1.5- dicarbonyl, from conjugate addition enolates

With unsymmetrical ketones, a mixture of regioisomeric enolates may be formed, resulting in a mixture of Michael adducts. Deprotonation in a protic solvent is reversible and leads predominantly to the thermodynamically favoured, more-substituted enolate. Reaction with a Michael acceptor then gives the product from reaction at the more-substituted side of the ketone carbonyl group. The 1,5-dicarbonyl compound 24 is the major product from conjugate addition of 2-methylcyclohexanone to methyl acrylate using potassium tert-butoxide in the protic solvent tert-butanol (1.39). In contrast, the major product from Michael addition... 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

We met enamines as specific enol equivalents in the last chapter and they are particularly good at conjugate addition. The pyrrolidine enamine from cyclohexanone 41 adds to acrylic esters 42 in conjugate fashion and the first-formed product 43 gives the enamine 44 by proton exchange.4 Acid hydrolysis via the imine salt 45 gives the 1,5-dicarbonyl compound 46. 

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

If the 1,5-dicarbonyl compound is required, then an aqueous work-up with either acid or base cleaves the silicon-oxygen bond in the product but the value of silyl enol ethers is that they can undergo synthetically useful reactions other than just hydrolysis. Addition of the silyl enol ether derived from acetophenone (PhCOMe) to a disubstituted enone promoted by titanium tetrachloride is very rapid and gives the diketone product in good yield even though a quaternary carbon atom is created in the conjugate addition. This is a typical example of this very powerful class of conjugate addition reactions. 

Likewise, the lithium enolate 89 reacts with cyclohexenone 90 at -78 °C to give the product of attack at the carbonyl carbon (direct attack) 91. However, warming the reaction mixture to room temperature allows this step to revert to the starting materials, which react again to form the thermodynamically more stable product of conjugate addition 92 [35]. The enolates formed from p-dicarbonyl compounds do not allow the isolation of the product of direct attack because the first step is even more easily reversible in these instances. 

Jones and colleagues have prepared 1,4-dicarbonyl compounds by conjugate additions of enolate and related anions to a,P-unsaturated sulfoxides [80,81]. For example, the lithium enolate of acetone dimethylhydrazone (83), in the presence of dimethyl sulfide-copper(I) bromide complex, underwent conjugate addition to 2-phenylsulfinyloct-l-ene (82). Quenching the reaction mixture with dimethyl disulfide gave the doubly protected 1,4-diketone derivative (84), which, on sequential hydrolysis with copper(II) acetate and trifluoroacetic acid gave the dodecane-2,5-dione (85) as the product in 54% yield from (82) (Scheme 5.27). Other examples of the addition of enolate-type species to a,p-unsaturated sulfoxides have also been reported [82.83]. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

In the late nineteenth century, Michael found that the enolate anion (46) derived from diethyl malonate reacts with ethyl acrylate at the P-carbon (as shown in the illustration) to give an enolate anion, 47, as the product. Remember from Chapter 22 (Section 22.7.4) that the a-proton of a 1,3-dicarbonyl compound such as diethyl malonate is rather acidic (pK of about 11), and even a relatively weak base will deprotonate to form the enolate anion. Michael addition of 46 with ethyl acrylate will give enolate anion 47, and aqueous acid workup leads to the isolated product, 48. Attack at the -carbon is possible because that carbon is less hindered than the acyl carbon, so reaction at the C=C unit is somewhat faster than attack at the acyl carbon. Michael addition occurs with relatively stable carbanion nucleophiles, such as malonate derivative 46 and some other common nucleophiles. Other conjugated carbonyl derivatives react similarly. 

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