Derivatives of 2-iodoxybenzenesulfonic acid: new pseudocyclic hypervalent iodine reagents

Amides and esters of 2-iodoxybenzenesulfonic acid were prepared by dimethyldioxirane oxidation of the respective monovalent iodine derivatives and isolated as stable, microcrystalline compounds. These new hypervalent iodine reagents with a pseudobenziodoxole structure are efficient oxidizers of alcohols, secondary amines and sulfides.


Introduction
In the past decade the hypervalent heterocyclic iodine reagents have emerged as reagents of choice for various synthetically useful transformations. 1 In particular, the heterocyclic λ 5 -iodane 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX, 1), has received a widespread application in organic synthesis as a highly efficient and mild oxidant that can be used for a selective oxidation of primary and secondary alcohols, selective oxidations of secondary amines and for a variety of other important oxidations. 1,2However, despite its useful oxidizing properties, practical application of IBX is restricted due to the potentially explosive nature and the extremely low solubility of this reagent.Several research groups have tried to improve IBX by structurally modifying it, 3,4 or by developing polymer supported analogs. 5Recently, we reported the synthesis of IBX-amides (2) 4a and IBX-esters (3), 4b which are stable and soluble reagents having oxidizing properties similar to IBX.

Figure 1
According to X-ray data, these new reagents (2 and 3) have the pseudobenziodoxole structure due to the intramolecular secondary bonding between iodine and carboxylic oxygen.In comparison with IBX and other benziodoxoles, pseudobenziodoxoles have much better solubility, which is explained by a partial disruption of their polymeric nature due to the redirection of I•••O secondary bonding. 4Very recently, Lee and co-workers reported the preparation of the polymer supported IBX-esters and IBX-amides, which showed excellent oxidative activity toward benzylic alcohols. 6e now report the preparation and reactivity of amides 7 and esters of 2iodoxybenzenesulfonic acid, which represent a new class of pseudocyclic hypervalent iodine reagents.These novel pseudobenziodoxoles are efficient oxidizers of alcohols, secondary amines and sulfides.

Results and Discussion
The starting materials for the preparation of 2-iodoxybenzenesulfonamides 5, were obtained from 2-iodobenzenesulfonyl chloride 4 and the appropriate amino compounds, 8 such as esters of natural amino acids (5a-d) or (R)-1-phenylethylamine (5e) (Scheme 1).The starting esters of 2-iodobenzenesulfonic acid 6 were prepared by a known method from the corresponding alcohols and 2-iodobenzenesulfonyl chloride 9 (Scheme 2).The dimethyldioxirane oxidation of iodoarenes 5 and 6 afforded the respective iodylarenes (7 and 8) in good yields (Scheme 3).All products were isolated by filtration of the reaction mixture in the form of stable, white, microcrystalline solids.In the case of esters of 2iodobenzenesulfonic acid 5 the procedure of oxidation was slightly modified: dimethyldioxirane was used in methylene chloride solution instead of acetone.

Scheme 3
Products 7 and 8 were identified on the basis of spectroscopic data and elemental analysis.In particular, IR spectra of all compounds showed a sulfonyl absorption at 1330-1340 cm -1 , the I=O absorption at 740-780 cm -1 , as well as the carbonyl stretch at 1720-1740 cm -1 for the amino acid derivatives 7a-d.In 1 H NMR spectra, the signals corresponding to the aromatic ring and the fragment R of the molecule were observed.In addition, the N-H protons in 2iodoxybenzenesulfonamides 7 were observed as characteristic doublets at 8.40-8.60 ppm.In 13 C NMR of iodoxyarenes 7 and 8, the most characteristic was the signal of C-IO 2 at 146 ppm.The ESI-HRMS spectra of compounds 7 and 8 demonstrated strong [M+Na] + peaks as well as weaker peaks corresponding to the dimers [2M+Na] + and the trimers [3M+Na] + .
Based on our previous X-ray studies 4 and on the literature data 10 we assume that compounds 7 and 8 have planar pseudocyclic structure with strong intramolecular interaction between hypervalent iodine center and the oxygen atom in the ortho-substituent.Several X-ray molecular structures of pseudobenziodoxoles were reported in the literature, 4,10 including the 2-sulfonyl substituted iodylarene.10a However, in contrast to the previously reported pseudobenziodoxoles 2 and 3, 4 compounds 7 and 8 have a relatively low solubility in non-polar organic solvents such as chloroform and methylene chloride.Moreover, the presence of 2M + and 3M + peaks in the ESI-MS data indicates the oligomeric or polymeric structure of these compounds.A similar oligomeric assembly directed by a relatively weak intermolecular I•••O secondary bonding was previously reported for IBX-amides 2 and IBX-esters 3. 4 Preliminary experiments demonstrate that 2-iodoxybenzenesulfonamides 7 show aspects of reactivity similar to previously reported IBX-amides 2. In particular, reagents 7a-e can cleanly oxidize benzyl alcohol to benzaldehyde in chloroform at 50 °C (Table 1).Reagent 7e shows the highest reactivity in this reaction and 7a the lowest reactivity, which is probably explained by the lowest solubility of 7a in chloroform.The oxidation of benzyl alcohol by reagents 7 in DMSO (Entries 2, 4, 6, 8, 10) under similar conditions afforded benzaldehyde with a very low conversion (0-7%) (Table 1).The low reactivity towards alcohols in DMSO can be explained by the formation of a stable complex of iodoxyarene 7 with a molecule of DMSO, which leads to a lower electrophilicity of the iodine reagent. 11ulfonate esters 8 were found to be completely nonreactive in the oxidation of alcohols.This is similar to the reactivity of IBX-esters 3 which can oxidize alcohols only in the presence of trifluoroacetic acid.4b However, the esters 8 were found useful toward oxidation of other organic functional groups, such as sulfides and secondary amines (Scheme 4).In particular, the oxidation of a secondary amine with reagent 8a proceeds at room temperature in dichloromethane with the formation of the respective imine 9 in good yield.Likewise, the reaction of organic sulfides with reagent 8a in refluxing acetonitrile leads to the formation of sulfoxides 10 without overoxidation to sulfones.

Scheme 4
In conclusion, we have reported the preparation of new pseudobenziodoxole-based pentavalent iodine compounds, amides and esters of 2-iodoxybenzenesulfonic acid.These compounds are potentially useful reagents for mild oxidation of alcohols, sulfides and secondary amines.

Experimental Section
General Procedures.All melting points were determined in an open capillary tube with a Meltemp II ® melting point apparatus and are uncorrected.Infrared spectra were recorded neat, as a CCl 4 mull, or as a KBr pellet on a Perkin-Elmer 1600 series FT-IR spectrophotometer.NMR spectra were recorded on a Varian UNITY INOVA 300 MHz NMR spectrometer at 300 MHz ( 1 H NMR), and 75 MHz ( 13 C NMR).Chemical shifts are reported in parts per million (ppm). 1 H chemical shifts are referenced relative to the residual nondeuteriated solvent of chloroform at δ 7.24.The 13 C chemical shifts are referenced relative to CDCl 3 at δ 77.0.Mass-spectra were obtained with a Bruker Biotof II instrument.Microanalyses were carried out by Atlantic Microlab, Inc., Norcross, Georgia.All commercial reagents were ACS reagent grade and used without further purification.Methylene chloride was distilled from CaH 2 immediately prior to use.All other reagents and solvents were of commercial quality from freshly opened containers.2-Iodobenzenesulfonyl chloride was prepared by a known method. 8Dimethyldioxirane was prepared from commercial acetone and OXONE (Aldrich) by a known method. 12Reaction flasks were oven-dried at 200 ˚C, flame-dried and flushed with dry nitrogen prior to use.

General procedures for preparation of amides of 2-iodobenzenesulfonic acid
To a stirred, ice-bath cooled mixture of L-amino acid methyl ester hydrochloride (4.0 mmol) in CH 2 Cl 2 (40 mL), triethylamine (8.0 mmol, 1.11 m1) and 2-iodobenzenesulfonyl chloride (1.51 g, 5.0 mmol) were slowly added.After two hours of additional stirring, water (40 mL) was added and organic layer was separated.The organic layer was washed with 10% HCl (1 x 20 m1).The solution was dried with MgSO 4 and the solvent evaporated to give a yellow solid.Recrystallization from ethyl acetate/hexane (in case of 5b and 5e) or column chromatography (in case of 5a, 5c and 5d, ethyl acetate/hexane 1:2 as eluent) and drying in vacuum resulted in the compounds 5. Preparation of esters of 2-iodobenzenesulfonic acid.Esters of 2-iodobenzenesulfonic acid 6 were prepared by a known method without any modifications. 9 General procedure for oxidation of amides of 2-iodobenzenesulfonic acid Freshly prepared 0.1 M solution of dimethyldioxirane in acetone (30 mL, 3 mmol) was added to a stirred mixture of the appropriate amino acid derivative 5 (1 mmol) in 5 mL of dry CH 2 Cl 2 at 0 o C. The color of the solution immediately changed from colorless to light yellow.The reaction mixture was stirred at room temperature for 8 hours and the resulting white microcrystalline precipitate was separated by filtration; then hexane was added to the filtered solution and the additional precipitate was filtered.Both precipitates were collected, washed with ether and dried in vacuum to afford analytically pure 7.

General procedure for oxidation of esters of 2-iodobenzenesulfonic acid
Freshly prepared dimethyldioxirane was extracted with methylene chloride according to the known procedure. 13The solution of dimethyldioxirane in methylene chloride (13 mL, 0.36 M) was added to the stirred mixture of ester 6 (1 mmol) in 5 mL of methylene chloride at 0 °C.The reaction mixture was stirred at room temperature for additional 8 hours, then the resulting white precipitate was collected by filtration, washed with ether and methylene chloride, and dried in vacuum to afford analytically pure sample of 8.

General procedure for oxidation of alcohols (Method A)
To the suspension of reagent 7 (20 mg) in 2 mL of d-chloroform in an NMR tube, the equivalent amount of benzyl alcohol was added.The reaction mixture was heated up to 22 hours at 50 °C.NMR spectra were recorded every 3 hours.The conversion of the benzyl alcohol was calculated from the relative integral intensity of the peaks at 10.06 ppm (benzaldehyde) and 4.70 ppm (benzyl alcohol).(Method B) To the solution of reagent 7 (20 mg) in 2 mL of DMSOd 6 in NMR tube, the equivalent amount of benzyl alcohol was added.The reaction mixture was heated up to 14 hours at 50 °C.NMR spectra were recorded every 3 hours.The conversion of the benzyl alcohol was calculated from the relative integral intensity of peaks at 10.06 ppm (benzaldehyde) and 4.70 ppm (benzyl alcohol).

General procedure for oxidation of sulfides
To a vigorously stirred suspension of ester 8a (0.15 mmol, 50 mg) in 5 mL of acetonitrile, the appropriate sulfide was added (0.25 mmol).The reaction mixture was stirred under reflux for approximately 1 hr, until the TLC showed consumption of the starting sulfide.Then the reaction ISSN 1424-6376 Page 14 © ARKAT USA, Inc mixture was concentrated on a rotary evaporator and separated by column chromatography (ethyl acetate/hexanes 1:2) to yield the final product.

Typical procedure for oxidation of amines
To a vigorously stirred suspension of ester 8a (0.15 mmol, 50 mg) in 5 mL of methylene chloride, methyl benzyl amine was added (0.3 mmol).The reaction mixture was stirred until the mixture became clear, and TLC showed consumption of the starting amine.Then the reaction mixture was concentrated on a rotary evaporator and separated by column chromatography (ethyl acetate/hexanes 1:2) to yield the final product 9 (65% yield), which was identical to the authentic commercial sample (from Aldrich) according to GC and NMR.

Table 1 .
Oxidation of benzyl alcohol with reagents 7 a,b a All reactions were conducted at 50 o C. b Benzaldehyde and the respective iodoarene 5 were the only reaction products detected by GC and NMR.c The ratio of PhCH 2 OH to reagent 6 was 1:1.d Determined by 1 H NMR.