Heck Alkynylation (Copper-Free Sonogashira Coupling) of Aryl and Heteroaryl Chlorides, Using Pd Complexes of <i>t</i>‑Bu₂(<i>p</i>‑NMe₂C₆H₄)P: Understanding the Structure–Activity Relationships and Copper Effects

L₂Pd­(0) and L₂Pd­(II) complexes, where L= <i>t</i>-Bu₂(<i>p</i>-NMe₂C₆H₄)­P, have been identified as efficient catalyst systems for the Heck alkynylation of a variety of aryl bromides (17 examples) and aryl/heteroaryl chlorides (31 examples) with a range of aryl- and alkyl-acetylenes in excellent yields, under relatively low Pd loadings. The single-crystal X-ray structure determination of the presumably active catalytic species, L₂Pd­(0), was carried out in this study to better understand the superior activity of the current catalyst system from a structure–activity relationship point of view. The P–Pd–P bond angle indicates that the complex is bent (174.7°) in comparison to the perfectly linear (180.0°) structure of the analogous Pd­(<i>t</i>-Bu₃P)₂. Preliminary mechanistic studies on the negative copper effect and substrate effect of aryl acetylenes were conducted to better understand the cross-coupling pathway of Heck alkynylation

Palladium-Catalyzed <i>N</i>‑Arylation of Cyclopropylamines

A general method has been developed for the previously challenging arylation of cyclopropyl­amine and <i>N</i>-arylcyclo­propyl­amines. Highly active, air-stable, and commercially available R-allylpalladium precatalysts provide access to a wide range of (hetero)­arylated cyclo­propyl­anilines in high yields. Precatalysts [(<i>t</i>BuBrettPhos)­Pd­(allyl)]­OTf and [(BrettPhos)­Pd­(crotyl)]­OTf, deliver monoarylated products, while (P<i>t</i>Bu₃)­Pd­(crotyl)Cl is suited for preparing unsymmetrical diarylated products. The developed conditions tolerate a range of functional groups and heterocycles, allowing access to an array of arylated cyclopropylamines, a motif present in prominent drug molecules

Catalyst-Directed Chemoselective Double Amination of Bromo-chloro(hetero)arenes: A Synthetic Route toward Advanced Amino-aniline Intermediates

A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine) selectivity is dictated by the catalyst employed. A Pd-crotyl<i>(t-</i>BuXPhos) precatalyst selectively coupled the Ar–Br of the polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)­Pd­(allyl)Cl coupled the Ar–Cl site with secondary amines

Convenient One-Pot Synthesis of L₂Pd(0) Complexes for Cross-Coupling Catalysis

A convenient one-pot synthesis of (tBu3P)2Pd(0) was successfully carried out by using various air-stable Pd(II) salts, such as Pd(cod)Cl2, Pd(nbd)Cl2, Pd(CH3CN)2Cl2, or Pd(PhCN)2Cl2, without the use of an external reducing agent. Using Pd(cod)Cl2 as the precursor, large-scale synthesis of (tBu3P)2Pd(0) was accomplished in excellent yield and purity. Another protocol was also developed for L2Pd(0) complexes via an atom economical one-pot method by reacting in situ generated LPd(R-allyl)Cl complexes (L = tBu3P, Cy3P, (o-Tol)3P, CataXCium A, AmPhos, QPhos: R = H, Me, Ph) with 1 equivalent of L in the presence of a base with yields ranging from 74% to 92%, although the process can be further optimized. These methods are superior to those reported in the literature

Can Palladium Acetate Lose Its “Saltiness”? Catalytic Activities of the Impurities in Palladium Acetate

Commercially available palladium acetate often contains two major impurities, whose presence can impact the overall catalytic efficacy. This systematic study provides a comparison of the differences in catalytic activity of pure palladium acetate, Pd₃(OAc)₆, with the two impurities: Pd₃(OAc)₅(NO₂) and polymeric [Pd­(OAc)₂]_<i>n</i> in a variety of cross-coupling reactions. The solid state ¹³C NMR spectra of all three compounds in conjunction with DFT calculations confirm their reported geometries

Generating Active “L-Pd(0)” via Neutral or Cationic π‑Allylpalladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure–Activity Studies in Challenging Cross-Coupling Reactions

Two new classes of highly active yet air- and moisture-stable π-R-allylpalladium complexes containing bulky biaryl- and bipyrazolylphosphines with extremely broad ligand scope have been developed. Neutral π-allylpalladium complexes incorporated a range of biaryl/bipyrazolylphosphine ligands, while extremely bulky ligands were accommodated by a cationic scaffold. These complexes are easily activated under mild conditions and are efficient for a wide array of challenging C–C and C–X (X = heteroatom) cross-coupling reactions. Their high activity is correlated to their facile activation to a 12-electron-based “L-Pd(0)” catalyst under commonly employed conditions for cross-coupling reactions, noninhibitory byproduct release upon activation, and suppression of the off-cycle pathway to form dinuclear (μ-allyl)­(μ-Cl)­Pd₂(L)₂ species, supported by structural (single crystal X-ray) and kinetic studies. A broad scope of C–C and C–X coupling reactions with low catalyst loadings and short reaction times highlight the versatility and practicality of these catalysts in organic synthesis

Iridium-Catalyzed C–H Borylation of Heterocycles Using an Overlooked 1,10-Phenanthroline Ligand: Reinventing the Catalytic Activity by Understanding the Solvent-Assisted Neutral to Cationic Switch

The preformed catalyst [Ir­(Cl)­(COD)­(1,10-phenanthroline)] (<b>2</b>; COD = cyclooctadiene) was found to be highly effective in a model reaction for the borylation of N-Boc-indole at the 3-position with B₂pin₂ (pin = pinacolato) as the borylating agent to give consistently 99% yield with 0.5 mol % catalyst loading. The corresponding in situ formed catalyst from [Ir­(Cl)­(COD)]₂ and 1,10-phenanthroline provided very inconsistent results for the same reaction (0–94% conversion). We propose this to be due to the competing formation of a catalytically inactive cationic complex, [Ir­(COD)­(1,10-phenanthroline)]⁺Cl^– (<b>1</b>), in a noncoordinating solvent such as octane. Complexes <b>1</b> and <b>2</b> were characterized using solid-state NMR (¹³C and ³⁵Cl) in conjunction with XPS to be cationic and neutral, respectively. The X-ray crystal structure of a pentavalent neutral Ir complex, [Ir­(Cl)­(COD)­(2,2′-bipyridine)] (<b>3</b>), was also obtained for comparison purposes. Using catalyst <b>2</b>, the total synthesis of <i>Meridianin G</i> was accomplished in 87% overall isolated yield in a one-pot, three-step process