Regioselective Synthesis of Benzofuran‐Annulated Six‐Membered Sulfur Heterocycles by Aryl Radical Cyclization

The tin hydride–mediated cyclization of a number of sulfides and sulfones under mild and neutral conditions has been investigated. The sulfides were in turn derived from 3(2H) benzothiofuranone and 2‐bromobenzyl bromides by phase‐transfer‐catalyzed reaction, and the corresponding sulfones were prepared by treatment of the corresponding sulfides with m‐CPBA at room temperature. The sulfides and sulfones were then reacted with ⁿ Bu₃SnH‐AIBN to afford regioselectively benzofuran‐annulated six‐membered sulfur heterocycles.     

Regioselective Synthesis of 1,8-Naphthyridinone-Annulated Oxygen and Sulfur Heterocycles by Tri-n-butyl Tinhydride–Mediated Aryl Radical Cyclization

The tin hydride–mediated cyclizations of a number of ethers, sulfides, and sulfones under mild, neutral conditions have been investigated. While the 2-bromobenzyloxy ethers were prepared in 62–65% yields by the alkylation of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one with 2-bromobenzyl bromides in refluxing acetone in the presence of anhydrous potassium carbonate, the sulfides were derived from 4-mercapto-1-phenyl-1,8-naphthyridin-2(1H)-one and 2-bromobenzyl bromides in 82–84% yields by a phase-transfer catalysis (PTC) reaction. The corresponding sulfones were prepared by treatment of the sulfides with m-CPBA in refluxing dichloromethane. The ethers, sulfides, and the sulfones were treated with ⁿ Bu₃SnH-AIBN to give regioselectively 1,8-naphthyridinone-annulated oxygen and sulfur heterocycles in 70–78% yields.     

One-pot preparation of Julia-Kocienski sulfides and sulfones from alcohols

A method for one-pot preparation of Julia-Kocienski sulfides and sulfones from alcohols and thiols is reported. A variety of primary alcohols were converted to the corresponding mesylates by methansulfonyl chloride and triethylamine in THF. After the reaction is complete, thiol (1 or 10) and either NaH or t-BuOK were added. The Julia-Kocienski sulfides 3, 9 and 11 were prepared by one-pot two steps procedure from alcohols in 76–96% yields (16 examples). Furthermore, after the sulfide formation, the reaction mixture was neutralized by p-toluenesulfonic acid and treated with H₂O₂ and ammonium molybdate in EtOH to give the Julia-Kocienski sulfones 4 in good yields except for trans-2-hexen-1-ol.     

Sulfoxides derived from Cinchona alkaloids—chiral ligands in palladium-catalyzed asymmetric allylic alkylation

Phenyl sulfides derived from Cinchona alkaloids, 9-PhS-epi-CD, 9-PhS-epi-QN, 9-PhS-epi-QD, and 9-PhS-QN were oxidized into the corresponding sulfoxides. Regardless of the oxidation system used (NaIO₄, TEMPO/NaOCl, VO(acac)₂/chiral Schiff base/H₂O₂) a similar stereochemical outcome of the oxidation was observed. Four pure epimers of sulfoxides 9-PhSO-epi-CD and 9-PhSO-epi-QN were isolated and fully characterized (X-ray, CD, ¹H NMR-pattern). The chiral sulfoxides as well as the corresponding sulfides and sulfones were tested in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenyl-2-propenyl acetate. The sulfoxides obtained from Cinchona alkaloids bearing the additional stereogenic center gave the main product of configuration dependent on the chirality of alkaloid framework only. Similar ees (up to 60%) but significantly higher yields (90%) were obtained as compared to the reaction with the corresponding thioethers. The results were in agreement with nucleophilic attack directed at the allylic carbon located trans to the sulfur atom in the M-shaped intermediate η³-allylpalladium complex.     

Selective Oxidation of Sulfides to Sulfones Using H2O2 and Anderson-Type Hexamolybdochromate(III) as Catalyst

An Anderson-type hexamolybdochromate(III) is found to be an effective catalyst for the selective oxidation of sulfides to their corresponding sulfones. The reaction was carried out in 60% aq. acetonitrile (v/v) using 30% H₂O₂ at 60°C. Various dialkyl, alkyl-aryl, and diaryl sulfides were selectively oxidized, giving high yields of sulfones after a simple workup procedure.     

Metal-free chemoselective oxidation of sulfides by in situ generated Koser’s reagent in aqueous media

Selective oxidation of sulfides was successfully performed by employing phenyliodine diacetate as an oxidant with the catalysis of TsOH in aqueous solution under mild conditions. Sulfoxides were formed with 1.1 equiv of PhI(OAc)₂ at room temperature; whereas sulfones were obtained in the presence of 2.1 equiv of PhI(OAc)₂ at 80 °C under otherwise identical conditions. Notably, various sulfides were converted to corresponding sulfoxides or sulfones in good to high yields by this metal-free protocol.     

Facile oxygenation of organic sulfides with H2O2 catalyzed by Mn-Me3TACN compounds

Two binuclear Mn-Me₃TACN (Me₃TACN is 1,4,7-N,N′,N″-trimethyl-1,4,7-triazacyclononane) compounds catalyze the oxygenation of organic sulfides utilizing H₂O₂ under ambient conditions. Both phenyl sulfide and ethyl phenyl sulfide were converted to the corresponding sulfones and chloroethyl phenyl sulfide proceeds to its elimination product of phenyl vinyl sulfone.     

Tantalum(V) or niobium(V) catalyzed oxidation of sulfides with 30% hydrogen peroxide

Tantalum(V) and niobium(V) are effective catalysts for the oxidation of sulfides with 30% hydrogen peroxide. The reaction of sulfides with 30% hydrogen peroxide catalyzed by tantalum(V) chloride or niobium(V) chloride in acetonitrile, i-propanol or t-butanol selectively provided the corresponding sulfoxides in high yields. The corresponding sulfones are efficiently obtained from the reaction of sulfides with 30% hydrogen peroxide in methanol catalyzed by tantalum(V) or niobium(V).     

Synthesis and oxidation of sulfides containing an isocyanurate fragment

The reaction of 1-(ω-haloalkyl)-3,5-dimethylisocyanurates with sodium salt of methyl thioglycolate afforded the corresponding 1-[ω-(methoxycarbonylmethylthio)alkyl]-3,5-dimethylisocyanurates, the oxidation of which with the system 34% aqueous H₂O₂-0.2 M NaHCO₃-Mn^II leads to the corresponding sulfones. The oxidation of these compounds with 34% aq. H₂O₂ in Ac₂O gives alternative products, viz., sulfones, sulfoxides, or α-acyloxy sulfides, depending on the temperature and number of methylene groups between the isocyanurate fragment and the sulfur atom.     

Selective and efficient oxidation of sulfides to sulfoxides with N-bromosuccinimide in the presence of β-cyclodextrin in water

A simple and highly selective oxidation of sulfides to sulfoxides with N-bromosuccinimide (NBS) catalyzed by β-cyclodextrin in water has been developed. A series of sulfides were oxidized selectively at room temperature in excellent yields. This reaction proceeds without over-oxidation to sulfones under mild conditions using water as a solvent and has many advantages over the existing methodologies.     

The determination of sulfoxide configuration in five-membered rings using NMR spectroscopy and DFT calculations

Cyclic five-membered ring sulfoxides and sulfones were prepared by a stepwise in situ oxidation of the corresponding sulfides with meta-chloroperbenzoic acid in an NMR tube. The oxidation was followed by NMR and both ¹H and ¹³C NMR data were collected. The geometries of all of the compounds were optimized using the DFT B3LYP/6-31G⁷ method and the ¹³C and ¹H chemical shifts were calculated for geometry-optimized structures with the DFT B3LYP/6-31++G⁷ method. The calculated ¹³C chemical shifts induced by oxidation (Δδ values) were in very good agreement with the experimental data and could be used to determine the oxidation state of the sulfur atom (–S–, –SO–, –SO₂–). The characteristic differences of the induced oxidation chemical shifts of the carbon atoms in the α-position and β-position to sulfur were successfully used to distinguish between the diastereoisomeric sulfoxides and allowed configuration determination.     

Selective synthesis of sulfoxides and sulfones by tantalum(V) catalyzed oxidation of sulfides with 30% hydrogen peroxide

The reaction of sulfides with 30% hydrogen peroxide catalyzed by tantalum(V) chloride in acetonitrile, i-propanol, or t-butanol selectively provided the corresponding sulfoxides in high yields. On the other hand, the reaction of sulfides with 30% hydrogen peroxide-catalyzed by tantalum(V) chloride or tantalum(V) ethoxide in methanol effectively gave the sulfones.     

Cyanuric chloride as promoter for the oxidation of sulfides and deoxygenation of sulfoxides

This Letter discusses the use of cyanuric chloride as an efficient promoter for the chemoselective oxidation of sulfides to the corresponding sulfones in the presence of H₂O₂ as the terminal oxidant. Sulfoxides were also found to undergo deoxygenation to sulfides with cyanuric chloride and potassium iodide system. The reaction is broad in scope and easy to perform.     

Studies on the reactivity of 3-methyl-4-nitro-5-styrylisoxazoles with S-nucleophiles

We have investigated the reactivity of 3-methyl-4-nitro-5-styrylisoxazoles with S-nucleophiles. This study revealed that the title compounds were optimal Michael acceptors toward thiols. A procedure was also established to prepare isoxazole-containing sulfides in one-pot and without the use of chromatography. Isoxazole-containing sulfides were converted into the corresponding sulfones in high yield.     

The determination of sulfoxide configuration in six-membered rings using NMR spectroscopy and DFT calculations

Cyclic six-membered ring sulfoxides and sulfones were prepared by a stepwise in situ oxidation of the corresponding sulfides with meta-chloroperbenzoic acid in an NMR tube. The oxidation was followed by NMR spectra and the ¹H and ¹³C NMR data were collected. The geometries of all of the compounds were optimized using the DFT B3LYP/6-31G^∗∗ method and the ¹³C and ¹H NMR chemical shifts were calculated for geometry-optimized structures with the DFT B3LYP/6-31++G^∗∗ method. The calculated ¹³C NMR chemical shifts induced by oxidation (Δδ values) are in very good agreement with the experimental data and can be used to determine the oxidation state of the sulfur atom (-S-, -SO-, -SO₂-). The characteristic differences of the induced oxidation chemical shifts of carbon atoms at the α- and β-position to sulfur were successfully used for distinguishing between the diastereoisomeric sulfoxides.     

Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO₂-insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO₂ insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.     

Synthesis of 3-Coumaryl Phenyl Sulfones or Sulfoxides

An unambiguous synthesis of a number of 3-coumaryl phenyl sulfones or sulfoxides have been described which were obtained by the oxidation of the corresponding sulfides with hydrogen peroxide. The sulfides were prepared by the Perkin-Oglialore reaction of o-hydroxyaldehyde with the sodium salt of different S-phenyl thioacetic acids. The sulfones did not exhibit any appreciable antitubercuious activity in the preliminary screening tests.     

TiCl4-promoted addition of nucleophiles to open chain α-amidoalkylphenyl sulfones

Linear α-amidoalkylphenyl sulfones are converted into the corresponding N-acyliminium ions by treatment with TiCl₄ at low temperature and then made to react with different nucleophiles such as allyltrimethylsilane, silyl ketene acetal, anisole and thiophene.     

Evidence of Two Key Intermediates Contributing to the Selectivity of P450‐Biomimetic Oxidation of Sulfides to Sulfoxides and Sulfones

A mild process for the selective oxidation of sulfides is in great demand. Therefore, probing the mechanism underlying the biological oxidation of sulfides under ambient conditions may provide valuable insights for the development of such a reaction. Based on porphyrin models of P450 enzymes, evidence of two key intermediates, Int0 and Int1 , in this reaction is provided. Spectroscopic studies indicated the formation of a hydroperoxide‐iron(III) species ( Int0 ) upon addition of H₂O₂. This intermediate proved to be highly selective for sulfoxide production. By contrast, a defined porphyrin oxoiron(IV) cation radical ( Int1 ) directly reacted with sulfoxides, leading selectively to the corresponding sulfones. Interestingly, the available sulfoxides reversibly act as a new axial ligand for Int0 forming a more active species Int0 _SO. The amount of Int0 increased in the presence of alkyl, aryl, or aromatic sulfides, while Int1 formed in the absence of these sulfides. Thus, sulfoxides and sulfones would selectively form under conditions that favor the corresponding intermediates, which elucidate the biological oxidation pathway.     

Reactivity of fluorinated sulfur-containing heterocycles towards nucleophilic and oxidizing reagents

The reaction of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene, 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene and 2,2-bis(trifluoromethyl)-3,6-dihydro-4,5-dimethyl-2H-thiopyran with i-C₃H₇MgCl leads to the formation of ring opening products as the result of nucleophilic attack of the Grignard reagent on the sulfur atom. According to DFT calculations the reactivity of the sulphur-containing substrate correlates with the strain energy of the heterocycle. The oxidation of 3-thia-4,4-bis(trifluoromethyl)tricyclo[5.2.1.0^2,5]non-7-ene by hydrogen peroxide in hexafluoro-iso-propanol solvent resulted in formation of the corresponding sulfoxide however, the reaction with m-chloroperoxybenzoic acid produced the product of exhaustive oxidation of sulfur and the double bond. In sharp contrast, the oxidation of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene and 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene by MCPBA (2d, 25 °C) proceeds with the preservation of the double bond, leading to the selective formation of the corresponding sulfones.