2- Thiolacetate

Methyl-4-oxoquinazolinyl-2-thiolacetic acid (378), obtained by the reaction of 6-methyl-4-oxoquinazoline-2-thione (377) and chloroacetic acid, upon treatment with acetic anhydride-pyridine, yields a cyclized product confirmed by the molecular ion peak [M] at m/z 232 and for which structure 7-methyl-2//-thiazolo[3,2-n]quinazolin-l,5-dione (379) was assigned on the basis of IR and H-NMR data in preference to possible... 

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. 

A qualitative difference in the type of solvation (not simply in the strength of solvation) in a series of nucleophiles may contribute to curvature. Jencks has examined this possibility. " " An example is the reaction of phenoxide, alkoxide, and hydroxide ions with p-nitrophenyl thiolacetate, the Br insted-type plot showing Pnuc = 0.68 for phenoxide ions (the weaker nucleophiles) and Pnu = 0.17 for alkoxide ions. It is suggested that the need for desolvation of the alkoxide ions prior to nucleophilic attack results in their decreased nucleophilicity relative to the phenoxide ions, which do not require this desolvation step. 

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. ... 

Attempted selective displacement (96) of the primary tosylate function in 34 with sodium iodide in refluxing 2-butanone led to the 6-deoxy-6-iodo derivative 35 in 32% yield only, while the di-iodo derivative 36 was formed in 45% yield. These results are to be compared with those reported by Owen and Ragg (85) who observed no reaction with either potassium thiolacetate or potassium thiocyanate in the corresponding / -series. 

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

Methyl dodecanoate V-Methylethanediamine 1-Methylethyl acetate 1-Methylethyl thiolacetate V-Methylformamide Methyl formate 7.45... 

The reference reaction is the formation of ethyl thiolacetate from ethanethiol and acetic acid (Gerstein and Jencks, 1964) c Storm and Koshland, 1972b... 

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. 

Phenylacetonitrile Ethyl thiolacetate Unidentified ketone (mol mass 138)... 

Irradiation of 5-phenyl thiolacetate (203) in benzene gives diphenyl disulfide (206) as major product (52%). However, minor amounts of ortho-rearranged (204) and para-rearranged (205) products are also formed, along with thiophenol (17%) and methyl phenyl thioether (208) (19%) (Scheme 54) [155],... 

Thiol esters can be reduced to sulfides or aldehydes. Alone generated from lithium aluminum hydride and boron trifluoride etherate [1099] or aluminum chloride [1100] in ether reduced the carbonyl group to methylene and gave yi-9y /o yields of sulfides. Phenyl thiolbenzoate failed to give the sulfide, and phenyl thiolacetate gave only an 8% yield of ethyl phenyl sulfide [1100]. 

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. ° ... 

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