Carboiodanation of Arynes: Organoiodine(III) Compounds as Nucleophilic Organometalloids.

Organic iodine(III) compounds represent the most widely used hypervalent halogen compounds in organic synthesis, where they typically perform the role of an electrophile or oxidant to functionalize electron-rich or -nucleophilic organic compounds. In contrast to this convention, we discovered their unique reactivity as organometallic-like nucleophiles toward arynes. Equipped with diverse transferable ligands and supported by a tethered spectator ligand, the organoiodine(III) compounds undergo addition across the electrophilic C-C triple bond of arynes while retaining the trivalency of the iodine center. This carboiodanation reaction can forge a variety of aryl-alkynyl, aryl-alkenyl, and aryl-(hetero)aryl bonds along with the concurrent formation of an aryl-iodine(III) bond under mild conditions. The newly formed aryl-iodine(III) bond serves as a versatile linchpin for downstream transformations, particularly as an electrophilic reaction site. The amphoteric nature of the iodine(III) group as a metalloid and a leaving group in this sequence enables the flexible and expedient synthesis of extended π-conjugated molecules and privileged biarylphosphine ligands, where all of the iodine(III)-containing compounds can be handled as air- and thermally stable materials.

Amino- and Alkoxybenziodoxoles: Facile Preparation and Use as Arynophiles.

We report here on the facile synthesis of amino- and alkoxy-λ3-iodanes supported by a benziodoxole (BX) template and their use as arynophiles. The amino- and alkoxy-BX derivatives can be readily synthesized by reacting the respective amines or alcohols with chlorobenziodoxole in the presence of a suitable base. Unlike previously known nitrogen- and oxygen-bound iodane compounds, which have primarily been employed as electrophilic group transfer agents or oxidants, the present amino- and alkoxy-BX reagents manifest themselves as nucleophilic amino and alkoxy transfer agents toward arynes. This reactivity leads to the aryne insertion into the N-I(III) or O-I(III) bond to afford ortho-amino- and ortho-alkoxy-arylbenziodoxoles, iodane compounds nontrivial to procure by existing methods. The BX group in these insertion products exhibits excellent leaving group ability, enabling diverse downstream transformations.

N-Terminal-Specific Dual Modification of Peptides through Copper-Catalyzed [3+2] Cycloaddition.

Site-specific introduction of multiple components into peptides is greatly needed for the preparation of densely functionalized and structurally uniform peptides. In this regard, N-terminal-specific peptide modification is attractive, but it can be difficult due to the presence of highly nucleophilic lysine ϵ-amine. In this work, we developed a method for the N-terminal-specific dual modification of peptides through a three-component [3+2] cycloaddition with aldehydes and maleimides under mild copper catalysis. This approach enables exclusive functionalization at the glycine N-terminus of iminopeptides, regardless of the presence of lysine ϵ-amine, thus affording the cycloadducts in excellent yields. Tolerating a broad range of functional groups and molecules, the present method provides the opportunity to rapidly construct doubly functionalized peptides using readily accessible aldehyde and maleimide modules.

Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species.

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc-mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N-heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol-derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring-opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate-determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

Dipolarophile-Steered Formal Stereodivergent Synthesis of 2,5-cis/trans-Pyrrolidines Based on Asymmetric 1,3-Dipolar Cycloaddition of Imino Lactones.

The stereodivergent asymmetric synthesis of 2,5-trans/cis pyrrolidines by 1,3-dipolar cycloaddition using two different types of activated alkenes is described. When ylidene-isoxazolones were employed as dipolarophiles, the Ag/(S,Sp )-iPr-FcPHOX-catalyzed asymmetric [3+2] cycloaddition of imino lactones proceeded with 2,5-trans selectivity. Subsequent decarboxylation of the isoxazolone rings produced pyrrolidines with 2,5-trans stereoretention. In the reaction using acyclic enones as activated alkenes, the Ag/(R,Sp )-ThioClickFerrophos complex-catalyzed asymmetric [3+2] cycloaddition afforded 2,5-cis substituted pyrrolidines in high yields and enantioselectivities. Therefore, these methods can be considered as a formal stereodivergent synthesis of 2,5-cis/trans pyrrolidines.

Chiral Silver Complex-Catalyzed Asymmetric Conjugate Addition of 1-Pyrroline-5-Carbonitrile to α-Enones.

The conjugated addition reaction of 1-pyrroline-5-carbonitrile to α-enones was effectively catalyzed by AgF/ThioClickFerrophos (TCF) in diethyl ether in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and nearly single diastereomers of adducts with good enantiomeric excesses (up to 97% ee) were obtained in high yields. The reduction of the nitrile group with H2/Raney Ni in ethanol successfully transformed the conjugate adduct to the corresponding spirocyclic piperidine (60% yield) as a single stereoisomer.

N-(Morpholine-4-dithio)phthalimide: A Shelf-Stable, Bilateral Platform Molecule Enabling Access to Diverse Unsymmetrical Disulfides.

Synthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf-stable and easy-to-prepare bilateral disulfurating platform molecule, N-(morpholine-4-dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron-rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C-S bond-forming reactions.

Cationic Iridium-Catalyzed Asymmetric Decarbonylative Aryl Addition of Aromatic Aldehydes to Bicyclic Alkenes.

We report an unprecedented catalytic protocol for the enantioselective decarbonylative transformation of aryl aldehydes. In this process, the decarbonylation of aldehydes catalyzed by chiral iridium complexes enabled the formation of asymmetric C-C bonds through the formation of an aryl-iridium intermediate. The decarbonylative aryl addition to bicyclic alkenes was fluidly performed without a stoichiometric aryl-metal reagent, such as aryl boronic acid, with a cationic iridium complex generated in situ from Ir(cod)2 (BArF 4 ) and the sulfur-linked bis(phosphoramidite) ligand ((R,R)-S-Me-BIPAM). This reaction has broad functional group compatibility, and no waste is generated, except carbon monoxide.

Cationic Iridium-Catalyzed Asymmetric Decarbonylative Aryl Addition of Aromatic Aldehydes to Bicyclic Alkenes.

Invited for the cover of this issue are Tomohiko Shirai and co-workers at the National Institute of Technology Kochi College and their collaborators at Chuo and Hokkaido Universities. The image depicts how asymmetric decarbonylative C-C bond formation by the Ir/S-Me-BIPAM complex takes precedence over aldehyde decarbonylation. Read the full text of the article at 10.1002/chem.202104347.

Silver/ThioClickFerrophos-Catalyzed 1,3-Dipolar Cycloaddition and Tandem Addition-Elimination Reaction of Morita-Baylis-Hillman Adducts.

The asymmetric 1,3-dipolar cycloaddition of glycine imino esters to Morita-Baylis-Hillman (MBH) adducts or acetylated MBH adducts is described. The reaction was efficiently catalyzed by AgOAc/(R,Sp)-ThioClickFerrophos at room temperature to afford pyrrolidine derivatives bearing a quaternary carbon as a single diastereomer with excellent enantioselectivity. When a cyclic pyrroline ester was used as the nucleophile instead of a glycine imino ester, the enantioselective tandem addition-elimination reaction with an acetylated MBH adduct proceeded with an excellent yield and enantioselectivity, resulting in the formation of an exo-olefin. The wide substrate scope of these reactions and the transformability of the products enable expeditious access to divergent multifunctionalized pyrrolidines in an optically pure fashion.

Functionalization of a Single C-F Bond of Trifluoromethylarenes Assisted by an ortho-Silyl Group Using a Trityl-Based All-in-One Reagent with Ytterbium Triflate Catalyst.

Catalytic thiolation and azidation of a single C-F bond of trifluoromethylarenes were achieved assisted by an ortho-silyl group with all-in-one reagents to generate a trityl cation and nucleophiles. The reactions catalyzed by ytterbium triflate efficiently afforded a wide variety of difluoromethylenes avoiding the further C-F bond cleavage, by virtue of the mild conditions without the generation of a Brønsted acid.

Copper-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Imino Esters to Unsaturated Sultones.

The asymmetric 1,3-dipolar cycloaddition of glycine imino esters to 1-propene-1,3-sultone or sulfocoumarins is described. The reaction was efficiently catalyzed by Cu(MeCN)4BF4/DTBM-Segphos or Cu(MeCN)4BF4/tBu-FcPhox at room temperature to afford fused pyrrolidines as single regioisomers with excellent diastereoselectivity and enantioselectivity. The broad substrate scope of this reaction provides convenient access to structurally diverse multisubstituted pyrrolidines in an optically pure fashion.

Amination of N-(Organodithio)phthalimides for the Modular Synthesis of Aminodisulfides.

Synthetic methods for unsymmetrical aminodisulfides are greatly needed due to their applications in drug discovery, linker chemistry, and materials sciences. In this study, an amination reaction of N-dithiophthalimides has been developed for the divergent synthesis of unsymmetrical aminodisulfides. The reaction proceeds under mild conditions and provides the aminodisulfides in excellent yields without cleavage of the disulfide bond. The N-dithiophthalimides are readily available from several bilateral disulfurating reagents, and the broad substrate scope of this reaction allows for the modular synthesis of a variety of unsymmetrical aminodisulfides in two-step operations.

Construction of Diverse Pyrrolidine-Based Skeletons through the Ag-Catalyzed Stereoselective Addition-Elimination Reaction of Azomethine Ylides with Nitroallyl Acetates.

Because scaffold diversity has a pronounced impact on biological screening, the efficient and expedient construction of skeletally diverse compound collections is a fundamental demand in drug discovery. In this regard, we report here an asymmetric tandem conjugate addition-elimination reaction of pyrroline esters with nitroallyl acetates and its application to the construction of various types of fused or spirocyclic pyrrolidines. A AgOAc/(R,Sp)-ThioClickFerrophos (TCF) catalyst efficiently promotes the addition-elimination reaction, setting vicinal chiral stereocenters featuring a tetrasubstituted carbon with excellent enantio- and diastereoselectivity while leaving the versatile nitroolefin moiety. The broad substrate scope of this reaction and the transformability of the resulting nitroolefin, imine, and ester moieties allow for the construction of diverse pyrrolidine-based fused or spiro bicyclic skeletons in optically active forms by various intramolecular cyclization processes.

Cationic Iridium-Catalyzed Decarboxylation of Aromatic Carboxylic Acids.

Practical synthetic applications of catalytic decarboxylation in producing useful molecules are limited. We report herein the cationic Ir-catalyzed decarboxylations of various electron-rich and -poor aromatic carboxylic acids to produce hydrocarbons in good yield (up to >99%). Additionally, this reaction is applicable in decarboxylative hydroarylation of bicyclic alkenes and decarboxylative fluorination, indicating the potential utility of this catalytic decarboxylation in synthetic chemistry.

exo'-Selective Construction of Spirobipyrrolidines by the Silver-catalyzed Asymmetric [3+2] Cycloaddition of Imino Esters with 4-Benzylidene-2,3-dioxopyrrolidines.

An unprecedented Ag-catalyzed exo'-selective [3+2] cycloaddition of imino esters with 4-benzylidene-2,3-dioxopyrrolidines is described. The reaction was efficiently catalyzed by Ag/(R, Sp )-ThioClickFerrophos (TCF) leading to the construction of the corresponding spirobipyrrolidine scaffolds in excellent enantio- and diastereoselectivities. This reaction is the first example of a silver-catalyzed exo'-selective asymmetric [3+2] cycloaddition, as well as the first exo'-selective spirobipyrrolidine construction via a [3+2] cycloaddition process using imino esters. The wide substrate scope of this reaction enabled the preparation of structurally diverse spirobipyrrolidine derivatives, which are attracting attention as targets for drug discovery. Mechanistic studies suggested that the unusual exo'-selectivity of this reaction is not due to epimerization following the common exo- or endo-selective cycloaddition, but instead is due to a stepwise Michael addition/Mannich sequence with bond rotation.

Palladium-Catalyzed Sulfinylation of Aryl- and Alkenylborons with Sulfinate Esters.

An efficient, direct sulfinylation of organoborons catalyzed by palladium is disclosed. Treatment of organoborons and sulfinate esters in the presence of a palladium precatalyst provided a broad range of sulfoxides. Various organosulfur compounds having oxidizable functional groups were successfully prepared through the sulfoxide synthesis.

Copper-Catalyzed Single C-H Amination of 8-Aminoquinoline-Directed Ferrocenes.

An unprecedented copper-catalyzed C-H monoamination of ferrocenes directed by an 8-aminoquinoline amide directing group is described. This reaction proceeds in the presence of a catalytic amount of copper catalyst with both cyclic and acyclic amines to afford the various aminoferrocenes. The C-H amination of ortho-substituted ferroceneamides was also achieved, enabling rapid access to multisubstituted ferrocenes that are useful for developing new functional molecules.

Acid-Mediated Sulfonylthiolation of Arenes via Selective Activation of SS-Morpholino Dithiosulfonate.

A trifluoroacetic-acid-mediated desulfurilative sulfonylthiolation of arenes using SS-morpholino dithiosulfonate is described. This system is based on selective activation of the morpholino group over the tosyl group of the doubly transformable sulfur surrogate. Mechanistic studies suggested that the reaction proceeds through electrophilic aromatic substitution followed by sulfur extrusion. The wide substrate scope of this reaction and the transformability of the resulting thiosulfonates enable expeditious access to divergent multifunctionalized sulfides.

Cationic Iridium/Chiral Bisphosphine-Catalyzed Enantioselective Hydroacylation of Ketones.

A facile and convenient synthesis of the chiral phthalide framework catalyzed by cationic iridium was developed. The method utilized cationic iridium/bisphosphine-catalyzed asymmetric intramolecular carbonyl hydroacylation of 2-keto benzaldehydes to furnish the corresponding optically active phthalide products in good to excellent enantioselectivities (up to 98% ee). The mechanistic studies using a deuterium-labelled substrate suggested that the reaction involved an intramolecular carbonyl insertion mechanism to iridium hydride intermediate. In addition, we investigated the kinetic isotope effect (KIE) of intramolecular hydroacylation with deuterated substrate and determined that the C-H activation step is not included in the turnover-limiting step.