Arene diazonium saccharin intermediates: a greener and cost-effective alternative method for the preparation of aryl iodide

In the current protocol, the arene diazonium saccharin derivatives were initially produced from various substituted aromatic amines; subsequently, these intermediates were treated with a greener organic iodide for the preparation of the aryl iodide. We tried to choose low-cost, commercially available, biodegradable, recoverable, ecofriendly, and safe reagents and solvents. The arene diazonium saccharin intermediates could be stored in the liquid phase into a refrigerator for a long time with no significant loss activity. The outstanding merits of the current protocol (a) included the partial recovering of saccharin and tetraethylammonium salt, (b) reduce the use of solvents and the reaction steps due to eliminating separation and purification of intermediates, (c) good yield of the sterically hindered substrates, and (d) avoid the generation of heavy metal or corrosive waste.


Introduction
In the course of our research regarding the synthesis of aromatic iodides through the Sandmeyer reaction or its alternatives, we required an efficient, low cost, and sustainable method for accessing relative stable arene diazonium salts. The most arene diazonium salts are often prepared in situ due to their instability and explosive risk [1]. It is clear that the anion nature can influence in situ the generation of the arene diazonium salts [2], and facilitated the preparation of aryl iodides. The preparation of relative stable benzenediazonium tetrafluoroborates was reported in ethanol using HBF 4 and isoamyl nitrite [3]. Most of the reported chemicals and reagents are expensive, toxic, nonbiodegradable, unrecoverable, and metal-containing, so we looked for a cheap, nontoxic, recoverable, biodegradable, and biocompatible reagent that show high efficiency under mild conditions.
In continuation of our previous work [4] and application of saccharin [5][6][7], we encouraged to investigate the potential of saccharin for the synthesis of the aryl iodides through in situ formation the arene diazonium saccharin salts which to the best of our knowledge has not been presented to date. According to the current strategy, aryl iodides are formed from diazotization of in situ generated arene diazonium salts which are in turn formed from aniline derivatives and tert-butyl nitrite (TBN) in the presence of saccharin. The intermediates are not isolated and purified in the current protocol which lead to minimizing the solvent waste, and energy efficiency is enhanced by the reaction performance at room temperature and shorter reaction times.

Results and discussion
TBN and tetraethylammonium iodide (TEAI) were preferred as a nitrating agent and iodide precursors due to their unique properties like safe handling, metal-free, inexpensive, and commercial availability [8,9].
Based on our previous works [4,5], the glacial acetic acid and TBN together with Sac-H were slowly stirred in ethanol at low temperatures (an ice bath). After 5 min, aniline 1a was slowly added at the same temperature. After completion of the first step (monitored by a colour test of azo coupling with 2-naphthol), the generated t -BuOH and unreacted TBN were removed under vacuum by a rotary evaporator. Then, the TEAI solution was added into the stirring intermediate 2a at one time and final product 3a was purified by the flash chromatography (Scheme 1).
The scope and generality of current methodology was evaluated through transformation of a variety of aniline derivatives into the corresponding iodides using the current protocol. The aryl iodides bearing electrondonating and electron-withdrawing groups were obtained from the corresponding anilines in good to excellent yields (Table 1). However, the steric hindered anilines viz. 2,6-dimethylaniline, 2,6-diethylaniline, and 2,6diisopropylaniline 3(d-f) were isolated in 67%, 40%, 42% yields, respectively as expected (Table 1,    Complete or partial recovering of the catalyst and reagents are very important in the industrial processes due to minimizing the waste, as well as lower raw material, energy, and waste disposal costs. According to the reported procedure in the literature [6], the saccharin and tetraethylammonium chloride (TEAC) could be recovered in the range of 77%-72% and 68%-64% yield, respectively.
The possible reaction of aniline and saccharin was investigated by a control experiment under optimal conditions. No 3-amino-1, 2-benzisothiazole-1, 1-dioxide were detected by LC-MS analysis.
Another experiment was performed to study the stability of the arene diazonium intermediate. After the first step, the intermediate 2a can be isolated by removing the excess TBN and t -BuOH under vacuum and stored in a refrigerator (4°C). After four days, the stored arene diazonium 2a was treated with a TEAI solution which afforded iodobenzene (3a) in a 74% yield.
A proposed mechanism is illustrated in Scheme 2 [6]. Saccharin and tert-butyl nitrite generate the nitroso electrophilic substitution reaction with TEAI, which finally affords the corresponding aryl iodides. Our group is working to investigate the detailed processes of reaction mechanism based on 2 routes A and B.
A large scale of the current protocol was also conducted for 1.9 g of 1a under optimal conditions, which afforded 3.12 g of 3a (ca.75%). Table 2 showed some of the reported methods and their conditions for the preparation of 2-nitro-1iodobenzene 2k. The previously reported methods have their own merits and limitations, for example, the use of metal-containing nitrites and iodides (

Conclusion
In summary, a telescopic reaction developed for the synthesis of aryl iodides in the presence of TBN, Sac-H, glacial acetic acid, and TEAI. The arene diazonium intermediates could be stored for relatively long periods with little reduce of activity. The current methodology is safe, cost-effective, broad substrate scope, and metalfree. All used reagents are commercially available and inert to moisture and air. Also, the saccharine and tetraethylammonium cation were easily isolated from the reaction mixture which reduces the cost and waste of the current protocol.

General
The analytical grade chemicals were provided from Merck and Sigma Aldrich Chemical Companies. The chemicals were used without further purification. Products were characterized by their physical constants

Typical procedure for the synthesis of aryl iodide
To a stirring mixture of glacial acetic acid (0.12 mL, 2.1 mmol) and TBN (0.30 mL,2 .3mmol)inethanol(10mL), Sac − −H(0.37g, 2.0mmol)wasslowlyaddedatlow  The recovery of reagents was conducted by adding the concentrated hydrochloric acid into the aqueous layer, and the water evaporated under reduced pressure. Then, the residue was extracted 5times with EtOAc (5 mL), and the collected extracts were dried over anhydrous Na 2 SO 4 and filtrated. The evaporation of solvent afforded Sac-H in 72% yield. The tetraethylammonium chloride (TEAC) was isolated in a yield of 0.25 g from the residue of the above procedure (68%). The melting points and FTIR spectra of recovered saccharin and TEAC were identical to the authentic compound (Sigma Aldrich ≥ 98%).  [6].

Physical and
Spectra data of the aryl iodides 3a-3l [6] Iodobenzene ( 3a): 1   Caution! The arene diazonium salts are known potentially explosive in the dry state, thus, they must be cautiously stored and handled in the laboratories. Avoid unnecessary heating and mechanical impact, especially when working on a large scale.

Supplementary material
Caution! The arene diazonium salts are known potentially explosive in the dry state.
Thus, they must be cautiously stored and handled in the laboratories. Avoid unnecessary heating and mechanical impact, especially when working on a large scale.