Michael thiophenol

Although a sulfhydryl group generally is not converted to an 5-phenyl thioether, the conversion can be accomplished through the use of a Pd-catalyzed arylation with an aryl iodide. Thiophenol can be used to introduce sulfur into molecules by simple displacement or by Michael additions, and thus, the phenyl group serves as a suitable protective group that can be removed by electrolysis (—2.7 V, DMF, R N X-). ... 

When having an Q ,/3-unsaturated carbonyl moiety, 2(5/7)-furanones are capable of undergoing 1,4-Michael-type additions. It was found that 1,4-addition reactions of thiophenols to the furanones 168,170, and 172 take place at room temperature in the presence of triethylamine to give a quantitative yield of the adducts 169, 171, and 173. Complete diastereoselective Michael-type addition occurred in all cases (Scheme 48) (88T7213). 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

It is not surprising that chloro esters 1, 2 readily add thiols, catalyzed by sodium thiolates or triethylamine, to give the corresponding 2-(r-organylthiocy-clopropyl)-2-chloroacetates 85,86 (Scheme 22) [15 b, 22b, 27]. This reaction with thiophenol has been used to quantify the Michael reactivity of 1-Me, 2-Me, 3-X in comparison to simple acrylates (see above). With an excess of PhSH, the nucleophilic substitution of the chlorine in 85 a (but not in 85h) proceeded to give the corresponding bis(phenylthio) derivative in 63% yield [15bj. Alkali thiolates (e.g. NaSMe, NaSBn) add smoothly onto 1-Me, 2c-Me and 2p-Me at - 78 °C, because at this temperature subsequent nucleophilic substitution of the chlorine is much slower [7l, 9]. The Michael additions of sodium phenylselenide and sodium arylsulfenates onto 1-Me and their synthetic utility have been discussed above (see Table 1). 

The Chen group early in 2005 constituted the novel class of thiourea-function-ahzed cinchona alkaloids with the first reported synthesis and application of thioureas 116 (8R, 9S) and 117 (8R, 9R) prepared from cinchonidine and cinchonine in over 60% yield, respectively (Scheme 6.112) [273]. In the Michael addition of thiophenol to an a,(5-unsaturated imide, the thioureas 116 and 117 displayed only poor stereoinduction (at rt 116 7% ee 117 17% ee), but high catalytic activity (99% yield/2h) (Scheme 6.112). 

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

Thiophenols undergo base-catalyzed, Michael addition to acetylenic acids and esters to give trans addition products. These vinyl thioethers have been used in the synthesis of thiochromones. " Recently, Undheim and Lie have shown that thiophenol adds to DMAD with concomitant cyclization to give benzo[6]thiophenes. 

Two principal routes yield thiochromones. The first involves Michael addition of a thiophenol to a propiolic acid, followed by Friedel-Crafts cyclization of the chloride of the resultant j8-phenylmercaptoacrylic acid169-174 [Eq. (18)]. The preferred cyclization catalyst is stannic... 

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 addition of thiophenol to cyclohexenone in the presence of a cinchona quat gave the Michael adduct in 85% yield and 36% op [47f]. Other C-S bond formations are also noted [ I le,26b,47d,47e,81]. 

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... 

Optically pure (+)-(i )-3-phenylsulfanyl-l,3-diarylpropan-l-ones are readily available by the enantioselective Michael addition of thiophenols to chalcones. After reduction, acidic dehydration of the racemic alcohol affords a mixture of the racemic cis- and trans- 2,4-disubstituted thiochromans (Scheme 164). A detailed consideration of the stereochemical outcome of the reaction with unsymmetrically substituted diaryl derivatives suggests the involvement of a [1,3] PhS shift via a four-membered sulfonium intermediate and this is backed up by theoretical calculations <2003T3621>. 

Michael addition of thiophenols to fluorinated alkynoic acids under basic conditions affords the (Z)-3-arylthio-2-alkenoic acids which undergo an intramolecular Friedel-Crafts acylation to give 2-fluoroalkylated thiochromones 520 (Scheme 204) <1994JFC(68)25>. 

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... 

Thiols also react with sulfinimines in a Michael fashion. Thus, thiophenol gave the thiol adduct 122 in 92% yield with sulfinimine 62.44... 

The Michael-aldol process with methacrylates described in Section II.B can be also applied to the synthesis of substituted tetrahydrofurans, 245. If the reaction is carried out in THF, the yield and selectivity of the sequence decrease. It was proposed that the lithium coordination with THF molecules hinders the formation of the product 245. The authors concluded that the Lewis acidity of naked lithium cation is the key driving force for the reaction to proceed successfully. The tandem reaction with lithium thiophenolate, fumarate ester and benzaldehyde constitutes an useful methodology for the preparation of y-butyrolactone (Scheme 75)89,90. 

After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, ortho-ammo thiophenols 52 and acetic acid are added and reacted in the same reaction vessel under dielectric heating for 30 min at 60°C to furnish 2,4-disubstituted benzo[h][l, 5] thiazepines 53 via a coupling-addition-cyclocondensation sequence (Scheme 31) [193]. In the concluding heterocyclization step, dielectric heating is clearly superior over conductive heating. Although the Michael addition and cyclocondensation are essentially completed after 10 min at 60°C in the microwave cavity for electronically diverse substitution a reaction time of 30 min at 60°C has proven to be optimal. In contrast to 2,4-disubstituted benzo[h][l,4]diazepines 51 (vide supra), benzo[h] [1, 5]thiazepines 53 are essentially nonfluorescent. 

The nucleophilic cleavage of aryl alkyl ethers gives the corresponding phenol with only 1 equiv. of thiophenol in the presence of N-methyl-2-pyrrolidinone (NMP) in a catalytic amount of potassium carbonate. The aromatic nitro and chloro substituents which are displaced with stoichiometric thiolates are preserved by this method. Moreover, a(B-unsaturated carbonyl compounds do not undergo Michael addition of thiolate under these conditions. 

An example of an indirect formation of a cyclopropyl ring from an activated olefin was also reported . A Michael addition of thiophenol to an a,j -unsaturated ketone followed by a chemical reduction (e.g. NaBH4) yielded an alcohol which was converted to the methanesulfonate of the y-phenylthioalcohol (8). When the latter is reduced electrochemi-cally a cyclopropyl derivative is obtained. 

A Michael addition of thiophenol to an a, j6-unsaturated carbonyl compound, followed by sodium borohydride reduction or addition of a metal-organic reagent, gives a y-phenylthioalcohol electrochemical reduction in dry DMF of the methanesulfonate of this alcohol yields a cyclopropane and a small amount of alkene [81] ... 

Michael addition of thiophenol (74) to /7-methoxychalcone (70f) also proceeded efficiently in a water suspension medium. When a mixture of 70f, 74, K2CO3, 72 and water was stirred for 24 h at room temperature and the reaction product was filtered and air dried, the addition product 75 was obtained in 92% yield. Although similar Michael addition reactions can be carried out in solution [35], the procedure of the solid state reaction is rather simple, economical and free from pollution problems involving organic solvents [34]. 

Kumar and coworkers described the Michael addition of thiophenol 13 to 2-phenylacrylates 19 using a catalytic amount of cinchona alkaloids [16]. Among the four natural alkaloids, quinine 20 and quinidine 3 afforded the best results with opposite enantioselectivity (Scheme 7.11). Methyl or isopropyl ester substrates 19a and 19b gave comparable selectivities whereas more sterically demanding esters (e.g., tBu or CH(iPr)2) gave lower optical inductions. Based on the previous considerations and a computational analysis, the authors suggested a transition state... 

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... 

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