Copper‐Catalyzed Decarboxylative Radical Silylation of Redox‐Active Aliphatic Carboxylic Acid Derivatives

A decarboxylative silylation of aliphatic N ‐hydroxyphthalimide (NHPI) esters using Si−B reagents as silicon pronucleophiles is reported. This C(sp³)−Si cross‐coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional‐group tolerance is generally excellent, and α‐heteroatom‐substituted substrates also participate well. This enables, for example, the synthesis of α‐silylated amines starting from NHPI esters derived from α‐amino acids. The new method extends the still limited number of C(sp³)−Si cross‐couplings of unactivated alkyl electrophiles.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

Decarboxylative C?H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step‐ and atom‐economical features and the pervasiveness of carboxylic acids and C?H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C?H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late‐stage functionalization of drug molecules.     

A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher''s attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

A non-classical ring opening radical clock reaction using the innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis has been demonstrated, providing a brand-new synthetic approach to access a variety of alkynyl derivatives.     

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

Decarboxylative C−H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step- and atom-economical features and the pervasiveness of carboxylic acids and C−H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C−H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late-stage functionalization of drug molecules.     

多相/均相TiO2/N-羟酰亚胺混合体系中可见光诱导分子氧可控光催化氧化苄基反应

均相催化和多相催化通常被认为是独立甚至相互对立的学科.本文提出了一种新型的用于分子氧选择性氧化烷基苯的杂多酸/均相混合催化体系.该催化体系由N-羟基邻苯二甲酰亚胺(NHPI,用于自由基链式反应的均相有机催化剂)和纳米TiO2(多相紫外光活性光氧化催化剂)两种组分组成.NHPI与TiO2的协同作用使光氧化活性从紫外光转移到可见光,并产生邻苯二甲酰亚胺-N-氧基(PINO)自由基.NHPI/PINO催化的自由基链式反应能够在没有额外光输入的情况下进行,从而从根本上提高能源效率.通过控制NHPI/TiO2比率优化产物选择性,进而使烷基芳烃优先形成过氧化氢或酮.     

Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single‐electron reduction of an α‐boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α‐amino, α‐oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron‐containing molecules of potential biological importance.     

Decarboxylative benzylation and arylation of nitriles

Decarboxylative benzylation of nitriles is achieved via coupling of metallated nitriles with Pd-π-benzyl complexes that are generated in situ from cyanoacetic benzyl esters. In addition, decarboxylative couplings of α,α-disubstituted 2-methylfuranyl cyanoacetates can lead to either decarboxylative arylation or benzylation depending on the reaction conditions.     

Dual Catalytic Decarboxylative Allylations of α‐Amino Acids and Their Divergent Mechanisms

The room temperature radical decarboxylative allylation of N‐protected α‐amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α‐amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.     

Alkyl Carbon–Carbon Bond Formation by Nickel/Photoredox Cross‐Coupling

The union of photoredox and nickel catalysis has resulted in a renaissance in radical chemistry as well as in the use of nickel‐catalyzed transformations, specifically for carbon–carbon bond formation. Collectively, these advances address the longstanding challenge of late‐stage cross‐coupling of functionalized alkyl fragments. Empowered by the notion that photocatalytically generated alkyl radicals readily undergo capture by Ni complexes, wholly new feedstocks for cross‐coupling have been realized. Herein, we highlight recent developments in several types of alkyl cross‐couplings that are accessible exclusively through this approach.     

A Chemoselective Polarity-Mismatched Photocatalytic C(sp3)−C(sp2) Cross-Coupling Enabled by Synergistic Boron Activation**

We report the development of a C(sp³)−C(sp²) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.     

Advances in Electrochemical Decarboxylative Transformation Reactions

Owing to their non-toxic, stable, inexpensive properties, carboxylic acids are considered as environmentally benign alternatives as coupling partners in various organic transformations. Electrochemical mediated decarboxylation of carboxylic acid has emerged as a new and efficient methodology for the construction of carbon-carbon or carbon-heteroatom bonds. Compared with transition-metal catalysis and photoredox catalysis, electro-organic decarboxylative transformations are considered as a green and sustainable protocol due to the absence of chemical oxidants and strong bases. Further, it exhibits good tolerance with various functional groups. In this Minireview, we summarize the recent advances and discoveries on the electrochemical decarboxylative transformations on C−C and C−heteroatoms bond formations.     

Direct Catalytic Decarboxylative Amination of Aryl Acetic Acids

The decarboxylative coupling of a carboxylic acid with an amine nucleophile provides an alternative to the substitution of traditional organohalide coupling partners. Benzoic and alkynyl acids may be directly aminated by oxidative catalysis. In contrast, methods for intermolecular alkyl carboxylic acid to amine conversion, including amidate rearrangements and photoredox‐promoted approaches, require stoichiometric activation of the acid unit to generate isocyanate or radical intermediates. Reported here is a process for the direct chemoselective decarboxylative amination of electron‐poor arylacetates by oxidative Cu catalysis. The reaction proceeds at (or near) room temperature, uses native carboxylic acid starting materials, and is compatible with protic, electrophilic, and other potentially complicating functionality. Mechanistic studies support a pathway in which ionic decarboxylation of the acid generates a benzylic nucleophile which is aminated in a Chan–Evans–Lam‐type process.     

Visible‐Light‐Induced Nickel‐Catalyzed Negishi Cross‐Couplings by Exogenous‐Photosensitizer‐Free Photocatalysis

The merging of photoredox and transition‐metal catalysis has become one of the most attractive approaches for carbon–carbon bond formation. Such reactions require the use of two organo‐transition‐metal species, one of which acts as a photosensitizer and the other one as a cross‐coupling catalyst. We report herein an exogenous‐photosensitizer‐free photocatalytic process for the formation of carbon–carbon bonds by direct acceleration of the well‐known nickel‐catalyzed Negishi cross‐coupling that is based on the use of two naturally abundant metals. This finding will open new avenues in cross‐coupling chemistry that involve the direct visible‐light absorption of organometallic catalytic complexes.     

Reductive Umpolung of Carbonyl Derivatives with Visible‐Light Photoredox Catalysis: Direct Access to Vicinal Diamines and Amino Alcohols via α‐Amino Radicals and Ketyl Radicals

Visible‐light‐mediated photoredox‐catalyzed aldimine–aniline and aldehyde–aniline couplings have been realized. The reductive single electron transfer (SET) umpolung of various carbonyl derivatives enabled the generation of intermediary ketyl and α‐amino radical anions, which were utilized for the synthesis of unsymmetrically substituted 1,2‐diamines and amino alcohols.     

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp²)–C(sp³) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp²)–C(sp³) coupling method using boronic esters and cyano heteroarenes under flow conditions.     

Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α‐Oxo Acids

The direct decarboxylative arylation of α‐oxo acids has been achieved by synergistic visible‐light‐mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α‐oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate.     

Nickel‐ and Photoredox‐Catalyzed Cross‐Coupling Reactions of Aryl Halides with 4‐Alkyl‐1,4‐dihydropyridines as Formal Nucleophilic Alkylation Reagents

A combination of nickel and photoredox catalysts promoted novel cross‐coupling reactions of aryl halides with 4‐alkyl‐1,4‐dihydropyridines. 4‐Alkyl‐1,4‐dihydropyridines act as formal nucleophilic alkylation reagents through a photoredox‐catalyzed carbon–carbon (C?C) bond‐cleavage process. The present strategy provides an alternative to classical carbon‐centered nucleophiles, such as organometallic reagents.     

Dual Hypervalent Iodine(III) Reagents and Photoredox Catalysis Enable Decarboxylative Ynonylation under Mild Conditions

A combination of hypervalent iodine(III) reagents (HIR) and photoredox catalysis with visible light has enabled chemoselective decarboxylative ynonylation to construct ynones, ynamides, and ynoates. This ynonylation occurs effectively under mild reaction conditions at room temperature and on substrates with various sensitive and reactive functional groups. The reaction represents the first HIR/photoredox dual catalysis to form acyl radicals from α‐ketoacids, followed by an unprecedented acyl radical addition to HIR‐bound alkynes. Its efficient construction of an mGlu5 receptor inhibitor under neutral aqueous conditions suggests future visible‐light‐induced biological applications.     

(Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity

The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch–Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.