Mild Reductive Conditions Research Articles

Nickel-catalyzed reductive formylation of aryl halides via formyl radical

Aromatic aldehydes are the most fundamentally important compounds used in organic synthesis. The development of new synthetic methods for introduction of a formyl group into an organic scaffold is highly desirable. In this report, a nickel-catalyzed reductive coupling between aryl halides and α‑chloro N-methoxyphthalimide has been documented for the synthesis of a diverse array of aromatic aldehydes. Because of mild reductive coupling conditions, excellent functional group tolerance, especially for substrates containing free -OH and -NH2, was observed. Due to the simple operation mode, a large library of aromatic aldehydes can be quickly constructed by this process. Moreover, the present protocol is amenable for late-stage functionalization of bioactive compound. A combined computational and experimental investigation suggested the reaction may undergo a reaction mechanism of active Ni(I) catalyst formation and the formation of key formyl radical intermediate under zinc reductive conditions.

Visible-light-driven three-component reductive 1,2-diarylation of alkenes

The intermolecular alkene 1,2-diarylation provides straightforward access to polyarylalkanes but suffers from substrate limitation, requiring directing auxiliaries or prefunctionalized aryl components. Herein, we report the development of a photocatalytic strategy that enables a three-component 1,2-diarylation of alkenes under mild reductive conditions using simple tertiary alkylamine as the terminal reductant. Readily accessible aryl iodides and cyanides serve as the C(sp2) electrophiles to simultaneously install two different aryl moieties across the olefins with high regioselectivity. This protocol exhibits a broad substrate scope for all of aryl, heteroatom-substituted, and even unactivated alkenes and can be easily scaled up to the gram-scale. Mechanistic studies reveal a halogen-atom transfer (XAT) of aryl iodides to transient aryl radicals while a single-electron transfer (SET) of aryl cyanides to persistent aryl radical anions, both allowing for a regiocontrollable radical relay sequence.

Iron-catalyzed cross-electrophile coupling of bromostyrenes and chlorosilanes

An efficient Fe-catalyzed cross-electrophile vinyl silylation protocol is reported for the first time. A set of 1,4-diene silanes are conveniently synthesized from simple vinyl chlorosilanes and alkenyl bromides under mild reductive conditions.

Secondary phosphine oxide-activated nickel catalysts for site-selective alkene isomerization and remote hydrophosphination

Catalytic systems that are readily modifiable to achieve olefin migration or remote functionalization are highly sought after in chemical synthesis. Here, we show that the combination of a commercially available nickel(II) pre-catalyst and a secondary phosphine oxide ligand enables site- and stereoselective alkene transposition for up to nine double-bond migrations within terminal and internal olefins under mild reductive conditions. Substrates bearing diverse functionalities including Brønsted acidic and reducible carbonyl groups are tolerated. Mechanistic and spectroscopic studies revealed the in situ generation of a catalytically active nickel-hydride species triggered by oxidative addition of the phosphine oxide. The reaction is amenable to regioconvergent isomerization as well as β-selective remote hydrophosphination when stoichiometric secondary phosphine oxide and base were employed.

Nickel-catalyzed alkene <i>ipso</i>-selective reductive hydroamination with nitroarenes

Aromatic amine synthesis via reductive coupling between alkenes and nitroarenes is attractive; however, it remains underdeveloped. Herein, we report a nickel-catalyzed alkene hydroamination with nitroarenes under mild reductive conditions. This reaction exhibited an <i>ipso</i>-selectivity and enabled repaid preparation of aromatic amines with primary and secondary alkyl groups. Many functional groups were well tolerated, providing an efficient approach for drug-like arylamine synthesis.

Iron-catalysed reductive coupling for the synthesis of polyfluorinated compounds.

Herein we reported the use of Earth-abundant iron as the catalytic metal in the presence of Mn to induce difluorobromoacetates to form carbon radicals, which reacted with trifluoromethyl olefins followed by β-F elimination to generate the corresponding gem-difluoroolefins. The cross-electrophile coupling displayed excellent functional group tolerance and broad substrate scope under mild reductive conditions, affording a large number of polyfluorinated compounds, which could be further transformed to other valuable molecules.

Palladium-Catalyzed Arylation of C(sp2)-H Bonds with 2-(1-Methylhydrazinyl)pyridine as the Bidentate Directing Group.

Palladium-catalyzed C(sp2)–H arylation of ortho C–H bonds involving 2-(1-methylhydrazinyl)pyridine (MHP) as the directing group has been investigated. The reaction proceeds smoothly under an air atmosphere to generate biaryl derivatives in an environmentally friendly manner while tolerating a wide range of functional groups. Notably, the directing group present in the product could be easily removed under mild reductive conditions.

Bathocuproine-Enabled Nickel-Catalyzed Selective Ullmann Cross-Coupling of Two sp2-Hybridized Organohalides

AbstractCross-coupling reactions are essential for the synthesis of complex organic molecules. Here, we report a nickel-catalyzed Ullmann cross-coupling of two sp2-hybridized organohalides, featuring high cross-selectivity when the two coupling partners are used in a 1:1 ratio. The high chemoselectivity is governed by the bathocuproine ligand. Moreover, the mild reductive reaction conditions allow that a wide range of functional groups are compatible in this Ullmann cross-coupling.

Dynamic Covalent Formation of Concave Disulfide Macrocycles Mechanically Interlocked with Single-Walled Carbon Nanotubes.

The formation of discrete macrocycles wrapped around single‐walled carbon nanotubes (SWCNTs) has recently emerged as an appealing strategy to functionalize these carbon nanomaterials and modify their properties. Here, we demonstrate that the reversible disulfide exchange reaction, which proceeds under mild conditions, can install relatively large amounts of mechanically interlocked disulfide macrocycles on the one‐dimensional nanotubes. Size‐selective functionalization of a mixture of SWCNTs of different diameters were observed, presumably arising from error correction and the presence of relatively rigid, curved π‐systems in the key building blocks. A combination of UV/Vis/NIR, Raman, photoluminescence excitation, and transient absorption spectroscopy indicated that the small (6,4)‐SWCNTs were predominantly functionalized by the small macrocycles 12, whereas the larger (6,5)‐SWCNTs were an ideal match for the larger macrocycles 22. This size selectivity, which was rationalized computationally, could prove useful for the purification of nanotube mixtures, since the disulfide macrocycles can be removed quantitatively under mild reductive conditions.

Construction of higher-order cellular microstructures by a self-wrapping co-culture strategy using a redox-responsive hydrogel

In this report, a strategy for constructing three-dimensional (3D) cellular architectures comprising viable cells is presented. The strategy uses a redox-responsive hydrogel that degrades under mild reductive conditions, and a confluent monolayer of cells (i.e., cell sheet) cultured on the hydrogel surface peels off and self-folds to wrap other cells. As a proof-of-concept, the self-folding of fibroblast cell sheet was triggered by immersion in aqueous cysteine, and this folding process was controlled by the cysteine concentration. Such folding enabled the wrapping of human hepatocellular carcinoma (HepG2) spheroids, human umbilical vein endothelial cells and collagen beads, and this process improved cell viability, the secretion of metabolites and the proliferation rate of the HepG2 cells when compared with a two-dimensional culture under the same conditions. A key concept of this study is the ability to interact with other neighbouring cells, providing a new, simple and fast method to generate higher-order cellular aggregates wherein different types of cellular components are added. We designated the method of using a cell sheet to wrap another cellular aggregate the ‘cellular Furoshiki’. The simple self-wrapping Furoshiki technique provides an alternative approach to co-culture cells by microplate-based systems, especially for constructing heterogeneous 3D cellular microstructures.

Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds

Summary Catalytic alkene difuntionalization is a convenient platform for introducing complexity in molecules and has wide applications in organic synthesis. Yet a compelling challenge that remains to be solved is the regioselective insertion of two highly functionalized carbon-based moieties, derived from stable and readily available organohalide electrophiles without the need for pre-synthesized organometallic reagents, across C=C bonds in unactivated alkyl-substituted alkenes. Here, we show that catalytic amounts of an inexpensive Ni-based catalyst, in combination with a readily recyclable 8-aminoquinoline directing group, promotes efficient and site-selective addition of two different organohalides (iodides and bromides) across aliphatic alkenes under mild reductive conditions. Compared to previous studies, this protocol exhibits broad and complementary functional group tolerance that extends to aryl-alkylation, alkenyl-alkylation, and dialkylation transformations. The utility of the strategy is demonstrated through concise synthesis of biologically active molecules. Kinetic studies and other control experiments shed further light on the mechanistic underpinnings of the multicomponent reaction.

PH/Redox-Triggered Photothermal Treatment for Cancer Therapy Based on a Dual-Responsive Cationic Polymer Dot.

In the present study, a pH/redox-responsive cationic polymer dot (CD) was successfully prepared for a near-infrared (NIR)-mediated, simultaneously controllable photothermal temperature guided imaging off/on system to monitor therapeutic delivery. Carbonized disulfide cross-linked branched polyethyleneimine (bPEI) was conjugated with folic acid (FA) as a targeting moiety and partially formed an ionic complex with anionic indocyanine green (ICG) to afford a bPEI-based CD (ICG-CD). This was responsive to mild reductive (glutathione, GSH) and acidic tumor conditions, which enabled the simultaneous biodegradation of those hydrophobic and complex sites. The ICG-CD internalized readily into the cytoplasm of cancer cells by a FA receptor and cationic-mediated endocytosis in the off state, whereas if ICG-CD met intracellular GSH at high concentrations, GSH contributed partially to the recovery of fluorescence and was then internalized into acidic endosomes to induce complete restoration of fluorescence. This tumor-sensitive degradability of the CD not only facilitated ICG release in the tumor location but also allowed controllable photothermal therapy effects of nanoparticles under NIR irradiation, which resulted in improved cancer therapy. Taken together, the results indicate great potential in tumor targeting, intracellular imaging, and controllable therapeutic delivery through a fluorescence off/on assay under the pH/redox conditions of cancer cells.

2,2,6,6-Tetramethylpiperidin-1-yloxycarbonyl: A Protecting Group for Primary, Secondary, and Heterocyclic Amines.

The 2,2,6,6-tetramethylpiperidin-1-yloxycarbonyl (Tempoc) protecting group is readily introduced by the reaction of amines with a new acyl transfer reagent, 4-nitrophenyl (2,2,6,6-tetramethylpiperidin-1-yl) carbonate (NPTC). Tempoc has a reactivity profile that complements the commonly used t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) protecting groups. Deprotection can be achieved under mild reductive conditions with in situ generated Cu(I) species or by thermolytic cleavage at 135 °C. Mechanistic studies on the deprotection of Tempoc-indole suggest a combination of ionic and radical fragmentation pathways under thermal conditions.

The True Fate of Pyridinium in the Reportedly Pyridinium-Catalyzed Carbon Dioxide Electroreduction on Platinum.

Protonated pyridine (PyH+ ) has been reported to act as a peculiar and promising catalyst for the direct electroreduction of CO2 to methanol and/or formate. Because of recent strong incentives to turn CO2 into valuable products, this claim triggered great interest, prompting many experiments and DFT simulations. However, when performing the electrolysis in near-neutral pH electrolyte, the local pH around the platinum electrode can easily increase, leading to Py and HCO3 - being the predominant species next to the Pt electrode instead of PyH+ and CO2 . Using a carefully designed electrolysis setup which overcomes the local pH shift issue, we demonstrate that protonated pyridine undergoes a complete hydrogenation into piperidine upon mild reductive conditions (near 0 V vs. RHE). The reduction of the PyH+ ring occurs with and without the presence of CO2 in the electrolyte, and no sign of CO2 electroreduction products was observed, strongly questioning that PyH+ acts as a catalyst for CO2 electroreduction.

The True Fate of Pyridinium in the Reportedly Pyridinium‐Catalyzed Carbon Dioxide Electroreduction on Platinum

AbstractProtonated pyridine (PyH+) has been reported to act as a peculiar and promising catalyst for the direct electroreduction of CO2 to methanol and/or formate. Because of recent strong incentives to turn CO2 into valuable products, this claim triggered great interest, prompting many experiments and DFT simulations. However, when performing the electrolysis in near‐neutral pH electrolyte, the local pH around the platinum electrode can easily increase, leading to Py and HCO3− being the predominant species next to the Pt electrode instead of PyH+ and CO2. Using a carefully designed electrolysis setup which overcomes the local pH shift issue, we demonstrate that protonated pyridine undergoes a complete hydrogenation into piperidine upon mild reductive conditions (near 0 V vs. RHE). The reduction of the PyH+ ring occurs with and without the presence of CO2 in the electrolyte, and no sign of CO2 electroreduction products was observed, strongly questioning that PyH+ acts as a catalyst for CO2 electroreduction.

Preparation of pH- and reductive-responsive prodrug nanoparticles via polymerization-induced self-assembly

pH- and reductive-responsive prodrug nanoparticles are constructed via a highly efficient strategy, polymerization-induced self-assembly (PISA). First, reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(diisopropylamino) ethyl methacrylate (DIPEMA) and camptothecin prodrug monomer (CPTM) using biocompatible poly( N -(2-hydroxypropyl) methacrylamide) (PHPMA-CPDB) as the macro RAFT agent is carried out, forming prodrug diblock copolymer PHPMA-P(DIPEMA- co -CPTM). Then, simultaneous fulfillment of polymerization, self-assembly, and drug encapsulation are achieved via RAFT dispersion polymerization of benzyl methacrylate (BzMA) using the PHPMA-P(DIPEMA- co -CPTM) as the macro RAFT agent. The prodrug nanoparticles have three layers, the biocompatible shell (PHPMA), the drug-conjugated middle layer (P(DIPEMA- co -CPTM)) and the PBzMA core, and relatively high concentration (250 mg/g). The prodrug nanoparticles can respond to two stimuli (reductive and acidic conditions). Due to reductive microenvironment of cytosol, the cleavage of the conjugated camptothecin (CPT) within the prodrug nanoparticles could be effectively triggered. pH-Induced hydrophobic/hydrophilic transition of the PDIPEMA chains results in faster diffusion of GSH into the CPTM units, thus accelerated release of CPT is observed in mild acidic and reductive conditions. Cell viability assays show that the prodrug nanoparticles exhibit well performance of intracellular drug delivery and good anticancer activity.

Synthesis of Supported Pd0 Nanoparticles from a Single-Site Pd2+ Surface Complex by Alkene Reduction

A surface metal–organic complex, (-AlOx)Pd(acac) (acac = acetylacetonate), is prepared by chemically grafting the precursor Pd(acac)2 onto γ-Al2O3 in toluene at 25 °C. The resulting surface complex is characterized by inductively coupled plasma atomic emission spectroscopy (ICP-AES), X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), and dynamic nuclear polarization surface-enhanced solid-state nuclear magnetic resonance spectroscopy (DNP SENS). This surface complex is a precursor in the direct synthesis of size-controlled Pd nanoparticles under mild reductive conditions and in the absence of additional stabilizers or pretreatments. Indeed, upon exposure to gaseous ethylene or liquid 1-octene at 25 °C, the Pd2+ species is reduced to form Pd0 nanoparticles with a mean diameter of 4.3 ± 0.6 nm, as determined by scanning transmission electron microscopy (STEM). These nanoparticles are catalytically relevant using the aerobic 1-phenylethanol oxidation as a probe reaction, with rates ...

Reductive N-Arylethylation of Aromatic Amines and N-Heterocycles with Enol Ethers

A convenient method for N-arylethylation of aromatic amines and heterocycles under mild reductive conditions was developed using (2-methoxyvinyl)(hetero)arenes as building blocks and triethylsilane/trifluoroacetic acid as reducing agent. This protocol is compatible with numerous functional groups, and aliphatic amines are inert due to protonation.

Tuning the synthetic cobalt(III)corroles electroreductive catalyzed lindane dehalogenation reactivity through meso-substituents

In this study, a facile dechlorination of lindane is achieved under mild electron reductive conditions with a series of Co(III)corroles used as electrocatalysts. Spectroscopic, electrochemical, and spectroelectrochemical measurements are used to determine the mechanism of the reaction. A GC–MS analysis of the dechlorination products indicates that the meso-aryl substituents of the cobalt(III)corroles have a significant influence on the dechlorination efficiency when a fixed potential is applied. Under reductive catalysis, the Co(III)corroles provide highly satisfactory dechlorination results, since lindane was ultimately converted to chlorobenzene.

Radical cyclizations of cyclic ene sulfonamides occur with β-elimination of sulfonyl radicals to form polycyclic imines.

Radical cyclizations of cyclic ene sulfonamides provide stable bicyclic and tricyclic aldimines and ketimines in good yields. Depending on the structure of the precursor, the cyclizations occur to provide fused and spirocyclic imines with five-, six-, and seven-membered rings. The initial radical cyclization produces an α-sulfonamidoyl radical that undergoes elimination to form the imine and a phenylsulfonyl radical. In a related method, 3,4-dihydroquinolines can also be produced by radical translocation reactions of N-(2-iodophenylsulfonyl)tetrahydroiso-quinolines. In either case, very stable sulfonamides are cleaved to form imines (rather than amines) under mild reductive conditions.