Metal-free Pathway Research Articles

Biocompatible Synthesis of Macrocyclic Thiazol(in)e Peptides.

Macrocyclic peptides containing a thiazole or thiazoline in the backbone are considered privileged structures in both natural compounds and drug discovery, owing to their enhanced bioactivity, stability, and permeability. Here, we present the biocompatible synthesis of macrocyclic peptides from N-terminal cysteine and C-terminal nitrile. While the N-terminal cysteine is incorporated during solid-phase peptide synthesis, the C-terminal nitrile is introduced during cleavage with aminoacetonitrile, utilizing a cleavable benzotriazole linker. This method directly yields the fully functionalized linear peptide precursor. The biocompatible cyclization reaction occurs in buffer at physiological pH and room temperature. The resulting thiazoline heterocycle remains stable in buffer but hydrolyzes under acidic conditions. While such hydrolysis enables access to macrocyclic peptides with a complete amide backbone, mild oxidation of the thiazoline leads to the stable thiazole macrocyclic peptide. While conventional oxidation strategies involve metals, we developed a protocol simply relying on alkaline salt and air. Therefore, we offer a rapid and metal-free pathway to macrocyclic thiazole peptides, featuring a biocompatible key cyclization step.

Access to Artemisinin-Triazole Antimalarials via Organo-Click Reaction: High In Vitro/In Vivo Activity against Multi-Drug-Resistant Malaria Parasites.

Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance against established antimalarial pharmaceuticals leads to an urge toward new antimalarial drugs. Hybridization of two chemically diverse compounds into a new bioactive product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds and also to overcome multidrug resistance. 1,2,3-Triazoles are a significant pharmacophore system among nitrogen-containing heterocycles with various applications, such as antiviral, antimalarial, antibacterial, and anticancer agents. Several marketed drugs possess these versatile moieties, which are used in a wide range of medical indications. While the synthesis of hybrid compounds containing a 1,2,3-triazole unit was described using Cu- and Ru-catalyzed azide-alkyne cycloaddition, an alternative metal-free pathway has never been reported for the synthesis of antimalarial hybrids. However, a metal-free pathway is a green method that allows toxic and expensive metals to be replaced with an organocatalyst. Herein, we present the synthesis of new artemisinin-triazole antimalarial hybrids via a facile Ramachary-Bressy-Wang organocatalyzed azide-carbonyl [3 + 2] cycloaddition (organo-click) reaction. The prepared new hybrid compounds are highly potent in vitro against chloroquine (CQ)-resistant and multi-drug-resistant Plasmodium falciparum strains (IC50 (Dd2) down to 2.1 nM; IC50 (K1) down to 1.8 nM) compared to CQ (IC50 (Dd2) = 165.3 nM; IC50 (K1) = 302.8 nM). Moreover, the most potent hybrid drug was more efficacious in suppressing parasitemia and extending animal survival in Plasmodium berghei-infected mice (up to 100% animal survival and up to 40 days of survival time) than the reference drug artemisinin, illustrating the potential of the hybridization concept as an alternative and powerful drug-discovery approach.

Photoredox Suzuki coupling using alkyl boronic acids and esters

Herein, we report a novel methodology for the one-step synthesis of olefins via a transition metal-free pathway.

Schematic Design of Metal-Free NHC-Mediated Sequestering and Complete Conversion of SO2 to Thiocarbonyl S-Oxide Derivatives at Room Temperature.

The sequestering and complete conversion of SO2 to valuable chemicals in a metal-free pathway is highly demanded. The recent success of SO2 fixation by N-heterocyclic carbenes instigated further studies in this regard. Previous reports were confined within the carbene-SO2 reaction mechanism and the stability of oxathiirane S-oxide derivatives. The complete conversion of captured SO2 to precious chemicals was not studied. The present inquisition has accomplished the scarcity of the earlier studies. It is observed that in the presence of an excess amount of carbene, the registered SO2 is converted to the ketone derivative and thiocarbonyl S-oxide derivative. An electronic level investigation of these reactions is carried out. From the change of the molecular orbitals along the reaction path, it is concluded that the reaction between the oxathiirane S-oxide derivative and carbene follows a frog's hunting mechanism.

Photocatalytic valorization of furfural to value-added chemicals via mesoporous carbon nitride: a possibility through a metal-free pathway

Renewable solar light-driven biomass furfural valorization.

High Chemoselectivity in the Construction of Aryl Methyl Sulfones via an Unexpected C–S Bond Formation between Sulfonylhydrazides and Dimethyl Phosphite

AbstractA highly chemoselective route to aryl methyl sulfones via an unexpected C–S bond formation between sulfonylhydrazides and dimethyl phosphite catalyzed by NaI under mild conditions has been established. This transformation provides an alternative and metal-free pathway to acquire various aryl methyl sulfones in good to excellent yields. Notably, dimethyl phosphite was employed as a stable and readily available alkyl source.

Synthesis and Spectroscopic Properties of 1,2,3-Triazole BOPAHY Dyes and Their Water-Soluble Triazolium Salts.

Water-soluble BOPAHY fluorophores have not yet been reported. The potential of 1,2,3-triazolium salts for the formation of water-soluble chromophores is explored. 1,2,3-Triazole-substituted pyrroles were synthesized in a metal-free pathway and alkylated to obtain water-soluble 1,2,3-triazolium BOPAHY dyes. High fluorescence quantum yields were observed for triazole-bridged BOPAHY dyes in DCM and moderate fluorescence quantum yields for 1,2,3-triazolium-bridged BOPAHY chromophores in DCM and water. The fluorescence of the freely rotatable 1,2,3-triazolium-linked BOPAHYs is partially quenched in water.

Correction: An efficient metal-free pathway to vinyl thioesters with calcium carbide as the acetylene source

Correction for ‘An efficient metal-free pathway to vinyl thioesters with calcium carbide as the acetylene source’ by Konstantin S. Rodygin et al., Green Chem., 2016, 18, 482–486. DOI: 10.1039/C5GC01552A.

Catalytic Adipic Acid Production on Zeolites from Biomass-Derived Tetrahydrofuran-2,5-dicarboxylic Acid

Adipic acid (AA) is an important precursor for the production of Nylon-66, and renewable routes for AA are being explored. Previously we have shown the use of HI and molecular H2 to be an effective combination for the selective ring-opening of tetrahydrofuran-2,5-dicarboxylic acid (THFDCA) in organic acids without the need for a metal catalyst. However, the use of HI could deter this system from large scale use for renewable AA. In this work, we employ zeolites as an effective proton source in combination with iodide salts (NaI), which obtains high AA rates in a similar metal-free pathway. Kinetic measurements coupled with zeolite characterization suggest that a dominant mechanism for THFDCA activation is bulk-phase protonation promoted by in situ ion-exchange via the metal cation from the iodide salt. Zeolites can be regenerated multiple times with minimal loss in reactivity, which enhances the commercial applicability of the system.

Novel 3,3-disubstituted oxindole derivatives. Synthesis and evaluation of the anti-proliferative activity

3,3-Disubstituted oxindole derivatives bearing a nitrogen atom at the C-3 position have been synthesized starting from 3-alkyl oxindole through a metal free pathway. These derivatives have been tested in five human tumor cell lines (PC3, MCF7, SW620, MiaPaca2 and A375) and on primary cells (PBMCs) from healthy donors providing compound 6d showing a strong anticancer effect in all cancer lines on the low micromolar range.

HX-DMSO: A novel liquid halogenating system for synthesis of 2-aminothiazoles via Csp3[sbnd]H bond functionalization

A new protocol developed for the synthesis of some 2-aminothiazoles from methylcarbonyl compounds using HX/DMSO liquid system as halogenating agent. This protocol provides an interesting new metal-free pathway for synthesis of 2-aminothiazole derivatives using Csp3H bond functionalization of simple methylcarbonyls as substrates and HX/DMSO (X=Br or I) as the best halogenating catalytic system. Different methylcarbonyls such as aldehyde, aromatic ketones, β-diketone, and β-ketoesters were used and gave the products in good yields without any catalyst. The mild and simple conditions make this strategy extremely attractive in the development of efficient synthesis of 2-aminothiazoles and other analogous heterocycles.

Transamidation of N-acyl-glutarimides with amines.

The development of new transamidation reactions for the synthesis of amides is an important and active area of research due to the central role of amide linkage in various fields of chemistry. Herein, we report a new method for transamidation of N-acyl-glutarimides with amines under mild, metal-free conditions that relies on amide bond twist to weaken amidic resonance. A wide range of amines and functional groups, including electrophilic substituents that would be problematic in metal-catalyzed protocols, are tolerated under the reaction conditions. Mechanistic experiments implicate the amide bond twist, thermodynamic stability of the tetrahedral intermediate and leaving group ability of glutarimide as factors controlling the reactivity of this process. The method further establishes the synthetic utility of N-acyl-glutarimides as bench-stable, twist-perpendicular, amide-based reagents in acyl-transfer reactions by a metal-free pathway. The origin of reactivity of N-acyl-glutarimides in metal-free and metal-catalyzed processes is discussed and compared.

Metal-free construction of primary sulfonamides through three diverse salts

The first metal-free pathway to access primary sulfonamides has been developed through three diverse salts Na2S2O5, NaN3, and aryldiazonium.

Porous conjugated polymer via metal-free synthesis for visible light-promoted oxidative hydroxylation of arylboronic acids

Porous conjugated polymers have emerged recently as efficient metal-free and visible light-active photocatalysts. However, the synthesis of this new class of materials usually requires transition metal catalysts such as palladium. A metal-free synthetic route still remains a huge challenge for the chemists. Here we report on a metal-free pathway of a porous conjugated polymer via simple Knoevenagel polycondensation under mild reaction conditions. The obtained polymer exhibited a high surface area and could be applied as a robust and efficient heterogeneous photocatalyst for the oxidative hydroxylation of arylboronic acids under visible light irradiation with a high functional group tolerance of the substrates.

ChemInform Abstract: A Single‐Step Acid Catalyzed Reaction for Rapid Assembly of NH‐1,2,3‐Triazoles.

NH-1,2,3-Triazole moieties are a part of the design of various biologically active compounds, pharmaceutical agents and functional materials. Unfortunately, the applications of this heterocycle are still underexplored due to the lack of a general synthetic protocol. Here we outline a novel, general and facile metal-free pathway that enables the direct synthesis of these heterocycles by combining readily accessible and abundant precursors such as enolizable ketones and NH4OAc with high levels of regioselectivity via an organocascade process. The developed chemistry has been successfully applied to the synthesis of several structurally diverse products, pharmaceutical agents and supramolecular receptors.

ChemInform Abstract: Metal‐Free Oxidative Cascade Cyclization of Isocyanides with Thiols: A New Pathway for Constructing 6‐Aryl(alkyl)thiophenanthridines.

AbstractThe title reaction tolerates various substituents in both partners and is proposed to proceed through a free radical mechanism.

Metal-free oxidative cascade cyclization of isocyanides with thiols: a new pathway for constructing 6-aryl(alkyl)thiophenanthridines

A metal-free pathway for constructing 6-aryl(alkyl)thiophenanthridines through oxidative cascade cyclization of isocyanides with thiols is developed. This pathway is characterized by SH bond cleavage of commercially available thiols, and subsequent CS/CC bond formation, which is suitable for a wide scope of substrates and by which a variety of 6-aryl(alkyl)thiophenanthridines could be synthesized in good to excellent yields.

An efficient metal-free pathway to vinyl thioesters with calcium carbide as the acetylene source

Acetylene was replaced with calcium carbide and utilized for the synthesis of practically useful vinyl thioesters in a simple and environmentally benign procedure.