Microwave-Accelerated or Conventionally Heated Iodination Reactions of Some Aromatic Amines, Using ortho-Periodic Acid as the Oxidant

Maciej Sosnowski, Lech Skulski* and Katarzyna Wolowik

Chair and Laboratory of Organic Chemistry, Faculty of Pharmacy, Medical University, PL 02-097 Warsaw, Poland, 1 Banacha Street

Abstract: A fast and simple method for the oxidative iodination of some aromatic amines, either under microwave irradiation or heated conventionally, is reported, using diiodine and ortho-periodic acid as the oxidant. The reactions were carried out in boiling CH₂Cl₂ solutions under a reflux condenser. For the microwave assisted reactions, their reaction times were always notably shorthened, but their yields were usually less influenced as compared with the conventional method.

Introduction

The development of the microwave technology in organic chemistry since the mid-1980s is mostly due to the increased availability of various commercial equipments and to an increased interest in shorter reaction times and expanded reaction ranges. A number of reflux systems have been developed in an affort 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] – just with such reflux system, the microwave enhaced reactions have been carried out in our laboratory during the last two years. We have always carried out the same, or nearly the same, conventionally heated reactions in order to compare the results afforded by the two different experimental techniques (vide infra).

Previously [5], we devised a novel (conventional) method for the oxidative iodination of several aromatic amines, carrying out the reactions in neat ethyl acetate (at room temperature within 30 minutes, next at 45 ºC for 2-3 hours), with the use of a urea-hydrogen peroxide stable complex (UHP) as the effective, safe, and commercially available oxidant; we reported 41-92% yields for the purified monoiodinated products. Later [6], we attempted to accelerate the aforementioned reactions with multimode microwave irradiation, under a reflux condenser attached outside. We however established that better results were attained by changing ethyl acetate (b.p. 77 ºC) to chloroform (b.p. 61 ºC) used as the solvent of choice. The reactions were complete after ca. 10 minutes. The isolated monoiodinated products were recrystallized to afford 40-80 % yields. It should be emphasized that our former paper [6] did report for the first time the use of microwave irradiation to enhance the oxidative iodination reactions of aromatics (exemplified there by reactive arylamines). At the end of our paper [6] we added the following remark: ”The results would probably be better with the use of focused monomode microwave irradiation”. Fortunately, in the present work we have already been able to use the focused monomode microwave irradiation to enhance our novel oxidative aromatic iodination reactions reported below.

Results and Discussion

In the present work we have decided to carry out the oxidative iodination reactions of several highly activated arylamines (Table), but with using ortho-periodic acid, H₅IO₆, as the oxidant. From preliminary experiments we had established that a most suitable solvent for the attempted reactions was neat dichloromethane (b.p. 42 ºC), much better than acetonitrile and carbon tetrachloride. We also had established that the following reaction stoichiometry was a most effective, which strongly favor the preponderant formation of transient iodine(I) species in the reaction mixtures, viz.

Thus, H₅IO₆ and powdered diiodine were suspended, with stirring, in a proper volume of CH₂Cl₂. Next, an appriopriate arylamine, ArH, was added, and such composite reaction mixtures were further reacted in two ways as follows:

a)    by conventional heating: the vigorously stirred reaction mixtures were gently boiled under a reflux condenser for 10-210 minutes (Table);

b)   by focused monomode microwave irradiation, under an externally attached reflux condenser and with stirring: the reaction mixtures were put into the microwave cavity and were irradiated for 2-20 minutes (Table); an appropriate power output (50%, 500W) was used to secure a slight, uninterrupted boil of the solvent.

After completing the reactions carried out in the two different ways (which was monitored by TLC), the cooled reaction mixtures were poured into a vigorously stirred excess of aqueous Na₂SO₃ solution (a reductor, used to destroy any unreacted diiodine and all possible oxidized species). The organic layers were separated, dried over anhydrous Na₂SO₄, the solvent was distilled off, and the solidified residues were recrystallized from appropriate organic solvents (see Experimental) to produce pure monoiodinated arylamines, ArI, in 8-79% yields (Table). The purities and homogeneities of the purified products were checked by TLC, ¹H and ¹³C NMR spectra, and satisfactory microanalyses (%I). The (uncorrected) melting points were very close to those reported in the literature (Table), which confirmed the chemical structures.  

From the Table it is seen that the microwave assisted iodination reactions afforded 11-79% yields for the purified products, whereas those heated conventionally gave 8-79% yields. But there is one evident advantage of the microwave-enhanced iodination reactions: they were always notably accelerated by microwave irradiation. Hence, the present results (Table) do confirm our former conclusions [6] that it is worth to apply microwave irradiation for the enhancement of, at least some, oxidative aromatic iodination reactions. Further studies are in progress to considerably extend our possessed until now experimental material.

Experimental

General

The melting points for the freshly recrystallized and microanalyzed (%I) monoiodinated amines were uncorrected (Table). All the reagents and solvents were commercial (Fluka, Riedel de Haën), and were used without purification. Elemental microanalyses were performed at the Analytical Laboratory, Institute of Organic Chemistry, Polish Academy of Sciences in Warsaw, Poland. The ¹H and ¹³C NMR spectra (not shown here) were recorded at r.t. with a Brucker 400 MHz spectrometer in CDCl₃ solutions, using TMS as an internal standard.

Our microwave experiments were performed using a microwave oven purchased from „Plazmatronika” (Wroclaw, Poland); it was described in detail in our former paper [6]. Few months ago the producer supplied us with the additional attachment, which allows to perform the experiments with focused monomode microwave irradiation at 2450 MHz, as well as with cylindrical glass vessels, each of a 50 mL volume.

Microwave-Accelerated Iodination Reactions

H₅IO₆ (0.63 g, 2.75 mmol; 10% excess) and finely powdered diiodine (1.9 g, 7.5 mmol; 0% excess) were suspended with stirring in CH₂Cl₂ (25 mL). Then, 19.25 mmol (10% excess) of an appropriate arylamine, ArH, was added, the reaction mixtures were put into the microwave cavity, and the magnetic stirrer was switched on. An appropriate power output was applied (50%, 500W) to secure a slight, uninterrupted boil of the solvent. For all mentioned reactions the power output was the same, while the reactions temperatures were as high as CH₂Cl₂ boils (40-41 ºC). After a definite time (2-20 min; see the Table), the reaction mixtures were cooled to r.t. Next, they were poured into a vigorously stirred aq. Na₂SO₃ solution (2 g Na₂SO₃ in 100 mL of water). The organic layers were separated, dried over anh. Na₂SO₄, filtered, and the solvent was distilled off. The residues were cooled to solidify (if they were still oily, they were cooled externally in an ice-water bath), and next they were mostly recrystallized from hexane; only 4-IC₆H₄NMe₂ and 4-IC₆H₄NEt₂ were recrystallized from EtOH, while 4-Br-2-I C₆H₃NH₂ was recrystallized from diethyl ether. The final yields are given in the Table, where they are compared with those obtained with the conventional heating (vide supra); the yields were calculated on the basis of the quantity of diiodine used in a strictly stoichiometric amount (0% excess).

The ¹H and ¹³C NMR spectra as well as TLC of the freshly recrystallized and analyzed products evidenced that the starting arylamines with their free para positions were mostly monoiodinated para in respect to their amino groups, with at least (if any at all) trace amounts of their ortho substitution. Only in the purified 3-Cl-4-IC₆H₃NH₂ two isomers were evidently identified (para : ortho 9 : 1). Of course, 4-bromoaniline was monoiodinated ortho to its amino group.

Table. Melting points (uncorrected) and final yields for the purified monoiodinated aromatic amines ^a)

a) Satisfactory microanalyses obtained for the purified products: I ±0.3%

b) Probably a new compound. For C₈H₁₀IN calcd C, 39.02; H, 4.07; I, 50.96%. Found: C, 39.0; H, 4.2; I, 50.9%.

c) Admixtured with ca. 10% of its ortho isomer (established from ¹H and ¹³C NMR spectra).

References

1.      a) Microwave-Enhanced Chemistry Fundamentals, Sample Preparation and Applications. Kingston, H. M.; Haswell, S. J., Eds.; American Chemical Society: Washington, D. C., 1997; b) Microwaves in Organic Synthesis; Loupy, A.; Ed.; Wiley-VCH: Weinheim, 2002; c) Microwave Synthesis; Chemistry at the Speed of Light; Hayes, B. L., Ed.; CEM Publishing, Matthews, NC, 2002.

2.      Perreux, L.; Loupy, A. A tentative realization of microwave effects in organic synthesis according to the reaction medium, and mechanistic consideration. Tetrahedron 2001, 57, 9199-9223. A review.

3.      Lindstroem, P.; Tierney, J.; Whathey, B.; Westman, J. Microwave assisted organic synthesis – a review. Tetrahedron, 2001, 57, 9225-9283.

4.      Fini, A.; Breccia, A. Chemistry by Microwaves., Pure Appl. Chem. 1999, 71, 573-579. A review.

5.      Lulinski, P.; Kryska, A.; Skulski, L. results communicated at the International Symposium on Frontiers in Molecular Science 2002, July 14-18, Qingdao, China; see Proceedings, p. 23. The extended work is just completed for its publishing.

6.      Sosnowski L.; Skulski, L. Molecules 2002, 7 (12), 867-880. Avail. at URL: http://www.mdpi.org/molecules/papers/71200867.pdf 

7.      Dictionary of Organic Compounds. 6^th ed.; Chapman & Hall: London, 1996.