- Catalyst-free visible light-mediated selective oxidation of sulfides into sulfoxides under clean conditions
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A facile and efficient visible-light-mediated method for directly converting sulfides into sulfoxides under clean conditions without using any photocatalysts is reported. This method exhibited favourable compatibility with functional groups and afforded a series of sulfoxides with high selectivity and yields. Moreover, in order to shed more light on such a transformation, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and eco-friendly nature of the developed method will endow it with attractive applications in chemical synthesis.
- Fan, Qiangwen,Zhu, Longwei,Li, Xuhuai,Ren, Huijun,Wu, Guorong,Zhu, Haibo,Sun, Wuji
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supporting information
p. 7945 - 7949
(2021/11/01)
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- Integrating hydrogen production with anodic selective oxidation of sulfides over a CoFe layered double hydroxide electrode
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Replacing the sluggish oxygen evolution reaction (OER) with oxidation reactions for the synthesis of complex pharmaceutical molecules coupled with enhanced hydrogen evolution reaction (HER) is highly attractive, but it is rarely explored. Here, we report an electrochemical protocol for selective oxidation of sulfides to sulfoxides over a CoFe layered double hydroxide (CoFe-LDH) anode in an aqueous-MeCN electrolyte, coupled with 2-fold promoted cathodic H2productivity. This protocol displays high activity (85-96% yields), catalyst stability (10 cycles), and generality (12 examples) in selective sulfide oxidation. We demonstrate its applicability in the synthesis of four important pharmaceutical related sulfoxide compounds with scalability (up to 1.79 g). X-ray spectroscopy investigations reveal that the CoFe-LDH material evolved into amorphous CoFe-oxyhydroxide under catalytic conditions. This work may pave the way towards sustainable organic synthesis of valuable pharmaceuticals coupled with H2production.
- Ma, Lina,Zhou, Hua,Xu, Ming,Hao, Peipei,Kong, Xianggui,Duan, Haohong
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p. 938 - 945
(2021/02/06)
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- Selective synthesis of sulfoxides and sulfonesviacontrollable oxidation of sulfides withN-fluorobenzenesulfonimide
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A practical and mild method for the switchable synthesis of sulfoxides or sulfonesviaselective oxidation of sulfides using cheapN-fluorobenzenesulfonimide (NFSI) as the oxidant has been developed. These highly chemoselective transformations were simply achieved by varying the NFSI loading with H2O as the green solvent and oxygen source without any additives. The good functional group tolerance makes the strategy valuable.
- Cao, Zhong-Yan,Li, Xiaolong,Lu, Hao,Wang, Panpan,Wang, Shengqiang,Xu, Xiaobo,Yan, Leyu,Yang, A-Xiu
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supporting information
p. 8691 - 8695
(2021/10/22)
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- Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides
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Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.
- Acosta-Guzmán, Paola,Mahecha-Mahecha, Camilo,Gamba-Sánchez, Diego
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supporting information
p. 10348 - 10354
(2020/07/13)
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- Synthesis, characterization and antiparasitic activity of organometallic derivatives of the anthelmintic drug albendazole
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Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Moreover, major intestinal protozoa have a significant impact on global public health. Albendazole (ABZ) is a broad-spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with ferroquine, an organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The ferrocene-containing ABZ analogue 2d exhibited over 70% activity against T. muris adults in vitro at 200 μM and no toxicity to mammalian cells (IC50 >100 μM). H. polygyrus adults were not affected by any of the derivatives tested. Against T. gondii, the ferrocene-containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. The activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro might be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the derivatives show a species specific in vitro activity and the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg kg-1 dose, the compounds showed moderate worm burden reductions but low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.
- Anghel, Nicoleta,Blacque, Olivier,Bouchene, Rafika,Cariou, Kevin,Gasser, Gilles,Gasser, Robin B.,H?berli, Cécile,Hemphill, Andrew,Karges, Johannes,Keiser, Jennifer,Keller, Sarah,Lin, Yan,Müller, Joachim,Manoury, Eric,Ong, Yih Ching,Taki, Aya C.
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p. 6616 - 6626
(2020/06/08)
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- Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis
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Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.
- Li, Yiming,Rizvi, S. Aal-e-Ali,Hu, Deqing,Sun, Danwen,Gao, Anhui,Zhou, Yubo,Li, Jia,Jiang, Xuefeng
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supporting information
p. 13499 - 13506
(2019/08/21)
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- Sulfoxide and sulfone compounds, as well as selective synthesis method and application thereof
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The invention discloses a method for selectively synthesizing a sulfoxide compound shown as a formula (II) and a sulfone compound shown as a formula (III). In a reaction solvent, thioether (I) is usedas a reaction raw material and oxygen as an oxidation reagent, under the catalytic action of visible light and a photosensitive reagent; under the assistance of an additive, when a large-polarity proton-containing additive such as an acid and an alcohol or a solvent or an additive with excellent electron donating ability is used, a sulfoxide compound (II) is selectively generated; and when a small-polarity aprotic additive or a solvent is used, a sulfone compound (III) is selectively generated. The synthesis method has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and excellent functional group tolerance. According to the invention, synthesis and modification of some medicines are realized, and an efficient method for selectively constructing sulfoxide and sulfone compounds is provided for medicinal chemistry research.
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Paragraph 0045-0048; 0205-0207
(2019/12/02)
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- Enantioselective oxidation of sulfides with H2O2 catalyzed by a pre-formed manganese complex
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A facile and environmentally friendly method is presented for the asymmetric oxidation of sulfides with H2O2, utilizing a pre-formed manganese complex. Just in the presence of a low catalytic amount of carboxylic acid (CA), a variety of sulfide substrates, including aryl alkyl, aryl benzyl and cyclic sulfides, reacted to form chiral sulfoxides in high yields (up to 95%) and excellent enantioselectivities (>99% ee) under mild conditions. Moreover, the practical utility of the method has been demonstrated by the synthesis of esomeprazole and albendazole sulfoxide (ABZO).
- Dai, Wen,Li, Guosong,Wang, Lianyue,Chen, Bo,Shang, Sensen,Lv, Ying,Gao, Shuang
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p. 46545 - 46554
(2014/12/10)
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- Preparative microfluidic electrosynthesis of drug metabolites
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In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. Electrochemistry can be used to simulate CYP450 oxidation, yet it is often confined to the analytical scale, hampering product isolation and full characterization. In an effort to replicate hepatic oxidations, while retaining high throughput at the preparative scale, microfluidic technology and electrochemistry are combined in this study by using a microfluidic electrochemical cell. Several commercial drugs were subjected to continuous-flow electrolysis. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. It is demonstrated that such metabolites can be synthesized by flow electrolysis at the 10 to 100 mg scale, and the purified products are fully characterized.
- Stalder, Romain,Roth, Gregory P.
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supporting information
p. 1119 - 1123
(2013/12/04)
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- Identification of novel substrates for human cytochrome P450 2J2
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Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 μl/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N-desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4. Copyright
- Lee, Caroline A.,Neul, David,Clouser-Roche, Andrea,Dalvie, Deepak,Wester, Michael R.,Jiang, Ying,Jones III,Freiwald, Sascha,Zientek, Michael,Totah, Rheem A.
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scheme or table
p. 347 - 356
(2010/11/18)
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- Synthesis and in vitro cysticidal activity of new benzimidazole derivatives
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Despite albendazole being the drug of choice in neurocysticercosis treatment, its low solubility limits its bioavailability; therefore, more research is required in order to find new molecules with cestocidal activity and adequate aqueous solubility. A set of 13 benzimidazole derivatives were synthesized and their in vitro activities were evaluated against Taenia crassiceps cysts, using albendazole sulfoxide as reference molecule, showing that two of them exhibited good activity. Molecular modelling revealed that the cysticidal efficacy depends on the presence on the molecule of an H in the 1-position, a planar carbamate group at 2-position, and if the substituent in 5-position is voluminous, it should be orthogonal to the benzimidazole ring.
- Palomares-Alonso, Francisca,Jung-Cook, Helgi,Perez-Villanueva, Jaime,Piliado, Juan Carlos,Rodriguez-Morales, Sergio,Palencia-Hernandez, Guadalupe,Lopez-Balbiaux, Nayeli,Hernandez-Campos, Alicia,Castillo, Rafael,Hernandez-Luis, Francisco
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body text
p. 1794 - 1800
(2009/07/18)
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- Small intestinal sulphoxidation of Albendazole
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The in vitro sulphoxidation of Albendazole (ABZ) by rat intestinal microsomes has been examined. The results revealed intestinal sulphoxidation of ABZ by intestinal microsomes in a NADPH-dependent enzymatic system. The kinetic constants for sulphoxidase activity were V(max) = 46 pmol/min/mg protein and Michaelis constant K(m) = 6.8 μM. The possible effect of inducers (Arochlor 1254 and ABZ pretreatment) and inhibitors (erythromycin, methimazole, carbon monoxide and fenbendazole), was also studied. In rat pretreated with Arochlor 1254, V(max) was 52 pmol/min/mg protein, whereas oral administration of ABZ increased the intestinal sulphoxidation of the drug, V(max) being 103 pmol/min/mg protein. Erythromycin did not change the enzymatic bioconversion of ABZ, but methimazole and carbon monoxide inhibited the enzyme activity by approximately 60 and 30% respectively. Fenbendazole (a structural analogue of ABZ) was a competitive inhibitor of the sulphoxidation process, characterized by a K(i) or 69 μM. These data demonstrate that the intestinal enzymes contributing to the initial sulphoxidation of ABZ may be similar to the hepatic enzymes involved in the biotransformation process by the P450 and FMO systems, a conclusion that needs to be further established.
- Villaverde,Alvarez,Redondo,Voces,Del Estal,Prieto
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p. 433 - 441
(2007/10/03)
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- Mild and Selective Oxygenation of Sulfides to Sulfoxides and Sulfones by Perfluoro-cis-2,3-dialkyloxaziridines
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Sulfides are oxidized to sulfoxides by stoichiometric amounts of perfluoro-cis-2,3-dialkyloxaziridines 2.The reactions proceed at -40 deg C with nearly complete selectivity and very good yields.Sulfoxides are also oxidized easily by 2 under mild conditions to corresponding sulfones.The oxidation of some bioactive sulfides (promazine, albendazole, biotin, and others) is also reported.
- DesMarteau, Darryl D.,Petrov, Viacheslav A.,Montanari, Vittorio,Pregnolato, Massimo,Resnati, Giuseppe
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p. 2762 - 2765
(2007/10/02)
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- Method of treating helminthiasis by parenteral or topical administration of sulfoxide derivatives of benzimidazoles
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A method is provided for treating or inhibiting helminthiasis by parenterally or topically administering sulfoxide derivatives of benzimidazoles having the structure STR1 wherein R1 is lower alkyl or phenyl-lower alkyl, and R2 is lower alkyl. Pharmaceutical compositions for use in the above method are also provided.
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