Synthesis of 5-(alkylthio or arylthio)-3 H-1,2-dithiol-3-one derivatives

5-( R,S )-3 H -1,2-dithiol-3-one derivatives with R=butyl, ethyl, phenyl, cyclopentyl, octyl, p-chlorophenyl, p-bromophenyl and p-methoxyphenyl were prepared in moderate to good yield from the reaction of the corresponding 5-( R,S )-3 H -1,2-dithiol-3-thione with Hg(CH 3 COO) 2 in glacial acetic acid.


1
A wide variety of alkyl and aryl derivatives have been synthesized and a great number of these compounds display biological activity and have industrial applications.For instance, Oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione) was originally used as an antischistosomal agent due to its remarkable activity against Schistosoma mansoni. 2 In addition, studies have demonstrated that Oltipraz inhibits HIV-1 (AIDS) 3 virus replication by irreversibly binding to the viral reverse transcriptase enzyme.5][6] Other derivatives like 4-aryl-5chloro-3H-1,2-dithiole-3-thiones have proven to be fungitoxic 7 and they have also been used as insecticides. 8We reported that several derivatives of 2 have interesting activity as antimycotic agents 9 and that their solubility increases in the presence of β-cyclodextrin. 10Besides, it has been claimed 11 that the antifungicidal activity of derivatives 1 increases when the thiocarbonyl group is replaced by a carbonyl group.

3
We therefore undertook a study in order to develop a method to synthesize 3 and the results are presented here.

Results and Discussion
Several methods have been used to exchange the sulfur by oxygen in 3H-1,2-dithiol-3-thione derivatives 1.Some examples include treatment with KMnO 4 in acidic acetone , 12 or the reaction with Cl 2 /CCl 4 and then with water. 13More recently Torroba has reported that EtO 2 C-CNO -in THF gives excellent yields of the oxidation products in compounds that have the same nucleus as 1. 14 The presence of an extra sulfur atom in compound 2 limits the use of oxidants because the alkyl or arylthio function can be easily oxidized to sulfoxide. 15The most frequently used method utilizes mercury acetate in acetic acid as reagent. 16We show here that derivatives 2a-i can be converted into the corresponding 3 in moderate to good yields using these reagents (see Table 1).
Although no other product could be isolated and the substrate was completely consumed, the low yield probably results from ring opening reactions giving rise to an untreatable mixture of products.
Attempts to do the reaction using KMnO 4 in acidic acetone gave only decomposition products while Cl 2 /CCl 4 led to about 5% yield of the expected product starting from compound 2a.It was reported that treatment with Bi(NO 3 ) 3 gave good results in the transformation of thioamides into amides 17 but this methodology applied to 2a yielded only 30 % of 3a.

Experimental Section
General Procedures. 1 H and 13 C NMR were recorded on a Bruker 200MHz instrument using TMS as an internal standard.Chemical shifts are reported in δ (ppm).IR spectra were recorded on a Nicolet 5SXC spectrometer using KBr pellets.Reagents used were obtained from commercial suppliers or synthesized as indicated below.The high resolution mass spectrometry analyses were carried out in the University of California, Riverside.

General synthetic procedures
Synthesis of compounds 2.The compounds 2 were prepared according to the method described in the literature. 18A typical run is the following: 15.7 mmol of P 2 S 5 , 9.7 mmol of S 8 , 0.032 mmol of 2-mercaptobenzothiazole (MBT) and 0.016 mmol of ZnO were loaded into a three-necked round bottomed flask and xylene (40 mL) was added.The mixture was then boiled under N 2 and the corresponding dithiolmalonate (15.7 mmol), dissolved in 40 mL of xylene, was added dropwise for 30 minutes under continuous stirring.The reaction was boiled for an additional 1.5 hour.The color changed from light yellow to dark reddish brown.Then, the crude reaction mixture was filtered and the solvent evaporated.The dried extract was purified by column chromatography over silica gel 70-230 mesh and CH 2 Cl 2 /hexane 50:50 was used as eluent.
Synthesis of compounds 3. 1 mmole of 2 dissolved in 30 mL of acetone, freshly distilled over KMnO 4 , was loaded into a dry three-necked round bottomed flask under a N 2 atmosphere and the solution warmed to 50 o C. Afterwards 2 mmoles of (CH 3 COO) 2 Hg dissolved in 2 mL of glacial acetic acid were slowly added and the solution was stirred additionally for 30 min.A saturated solution of NaHCO 3 was added to stop the reaction and after filtering it, it was extracted with CHCl 3. The product was purified by column chromatography on silica gel eluted with solvents of ARKAT USA, Inc.