Palladium-Catalyzed Chemoselective Phosphorylation of Poly(pseudo)halides: A Route for Organophosphorus Synthesis.

We present an advancement in synthesizing organophosphorus compounds via chemoselective phosphorylation achieved by a palladium and SelectPhos ligand system (Pd/L1). This catalysis system exhibits remarkable chemoselectivity, even in poly(pseudo)halide substrates and overcoming toxicity and substrate scope limitations. The catalytic system is robust, which is demonstrated across diverse substrates such as chloroaryl and bromoaryl triflates. Furthermore, we present a one-pot sequential strategy combining phosphorylation with Suzuki-Miyaura coupling, providing a versatile platform for the efficient synthesis of complex organophosphorus compounds, challenging conventional reactivity paradigms.

An indole-amide-based phosphine ligand enabling a general palladium-catalyzed sterically hindered Suzuki-Miyaura cross-coupling reaction.

A novel family of indole-amide-based phosphine ligands was designed and synthesized. The Pd/InAm-phos (L1) catalytic system exhibited excellent efficiency in the Suzuki-Miyaura cross-coupling of sterically hindered (hetero)aryl chlorides to synthesize tri-ortho-substituted biaryls. Excellent product yields were obtained in a short reaction time (e.g., 10 min), and a Pd catalyst loading down to 50 ppm was also achieved. The oxidative addition adduct of Pd-L1 with 2-chlorotoluene was also well-characterized by single-crystal X-ray crystallography and showed a κ2-P,O-coordination of L1 with palladium.

Ligand Control of Palladium-Catalyzed Site-Selective α- and γ-Arylation of α,ß-Unsaturated Ketones with (Hetero)aryl Halides.

This study describes the first palladium-catalyzed, site-selective α- and γ-arylation of α,ß-unsaturated ketones with (hetero)aryl halides. A wide range of hetero(aryl)halides coupled with α,ß-unsaturated ketones, and transformation into the arylated products proceeded with excellent to good yields. The site selectivity of the reaction is switchable by simply changing the phosphine ligand to access either α-arylated or γ-arylated products in good to excellent yields by using a low catalyst loading, and the method demonstrates good functional-group compatibility.

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.

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.

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.

Palladium-Catalyzed Deuterodehalogenation of Halogenated Aryl Triflates Using Isopropanol-d8 as the Deuterium Source.

In this study, a novel and efficient Pd-catalyzed chemoselective deuterodehalogenation reaction of halogenated aryl triflates was developed using isopropanol-d8 as the deuterium source. This chemoselective reaction afforded an unconventional chemoselectivity order of C-Br > C-Cl > C-OTf. This catalytic system was successfully applied to chemoselective hydrodehalogenation of chloroaryl triflates, providing excellent C-Cl chemoselectivity over C-OTf.

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.

Palladium-catalyzed chemoselective direct α-arylation of carbonyl compounds with chloroaryl triflates at the C-Cl site.

This study described palladium-catalyzed chemoselective direct α-arylation of carbonyl compounds with chloroaryl triflates in the Ar-Cl bond. The Pd/SelectPhos system showed excellent chemoselectivity toward the Ar-Cl bond in the presence of the Ar-OTf bond with a broad substrate scope and excellent product yields. The electronic and steric hindrance offered by the -PR2 group of the ligand with the C2-alkyl group was found to be the key factor affecting the reactivity and chemoselectivity of the α-arylation reaction. The chemodivergent approach was also successfully employed in the synthesis of flurbiprofen and its derivatives (e.g., -OMe and -F).

Rapid Access of Alkynyl and Alkenyl Coumarins via a Dipyridinium Methylide and Propargylamine Cascade Reaction.

A DMAP-catalyzed cascade approach allowing facile assembly of alkynyl coumarins is reported. By virtue of reactive o-AQM (in situ generated from modular propargylamine) and a new synthetic equivalent of acyl carbene (from pyridinium ylide), the reaction proceeds smoothly to afford a variety of alkynyl coumarins in good-to-excellent yields. This transition-metal-free and oxidant-free process features moderate functional group tolerance, particularly the -Br group; thus, this protocol circumvents the inherent shortcomings of the existing Sonogashira coupling of coumarin triflates. This versatile method is also found to be applicable to the preparation of ß-alkenyl coumarins, resembling the outcomes of the current Heck-type coupling reaction.

DMAP-Catalyzed Annulation Approach for Modular Assembly of Furan-Fused Chromenes.

With a tandem DMAP-catalyzed reaction between o-AQM, in which it is generated in situ from propargylic amine, and acyl carbene surrogate (from pyridinium ylide), a variety of polyarylated chromenes are assembled in good yields. This process does not require transition-metal catalyst and exhibits easy manipulation of the arene group and good functional group compatibility, particularly the -Br group which can be further transformed to other functionalities by cross-coupling reactions. The modular feature of o-AQM substrates and the simple operation procedures add further advantages to this synthetic method.

A ZnI2-catalyzed regioselective cascade 1,4-conjugate addition/5-exo-dig annulation pathway for one-pot access to heterobiaryl frameworks.

Facile access to π-extended heterobiaryl compounds via a non-cross-coupling strategy has been achieved. In the presence of an inexpensive ZnI2 catalyst and versatile propargylamine and ß-naphthol (or ß-naphthylamine and ß-naphthyl mercaptan) starting materials, a variety of sterically hindered heterobiaryl frameworks can be easily obtained. The present catalytic system offers excellent selectivity, good-to-excellent product yields, and good functional group tolerance including, for instance, -CN, -COOH, -C(O)R, -Br and -Cl groups. This cyclization process is proposed to proceed via in situ generated alkynyl o-quinone methides (o-AQMs), following a cascade intermolecular 1,4-conjugate addition/5-exo-dig annulation/1,3-H shift pathway.

Exploiting Aryl Mesylates and Tosylates in Catalytic Mono-α-arylation of Aryl- and Heteroarylketones.

The first general palladium catalyst for the catalytic mono-α-arylation of aryl- and heteroarylketones with aryl mesylates and tosylates is described. The newly developed indolyl-derived phosphine ligand L7 has been identified to promote this reaction efficiently. The key to success is attributed to the enhanced steric congestion of the catalyst and effective oxidative addition of the C(Ar)-OMs bond. In the presence of Pd(OAc)2 (0.25-2.5 mol %) and L7, selective monoarylations are achieved with ample reaction scope and product yields up to 95%. Importantly, we demonstrated the applicability of this protocol with the modification of biological phenolic compounds, rendering it amenable for functionalization of phenolic (pro)drugs.

A general direct arylation of polyfluoroarenes with heteroaryl and aryl chlorides catalyzed by palladium indolylphosphine complexes.

The first general examples of direct coupling of heteroaryl chlorides, especially substituted 2-pyridyl chlorides which were previously found to be problematic, with electron-deficient polyfluoroarenes are reported. Pd(OAc)2 associated with 3-(dicyclohexylphosphino)-2-phenylindole L1 serves as the effective catalyst which allows the challenging direct coupling of heteroaryl chlorides and polyfluoroarenes. In addition to heterocycles, a wide range of non-activated and activated aryl chlorides and alkenyl chlorides were also applicable under this catalyst system. A catalyst loading down to 1 mol % Pd can be achieved.

Design of an Indolylphosphine Ligand for Reductive Elimination-Demanding Monoarylation of Acetone Using Aryl Chlorides.

The rational design of a phosphine ligand for the reductive elimination-demanding Pd-catalyzed mono-α-arylation of acetone is demonstrated and reported. The catalyst is tolerant of previously proven challenging electron-deficient aryl chlorides and provides excellent product yields with down to 0.1 mol % Pd. Preliminary investigations suggest that the rate-limiting step for the proposed system is the oxidative addition of aryl chlorides, in which it contradicts previous findings regarding the α-arylation of acetone with aryl halides.