Conjugate addition/aldol sequence

Multiple-component difunctionalization reactions of a,/ -unsaturated carbonyl systems have been achieved by catalytic conjugate addition/aldol sequences. As Scheme 8.13 illustrates, an efficient method reported by Montgomery [46] allows regioselective addition of an aryl iodide to the /i-position of an unsaturated ester under nickel catalysis and subsequent trapping with an aldehyde to give / -hydroxyesters (e.g. 33). Significantly, premature termination of the sequence by the /Miydride elimination process that is usually observed in Pd-catalyzed Heck reactions does not occur here. 

Another version of the Robinson annulation procedure involves the use of methyl 1-trimethylsilylvinyl ketone. The reaction follows the normal sequence of conjugate addition, aldol cyclization, and dehydration. 

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>. 

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...

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

Wang identified a series of Michael/Michael and Michael/aldol sequences catalysed by diarylprolinol ethers that led directly to densely functionalised five-mem-bered rings [172-174]. For example, highly diastereoselective and enantioselective double Michael addition reactions were achieved by treatment of a,p-unsaturated aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition... 

A new method for a-phenol annulation involving base-induced cycloaromatization of readily available 4-bis (methylthio)-3-buten-2-one 114 was applied to 3,4-dihydro-l-benzothiepin-5(2//)-one 113 (Scheme 14) <2002JOC5398>. Equimolar quantities of the benzothiepinone 113 and 114 in the presence of sodium hydride were stirred in dimethylformamide (DMF) at 25 °C. Treatment of the reaction mixture with/>-toluenesulfonic acid in refluxing benzene furnished the phenol-annulated dihydrothiepine 116 in 62% yield. The reaction sequence involved formation of conjugate addition-elimination adduct 115, followed by intramolecular aldol condensation and cycloaromatization, affording 116. 

Combining aldol and Michael reactions in one sequence is very powerful, particularly if one of the reactions is a cyclisation. The Robinson annelation9 makes new rings in compounds like 73 that were needed to synthesise steroids. Disconnection of the enone reveals triketone 74 having 1,3- and 1,5-dicarbonyl relationships. The 1,3-disconnection would not remove any carbon atoms but the 1,5-disconnection at the branchpoint gives a symmetrical 3-diketone that should be good at conjugate addition. 

Closely related to the Robinson annelation is the sequence of conjugate addition and acylation used to make dimedone 83. Either disconnection of the 1,5-dicarbonyl compound 84 is good but we prefer 84a as the enone 85 is the aldol dimer of acetone (chapter 19) and is readily available. 

The reaction has been further extended into a tandem conjugate addition/ enolate trapping sequence, whereby the in situ generated zinc enolate was trapped with benzaldehyde. This resulted in an approximately 3 7 mixture of trans-erythro trans-threo aldol adducts, isolated in 88% yield. Subsequent oxidation of these products gave a single isomer of the corresponding diketone with 95% ee. 

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

Disubstituted furans are available from a,/3-unsaturated enones in a two-step sequence. At first, conjugate addition of a cuprate generates an enolate, which undergoes an aldol reaction with (tetrahydropyranyloxy)acetalde-hyde under zinc chloride catalysis (Scheme 19) <20000 L4095>. Treatment of the reaction product with acid affords the disuhstituted furans in good yields. 

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). 

Stereochemical control in the double conjugate addition Tandem Reactions as Polymerisation Terminated by Cyclisation The MIMIRC sequence with vinylphosphonium salts Tuning the MIMIRC sequence with different Michael acceptors Heterocycles by Tandem Conjugate Additions Tandem conjugate addition and Mannich reaction Tandem Conjugate Addition and Aldol Reaction... 

The initial radical addition reactions can also be sequenced with a second, nucleophilic reaction. Thus radical conjugate addition and subsequent reduction leads to an enolate. Enolates thus generated can undergo a variety of reactions [8] including aldol reactions [9], Claisen condensations, intramolecular Michael reactions, and intermolecular Tischenko redox processes (Eqs. 7, 8). 

Formally, the MBH reaction involves a sequence of Michael addition, aldol reaction and P-elimination. The commonly proposed mechanism consists in a reversible conjugate addition of the nncleophile to the starting enone 237, generating an intermediate enolate 238. This enolate reacts with the electrophilic aldehyde in an aldol-type process, in which two stereogenic centers are formed, to give 239, which suffers an intramolecnlar acid-base eqnilibrinm to give another enolate 240. From this intermediate, the p-elimination of the nncleophile provides the MBH product... 

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