Radical-polar Crossover Mechanism Research Articles

Visible-Light-Mediated Vicinal Dihalogenation of Unsaturated C-C Bonds Using Dual-Functional Group Transfer Reagents.

The growing demand for chemical production continues to drive the development of sustainable and efficient methods for introducing molecular complexity. In this context, the exploration of unconventional functional group transfer reagents (FGTRs) has led to significant advancements in practical and atom-efficient synthetic protocols. Aiming to advance the field of valuable organic synthesis, herein we report the successful development of carbon-based, bench-stable, modular, and inexpensive reagents implemented in dual halogen transfer to unsaturated hydrocarbons via photocatalytic activation of reagents based on a radical-polar crossover mechanism. This method beneficially enables vicinal dichlorination, dibromination, and bromo-chlorination reactions of olefins, offering practical alternatives to the use of toxic binary halogens. Detailed mechanistic studies, combining experimental, spectroscopic, and theoretical investigations, revealed a distinctive photocatalytic single-electron transfer reduction of FGTR. This process triggers mesolytic carbon-halogen bond cleavage, followed by a radical 1,2-halide rearrangement, leading to the continuous generation of dihalogen species in the reaction medium. The wide applicability of the developed protocol is demonstrated through an extensive scope of unsaturated molecules, including additional operations on strain-release dihalogenation.

Amine-Ligated Boryl Radical Enabled Hydrofunctionalization of Styrenes via Halogen-Atom Transfer of Alkyl and Aryl Bromides

AbstractHerein, we demonstrate an amine-ligated boryl radical mediated halogen-atom transfer (XAT) strategy with alkyl and aryl bromides to construct C(sp 3)–C(sp 3) and C(sp 3)–C(sp 2) bonds, respectively. The first step involves the photocatalytic and decarboxylative generation of amine-ligated boryl radicals from a carboxylic acid containing amine-ligated borane. The resulting amine-ligated boryl radical undergoes XAT with organobromides to generate carbon-centered radicals, which react with styrenes to afford hydrofunctionalized products. Furthermore, this photocatalytic XAT strategy can be applied to synthesize gem-difluorostyrene and 1,1-disubstituted cyclopropane through a radical-polar crossover mechanism.

Synthesis of silacycles via metal hydrogen atom transfer and radical-polar crossover mechanism

In this study, we have developed an efficient method for silacycle synthesis using metal hydride hydrogen atom transfer (MHAT) and radical-polar crossover (RPC) mechanism. Allylic silanols were synthesized via one-step condensation and then cyclized under mild conditions using N-fluoropyridinium tetrafluoroborate (Me3NFPY·BF4) as the oxidant under cobalt catalysis. This approach yielded five-, six-, and seven-membered silacycles with high selectivity, with the six-membered rings being the favored products. Density functional theory (DFT) calculations provided valuable insights into the reaction mechanisms and highlighted the role of ring strain in determining product selectivity. This study demonstrated the effectiveness of combining MHAT/RPC methodologies with silicon tethering, thus offering a robust platform for expanding the use of silicon-based strategies in synthetic chemistry.

Chromium Catalyzed Asymmetric Reformatsky Reaction.

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral β-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, we achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism. Preliminary mechanistic insights, supported by DFT calculations, identify the nucleophilic aldehyde addition as the key stereo-determining step. This approach not only overcomes the limitations of existing Reformatsky reactions but also provides a versatile strategy for accessing complex chiral molecules.

Intermolecular Aza-Wacker Coupling of Alkenes with Azoles by Photo-Aerobic Selenium-π-Acid Multicatalysis.

Herein, the intermolecular, photoaerobic aza-Wacker coupling of azoles with alkenes by means of dual and ternary selenium-π-acid multicatalysis is presented. The title method permits an expedited avenue toward a broad scope of N-allylated azoles and representative azinones under mild conditions with broad functional group tolerance, as is showcased in more than 60 examples including late-stage drug derivatizations. From a regiochemical perspective, the protocol is complementary to cognate photoredox catalytic olefin aminations, as they typically proceed through either allylic hydrogen atom abstraction or single electron oxidation of the alkene substrate. These methods predominantly result in C-N bond formations at the allylic periphery of the alkene or the less substituted position of the former π-bond (i.e., anti-Markovnikov selectivity). The current process, however, operates through a radical-polar crossover mechanism, which solely affects the selenium catalyst, thus allowing the alkene to be converted strictly through an ionic two-electron transfer regime under Markovnikov control. In addition, it is shown that the corresponding N-vinyl azoles can also be accessed by sequential or one-pot treatment of the allylic azoles with base, thus emphasizing the exquisite utility of this method.

Electroreductive Arylcarboxylation of Styrenes with CO2 and Aryl Halides via a Radical-Polar Crossover Mechanism.

2,3-Diaryl propanoic acids are important structures as a result of their widespread presence in numerous bioactive compounds. However, the limitations of existing synthetic techniques include the requirement for costly catalysts and limited substrates. Here, we developed a novel electroreductive arylcarboxylation of alkenes with CO2 based on a radical-polar crossover pathway assisted by easily accessible dimethyl terephthalate as a reductive mediator. This method will provide an efficient strategy for the synthesis of 2,3-diarylpropanoic acids.

Selective 1,4-syn-Addition to Cyclic 1,3-Dienes via Hybrid Palladium Catalysis.

1,4-cis-Disubstituted cyclic compounds play a pivotal role in pharmaceutical development, offering enhanced potency and bioavailability. However, their stereoselective and modular synthesis remains a long-standing challenge. Here, we report an innovative strategy for accessing these structures via mild conditions employing cyclic 1,3-dienes/alkyl(aryl)halides and amines. This procedure exhibits a wide substrate scope that tolerates various functional groups. The utility of this method is demonstrated in the efficient synthesis of a TRPV6 inhibitor, CFTR modulator, and other bioactive molecules. Combined experimental and computational studies suggest that the hybrid palladium-catalyzed radical-polar crossover mechanism is crucial for achieving exceptional 1,4-syn-addition selectivity (dr > 20:1).

Photoinduced Decarboxylative Radical Phosphinylation.

Reported herein is an unprecedented protocol for C(sp3 )-phosphinylation. With 1 mol % 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.

Electroreductive Radical Addition-Polar Cyclization Cascade to Access Cycloalkanes.

Compared with flat aromatic scaffolds, three-dimensional aliphatic ring systems feature high structural complexity and topological diversity and, thus, have received increasing attention in drug discovery. Herein, we describe a mild and general electrochemical method for the modular synthesis of structurally distinct cyclic compounds, including monocyclic alkanes, benzo-fused ring systems, and spirocycles, from readily available alkenes and alkyl halides via a radical-polar crossover mechanism.

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.

Late-Stage Isotopic Exchange of Primary Amines.

Stable isotopes such as 2H, 13C, and 15N have important applications in chemistry and drug discovery. Late-stage incorporation of uncommon isotopes via isotopic exchange allows for the direct conversion of complex molecules into their valuable isotopologues without requiring a de novo synthesis. While synthetic methods exist for the conversion of hydrogen and carbon atoms into their less abundant isotopes, a corresponding method for accessing 15N-primary amines from their naturally occurring 14N-analogues has not yet been disclosed. We report an approach to access 15N-labeled primary amines via late-stage isotopic exchange using a simple benzophenone imine as the 15N source. By activating α-1 and α-2° amines to Katritzky pyridinium salts and α-3° amines to redox-active imines, we can engage primary alkyl amines in a deaminative amination. The redox-active imines proceed via a radical-polar crossover mechanism, whereas the Katritzky salts are engaged in copper catalysis via an electron donor-acceptor complex. The method is general for a variety of amines, including multiple drug compounds, and results in complete and selective isotopic labeling.

An Electrochemical Strategy to Synthesize Disilanes and Oligosilanes from Chlorosilanes.

Silanes are important compounds in industrial and synthetic chemistry. Here, we develop a general approach for the synthesis of disilanes as well as linear and cyclic oligosilanes via the reductive activation of readily available chlorosilanes. The efficient and selective generation of silyl anion intermediates, which are arduous to achieve by other means, allows for the synthesis of various novel oligosilanes by heterocoupling. In particular, this work presents a modular synthesis for a variety of functionalized cyclosilanes, which may give rise to materials with distinct properties from linear silanes but remain challenging synthetic targets. In comparison to the traditional Wurtz coupling, our method features milder conditions and improved chemoselectivity, broadening the functional groups that are compatible in oligosilane preparation. Computational studies support a mechanism whereby differential activation of sterically and electronically distinct chlorosilanes are achieved in an electrochemically driven radical-polar crossover mechanism.

Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis.

Interest in deuterated active pharmaceutical ingredients (APIs) is increasing as deuteration holds promise for kinetic isotope effect (KIE) regulated fine-tuning of API performance. Moreover, deuterium isotope labeling is frequently carried out to study organic and bioorganic reaction mechanisms and to facilitate complex target synthesis. As such, methods for highly selective deuteration of organic molecules are highly desirable. Herein, we present an electrochemical method for the selective deuterodehalogenation of benzylic halides via a radical-polar crossover mechanism, using inexpensive deuterium oxide (D2 O) as the deuterium source. We demonstrate broad functional group compatibility across a range of aryl and heteroaryl benzylic halides. Furthermore, we uncover a sequential paired electrolysis regime, which permits switching between net reductive and overall redox-neutral reactions of sulfur-containing substrates simply by changing the identity of the sacrificial reductant employed.

Light-driven Radical-polar Crossover Catalysis Enabling Decarboxylative Fluorination of Redox Active Esters

This manuscript represents an organophotoredox-catalyzed decarboxylative fluorination of alkyl redox active esters with triethylamine trihydrofluoride. The reaction proceeds through a radical-polar crossover mechanism to generate a carbocation equivalent under non-acidic and transition metal free conditions. This protocol allows delivery of various tertiary alkyl and benzyl fluorides in an environmentally benign manner.

Photocatalytic Hydroalkylation of Aryl-Alkenes.

Here, we present a visible light-catalyzed hydroalkylation of aryl-alkenes affording C–C bonds using aryl-alkenes and alkyl iodides. We demonstrate the formation of various hydroalkylation products in excellent yields, with primary, secondary, and tertiary alkyl iodides being tolerated in the reaction. Mechanistic experiments reveal a pathway consisting of halogen atom transfer followed by a radical-polar crossover mechanism delivering the desired hydroalkylation products.

(Invited, Digital Presentation) Carbocation Generation By Organophotoredox Catalyzed Radical-Polar Crossover

Carbocation is one of the most common and reactive chemical species in organic chemistry, which has been broadly utilized for alkylation of various nucleophiles and rearrangement reaction. Conventionally, carbocation is generated from alkyl electrophiles or alkenes in the presence of strong Lewis acids and Brønsted acids, which narrows usable nucleophiles and coexistable functional groups. The requirement of strong acidic conditions would originate from the difficulty of two electron abstraction from carbocation precursors at once. Recently, to solve this problem, activation of substrates via single electron transfer was presented. Knowles and co-workers reported the carbocation generation from the mesolytic cleavage of alkoxyamine-derived radical cation, that is generated by a visible-light mediated photoredox catalysis. Although this protocol does not require the strong acids, the low accessibility of alkoxyamine substrates restricted the introducible alkyl groups. In this presentation, a new approach to catalytic generation of carbocation by a visible light-mediated organophotoredox catalysis is provided. We were interested in an organocatalysis merging with the radical-polar crossover (RPC) mechanism as an approach to non-acidic and catalytic generation of carbocations. Details of our scenario for the RPC are described in Figure. We selected N-Ph-benzo[b]phenothiazine (PTH) as a suitable organophotoredox RPC catalyst due to three features: excitation in the UV-visible area, high reduction potential and potential persistent properties of the corresponding radical cation. Aliphatic carboxylic acid-derived redox active esters were chosen as carbocation precursors due to the availability and the well-studied reactivity. The catalytic system is initiated by single electron transfer from a phenothiazine catalyst to a redox active ester under irradiation of a blue light-emitting diode (LED) to generate the radical cation form of the catalyst (A) and an alkyl radical (B). Then, recombination process between A and B affords an alkylsulfonium intermediate C, which acts as a carbocation equivalent. The carbocation equivalent was applied to alkylation of various nucleophiles and the semipinacol rearrangement reactions. First, the catalytic system was exploited to alkylation of various nucleophiles. After screening of reaction conditions, the combination of N-phenyl benzo[b]phenothiazine and lithium tetrafluoroborate was found to be effective in this alkylation protocol. Aliphatic alcohol, water, amide, thiol, fluoride anion and allylsilane could participate in this organophotoredox catalysis as nucleophiles. This protocol allowed to use secondary or tertiary aliphatic carboxylic acid-derived redox active esters as alkylating reagents, providing sterically hindered molecules with functional group compatibility.Subsequently, we applied the photochemically-generated carbocation equivalent to the semipinacol rearrangement reaction. Although the semipinacol rearrangement reaction has been utilized in key steps for construction of complex carbon frameworks in total synthesis of natural products, the conventional methods require specific design of the substrates and harsh reaction conditions to control the reactivity and regioselectivity. Since our method has the advantage of using carboxylic acids as the carbocation precursors, the substrates are easily synthesized from the corresponding enolate species derived from aliphatic carboxylic acids and carbonyl compounds. Then, we found the b-hydroxy redox active ester derivatives underwent the decarboxylative semipinacol rearrangement reaction, affording the complex carbonyl compounds. For example, the reaction with substrate prepared from aromatic aldehyde and secondary aliphatic carboxylic acid proceeded to give the aldehyde bearing an a-quaternary carbon center through migration of the aromatic ring. The reactions with cyclic ketone-derived substrates also occurred to furnish the ring expansion products. Figure 1

Isothiourea-catalysed enantioselective radical conjugate addition under batch and flow conditions.

The photocatalytic generation of α-amino radicals is combined with chiral isothiourea derived α,β-unsaturated acyl ammonium intermediates. The reaction proceeds VIA a [3+2] radical-polar crossover mechanism to generate γ-lactams in good yields and enantioselectivities. The enantioselective radical conjugate addition was carried out under batch and flow conditions.

The Direct Decarboxylative N-Alkylation of Azoles, Sulfonamides, Ureas, and Carbamates with Carboxylic Acids via Photoredox Catalysis

Herein, we describe a method for the direct decarboxylative C-N coupling of carboxylic acids with a range of nitrogen nucleophiles. This platform employs visible-light-mediated photoredox catalysis and an iodine(III) reagent to generate carbocation intermediates directly from aliphatic carboxylic acids via a radical-polar crossover mechanism. A variety of C-N bond-containing products are constructed from a diverse array of nitrogen heterocycles, including pyrazoles, imidazoles, indazoles, and purine bases. Furthermore, sulfonamides, ureas, and carbamates can also be utilized as the nucleophile to generate a selection of N-alkylated products. Notably, a two-step approach to construct free amines directly from carboxylic acids is accomplished using Cbz-protected amine as the nucleophile.

Electrochemistry enabled selective vicinal fluorosulfenylation and fluorosulfoxidation of alkenes

Both sulfur and fluorine play important roles in organic synthesis, the life science, and materials science. The direct incorporation of these elements into organic scaffolds with precise control of the oxidation states of sulfur moieties is of great significance. Herein, we report the highly selective electrochemical vicinal fluorosulfenylation and fluorosulfoxidation reactions of alkenes, which were enabled by the unique ability of electrochemistry to dial in the potentials on demand. Preliminary mechanistic investigations revealed that the fluorosulfenylation reaction proceeded through a radical-polar crossover mechanism involving a key episulfonium ion intermediate. Subsequent electrochemical oxidation of fluorosulfides to fluorosulfoxides were readily achieved under a higher applied potential with the adventitious H2O in the reaction mixture.

Total Synthesis of Talatisamine: Exploration of Convergent Synthetic Strategies

Abstract Talatisamine (1) is a highly oxygenated C19-diterpenoid alkaloid with K+ channel inhibitory, antiarrhythmic, and neuroprotective activities. Its intricately fused 6/7/5/6/6/5-membered hexacyclic structure (ABCDEF-ring) possesses one nitrogen functionality, five oxygen functionalities, and 12 contiguously aligned stereocenters. This account describes the development of convergent strategies to efficiently assemble this synthetically challenging natural product. First, we explored two radical-based strategies. Treatment of the AE-ring with Et3B and O2 generated a highly reactive C11-bridgehead radical, which sequentially added to the C-ring and the aldehyde via a radical-polar crossover mechanism to afford ACE-ring substructure 6 in a single step. Alternatively, after coupling of the AE-ring and C-ring, the C11-bridgehead radical was utilized to cyclize the central 7-membered B-ring. The 6-membered D-ring was then forged by selenium-induced 6-endo cyclization to furnish ABCDE-ring 3. Second, we pursued a skeletal rearrangement strategy, which culminated in the total synthesis of 1. The D-ring was coupled with the AE-ring as the aromatic ring. Oxidative dearomatization, followed by Diels-Alder reaction, led to the 6/6-membered ring system, which was transformed into the 7/5-membered BC-ring through a stereospecific Wagner-Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza-Prins cyclization to form the remaining 5-membered F-ring, thereby completing the chemical construction of 1.