Sulfonamides as N-Centered Radical Precursors for C-N Coupling Reactions To Generate Amidines.

Nitrogen-centered radicals (NCRs) are valuable intermediates for the construction of C-N bonds. Traditional methods for the generation of NCRs employ toxic radical initiators, transition metal catalysts, photocatalysts, or organometallic reagents. Herein, we report a novel strategy for the generation of NCRs toward the construction of C-N bonds under transition-metal-free conditions. Thus, super-electron-donor (SED) 2-azaallyl anions undergo single-electron transfer (SET) with sulfonamides, forming aminyl radicals (R2N•, R = alkyl) and culminating in the generation of amidines bearing various functional groups (33 examples, up to 96% yield). Broad substrate scope and gram-scale telescoped preparation demonstrate the practicality of this method. Radical clock and electron paramagnetic resonance (EPR) experiments support the proposed radical coupling pathway between the generated N-centered radical and the C-centered 2-azaallyl radical.

Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives.

Hydrogen atom transfer (HAT) processes are among the most useful approaches for the selective construction of C(sp3)-C(sp3) bonds. 1,5-HAT with heteroatom-centered radicals (O•, N•) have been well established and are favored relative to other 1,n-HAT processes. In comparison, net 1,2-HAT processes have been observed infrequently. Herein, the first amidyl radicalls are reported that preferentially undergo a net 1,2-HAT over 1,5-HAT. Beginning with single electron transfer from 2-azaallyl anions to N-alkyl N-aryloxy amides, the latter generate amidyl radicals. The amidyl radical undergoes a net-1,2-HAT to generate a C-centered radical that participates in an intermolecular radical-radical coupling with the 2-azaallyl radical to generate 1,2-diamine derivatives. Mechanistic and EPR experiments point to radical intermediates. Density functional theory calculations provide support for a base-assisted, stepwise-1,2-HAT process. It is proposed that the generation of amidyl radicals under basic conditions can be greatly expanded to access α-amino C-centered radicals that will serve as valuable synthetic intermediates.

Super-Electron-Donor 2-Azaallyl Anions Enable Construction of Isoquinolines.

Herein is introduced the application of "super-electron-donor"(SED) 2-azaallyl anions in a tandem reduction/radical cyclization/radical coupling/aromatization protocol that enables the rapid construction of isoquinolines. The value of this transition-metal-free method is highlighted by the wide range of isoquinoline ethyl amines prepared with good functional group tolerance and yields. An operationally simple gram scale synthesis is also conducted, confirming the scalability.

Aryl acrylonitriles synthesis enabled by palladium-catalyzed α-alkenylation of arylacetonitriles with vinyl halides/triflates.

Aryl acrylonitriles are an important subclass of acrylonitriles in the medicinal chemistry and pharmaceutical industry. Herein, an efficient synthesis of aryl acrylonitrile derivatives using a Palladium/NIXANTPHOS-based catalyst system was developed. This approach furnishes a variety of substituted and functionalized aryl acrylonitriles (up to 95% yield). The scalability of the transformation and the synthetic versatility of aryl acrylonitrile were demonstrated.

Nickel-catalyzed enantioselective vinylation of aryl 2-azaallyl anions.

A unique enantioselective nickel-catalyzed vinylation of 2-azaallyl anions is advanced for the first time. This method affords diverse vinyl aryl methyl amines with high enantioselectivities, which are frequently occurring scaffolds in natural products and medications. This C-H functionalization method can also be extended to the synthesis of enantioenriched 1,3-diamine derivatives by employing suitably elaborated vinyl bromides. Key to the success of this process is the identification of a Ni/chiraphos catalyst system and a less reducing 2-azaallyl anion, all of which favor an anionic vinylation route over a background radical reaction. A telescoped gram scale synthesis and a product derivatization study confirmed the scalability and synthetic potential of this method.

Transition-metal-free allylation of 2-azaallyls with allyl ethers through polar and radical mechanisms.

Allylation of nucleophiles with highly reactive electrophiles like allyl halides can be conducted without metal catalysts. Less reactive electrophiles, such as allyl esters and carbonates, usually require a transition metal catalyst to facilitate the allylation. Herein, we report a unique transition-metal-free allylation strategy with allyl ether electrophiles. Reaction of a host of allyl ethers with 2-azaallyl anions delivers valuable homoallylic amine derivatives (up to 92%), which are significant in the pharmaceutical industry. Interestingly, no deprotonative isomerization or cyclization of the products were observed. The potential synthetic utility and ease of operation is demonstrated by a gram scale telescoped preparation of a homoallylic amine. In addition, mechanistic studies provide insight into these C(sp3)-C(sp3) bond-forming reactions.

Transition-metal-free C(sp3)-H/C(sp3)-H dehydrogenative coupling of saturated heterocycles with N-benzyl imines.

A unique C(sp3)-H/C(sp3)-H dehydrocoupling of N-benzylimines with saturated heterocycles is described. Using super electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with formation of new C-C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which determines the chemoselectivity of the radical-radical coupling reaction. It is noteworthy that this procedure avoids the use of traditional strong oxidants and transition metals.

Synthesis and antitumor activity of novel steroidal imidazolium salt derivatives.

Sixty-one novel steroidal imidazolium salt derivatives were synthesized and evaluated in vitro against a panel of human tumor cell lines. The results showed that diosgenin‒imidazolium salt derivatives displayed much higher cytotoxic activities than cholesterol‒imidazolium salts and dehydroepiandrosterone‒imidazolium salts. The SARs results suggested that the existence of substituted 5,6-dimethyl-benzimidazoles or benzimidazole ring and substitution of the imidazolyl-3α-position with a 2-bromobenzyl or 2-naphthylmethyl group could be critical for promoting cytotoxic activity. Diosgenin‒imidazolium salt a30 was found to be the most potent compound with IC50 values of 0.44-0.79 µM against five human tumor cell lines. Compound a24 showed inhibitory activity selectively against SMMC-7721 cell lines with IC50 value of 0.21 µM and 54-fold more sensitive to DDP. Moreover, compound a30 inhibited cell proliferation through inducing the G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.

Synthesis of Benzofuran Derivatives through Cascade Radical Cyclization/Intermolecular Coupling of 2-Azaallyls.

Benzofurans are among the most popular structural units in bioactive natural products, however, the synthesis of such structures by radical cyclization cascade reactions is rare. Herein, we report a mild and broadly applicable method for the construction of complex benzofurylethylamine derivatives through a unique radical cyclization cascade mechanism. Single-electron transfer (SET) from 2-azaallyl anions to 2-iodo aryl allenyl ethers initiates a radical cyclization that is followed by intermolecular radical-radical coupling. This expedient approach enables the synthesis of a range of polycyclic benzofurans that would otherwise be difficult to prepare.

Transition-Metal-Free Radical C(sp3)-C(sp2) and C(sp3)-C(sp3) Coupling Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-Partners.

The past decade has witnessed the rapid development of radical generation strategies and their applications in C-C bond-forming reactions. Most of these processes require initiators, transition metal catalysts, or organometallic reagents. Herein, we report the discovery of a simple organic system (2-azaallyl anions) that enables radical coupling reactions under transition-metal-free conditions. Deprotonation of N-benzyl ketimines generates semistabilized 2-azaallyl anions that behave as "super-electron-donors" (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2-azaallyl anions into persistent 2-azaallyl radicals, which capture the aryl and alkyl radicals to form C-C bonds. The radical coupling of aryl and alkyl radicals with 2-azaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogenous radical initiators or transition metal catalysts. Radical clock studies and 2-azaallyl anion coupling studies provide mechanistic insight for this unique reactivity.

Synthesis and antitumor activity of novel N-substituted tetrahydro-ß-carboline-imidazolium salt derivatives.

The synthesis of a series of novel N-substituted tetrahydro-ß-carboline-imidazolium salt derivatives is presented. The biological properties of the compounds were evaluated in vitro against a panel of human tumor cell lines. The results suggest that the benzimidazole ring and 1-(naphthalen-2-yl)ethan-1-one or 2-naphthylmethyl substituent at the imidazolyl-3-position were vital for modulating cytotoxic activity. Compound 41 was observed as a potent derivative with IC50 values of 3.24-8.78 µM and exhibited cytotoxic activity selectively against HL-60, A-549 and MCF-7 cell lines. Meanwhile, high inhibitory activities selectively against HL-60 and MCF-7 cell lines were observed for compound 51. Moreover, compound 51 was able to induce G1 phase cell cycle arrest and apoptosis in MCF-7 cells. The cytotoxicity of compound 51 against human normal lung epithelial cell line BEAS-2B was further evaluated.

Indicator displacement assay for cholesterol electrochemical sensing using a calix[6]arene functionalized graphene-modified electrode.

A novel electrochemical method has been developed towards cholesterol detection based on competitive host-guest interaction by selecting methylene blue (MB) and calix[6]arene functionalized graphene (CX6-Gra) as the "reporter pair". In the presence of cholesterol, the MB molecules are displaced by cholesterol in the CX6-Gra.MB complex, leading to a "switch off" electrochemical response. A linear response range of 0.50 to 50.00 µM for cholesterol with a low detection limit of 0.20 µM (S/N = 3) was obtained by using the proposed method. This method could be successfully utilized to detect cholesterol in serum samples, and may be expanded to the analysis of other non-electroactive species. Besides, the host-guest interaction between cholesterol and CX6 was studied by molecular modeling calculations, which revealed that the complexation could reduce the energy of the system and the complex of a 1 : 1 host-guest stoichiometry had the lowest binding free energy of -8.01 kcal mol(-1). In addition, the constructed electrochemical sensing platform is important as it does not use any enzyme or antibody for the detection of cholesterol efficiently and selectively over common interfering species.

Fluorescent Detection of Tadalafil Based on Competitive Host-Guest Interaction Using p-Sulfonated Calix[6]arene Functionalized Graphene.

A competitive fluorescence method toward tadalafil detection has been developed based on host-guest recognition by selecting rhodamine B (RhB) and p-sulfonated calix[6]arene functionalized graphene (CX6-Gra) as the "reporter pair". Upon the presence of tadalafil to the performed CX6-Gra-RhB complex, the RhB molecules are displaced by tadalafil, leading to a "switch-on" fluorescence signal. The observed fluorescence signal can be used for quantitative detection of tadalafil ranging from 1.00 to 50.00 µM with a detection limit of 0.32 µM (S/N = 3). The inclusion complex of tadalafil and CX6 was studied by molecular docking and the results indicated that a 1:1 host-guest stoichiometry had the lowest ΔG value of -7.18 kcal/mol. The docking studies demonstrated that the main forces including π-π interactions, electrostatic interactions, and hydrophobic interactions should be responsible for the formation of this inclusion compound. The mechanism of the competitive host-guest interaction was clarified. The binding constant (K) of the tadalafil/CX6 complex was more than 5 times greater than that of RhB/CX6.

Highly sensitive electrochemical sensor based on ß-cyclodextrin-gold@3, 4, 9, 10-perylene tetracarboxylic acid functionalized single-walled carbon nanohorns for simultaneous determination of myricetin and rutin.

The application of macrocyclic hosts for construction of different electrochemical devices and separation matrices has attracted much attentions due to their benign biocompatibility and simplicity of synthesis. Myricetin and rutin are considered two of the most bioactive flavonoids, which have been proved to exhibit various physiological functions. This work reports a simple and facile approach for the synthesis of ß-cyclodextrin-gold@3, 4, 9, 10-perylene tetracarboxylic acid functionalized single-walled carbon nanohorns (ß-CD-Au@PTCA-SWCNHs) nanohybrids. The simultaneous electrochemical determination of myricetin and rutin using a ß-CD-Au@PTCA-SWCNHs-modified glassy carbon electrode was established. The results show that the ß-CD-Au@PTCA-SWCNHs-modified electrode displayed electrochemical signal superior to those of Au@PTCA-;SWCNHs and SWCNHs towards myricetin and rutin. The proposed modified electrode has a linear response range of 0.01-10.00 µM both for myricetin and rutin with relatively low detection limits of 0.0038 µM for myricetin and 0.0044 µM (S/N = 3) for rutin, respectively. The excellent performance of the sensing platform is considered to be the synergic effects of the SWCNHs (e.g. their good electrochemical properties and large surface area) and ß-CD (e.g. a hydrophilic external surface, a high supramolecular recognition, and a good enrichment capability).

Bridged ß-cyclodextrin-functionalized MWCNT with higher supramolecular recognition capability: the simultaneous electrochemical determination of three phenols.

A rapid and sensitive electrochemical sensor based on disulfides bridged ß-cyclodextrin dimer-functionalized multi-walled carbon nanotube (DBß-CD-MWCNT) nanohybrids with higher supramolecular recognition capability was successfully constructed for the first time. Simultaneous trace analysis of three phenols (4-aminophenol, 4-AP; 4-chlorophenol, 4-CP; 4-nitrophenol, 4-NP) in tap-water and wastewater samples was performed based on the constructed sensor. Cyclic voltammetry, differential pulse voltammetry, and electrochemical impedance spectroscopy were utilized to characterize the properties of the modified electrode. The proposed DBß-CD-MWCNT-modified electrode displayed electrochemical signal superior to those of ß-CD-MWCNT and MWCNT towards 4-AP, 4-CP, and 4-NP. Under optimal conditions, differential pulse voltammetry was used to simultaneously quantify 4-AP, 4-CP, and 4-NP within the concentration range of 0.01-20, 0.1-200, and 0.1-200 µM, respectively. The detection limits (S/N=3) of the DBß-CD-MWCNT nanohybrid electrode for 4-AP, 4-CP, and 4-NP were 0.0042, 0.028, and 0.048 µM, respectively. Satisfactory results revealed that this proposed electrochemical sensor can provide a promising candidate for the simultaneous trace analysis of 4-AP, 4-CP, and 4-NP in environmental monitoring of water and wastewater samples. The present work might broaden the channel toward the application of bridged CD in the electrochemical sensing or biosensing.