HIO 3 /KI: A new combination reagent for iodination of aromatic amines and trimethylsilylation of alcohols and phenols through in situ generation of iodine under mild conditions

A combination of iodic acid and potassium iodide has been used for trimethylsilylation of alcohols and phenols in the presence of HMDS and iodination of aromatic amines. The reactions occur very rapidly to provide the products in good to high yields in dichloromethane at room temperature while the use of toxic and corrosive molecular iodine is avoided

7][28] Therefore, the development of quick, inexpensive, widely applicable, and environmentally benign iodinating agents is still an active area of research.
0][31][32][33][34] The use of iodic acid has been known for a long time and has been widely employed in numerous and different organic reactions such as iodination 29,35 and deprotection, 36 but no report seems to be found in literature on the in situ generation of molecular iodine by the reaction of iodide salts and iodic acid.This reagent has several advantages such as cost-effectiveness, low-toxicity to humans 37 and the exceedingly simple and clean workup of products.

Results and Discussion
Against the background presented above, we have carried out a detailed investigation aimed at the preparation of in situ generation of the molecular iodine by the reaction of potassium iodide and iodic acid and found that this system could play a dual role as a reagent system for the iodination of aromatic amines and as a catalyst system for trimethylsilylation of alcohols and phenols.We believe that the present method is general, simple, mild, rapid, inexpensive, and new to the literature.
At the inception of this work, we studied the reaction of N-phenylmorpholine as a model with potassium iodide and iodic acid in different solvents (Table 1).Our observation revealed that, amongst the various solvents, the mixture of CH 2 Cl 2 /H 2 O (1:1) was the most effective, as a change of color was evident.Also the influence of amount of iodic acid on the yield of reaction was studied, as summarized in With a better understanding of the reaction variables, a series of aromatic amines were subjected to iodination with potassium iodide and iodic acid at room temperature in CH 2 Cl 2 /H 2 O (1:1) as a two phase system.In all reactions, we observed that mono-iodination took place and regioselective iodination occurred at the more active and less hindered sites (Table 3, Scheme 1).Even though it seems that HIO 3 /KI is capable of oxidizing alcohol, 34 it remains intact during the iodination of aromatic nucleus (Entry 4).Several attempts to produce mono iodinated derivative of phenol were unsuccessful and led to a sluggish mixture.We have extended our reaction to a series of unactivated aromatic compounds as depicted in Table 3, these compounds were unreacted even after 2 h (Entries 8, 9).To extend application of this method in organic reactions and transformations, we have employed our method as a catalytic system for trimethylsilylation of alcohols and phenols.In this context, we have found that a combination of iodic acid and a catalytic amount of KI in the presence of HMDS generate I 2 in situ as an efficient catalyst for the trimethylsilylation of alcohols and phenols (Scheme 2).To find the best system for in situ generation of I 2 , first we studied a number of oxidizing agents in combination of KI for the trimethylsilylation of alcohols and phenols.As it can be seen in Table 4, the best results are related to the HIO 3 /KI system.In addition to KI, we used catalytic amount of KCl and KBr for the described system and the obtained results are depicted in Table 5.From these results, it is clear that KI is more efficient than KCl or KBr.Also as a model we studied the trimethylsilylation of benzyl alcohol in different solvents (Table 6).Thus, a variety of alcohols and phenols were subjected to silylation reaction with a combination of iodic acid and a catalytic amount of KI in the presence of HMDS.All protection reactions were performed under mild and homogeneous conditions, at room temperature with good to high yields.These reactions were carried out in wet CH 2 Cl 2 (Table 7).
As shown in Table 7, in the cases of primary and secondary alcohols the reactions were completed rapidly.Also, different types of highly hindered tertiary alcohols were successfully converted to the corresponding trimethylsilyl ethers in almost quantitative yields at room temperature (Table 7, Entries 18-20).Moreover, no side products were observed in these reactions.The data in Table 8 clearly show that different types of phenols were successfully converted to the corresponding silyl ethers in short reaction times and in almost quantitative yields.We observed that amines and thiols were not silylated under these reaction conditions even after prolonged times (Table 8, Entries 5,6).To prove this claim that molecular iodine is an actual catalyst, we conducted trimethylsilylation of benzyl alcohol with hexamethyldisilazane in the presence of catalytic amounts of iodic acid (0.2 mmol) instead of the system of HIO 3 /KI.The reaction was not completed after 6 h (Table 4, Entry 6), while benzyl alcohol was trimethylsilylated with hexamethyldisilazane in the presence of HIO 3 /KI, in very short reaction times (Table 7, Entry 1).

Conclusions
In conclusion, we have developed a simple protocol using commercially available materials that could be utilized for a dual role: as a combination reagent for iodination of aromatic amines and as a catalyst system for trimethylsilylation of alcohols and phenols.

Experimental Section
Typical procedure for iodination of N-phenylmorpholine KI (1.2 mmol, 199 mg) and a solution of HIO 3 (1.2mmol, 211 mg) in H 2 O (5 mL) were added to a solution of N-phenylmorpholine (1.0 mmol, 163 mg) in CH 2 Cl 2 (5 mL) at room temperature and the mixture was stirred vigorously for 15 min.at room temperature.After completion of reaction that was indicated by TLC, the reaction mixture was transferred to a separatory funnel and a 10 % aqueous Na 2 S 2 O 3 solution (25 mL) was added.The aqueous fraction was extracted with CH 2 Cl 2 (3 × 15 mL).The organic layer was dried with Na 2 SO 4 .The solvent was removed by simple distillation to give a crude product (283 mg; 98 %).Further purification was carried out by crystallization from cold hexane to afford a pale yellow crystalline product (265 mg; 92 %), mp 128-130 °C, which showed satisfactory analytical and spectroscopic properties.

General procedure for trimethylsilylation of alcohols and phenols
The alcohol or phenol (1.0 mmol) was added to a mixture of HIO 3 (0.2 mmol) and KI (0.2 mmol) in CH 2 Cl 2 (1 mL) and one drop of H 2 O. Then HMDS (1.0 mmol in 1 mL CH 2 Cl 2 ) was added drop wise to this mixture within 5 min.The mixture was stirred vigorously at room temperature for the specified time (Table 7,8).After completion of the reaction (TLC), the mixture was filtered and the solids were washed with CH 2 Cl 2 (5 mL).Powdered Na 2 S 2 O 3 (2 g) was added, the mixture was stirred for additional 5 min, and the resulting mixture was filtered.Finally, H 2 O (10 mL) was added to destroy the extra amount of HMDS, the organic layer was separated and the filtrate was dried with Na 2 SO 4 .Evaporation of the solvent under reduced pressure gave almost pure product.

a
Refers to isolated yields (The products were characterized by comparison of their spectroscopic and physical data with those of the samples synthesized by reported procedures).

a
Refers to isolated yields (The products were characterized by comparison of their spectroscopic and physical data with those of samples synthesized by reported procedures).

Table 2 ,
1.2 mmol of iodic acid gives a short reaction time and high yield.

Table 2 .
Amount of HIO 3 on the iodination yield of N-phenylmorpholine a b Isolated yields.

Table 3 .
Iodination of aromatic amines to mono iodo derivatives with HIO 3 (1.2mmol) in the presence of KI (1.2 mmol) in CH 2 Cl 2 and H 2 O (1:1) at room temperature

Table 5 .
Comparison of different types of MX for the trimethylsilylation of benzyl alcohol a

Table 6 .
Comparison of various solvents for the trimethylsilylation of benzyl alcohol using I 2 generated in situ from HIO 3 (0.2 mmol) in the presence of a catalytic amount of KI (0.2 mmol) a GC yield.

Table 7 .
Trimethylsilylation of alcohols (1.0 mmol) using HMDS (1.0 mmol) catalyzed with I 2 generated in situ from HIO 3 (0.2 mmol) in the presence of a catalytic amount of KI (0.2) in dichloromethane and one drop of water at room temperature

Table 8 .
Trimethylsilylation of phenols (1.0 mmol) using HMDS (1.0 mmol) catalyzed with I 2 generated in situ from HIO 3 (0.2 mmol) in the presence of a catalytic amount of KI (0.2) in CH 2 Cl 2 and one drop of H 2 O at room temperature b Isolated yields