Phosphoranyl Radicals Research Articles

Synthesis of β‐Trifluoromethylated Ketones by Photocatalyzed Deoxygenative Coupling of Aromatic Acids with α‐CF3‐Substituted Styrenes

Abstractα‐Trifluoromethyl alkenes are versatile CF3‐containing feedstocks. They have been widely used to construct gem‐difluoroalkene scaffolds through β−F elimination. The application of α−CF3 alkenes as trifluoromethylating reagents has been less explored. Herein, we report an efficient route for the synthesis of β‐trifluoromethylated ketones from readily accessed α−CF3 styrenes and aromatic carboxylic acids under photoredox catalysis. The reactions proceed by phosphoranyl radical promoted deoxygenation of aromatic acids, generating acyl radicals for subsequent hydroacylation of α−CF3 styrenes. The valuable trifluoromethyl‐containing compounds could be produced in good yields under mild conditions.

Cooperative Phosphine-Photoredox Catalysis Enables N-H Activation of Azoles for Intermolecular Olefin Hydroamination.

Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N-H azoles with unactivated olefins remains an unsolved problem in synthesis. We report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N-H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N-H bond activation is proposed to proceed via polar addition of the N-H azole to a phosphine radical cation, followed by P-N α-scission from a phosphoranyl radical intermediate. Reactivity and N-site selectivity are classified by azole N-H BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition

AbstractA general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross‐couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition.

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

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.

Photoinduced Decarboxylative Radical Phosphinylation

AbstractReported 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.

Photoredox catalyzed hydroazolylation of alkenes via phosphoranyl radicals

A general protocol for the hydroazolylation of alkenes with N-hydroxyl azoles is reported. These reactions proceed via a phosphoranyl radical, followed by radical coupling of the resulting azole radical to the alkene radical.

Photoredox-Catalyzed Selective α-Scission of PR3-OH Radicals to Access Hydroalkylation of Alkenes.

Photoinduced generation of phosphoranyl radicals offers a versatile strategy to access a variety of synthetically valuable radicals. A long-standing challenge remains in the regulation of phosphoranyl radical to undergo α-scission pathway, although the β-scission mode has been intensively studied. We herein developed an unprecedented protocol for selective α-scission of the P(OH)R3 radical intermediate under photocatalytic conditions. This efficient P-C bond cleavage via α-scission of the P(OH)R3 radicals has been successfully utilized in the alkylation/fluoroalkylation of alkenes.

Radical Coupling Initiated by Organophosphine Addition to Ynoates

AbstractDual nucleophilic phosphine photoredox catalysis is yet to be developed due to facile oxidation of the phosphine organocatalyst to the phosphoranyl radical cation. Herein, we report a reaction design that avoids this event and exploits traditional nucleophilic phosphine organocatalysis with photoredox catalysis to allow the Giese coupling with ynoates. The approach has good generality, while its mechanism is supported by cyclic voltametric, Stern–Volmer quenching, and interception studies.

Radical Coupling Initiated by Organophosphine Addition to Ynoates.

Dual nucleophilic phosphine photoredox catalysis is yet to be developed due to facile oxidation of the phosphine organocatalyst to the phosphoranyl radical cation. Herein, we report a reaction design that avoids this event and exploits traditional nucleophilic phosphine organocatalysis with photoredox catalysis to allow the Giese coupling with ynoates. The approach has good generality, while its mechanism is supported by cyclic voltametric, Stern-Volmer quenching, and interception studies.

Application of Phosphoranyl Radical in Organic Synthesis

Many useful organic reactions have been developed by taking advantage of the high affinity of phosphorus atoms with some heteroatoms such as oxygen and sulfur atoms. Although the reactions proceed via phosphorus ylides, phosphonium salts and phosphoranyl radicals as active species, the reactions via phosphoranyl radicals are only a few reports. In this short review, the three reactions via phosphoranyl radicals reported recently are described.

Synthesis of Phosphinic Amides from Chlorophosphines and Hydroxyl Amines via P(III) to P(V) Rearrangement.

Phosphoranyl radicals are essential mediators to bring about new radicals but often produce a stoichiometric amount of phosphine oxide/sulfide waste. Herein, we devised a phosphorus-containing species as a radical precursor, but without the generation of phosphorus waste. Accordingly, a catalyst-free synthesis of phosphinic amides from hydroxyl amines and chlorophosphines via P(III) to P(V) rearrangement is described. Mechanistically, it may involve the initial formation of a R2N-O-PR2 species that undergoes homolysis of N-O bonds and subsequent radical recombination.

Dehydroxylative Arylation of Alcohols via Paired Electrolysis.

Nonactivated alcohols along with arene compounds are used in electrochemical dehydroxylative arylation for constructing C(sp3)-C(sp2) bonds. The PIII reagent undergoes single-electron anodic oxidation to form its radical cation, which reacts with the alcohol to produce an alkoxytriphenylphosphine radical. Through spontaneous β-scission of the phosphoranyl radical, the C-O bond is cleaved to form an alkyl radical species, which couples with the radical anion generated by cathodic reduction of the electron-poor arene to afford the dehydroxylative arylated product.

Photoredox Catalytic Phosphine-Mediated Deoxygenation of Hydroxylamines Enables the Construction of N-Acyliminophosphoranes.

The chemistry of phosphoranyl radicals has received increasing attention in recent years. Here, we report the generation of amidyl radicals through photocatalytic deoxygenation of hydroxylamines with triphenylphosphine. This methodology offers a novel and convenient route to a diverse range of N-acyliminophosphoranes in moderate to good yields under visible-light photoredox conditions. Fluorescence quenching experiments suggest that the excited-state of the organic photocatalyst (4CzIPN) was oxidatively quenched by a Cu(II) salt.

Visible-Light Mediated Arbuzov-Like Reaction with Thiophenols.

We hereby disclose, a visible light mediated addition of sulfenyl radicals to trialkyl phosphites to access functionalized phosphorothioates. The use of cheap and readily available Eosin Y as a photocatalyst under mild energy efficient conditions bypassing the use of external oxidants forms the chief highlight of the work. The protocol is scalable and mechanistic studies indicate that the reaction proceeds through an ionic-Arbuzov like pathway from phosphoranyl radicals.

Geometrically constrained square pyramidal phosphoranide.

Geometrical constriction of main group elements leading to a change in the reactivity of these main group centers has recently become an important tool in main group chemistry. A lot of focus on using this modern method is dedicated to group 15 elements and especially to phosphorus. In this work, we present the synthesis, isolation and preliminary reactivity study of the geometrically constrained, square pyramidal (SP) phosphoranide anion (1−). Unlike, trigonal bipyramidal (TBP) phosphoranides that were shown to react as nucleophiles while their redox chemistry was not reported, 1− reacts both as a nucleophile and reductant. The chemical oxidation of 1− leads to a P–P dimer (1-1) that is formed via the dimerization of unstable SP phosphoranyl radical (1˙), an unprecedented decay pathway for phosphoranyl radicals. Reaction of 1− with benzophenone leads via a single electron transfer (SET) to 1-OK and corresponding tetraphenyl epoxide (4).

Phosphine/Photoredox Catalyzed Anti-Markovnikov Hydroamination of Olefins with Primary Sulfonamides via α-Scission from Phosphoranyl Radicals.

New strategies to access radicals from common feedstock chemicals hold the potential to broadly impact synthetic chemistry. We report a dual phosphine and photoredox catalytic system that enables direct formation of sulfonamidyl radicals from primary sulfonamides. Mechanistic investigations support that the N-centered radical is generated via α-scission of the P-N bond of a phosphoranyl radical intermediate, formed by sulfonamide nucleophilic addition to a phosphine radical cation. As compared to the recently well-explored β-scission chemistry of phosphoranyl radicals, this strategy is applicable to activation of N-based nucleophiles and is catalytic in phosphine. We highlight application of this activation strategy to an intermolecular anti-Markovnikov hydroamination of unactivated olefins with primary sulfonamides. A range of structurally diverse secondary sulfonamides can be prepared in good to excellent yields under mild conditions.

Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon.

Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.

Photocatalytic Hydroacylation of Alkenes by Directly Using Acyl Oximes

Acyl oximes are directly used as the acyl radical precursors in the hydroacylation reactions for the first time. In this work, acyl radicals can be effectively generated via β-scission of a phosphoranyl radical under photocatalytic conditions. As a result, the hydroacylation of alkenes triggered by the resulting acyl radicals leads to facile syntheses of a range of valuable ketones.

Light-Driven Metal-Free Direct Deoxygenation of Alcohols under Mild Conditions.

SummaryHydroxyl is widely found in organic molecules as functional group and its deprivation plays an inevitable role in organic synthesis. However, the direct cleavage of Csp3-O bond in alcohols with high selectivity and efficiency, especially without the assistance of metal catalyst, has been a formidable challenge because of its strong bond dissociation energy and unfavorable thermodynamics. Herein, an efficient metal-free strategy that enables direct deoxygenation of alcohols has been developed for the first time, with hydrazine as the reductant induced by light. This protocol features mild reaction conditions, excellent functional group tolerance, and abundant and easily available starting materials, rendering selective deoxygenation of a variety of 1° and 2° alcohols, vicinal diols, and β-1 and even β-O-4 models of natural wood lignin. This strategy is also highlighted by its “traceless” and non-toxic by-products N2 and H2, as readily escapable gases. Mechanistic studies demonstrated dimethyl sulfide being a key intermediate in this transformation.