Molybdate sulfuric acid (MSA): a novel and efficient solid acid reagent for the oxidation of thiols to symmetrical disulfides

Wet molybdate sulfuric acid (MSA), as a new solid acid can be used in combination with sodium nitrite to transform a variety of thiols to the corresponding symmetric disulfides under mild and heterogeneous conditions. The process has several advantages: the reagents are inexpensive and non-hazardous, the reaction is clean, fast, high-yielding and MSA can be readily removed by filtration and re-used after treatment with HCl without loss of activity. Further, only thiol oxidation to disulfide was observed.


Introduction
Currently, the search about application of heterogeneous chemical systems is an active field both in industry and academia especially in view of simplified handling procedures, reduction of corrosion, avoidance of undesired by-products, clean and easily work-up procedures.With regard to the wide application of acids as reagents or catalysts in organic chemistry, the introduction of an inorganic solid acid can be useful in this direction.Several solid acids such as silica sulfuric acid 1 and Nafion-H 2 have been used for a wide variety of chemical transformations, e.g., preparation of disulfides from thiols 1 , oxidation of 1,4-dihydropyridines, 3 N-nitrosation of secondary amines, 4 acetal deprotection, 5 oxidation of alcohols, 6 alkylation and acylation, 7 isomerization, 8 transalkylation, 9 nitration, 10 ether and ester synthesis, 11 acetal formation, 12 and rearrangements. 13Disulfides have an important role in chemical synthesis.] Several methods based on oxidative S-S coupling have been reported for the synthesis of disulfides from thiols and protected thiols including coupling with redox dyes 16 , diazocompounds, 17 sulfoxides, 18 halogens, 19 H 2 O 2 , 20 KMnO 4 /CuSO 4 , 21 DMSO/I 2 , 22 sodium perborate, 23 Bismuth(III) Nitrate Pentahydrate, 24 1,3-Dibromo-5,5-Dimethylhydantoin 25 and electrochemical methods. 26In continuation of our recent studies 27 on the application of inorganic solid acids, we herein present molybdate sulfuric acid (MSA) as a new solid acid.MSA (1) was prepared according to a previously published protocol 27 as shown in Scheme 1.This inorganic solid acid in combination with NaNO 2 was observed to be an efficient and heterogeneous system for the oxidation of thiols.

Results and Discussion
First, we were interested to examine MSA (1) as a H + source in combination with various oxidants in organic solvents.For this reason, we chose wet 10% (w/w) MSA/NaNO 2 for the oxidative coupling of a series of aliphatic and aromatic thiols (1-13a) which were transformed to the corresponding disulfides (1-13b) in CH 2 Cl 2 or methanol.All reactions were run under mild and heterogeneous conditions at room temperature and gave the expected disulfides in good-toexcellent yields (Table 1).Based on other literature reports, 1a, [28][29] we propose that the reactions proceed via formation of NO + upon reaction of wet MSA(1) with NaNO 2 producing thionitrite 2 which converts to the related disulfides due to its instability under the reaction conditions according to Scheme 2.
The above proposed mechanism shows that the MSA (1) after a process remains as its sodium salt and therefore can be reusable acidic reagent.Thus, the recovered MSA from the oxidation reaction of, e.g., 5a was used again in another reaction with NaNO 2 , which afforded the related disulfide 5b in 92% yield (compared to 98% in the first run; see Table 1).
For increasing the rate of the oxidation reaction one could use an excess of NaNO 2 , but because of the probable nitrosation of the formed disulfides, this was avoided (Table 1).Finally, it is noteworthy to point to the role of H 2 O in the MSA/NaNO 2 system.We decided to run a series of parallel reactions under anhydrous conditions or hydrous conditions (wet MSA(1)).The results clearly indicate that H 2 O is essential for the generation of HNO 2 (see Scheme 2), since no oxidation was observed under strictly anhydrous conditions.

Conclusions
In this paper we have reported the use of molybdate sulfuric acid MSA, (1) as a novel heterogeneous solid acid in a convenient, efficient and practical method for the effective oxidation of thiols.The availability of the reagents, facile synthesis of MSA(1), the easy and clean work-up of products and the high yields make this method a useful alternative to literature methodologies.

Experimental Section
Thiols and the other chemicals were purchased from Merck, Fluka and Aldrich.The reactions were monitored by TLC (silica-gel 60 F 254, n-hexane: ethyl acetate).[30][31][32] IR spectra were recorded on a FT-IR JASCO-680 spectrometer and the 1 HNMR spectra were obtained on a Brucker-instrument DPX-300 MHz Avance 2 model.

Preparation of molybdate sulfuric acid (MSA).
To chlorosulfonic acid (23.304 g, 0.2 mol) in a 250 mL round-bottom flask immersed in an ice bath, anhydrous sodium molybdate (20.58 g, 0.1 mol) was added gradually.After completion of the addition, the mixture was shaken for 1 h, which gave rise to crude MSA as a bluish-white solid, which was filtered off and washed with cold H 2 O. Yield: 28 g (87.5%; m.p.( o C)= 356 (dec.)).The Compound is dissolved a little in Scheme 1

Table 1 .
Oxidation of thiols to the corresponding disulfides with wet MSA(1)/ NaNO 2 in dichloromethane or methanol at room temperature aIdentified by comparison with those reported in the literature.bRefers to isolated yields.*Chemical and Reagents 2005-2007 MERCK.ARKAT USA, Inc.