Tetrathiomolybdate : a versatile reagent in organic synthesis

Abstract

The simplest binary Mo–S moiety is MoS². Although this ion has been known in the literature for many years, its chemical reactivity has only recently been appreciated. MoS² has been extensively used by synthetic inorganic chemists and bioinorganic chemists to construct enzyme models (e.g., nitrogenases), but its reactivity toward organic substrates remained largely unexplored.

The thesis entitled “Tetrathiomolybdate: A Versatile Reagent in Organic Synthesis” is divided into two parts.

Part A of the thesis deals with sulfur transfer reactions mediated by benzyltriethylammonium tetrathiomolybdate (1). A general methodology for the direct conversion of amines to disulfides is described in Chapter 1. A variety of aryl diazonium salts (derived from the amines) are smoothly converted to their corresponding disulfides when reacted with 1 in moderate to good yields. Interestingly, the diazonium fluoroborate derived from the corresponding binaphthyl amine reacts readily with 1 to yield 1,1'-binaphthalene-2,2'-dithiol as the only product [Scheme-1].

Scheme 1 NBF (PhCHNEt)MoS CHCN, 0–25 °C NBF Yield: 61% (55–75%)

An interesting reaction of tetrathiomolybdate 1 with sugar halides is elaborated in Chapter 2. The anomeric bromides derived from glucose and xylose, on treatment with 1, yield the corresponding disulfides in moderate isolated yields. The primary bromide, derived from glucose, both protected and unprotected, forms the corresponding disulfide in high yield when treated with 1. The dibromo derivative derived from sucrose also undergoes a smooth sulfur transfer reaction with 1 to form the cyclic disulfide in 30% isolated yield [Scheme-2].

Scheme 2 OAc AcO MOS² 24 h, 0 °C Br OM. 72 h, RT, CHCN/DMF OAc AcO Yield: 65–70%

Treatment of a number of -halo acid chlorides with benzyltriethylammonium tetrathiomolybdate (1) in dry chloroform or acetonitrile leads to the formation of corresponding thiolactones under very mild conditions. Reaction is very facile with small-chain acid chlorides. Medium- or long-chain acid chlorides, when treated with tetrathiomolybdate at room temperature, produce monomeric and dimeric thiolactones. The same reactions could also be carried out in the solid state. Like in the solution phase, reaction is only facile for small-chain acid chlorides [Scheme-3].

Scheme 3 MoS² Br–CH–COCl 2 h, 65% Br–CH(CH)COCl Monomer 11%, Dimer 24%

Part B of the thesis mainly deals with reductions mediated by tetrathiomolybdate.

Nitrogen fixation is a fundamental synthetic process of nature and is catalyzed by nitrogenase. The nitrogenase enzyme is not as specific as many other enzymes. In addition to reducing nitrogen, it also reduces a variety of nitrogen-like substrates, e.g., azides, acetylenes, isocyanides, etc. In Chapter 1 of Part B, we demonstrate that tetrathiomolybdate, although not catalytic in nature, behaves somewhat similarly to the nitrogenase enzyme. A number of azo compounds with electron-withdrawing substituents undergo a facile reduction with tetrathiomolybdate at room temperature to give the corresponding hydrazo compounds, while azo compounds which are unsubstituted or substituted with electron-donating groups do not undergo any reduction under normal conditions [Scheme-4]. Not only N=N double bonds but also N–N single bonds can be cleaved, albeit slowly, by tetrathiomolybdate 1. Phenylhydrazine, after treatment with tetrathiomolybdate 1, produces aniline in 20% yield.

The next logical step was to examine whether tetrathiomolybdate 1 can mediate reduction of the most unreactive N molecule. Although it was not expected to be a facile reaction, when tetrathiomolybdate 1 was treated with nitrogen in CHCl/HO (25 °C, 5 days), ammonia was formed in about 2% yield [Scheme-4]. Control experiments were performed to substantiate the formation of ammonia in this reaction. The reduction of N, however slow, with 1 is indeed surprising.

Scheme 4 R–N=N–R + 1 PhNHNH CHCN/HO, DMF/HO, 4 days, RT R–N–N–R H CHCl/HO, 5 days, RT NH Yield: 40–90% (hydrazo), 20% (phenylhydrazine aniline), 2% (N NH)

In Chapter 2, we discuss the reactivity of tetrathiomolybdate toward nitrate esters.

Isosorbide-2,5-dinitrate 2 is a well-established compound used in the treatment of coronary diseases. It is rapidly metabolized in the organism, and isosorbide-2-nitrate and isosorbide-5-nitrate 3 occur as metabolites. The mononitrates are advantageously distinguished by various therapeutically important parameters such as resorption behavior, half-life, toxicity, and oral applicability. Because of this fundamental difference in the pharmaceutical application of the two compounds, it is necessary to devise methods to obtain isomerically pure mononitrates.

We demonstrated that tetrathiomolybdate 1 reduces selectively isosorbide dinitrate to isosorbide-5-nitrate in good yield. However, when reactions were carried out with simple aliphatic nitrate esters, tetrathiomolybdate 1 behaves like a sulfur transfer reagent rather than as a reducing agent [Scheme-5]