An organocatalytic cascade approach toward polysubstituted quinolines and chiral 1,4-dihydroquinolines-unanticipated effect of N-protecting groups

A matter of protection: The outcome of a divergent organocatalytic aza-Michael/aldol cascade process toward quinolines and 1,4-dihydroquinolines depends on the choice of the N-protecting group (see scheme; TEA = triethylamine, TMS = trimethylsilyl). Use of an electron-donating sulfonyl group results in an unanticipated aza-Michael/aldol/aromatization cascade to give polysubstituted quinolines (right). In contrast, chiral 1,4-dihydroquinolines are obtained with an electron-withdrawing sulfonyl group (left).     

Regioselectivity and the nature of the reaction mechanism in nucleophilic substitution reactions of 2,4-dinitrophenyl X-substituted benzenesulfonates with primary amines

Second-order rate constants have been measured for the reaction of 2,4-dinitrophenyl X-substituted benzenesulfonates with a series of primary amines. The nucleophilic substitution reaction proceeds through competitive S-O and C-O bond fission pathways. The S-O bond fission occurs dominantly for reactions with highly basic amines or with substrates having a strong electron-withdrawing group in the sulfonyl moiety. On the other hand, the C-O bond fission occurs considerably for the reactions with low basic amines or with substrates having a strong electron-donating group in the sulfonyl moiety, emphasizing that the regioselectivity is governed by both the amine basicity and the electronic effect of the sulfonyl substituent X. The apparent second-order rate constants for the S-O bond fission have resulted in a nonlinear Br?nsted-type plot for the reaction of 2,4-dinitrophenyl benzenesulfonate with 10 different primary amines, suggesting that a change in the rate-determining step occurs upon changing the amine basicity. The microscopic rate constants (k(1) and k(2)/k(-)(1) ratio) associated with the S-O bond fission pathway support the proposed mechanism. The second-order rate constants for the S-O bond fission result in good linear Yukawa-Tsuno plots for the aminolyses of 2,4-dinitrophenyl X-substituted benzenesulfonates. However, the second-order rate constants for the C-O bond fission show no correlation with the electronic nature of the sulfonyl substituent X, indicating that the C-O bond fission proceeds through an S(N)Ar mechanism in which the leaving group departure occurs rapidly after the rate-determining step.     

砜类化合物合成研究进展

砜类化合物具有广谱的生物活性,广泛应用于化学、医药、农药、材料科学等领域。同时作为强吸电子基团,砜类化合物可以通过碱和亲电试剂反应延长碳链,因此该类化合物的合成方法引起了国内外研究人员的高度重视,本文结合国内外学者对这方面的相关研究,重点从硫醚氧化、磺酰氯的磺酰化和亚磺酸盐的偶联三个方面对近几年来砜类化合物合成方法进行了综述。     

The Diels-Alder Reaction of 2,3-Disulfur-Substituted 1,3-Butadienes

The 2,3-disulfur-substituted 1,3-dienes (1) can be readily prepared from their stable 3-sulfolene precursors (2) by thermal extrusion of SO₂. The Diels-Alder reaction of diene (1) with several dienophiles has been studied. The substituent effect on the reactivity and regioselectivity follows the order of PhS >PhSO >PhSO₂. Lewis acid can greatly increase the regioselectivity of this reaction. The diene (1c), bearing a strong electron-withdrawing sulfonyl group, also reacted as a dienophile.     

Sulfonylation of 1,4-Diazabicyclo[2.2.2]octane: Charge-Transfer Complex Triggered C−N Bond Cleavage

A novel charge-transfer complex triggered sulfonylation of 1,4-diazabicyclo[2.2.2]octane (DABCO) with mild reaction conditions has been developed. The formation of a charge-transfer complex between electron-withdrawing (hetero)aryl sulfonyl chloride and DABCO allows the synthesis of N-ethylated piperazine sulfonamide in good yields. The reaction has a high functional group tolerance. Spectroscopic studies confirmed the charge-transfer complex formation between sulfonyl chlorides and DABCO, which facilitates the C−N bond cleavage of DABCO.     

Sulfur-based protecting groups for pyrroles and the facile deprotection of 2-(2,4-dinitrobenzene)sulfinyl and sulfonyl pyrroles

[reaction: see text] The effectiveness of simple sulfinyl and sulfonyl groups as electron-withdrawing protecting groups for pyrroles has been analyzed using (13)C NMR spectroscopy and confirmed by consideration of X-ray crystal structures. Additionally, the 2,4-dinitrobenzenesulfinyl and sulfonyl groups are shown to be effective electron-withdrawing protecting groups for pyrroles, and they can be removed by treatment with benzene thiol or thiolate under mild and specific conditions.     

Electrochemical investigation on the interaction of benzene sulfonyl 5-fluorouracil derivatives with double-stranded DNA and G-quadruplex DNA

The interaction of double-stranded(ds) and G-quadruplex(G4) DNA with sulfonyl 5-fluorouracil derivatives(5-fluoro-1-(arylsulfonyl) pyrimidine-2,4(1H,3H)-diones) was investigated in this research,in which Au electrodes modified with ds-DNA or G4-DNAs were used as a working electrode.The investigation showed that the binding affinity with G4-DNA was significantly increased when 5-fluorouracil(5-FU) was modified with arylsulfonyl groups.The presence of strong electron-withdrawing groups on benzene sulfonyl 5-FU greatly enhanced the binding selectivity(k G4-DNA /k ds-DNA).Such results provided new insights into the potential connections between the chemical structure of drug candidates and their anticancer activities.     

Carbohydrate sulfonyl chlorides for simple, convenient access to glycoconjugates

[reaction: see text] The use of carbohydrate sulfonyl chlorides is introduced as a new, facile glycoconjugation method which could find broad applications. We demonstrate the approach by synthesizing a number of glycosylated cholesterol absorption inhibitors which display high inhibitory efficacies in our recently established in vitro assay. Furthermore, we highlight an advantage of the electron-withdrawing nature of the sulfonyl linkage which allowed the synthesis of otherwise unstable azetidine conjugates.     

Rh2(II)-catalyzed nitro-group migration reactions: selective synthesis of 3-nitroindoles from β-nitro styryl azides

Rhodium carboxylate complexes (1 mol %) catalyze the migration of electron-withdrawing groups to selectively produce 3-substituted indoles from β-substituted styryl azides. The relative order of migratorial aptitude for this transformation is ester ? amide < H < sulfonyl < benzoyl ? nitro.     

Application of the dissociative electron transfer theory and its extension to the case of in-cage interactions in the electrochemical reduction of arene sulfonyl chlorides

Important aspects of the electrochemical reduction of a series of substituted arene sulfonyl chlorides are investigated. An interesting autocatalytic mechanism is encountered where the starting material is reduced both at the electrode and through homogeneous electron transfer from the resulting sulfinate anion. This is due to the homogenous electron transfer from the two-electron reduction produced anion (arene sulfinate) to the parent arene sulfonyl chloride. As a result, the reduction process and hence the generated final products depend on both the concentration of the substrate and the scan rate. A change is also observed in the reductive cleavage mechanism as a function of the substituent on the phenyl ring of the arene sulfonyl chloride. With 4-cyano and 4-nitrophenyl sulfonyl chlorides a "sticky" dissociative ET mechanism takes place where a concerted ET mechanism leads to the formation of a radical/anion cluster before decomposition. With other substituents (MeO, Me, H, Cl, and F) a "classical" dissociative ET is followed, where the ET and bond cleavage are simultaneous. The dissociative electron transfer theory, as well as its extension to the case of strong in-cage interactions between the produced fragments, along with gas phase chemical quantum calculations results helped us to rationalize both the observed change in the ET mechanism and the occurrence of the "sticky" dissociative ET mechanism. The radical/anion pair interactions have been determined both in solution as well as in the gas phase. The study also shows that despite the low magnitude of in-cage interactions in acetonitrile compared to the gas phase their existence strongly affects the dynamics of the involved reactions. It also shows that, as expected, these interactions are reinforced by the existence of strong electron-withdrawing substituents. The occurrence of an autocatalytic process and the existence of the radical/anion interaction may explain the differences previously observed in the reduction of these compounds in different media.     

Rhamnosylation: diastereoselectivity of conformationally armed donors

The α/β-selectivity of super-armed rhamnosyl donors have been investigated in glycosylation reactions. The solvent was found to have a minor influence, whereas temperature was crucial for the diastereoselectivity. At very low temperature, a modest β-selectivity could be obtained, and increasing temperature gave excellent α-selectivity. The donors were highly reactive, and activation was observed at temperatures as low as -107 °C. Different promoter systems and leaving groups were investigated, and only activation with a heterogeneous catalyst increased the amount of the β-anomer significantly. By introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in β-product was observed.     

电化学法研究苯磺酰类5-氟尿嘧啶衍生物与双链和G-四链DNA的相互作用

本文以自组装法制得的双链DNA（ds．DNA）和G-四链体DNA（G4-DNA）修饰的金电极为工作电极,以Fe（CN）63-／4-为电活性指示剂,采用循环伏安法和微分脉冲伏安法研究了非电活性苯磺酰类5-氟尿嘧啶衍生物与ds-DNA和G4．DNA的相互作用．实验结果表明：苯磺酰类5-氟尿嘧啶与ds-DNA或G4．DNA的结合常数与苯环上邻、对位取代基的得失电子能力密切相关,强吸电子基团取代有利于苯磺酰类5-氟尿嘧啶选择性结合G-四链体DNA．     

Liquid structure of the ionic liquid, 1-methyl-4-cyanopyridinium bis{(trifluoromethyl)sulfonyl}imide determined from neutron scattering and molecular dynamics simulations

The liquid structure of 1-methyl-4-cyanopyridinium bis{(trifluoromethyl)sulfonyl}imide, a prototypical ionic liquid containing an electron-withdrawing group on the cation, has been investigated at 368 K. Experimental neutron scattering combined with empirical potential structure refinement analysis of the data and classical molecular dynamics simulations have been used to probe the liquid structure in detail. Both techniques generated highly consistent results that provide valuable validation of the force fields and refinement approaches. A significant degree of apparent charge ordering is found in the liquid structure, although the nonspherical shape of the ions results in interpenetration of cations into the first shell of adjacent cations, with much shorter closest contact distances than the averaged center-of-mass cation-cation and cation-anion separations.     

Ruthenium-catalyzed meta sulfonation of 2-phenylpyridines

A selective catalytic meta sulfonation of 2-phenylpyridines was found to occur in the presence of (arene)ruthenium(II) complexes upon reaction with sulfonyl chlorides. The 2-pyridyl group facilitates the formation of a stable Ru-C(aryl) σ bond that induces a strong para-directing effect. Electrophilic aromatic substitution proceeds with the sulfonyl chloride to furnish a sulfone at the position meta to the chelating group. This new catalytic process offers access to atypical regioselectivity for reactions involving chelation-assisted cyclometalation.     

Bench-Stable Electrophilic Fluorinating Reagents for Highly Selective Mono- and Difluorination of Silyl Enol Ethers

Efficient methods for the synthesis of fluorinated compounds have been intensively studied, recently. Development of practical fluorinating reagents is indispensable for this purpose. Herein, bench-stable electrophilic fluorinating reagents were synthesized as N-fluorobenzenesulfonimide (NFSI) substitutes. Reagents obtained by replacing one of the NFSI sulfonyl groups with an acyl group led to the highly selective monofluorination of silyl enol ethers with suppression of undesired overreaction, that is, difluorination. On the other hand, reagents bearing electron-withdrawing substituents at NFSI benzenesulfonyl groups efficiently facilitated the difluorination of silyl enol ethers under base-free conditions. Thus, both mono- and difluorinated target materials were prepared from the same substrate.     

Effect of para-substituents on alkaline earth metal ion extraction by proton di-ionizable calix[4]arene-crown-6 ligands in cone, partial-cone and 1,3-alternate conformations

Two carboxylic acid or N-(X)sulfonyl carboxamide groups were incorporated into calix[4]arene-crown-6 compounds to afford di-ionizable ligands for use in divalent metal ion separations. Acidities of the N-(X)sulfonyl carboxamide groups were tuned by variation of the electron-withdrawing properties of X. Cone, partial-cone and 1,3-alternate conformations were obtained by different synthetic strategies and their structures verified by NMR spectroscopy. Competitive solvent extractions of alkaline earth metal cations from aqueous solutions into chloroform were performed and the results compared with those reported previously for di-ionizable p-tert-butylcalix[4]arene-crown-6 analogues to probe the influence of the para-substituent on the calix[4]arene scaffold on extraction selectivity and efficiency.     

Synthesis of 3-sulfonyl coumarins through radical sulfonylation with disulfides under catalyst-free conditions

An efficient and convenient aryl sulfonyl introducing strategy for the synthesis of 3-sulfonyl coumarins via ipso-cyclization/1,2-ester migration from substituted phenyl 3-phenylpropiolates with disulfides and potassium persulfate as sulfonylating reagents was developed, halogen and many other electron-withdrawing or -donating functional groups are tolerated. When naphthalen-1-yl 3-phenylpropiolate was used as a starting material, a spiro compound was obtained via ipso-cyclization.     

Diamidophosphites with isomeric carborane fragments: a comparison of catalytic activity in asymmetric Pd-catalyzed allylic substitution reactions

New chiral diamidophosphite ligands containing electron-donating 9-meta-carborane and electron-withdrawing 1-meta-carborane substituents have been synthesized. The ligand 3a with an electron-donating group demonstrated high enantioselectivity in Pd-catalyzed allylic substitution reactions with C-, S- and N-nucleophiles (up to 98% ee). The isomeric diamidophosphite 3b bearing an electron-withdrawing substituent showed in all cases, moderate-to-poor conversion and lower enantioselectivity.     

Substituted 2-norbornyl carbenes

A series of endo-6-substituted bicyclo[2.2.1]hept-2-yl carbenes have been generated by pyrolysis of the sodium salt of the tosylhydrazone precursors. The endo-6-trimethylsilyl and endo-6-thiomethoxy substituted carbenes give 1,3-migration of these substituents to the carbene center. However groups such as methyl, CH₂SiMe₃, phenyl, and methoxy are ineffective 1,3-migrating groups. The facile 1,3-migration of trimethylsilyl and thiomethoxy has been rationalized in terms of stabilized transition states where the migrating group interacts effectively with the carbene vacant orbital. In the cases of endo-6-thiomethoxy and methoxy derivatives, the carbene also inserts effectively into the methyl group of the substituent. Heteroatom stabilization of the transition state for C-H insertion facilitates these processes. Certain exo-6-substituted bicyclo[2.2.1]hept-2-yl carbenes have also been generated. While the exo-6-thiomethoxy and carbomethoxy systems give exclusive 1,3-hydrogen migration, the exo-6-sulfonyl derivative gives, in addition to 1,3-hydrogen migration, an alkene product derived from 1,2-hydrogen migration. The lowered propensity for 1,3-hydrogen migration is attributed to the strong electron-withdrawing sulfonyl group, which decreases the hydridic 1,3-interaction with the carbene vacant orbital.     

Kinetic enolate formation by lithium arylamide: effects of basicity on selectivity

Five ketones R1COCH2R2 (1a-e) were enolized in tetrahydrofuran solvent employing lithium arylamides with different electron-withdrawing and -donating substituents on the phenyl ring (4a-e). Enolate selectivity is unaffected by a moderate electron-releasing or -withdrawing group, but significantly enhanced by strong electron-withdrawing substituents to yield predominantly Z-enolate. Outstanding selectivity was achieved with lithium trichloroanilide (5) and lithium diphenylamide (6). The results are rationalized in terms of electronic effects on the tightness of the transition states.