Thiocarbamate sulfoxides

Casida, J.E., Gray, R.A., and Tides, H. Thiocarbamate sulfoxides potent, selective, and biodegradable herbicides. Science (Washington, DC), 184(4136) 573-574, 1974. 

Many organosulfur compounds undergo biological oxidation at the sulfur atom to yield products which have pronounced physiological activity or serve as intermediates in generating bioactive compounds. Three examples are the lachrymating agent in onions ( ) (1), the oxo intermediate ( ) in metabolic desulfuration of phosphorothionate insecticides to form potent cholinesterase inhibitors (2), and the sulfoxides QJ produced on metabolism of thiocarbamate herbicides (3). 

The herbicidal activity of -alkyl thiocarbamates (3-5) and the mutagenic activity of an -(2,3-dichloroallyl) thiocarbamate (6) are probably due to the reactivity or decomposition products of their metabolically-formed sulfoxides. 

Synthesis. Oxidation of -alkyl or -benzyl IJ,IJ-dialkylthio-carbamates with one equivalent of m-chloroperoxybenzoic acid (MCPBA) in chloroform or methylene chloride at -25° to 25°C yields the corresponding carbamoyl sulfoxide (3) in essentially quantitative yield (3-5). The -chloroallyl thiocarbamate sulfoxides (e.g., 4-7) are obtained in the same manner except that the temperature is maintained between -20°C and 0°C for the oxidation and extraction of the reaction mixture with 5% sodium carbonate aqueous solution (7, 8). 

The NMR chemical shifts for the carbamoyl sulfoxides (Table I) support their proposed structures. In examining the oxidation reactions, it is convenient to add MCPBA to a solution of the thiocarbamate in CDCI3 at -20°C and take frequent spectra during oxidation as the reaction mixture warms up to 40°C. Comparison of these spectra with that of the parent compound at -20 to 40°C allows recognition of short-lived intermediates and terminal products. With the parent thlocarbamates for compounds 5-2, the methyl group signals appear as one doublet at 40°C but two... 

H Chemical Shift Data (ppm) for -Chloroallyl Thiocarbamates and Thiocarbamate Sulfoxides (2, 8). Solutions in CDCl at 20 -40°C with tetramethylsilane as the internal standard. Proton coupling in Hz ... 

Protons 2-Chloroallyl thiocarbamate U Sulfoxide 4 3-Chloroallyl thiocarbamate Sulfoxide 5 Diallate cis (trans) Sulfoxide ( cis (trans) Triallate Sulfoxide X... 

Chloroallyl) thiocarbamate sulfoxides (. ., 5-2) un-.doubtedly rearrange in an analogous manner but in tbis case tbe sulfenate quickly undergoes an additional 1,2-elimination reaction (7 ). Tbe resulting products are tbe IJ, -dialkylcarbamoyl-sulfenyl chloride (M) and tbe carbonyl compound, aldehydes... 

Carbamylation Reactions. -Alkyl, -benzyl and -chloroallyl thiocarbamates do not readily react with GSH. In contrast, their sulfoxide derivatives ( and 6,) are very effective carbamylating agents for many thiols including GSH (19, ). The GSH conjugates formed vivo via 3 and 6 are quickly cleaved, acetylated and further metabolized as follows (19-21. 23. 24). 

Proherbicides. Thio- and dithiocarbamates probably require metabolic activation prior to exerting their herbicidal effects. Sulfoxide metabolites of the -alkyl thiocarbamates are generally more potent herbicides than the parent compounds ( -5). The herbicidal action of these sulfoxides probably results from their carbamylating action for thiols, although the specific target site or receptor is not defined (23, 24). It is conceivable that the -chloroallyl thiocarbamate herbicides may act in the same way, since their sulfoxides are also potent carbamylating agents... 

Figure 1. Oxidation and other reactions of dialiate and triallate indicating mutagenic activities of the products in the S. typhimurium TA 100 assay (revertants/ nanomole without activation/with activation / designates no data available). 2-Chloroacrolein is a dialiate metabolite in the mouse liver microsome-NADPH system. Dichloroallylsulfonic acid is a urinary metabolite of dialiate. The other compounds are potential metabolites of the respective thiocarbamates. The thio-carbamate sulfoxides are unstable at 25°C.

As in the case of propachlor mercapturic acid sulfoxide, the biological significance of xenobiotic mercapturic acids that contain oxidized sulfur is not known. Casida et al. (39) have reported that sulfoxidation of some thiocarbamate herbicides is a beneficial step in the detoxication process. However, cysteine conjugates can exhibit adverse biological activities. Smith (40) has reviewed work on the metabolism of the toxic principle in kale and has shown that C-S lyase action on S-methylcysteine sulfoxide produces the toxic principle. Virtanen ( ) has reviewed the processes in other plants that lead to the production of compounds with biological activity from -substituted cysteine sulfoxides. 

The oxidation of the thiocarbamates to form sulfoxides is another activating process as it has been shown that the sulfoxides are more... 

Patched, G.G., Gray, R.A., Reed, A., Hyzak, D.L. (1983) Thiocarbamate sulfoxides protected against dry soil deactivation. U.S. Patent 4,389,237. 

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