Michael addition of thiols

By using LaNa3-tris(binaphthoxide) (LSB) 55, catalytic asymmetric Michael addition of thiols to cycloalkenones took place to provide the adduct 56 with high ees in good yields (Eq. 7.41) [48]. 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

Furthermore, a neighboring group participation of a phenylthio function is observed in the Lewis acid-catalyzed nucleophilic substitution reaction of various P-nitrosulfides. Because the P-nitrosulfides are readily available, by the Michael addition of thiols to nitroalkenes (see Michael addition Chapter 4), this reaction is very useful. The P-nitrosulfides are prepared stereoselectively, and the reaction proceeds in a stereo-specific way (retention of configuration) as shown in Eqs. 31-34.35... 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

E Emori, T. Arai, H. Sasai, M Shibasaki, A Catalytic Michael Addition of Thiols to a, -Unsaturated Carbonyl Compounds Asymmetric Protonations, J. Am Chem Soc 1998,120, 4043-4044. 

Asymmetric induction of the Michael addition of thiols to electron-deficient alkenes (4.6.1) has been achieved in high overall conversion using both free [e.g. 12-20] and polymer-supported [e.g. 21, 22] cinchona alkaloids and their salts [23-25], but with varying degrees of optical purity. The corresponding asymmetric Michael addition of selenophenols to cyclohex-2-enones is promoted by cinchoni-dine to give a chiral product (43% ee) [26],... 

An efficient asymmetric Michael addition of thiols to cycloalkenones (103) (56-90% ee) and an effective asymmetric protonation in Michael additions of thiols to non-cyclic enones (104) (75-90% ee), catalysed by LaNas tris(binaphthoxide) (105) and SmNas-tris(binaphthoxide) (106) complexes, respectively, has been reported. ... 

Shi, B. Greaney, M. F. Reversible Michael addition of thiols as a new tool for dynamic combinatorial chemistry. Chem. Commun. 2005, 886-888. 

Scheme 22. Michael addition of thiols onto chlorocyclopropylideneacetates 1-Me, 2 [7l, 9,15b, 22 b, 27]...

Asymmetric Michael addition. This pyrrolidine is an efficient catalyst for asymmetric Michael addition of thiols to cyclohexenone (cf. 8, 431). (S)-2-(Anilinomethyl)-1-ethylpyrrolidine, which lacks the 4-hydroxyl group of 1, has little effect on enantioselection. The important role of a hydroxyl group in several asymmetric inductions has already been noted. 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

We rationally launched this line by exploiting the Michael addition of thiols to enones with example 82 [157], The n-electron system of maleimide is... 

A supramolecular aqueous system for the Michael addition of thiols ArSH from the secondary side of (3-cyclodextrin to a,j3-unsaturated compounds residing at the primary side has been developed and shown to proceed in quantitative yields products of side-reactions, resulting from polymerization, were not observed. The use of cyclodextrin precludes the use of either acid or base and the catalyst can be recovered and reused.208... 

Copper(II) tetrafluoroborate Cu(BF4)2xH20 has been identified as a new and highly efficient catalyst for Michael addition of thiols to o ,/5-unsaturated carbonyl compounds under solvent-free conditions and in H20 at room temperature. The reactions are very fast and are completed within 2 min to 1 h. The rate of thiol addition is dependent on the steric hindrance at the /3-carbon of the o ,/3-unsaturated carbonyl substrate. In the case of chalcones, the reactions are best carried out in MeOH as solvent.237... 

Heterobimetallic asymmetric complexes developed by Shibasaki et al. are known as effective catalysts for asymmetric Michael additions. They achieved a catalytic asymmetric protonation in Michael additions of thiols to a,P-unsaturated carbonyl compounds using LaNa3tris(binaphthoxide) and SmNa3tris(binaphthoxide) complexes (SmSB) 37 [42]. For instance, treatment of thioester 48 with 4-fert-butyl(thiophenol) and 0.1 equivalents of (P)-SmSB 37 (Ln=Sm) in CH2C12 at -78°C gave the adduct 49 in 93% ee and in 86% yield (Scheme 4). The high enantiomeric ratio is considered to be attributable to an... 

Further reports on asymmetric synthesis in the presence of Cinchona alkaloids have been made.142 " For example, hydrogenation of methyl pyruvate with a platinum-alumina catalyst containing quinine gives (+)-(/ )-methyl lactate in 87% optical yield.1426 Asymmetric induction with optical yields up to 36 and 26% has been observed in the Michael addition of thiols and nitro-alkanes to ct/ -unsaturated ketones in the presence of quaternary salts derived from the Cinchona alkaloids.142"... 

Recently, thiols have also been shown to participate in a series of new reversible reactions suitable for DCC. Such reactions include (1) the thioester exchange reaction (Fig. 6b), (2) the thiazolidine exchange reaction (Fig. 6c), and (3) the reversible Michael addition of thiols (Fig. 6d). 

Fig. 6 (a) Thiol-disulfide exchange, (b) Thiol-thioester exchange, (c) Thiazolidine exchange, (d) Reversible Michael addition of thiols... 

In 2005, the Michael addition of thiols to enones was added to the list of reversible reactions compatible with the concept of DCC (Fig. 6d). Shi and Greaney investigated the reactivity of glutathione (GSH) toward a series of ethacrynic acid (EA) derivatives in a mixture of DMSO and water at pH 8 [51]. A DCL of six GSH-EA derivatives, products of the Michael addition, was generated which proved responsive to changes in pH. Thermodynamic equilibrium was typically attained after 3 h. Acidification to pH 4 has the immediate effect of switching off the Michael addition and therefore represents a practical way to freeze the equilibrium before analyzing the composition of the DCL. 

Only recently, Shibasaki et al. reported on the application of a Sm-Na-(R)-BINOL-complex as catalyst in a reaction cascade consisting of an a.symmetric Michael addition of thiols to a,fS- xn-saturated carbonyl compounds followed by an asymmetric enolate protonation [20]. 

Cathodically initiaited Michael addition of thiols to levoglucosenone provides threo or ervthro addition products selectively depending on the amount of charge passed [Eq. (28)] [205]. 

Michael addition of thiols to conjugated system of levoglucosenone [64,65,66,67]... 

La-linked-BINOL complex 23 was introduced as a stable, storable, and reuse-able asymmetric catalyst for the Michael reaction [120]. Optimization of the reaction between dibenzyl malonate and 2-cyclohexene-1-one in DME afforded the Michael adduct in 94% yield and >99% ee. The extraordinary versatility of LnLB catalyts is also documented in the highly efficient Michael addition of thiols to a,y9-unsaturated carbonyl compounds [121] and tandem Michael-aldol reactions [122]. 

Enantioselective Michael addition of thiols to enones is a useful reaction for the synthesis of sex pheromones [26] and terpenes [27]. For example, enantioselective Michael additions of thiols to 2-cyclohexenone (64) and maleic acid esters in the presence of chiral bases such as cinchona alkaloids [28, 29] and optically active amino alcohols [30, 31] have been reported. It has also been found that the enantioselective Michael addition reaction proceeds efficiently in an inclusion crystal... 

Michael addition of thiols across the 10,11-double bond has occurred in tylosin derivatives in which the aldehyde had been protected as its dithioketal [134, 139] a comment about successful Michael additions of amines was also... 

Michael addition of thiols to levoglucosenone (5) in triethylamine gave the 4-nlkylthio-3-deoxy-2-uloses (6) in yields greater than 80%. ... 

Sulfur uucleophiles Asymmetric Michael addition of thiols to enones, for example, BnSH to PhCH=CHCOMe, can be catalysed by a complex of (TfO)3Sc with chiral bipyridine (133) at room temperature in water without using any organic solvents to afford the corresponding adduct at <93% ee ... 

An enantioselective sulfa-Michael addition of thiols to a,y3-unsaturated A-acylated oxazolidinones, catalysed the quinine-derived squaramide (134), has been reported to afford the corresponding products with <99% ee °... 

Michael addition of thiol HOCH2CH2SH to alkynyl ketones R C CCOR can be catalysed by BujP (10mol%) to afford the (Z)-configured product. ... 

Other examples of Michael additions are the reaction of nitroolefins with acetone on L-proline-modified Mg-Al mixed oxides (51) or with diethyl malonate on metalorganic MCM-41 (52), or the addition of nitromethane to unsaturated carbonyl compounds on KF-modified alumina (53). Furthermore, solid catalysts such as montmorillonite clays and hydroxyapatite have recently been employed for the construction of S—C bonds by /lia-Michael addition of thiols to unsaturated ketones and other carbonyl compounds (54,55). Similarly, aza-Michael additions of amines to alkenes activated by -CN, -COOR, or -COR groups, lead to C—N bond containing products on Amberlyst-15 or polyaniline supported Cul (56,57). 

The first example of enantioselective trimethylsilylcyanation of aldehydes catalyzed by chiral binaphthol and binaphthol-modified lanthanum alkoxides shows an obvious effect of substituents at the 3,3 -positions of BINOL. The 3,3 -bis(methoxyethyl)-BINOL had the advantage over simple BINOL to give (S)-products in excellent yields with 73% ee (119). Chiral lanthanum and samarium complexes catalyze the Michael addition of thiols to a, )3-unsaturated carbonyl compounds (120). 

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