Radical-polar Crossover Mechanism Research Articles

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.

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.

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.

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.

Radical Carbonyl Propargylation by Dual Catalysis.

Carbonyl propargylation has been established as a valuable tool in the realm of carbon-carbon bond forming reactions. The 1,3-enyne moiety has been recognized as an alternative pronucleophile in the above transformation through an ionic mechanism. Herein, we report for the first time, the radical carbonyl propargylation through dual chromium/photoredox catalysis. A library of valuable homopropargylic alcohols bearing all-carbon quaternary centers could be obtained by a catalytic radical three-component coupling of 1,3-enynes, aldehydes and suitable radical precursors (41 examples). This redox-neutral multi-component reaction occurs under very mild conditions and shows high functional group tolerance. Remarkably, bench-stable, non-toxic, and inexpensive CrCl3 could be employed as a chromium source. Preliminary mechanistic investigations suggest a radical-polar crossover mechanism, which offers a complementary and novel approach towards the preparation of valuable synthetic architectures from simple chemicals.

Electroreductive Carbofunctionalization of Alkenes with Alkyl Bromides via a Radical-Polar Crossover Mechanism.

Electrochemistry grants direct access to reactive intermediates (radicals and ions) in a controlled fashion toward selective organic transformations. This feature has been demonstrated in a variety of alkene functionalization reactions, most of which proceed via an anodic oxidation pathway. In this report, we further expand the scope of electrochemistry to the reductive functionalization of alkenes. In particular, the strategic choice of reagents and reaction conditions enabled a radical-polar crossover pathway wherein two distinct electrophiles can be added across an alkene in a highly chemo- and regioselective fashion. Specifically, we used this strategy in the intermolecular carboformylation, anti-Markovnikov hydroalkylation, and carbocarboxylation of alkenes-reactions with rare precedents in the literature-by means of the electroreductive generation of alkyl radical and carbanion intermediates. These reactions employ readily available starting materials (alkyl halides, alkenes, etc.) and simple, transition-metal-free conditions and display broad substrate scope and good tolerance of functional groups. A uniform protocol can be used to achieve all three transformations by simply altering the reaction medium. This development provides a new avenue for constructing Csp3-Csp3 bonds.

Photocatalytic Difunctionalization of Vinyl Ureas by Radical Addition Polar Truce-Smiles Rearrangement Cascades.

We report tandem alkyl-arylations and phosphonyl-arylations of vinyl ureas by way of a photocatalytic radical-polar crossover mechanism. Addition of photoredox-generated radicals to the alkene forms a new C-C or C-P bond and generates a product radical adjacent to the urea function. Reductive termination of the photocatalytic cycle generates an anion that undergoes a polar Truce-Smiles rearrangement, forming a C-C bond. The reaction is successful with a range of α-fluorinated alkyl sodium sulfinate salts and diarylphosphine oxides as radical precursors, and the conformationally accelerated Truce-Smiles rearrangement is not restricted by the electronic nature of the migrating aromatic ring. Formally the reaction constitutes an α,β-difuctionalisation of a carbon-carbon double bond, and proceeds under mild conditions with visible light and a readily available organic photocatalyst. The products are α,α-diaryl alkylureas typically functionalized with F or P substituents that may be readily converted into α,α-diaryl alkylamines.

Hydroarylation of Arenes via Reductive Radical-Polar Crossover.

A photocatalytic system for the dearomative hydroarylation of benzene derivatives has been developed. Using a combination of an organic photoredox catalyst and an amine reductant, this process operates through a reductive radical-polar crossover mechanism where aryl halide reduction triggers a regioselective radical cyclization event, followed by anion formation and quenching to produce a range of complex spirocyclic cyclohexadienes. This light-driven protocol functions at room temperature in a green solvent system (aq. MeCN) without the need for precious metal-based catalysts or reagents or the generation of stoichiometric metal byproducts.