Thiols were effectively oxidized into disulfides by reacting with hydrogen peroxide in the presence of a catalytic amount of iodide ion or iodine.The controlled oxidative coupling of thiols to disulfides is important in organic synthesis, and a wide range of methods have been developed for this transformation. 1 Thiols are among the functional groups which can be easily over oxidized, therefore, extensive studies have been carried out for their controlled oxidation with molecular oxygen, 2 peroxide, 3 metal oxidants, 4 halogens and derivatives, 5 sulfoxide, 6 and N-oxide. 7 In particular, the methods of oxidative coupling of disulfides with halogens such as I 2 , 5a I 2 /HI, 5b and Br 2 /KHCO 3 5c were carried out under mild reaction conditions, and gave the disulfides in good yields. However, these reactions require a stoichiometric amount of oxidants and long reaction times. Oae and co-workers developed the oxidative coupling of thiols to disulfides by dimethyl sulfoxide in the presence of a catalytic amount of molecular iodine. 5b Although this reaction affords the products in high yield under very mild reaction conditions, there are still some problems such as the requirement of a long reaction time and the production of foulsmelling dimethyl sulfide as a waste product.To develop an environmentally benign oxidative coupling of thiols, we planned to use hydrogen peroxide as a cooxidant for the oxidation of thiols with molecular iodine, because the iodide ion (iodoanion) is easily oxidized to molecular iodine by hydrogen peroxide.Hydrogen peroxide itself can oxidize thiols to the corresponding disulfides; however, alkaline conditions were required. 3a Recently, Bégué et al. reported that disulfides can be efficiently prepared from thiols using 30% hydrogen peroxide in fluoroalcohols at ambient temperature under neutral conditions. 3b Although this method provides the desired compounds in high yields in most cases, fluoroalcohols are expensive for industrial use. Furthermore, the thiols, which are less soluble in the fluoroalcohols, produced the desired disulfides in poor yields. In this paper, we describe a method for the oxidation of thiols 1 to disulfides 2 using 30% hydrogen peroxide catalyzed by iodide ion (Scheme 1). Scheme 1

Intramolecular nonbonded S · · · X (XϭS, O, N, etc.) interactions have been observed in a large number of organosulfur compounds controlling the conformation of small and large molecules. [1][2][3][4][5][6][7][8][9][10][11][12] Some of these compounds showed the strong bioactivity, and we suggested that the intramolecular nonbonded S · · · X interactions play an important role on the mechanism of several biological effects.1,2,6-12) For example, the clear S · · · O close contact in the complex crystalline structure of carbonic anhydrase I and acetazolamide was recognized.12) The same nonbonded interaction was observed in the crystalline structure of acyliminothiadiazoline, which has potent angiotensin II receptor antagonistic activity. 6,11) It is estimated that the ring structure consisted of the intramolecular nonbonded S · · · X interactions was more flexible than that of covalent bonding, and this flexibility increased the binding affinity of the active compound to the flexible pocket of the enzyme or the receptor. These results prompted us to disclose the new roles of intramolecular nonbonded S · · · X interactions in other drugs. Herein, we focus on rabeprazole, [13][14][15][16] and discuss the intramolecular nonbonded S · · · N interaction in rabeprazole and its role.Sodium rabeprazole (1) is one of the inhibitors of the gas-13,14) As a result of the investigations on the mechanism of action of these inhibitors, it has been expected that 1 will be activated by protonation in the parietal cell (intermediate 2), converted into the sulfenamide 5 via the spiro sulfoxide 3 and sulfenic acid 4, and the active principle 5 can react with the accessible cysteines of the gastric (H ϩ -K ϩ )-ATPase followed by the inhibition of the enzyme (compound 6), as shown in Chart 1. 14,[17][18][19][20] In this reaction cascade, the key step is the formation of the putative spiro sulfoxide 3 arising from nucleophilic attack of the pyridine nitrogen on the activated 2-position of the benzimidazole moiety.18) The fact that the nucleophilic attack of the pyridine nitrogen smoothly proceeds despite the week nucleophilicity is very interest, and made us guess that the intramoleculer nonbonded S · · · N interaction influenced this step. Because, if such intramoleculer nonbonded S · · · N interaction is possible in rabeplazole, the 4-membered quasiring in 2 containing the rabeplazole structure would be formed and bring the nitrogen atom of pyridine close to the electrophilic position of benzimidazole moiety, as shown in Fig. 1. Therefore, in order to make clear the presence of the intramoleculer nonbonded S · · · N interaction in 1, we characterized the crystal structures of derivatives of 1 at first, since 1 itself could hardly be crystallized. 21)The reactions of 1 with various electrophiles in the presence of amines gave the corresponding derivatives of 1 in 36-92% yields, as shown in Chart 2. The resultant derivatives 7a-d were recrystallized from suitable solvents to obtain the corresponding crystals available for X-ray crystal...

Active methylene and methyne compounds can be chemoselectively brominated in high yields using potassium bromide, hydrochloric acid, and hydrogen peroxide at room temperature.Halogenated active methylene and methyne compounds are very important synthetic intermediates for the nucleophilic substitutions in synthetic organic chemistry. The classical methods of halogenation of active methylene and methyne compounds 1 are the reaction with bromine 1 or sulfuryl chloride, 2 however, they suffer from drawbacks such as toxicity of the reagents, generation of acidic gasses after the reaction, or overhalogenation of the aromatic rings in 1. Although a number of new methods of this transformation have previously been developed, most of them have severe disadvantages such as the production of undesirable waste. [3][4][5] Khan and co-workers recently developed chemoselective bromination of active methylene compounds by employing the vanadium pentoxide catalyzed (V 2 O 5 ) oxidation of ammonium bromide (NH 4 Br) by hydrogen peroxide (H 2 O 2 ). 5 The reaction conditions of this method are very mild, and the reaction affords a product in high yield with high chemoselectivity. However, there are still some problems such as the use of a toxic vanadium compound as the catalyst and dichloromethane as the solvent.We now describe the chemoselective bromination of 1 by potassium bromide, hydrochloric acid and 30% hydrogen peroxide in toluene (Scheme 1). This method provides the desired monobromide 2 in high yields, while producing only nontoxic potassium chloride and water as waste.During the course of our study of the tantalum(V)-catalyzed oxidation of halogen anions to halogen cation equivalents, 6-8 we found that 1,3-diphenylpropane-1,3-dione could be quantitatively monobrominated by treatment with TaCl 5 (0.1 equiv), KBr (8.0 equiv), H 2 O 2 (8.0 equiv) and aqueous HCl (8.0 equiv) in chloroform. 6 We further examined the reaction, and found that the monobrominated compound could be obtained in the absence of the tantalum(V) catalyst. The most appropriate conditions are the treatment of 1 with KBr (5.0 equiv), HCl (5.0 equiv), and H 2 O 2 (20.0 equiv) in toluene at room temperature with stirring by a magnetic stirrer (Table 1).Several compounds with general structure 1 were examined under the reaction conditions, and the monobrominated compounds 2 quantitatively obtained in most cases. These results are summarized in Table 2. It is notable that the aromatic ring (entries 1 and 2), the ester group (entries 3-6), the amide group (entries 1 and 2) were inert under the given reaction conditions. Unfortunately, allyl acetoacetate (1k) did not provide the desired compound but complex mixture (entry 8). In this case, the alkene part of 1k also might react with the bromonium ion equivalent. Furthermore, we found that the use of a mechanical stirrer instead of a magnetic stirrer is effective in driving the reaction. In the case of using a mechanical stirrer, 1 quantitatively reacted with KBr (1.0 equiv), HCl (1.0 equiv), and H 2 O 2 (1.2 e...

Tetrasubstituted (Z )-alkenes were readily prepared through the Horner-Wadsworth-Emmons reactions of methyl 2-[bis(2,2,2-trifluoroethyl)phosphono]propionate with aryl alkyl ketones by employing Sn(OSO 2 CF 3 ) 2 and N-ethylpiperidine.

The nucleophilic addition of organometallics to α-keto amides having (2R,5R)-trans-2,5-bis(methoxymethoxymethyl)pyrrolidine as a chiral auxiliary was studied and it was found that the sense and degree of diastereoselection strongly depended on organometallics and the reaction conditions used and that the diastereomeric hydroxy amides was obtained with high stereoselectivity by the choice of appropriate reaction conditions.