An effective room temperature nuclear iodination of aromatic compounds using molecular iodine and ammonium acetate

Abstract

The iodination of aromatic compounds using a simple and benign iodinating agent such as molecular iodine (I₂) under oxidant free mild conditions is a difficult and highly important task in organic synthesis since aryl iodides are the highly reactive starting materials in a variety of organic transformations. We have developed a mild and effective method for the aromatic iodination using challenging iodinating agent, I₂ under the catalytic performance of ammonium acetate (NH₄OAc). A variety of aromatic compounds are converted efficiently into their corresponding aryl iodides under developed condition with high regioselectivity.

Graphical abstract

Introduction

The marine organism is a significant source of organic iodides and many of these show their significance in biology [1,2,3]. These are used in medical imagining in the identification of diseases related to oncology and neurology [4, 5]. Moreover, the aryl halides are the most reactive starting materials in several organic reactions including cross-couplings, radical-induced reactions, and nucleophilic reactions in the presence of metals [6,7,8,9]. Aryl iodides are highly reactive than other aryl halides due to the easy cleavage of the C-I band than other C-halogen bonds [10, 11]. Besides the high reactivity of aryl iodides, the less availability and high cost of aryl iodides are because of less available iodinating agents and the requirement of oxidants, additives, and high temperature [12, 13]. In addition, N-iodosuccinimide [14,15,16,17,18], I₂ [19,20,21,22,23,24,25,26,27,28,29,30], KI [31,32,33], and mixed halides [34,35,36,37] are the frequently used reagents for the iodination of aromatic compounds. The substitution reactions of aryl diazonium/boronic acid compounds with nucleophiles [38,39,40,41,42] are the other alternatives for the synthesis of aryl iodides but these suffer from the requirement of harsh reaction conditions and metals. The applications of I₂ as an iodinating agent represents the natural process of synthesizing organic iodides and iodine is also accepted as an environmentally benign reagent [43]. Further, I₂ is a readily available and inexpensive substance. Despite these advantages, the low reactivity of I₂ with aromatic substances is the limitation and it requires an external oxidant. In this connection H₅PV₂Mo₁₀O₄₀-O₂ [19], Fe(NO₃)₃·1.5N₂O₄-charcoal [20], graphene oxide-CH₃NO₂ [21], NO₂ [12], [bis(trifluoroacetoxy)iodo]benzene-pyridine [22], silver sulfate [23], silica supported ferric nitrate monohydrate [24], ammonium cerium(IV) nitrate (CAN) [25], tetra-n-butylammoniumperoxydisulfate [26], NaNO₂-HCl-trifluoroethanol [27], lead(IV) acetate-AcOH-(CH₃CO)₂O [28], and IBX-CH₃CN-TFA [29] in the presence of I₂ are reported as efficient catalytic systems for aryl iodination. Most of these systems suffer from drawbacks including the necessity of oxidant, high temperature, costly catalysts, or no control over monoiodination products. Hence, it is necessary in developing a simple protocol for the synthesis of aryl/heteroaryl iodides. Therefore, we directed to develop an economical protocol for the easy synthesis of aryl iodides under added oxidant free conditions and found NH₄OAc–I₂ as an advantageous catalyst–reagent system in CH₃CN (Scheme 1) in this search. Moreover, NH₄OAc is a rich source of nitrogen and is a highly convenient alternative to ammonia in a wide range of organic transformations [44,45,46,47]. NH₄OAc was also utilized as an effective catalyst in synthetic methodologies [44, 48,49,50]. This method can be an extra attractive addition towards the application of NH₄OAc in organic synthesis.

Results and discussion

We have initiated the present iodination protocol using the reaction of o-toluidine (1a) (1.0 mmol) with I₂ (1.05 mmol) employing 0.5 mmol of NH₄OAc as a catalyst in 4 cm³ ethanol and observed the formation of 34% of mono iodinated product, 4-iodo-2-methylaniline (2a) and 15% of diiodo product, 2,4-diiodo-6-methylaniline (2aa) in 1 h (Table 1, entry 3). To our delight, the reaction was preceded without the aid of an external oxidant. The reaction was then screened using solvents methanol, tetrahydrofuran (THF), CH₃Cl, CH₂Cl₂, CH₃CN, n-hexane, (CH₃)₂SO, and water (Table 1, entries 4–11) and identified that the CH₃CN is appropriate for the mono iodination of 1a (Table 1, entry 7). The increase of the quantity of catalyst, NH₄OAc to 0.75 mmol and 1.0 mmol, the reaction resulted from 2a with 89% yields in CH₃CN (Table 1, entries 11, 12) was indicated the requirement of 0.75 mmol of NH₄OAc for this selective iodination of 1a. Other ammonium salts such as NH₄OH, NH₄Cl, NH₄OCHO, CAN, and (NH₄)₆Mo₇O₂₄ are also screened for the selective iodination of 1a (Table 1, entries 13–17), and observed that the NH₄OAc was suitable among these (Table 1, entry 7).

Table 1 Screening for reaction conditions

With the developed conditions, we have screened a variety of substrates for the selective monoiodination and the results were shown in Table 2. Aniline was observed as a good substrate under NH₄OAc catalyzed iodination and provided 99% of monoiodination product in 0.25 h (Table 2, entry 2). The occurrence of diiodo products was reported with several reported procedures. The substituted anilines with the functional groups such as methyl, chloro and fluoro provided 83–89% of monoiodination products, 2a [52, 53], 2b-2f [54,55,56,57,58] in 0.25—1.0 h (Table 2, entries 1, 3–6). Phenol 2h [59] and substituted phenols 2i [60], 2j [61], 2k [62, 63], and 2n [52, 64] with the functional groups such as methyl and carboxyl produced the corresponding monoiodination products with excellent yields (Table 2, entries 8–11, 13). Anisole (1m) are also observed as good substrate under the present iodination procedure for 2m [65, 66] (Table 2, entry 12). The method has also been studied for its successful application to the iodination of heteroaryl substance such as 2-aminopyridine 2l [52, 67] and 2-amino-5-bromopyridine (2g) [68,69,70] (Table 2, entries 7, 14).

Table 2 Substrate scope

The possible mechanism of NH₄OAc catalysed iodination of aryl or heteroaryl compounds has been shown in Scheme 2. The reaction of ammonium acetate with I₂ may form acetyl hypoiodite A and ammonium iodide. The electrophilic iodine species, A on reaction with aryl or heteroaryl compounds results in the aryl iodides or heteroaryl iodides and acetic acid through a usual electrophilic substitution mechanism of aromatic compounds.

Conclusion

In conclusion, an easy and simple procedure has been developed for the monoiodination of aromatic compounds using I₂ in the presence of NH₄OAc as an efficient catalyst. A variety of arylamino, phenolic, and heteroaryl compounds are regioselectively iodinated using the developed protocol at ambient conditions under external oxidant and additive-free conditions. The substrates with a wide range of functional groups such as methyl, amine, hydroxyl, methoxy, bromo, chloro, fluoro, and carboxyl are tolerated under present conditions. Quick reactions, high regioselectivity, simple reaction conditions, ambient conditions, and oxidant, and additive-free conditions are the important attributes of this iodination protocol.

Experimental

All starting materials and solvents were obtained from Sigma-Aldrich (USA). All reagents were used as it is without further purification. All reactions were conducted under standard operating conditions without the use of any stringent conditions. The reaction progress was monitored on Merck TLC Silica gel 60 F254 plates, and the spots were visualized under ultraviolet (UV) light, followed by iodine or KMnO₄ staining solution followed by heating. Chromatographic purifications were carried out using flash-grade silica gel (SDS Chromatogel 60 ACC, 40–60 µm). NMR spectra were recorded at 23 ºC on Varian 400 Ultrashield apparatus. ¹H and ¹³C NMR spectra were recorded on 400 MHz NMR spectrometer using CDCl₃ as solvent unless otherwise stated. Mass spectra were recorded on a Waters Acquity TQDLC/MS/MS system.

General experimental procedure

To a mixture of aromatic compound 1 (1.0 mmol), I₂ (1.05 mmol), and NH₄OAc (0.75 mmol) was added 4 cm³ CH₃CN and stirred the resultant mixture at room temperature for an appropriate time. After the completion of the reaction, as indicated by TLC, the reaction mixture was added 5 cm³ of water. Extracted the mixture using EtOAc (3 × 5 cm³) and the combined portions of EtOAc were subjected for evaporation to obtain crude aryl iodide. The crude aryl iodides were purified by using silica packed columns using varying ratios of EtOAc and hexanes as eluent. Pure aryl iodide was subjected to the confirmation of their structures using ¹H NMR, ¹³C NMR, and mass spectral data. The spectral data of representative iodo (hetero)arenes is provided in supporting material and the spectral and physical properties have been found to coincide with the reported data.