Crotonaldehyde, Michael addition

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

Michael addition of thiolacetic acid to acrolein and crotonaldehyde... 

The same authors (77) also investigated the Michael addition of nitromethane to a,/l-unsaturated carbonyl compounds such as methyl crotonate, 3-buten-2-one, 2-cyclohexen-l-one, and crotonaldehyde in the presence of various solid base catalysts (alumina-supported potassium fluoride and hydroxide, alkaline earth metal oxides, and lanthanum oxide). The reactions were carried out at 273 or 323 K the results show that SrO, BaO, and La203 exhibited practically no activity for any Michael additions, whereas MgO and CaO exhibited no activity for the reaction of methyl crotonate and 3-buten-2-one, but low activities for 2-cyclohexen-l-one and crotonaldehyde. The most active catalysts were KF/alumina and KOH/alumina for all of the Michael additions tested. 

Base-catalyzed The parent phenol complex 85 undergoes a variety of base-catalyzed Michael addition reactions at room temperature to generate 4H-phenol complexes in yields in the range 79-99 % (Table 14) [29]. Michael additions with MVK, methyl acrylate, acrylonitrile, N-methylmaleimide, cydopentenone, and crotonaldehyde (entries 1-6, respectively) proceed with high regio- and stereocontrol. Demetalation and isolation of the dienone is typically accompanied by tautomerization to the aromatic substitution product. 

The reaction between the perchlorate salt of 2,3,3-trimethylindolenine and crotonaldehyde involves Michael addition (at the 2-methyl group, not the N atom) and spontaneous cyclization to give 8.8,10-trimcthyl-l ()//-pyrido l,2-a indolium perchlorate (16) in 26% overall yield. This can be considered a vinylog of a Fischer s base salt (and also a 4-picolinium salt). This salt has been condensed with aromatic aldehydes to give styryl dyes, but there is no report of reaction with salicylaldehydes.26... 

Scheme 9.1 l,/V2-dG cyclic adducts arising from Michael addition of acrolein, crotonaldehyde, and 4-HNE to dG. 

On the other hand, a computational study [159] of the Michael addition of propionaldehyde lithium enolate adding to E-crotonaldehyde indicates an anticlinal conformation around the forming bond (i.e. A eclipsing R2 in the ul topicity and A eclipsing H in the Ik topicity of Figure 5.9). 

A more recent example was published by Bergonzini and Melchiorre [36], who envisioned an organocatalytic Michael addition reaction to achieve maremycin A (100), a diketopiperazine alkaloid that was isolated from the culture broth of marine Streptomyces species B 9173 [37]. Their synthetic plan commenced from the addition of A -Me-substituted dioxindole 97 to crotonaldehyde 98 on gram scale (Scheme 17.16). After PCC oxidation, the major diastereomer of the spiroxindole 7-butyrolactone 99 was purified by chromatography in 63% yield with 95% ee. Another five more steps were carried out to finish the total synthesis of maremycin A (100) in 15% overall yield. 

The generation of an iminium ion of a, 3-unsaturated carbonyl compounds lowers the LUMO energy. As a result, the cx-CH acidity increases as well as the ability to participate in conjugate additions. The first organocatalyzed 1,4-addition to a,j3-unsaturated aldehydes was reported by the MacMillan group [78]. For theoretical explorations of the configurative outcome of Michael additions of pyrroles and indoles to crotonaldehyde see Reference [79]. This transformation has been widely used in Friedel-Crafts alkylations of a,(5-unsaturated carbonyl compounds (see Reference [lb] and reports cited therein). Comparable examples of this transformation with ( )-crotonaldehyde in the intermolecular series were found in aryl alkylation with trifluoroborate (58 and 60) [80], indole alkylation (62) [81], Friedel-Crafts alkylation of electron-rich benzenes (64) [82], and Friedel-Crafts alkylation with phosphonates (65) [83] (Scheme 4.21). 

Olefin cross-metathesis followed by intramolecular oxa-Michael addition, catalysed by the second-generation Hoveyda-Gmbbs catalyst, has been developed as a cascade, one-pot procedure for 5-hydroxy olefins (147) and a,/ -unsaturated carbonyl compounds (148) (trani-crotonaldehyde or A-acryloyl-2,5-dimethylpyrrole, etc.) as the reacting partners. In the presence of a Brpnsted acid in CH2CI2 at 25-35 °C, the resulting 2,6-cA-substituted tetrahydropyrans (149) were obtained with excellent diastereoselectivity. The role of ruthenium hydride intermediates has been investigated in detail. 

An accessory proposal was Arthur Michael s hypothesis that many reactions proceed by addition, for example, a polymerization of acetaldehyde (CH3CH = O) in the presence of bases (OH) to an aldol (CH3CHOHCH2CHO), with subsequent loss of water to form crotonaldehyde (CH3CH = CHCHO). Michael, educated in America, Germany, and France, made use of Kekule s idea that two molecules may form a "polymolecule" or molecular compound, which, in turn breaks up to yield the final products.33 Lachman expressed fairly standard misgivings about this proposal of an intermediary and transition form "If we are going to explain reactions by means of addition products which we do not or cannot isolate, our explanation loses its definiteness. It becomes simply a possible explanation, and its conclusions are by no means binding."34... 

N,P P, P] Danishefsky and Simoneau utilized the sequential Michael-aldol reaction for the synthesis of compactin and ML-236A (51.1 and 51.2 in Scheme 51) (101). In this context, the HgI2-promoted addition of the rerf-butyldimethylsilyl ketene acetal derived from ethyl acetate to cyclohex-enone 51.3 followed by reaction with crotonaldehyde and acidic work-up produces 35-42% of lactone 51.4 as one stereoisomer. As enone 51.3 is available in optically pure form from quinic acid (102), the naturally occurring enantiomer of compactin can be obtained. 

The azadienyllithium reagent derived from the yvjv-dimethylhydrazone of crotonaldehyde when allowed to react with simple ketones yielded a,p-unsaturated-8-hydroxy-N,N-dimethylhydrazone products, resulting from 1,2-addition at the 7-carbon. This is in contrast to alkylation which occurs at the a-carbon (cf. equation 13) and to the reactivity of (42 equation 16) with cyclohexenone which led to mixtures of Michael adducts arising from electrophilic substitution at both the a- and 7-carbons. ... 

---