Computational Insight into Nickel‐Catalyzed Carbon–Carbon versus Carbon–Boron Coupling Reactions of Primary,Secondary, and Tertiary Alkyl Bromides

The nickel‐catalyzed alkyl–alkyl cross‐coupling (C?C bond formation) and borylation (C?B bond formation) of unactivated alkyl halides reported in the literature show completely opposite reactivity orders in the reactions of primary, secondary, and tertiary alkyl bromides. The proposed Ni^I/Ni^III catalytic cycles for these two types of bond‐formation reactions were studied computationally by means of DFT calculations at the B3LYP level. These calculations indicate that the rate‐determining step for alkyl–alkyl cross‐coupling is the reductive elimination step, whereas for borylation the rate is determined mainly by the atom‐transfer step. In borylation reactions, the boryl ligand involved has an empty p orbital, which strongly facilitates the reductive elimination step. The inability of unactivated tertiary alkyl halides to undergo alkyl–alkyl cross‐coupling is mainly due to the moderately high reductive elimination barrier.     

Copper‐Catalyzed Reductive Cross‐Coupling of Nonactivated Alkyl Tosylates and Mesylates with Alkyl and Aryl Bromides

A copper‐catalyzed reductive cross‐coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost‐effective construction of aryl–alkyl and alkyl–alkyl C?C bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo‐ or heterocycles, such as 2,3‐dihydrobenzofuran and benzochromene derivatives.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

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.     

Nickel‐Mediated Inter‐ and Intramolecular Reductive Cross‐Coupling of Unactivated Alkyl Bromides and Aryl Iodides at Room Temperature

A nickel‐mediated intermolecular reductive cross‐coupling reaction of unactivated alkyl bromides and aryl iodides at room temperature has been developed and successfully extended to less explored intramolecular versions and tandem cyclization‐intermolecular cross‐coupling. Highly stereoselective (or stereospecific) synthesis of linear‐fused perhydrofuro[2,3‐b]furan (pyran) and spiroketal skeletons allows rapid access to these useful building blocks, which would be potentially valuable in the synthesis of relevant natural products. A rational explanation for the formation of contiguous stereogenic centers is given.     

Nickel‐Catalyzed Chain‐Walking Cross‐Electrophile Coupling of Alkyl and Aryl Halides and Olefin Hydroarylation Enabled by Electrochemical Reduction

The first electrochemical approach for nickel‐catalyzed cross‐electrophile coupling was developed. This method provides a novel route to 1,1‐diarylalkane derivatives from simple and readily available alkyl and aryl halides in good yields and excellent regioselectivity under mild conditions. The procedure shows good tolerance for a broad variety of functional groups and both primary and secondary alkyl halides can be used. Furthermore, the reaction was successfully scaled up to the multigram scale, thus indicating potential for industrial application. Mechanistic investigation suggested the formation of a nickel hydride in the electroreductive chain‐walking arylation, which led to the development of a new nickel‐catalyzed hydroarylation of styrenes to provide a series of 1,1‐diaryl alkanes in good yields under mild reaction conditions.     

Bench‐Stable Stock Solutions of Silicon Grignard Reagents: Application to Iron‐ and Cobalt‐Catalyzed Radical C(sp3)–Si Cross‐Coupling Reactions

A robust method for the preparation of silicon‐based magnesium reagents is reported. The MgBr₂ used in the lithium‐to‐magnesium transmetalation step is generated in situ from 1,2‐dibromoethane and elemental magnesium in hot THF. No precipitation of MgBr₂ occurs in the heat, and transmetalation at elevated temperature leads to homogeneous stock solutions of the silicon Grignard reagents that are stable and storable in the fridge. This method avoids the preparation of silicon pronucleophiles such as Si?Si and Si?B reagents. The new Grignard reagents were applied to unprecedented iron‐ and cobalt‐catalyzed cross‐coupling reactions of unactivated alkyl bromides. The functional‐group tolerance of these magnesium reagents is excellent.     

Theoretical Study on the Mechanism of Ni‐Catalyzed Alkyl–Alkyl Suzuki Cross‐Coupling

Ni‐catalyzed cross‐coupling of unactivated secondary alkyl halides with alkylboranes provides an efficient way to construct alkyl–alkyl bonds. The mechanism of this reaction with the Ni/ L1 ( L1 =trans‐N,N′‐dimethyl‐1,2‐cyclohexanediamine) system was examined for the first time by using theoretical calculations. The feasible mechanism was found to involve a Ni^I–Ni^III catalytic cycle with three main steps: transmetalation of [Ni^I( L1 )X] (X=Cl, Br) with 9‐borabicyclo[3.3.1]nonane (9‐BBN)R₁ to produce [Ni^I( L1 )(R₁)], oxidative addition of R₂X with [Ni^I( L1 )(R₁)] to produce [Ni^III( L1 )(R₁)(R₂)X] through a radical pathway, and C? C reductive elimination to generate the product and [Ni^I( L1 )X]. The transmetalation step is rate‐determining for both primary and secondary alkyl bromides. KOiBu decreases the activation barrier of the transmetalation step by forming a potassium alkyl boronate salt with alkyl borane. Tertiary alkyl halides are not reactive because the activation barrier of reductive elimination is too high (+34.7 kcal mol^?1). On the other hand, the cross‐coupling of alkyl chlorides can be catalyzed by Ni/ L2 ( L2 =trans‐N,N′‐dimethyl‐1,2‐diphenylethane‐1,2‐diamine) because the activation barrier of transmetalation with L2 is lower than that with L1 . Importantly, the Ni⁰–Ni^II catalytic cycle is not favored in the present systems because reductive elimination from both singlet and triplet [Ni^II( L1 )(R₁)(R₂)] is very difficult.     

Linear Alkane CC Bond Chemistry Mediated by Metal Surfaces

Linear alkanes undergo different C?C bond chemistry (coupling or dissociation) thermally activated on anisotropic metal surfaces depending on the choice of the substrate material. Owing to the one‐dimensional geometrical constraint, selective dehydrogenation and C?C coupling (polymerization) of linear alkanes take place on Au(110) surfaces with missing‐row reconstruction. However, the case is dramatically different on Pt(110) surfaces, which exhibit similar reconstruction as Au(110). Instead of dehydrogenative polymerization, alkanes tend to dehydrogenative pyrolysis, resulting in hydrocarbon fragments. Density functional theory calculations reveal that dehydrogenation of alkanes on Au(110) surfaces is an endothermic process, but further C?C coupling between alkyl intermediates is exothermic. On the contrary, due to the much stronger C?Pt bonds, dehydrogenation on Pt(110) surfaces is energetically favorable, resulting in multiple hydrogen loss followed by C?C bond dissociation.     

Zinc‐Catalyzed Borylation of Primary,Secondary and Tertiary Alkyl Halides with Alkoxy Diboron Reagents at Room Temperature

A new catalytic system based on a Zn^II NHC precursor has been developed for the cross‐coupling reaction of alkyl halides with diboron reagents, which represents a novel use of a Group XII catalyst for C? X borylation. This approach gives borylations of unactivated primary, secondary, and tertiary alkyl halides at room temperature to furnish alkyl boronates, with good functional‐group compatibility, under mild conditions. Preliminary mechanistic investigations demonstrated that this borylation reaction seems to involve one‐electron processes.     

Cobalt‐Catalyzed Negishi Cross‐Coupling Reactions of (Hetero)Arylzinc Reagents with Primary and Secondary Alkyl Bromides and Iodides

We report a cobalt‐catalyzed cross‐coupling of di(hetero)arylzinc reagents with primary and secondary alkyl iodides or bromides using THF‐soluble CoCl₂?2 LiCl and TMEDA as a ligand, which leads to the corresponding alkylated products in up to 88 % yield. A range of functional groups (e.g. COOR, CN, CF₃, F) are tolerated in these substitution reactions. Remarkably, we do not observe rearrangement of secondary alkyl iodides to unbranched products. Additionally, the use of cyclic TBS‐protected iodohydrins leads to trans‐2‐arylcyclohexanol derivatives in excellent diastereoselectivities (up to d.r.=99:1).     

Enantioselective Cross‐Exchange between C−I and C−C σ Bonds

A palladium‐catalyzed enantioselective intramolecular σ‐bond cross‐exchange between C?I and C?C bonds is realized, providing chiral indanones bearing an alkyl iodide group and an all‐carbon quaternary stereocenter. Pd/TADDOL‐derived phosphoramidite is found to be an efficient catalytic system for both C?C bond cleavage and alkyl iodide reductive elimination. In addition to aryl iodides, aryl bromides can also be used for this transformation in the presence of KI. Density‐functional theory (DFT) calculation studies support the ring‐opening of cyclobutanones occuring through an oxidative addition/reductive elimination process involving Pd^IV species.     

Palladium‐Catalyzed Oxygenative Cross‐Coupling of Ynamides and Benzyl Bromides by Carbene Migratory Insertion

A palladium‐catalyzed oxygenative cross‐coupling of ynamides and benzyl bromides has been developed. After subsequent hydrogenation, α,α‐disubstituted amide derivatives were obtained in good yields. Migratory insertion of α‐oxo palladium carbene species, generated by intermolecular oxidation, is proposed as the key step in this reaction. The study demonstrates the potential of ynamides to serve as carbene precursors in palladium‐catalyzed C?C bond‐forming cross‐coupling reactions.     

Palladium‐Catalyzed Oxidative Difunctionalization of Alkenes with α‐Carbonyl Alkyl Bromides Initiated through a Heck‐type Insertion: A Route to Indolin‐2‐ones

The oxidative interception of various σ‐alkyl palladium(II) intermediates with additional reagents for the difunctionalization of alkenes is an important research area. A new palladium‐catalyzed oxidative difunctionalization reaction of alkenes with α‐carbonyl alkyl bromides is described, in which the σ‐alkyl palladium(II) intermediate is generated through a Heck insertion and trapped using an aryl C(sp²)? H bond. This method can be applied to various α‐carbonyl alkyl bromides, including primary, secondary, and tertiary α‐bromoalkyl esters, ketones, and amides.     

Mechanistic Dichotomy of Magnesium‐ and Zinc‐Based Germanium Nucleophiles in the C(sp3)−Ge Cross‐Coupling with Alkyl Electrophiles

Robust procedures for two mechanistically distinct C(sp³)?Ge bond formations from alkyl electrophiles and germanium nucleophiles are reported. The germanium reagents were made available as bench‐stable solutions by lithium‐to‐magnesium and lithium‐to‐zinc transmetalation, respectively. The germanium Grignard reagent reacts with various primary and secondary alkyl electrophiles by an ionic nucleophilic displacement. Conversely, the coupling of the corresponding zinc reagent requires a nickel catalyst, which then engages in radical bond formations with primary, secondary, and even tertiary alkyl bromides. Both methods avoid the regioselectivity issue of alkene hydrogermylation and enable the synthesis of a wide range of functionalized alkyl‐substituted germanes.     

Copper‐Catalyzed Enantioconvergent Cross‐Coupling of Racemic Alkyl Bromides with Azole C(sp2)−H Bonds

The development of enantioconvergent cross‐coupling of racemic alkyl halides directly with heteroarene C(sp²)?H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona‐alkaloid‐derived N,N,P‐ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp²)?H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α‐chiral alkylated azoles, such as 1,3,4‐oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4‐triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp²)?H bond and the involvement of alkyl radical species under the reaction conditions.     

Visible‐Light Photocatalytic Radical Alkenylation of α‐Carbonyl Alkyl Bromides and Benzyl Bromides

Through the use of [Ru(bpy)₃Cl₂] (bpy=2,2′‐bipyridine) and [Ir(ppy)₃] (ppy=phenylpyridine) as photocatalysts, we have achieved the first example of visible‐light photocatalytic radical alkenylation of various α‐carbonyl alkyl bromides and benzyl bromides to furnish α‐vinyl carbonyls and allylbenzene derivatives, prominent structural elements of many bioactive molecules. Specifically, this transformation is regiospecific and can tolerate primary, secondary, and even tertiary alkyl halides that bear β‐hydrides, which can be challenging with traditional palladium‐catalyzed approaches. The key initiation step of this transformation is visible‐light‐induced single‐electron reduction of C? Br bonds to generate alkyl radical species promoted by photocatalysts. The following carbon? carbon bond‐forming step involves a radical addition step rather than a metal‐mediated process, thereby avoiding the undesired β‐hydride elimination side reaction. Moreover, we propose that the Ru and Ir photocatalysts play a dual role in the catalytic system: they absorb energy from the visible light to facilitate the reaction process and act as a medium of electron transfer to activate the alkyl halides more effectively. Overall, this photoredox catalysis method opens new synthetic opportunities for the efficient alkenylation of alkyl halides that contain β‐hydrides under mild conditions.     

Nickel‐Catalyzed Cross‐Electrophile Coupling of Aryl Bromides with Pyrimidin‐2‐yl Tosylates

A new protocol for the NiCl₂ ‐catalyzed cross‐electrophile coupling of aryl bromides with pyrimidin‐2‐yl tosylates to give the corresponding C2 ‐arylation pyrimidine derivatives has been developed. This study provides an improvement over previous methods by using pyrimidin‐2‐yl tosylates instead of halides as coupling partners that are stable and easily available.     

Palladium/Copper Dual Catalysis for the Cross‐Coupling of Aryl(trialkyl)silanes with Aryl Bromides

Whereas aryl(trialkyl)silanes are considered to be ideal organometallic reagents for cross‐coupling reactions owing to their stability, low toxicity, solubility, and easy accessibility, they are generally inert under typical cross‐coupling conditions. Disclosed herein is a palladium/copper catalytic system that enables the cross‐coupling of trimethyl, triethyl, tert‐butyldimethyl, and triisopropyl aryl silanes with aryl bromides. This process is applicable to the sequential C?H and C?Si bond arylation of thiophenes and the synthesis of poly(thiophene–fluorene)s.     

Oxygen Activated,Palladium Nanoparticle Catalyzed,Ultrafast Cross‐Coupling of Organolithium Reagents

The discovery of an ultrafast cross‐coupling of alkyl‐ and aryllithium reagents with a range of aryl bromides is presented. The essential role of molecular oxygen to form the active palladium catalyst was established; palladium nanoparticles that are highly active in cross‐coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High selectivities were observed for a range of heterocycles and functional groups as well as for an expanded scope of organolithium reagents. The applicability of this method was showcased by the synthesis of the [¹¹C]‐labeled PET tracer celecoxib.