Hetero-Michael reactions activation

The phospha-Michael reaction has been the last hetero-Michael reaction to be developed under iminium activation. In addition to the selectivity issues that have to be addressed, the identification of a suitable phosphorous nucleophile has been the most difficult task to overcome when developing the reaction because of the high tendency of phosphines toward oxidation in the presence of air. The first example was developed independently by Melchiorre and... 

Remaining in the field of hetero-Michael reaction, Gong et al. disclosed a four-component quadruple cascade reaction activation initiated by oxa-Michael addition of alcohol to acroleins providing an easy and direct access to highly functionalized chiral trisubstituted cyclohexene derivatives 170 (Scheme 2.54) [81]. 

By far most of the reports on addition reactions of hetero-nucleophiles to activated dienes deal with sulfur-nucleophiles17,48,80,120-137, in particular in the synthesis of 7/3-sulfur-substituted steroids which, like their carbon-substituted counterparts (Section n.A), are of interest because of their ability to inhibit the biosynthesis of estrogens80,129-137. Early investigations17,120-122 concentrated on simple acyclic Michael acceptors like methyl sorbate and 2,4-pentadienenitrile. Bravo and coworkers120 observed the formation of a 3 1 mixture of the 1,6- and 1,4-adduct in the reaction of methyl sorbate with methanethiol in basic medium (equation 39). In contrast to this, 2,4-pentadienenitrile adds various thiols regioselectively at C-5, i.e. in a 1,6-fashion (equation 40)17,121,122, and the same is true for reactions of this substrate with hydrogen sulfide (equation 41), sodium bisulfite and ethyl thioglycolate17. 

Nafion resins have been used not only for the opening of epoxides but also for their isomerization to aldehydes or ketones [137]. Various other rearrangements and isomerizations are catalyzed by this solid acid, in some cases with selectivities higher than those obtained with other solid catalysts [138-140]. Other reactions that have been studied include the Peterson methylenation of carbonyl compounds [141], hetero-Michael additions to unsaturated ketones [142], the Koch-type carbon-ylation of alcohols to form carboxylic acids [143], dimerization of a-methylstyrene [144], addition of carboxylic acids to olefins [145] and Diels-Alder reactions [146]. Notably, in most cases, reutilization of the catalyst is considered but only after an appropriate washing protocol to regenerate its acidity/activity. 

In 2009, Feng and coworkers developed new guanidine catalysts with an amino amide skeleton [139]. Among the various catalysts tested, guanidine 49 was found to be the most active for the enantioselective Michael reaction of a (i-ketoester with nitroolefins (Scheme 10.46). The conjugate addition products were obtained in high yields and excellent diastereo- and enantioselectivities. The same researchers used bis-guanidine catalysts for the enantioselective inverse-electron-demand hetero-Diels-Alder reaction of chalcones with azlactones (Scheme 10.47) [140] and enantioselective Mannich-type reaction of a-isothiocyanato imide and sulfonyl imines (Scheme 10.48) [141]. 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

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. ... 

The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated olefin 4a for the formation of five membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the 7r-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated olefin 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner 7r-allylic carbon atom to give the cy-clized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-losylimincs 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44,45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

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