Thiolacetic acid

In 1902, Wheeler and Johnson (63) obtained 5-substituted rhodanines (54) by condensing substituted bromornalonic esters with postassium thiocyanate, then thiolacetic acid, the cydization resulting from an alkaline treatment. 

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. ... 

Thiobenzoic acid, 32,101 Thiocarbonyl perchloride, 32, 69 Thiolacetic acid, 31,105... 

D. Addition of Thiolacetic Acid to Electron-Poor Olefins.107... 

The latter compounds are of biological importance—cysteine, glutathione, and proteins are examples—and a novel antihypertensive drug, Captopril (Figure 9), also contains this functionality (59). Mercaptans can be prepared by the solvolysis of the thiolacetic acid adducts to olefins. 

Although thiolacetic acid additions are free-radical reactions (60), it was found recently that the addition to electron-poor olefins can be base catalyzed (61) (eqs. [14], [15]). Thus the (S)-(-) adduct is obtained with an e.e. of 54% when cyclohexenone is treated with thiolacetic acid in benzene in the presence of catalytic amounts of cinchonine. The reaction appears to be quite general, although very high e.e. s (>80%) have not yet been achieved. 

The quinine-catalyzed reaction of thiolacetic acid with methyl methacrylate has been studied in several laboratories, but no results have been published, probably because of its potential importance in the commercial synthesis of (- )-Captopril (59). Indications are that optical yields of 20 to 30% can be achieved. 

Tartaric acid, 1545 Terephthalic acid, 2924 f Thiolacetic acid, 0832... 

The analogous two-phase reaction of acrolein with thiolacetic acid under basic conditions in the presence of tetra-n-butylammonium iodide initially forms the Michael adduct which, upon hydrolysis, reacts further to produce l-formyl-5-thia-cyclohexene (see Scheme 4.17). In a similar manner, crotonaldehyde produces 1 -formyl-4,6-dimethyl-5-thiacyclohexene [13]. 

Crossed reactions of the two aldehydes under phase-transfer catalytic conditions with the intermediate thioacetates, which can be isolated under controlled reaction conditions [14], leads to the formation of three products [13], as result of retro-Michael reactions (Scheme 4.18). In the case of the reactions involving crotonaldehyde, the major product results from the reaction of the aldehyde with the released thiolacetic acid, with lesser amounts of the expected crossed reaction products (Table 4.23). In contrast, the reaction of acrolein with the thioacetate derived from crotonaldehyde produces, as the major product, the crossed cycloadduct. These observations reflect the relative stabilities of the thioacetates and the relative susceptibilities of acrolein and crotonaldehyde to the Michael reaction. 

Michael addition of thiolacetic acid to acrolein and crotonaldehyde... 

The unsaturated aldehyde (0.1 mol) is added to a two-phase system of thiolacetic acid (7.6, 0.1 mol) in aqueous NaOH (50%, 16 ml) and TBA-I (0.1 g, 0.27 mmol) in CH2CI2 (100 ml) over a period of ca. 30 min at 0°C. The mixture is stirred for 2.5 h at 0°C and then heated under reflux for 20 min. The organic phase is separated, diluted with Et20 (50 ml), washed with H20 (3 x 25 ml), and dried (MgS04). Evaporation of the solvent gives i-formyl-5-thiacyclohex-l-ene (41%) from acrolein and 1-formyl-4,6-dimethyl-5-thiacyclo-hex-l-ene (81%) from crotonaldehyde. 

The yields of thietanone depend on the number of methyl groups attached to the 1,3-dihaloketones, a relationship attributed to the gem effect. Thus the unsubstituted thietane failed to form. Thietanes have been synthesized by a series of reactions involving addition of thiolacetic acid to a vinyl ketone, reduction with LiAlH4, substitution of the acyl group by the nitrile function, and subsequent ring closure to a cis-trans mixture of 119 (Eq. 11). 

Nucleophilic attack at the 5-position of an oxazoline normally proceeds under acidic conditions. For example, in their total synthesis of thiangazole, Wipf and coworkers used thiolacetic acid to convert the trisoxazoline 337 to the S-protected cysteine derivative 338 that was further elaborated to thiangazole through aminol-... 

Other useful nucleophiles for this type of substitution include azide and thiolacetic acid. Glaxo researchers utilized such a strategy in their synthesis of the neuraminic acid analogue 346 (Scheme 8.109). ° Itzstein and co-workers used a similar strategy to synthesize a thio analogue of neuraminic acid 347 °" and reported that thiolacetic acid was also a suitable nucleophile. ° ... 

Where it is possible to distinguish the products, thiol additions show stereospecificity. The products of addition of hydrogen sulfide, thio-phenol, and thiolacetic acid to 1-chlorocyclohexene are to be 75%, 94%, and 66% cis-l, 2-disubstituted cyclohexane, respectively.88 The addition of thiolacetic acid is less stereopecific than the other thiols. The stereospecificity apparently depends upon the ratio of addendum to 1-chlorocyclohexene, Phenylthiyl radical addition to 1-methylcyclo-... 

Resonance energies have been reported164 (see also ref. 154a) for a few conjugated sulfur compounds thiolacetic acid (4-5 kcalmole-1), thiourea (27 kcalmole-1), thiosemicarbazide (28 kcalmole-1), thiophene (20 kcalmole-1), and thianthrene (17 kcalmole-1 difference between the resonance energy of thianthrene and that of two benzene molecules). These values were calculated from the heats of combustion and bond energies, which are 61.5 kcal for the C—S, 115 kcal for the C=S, 87.5 kcal for the S—H, and 67 kcal for the S—S bonds.156 Calorimetry of sulfones has been studied intensively.156... 

Various p-amino thiols are synthesized from the corresponding P-amino alcohols 1 by activation of the hydroxy group to form a tosylate intermediate 2 and then conversion into a thioester 3 5 or direct thioacetylation of the hydroxy group of 1 using the Mitsunobu reaction with diisopropyl azodicarboxylate, triphenylphosphine, and thiolacetic acid as reagents (Scheme l). 6,7 The thioesters 3 are then hydrolyzed and the corresponding disulfide derivatives 4 are produced by iodine oxidation. 7 ... 

Sulfanylalkanoyl amino acids and peptides are prepared by reaction of the (acetyl-sulfanyl)- or (benzoylsulfanyl)alkanoic acids or acid chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 101114 16 27 29 For example, the 3-(acetylsulfanyl)alkanoic acids 7 are prepared from the condensation of ethyl (diethoxyphosphoryl) acetate 5 with various aldehydes according to the Horner-Emmons reaction, providing the a, 3-unsaturated ethyl esters 6 (a mixture of Z- and E-isomers, 50 50), followed by saponification of the ethyl esters and Michael addition of thiolacetic acid. The 3-(acetylsulfanyl)alkanoic acids 7 can be coupled with a-amino esters or peptide esters and subsequent hydrolysis of the 3-(acetylsulfanyl) derivatives provides the desired products 8 (Scheme 2). 14 ... 

The 3-(acetylsulfanyl)alkanoic acids 7 are obtained as a mixture of stereoisomers that are not separated in subsequent synthetic steps. In most cases, these sulfanylalkanoyl compounds are obtained as a mixture of four stereoisomers. The stereochemistry of one derivative [8, R1 = Bzl R2= iBu R3= Me) has been determined using HPLC and NMR data.1141 The ratio of the isomers is 3.5 3.5 1 1 for 8a/8b/8c/8d, respectively. This indicates that one set of enantiomers of the precursor 7, which is obtained by addition of thiolacetic acid to 6, is formed in a greater proportion than the other set of enantiomers. Therefore, it was concluded that isomers 8a and 8b are obtained from the major set of enantiomers of 7, while 8c and 8d are formed from the minor set of enantiomers. The NMR spectra of the separated isomers, 8a/8b/8c/8d, was compared to the spectrum of Phe-Ala. This allowed determination of the relative configuration of the benzyl group at the C5 asymmetric carbon of the 8 related to the adjacent Ala residue. The configuration at C5 of all four stereoisomers is shown in Scheme 2. The configuration at C6 has not been determined. 

Thio-6-azauraci1, AB37 Thioglycolic acid, AA78 Thiolacetic acid, AA75... 

---