Michael acceptors enals

An enamine intermediate has been proposed as being formed by hydride reduction of a transient iminium ion [14, 15]. The electrophilic capture of the enamine is possible by a Michael acceptor thus, reductive Michael cyclizations of enal enones such as 9 or 11 were described in many cases (intramolecular reactions) (Scheme 11.5) [16]. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Several catalytic protocols have been developed for the 1,4-addition of silylcopper reagents to enones and other Michael acceptors. Lipshutz et al.183 treated phenyldimethylsilyllithium with dimethylzinc and used the silylzinc reagent PhMe2SiZnMe2Li thus formed as the nucleophile in copper-catalyzed 1,4-additions to various enones and enals, for instance, verbenone 248 which afforded the desired product 249 in almost quantitative yield (Equation (14)). Interestingly, the rather slow addition reaction is strongly accelerated by catalytic amounts of scandium triflate. 

A different approach that even obviates the use of a preformed silyllithium reagent takes advantage of the cleavage of the Si-Si bond of a disilane by a copper salt. Hosomi and co-workers185 have reported on the reaction of various enones or enals 250 with hexamethyldisilane or l,l,2,2-tetramethyl-l,2-diphenyldisilane, catalyzed by copper(i) triflate-benzene complex (Scheme 61). The transformation requires heating to 80-100 °C in DMF or DMI and the presence of tri-/z-butylphosphine in order to stabilize the copper catalyst under these harsh conditions. The addition products 251 were obtained with high yield after acidic work-up. The application of the method to alkylidene malonates as the Michael acceptor was recently disclosed.1... 

Bis(phenylsulfonyl)methane has also been employed as an acidic carbon pronucleophile related to malonates and 1,3-diketones with success in the Michael reaction with ot,p-unsaturated aldehydes using 31c as catalyst (Scheme 3.6). The reaction showed a remarkable substrate scope when alkyl-substituted enals were employed but failed when cinnamaldehyde was tested as Michael acceptor. Alternatively, a more acidic cyclic gem-bissulfone has been used as Michael donor, keeping the high yields and enantioselectivities observed for the reaction and also allowing to expand the scope of the reaction to several aromatic enals.In all cases, the chemistry of the sulfonyl group was employed to generate a methyl group after metal-mediated desulfuration or, alternatively. 

The use of ot,p-unsaturated aldehydes as Michael acceptors always represents a challenging situation because of the tendency of enals to undergo 1,2- rather than the desired 1,4- addition reaction. Moreover, working under phase-transfer catalysis conditions incorporates an additional element of difficulty, because of the propensity of enolizable enals to undergo self-condensation side reactions. For this reason, there are only a few examples reporting enantioselective Michael reactions with ot,p-unsaturated aldehydes as Michael acceptors under PTC conditions, both coming from the Maruoka research team and also both making use of chiral tV-spiro quaternary ammonium salts as catalysts. 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

The Chi group reported in 2011 the enantioselective Stetter reaction between enals and modified chalcones proceeding through a Michael-type addition of NHC-bound enal acyl anions to the Michael acceptors. The Stetter reaction with p-alkyl enals afforded the Michael addition products with good enantioselectivity and yields (14 examples, up to 93% yield, 94% ee). While P-aryl enals were tested in this reaction, up to moderate yield was achieved. This was because the enolate pathway (giving Diels-Alder products)" dominated, which was difficult to suppress under these reaction conditions (Scheme 7.26). 

Not only simple, unactivated olefins but also a,P-unsaturated carbonyl compounds undergo gold-catalyzed addition reactions. Electron-rich arenes or heteroarenes (e.g., indoles) are suitable carbon nucleophiles for these Michael additions. For the 1,4-addition of indoles to enones, enals, and related Michael acceptors, simple gold(III) catalysts like NaAuCl4-2 or AuCU can be used... 

The asymmetric conjugate addition of activated methylenes is one of the most studied organocatalytic reactions. A wide variety of Michael acceptors such as enals, enones, a,P-unsaturated nitriles, nitroolefins, a,(i-unsaturated imides, and vinyl sulfones have been successfully employed as elechophiles with high degree of stereocontrol. 

Subsequent studies demonstrated that the asymmetric Michael addition of trisubstituted carbon nucleophiles promoted by 6 -demethylated Cinchona alkaloids (CPD, CPN, RO-CPD and RO-CPN) could be efficiently achieved using a,p-unsaturated sulfones, enones and enals as Michael acceptors in a highly enantioselective and diastereoselective fashion. 

In 2011, Chi and coworkers disclosed the Stetter reaction of enals with 1,1-diactitvated Michael acceptors, providing the corresponding triketones 46 in good yields and with high enantioselectivities (Scheme 20.22). 

Very recently, Chi and co-workers [58] reported the Stetter reaction of enals with 1,1-diactitvated Michael acceptors, providing the corresponding producst in good yields with high enantioselectivities (Scheme 7.38). (B.y-Unsaturated-a-ketoesters were also successfully employed as acceptors for the intermolecular Stetter reaction. A variety of aldehydes worked well under the optimized conditions and afforded die corresponding products in up to 92% yield with up to 91% ee (Scheme 7.39) [59]. 

Amine Catalysis (Via Iminium Ion Activation). a,p-Unsaturated aldehydes and ketones are common Michael acceptors susceptible to be activated by an amine catalyst via ion iminium formation [64]. This general activation strategy for enals and enones has been applied to aza-Michael reactions with relative success [65]. One complication of the approach is that both the catalyst and the nucleophile are amine species that could mix their preconceived roles and lead to either catalyst... 

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