Ketones by conjugate addition

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

The Michael reaction is an alkylation in which carbanions, such as the enolates derived from (3-diketones, p-keto esters, and diethyl malonate, react with a,p-unsaturated ketones by conjugate addition. The a,p-unsaturated ketone serves the same kind of electrophilic role that alkyl halides do toward the enolate. 

The p carbon of an a,p-unsaturated carbonyl compound is electrophilic nucleophiles, especially weakly basic ones, react with a,p-unsaturated aldehydes and ketones by conjugate addition. The nucleophile bonds to the p carbon. 

Outline two ways in which 4 methyl 2 octanone can be pre pared by conjugate addition of an organocuprate to an a p unsaturated ketone... 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

Water can add reversibly to o ,/3-unsalurated aldehydes and ketones to yield /3-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. A related addition to an c /S-unsaturated carboxylic acid occurs in numerous biological pathways, such as the citric acid cycle of food metabolism where ds-aconitate is converted into isocitrate by conjugate addition of water to a double bond. 

Trimethylstannyl)ethylidene]phosphoranes have been generated by conjugate addition of trimethylstannyllithium to triphenylvinylphosphonium bromide30 and, more efficiently, by deprotonation of the corresponding / -(trimethylstannyl)phosphonium salt31, and condensed with aldehydes and ketones. 

Wender and Dreyer have demonstrate that meta-areiw photocycloaddition chemistry can lead expediently to modhephene A( tate 7S>5, a photoproduct derived from indane and vinyl acetate was converted to tetracyclic ketone 797 (Scheme XCVI). Because the enolate of 797 partakes of the dynamic behavior of semibuUvalenes, it proved possible to trimethylate the substance to produce 798. A fourth methyl group was introduced by conjugate addition and the carbonyl was simultaneously converted to an olefinic center. Selective hydrogenation of799 provided modhephene in seven steps. 

JONES OXIDATION. The oxidation of primary and secondary alcohols to acids and ketones by the addition of the calculate amount of chromic anhydride in dilute sulfuric acid to a solution of the alcohol in acetone. This procedure dues not attack triple bonds or shift douhle bonds into conjugation with the ketone formed in the oxidation. 

A second solution to the synthesis of 4-methyl-2-octanone by conjugate addition of a lithium dialkylcuprate reagent to an a,[3-unsaturated ketone is revealed by the disconnection shown ... 

This is a fairly difficult problem because it is not obvious at the outset which of the two possible enolates of benzyl ethyl ketone undergoes conjugate addition to the o,/3-unsaturated ketone. A good idea here is to work backward from the final product—in effect, do a ret-rosynthetic analysis. The first step is to recognize that the enone arises by dehydration of a /Thydroxy ketone. 

This is the time to reveal a potential problem. In this synthesis we want conjugate addition. But we might on another occasion want to make the amide 18 so how do we control whether the nucleophile adds direct to the carbonyl group or by conjugate addition 17 In general the reactivity of the electrophile is crucial. Very electrophilic compounds such as acid chlorides or aldehydes tend to prefer direct addition while less electrophilic compounds such as esters or ketones tend to do conjugate addition. 

Disconnection of the bicyclic diketone 21 starts reasonably to reveal 22 but the two carbonyl groups are now 1,6-related suggesting a reconnection strategy (chapter 27). But this is impossible as the bridgehead alkene 23 is too strained to exist. However, if we extrude the carbon atom in the seven-membered ring between the ketone and the branchpoint 22a, we get a new ketoester 24 with a 1,5 relationship that can be made by conjugate addition (chapter 21). 

A new approach to a variety of a-branched alkynes 70 was achieved by a Knoevenagel type condensation of 4-unsubstituted isoxazolin-5-ones 66 with aldehydes or ketones 67, followed by conjugate addition of an organometallic species and nitrosative cleavage of the heterocyclic ring <02SL1257>. 

Substituted pyrrolidines 46 can be prepared by a one-pot approach via the reductive cyclization of the precursor 45, which is prepared by conjugate addition of the -(alkylideneamino)nitrile 44 to methyl vinyl ketone (Scheme 34) C2005S945, CHEC-III(3.03.7)321>. 

With acyclic a,/ -unsaturated ketones and some cyclic unsaturated ketones, the situation is sometimes complicated by conjugate addition of the amine to the carbon-... 

A one-pot approach giving a series of l-(2-naphthyl)methylene- or l-(3,4-dimethoxybenzyl)pyrrolidines 432 has been developed, as illustrated by the reductive cyclization of the four-carbon precursor 433, which was prepared by conjugate addition of the a-(alkylideneamino)nitrile 434 to methyl vinyl ketone (Scheme 55) <2005S945>. 

Chiral -substituted ketones.2 Conjugate addition of (CH3)3A1 to the ketal (2) of cyclohexenone derived from (S,S)-1 followed by acetylation results in the adduct 3, which is hydrolyzed by acid to (S)-3-methylcyclohexanone (4) in 77% ee. The ketal derived from (2R,3R)-2,3-butanediol undergoes a similar conjugate addition with low asymmetric... 

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