Cyclohexenones Michael/aldol/dehydration

Scheme 7.16 Synthesis of cyclohexenones by cascade Michael/aldol/dehydration sequence.

Scheme 7.17 One-pot procedure for the synthesis of cyclohexenones by Michael/ aldol/dehydration/decarboxylation sequence.

Zhao and coworkers devised enantioselective syntheses of chiral cyclohexenones using primary-secondary diamine-catalyzed cascade reactions (Scheme 3.17). Diamine 13b promoted a cascade Michael-aldol-dehydration reaction between ketoester 77 and enones 78, affording highly functionalized chiral cyclohexenones 79 in good yields and with high enantioselectivities, although the diastereoselectiv-ity was poor [52]. The same group also applied a similar approach for an enantioselective synthesis of fluorinated cyclohexenones via Robinson annulation reaction [53]. 

Scheme 3.17 Synthesis of chiral cyclohexenones via Michael-aldol-dehydration reaction.

Michael reaction with an o , S-unsaturated ketone followed by an intramolecular aldol reaction has proven to be a valuable method for the synthesis of 2-cyclohexenones. An especially important example of a Michael-aldol sequence is the Robinson annulation, in which treatment of a cyclic ketone, 8-ketoester, or S-diketone with an a,)8-unsaturated ketone in the presence of a base catalyst forms a cyclohexenone ring fused to the original ring. When the following racemic 8-ketoester, for example, is treated with methyl vinyl ketone in the presence of sodium ethoxide in ethanol, the Michael adduct forms and then, in the presence of sodium ethoxide, undergoes a base-catalyzed intramolecular aldol reaction followed by dehydration to give a racemic substituted cyclohexenone. 

It is not difficult to predict the products of the Robinson annulation and to draw the mechanisms if you remember that the Michael addition is first, followed by an aldol condensation with dehydration to give a cyclohexenone. 

Show how you would use Robinson annulations to synthesize the following compounds. Work backward, remembering that the cyclohexenone is the new ring and that the double bond of the cyclohexenone is formed by the aldol with dehydration. Take apart the double bond, then see what structures the Michael donor and acceptor must have. 

You can usually spot a product of Robinson annulation because it has a new cyclohexenone ring. The mechanism is not difficult if you remember "Michael goes first," followed by an aldol with dehydration. 

Formation of a cyclohexenone ring by condensation of methyl vinyl ketone (MVK) or a substituted MVK derivative with a ketone. Robinson annulation proceeds by Michael addition to MVK, followed by an aldol condensation with dehydration, (p. 1088)... 

The Robinson annulation has three distinct steps the Michael addition of the enol or enolate across the double bond of the a,(3-unsaturated ketone to produce a 1,5-diketone (Michael adduct), followed by an intramolecular aldol reaction, which affords a cyclic (3-hydroxy ketone (keto alcohol), and finally a base-catalyzed dehydration which gives rise to the substituted cyclohexenone. An alternative mechanism via disrotatory electrocyclic ring closure is possible. ... 

The Robinson annulation combines two of the reactions above to create a cyclic product. It begins with the Michael addition of an enolate nucleophile (often a cyclic ketone) onto methyl vinyl ketone (MVK), or a derivative of MVK. The resulting 1,5-dicarbonyl product can undergo an intramolecular aldol reaction with dehydration to give a cyclohexenone structure. If this pattern is present in a target molecule, it is an indication that the TM could be the result of a Robinson annulation. 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

Robinson Annulation (Section 19.8C) A Robinson annulation comprises a Michael reaction followed by an intramolecular aldol reaction and dehydration to form a substituted 2-cyclohexenone. 

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