Palladium‐Catalyzed Asymmetric Benzylic Alkylation of Active Methylene Compounds with α‐Naphthylbenzyl Carbonates and Pivalates

A Pd/(R)‐H₈‐BINAP‐catalyzed asymmetric benzylic alkylation of active methylene compounds has been developed. The reaction proceeds without the use of an external base, and the starting racemic diarylmethyl carbonates are converted into the optically active coupling products which contain the benzylic chiral stereocenter by a dynamic kinetic asymmetric transformation (DYKAT). Additionally, with suitable carbonates bases, the same palladium catalysis allows the corresponding pivalates to be adopted in the same DYKAT process.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Palladium‐Catalyzed Cross‐Dehydrogenative Functionalization of C(sp2)H Bonds

The catalytic cross‐dehydrogenative coupling (CDC) reaction has received intense attention in recent years. The attractive feature of this coupling process is the formation of a C? C bond from two C? H moieties under oxidative conditions. In this Focus Review, recent advances in the palladium‐catalyzed CDC reactions of C(sp²)? H bond are summarized, with a focus on the period from 2011 to early 2013.     

Palladium‐Catalyzed Intermolecular Oxidative Coupling Reactions of (Z)‐Enamines with Isocyanides through Selective β‐C(sp2)‐H and/or C=C Bond Cleavage

Herein, two efficient palladium‐catalyzed intermolecular oxidative coupling reactions of (Z)‐enamines with isocyanides via selective β‐C(sp²)‐H and/or C=C bond cleavage have been developed, leading to controllable chemodivergent and stereoselective construction of a wide range of (E)‐β‐carbamoylenamine derivatives containing strong intramolecular hydrogen bonds. Furthermore, possible reaction pathways for these transformations are proposed on the basis of preliminary mechanism studies.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Enantioselective palladium-catalyzed C(sp2)-H carbamoylation

An enantioselective palladium-catalyzed C(sp²)-H carbamoylation for the preparation of chiral isoindolines was described for the first time. With chiral monophosphorus ligand (R)-AntPhos as the ligand, a series of chiral isoindolines were prepared from diarylmethyl carbamoyl chlorides in excellent yields and enantioselectivities with the palladium loading as low as 1 mol%. Initial mechanistic studies indicated the asymmetric cyclization catalyzed a palladium species with a single chiral monophosphorus ligand.     

Nitrimines as Reagents for Metal‐Free Formal C(sp2)–C(sp2) Cross‐Coupling Reactions

Nitrimines are employed as powerful reagents for metal‐free formal C(sp²)–C(sp²) cross‐coupling reactions. The new chemical process is tolerant of a wide array of nitrimine and heterocyclic coupling partners giving rise to the corresponding di‐ or trisubstituted alkenes, typically in high yield and with high stereoselectivity. This method is ideal for the metal‐free construction of heterocycle‐containing drug targets, such as phenprocoumon.     

Palladium‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.     

Rollover‐Assisted C(sp2)C(sp3) Bond Formation

Rollover cyclometalation involves bidentate heterocyclic donors, unusually acting as cyclometalated ligands. The resulting products, possessing a free donor atom, react differently from the classical cyclometalated complexes. Taking advantage of a “rollover”/“retro‐rollover” reaction sequence, a succession of oxidative addition and reductive elimination in a series of platinum(II) complexes [Pt(N,C)(Me)(PR₃)] resulted in a rare C(sp²)?C(sp³) bond formation to give the bidentate nitrogen ligands 3‐methyl‐2,2′‐bipyridine, 3,6‐dimethyl‐2,2′‐bipyridine, and 3‐methyl‐2‐(2′‐pyridyl)‐quinoline, which were isolated and characterized. The nature of the phosphane PR₃ is essential to the outcome of the reaction. This route constitutes a new method for the activation and functionalization of C?H bond in the C(3) position of bidentate heterocyclic compounds, a position usually difficult to functionalize.     

Highly stable magnetically separable copper nanocatalyst as an efficient catalyst for C(sp2)–C(sp) and C(sp2)–C(sp2) cross‐coupling reactions

A copper catalyst has been explored as an efficient and recyclable catalyst to effect Sonogashira and Suzuki cross‐coupling reactions. After modification of 2‐(((piperazin‐1‐ylmethyl)imino)methyl)phenol (PP) on the surface of amorphous silica‐coated iron oxide (Fe₃O₄@SiO₂@Cl) magnetic core–shell nanocomposite, copper(II) chloride was employed to synthesize the Fe₃O₄@SiO₂@PP‐Cu catalyst, affording a copper loading of 1.52 mmol g⁻¹. High yield, low reaction times, non‐toxicity and recyclability of the catalyst are the main merits of this protocol. The catalyst was characterized using Fourier transform infrared, X‐ray photoelectron, energy‐dispersive X‐ray and inductively coupled plasma optical emission spectroscopies, X‐ray diffraction, scanning and transmission electron microscopies, and vibrating sample magnetometry.     

Piperazine‐ and DABCO‐bridged dinuclear N‐heterocyclic carbene palladium complexes: synthesis,structure and application to Hiyama coupling reaction

Four dinuclear N ‐heterocyclic carbene (NHC) palladium complexes were prepared by reaction of imidazolinium salts, PdCl₂ and bridging ligands (piperazine and DABCO) in one pot or by direct cleavage of the chloro‐bridged dimeric compounds [Pd(μ ‐Cl)(Cl)(NHC)]₂ with bridging ligands. All of the complexes were fully characterized using ¹H NMR, ¹³C NMR, high‐resolution mass and infrared spectroscopies, elemental analysis and single‐crystal X‐ray diffraction. The catalytic activities of the obtained palladium catalysts towards Hiyama coupling of aryl chlorides with phenyltrimethoxysilane were investigated and the results showed that the dinuclear palladium complexes were considerably active for the coupling reaction. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis and characterization of functional polysilanes [RMe2Si(CH2)x(Me)Si]n (R = 2‐Fu, 5‐Me‐2‐Fu, 2‐Th, 4‐Me‐2‐Th; x = 2, 3) with appended furyl/thienyl groups on the carbosilyl side chains and their application in the generation and stabilization of palladium nanoparticles

The polysilanes [RMe₂Si(CH₂)_x(Me)Si]_n [x = 2, 3; R = 2‐Fu ( 1, 2 ), 5‐Me‐2‐Fu ( 3, 4 )] bearing furyl‐substituted carbosilyl side chains have been synthesized by dehalocondensation reaction (Wurtz coupling) of the corresponding carbosilanes using sodium dispersion in refluxing toluene. On the other hand, analogous polysilanes with appended thienyl groups [x = 2, 3; R = 2‐Th ( 5, 6 ), 4‐Me‐2‐Th ( 7, 8 )] are only accessible by the reaction of the corresponding carbosilane precursors under mild Wurtz coupling conditions (THF, RT). These polysilanes reveal monomodal molecular weight distribution with M_w/PDI = 3.3–5.4 × 10⁴/1.22–1.47 ( 1–4 ) and 9.1–14.4 × 10⁴/1.45–1.61 ( 5–8 ) and are characterized by FT‐IR, multinuclear (¹H, ¹³C{¹H}, ²⁹Si{¹H}) NMR, and UV/PL spectral studies as well as thermogravimetric analysis (TGA). Preliminary studies on the reactivity of polysilane 2 with palladium acetate (toluene, RT) reveal the formation of spherical palladium nanoparticles of size 8.2 ± 0.6 nm, which remain stable in solution for several weeks. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7816–7826, 2008     

Palladium‐Catalyzed Suzuki–Miyaura Cross‐Coupling of Secondary α‐(Trifluoromethyl)benzyl Tosylates

A palladium‐catalyzed C(sp³)−C(sp²) Suzuki–Miyaura cross‐coupling of aryl boronic acids and α‐(trifluoromethyl)benzyl tosylates is reported. A readily available, air‐stable palladium catalyst was employed to access a wide range of functionalized 1,1‐diaryl‐2,2,2‐trifluoroethanes. Enantioenriched α‐(trifluoromethyl)benzyl tosylates were found to undergo cross‐coupling to give the corresponding enantioenriched cross‐coupled products with an overall inversion in configuration. The crucial role of the CF₃ group in promoting this transformation is demonstrated by comparison with non‐fluorinated derivatives.     

Synthesis,characterization and catalytic activity of new aminomethyldiphosphine–Pd(II) complexes for Suzuki cross‐coupling reaction

A new range of CF₃‐substituted aminomethyldiphosphine (P―C―N) ligands ((C₆H₅)₂PCH₂)₂NR (R = ―C₆H₄(2‐CF₃) ( 1 ), ―C₆H₄(3‐CF₃) ( 1b ) has been synthesized from 2‐(trifluoromethyl)aniline and 3‐(trifluoromethyl)aniline with diphenylphosphine. The aminomethyldiphosphine ligands were reacted with Pd(cod)Cl₂ to give corresponding metal complexes, PdLCl₂ ( 2a , 2b ). The aminomethyldiphosphine–palladium compounds were characterized by utilizing several methods including NMR (¹H, ¹³C, ³¹P) and elemental analysis. These compounds were used as catalysts in Suzuki cross‐coupling reaction of aryl chlorides and bromides. The effect of base was also investigated in this current project. CF₃‐substituted aminomethyldiphosphine–palladium complexes were found to be efficient catalysts in Suzuki cross‐coupling reaction of activated and deactivated aryl boronic acids. Copyright © 2013 John Wiley & Sons, Ltd.     

Trifluoromethylthiolation of Aryl Iodides and Bromides Enabled by a Bench‐Stable and Easy‐To‐Recover Dinuclear Palladium(I) Catalyst

While palladium catalysis is ubiquitous in modern chemical research, the recovery of the active transition‐metal complex under routine laboratory applications is frequently challenging. Described herein is the concept of alternative cross‐coupling cycles with a more robust (air‐, moisture‐, and thermally‐stable) dinuclear Pd^I complex, thus avoiding the handling of sensitive Pd⁰ species or ligands. Highly efficient C? SCF₃ coupling of a range of aryl iodides and bromides was achieved, and the recovery of the Pd^I complex was accomplished via simple open‐atmosphere column chromatography. Kinetic and computational data support the feasibility of dinuclear Pd^I catalysis. A novel SCF₃‐bridged Pd^I dimer was isolated, characterized by X‐ray crystallography, and verified to be a competent catalytic intermediate.     

Chemo‐ and Regioselective C(sp3)H Arylation of Unactivated Allylarenes by Deprotonative Cross‐Coupling

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)₂, allylbenzene derivatives undergo reversible deprotonation. Transmetalation of the resulting allyllithium intermediate to LPdAr(Br) and reductive elimination provide the 1,1‐diarylprop‐2‐enes, which are not accessible by the Heck reaction. The regioselectivity in this deprotonative cross‐coupling process is catalyst‐controlled and very high.     

Enantioselective Construction of α‐Chiral Silanes by Nickel‐Catalyzed C(sp3)−C(sp3) Cross‐Coupling

An enantioselective C(sp³)?C(sp³) cross‐coupling of racemic α‐silylated alkyl iodides and alkylzinc reagents is reported. The reaction is catalyzed by NiCl₂/(S,S)‐Bn‐Pybox and yields α‐chiral silanes with high enantiocontrol. The catalyst system does not promote the cross‐coupling of the corresponding carbon analogue, corroborating the stabilizing effect of the silyl group on the alkyl radical intermediate (α‐silicon effect). Both coupling partners can be, but do not need to be, functionalized, and hence, even α‐chiral silanes with no functional group in direct proximity of the asymmetrically substituted carbon atom become accessible. This distinguishes the new method from established approaches for the synthesis of α‐chiral silanes.     

Direct C(sp2)C(sp3) Cross‐Coupling of Diaryl Zinc Reagents with Benzylic,Primary, Secondary,and Tertiary Alkyl Halides

The direct C(sp²)? C(sp³) cross‐coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²)? C(sp³) cross‐coupling showed excellent functional‐group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²)? C(sp³) bonds.     

Palladium‐Catalyzed C(sp3)H Arylation of N‐Boc Benzylalkylamines via a Deprotonative Cross‐Coupling Process

Diarylmethylamines are key intermediates and products in the pharmaceutical industry. Herein we disclose a novel method toward the synthesis of these important compounds via C?H functionalization. Presented is a reversible deprotonation of N‐Boc benzylalkylamines at the benzylic C?H with in situ arylation by a NiXantPhos‐based palladium catalyst (50–93 % yield, 29 examples). The method is also successful with N‐Boc‐tetrahydroisoquinolines. The advantages of this method are it avoids strong bases, low temperatures, and the need to transmetallate to main group metals for the coupling.     

Palladium–N‐Heterocyclic Carbene (NHC)‐Catalyzed Asymmetric Synthesis of Indolines through Regiodivergent C(sp3)H Activation: Scope and DFT Study

Two bulky, chiral, monodentate N‐heterocyclic carbene ligands were applied to palladium‐catalyzed asymmetric C?H arylation to incorporate C(sp³)?H bond activation. Racemic mixtures of the carbamate starting materials underwent regiodivergent reactions to afford different trans‐2,3‐substituted indolines. Although this C_Ar?C_alkyl coupling requires high temperatures (140–160 °C), chiral induction is high. This regiodivergent reaction, when carried out with enantiopure starting materials, can lead to single structurally different enantiopure products, depending on the catalyst chirality. The C?H activation at a tertiary center was realized only in the case of a cyclopropyl group. No C?H activation takes place alpha to a tertiary center. A detailed DFT study is included and analyses of methyl versus methylene versus methine C?H activation is used to rationalize experimentally observed regio‐ and enantioselectivities.