Practical Synthesis of 2-Iodosobenzoic Acid (IBA) without Contamination by Hazardous 2-Iodoxybenzoic Acid (IBX) under Mild Conditions

2.1. Selective Synthesis of IBA and Its Analogs

1a using 1.0 equivalent of Oxone® to obtain IBA 2a as a representative compound, and the results are summarized in 2a in 82% yield (2a was not produced in organic solvent in the absence of water (no reaction because Oxone® was not dissolved) (see entry 1). This result indicates that water plays an essential role in the formation of IBA. Therefore, we assumed that an aqueous system similar to the selective formation of

p

-quinone from alkoxybenzenes catalyzed by 2-IB 1a with Oxone® [2a using Oxone®.

We started our investigation on the selective preparation of IBAs by evaluating the solvent effects on the oxidation of 2-IBusing 1.0 equivalent of Oxoneto obtain IBAas a representative compound, and the results are summarized in Figure 3 . First, the reaction in water led to the successful production of IBAin 82% yield ( Figure 3 , entry 2), whereas IBAwas not produced in organic solvent in the absence of water (no reaction because Oxonewas not dissolved) (see entry 1). This result indicates that water plays an essential role in the formation of IBA. Therefore, we assumed that an aqueous system similar to the selective formation of-quinone from alkoxybenzenes catalyzed by 2-IBwith Oxone 94 ] could be suitable for the present reaction. We then investigated in detail the effect of a series of organic solvents on the aqueous preparation of IBAusing Oxone

1a in this reaction. The preparation of IBA 2a using acetonitrile (MeCN) in aqueous condition (

N

,

N

-dimethylformamide (DMF) were also examined, finding that the use of highly polar dioxane and DMF led to excellent yields of IBA 2a (2a in high yields; however, they also worked as a ligand for IBA, causing the formation of very small amounts of ligand-exchanged byproducts 3a–c (2a obtained after the water and acetone washings did not contain any other byproducts. Although this result indicated that protic organic solvents were not suitable for the selective preparation of IBAs, it also revealed that the IBA hydroxyl group could undergo substitution reactions under mild conditions (vide infra). The yields indicated in 1a.

Various water-miscible organic solvents were investigated to dissolve 2-IBin this reaction. The preparation of IBAusing acetonitrile (MeCN) in aqueous condition ( Figure 3 , entry 3) was similar to that performed in the absence of organic solvents ( Figure 3 , entry 2). Tetrahydrofuran (THF), dioxane, benzene and-dimethylformamide (DMF) were also examined, finding that the use of highly polar dioxane and DMF led to excellent yields of IBA Figure 3 , entries 5 and 7), whereas benzene, the least polar solvent among these aprotic solvents, significantly reduced the yield of the desired product ( Figure 3 , entry 6). The reason for this very low yield IBA formation was interpreted as being due to that benzene forms a two-phase system and interferes with the dissolution of 2-IB into water. Protic solvents such as MeOH, EtOH and 2,2,2-trifuoroethanol (TFE) gave IBAin high yields; however, they also worked as a ligand for IBA, causing the formation of very small amounts of ligand-exchanged byproducts Figure 3 , entries 8–10). The white solid IBAobtained after the water and acetone washings did not contain any other byproducts. Although this result indicated that protic organic solvents were not suitable for the selective preparation of IBAs, it also revealed that the IBA hydroxyl group could undergo substitution reactions under mild conditions (vide infra). The yields indicated in Figure 3 are almost equal to the conversion of 2-IB

® under aqueous conditions with MeCN, and the results are shown in 1. By oxidation of 5-substituted 2-IBs, IBAs 2b–d containing fluoro-, chloro-, and bromo-substituents were smoothly obtained in excellent yields from the corresponding halo-substituted 2-IBs 1b–d. From 2-IBs 1e–j with electron-donating groups such as methyl-, methoxy-, and acethoxy-substituents (1e–g) and electron-withdrawing groups such as trifluoromethyl-, nitro- and cyano-substituents (1h–j), the desired IBAs 2e–j were also produced in good yields. However, 2-IB bearing a hydroxy-substituent 1k afforded the desired product 2k in a moderate yield under the same conditions. In the oxidation of 4-substituted 2-IBs, fluoro-, chloro-, bromo-, trifluoromethyl-, and carboxy-substituted IBAs 2l–p were obtained in excellent yields from the corresponding 2-IBs 1l–p. In addition, the oxidized products of 4,5-disubstituted 2-IBs containing difluoro-substituents 2q and dimethoxy-substituents 2r were obtained in high yields. Meanwhile, with regard to 3-substituted 2-IBs, the reaction of methyl-substituted 1t with a slight excess of Oxone® afforded the expected IBA 2t in a good yield, whereas the yield of bromo-substituted IBA 2s was lower even at the elevated temperature and in the presence of a large excess of Oxone®. Steric effects are probably important in the formation of the cyclic λ3-iodanes. Indeed, the presence of a substituent at the

ortho

position of the iodine atom (3-position) interfered in the synthesis of the corresponding product for 3-bromo-substituted 2-IB 1s. In the case of 6-substituted 2-IBs, fluoro-substituted IBA 2u and methyl-substituted 2v were obtained in good yields. Finally, the reaction of 3-iodonaphthalene-2-carboxylic acid 3 under the present conditions led to the expected tricyclic hypervalent iodine compound 4 in an excellent yield (

Next, we investigated the substrate scope for the synthesis of IBAs using Oxoneunder aqueous conditions with MeCN, and the results are shown in Figure 4 . MeCN was used as a component of the solvent to dissolve substrates. By oxidation of 5-substituted 2-IBs, IBAscontaining fluoro-, chloro-, and bromo-substituents were smoothly obtained in excellent yields from the corresponding halo-substituted 2-IBs. From 2-IBswith electron-donating groups such as methyl-, methoxy-, and acethoxy-substituents () and electron-withdrawing groups such as trifluoromethyl-, nitro- and cyano-substituents (), the desired IBAswere also produced in good yields. However, 2-IB bearing a hydroxy-substituentafforded the desired productin a moderate yield under the same conditions. In the oxidation of 4-substituted 2-IBs, fluoro-, chloro-, bromo-, trifluoromethyl-, and carboxy-substituted IBAswere obtained in excellent yields from the corresponding 2-IBs. In addition, the oxidized products of 4,5-disubstituted 2-IBs containing difluoro-substituentsand dimethoxy-substituentswere obtained in high yields. Meanwhile, with regard to 3-substituted 2-IBs, the reaction of methyl-substitutedwith a slight excess of Oxoneafforded the expected IBAin a good yield, whereas the yield of bromo-substituted IBAwas lower even at the elevated temperature and in the presence of a large excess of Oxone. Steric effects are probably important in the formation of the cyclic λ-iodanes. Indeed, the presence of a substituent at theposition of the iodine atom (3-position) interfered in the synthesis of the corresponding product for 3-bromo-substituted 2-IB. In the case of 6-substituted 2-IBs, fluoro-substituted IBAand methyl-substitutedwere obtained in good yields. Finally, the reaction of 3-iodonaphthalene-2-carboxylic acidunder the present conditions led to the expected tricyclic hypervalent iodine compoundin an excellent yield ( Scheme 1 ).