1,3-dicarbonyl compounds Michael reactions

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

More than forty years ago, Stetter reported for the first time a different reactivity of the Breslow intermediate that involved a nucleophilic attack to an electron-deficient alkene, a Michael acceptor, giving access to 1,4-dicarbonyl compounds.This reaction can happen under conditions where the benzoin condensation is reversible and allows the use of a,p-unsaturated esters, ketones, nitriles, sulfones or phosphonates. " Regarding the mechanism, studies have yet to be conducted, and the current proposal is based on the one disclosed by Breslow for the benzoin reaction (Scheme 2.20). ... 

Enolate ions of /3-diketones, /3-diesters, j8-keto esters, and /3-keto nitriles undergo Michael reactions with a,j8-unsaturated carbonyl compounds. Michael reactions form 1,5-dicarbonyl compounds. 

Conventional synthetic schemes to produce 1,6-disubstituted products, e.g. reaction of a - with d -synthons, are largely unsuccessful. An exception is the following reaction, which provides a useful alternative when Michael type additions fail, e. g., at angular or other tertiary carbon atoms. In such cases the addition of allylsilanes catalyzed by titanium tetrachloride, the Sakurai reaction, is most appropriate (A. Hosomi, 1977). Isomerization of the double bond with bis(benzonitrile-N)dichloropalladium gives the y-double bond in excellent yield. Subsequent ozonolysis provides a pathway to 1,4-dicarbonyl compounds. Thus 1,6-, 1,5- and 1,4-difunctional compounds are accessible by this reaction. 

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. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

The reactions [OS 52], [OS 53], [OS 54] and [OS 55] were chosen as test reactions among a wide class of reagents employed for Michael additions. 1,3-Dicarbonyl compounds were chosen because of their relatively high acidity since they enable one to use weak bases instead of strong bases such as sodium efhoxide. The latter is labile to moisture and can react with the Michael acceptor [8]. Diisopropylethyl-amine was chosen as a weak base. 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

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 use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Sc(OTf)3 is effective for Mukaiyama-Michael reactions under extremely mild conditions to give the corresponding 1,5-dicarbonyl compounds in high yields after acidic work-up (Scheme 10). 8... 

As depicted in the following scheme, in the presence of sodium iodate and pyridine, several 5,6-dihydroxylated benzofuran derivatives were synthesized via an oxidation-Michael addition of P-dicarbonyl compounds to catechols in a one-pot procedure <06TL2615 06JHC1673>. A novel additive Pummerer reaction of 2-benzo[fc]furan sulfilimines with carbon nucleophiles derived from P-dicarbonyl compounds was also employed to the synthesis of 2,3-disubstituted benzo[b]furans <06TL595>. 

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

The formation of an allenyl ketone as the sole product can be achieved by using an excess (2 equiv.) of propargyl bromide (entries 3—6, Table 5.9). Use of an increased amount (3 equiv.) of the acylzirconocene chloride in the reaction with propargyl bromide and/or tosylate yields a significant amount of a 1,4-dicarbonyl compound derived from Michael-type addition of the acylzirconocene chloride to the initially formed allenyl ketone (entry 2, Table 5.9). The Michael-type addition of acylzirconocene chlorides to allenyl ketones under Cu(I)-catalyzed conditions has been confirmed by an independent experiment (Scheme 5.31). 

Selective formation of 1,5-dicarbonyl compounds by 1,4-addition (Michael addition) of enolates to enones is facilitated by the use of enol silyl ethers as enolate equivalents [37]. The reaction is catalyzed by... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Takemoto et al. were the first to report that bifunctional organocatalysts of the thiourea-tert-amine type efficiently promote certain Michael reactions, for example, the addition of 5-dicarbonyl compounds to nitro olefins [29-31]. 

Aromatic aldehydes react very easily with tetramic acid under acidic conditions to give 3-benzylidene compounds (41). The yields are moderate, because often there are subsequent reactions. As a,/3-unsaturated carbonyl compounds, (41) react in a Michael addition with excess tetramic acid to form (67), but it can also react with other acyclic and cyclic 1,3-dicarbonyl compounds. In these reactions the aryl substituents may vary over a wide range. Thus, (67) and (68) can be cyclized with ammonium acetate to afford pharmacologically interesting compounds (70) and (71) (90TH1). The latter are dihydropyridines. Curiously, (69) does not cyclize under these conditions. (See Fig. 32.)... 

Michael-type condensation of cyanoacetohydrazide (NCCH2CONHNH2, CAH) with 1,3-dicarbonyl compounds gave pyrazolo[3,4-b]pyridines under certain conditions. With l,l,l-trifluoropentane-2,4-dione in the presence of piperidine a 1 3 mixture of pyrazolone 92a and the expected aminopyridone 91a was obtained.15 The bicycle was also obtained from hydrazone (90) or by thermal reaction between its two precursors.32 Reaction of CAH and / -keto aldehydes gave good yields of only bicyclic products 92b,20 whereas ethyl benzoylacetate in the presence of piperidine gave bicycle 92c (Ar = Ph)... 

The competition between Michael addition of a,(3-unsaturated ketones and Diels-Alder reactions involving furan and 2-methylfuran is affected by the catalyst used. Methyl vinyl ketone gives the alkylation product with furan and 2-methylfuran in the presence of silica gel (88TL175). Bis(alkylated) products have also been obtained in reactions of 2-methylene-1,3-dicarbonyl compounds (90H(31)1699). An intramolecular proton catalyzed alkylation reaction of an a,(3-unsaturated ketone provided a straightforward synthesis of norpinguisone (90TL4343) and in the example shown in Equation (4) the cyclization reaction involved an a,(3-y,8-dienone (94TL4887). 

A variety of nucleophilic agents can be used propanedinitrile, 3-oxo-butanoate esters, and cyanoethanoate esters all form relatively stable car-banions and function well in Michael addition reactions. Obviously, if the carbanion is too stable, it will have little or no tendency to attack the double bond of the a./8-unsaturated acid derivative. The utility of the Michael addition for preparing 1,5-dicarbonyl compounds is illustrated by the examples in Exercise 18-49. 

Keywords 1,3-dicarbonyl compound, a,/ -unsaturated ketone, Michael reaction, FeCl3H20, 1,5-dicarbonyl compound... 

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