Group Transfer Radical Research Articles

Preparation of Degradable and Sequence-Controlled Aliphatic Polysulfones by Group Transfer Radical Polymerization.

The incorporation of sulfur atoms into polymer backbones for the synthesis of sulfur-containing polymers, such as aliphatic polysulfones, not only enhances degradability but also imparts many distinctive properties to these materials. Traditional synthetic methods encounter substantial challenges in achieving sequence-controlled aliphatic polysulfones with high molecular weights (MW), which significantly limits their applications. We report a novel approach for synthesizing aliphatic polysulfones using the strategy of sulfonyl radical-mediated group transfer radical polymerization (GTRP). This protocol employs a practical SO2-free pathway and produces a series of ABC sequence-defined high-MW polymers (up to 199 kg/mol). The resultant aliphatic polysulfone exhibits remarkable full-degradability at ambient temperature under strong basic conditions, and offers optical properties-including refractive index and Abbe number-comparable to those of commercially utilized polycarbonate. Additionally, density functional theory (DFT) calculations have been performed to corroborate the non-desulfonylative Smiles rearrangement mechanism implicated in the GTRP process.

Preparation of Degradable and Sequence‐Controlled Aliphatic Polysulfones by Group Transfer Radical Polymerization

The incorporation of sulfur atoms into polymer backbones for the synthesis of sulfur‐containing polymers, such as aliphatic polysulfones, not only enhances degradability but also imparts many distinctive properties to these materials. Traditional synthetic methods encounter substantial challenges in achieving sequence‐controlled aliphatic polysulfones with high molecular weights (MW), which significantly limits their applications. We report a novel approach for synthesizing aliphatic polysulfones using the strategy of sulfonyl radical‐mediated group transfer radical polymerization (GTRP). This protocol employs a practical SO2‐free pathway and produces a series of ABC sequence‐defined high‐MW polymers (up to 199 kg/mol). The resultant aliphatic polysulfone exhibits remarkable full‐degradability at ambient temperature under strong basic conditions, and offers optical properties—including refractive index and Abbe number—comparable to those of commercially utilized polycarbonate. Additionally, density functional theory (DFT) calculations have been performed to corroborate the non‐desulfonylative Smiles rearrangement mechanism implicated in the GTRP process.

Group transfer radical polymerization for the preparation of carbon-chain poly(α-olefins).

Radical polymerization is a powerful technique for producing a variety of polymeric materials. However, the chain transfer reaction impedes the formation of polymers from many common α-olefins such as propene and 1-butene using this method. Consequently, poly(α-olefins) are predominantly produced via coordination polymerization. To address this limitation, we have devised a strategy involving group transfer radical polymerization (GTRP) to facilitate the radical homopolymerization to access carbon-chain poly(α-olefins). This approach enables the precise construction of a diverse array of carbon-chain poly(α-olefins) with high molecular weights. Furthermore, by using nonconventional monomers, we extend the applicability of this technique to the copolymerization of α-olefins with acrylonitrile, paving the way for the synthesis of copolymers with different monomers. To investigate the properties of the polymers obtained by this method, one of the poly(α-olefins) is studied as an interphase layer material in anode-free Li metal batteries, and the results indicate the potential of the polymer in energy storage applications.

Stereoconvergent Approach to the Enantioselective Construction of α-Quaternary Alcohols by Radical Epoxide Allylation.

We describe a highly stereoconvergent radical epoxide allylation towards diastereomerically and enantiomerically enriched α-quaternary alcohols in two steps from olefins. Our approach combines the stereospecifity and enantioselectivity of the Shi epoxidation with the unprecedented Ti(III)-promoted intramolecular radical group transfer allylation of epoxides. A directional isomerization step via configurationally labile radical intermediates enables the selective preparation of all-carbon quaternary stereocenters in a unique fashion.

Stereoconvergent Approach to the Enantioselective Construction of α‐Quaternary Alcohols by Radical Epoxide Allylation

AbstractWe describe a highly stereoconvergent radical epoxide allylation towards diastereomerically and enantiomerically enriched α‐quaternary alcohols in two steps from olefins. Our approach combines the stereospecifity and enantioselectivity of the Shi epoxidation with the unprecedented Ti(III)‐promoted intramolecular radical group transfer allylation of epoxides. A directional isomerization step via configurationally labile radical intermediates enables the selective preparation of all‐carbon quaternary stereocenters in a unique fashion.

Alkoxy Radical Generation Mediated by Sulfoxide Cation Radicals for Alcohol-Directed Aliphatic C-H Functionalization.

The C-H functionalization of remote, unactivated C-H bonds offers a unique method of garnering structural complexity in a synthesis. The use of directing groups has provided a means of enacting C-H functionalization on these difficult-to-access bonds; however, the installation and removal of directing groups on a substrate require additional synthetic manipulations, detracting from both the efficiency and economic feasibility of a transformation. The use of alkoxy radicals as transient directing groups for the functionalization of remote C-H bonds allows access to the synthesis of complex molecules without the need for additional functionality. Herein, we report a method for alkoxy radical formation from unactivated alcohols and reactivity mediated by photoredox-generated sulfoxide cation radicals. This protocol leverages the unique reactivity of alkoxy radicals to implement different reaction manifolds: 1,5-hydrogen atom transfer (HAT), cyclization, and β-scission. Furthermore, it was discovered that this methodology could be utilized to impose radical group transfer reactions via the β-scission pathway. Stern-Volmer analysis supports the formation of an alkoxy radical via the intermediacy of a sulfurane radical rather than a proton-coupled electron transfer (PCET) mechanism.

Expanding the Scope of Group Transfer Radical Reaction: Toward the Synthesis of Fluorinated Nucleoside Analogues Incorporating Difluorophosphonylated Allylic Ether Moieties.

Scope and limitations of the group transfer radical reaction of diisopropyl iododifluoromethylphosphonate onto carbohydrates and nucleosides are described. This key step allowed us to explore the synthesis of new fluorinated nucleoside analogues containing a difluorophosphonylated allylic ether moiety onto the 2'-position, in purine and pyrimidine series (B = A, C, G, T, U). Indeed, two unprecedented chemical approaches involving a late introduction of either the nucleobase or the fluorinated moiety are discussed.

Visible-Light-Driven Unsymmetric gem-Difunctionalization of Vinyl Azides with Thiosulfonates or Selenosulfonates.

Thiosulfonylation and selenosulfonylation of vinyl azides with thiosulfonates and selenosulfonates were achieved using Cu(dap)2Cl as a photosensitizer under visible-light irradiation. This reaction is the application of a vinyl azide substrate in a group transfer radical addition (GTRA) reaction, through β-difunctionalization, to obtain a variety of unsymmetric difunctionalized N-unprotected enamines.

Ketone-Derived Pro-aromatic Reagents for Radical Group Transfer Reactions and Deconstructive Functionalizations

AbstractThe recent prominence of ketones as handles for sp3-rich radicals has expanded the paradigm of synthetic utility of ketones, putting the ubiquitous functional group once again into the spotlight in recent years. One emerging strategy arose through ketone-derived pro-aromatic reagents in the form of dihydrobenzothiazoline (BTZ), dihydroquinazolinone (DHQZ), dihydropyrazole (DHP), and dihydro-1,2,4-triazole (DHT) as key intermediates for aromaticity-promoted C–C bond homolytic fission. The formed sp3-radicals could then participate in various radical functionalizations, including alkylations, arylations, olefination, alkynylation, silylations, amination, thiolation, and deuteration, among others, either in photocatalytic, thermal, or oxidative conditions. In this review, we highlight the implications and recent advances in using these pro-aromatic reagents in radical group transfer reactions and deconstructive functionalization.1 Introduction2 Aromatization-Driven C–C Bond Scission of Ketones3 Photochemical Reactions of Ketone-Derived Pro-aromatic Reagents4 Non-photochemical Reactions of Ketone-Derived Pro-aromatic Reagents5 Conclusion and Future Outlook

Radical Group Transfer of Vinyl and Alkynyl Silanes Driven by Photoredox Catalysis.

Radical group transfer is a powerful tool for the formation of C-C bonds. These processes typically involve radical addition to C-C π bonds, followed by fragmentation of the resulting cyclic intermediate. Despite the advantageous lability of organosilanes in this context, silicon-tethered radical acceptor groups have remained underexplored in radical group transfer reactions. We report a general photoredox-catalyzed protocol for the radical group transfer of vinyl and alkynyl silanes onto sp3 carbons, using activated and unactivated iodides as radical precursors. Our method displays high diastereoselectivity and excellent functional group tolerance, and enables direct formation of group transfer products by in situ ring opening. Mechanistic investigations revealed that the reaction proceeds via an unusual dual catalytic cycle, resulting in an overall redox-neutral process.

Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of tertiary electrophiles with alkynes.

In contrast with the well-established enantioconvergent radical C(sp3)-C cross-coupling of racemic secondary alkyl electrophiles, the corresponding coupling of tertiary electrophiles to forge all-carbon quaternary stereocentres remains underexplored. The major challenge arises from the steric hindrance and the difficult enantio-differentiation of three distinct carbon substituents of prochiral tertiary radicals. Here we demonstrate a general copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of diverse racemic tertiary alkyl halides with terminal alkynes (87 examples). Key to the success is the rational design of chiral anionic N,N,N-ligands tailor-made for the computationally predicted outer-sphere radical group transfer pathway. This protocol provides a practical platform for the construction of chiral C(sp3)-C(sp/sp2/sp3) bonds, allowing for expedient access to an array of synthetically challenging quaternary carbon building blocks of interest in organic synthesis and related areas.

Copper-catalyzed enantioselective synthesis of bridged bicyclic ketals from 1,1-disubstituted-4-methylene-1,6-hexanediols and related alkenols

Bicyclic ketals via copper-catalyzed enantioselective bis(cyclization) involving radical group transfer is disclosed.

Methyl Radical Initiated Kharasch and Related Reactions

AbstractAn improved procedure to run halogen atom and related chalcogen group transfer radical additions is reported. The procedure relies on the thermal decomposition of di‐tert‐butylhyponitrite (DTBHN), a safer alternative to the explosive diacetyl peroxide, to produce highly reactive methyl radicals that can initiate the chain process. This mode of initiation generates byproducts that are either gaseous (N2) or volatile (acetone and methyl halide) thereby facilitating greatly product purification by either flash column chromatography or distillation. In addition, remarkably simple and mild reaction conditions (refluxing EtOAc during 30 minutes under normal atmosphere) and a low excess of the radical precursor reagent (2 equivalents) make this protocol particularly attractive for preparative synthetic applications. This initiation procedure has been demonstrated with a broad scope since it works efficiently to add a range of electrophilic radicals generated from iodides, bromides, selenides and xanthates over a range of unactivated terminal alkenes. A diverse set of radical trap substrates exemplifies a broad functional group tolerance. Finally, di‐tert‐butyl peroxyoxalate (DTBPO) is also demonstrated as alternative source of tert‐butoxyl radicals to initiate these reactions under identical conditions which gives gaseous by‐products (CO2).magnified image

Intermolecular Aminoallylation of Alkenes Using Allyl‐Oxyphthalimide Derivatives: A Case Study in Radical Polarity Effects

A case study on the polarity effects of radical mediated intermolecular alkene aminoallylation is presented herein. This radical group transfer method pairs vinyl ethers with electronically deficient allyl‐oxyphthalimide derivatives to give difunctionalized products while illustrating the guiding effects of polarity on this radical reactivity.

Regioselective Radical Alkene Amination Strategies by Using Phosphite-Mediated Deoxygenation

Nitrogen-containing compounds are an essential motif in all disciplines of chemistry and the efficient synthesis of these frameworks is a highly sought-after goal. Presented here is a summary of recent efforts conducted by our group to develop radical-mediated amination strategies for the formal synthesis of primary amines from alkenes with exclusive anti-Markovnikov regioselectivity. We have found that N-hydroxyphthalimide is an effective reagent capable of supplying both the N and H atoms for alkene hydroamination in a group transfer radical addition-type mechanism. Furthermore, allyl-oxyphthalimide derivatives are similarly capable of radical group transfers and allow for the aminoallylation of an external alkene.

Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex.

We report the development of a new aminoxyl radical catalyst, CHAMPO, for the electrochemical diazidation of alkenes. Mediated by an anodically generated charge-transfer complex in the form of CHAMPO-N3, radical diazidation was achieved across a broad scope of alkenes without the need for a transition metal catalyst or a chemical oxidant. Mechanistic data support a dual catalytic role for the aminoxyl serving as both a single-electron oxidant and a radical group transfer agent.

Intermolecular Carboamination of Unactivated Alkenes.

Herein, we report the first example of group transfer radical addition of O-vinylhydroxylamine derivatives onto unactivated alkenes. By utilizing O-vinylhydroxylamine derivatives as both the N- and C-donors, this reaction enables intermolecular carboamination of unactivated alkenes in an atom economical fashion. As the process is initiated through N-radical addition followed by C-transfer, linear carboamination products are afforded. This differs from canonical radical carbofunctionalization of olefins, which typically favors branched product owing to initiation by C-radical addition.

Catalytic, metal-free sulfonylcyanation of alkenes via visible light organophotoredox catalysis.

The group transfer radical addition of olefins with tosyl cyanide has been accomplished via visible light-induced organophotoredox catalysis. A diverse array of olefins is amenable to this protocol, furnishing β-sulfonyl nitriles with excellent efficiency under metal-free and redox-neutral conditions. A closed catalytic cycle is operative in this transformation, providing complementary reactivity to the classic radical chain process.

Toluene as a novel carrier of xanthates—preparation, use and surrogate of S-tri- and di-chloromethyl xanthates

Toluene has been identified as a novel carrier of xanthates. Their corresponding fragmentative precursors proved to behave efficiently in radical group transfer reactions. As examples, unprecedented S-tri/di-chloromethyl xanthates could be prepared, isolated and further used in radical additions to olefins. Their precursors (de-aromatized toluene upon which is grafted, at one end, a tri/di-chloromethyl-group and, at the other end, a dithiocarbonyl group) can also be used directly in the transfer of both groups to olefins. The re-aromatizing loss of toluene by radical initiated fragmentation of the precursors brings thus new opportunities to the chemistry of xanthates, exemplified here in the intermolecular additions to olefins of new S-tri/di-chloromethyl xanthates.

Enantiospecific Synthesis and Cytotoxicity Evaluation of Ligudentatol: A Programmed Aromatization Approach to the 2,3,4‐Trisubstituted Phenolic Motif via Visible‐Light‐Mediated Group Transfer Radical Cyclization

A facile enantiospecific approach to (+)-ligudentatol (1) and (-)-ligudentatol (ent-1) is reported. The approach features the construction of a trisubstituted phenolic motif fused to a chiral aliphatic ring by a sequence of visible-light-mediated radical seleno transfer cyclization, bromination, concomitant selenoxide elimination-dehydrobromination, and demethoxycarbonylation, namely, a programmed aromatization. Biological evaluation of the enantiomers of ligudentatol obtained by the present route revealed for the first time their cytotoxicity towards various cancer cell lines.