Homolytic Aromatic Substitution Research Articles

Photo-Induced α-Oxyalkylation of Aryl Chlorides with Ethers and Alcohols through Homolytic Aromatic Substitution

AbstractThe α-oxyalkylation of aryl chlorides with ethers and alcohols using a small amount of a peroxide was found to be induced by photoirradiation. The reaction proceeds through a homolytic aromatic substitution (HAS) mechanism consisting of addition of an α-oxyalkyl radical to an aryl chloride and elimination of the chlorine atom to give the α-oxyalkylation product, where photoirradiation is considered to effect not only the initiation step to facilitate homolysis of a peroxide, but also the propagating radical chain.

Benchtop Nickel Catalysis Invigorated by Electron-Deficient Diene Ligands.

ConspectusDue to the rarity of precious metals like palladium, nickel catalysis is becoming an increasingly important player in organic synthesis, especially for the formation of bonds with sp3-hybridized carbon centers. Traditionally, catalytic processes involving active Ni(0) species have relied on Ni(COD)2 or in situ reduction of Ni(II) salts. However, Ni(COD)2 is an air- and temperature-sensitive material that requires use in an inert-atmosphere glovebox, and in situ reduction protocols of Ni(II) salts using metallic or organometallic reductants add additional complications to reaction development.This Account chronicles the development of air-stable Ni(0) precursors as replacements for Ni(COD)2 or in situ reduction. Based on Schrauzer's seminal discovery of Ni(COD)(DQ) as an air-stable zerovalent organonickel complex, our research laboratories at Scripps Research and Bristol Myers Squibb have developed a class of precatalysts based on the Ni(COD)(EDD) (EDD = electron-deficient diene) framework, relying on the steric and electronic properties of the supporting diene to render the metal center stable to air, moisture, and even silica gel but reactive to ligand substitution and redox changes.The stable Ni(0) complexes can be accessed through ligand exchange with Ni(COD)2, through reduction of Ni(acac)2 using DIBAL-H, or electrochemically via cathodic reduction of Ni(acac)2 to Ni(COD)2, followed by addition of an EDD ligand in one pot. As a toolkit, the complexes demonstrate reactivity that is equivalent or enhanced compared to Ni(COD)2, catalyzing C-C and C-N cross-couplings, Miyaura borylations, C-H activations, and other transformations. Since the initial report on Ni(COD)(DQ), its reactivity in C(sp2)-CN activation, metallophotoredox, and electric field-induced cross-coupling have also been demonstrated.By incorporating the precatalyst toolkit into reaction discovery campaigns, our laboratories have been able to perform C(sp3)-S(alkyl) couplings and metallonitrenoid carboamination, both of which represent challenging transformations that were inaccessible with traditional phosphine, nitrogen, or electron-deficient olefin ligands. Computational and experimental studies demonstrate how the quinone ligands are hemilabile, adopting η1(O)-bound geometries to relieve steric strain or stabilize transition states and intermediates; redox-active, able to transiently oxidize the metal center; and electron-withdrawing or -donating, depending on metal oxidation state and coordination geometry. These studies show how the ligands enable key steps in catalysis beyond imparting air-stability.Since our report documenting the catalytic activity of Ni(COD)(DQ), many other laboratories have also observed unique reactivity with this precatalyst. Ni(COD)(DQ) was found to offer superior reactivity to Ni(COD)2 in C-N cross coupling to form N,N-diaryl sulfonamides and in preparation of biaryls from aryl halides and benzene through a Ni-mediated, base-assisted homolytic aromatic substitution.

An assay for aryl radicals using BHAS coupling.

Aryl radicals are intermediates in many reactions, but determining their presence unambiguously is often challenging. As we recently reported, reaction of 2-iodo-1,3-dimethylbenzene (7) in benzene with KOtBu and a suitable organic additive, leads to a base-induced homolytic aromatic substitution (BHAS) coupling reaction giving 2,6-dimethylbiphenyl (12) and biphenyl (3) as coupled products, together with xylene (13). In this case, biphenyl arises from a radical translocation and is the major coupling product. This paper now quantitatively investigates that reaction, which shows a very similar ratio for 3 : 12 [ca. 4 : 1] when using different sources of radical initiation. Deuterium isotope studies provide detailed mechanistic support for the proposed mechanism; when carried out in C6D6vs. C6H6, the reaction is characterised by a strong isotope effect for formation of 3-d10vs. 3, but not for formation of 12-d5vs. 12. These distinctive properties mean that the transformation can act as an assay for aryl radicals. An advantage of such a BHAS process is its sensitivity, since it involves a chain reaction that can amplify radical activity.

Exploring Homolytic Aromatic Substitution as a Driver for Fuel Deposition with Quantum Chemistry and Experiments

Liquid phase insoluble formation in fuels can cause performance and safety issues. To understand the formation of insolubles in fuels from first principles, a series of density functional theory (DFT) calculations were run to calculate the energetic barriers of the autoxidation and coupling reactions for several common fuel aromatics/heteroatoms. Thesixcompounds chosen were phenol, toluene, naphthalene, pyrrole, quinoline, and indole. Using a combination of DFT calculations and gravimetric and petroxy experimental work,a novelhomolytic aromatic substitution (HAS)coupling pathwaywasidentified for each compound.While previous studies have treated deposition steps implicitly, our detailed calculations of HAS reactions and bulk fuel (RH) oxidation reaction barriers afforded the development of bespoke pseudo-detailed mechanisms for each aromatic compound with explicit reaction steps. These mechanismswere then used to predicttrends indeposition behavior of the compounds tested in a simplen-dodecane surrogate.Thenovel HAS mechanism suggested for fuels was proposed to start with thereaction of an aromatic radical (Ar·) to an aromatic (ArH), which then formed a radical(ArHAr·) σ-intermediate. It wasthenfound that hydroperoxides (ROOH) could re-aromatize the radical intermediate (ArHA·),forming a deposit dimer (ArAr). Although our sensitivity analysis revealed that alkyl fuel radical and fuek alkoxyl radical abstraction steps influenced the final mass of the deposit, the Ar. + ArH HAS coupling step was found to have the largest influence. Finally, an aromatic/heteratom model containing phenol and toluene was built, which showed that phenol suppressed deposition from toluene, and peaked in deposit mass at a phenol:toluene ratio of 25:75.Although our study was limited to Ar self-reactions, we hypothesize that bulk fuel – aromatic coupling could also be governed by HAS reactions, allowing researchers to move towards a more first-principles based deposition model.

General Synthesis of N-Alkylindoles from N,N-Dialkylanilines via [4 + 1] Annulative Double C-H Functionalization.

Strategies enabling the construction of indoles and novel polycyclic heterocycles from simple building blocks streamline syntheses in synthetic and medicinal chemistry. Herein, we report a C-H functionalization approach to N-alkylindoles proceeding via a double, site-selective C(sp3)-H/C(sp2)-H [4 + 1] annulation of readily accessed N,N-dialkylanilines. This protocol features a site-selective hydrogen atom transfer by a tuned N-tBu amidyl radical and addition of a sulfonyl diazo coupling partner, which promotes highly site-selective homolytic aromatic substitution of the (hetero)aromatic core. Mild decarboxylation of the annulation product enables the overall introduction of a carbyne equivalent into the N,N-dialkylaniline scaffold. Furthermore, the site-selectivity and mild conditions of the indolization facilitate direct access to N-alkyl indole scaffolds in late-stage functionalization (LSF) settings.

Photoinduced α-Aminoalkylation of Sulfonylarenes with Alkylamines.

α-Aminoalkylation of sulfonylarenes with alkylamines was found to be induced by photoirradiation. Here various types of alkylamines, such as trialkylamines, dialkylamines, N,N-dialkylanilines and N-alkylanilines as well as sulfonylarenes containing an azole, azine, heterole or benzene ring are available. The reaction proceeds through a homolytic aromatic substitution (HAS) process consisting of addition of an α-aminoalkyl radical to a sulfonylarene and elimination of the sulfonyl radical to give the α-arylalkylamine, where photoirradiation is considered to induce homolysis of sulfonylarenes leading to the generation of α-aminoalkyl radicals that make a radical chain operative.

DABCO‐Promoted Selective Photochemical C−N Coupling: Access to Unsymmetrical Azahelicenes

AbstractA multifaceted study on the effect of various factors on the efficiency of photocyclization of naphthofuran O‐acyl oximes was performed. It showed that without any additives or in the presence of electron acceptors, the reaction occurs by a radical pathway and with low chemoselectivity, while DABCO promotes intramolecular cyclization to give naphthofuroquinolines (NFQs) in 34–87% yields. The iminyl radical formed under UV irradiation in the presence of DABCO due to single electron transfer (SET) and N−O bond cleavage undergoes selective intramolecular homolytic aromatic substitution (HAS) with formation of a new C−N bond. This route to quinoline‐annulated scaffolds is based on the use of DABCO both as an electron transfer agent and a proton acceptor.

A Hierarchy of Ligands Controls Formation and Reaction of Aryl Radicals in Pd-Catalyzed Ground-State Base-Promoted Coupling Reactions.

Palladium salts and complexes were tested separately and in the presence of added ligands as potential sources of aryl radicals in ground-state coupling reactions of aryl halide with arenes under basic conditions (KOtBu). Our recently developed assay for aryl radicals was employed to test for aryl radicals. In this assay, aryl radicals derived from the test substrate, 1-iodo-2,6-dimethylbenzene 7, undergo base-promoted homolytic aromatic substitution (BHAS) with benzene to produce 2,6-dimethylbiphenyl 8 and biphenyl 9 in an approximately 1:4 ratio as well as m-xylene 10. The biphenyl arises from a diagnostic radical transfer reaction with the solvent benzene. Using substrate 7 with a range of Pd sources as potential initiators led to formation of 8, 9, and 10 in varying amounts. However, when any one of a range of diphosphinoferrocenes (e.g., dppf or dippf) or BINAP or the monophosphine, diphenylphosphinoferrocene, was added as a ligand to Pd(OAc)2, the ratio of [2,6-dimethylbiphenyl 8: biphenyl 9] moved decisively to that expected from the BHAS (radical) pathway. Further studies were conducted with dppf. When dppf was added to each of the other Pd sources, the ratio of coupled products was also diverted to that expected for radical BHAS chemistry. Deuterium isotope studies and radical trap experiments provide strong additional support for the involvement of aryl radicals. Accordingly, under these ground-state conditions, palladium sources, in the presence of defined ligands, convert aryl iodides to aryl radicals. A rationale is proposed for these observations.

Visible‐Light‐Driven Synthesis of Phenanthridin‐6(5H)‐one and N‐Substituted Carbazole Derivatives through Intramolecular C‐H Arylation

AbstractA visible‐light‐driven approach towards phenanthridin‐6(5H)‐one and carbazole rings synthesis under transition‐metal‐free conditions is here reported. Phenanthridinones and carbazoles are synthesized through an intramolecular arylation of the corresponding N‐(2‐halobenzyl)‐N‐methylanilines or N‐substituted‐N‐phenyl anilines using KOtBu as base in dimethyl sulfoxide (DMSO) at room temperature (rt), employing blue light emitting diodes (LEDs) as the light source. The reaction proceeds through photo‐ and base‐promoted homolytic aromatic substitution via photoinduced electron transfer mechanism and it exhibits good tolerance to different functional groups, resulting in good to very good yields (up to 86 %).

Electrochemical Direct α-Arylation of Alkylamines with Sulfonylarenes.

The electrochemical α-arylation of alkylamines with sulfonylarenes has been developed. Here, diverse trialkylamines and aryl(dimethyl)amines are applicable to the α-arylation with sulfonylarenes having an azole, azine, and benzene nucleus. The α-arylation was scaled up using an electrolysis flow cell. Mechanistic studies show that anodic oxidation of an alkylamine with a sulfinate as a mediator followed by deprotonation gives an α-aminoalkyl radical, which undergoes homolytic aromatic substitution (HAS) on a sulfonylarene to give the corresponding α-arylalkylamine.

Electronic Structures and Photoredox Chemistry of Tungsten(0) Arylisocyanides.

ConspectusThe high energy barriers associated with the reaction chemistry of inert substrates can be overcome by employing redox-active photocatalysts. Research in this area has grown exponentially over the past decade, as transition metal photosensitizers have been shown to mediate challenging organic transformations. Critical for the advancement of photoredox catalysis is the discovery, development, and study of complexes based on earth-abundant metals that can replace and/or complement established noble-metal-based photosensitizers.Recent work has focused on redox-active complexes of 3d metals, as photosensitizers containing these metals most likely would be scalable. Although low lying spin doublet ("spin flip") excited states of chromium(III) and metal-to-ligand charge transfer (MLCT) excited states of copper(I) have relatively long lifetimes, the electronic excited states of many other 3d metal complexes fall on dissociative potential energy surfaces, owing to the population of highly energetic σ-antibonding orbitals. Indeed, we and other investigators have shown that low lying spin singlet and triplet excited states of robust closed-shell metal complexes are too short-lived at room temperature to engage in bimolecular reactions in solutions. In principle, this problem could be overcome by designing and constructing 3d metal complexes containing strong field π-acceptor ligands, where thermally equilibrated MLCT or intraligand charge transfer excited states might fall well below the upper surfaces of dissociative 3d-3d states. Notably, such design elements have been exploited by investigators in very recent work on redox-active iron(II) systems. Another approach, one we have actively pursued, is to design and construct closed-shell complexes of earth-abundant 5d metals containing very strong π-acceptor ligands, where vertical excitation of 5d-5d excited states at the ground state geometry would require energies far above minima in the potential surfaces of MLCT excited states. As this requirement is met by tungsten(0) arylisocyanides, these complexes have been the focus of our work aimed at the development of robust redox-active photosensitizers.In the following Account, we review recent work on homoleptic tungsten(0) arylisocyanides. Originally reported by our group 45 years ago, W(CNAr)6 complexes have exceptionally large one- and two-photon absorption cross-sections. One- or two-photon excitation produces relatively long-lived (hundreds of nanoseconds to microsecond) MLCT excited states in high yields. These MLCT excited states, which are very strong reductants with E°(W+/*W0) = -2.2 to -3.0 V vs Fc[+/0], mediate photocatalysis of organic reactions with both visible and near-infrared (NIR) light. Here, we highlight design principles that led to the development of three generations of W(CNAr)6 photosensitizers; and we discuss likely steps in the mechanism of a prototypal W(CNAr)6-catalyzed base-promoted homolytic aromatic substitution reaction. Among the many potential applications of these very bright luminophores, two-photon imaging and two-photon-initiated polymerization are ones we plan to pursue.

Facile Synthesis of Isoindolinones via Radical-Mediated Intramolecular Coupling of Two C–H Bonds

AbstractA metal-free method for the construction of 3,3-dimethyl isoindolinones via radical-mediated intramolecular coupling of two C–H bonds of N,N-diisopropyl benzamides was developed. The reactions can proceed in moderate to high yield and with excellent chemoselectivity. A reaction sequence of the formation of an alkyl radical via oxidative cleavage of alkyl C–H bond and the formation of lactam ring via intramolecular homolytic aromatic substitution was proposed.

Mechanistic investigation into the formation of insolubles in bulk fuel jet fuel using quantum chemical and experimental techniques

The SMORS mechanism describing the formation of insoluble material in bulk jet fuel was investigated using density functional and experimental techniques. The first part of the SMORS mechanism, the formation of quinones from the oxidation of indigenous fuel phenols, was shown to proceed via two possible pathways. First, a single-step pathway yielding two quinones and a hydrogen peroxide. Secondly, a two-step pathway yielding a quinone, p-chinole and singlet oxygen. The second step of the SMORS mechanism, the reaction of quinones with electron-rich heterocycles in fuels, was shown to proceed via a homolytic aromatic substitution pathway. These findings, allow us to propose a modified SMORS mechanism, built on our enhanced mechanistic understanding of fuel deposit formation.

Homolytic aromatic substitution of acyl radicals: Oxidative coupling of 2-methylquinolines with quinoxalines

Oxidative coupling of 2-methylquinolines with quinoxalines via a TBHP ( t-butyl hydroperoxide) and TFA (trifluoroacetic acid) mediated Minisci reaction affords quinolin-2-yl(quinoxalin-2-yl)methanone derivatives. This approach provides a simple and efficient method to construct various acyl derivatives in moderate to good yields (45%–92%) without any metal catalyst. Mechanistically, homolytic aromatic substitution (HAS) of acyl radicals mediated by TBHP is crucial for the construction of the quinolin-2-yl(quinoxalin-2-yl)methanone products.

Photoredox Catalysis Mediated by Tungsten(0) Arylisocyanides.

W(CNAr)6 (CNAr = arylisocyanide) photoreductants catalyze base-promoted homolytic aromatic substitution (BHAS) of 1-(2-iodobenzyl)-pyrrole in deuterated benzene. Moderate to high efficiencies correlate with W(CNAr)6 excited-state reduction potentials upon one-photon 445 nm excitation, with 10 mol % loading of the most powerful photoreductants W(CNDipp)6 (CNDipp = 2,6-diisopropylphenylisocyanide) and W(CNDippPhOMe3)6 (CNDippPhOMe3 = 4-(3,4,5-trimethoxyphenyl)-2,6-diisopropylphenylisocyanide) affording nearly complete conversion. Stern-Volmer quenching experiments indicated that catalysis is triggered by substrate reductive dehalogenation. Taking advantage of the large two-photon absorption (TPA) cross sections of W(CNAr)6 complexes, we found that photocatalysis can be driven with femtosecond-pulsed 810 nm excitation. For both one- and two-photon excitation, photocatalysis was terminated by the formation of seven-coordinate WII-diiodo [WI2(CNAr)5] complexes. Notably, we discovered that W(CNDipp)6 can be regenerated by chemical reduction of WI2(CNDipp)5 with excess ligand present in solution.

Metal-Free Aminomethylation of Aromatic Sulfones Promoted by Eosin Y.

A metal-free α-aminomethylation of heteroaryls promoted by eosin Y under green light irradiation is reported. A large variety of α-trimethylsilylamines as precursor of α-aminomethyl radical species were engaged to functionalize sulfonyl-heteroaryls following a Homolytic Aromatic Substitution (HAS) pathway. This method has provided a range of α-aminoheteroaryl compounds including a functionalized natural product. The mechanism of this late-stage functionalization of aryls was investigated and suggests the formation of a sulfonyl radical intermediate over a reductive quenching cycle.

Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles.

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular.

Urea‐Promoted Metal‐Free Homolytic Alkynyl Substitution (HAS): Metal‐Free C−C Coupling of Alkynyl Bromides Formed In Situ from 1,1‐Dibromoalkenes

AbstractHerein, the unique method reports the efficacy of abundantly available urea for the generation of alkynyl radicals from 1‐bromoalkynes under metal‐free conditions. Urea as a sole reagent enabled the transformation of 1,1‐dirbomoalkenes or 1‐bromoalkynes to 1,3‐diynes via Homolytic Alkynyl Substitution (HAS). Urea further showed efficiency in synthesizing disubstituted alkyne via Sonogashira type cross‐coupling of 1,1‐dibromalkene/1‐bromoalkyne with aryl iodide. The Azobisisobutyronitrile (AIBN) trap detected the existence of short‐lived alkynyl radical during the reaction. This method might be the first report with Homolytic Alkynyl Substitution under metal‐free conditions, whereas Homolytic Aromatic Substitution is well reported.

Alkylation of Heteroaryl Chlorides through Homolytic Aromatic Substitution by Alkyl Radicals Derived from Alkyl Formates

The alkylation of heteroaryl chlorides through a homolytic aromatic substitution (HAS) mechanism was achieved by the use of alkyl formates as alkylating agents in the presence of a tert-butoxy radical precursor, where alkyl radicals are generated from alkyl formates through hydrogen abstraction followed by β-scission with decarboxylation.

Amidoalkylation of Sulfonylheteroarenes with Alkylamides through a Radical Chain Mechanism

AbstractIn the presence of a substoichiometric amount of a tert‐butoxy radical precursor and a base, alkylamides were found to be heteroarylated at their α‐C−H bonds with sulfonylheteroarenes through homolytic aromatic substitution, where a radical chain is operative.