Aldehydes Michael additions, sulfones

Another important reaction in synthetic chemistry leading to C-C bond formation is the Michael addition. The reaction typically involves a conjugate or nucleophilic 1,4-addition of carbanions to a,/l-unsaturated aldehydes, ketones, esters, nitriles, or sulfones 157) (Scheme 21). A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor), which attacks the alkene (acceptor). Strong bases are usually used in this reaction, leading to the formation of byproducts arising from side reactions such as condensations, dimerizations, or rearrangements. 

The first asymmetric direct Michael addition of enolizable aldehydes RCH2CH=0 to vinyl sulfones CH2=C(S02Ph)2 catalysed by /V-Pr -2,2 -bipyrrolidine (146) has been reported. The 1,4-adducts were obtained in good yields and enantioselectivities... 

The selective nucleophilic displacement of one ortho nitro group from 2,4,6-trinitrotoluene by esters of mercap-toacetic acid followed by oxidation leads to 2-(alkoxycarbonyl)methylsulfonyl compounds. These sulfones react with aromatic aldehydes under Knoevenagel conditions to produce thiochroman 1,1-dioxides 477, probably via a stilbene and a subsequent intramolecular Michael addition. Activating groups other than nitro are compatible with the route (Scheme 167) <2003RJ0397>. 

The synthesis of the C1-C7 fragment, which corresponds to the lactone, starts with the homoallylic alcohol 2 which was prepared from 1. The existing stereocenter and the conjugate addition method of Evans [21] allow the control of the C5 stereocenter. The homoallylic alcohol 2 was oxidatively cleaved and homologated to the trans enoate 3 by a Wittig olefination. Treatment of 3 with benzaldehyde and a catalytic amount of KHMDS provided acetal 4. The internal Michael addition of the hemiacetal intermediate proceeds with complete stereoselectivity [22]. After deprotection and oxidation, the corresponding aldehyde was treated with Amberlyst-15 and then with camphor sulfonic acid (CSA), to yield pyrane 5 as a mixture of (3- and a-anomers (1.8/1). This compound was converted to the thiophenyl acetal 6 (4 steps) as this compound can be hydrolyzed later under mild conditions (Hg +) with subsequent oxidation of the lactol to the desired lactone. Compound 6 represents the C1-C7 fragment of discodermolide (Scheme 1). 

For example, the addition to vinyl sulfones has attracted a lot of attention mainly because of the synthetic possibilities that the sulfone group affords in terms of its wide possibilities to undergo a wide variety of transformations. iPBP 15a and prolinal-deiived aminal 12b catalysts have proved their usefulness in the Michael addition of aldehydes to this particular class of Michael acceptors, showing that good yields of the desired Michael adducts could be obtained under the optimized conditions, although with moderate enantios-electivities (Scheme One of the main problems of this particular... 

Other Michael acceptors that were used in addition of aldehydes were vinyl sulfones. Zhu and Lu showed that the most efficient catalyst for this reaction was catalyst C2a with 3,5-bis(trifluoromethyl)phenyl groups (Scheme 8.5). It provided the corresponding products in high yields, with good to high diastereomeric and high enantiomeric purities. Palomo and coworkers also came to the same conclusion. They also extended the scope of the addition to E-a-ethoxycarbonyl vinyl sulfones. 

Scheme 8.5 Michael addition of aldehydes to vinyl sulfones.

A series of aminal-pyrrolidine-derived organcatalysts was synthesised by Alexakis and coworkers. ° Initially, this family of aminal catalysts was evaluated for catalysing the Michael addition of aldehydes to nitro-olefins. When Ik was used, the products obtained had moderate to good stereoselectivities (up to 79% ee) at ambient temperature (Scheme 9.17). The reaction of vinyl-sulfone with linear aldehydes yielded more satisfactory results. Impressive reactivity and good enantioselectivities were obtained when only 10 mol% of Ik was used and representative examples are presented in Scheme 9.17. The stereocontrol exhibited by the catalyst was possibly associated with the strong interaction between the sulfonyl group and the aminal catalyst. 

The constrained tricyclic chiral secondary amine 43 was proposed hy Loh et al. in 2011 for the highly enantioselective organocatalytic Michael addition of aliphatic aldehydes to vinyl sulfones (Scheme 11.44). DFT calculations revealed that only 42-derived sy -enamine is formed due to steric congestions and that the naphthyl ring is puckered in the chiral pocket of the tricyclic system, efficiently shielding only one of the diastereotopic faces of the reactive enamine. ... 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

Substituted a,(3-unsaturated mono(sulfone) with other activating groups such as nitrile or ester were also applicable in the Michael addition with aldehydes. As reported by the group headed by Palomo [26], a-ethoxycarbonyl vinyl sulfones could react with aldehydes in the presence of 7 or 25 to give, after reduction and cyclization, the corresponding lactone adducts in nearly optical pure form with reasonable diastereoselectivity. Similar results were also obtained for a-cyano vinyl sulfones (Scheme 5.14). 

SCHEME 5.12. Michael addition of aldehydes to a,p-unsaturated his(sulfones) catalyzed by diarylprolinol silyl ether. 

SCHEME 5.14. Michael addition of aldehydes with substituted mono(sulfone). 

S.2.2.3. a, -Unsaturated Sulfones, Malononitriles, and Maleimides as Acceptors, Base on their previous achievements on the asymmetric Michael addition of aldehydes [24], Lu and co-workers [55] developed the first enantiose-lective conjugate addition of cyclic ketones to vinyl sulfone catalyzed by a primary amine 57 (Scheme 5.28). Various cyclic ketones could be applied, affording the corresponding adducts in good yields and with high to excellent enantioselectivities. However, linear ketones were not suitable substrates for this catalytic system. Performing the desulfonylation procedure on a-substituted ketones and in combination... 

Oxindoles with an all-carbon quaternary center at the C3 position are privileged structural motifs found in many pharmaceuticals and alkaloid natural products [90]. The asymmetric Michael addition of oxindoles proved to be an efficient method for the construction of these structural motifs and a wide range of electrophiles such as a,(3-unsaturated aldehydes [91], ketones [92], sulfones, nitroalkenes [93], and 2-chloroacrylonitrile [94] have been weU studied in recent years (Scheme 5.45). 

Further extension of the scope of Michael acceptors to vinyl sulfones was realized by Alexakis and co-workers [112] recently. 7>an5-4-hydroxyprolylamide 117 was found to be the optimal catalyst to promote the intramolecular Michael addition of aldehydes to vinyl sulfone, furnishing the desired products 116 in good yields, together with good diastereoselectivities and enantioselectivities (Scheme 5.54). 

Similar Michael additions of various aldehydes to vinyl sulfones to some of those depicted above have also been developed by Alexakis et al. in the presence of an aminal-pyrrolidine organocatalyst derived from proline, albeit leading to... 

The Michael addition, i.e the fusion of an enolate with an a,P-unsaturated aldehyde, ketone, ester, carboxamide, or nitrile, belongs to the most prominent organic reactions/ " The literature abounds with impressive examples as is the manufacture of chrysanthemic acid from two isoprene building blocks, namely, ethyl P,P-dimethylacrylate and 4-chlorophenyl prenyl (3-methyl-2-butenyl) sulfone. ... 

Mosse and Alexakis reported on the first asymmetric direct Michael addition of aldehydes to vinyl sulfones... 

SCHEME 2231. Organo-catalyzed asymmetric Michael additions of nitroalkanes (A) and aldehydes (B) to a,(3-unsaturated sulfones. 

Aleman J, Marcos V, Marzo L, Garci a-Ruano JL. Influence of the reaction conditions on the evolution of the Michael addition of (3-keto sulfones to alpha,beta-unsaturated aldehydes. 7. Org. Chem. 2010 (23) 4482 491. 

Sulzer-Mosse S, Alexakis A, Mareda J, Bollot G, Bemardi-nelli G, Filinchuk Y. Enantioselective organocatalytic conjugate addition of aldehydes to vinyl sulfones and vinyl phosphonates as challenging Michael acceptors. Chem. Eur. J. 2009 15(13) 3204-3220. 

Bournaud C, Marchal E, Quintard A, Sulzer-Mosse S, Alexakis A. Organocatalyst-mediated enantioselective intramolecular Michael addition of aldehydes to vinyl sulfones. Tetrahedron Asymm. 2010 21(13-14) 1666-1673. 

Various electron-withdrawing groups, such as aldehyde, nitrile, esters, ketones, sulfones, etc. have been utilized to activate the vinyl moiety. The generally accepted mechanism (1) shown in Scheme 2 involves the Michael addition of Ae amine catalyst to the alkene, followed by an aldol type addition to the carbonyl or imine com und. Subsequent elimination releases the catalyst, and the cycle continues. 

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