A Comparison of Microwave-Accelerated Conventionally Heated Iodination Reactions of Some Arenes and Heteroarenes, Using ortho-Periodic Acid as the Oxidant †

A fast and simple method for the oxidative iodination of some activated arenes and heteroarenes, either under microwave irradiation or by conventional heating, is reported, using diiodine and ortho-periodic acid as the oxidant. The reactions were carried out in hot 95% ethanol under a reflux condenser. For the microwave assisted reactions, the reaction times were always notably shortened, but the yields were nearly the same as those afforded by the conventional method.


Introduction
The use of microwave irradiation to simplify and improve classic organic reactions has become a very popular technique, because it sometimes results in shorter reaction times, higher yields and cleaner reactions [1][2][3][4]. A number of reflux systems have been developed in an effort to use solvents in microwave assisted organic synthesis without the risk of explosion, since they work at atmospheric pressure and flammable organic vapors cannot be released into the microwave cavity [1-4] -precisely with such a reflux system, with using also the focused monomode microwave irradiation, some microwave enhanced oxidative iodination reactions of a number of arylamines (highly activated arenes) have been carried out in our laboratory since 2003. In parallel, we have always carried out the same, or nearly the same, conventionally heated oxidative iodination reactions of the same arylamines in order to compare results, i.e. the reaction times and the yields of the purified iodinated products afforded by the two different experimental techniques. Our earlier microwave-accelerated iodination reactions were carried out under a reflux condenser using either boiling CHCl 3 (b.p. 61 °C) as the solvent of choice and a urea-hydrogen peroxide addition compound (UHP) as the oxidant [5], or boiling CH 2 Cl 2 (b.p. 42 °C) as the solvent of choice and ortho-periodic acid (H 5 IO 6 ) as the oxidant [6]. In the both cases, the microwave assisted oxidative iodination reactions of several arylamines afforded nearly the same yields of the purified iodinated products as those heated conventionally, but the reactions were always notably accelerated by microwave irradiation; for more details see our former papers [5,6]. However, we could hardly iodinate effectively some less activated arenes under the aforesaid experimental conditions. The aim of this work is thus the extension of the scope of our former iodination methods to other substrates, i.e. to a number of activated arenes or heteroarenes (Table 1), all less active than arylamines in their electrophilic substitution reactions.
It is necessary to strongly emphasize that our former paper [5], published in 2002, was the first one in the literature to report that oxidative iodination of arenes (viz. highly activated arylamines) was notably accelerated by microwave irradiation. In 2003 Italian chemists [7] reported the direct microwave-assisted iodination of several pyrimidinones and pyrimidine nucleosides mixed with N-iodosuccinimide and DMF to give the corresponding 5-iodo derivatives in high yields; the samples were irradiated for 3 minutes in a microwave oven at 200 W, whereas the same yields were obtained under thermal conditions for 360 minutes at 70 °C. Application of this microwave-assisted reaction to polymer-bound pyrimidinones was also investigated there. In 2004 Bogdal and co-workers [8] reported the effective application of microwave irradiation to the oxidative chlorination, bromination, and iodination of carbazole and several aromatic compounds, in the presence of hydrogen peroxidehydrohalic acids (water solutions of HCl, HBr or HI) system.

Results and Discussion
It is known from the literature [9,10]  EtOH/H + Thus, H 5 IO 6 and finely powdered diiodine were suspended, with stirring, in a suitable volume of 95% ethanol. Next, a chosen arene or heteroarene, ArH, was added, and such composite reaction mixtures were further reacted in two different ways as follows: a) by conventional heating: the vigorously stirred reaction mixtures were heated under a reflux condenser at 60 °C for 30-60 minutes (Table 1); b) by focused monomode microwave irradiation under an externally attached reflux condenser and with stirring: the reaction mixtures were placed into the microwave cavity and were then irradiated for 1-10 minutes (Table 1); an appropriate power output was used to secure mild, uninterrupted reflux of the solvent.
After completing the reactions (which were monitored by TLC), the cooled reaction mixtures were poured into a vigorously stirred excess of aq. Na 2 SO 3 solution (a reductant used to destroy any unreacted diiodine and all possible oxidized species). The liquid suspensions were extracted with CHCl 3 , the organic layers were dried over anhydrous MgSO 4 , filtered, the solvent was distilled off and the oily residues were fractionated under vacuum to obtain the purified liquid products. The precipitated crude solid products were collected by filtration, washed well with cold water, air-dried in the dark, and recrystallized from appropriate organic solvents to give the purified solid products. The purities and homogeneities of the purified products were first checked by TLC, then their 1 H-and 13 C-NMR spectra (not shown here) were compared with those of authentic specimens [12]. Fairly sharp melting points (uncorrected) were very close to those reported in the literature [13], as well as correct microanalyses (I ± 0.4%) which further confirmed the chemical structures of the purified iodinated products.
Only the purified 4-iodotoluene obtained from toluene, the 4-iodo-1,2-dimethylbenzene obtained from o-xylene, and the 2-iodoimidazole obtained from imidazole were admixed with ca. 5-8% of their isomeric monoiodinated side products, as revealed by TLC and the NMR spectra; these byproducts could not be removed by simple repeated recrystallizations or by repeated fractionations under vacuum. Such isomeric mixtures can be resolved only by chromatographic techniques or by tedious fractional crystallizations from appropriate solvents [14].
From Table 1 it is seen that the microwave assisted iodination reactions afforded 44-91% yields, whereas conventionally heated ones also gave 41-92% yields, but the former ones were always notably accelerated as compared with the "classical" ones (Table 1), hence it is worthwhile to apply microwaves for the enhancement of some oxidative aromatic iodination reactions. However, we have established that for the iodination reactions carried out in very strongly polar and acidic media, e.g. in anhydrous AcOH/Ac 2 O/concd H 2 SO 4 solutions [10] or in 90% (v/v) sulfuric acid [15], the strict temperature control during the irradiation by microwaves is hardly possible, due to the easy overheating of such reaction mixtures, which very often ends up in overboiling.

General
The melting points for the freshly recrystallized and microanalyzed (%I) iodinated products are uncorrected (Table 1). All reagents were commercial (Aldrich), only 95% ethanol was produced in Poland. Elemental microanalyses (%I) were performed at the Institute of Organic Chemistry, Polish Academy of Sciences in Warsaw, while 1 H-and 13 C-NMR spectra (not given here) were recorded at r.t. with a Brucker AVANCE DMX 400 MHz spectrometr, and next they were compared with the same spectra of authentic specimens [12]. Our microwave experiments were performed with a microwave oven (at 2450 MHz) purchased from "Plazmatronika" (Wroclaw, Poland), described in detail in our former papers [5,6]; Our present iodination experiments were carried out with a focused monomode MW irradiation.

Conventionally Heated Iodination Reactions
H 5 IO 6 (1.43 g, 6.25 mmol; 25% excess), finely powdered I 2 (3.81 g, 15.0 mmol; 0% excess), and then an appropriate arene (35.0 mmol; 0% excess) [for the diiodination of thiophene 17.5 mmol, 0% excess] were suspended in 95% ethanol (15 mL). The reaction mixtures were stirred and heated under a reflux condenser at ca. 60 °C for 30-60 min ( Table 1). The cooled reaction mixtures were quenched by pouring them into stirred ice-water (100 g) containing prior dissolved Na 2 SO 3 (5 g). The oily crude iodinated products were extracted with CHCl 3 (3 x 20 mL), the collected extracts were dried over anh. MgSO 4 , filtered, the solvent was distilled off, and the oily residues were fractionated under vacuum to give the purified liquid products ( Table 1). The solid crude products were collected by filtration, washed well with cold water, dried preliminarily by the suction, and next air-dried in the dark. They were recrystallized from appropriate organic solvents to give the purified solid products (Table 1).

Microwave-Accelerated Iodination Reactions
The same as above amounts of H 5 IO 6 , I 2 , and the appropriate arene were suspended in 95% ethanol (25 mL). The reaction mixtures were put into the microwave cavity, and the magnetic stirrer was switched on. An appropriate power output was applied (50%, 500 W) to secure a slight, uninterrupted boil of the solvent under a reflux condenser attached outside. After a definite time (1-10 min, see the Table 1), the reaction mixtures were cooled to r.t., and then they were poured, as above, into stirred ice-water (100 g) containing Na 2 SO 3 (5 g). The following workups and purification of the oily or solid crude products were quite the same as above. For the final results thus obtained see the Table 1.