Radical Cascade Reaction Research Articles

Additive-Free Radical Cascade Reaction of Oxime Esters: Synthesis of Pyrroline-Functionalized Phenanthridines.

A variety of dihydropyrrole-functionalized phenanthridines were efficiently synthesized by the metal-free, radical cascade cyclization reaction of 2-isocyanobiphenyls with γ,δ-unsaturated oxime esters. The C-N/C-C/C-C bonds were formed via the oil bath method in a one-pot procedure with broad substrate applicability. The radical process was supported by kinetic isotope effect studies and radical inhibition studies.

Iron-Catalyzed Redox-Neutral Radical Cascade Reaction of [60]Fullerene with γ,δ-Unsaturated Oxime Esters: Preparation of Free (N-H) Pyrrolidino[2',3':1,2]fullerenes.

Herein an unprecedented iron(II)-catalyzed redox-neutral radical cascade reaction of [60]fullerene with γ,δ-unsaturated oxime esters is reported for the preparation of novel free (N-H) pyrrolidino[2',3':1,2]fullerenes. The transformation undergoes an intramolecular cyclization/intermolecular cyclization/oxidation/hydrolysis cascade, and features simple operation, broad substrate scope/high functional group compatibility as well as suitable for scale-up synthesis, providing a facile and practical access to a range of free pyrrolidino[2',3':1,2]fullerenes.

Recent Advances in the Construction of Spiro Compounds via Radical Dearomatization

AbstractThe field in dearomatization of aromatic compounds for the construction of spirocycle compounds has been developed rapidly over the last two decades and it provides alternative synthetic method without using extra stoichiometric amounts of chemical oxidants or reductants. In addition, the radical cascade reactions of alkenes or alkynes that produce multiple chemical bonds in one‐step are significant in the direct and efficient building of complex molecules. By combining these two concepts, dearomatization and radical cascade reactions of alkenes or alkynes opens a new and powerful avenue in accessing spirocycle molecules. These cascade reactions have been well explored in the past decade. As a result, we summarize recent eventful advances in this rapidly growing area as a review, in which the typical examples are listed and mechanism are also discussed.magnified image

Arene dearomatization through a catalytic N-centered radical cascade reaction

Arene dearomatization reactions are an important class of synthetic technologies for the rapid assembly of unique chemical architectures. Herein, we report a catalytic protocol to initiate a carboamination/dearomatization cascade that proceeds through transient sulfonamidyl radical intermediates formed from native sulfonamide N–H bonds leading to 1,4-cyclohexadiene-fused sultams. Importantly, this work demonstrates a facile approach to employ two-dimensional aromatic compounds as modular building blocks to generate richly substituted, three-dimensional compounds. These reactions occur at room temperature under visible light irradiation and are catalyzed by the combination of an iridium(III) photocatalyst and a dialkyl phosphate base. Reaction optimization, substrate scope, mechanistic features, and synthetic applications of this transformation are presented.

Catalytic radical generation of π-allylpalladium complexes

Transition metal catalysed allylic substitution is one of the most powerful and frequently used methods in organic synthesis. In particular, palladium-catalysed allylic functionalization has become a well-established strategy for constructing carbon–carbon or carbon–heteroatom bonds, and its utility has been demonstrated in natural product synthesis, drug discovery and materials science. Several methods have been developed to generate π-allylpalladium complexes through ionic mechanisms; however, these methods typically require either prefunctionalized starting materials or stoichiometric oxidants, which naturally limits their scope. Here, we show a radical approach for the generation of π-allylpalladium complexes by employing N-hydroxyphthalimide esters as bifunctional reagents in combination with 1,3-dienes. Using this strategy, we report the 1,4-aminoalkylation of dienes. The remarkable scope and functional group tolerance of this redox-neutral and mild protocol was demonstrated across >60 examples. The utility of this strategy was further demonstrated in radical cascade reactions and in the late-stage modification of drugs and natural products. Palladium-catalysed allylic substitution is a widely used method in organic synthesis, although it requires prefunctionalized starting materials or stoichiometric oxidants. Here the authors report a radical route to form π-allylpalladium complexes, and develop a 1,4-aminoalkylation of dienes under redox-neutral conditions.

Highly Cumulated Radical Cascade Reaction of aza‐1,6‐Enyenes: Stereoselective Synthesis of exo‐Methylene Piperidines

Treatment of 1,6‐azaeneyne compounds with Ph3SnH resulted in the stereoselective formation of 5‐(E)‐alkylidene‐2,3‐cis‐piperidine in moderate to good yields. Intermediate products including methylenepyrrolidine and stannomethylene pyrrolidine were also detected in the reaction mixture, suggesting that the reaction progressed via a highly cumulated radical cascade process involving sequential six radical processes, i.e. radical addition, 5‐exo cyclization, substitution (1,4‐tin migration), 3‐exo cyclization, ring cleavage of cycloprolane, and hydrogen abstraction from Ph3SnH. The product distribution depended on the lower Ph3SnH concentration, resulting in higher piperidine yields. The E/Z selectivity of the exo‐methylene unit was also sensitive to the reaction temperature. The vinylic triphenyltin group was converted into hydrogen and iodine. A kinetic analysis of the reaction indicated that the 1,4‐tin migration and ring expansion progressed as irreversible reactions and that their reaction rates were large enough to progress the cascade reaction smoothly and to prevent side reactions such as hydrogen abstraction from Ph3SnH.

Cascades, Catalysis and Chiral Ligand Control with SmI₂; The Rebirth of a Reagent.

This review focuses on recent developments from our laboratory in the field of radical reactions mediated by the archetypal reductive single electron transfer (SET) reagent, SmI₂. Namely, we have expanded the scope of reducible carbonyl moieties to esters and amides and have exploited the resultant ketyl radicals in radical cascade reactions that generate unprecedented scaffolds. Moreover, we have taken the first steps to address the long-standing challenges of catalysis and chiral ligand control associated with the reagent.

Radical cascade cyclization for synthesizing 3,4-fused tricyclic benzofuran derivatives

A new method for synthesizing 3,4-fused tricyclic 3-alkylidene dihydrobenzofuran derivatives was developed. Treatment of propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions under the radical cascade reaction conditions induced the reaction of the generated vinyl radical intermediates with the internal alkene, producing tricyclic 3-alkylidene dihydrobenzofurans in 25%–93% yield. The reaction products could be utilized as the precursors for 3,4-fused tricyclic benzofurans.

The Introduction of the Radical Cascade Reaction into Polymer Chemistry: A One-Step Strategy for Synchronized Polymerization and Modification.

SummaryPolymerization and modification play central roles in polymer chemistry and are generally implemented in two steps, which suffer from the time-consuming two-step strategy and present considerable challenge for complete modification. By introducing the radical cascade reaction (RCR) into polymer chemistry, a one-step strategy is demonstrated to achieve synchronized polymerization and complete modification in situ. Attributed to the cascade feature of iron-catalyzed three-component alkene carboazidation RCR exhibiting carbon-carbon bond formation and carbon-azide bond formation with extremely high efficiency and selectivity in one step, radical cascade polymerization therefore enables the in situ synchronized polymerization through continuous carbon-carbon bond formation and complete modification through carbon-azide bond formation simultaneously. This results in a series of α, β, and γ poly(amino acid) precursors. This result not only expands the methodology library of polymerization, but also the possibility for polymer science to achieve functional polymers with tailored chemical functionality from in situ polymerization.

Synthetic studies towards (–)-deserpidine: Total synthesis of the stereoisomer and derivative of (–)-deserpidine

The asymmetric synthesis of 16,17,20-epi-deserpidine and a derivative of (–)-deserpidine has been achieved. Key features in the assembly of the pentacyclic framework include a visible-light photocatalytic intra-/inter-/intramolecular radical cascade reaction to construct the tetracyclic ABCD ring system in one-pot and an intramolecularaldol reaction to forge the cyclohexane E ring.

Visible-light-promoted acyl radical cascade reaction for accessing acylated isoquinoline-1,3(2H,4H)-dione derivatives.

A visible-light-promoted decarboxylative acyl radical acylation/cyclization cascade reaction of N-methacryloylbenzamides for accessing acylated isoquinoline-1,3(2H,4H)-dione derivatives was described. In this report, α-keto acids were used for generating acyl radicals and inducing radical acylations. This protocol features mild reaction conditions, operational practicality and a broad substrate scope.

Synthesis of 3-sulfonylquinolines by visible-light promoted metal-free cascade cycloaddition involvingN-propargylanilines and sodium sulfinates

A visible-light promoted radical cascade reaction ofN-propargylanilines with sodium sulfinates as sulfonyl radical precursors was developed under metal-free conditions.

Radical cascade reactions of unsaturated C-C bonds involving migration

During the past few years, with the rapid development of mild methods for the generation of radical species, great progress in radical cascade reactions of unsaturated C–C bonds has been made. Many radical cascade reactions involve functional groups migration, which leads structurally much more diverse, complex and valuable compounds not easily obtained through other methods. In this review, the recent achievements in unsaturated C–C bonds radical cascade reactions involving migration are summarized.

Asymmetric Synthesis of Heterocyclic γ‐Amino‐Acid and Diamine Derivatives by Three‐Component Radical Cascade Reactions

AbstractAn enantioselective three‐component radical reaction of quinolines or pyridines with enamides and α‐bromo carbonyl compounds by dual photoredox and chiral Brønsted acid catalysis is presented. A range of valuable chiral γ‐amino‐acid derivatives are accessible in high chemo‐, regio‐, and enantioselectivity from simple, readily available starting materials under mild reaction conditions. Using the same strategy, the asymmetric synthesis of 1,2‐diamine derivatives is also reported.

Asymmetric Synthesis of Heterocyclic γ-Amino-Acid and Diamine Derivatives by Three-Component Radical Cascade Reactions.

An enantioselective three-component radical reaction of quinolines or pyridines with enamides and α-bromo carbonyl compounds by dual photoredox and chiral Brønsted acid catalysis is presented. A range of valuable chiral γ-amino-acid derivatives are accessible in high chemo-, regio-, and enantioselectivity from simple, readily available starting materials under mild reaction conditions. Using the same strategy, the asymmetric synthesis of 1,2-diamine derivatives is also reported.

Iron(III) Chloride/Phenylsilane‐Mediated Cascade Reaction of Allyl Alcohols with Maleimides: Synthesis of Poly‐Substituted γ‐Butyrolactones

AbstractA iron‐catalyzed free radical cascade reaction of allyl alcohols with N‐substituted maleimides for accessing poly‐substituted γ‐butyrolactones has been developed. In this protocol, various allyl alcohols can open N‐substituted maleimide rings to form allyl ester intermediates, and the allyl ester intermediates can be converted into an allyl ester alkyl radicals and undergo intramolecular free radical addition cyclization to form a polysubstituted γ‐butyrolactones. In this protocol, spiro γ‐butyrolactone compounds can be also synthesized. Meanwhile, the strategy could be applied to further construct a fully substituted tetrahydrofuran. The reaction is not sensitive to oxygen or moisture and has been performed on gram‐scale.magnified image

1,2-Boron Shifts of β-Boryl Radicals Generated from Bis-boronic Esters Using Photoredox Catalysis.

1,2-Bis-boronic esters are versatile intermediates that enable the rapid elaboration of simple alkene precursors. Previous reports on their selective mono-functionalization have targeted the most accessible position, retaining the more hindered secondary boronic ester. In contrast, we have found that photoredox-catalyzed mono-deboronation generates primary β-boryl radicals that undergo rapid 1,2-boron shift to form thermodynamically favored secondary radicals, allowing for selective transformation of the more hindered boronic ester. The pivotal 1,2-boron shift, which has been demonstrated to be stereoretentive, enables access to a wide range of functionalized boronic esters and has been applied to highly diastereoselective fragmentation and transannular cyclization reactions. Furthermore, its generality has been shown in a radical cascade reaction with an allylboronic ester.

Enantioselective Total Synthesis of (-)-Caldaphnidine O via a Radical Cyclization Cascade.

The synthetically challenging, diverse chemical skeletons and promising biological profiles of the Daphniphyllum alkaloids have generated intense interest from the synthetic chemistry community. Herein, the first and enantioselective total synthesis of (-)-caldaphnidine O, a complex bukittinggine-type Daphniphyllum alkaloid, is described. The key transformations in this concise approach included an intramolecular aza-Michael addition, a ring expansion reaction sequence, a Sm(II)/Fe(III)-mediated Kagan-Molander coupling, and the rapid formation of the entire hexacyclic ring skeleton of the target molecule via a radical cyclization cascade reaction, which was inspired by an unexpected radical detosylation observed in our recent dapholdhamine B synthesis.

Total Synthesis of Leuconoxine, Melodinine E, and Mersicarpine through a Radical Translocation–Cyclization Cascade

AbstractThe Aspidosperma alkaloids leuconoxine, melodinine E, and mersicarpine were synthesized. The approach features a key cascade radical reaction. A 1,5‐hydrogen atom transfer is followed by spontaneous 5‐exo‐trig cyclization to construct the central indoline architecture. Late‐stage differentiation of the radical cyclization product by chemoselective oxidation allows production of either the leuconoxine/melodinine E or mersicarpine structure.

Total Synthesis of Leuconoxine, Melodinine E, and Mersicarpine through a Radical Translocation-Cyclization Cascade.

The Aspidosperma alkaloids leuconoxine, melodinine E, and mersicarpine were synthesized. The approach features a key cascade radical reaction. A 1,5-hydrogen atom transfer is followed by spontaneous 5-exo-trig cyclization to construct the central indoline architecture. Late-stage differentiation of the radical cyclization product by chemoselective oxidation allows production of either the leuconoxine/melodinine E or mersicarpine structure.