Photocatalyst-free Conditions Research Articles

Visible-Light-Promoted Cascade Coupling of 2-Isocyanonaphthalenes with Elemental Sulfur and Amines to Construct Naphtho[2,1-d]thiazol-2-Amines.

A visible-light-induced strategy has been explored for the synthesis of naphtho[2,1-d]thiazol-2-amines through ortho-C-H sulfuration of 2-isocyanonaphthalenes with elemental sulfur and amines under external photocatalyst-free conditions. This three-component reaction, which utilizes elemental sulfur as the odorless sulfur source, molecular oxygen as the clean oxidant, and visible light as the clean energy source, provides a mild and efficient approach to construct a series of naphtho[2,1-d]thiazol-2-amines. Preliminary mechanistic studies indicated that visible-light-promoted photoexcitation of reaction intermediates consisting of thioureas and DBU might be involved in this transformation.

Visible-light-mediated direct C3 alkylation of quinoxalin-2(1H)-ones using alkanes.

Due to the high C-H bond dissociation energy of alkanes, the utilization of alkanes as alkyl radical precursors for C-H functionalization of heteroarenes is synthetically captivating but practically challenging, especially under metal- and photocatalyst-free conditions. We report herein a mild and practical visible-light-mediated method for C-H alkylation of quinoxalin-2(1H)-ones using trifluoroacetic acid as a hydrogen atom transfer reagent and air as an oxidant. This mild protocol was performed under metal- and photocatalyst-free circumstances and presented good functional-group tolerance as well as a broad substrate scope.

Photoinduced C(sp3)-H Functionalization of Glycine Derivatives: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides.

ConspectusPeptides are essential components of living systems and contribute to critical biological processes, such as cell proliferation, immune defense, tumor formation, and differentiation. Therefore, peptides have attracted considerable attention as targets for the development of therapeutic products. The incorporation of unnatural amino acid residues into peptides can considerably impact peptide immunogenicity, toxicity, side effects, water solubility, action duration, and distribution and enhance the peptides' druggability. Typically, the direct modification of natural amino acids is a practical and effective approach for promptly obtaining unnatural amino acids. However, selective functionalization of multiple C(sp3)-H bonds with comparable chemical reactivities in the peptide side chains remains a formidable challenge. Furthermore, chemical modifications aimed at highly reactive (nucleophilic and aromatic) groups on peptide side chains can interfere with the biological activity of peptides.In recent years, the rapid advancement of photoinduced radical reactions has made photoredox radical-radical cross-coupling a practical approach for constructing C(sp3)-C(sp3) bonds under mild conditions. Glycine, a naturally occurring amino acid and the fundamental skeleton of all α-amino acids, provides a basis for the alkylated modification of its own α-C(sp3)-H bond under mild conditions. This Account describes our recent research endeavors for systematically investigating the photocatalytic α-C(sp3)-H alkylation of glycine derivatives via radical-radical coupling between N-aryl glycinate-derived radicals and various alkyl radicals. In 2018, we disclosed the photoinduced Cu-catalyzed decarboxylative α-C(sp3)-H alkylation of glycine derivatives. Subsequently, we developed a catalyst-free method for alkylating glycine derivatives and glycine residues in peptides via electron donor-acceptor (EDA)-complex-promoted single electron transfer. Moreover, we developed a photoinduced method for the radical alkylation of N-aryl glycinate α-C(sp3)-H bonds using unactivated alkyl chlorides (iodides) under photocatalyst-free conditions. Notably, by building on racemic alkylations of glycine derivatives and glycine-residue-containing peptides, we recently stereoselectively alkylated the N-aryl glycinate α-C(sp3)-H bond using a dual-functional Cu catalyst generated in situ for synthesizing a series of unnatural chiral α-amino and C-glycoamino acids.We have developed a series of methods for synthesizing unnatural amino acids through the α-C(sp3)-H alkylation of glycine derivatives using photoredox-promoted radical coupling as a key strategy. These methods are efficient and versatile and can be used for the late-stage modification of peptides in various contexts. Our work builds on the fundamental importance of glycine as the basic scaffold of all α-amino acids and highlights the potential of radical-based chemistry for developing chemical transformations in peptide synthesis. These findings have broad implications for chemical biology and may open doors for discovering peptide drugs and developing therapeutics.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals. These open-shell intermediates subsequently undergo the radical-radical cross-coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three-component reactions involving alkenes and enynes, resulting in structurally diverse cross-coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

External photocatalyst-free C-H alkylation of N-sulfonyl ketimines with alkanes under visible light

A simple, practical and eco-friendly visible light-induced alkylation of N-sulfonyl ketamine under metal-, additive-, external photocatalyst-free conditions was developed. This photocatalytic method utilized low cost and abundant alkanes as the atom economy alkyl sources with H2O2 as the environmentally beneficial oxidant, allowing for the efficient construction of diverse valuable 4-alkylated sulfonyl ketamines. The N-sulfonyl ketamine played a dual role of reactant and photocatalyst, thus simplifying the reaction system.

Visible Light-Induced Cascade Sulfonylation/Cyclization to Produce Quinoline-2,4-Diones under Metal-Free Conditions

A general visible light-induced sulfonylation/cyclization to produce quinoline-2,4-diones was achieved under photocatalyst-free conditions. The reactions were performed at room temperature, and various substituents (halogen, alkyl, aryl) and substituted products were obtained with 29 examples within 2 h. Large-scale synthesis and derivatization study via carbonyl reduction to produce easily modified hydroxyl groups and convenient N-Ts deprotection showed the potential utility of this strategy.

Selectfluor-Mediated Regioselective C-3 Alkoxylation, Amination, Sulfenylation, and Selenylation of Quinoxalin-2(1H)-ones.

A Selectfluor-promoted oxidative coupling of quinoxalin-2(1H)-ones with alcohols, amines, thiols, and selenols leading to the formation of C-O, C-N, C-S, and C-Se bonds has been developed. The protocol provided good to excellent (53-95%) yields of a wide range of quinoxalin-2(1H)-ones decorated with alkoxy, alkylamino, alkylthio, and arylselenyl groups at the C3-position under metal- and photocatalyst-free conditions. The reaction is believed to proceed through a radical pathway. A broad substrate scope including bioactive molecules, mild reaction conditions, readily available coupling partners, high yields, scalability, step-economy, and metal- and photocatalyst-free conditions are the highlighting features of the method. The synthetic utility of the developed protocol was demonstrated by gram-scale synthesis, C3-alkoxylation of quinoxaline-2(1H)-one with natural alcohols, and synthesis of aldose reductase (ALR2) inhibitor and histamine-4 receptor antagonist in good yields.

Visible-light-induced photocatalyst-free activation of alkynyl triflones for trifluoromethylalkynylation of unactivated 1,6-dialkenes

A visible-light-induced trifluoromethylalkynylation of 1,6-dialkenes was developed under transition-metal-free and photocatalyst-free conditions, enabling the construction of three C–C bonds in a single preparation step.

Visible-light-induced direct perfluoroalkylation/heteroarylation of [1.1.1]propellane to diverse bicyclo[1.1.1]pentanes (BCPs) under metal and photocatalyst-free conditions

This study describes a green and novel multi-component reaction for direct perfluoroalkylation/heteroarylation of [1.1.1]propellane with heteroarenes and perfluoroalkyl iodines to diverse bicyclo[1.1.1]pentanes (BCPs).

Photoinduced tandem radical cyclization/heteroarylation of N-allylbromodifluoroacetamides with quinoxalin-2(1H)-ones or coumarins under metal- and photocatalyst-free conditions

A photocatalyst-free visible-light-promoted tandem intramolecular cyclization/heteroarylation between bromodifluoroacetamides and quinoxalin-2(1H)-ones or coumarins was developed. The process could generate a broad range of α,α-difluoro-γ-lactams.

Photocatalyst-free visible-light-induced highly selective acylation of purine nucleosides at the C6 position.

A protocol for visible-light-induced C-H acylation selectively at the C6 position of purine nucleosides with aldehydes under photocatalyst-free conditions was established herein. This protocol allows the green, mild, and efficient functionalization of various purine nucleosides with a broad range of alkyl and aryl aldehydes.

Photocatalyst- and transition-metal-free syntheses of furan-fused dihydroazepines by visible light

A visible light-induced, atom-economical synthesis of furan-fused dihydroazepine derivatives under transition metal- and photocatalyst-free conditions is described.

A visible-light-mediated cascade reaction of quinoxalin-2(1H)-ones, alkenes, and sulfinic acids.

A photocatalytic three-component cascade reaction of quinoxalin-2(1H)-ones, alkenes, and sulfinic acids under metal-, strong oxidant-, and external photocatalyst-free conditions was developed. The reaction was performed at room temperature using air as a green oxidant. Various sulfonated quinoxalin-2(1H)-ones were obtained in satisfactory yields with good functional group compatibility. The preliminary study showed that the current transformation was enabled by the formation of an electron donor-acceptor (EDA) complex between quinoxalin-2(1H)-ones and sulfinic acids.

C4-Selective C–H Borylation of Pyridinium Derivatives Driven by Electron Donor–Acceptor Complexes

The photoinduced C4-selective C-H borylation of pyridines was achieved using electron donor-acceptor complexes derived from a Lewis base and N-amidopyridinium salts under external oxidant- and photocatalyst-free conditions. Notably, the nucleophilic character of phosphite-ligated boryl radicals enables addition of a radical to position C4 of pyridinium salts to afford C4-borylated heteroarenes that are otherwise difficult to obtain. This approach provides a versatile platform for the installation of both phosphite- and amine-coordinated boron groups on a series of pyridines under mild conditions, demonstrating excellent C4-positional selectivity for the pyridine scaffolds.

Visible-Light-Driven Solventylation Strategy for Olefin Functionalization.

Amphiphilic aryl radicals generated upon visible light irradiation of arylazo sulfones have been exploited in the development of a solventylation strategy via hydrogen atom transfer (HAT). The present protocol succeeded in the versatile functionalization of various olefins with carbon-centered radicals deriving from acetone, acetonitrile, chloroform, methylene chloride, nitromethane, methyl acetate, and methyl formate under metal- and photocatalyst-free conditions. The direct addition of the aryl radicals onto the olefin substrates was suppressed under high dilution conditions.

Lone pair-π interaction induced regioselective sulfonation of ethers under light irradiation

Non-covalent interactions are of significance in supramolecular chemistry and biochemistry, while synthetic procedures driven by these weak interactions remain challenging and rare. Inspired by the lone pair-π interaction presence in the Z-DNA structure, a light-induced regioselective sulfonation of ethers taking advantage of the lone pair-π interaction between the oxygen of ethers and sulfonyl chlorides has been disclosed. Moreover, this strategy is also applicable to the sulfonation of aniline derivatives. Features of the methods include readily accessible starting materials, high atom-economy, green and photocatalyst-free conditions and broad functional group tolerance. Mechanism studies suggest that the lone pair-π interaction plays an important role to initiate the transformation.

Site-Selective Pyridine C-H Alkylation with Alcohols and Thiols via Single-Electron Transfer of Frustrated Lewis Pairs.

A unified strategy for the deoxygenative or desulfurative pyridylation of various alcohols and thiols has been developed through a single-electron transfer (SET) process of frustrated Lewis pairs (FLPs) derived from pyridinium salts and PtBu3 . Mechanistic studies revealed that N-amidopyridinium salts serve as effective Lewis acids for the formation of FLPs with PtBu3 , and the generated phosphine radical cation ionically couples with the in situ generated xanthate, eventually affording the alkyl radical through facile β-scission under photocatalyst-free conditions. The reaction efficiency was further accelerated by visible-light irradiation. This method is conceptually appealing by using encounter complexes in FLP chemistry to promote SET, which provides a previously unrecognized opportunity for the selective heteroarylation of a diverse range of alcohols and thiols with various functional groups, even in complex settings under mild reaction conditions.

Decarboxylative Selective Phosphorylation of Aliphatic Acids: A Transition‐Metal‐ and Photocatalyst‐Free Avenue to Dialkyl and Trialkyl Phosphine Oxides from White Phosphorus

Developing practical and mild strategies for the direct functionalization of white phosphorus (P4 ) without chlorination is an appealing but formidable challenge. To this end, we report a breakthrough in the preparation of structurally diverse dialkylphosphines and trialkylphosphines that rely on the successive generation of carbon-centered radicals from N-hydroxyphthalimide (NHPI) esters and the controllable alkylation of the P4 molecule under transition-metal- and photocatalyst-free conditions. To facilitate separation and prevent product losses during purification, the corresponding oxidation products dialkylphosphine oxides (DAPOs) and trialkylphosphine oxides (TAPOs) were isolated. This photoinduced phosphorylation reaction features one-pot operation, high product selectivity, and tolerates a broad range of alkyl NHPI esters, including derivatives of complex natural products and pharmaceuticals. Further diversified transformation of DAPOs to construct P-F, P-C, P-N, and P-O bonds was also demonstrated.

3-Sulfonylindoles via Gold- or Silver-Catalyzed Cyclization─1,3-Sulfonyl Migration Sequences under Visible Light Irradiation

A pathway for the synthesis of 3-sulfonylindoles has been devised. Upon blue LED irradiation, in the presence of a gold(I) or a silver(I) salt, ortho-alkynyl N-sulfonyl precursors readily undergo a 5-endo-dig cyclization concomitant with a 1,3-sulfonyl migration. While the gold-catalyzed reaction takes place in photocatalyst-free conditions, an iridium photocatalyst (Ir[dF(CF3)ppy]2(dtbbpy)PF6) is necessary with silver catalysis. Mechanistic studies featuring the generation of a sulfonyl radical support this dichotomy.

N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C-H Functionalization via Radical-Based Processes under Visible Light Irradiation.

The radical-mediated C-H functionalization of pyridines has attracted considerable attention as a powerful tool in synthetic chemistry for the direct functionalization of the C-H bonds of the pyridine scaffold. Classically, the synthetic methods for functionalized pyridines often involve radical-mediated Minisci-type reactions under strongly acidic conditions. However, the site-selective functionalization of pyridines in unbiased systems has been a long-standing challenge because the pyridine scaffold contains multiple competing reaction sites (C2 vs C4) to intercept free radicals. Therefore, prefunctionalization of the pyridine is required to avoid issues observed with the formation of a mixture of regioisomers and overalkylated side products.Recently, N-functionalized pyridinium salts have been attracting considerable attention in organic chemistry as promising radical precursors and pyridine surrogates. The notable advantage of N-functionalized pyridinium salts lies in their ability to enhance the reactivity and selectivity for synthetically useful reactions under acid-free conditions. This approach enables exquisite regiocontrol for nonclassical Minisci-type reactions at the C2 and C4 positions under mild reaction conditions, which are suitable for the late-stage functionalization of bioactive molecules with greater complexity and diversity. Over the past five years, a variety of fascinating synthetic applications have been developed using various types of pyridinium salts under visible light conditions. In addition, a new platform for alkene difunctionalization using appropriately designed N-substituted pyridinium salts as bifunctional reagents has been reported, offering an innovative assembly process for complex organic architectures. Intriguingly, strategies involving light-absorbing electron donor-acceptor (EDA) complexes between pyridinium salts and suitable electron-rich donors further open up new reactivity under photocatalyst-free conditions. Furthermore, we developed enantioselective reactions using pyridinium salts to afford enantioenriched molecules bearing pyridines through single-electron N-heterocyclic carbene (NHC) catalysis.Herein, we provide a broad overview of our recent contributions to the development of N-functionalized pyridinium salts and summarize the cornerstones of organic reactions that successfully employ these pyridinium salts under visible light conditions. The major advances in the field are systematically categorized on the basis of the pyridines' N-substituent, N-X (X = O, N, C, and SO2CF3), and its reactivity patterns. Furthermore, the identification of new activation modes and their mechanistic aspects are discussed by providing representative contributions to each paradigm. We hope that this Account will inspire broad interest in the continued innovation of N-functionalized pyridinium salts in the exploration of new transformations.