Radical-polar Crossover Reaction Research Articles

Et3Al/Light-Promoted Radical-Polar Crossover Reactions of α-Alkoxyacyl Tellurides.

Here, we report new radical-polar crossover reactions of α-alkoxy carbon radicals for constructing highly oxygenated molecules with contiguous stereocenters. The method employs a 370 nm UV light-emitting diode (LED) for the photoexcitation of α-alkoxyacyl telluride, and Et3Al as the radical initiator and terminator. First, Et3Al and UV LED promoted radical coupling between the α-alkoxyacyl telluride and cyclopentenone via C-Te bond homolysis, CO expulsion, and C-C bond formation. Second, Et3Al converted the radical species to the corresponding aluminum enolate. Third, the second C-C bond formation occurred via a polar mechanism: intermolecularly with aldehydes/ketones and intramolecularly with epoxide, producing aldol and SN2 adducts, respectively. The present coupling reactions increase the molecular complexity in a single step by stereoselective formation of the two hindered C-C bonds. The devised method is expected to be useful for the expeditious assembly of densely oxygenated natural products.

Radical Fluorosulfonamidation: A Facile Access to Sulfamoyl Fluorides.

Recently, the introduction of fluorosulfonyl (-SO2F) groups have attracted considerable research interests, as this moiety could often afford enhanced activities and new functions in the context of chemical biology and drug discovery. Herein, we report the design and synthesis of 1-fluorosulfamoyl-pyridinium (FSAP) salts, which could serve as an effective photoredox-active precursor to fluorosulfamoyl radicals and enable the direct radical C-H fluorosulfonamidation of a variety of (hetero)arenes. This method features mild conditions, visible light, broad substrate scope, good group tolerance, etc., and a metal-free protocol is also viable by using organic photocatalysts. Further, FSAP can also be applied to the radical functionalization of alkenes via 1,2-difunctionalization, radical distal migration, tandem radical-polar crossover reactions, etc. In addition, a formal C-H methylamination of (hetero)arenes by combining this radical C-H fluorosulfonamidation with subsequent hydrolysis as well as product derivatization are also demonstrated.

Polarity-Matched Initiation of Radical-Polar Crossover Reactions for the Synthesis of C-Allyl Glycosides with gem-Difluoroalkene Groups.

Herein, we disclose a general method for the assembly of C-allyl glycosides containing gem-difluoroalkene groups via a radical-polar crossover strategy. Central to the success of this process is the polarity matching between the benzenesulfinate radical and the glycosyl donor, which facilitates the initiation of the glycosyl radical and the subsequent formation of gem-difluoroalkene sugar derivatives. This method demonstrated good compatibility with various glycosyl donors and functional groups. Furthermore, we showcase the utility of this method in modifying amino acids, potentially paving the way for analogous modifications to peptides.

Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Radical-polar crossover reaction of glycine derivatives.

Here we report a visible-light facilitated radical addition strategy for the preparation of various natural or unnatural α-amino acids from readily available glycine derivatives and alkenes. A key aspect in achieving this side carbon chain introduction reaction, while circumventing the well-documented cyclization pathway, was the employment of a radical-polar crossover strategy under redox neutral conditions.

Simulating Electron Transfer Reactions in Solution: Radical-Polar Crossover.

Single-electron transfer (SET) promotes a wide variety of interesting chemical transformations, but modeling of SET requires a careful treatment of electronic and solvent effects to give meaningful insight. Therefore, a combined constrained density functional theory and molecular mechanics (CDFT/MM) tool is introduced specifically for SET-initiated reactions. Mechanisms for two radical-polar crossover reactions involving the organic electron donors tetrakis(dimethylamino)ethylene (TDAE) and tetrathiafulvalene (TTF) were studied with the new tool. An unexpected tertiary radical intermediate within the TDAE system was identified, relationships between kinetics and substitution in the TTF system were explained, and the impact of the solvent environments on the TDAE and TTF reactions were examined. The results highlight the need for including solvent dynamics when quantifying SET kinetics and thermodynamics, as a free energy difference of >20 kcal/mol was observed. Overall, the new method informs mechanistic analysis of SET-initiated reactions and therefore is envisioned to be useful for studying reactions in the condensed phase.

Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions

Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2’-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study.

Visible-Light-Induced Synthesis of Branched Ethers via Multicomponent Reactions.

The Spin-Center Shift (SCS) elimination is a specific way for the generation of radicals with relevance in synthetic and biochemical pathways. The combination of SCS-mediated radical chemistry and atom-transfer radical addition (ATRA) offers new directions in diversity-oriented chemical synthesis. Herein, we report a photoredox three-component reaction of α-acyloxy-N-heterocycles as radical precursors, styrene derivatives as radical trapping agents, and alcohols as nucleophilic quenchers. The novel radical-polar crossover reaction provides access to a diverse set of branched ethers possessing high structural complexity. The utility of the transformation was also demonstrated by the synthesis of a complex drug derivative and it was easily scalable to the multigram level. The scope and limitations were also explored and a plausible mechanism was proposed.

FSO2 Radical-Initiated Tandem Addition Reaction of Two Different Olefins: A Facile Access to Multifunctional Aliphatic Sulfonyl Fluorides.

Multicomponent reactions represent a powerful method for building complex molecules from structurally simple starting materials. Herein, we report a novel three-component radical-polar crossover reaction involving a tandem addition reaction of two different olefins, which is initiated by the selective addition of fluorosulfonyl radicals to alkyl alkenes. This tandem process provides facile and effective access to multiple functionalized aliphatic sulfonyl fluoride molecules. Further transformation of the products is also demonstrated.

Catalytic Photoinduced Intramolecular Decarboxylative and Desulfonylative sp3Allylation Enabled by Sulfinate Salts.

Herein, we describe a catalytic intramolecular decarboxylative/desulfonylative sp3 allylation triggered by sulfinate salts under light irradiation. The reaction is likely enabled by a non-classical, radical-polar crossover reaction, allowing to rapidly and reliably access valuable allyl architectures from readily accessible precursors. The protocol is characterized by its operational simplicity and scalability, employing abundant, commercially available catalysts.

Photoinduced Palladium-Catalyzed 1,2-Difunctionalization of Electron-Rich Olefins via a Reductive Radical-Polar Crossover Reaction

Palladium-catalyzed cross-coupling reactions belong to the most important transformations for the construction of C–C or C-heteroatom bonds. More recently, the photochemical activation of palladium complexes emerged as a key strategy to leverage palladium catalysis at room temperature beyond the scope of conventional cross-coupling chemistry. Herein, we report on the photoinduced palladium-catalyzed 1,2-difunctionalization reaction of electron-rich olefins. Mechanistic experiments and computational studies reveal that this reaction proceeds via the addition of an alkyl radical, followed by the oxidation of a radical intermediate to access carbocation intermediates, which are inaccessible via classic thermal reaction conditions. The carbocation can then be applied to a variety of secondary C–C or C–N bond-forming reactions. This strategy now allows a general approach toward densely functionalized unsymmetric 1,1-bis(heterocyclyl)alkanes.

Photocatalyzed Dowd-Beckwith radical-polar crossover reaction for the synthesis of medium-sized carbocyclic compounds.

The Dowd-Beckwith reaction, a ring-expansion of carbonyl compounds via alkoxy radicals, is a powerful approach for synthesizing medium to large-sized carbocyclic scaffolds, which takes advantage of existing ring structures and avoids entropic and enthalpic factors that arise from the end-to-end cyclization strategies. However, the Dowd-Beckwith ring-expansion followed by H-atom abstraction is still the dominating pathway, which hampers its synthetic applications, and there currently exist no reports on the functionalization of ring-expanded radicals using non-carbon based nucleophilic reagents. Herein, we report a redox-neutral decarboxylative Dowd-Beckwith/radical-polar crossover (RPC) sequence that delivers functionalized medium-sized carbocyclic compounds with broad functional group tolerance. The reaction allows one-carbon ring-expansion of 4-, 5-, 6-, 7-, and 8-membered ring substrates and can also be applied to three-carbon chain incorporation, enabling remote functionalization in medium-sized rings.

An Olefinic 1,2‐α‐Boryl Migration Enables 1,2‐Bis(boronic esters) via Radical‐Polar Crossover Reaction

Comprehensive SummaryA radical‐induced 1,2‐α‐boryl migration through radical polar crossover reactions has been described. In this work, in situ formed vinyldiboron “ate” complexes from alkenyl Grignard reagent and diborylalkanes react with commercial radical precursors under light initiation. This three‐component process enables diborylation of alkene. This protocol features high atom economy, a broad substrate scope as well as good functional group toleration with mild conditions.

Application of the stabilization effect of a silyl group in radical-polar crossover reactions enabled by photoredox-neutral catalysis

Taking advantage of the stabilization effect of a silyl group, with a bulky but positive nature, a range of less investigated organosilanes could be generally accessed via photoredox-catalysed radical-polar crossover reactions.

Divergent Ritter-type amination via photoredox catalytic four-component radical-polar crossover reactions

Divergent Ritter-type amination via photoredox catalytic four-component radical-polar crossover reactions with high atom-, step- and redox economy.

Xiaohua Liu.

"In a spare hour, I walk my dog … My favorite time of day is when I enjoy my walks in the garden…" Find out more about Xiaohua Liu in her Author Profile.

Enantioselective Radical-Polar Crossover Reactions of Indanonecarboxamides with Alkenes.

Highly efficient asymmetric intermolecular radical-polar crossover reactions were realized by combining a chiral N,N'-dioxide/NiII complex catalyst with Ag2 O under mild reaction conditions. Various terminal alkenes and indanonecarboxamides/esters underwent radical addition/cyclization reactions to afford spiro-iminolactones and spirolactones with good to excellent yields (up to 99 %) and enantioselectivities (up to 97 % ee). Furthermore, a range of different radical-mediated oxidation/elimination or epoxide ring-opening products were obtained under mild reaction conditions. The Lewis acid catalysts exhibited excellent performance and precluded the strong background reaction.

Coupling Reaction between Aldehydes and Non-Activated Hydrocarbons via the Reductive Radical-Polar Crossover Pathway.

Herein, we describe the generation of an organochromium-type carbanion species from a non-activated C-H bond and its nucleophilic addition to aldehydes. The catalytic carbanion generation occurred through formal deprotonation of a non-activated C-H bond under mild conditions and did not need the prefunctionalization or anion stabilizing group. Carbon radical intermediates generated by decatungstate photocatalyst-mediated hydrogen abstraction were captured by a chromium salt with the reductive radical-polar crossover reaction to produce organochromium carbanions.

Reductive radical-initiated 1,2-C migration assisted by an azidyl group.

We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group. The reaction tolerates diverse migrating groups, such as alkyl, alkenyl, and aryl groups, allowing access to n+1 ring expansion of small to large rings. The possibility of directly using propargyl alcohols in one-pot is also described. Mechanistic studies indicated that an azidyl group is a good leaving group and provides a driving force for the 1,2-C migration.

Catalytic Asymmetric Radical-Polar Crossover Hydroalkoxylation.

Asymmetric intramolecular hydrofunctionalization of tertiary allylic alcohols is described. This metal hydride-mediated catalytic radical-polar crossover reaction delivers corresponding epoxides in good to high enantioselectivity and constitutes the first example of asymmetric hydrogen atom transfer-initiated process. A series of modified cobalt salen complexes has proven optimal for achieving good efficiency and asymmetric induction. Experimental data suggest that cationic cobalt complexes may be involved in the enantiodetermining step, where cation-π interactions in the catalyst contribute to the asymmetric induction.