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.

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.

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles.

A stereoselective N-alkenylation of azoles with alkynes and iodine(III) electrophile is reported. The reaction between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl group in the product can be leveraged as a versatile synthetic handle, allowing for the preparation of hitherto inaccessible types of densely functionalized N-vinylazoles.

Stereoselective Approach to Multisubstituted Enolates from Unactivated Alkynes: Oxyalkylidenation of Alkynyl Ketone Enolates with Aldehydes.

The preparation of multisubstituted enolates with precise regio- and stereocontrol is a nontrivial task when conventional deprotonation methods are used on the corresponding carbonyl compounds. We describe herein an approach to preparing stereodefined enolates by leveraging the stereoselective oxyfunctionalization of unactivated alkynes, particularly in the context of the alkynylogous aldol reaction. trans-Iodo(III)acetoxylation of alkynes and subsequent Sonogashira coupling allow for the facile preparation of multisubstituted enynyl acetates, which can be deacetylated by MeLi into the corresponding enolates. The alkynyl enolates react with aldehydes to afford γ,δ-unsaturated ß-diketones through a cascade of alkynylogous aldol addition, intramolecular Michael addition, and ring opening of the oxetene intermediate.

Site-Selective C-H Alkenylation of N-Heteroarenes by Ligand-Directed Co/Al and Co/Mg Cooperative Catalysis.

We report herein the design and development of Co/Al and Co/Mg bimetallic catalysts, supported by a phosphine/secondary phosphine oxide (PSPO) bifunctional ligand, for the site-selective C-H alkenylation of nitrogen-containing heteroarenes with alkynes. These catalysts enable the alkenylation of pyridine, pyridone, and imidazo[1,2-a]pyridine derivatives at the C-H site proximal to the Lewis basic nitrogen or oxygen atom, which represents a selectivity profile distinct from that of the previously developed cobalt-diphosphine/aluminum catalyst. The alkenylated products were obtained in moderate to good yields using various heterocycles and differently substituted internal alkynes. Kinetic isotope effect experiments suggest the irreversibility of the C-H activation step, the relevance of which to the rate-limiting step depends on the reaction conditions. Density functional theory calculations indicate that ligand-to-ligand hydrogen transfer is the common mechanism of C-H activation.

Zinc-Catalyzed ß-Functionalization of Cyclopropanols via Enolized Homoenolate.

We report herein a zinc-catalyzed ß-allylation of cyclopropanols with Morita-Baylis-Hillman (MBH) carbonates with retention of the cyclopropane ring. The reaction is promoted by a zinc aminoalkoxide catalyst, affording cyclopropyl-fused α-alkylidene-δ-valerolactone derivatives in moderate to good yields. Mechanistic experiments suggest that the present reaction does not proceed via direct ß-C-H cleavage of the cyclopropanol, but involves zinc homoenolate and its enolization to generate a key bis-nucleophilic species. α-Allylation of this "enolized homoenolate" with MBH carbonate would be followed by regeneration of the cyclopropane ring and irreversible lactonization. The enolized homoenolate mechanism has also been proven to allow for ß-functionalization with alkylidenemalononitrile as the reaction partner. A sequence of the present reaction and known cyclopropanol transformation provides an opportunity to transform a simple cyclopropanol into α,ß- or ß,ß-difunctionalized ketones.

Enantioselective Conjugate Addition of Catalytically Generated Zinc Homoenolate.

We report herein an enantioselective conjugate addition reaction of a zinc homoenolate, catalytically generated via ring opening of a cyclopropanol, to an α,ß-unsaturated ketone. The reaction is promoted by a zinc aminoalkoxide catalyst generated from Et2Zn and a chiral ß-amino alcohol to afford 1,6-diketones, which undergo, upon heating, intramolecular aldol condensation to furnish highly substituted cyclopentene derivatives with good to high enantioselectivities. The reaction has proved applicable to various 1-substituted cyclopropanols as well as chalcones and related enones. The chiral amino alcohol has proved to enable ligand-accelerated catalysis of the homoenolate generation and its conjugate addition. Positive nonlinear effects and lower reactivity of a racemic catalyst have been observed, which can be attributed to a stable and inactive heterochiral zinc aminoalkoxide dimer.

Robust Cobalt Catalyst for Nitrile/Alkyne [2+2+2] Cycloaddition: Synthesis of Polyarylpyridines and Their Mechanochemical Cyclodehydrogenation to Nitrogen-Containing Polyaromatics*.

The transition-metal-catalyzed [2+2+2] cycloaddition of nitriles and alkynes is an established synthetic approach to pyridines; however, these cycloadditions often rely on the use of tethered diynes or cyanoalkynes as one of the reactants. Thus, examples of efficient, fully intermolecular catalytic [2+2+2] pyridine synthesis, especially those employing unactivated nitriles and internal alkynes leading to pentasubstituted pyridines, remain scarce. Herein, we report on simple and inexpensive catalytic systems based on cobalt(II) iodide, 1,3-bis(diphenylphosphino)propane, and Zn that promote [2+2+2] cycloaddition of various nitriles and diarylacetylenes for the synthesis of a broad range of polyarylated pyridines. DFT studies support a reaction pathway involving oxidative coupling of two alkynes, insertion of the nitrile into a cobaltacyclopentadiene, and C-N reductive elimination. The resulting tetra- and pentaarylpyridines serve as precursors to hitherto unprecedented nitrogen-containing polycyclic aromatic hydrocarbons via mechanochemically assisted multifold reductive cyclodehydrogenation.

Stereoselective Access to Highly Substituted Vinyl Ethers via trans-Difunctionalization of Alkynes with Alcohols and Iodine(III) Electrophile.

A method for the regio- and stereoselective synthesis of highly substituted vinyl ethers via trans-1,2-difunctionalization of alkynes with a cyclic λ3-iodane electrophile (benziodoxole triflate) and alcohols is reported. The reaction tolerates a variety of internal and terminal alkynes as well as various alcohols, affording ß-λ3-iodanyl vinyl ethers in good yields with high regio- and stereoselectivities. The benziodoxole moiety of the products can be used as a versatile linchpin for the synthesis of structurally diverse vinyl ethers that are difficult to access by other means.

Cobalt/Lewis Acid Catalysis for Hydrocarbofunctionalization of Alkynes via Cooperative C-H Activation.

A catalytic system comprising a cobalt-diphosphine complex and a Lewis acid (LA) such as AlMe3 has been found to promote hydrocarbofunctionalization reactions of alkynes with Lewis basic and electron-deficient substrates such as formamides, pyridones, pyridines and related azines, imidazo[1,2-a]pyridines, and azole derivatives through site-selective C-H activation. Compared with known Ni/LA catalytic systems for analogous transformations, the present catalytic systems not only feature convenient setup using inexpensive and bench-stable precatalyst and ligand such as Co(acac)3 and 1,3-bis(diphenylphosphino)propane (dppp) but also display distinct site-selectivity toward C-H activation of pyridone and pyridine derivatives. In particular, a completely C4-selective alkenylation of pyridine has been achieved for the first time. Meanwhile, the present catalytic system proved to promote exclusively C5-selective alkenylation of imidazo[1,2-a]pyridine derivatives. Mechanistic studies including DFT calculations on the Co/Al-catalyzed addition of formamide to alkyne have suggested that the reaction involves cleavage of the carbamoyl C-H bond as the rate-limiting step, which proceeds through a ligand-to-ligand hydrogen transfer (LLHT) mechanism leading to an alkenyl(carbamoyl)cobalt intermediate.

Cobalt-Catalyzed Intramolecular Hydroacylation Involving Cyclopropane Cleavage.

A simple cobalt-diphosphine catalyst has been found to efficiently promote intramolecular cyclization of ortho-cyclopropylvinyl- and cyclopropylidenemethyl-substituted benzaldehydes into benzocyclooctadienone and benzocycloheptadienone derivatives, respectively. This ring-opening hydroacylation likely involves aldehyde C-H oxidative addition, olefin insertion, cyclopropane cleavage by ß-carbon elimination, and C-C bond-forming reductive elimination, as was supported by mechanistic experiments and DFT calculations.

Synthesis of triphenylene-fused phosphole oxides via C-H functionalizations.

The synthesis of triphenylene-fused phosphole oxides has been achieved through two distinct C-H functionalization reactions as key steps. The phosphole ring was constructed by a three-component coupling of 3-(methoxymethoxy)phenylzinc chloride, an alkyne, and dichlorophenylphosphine, involving the regioselective C-H activation of the C2 position of the arylzinc intermediate via 1,4-cobalt migration. The resulting 7-hydroxybenzo[b]phosphole derivative was used for further π-extension through Suzuki-Miyaura couplings and a Scholl reaction, the latter closing the triphenylene ring. The absorption and emission spectra of the thus-synthesized compounds illustrated their nature as hybrids of triphenylene and benzo[b]phosphole.

Stereocontrolled Synthesis of Halovinylbenziodoxoles by Hydro- and Iodochlorination of Ethynylbenziodoxoles.

We report herein the synthesis of highly substituted and stereochemically well-defined vinylbenziodoxole (VBX) derivatives through hydrochlorination and iodochlorination of ethynylbenziodoxoles. The hydrochlorination is achieved using pyridine hydrochloride as an HCl source in an anti-fashion under mild, open-air conditions to afford a 2-chlorinated VBX product, which serves as a useful building block for the stereoselective synthesis of trisubstituted alkenes. Meanwhile, iodochlorination with iodine monochloride proceeds in an unusual syn-pathway, stereoselectively affording a tetrasubstituted VBX derivative.

Pd-Catalyzed Annulation of 1-Halo-8-arylnaphthalenes and Alkynes Leading to Heptagon-Embedded Aromatic Systems.

A palladium-catalyzed heptagon-forming annulation reaction between 1-halo-8-arylnaphthalene and diarylacetylene is reported. The reaction is promoted using a catalytic system comprised of Pd(OAc)2 , moderately electron-deficient triarylphosphine P(4-ClC6 H4 )3 , and Ag2 CO3 to afford benzo[4,5]cyclohepta[1,2,3-de]naphthalene derivatives in moderate to good yields, in preference to fluoranthene as a competing byproduct. Twofold annulation can also be achieved to access a novel heptagon-embedded polycyclic aromatic hydrocarbon compound.

Cobalt-Catalyzed, N-H Imine-Directed Arene C-H Benzylation with Benzyl Phosphates.

A cobalt-catalyzed ortho-C-H benzylation reaction of pivalophenone N-H imines with benzyl phosphates is reported. The reaction is promoted at room temperature by a ternary catalytic system comprising Co(acac)3, a pyridylphosphine ligand, and a Grignard reagent and tolerates a series of substituted pivalophenone imines and benzyl phosphates to afford various diarylmethane derivatives in moderate yields.

Cobalt-Catalyzed Intermolecular [2+2] Cycloaddition between Alkynes and Allenes.

An intermolecular [2+2] cycloaddition reaction between an alkyne and an allene is reported. In the presence of a cobalt(I)/diphosphine catalyst, a near equimolar mixture of the alkyne and allene is converted into a 3-alkylidenecyclobutene derivative in good yield with high regioselectivity. The reaction tolerates a variety of internal alkynes and mono- or disubstituted allenes bearing various functional groups. The reaction is proposed to involve regioselective oxidative cyclization of the alkyne and allene to form a 4-alkylidenecobaltacyclopentene intermediate, with subsequent C-C reductive elimination.

Cobalt-Catalyzed Intramolecular Reactions between a Vinylcyclopropane and an Alkyne: Switchable [5+2] Cycloaddition and Homo-Ene Pathways.

Cobalt-diphosphine catalysts have been found to promote intramolecular reactions between a vinylcyclopropane and an alkyne to selectively afford either the [5+2] cycloaddition product or the homo-ene reaction product under solvent control. The former product is exclusively formed in noncoordinating 1,2-dichloroethane, whereas the latter is dominant in coordinating solvents, such as acetonitrile and dimethylacetamide. Furthermore, a highly enantioselective variant of the homo-ene reaction afforded chiral tetrahydrofuran, pyrrolidine, and cyclopentane derivatives bearing 1,3-diene and alkylidene substituents.

Cobalt-catalyzed directed C-H alkenylation of pivalophenone N-H imine with alkenyl phosphates.

A cobalt-N-heterocyclic carbene (NHC) catalyst efficiently promotes an ortho C-H alkenylation reaction of pivalophenone N-H imine with an alkenyl phosphate. The reaction tolerates various substituted pivalophenone N-H imines as well as cyclic and acyclic alkenyl phosphates.

Pd-Catalyzed, Ligand-Enabled Stereoselective 1,2-Iodine(III) Shift/1,1-Carboxyalkynylation of Alkynylbenziodoxoles.

A PdII -catalyzed 2:1 coupling reaction of alkynylbenziodoxole with carboxylic acid to afford (alk-1-en-3-ynyl)benziodoxole, which is efficiently promoted by an octahydrophenazine ligand, is reported. The reaction involves a Pd-assisted 1,2-iodine(III) shift of the alkynylbenziodoxole followed by stereoselective introduction of carboxy and alkynyl groups (the latter originating from another molecule of the alkynylbenziodoxole) into the 1-position of the transient Pd-vinylidene species. The product of this 1,1-carboxyalkynylation reaction serves as a new functionalized enyne-type building block for further synthetic transformations.