Decarboxylative Radical Addition Research Articles

Dual Acridine/Decatungstate Photocatalysis for the Decarboxylative Radical Addition of Carboxylic Acids to Azomethines.

A concept for the dual use of acridine and tetrabutylammonium decatungstate photocatalysts in the reactions of carboxylic acids is proposed. Imines generated in situ from aldehydes and p-methoxyaniline, as well as other azomethines, were used as radical acceptors. The role of the decatungstate is believed to facilitate the turnover of the acridine photocatalyst by means of hydrogen atom transfer.

Iron-catalyzed decarboxylative radical addition to chiral azomethine imines upon visible light.

Herein, we disclose an eco-efficient redox-neutral iron-catalyzed decarboxylative radical addition to chiral azomethine imines upon visible light (427 nm) giving cyclic hydrazine derivatives with dr ranging from 82 : 18 to >96 : 4. This earth-abundant metal promoted sequence proceeds efficiently under ligand-free conditions based on a LMCT process and opens a route to new chiral heterocycles.

Photoredox/Enzymatic Catalysis Enabling Redox-Neutral Decarboxylative Asymmetric C-C Coupling for Asymmetric Synthesis of Chiral 1,2-Amino Alcohols.

Photocatalysis offers tremendous opportunities for enzymes to access new functions. Herein, we described a redox-neutral photocatalysis/enzymatic catalysis system for the asymmetric synthesis of chiral 1,2-amino alcohols via decarboxylative radical C-C coupling of N-arylglycines and aldehydes by combining an organic photocatalyst, eosin Y, and carbonyl reductase RasADH. Notably, this protocol avoids using any sacrificial reductants. A possible reaction mechanism proposed is that the transformation proceeds through sequential photoinduced decarboxylative radical addition to an aldehyde and a photoenzymatic deracemization pathway. This redox-neutral photoredox/enzymatic strategy is promising not only for effective synthesis of a series of chiral amino alcohols in a green and sustainable manner but also for the design of other novel C-C radical coupling transformations for the synthesis of bioactive molecules.

Total Synthesis of (–)-Naphthospironone A

Key words (–)-naphthospironone - decarboxylative radical addition - Stille coupling - aldol addition - Mukaiyama hydration

Strategic design of gold nanocatalysts for effective photocatalytic organic transformation.

We demonstrate the design strategy of free-standing Au nanocatalysts by correlating their physicochemical characteristics with photocatalytic performance. By tailoring the particle size and surface characteristics, we found that small Au nanocatalysts called Au nanoclusters with discrete energy levels are more effective than large metallic Au nanoparticles, while the microenvironments (e.g., charge status and hydrophilicity/hydrophobicity) around the surface of Au-nanoclusters are crucial in determining the performance. With the optimized Au nanocatalyst, under visible light, decarboxylative radical addition reactions for C-C bond formation (i.e., Giese reaction) were first achieved with high yields and further utilized for the preparation of one of the bioactive γ-aminobutyric acid derivatives, pregabalin (Lyrica®), demonstrating its potential in pharmaceutical applications.

Visible-Light-Induced Cascade Difunctionalization of Indoles Enabled by the Synergy of Photoredox and Photoexcited Ketones: Direct Access to Alkylated Pyrrolophenanthridones

Herein, we describe a methodology to construct polycyclic pyrrolophenanthridones with an (amino)alkyl side chain that involves visible-light-induced decarboxylative radical addition for the intermolecular dearomatization of indoles and subsequent photoinduced C(sp2)-X bond activation via photoexcited ketones for an intramolecular cyclization cascade. Carboxylic acids serve both as a radical source toward indole dearomatization and as reductants to initiate an electron transfer with photoexcited N-acylindole derivatives in the reaction toward pyrrolophenantridone skeletons, which occurs under mild reaction conditions with good functional group tolerance.

Visible‐Light‐Induced Decarboxylative and Deboronative Radical Addition to Alkenes in Two‐Molecule Photoredox System Using Dibenzo[g,p]chrysene

AbstractVisible‐light‐induced decarboxylative and deboronative radical addition of aliphatic carboxylic acids and arylboronic acid pinacol esters to electron‐deficient alkenes using two‐molecule organic photoredox catalysts, such as dibenzo[g,p]chrysene as an electron donor and 1,4‐dicyanobenzene as an electron acceptor, proceeded efficiently to furnish radical adducts via the generation of alkyl and aryl radicals. The base and substrate play important roles in this photochemical system, and the sequential photoinduced decarboxylation of glutamic acid having two different carboxy groups was successful.

Decarboxylative Side-Chain Functionalization of Aspartic/Glutamic Acids Using Two-Molecule Photoredox Catalysts.

The side-chain functionalization of aspartic/glutamic acid derivatives through photoinduced decarboxylation was achieved by using organic two-molecule photoredox catalysts without racemization under mild conditions. A facile process involving the preparation of substrates and photoinduced decarboxylative radical additions can provide easy access to the linked amino acids with carbohydrates and amino acids at the side chain.

Decarboxylative Radical Addition to Methylideneoxazolidinones for Stereocontrolled Synthesis of Selectively Protected Diamino Diacids.

Syntheses of stereochemically pure and selectively protected diamino diacids can be achieved by redox decarboxylation of distal N-hydroxyphthalimide esters of protected aspartic, glutamic or α-aminoadipic acids via radical addition to methylideneoxazolidinones. The products are useful for solid-supported syntheses of robust bioactive carbocyclic peptide analogs. Yields of reactive primary radical addition are superior to those of more stabilized radicals, and the reaction fails if the alkylideneoxazolidinone has a methyl substituent on its terminus (i.e., 13a/13b).

Photoinduced Decarboxylative Radical Addition Reactions for Late Stage Functionalization of Peptide Substrates

AbstractPhotoredox chemistry has greatly stimulated the application of radical based transformations in medicinal chemistry and early drug discovery in recent years. Carboxylate groups have been identified as traceless leaving groups that can be converted into radical intermediates capable of undergoing 1,4‐conjugate addition reactions to Michael acceptors. Herein, we show the successful C‐terminal derivatization of small peptide substrates by using this methodology in a parallel synthesis setting. Finally, we outline a general strategy for the γ‐homologation of several drugs derived from α‐amino acids in a late stage functionalization (LSF) approach.

Visible-Light-Mediated Decarboxylative Radical Addition Bifunctionalization Cascade for the Production of 1,4-Amino Alcohols.

A photocatalytic decarboxylative radical addition bifunctionalization cascade for the synthesis of functionalized alcohols is described. The catalytic cycle is completed through single-electron transfer. The advantages of this reaction are the commercially available materials, wide functional group compatibility, and mild conditions. Notably, some amino acids and bioactive carboxylic acids can provide corresponding products in moderate to good yields, reflecting the potential value in drug development.

Photoredox-Mediated Reaction of gem-Diborylalkenes: Reactivity Toward Diverse 1,1-Bisborylalkanes.

The use of gem-diborylalkenes as radical-reactive groups is explored for the first time. These reactions provide an efficient and general method for the photochemical conversion of gem-diborylalkenes to rapidly access 1,1-bisborylalkanes. This method exploits a novel photoredox decarboxylative radical addition to gem-diborylalkenes to afford α-gem-diboryl carbon-centered radicals, which benefit from additional stability by virtue of an interaction with the empty p-orbitals on borons. The reaction offers a highly modular and regioselective approach to γ-amino gem-diborylalkanes. Furthermore, EPR spectroscopy and DFT calculations have provided insight into the radical mechanism underlying the photochemistry reaction and the stability of the bis-metalated radicals, respectively.

Photochemical Strain-Release-Driven Cyclobutylation of C(sp3 )-Centered Radicals.

A new photoredox-catalyzed decarboxylative radical addition approach to functionalized cyclobutanes is described. The reaction involves an unprecedented formal Giese-type addition of C(sp3 )-centered radicals to highly strained bicyclo[1.1.0]butanes. The mild photoredox conditions, which make use of a readily available and bench stable phenyl sulfonyl bicyclo[1.1.0]butane, proved to be amenable to a diverse range of α-amino and α-oxy carboxylic acids, providing a concise route to 1,3-disubstituted cyclobutanes. Furthermore, kinetic studies and DFT calculations unveiled mechanistic details on bicyclo[1.1.0]butane reactivity relative to the corresponding olefin system.

Photochemical Strain‐Release‐Driven Cyclobutylation of C(sp3)‐Centered Radicals

AbstractA new photoredox‐catalyzed decarboxylative radical addition approach to functionalized cyclobutanes is described. The reaction involves an unprecedented formal Giese‐type addition of C(sp3)‐centered radicals to highly strained bicyclo[1.1.0]butanes. The mild photoredox conditions, which make use of a readily available and bench stable phenyl sulfonyl bicyclo[1.1.0]butane, proved to be amenable to a diverse range of α‐amino and α‐oxy carboxylic acids, providing a concise route to 1,3‐disubstituted cyclobutanes. Furthermore, kinetic studies and DFT calculations unveiled mechanistic details on bicyclo[1.1.0]butane reactivity relative to the corresponding olefin system.

Retention of chirality of 5-membered alicyclic α-amino acids bearing N-(2-phenyl)benzoyl group in photoinduced decarboxylative intermolecular radical addition to acrylonitrile

Photoinduced decarboxylative radical additions of 5-membered alicyclic α-amino acids bearing a (2-phenyl)benzoyl protective group to acrylonitrile under mild organic photoredox catalysis conditions furnished γ-amino acid derivatives with high retention of chirality via the memory of chirality (MOC) strategy. The retention of chirality in the photoinduced decarboxylation was strongly dependent on the structure of the alicyclic α-amino acids and alkenes. To the best of our knowledge, this is the first example of the decarboxylative intermolecular radical addition to alkenes with retention of chirality at the position of radical generation using the MOC strategy.

A Formal Synthesis of Camptothecin via a Photocatalytic Decarboxylative Radical Addition

A convergent fragment‐coupling strategy for the synthesis of camptothecin is described. The key step is a photocatalytic decarboxylative radical Michael addition that attaches the ABC rings to the E ring fragment, constructing the main structure of camptothecin in five steps. This work illustrates a new strategy for the synthesis of alkaloids of the camptothecin family.

Transition metal-free, visible-light-mediated construction of α,β-diamino esters via decarboxylative radical addition at room temperature

A metal-free photoredox catalyzed decarboxylative radical coupling of free-carboxylic acids and glyoxylic oximes was developed to synthesize α,β-diamino acids.

Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition-Polar Cyclization Cascade.

Herein, we describe the development of a photoredox‐catalyzed decarboxylative radical addition–polar cyclization cascade approach to functionalized cyclopropanes. Reductive termination of radical–polar crossover reactions between aliphatic carboxylic acids and electron‐deficient alkenes yielded carbanion intermediates that were intercepted in intramolecular alkylations with alkyl chlorides appended to the alkene substrate. The mild conditions, which make use of a readily available organic photocatalyst and visible light, were demonstrated to be amenable to a broad range of structurally complex carboxylic acids and a wide variety of chloroalkyl alkenes, demonstrating exquisite functional group tolerance.

Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition–Polar Cyclization Cascade

AbstractHerein, we describe the development of a photoredox‐catalyzed decarboxylative radical addition–polar cyclization cascade approach to functionalized cyclopropanes. Reductive termination of radical–polar crossover reactions between aliphatic carboxylic acids and electron‐deficient alkenes yielded carbanion intermediates that were intercepted in intramolecular alkylations with alkyl chlorides appended to the alkene substrate. The mild conditions, which make use of a readily available organic photocatalyst and visible light, were demonstrated to be amenable to a broad range of structurally complex carboxylic acids and a wide variety of chloroalkyl alkenes, demonstrating exquisite functional group tolerance.

Strategy for O-Alkylation of Serine and Threonine from Serinyl and Threoninyl Acetic Acids by Photoinduced Decarboxylative Radical Reactions: Connection between Serine/Threonine and Carbohydrates/Amino Acids at the Side Chain.

O-Alkylations of serine and threonine derivatives at the hydroxy group were achieved using photoinduced decarboxylative radical reactions of serinyl and threoninyl acetic acids with an organic photocatalyst without racemization under mild conditions. Photoinduced decarboxylative radical additions of serinyl and threoninyl acetic acids to electron-deficient alkenes provided linked serine and threonine with carbohydrates and amino acids at the side chain. In addition, O-methylations containing deuterium and O-benzylation of serine were performed under similar photochemical conditions.