A,P-Unsaturated thiol esters

E)-a 9 -Umaturated thiol esters.1 The reagent converts aldehydes mainly into (E)-a,p-unsaturated thiol esters. The trans-selectivity can be increased by addition of DMAP (E/Z 90-97 10-3). 

Carbonyl transposition.1 Tetrafluoroboric acid is the most effective acid for rearrangement of a-hydroxy ketene dithioketals to a,p-unsaturated thiol esters. This rearrangement is particularly useful for rearrangement of the tertiary allylic alcohols formed by addition of organometallic reagents to a-keto ketene dithioketals, which are readily available by reaction of ketone enolates with carbon disulfide followed by alkylation with methyl iodide. 

Acylation of a simple thiol with an alkyl carboxylate is not a very suitable method for preparation of S-alkyl thiocarboxylates. Transesterification is, however, possible if either the thiol or the carboxylic ester is activated. The enhanced reactivity of boron, aluminum and silicon thiolates has been utilized for the synthesis of a large variety of thiocarboxylic S-esters, including hydroxy derivatives (from lactones). a,P-Unsaturated thiol esters, e.g. cinnamoyl or 2-butenoyl derivatives, are also accessible. Michael addition, an undesirable side reaction of thiols, is completely avoided if alkyl trimethylsilyl sulfides ortris(arylthio)boranes are applied. ... 

Ma and coworkers described the first organocatalytic asymmetric Michael addition of aldehydes to a,p-unsaturated thiol esters promoted by catalyst Cla. The reaction proceeded with good yields, diastereoselectivity and excellent enantioselectivity. 

Scheme 2.16 Enantioselective conjugate addition of aldehydes to a,p-unsaturated thiol esters...

By using 10 mol% of 51, MS4A, and t-BuSH, the desired product 52 was obtained in up to 98% ee in 80% yield. A complementary role by two metals (Ga and Li) in activating and positioning both of the substrates has been proposed. The MS4A (sodium aluminosilicate) accelerated the reaction however, the actual role of this additive was not clearly defined, although the possibilty that MS4A delivers Na ions was pointed out. Tomioka et al. reported the asymmetric Michael addition of an aromatic thiol to a,P-unsaturated esters in the presence of 8 mol% of 53 to provide 54 in up to 97% ee in 99% yield (Eq. 7.40) [47]. 

The base-catalyzed joint reaction of nitroalkenes with thiophenol in the presence of aldehydes gives y-phenylthio-P-nitro alcohols in one pot (Eq. 4.5).8 The joint reaction of nitroalkenes with thiols and a,p-unsaturated nitriles (or esters) has also been achieved. (Eq. 4.6).9 P-Nitro sulfides thus prepared show unique reactivity toward nucleophiles or tin radicals. The nitro... 

The Michael reaction involves conjugate addition of a nucleophile onto an a,P-unsaturated carbonyl compound, or similar system. Such reactions take place in nature as well, and some can be potentially dangerous to us. For example, the a,P-unsaturated ester ethyl acrylate is a cancer suspect agent. This electrophile can react with biological nucleophiles and, in so doing, bind irreversibly to the nucleophile, rendering it unable to carry out its normal functions. A particularly important enzyme that can act as a nucleophile is DNA polymerase, which is responsible for the synthesis of strands of DNA, especially as part of a DNA repair mechanism (see Section 14.2.2). The nucleophilic centre is a thiol grouping, and this may react with ethyl acrylate as shown. 

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). 

Tomioka et al. reported the asymmetric Michael addition of lithium thiolates catalyzed by chiral aminoether 31 (Scheme 8D. 18) [39]. Thus, in the presence of catalytic amounts of 31 (10 mol %) and lithium 2-(trimethylsilyl)thiophenolate 32-Li (8 mol %), thiol 32 (3 equiv.) reacted with a,p-unsaturated esters at -78°C in toluene-hexane solvent to give the Michael adduct with up to 97% ee. In the ahsence of 31, the reaction of thiophenol proceeded in only 0.5% yield at room temperature. A monomeric complex consisting of 31 and lithium is proposed as the key reactive species in this asymmetric reaction. The trimethylsilyl group at the ortho-po-sition of the thiol moiety in 32 contributes to the formation of the stereochemically defined monomeric chelated structure, wherein the lithium cation is coordinated with the three heteroatoms of the tridentate ligand 31. The reactions of acyclic /nmv-a,P-unsaturated esters (R1 = Me, Et, Pr, Bu, Bu, PhCH9 R2 = H) proceeds with high enantioselectivity in... 

Both ketones and aldehydes, as well as acylsilanes can be employed as carbonyl substrates in the new p-lactone synthesis (Table). Reactions involving ketones are most conveniently carried out by adding the neat carbonyl compound to the thiol ester enolate solution. Under these conditions aliphatic aldehydes react to form substantial quantities of 2 1 adducts however, formation of these side products can be suppressed simply by slowly adding the aldehyde component as a precooled (-78°C) solution to the reaction mixture. Wide variation is also possible in the thiol ester component, although a few limitations of the method have been noted. For example, a,p-unsaturated ketones such as methyl vinyl ketone and cyclohexenone fail to yield p-lactones, and attempts to generate p-lactones with severe steric crowding have also met with limited success.3... 

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). 

The chiral P-amino thiol ester (198) gives a lithium enolate that shows excellent diastereofacial preference in its reactions with a,p-unsaturated and aryl aldehydes (equation 119 Table 22). The stereochemistry of the major isomer (199) is consistent with attack of the aldehyde on a relatively rigid enolate chelate. 

Product equilibration is not likely under room temperature reaction conditions, but there are some cases where it has been deliberately used to enhance the ( )-enoate selectivity of reactions that otherwise afford mixtures. Entries 47-49 in Table 19 demonstrate that catalytic amounts of p-dimethyl-aminopyridine (DMAP) will induce the Z E equilibration of a, -unsaturated thiol esters at room temperature (chloroform solution), resulting in enhanced ( )-enoate selectivity (101b). This procedure is not effective with the corresponding oxygen esters, however. 

In 1974,Mukaiyama and co-workers reported the first examples of Lewis acid-catalyzed Michael reactions between silyl enolates and a,p-unsaturated carbonyl compounds [33]. Evans and co-workers developed a catalytic asymmetric Michael reaction of silyl enol ethers of thiol esters to alkylidene malonates. For example, the reaction of alkylidene malonate 23 with 2.2 equiv of silyl enol ether 22 was carried out in the presence of 10 mol % of catalyst 25 and 2 equiv of hexa-fluoro-2-propanol (HFIP) in PhMe/CH2Cl2 (3 1) at -78 °C to give the expected adduct 24 in 93% ee (Scheme 5) [34]. Borane complex-catalyzed asymmetric Michael addition has also been reported [35]. 

Thiolates, generated in situ by the action of ammonium tetra-thiomolybdate on alkyl halides, thiocyanates, and disulfides, undergo conjugate addition to a, P-unsaturated esters, nitriles, and ketones in water under neutral conditions (Eq. 10.11). Conjugate addition of thiols was also carried out in a hydrophobic ionic liquid [bmimjPFe/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 Mquids helps to avoid the use of either acid or base catalysts... 

A nitroalkane with a chiral centre on the beta-carbon, which is generated by Michael reaction of a thiol to an a,p-unsaturated nitro compound, racem-izes under reversible Michael conditions and may be applied for DKR [108]. The racemic Michael adduct from ethyl 3-(2-mercaptophenyl)-2-propenoate and P-nitrostyrene is racemized in thepresence of thiourea and cychzes by a second Michael reaction of the carbon alpha to the nitro group to the a,p-unsaturated ester to give thiochromene, which has three consecutive stereogenic centres, in 95% yield with 95% ee as almost a single diastereomer (Scheme 5.35) [108aj. 

Literature survey reveals that the Michael addition reaction is highly accelerated in IL. Copper(II)triflate immobilized in [bmimJBF IL is used as reaction medium for Michael addition of p-ketoesters to alkenes [10,11]. [bmim]OH has been used in Michael addition of active methylene corrtpotmds to corrugated ketones, carboxylic esters, and nitriles [12]. Michael addition of thiols and thiophosphate to conjugated alkenes in IL [pmim]Br [13] has been reported. Conjugate addition of azide ion to a,p-unsaturated carbonyl compoimds and aza-Michael addition reactions are also reported [14-17]. Recently, Zare et al. [18] reported MW-assisted aza-Michael addition of aromatic sulfonamides to various a,P-unsatirrated esters [ 19] in the presence of a catalytic amount of MgO or ZnO with [bmim]Br as the reaction solvent. Aryl nitriles can be synthesized via the Rosenmimd von Braim reaction from the corresponding hahdes in IL imder MW [20]. 

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