Sulfones Michael addition acceptors

Vinyl sulfones, being good Michael acceptors, have been regarded as useful reagents for carbon-carbon bond formation. Nucleophiles used often are organometallic reagents, enamines and enolate anions and the Michael addition products are usually obtained in... 

Some particular features should be mentioned. Instead of Michael additions, a-nitroolefins are reported to yield allyl sulfones under Pd catalysis (equation 21). Halogenated acceptor-olefins can substitute halogen P to the acceptor by ipso-substitution with sulfinate (equation 22 , equation 23 ) or can lose halogen a to the acceptor in the course of a secondary elimination occurring P to the introduced sulfonyl groups (equation 24). On the other hand, the use of hydrated sodium sulfinates can lead to cleavage at the C=C double bond (equation 25). 

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. 

Sulfones have become increasingly important in organic synthesis in recent years and a, P-unsaturated sulfones especially are known to be excellent Michael acceptors. Following our concept of using SAMP derivatives as chiral equivalents of ammonia, the enantioselective aza-Michael addition has been investigated in order to provide a new method for the synthesis of P-aminosulfones [15]. 

Other synthetic approaches via sulfones make use of the Michael addition and cycloaddition to vinyl sulfones (see [401] and [402] for reviews on vinyl sulfones as dienophiles and Michael acceptors). The... 

Michael additions of /i-keto sulfoxides (142) and /i-kcto sulfones to highly activated acceptors (143) has been shown to produce 2-amino-4//-pyran adducts (144) under mild conditions.106... 

Acceptor-substituted alkenes that are employed as substrates in Michael additions include a./l-unsaturated ketones (for example, see Figure 10.59), a,/3-unsaturated esters (Figure 10.60), and a,/3-unsaturatcd nitriles (Figure 10.61). The corresponding reaction products are bifunctional compounds with C=0 and/or C=N bonds in positions 1 and 5. Analogous reaction conditions allow Michael additions to vinyl sulfones or nitroalkenes. These reactions lead to sulfones and nitro compounds that carry a C=0 and/or a O N bond at the C4 carbon. 

In analogy to hydroformylation, alkenes react with SO2 and H2 to give a so-called hydrosulftnation product, sulfinic acids [116]. Cationic Pd(II) and Pt(II) complexes bearing bidentate phosphine ligands are effective catalyst precursors. A plausible mechanism for the hydrosulfination involves formation of alkyl intermediates by olefin insertion into metal hydrides, subsequent insertion of SO2, and reformation of the hydrides with the release of sulfinic acids (Scheme 7.19). However, ahphatic sulfinic acids readily undergo disproportionation to give thiosulfinic acid esters, sulfonic acids, and water at the reaction temperature. The unstable sulfinic acids can be conveniently converted into y-oxo sulfones by addition of a,-unsaturated carbonyl compounds as Michael acceptors to the reaction mixtine (Eq. 7.23) [117]. 

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... 

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. 

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. 

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... 

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). 

In 2009, Zhu and Lu reported organocatalytic asymmetric Michael additions of nitroalkanes to another Michael acceptor such as vinyl sulfone mediated by another cinchona alkaloid-derived thiourea catalyst, which afforded the desired Michael products with good enantioselectivities of up to 84% ee (Scheme 1.20). This method in combination with a ready desulfonation represented a new approach to access a-alkylated chiral amines. 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

The electrophilic character of sulfur dioxide does not only enable addition to reactive nucleophiles, but also to electrons forming sulfur dioxide radical anions which possess the requirements of a captodative" stabilization (equation 83). This electron transfer occurs electrochemically or chemically under Leuckart-Wallach conditions (formic acid/tertiary amine - , by reduction of sulfur dioxide with l-benzyl-1,4-dihydronicotinamide or with Rongalite The radical anion behaves as an efficient nucleophile and affords the generation of sulfones with alkyl halides " and Michael-acceptor olefins (equations 84 and 85). 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

The vinyl substituent at C-2 can also act as a Michael acceptor and reaction with certain nucleophiles gives rise to 1,4-addition compounds. For example, p-toluene-sulfonic acid catalyzed addition of thiols to 2-vinyl- or 2-isopropenyl-5(47/)-oxazolones 136 gave, almost exclusively, the Michael adducts 137 that were used... 

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