Conjugate addition-aldol reaction

Several attempts to take advantage of the intermediate boron enolate to achieve tandem conjugate addition-aldol reaction have been proposed [71]. Recently, Chandrasekhar [72] reported the addition of triethylborane to methyl vinyl ketone followed by the in situ trapping of the enolate by aromatic aldehyde (Scheme 26). 

Scheme 26 Tandem conjugate addition-aldol reaction...

Scheme 7.14. Enantioselective tandem conjugate addition-aldol reactions.

Subsequent ion exchange of the metal cation with the quaternary ammonium ion catalyst provides a lipophilic ion pair (step 2), which either reacts with the requisite alkyl electrophile at the interface (step 3) or is partitioned into the electrophile-containing organic phase, whereupon alkylation occurs and the catalyst is reconstituted. Enantioselective PTC has found apphcation in a vast number of chemical transformations, including alkylations, conjugate additions, aldol reactions, oxidations, reductions, and C-X bond formations." ... 

Krische reported an intramolecular version of the tandem conjugate addition-aldol reaction. The reaction of enone-ketone 58 with phenylboronic acid 2 m occurs in diox-... 

The three-component method is applicable to the synthesis of various C(6)- or C(7)-functionalized PGs. Scheme 11 illustrates the tandem conjugate addition-aldol reaction that affords 7-hydroxy-PGE derivatives (18). Both saturated and unsaturated C7 aldehydes can be used as a side-chain units. The aldol adducts can be transformed to naturally occurring PGs (5a, 19) and, more importantly, to a variety of analogues such as tumor-suppressing A7-PGA, (20) or 7-fluoro-PGI2, a stabilized prostacyclin (21). The unique cellular behavior displayed by A7-PGA methyl ester is well correlated to its chemical reaction with thiols (20). 

Conjugate addition-aldol reactions. A novel synthesis of a-substituted a,(3-enones involves conjugate addition of 1 to an a,p-enone the resulting 0-phenyl-selenoboron enolate undergoes aldol condensation with aldehydes. The adduct on oxidative elimination furnishes unsaturated p-hydroxy ketones.1 Example ... 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

Scheme 9.11. Catalytic enantioselective tandem conjugate addition-aldol reaction of dialkylzincs.

Naphthoquinone and 2-acylbenzenethiols react by sequential conjugate addition, aldol reaction, and atmospheric oxidation to produce 1277-benzo[3]thioxanthene quinones 423. The exact conditions required depend on the nature of the thiol, but are quite mild (Equation 123) <2004BCJ2095>. 

A remarkable example of tandem conjugate addition-aldol reaction has been recently reported by Tomioka and coworkers. The transient lithium enolate, generated by 1,4-addition of benzyl lithium thiolate onto the corresponding a,-unsaturated ester182,595, is followed by an intramolecular aldol tandem cyclization, resulting in a five-membered... 

A general two-step synthesis of arylnaphthalenes from 0-/-butyldimethyl-silylcyanohydrins involving a tandem conjugate addition-aldol reaction, followed by... 

Most chemists would consider that there are four separate steps in this reaction elimination, conjugate addition, aldol reaction and dehydration. Mechanistically we should double this number as each step requires preliminary enolate ion formation. 

High yields of hydroxythioxanthones are readily obtained with good regioselectivity when a mixture of alumina and methanesulfonic acid is used to effect the reaction between thiosalicylic acid and phenols <04S2900> and a one-pot conjugate addition - aldol reaction sequence provides benzo[6]thioxanthene-6,l 1-diones from naphthoquinone and 2-acylthiophenols (Scheme 24) <04BCJ2095>. 

In this chapter, remarkable advances in the research devoted to peptide catalysed alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxida-tion are discussed. 

Since the introduction of the first peptide organocatalyst in the 1980s, a considerable number of new peptide frameworks have been developed that are able to effectively catalyse several important transformations including alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxidation are discussed. A few successful examples of solid-supported peptides and reactions in ball milling under solvent-free conditions have been demonstrated. These methods combine the advantages of being economically and environmentally friendly processes. 

Scheme 11.6 Conjugate addition/aldol reaction of coumarin 25 [13],...

Most of the currently applied protocols for rhodium-catalyzed conjugate addition chemistry involve the use of aqueous solvent systems which ensure catalytic turnover by protonation of the intermediate rhodium enolate. Consequently, tandem reaction sequences with electrophiles other than a proton are troublesome. In early investigations, Hayashi reported a rhodium/BINAP-catalyzed conjugate addition-aldol reaction under anhydrous conditions by use of 9-aryl-9-borabicyclo[3.3.1]no nanes (9-Ar-9-BBN) as aryl sources [117]. The reaction between tert-butyl vinyl ketone (145) with 9-(4-fluorophenyl)-9-BBN (146) and propionaldehyde (147) led to the formation of a syn/anti-mixiuve of 148 in a 0.8 to 1 ratio (Scheme 8.39). 

Scheme 11 1,6-Conjugate addition-aldol reaction domino sequence...

The boron enolates (up to 98% ee) were used for further transformation by treatment with electrophiles. The rhodium-catalyzed reaction of B-Ph-9BBN was extended to a new type of catalytic tandem conjugate addition-aldol reaction by combination with vinyl ketones and aldehydes [39]. 

Krische and co-workers reported an intramolecular version of the tandem conjugate addition-aldol reaction. Enone-ketone 59 reacts with phenylboronic add (2m) in dioxane containing 5 equiv. of water [40] (Scheme 4.26). This cyclization probably proceeds through the (oxa-7t-allyl)rhodium intermediate. Because the intramolecular addition of the intermediate to the ketone is faster than protonolysis with water, the al-dol product is obtained in high yields. Binap is a ligand of choice, leading to the conjugate addition-aldol product in up to 95% ee. 

Scheme 5.116 Proposed catalytic cycle of conjugate addition/aldol reaction mediated by the complex 449.

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