Thioacetates conjugate additions

The mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

Another example of resort to heteroatoms to obtain both oral potency and a split between androgenic and anabolic activities Ls tiomestrone (99). Trienone, 98, prepared in much the same way as 23, undergoes sequential 1,6 and 1,4 conjugate addition of thioacetic acid under either irradiation or free radical catalysis to afford the compound containing two sulfur atoms. 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

The reaction of crotonaldehyde and methyl vinyl ketone with thiophenol in the presence of anhydrous hydrogen chloride effects conjugate addition of thiophenol as well as acetal formation. The resulting j3-phenylthio thioacetals are converted to 1-phenylthio-and 2-phenylthio-1,3-butadiene, respectively, upon reaction with 2 equivalents of copper(I) trifluoromethanesulfonate (Table I). The copper(I)-induced heterolysis of carbon-sulfur bonds has also been used to effect pinacol-type rearrangements of bis(phenyl-thio)methyl carbinols. Thus the addition of bis(phenyl-thio)methyllithium to ketones and aldehydes followed by copper(I)-induced rearrangement results in a one-carbon ring expansion or chain-insertion transformation which gives a-phenylthio ketones. Monothioketals of 1,4-diketones are cyclized to 2,5-disubstituted furans by the action of copper(I) trifluoromethanesulfonate. ... 

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. 

The search for compounds that had improved oral activity led initially to the 7a-thioacetyl derivative (51-2) [48]. Dehydrogenation of the enone function in (50-5) using the now-familiar quinone, chloranU, leads to the dienone (51-1). This undergoes 1,6 conjugate addition on treatment with the sodium salt from thioacetic acid to give the la derivative (51-2) this compound, under the name spironolactone, was the first clinical aldosterone antagonist. Studies on the metabolic disposition of... 

Michael additions. Gerlach and Kiinzler report that the lithium enolate of S-t-butyl thioacetate undergoes 1,4-addition to cyclopentenone. They have extended this Michael reaction to a synthesis of methyl jasmonate (5), based on the similar conjugate addition of the trimethylsilyl enolate 1 promoted by tetra-n-butylam-monium fluoride. The adduct 2 was alkylated by l-bromo-2-pentyne in the presence of tetra-n-butylammonium fluoride to give 3 in rather low yield. Remaining steps to 5 were methanolysis and partial hydrogenation of the triple bond. 

THIOACETALS Methyl iodide. Silver oxide. Tricthyloxonium tetrafluoroborate. CONJUGATE ADDITION Cuprous bromide. Dimethylcopperlithium. Tri-n-butyl-phosphine-copperfl) iodide complex. CONVERSION OF - Br TO - OIID Silver sulfate. 

Lanthanide triflates and Sc(OTf)3 effectively catalyze conjugate addition of SEE, KSA, and ketene silyl thioacetals under mild conditions (0°C to room temperature, 1-10 mol% catalyst) (Scheme 10.86) [69, 238]. After an aqueous work-up these Lewis acids can be recovered almost quantitatively from the aqueous layer and can be re-used without reduction of fheir catalytic activity. Eu(fod)3 also is effective in not only aldol reactions but also Michael addition of KSA [239]. The Eu(fod)3-catalyzed addition of KSA is highly chemoselective for enones in the presence of ketones. 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

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 addition. The metalated thioacetal (1), unlike the corresponding... 

Few examples have been reported for the organocatalytic asymmetric conjugate addition of sulfur nucleophiles other than thiols. The reaction of thiocarboxylic acids to cyclohex-2-enones [390] and a,p-nnsatnrated esters [391] was initially studied by Wynberg et al. employing Cinchona alkaloid catalysts with limited success in terms of selectivity (up to 54% ee). Slightly better enantioselectivities have been recently obtained by Wang et al. in the 1,4-addition of thioacetic acid to P-nitrostyrenes (up to 78% ee) [392] and trani-chalcones (up to 65% ee) [393], using Takemoto s thiourea 142 as catalyst (2-10 mol%). 

Scheme 2.136 Asymmetric conjugate addition of thioacetic acid to nitroolefins...

Conjugate additions of thioacetals (159) to a,3-unsaturated esters (158) followed by alkylation using iodomethane leads... 

An interesting method for the introduction of the isopropylidene moiety has been described, using keten thioacetal chemistry. Thus, the reaction of the enolate of ketone (27) with carbon disulphide followed by methylation gives the keten thioacetal (28). Double conjugative addition and elimination, using lithio-dimethyl cuprate, then affords the isopropylidene ketone (29). Similar method-... 

Scheme 2.36 Enolates 122 in consecutive conjugate additions of lithiated thioacetals to butenolide 120 and subsequent and hydroxyalkylation/alkylation.

The Takemoto s catalyst (9) was extensively employed for the enantioselective addition of arylthiols to a,P-unsaturated carbonyl compounds and P-arylthio ketones were obtained in good ees [90]. Conjugate addition of thioacetic acid to nitroalkene and to enone have been also reported by Wang [91]. 

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