Michael-Henry cascade

Scheme 7.62 Michael/Henry cascade reactions for the synthesis of highly substituted cyclopentanes and cyclohexanes.

In 2010, Zhong and co-workers [32] tried a similar approach using nitrotyrenes and cyclic ketoesters. The reaction occurs through a Michael-Henry cascade reaction catalyzed by bifunctional thiourea catalysts derived from cinchona alkaloids. The reaction furnished the desired bicyclic products 43 in good yields and excellent stereoselectivities (Scheme 10.14). 

Albertshofer, K. Tan, B., Barbas III, C. F. (2012). Assembly of spirooxindole derivatives containing four consecutive stereocenters via organocatalytic Michael-Henry cascade reactions. Organic Letters, 14,1834-1837. 

SCHEME 137 Catalytic asymmetric Michael-Henry cascade. 

SCHEME 1.79 Organocatalyzed asymmetric nitro-Michael/Henry cascade. 

SCHEME 2.57 Asymmetric aza-Michael—Henry cascade reaction of 2-aminobenzaldehydes with nitroolefins. 

The organocatalyzed asymmetric synthesis of bicylco[3.2.1]octan-8-ones 214 was described independently by Rueping et al. [84a] and Ding et al. [84b] respectively (Scheme 2.58). The bifunctional thioureas were found to be optimal catalysts to promote the Michael-Henry cascade reaction of cyclohexa-l,2-dione 177 with the P-nitrostyrenes 165, which afforded the bicycles desired, 214 in good yields and stereoselectivities. 

A Michael-Henry cascade organocatalysed by a quinidine derivative has enabled the formation of spiroindoles having four consecutive stereocentres (Scheme 24). 0... 

Quinidine derivative (391) has been reported to catalyse the Michael-Henry cascade reaction of 3-substituted oxindoles (393) with nitrostyrenes (394), giving rise to spiro-cyclopentaneoxindoles (395) with <18 1 dr and <93%... 

Scheme 7.22 Cascade nitro-Michael/Henry reaction for the formation of cyclohexanes with five stereogenic centers.

Michael/Henry and Michael/Aza-Henry Cascade Reactions... 

An unprecedented enantio-selective Michael/hemiketalization/retro-Henry cascade sequence catalysed by a simple bifunctional indane amine-thiourea organocatalyst (7)... 

Oxabicyclo[3.3.1]nonan-2-ones (113) containing four consecutive stereogenic centres have been prepared in >99% ee by a cascade organocatalytic Michael-Henry acetalization-oxidation reaction of glutaraldehyde (114) and 3-aryl-2-nitroprop-2-enols (115). The structures and absolute configurations of the products were confirmed by X-ray crystallography. 

These naturally occurring products were targeted by Hayashi and coworkers in 2013 in a similar manner using a Michael/Henry reaction cascade, employing prolinol 17 to effect the highly stereoselective Michael addition at room temperature [13], Subsequent base (DtPEA) addition enhances the slow Henry reaction to completion in high selectivity. Finally, phosphonate 36 initiates a Horner-Wadsworth-Eimnons (HWE) reaction in the same pot to yield the intermediate 37 (76 17 7 dr) (Scheme 14.5). 

Finally, the most recent efforts of the Hong group provided the tetracyclic scaffold of steroids in a two-component, three-step Michael/Michael/aldol/Henry cascade (Scheme 14.8c) [19]. The preferred catalyst ent)-ll, however, could not deliver the high diastereoselectivity that was obtained in the previous syntheses (56 44 dr). The excellent enantiomeric excess (98/99% ee), on the other hand, encouraged further development of the cascade (Scheme 14.8c). After the Michael/Michael sequence, the medium was acidified to complete the Robinson annulation to enone 64. Interestingly, subsequent treatment with only 0.5 equiv of tetrabutylammonium fluoride (TBAF) effected a very fast reaction to the target tetracycle (63%) at low temperature. 

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

On the other hand, there is a report regarding a cascade Michael reaction followed by intramolecular nitro-Mannich (aza-Henry) reaction occurring between imides derived from diethyl aminomalonate and nitrostyrenes using thiourea 68a as catalyst (Scheme 7.63). This reaction results in a formal [3 + 2] cycloaddition between these two reagents, with this aminomalonate-derived... 

A cascade, including Michael addition, hemiketalization, and retro-Henry reaction, has been reported as a result of the reaction of a-nitroketones R COCH2N02 and the... 

Jhuo, D.-H., Hong, B.-C., Chang, C.-W., Lee, G.-H. (2014). One-pot organocatalytic enantioselective Michael-Michael-Aldol-Henry reaction cascade. A facile entry to the steroid system with six contiguous stereogenic centers. Organic Letters, 16, 2724-2727. 

A triple cascade reaction that includes a sequenhal Michael addihon/aza-Henry reachon/cyclizahon has been described employing BB catalyst 33 (Scheme 29.16) [39]. The three-component cascade reachon catalyzed by two organocatalysts made possible the synthesis of fully subshtuted highly enanhoenriched piperidines. 

Enamine-intermolecular Addition Cascades It was suggested that the intermediate y-nitroaldehyde 91 in Scheme 1.31 might react with an aldehyde via an oxo-Henry sequence, and subsequent hemiacetalization would provide tetrahydropy-ran derivatives. Uehara et al. [50] and Iskikawa et al. [51] realized this hypothesis independently through a four-component reaction in one pot to furnish highly substituted tetrahydropyran derivatives 102 with excellent diastereo- and enantioselec-tivity (up to 98 2 dr and 99% ee) (Scheme 1.35). These two methods are complementary because anti-Michael products were synthesized using catalyst 101 [50], while syn-Michael products were obtained with diphenylprolinol silyl ether catalyst 34 [51]. 

Enamine-Intramolecular Addition Cascades Hayashi et al. envisioned that an enamine generated from one carbonyl of pentane-1,5-dial with catalyst 34 reacted with a nitroalkene in a Michael addition, followed by an intramolecular Henry reaction with the other aldehyde, would provide substituted nitrocyclohexan-ecarbaldehyde 104 (Scheme 1.37) [54],... 

Jia et al. reported a novel Michael/aza-Henry reaction of well-designed chalcones 217 and nitromethane 218 catalyzed by thiourea 130c (Scheme 2.60). Initiated by the Michael addition of nitromethane to an electron-deficient double bond, the resulting intermediate subsequently underwent an aza-Henry reaction to furnish multisubsti-tuted tetrahydroquinolines 219a with up to 20 1 dr and >99% ee [86a], Later, the same group presented an alternative way to construct the same skeletons with different diastereoselectivities [86b], which employed nitrogen as the nucleophilic site to trigger the cascade process (Scheme 2.60). Very recently, a multifunctional... 

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