Michael additions aldol condensation

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

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

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). 

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess. 

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. 

Once you understand the mechanisms, concentrate on the synthetic applications of the process. Focus on the carbon-carbon bond-forming examples, with particular emphasis on the Michael addition, the 1,4-addition of enolatcs to enoncs orenals. The combination Michael addition-aldol condensation provides a powerful means of kynihesis of six-membered rings, the Robinson annulation. Don t worry about all these people s names learn the relrosynthetic analysis for compounds containing six-membered rings. 

Use as a Base. TBAF has been widely used for a variety of base-catalyzed reactions such as alkylation, elimination, halogenation, Michael addition, " aldol condensation, and intramolecular cycUzations. " It is especially useful when other inorganic bases face solubility problems in organic solvents. The reactions are usually carried out below 100 °C due to the low thermal stability of TBAF. ... 

Jorgensen used p-ketoesters with a,p-unsaturated aldehydes for the construction of optically active 5-(triallq7lsilyl)cyclohex-2-enones. These compounds served as suitable starting material for other syntheses. Enders developed a domino nitroalkane-Michael addition/aldol condensation. This process provided an efficient asymmetric synthesis of trisubstituted... 

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]. 

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. 

A method for the preparation of higher sugars with an aromatic branch has been developed which involves a Michael addition - aldol condensation sequence and uses carbohydrate silylenol ethers, e.g. compound (42), as starting materials. As is demonstrated in Scheme 9, the Michael addition product was obtained as the stable silylenol ether (43). On desilylation, aldol condensation took place to give the cyclic hydroxyketone (44) which aromatised under acetylation conditions. The introduction of an aromatic branch by Diels-Alder cyclisation of a carbohydrate diene is referred to in Chapter 19. 

Other strong base reactions such as Michael additions, aldol condensations, Wittig reactions, Darzens condensations, carbene reactions Oxidations using hypochlorite, hydrogen peroxide, oxygen, permanganate Epoxidations... 

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