Conjugate addition of thiols

Thiolates, generated in situ by the action of ammonium tetra-thiomolybdate on alkyl halides, thiocyanates, and disulfides, undergo conjugate addition to a, (1-unsaturatcd esters, nitriles, and ketones in water under neutral conditions (Eq. 10. II).29 Conjugate addition of thiols was also carried out in a hydrophobic ionic liquid [bmim]PF6/water-solvent system (2 1) in the absence of any acid catalyst to afford the corresponding Michael adducts in high to quantitative yields with excellent 1,4-selectivity under mild and neutral conditions (Eq. 10.12). The use of ionic liquids helps to avoid the use of either acid or base catalysts... 

Shibasaki s lanthanide-alkaline metal-BINOL system, discussed in Chapters 2 and 3, can also effect the asymmetric conjugate addition reaction. As shown in Scheme 8-35, enantioselective conjugate addition of thiols to a,/ -unsaturated carbonyl compounds proceeds smoothly, leading to the corresponding products with high yield and high ee.76... 

Scheme 8-35. LSB-promoted catalytic asymmetric conjugate addition of thiols to enones. Reprinted with permission by Am. Chem. Soc., Ref. 76.

Conjugate additions of thiols to a 2,3-allenoate proceed easily [236b, 249, 250],... 

Conjugate addition of thiols to a,p-unsaturated carbonyl compounds... 

Greaney and coworkers have introduced the conjugate addition of thiols to Michael acceptors as an effective adaptive DCL strategy [46,47]. The reaction is well suited for biological DCL synthesis, taking place in water with no requirement for external reagents. As with disulfide bond formation, the reaction is subject to simple and effective pH control. Under mildly basic conditions, the thiolate anion adds rapidly to Michael acceptors under equilibrium conditions. Acidification effectively switches the reaction... 

Schistosoma japonica glutathione-S -transferase [24] Conjugate addition of thiols to enones -300 HPLC... 

The conjugate additions of thiols to a,p-unsaturated electrophiles was extended by Wang [96]. Catalyst 166 promoted the addition of thioacetic acid to a variety of enones, including aliphatic, aromatic and heteroaromatic substituents (Scheme 42). Wang expanded the scope of the reaction to include asymmetric additions of thioacetic acid to nitro-olefms (Scheme 43) [97]. Thiourea catalyst 166 promoted the addition reactions in high yields and high enantiomeric ratios for a variety of P-substituted nitro-olefms. 

Tetraalkylammonium bromide was found to be a good catalyst for the conjugate addition of thiols to a,p-unsaturated nitriles, carboxylic esters, ketones, aldehydes, and nitro alkenes. The reactions proceeded rapidly and gave high yields of products (typically, 90%) (160). 

In the conjugate addition of thiols to a,j3-unsaturated carbonyl compounds, carried out in aqueous conditions, water was found to play a dual role in simultaneously activating the a -unsaturated carbonyl compound and the thiol.130... 

Antieancer drugs that work hy conjugate addition of thiols... 

Marigo M, Schulte T, Franzen J, Jprgensen KA (2005b) Asymmetric multicomponent domino reactions and highly enantio selective conjugated addition of thiols to alpha,beta-unsaturated aldehydes. J Am Chem Soc 127 15710-15711... 

Asymmetric conjugate addition of thiols to chiral -substituted 7V-enoylsultams 19, catalyzed by 1.5 equivalents of titanium(IV) chloride, affords the adducts 20 in good chemical yields and variable diastereoselectivities 3S. 

Asymmetric conjugate addition of thiols to 3-crotonyl-2-oxazolidinone is effectively catalyzed by the aqua nickel(II) complex of (i ,l )-DBFOX/Ph to produce conjugate adducts in high chemical yields and with high enantioselectivity [125] (Sch. 27). 

In contrast to HBr, the acids HC1 and HI do not undergo free-radical addition to alkenes, even in the presence of peroxides or O2. Abstraction of H- from HC1 is too endothermic, and addition of I- to an alkene is too endothermic. However, thiols (RSH) add to alkenes by a free-radical mechanism exactly analogous to the addition of HBr. The initiator is usually AIBN or (BzO)2- The alkene may be electron-rich or electron-poor. Note that the conjugate addition of thiols to electron-poor alkenes can occur either by a free-radical mechanism or by a polar, nucleophilic mechanism. 

Conjugate additions of thiols or thioacetates to a-enones, a,P-unsaturated esters or nitrostyrenes are catalyzed by cinchona alkaloids [173, 1058]. Even under pressure [1388], the adducts are obtained with an enantioselectivity lower than 75%. However, the use of 7.41 as catalyst induces higher selectivities [173] (Figure 7.36). 

Conjugate additions of thiols to N-enoyloxazolidinones E- or Z-7.42 derived from 1.116 [415] or to lactone derivative 1.31 [66] take place with a good selectivity. After removal of the chiral auxiliary, the corresponding adducts are readily obtained. Conjugate additions of amines to lactone 1.36 (G = menthyl) [66, 1396] are also highly selective. Reduction of the resulting adducts with LAH provides... 

Addition reactions. CAN serves as a catalyst for the conjugate addition of thiols and selenols to enones under solvent-free conditions. Glycals are transformed into glycosides containing a nitromethyl group at C-2. ... 

In the Michael addition of azide ion to o ,j8-unsattu ated carbonyl compounds, Xia et al. found the reaction worked well with or without an amine base catalyst in up to 95% yield [204]. Two descriptions of the conjugate addition of thiols to alkenes were reported by Ranu [205] and Yadav [206]. Both authors found that thiols such as thiophenol add to cyclohexenone in 92% yield in the ionic liquids [(C4H9>4N]Br or [BMIM][PF6] (Scheme 5.2-82). 

Scheme 3.32 Enantioselective conjugate addition of thiols to a,P-unsaturated aldehydes and ketones.

Ar = 3,5-(CF3)2C6H3 Fig. Z28 Conjugate addition of thiols to cyclopentenone and acyclic enones... 

Fig. 2.29 Conjugate addition of thiols to nitroacrylates and a,p-unsaturated IV-acylated oxazoU-din-2-ones...

Pore et al. (2006) documented the thia-Michael addition involving the conjugate addition of thiols to a,p-unsaturated ketones in the presence of SSA as a heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 5.53). The catalytic activity was comparatively studied with potassium phosphate. Studies revealed that SSA is suitable for electron-deficient a,P-unsaturated compounds, whereas K3PO4 catalyzed the reactions of both electron-deficient as well as electron-rich enones. SSA catalyzes a rapid, green, and chemoselective aza-Michael addition of amines and thiols... 

Pore, D.M., Soudagar, M.S., Desai, U.V., Thopate,T.S. and Wadagaonkar, P.P. 2006. Potassium phosphate or silica sulfuric acid catalyzed conjugate addition of thiols to a,P-unsaturated ketones at room temperature under solvent-free conditions. Tetrahedron Lett. 47(52) 9325-9328. 

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