Aryl Thioethers Research Articles

Biocatalytic synthesis of oxa(thia)diazole aryl thioethers

A novel approach for the synthesis of 1,3,4-oxa(thia)diazole aryl thioethers through a biocatalytic strategy has been introduced. By leveraging Myceliophthora thermophila laccase (Novozym 51003) as a catalyst, catechol undergoes oxidation to ortho-quinone, facilitating subsequent 1,4-thia-Michael addition reactions. The method offers efficiency and mild reaction conditions, demonstrating promise for sustainable synthesis pathways in organic chemistry. Using this approach, 13 new derivatives of 2,5-disubstituted-1,3,4-oxa(thia)diazole aryl thioethers, with a yield of 46–94%, were synthesized.

Ru-Mediated and Sulfur-Directed ortho-C–H Activation of Benzyl Thioethers with Internal Alkynes and Selective Hydrothiolation of Acetylene Dicarboxylates

AbstractIn this report, we have established a Ru(η6-C6H6)Cl2 catalysed ortho-C–H activation of benzyl thioethers with alkynes under milder reaction conditions. The sulfur atom of benzyl thioethers worked as a directing group for ortho-C–H activation of benzyl thioethers. The reaction was found to tolerate a range of benzyl thioethers as well as alkynes. Moreover, the reaction is significantly influenced by the length of alkyl and aryl thioethers, with the best results being obtained with benzyl thioethers. Kinetic isotopic experiments suggest that the ortho-C–H bond-breaking is not a rate-determining step for the present reaction. In an unusual observation that has not been reported, apart from ortho-C–H activation, under the same reaction conditions, a selective debenzylative hydrothiolation was exclusively obtained with acrylates, which broadens the synthetic impact of benzyl thioethers for the preparation of mixed chalcogen ethers.

Expedient Synthesis of Alkyl and Aryl Thioethers Using Xanthates as Thiol-Free Reagents.

Thioethers are critical in the fields of pharmaceuticals and organic synthesis, but most of the methods for synthesis alkyl thioethers employ foul-smelling thiols as starting materials or generate them as by-products. Additionally, most thiols are air-sensitive and are easily oxidized to produce disulfides under atmospheric conditions; thus, a novel method for synthesizing thioethers is necessary. This paper reports a simple, effective, green method for synthesizing dialkyl or alkyl aryl thioether derivatives using odorless, stable, low-cost ROCS2K as a thiol surrogate. This transformation offers a broad substrate scope and good functional group tolerance with excellent selectivity. The reaction likely proceeds via xanthate intermediates, which can be readily generated via the nucleophilic substitution of alkyl halides or aryl halides with ROCS2K under transition-metal-free and base-free conditions.

2-Pyridone-Directed CuII-Catalyzed General Method of C(sp2)-H Activation for C-S, C-Se, and C-N Cross-Coupling: Easy Access to Aryl Thioethers, Selenide Ethers, and Sulfonamides and DFT Study.

We have demonstrated N-substituted 2-pyridones as an N,O-directing group for selective C(sp2)-H-activated thiolation, selenylation, and sulfonamidation of ortho C-H bonds of benzamides. This method utilizes a cost-effective Cu(II)-salt catalyst instead of precious metal catalysts, achieving high yields, including gram-scale synthesis and excellent functional group tolerance. We applied this protocol to access 30 different compounds with high yields, demonstrating thiolation of fluorine-substituted benzamides as well. Density functional theory (DFT) calculations support the mechanism, including acetate-supported concerted metalation deprotonation (CMD) steps and the unique role of dimethyl sulfoxide (DMSO) solvent. The facile synthesis of pharmaceutically important sulfonamides and other compounds highlights the method's potential in chemistry and medicinal chemistry.

Gold-Catalyzed Oxidation Reactions of Thioalkynes with Quinoline N-Oxides: A DFT Study.

Mechanistic investigation of the gold-catalyzed oxidative reactions of thioalkynes with quinoline N-oxides was performed using density functional theory (DFT) calculations. For the oxidative rearrangement of thioalkynes with quinoline N-oxide to yield the same products, the Cβ-oxidation of thioalkynes was predicted to be competitive with Cα-oxidation, with the Cβ-oxidative process slightly more favorable. However, for the oxidative alkenylation of propargyl aryl thioethers with quinoline N-oxides, the Cβ-oxidation of thioether by quinoline N-oxide generated the product 3-hydroxy-1-alkylidene phenylthiopropan-2-one. Moreover, the ring opening of the four-membered sulfonium intermediate was achieved by the nucleophilic attack of quinoline N-oxide rather than a water molecule.

Photoinduced Formation of Cubyl Aryl Thioethers and Synthesis of Monocubyl Analogue of Dapsone

Photoinduced Formation of Cubyl Aryl Thioethers and Synthesis of Monocubyl Analogue of Dapsone

Overcoming the Potential Window-Limited Functional Group Compatibility by Alternating Current Electrolysis.

The functional group compatibility of an electrosynthetic method is typically limited by its potential reaction window. Here, we report that alternating current (AC) electrolysis can overcome such potential window-limited functional group compatibility. Using alkene heterodifunctionalization as a model system, we design and demonstrate a series of AC-driven reactions that add two functional groups sequentially and separately under the cathodic and anodic pulses, including chloro- and bromotrilfuoromethylation as well as chlorosulfonylation. We discovered that the oscillating redox environment during AC electrolysis allows the regeneration of the redox-active functional groups after their oxidation or reduction in the preceding step. As a result, even though redox labile functional groups such as pyrrole, quinone, and aryl thioether fall in the reaction potential window, they are tolerated under AC electrolysis conditions, leading to synthetically useful yields. The cyclic voltammetric study has confirmed that the product yield is limited by the extent of starting material regeneration during the redox cycling. Our findings open a new avenue for improving functional group compatibility in electrosynthesis and show the possibility of predicting the product yield under AC electrolysis from voltammogram features.

A Thiol-Free Route to Alkyl Aryl Thioethers.

Most existing methods for the synthesis of alkyl aryl thioethers require the use of mercaptans as the starting materials, which comes with practical limitations. Reactions of diaryliodonium salts with xanthate salts, easily prepared from the corresponding alcohols and CS2, under the developed conditions represent an operationally simple, thiol-free method for the synthesis of these valuable compounds. The protocol features high functional group tolerance and can be applied to the late-stage C-H functionalization and for the introduction of a CD3S group.

Manganese‐Catalyzed Redox‐Neutral Thiolation of Alkyl Halides with Thioformates

AbstractTransition metal‐catalyzed C−S cross‐coupling has emerged as an important strategy to furnish thioethers; however, the dominant utilization of noble metal catalysts as well as the construction of challenging C(sp3)−S bonds by transition metal‐catalysis remain highly problematic. Earth‐abundant manganese has gathered increasing interest as an attractive catalyst for new reaction development; nevertheless, C(sp3)−S cross‐coupling reaction by manganese catalysis has not been reported. Herein, we disclose a highly efficient manganese‐catalyzed redox‐neutral thiolation of a broad range of alkyl halides with thioformates as practical sulfuration agents. Strategically, employing easily synthesized thioformates as thiyl radical precursors allows access to various aryl and alkyl thioethers in good to excellent yields. Notably, this redox‐neutral method avoids the utilization of strong bases, external ligands, forcing reaction conditions, and stoichiometric manganese, thus presenting apparent advantages, such as broad substrate scope, excellent functional group compatibility, and mild reaction conditions. Finally, the utilities of this method are also illustrated by downstream transformations and late‐stage thiolation of structurally complex natural products and pharmaceuticals.

Manganese-Catalyzed Redox-Neutral Thiolation of Alkyl Halides with Thioformates.

Transition metal-catalyzed C-S cross-coupling has emerged as an important strategy to furnish thioethers; however, the dominant utilization of noble metal catalysts as well as the construction of challenging C(sp3 )-S bonds by transition metal-catalysis remain highly problematic. Earth-abundant manganese has gathered increasing interest as an attractive catalyst for new reaction development; nevertheless, C(sp3 )-S cross-coupling reaction by manganese catalysis has not been reported. Herein, we disclose a highly efficient manganese-catalyzed redox-neutral thiolation of a broad range of alkyl halides with thioformates as practical sulfuration agents. Strategically, employing easily synthesized thioformates as thiyl radical precursors allows access to various aryl and alkyl thioethers in good to excellent yields. Notably, this redox-neutral method avoids the utilization of strong bases, external ligands, forcing reaction conditions, and stoichiometric manganese, thus presenting apparent advantages, such as broad substrate scope, excellent functional group compatibility, and mild reaction conditions. Finally, the utilities of this method are also illustrated by downstream transformations and late-stage thiolation of structurally complex natural products and pharmaceuticals.

An Efficient Direct Arylation Polycondensation via C-S Bond Cleavage.

The direct arylation polycondensation (DArP) has become one of the most important methods to construct conjugated polymers (CPs). However, the homocoupling side-reactions of aryl halides and the low regioseletive reactivities of unfunctionalized aryls hinder the development of DArP. Here, an efficient Pd and Cu co-catalyzed DArP was developed via inert C-S bond cleavage of aryl thioethers, of which robustness was exemplified by over twenty conjugated polymers (CPs), including copolymers, homopolymers, and random polymers. The capture of oxidative addition intermediate together with experimental and theoretic results suggested the important role of palladium (Pd) and copper (Cu) co-catalysis with a bicyclic mechanism. The studies of NMR, molecular weights, trap densities, X-ray diffraction, and the charge transport mobilities revealed that the homocoupling reactions were significantly suppressed with high regioselectivity of unfunctionalized aryls, suggesting this method is an excellent choice for synthesizing high performance CPs.

An Efficient Direct Arylation Polycondensation via C−S Bond Cleavage

AbstractThe direct arylation polycondensation (DArP) has become one of the most important methods to construct conjugated polymers (CPs). However, the homocoupling side‐reactions of aryl halides and the low regioseletive reactivities of unfunctionalized aryls hinder the development of DArP. Here, an efficient Pd and Cu co‐catalyzed DArP was developed via inert C−S bond cleavage of aryl thioethers, of which robustness was exemplified by over twenty conjugated polymers (CPs), including copolymers, homopolymers, and random polymers. The capture of oxidative addition intermediate together with experimental and theoretic results suggested the important role of palladium (Pd) and copper (Cu) co‐catalysis with a bicyclic mechanism. The studies of NMR, molecular weights, trap densities, two‐dimensional grazing‐incidence wide‐angle X‐ray scattering (2D‐GIWAXS), and the charge transport mobilities revealed that the homocoupling reactions were significantly suppressed with high regioselectivity of unfunctionalized aryls, suggesting this method is an excellent choice for synthesizing high performance CPs.

Syntheses of Aryl Thioethers via Aromatic Substitution of Aryl Halides at 0 to 25 °C.

In this study, we developed mild conditions for the synthesis of an aryl thioether via aromatic substitution using aryl halides, which is a process that has rarely been studied. Aromatic substrates such as aryl fluorides activated with a halogen substituent are difficult to use for substitution reactions, but by using 18-crown-6-ether as an additive, these were successfully converted to their corresponding thioether products. Under the conditions we established, in addition to a wide variety of thiols, less-toxic and odorless disulfides could be used directly as nucleophiles at 0 to 25 °C.

Nickel‐catalyzed umpolung C[sbnd]S radical reductive cross coupling of S‐(trifluoromethyl)arylsulfonothioates with alkyl halides

A new cooperative nickel reductive catalysis and N,N-dimethylformamide-mediated strategy for umpolung CS radical reductive cross coupling of S-(trifluoromethyl)arylsulfonothioates with alkyl halides to produce alkyl aryl thioethers is described. This reaction features excellent selectivity, wide functionality tolerance, broad substrate scope, and facile late-stage modification of biologically relevant molecules. Mechanistic studies recognize initial generation of an amidyl radical anion via thermoinduced reduction of DMF with Sn, followed by umpolung reduction and single electron transfer of the nucleophilic sulfonyl moiety to form a sulphydryl radical and engage the Ni0/NiI/NiIII/NiI catalytic cycle.

Innentitelbild: Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SNAr for Tunable Bandgap and Porosity (Angew. Chem. 28/2023)

A scrambled but selective polycondensation reaction introduced the simplest route to generate porous poly(aryl thioether)s. Through a multi-para nucleophilic substitution of perfluoroaromatic compounds with sodium sulfide, temperature-dependent formation of thioether linkages leads to stepwise transition of the polymers into network structures with controllable porosity and bandgap, as reported by Jeehye Byun, Sheng Li, Cafer T. Yavuz et al. in their Research Article (e202304378).

Inside Cover: Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SNAr for Tunable Bandgap and Porosity (Angew. Chem. Int. Ed. 28/2023)

A scrambled but selective polycondensation reaction introduced the simplest route to generate porous poly(aryl thioether)s. Through a multi-para nucleophilic substitution of perfluoroaromatic compounds with sodium sulfide, temperature-dependent formation of thioether linkages leads to stepwise transition of the polymers into network structures with controllable porosity and bandgap, as reported by Jeehye Byun, Sheng Li, Cafer T. Yavuz et al. in their Research Article (e202304378).

Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SNAr for Tunable Bandgap and Porosity

AbstractPorous poly(aryl thioether)s offer stability and electronic tunability by robust sulfur‐aryl conjugated architecture, but synthetic access is hindered due to limited control over the nucleophilic nature of sulfides and the air sensitivity of aromatic thiols. Here, we report a simple, one‐pot, inexpensive, regioselective synthesis of highly porous poly(aryl thioether)s through polycondensation of perfluoroaromatic compounds with sodium sulfide. The unprecedented temperature‐dependent para‐directing formation of thioether linkages leads to a stepwise transition of the polymer extension into a network, thereby allowing fine control of the porosity and optical band gaps. The obtained porous organic polymers with ultra‐microporosity (<1 nm) and sulfur as the surface functional groups show size‐dependent separation of organic micropollutants and selective removal of mercury ions from water. Our findings offer easy access to poly(aryl thioether)s with accessible sulfur functionalities and higher complexity, which will help in realizing advanced synthetic designs in applications such as adsorption, (photo)catalysis, and (opto)electronics.

Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SN Ar for Tunable Bandgap and Porosity.

Porous poly(aryl thioether)s offer stability and electronic tunability by robust sulfur-aryl conjugated architecture, but synthetic access is hindered due to limited control over the nucleophilic nature of sulfides and the air sensitivity of aromatic thiols. Here, we report a simple, one-pot, inexpensive, regioselective synthesis of highly porous poly(aryl thioether)s through polycondensation of perfluoroaromatic compounds with sodium sulfide. The unprecedented temperature-dependent para-directing formation of thioether linkages leads to a stepwise transition of the polymer extension into a network, thereby allowing fine control of the porosity and optical band gaps. The obtained porous organic polymers with ultra-microporosity (<1 nm) and sulfur as the surface functional groups show size-dependent separation of organic micropollutants and selective removal of mercury ions from water. Our findings offer easy access to poly(aryl thioether)s with accessible sulfur functionalities and higher complexity, which will help in realizing advanced synthetic designs in applications such as adsorption, (photo)catalysis, and (opto)electronics.

Direct Thiolation of the C(sp3)−H Bond Adjacent to Heteroatoms with Thiols under Alkaline Conditions

AbstractHerein, an operationally facile method for the construction of C−S bond through direct functionalization of C (sp3)−H bond adja‐cent to heteroatoms with thiols has been developed under weakly alkaline conditions. This methodology provides a convenient and efficient strategy to synthesize various aryl thioethers using a cheap and common solvent and base in moderate to good yields. The mechanistic studies indicate that a radical process is possibly involved and the sulfur radical (RS⋅) may be a reactive species during the transformations.

Bifunctional 1-Hydroxypyrene Photocatalyst for Hydrodesulfurization via Reductive C(Aryl)–S Bond Cleavage

We developed the visible-light-induced hydrodesulfurization of alkyl aryl thioethers via the reductive cleavage of the C(aryl)-S bond using 1-hydroxypyrene as a Brønsted acid-reductant bifunctional photocatalyst. The hydrodesulfurization reaction proceeded under simple reaction conditions (1-hydroxypyrene and Et3N in THF under purple LED illumination); this reaction did not require chemicals commonly used for hydrodesulfurization, such as hydrosilanes, transition metal catalysts, and/or stoichiometric amounts of metal reagents. Detailed mechanistic studies based on control experiments, spectroscopic measurements, and computational studies revealed that the cleavage of the C(aryl)-S bond and the formation of the C(aryl)-H bond proceeded via the formation of the ion pair between the radical anion of alkyl aryl thioether and Et3N+H, resulting in the generation of a sulfur radical. In addition, the 1-hydroxypyrene catalyst was regenerated via hydrogen atom transfer (HAT) from Et3N.