Michael 1,4-diketones

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

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... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

Boron trifluoride etherate, is also a good catalyst for this hydride transfer to chalcone. Unlike triphenylmethyl perchlorate, however, chalcone is able to enter Michael additions with the 1,5-diketone followed by eliminations leading to unexpected products, e.g., 3-benzyl-2,4,6-triphenylpyrylium from 2-carbethoxy-l,3,5-tri-phenylpentane-l,5-dione and chalcone the benzyl group originates from chalcone, the elimination product being ethyl benzoylacetate. ... 

Another important feature of the Nef reaction is the possible use of a CH-NO2 function as an umpoled carbonyl function. A proton at a carbon a to a nitro group is acidic, and can be abstracted by base. The resulting anionic species has a nucleophilic carbon, and can react at that position with electrophiles. In contrast the carbon center of a carbonyl group is electrophilic, and thus reactive towards nucleophiles. 1,4-Diketones 4 can for example be prepared from a-acidic nitro compounds by a Michael additionfNef reaction sequence " ... 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

The Michael addition of ct-nitro ketones to a,fi-unsaiurated ketones followed by radical denitration provides a useful strategy for the preparation of 1,4-diketones TPhenylheptane-1,5-dione, isolated from the decayed heart wood of aspens, is prepared by this strategy fEq... 

The Michael addition of nitro ilkanes to enones followed by reaction with TiCT provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cii -jasmone is readily obtained," as shown in Eq. 6.18. 

The Michael additkin of Lithium etiolates to tiitroalkenes folbwed by reaction with acetic anhydnde gives acetic niironic anhydndes, which are good precursors for 1,4-diketones, pyrroles, and pyrrolidines fEq. 10.73. ... 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

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 net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

Figure 23.8 The Stork reaction between cyclohexanone and 3-buten-2-one. Cyclohexanone is first converted into an enamine, the enamine adds to the a -unsaturated ketone in a Michael reaction, and the conjugate addition product is hydrolyzed to yield a 1,5-diketone.

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Problem 23.22 How would you prepare the following compound using a Robinson annulation reaction between a jS-diketone and an, /3-unsaturated ketone Draw the structures of both reactants and the intermediate Michael addition product. 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

The Enders method has also been used as a key step in the synthesis of optically active Ar-heterocycles. The use of cyclic 1,3-diketones for the preparation of the SAMP or RAMP lithium azaenolates is shown by the synthesis of substituted 4,6,7,8-tetrahydro-2,5(l//,3//)-quinolinediones 2. Michael addition of 1 with, for example, benzylidene propanedioates followed by removal of the auxiliary and lactamization gives 2 with > 98% ee201. 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

OS 52[ [OS 53[ [OS 54[ [OS 55[ [R 4b[ [P 38[ In a two-micro-mixing tee chip reactor, substrates with diketone moieties of known different reactivity, such as 2,4-pentanedione, benzoylacetone and diethyl malonate, were processed, each with the same acceptor ethyl propiolate [8]. Also, a reaction with the less alkynic Michael acceptor methyl vinyl ketone was carried out. 

The selectivity of the aldol addition can be rationalized in terms of a Zimmer -man-Traxler transition-state model with TS-2-50 having the lowest energy and leading to dr-values of >95 5 for 2-51 and 2-52 [18]. The chiral copper complex, responsible for the enantioselective 1,4-addition of the dialkyl zinc derivative in the first anionic transformation, seems to have no influence on the aldol addition. To facilitate the ee-determination of the domino Michael/aldol products and to show that 2-51 and 2-52 are l -epimers, the mixture of the two compounds was oxidized to the corresponding diketones 2-53. 

Yosikoshi reported the synthesis of furan derivatives by the reaction of 1,3-diketones with nitroalkenes, in which the Michael addition of the anions of 1,3-diketones and the subsequent intramolecular displacement of the nitro group by enolate oxygen are involved as key steps (Eq. 7.40).42... 

Chromones are also Michael acceptors, and Scheme 18 shows how 3-bromochromone reacts with 1,3-diketones in basic media. The reaction is fairly general and the yields can be as high as 90%, moreover, phenolic furans are not common and the approach provides an effective way of protecting the phenolic hydroxy group during furan ring formation.100... 

Annulation reaction of (benzotriazol-l-yl)acetone 531 with chalcones provides an efficient route to 3,5-diarylphenols 538. The reaction is catalyzed by NaOH in ethanol. In the first step, Michael addition of ketone 531 to the C=C bond of a chalcone gives diketone 532. In the second step, condensation between the carbonyl... 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

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