Facile Assembly of Modular-Type Phosphines for Tackling Modern Arylation Processes.

This Account presents an overview of a promising collection of phosphine ligands simply made from the modular Fischer indolization process and their applications in modern arylation processes. Using one easily accessible 2-arylindole scaffold, three major phosphino-moiety-positioned ligand series can be readily generated. We have attempted to explore challenging electrophilic and nucleophilic partners for the coupling reaction using the modular ligand tool. For the electrophilic partner study, CM-phos-type ligands, where the phosphino group is located at the 2-arene position of 2-arylindole, allow the successful cross-coupling of aryl mesylates. The CM-phos ligand forms a palladacycle before entering the cross-coupling catalytic cycle. For the nucleophilic partner investigation, the indole C3-positioned phosphines show the first accomplishment of Pd-catalyzed organotitanium nucleophile arylation. Indeed, the aryl-titanium nucleophile undergoes cross-coupling more efficiently than does the organoboron coupling partner in particular cases. Moreover, in the indole C3-positioned phosphine series, the -PPh2-containing ligands perform better in the highly sterically hindered cross-coupling of aryl chlorides than do ligands containing the -PCy2 moiety. The catalyst loading can even be reduced to 0.2 mol % Pd for tetra-ortho-substituted biaryl synthesis. This finding offers a new perspective on the next-generation design of phosphine ligands in which the sterically bulky and electron-rich -PR2 group (R = alkyl) may not be necessary for the cross-coupling of aryl chlorides. In general, we hypothesize that a good balance of steric and electronic properties for entertaining the oxidative addition and reductive elimination steps is crucial to the success of the reaction. For the steric factor, the highly sterically congested -PR2 group normally favors the reductive elimination, yet we conjecture that this sterically bulky group would serve as an obstacle for the incoming aryl halides. For the electronic factor, the electron rich -PR2 group is believed to support the oxidative cleavage of the C(Ar)-Cl bond by donating more electron density to the corresponding σ* orbital. Nevertheless, the high electron richness of the -PR2 group may disfavor the reductive elimination electronically. Overall, an appropriate balance of both electron density and steric bulkiness is suggested to allow the sterically hindered cross-coupling to proceed smoothly. We have found that the -PPh2-containing ligand is a good starting point for this investigation. The formation of aromatic carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds from aryl chlorides was successfully realized using our proprietary phosphines.In addition to the indole-core-bearing ligand skeleton, we also explored the relevant imidazolyl and carbazolyl phosphines for their unique applications. Interestingly, the carbazolyl ligand, having more flexible C-N axial chirality, displays particular interchangeable Pd-N and Pd-arene coordination, which facilitates both oxidative addition and reductive elimination processes. Moreover, this C-N axially chiral ligand allows the successful asymmetric Suzuki-Miyaura coupling for attaining the most sterically hindered tetra-ortho-substituted biaryls with excellent enantioselectivity. The rationale behind these scientifically interesting findings is presented in detail.

Cascade Annulation Strategy for Expeditious Assembly of Hydroxybenzo[c]chromen-6-ones and Their Photophysical Property Studies.

A 1,8-diazabicyclo[5.4.0]undec-7-ene-promoted cascade double-annulation of ortho-alkynyl quinone methide (in situ generated from modular propargylamine) for constructing of 2-aryl-4-hydroxybenzo[c]chromen-6-ones is developed. This synthetic strategy offers remarkable operational simplicity as it allows the use of benchtop-grade solvents without the need for predrying measures and inert atmosphere protection. Additionally, it demonstrates good functional group compatibility. The photophysical properties of these compounds were also examined, revealing bright fluorescence with high quantum yields.

Atropisomeric Phosphine Ligands Bearing C-N Axial Chirality: Applications in Enantioselective Suzuki-Miyaura Cross-Coupling Towards the Assembly of Tetra-ortho-Substituted Biaryls.

Biaryl phosphines bearing C(Ar)-C(Ar) axial chirality are commonly known and have been successfully applied in many asymmetric catalyses. Nevertheless, the development of a chiral ligand having an axially chiral C(Ar)-N backbone remains elusive due to its undesirable less restricted rotational barrier. In fact, it is highly attractive to overcome this challenge in ligand development as the incorporation of an N-donor component at the chiral axis is more favorable toward the transient metal coordination, and thus, a better outcome of stereocommunication is anticipated to the approaching substrates. Herein, we present a rational design of a new collection of chiral phosphines featuring a C-N axial chirality and their applications in enantioselective Suzuki-Miyaura cross-coupling for accessing highly steric hindered tetra-ortho-substituted biaryls (26 examples up to 98:2 er). It is worth noting that the embodied carbazolyl framework is crucial to succeed the reaction, by the fruitful steric relief of bulky substrate coordination and transmetalation via a fleeting Pd-N jumping to Pd-π fashion. DFT calculation reveals an interesting Pd-arene-walking characteristic across the carbazolyl plane for attaining a lower energy-preferred route in a catalytic cycle. The theoretical study successfully predicts the stereooutcome and matches the enantioselectivity with the experimental results.

N-Difluoromethylation of N-pyridyl-substituted anilines with ethyl bromodifluoroacetate.

A general protocol for N-difluoromethylation of aniline derivatives is developed. Commercially available ethyl bromodifluoroacetate serves as a difluorocarbene source in the presence of a base. This carbene surrogate is attractive owing to its favorable stability, environmental friendliness and inexpensiveness. This reaction system features notable operational simplicity (bench top-grade solvents can be used without any pre-drying and do not require inert atmosphere protection). A wide range of functional groups in aniline derivatives are well-tolerated, and good-to-excellent product yields are generally obtained.

Palladium-Catalyzed Monoarylation of Arylhydrazines with Aryl Tosylates.

A palladium-catalyzed C-N bond coupling reaction between arylhydrazines and aryl tosylates for facile synthesis of unsymmetrical N,N-diarylhydrazines has been developed. Employing the catalyst system of Pd(TFA)2 associated with newly developed phosphine ligand L1, the monoarylation of arylhydrazine proceeds smoothly to afford desired products in good-to-excellent yields (up to 95%) with good functional group compatibility. This method provides an alternative synthetic pathway for accessing structurally diversified N,N-diarylhydrazines from simple and easily accessible coupling components.

Palladium-Catalyzed Direct Arylation of Polyfluoroarenes for Accessing Tetra- ortho-Substituted Biaryls: Buchwald-type Ligand Having Complementary -PPh2 Moiety Exhibits Better Efficiency.

The first general examples of direct C-H arylation of electron-deficient polyfluoroarenes with challenging di- ortho-substituted aryl(heteroaryl) chlorides for tetra- ortho-substituted biaryl synthesis are reported. Key to success is the use of Buchwald-type biaryl phosphine ligand, notably with inexpensive -PPh2 moiety (instead of -PCy2 group). Pd(OAc)2 associated with ligand L9 exhibits even higher efficiency than the corresponding SPhos toward this reaction. A wide range of sterically hindered di- ortho-substituted chloroarenes bearing electron-donating or -withdrawing groups are found applicable. Excellent product yields are obtained under mild reaction conditions, and the catalyst loading down to 0.25 mol % of Pd can also be achieved.

Palladium-Catalyzed N-Arylation of Sulfoximines with Aryl Sulfonates.

Palladium-catalyzed C-N bond coupling reaction between NH-sulfoximines and aryl halides (e.g., -Br, -I, and -Cl and pseudohalides -OTf and -ONf) was successfully achieved. Nevertheless, aryl tosylates/mesylates left much to be achieved. In this report, a general N-arylation of sulfoximines with aryl sulfonates is described. Using Pd(OAc)2/MeO-CM-phos complex, the N-aryl sulfoximine products can be obtained in good-to-excellent yields (up to 99%) with good common functional group compatibility. In addition to arene moieties, alkenyl tosylates are shown to be successful coupling partners.

Cobalt-Catalyzed Tandem C-H Activation/C-C Cleavage/C-H Cyclization of Aromatic Amides with Alkylidenecyclopropanes.

A cobalt-catalyzed chelation-assisted tandem C-H activation/C-C cleavage/C-H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C-C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C-N bonds. Here the inexpensive catalyst system exhibits good functional-group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m-CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C-H cobaltation, ß-carbon elimination, and intramolecular C-H cobaltation sequence.

Palladium-Catalyzed Regioselective Aromatic Extension of Internal Alkynes through a Norbornene-Controlled Reaction Sequence.

A regioselective aromatic π-extension reaction of internal alkynes is reported. The proposed method employs three easily available components, namely aryl halides, 2-haloarylcarboxylic acids, and disubstituted acetylenes. The transformation is driven by a controlled reaction sequence of C-H activation, decarboxylation, and annulation to give poly(hetero)aromatic compounds in a site-selective fashion. Unlike in previously reported palladium-catalyzed three-component annulations, alkyne carbopalladation is the last step of this tandem reaction.

A Palladium-Catalyzed α-Arylation of Oxindoles with Aryl Tosylates.

A palladium-catalyzed monoselective C3 arylation of 2-oxindoles with aryl tosylates is described. With the Pd/CM-phos catalyst system, the corresponding 3-arylated oxindoles can be obtained in good to excellent yields (≤97%). The reaction conditions are mild (using 0.5 mol % Pd in general and KF as a base), and functional groups such as methyl ester, NH amido, and enolizable keto moieties are found to be compatible.

Regioselective Synthesis of Polycyclic and Heptagon-embedded Aromatic Compounds through a Versatile π-Extension of Aryl Halides.

A versatile π-extension reaction was developed based on the three-component cross-coupling of aryl halides, 2-haloarylcarboxylic acids, and norbornadiene. The transformation is driven by the direction and subsequent decarboxylation of the carboxyl group, while norbornadiene serves as an ortho-C-H activator and ethylene synthon via a retro-Diels-Alder reaction. Comprehensive DFT calculations were performed to account for the catalytic intermediates.

A General Palladium-Catalyzed Hiyama Cross-Coupling Reaction of Aryl and Heteroaryl Chlorides.

A general palladium-catalyzed Hiyama cross-coupling reaction of aryl and heteroaryl chlorides with aryl and heteroaryl trialkoxysilanes by a Pd(OAc)2 /L2 catalytic system is presented. A newly developed water addition protocol can dramatically improve the product yields. The conjugation of the Pd/L2 system and the water addition protocol can efficiently catalyze a broad range of electron-rich, -neutral, -deficient, and sterically hindered aryl chlorides and heteroaryl chlorides with excellent yields within three hours and the catalyst loading can be down to 0.05 mol % Pd for the first time. Hiyama coupling of heteroaryl chlorides with heteroaryl silanes is also reported for the first time. The reaction can be easily scaled up 200 times (100 mmol) without any degasification and purification of reactants; this facilitates the practical application in routine synthesis.

Oxidative coupling between C(sp²)-H and C(sp³)-H bonds of indoles and cyclic ethers/cycloalkanes.

Cross-dehydrogenative-coupling (CDC) between C-H/C-H bonds of indoles and cyclic ethers/cycloalkanes is made viable through a simple transition-metal-free pathway. With the aid of only di-tert-butyl peroxide, a number of inactive cyclic ethers and cycloalkanes can be directly coupled with indole derivatives in satisfactory yields.

Copper-Catalyzed Oxidative C-H Amination of Tetrahydrofuran with Indole/Carbazole Derivatives.

A simple α-C-H amination of cyclic ether with indole/carbazole derivatives has been accomplished by employing copper(II) chloride/bipy as the catalyst system. In the presence of the di-tert-butyl peroxide oxidant, cyclic ethers such as tetrahydrofuran, 1,4-dioxane, and tetrahydropyran successfully undergo C-H/N-H cross dehydrogenative coupling (CDC) with various carbazole or indole derivatives in good-to-excellent yields.

Regioselective direct C-3 arylation of imidazo[1,2-a]pyridines with aryl tosylates and mesylates promoted by palladium-phosphine complexes.

Direct C-3 arylation of imidazo[1,2-a]pyridines with aryl tosylates and mesylates has been accomplished by employing palladium(II) acetate associated with SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) or L1 (2-(2-(diisopropylphosphino)phenyl)-1-methyl-1H-indole). This catalyst system can be applied to a wide range of aryl sulfonates and shows excellent C-3 regioselectivity of imidazo[1,2-a]pyridine. These results represent the first examples of using tosylate- and mesylate-functionalized arenes as the electrophile partners for this regioselective direct arylation.

Direct intermolecular C-H arylation of unactivated arenes with aryl bromides catalysed by 2-pyridyl carbinol.

Direct intermolecular C-H arylation employing aryl bromide as the arene source has been developed. This process proceeds via a simple transition-metal-free pathway. With the aid of inexpensive and commercially available 2-pyridyl carbinol and potassium tert-butoxide, various unactivated arene C-H bonds can be directly arylated by aryl bromides through homolytic aromatic substitution.

A radical process towards the development of transition-metal-free aromatic carbon-carbon bond-forming reactions.

Transition-metal-free cross-coupling reactions have been a hot topic in recent years. With the aid of a radical initiator, a number of unactivated arene C-H bonds can be directly arylated/functionalized by using aryl halides through homolytic aromatic substitution. Commercially available or specially designed promoters (e.g. diamines, diols, and amino alcohols) have been used to make this synthetically attractive method viable. This protocol offers an inexpensive, yet efficient route to aromatic C-C bond formations since transition metal catalysts and impurities can be avoided by using this reaction system. In this article, we focus on the significance of the reaction conditions (e.g. bases and promoters), which allow this type of reaction to proceed smoothly. Substrate scope limitations and challenges, as well as mechanistic discussion are also included.

Synthesis of 3-cyanoindole derivatives mediated by copper(I) iodide using benzyl cyanide.

Copper-mediated direct and regioselective C3-cyanation of indoles using benzyl cyanide as the cyanide anion source is presented. A wide range of indoles undergo cyanation smoothly by employing a reaction system of copper(I) iodide under open-to-air vessels.

Recent Expedition in Pd- and Rh-Catalyzed C(Ar) -B Bond Formations and Their Applications in Modern Organic Syntheses.

Transition metal-catalyzed borylation has emerged as a powerful and versatile strategy for synthesizing organoboron compounds. These compounds have found widespread applications in various aspects, including organic synthesis, materials science, and medicinal chemistry. This review provides a concise summary of the recent advances in palladium- and rhodium-catalyzed borylation from 2013 to 2023. The review covers the representative examples of catalysts, substrates scope and reaction conditions, with particular emphasis on the development of catalyst systems, such as phosphine ligands, NHC-carbene, and more. The diverse array of borylative products obtained for further applications in Suzuki-Miyaura coupling, and other transformations, are also discussed. Future directions in this rapidly evolving field, with the goal of designing more efficient, selective borylation methodologies are highlighted, too.

Carbon-boron bond cross-coupling reaction catalyzed by -PPh(2) containing palladium-indolylphosphine complexes.

This study describes the application of indolylphosphine ligands with a diphenylphosphino moiety to the palladium-catalyzed borylation of aryl chlorides. The combination of palladium metal precursor with PPh(2)-Andole-phos, which comprises an inexpensive -PPh(2) group, provides highly effective catalysts for the borylation of aryl chlorides. A range of functional groups such as -CN, -NO(2), -CHO, -COMe, -COOMe, and -CF(3) was compatible, and the catalyst loading down to 0.025 mol % of Pd can be achieved. The Pd/PPh(2)-Andole-phos system is able to catalyze both borylation reaction and Suzuki-Miyaura coupling reaction in a one-pot sequential manner for the direct synthesis of biaryl compounds in excellent yields.