Sulfonyl Research Articles

Correlating Solution- and Solid-State Structures of Conformationally Flexible Resorcinarenes: Significance of a Sulfonyl Group in Intramolecular Self-Inclusion.

The synthesis of tetramethoxyresorcinarene podands bearing p‐toluene arms connected by ‐SO3‐ (1) and ‐CH2O‐ (2) linkers is presented herein. In the solid state, the resorcinarene podand 1 forms an intramolecular self‐inclusion complex with the pendant p‐toluene group of a podand arm, whereas the resorcinarene podand 2 does not show self‐inclusion. The conformations of the flexible resorcinarene podands in solution were investigated by variable‐temperature experiments using 1D and 2D NMR spectroscopic techniques as well as by computational methods, including a conformational search and subsequent DFT optimisation of representative structures. The 1H NMR spectra of 1 and 2 at room temperature show a single set of proton signals that are in agreement with C 4v symmetry. At low temperatures, the molecules exist as a mixture of boat conformations featuring slow exchange on the NMR timescale. Energy barriers (ΔG ≠ 298) of 55.5 and 52.0 kJ mol−1 were calculated for the boat‐to‐boat exchange of 1 and 2, respectively. The results of the ROESY experiments performed at 193 K and computational modelling suggest that in solution the resorcinarene podand 1 adopts a similar conformation to that present in its crystal structure, whereas podand 2 populates a more versatile range of conformations in solution.

A remarkable adsorbent for removal of bisphenol S from water: Aminated metal-organic framework, MIL-101-NH2

Purification of water contaminated with organics has recently attracted much attention. In this study, the adsorptive removal of bisphenol S (BPS) from water was studied by using a metal-organic framework (MOF) MIL-101 with or without –NH2 functionality. In order to understand the adsorption of BPS in detail, adsorption of other relevant materials, such as bisphenol A (BPA) and sulfamethoxazole (SMZ), was also carried out. The adsorbed quantity increased significantly for SMZ and BPS (different from BPA adsorption) with the introduction of –NH2 groups onto MIL-101 even though the surface area of MIL-101-NH2 is much smaller than that of the pristine MIL-101. Moreover, adsorption of BPS was carried out over a wide pH range in order to understand the adsorption mechanism. It could be suggested that hydrogen bonding (with six-membered ring structure) between –S(O)2 and NH2 of MIL-101-NH2 could be an important contribution to the adsorption of BPS and SMZ. Moreover, H-bonding between –NH2 of the MOF and –OH (of BPS and BPA) or –NH2 (of SMZ) might also be possible. SMZ adsorption could remarkably be increased by loading –NH2 on MIL-101, because of another mechanism of ion-dipole interaction between the anionic N of SMZ and the –NH2 of MIL-101-NH2. Finally, MIL-101-NH2 showed the highest adsorption capacity for BPS (513 mg/g, at pH 7), compared with any reported results, and was recyclable after simple ethanol washing, suggesting the possible application of aminated MOFs in the adsorption of organics with sulfonyl group like BPS.

Synthesis, characterization and molecular docking studies of Co(II) metal complex of sulfathiazole

Sulfathiazole (SFTZ) is a sulfonamide used for the treatment of bacterial infection. The cobalt complex of sulfathiazole was synthesized by reaction of sulfathiazole with CoCl2.6H2O. The metal complex was characterized based on AAS, UV, IR, 1H NMR spectroscopy and X-ray powder diffraction. The electronic spectrum of the ligand showed intra ligand charge transfer (ILCT) which were assigned to the chromophores present in the ligand, while that of the complex suggested intra ligand charge transfer (ILCT) and ligand to metal charge transfer (LMCT). The IR spectra of the complexes showed the involvement of amine, sulfonyl and cyano group in coordination to the metal ion. This showed that sulfathiazole acted as a tridentate ligand. 1H NMR spectrum of [Co(SFTZ)] complex further showed the involvement of the amine and sulfonyl group in coordination to the metal ions. The structure of [Co(SFTZ)] complex was assigned as trigonal. The crystal structure of [Co(SFTZ)] complex belongs to cubic system, space group P1, with cell parameters of a = 4.007 Å, b = 5.0078 Å, c = 5.9844 Å, 𝑉 = 30.61 Å3, α = 90o, β 90o, γ = 90o. Molecular docking suggested that the ligand/complex binded effectively with the E. Coli and S. aureus because their global binding energies were negative. The binding interactions of ligand/complex with E. Coli and S. Aureus were predicted. Molecular docking predicted the feasibility of the biochemical reactions before experimental investigation.
 
 Bull. Chem. Soc. Ethiop. 2020, 34(1), 83-92.
 DOI: https://dx.doi.org/10.4314/bcse.v34i1.8

Diastereo- and Enantioselective Catalytic Radical Oxysulfonylation of Alkenes in β,γ-Unsaturated Ketoximes

Summary The asymmetric radical-initiated difunctionalization of internal alkenes, which creates two vicinal stereocenters, has been a significant synthetic challenge despite the tremendous progress achieved for terminal alkenes. This is attributable to the common stepwise mechanism that involves an initial free radical addition to the alkene in a nonstereoselective fashion. We report here the first asymmetric radical 1,2-oxysulfonylation of both terminal and internal aryl alkenes in β,γ-unsaturated ketoximes in the presence of copper(I)-cinchona alkaloid-based sulfonamide catalyst. The experimental and computational mechanistic studies collectively support a CuII-CuI mechanism featuring fast, reversible addition of sulfonyl radicals to alkenes and subsequent rate- and stereo-determining C–O bond formation, namely, a scenario under Curtin-Hammett kinetic control. The method provides a robust platform for collective synthesis of a diverse array of valuable chiral sulfonyl-containing building blocks.

Computational Prediction of Chiral Iron Complexes for Asymmetric Transfer Hydrogenation of Pyruvic Acid to Lactic Acid.

Density functional theory calculations reveal a formic acid-assisted proton transfer mechanism for asymmetric transfer hydrogenation of pyruvic acid catalyzed by a chiral Fe complex, FeH[(R,R)-BESNCH(Ph)CH(Ph)NH2](η6-p-cymene), with formic acid as the hydrogen provider. The rate-determining step is the hydride transfer from formate anion to Fe for the formation and dissociation of CO2 with a total free energy barrier of 28.0 kcal mol−1. A series of new bifunctional iron complexes with η6-p-cymene replaced by different arene and sulfonyl groups were built and computationally screened as potential catalysts. Among the proposed complexes, we found 1g with η6-p-cymene replaced by 4-isopropyl biphenyl had the lowest free energy barrier of 26.2 kcal mol−1 and excellent chiral selectivity of 98.5% ee.

Site-Selective C-H Functionalization-Sulfination Sequence to Access Aryl Sulfonamides.

Aryl sulfinates are precursors to a diverse number of sulfonyl-derived arenes, which are common motifs in pharmaceuticals and agrochemicals. Here, we report a site-selective two-step C–H sulfination sequence via aryl sulfonium salts to access aryl sulfonamides. Combined with site-selective aromatic thianthrenation, an operationally simple one-pot palladium-catalyzed protocol introduces the sulfonyl group using sodium hydroxymethylsulfinate (Rongalite) as a source of SO22–. The hydroxymethyl sulfone intermediate generated from the catalytic process can be employed as a synthetic handle to deliver a variety of sulfonyl-containing compounds.

Photocatalyst-free visible light driven synthesis of (E)-vinyl sulfones from cinnamic acids and arylazo sulfones

A photocatalyst-free visible light mediated decarboxylative sulfono functionalization protocol has been explored for the synthesis of (E)-vinyl sulfones from cinnamic acids and bench-stable arylazo sulfones. The latter have been utilized as sulfonyl radical precursors under blue LED irradiation along with Cs2CO3, air and KI to obtain the vinyl aryl sulfones as well as vinyl alkyl sulfones in moderate to excellent yields. Besides the non-photocatalytic conditions, high ecosustainability, low cost, ease of operation and access to vinyl alkyl sulfones are certain indispensable traits of the developed method.

C-H Sulfonylation via 1,3-Rearrangement of Sulfonyl Group in N-Protected 3-Bis-sulfonimidoindole Derivatives Using Fluorine Reagent.

A C-H sulfonylation of N-protected 3-bis-sulfonimidoindole derivatives via a 1,3-rearrangement of a sulfonyl group on a bis-sulfonimide moiety using tetra-n-butylammonium fluoride (TBAF) was developed to provide 2-sulfonyl-3-sulfonamidoindole derivatives in high yields as a novel Csp2-H functionalization of heterocycles. The rearrangement of the sulfonyl group proceeded through an intermolecular addition of the desorbed sulfinyl ion from the bis-sulfonimide moiety in the substrate.

Dioxygen-Triggered Oxo-Sulfonylation of Hydrazones.

A simple and highly efficient method for the oxo-sulfonylation of aldehyde-derived hydrazones has been developed using sulfinic acid as a source of sulfonyl group and oxygen as a green oxidant under metal-free conditions at room temperature. The present C-O and N-S bond-forming difunctionalization strategy affords diversely functionalized N-acylsulfonamides in good yield. Experimental results suggest a radical mechanistic pathway of the present reaction.

Stabilizing Formamidinium Lead Iodide Perovskite by Sulfonyl‐Functionalized Phenethylammonium Salt via Crystallization Control and Surface Passivation

Bulky organic ammonium cations have been widely used to stabilize lead halide perovskites via surface passivation or dimensionality modulation. Herein, a sulfonyl fluoride‐functionalized phenethylammonium salt (SF‐PEA) is reported as a bifunctional additive to stabilize the formamidinium lead iodide (FAPbI3) perovskite. The sulfonyl group is found to interact with PbI2 in the precursor and slow down the crystallization of FAPbI3 during thermal annealing, leading to improved crystalline quality and decreased structural defects. After annealing, the spontaneous assembly of SF‐PEA on the crystal surface of FAPbI3 not only passivates the surface defects, but also protects the perovskite from phase transition that is caused by strain or moisture invasion. The resulting FAPbI3 films are extremely stable, which can maintain their black phase for more than 3 months in air with 40–50% relative humidity, much better than pristine and unsubstituted phenethylammonium (PEA)‐based samples. Because of the greatly improved phase stability and crystallization quality, a champion power conversion efficiency (PCE) of 21.25% (certified PCE of 20.70%) is achieved in planar n–i–p structured solar cells, which is the highest one among “methylammonium‐free” FAPbI3 perovskite photovoltaics.

Sulfonyl Group Dance: A Tool for the Synthesis of 6-Azido-2-sulfonylpurine Derivatives.

9-Substituted 2-chloro-6-sulfonylpurines provide 6-azido-2-sulfonylpurine derivatives with 61-83% yields when treated with sodium azide. Under optimized reaction conditions, the title compounds are obtained in a one-pot process, which involves a sequential treatment of 2,6-dichloropurines with a selected sodium sulfinate and sodium azide. Such a sulfonyl group dance (functional group swap) results from a cascade of SNAr reactions, which are facilitated by azidoazomethine-tetrazole (azide-tetrazole) tautomeric equilibrium. The formation of Meisenheimer-type intermediates as tetrazolopurine tautomers was supported by various spectroscopic methods, including 15N NMR.

Catalytic Decarboxylative Radical Sulfonylation

Summary Sulfones are key structural motifs in pharmaceuticals and agrochemicals, and their synthesis is of paramount importance in organic chemistry. While nucleophilic and electrophilic C(sp3)-sulfonylation are well documented, radical C(sp3)-sulfonylation remains elusive. Herein, we report the decarboxylative radical sulfonylation with sulfinates. With the merger of 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) and Cu(OTf)2 as catalysts, the visible-light-induced reaction of redox-active esters of aliphatic carboxylic acids with organosulfinates at room temperature provides the corresponding decarboxylative sulfonylation products in satisfactory yields. This redox-neutral protocol exhibits broad substrate scope and wide functional group compatibility, enabling the late-stage modification of complex natural products and bioactive pharmaceuticals. The synthetic utility of the method is further demonstrated by the improved synthesis of anti-prostate cancer drug bicalutamide. A mechanism involving sulfonyl group transfer from Cu(II)–SO2R to alkyl radicals is proposed.

Structure Activity Relationship of 4‐Phenyl‐1‐(1‐Acylindolin‐5‐Ylsulfonyl)Pyrrolidin‐2‐Ones on Anticancer Activity

Microtubules play a dynamic role during cell division. In our early studies 4‐phenyl‐1‐(1‐acylindoline‐5‐sulfonylimidazolones were thoroughly explored and found that the indoline bicyclic system next to the sulfonyl group is very important for cytotoxicity. In this research, imidazolone motif was replaced with pyrrolidin‐2‐one and this isosteric replacement led to show some promising activity. Thus, the structure activity relationship of 4‐phenyl‐1‐(1‐acylindolin‐5‐ylsulfonyl)pyrrolidin‐2‐ones with the various acyl group at the indoline NH was explored. The presence of benzoyl groups with electron donating group was the more favorable for cytotoxicity while less bulky alkanoyl groups led to decrease cytotoxicity.

Crystal structure of ethyl 2-(5-amino-1-benzene-sulfonyl-3-oxo-2,3-di-hydro-1H-pyrazol-2-yl)acetate.

In the title compound, C13H15N3O5S, the two rings face each other in a 'V' form at the S atom, with one N-H⋯O=S and one C-H⋯O=S contact from the pyrazolyl substituents to the sulfonyl group. Two classical hydrogen bonds from the amine group, one of the form N-H⋯O=S and one N-H⋯O=Coxo, link the mol-ecules to form layers parallel to the bc plane.

Grafting density-induced smectic A to hexagonal columnar transition in mesogen-free isotactic liquid crystalline polyethers with n-dodecylsulfonyl side groups

Highly dipolar mesogen-free liquid crystalline polymers are excellent candidates for achieving large spontaneous polarization under relatively low electric fields for advanced electrical and optical applications. In this report, the effect of grafting density of n-dodecylsulfonyl side chains on the mesogen-free liquid crystalline self-assembly of comb-like isotactic poly(oxypropylene) was studied. When the grafting density was 80–100%, a stable 21 helical chain conformation was induced by the strong dipole-dipole interactions among the sulfonyl groups in the side chains. Consequently, a smectic A self-assembly was induced. When the grafting density decreased to 60–80%, a poor and possibly imbalanced 21 helical chain conformation was formed due to the frequent absence of the n-dodecylsulfonyl side chains along the main chain. As a result, a hexagonal columnar self-assembly was realized. This study demonstrated that a delicate interplay between the molecular defects and dipole-dipole interactions can lead to different self-assembly structures.

Synthesis and Structural Elucidation of 1,2‐Disubstituted 3‐Fluoropiperidines

The work described details the reaction between Selectfluor® and a series of 1‐carbonyloxy and 1‐sulfonyl 2‐piperidines in order to generate 3‐fluoro‐2‐methoxypiperidines 3a–f. Their subsequent reaction with allyltrimethylsilane, in the presence of BF3 and TiCl4, is then reported. Studies involving a combination of single‐crystal X‐ray crystallography and NMR spectroscopy indicate that the allylation process is cis‐selective for both carbamate and sulfonamide variants and that optimal levels of diastereoselectivity are obtained using the N‐2‐nitrobenzene sulfonyl (2‐Ns) group. In this manner, the synthesis of a series of 2‐allyl 3‐fluoro‐substituted piperidines (5a, c–f) was achieved. The conversion of both the cis and trans‐N‐tosyl adducts (5d) into 3‐fluorinated analogues of the natural products pelletierine (10) and coniine (11) is subsequently detailed.

Synthesis of N‐Sulfonyl Pyrazoles Through Cyclization Reactions of Sulfonyl Hydrazines with Enaminones Promoted by p‐TSA

A strategy for the rapid synthesis of 3‐substituted N‐sulfonyl pyrazoles via p‐TSA‐promoted cyclization reactions of sulfonyl hydrazines with N,N‐dimethyl enaminones has been developed. This method achieves both the formation of pyrazole ring and the continued retention of sulfonyl group, providing a series of 3‐substituted N‐sulfonyl pyrazoles in moderate to good yields with good functional group tolerance, easily available starting materials, and can be scaled‐up.

Activated Monomer Polymerization of an N-Sulfonylazetidine.

Previously, N-(methanesulfonyl)azetidine (MsAzet) was found to polymerize anionically via ring-opening at temperatures >100 °C to form p(MsAzet) in the presence of an anionic initiator. In the current report, potassium(azetidin-1-ylsulfonyl) methanide (KMsAzet), formed from deprotonation of the methanesulfonyl group of MsAzet by KHMDS, is shown to undergo spontaneous AROP at room temperature to form p(N-K-MsAzet). The structure of p(N-K-MsAzet) differs from that of p(MsAzet), as the sulfonyl groups are incorporated into the polymer backbone of p(N-K-MsAzet). Reaction of p(N-K-MsAzet) with MeOH produces p(N-H-MsAzet), a semicrystalline polymer with a structure like that of polyamides, but with sulfonylamides in place of the carboxamides found in polyamides. Reaction of p(N-K-MsAzet) with benzyl bromide results in the formation of amorphous p(N-Bn-MsAzet). P(N-K-MsAzet) is hypothesized to form via an activated monomer anionic polymerization; this is supported by polymerization kinetic data and structural characterization of the resulting polymers.

Copper-mediated synthesis of drug-like bicyclopentanes.

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles 3-13. The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.

Investigating the binding mechanism of sphingosine kinase 1/2 inhibitors: Insights into subtype selectivity by homology modeling, molecular dynamics simulation and free energy calculation studies

Sphingosine 1-phosphate (S1P) is a lipid signaling molecule that is implicated in a variety of pathologies, including cancer, inflammation and pulmonary arterial hypertension. Sphingosine kinases (SPHK1 and SPHK2) are the key targets in the synthesis of S1P. However, selective and potent inhibitors of SPHK are lacking, especially for SPHK2. In this work, we predicted the detailed interactions between the inhibitors and SPHK using various molecular modeling methods. As a result, some residues (Asp 81, Ile174, Asp178, Phe288 of SPHK1 and Leu297, Ser298, Asp308 of SPHK2) were found as key binding sites of their inhibitors. The reason why PF543 is highly SPHK1 selective might be that its sulfonyl group conflicts with residue His556 of SPHK2. In SPHK1, the corresponding residue is His397. Compounds with a substituent occupying the pocket made up by His397 may show high selectivity towards SPHK1. Moreover, in case of SPHK2, introducing suitable substituents that insert into the region of Cys533 or designing a flexible polar head that interacts with Leu297 and Ser298 might improve the selectivity towards SPHK2.