Michael addition with methyl vinyl ketone

Michael addition of methyl vinyl ketone to 24, followed by base-catalyzed cyclization, afforded the j8-diketone 25. Reaction of 25 with phosphorus oxychloride in dimethylformamide gave the vinylogous acid chloride 26 which afforded the corresponding chloro alcohol on reduction with lithium aluminum tri-f-butoxyhydride. Hydrolysis and concomitant dehydration of this chloro alcohol then gave the desired unsaturated ketone (23). 

A synthesis of ds-jasmone [293] illustrates the Michael addition to methyl vinyl ketone of a stabilized carbanion and the hydrolytic step with a protonic acid. 

The starting illylic rutro compound is obtained by nitranon of 2-methylpropene with NO Subsequent Michael addition to methyl vinyl ketone followed by Pd-catalyzed allylic alkylation affords terpenoids 

The t]2 complex 333 can be prepared in 98% yield by the reaction of anisole with Os(NH3)5(OTf)3 in the presence of Mg. Michael addition of methyl vinyl ketone to the complex at 20 °C using TfOH afforded 336, which was converted to 337 by deprotonation with tertiary amine [83]. The diketone 340 was obtained by the Michael addition of methyl vinyl ketone to C-4 of the 4-methylanisole complex 338 to generate 339, followed by intramolecular nucleophilic attack of the keto enolate in 339. 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

Simple addition to carbonyl compounds occnrs nnder mild acidic conditions. Examples given illns-trate reaction with acetone, an aldol-like reaction, and conjngate addition to methyl vinyl ketone, a Michael-like reaction. The first-formed alcohol products in aldol-like reactions usually dehydrate to give a 3-alkylidene-3//-indolium cation. 

Recently, lithiodifluoromethylphosphonate was reacted with methyl vinyl ketone followed by rearrangement of the allylic alcohol to give the difluoromethylphosphonate derivative as the E isomer [263] (Scheme 89). This lithium reagent was also reacted with nitroalkenes in the presence of CeCl3 to produce the corresponding Michael addition products in moderate yield [264] (Scheme 90). 

Each of the respective research groups effected the transformation of the endocyclic enamine 62 to ( )-mesembrine by means of a Michael addition with methyl vinyl ketone (Scheme 16). The yields for this reaction reported 

Reduction of 2,2-dimethyl-cyclohexane-1,3-dione (50) with Baker s yeast gave alcohol (ee 98.3%) whose tetrahydropyranyl derivative on methoxycarbonylation produced (51) quantitatively. Michael addition of (51) with methyl vinyl ketone followed by heating the adduct under reflux with pyrrolidine in benzene yielded (52) in 85% yield as stereoisomeric mixture whose separation presented problems. In order to eliminate the complexity due to a chiral center in tetrahydropyranyl protective group, deprotection of (52) was achieved by treatment with p-toluenesulphonic acid in methanol. The product obtained was a mixture of the lactone (53) and hydroxy ester (54). Probably the stereoisomer of 

Fig (7) The transformation of cyclohexene-l,3-dione (50) to ketone (52) is described. This involves reduction, terahydropyranilation, methoxy-carbonylation and Michael addition, with methyl vinyl ketone. Treatment of (52) with p-TsOH in methanol, leads the formation of lactone (53) and hydroxy ester (54). The lactone (53) is regarded as an appropiate intermediate for natural o-methyl pisiferic acid (+)(2)and hydroxi ester (54) is intermediate for (-)(55). 

Reactions of furan (5) under solvent-free conditions, catalyzed by Montmorillonite K10, have been described by Cintas [27]. The reaction with methyl vinyl ketone (32) produced Michael addition in positions 2 and 5, whereas reaction with symmetrically substituted cyclic dienophiles produced a mixture of the endo and exo adducts with the kinetically favored endo adduct predominating, except when maleic anhydride (39) was used as the dienophile (Scheme 9.2). 

Very recently, it has been demonstrated [76] that the hosts (RR)-(29) and (R)- 59), complexed to KOCMej or KNHj, catalyse the Michael additions of methyl vinyl ketone and methyl acrylate to the phenyl acetic esters (61) and (62), and the )8-ketoester (63) with high catalytic turnover numbers (CTN = mmoles of product 

The first successful results of the asymmetric Michael addition under phase transfer catalyzed conditions were achieved by use of ingeniously designed chiral crown ethers 13 and 52.1441 The 3-keto ester 49 reacted with methyl vinyl ketone by use of 13 to give the Michael product 50 with excellent enantioselectivity but in moderate yield, as shown in Scheme 18. The Michael addition of methyl 2-phenylpropionate 51 to methyl acrylate afforded the diester 53 by use of another crown ether 52 in good yield with good enantioselectivity.1441 Various chiral crown ethers were studied to 

The same hyperbranched polyglycerol modified with hydrophobic palmitoyl groups was used for a noncovalent encapsulation of hydrophilic platinum Pincer [77]. In a double Michael addition of ethyl cyanoacetate with methyl vinyl ketone, these polymer supports indicated high conversion (81 to 59%) at room temperature in dichloromethane as a solvent. The activity was stiU lower compared with the noncomplexed Pt catalyst. Product catalyst separation was performed by dialysis allowing the recovery of 97% of catalytic material. This is therefore an illustrative example for the possible apphcation of such a polymer/catalyst system in continuous membrane reactors. 

Several structurally different diketones (acetylacetone, methyl 2-oxocyclohex-ane carboxylate) and active methylene compounds (diethyl malonate, ethyl aceto-acetate) and thiols (methyl thioglycolate) underwent clean, fast, and efficient Michael addition with methyl vinyl ketone, acrolein, and methyl acrylate over NaY and Na beta zeolites [88] in high yield (70-80%). The reactions were performed in the absence of solvent, at room temperature, with 1 g catalyst per mmol donor. When HY zeolite was used instead of NaY formation of the desired Michael adduct was low and polymerization of Michael acceptor was the main reaction. 

Details of an alternative synthesis of 13-methyl-protoberberines have been published. The starting point is an N-phenethyl-homophthalimide of the type (83), and monomethylation is achieved by its Michael addition to methyl vinyl ketone to give the ketone (84 R = H), followed by methylation of this to the intermediate (84 R = M). Conversion of this into the ethylene ketal, followed by reduction with sodium borohydride and heating with toluene-p-sulphonic acid, results in the unsaturated lactam (85), and cyclization of this compound yields the lactam (86), which can be reduced to the 13-methyl-tetrahydroberberine.  

Of the reagents listed in Table 8.1, dialkyllithiocuprates stand out because of their unique ability to participate in 1,4-addition reactions. Such reactions, also known as conjugate additions, are generally referred to as Michael additions. This name reaction is illustrated in Scheme 8.16 with the reaction of dimethyllithiocuprate with methyl vinyl ketone. 

An interesting synthesis of (-l-)-mesembrine has been described by Otani and Yamada (55). The approach follows from earlier studies (56) by these authors on the enantioselective synthesis of chiral 4,4-disubstituted cyclo-hexenones (see Scheme 26) in which construction of the t clohexenone ring is effected with Michael addition of methyl vinyl ketone to an enamine (103) formed from L-proline pyrrolidide and the aldehyde 104. In the reactions presented in Scheme 26, the il-(-l-)-isomer of 4-methyM-phenylcyclohexe-none was obtained in S0% enantiomeric access. 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200 

The starting material for the present synthesis was Wieland-Miescher ketone (24), which was converted to the known alcohol (25) by the published procedure [10], Tetrahydropyranylation of alcohol (25) followed by hydroboration-oxidation afforded the alcohol (26), which on oxidation produced ketone (27). Reduction of (27) with metal hydride gave the alcohol (28) (56%). This in cyclohexane solution on irradiation with lead tetraacetate and iodine produced the cyclic ether that was oxidized to obtain the keto-ether (29). Subjection of the keto-ether (29) to three sequential reactions (formylation, Michael addition with methyl vinyl ketone and intramolecular aldol condensation) provided tricyclic ether (30) whose NMR spectrum showed it to be a mixture of C-10 epimers. The completion of the synthesis of pisiferic acid (1) did not require the separation of epimers and thus the tricyclic ether (30) was used for the next step. The conversion of (30) to tricyclic phenol (31) was 

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