N-heterocyclic carbenes (NHCs) was uncovered as an efficient ligand in promoting allylic C–H bond functionlizations. Notably, the catalytic [Pd(η3-cin)(IPr)Cl] complex (where cin = cinnamyl) was formed in situ from direct C–H activation of allylic precursors, and was obtained by way of one-pot strategy with available IPr·HCl and allylbenzene. The catalyst exhibits high regioselectivity and stereoselectivity of the allylic C–H alkylation with oxindoles with a broad scope.Keywords: Alkylation; Allylic C−H activation; Oxindoles; Selectivity-Control; [Pd(η3-cin)(IPr)Cl];

ConspectusGiven the important influence of phosphine ligands in transition metal-catalyzed reactions, chemists have searched for straightforward and efficient methodologies for the synthesis of diverse phosphine ligands. Although significant progress has been made in this aspect over the past decades, the development of new phosphorus-containing ligands with properties superior to their predecessors remains a central task for chemists. Recently, researchers have demonstrated that biphenyl monophosphine ligands function as highly efficient ligands for transition-metal-catalyzed organic transformations, especially for reactions where chelating bisphosphine ligands cannot be used. In 1998, Buchwald introduced a new class of air-stable phosphine ligands based on the dialkylbiaryl phosphine backbone. These ligands have been successfully used for a wide variety of palladium-catalyzed carbon–carbon, carbon–nitrogen, and carbon–oxygen construction processes as well as serving as supporting ligands for a number of other reactions. At the same time, the use of the biphenyl monophosphine ligands often allows reactions to proceed with short reaction times and low catalyst loadings and under mild reaction conditions. However, the synthesis of chiral biphenyl monophosphine ligands, especially those the chirality of which is due to biaryl axial chirality, is very limited.In this Account, we summarize our methodologies for the synthesis of this kind of biphenyl monophosphine ligands including the P═O directed C–H functionalization, P═O directed diastereoselective C–H functionalization, P═O directed enantioselective C–H functionalization, and metal-free diastereoselective radical oxidative C–H amination under mild reaction conditions. With these methods, a series of biphenyl phosphine ligand precursors containing achiral or axially chiral centers and precursors possessing both axial chirality and a chirogenic phosphorus center with different electronic properties and steric effect have been obtained under different reaction conditions. For the preparation of chiral biphenyl monophosphine ligands, which not only possess axial chirality but in many cases also possess chirality at phosphorus, the primary means of introducing chirality is through the use of the menthyl phenylphosphinate. As a chiral auxiliary group, the menthyl phenylphosphinate has some unique features: (i) it is easy to prepare; (ii) the products contain both axial chirality and central chirality on the phosphorus atom; (iii) the menthyl group could easily be transformed into other functional groups, which is crucial for the diversity of the corresponding biphenyl ligands. In our reaction, the P═O group not only acts as the directing group but also facilitates the construction of the phosphine ligands. In addition, the application of these products in asymmetric catalysis has also been studied with good results obtained in some reactions. The further application of these ligands, especially the chiral biphenyl monophosphine ligands in catalysis reactions is underway in our laboratory, and we hope different kinds of reactions will be achieved with these ligands.

Chiral γ-phosphono-α-amino acids play a crucial role in inhibitors of natural enzymes, as well as agonists and antagonists of metabotropic glutamate receptors. In this paper, an efficient and general protocol for the construction of chiral γ-phosphono-α-amino acids via Pd-catalyzed AQ-directed C(sp3)–H alkylation of α-amino acid derivatives is developed. The reaction shows reactivity between methylene C(sp3)–H bonds with phosphonated alkyl iodides with high yields, enantioselectivity, and diastereomeric ratios, which enables access to a wide range of challenging and important γ-phosphono-α-amino acids in large scale. Meanwhile, δ-phosphono-α-amino acid and δ-phosphono-propionic acid derivatives can also be successfully obtained. The derivatization reaction in the synthesis of l-AP4 and l-phosphinothricin highlight the applicability of this method.Keywords: alkylation; C−H activation; palladium; synthetic methods; γ-phosphono-α-amino acids;

An effective synthesis of chiral atropoisomeric biaryl phosphine–olefin compounds via palladium-catalyzed enantioselective C–H olefination has been developed for the first time. The reactions are operationally simple, tolerate wide functional groups, and have a good ee value. Notably, P(O)R2 not only acts as the directing group to direct C–H activation in order to make a useful ligand but also serves to facilitate composition of the product in a useful manner in this transformation.

The cover picture shows a concise and effective protocol for the synthesis of valuable exocyclic phosphine oxides via the process of free radical cascade cyclization. Waterwheel in series shows the implied meaning in the process of phosphorylation/ cascade cyclization of various 1,6-dienes involving the C—P and C—C bonds formation. More details are discussed in the article by Yang et al. on page 316–322.

A new class of chiral atropoisomeric (P, N) ligand precursors has been obtained with excellent diastereoselectivities and high yields through diastereoselective metal-free intramolecular radical oxidative C–H amination with chiral phosphamide as the auxiliary group. This method provides a concise and highly valuable pathway for the synthesis of enantiopure aminophosphine ligands in large-scale.

A Rh/Ni-catalyzed cascade sequence of allylamine isomerization and hydrophosphonylation to synthesize α-aminophosphonates has been disclosed. The reaction, which not only allows the generation of widespread valuable α-aminophosphonates under simple systems and mild conditions, but also enriches the process of olefin isomerization–addition both in catalytic systems and various reaction types.

AbstractA silver-catalyzed phosphorylation/cyclization radical cascade of 1,6-dienes has been developed. The reaction process involves in a one-pot operation described as an autotandem catalytic process with a cascading radical cyclization for the construction of C—P and C—C bond with high stereoselectivity. Moreover, it also affords an efficient method for the synthesis of valuable exocyclic phosphine oxides compounds with broad substrate applicability, mild reaction condition and succinct reaction system.

An efficient method for the synthesis of C-phosphonoketenimines through palladium-catalyzed migratory insertion of isocyanides has been developed for the first time. This procedure tolerates wide functional groups and has a good atom economy. Further transformations of the products, which are useful building blocks for the β-aminophosphonates, β-aminovinylphosphonates, and C-phosphorylated tetrazoles, indicate potential synthetic utility.Keywords: C-phosphonoketenimines; isocyanides; palladium; phosphonylated; synthetic method

The first Pd-catalyzed allylic dearomatization of substituted indoles triggered by C–H bond activation is reported. The presence of a catalytic amount of 2,5-DMBQ is proven to be a key factor for the high yield. This one-pot tandem allylic C–H activation/dearomatization sequence provides a straightforward access to 3,3-disubstituted indolines.

A new strategy for the synthesis of chiral α-amino phosphonates by enantioselective C–H phosphonylation of allylamine with phosphite in the presence of a chiral Brønsted acid catalyst has been developed. This protocol successfully integrates direct C–H oxidation with asymmetric phosphonylation and exhibits high enantioselectivity.

Various difunctionalizations of acrylamide can not only provide a simple approach to form a wide scope of functionalized oxindoles, but can also be applied and generated easily. This review concludes different difunctionalizations of acrylamide to synthesize oxindoles based on the mechanistic aspects. The goal is to encourage further mechanistic studies hopefully leading to an in-depth understanding of this strategy.

The first rhodium(I)-catalyzed difunctionalization of arylacrylamides to synthesize oxindoles is developed, and it does not require the assistance of an oxidant. This method provides an efficient approach to generate various useful functionalized oxindoles, some of which cannot be easily accessed by previous approaches.

An efficient method of Pd(II)-catalyzed P(O)R1R2-directed asymmetric C–H activation and dynamic kinetic resolution for synthesis of chiral phosphinate ligands has been performed and exhibits a wide scope of substrates and an excellent diastereomeric ratio (>95:5).

A new method for the synthesis of chiral α-amino acid derivatives by enantioselective C–H arylation of N-aryl glycine esters with aryl boric acids in the presence of a chiral Pd(II)-catalyst has been developed. This work successfully integrates the direct C–H oxidation with asymmetric arylation and exhibits excellent enantioselectivity.

A novel and convenient approach to the synthesis of various phosphorated indolines via a copper-catalyzed radical cascade cyclization reaction has been developed. The reaction employs cheap copper as the catalyst and K2S2O8 as the oxidant under mild conditions. Various alkenes and P-radical precursors are compatible with this transformation. Preliminary mechanistic studies reveal that the addition of the P-radical may initiate the reaction, and then oxidative cyclization may be achieved to afford the desired product.

The first Cu-catalyzed cascade sp3 C–H bond oxidative functionalization of the 2-ethylazaarenes has been developed. The two different sp3 C–H bonds in 2-ethylazaarenes are selectively oxidized and four new types of bonds (CO, CN, C–C, C–O) are constructed in one operation. Starting from the simple substrates and cheap nitro source, this reaction provides an efficient approach to produce new kinds of isoxazolines.

An efficient copper-catalyzed allylic C–H phosphonation reaction has been developed under mild reaction conditions. This method exhibits high regioselectivity and stereoselectivity. Various alkenes with useful functional groups are compatible in this transformation. Preliminary mechanistic studies reveal that the pH value and the loading of Ag-salt were the key factors to change the composition of products.

In recent years, transition-metal-catalyzed inert C-H bond activation has developed rapidly and is a powerful protocol for the construction of new C-C or C-X bonds and the introduction of new functional groups. Our group has also developed a series of R2(O)P-directed Pd-catalyzed C-H functionalizations involving olefination, hydroxylation, acetoxylation, arylation, and acylation through an uncommon seven-membered cyclo-palladium pretransition state. Unlike previously used directing groups, the R2(O)P group acts as a directing group and is also involved in the construction of P,-hetero-ligands.

The first Cu(I)-catalyzed cross-coupling reaction by hydrogen (H2) removal for the stereoselective synthesis of 3-phosphoindoles is reported. Going beyond the oxidative dehydrogenative coupling reactions reported recently, this reaction completely omits the oxidant and base, producing hydrogen (H2) as the only byproduct.

A novel and efficient Pd-catalyzed C–H acetoxylation is described. The approach uses R2(O)P as a directing group to synthesize various substituted 2′-phosphorylbiphenyl-2-OAc compounds. Notably, the reaction exhibits smooth operation under mild conditions and shows good functional group tolerance. Products are obtained with high selectivity and yields.

Palladium-catalyzed arylation of (diisopropylphosphoryl)biphenyl skeleton derivatives by the P(O)R2 directed C–H functionalization was reported. The related products were obtained in high regioselectivity and good functional group tolerance was observed. This reaction provided a new and efficient pathway for the synthesis of polyaromatic monophosphorus ligands.

A palladium-catalyzed allylic C–H arylation reaction with electron-deficient arenes with high regio- and stereoselectivity is reported. This work represents the first successful use of 1,1′-bi-2-naphthol as the ancillary ligand in allylic C–H activation, which is the key factor for chemoselectivity. Furthermore, high selectivity allylic C–H acetoxylation and amination were also successfully achieved under the same catalytic system.

A novel oxyfluorination of olefin reactions has been developed. The reactions involve a metal-free and green catalytic system for the synthesis of α-fluoroketones which is an important building block for organic synthesis. Moreover, this reaction system exhibits great functional group tolerance.

An efficient method for the synthesis of phosphoric fluoride via oxidative coupling between hydrophosphine oxide and NaF is reported. DDQ serves as the oxidizing reagent as well as the hydrogen acceptor. The process involves a Cu(II) catalysis and exhibits great functional group tolerance under mild reaction conditions.

A three-component reaction for high diastereoselective synthesis of chiral α-amino phosphine oxides has been developed and displayed environmentally friendly and atom efficient characteristics. The reaction proceeds smoothly without catalysts or additives.

A novel metal-free oxidative carbonitration of alkenes by a nitration and C–H functionalization cascade process has been developed. This methodology provides an efficient way to construct valuable nitro-containing oxindoles.

A novel method has been developed for the synthesis of substituted N-methylacridones from 2-(N-methyl-N-phenylamino)benzaldehydes via dehydrogenative cyclization. This transformation involves two primary processes: the aldehyde first coordinates with Sc(OTf)3 and induces the aromatic electrophilic substitution (SEAr) reaction to form the active intermediate N-methyl-acridin-9-ol, which is then quickly oxidized in situ to afford the acridones. Furthermore, the procedure involved is both environmental friendly and atom efficient; H2O is the only byproduct in this reaction.

A novel and inexpensive method of nontoxic, silver-salt-catalyzed carboazidation of arylacrylamides to afford corresponding azide oxindoles is reported. This reaction system exhibits great functional group tolerance. All products form a crucial skeleton for the synthesis of various indole alkaloids.

A novel and selective method of simple copper-salt catalyzed phosphonation of α-amino carbonyl compounds to afford imidoylphosphonates is reported. This reaction system has a broad reaction scope. The convenient and environmentally benign process makes this protocol very attractive.

The Pd(II)-catalyzed Ph2(O)P-directed C–H olefination to synthesize alkene–phosphine compounds is reported. In contrast to previous examples of various directing groups that guide selective C–H activation, the Ph2(O)P group not only acts as the directing group but also serves to construct the alkene–phosphine ligands. The monoprotected amino acid (MPAA) ligand Ac-Leu-OH is found to promote this reaction in a significant manner.

The first Pd(II)-catalyzed C–H addition to isatins by direct sp2/sp3 C–H bond activation for the construction of 3-substituted-3-hydroxy-2-oxindoles is reported. The bidentate nitrogen ligands were found to promote this reaction. Specifically, the preliminary bioassay indicated that 3-(5-chlorobenzoxazole)-3-hydroxy-N-benzyl-2-oxindole (2w) is a new inhibitor of human kidney cancer and hepatocellular carcinoma cells. Moreover, this reaction system exhibits great functional group tolerance and requires no directing group, extra base, or additives.

A novel R2(O)P-directed Pd(II)-catalyzed C–H hydroxylation to synthesize various substituted 2′-phosphorylbiphenyl-2-ol compounds is described. Notably, the reaction operates under mild conditions and shows good functional group tolerance, high selectivity, and yield.

A new method for the synthesis of tricyclic 2,3-dihydro-4-quinolones by the NiCl2(PMe3)2-catalyzed carboamination of alkenes by intermolecular decarboxylative cycloaddition reaction is reported here. Isatoic anhydrides were reacted with various norbornenes to afford the novel structure of quinolones. This protocol is simple and easy to handle.

A novel protocol for the preparation of various diarylphosphine oxide compounds via a Ni-catalyzed cross-coupling of aryl chlorides with R2P(O)H has been developed. Notably, this process exhibits the following very attractive features: (i) the process is simpler and operates under mild reaction conditions; (ii) the process is generally cheaper in part because the more accessible aryl chloride is used to form the C–P bond; (iii) the process avoids the need for simultaneous preparation and use of Ar2P(O)M.

A novel protocol for the preparation of various 3-alkylideneoxindoles via a silver-catalyzed aromatic C–H functionalization has been developed. The process is simple, environmentally conscious, and avoids the use of abundant bases, oxidants, or other additives.

A variety of substituted 4H-pyrans are readily prepared in moderate to good yields under the mild reaction conditions by nucleophilic addition to electron-deficient 1,3-conjugated enynes with phase-transfer catalysis (PTC).

An efficient copper-catalyzed allylic C–H phosphonation reaction has been developed under mild reaction conditions. This method exhibits high regioselectivity and stereoselectivity. Various alkenes with useful functional groups are compatible in this transformation. Preliminary mechanistic studies reveal that the pH value and the loading of Ag-salt were the key factors to change the composition of products.

A variety of substituted 4H-pyrans are readily prepared in moderate to good yields under the mild reaction conditions by nucleophilic addition to electron-deficient 1,3-conjugated enynes with phase-transfer catalysis (PTC).

A novel and convenient approach to the synthesis of various phosphorated indolines via a copper-catalyzed radical cascade cyclization reaction has been developed. The reaction employs cheap copper as the catalyst and K2S2O8 as the oxidant under mild conditions. Various alkenes and P-radical precursors are compatible with this transformation. Preliminary mechanistic studies reveal that the addition of the P-radical may initiate the reaction, and then oxidative cyclization may be achieved to afford the desired product.

An efficient method for the synthesis of phosphoric fluoride via oxidative coupling between hydrophosphine oxide and NaF is reported. DDQ serves as the oxidizing reagent as well as the hydrogen acceptor. The process involves a Cu(II) catalysis and exhibits great functional group tolerance under mild reaction conditions.

A new method for the synthesis of chiral α-amino acid derivatives by enantioselective C–H arylation of N-aryl glycine esters with aryl boric acids in the presence of a chiral Pd(II)-catalyst has been developed. This work successfully integrates the direct C–H oxidation with asymmetric arylation and exhibits excellent enantioselectivity.

A novel protocol for the preparation of various 3-alkylideneoxindoles via a silver-catalyzed aromatic C–H functionalization has been developed. The process is simple, environmentally conscious, and avoids the use of abundant bases, oxidants, or other additives.

A novel and efficient Pd-catalyzed C–H acetoxylation is described. The approach uses R2(O)P as a directing group to synthesize various substituted 2′-phosphorylbiphenyl-2-OAc compounds. Notably, the reaction exhibits smooth operation under mild conditions and shows good functional group tolerance. Products are obtained with high selectivity and yields.

The first Cu(I)-catalyzed cross-coupling reaction by hydrogen (H2) removal for the stereoselective synthesis of 3-phosphoindoles is reported. Going beyond the oxidative dehydrogenative coupling reactions reported recently, this reaction completely omits the oxidant and base, producing hydrogen (H2) as the only byproduct.

Various difunctionalizations of acrylamide can not only provide a simple approach to form a wide scope of functionalized oxindoles, but can also be applied and generated easily. This review concludes different difunctionalizations of acrylamide to synthesize oxindoles based on the mechanistic aspects. The goal is to encourage further mechanistic studies hopefully leading to an in-depth understanding of this strategy.

The first Cu-catalyzed cascade sp3 C–H bond oxidative functionalization of the 2-ethylazaarenes has been developed. The two different sp3 C–H bonds in 2-ethylazaarenes are selectively oxidized and four new types of bonds (CO, CN, C–C, C–O) are constructed in one operation. Starting from the simple substrates and cheap nitro source, this reaction provides an efficient approach to produce new kinds of isoxazolines.

A Rh/Ni-catalyzed cascade sequence of allylamine isomerization and hydrophosphonylation to synthesize α-aminophosphonates has been disclosed. The reaction, which not only allows the generation of widespread valuable α-aminophosphonates under simple systems and mild conditions, but also enriches the process of olefin isomerization–addition both in catalytic systems and various reaction types.

A novel method for the Pd(II)-catalyzed C–H acylation of 2-phosphorylbiphenyl with α-oxocarboxylic acids, aldehydes, alcohols and toluene is described. This reaction provides efficient access to various substituted 2′-phosphorylbiphenyl-2-acyl compounds.

Palladium-catalyzed arylation of (diisopropylphosphoryl)biphenyl skeleton derivatives by the P(O)R2 directed C–H functionalization was reported. The related products were obtained in high regioselectivity and good functional group tolerance was observed. This reaction provided a new and efficient pathway for the synthesis of polyaromatic monophosphorus ligands.

A novel metal-free oxidative carbonitration of alkenes by a nitration and C–H functionalization cascade process has been developed. This methodology provides an efficient way to construct valuable nitro-containing oxindoles.

A novel protocol for the preparation of various diarylphosphine oxide compounds via a Ni-catalyzed cross-coupling of aryl chlorides with R2P(O)H has been developed. Notably, this process exhibits the following very attractive features: (i) the process is simpler and operates under mild reaction conditions; (ii) the process is generally cheaper in part because the more accessible aryl chloride is used to form the C–P bond; (iii) the process avoids the need for simultaneous preparation and use of Ar2P(O)M.