Alkylation Strategy Research Articles

Palladium-Catalyzed Asymmetric Allylic Alkylation of Azlactones: An Efficient Access to Unsaturated Trifluoromethylated α-Amino Acid Derivatives Possessing α-Quaternary Stereogenic Centers

AbstractA new strategy for the asymmetric allylic alkylation of azlactones with α-(trifluoromethyl)allyl acetates catalyzed by Pd(OAc)2/(R)-BINAP is designed and developed, providing access to unsaturated α-quaternary α-amino acid derivatives bearing a trifluoromethyl group and contiguous quaternary and tertiary stereogenic centers. The products are obtained in good yields with exclusive regioselectivity and excellent stereoselective control under relatively mild reaction conditions. A scale-up experiment shows no loss of reactivity or stereoselectivity. The synthetic utility of the current strategy is demonstrated through transformations of a representative product to afford several potentially bioactive species.

Visible-Light-Promoted Deoxygenative Alkylation of Quinoxalin-2(1H)-ones with Activated Alcohols.

A one-pot strategy for deoxygenative alkylation of alcohols with quinoxalin-2(1H)-ones was developed by using xanthate salts as alcohol-activating groups for radical generation in the presence of tricyclohexylphosphine under visible-light-promoted conditions. The remarkable features of this reaction include a broad substrate scope, excellent functional group tolerance, mild conditions, and simple operation. Moreover, the synthetic utility of this reaction was validated by the success of two-step one-pot reactions, scale-up synthesis, and chemoselective radical monodeoxygenation of diols.

Friedel–Crafts Acylation for Accessing Multi‐Bridge‐Functionalized Large Pillar[n]arenes

AbstractPillar[n]arenes can be constructed using a Friedel–Crafts alkylation process. However, due to the reversible nature of the alkylation, mixture of large pillar[n]arenes (n≥7) are obtained as minor products, and thus laborious purification are necessary to isolate the larger pillar[n]arenes. Moreover, inert methylene bridges are introduced during the alkylation process, and the multi‐functionalization of the bridges has never been investigated. Herein, an irreversible Friedel–Crafts acylation is used to prepare pillar[n]arenes. Due to the irreversible nature of the acylation, the reaction of precursors bearing carboxylic acids and electron‐rich arene rings results in a size‐exclusive formation of pillar[n]arenes, in which the ring‐size is determined by the precursor length. Because of this size‐selective formation, laborious separation of undesired macrocycles is not necessary. Moreover, the bridges of pillar[n]arenes are selectively installed with reactive carbonyl groups using the acylation method, whose positions are determined by the precursor used. The carbonyl bridges can be easily converted into versatile functional groups, leading to various laterally modified pillar[n]arenes, which cannot be accessed by the alkylation strategy.

Friedel-Crafts Acylation for Accessing Multi-Bridge-Functionalized Large Pillar[n]arenes.

Pillar[n]arenes can be constructed using a Friedel-Crafts alkylation process. However, due to the reversible nature of the alkylation, mixture of large pillar[n]arenes (n≥7) are obtained as minor products, and thus laborious purification are necessary to isolate the larger pillar[n]arenes. Moreover, inert methylene bridges are introduced during the alkylation process, and the multi-functionalization of the bridges has never been investigated. Herein, an irreversible Friedel-Crafts acylation is used to prepare pillar[n]arenes. Due to the irreversible nature of the acylation, the reaction of precursors bearing carboxylic acids and electron-rich arene rings results in a size-exclusive formation of pillar[n]arenes, in which the ring-size is determined by the precursor length. Because of this size-selective formation, laborious separation of undesired macrocycles is not necessary. Moreover, the bridges of pillar[n]arenes are selectively installed with reactive carbonyl groups using the acylation method, whose positions are determined by the precursor used. The carbonyl bridges can be easily converted into versatile functional groups, leading to various laterally modified pillar[n]arenes, which cannot be accessed by the alkylation strategy.

Chloroform/Methanol Protein Extraction and In-solution Trypsin Digestion Protocol for Bottom-up Proteomics Analysis.

Bottom-up proteomics utilizes sample preparation techniques to enzymatically digest proteins, thereby generating identifiable and quantifiable peptides. Proteomics integrates with other omics methodologies, such as genomics and transcriptomics, to elucidate biomarkers associated with diseases and responses to drug or biologics treatment. The methodologies employed for preparing proteomic samples for mass spectrometry analysis exhibit variability across several factors, including the composition of lysis buffer detergents, homogenization techniques, protein extraction and precipitation methodologies, alkylation strategies, and the selection of digestion enzymes. The general workflow for bottom-up proteomics consists of sample preparation, mass spectrometric data acquisition (LC-MS/MS analysis), and subsequent downstream data analysis including protein quantification and differential expression analysis. Sample preparation poses a persistent challenge due to issues such as low reproducibility and inherent procedure complexities. Herein, we have developed a validated chloroform/methanol sample preparation protocol to obtain reproducible peptide mixtures from both rodent tissue and human cell line samples for bottom-up proteomics analysis. The protocol we established may facilitate the standardization of bottom-up proteomics workflows, thereby enhancing the acquisition of reliable biologically and/or clinically relevant proteomic data. Key features • Tissue/cell pellet sample preparation for bottom-up proteomics. • Chloroform/methanol protein extraction from murine tissue samples. • In-solution trypsin digestion proteomics workflow.

S-Alkylation of cysteine-containing peptides using thianthenium salts as an alkyl source in flow

A green strategy for the selective alkylation of cysteine-containing peptides in a continuous flow reactor has been developed, providing an efficient pathway to alkylated cysteine-containing peptides under mild conditions.

Tryptophan-specific peptide modification through metal-free photoinduced N-H alkylation employing N-aryl glycines

Tryptophan (Trp) carries a unique heteroaromatic indole side chain and plays a critical role in peptide or protein modification. Herein, we have reported a metal-free photoinduced N-H alkylation strategy using N-aryl glycines for specific modification of tryptophan-containing peptides. The robustness of our approach is demonstrated by its wide substrate scope, excellent isolated yields, as well as almost unobservable side effects. Using this highly efficiently metal-free condition, alkylated Trp-containing peptides can be smoothly assembled. This study provides a reliable and practical tool for the chemo-selective modification of various tryptophan containing oligopeptides.

Organo-photoredox-Catalyzed Selective Mono- and Bis-C-H Alkylation of Electron-Rich (Hetero)Arenes.

Herein, we disclose a simple strategy for the C-H alkylation of electron-rich (hetero)arenes with alkyl bromides employing visible-light-mediated organo-photocatalytic SET processes. The generality of this method has been evidenced by the inclusion of a variety of alkyl radicals (α-alkyl-carbonyl, benzyl, cyanomethyl) as well as diverse biologically active electron-rich arenes and (hetero)arenes under mild conditions. The extent of alkylation with alkyl bromides was found to be controlled by introducing Zn(OAc)2 as a bromide scavenger, ensuring the blocking of potential bromo-arene byproduct formation under photoredox conditions. In addition, a sequential C-H alkylation strategy for selective bis-alkylation has also been developed via chronological incorporation of different alkyl radical precursors in one pot quite efficiently.

Merger of Visible Light-Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α-Alkylation of Aldehydes.

The electron donor-acceptor complex-enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α-alkylated aldehydes without an external photoredox catalyst. The photosensitizer-free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α-alkylation of aldehydes based on the synergistic combination of visible light-driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer-free enantioselective α-alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α-alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.

Direct Catalytic Asymmetric and Regiodivergent N1‐ and C3‐Allenylic Alkylation of Indoles

AbstractHerein we report a Pd‐catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H‐indoles by employing P‐chiral BIBOP‐type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs2CO3 at elevated temperatures in MeCN, N1‐alkylated indoles bearing axial chirality with a stereocenter non‐adjacent (β) to the nitrogen are produced in good yields with high enantioselectivity and complete N1‐regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K2CO3 at room temperature in CH2Cl2, chiral C3‐alkylated indoles can also be obtained. Notably, we introduce a new class of tri‐substituted allenylic electrophiles that proceeded through different pathways from di‐substituted allenylic electrophiles.

Direct Catalytic Asymmetric and Regiodivergent N1- and C3-Allenylic Alkylation of Indoles.

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs2 CO3 at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with a stereocenter non-adjacent (β) to the nitrogen are produced in good yields with high enantioselectivity and complete N1-regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K2 CO3 at room temperature in CH2 Cl2 , chiral C3-alkylated indoles can also be obtained. Notably, we introduce a new class of tri-substituted allenylic electrophiles that proceeded through different pathways from di-substituted allenylic electrophiles.

Chiral Phosphine Catalyzed Allylic Alkylation of Benzylidene Succinimides with Morita–Baylis–Hillman Carbonates

Owing to their unique chemical properties, α-alkylidene succinimides generally act as versatile synthons in organic synthesis. Compared with well-established annulations, nucleophilic alkylations of α-alkylidene succinimides are very limited. Accordingly, an organocatalytic allylic alkylation of α-benzylidene succinimides with Morita-Baylis-Hillman (MBH) carbonates was established. In the presence of a chiral phosphine catalyst, α-benzylidene succinimides reacted smoothly with MBH carbonates under mild conditions to furnish a series of optical active succinimides in high yields and enantioselectivities. Different from the reported results, the organocatalytic enantioselective construction of pyrrolidine-2,5-dione frameworks bearing contiguous chiral tertiary carbon centers was achieved via this synthetic strategy. Scaling up the reaction indicated that it is a practical strategy for the organocatalytic enantioselective alkylation of α-alkylidene succinimides. A possible reaction mechanism was also proposed.

Photocatalytic Radical Addition to N-Sulfonyl Hydrazones as a C–H Alkylation Strategy

Key words C–H alkylation - photochemistry - hydrazones - H-atom transfer

Photoinduced defluorinative alkylation of trifluoromethyl alkenes with carbonyl derivatives by C–C bond scission

A practical strategy for the photoinduced defluorinative alkylation of α-trifluoromethyl styrenes with carbonyl derivatives via C–C bond cleavage was disclosed.

Putting forward a Ni-metallosalphen-based porous organic polymer for detoxification of sulfur mustard gas simulant.

We have introduced a Friedel-Crafts alkylation strategy of a Ni-salphen complex as derived from 2-hydroxy-5-methoxybenzaldehyde, an isomer of biomass derived vanillin, to construct a Ni-salphen based porous organic polymer (Ni@T-POP). The X-ray absorption spectroscopy (XAS) analysis revealed the existence of Ni-N2O2 core sites in the Ni@T-POP framework, which demonstrates unprecedented catalytic efficiency towards oxidative decontamination of sulfur mustards (HD's) compared to its complex precursor.

Synergistic catalysis of hypercrosslinked ionic polymers with multi-ionic sites for conversion of CO2 to cyclic carbonates

High catalytic activity for the conversion of CO2 into cyclic carbonates requires the preparation of porous ionic catalysts with multi-active sites and high ionic density. Herein, a series of hypercrosslinked ionic polymers (HIPs) with multi-ionic sites, high ionic density and hydrogen bond donors (imino group) were synthesized through the one-pot Friedel–Crafts alkylation and post-synthetic strategies. Adsorption measurements showed that HIPs exhibited outstanding CO2 uptakes (1.80−2.97 mmol g − 1, 273 K and 1 bar). Importantly, under the synergistic effects of multi-ionic sites, high ionic density and hydrogen bond donors, the metal-free catalyst HBIM(0.5)@QA-Br showed excellent catalytic yield (99%) and selectivity (99%) for cycloaddition of CO2 with epichlorohydrin at 140 °C, 0.1 MPa CO2 in 2 h. By extending the time appropriately, high catalytic yields (styrene oxide, 140 °C, 4 h, 99% yield; 120 °C, 6.5 h, 93% yield; 100 °C, 16 h, 94% yield) were achieved at low temperature. In addition, the catalyst can be easily reused with stable recyclability. This work not only provides a new strategy to prepare metal-free porous ionic catalysts with multi-ionic sites and hydrogen bond donors but also demonstrated that the synergistic catalysis of multi-ionic sites is helpful to promote CO2 conversion.

Mesityl‐Appended 1,4‐Bis(β‐acrylonitrile)‐2,5‐dimethoxybenzene: Blue and Green Fluorescent Crystals from a Soluble Donor–Acceptor Molecular System

AbstractBecause acrylonitrile‐phenylene‐based π‐conjugated molecules have highly rigid structures (or low structural flexibility), these molecules have low solubility in various organic solvents, including nonpolar and polar solvents such as hexane, ethanol, and dimethyl sulfoxide. Alkylation or PEGulation strategies are useful approaches for designing highly soluble acrylonitrile‐phenylene compounds, but the number of good solvents is limited. Herein, we report mesityl‐appended 1,4‐bis(β‐acrylonitrile)‐2,5‐dimethoxybenzene including an electron donor–acceptor system. The molecule shows good solubility in various organic solvents, such as hexane, toluene, chloroform, dichloromethane, acetone, ethanol, N,N‐dimethylformamide, acetonitrile, and dimethyl sulfoxide, owing to the appended bulky mesityl groups. Spectroscopic measurements were performed in various solutions. The solvatochromic behaviour was investigated according to the polarity and affinities by absorption and photoluminescence (PL) spectroscopic analyses in various solvents. The acrylonitrile unit in the π‐conjugated structure allows rotation under ambient light. E−Z isomerisation was observed owing to its structural flexibility. This feature gave two fluorescent molecular crystals: blue‐PL Z,Z‐molecular crystal BC (minor material, CCDC 2108373, λem=473 nm) and green‐PL E,E‐molecular crystal GC (major material, CCDC 2108365, λem=508 nm). It is reasonable that the more planar donor–acceptor core structure of the E,E‐crystal shows lower energy fluorescence than the slightly twisted structure of the Z,Z‐crystal.

Cobalt-Catalyzed Asymmetric Alkylation of (Hetero)Arenes with Styrenes.

An efficient and general intermolecular Cobalt(II)-catalyzed asymmetric alkylation of styrenes with (hetero)arenes including indoles, thiophene and electron rich arenes has been developed, providing straightforward access to enantioenriched alkyl(hetero)arenes with high enantioselectivity. Mechanistic studies suggest that the reaction underwent a CoH-mediated hydrogen atom transfer (HAT) with alkenes, followed by a pivotal catalyst-controlled SN 2-like pathway between in situ generated organocobalt(IV) species and aromatic nucleophiles. This is the first CoH-catalyzed asymmetric hydrofunctionalization using carbon nucleophiles, providing a new strategy for asymmetric Friedel-Crafts type alkylation.

Phenanthrenequinone (PQ) catalyzed cross-dehydrogenative coupling of alkanes with quinoxalin-2(1H)-ones and simple N-heteroarenes under visible light irradiation.

A direct and convenient strategy to 3-alkylquinoxalin-2(1H)-ones and other alkyl N-heteroarenes via a photocatalyzed alkylation of quinoxalin-2(1H)-ones and other N-heterocycles with commercially available, low-cost alkanes under ambient conditions using phenanthrenequinone (PQ) as a photocatalyst was developed. This transformation has advantages of environment-friendly protocol, mild conditions, good functional-group tolerance, and high yields of products.

A metal-free hydroxyl functionalized quaternary phosphine type ionic liquid polymer for cycloaddition of CO2 and epoxides.

Quaternary phosphine type hypercrosslinked polymer catalysts were successfully prepared using the Friedel-Crafts alkylation reactions, which benefit from the synergistic effects between the Brønsted acidity of the hydroxyl group and nucleophilicity of the Br- group as well as the CO2 capture of the ionic liquids. The as-obtained metal-free catalysts facilitate the cycloaddition and synthesis of high value-added fine chemicals.