Hypervalent iodine(III) promoted synthesis of isothiocyanates in water

Abstract Here, we have established method for the synthesis of isothiocyanates using diacetoxyiodobenzene as a desulfurizing agent under micellar condition in water. We have explored functional group tolerance under optimized reaction conditions. All electron donating and withdrawing amines carried out the reaction to produce their corresponding desired isothiocyanates 1a–17a in moderate to good yield. This synthetic process in water can be applied to prepare isothiocyanates at gram-scale quantity. Our aqueous micellar medium also demonstrated high reusability as the reaction can be performed for several cycles without losing its efficiency. The reaction is metal-free, utilize water as solvent and practical at room temperature and open flask. Graphical abstract


Introduction
Generally, solvents like toluene, THF, DMSO, DMF, dioxane, etc., are used for the synthesis of heterocyclic compounds [1] and functional group transformation [2] in both academic and industry. Due to the usage of organic solvents the environment may be polluted, therefore, green solvent like water may be used for organic reactions to reduce the pollution. In this connection, "on-water" reaction was initially introduced by Sharpless, [3] since then, many researchers have reported reactions with water. [4] Onwater reactions have many benefits, however, due to its heterogeneous behavior their adoption has been limited in traditional chemical transformation reactions. Recently, Lipshutz et al. [5] have developed reactions with water in the presence of surfactant which reduces the surface tension between two liquids. Many other reports [6] have dramatically established aqueous reactions and thereby providing high reactivity, selectivity, and reproducibility.
In recent decades, hypervalent iodine have received much attention as oxidants due to their environmentally friendly character, ease of handling, selectivity and reasonable cost. [30] Because of the broad synthetic potential of hypervalent iodine, diacetoxyiodobenzene (DIB) has been reported as desulfurization agents for the preparation of isothiocyanate [29] and guanidines. [31] However, they require organic solvent as medium and stoichiometric organic amine base. In the view of green chemistry, the use of harmful organic solvent/base and multiple-step process would increase the operating cost and risk in large scale production. Therefore, a mild, scalable, metal-free and more practical approach for isothiocyanate synthesis in a greener medium would be highly desirable for both academia and industry. In view of this new development, herein we report an efficient one-pot synthesis of isothiocyanate directing from aniline mediated by DIB as oxidant in water. The reaction was performed in a micellar system, TPGS (Tocopheryl Polyethylene Glycol Succinate)-750-M/H 2 O, in the presence of nonhazardous and inexpensive sodium hydroxide as base at room temperature under openflask condition (Scheme 1).

Results and discussion
We have selected aniline as an initial material to conduct a multi-step order isothiocyanate preparation using hypervalent iodine(III), DIB. Previously, hypervalent (V) IBX was used for desulphurization, [32] however, due to its potential shock sensitive nature it can't be used more. Thus, we would like to use a nonexplosive hypervalent iodine(III) such as DIB as oxidant instead. Initially, the reaction was conducted in ethanol, and resulting in the formation of isothiocyanate 1a in 62% yield (Table 1, entry 1). Transforming from conventional organic solvent to neat water, as expected, reduced 1a to 19% yield along with starting material intact (Table 1, entry 2). Very lower conversion may be reasoned by heterogeneous character on water reaction. In order to conversion from heterogeneous to homogeneous, next, surfactant (TPGS-750-M) was chosen and the yield of the target product 1a was dramatically increased from 19 to 52% (Table 1, entry 3) The superiority of this surfactant over the other could be explained by highly stable and suitable size of particle formed in water, which could accelerate the reaction. [15] Later, we investigated the effect of base (Table 1, entries 4-6). The reaction provided target product in quantitative yield when 1.5 equivalents NaOH was used (Table 1, entry 7). As we set the goal to create an atom-economy guanidine synthesis, large excess of reagents must be reduced as much as possible. Lowering TPGS-750-M from 2 to 1% w/w still provided a comparable yield but when 0.5% w/w were employed, only 42% yield of 1a was isolated (Table 1, entry 9). This was likely because the reaction was carried near the critical micelle concentration of TPGS-750-M. [33] Finally, control experiments was performed in the absence of base ( that Base and hypervalent Iodine (III) reagent are necessarily required to enhance this method.
Having established an optimized reaction condition, we then explored the generality and scope of the reaction across a series of amines (Scheme 2). All electron donating and electron withdrawing substituted aniline readily undergone the reaction under optimal reaction conditions to produce corresponding isothiocyanates 1a-17a in 55-99% yields. 4-Methyl, 4-methoxy and 4-hydroxy anilines proceed the reaction to give expected isothiocyanates 2a, 3a, and 4a in 97, 99, and 90% yields, respectively. On the other hand phenyl having 4-Cl and 4-F readily underwent the reaction to produce the desired products 5a in 87% yield and 6a in 80% yield. While, aniline holds EWG resulting formation of the product 7a and 8a in lower yields. This method was also tried with a various of other functional groups such as -COR, -OCOR, -O allyl and they obtain their corresponding isothiocyanates 9a, 10a, and 11a, respectively, in moderate to good yield. In addition, 2,4-dimethyl aniline were smoothly converted to their corresponding isothiocyanate 12a in satisfactory yield. Benzylic amines gave corresponding isothiocyanates 13a and 14a in 82-90% yields. This method was also extremely successful in the preparation isothiocyanates. For example, aliphatic amines like cyclohexyl, cyclopropyl, and butyl amines were also proceeded the reaction offering the final products 15a-17a in 83-94% yields.
As we identified heterogeneity in the reaction, we have examined the recyclability of the wastewater containing surfactant TPGS-750-M (Scheme 3). After each reaction, small amount of ethyl acetate was added, and this organic layer containing product 1a was collected and purified. The aqueous layer containing TPGS-750-M was then reused for three subsequent fresh reaction batches. Excellent results were obtained without any significant loss in product yields. Importantly, after 3 recycles, E-factor of 9.8 was found, indicating the low waste process of this protocol. This method was conducted on gram scale (Scheme 4). Treatment of aniline (10 g) under optimized conditions and it resulted in the formation of 1a in nearly good yield. Notably, 1 H NMR of 1a is clean showing no signal of surfactant, by-product iodobenzene or remaining amine.
We have compared our method with reported catalysts and results are shown in the Table 2. The above-mentioned previous methods have drawbacks such as (i) used toxic and expensive catalysts, (ii) carried the reactions under reflux conditions, (iii) longer reaction time, (iv) used organic solvents, (v) not ecofriendly reagents were used. However, our present reported method is green, took short reaction time and used environment friendly reagents. In addition, gram scale reaction was also developed under optimized reaction conditions. Due to above-mentioned benefits, we strongly believe that our present work is better than other reported methods.

Experimental section
General method for the construction of phenyl isothiocyanate In a 10 mL round bottom flask containing a magnetic stir bar, aniline (1.0 equivalents), NaOH (1.5 equivalents) and TPGS-750-M/H 2 O (1 wt%, 0.4 mL, 1.0 M) were sequentially added. The reaction mixture was stirred at room temperature for 2 h. After starting material was completely consumed, as monitored by TLC, DIB (1.5 equivalents) and NaOH (1.5 equivalents) were sequentially added and stirring continued for 60 min. Then ethyl acetate (2 Â 1 mL) was added to the reaction mixture, which was stirred for 5 min. The organic layer was transferred using a Pasteur pipet and evaporated under reduced pressure to give the crude product. The residue was purified by column chromatography over silica gel by using 100% hexane as eluent to obtain isothiocyanate derivative.

Conclusions
In summary, we developed synthesis method for isothiocyanates directly from aniline using DIB as desulfurizing reagent under aqueous micellar medium. The protocol has high selectivity and high functional group compatibility providing isothiocyanates in NH 2 (i) CS 2 (10 eq), NaOH (1.5 eq), TPGS-750-M/H2O, rt, 4 h NCS (ii) DIB (1.5 eq), NaOH (1.5 eq), rt, 3 h (10 gr) (11.88 gr) Yield: 82% Scheme 4. Gram scale synthesis of 1a. good to excellent yields under mild reaction condition. The reactions are operationally very simple performing at room temperature in an open-air system. Importantly, micellar medium can be reused, providing a green and low waste process. Full experimental detail, 1H and 13 C NMR spectra. This material can be found via the"Supplementary Content" section of this article's webpage.