Electrochemical Oxidative Cascade Cyclization of Alkenyl Alcohols with External Nucleophiles to Access Amino- and Hydroxy-Functionalized -Heterocycles.

A convenient electrochemical oxidative cascade cyclization of alkenes equipped with pendant alcohols with general nucleophiles was developed. Using readily available diarylmethanimine and carboxylic acids as nucleophilic sources, a broad range of internal alkene and terminal alkene substrates could produce RCO- and ArCN-functionalized -heterocycles in moderate to high yields without the requirement for external oxidants and metals. These resulting products can subsequently be hydrolyzed to yield valuable NH- and OH-functionalized tetrahydrofurans and tetrahydropyranes under mild conditions.

generated CFCHN with 3-ylideneoxindoles to access CF-containing pyrazolo[1,5-]quinazolines derivatives.

Toward a selective and facile method for the synthesis of CF-containing pyrazolo[1,5-]quinazolines, we developed a [3 + 2] cycloaddition/1,3-H shift/rearrangement/dehydrogenation cascade involving generated CFCHN and 3-ylideneoxindoles with DBU as a base. The reaction is distinguished by its mild conditions, metal-free process, operational simplicity, and broad functional group tolerance, thus presenting a convenient protocol for the construction of pyrazolo[1,5-]quinazolines that are of interest in medicinal chemistry.

Copper-Catalyzed Asymmetric [3 + 2] Cycloaddition of -2,2,2-Trifluoroethylisatin Ketimines to Access Three Classes of Polyfunctionalized Spiro-Pyrrolidine-Oxindole Motifs.

A facile copper-catalyzed [3 + 2] cycloaddition of -2,2,2-trifluoroethylisatin ketimines with various electron-deficient alkenes to access structurally polyfunctionalized spiro-pyrrolidine-oxindole motifs has been developed. Under the catalytic system, the -2,2,2-trifluoroethylisatin ketimines could be utilized to react with a series of exocyclic alkenes, including 2-acylamino acrylates, 3-methylene-β-lactams, and sterically hindered cycloalkenes represented by cyclobutenone, to obtain a variety of densely functionalized spiro-pyrrolidine frameworks bearing an α-amino acid ester, β-lactam, and cyclobutanone, respectively, in generally good yields with excellent diastereo- and enantioselectivities.

Photomediated One-Pot Three-Component Approach Enables the Formal Direct -Acylation/Sulfonylation and α-C-H Functionalization of 1,2,3,4-Tetrahydroisoquinoline.

-Acyl/sulfonyl-α-functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs) are significant structural motifs in organic synthesis and drug discovery. However, the one-pot approach enabling direct difunctionalization of THIQs remains challenging. Herein we report a photomediated one-pot three-component strategy to access -acyl/sulfonyl-α-functionalized THIQs.

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge.

Regioselective and enantioselective propargylic hydroxylations catalyzed by P450tol monooxygenases.

Regioselective and enantioselective hydroxylation of propargylic C-H bonds are useful reactions but often lack appropriate catalysts. Here a green and efficient asymmetric hydroxylation of primary and secondary C-H bonds at propargylic positions has been established. A series of optically active propargylic alcohols were prepared with high regio- and enantioselectivity (up to 99% ee) under mild reaction conditions by using P450tol, while the C≡C bonds in the molecule remained unreacted.

Iron(II)-Catalyzed Radical [3 + 2] Cyclization of -Aryl Cyclopropylamines for the Synthesis of Polyfunctionalized Cyclopentylamines.

A facile iron(II)-catalyzed radical [3 + 2] cyclization of -aryl cyclopropylamines with various alkenes to access the structurally polyfunctionalized cyclopentylamine scaffolds has been developed. Using low-cost FeCl·4HO as catalyst, -aryl cyclopropylamines could be utilized to react with a wide range of alkenes including exocyclic/acyclic terminal alkenes, cycloalkenes, alkenes from the natural-occurring compounds (Alantolactone, Costunolide), and known drugs (Ibuprofen, l-phenylalanine, Flurbiprofen) to obtain a variety of cyclopentylamines fused with different useful motifs in generally good yields and diastereoselectivities. The highlight of this protocol is also featured by no extra oxidant, no base, EtOH as the solvent, gram-scale synthesis, and further diverse transformations of the synthetic products.

2,2'-Bipyridine-Enabled Photocatalytic Radical [4+2] Cyclization of -Aryl-α-amino Acids for Synthesizing Polysubstituted Tetrahydroquinolines.

A facile photocatalytic radical [4+2] cyclization of -aryl-α-amino acids with various alkenes to access structurally polysubstituted tetrahydroquinolines has been developed. Using a simple bipyridine as a catalyst, different -aryl-α-amino acids could be utilized as the radical precursors to react with diverse electrophilic alkenes, including exocyclic terminal alkenes, acyclic terminal alkenes, and cycloalkenes, producing 10 types of nitrogen-containing heterocyclic compounds fused in multiple frameworks in generally moderate yields with good diastereoselectivities. Scale-up synthesis and transformations of the products further demonstrated the synthetic application of this protocol.

Iodomethane in C1 chemistry: application in palladium-catalyzed [2 + 2 + 1] annulation.

An efficient palladium-catalyzed [2 + 2 + 1] annulation of 3-iodochromones, bridged olefins, and iodomethane is described, affording a range of chromone-containing polycyclic compounds. Additionally, the corresponding deuterated products were smoothly obtained with iodomethane- instead of iodomethane. Moreover, the synthetic utility of this method is further substantiated by gram scale preparation and application to late-stage modification of estrone.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF C :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF C =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF C =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog.

Constructing a CdS QDs/silica gel composite with high photosensitivity and prolonged recyclable operability for enhanced visible-light-driven NADH regeneration.

Visible-light-driven nicotinamide adenine dinucleotide (NADH) regeneration is one of the most effective measures, and cadmium sulfide (CdS) materials are typically used as low-cost photocatalysts. The CdS photocatalysts, however, still suffer from low regeneration efficiency and poor cycle stability. In this work, the CdS quantum dots (QDs) less than 10 nm embedded onto silica gel (CdS QDs/Silica gel) were constructed for visible-light-driven NADH regeneration by a successive ionic layer adsorption reaction and ball milling method.

Biocatalytic Synthesis of Metaxalone and Its Analogues.

A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from . Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ) for chiral forms and 77-92% yields for racemic forms.

Enantiocomplementary synthesis of β-adrenergic blocker precursors via biocatalytic nitration of phenyl glycidyl ethers.

Enantiopure β-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of β-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral β-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee).

Electrochemically Enabled Intramolecular Amino- and Oxysulfonylation of Alkenes with Sodium Sulfinates to Access Sulfonylated Saturated Heterocycles.

A practical and efficient electrochemical intramolecular amino- or oxysulfonylation of internal alkenes equipped with pendant nitrogen or oxygen-centered nucleophiles with sodium sulfinate was developed. Under undivided electrolytic cell conditions, a variety of sulfonylated -heterocycles and -heterocycles, such as tetrahydrofurans, tetrahydropyrans, oxepanes, tetrahydropyrroles, piperidines, δ-valerolactones, etc., were efficiently prepared from easily accessible unsaturated alcohols, carboxylic acids, and -tosyl amines without the need for additional metal or exogenous oxidant.

Cooperative Tertiary Amine/Palladium-Catalyzed Sequential [4 + 3] Cyclization/[1,3]-Rearrangement for Stereoselective Synthesis of Spiro [Methylenecyclopentane-1,3'-oxindolines].

A cooperative tertiary amine/palladium-catalyzed sequential reaction process, proceeding via a [4 + 3] cyclization of isatin-derived Morita-Baylis-Hillman Expansion (MBH) carbonates and -butyl 2-(hydroxymethyl)allyl carbonates followed by a [1,3]-rearrangement, has been found and developed. A range of structurally diverse spiro[methylene cyclopentane-1,3'-oxindolines] bearing two adjacent β,γ-acyl quaternary carbon stereocenters, which are difficult to obtain by conventional strategies, were obtained in good yields. Further synthetic utility of this protocol is highlighted by its excellent regio- and stereocontrol as well as the large-scale synthesis and diverse functional transformations of the synthetic compounds.

Palladium-Catalyzed Domino Reaction for the Assembly of Norbornane-Containing Chromones with Dimethyl Squarate as the Solid C1 Source.

Reported herein is a novel palladium-catalyzed [2 + 2 + 1] domino annulation of 3-iodochromones, bridged olefins, and dimethyl squarate allowing the construction of chromone-containing polycyclic compounds in good to high yields. Importantly, dimethyl squarate is first employed as the solid C1 source in organic synthesis. Gram-scale experiments, late-stage modification of natural products, as well as transformations of products show potential for further synthetic elaborations.

Identification and Structure Analysis of an Unusual Halohydrin Dehalogenase for Highly Chemo-, Regio- and Enantioselective Bio-Nitration of Epoxides.

We report the discovery of an unusual halohydrin dehalogenase, HHDHamb, that can work under relatively low acidic conditions and extremely low temperatures for the bio-nitration of epoxides using nitrite as a nitrating agent. The bio-nitration strategy exhibits high chemo-, regio-, and enantioselectivity, catalyzing the kinetic resolution of various epoxides to enantiopure β-nitroalcohols with nitro-bearing stereocenters in up to 41 % isolated yield and >99 % enantiomeric excess (ee). Additionally, the bio-nitration method displays a high reaction efficiency and can be performed on a gram scale.

Copper-Catalyzed [5 + 1] Cyclization of -Pyrrolo Anilines and Heterocyclic -Tosylhydrazones for Access to Spiro-dihydropyrrolo[1,2-]quinoxaline Derivatives.

An inexpensive copper-catalyzed sequential reaction process, proceeding via a nucleophilic attack of amine to Cu-carbene generated in situ from heterocyclic -tosylhydrazone precursors followed by a 1,2-H shift/oxidative cyclization cascade of -ylides, has been described, smoothly generating the corresponding structurally various spiro-dihydropyrrolo[1,2-]quinoxaline derivatives. Furthermore, the significance of this protocol can be also highlighted by its diverse conversions of the synthetic compounds to the potentially bioactive molecules such as the 2-substituted pyrrolo[1,2-]quinoxalins.

Complementary Copper-Catalyzed and Electrochemical Aminosulfonylation of -Homoallyl Benzimidates and -Alkenyl Amidines with Sodium Sulfinates.

A complementary copper-catalyzed and electrochemical aminosulfonylation of -homoallyl benzimidates and -alkenyl amidines with sodium sulfinates was developed. The terminal alkene substrate produced sulfone-containing 1,3-oxazines and tetrahydropyrimidines in the presence of Cu(OAc), AgCO, and DPP, and under similar reaction conditions, sulfonylated tetrahydro-1,3-oxazepines were prepared from 1-aryl-substituted -homoallyl benzimidates in moderate to good yields. For certain electron-rich 1,1-diaryl-substituted alkene substrates, the corresponding tetrahydro-1,3-oxazepines could also be obtained in similar or even higher yields via a green electrochemical technique.

Diazotrifluoroethyl Radical: A CF-Containing Building Block in [3 + 2] Cycloaddition.

We present herein a visible-light-induced [3 + 2] cycloaddition of a hypervalent iodine(III) reagent with α-ketoacids for the construction of 5-CF-1,3,4-oxadiazoles that are of importance in medicinal chemistry. The reaction proceeds smoothly without a photocatalyst, metal, or additive under mild conditions. Different from the well-established trifluorodiazoethane (CFCHN), the diazotrifluoroethyl radical [CFC(·)N], a trifluoroethylcarbyne (CFCĊ:) equivalent and an unusual CF-containing building block, is involved in the present reaction system.

Regiodivergent and stereoselective hydroxyazidation of alkenes by biocatalytic cascades.

Asymmetric functionalization of alkenes allows the direct synthesis of a wide range of chiral compounds. Vicinal hydroxyazidation of alkenes provides a desirable path to 1,2-azidoalcohols; however, existing methods are limited by the control of stereoselectivity and regioselectivity. Herein, we describe a dual-enzyme cascade strategy for regiodivergent and stereoselective hydroxyazidation of alkenes, affording various enantiomerically pure 1,2-azidoalcohols.

Design, synthesis, and herbicidal activity of novel phenoxypyridine derivatives containing natural product coumarin.

Background: In recent years, protoporphyrinogen oxidase (PPO, EC 1.3.3.

Palladium-catalyzed asymmetric allylic alkylation of 3-aminooxindoles to access chiral homoallylic aminooxindoles.

An organometal catalytic conversion of 3-aminooxindoles for the diastereo- and enantioselective synthesis of homoallylic aminooxindoles has been described. The asymmetric allylic alkylation of 3-aminooxindoles with allyl carboxylates proceeded smoothly to afford a series of chiral 3-allyl-3-aminooxindoles. This work offers an alternative route to build these scaffolds.

Catalytic Enantioselective Dearomatization/Rearomatization of 2-Nitroindoles to Access 3-Indolyl-3'-Aryl-/Alkyloxindoles: Application in the Formal Synthesis of Cyclotryptamine Alkaloids.

The first catalytic enantioselective dearomatization/rearomatization of 2-nitroindoles triggered by the Michael addition of 3-monosubstituted oxindoles was established. A wide range of 3-indolyl-3'-alkyloxindoles (up to 99% yield, 97% ee) and 3-indolyl-3'-aryloxindoles (up to 95% yield, 99% ee) were obtained by using an organocatalyst. This method provides an unprecedented strategy to access structurally diverse 3,3'-disubstituted oxindoles bearing a sterically congested triaryl-containing all-carbon quaternary stereocenter.