Dithiazolidine-3,5-dione

Solubility 1 is soluble in most common organic solvents, except those of very low polarity. 2 is soluble in A(Atdimethylforma-mide, acetonitrile, and ethanol. 

Form Supplied in At the time of writing, neither 1 nor 2 is commercially available. Purification details for both compounds are given below. 

Preparative Method The parent heterocycle 1 can be readily prepared on a multigram scale by acidic hydrolysis of 3-ethoxy-l,2,4-dithiazolin-5-one 3 (eq 1).  

The latter reagent is obtained from the reaction between ethyl thiocarbamate (4) and commercially available chlorocarbonyl-sulfenyl chloride (5) in the presence of triethylamine (eq 2). The outcome of this key reaction is highly solvent dependent, with anhydrous diethyl ether giving the optimum yield, while also minimizing the formation of unwanted by-products. (Note Reference details the fully optimized preparations of 3 and 1). 

Two methods facilitate the preparation of the potassium salt 2 of 1. Firstly in a procedure analogous to that used in the preparation of potassium phthaUmide, 2 can be obtained by treatment of 

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Only a few examples of a nucleophilic attack at the nitrogen atom of 1,2,4-dithiazolidine derivatives are known. 5-Imino-l,2,4-dithiazolidine-3-thione gives tribenzyl-substituted 5-imino-l,2,4-thiadiazolidine-3-thione with an excess of boiling benzylamine <1996CHEC-II(4)453>. l,2,4-Dithiazolidine-3,5-dione 12 forms the potassium salt 11 under the action of KOH in ethanol or KH in MeCN (Scheme 15) <2000SL1622>. 

Another approach to the preparation of iV-alkyl derivatives 26 is the Mitsunobu reaction. The Mitsunobu procedure is now a well-known method for preparing amines from alcohols using acidic imide derivatives as a nitrogen nucleophile < 198IS 1, 19960PP127>. The remarkably high acidity of l,2,4-dithiazolidine-3,5-dione 12 (pA), 2.8) <2000SL1622>... 

The same approach was used for introducing AM Its protection into the peptide monomer <1995J(P1)405> and glycosyl donor 134 <1996JA3148> (Equation 19). In this case, however, triethylamine was not added and the 1,2,4-dithiazolidine-3,5-dione fragment was formed with extmsion of EtCl and HC1. 

Recently, a new efficient approach for the preparation of 4-alkyl-l,2,4-dithiazolidine-3,5-diones (Dts-amines) 26 was developed by G. Barany and co-workers <2005JA508>. They have shown that Dts-amines 26 can be synthesized directly in a simple and robust reaction of bis(chlorocarbonyl)disulfane with bis(trimethylsilyl)amines that uses the trimethylsilyl group as a large proton to circumvent extant synthetic problems. The reaction occurs in a dry medium with extrusion of two molecules of trimethylchlorosilane (Scheme 39). This simplification and improvement in the synthesis of Dts-amines 26 promises to open new avenues for the application of Dts-based protection strategies. 

N-AIfylation of Potassium l,2,4-Dttbiazolidine-3,5-dione (2). The most direct method for the preparation of TYalkylated l,2,4-dithiazolidine-3,5-diones (6) uses the straightforward nucleophilic displacement reaction between potassium 1,2,4-dithiazolidine-3,5-dione (2) and an alkyl balide in a procedure analogous to the W-alkylation of potassium phthalimide in the traditional Gabriel s)mthesis of primary amines (eq 5). 

N-AUcylation of l,2,4-Dithiazolidine-3,5-dione (1). The very low piifa value of 1 (p/fa = 2.85 ) compared with other imides such as phthalimide (typically ca. 9.5-10) facilitates 7V-deprotonation with a wide range of bases. These include sodium or potassium hydride, sodium acetate, sodium bicarbonate, potassium tert-butoxide, and caesium carbonate. The optimum stoichiometry of 1 to base is dependent on the base and alkyl halide in question, with acetonitrile proving to be the preferred solvent (eq 6). ... 

Mitsunobu-type N-AIkylation of l,2,4-Dithiazolidine-3,5-dione (1). Despite its high acidity suggesting that it should be an excellent nucleophile in Mitsunobu displacement reactions of alcohols (cf. phthalimide. " ), the parent heterocycle 1 is degraded by the triphenylphosphine used in this process (see later). Similar stereoselective displacement reactions of alcohols with 1 can, however, be mediated using the readily prepared betaine reagent 7. ... 

Alternative Routes to N-AUsylated l,2,4-Dithiazolidine-3,5-diones (6). It should be noted that the routes (V alkylated 1,2,4-dithiazolidine-3,5-diones (6) described above may not always be appropriate, and alternative methods that do not employ 1 or 2 directly may also be used. 

More recently, it has been shown that A alkyl and aryl l,2,4-dithiazolidine-3,5-diones (6) can also be accessed directly from the reaction between bis(trimethylsilyl)amines (11) and bis (chlorocarbonyl)disulfane (12) (eq 10). ... 

N-Alfylated l,2,4-Dithiamlidine-3,5-diones (6) as Prelected Isocyanates. The sulfur-transfer reaction described above lays the foundation for this use of ) Zalkylated 1,2,4-dithiazolidine-3,5-diones (6). If A alkylated I,2,4-dithiazoIidine-3,5-diones (6) are treated with a trialkyl- or triarylphosphine in the presence of water, the corresponding primary amine (13) is obtained along with the phosphine oxide (eq 14). ... 

The sulfonamide betaine 26 was usefiil for the preparation of N-alkylated l,2,4-dithiazolidine-3,5-diones in cases were the traditional Mitsunobu conditions failed. ... 

Special features of the interaction of pyridine, quinoline, and related compounds with triphenylphosphine have been reported." The mechanism of sulfurization of substituted triphenylphosphines with 4-(3- and 4-substituted)-l,2,4-dithiazolidine-3,5-diones in acetonitrile, dichloromethane, tetrahydrofuran, and toluene at 25 C has been studied." The reaction pathway involves rate-limiting initial nucleophilic attack of the phosphorus at sulfur followed by fast decomposition of the phosphonium intermediate to the corresponding phosphine sulfide, phenylisocyanate, and carbonylsulfide. From the Hammett correlations and solvent dependency, it was concluded that the transition-state structure is very polar and resembles the zwitter-ionic intermediate. 

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