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.

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.

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.

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.

Stereoselective Synthesis of ß-Alkoxy-ß-amido Vinylbenziodoxoles via Iodo(III)etherification of Ynamides.

A trans-iodo(III)etherification reaction of ynamides with benziodoxole triflate and alcohols is reported. Despite the sensitivity of ynamides and enamides toward Brønsted acid, the reaction could be successfully performed under carefully controlled conditions to afford ß-alkoxy-ß-amido vinylbenziodoxoles in moderate to good yields. The products could be subjected to a sequence of cross-coupling via C-I(III) bond cleavage and electrophilic halogenation of the resulting α-alkoxyenamides, allowing for the preparation of densely functionalized esters.

Zinc-Mediated Hydroxyallylation of Aldehydes with Cyclopropanols: Direct Access to Vicinal anti-sec,tert-Diols via Enolized Homoenolates.

Direct and diastereoselective synthesis of vicinal anti-sec,tert-diols has been achieved by zinc-mediated α-hydroxyallylation of aldehydes with cyclopropanols. The reaction features the action of the zinc-enolized homoenolate as a γ-oxyallyl nucleophile toward the carbonyl electrophile. The diastereoselectivity of the present reaction is ascribed to the strong preference for a chelated (Z)-configuration of the enolized homoenolate as well as the bicyclic chairlike transition state it forms with the aldehyde, where the aldehyde substituent prefers to occupy the pseudoaxial position.

Regio- and Stereoselective Synthesis of Enol Carboxylate, Phosphate, and Sulfonate Esters via Iodo(III)functionalization of Alkynes.

ß-Iodo(III)enol carboxylates, phosphates, and tosylates can be efficiently synthesized through regio- and stereoselective iodo(III)functionalization of alkynes. The combination of chlorobenziodoxole and silver salt has proven to generate a versatile cationic iodine(III) electrophile to activate alkynes and engage various carboxylic acids, triethyl phosphate, and p-toluenesulfonic acid as nucleophiles. The ß-iodo(III)enol esters serve as starting materials for the synthesis of multisubstituted alkenes through sequential cross-coupling of the C-I(III) and C-O bonds.

Ritter-type iodo(iii)amidation of unactivated alkynes for the stereoselective synthesis of multisubstituted enamides.

The Ritter reaction, Brønsted- or Lewis acid-mediated amidation of alkene or alcohol with nitrile via a carbocation, represents a classical method for the synthesis of tertiary amides. Although analogous reactions through a vinyl cation or a species alike may offer a route to enamide, an important synthetic building block as well as a common functionality in bioactive compounds, such transformations remain largely elusive. Herein, we report a Ritter-type trans-difunctionalization of alkynes with a trivalent iodine electrophile and nitrile, which affords ß-iodanyl enamides in moderate to good yields. Mediated by benziodoxole triflate (BXT), the reaction proves applicable to a variety of internal alkynes as well as to various alkyl- and arylnitriles. The benziodoxole group in the product serves as a versatile handle for further transformations, thus allowing for the preparation of various tri- and tetrasubstituted enamides that are not readily accessible by other means.

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.

Nickel-Catalyzed Ring-Opening Allylation of Cyclopropanols via Homoenolate.

We report herein a nickel-catalyzed ring-opening allylation of cyclopropanols with allylic carbonates that occurs under mild and neutral conditions. The reaction displays linear selectivity for both linear and branched acyclic allylic carbonates and is also applicable to cyclic allylic carbonates, affording a variety of δ,ε-unsaturated ketones in moderate to good yields. Mechanistic experiments are in accord with a catalytic cycle involving decarboxylative oxidative addition of allylic carbonate to Ni(0), alkoxide exchange with cyclopropanol, cyclopropoxide-to-homoenolate conversion on Ni(II), and C-C reductive elimination.

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.

Iodo(III)-Meyer-Schuster Rearrangement of Propargylic Alcohols Promoted by Benziodoxole Triflate.

Benziodoxole triflate (BXT), a cyclic iodine(III) electrophile, has been found to promote a rearrangement of propargylic alcohols into α,ß-unsaturated ketones bearing an α-λ3-iodanyl group. This iodo(III)-Meyer-Schuster rearrangement proceeds under mild conditions and tolerates a variety of functionalized propargylic alcohols, thus complementing previously reported halogen-intercepted Meyer-Schuster rearrangement. The α-λ3-iodanylenones can be utilized for facile Pd-catalyzed cross-coupling for the synthesis of multisubstituted enones.

Fluorobenziodoxole-BF3 Reagent for Iodo(III)etherification of Alkynes in Ethereal Solvent.

A combination of fluorobenziodoxole (FBX) and BF3 ⋅ OEt2 in cyclopentyl methyl ether promotes regio- and stereoselective addition of benziodoxole and methoxy groups to alkynes. This difunctionalization reaction tolerates a variety of functionalized internal and terminal alkynes to afford trans-ß-alkoxyvinylbenziodoxoles, which represent versatile precursors to stereochemically well-defined multisubstituted vinyl ethers. The reaction is proposed to involve cleavage of the I-F bond of FBX by BF3 , followed by electrophilic activation of the alkyne by the resulting cationic IIII species that triggers the nucleophilic addition of the ethereal oxygen.

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.

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-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.

Site-selective aromatic C-H λ3-iodanation with a cyclic iodine(iii) electrophile in solution and solid phases.

An efficient and site-selective aromatic C-H λ3-iodanation reaction is achieved using benziodoxole triflate (BXT) as an electrophile under room temperature conditions. The reaction tolerates a variety of electron-rich arenes and heteroarenes to afford the corresponding arylbenziodoxoles in moderate to good yields. The reaction can also be performed mechanochemically by grinding a mixture of solid arenes and BXT under solvent-free conditions. The arylbenziodoxoles can be used for various C-C and C-heteroatom bond formations, and are also amenable to further modification by electrophilic halogenation. DFT calculations suggested that the present reaction proceeds via a concerted λ3-iodanation-deprotonation transition state, where the triflate anion acts as an internal base.