Bench-stable Reagents Research Articles

Ru(II)-Catalyzed C7 Trifluoromethylthiolation and Thioarylation of Indolines Using Bench-Stable Reagents.

A Ru(II)-catalyzed C(sp2)-H trifluoromethylthiolation and thioarylation of indolines using bench-stable reagents have been explored. Diversely substituted indolines were functionalized at C7 position in good to excellent yields. Radical quenching, deuterium labeling, KIE, and reaction order determination experiments were performed to support the proposed reaction pathway. Gram-scale synthesis and post-transformation of the synthesized products have also been carried out to demonstrate the applicability of the developed catalytic protocol.

Stereoselective Synthesis of Silyl Enol Ethers with Acylsilanes and α,β-Unsaturated Ketones.

Acylsilanes are emerging bench-stable reagents for the generation of electron-rich oxycarbenes that are difficult to access with unstable diazo compounds. Herein, we report a siloxycarbene-mediated stereoselective synthesis of silyl enol ethers through visible-light-induced intermolecular reactions between acylsilanes and α,β-unsaturated ketones. Both the solvent and low temperature are important for the success of the reaction. This approach features atomic economics, exclusive stereocontrol, and broad substrate scope. The synthetic potential of this methodology is demonstrated by gram-scale reaction and various downstream transformations including that requiring configuration purity of the silyl enol ethers.

Fully Automated Flow Protocol for C(sp3)-C(sp3) Bond Formation from Tertiary Amides and Alkyl Halides.

Herein, we present a novel C(sp3)-C(sp3) bond-forming protocol via the reductive coupling of abundant tertiary amides with organozinc reagents prepared in situ from their corresponding alkyl halides. Using a multistep fully automated flow protocol, this reaction could be used for both library synthesis and target molecule synthesis on the gram-scale starting from bench-stable reagents. Additionally, excellent chemoselectivity and functional group tolerance make it ideal for late-stage diversification of druglike molecules.

Fully Aqueous and Air-Compatible Cross-Coupling of Primary Alkyl Halides with Aryl Boronic Species: A Possible and Facile Method.

Aqueous transformations confer many advantages, including decreased environmental impact and increased opportunity for biomolecule modulation. Although several studies have been conducted to enable the cross-coupling of aryl halides in aqueous conditions, until now a process for the cross-coupling of primary alkyl halides in aqueous conditions was missing from the catalytic toolbox and considered impossible. Alkyl halide coupling in water suffers from severe problems. The reasons for this include the strong propensity for β-hydride elimination, the need for highly air- and water-sensitive catalysts and reagents, and the intolerance of many hydrophilic groups to cross-coupling conditions. Here, we report a broadly applicable and readily accessible process for the cross-coupling of water-soluble alkyl halides in water and air by using simple and commercially available bench-stable reagents. The trisulfonated aryl phosphine TXPTS in combination with a water-soluble palladium salt Na2PdCl4 allowed for the Suzuki-Miyaura coupling of water-soluble alkyl halides with aryl boronic acids, boronic esters, and borofluorate salts in mild, fully aqueous conditions. Multiple challenging functionalities, including unprotected amino acids, an unnatural halogenated amino acid within a peptide, and herbicides can be diversified in water. Structurally complex natural products were used as testbeds to showcase the late-stage tagging methodology of marine natural products to enable liquid chromatography-mass spectrometry (LC-MS) detection. This enabling methodology therefore provides a general method for the environmentally friendly and biocompatible derivatization of sp3 alkyl halide bonds.

Bench-Stable Reagents for Introduction of Highly Lipophilic Thiofluoroalkyl Fragments

Key words thiofluoroalkyl motifs - lipophilicity - indoles - saccharin - late-stage functionalization

An organo-photocatalyzed visible-light-driven multi-component approach for carbothioaryl/alkylation of activated alkenes via C(sp3)-H bond functionalization.

A visible-light-driven organophotocatalyzed multi-component approach for carbothiolation of activated alkenes is demonstrated under environmentally benign and redox-neutral conditions, involving direct C(sp3)-H functionalization followed by electrophilic alkyl/arylthiolation. The three-component difunctionalization reaction is a complete transition-metal and peroxide-free process conducted under milder conditions. In this composite reaction, by employing bench-stable reagents, the formation of two new C(sp3)-C(sp3) and C(sp3)-S bonds is achieved for a wide variety of substrates, showcasing the excellent functional group tolerance and chemoselectivity of the methodology. Furthermore, the scalability and utilization of natural sunlight instead of artificial blue LEDs, along with the use of an inexpensive and easy-to-prepare pyrylium salt as an organo-photocatalyst, make this protocol greener and more energy efficient.

Mild and Chemoselective Carboxylic Acid Reduction Promoted by Borane Catalysis.

Although considerable advances have been made in developing chemoselective transformations of ubiquitous carboxylic acid groups, many challenges still exist. For instance, their selective reduction is problematic if both more nucleophilic and more electrophilic groups are present in the starting material. Here, we address this problem with a simple and mild protocol using bench-stable reagents at ambient temperatures. This platform is able to tolerate a diverse range of functionality, leaving ketones, esters, nitro-groups, olefins, nitriles and amides untouched. A combination of experimental and computational mechanistic experiments demonstrate that this reaction proceeds via hidden borane catalysis with small quantities of in situ generated BH3 playing a key role in the exquisite selectivity that is observed.

Acceleration effect of mild organocatalytic system 2,2′-biphenol/B(OH)3 for 2-aza-Cope rearrangement

Organocatalysis by the combination of weak acids, namely, 2,2′-biphenol and B(OH)3, for 2-aza-Cope rearrangement is described. Aldehydes and 1,1-diphenyl homoallylamine were converted into the corresponding homoallylamines in moderate-to-high yield in the presence of 10 mol% 2,2′-biphenol and 30 mol% B(OH)3. In contrast to the conventional 2-aza-Cope rearrangement catalyzed by strong activators, a user- and environment-friendly organocatalytic system was established using a combination of inexpensive, easy-to-handle, non-hazardous, and bench-stable reagents.

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

Palladium-Catalyzed Regiodivergent Decarboxylative Hydrothiocarbonylation of Vinylarenes Using Oxalic Acid Monothioesters

AbstractOxalic acid monothioester (OAM), an easily accessible and bench-stable reagent, is reported herein as a synthetic equivalent of thioester for palladium-catalyzed decarboxylative hydrothiocarbonylation of vinylarenes to achieve both branched and linear regioselectivity. The reactions provided user-friendly synthetic methods for preparation of α- or β-arylated propionic acid thioesters from vinylarenes without directly handling toxic carbon monoxide and odorous thiols.

A bench-stable reagent for C-4 selective deuteriodifluoromethylation of azines

Deuteriodifluoromethyl (CF2D) is a challenging and important functional group due to difficult deuterium incorporation and lack of effective precursor reagents. Herein, we report a bench-stable reagent, deuteriodifluoromethyl phosphine (DDFP) from cheap deuterium source for selectivity deuteriodifluoromethylation of azines with a high deuterium incorporation yield. The late-stage modification of complex molecules further confirmed the potential of this reagent for practical applications. We expect that our reagent to find applications in synthesis of isotope-labelled molecules of interests for drug-discovery and related ilucidation of mechanism of action.

Copper-Catalyzed Synthesis of 5-Carboxyl-4-perfluoroalkyl Triazoles.

A facile, scalable synthesis of previously inaccessible trifluoromethyl and perfluoroalkyl triazoles is disclosed. Mediated by copper, this catalytic protocol enables access to 4-perfluoroalkyl triazoles from commodity chemicals. A catalytic Cu(II) system wherein copper serves two roles (generation of N-tosyl-2-vinyldiazenes and N-N bond formation) allows for rapid assembly of 5-carboxyl-4-perfluoroalkyl-triazoles from N-tosylhydrazide and perfluoroalkyl acetoacetates. Ethyl 4,4,4-trifluoro-3-(2-tosylhydrazineylidene)butanoate, a previously unknown air and bench stable reagent for access to CF3-triazoles, was developed to enable this chemistry. This led to the identification of a series of crystalline hydrazone reagents that could be used as templates to construct an array of triazoles. Hydrolysis and decarboxylation parlay this approach into a means to access 5-H-4-CF3-triazoles. The approach exhibits high functional group tolerance and can be executed on a multigram scale.

Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination.

Nucleophilic aromatic fluorination (SNAr) is among the most common methods for the formation of C(sp2)-F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me4NF·ROH) as fluoride sources for SNAr fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me4NF·t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for SNAr fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated.

C-H Electrophilic (phenylsulfonyl)difluoromethylation of (hetero)arenes with a newly designed reagent.

The synthesis of an original electrophilic difluoromethylating reagent was successfully achieved upon a straightforward protocol (3 steps). Like a Swiss army knife, this bench-stable reagent allowed the functionalization of various classes of compounds under mild and transition metal-free conditions. Hence, an efficient and operationally simple tool for the construction of C(sp2)-, C(sp3)- and S-CF2SO2Ph bonds was provided, expanding the chemical space of PhSO2CF2-containing molecules. Late-stage functionalization of bioactive molecules and the synthesis of PhSO2CF2- and HCF2-analogs of Lidocaine were also successfully achieved.

Cp*Rh(III)-Catalyzed Regioselective C(sp3)-H Methylation of 8-Methylquinolines with Organoborons.

Rh(III)-catalyzed highly regioselective methylation of the unactivated C(sp3)-H bond of 8-methylquinolines with bench stable organoboron reagents is described. A variety of substituted 8-methylquinolines provided the highly regioselective monomethylated products with potassium methyltrifluoroborates/methylboronic acid through primary C(sp3)-H bond activation. Complete chemoselectivity and regioselectivity were observed in all cases as methylation at the C2 position or dimethylation of the C(sp3)-H bond of 8-methylquinoline was not detected. The mechanistic study uncovered the fact that the reaction may proceed through the five-membered rhodacycle intermediate.

Electroorganic Synthesis under Flow Conditions.

Despite the long history of electroorganic synthesis, it did not participate in the mainstream of chemical research for a long time. This is probably due to the lack of equipment and standardized protocols. However, nowadays organic electrochemistry is witnessing a renaissance, and a wide range of interesting electrochemical transformations and methodologies have been developed, not only for academic purposes but also for large scale industrial production. Depending on the source of electricity, electrochemical methods can be inherently green and environmentally benign and can be easily controlled to achieve high levels of selectivity. In addition, the generation and consumption of reactive or unstable intermediates and hazardous reagents can be achieved in a safe way. Limitations of traditional batch-type electrochemical methods such as the restricted electrode surface, the necessity of supporting electrolytes, and the difficulties in scaling up can be alleviated using electrochemical flow cells. Microreactors offer high surface-to-volume ratios and enable precise control over temperature, residence time, flow rate, and pressure. In addition, efficient mixing, enhanced mass and heat transfer, and handling of small volumes lead to simpler scaling-up protocols and minimize safety concerns. Electrolysis under flow conditions reduces the possibility of overoxidation as the reaction mixture is flown continuously out of the reactor in contrast to traditional batch-type electrolysis cells. In this Account, we highlight our contributions in the area of electroorganic synthesis under flow conditions over the past decade. We have designed and manufactured different generations of electrochemical flow cells. The first-generation reactor was effectively used in developing a simple one-step synthesis of diaryliodonium salts and used in proof-of-concept reactions such as the trifluoromethylation of electron-deficient alkenes via Kolbe electrolysis of trifluoroacetic acid in addition to the selective deprotection of the isonicotinyloxycarbonyl (iNoc) group from carbonates and thiocarbonates. The improved second-generation flow cell enabled the development of efficient synthesis of isoindolinones, benzothiazoles, and thiazolopyridines, achieving gram-scale for some of the products easily without changing the reactor design or reoptimizing the reaction parameters. In addition, the same reactor was used in the development of an efficient continuous flow electrochemical synthesis of hypervalent iodine reagents. The generated unstable hypervalent iodine reagents were easily used without isolation in various oxidative transformations in a coupled flow/flow manner and could be easily transformed into bench-stable reagents via quantitative ligand exchange with the appropriate acids. Our second-generation reactor was further improved and commercialized by Vapourtec Ltd. We have demonstrated the power of online analysis in accelerating optimizations and methodology development. Online mass spectrometry enabled fast screening of the charge needed for the cyclization of amides to isoindolinones. The power of online 2D-HPLC combined with a Design of Experiments approach empowered the rapid optimization of stereoselective electrochemical alkoxylations of amino acid derivatives.

Design and synthesis of a highly efficient labelling reagent for incorporation of tetrafluorinated aromatic azide into proteins

Chemical labelling can significantly extend the structures and functions of proteins for advanced applications. Herein, a highly efficient bench-stable reagent diazo-azide was designed and synthesized for the incorporation of tetrafluorinated aromatic azides into proteins via the diazonium coupling. The diazo-azide-labelled proteins could be further functionalized via the nonhydrolysis Staudinger reaction to achieve fluorescence labelling, PEGylation and biotinylation. The whole protein labelling processes were catalysis-free and could be finished within several hours under the mild conditions. To this end, we have prepared thickened viral nanoparticles with controllable diameters.

1,1-Diacyloxy-1-phenylmethanes as versatile N-acylating agents for amines

1,1-Diacyloxy-1-phenylmethanes and 1-pivaloxy-1-acyloxy-1-phenylmethanes have been used as bench stable N-acylating reagents for primary and secondary amines and anilines under solvent-free conditions to afford their corresponding amides in good yield.

Tunable Blocking Agents for Temperature-Controlled Triazolinedione-Based Cross-Linking Reactions

The remarkable reactivity of triazolinediones (TADs) toward olefin-type substrates marks them as highly attractive click reagents, in particular for polymer modification and cross-linking. Critically, their ultrafast reaction rates result in handling issues and a rather limited shelf life whereas a particular concern for polymer material applications is homogeneous network formation. Herein, we introduce 2-phenylindoles as highly promising blocking agents for TADs, giving bench-stable reagents at ambient temperature from which the initial TADs can be released upon heating. A set of 11 indoles with varying substitution patterns was synthesized, leading to a precise control for the temperature of deblocking within a broad range of 35–100 °C. The established indole–TAD platform was next applied to bivalent TAD reagents to enable on-demand TAD-based cross-linking reactions of a diene-containing polyurethane (Mn = 12.5 kDa). Fine-tuning of the curing temperatures, down to 50 °C, was evidenced via rheological measurements.

An electrophilic reagent for the synthesis of OCHFMe-containing molecules.

Herein the synthesis of a novel and bench stable electrophilic reagent to construct the OCFHMe motif from O-nucleophiles has been described. This sulfonium salt, readily obtained in 5 steps, reacted with various phenols and alcohols. The resulting products, including complex molecules, were obtained in good yields. This reagent was also used for the functionalization of thiol derivatives.