Preparation of Polyfunctional Organozinc Halides by an InX3 - and LiCl-Catalyzed Zinc Insertion to Aryl and Heteroaryl Iodides and Bromides.

We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts containing sterically hindered chelating alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005-0.05 mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes.

Molecules bearing fluorine are increasingly prevalent in pharmaceuticals, agrochemicals, and functional materials. The cyanodifluoromethyl group is unique because its size is closer than that of any other substituted difluoromethyl group to the size of the trifluoromethyl group, but its electronic properties are distinct from those of the trifluoromethyl group. In addition, the presence of the cyano group provides synthetic entry to a wide range of substituted difluoromethyl groups. However, the synthesis of cyanodifluoromethyl compounds requires multiple steps, highly reactive reagents (such as DAST, NSFI, or IF5), or specialized starting materials (such as α,α-dichloroacetonitriles or α-mercaptoacetonitriles). Herein, we report a copper-mediated cyanodifluoromethylation of aryl and heteroaryl iodides and activated aryl and heteroaryl bromides with TMSCF2CN. This cyanodifluoromethylation tolerates an array of functional groups, is applicable to late-stage functionalization of complex molecules, yields analogues of FDA-approved pharmaceuticals and fine chemicals, and enables the synthesis of a range of complex molecules bearing a difluoromethylene unit by transformations of the electron-poor CN unit. Calculations of selected steps of the reaction mechanism by Density Functional Theory indicate that the barriers for both the oxidative addition of iodobenzene to [(DMF)CuCF2CN] and the reductive elimination of the fluoroalkyl product from the fluoroalkyl copper intermediate lie in between those of [(DMF)CuCF3] and [(DMF)CuCF2C(O)NMe2].

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.

Unparalleled rates for the activation of aryl chlorides and bromides: coupling with amines and boronic acids in minutes at room temperature.

Tris(trimethylsilyl)silane (TTMSS) and azobisisobutironitrile (AIBN) promoted the easy intermolecular arylation of aryl and heteroaryl bromides under thermal conditions via a radical pathway.

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

CuO/AB was found to be a simple and efficient catalyst for the N-arylation of a variety of nitrogen-containing heterocycles, giving the products in excellent yields.

Palladium catalysts have been studied for the Sonogashira-Hagihara coupling of aryl and heteroaryl bromides with terminal alkynes. Among the different biarylphosphines tested, 2-(di-tert-butylphosphino)-N-phenylindole (cataCXium Plntb) allows the efficient coupling of both activated and deactivated (hetero)aryl bromides in the presence of sodium tetrachloropalladate in tetramethylethylenediamine (TMEDA) at 80 degrees C. The catalyst system gives high turnover numbers (up to 14 100) and shows a broad tolerance towards functional groups such as OH and NH2, as well as heterocycles.

We report a new protocol for the annulative difunctionalization of acetylenes via tandem carbocyclization–coupling of ε‐acetylenic β‐ketoesters with aryl and heteroaryl bromides and chlorides catalyzed by the palladium species derived from an air‐ and moisture‐stable palladacyclic precatalyst. In the tandem process, the palladium complex combines appropriate carbophilic Lewis acidity and redox activity to catalyze two mechanistically distinct reactions ‐ nucleophilic addition of the enolate to unactivated alkyne, followed by CC coupling.We found that a broad range of electronically varied aryl and heteroaryl bromides and chlorides underwent this reaction with various ε‐acetylenic β‐ketoesters, providing corresponding substituted vinylidenecyclopentanes in high yield with excellent functional group tolerance.magnified image

Cu-catalysed cross-coupling for mono- and di-arylations of aryl and heteroaryl iodides and bromides is achieved with arylboronate esters.

Copper-catalyzed conversion of aryl and heteroaryl bromides into the corresponding iodide

A new strategy for the regiospecific construction of unsymmetrical biaryls is presented, in which easily available salts of carboxylic acids are decarboxylated in situ to give arylmetal species that serve as the nucleophilic component in a catalytic cross-coupling reaction with aryl halides. The catalyst system consists of a copper phenanthroline complex that mediates the extrusion of CO2 from aromatic carboxylates to generate arylcopper species, and a palladium complex that catalyzes the cross-coupling of these intermediates with aryl halides. This bimetallic system allows the direct coupling of various aryl, heteroaryl, or vinyl carboxylic acids with aryl or heteroaryl iodides, bromides, or chlorides at 160 degrees C in the presence of a mild base such as potassium carbonate. The present scope and potential economic impact of the reaction are demonstrated by the synthesis of 42 biaryls, some of which are of substantial industrial relevance. Remaining challenges and future perspectives of the new transformation are discussed.

First-row metal complexes often undergo undesirable one-electron redox processes during two-electron steps of catalytic cycles. We report the amination of aryl chlorides and bromides with primary aliphatic amines catalyzed by a well-defined, single-component nickel precursor (BINAP)Ni(η2-NC-Ph) (BINAP = 2,2′-bis(biphenylphosphino)-1,1′-binaphthalene) that minimizes the formation of Ni(I) species and (BINAP)2Ni. The scope of the reaction encompasses electronically varied aryl chlorides and nitrogen-containing heteroaryl chlorides, including pyridine, quinoline, and isoquinoline derivatives. Mechanistic studies support the catalytic cycle involving a Ni(0)/Ni(II) couple for this nickel-catalyzed amination and are inconsistent with a Ni(I) halide intermediate. Monitoring the reaction mixture by 31P NMR spectroscopy identified (BINAP)Ni(η2-NC-Ph) as the resting state of the catalyst in the amination of both aryl chlorides and bromides. Kinetic studies showed that the amination of aryl chlorides and bromides is first order in both catalyst and aryl halide and zero order in base and amine. The reaction of a representative aryl chloride is inverse first order in PhCN, but the reaction of a representative aryl bromide is zero order in PhCN. This difference in the order of the reaction in PhCN indicates that the aryl chloride reacts with (BINAP)Ni(0), formed by dissociation PhCN from (BINAP)Ni(η2-NC-Ph), but the aryl bromide directly reacts with (BINAP)Ni(η2-NC-Ph). The overall kinetic behavior is consistent with turnover-limiting oxidative addition of the aryl halide to Ni(0). Several pathways for catalyst decomposition were identified, such as the formation of the catalytically inactive bis(amine)-ligated arylnickel(II) chloride, (BINAP)2Ni(0), and the Ni(I) species [(BINAP)Ni(μ-Cl)]2. By using a well-defined nickel complex as catalyst, the formation of (BINAP)2Ni(0) is avoided and the formation of the Ni(I) species [(BINAP)Ni(μ-Cl)]2 is minimized.

First-row metal complexes often undergo undesirable one-electron redox processes during two-electron steps of catalytic cycles. We report the amination of aryl chlorides and bromides with primary aliphatic amines catalyzed by a well-defined, single-component nickel precursor (BINAP)Ni(η(2)-NC-Ph) (BINAP = 2,2'-bis(biphenylphosphino)-1,1'-binaphthalene) that minimizes the formation of Ni(I) species and (BINAP)2Ni. The scope of the reaction encompasses electronically varied aryl chlorides and nitrogen-containing heteroaryl chlorides, including pyridine, quinoline, and isoquinoline derivatives. Mechanistic studies support the catalytic cycle involving a Ni(0)/Ni(II) couple for this nickel-catalyzed amination and are inconsistent with a Ni(I) halide intermediate. Monitoring the reaction mixture by (31)P NMR spectroscopy identified (BINAP)Ni(η(2)-NC-Ph) as the resting state of the catalyst in the amination of both aryl chlorides and bromides. Kinetic studies showed that the amination of aryl chlorides and bromides is first order in both catalyst and aryl halide and zero order in base and amine. The reaction of a representative aryl chloride is inverse first order in PhCN, but the reaction of a representative aryl bromide is zero order in PhCN. This difference in the order of the reaction in PhCN indicates that the aryl chloride reacts with (BINAP)Ni(0), formed by dissociation PhCN from (BINAP)Ni(η(2)-NC-Ph), but the aryl bromide directly reacts with (BINAP)Ni(η(2)-NC-Ph). The overall kinetic behavior is consistent with turnover-limiting oxidative addition of the aryl halide to Ni(0). Several pathways for catalyst decomposition were identified, such as the formation of the catalytically inactive bis(amine)-ligated arylnickel(II) chloride, (BINAP)2Ni(0), and the Ni(I) species [(BINAP)Ni(μ-Cl)]2. By using a well-defined nickel complex as catalyst, the formation of (BINAP)2Ni(0) is avoided and the formation of the Ni(I) species [(BINAP)Ni(μ-Cl)]2 is minimized.

Polymer-supported palladium catalysed Suzuki–Miyaura reactions in batch and a mini-continuous flow reactor system