Formation Of Electron Donor-acceptor Complexes Research Articles

Photodecarboxylative Radical Cascade Involving N-(Acyloxy)phthalimides for the Synthesis of Pyrazolones.

We disclose N'-arylidene-N-acryloyltosylhydrazides as novel skeletons for the synthesis of biologically relevant alkylated pyrazolones through a photoinduced radical cascade with N-(acyloxy)pthalimides as readily available alkyl surrogates. The reaction proceeds through the formation of a photoactivated electron donor-acceptor (EDA) complex between alkyl N-(acyloxy)phthalimide (NHPI) esters and LiI/PPh3 as a commercially available donor system. The reaction exhibits a broad scope and scalability, thereby enabling synthesis of a broad spectrum of functionally orchestrated alkylated pyrazolones under mild and transition-metal-free conditions.

Metal- and photocatalyst-free approach to visible-light-induced acylation of quinoxalinones.

A transition-metal- and photocatalyst-free photochemical reaction was successfully developed for the direct acylation of quinoxalin-2(1H)-ones, which was enabled by the formation of electron donor-acceptor (EDA) complexes. The use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the electron donor allows efficient and operationally simple access to a series of C3-aroylated and acylated quinoxalin-2(1H)-ones with moderate to good yields.

Photoenzymatic Enantioselective Synthesis of Oxygen-Containing Benzo-Fused Heterocycles.

New-to-nature biocatalysis in organic synthesis has recently emerged as a green and powerful strategy for the preparation of valuable chiral products, among which chiral oxygen-containing benzo-fused heterocycles are important structural motifs in pharmaceutical industry. However, the asymmetric synthesis of these compounds through radical-mediated methods is challenging. Herein, a novel asymmetric radical-mediated photoenzymatic synthesis strategy is developed to realize the efficient enantioselective synthesis of oxygen-containing benzo-fused heterocycles through structure-guided engineering of a flavin-dependent 'ene'-reductase GluER. It shows that variant GluER-W100H could efficiently produce various benzoxepinones, chromanone and indanone with different benzo-fused rings in high yields with great stereoselectivities under visible light. Moreover, these results are well supported by mechanistic experiments, revealing that this photoenzymatic process involves electron donor-acceptor complex formation, single electron transfer and hydrogen atom transfer. Therefore, we provide an alternative green approach for efficient chemoenzymatic synthesis of important chiral skeletons of bioactive pharmaceuticals.

Photoinduced Five-Component Radical Relay Aminocarbonylation of Alkenes.

Radical single carbonylation reactions with CO constitute a direct and robust strategy toward various carbonyl compounds from readily available chemicals, and have been extensively studied over the past decades. However, realizing highly selective catalytic systems for controlled double radical carbonylation reactions has remained a substantial challenge, particularly for the more advanced multi-component variants, despite their great potential value. Herein, we report a visible light-driven radical relayed five-component radical double aminocarbonylation reaction of unactivated alkenes using CO under metal-free conditions. This protocol provides direct access to valuable γ-trifluoromethyl α-ketoamides with good yields and high selectivity. Crucial was the identification of distinct dual roles of amine coupling partners, sequentially acting as electron donors for the formation of photoactive electron donor-acceptor (EDA) complexes with radical precursors and then as a CO acceptor via nitrogen radical cations to form carbamoyl radicals. Cross-coupling of carbamoyl radicals with the acyl radicals that are formed in an alkene-based relay process affords double aminocarbonylation products.

Metal- and Photocatalyst-Free, Visible-Light-Initiated C3 α-Aminomethylation of Quinoxalin-2(1H)-ones via Electron Donor-Acceptor Complexes.

We report a metal- and photocatalyst-free C3 α-aminomethylation of quinoxalin-2(1H)-ones with N-alkyl-N-methylanilines. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between quinoxalin-2(1H)-ones and N-alkyl-N-methylanilines. The present method provides a mild and environmentally friendly protocol that exhibits good atom economy and excellent functional group tolerance to obtain a library of biologically significant C3 α-aminomethylated quinoxalin-2(1H)-ones in good yields.

Difluoroalkylation of Anilines via Photoinduced Methods.

The development of sustainable and mild protocols for the fluoroalkylation of organic backbones is of current interest in chemical organic synthesis. Herein, we present operationally simple and practical transition-metal-free methods for the preparation of difluoroalkyl anilines. First, a visible-light organophotocatalytic system working via oxidative quenching is described, providing access to a wide range of difluoroalkyl anilines under mild conditions. In addition, the formation of an unprecedented electron donor-acceptor (EDA) complex between anilines and ethyl difluoroiodoacetate is reported and exploited as an alternative, efficient, and straightforward strategy to prepare difluoroalkyl derivatives.

Photodecarboxylative C-H Alkylation of Azauracils with N-(Acyloxy)phthalimides.

We disclose a transition-metal-free NaI/PPh3-mediated direct C-H alkylation of azauracils using N-(acyloxy)pthalimides (NHPIs) as readily available alkyl surrogates under visible light irradiation. Detailed mechanistic studies reveal formation of a photoactivated electron donor-acceptor (EDA) complex between NaI/PPh3, TMEDA, and alkyl NHPI ester and establish the crucial role of TMEDA in increasing the activity of the photoredox system. The reaction demonstrates a broad scope, scalability, and appreciable functional group tolerance. A variety of azauracils are shown to undergo alkylation by primary, secondary, and tertiary NHPI esters under mild conditions, furnishing the desired products in good to excellent yields.

Deconstructive Pyridylation of Unstrained Cyclic Amines through a One-Pot Umpolung Approach.

A one-pot umpolung method for the ring-opening pyridylation of unstrained cyclic amines was developed using N-amidopyridinium salts. This process involves the formation of electron donor-acceptor complexes between bromide and N-amidopyridinium salts, ultimately leading to the functionalization of pyridines. This protocol is compatible with a range of 5- or 6-membered cyclic amines and pyridines, thereby providing a powerful synthon for preparing C4-functionalized pyridines under visible-light conditions in the absence of an external photocatalyst.

Visible-Light-Driven Photocatalyst-Free Deoxygenative Radical Transformation of Alcohols to Oxime Ethers.

A visible-light-driven deoxygenative cross-coupling of alcohols with sulfonyl oxime ethers has been developed by using xanthate salts as alcohol-activating groups. Upon convenient generation and direct photoexcitation of xanthate anions, a broad range of alcohols including primary ones can efficiently undergo this transformation to afford diverse oxime ethers and derivatives. This one-pot protocol features mild conditions, broad substrate scope, and late-stage applicability, without the need for any external photocatalysts or electron donor-acceptor complex formation.

Photoinduced Electron Donor-Acceptor Complex-Mediated Radical Cascade Involving N-(Acyloxy)phthalimides: Synthesis of Tetrahydroquinolines.

We conceptualized a novel disconnection approach for the synthesis of fused tetrahydroquinolines that exploits a visible light-mediated radical (4 + 2) annulation between alkyl N-(acyloxy)phthalimides and N-substituted maleimides in the presence of DIPEA as an additive. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between alkyl NHPI esters and DIPEA, and the final tetrahydroquinolines were obtained in a complete regioselective fashion. The methodology features a broad scope and good functional group tolerance and operates under metal- and catalyst-free reaction conditions. Detailed mechanistic investigations including density functional theory studies provide insight into the reaction pathway.

A transition metal- and photosensitizer-free approach for site-selective (hetero)arylation of polychlorinated heteroarenes.

We have developed an effective photochemical method for site-selective (hetero)arylation of polychlorinated heteroarenes. This approach eliminates the need for transition metal catalysts and photosensitizers by relying on in situ formation of unconventional electron donor-acceptor (EDA) complexes between two substrates and a basic additive. Our protocol yields chlorine-containing biaryl heterocyclic compounds with high levels of site-selectivity, which are of significant importance in both synthetic and medicinal chemistry.

Effective Formation of New C(sp2 )-S Bonds via Photoactivation of Alkylamine-based Electron Donor-Acceptor Complexes.

A novel visible light promoted formation of CAryl- S bonds through electron donor-acceptor (EDA) complexes of alkylamines with 5- and 6-membered (hetero)arene halides is presented. This represents the first EDA-based thiolation method not relying on π-π or a thiolate-anion-π interactions and provides a facile access to heteroarene radicals, which can be suitably trapped by disulfide derivatives to form the corresponding versatile arylsulfides. Mechanistic investigations on the aspects of the whole process were conducted by spectroscopic measurements, demonstrating the hypothesized EDA complex formation. Moreover, the strength of this method has been proven by a gram-scale synthesis of thiolated products and the late-stage derivatization of an anticoagulant drug.

Dual-Role Halogen-Bonding-Assisted EDA-SET/HAT Photoreaction System with Phenol Catalyst and Aryl Iodide: Visible-Light-Driven Carbon-Carbon Bond Formation.

Electron donor-acceptor (EDA) complex-mediated single-electron transfer (SET) is a crucial method for generating carbon radicals. Hydrogen atom transfer (HAT) enables the direct generation of alkyl radicals. We report a dual-role EDA-SET/HAT photoreaction system for carbon-carbon bond formation using a phenol catalyst and aryl iodide. This system facilitates addition of alkyl radicals generated from ethers, amide, sulfide, and cycloalkane to arenes. Mechanistic studies revealed that EDA complex formation is mediated by halogen bonding between phenoxide and aryl iodide. Irradiation of the EDA complex with visible light generates an aryl radical, which abstracts a hydrogen atom from an sp3 carbon to form an alkyl radical.

Catalyst-Free C(sp2)-H Borylation through Aryl Radical Generation from Thiophenium Salts via Electron Donor-Acceptor Complex Formation.

Aryl borates lie at the heart of carbon-carbon bond couplings, and they are widely applied to the synthesis of functional materials, pharmaceutical compounds, and natural products. Currently, synthetic methods for aryl borates are mostly limited to metal-catalyzed routes, and nonmetallic strategies remain comparatively underdeveloped. Herein, we report a mild, scalable, visible-light-induced cross-coupling between aryl dibenzothiophenium triflate salts and bis(catecholato)-diboron for the construction of C-B bonds in the absence of base, transition metal-ligand complex, or photoredox catalyst. Mechanistic studies reveal that this transformation is achieved through an electron donor-acceptor (EDA) complex activation in the absence of a catalyst. The mild reaction conditions allow the preparation of aromatic borates in good yields with excellent functional group tolerance. This photochemical protocol was also successfully applied to the late-stage modification of natural products and the synthesis of a drug intermediate, greatly demonstrating broadened utility.

Tetrachlorophthalimides as Organocatalytic Acceptors for Electron Donor-Acceptor Complex Photoactivation.

Excitation of photoactive electron donor-acceptor (EDA) complexes is an effective way to generate radicals. Applications in a catalytic regime typically use catalytic donors. Herein, we report that readily available electron-poor tetrachlorophthalimides can act as effective organocatalytic acceptors to trigger the formation of EDA complexes with a variety of radical precursors not amenable to previous catalytic methods. Excitation with visible light generates carbon radicals under mild conditions. The versatility of this EDA complex catalytic platform allowed us to develop mechanistically distinct radical reactions, including in combination with a cobalt-based catalytic system. Quantum yield measurements established that a closed catalytic cycle is operational, which hints at the ability of tetrachlorophthalimides to readily turn over and govern each catalytic cycle.

Sustainable Thioetherification via Electron Donor-Acceptor Photoactivation Using Thianthrenium Salts.

The synthesis of sulfides has been widely studied because this functional subunit is prevalent in biomolecules and pharmaceuticals, as well as being a useful synthetic platform for further elaboration. Thus, various methods to build C-S bonds have been developed, but typically they require the use of precious metals or harsh conditions. Electron donor-acceptor (EDA) complex photoactivation strategies have emerged as versatile and sustainable ways to achieve C-S bond formation, avoiding challenges associated with previous methods. This work describes an open-to-air, photoinduced, site-selective C-H thioetherification from readily available reagents via EDA complex formation that tolerates a wide range of different functional groups. Moreover, C(sp2 )-halogen bonds remain intact using this protocol, allowing late-stage installation of the sulfide motif in various bioactive scaffolds, while allowing yet further modification through more traditional C-X bond cleavage protocols. Additionally, various mechanistic investigations support the envisioned EDA complex scenario.

Sustainable Thioetherification via Electron Donor–Acceptor Photoactivation Using Thianthrenium Salts

AbstractThe synthesis of sulfides has been widely studied because this functional subunit is prevalent in biomolecules and pharmaceuticals, as well as being a useful synthetic platform for further elaboration. Thus, various methods to build C−S bonds have been developed, but typically they require the use of precious metals or harsh conditions. Electron donor–acceptor (EDA) complex photoactivation strategies have emerged as versatile and sustainable ways to achieve C−S bond formation, avoiding challenges associated with previous methods. This work describes an open‐to‐air, photoinduced, site‐selective C−H thioetherification from readily available reagents via EDA complex formation that tolerates a wide range of different functional groups. Moreover, C(sp2)−halogen bonds remain intact using this protocol, allowing late‐stage installation of the sulfide motif in various bioactive scaffolds, while allowing yet further modification through more traditional C−X bond cleavage protocols. Additionally, various mechanistic investigations support the envisioned EDA complex scenario.

Visible-light-induced N-heterocyclic carbene mediated cascade transformation of N-alkenoxypyridinium salts

While N-alkenoxypyridinium salts are widely used for the synthesis of α-functionalized ketones via umpolung strategy, such approaches are usually limited to special nucleophiles at high temperatures. Herein, we developed an alternative photoinduced N-heterocyclic carbene (NHC)- mediated functionalization of N-alkenoxypyridinium salts with various nucleophiles, including tetramethylammonium azide, secondary amines, aryl and alkyl thiols, and even the challenging C(sp3)-nucleophiles, under mild conditions. A cascade radical-radical coupling/nucleophilic substitution sequence was proposed, wherein the NHC enabled the formation of a photoactive electron donor-acceptor complex for α-iodo ketone synthesis.

Photochemical Organocatalytic Benzylation of Allylic C-H Bonds.

We report a radical-based organocatalytic method for the direct benzylation of allylic C-H bonds. The process uses nonfunctionalized allylic substrates and readily available benzyl radical precursors and is driven by visible light. Crucial was the identification of a dithiophosphoric acid that performs two distinct catalytic roles, sequentially acting as a catalytic donor for the formation of photoactive electron donor-acceptor (EDA) complexes and then as a hydrogen atom abstractor. By mastering these orthogonal radical generation paths, the organic catalyst enables the formation of benzylic and allylic radicals, respectively, to then govern their selective coupling. The protocol was also used to design a three-component radical process, which increased the synthetic potential of the chemistry.

Photoinduced Deaminative Alkylation for the Synthesis of γ-Ketoesters via Electron Donor–Acceptor Complex Formation

Visible-light-induced deaminative alkylation of Katritzky salts with silyl enol ethers has been developed. The reaction can proceed efficiently through electron donor-acceptor complex formation, avoiding the use of precious metal complexes or synthetically elaborate organic dyes. A series of functionalized γ-ketoesters was successfully obtained with good functional group tolerance and compatibility under mild and straightforward conditions.