Desulfurizing agents for thioureas

Heavy metals salts and oxides.

Heavy metal salts and oxides (HgCl2, Hg(OAc)2, HgO, Pb2O4) have been the most used desulfurizing agents over the time. They required a full equivalent of heavy metal (e.g. Hg²⁺) and produce undesirable by-products that must then be removed and properly disposed.

There has been an increasing interest to replace the use of heavy metals by more convenient desulfurizing reagents. Some of them are discussed hereafter.

Carbodiimides

The use of carbodiimides as amide coupling agents is of particular significance^29,46 but they have also been employed as desulfurizing agents of thioureas. In the latter case, the newly formed carbodiimide usually reacts with a nucleophile in a second step (Scheme 33).

NH N Scheme 33. Carbodiimides as desulfurizing agents of thioureas.

There are many commercially available carbodiimides (DCC, EDC, DIC, etc.) or readily accessible by various methods.^29,46 Among these methods, dehydration of isocyanates in presence of catalytic phosphine oxides has shown to be an efficient approach for the industrial scale production of symmetric carbodiimides to be later used in many manufacturing processes.

Probably the main disadvantage of the use of carbodiimides as a coupling or desulfurizing agent is the necessity to remove the corresponding urea (or thiourea) that is formed as by-product. This fact prompted Weinshenker et al. to develop a polymer supported version which allowed the by-product removal by simple filtration while it is bound to the insoluble support.⁴⁷ Commonly used carbodiimides and their polymer-supported analogues are depicted in Figure 8.

N N

N N

N N

N N⁺ N N

HCl

Cl-DCC

EDC

DCC polymer-supported analogue

EDC polymer-supported analogue Figure 8. Common carbodiimides and their polymer-supported analogues.

While there are some polymer-supported carbodiimides commercially available, they can be prepared from aminomethylpolystyrene resin and the corresponding isocyanate upon a dehydration step (Scheme 34).⁴⁷ On an industrial scale, the dehydration reaction is executed by using p-toluenesulfonyl chloride and triethylamine. However, some authors claimed that better results are obtained when the dehydration is promoted by carbon tetrabromide/triphenylphosphine mixture⁴⁸ or by Burgess reagent.⁴⁹

O R

Chapter 3 Synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines

Mukaiyama's reagent.

2-Chloro-1-methylpyridinium iodide (Mukaiyama's reagent) have been extensively used to activate under mild conditions carboxylic acids to then be transformed in various common functional groups such as esters, amides and thiol esters.⁵² Furthermore, this reagent can effectively transform thioureas into carbodiimides in presence of a weak base like triethyamine (Scheme 35).⁵³ This process is based on the ability of the sulfidopyridinium function to act as an effective leaving group affording the carbodiimide in good yields. This method is of quite general utility; aromatic and aliphatic carbodiimides can be obtained by a simple procedure. 2-Chloro-1-methylpyridinium iodide is commercially available but it can easily be prepared via N-methylation of 2-chloropyridine with methyl iodide.

NH N H S

R2

R1 Cl N⁺

I N NH

S R1

N⁺

R2

N N N S

R1

+ ^TEA R2

R1, R2 = aryl, alkyl TEA +

Scheme 35. Mukaiyama's reagent as desulfurizing agent of thioureas.

The use of Mukaiyama's reagent has two main drawbacks: i) the low solubility in the most common organic solvents and ii) the chromatographic purification of the desired product is generally needed to completely remove 1-methylpyridin-2-(thio)one that is formed as a by-product. Once again, different polymer-supported versions of the Mukaiyama's reagent were developed to overcome these issues.

In 2004 Convers et al. described the first synthesis of polymer-supported Mukaiyama's reagent from Merrifield's resin and 2-chloropyridine in presence of potassium iodide (Scheme 36, pathway a).⁵⁴ The loading obtained with this protocol^e showed low reproducibility and the attachment varied between 33-72% depending on the scale, mode of stirring and loading of the starting Merrifield resin. ⁵⁴

e Active loading: determined by "end-use" assay, i.e. assuming 100% conversion in a known reaction.

N⁺

Scheme 36. Polymer-supported Mukaiyama's reagent analogues described in the literature.

In our group, Crosignani et al. decided to use a better and non-nucleophilic leaving group like the triflate ester (Scheme 36, pathway b).⁵⁵ In this one-pot synthesis, Wang resin was activated in situ with trifluoromethansulfonic anhydride forming the triflate ester, which was immediately substituted by the 2-chloropyridine present in the reaction mixture. The excess of the 2-chloropyridine also acted as the base necessary for the formation of the triflate ester, so that the addition of another base was not necessary. Through this protocol, complete conversion of the Wang resin to the chloropyridinium salt was obtained, as judged by elemental analysis (based on nitrogen and sulfur) and mass increase of the resin. This resin is now commercialized by two of the major vendors of polymer-supported reagents^f proving the simplicity and efficiency of this one-pot method.

Chapter 3 Synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines

The polymer-supported Mukaiyama reagents presented before have been used in the synthesis of guanidines,⁵⁴ esters,^55,57 amides,^55,58 and lactames.⁵⁶

3.1.4. Objectives

The synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines (2) via cyclodesulfurization of the corresponding thiosemicarbazide (77) was chosen for further investigations (Scheme 37).

N N

Scheme 37. Proposed pathway for the synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines

Despite the previously reported route described the synthesis of N-aryl derivatives, the substrate scope has not been explored (only three examples).²⁸ We considered this route attractive for many reasons: i) simple starting materials: thiosemicarbazides 77 can be prepared from hydrazines 78 and isothiocyanates, both reagents commercially or readily accessible; ii) it could be a general approach to alkyl, aryl and acyl derivatives; iii) N-unsubstituted derivatives (R1 = H) could be obtained in two steps: synthesis of the N-tert-octyl derivative followed by acidic cleavage.¹⁰ iv) It could be extended to other related fused heterocycles (Scheme 38).

Scheme 38. Extension to other related fused 3-aminotriazoles

The objective in the present work was to find an adequate desulfurizing agent that could allow the a straightforward synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines.

3.2. Discussion