Radical Translocation Research Articles

Chemoselective Dehydrogenation and Hetero-Arylation of Amides via Radical Translocation Enabled by Photoexcited Triplet Ketone Catalysis.

We herein report the chemoselective dehydrogenation and heteroarylation of amides through photoexcited triplet ketone catalysis. Under mild reaction conditions, the generated aryl radical through the halogen atom transfer (XAT) process further undergoes an intramolecular 1,5-HAT event to generate an α-amido alkyl radical, which then intercepted with either cobalt or a reduced cyano arene radical leads to dehydrogenated and heteroarylated products, respectively, in good yields.

Iron-Mediated Segment Coupling of Alkenols with Acceptors via C-C Radical Translocation and Remote Oxidative 1,5/6-Hydrogen Atom Transfer.

Iron-mediated segment coupling followed by oxidative 1,5/6-hydrogen atom transfer (HAT) for synthesis of ε-oxo alkene derivatives is developed. This transformation involved translocation of the radical from H-to-C-to-C-to-C followed by the oxidation under MHAT conditions providing rapid access to 1,6/1,7-keto functionalized esters/ketone/sulfones/phosphonates/arenes. The different outcomes of coupling with acceptors could be explained by bond dissociation energies (BDEs), and mechanistic insights were gained through control experiments, including deuterium labeling studies.

Di-π-ethane Rearrangement of Cyano Groups via Energy-Transfer Catalysis.

Molecular rearrangement occupies a pivotal position among fundamental transformations in synthetic chemistry. Radical translocation has emerged as a prevalent synthetic tool, efficiently facilitating the migration of diverse functional groups. In contrast, the development of di-π-methane rearrangement remains limited, particularly in terms of the translocation of cyano functional groups. This is primarily attributed to the energetically unfavorable three-membered-ring transition state. Herein, we introduce an unprecedented di-π-ethane rearrangement enabled by energy-transfer catalysis under visible light conditions. This innovative open-shell rearrangement boasts broad tolerance toward a range of functional groups, encompassing even complex drug and natural product derivatives. Overall, the reported di-π-ethane rearrangement represents a complementary strategy to the development of radical translocation enabled by energy-transfer catalysis.

Asymmetric, Remote C(sp3)−H Arylation via Sulfinyl‐Smiles Rearrangement

AbstractAn efficient asymmetric remote arylation of C(sp3)−H bonds under photoredox conditions is described here. The reaction features the addition radicals to a double bond followed by a site‐selective radical translocation (1,n‐hydrogen atom transfer) as well as a stereocontrolled aryl migration via sulfinyl‐Smiles rearrangement furnishing a wide range of chiral α‐arylated amides with up to >99 : 1 er. Mechanistic studies indicate that the sulfinamide group governs the stereochemistry of the product with the aryl migration being the rate determining step preceded by a kinetically favored 1,n‐HAT process.

Asymmetric, Remote C(sp3)-H Arylation via Sulfinyl-Smiles Rearrangement.

An efficient asymmetric remote arylation of C(sp3)-H bonds under photoredox conditions is described here. The reaction features the addition radicals to a double bond followed by a site-selective radical translocation (1,n-hydrogen atom transfer) as well as a stereocontrolled aryl migration via sulfinyl-Smiles rearrangement furnishing a wide range of chiral α-arylated amides with up to >99 : 1 er. Mechanistic studies indicate that the sulfinamide group governs the stereochemistry of the product with the aryl migration being the rate determining step preceded by a kinetically favored 1,n-HAT process.

Photoinduced copper catalyzed nitrogen-to-alkyl radical relay Sonogashira-type coupling of o-alkylbenzamides with alkynes.

This report describes a copper-catalyzed, photoinduced N-to-alkyl radical relay Sonogashira-type reactions at benzylic sites in o-alkylbenzamides with alkynes. The process employs an N-to-alkyl radical mechanism, initiated through the copper-catalyzed reductive generation of nitrogen radicals. Radical translocation is facilitated by a 1,5-hydrogen atom transfer (1,5-HAT), leading to the formation of translocated carbon radicals. These radicals are then subjected to copper-catalyzed alkynylation. The methodology exhibits broad sub-strate scope and applicability to the synthesis of complex natural products.

An assay for aryl radicals using BHAS coupling.

Aryl radicals are intermediates in many reactions, but determining their presence unambiguously is often challenging. As we recently reported, reaction of 2-iodo-1,3-dimethylbenzene (7) in benzene with KOtBu and a suitable organic additive, leads to a base-induced homolytic aromatic substitution (BHAS) coupling reaction giving 2,6-dimethylbiphenyl (12) and biphenyl (3) as coupled products, together with xylene (13). In this case, biphenyl arises from a radical translocation and is the major coupling product. This paper now quantitatively investigates that reaction, which shows a very similar ratio for 3 : 12 [ca. 4 : 1] when using different sources of radical initiation. Deuterium isotope studies provide detailed mechanistic support for the proposed mechanism; when carried out in C6D6vs. C6H6, the reaction is characterised by a strong isotope effect for formation of 3-d10vs. 3, but not for formation of 12-d5vs. 12. These distinctive properties mean that the transformation can act as an assay for aryl radicals. An advantage of such a BHAS process is its sensitivity, since it involves a chain reaction that can amplify radical activity.

Visible-Light-Mediated Synthesis of C-Alkyl Glycosides via Glycosyl Radical Addition and Aryl Migration.

A visible-light-induced glycoarylation of activated olefins has been accomplished. Glycosyl radicals are generated via radical transfer strategies between (TMS)3SiOH and glycosyl bromides. Subsequent radical translocation and rapid 1,4-aryl migration form β-sugar amide derivatives, and eight types of sugars are compatible with this reaction. Further, the cascade reaction produced a quaternary carbon center with good functional group adaptability and high regioselectivity in mild conditions.

Copper/Photoredox dual Catalyzed Syntheses of Allenenitriles via 1,5‐HAT

AbstractThe first example of merging photoredox catalysis and copper catalysis for 1,4‐difunctionalization of 1,3‐enynes via 1,5‐HAT (hydrogen atom transfer) has been developed. The synthetic strategy exploits a radical translocation from an oxygen‐centered to a carbon‐centered radical with a subsequent radical addition to the 1,3‐enynes, affording tetrasubstituted allenenitriles in up to 90% yield. This strategy has mild reaction conditions, broad substrate scope and excellent functional group tolerance.

Short I⋯O Interactions in the Crystal Structures of Two 2-Iodo-Phenyl Methyl-Amides as Substrates for Radical Translocation Reactions

Radical translocation reactions are finding various uses in organic synthesis, in particular the stereospecific formation of complex natural products. In this work, the syntheses and single-crystal structures of two substituted 2-iodo-phenyl methyl-amides are reported, namely cyclo-propane carboxylic acid (2-iodo-phenyl)-methyl-amide, C11H12INO (1), and cyclo-heptane carboxylic acid (2-iodo-phenyl)-methyl-amide, C15H20INO (2). In each case, the methyl-amide group has a syn conformation, and this grouping is perpendicular to the plane of the benzene ring: these solid-state conformations appear to be well setup to allow an intramolecular hydrogen atom transfer to take place as part of a radical translocation reaction. Short intermolecular I⋯O halogen bonds occur in each crystal structure, leading to [010] chains in 1 [I⋯O = 3.012 (2) Å] and isolated dimers in 2 [I⋯O = 3.024 (4) and 3.057 (4) Å]. The intermolecular interactions are further quantified by Hirshfeld surface analyses.

Kinetic model for reversible radical transfer in ribonucleotide reductase

The enzyme ribonucleotide reductase (RNR), which catalyzes the reduction of ribonucleotides to deoxynucleotides, is vital for DNA synthesis, replication, and repair in all living organisms. Its mechanism requires long-range radical translocation over ∼32 Å through two protein subunits and the intervening aqueous interface. Herein, a kinetic model is designed to describe reversible radical transfer in Escherichia coli RNR. This model is based on experimentally studied photoRNR systems that allow the photochemical injection of a radical at a specific tyrosine residue, Y356, using a photosensitizer. The radical then transfers across the interface to another tyrosine residue, Y731, and continues until it reaches a cysteine residue, C439, which is primed for catalysis. This kinetic model includes radical injection, an off-pathway sink, radical transfer between pairs of residues along the pathway, and the conformational flipping motion of Y731 at the interface. Most of the input rate constants for this kinetic model are obtained from previous experimental measurements and quantum mechanical/molecular mechanical free-energy simulations. Ranges for the rate constants corresponding to radical transfer across the interface are determined by fitting to the experimentally measured Y356 radical decay times in photoRNR systems. This kinetic model illuminates the time evolution of radical transport along the tyrosine and cysteine residues following radical injection. Further analysis identifies the individual rate constants that may be tuned to alter the timescale and probability of the injected radical reaching C439. The insights gained from this kinetic model are relevant to biochemical understanding and protein-engineering efforts with potential pharmacological implications.

Copper‐Catalyzed 1,2,5‐Trifunctionalization of Terminal Alkynes Using SR as a Transient Directing Group for Radical Translocation

Comprehensive SummaryThe first Cu‐catalyzed 1,2,5‐trifunctionalization of abundant terminal alkynes is realized by merging hydrogen atom transfer and traceless directing strategy with SR as a transient group, delivering highly functionalized aldehydes in moderate to excellent yields with broad substrate scope. The synthetic utility of this method was demonstrated by the gram‐scale reaction and downstream transformations of the resultant products. Given the high efficient installation of three different functional groups in a single reaction, it can serve as a very attractive method for rapidly assembling complex molecules from readily available starting materials.

Cobalt-catalyzed chemoselective dehydrogenation through radical translocation under visible light.

The transformations that allow the direct removal of hydrogen from their corresponding saturated counterparts by the dehydrogenative strategy are a dream reaction that has remained largely underexplored. In this report, a straightforward and robust cobaloxime-catalyzed photochemical dehydrogenation strategy via intramolecular HAT is described for the first time. The reaction proceeds through an intramolecular radical translocation followed by the cobalt assisted dehydrogenation without needing any other external photosensitizers, noble-metals or oxidants. With this approach, a series of valuable unsaturated compounds such as α,β-unsaturated amides, enamides and allylic and homoallylic sulfonamides were obtained in moderate to excellent yields with good chemo- and regioselectivities, and the synthetic versatility was demonstrated by a range of transformations. And mechanistic studies of the method are discussed.

Oxidation Under Reductive Conditions: From Benzylic Ethers to Acetals with Perfect Atom‐Economy by Titanocene(III) Catalysis

AbstractDescribed here is a titanocene‐catalyzed reaction for the synthesis of acetals and hemiaminals from benzylic ethers and benzylic amines, respectively, with pendant epoxides. The reaction proceeds by catalysis in single‐electron steps. The oxidative addition comprises an epoxide opening. An H‐atom transfer, to generate a benzylic radical, serves as a radical translocation step, and an organometallic oxygen rebound as a reductive elimination. The reaction mechanism was studied by high‐level dispersion corrected hybrid functional DFT with implicit solvation. The low‐energy conformational space was searched by the efficient CREST program. The stereoselectivity was deduced from the lowest lying benzylic radical structures and their conformations are controlled by hyperconjugative interactions and steric interactions between the titanocene catalyst and the aryl groups of the substrate. An interesting mechanistic aspect is that the oxidation of the benzylic center occurs under reducing conditions.

Regioselective side-chain amination of 2-alkyl azacycles by radical translocation: total synthesis of tetraponerine T8.

The regioselective γ-C-H amination of the side-chain of saturated 2-alkyl nitrogen heterocycles is reported, proceeding through a sulfamide-directed 1,6-radical translocation. The practicality of this rapid access to 1,3-diamines is highlighted in a short synthesis of the alkaloid tetraponerine T8 and non-natural analogues.

Conformational Motions and Water Networks at the α/β Interface in E. coli Ribonucleotide Reductase.

Ribonucleotide reductases (RNRs) catalyze the conversion of all four ribonucleotides to deoxyribonucleotides and are essential for DNA synthesis in all organisms. The active form of E. coli Ia RNR is composed of two homodimers that form the active α2β2 complex. Catalysis is initiated by long-range radical translocation over a ∼32 Å proton-coupled electron transfer (PCET) pathway involving Y356β and Y731α at the interface. Resolving the PCET pathway at the α/β interface has been a long-standing challenge due to the lack of structural data. Herein, molecular dynamics simulations based on a recently solved cryogenic-electron microscopy structure of an active α2β2 complex are performed to examine the structure and fluctuations of interfacial water, as well as the hydrogen-bonding interactions and conformational motions of interfacial residues along the PCET pathway. Our free energy simulations reveal that Y731 is able to sample both a flipped-out conformation, where it points toward the interface to facilitate interfacial PCET with Y356, and a stacked conformation with Y730 to enable collinear PCET with this residue. Y356 and Y731 exhibit hydrogen-bonding interactions with interfacial water molecules and, in some conformations, share a bridging water molecule, suggesting that the primary proton acceptor for PCET from Y356 and from Y731 is interfacial water. The conformational flexibility of Y731 and the hydrogen-bonding interactions of both Y731 and Y356 with interfacial water and hydrogen-bonded water chains appear critical for effective radical translocation along the PCET pathway. These simulations are consistent with biochemical and spectroscopic data and provide previously unattainable atomic-level insights into the fundamental mechanism of RNR.

Total Synthesis of (−)-Lepadiformine A via Radical Translocation–Cyclization Reaction

Total synthesis of (-)-lepadiformine A featuring construction of the 1-azaspiro[4.5]decane skeleton by a highly diastereoselective radical translocation-cyclization reaction of a γ-lactam derivative bearing a chiral butenolide moiety is described. The enantioselective construction of butenolide is conducted via Krische's catalytic asymmetric allylation protocol. After the radical translocation-cyclization reaction, a hydroxymethyl group at the C-13 position was stereoselectively introduced by a one-pot partial reduction-allylation protocol of the unprotected lactam derivative. Finally, the total synthesis is completed by formation of a C ring.

Functionalization of remote C(sp3)-H bonds enabled by copper-catalyzed coupling of O-acyloximes with terminal alkynes

Transition metal catalyzed Sonogashira cross-coupling of terminal alkynes with aryl(vinyl) (pseudo)halides has been successfully extended to alkyl halides for the synthesis of functionalized internal alkynes. The direct alkynylation of remote unfunctionalized sp3 carbon by terminal alkynes remains difficult to realize. We report herein an approach to this synthetic challenge by developing two catalytic remote sp3 carbon alkynylation protocols. In the presence of a catalytic amount of Cu(I) salt and a tridentate ligand (tBu3-terpyridine), O-acyloximes derived from cycloalkanones and acyclic ketones are efficiently coupled with terminal alkynes to afford a variety of γ- and δ-alkynyl nitriles and γ-alkynyl ketones, respectively. These reactions proceed through a domino sequence involving copper-catalyzed reductive generation of iminyl radical followed by radical translocation via either β-scission or 1,5-hydrogen atom transfer (1,5-HAT) and copper-catalyzed alkynylation of the resulting translocated carbon radicals. The protocols are applicable to complex natural products.

Radical Philicity Inversion in Co- and Fe-Catalyzed Hydrogen-Atom-Transfer-Initiated Cyclizations of Unsaturated Acylsilanes

[1,2]-Radical Brook rearrangement (RBR) has been identified as a viable pathway in M–H (M = Co, Fe) catalyzed hydrogen-atom-transfer reactions involving unsaturated acylsilanes. Guided by the same concept, we have explored two transformations, namely, a Co-catalyzed cycloisomerization reaction and a Fe-catalyzed cyclization/Giese addition reaction. Both reactions involve the generation of a versatile α-siloxy radical intermediate via concomitant philicity inversion and radical translocation, which is mechanistically distinct from coupling reactions involving fragmentation/reduction pathways. Synthesis of cyclic silyl enol ethers and sterically congested cyclopentanol derivatives have been thus achieved with high regio- and diastereo-selectivity.

Site-Tunable Csp3-H Bonds Functionalization by Visible-Light-Induced Radical Translocation of N-Alkoxyphthalimides.

Site-tunable functionalization of C(sp3)-H bonds has been accomplished through radical translocation and cross-coupling. Upon irradiation with visible light, copper-based photocatalyst [Cu(Xantphos)(dmp)]BF4 enabled cross-coupling of N-alkoxyphthalimides with amino acid esters or amino acids to provide δ-C(sp3)-H alkylated alcohols (31 examples, up to 92% yield) with additive BNDHP or α-C(sp3)-H alkylated alcohols (18 examples, up to 86% yield) with additive DABCO in a highly regioselective fashion.