Thiophenol, asymmetric addition

Whereas the results summarized in Scheme 4.32 were achieved under homogeneous reaction conditions, Colonna et al. reported the use of chiral phase-transfer catalysts for asymmetric addition of benzyl mercaptan and thiophenols to cyclohexenone and derivatives [55b], The best result was 85% yield and 36% enantiomeric excess in the addition of thiophenol to cyclohexenone, catalyzed by ca 0.4 mol% N-(o-nitrobenzyl)quininium chloride at 25 °C. In this experiment, CCI4 served as solvent and solid KF as the base. Finally, Aida et al. reported in 1996 that chiral... 

N-alkylated porphyrins can also serve as catalytic bases in the asymmetric addition of thiophenols to enones [55c], In the most selective example (addition of 2-methylthiophenol to cyclohexenone), 55% ee was achieved. 

Diisopropyl phenylthiosuccinate (81 % ee) is prepared in 95% yield by the asymmetric addition of thiophenol to diisopropyl maleate in the presence of a catalytic amount of cinchonine136. 

The corresponding o-nitrobenzyl chloride 43b catalyzed the asymmetric addition of thiophenol to 2-cyclohexen-l-one under solid-liquid PTC conditions (e.e. up to... 

Natural cinchona alkaloids were reported to promote the sulfa-Michael addition to different electron-poor alkenes as well. Catalysts 1 and 2 were employed by Pracejus et al. [11] in the moderately enantioselective additions (up to 54% ee) of benzylmercaptan to a-phthalimidomethacrylate. The same bases were found to promote the asymmetric addition of benzylmercaptan and tritylmercaptan to nitro-alkenes. Similar results were later reported with thioglycolic acid as the nucleophile [12]. Low enantioselectivities were obtained in the process catalyzed by different alkaloids such as bmcine, strychnine, and A-methyl ephedrine [11]. Catalyst 4 was successfully employed in the sulfa-Michael addition of thiophenol to maleic acid... 

Allyl p-tolyl sulphoxide 535 reacts with sodium methoxide in methanol by initial prototropic isomerization and subsequent addition of methanol to give 536 (equation 333). Protic solvents are photochemically incorporated by the open chain olefinic bond of trans methyl )S-styryl sulphoxide 537 in a Markovnikov regiospecificity (equation 334). Mercaptanes and thiophenols add to vinyl sulphoxides in a similar manner (compare also Reference 604 and Section IV.B.3) to give fi-alkylthio(arylthio)ethyl sulphoxides 538 (equation 335). Addition of deuteriated thio-phenol (PhSD) to optically active p-tolyl vinyl sulphoxide is accompanied by a low asymmetric a-induction not exceeding 10% (equation 336) . Addition of amines to vinyl sulphoxides proceeds in the same way giving )S-aminoethyl sulphoxides in good to quantitative yields depending on the substituents at the vinyl moiety When optically active p-tolyl vinyl sulphoxides are used in this reaction, diastereoisomeric mixtures are always formed and asymmetric induction at the p- and a-carbon atoms is 80 20 (R = H, R = Me) and 1.8 1 (R = Me, R = H), respectively (equation 337) ... 

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... 

The asymmetric conjugate addition of thiophenol to ( >3-crotonoyloxazolidin-2-one, catalysed by the scandium(III) triflate complex of Ph-PYBOX, gave the corre- sponding adduct in 66% ee. Lanthanoid triflates gave lower enantioselectivities (<28% ee).132... 

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

The Chen group also demonstrated a successful conjugate addition/ asymmetric protonation of a-prochiral imide 4 using thiophenol in the presence of 10 mol% 3 (Scheme 6.1) [43]. It was hypothesized that the ammonium group of the catalyst serves as a chiral proton source for the catalyst-stabilized enone intermediate formed after initial 1,4-addition of the thiol (Fig. 6.4). 

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... 

The heterobimetallic catalyst prepared from (R,R)-3-aza-benzyl-l,5-dihydroxy-l,5-diphenylpentane was used for the asymmetric Michael addition reaction of malo-nates and thiophenols to enones [49]. The polymer-supported version of the chiral... 

Later, the same group showed that an asymmetric protonation of preformed lithium enolate was possible by a catalytic amount of chiral proton source 23 and stoichiometric amount of an achiral proton source [45]. For instance, when hthium enolate 44, generated from ketene 41 and -BuLi, was treated with 0.2 equiv of 23 followed by slow addition of 0.85 equiv of phenylpropanone, (S)-enriched ketone 45 was obtained with 94% ee (Scheme 4). In this reaction, various achiral proton sources including thiophenol, 2,6-di-ferf-butyl-4-methylphenol, H2O, and pivalic acid were used to provide enantioselectivity higher than 90% ee. The value of the achiral acid must be smaller than that of 45 to accomplish a high level of asymmetric induction. The catalytic cycle shown in Scheme 2 is the possible mechanism of this reaction. 

The asymmetric a-sulfenylation of ketones is a particularly challenging reaction, as demonstrated by the poor success reported in the stereoselective variants via classical enolate/azaenolate reaction with an electrophilic sulfur reagent [71]. An umpolung approach has been devised by Coltart and co-workers [72] to effect the first asymmetric a-sulfenylation of ketones with arene thiols. Nitroso alkene derivatives, in i/tM-generated under basic conditions from a-chloro oximes, reacted with arene thiols in the presence of cinchona thiourea 27, which promoted the conjugate addition of thiophenol (Scheme 14.25). The chiral nonracemic a-sulfenylated oximes were directly hydrolyzed by IBX to ketones in high yield and good enantioselectivity. 

In 1997, the Sundararajan group reported a heterobimetallic complex Al-Li-(21a)2 as a promoter for the asymmetric sulfur-Michael addition of thio-phenols to cyclic enones with 96-97% yields and 26-45% enantiomeric excess. " Later in 2001, they described a new polymer-anchored chiral catalyst Al-Li-(28)2 for the addition of thiols to cycloalkenones (Scheme 19.36). With thiophenol and p-methylthiophenol as the sulfur-based nucleophiles, the adducts were obtained in excellent yields but moderate enantioselectivities (33-57% enantiomeric excess). 

Scheme 19.36 Asymmetric Michael addition of thiophenols to cyclic enones catalysed by a polymer-supported aluminium complex.

An intermediate for the antiglaucoma drug dorzolamide was synthesized in 67% ee through asymmetric conjugate addition of thiophene-2-thiol to E)-3-crotonoyloxazolidin-2-one catalyzed by Sc(OTf)3 and Ph-pybox [126]. In addition, this catalytic system was proved to be successful in the Michael addition of thiophenol to the previous substrate (66% ee). 

An example is the asymmetric conjugate addition of a thiophenol to cyclohexenone to give (42) catalysed by the alkaloid cinchonidine. 

Catalysts 1 and 4 are reported to give the best results for the conjugate addition of thiophenol to 2-phenylacrylates (Scheme 6.2) [17]. The products were obtained with opposite enantioselectivity in the reaction with 1 and 4, respectively, as the catalyst. Based upon a computational analysis, it was proposed that the transition state for the reaction involves hydrogen bonding between the hydroxy group of the catalyst and the carbonyl group of the ester and asymmetric proton transfer from the thiol to enolate anion (Scheme 6.2). 

Early in the 1990s, Kumar and co-workers described an asymmetric synthesis of (5)-naproxen by means of a thia-Michael addition of thiophenol to acrylate 115 (Scheme 31.39). Desulfurization followed by acid cleavage... 

Several decades later, Simpkins et al. [19] successfully applied Pracejus pioneering work to the stereoselective preparation of a-silylthioesters 41. For example, addition of thiophenol to readily available silylketenes 40a-d in the presence of 0-benzoyl quinine 39 (2-10 mol%) afforded the corresponding a-silylthioesters 41a-d in good yields and enantioselectivities up to 93% (Scheme 3.14). The use of the pseudoenantiomer 0-benzoyl quinidine 42 led to the formation of the opposite enantiomer with a comparable level of asymmetric induction during addition of thiophenol to silylketenes 40a-d. 

Catalytic asymmetric conjugate additions of heteroatoms such as nitrogen or sulfur nucleophiles provide access to important / -substituted carbonyl deri-vates, and a number of successful strategies have been devised (38, 39, 41). Tomioka developed enantioselective additions of thiophenols to ,/i-unsatu-rated esters (Equation 42) [164]. This reaction proceeds in the presence of the presumed lithium complex 220, which was suggested as the catalytically active species. As a control experiment, the chiral amino diether itself is not a catalyst for the addition of thiophenol 219 to 218. A variety of trans enoates were shown to undergo addition to give the products with high levels of induction, as illustrated by the formation of thioether 221 (99 % yield, 97 % ee). 

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