Conjugate addition of sulfur nucleophiles

For a recent review covering the catalytic asymmetric conjugate addition of sulfur nucleophiles see D. Enders, K. Liitgen and A. A. Narine, Synthesis, 2007, 959. 

In 2005, J0rgensen et al. extended the conjugate addition of sulfur nucleophiles to a,P-unsaturated aldehydes under iminium catalysis with trimethylsilyl ether 56 (10 mol%) as catalyst [385]. Very high enantioselectivities (89-97% ee) were reported for the addition of aliphatic thiols to different aromatic and aliphatic enals at low temperatures (-24°C) where the employment of an acid cocatalyst (PhCOjH, 10 mol%) was mandatory in order to improve the reaction rate. This methodology has been incorporated into domino reactions by the same group and others to successfully prepare optically active sulfur-containing heterocyclic compounds [385, 386],... 

Recently an expansion of the electrophile scope of the conjugate addition of sulfur nucleophiles has been reported by different groups. As depicted in Fig. 2.29 for selected examples, Cinchona-denwed catalysts 203 and 205 promote highly enantioselective additions to nitrooleflns [387] and a,p-unsaturated V-acylated oxazolidin-2-ones [388] through non-covalent catalysis. Especially interesting results the Michael reaction to P-substituted nitroacrylates catalyzed by chiral thio-... 

Few examples have been reported for the organocatalytic asymmetric conjugate addition of sulfur nucleophiles other than thiols. The reaction of thiocarboxylic acids to cyclohex-2-enones [390] and a,p-nnsatnrated esters [391] was initially studied by Wynberg et al. employing Cinchona alkaloid catalysts with limited success in terms of selectivity (up to 54% ee). Slightly better enantioselectivities have been recently obtained by Wang et al. in the 1,4-addition of thioacetic acid to P-nitrostyrenes (up to 78% ee) [392] and trani-chalcones (up to 65% ee) [393], using Takemoto s thiourea 142 as catalyst (2-10 mol%). 

The organocatalyzed conjugate addition of sulfur nucleophiles to electron-poor alkenes is probably the most frequently used process for the asymmetric formation of C—S bond [2b, 5]. Analogously, the employment of selenium nucleophiles may, in principle, be used for the formation of C—Se bonds. Because previous reviews were already reported on this topic, more recent reports are especially highlighted in this chapter. 

Scheme 33 Conjugate addition of sulfur based nucleophiles...

The stereochemical outcome of the conjugate addition of sulfur-stabilized nucleophiles to the 5-lactam unit of tetrahydrobenzo[a]benzoquinolizines (83) has been (g) shown to depend on the nature of the substituent at the angular position (R1) thus,... 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

The asymmetric conjugate addition of sulfur-based nucleophiles to Michael acceptors has been achieved using enantiomerically pure metal-based catalysts and organocatalysts. Sulfur nucleophiles are soft, and preferentially react by conjugate addition with a, p-unsaturated carbonyl compounds. Only catalytic amounts of the lithium thiolate (11.65) are required, since addition to the enone (11.66) generates the enolate (11.67). The enolate is then able to deprotonate thiol (11.68), regenerating thiolate (11.65) with formation of the product (11.69). 

A one-pot oxidative conjugate addition of sulfur-centered nucleophiles to MBH adducts has been developed by Yadav et The reaction involves... 

Conjugated dienes and activated olefins like indene undergo intermolecular gold-catalyzed additions of sulfur nucleophiles. Aliphatic and aromatic thiols, as well as thioacids, afforded the hydrothiolation products with good yield in the... 

The organocatalytic asymmetric conjugate addition of heteroatom nucleophiles to different electrophilic olefins has become a very popular reaction during the last few years. Different nitrogen, oxygen, sulfur, and selenium nucleophilic species have been successfully used leading to enantiomerically emiched heterofunctionalized derivatives. 

Optically active sulfur containing compounds play a very important role in biochemistry as well as synthetic chemistry. The asymmetric conjugate addition of sulphur nucleophiles, or sulfa-Michael addition [379], provides a direct and versatile approach toward optically active sulfur compounds. This strategy is particularly valuable, since enantioselective nucleophilic additions to a C-S double bond, unlike those to carbonyls and imines, are not synthetically feasible. 

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

Intramolecular conjugate addition occurs in the /3-sulfonylstyrenes (196) (72BCJ1893) and (197) (74JMC549) to give 1,2,4-thiadiazines. In the case of (197), subsequent elimination of HBr gave the fully unsaturated system. Similar intramolecular conjugate addition of oxygen and sulfur nucleophiles to sulfonylstyrenes and sulfonylalkynes also occurs. 

This looks complicated but it s just a question of working through each reaction. The stereochemistry needs some thought. The first reaction is a conjugate addition of a sulfur nucleophile to a very electrophilic alkene. The base used, piperidine, is an ordinary secondary amine but that is basic enough (pKaH about 11) to produce reasonable amounts of anion from the thiol pfCa also about 10). There is no stereochemistry in this step. 

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