Dicarbonyl compounds conjugate addition

Keywords /i-dicarbonyl compound, conjugate-addition, dihydrofuran... 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

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. 

Conjugate addition of enolate anions to a, jS-unsaturated sulphoxides followed by a sulphoxide- ketone transformation were used for the preparation of 1,4-dicarbonyl compounds and cyclopentenone derivatives (equation 355)648. 

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. 

Recently, very effective asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported, as shown in Scheme 4.10. The reaction of ethyl acetoacetate with nitrostyrene is carried out in the presence of 5 mol% of the preformed complex of magnesium triflate and chiral bis(oxazoline) ligands and a small amount ofW-methylmorpholine (NMM) to give the adduct with selectivity of 91%. The selectivity depends on ligands. The effect of ligands is presented in Scheme 4.10.63... 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

The majority of recent contributions for the conjugate addition of C-H acids to a,p-unsaturated carbonyl compounds catalysed through iminium ion intermediates have come from the laboratories of Jprgensen. The ease with which 1,3-dicarbonyl compounds and nitroalkanes can be deprotonated, together with the soft nature of the nucleophile mean this is a particularly facile reaction which conveniently leads to useful precursors for further synthetic manipulation. 

Scheme 22 Conjugate addition of cyclic 1,3-dicarbonyl compounds to a,p-unsaturated ketones...

The disulfide dimers of 2-aminothiophenols have also been used in the syntheses of benzothiazines. In this case, nitrogen acts as a nucleophile and sulfur as an electrophile. Reagents that have nucleophilic carbons adjacent to an electrophilic carbon can be reacted with these disulfides. Examples include a,(3-unsaturated esters that undergo conjugate addition followed by enolate addition to sulfur (Equation 86) <1983J(P1)567>, and 1,3-dicarbonyl compounds such as ethyl acetoacetate <2005AXEo2716> and dimethyl malonate <2006ARK(xv)68> (Scheme 63). 

In those cases, where conjugated 1,3-dicarbonyl compounds have a leaving group in the p-position, reaction with a 5(4//)-oxazolone occurs via an addition-elimination reaction sequence to give, after cyclization, pyran-2-ones 165... 

Michael additions. Conjugate addition of / -dicarbonyl compounds to various Michael acceptors is catalyzed efficiently by Ni(acac),. Yields arc usually higher than those obtained with traditional bases. 

Michael addition of 1,3-dicarbonyl compounds to conjugated prochiral nitroalkenes catalysed by (acac)2Ni and (acac)2Co has been reported to give up to 30% ee when carried out in the presence of cinchonidine.100... 

Conjugate addition. The reagent (1) undergoes selective 1,4-addition to enones to give potential precursors to 1,5-dicarbonyl compounds.1 Example ... 

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. 

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

The conjugate addition of carbonyl anions catalysed by thiazolium salts (via umpol-ung) that is fully operative under neutral aqueous conditions has been accomplished. The combination of a-keto carboxylates (157) and thiazolium-derived zwitterions (e.g. 160) in a buffered protic environment (pH 7.2) generates reactive carbonyl anions that readily undergo conjugate additions to substituted o /3-unsaturated 2-acylimidazoles (158) to produce (159). The scope of the reaction has been examined and found to accommodate various a-keto carboxylates and /3-aryl-substituted unsaturated 2-acylimidazoles. The optimum precatalyst for this process is the commercially available thiazolium salt (160), a simple analogue of thiamine diphosphate. In this process, no benzoin products from carbonyl anion dimerization were observed. The resulting 1,4-dicarbonyl compounds (159) can be efficiently converted into esters and amides by way of activation of the A-methylimidazole ring via alkylation.181... 

The second point was made in chapter 6 where we said Very electrophilic compounds such as acid chlorides or aldehydes tend to prefer direct addition while less electrophilic compounds such as esters or ketone tend to do conjugate addition. That remains true and the same idea applies to the enolates very nucleophilic enolates such as lithium enolates tend to prefer direct addition while less nucleophilic enols and enolates such as enamines or 1,3-dicarbonyl compounds tend to do conjugate addition. 

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. 

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. 

If the 1,4-dicarbonyl compound is unsymmetrical, it will have to be made by methods such as those described in chapter 25. Examples such as 22 appear in papers by Yadav.3 The 1,4-diketone 23 can be disconnected at a branchpoint with the idea of using a d1 reagent for BuCHO in conjugate addition to the enone 24. 

Jacobsen et al. have shown that cyanoacetate derivatives undergo conjugate addition to ,/i-unsaturated imides in the presence of a chiral Al-oxo salen complex 32 to afford the corresponding product in up to 98% ee (Scheme 16) [19]. When an a-amino cyanoacetate was used, a highly functionalized lactam 33 was obtained in one step. Another example of Lewis acid-catalyzed conjugate addition of cyclic 1,3-dicarbonyl compounds to 2-oxobutenoate employed the chiral Cu-bisoxazoline complex 34 (Scheme 17) [20]. 

---