Regioselective and facile oxidative thiocyanation of anilines and indoles with trans-3,5‐dihydroperoxy-3,5‐dimethyl‐1,2‐dioxolane

b Faculty of Chemistry, Isfehan University of Technology, Post Code 84154, Isfahan, I. R. Iran m.pirway1984@gmail.com Corresponding author: E-mail: azarifar@basu.ac.ir; Tel: +98(811)8380647 ABSTRACT Oxidative potential of trans‐3,5‐dihydroperoxy‐3,5‐dimethyl‐1,2‐dioxolane (DHPODMDO) has been explored in the facile thiocyanation of anilines and indoles through the efficient and in situ generation of SCN + ion from sodium thiocyanate. The reactions proceed with regioselectivity under mild conditions at room temperature to afford the respective thiocyanate derivatives in excellent yields and low reaction times.


INTRODUCTION
Organic thiocyanates are well-documented and important industrial compounds [1]. These compounds have played important roles in the synthesis of organic compounds and various pharmaceutically important products [2]. The compounds containing thiocyanate group are considered as versatile intermediates in which the thiocyanate group can be readily transferred into different functional groups such as sulfides [3], thiocarbamates [4] and thionitriles [5]. For this reason, there is significant interest in the development of new and more convenient synthetic approaches to thiocyanate containing compounds including aromatic derivatives [6].

Material and instruments
Chemicals were purchased from Merck chemical company and used without further purification. FT-IR spectra were recorded on a Shimadzu 435-U-04 spectrophotometer (KBr pellets). The NMR spectra were recorded on a JEOL FX 90 MHz spectrometer in CDCl3 or DMSO-d6 solutions using TMS as internal standard. Melting points were determined in open capillary tubes with a Stuart SMP3 apparatus and were uncorrected.
Caution: Although we did not encounter any problem with trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane, it is potentially explosive and should be handled with precautions; all reactions should be carried out behind a safety shield inside a fume hood and transition metal salts or heating should be avoided.
To a solution of acetylacetone (100 mg, 1 mmol) in CH3CN (5 mL) was added SnCl2.2H2O (45 mg, 0.2 mmol) and the resulting mixture was stirred for 5 min at room temperature. Then, aqueous 30% H2O2 (5 mmol) was added to the reaction mixture and let to stir for 12h at room temperature. After completion of the reaction as monitored by TLC,distilled water (15 mL) was added and the product was extracted with ethylacetate (2×10 mL). The combined organic layer was dried over anhydrous MgSO4 and evaporated under reduced pressure to leave almost pure white crystalline product in 85% yield (140 mg); mp 98-100 ˚C. N o v e m b e r 1 5 , 2 0 1 4

General procedure for synthesis of thiocyanate derivatives
To a solution of aniline (or indole) 1 (1 mmol), sodium thiocyanate (89 mg, 1.1 mmol), and catalytic amount of glacial acetic acid (2 drops) in acetonitrile (3 mL), was added trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane (166 mg, 1 mmol). The resulting mixture was allowed to stir at room temperature for an appropriate time (Table 2). After completion of the reaction as monitored by TLC, the reaction mixture was diluted with distilled water (10 mL) and the product was extracted in chloroform (3 × 5 mL). The combined organic layer was washed with water (2 × 5 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure gave almost pure products. Structures of the known products were established on the basis of their physical and spectroscopic (IR, 1 H NMR, and 13 C NMR) data that were consistent with those previously reported [16,42].
In the present method, NaSCN has been used as the source of HOSCN which is produced upon the initial degradation of trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane with NaSCN. The reactions proceed rapidly under mild conditions at room temperature in acetonitrile to afford the corresponding thiocyanated aromatic products in high to excellent yields. The experimental data resulted from the reactions are summarized in Table 1. The products were characterized based on their physical and spectral (IR, 1 H NMR and 13 C NMR) analysis and compared with the reported data [16,42].
To establish the reaction conditions, we preliminarily studied the model reaction of indole 1q with NaSCN using trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane at room temperature. The effects of solvent and the oxidant loading on the reaction were studied using different solvents such as n-hexane, CH2Cl2, H2O, Et2O, AcOH and CH3CN with various molar ratios of the oxidant DHDMDO (Table 1). As seen in Table 1, the best results in terms of the yield and reaction time were obtained when AcOH and CH3CN were used as the solvents with using equimolar amount of the oxidant (entries 5 and 6). However, due to the probable acetylation and protonation of the amino group by acetic acid in anilines that may result in the reduction of their reactivity, thiocyanation reactions were preferably conducted in acetonitrile as the solvent of choice. The partial protonation of amino group with acetic acid can also increase the solubility of the products in aqueous layer and render their separation more difficult in the course of work up. In addition, the optimum amount of the oxidant used in this reaction was found to be one equimolar when activated with a catalytic amount (two drops) of acetic acid. It is noticed that, using lower amount of the oxidant brings about unfavorable changes in the yield and reaction time (entry 7). Moreover, no improving effect on the yield was observed with using higher amounts of the oxidant (entry 8). It is noteworthy that, when the reaction was carried out using 30% H2O2 as the oxidant, only a very low yield of the expected product was obtained with longer reaction time (entry 9). It should be noted that, the reaction was conducted at room temperature since heating the reaction mixture to higher temperatures can cause explosion of the oxidant. The role of the oxidant used in this reaction was substantiated by conducting the reaction in the absence of the oxidant that left the starting indole untouched after a long reaction time (entry 10). N o v e m b e r 1 5 , 2 0 1 4 To explore the scope of the reaction, we extended the model reaction to a series of differently substituted anilines 1a-p and indoles 1q-v under the aforementioned optimized conditions (DHPDMDO one equimolar, CH3CN as solvent, r.t.). The results obtained are summarized in Table 2. In general, all the reactions proceeded very smoothly at room temperature to provide the thiocyanated products 2a-v in high to excellent yields (80-98%). As shown in Table 2, the anilines and indoles carrying electron-donating groups react more readily compared with those carrying electron-withdrawing groups. It is noticed that, under the present conditions the reactions occur para-selectively. In consequence, the para-substituted anilines remained unreacted in this reaction (entries c-e). These observations are also supported by other reports [9,10,[43][44][45].   As mentioned before, most of the methods reported in the literature for thiocyanation of organic compounds suffer from certain drawbacks such as long reaction times, requirement for high reaction temperatures or ultrasonic irradiation, low yield, and use of explosive and/or toxic reagents. While, the reactions involved in the present method proceed very smoothly under mild conditions at room temperature. Our procedure may be considered as environmentally friendly since no additional catalyst is necessary for activation of the reactions and the oxidant used in this method is regarded as nonpolluting reagent. As summarized in Table 3, the preference of the present method in terms of the reaction time and yield is revealed in comparison with a number of other methods reported in the literature based on the model reaction with indole. A probable mechanism to explain the conversion of anilines and indole derivatives into corresponding thiocyanosubstituted products 2a-v with NaSCN using trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane as the oxidant is depicted in Scheme 3. As shown in this scheme, it is likely that the reactions take place preliminarily with in situ generation of SCN + ion in two successive degradation steps upon the effect of SCN anion on trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane. Subsequently, the regioselective electrophilic substitution of indoles (or anilines) with protonated HOSCN proceeds to afford the respective products 2.

CONCLUSIONS
In summary, the oxidative potential of trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane for in situ generation of SCN + ion with NaSCN has been explored. Subsequently, SCN + ion acts as a powerful electrophile in regioselective substitution a Isolated yield. N o v e m b e r 1 5 , 2 0 1 4 reaction with anilines and indoles to afford the respective thiocyanated products in quantitative yields. All the reactions proceed efficiently and smoothly under mild conditions at room temperature. High regioselectivity, improved yields and reaction times, simple work up, absence of toxic catalyst in the reactions, and avoidance of polluting and hazardous reagents are the main merits of the present protocol.