Novel Easy Preparations of Some Aromatic Iodine(I, III, and V) Reagents, Widely Applied in Modern Organic Synthesis

We report our novel (or considerably improved) methods for the synthesis of aromatic iodides, (dichloroiodo)arenes, (diacetoxyiodo)arenes, [bis(trifluoroacetoxy)-iodo]arenes, iodylarenes and diaryliodonium salts, as well as some facile, oxidative anion metatheses in crude diaryliodonium or tetraalkylammonium halides and, for comparison, potassium halides. All our formerly published papers were discussed and explained in our review “Organic Iodine(I, III, and V) Chemistry: 10 Years of Development at the Medical University of Warsaw, Poland” (1990-2000) [1]. Our newest results are discussed below.


Introduction
Aromatic iodides, ArI, are generally more reactive, though also more costly, than the respective bromides and chlorides. There are a considerable number of different methods, both direct and indirect, for their synthesis [2], and they are widely used in chemical laboratories and, to a lesser extent, in chemical industry. Moreover, ArI are able to form a large variety of aromatic hypervalent iodine derivatives, which found quickly increasing applications in modern organic synthesis [3].
In 1990 we decided that nearly all future research in our organic laboratory should be directed towards the title topics. We have placed special emphasis on the development of novel, easy and effective oxidative iodination procedures, applicable for both activated and deactivated aromatics, ArH, and the resulting aryl/heteroaryl iodides, ArI, were often next applied in our subsequent novel (or improved) syntheses of the corresponding aromatic hypervalent iodine derivatives, mainly: (dichloroiodo)arenes, ArICl 2 , (diacetoxyiodo)arenes, ArI(OAc) 2 , [ bis(trifluoroacetoxy)iodo]arenes, ArI(OCOCF3)2, iodylarenes, ArIO2, and various diaryliodonium salts, Ar2I + Xor Ar(Ar')I + X -.

Syntheses of Aromatic Iodides
Since 1980 we have indirectly synthesized (in excellent yields) a number of heteroaromatic iodides from both symmetric and unsymmetric heteroaromatic mercurials, by applying the "classic" iododemercuration procedures. This topic is related in our newest review "Some Heteroaromatic Organomercurials, Their Syntheses and Reactions: A Review of Our Research (1980 -2000)" ( [4], pp 949-950); alternatively see [1] p 1333.
In the beginning, we oxidatively monoiodinated several highly activated arenes or heteroarenes using pure Pb(OAc) 4 as the oxidant in glacial AcOH at room temperature within 0.5 -12 hours. With hot Pb(OAc) 4 solutions prepared in situ from commercial minium, Pb 3 O 4 , the iodination yields were often somewhat better than those obtained with the pure oxidant ([1], p 1333). Later, several activated aromatics were effectively mono-, di-, or even triiodinated at or near room temperature and within at most 1 5 minutes, with PhI(OAc)2 in anhydrous AcOH/Ac2O mixtures acidified with catalytic quantities of conc. H 2 SO 4 ([1], p 1343). In the both cases, some transient iodine(I) species, briefly denoted as I + , were the effective iodinating agents. In our next series of publications ( [1], pp 1334-1345) we oxidatively iodinated/diiodinated a number of activated or deactivated aromatics (mostly arenes, ArH) with transient either iodine(I) species, I + , or iodine(III) species, I 3+ , always in anhydrous AcOH/Ac 2 O/conc. H 2 SO 4 mixtures. So far we have used the following oxidants for this purpose: CrO 3 , KMnO 4 , activated MnO 2 , NaIO 4 or NaIO 3 , a stable urea-H 2 O 2 addition compound [1], sodium percarbonate [5], or sodium perborate [5]. In order to generate in the iodinating mixtures either I + (appropriate to iodinate benzene, halobenzenes, and activated arenes) or more electrophilic I 3+ transient species (appropriate to iodinate halobenzenes and deactivated arenes), we deliberately changed the proportions of the reactants and, consequently, the iodination reaction mechanisms. For example, when CrO 3 was used as the oxidant, the following proportions of the reactants were used to generate either I + or I 3+ preponderant transient species in the anhydrous mixtures acidified with varied quantities of conc. H 2 SO 4 (a catalyst): 3 I2 + 2 Cr(VI) → 6 I + + 2 Cr(III) I 2 + 2 Cr(VI) → 2 I 3+ + 2 Cr(III) Next, the following reactions took place in the iodinating mixtures: After pouring the final reaction mixtures into excess aq. Na2SO3 solutions, ArI were isolated in high yields: ArISO4 (not isolated) + Na2SO3 + H2O →ArI + 2 NaHSO4 Our novel eco-friendly method for the iodination of both activated and deactivated arenes, using a stable urea-H 2 O 2 ( UHP) addition compound as the oxidant, was earlier briefly explained in [1], p. 1345. Full details were disclosed at the International Symposium on Frontiers in Molecular Science 2002, July 14-18, Qingdao (China), and will be published elsewhere soon. Several examples of the oxidative iodination of some arylamines, accelerated with multimode microwave irradiation, using UHP as the oxidant, have just been published in [6].

Syntheses of (Dichloroiodo)arenes
Yellow crystalline (dichloroiodo)arenes, ArICl 2 , known since 1885, have found growing importance in organic synthesis as potent, safe and fairly selective chlorinating and/or oxidizing agents. They may also be readily converted to other important hypervalent iodine reagents, viz. ArIF 2 , ArI(OAc)2, ArIO, ArIO2, diaryliodonium salts, etc. [1,3]. They are light-and heat-sensitive and often unstable to storage, hence they are usually used immediately after their preparation. Up to now the most common method for preparing ArICl 2 depends on passing the stream of Cl 2 through cold solutions of ArI in chlorinated solvents. To avoid the hazardous use of gaseous Cl 2 to prepare ArIC l 2 from ArI, a large number of various either two-phase (CCl 4 /conc. aq. HCl) or monophasic liquidphase methods were reported; the full account of those methods (including the nove l ones developed in our laboratory) is given in [1], Section 3. Cl 2 was generated there in situ from conc. hydrochloric acid, used either as a separate phase or as cosolvent, under the action of various oxidants: 2 HCl + [O] → C l 2 + H 2 O; mostly, such procedures are easy and relatively safe. However, all former methods required the use of iodoarenes, ArI, as the starting substrates, which were then chlorinated at their iodine atoms to afford ArICl2 .
In 2001 we published two papers [7,8], where we reported quite simple, two-or three-stage procedures for the one-pot conversions of various arenes, ArH, to the corresponding ArICl 2 obtained in high crude yields. The starting ArH were, at first, oxidatively iodinated with some iodine(III) transient species, I 3+ , to form the respective aromatic iodine(III) intermediates, ArISO4 (not isolated; cf. Section 1 above). Next, by adding excess conc. hydrochloric acid to the final reaction mixtures, the soluble ArISO 4 were effectively metathesized into the insoluble ArICl 2 [7]. Alternatively [8], the starting more active ArH (benzene, halobenzenes, activated arenes) were, at first, oxidatively iodinated H 2 SO 4 ArISO 4 (aromatic iodine(III) intermediates) -2H + with some iodine(I) transient species, I + , to form the corresponding ArI (not isolated). Next, the second portion of CrO 3 was added, followed by excess conc. hydrochloric acid, which oxidatively chlorinated the ArI intermediates to form the final products, i.e. ArICl 2 . So far, only NaIO 4 and NaIO 3 [7], or CrO 3 [8] have been used by us as the oxidants -but it is possible to apply other oxidants for the same purpose [5]. Our novel eco-friendly method [7] for the effective preparation of crude ArICl 2 from the respective arenes and I 2 avoids the hazardous use of gaseous Cl2 and chlorinated solvents, and the use of costly ArI. Strongly acidic wastes, after their neutralization and dilution, did not contain any toxic by-products. Thus, our novel method [7] would be particularly suitable for large-scale preparations of ArICl2 from arenes. Of course, only those isomeric RC 6H4ICl2 may predominantly be obtained from the monosubstituted benzenes, RC 6 H 5 , which are formed in agreement with common orientation rules in the electrophilic substitutions of the used RC 6 H 5 by the said electrophilic transient species, I 3+ or I + .
[3]. ArI(OAc) 2 are crystalline compounds, which may be stored in the dark, preferably in a cooler. They were previously prepared from ArIO by the action of hot glacial AcOH, from ArICl 2 by the exchange of the chlorine atoms by acetoxy groups, and from ArI by their oxidation in warm AcOH by either NaBO 3 ·4H 2 O, or by peracetic acid, or electrolytically [1, p 1352]. In our laboratory, we primarily applied CrO 3 as the oxidant in AcOH/Ac 2 O/conc. H 2 SO 4 mixtures to transform a number of ArI to ArI(OAc)2 in 58 -82% yields (for the purified compounds); this method is unsuitable for ArI bearing e.g. the OMe and NHAc groups, and is hardly applicable for iodotoluenes [1, p 1353]. For the preparation of pure PhI(OAc) 2 from PhI (in 79% yield) our method is 8 -16 times faster and ca. 5 times less expensive than the method of McKillop and Kemp [9], who used NaBO 3 ·4H 2 O as the oxidant in a large volume of warm glacial AcOH.
In 2001 we published an easy method for preparing ArI(OAc) 2 from ArI substituted with the Me and OMe groups -which nicely complements our former method ( vide supra) [10]. PhI, halogenoiodoarenes, iodotoluenes, and iodoanisoles were refluxed for 2 hours in NaIO4/AcOH/Ac2O/AcONa solutions to give finally the purified ArI(OAc) 2 in 44 -77% yields; this novel method is not applicable, however, for ArI substituted with strong electron-withdrawing groups.
Recently, in our laboratory we have devised an easy and effective method for preparing ArI(OCOCF 3 ) 2 directly from ArI, using a sodium percarbonate/(CF 3 CO) 2 O/CH 2 Cl 2 anhydrous system to afford high yields of the nearly pure products, ArI(OCOCF 3 ) 2 (98-99% purity by iodometry). After completing the reactions, the precipitated CF 3 CO 2 Na was filtered off, the filtrates were concentrated, the residues were triturated with hexane, washed with hexane on the filter, and quickly air-dried by the suction. For example, the nearly pure (98-99%) Ph(OCOCF 3 ) 2 was repeatedly prepared from PhI in 87% crude yield; details of this novel method have just been published in [11]. Similarly, we have just published in [12] our novel method for preparing the nearly pure (96-99%) ArI(OAc)2 from ArI, using a sodium percarbonate /AcOH/Ac 2 O/CH 2 Cl 2 anhydrous system. As an example, the PhI(OAc) 2 thus prepared in 79% crude yield, was 99% pure (by iodometry).

Syntheses of Iodylarenes
Some iodylarenes, ArIO2, are nowadays used as versatile selective oxidants. There are plenty of different methods for their preparation from ArI, ArICl 2 , or ArIO [1, p 1355]. They are rather stable thermally, but their melting points are often accompanied by explosions, and their violent decomposition may be induced, e.g. by scraping them with a spatula or upon impact [3].
In 2001 we reported an easy, safe and effective method for preparing a number of various ArIO 2 from the corresponding ArI, using NaIO 4 as the oxidant [10]. ArI were vigorously stirred and refluxed for 8 -16 hours with aq. solutions of NaIO 4 to give the respective ArIO 2 in 58 -91% crude yields. Iodometric titrations showed that the crude ArIO 2 thus obtained were 98 -99% pure; after their recrystallization from boiling water we obtained a nalytically pure specimens. When sodium salts of 2iodo-and 4-iodobenzoic acids (prepared in situ) were stirred and boiled with aq. NaIO 4 solutions, then this resulted in the formation and next isolation of "2 -iodylbenzoic acid" (i.e. 1 -hydroxy-1,2benzio doxol-3(1H)-one 1 -oxide, IBX) or 4 -iodylbenzoic acid in 71% or 88% crude yields, respectively; iodimetric titrations showed that they also were 98-99% pure. We tried, in vain, to accelerate these reactions with microwave irradiation. Finally, we have shortened the reaction times to 3 -6 hours, by the use of a dilute aq. AcOH (30% by vol.) as the solvent of choice, instead of neat water, with preserving the same good yields and high purities (96-99%) of the crude final products, ArIO 2 . 2-Iodobenzoic acid, after 4 hours of its boiling and stirring with a solution of NaIO 4 in 30% (by vol.) aq. AcOH, gave the nearly pure (98-99%) "2-iodosylbenzoic acid" (i.e. 1 -hydroxy-1,2benziodoxol-3(1H)-one) in 91-93% crude yields; these novel results will be published soon [5].

Syntheses of Diaryliodonium Salts
Solid symmetric and unsymmetric diaryliodonium salts, Ar 2 I + Xand Ar(Ar')I + X -, are widely used in organic synthesis as arylating reagents for various organic and inorganic nucleophiles, and some of them display biological activity and photochemical properties. They are mostly fairly stable towards heat, oxygen and humidity, but should preferably be stored in the dark. A large number of methods are available for their preparation [1,3,13], but many of them are rather costly and/or too complicated. We hope that our two novel methods related below are quite easy, cheap, and fairly effective.
In 1995 we reported [1, p 1358] a one-pot ("short-cut") synthesis of sparingly soluble diaryliodonium bromides and iodides ( obtained in 20 -89% crude yields) from various ArI oxidized firstly with anhydrous CrO 3 /AcOH/Ac 2 O/conc. H 2 SO 4 mixtures, then coupled in situ with benzene and various activated arenes or heteroarenes [1, pp 1358-1360] and, finally, precipitated out with excess aq. KBr or KI solutions. In 2001 we published a similar, albeit more eco-friendly method, using anhydrous NaBO 3 ·H 2 O/Ac 2 O/conc. H 2 SO 4 mixtures [13]. In our latter paper diaryliodonium bromides were obtained in 23 -98% crude yields; no toxic residues are left after the reactions -in a strong contrast to our former method.
In 1999 we also improved considerably the old Willgerodt method (1897), which allows one to obtain various symmetric and unsymmetric diaryliodonium chlorides by reacting hot aqueous suspensions of equal masses of powdered ArIC l 2 with powdered A r 2 Hg; sparingly soluble sideproducts, ArHgCl and ArIO, are hot-filtered off and discarded, whereas diaryliodonium bromides may be precipitated out from the filtrates with excess aq. KBr solutions; for more details see [1, p 1360] or [4, p 952].

Oxidative Anion Metatheses in Diaryliodonium Halides
For the arylation of organic and inorganic nucleophiles with diaryliodonium salts, the best yields are achieved by the use of diaryliodonium salts with substantially non-nucleophilic counterions, viz. tetrafluoroborates, tosylates, triflates, trifluoroacetates, etc.
[3]. In our two earlier papers [1, pp 1362 -1365] we reported numerous examples of oxidative anion metatheses in crude diaryliodonium bromides, iodides, and chlorides (see Section 5 above), which produced the corresponding pure diaryliodonium tetrafluoroborates, tosylates, trifluoroacetates, triflates as well as hydrogensulfates and nitrates, etc. in 54 -86% yields. These new procedures are shorter and less expensive than many earlier methods. They are also applicable to some other ionic halides, e.g. tetraalkylammonium or potassium halides. The starting crude halides were suspended in boiling MeOH acidified with an excess of appropriate strong acid, HX, and then excess 30% aq. H 2 O 2 was added dropwise to oxidize the halide anions (I -> Br -> Cl -; the fluorides do not react) to the respective dihalogens; 100% excess cyclohexene, acting there as a "halogen scavenger", was added there for the metatheses in diaryliodonium bromides and chlorides. For the diaryliodonium iodides, the diiodine evolved was simply washed off from the crude metathesized products with anhydrous Et 2 O. When dry acetone was used as the solvent of choice for the oxidative anion metatheses in crude diaryliodonium bromides and chlorides, the addition of cyclohexene was not necessary _ since the strongly acidified Me 2 CO acts itself as a very efficient "halogen scavenger" [1, p 1363], due to the presence of its very quickly equilibrating and very reactive enol form. The crude metathesized products were recrystallized from appropriate o rganic solvents to afford the analytically pure diaryliodonium salts in the yields given above.