In addition, reagents have been developed that allow direct incorporation of the enones [93,94]. The latter example is an interesting case of a tandem Claisen/Diels-Alder sequence. 

Zirconium tetrachloride promotes a tandem nucleophilic addition and aldol-type condensation reaction of methyl propynoate, or /V,/V-dimethylpropynamidc, with aldehydes, or ketones, in the presence of tetra-n-butylammonium iodide (Scheme 6.13) [8] with a high selectivity towards the formation of Z-isomers. A similar reaction occurs between aliphatic and aromatic aldehydes and penta-3,4-dien-2-one to yield 1-substituted 2-acetyl-3-iodobut-3-enols (50-75%) [9]. 

Tandem conjugate addition ofenolates and aldol reactions Tandem conjugate addition of chiral amines and aldol reactions Part III - Intermediate is an Unstable Imine or Enamine Intermediate Would Be Formed by Amide Condensation... 

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