Density Functional Theory Investigation of the Alkyl–Alkyl Negishi Cross‐Coupling Reaction Catalyzed by N‐Heterocyclic Carbene (NHC)–Pd Complexes

Why bigger is better : A “steric wall” created by the N‐(2,6‐diisopropylphenyl) substituent on the bulky NHC ligand IPr (1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene) guides the reactants to and from the Pd center through weak, fleeting (IPr)H–Pd interactions that help the oxidative addition intermediate escape “the anti‐trap”. The alternative “side” approach leads to transmetalation (the rate‐limiting step) for which a novel Pd–Zn interaction was identified.

     

tBuLi‐Mediated One‐Pot Direct Highly Selective Cross‐Coupling of Two Distinct Aryl Bromides

A Pd‐catalyzed direct cross‐coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd‐PEPPSI‐IPr] or [Pd‐PEPPSI‐IPent] as catalyst allows for the efficient one‐pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross‐coupling is the use of an ortho‐substituted bromide that undergoes lithium–halogen exchange preferentially.     

Palladium‐Catalyzed Amination of Aryl Sulfides with Anilines

A combination of a palladium–NHC catalyst and potassium hexamethyldisilazide enables the amination of aryl sulfides with anilines to afford a wide variety of diarylamines. The reaction conditions are versatile enough for the reaction of even bulky ortho‐substituted aryl sulfides. This amination can be applied to the modular synthesis of N‐aryl carbazoles from the corresponding ortho‐bromothioanisoles. As aryl sulfoxides undergo extended Pummerer reactions to afford ortho‐substituted aryl sulfides, the Pummerer products are thus useful substrates for the amination to culminate in efficient syntheses of a 2‐anilinobenzothiophene and an indole as proof‐of‐principle of the utility of the extended Pummerer reaction/amination cascade.     

Experimental and Theoretical Approaches to the Influence of the Addition of Pyrene to a Series of Pd and Ni NHC‐Based Complexes: Catalytic Consequences

A series of Ni and Pd complexes with three different N‐heterocyclic carbene (NHC)‐based ligands (imidazolylidene, benzimidazolylidene and pyrene–imidazolylidene) has been prepared and fully characterized. The influence of the addition of pyrene to solutions containing these complexes is studied by means of NMR and UV/Vis spectroscopies and by cyclic voltammetry. The addition of pyrene to the pyrene–NHC‐containing Pd and Ni complexes gives rise to the formation of adducts by π–π stacking interactions between pyrene and the pyrene group of the NHC ligand. This interaction causes a modification of the electronic properties of the metal, as demonstrated by cyclic voltammetric studies of the Ni–NHC complexes. Theoretical calculations support this type of π‐interactions, and justify the higher interactions observed with the pyrene–NHC containing complexes. The catalytic activities of the complexes were tested in the Suzuki–Miyaura C?C coupling and in the α‐arylation of ketones. The addition of pyrene as an external π‐stacking additive does not affect the activities of the complexes in the Suzuki–Miyaura coupling, but this observation may be justified due to the fact that the process is heterogeneously catalyzed, as indicated by the mercury‐drop test. The addition of pyrene to the catalytic α‐arylation of ketones results in a decrease in the activity of the reactions catalyzed by the pyrene–imidazolylidene palladium complex, whereas the other two catalysts do not modify their activity in the presence of this π‐stacking additive.     

Skeleton Decoration of NHCs by Amino Groups and its Sequential Booster Effect on the Palladium‐Catalyzed Buchwald–Hartwig Amination

A challenging synthetic modification of PEPPSI‐type palladium pre‐catalysts consisting of a stepwise incorporation of one and two amino groups onto the NHC skeleton was seen to exert a sequential enhancement of the electronic donor properties. This appears to be positively correlated with the catalytic performances of the corresponding complexes in the Buchwald–Hartwig amination. This is illustrated, for example, by the quantitative amination of 4‐chloroanisole by morpholine within 2 h at 25 °C with a 2 mol % catalyst/substrate ratio or by a significant reduction of catalytic loading (down to 0.005 mol %) for the coupling of aryl chlorides with anilines (max TON: 19 600).     

Room‐Temperature Amination of Deactivated Aniline and Aryl Halide Partners with Carbonate Base Using a Pd‐PEPPSI‐IPentCl‐ o‐Picoline Catalyst

Current state‐of‐the‐art protocols for the coupling of unreactive amines (e.g., electron‐poor anilines) with deactivated oxidative‐addition partners (e.g., electron‐rich and/or hindered aryl chlorides) involve strong heating (usually >100 °C) and/or tert‐butoxide base, and even then not all couplings are successful. The aggressive base tert‐butoxide reacts with and in many instances destroys the typical functional groups that are necessary for the function of most organic molecules, such as carbonyl groups, esters, nitriles, amides, alcohols, and amines. The new catalyst described herein, Pd‐PEPPSI‐IPent^Cl‐o‐picoline, is able to aminate profoundly deactivated coupling partners when using only carbonate base at room temperature.     

Synthesis of an [(NHC)2Pd(SiMe3)2] Complex and Catalytic cis‐Bis(silyl)ations of Alkynes with Unactivated Disilanes

The novel complex cis‐[(ITMe)₂Pd(SiMe₃)₂ (ITMe=1,3,4,5‐tetramethylimidazol‐2‐ylidene) has been synthesized by mild oxidative cleavage of Me₃SiSiMe₃ using [(ITMe)₂Pd⁰]. The use of this complex as precatalyst for the cis‐bis(silyl)ation of alkynes using unactivated disilanes is reported.     

Ni‐Catalyzed Amination Reactions: An Overview

Nitrogen‐containing organic compounds are valuable in many fields of science and industry. The most reliable method for the construction of C(sp²)–N bonds is undoubtedly palladium‐catalyzed amination. In spite of the great achievements made in this area, the use of expensive Pd‐based catalysts constitutes an important limitation for large‐scale applications. Since nickel is the least expensive and most abundant among the group 10 metals, the interest in Ni‐based catalysts for processes typically catalyzed by palladium has grown considerably over the last few years. Herein, we revise the development of Ni‐catalyzed amination reactions, emphasizing the most relevant and recent advances in the field.     

Phase‐Separable Polyisobutylene Palladium‐PEPPSI Precatalysts: Synthesis and Application in Buchwald–Hartwig Amination

This paper reports the efficient synthesis of the first class of polyisobutylene(PIB)‐supported palladium‐PEPPSI precatalyst (PEPPSI = pyridine‐enhanced precatalyst preparation, stabilization, and initiation). The new complexes are employed in Buchwald–Hartwig amination of aryl chlorides and are found to be reasonably active in the titled cross‐coupling reaction. The supported catalysts are tested in polar (1,4‐dioxane and 1,2‐dimethoxyethane) as well as in aliphatic reaction media (toluene and n‐heptane) and display superior activity in the highly lipophilic solvent (n‐heptane). The catalytic efficacy of PIB‐Pd‐PEPPSI precatalyst is measured to be comparable to its nonsupported analog. Pd‐leaching is determined by inductively coupled plasma mass spectrometry (ICP‐MS) after a simple liquid/liquid extraction and is found to be 2 ppb in the product phase, translating into a recovery of ≈99.8% of the palladium.     

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

Over the past two decades, considerable attention has been given to the development of new ligands for the palladium‐catalyzed arylation of amines and related NH‐containing substrates (i.e., Buchwald–Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH‐containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]₂ catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH‐containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd(cinnamyl)Cl]₂ as exhibiting the broadest demonstrated substrate scope for metal‐catalyzed cross‐coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]₂ to catalyze both the selective monoarylation of ammonia and the N‐arylation of indoles was exploited in the development of a new one‐pot, two‐step synthesis of N‐aryl heterocycles from ammonia, ortho‐alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N‐arylation/hydroamination reactions. Although the scope in the NH‐containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]₂ also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH‐containing moieties.     

Nickel‐Catalyzed Amination of Aryl Chlorides with Ammonia or Ammonium Salts

The nickel‐catalyzed amination of aryl chlorides to form primary arylamines occurs with ammonia or ammonium sulfate and a well‐defined single‐component nickel(0) precatalyst containing a Josiphos ligand and an η²‐bound benzonitrile ligand. This system also catalyzes the coupling of aryl chlorides with gaseous amines in the form of their hydrochloride salts.     

[(IPent)PdCl2(morpholine)]: A Readily Activated Precatalyst for Room‐Temperature,Additive‐Free Carbon–Sulfur Coupling

A series of new, easily activated NHC–Pd^II precatalysts featuring a trans‐oriented morpholine ligand were prepared and evaluated for activity in carbon‐sulfur cross‐coupling chemistry. [(IPent)PdCl₂(morpholine)] (IPent=1,3‐bis(2,6‐di(3‐pentyl)phenyl)imidazol‐2‐ylidene) was identified as the most active precatalyst and was shown to effectively couple a wide variety of deactivated aryl halides with both aryl and alkyl thiols at or near ambient temperature, without the need for additives, external activators, or pre‐activation steps. Mechanistic studies revealed that, in contrast to other common NHC–Pd^II precatalysts, these complexes are rapidly reduced to the active NHC–Pd⁰ species at ambient temperature in the presence of KOtBu, thus avoiding the formation of deleterious off‐cycle Pd^II–thiolate resting states.     

The Selective Cross‐Coupling of Secondary Alkyl Zinc Reagents to Five‐Membered‐Ring Heterocycles Using Pd‐PEPPSI‐IHeptCl

The ability to cross‐couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to β‐hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non‐rearranged) cross‐coupled product with aryl or heteroaryl oxidative‐addition partners, none have shown reliable selectivity with five‐membered‐ring heterocycles. In this report, a new, rationally designed catalyst, Pd‐PEPPSI‐IHept^Cl, is demonstrated to be effective in selective cross‐coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo‐fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time.