Thiocarbamates, synthetic

The synthetic thiocarbamates, of which tolnaftate (Fig. 5.20J) is an example, also inhibit squalene epoxidase. Tolnaftate inhibits this enzyme from C. albicans, but is inactive against whole cells, presumably because of its inability to penetrate the cell wall. Tolnaftate is used topically in the treatment or prophylaxis of tinea. 

This work has been extended from aryl and alkyl substituted systems (42) (R = aryl, alkyl) to analogues where R is an amino group, so giving access to synthetic equivalents of the nonstabilized amino nitrile ylides (45). Adducts were obtained in good-to-moderate yield with A-methyhnaleimide (NMMA), DMAD, electron-deficient alkenes and aromatic aldehydes (27,28), and with sulfonylimines and diethyl azodicarboxylate (29). Similarly the A-[(trimethylsilyl)methyl]-thiocarbamates (46) undergo selective S-methylation with methyl triflate and subsequent fluorodesilylation in a one-pot process at room temperature to generate the azomethine ylides 47. 

This method, initiated by Marchesini in 1893 (i893G(24)65) (Scheme 177), consists of the condensation of an a-halocarbonyl compound with ammonium thiocarbamate (244 R2 = NH4) or its esters (244 R2 = alkyl). The reaction is carried out at low temperature in aqueous medium and then allowed to stand overnight. 2-Hydroxythiazoles (244 R2 = H) give 2-chlorothiazole derivatives almost quantitatively upon treatment with phosphorus oxychloride. This constitutes a convenient synthetic method for these compounds when the conversion of 2-amino- into 2-chloro-thiazole fails. 

As the key precursor towards the realization of 1,7-epoxy cyclononanes and 1,8-epoxycyclodecanes, an 1 l-oxatricyclo[6.2.1.02,6]decane skeleton was constructed by using the Hoffmann [4+3] cycloaddition methodology <07EJO4383>. In Majetich s total synthesis of (-)-salviasperanol, the key step was the trifluoroacetic acid-promoted isomerization of a vinyl epoxide to 2,5-dihydrofuran, whose O-thiocarbamate was removed by radical reaction to produce salviasperanol dimethyl ether <07OL85>. The synthetic route is depicted below. 

Readily available thiocarbamates, thioamides, and thioureas provide direct routes to quinolines in moderate to good yields <03OL1765>. The reactive intermediate postulated is the synthetic equivalent of an imidoyl radical, but with greater utility. 

Thioacyl chlorides, RCSCl, are powerful thioacylating agents as is obvious from the quantitative thiobenzoylation of the only moderately nucleophilic nitrogen in thiocarbamate (13 equation 5). However, severe limitations are the difficult accessibility of thioacyl chlorides and their thermal lability. Even if they are prepared from dithiocarboxylic acids using an improved procedure, only thioaroyl chlorides, particularly PhCSCl (12), can be handled sufficiently easily to be used in synthetic work. Thus, various azoles react with (12) to furnish /V-thiobenzoyl azolides (14) in the presence of excess azole or NEts (equation 6) a particularly clean and fast reaction is achieved if IV-silylated azoles are employed. However, considering the fact that the chloride has to be prepared from the dithiocarboxylic acid, the approach of equation (4) presents a shortcut to the products. 

The kinetics of the reaction of hydroxyl groups of monosaccharides and polyols with benzyl isothiocyanate has been checked by Augustin and Balaz using UV spectroscopy.289 However, because of the reversibility of the reaction, this procedure is not. of synthetic utility. O-Sugar thiocarbamates have been more conveniently prepared by aminolysis of thiocarbonate derivatives290,291 or by thiocarbamoylation of free hydroxy] groups with 1,1 -tbiocarbonyldiimidazoie.7 286 288... 

Abstract The high synthetic versatiUty exhibited by the isothiocyanato motif has allowed its use as a building block in the preparation of a plethora of derivatives. When present in carbohydrates, the strong electrophilicity shown by isothiocyanates, together with the possibility of undergoing cycloaddition reactions has made it possible to access a broad spectrum of heterocyclic compounds, of either synthetic or pharmaceutical interest. Among them, noteworthy are 1,3-oxazolidine- and l,3-oxazinane-2-thiones (cyclic thiocarbamates), 2-amino-2-oxazolines (cyclic isoureas), 2-amino-2-thiazolines (cyclic isothioureas), nucleosides, and spironucleosides. 

Various heterocycles 860 can be synthesized by the treatment of unsaturated aryl amides, carbamates, thiocarbamates and ureas 859 with IBX (Scheme 3.343) [1176,1177]. The mechanism of this reaction has been investigated in detail [1178]. On the basis of solvent effects and D-labeling studies, it was proposed that the IBX-mediated cyclization of anilides in THF involves an initial single-electron transfer (SET) to a THF-IBX complex followed by deprotonation, radical cyclization and concluding termination by hydrogen abstraction from THF [1178]. A similar IBX-mediated cyclization has been applied in the synthetic protocol for the stereoselective preparation of amino sugars [1179]. 

The formation of S-alkyl thiocarbamates was studied from fundamental and applied viewpoints. These compounds represent an important synthetic target due to their pesticide properties. The conventional method implies the alkylation of sodium thiocarbamates by alkyl chlorides (Eq. 58). This lengthy reaction requires heating but the thermally unstable products suffer partial... 

It was recently reported that a new synthetic route of thiocarbamate was developed. The new synthetic route refers to that thiocarbamate is directly synthesized by the reaction of aliphatic amine and xanthate in the presence of nickel salt or palladium salt. 

The evolution of new variations of transition metal catalyzed cross couplings, the only area in which "... are there new reactions waiting to be discovered...", [62] will undoubtedly also play a significant role in synthetic aromatic chemistry. Three such methods are currently under study in our laboratories (Scheme 21) aryl O-carbamate and aryl triflate - aryl Grignard (Methods a and b), [63] aryl 0-thiocarbamate - aryl Grignard (Method c), [64] and aryl triflate - aryl zinc (Method d) [65]. A selected example for each method is shown. These processes, which may all be linked to DoM, will allow ehancement of current technology (Scheme 14) and contemplation of conceptually new ways for aryl - aryl bond formation. 

Reaction conditions Solvent-free (neat condition), room temperature Synthetic strategy One-pot synthesis for S-alkyl thiocarbamates Catalyst Catalyst-free... 

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