A method for highly selective anti-Markovnikov hydroamination of terminal alkenes is reported. The one-pot procedure involves hydroboration of the alkene followed by a novel electrophilic amination of the alkyl borane catalyzed by an NHC-Cu complex. Terminal alkenes are successfully transformed into tertiary alkyl amines in the presence of a variety of functional groups in yields ranging from 80 to 97% with excellent regioselectivity. Results of a preliminary study of the reaction mechanism are also described.

Over the past decade, the use of Pd-NHC complexes in cross-coupling applications has blossomed, and reactions that were either not previously possible or possible only under very forcing conditions (e.g., > 100 °C, strong base) are now feasible under mild conditions (e.g., room temperature, weak base). Access to tools such as computational chemistry has facilitated a much greater mechanistic understanding of catalytic cycles, which has enabled the design of new NHC ligands and accelerated advances in cross-coupling. With these elements of rational design, highly reactive Pd-NHC complexes have been invented to catalyze the selective formation of single products in a variety of transformations that have the potential to afford multiple compounds (e.g., isomers). Pd-NHC catalysts may be prepared as stable Pd(II) precatalysts that are readily reduced to the active Pd(0) species in the presence of an organometallic cross-coupling partner or nucleophile possessing β-hydrogens. It has been found from computational and experimental results that Pd-NHC complexes bearing a single bulky NHC ligand are well-suited to tackle challenging cross-coupling reactions. N-Aryl-substituted imidazole-2-ylidenes with branched alkyl chains at the ortho positions of the aryl group are effective for the challenging couplings of hindered biaryls, secondary alkyl organozincs, electron-deficient anilines, α-amino esters, primary alkylamines, and ammonia. The bulk of the NHC has been tuned by increasing the size of the alkyl groups at the ortho positions and substituting the NHC core with chlorine substituents. All of the cross-coupling transformations studied benefit from the increased bulk when the ortho groups are changed from methyl to 2-propyl to 3-pentyl. However, there is a limit to the positive effect of steric bulk, as some reactions do not benefit from the increased size of the 4-heptyl group compared with 3-pentyl. Thus, there is an optimum size for the NHC ligand that depends upon whether reactivity (turnover frequency and turnover number), selectivity, or both are needed to obtain the desired reaction outcome. In the cases that we have studied, reactivity and selectivity increase together (i.e., the fastest catalyst is also the most selective), allowing cross-couplings to be carried out under mild conditions to obtain one product with high selectivity. This Account focuses on seminal literature reports that have disclosed new Pd-NHC complexes that have led to significant breakthroughs in efficacy for challenging couplings while demonstrating high selectivity for the desired target. These catalysts have been used widely in materials science, pharmaceutical, and agrochemical applications.

A single set of reaction conditions for the palladium-catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI-IPent(Cl) catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6-di-tert-butyl-hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination.

No longer a hindrance: copper-catalyzed electrophilic amination of aryl boronic esters is accomplished under mild reaction conditions using 2.5-5.0 mol % of a catalyst derived from copper tert-butoxide and Xantphos ligand. The reaction tolerates a wide range of functional groups and can be used to prepare some of the most hindered anilines made to date.

We have developed the first catalytic method for anti-Markovnikov hydrobromination of alkynes. The reaction affords terminal E-alkenyl bromides in high yield and with excellent regio- and diastereoselectivity. Both aryl- and alkyl-substituted terminal alkynes can be used as substrates. Furthermore, the reaction conditions are compatible with a wide range of functional groups, including esters, nitriles, epoxides, aryl boronic esters, terminal alkenes, silyl ethers, aryl halides, and alkyl halides. A preliminary study of the reaction mechanism suggests that the hydrobromination reaction involves hydrocupration of an alkyne, followed by the bromination of the alkenyl copper intermediate. This study also suggests that 2-tert-butyl potassium phenoxide functions as a mild catalyst turnover reagent and provides a better understanding of the unique effectiveness of (BrCl2C)2 among brominating reagents.

A copper-catalyzed S(N)2'-selective arylation of allylic chlorides has been achieved using arylboronic esters as nucleophiles. Arylation products were obtained in high yield with a variety of allylic chlorides and arylboronic esters in the presence of a wide range of functional groups. A mechanism is proposed on the basis of the results of stoichiometric experiments and the isolation of the proposed intermediate.

A new procedure for direct transformation of alkenes to tertiary alkylamines based on hydroboration and copper-catalyzed amination of alkylboranes is described. The new method is presented in a broader context provided by a brief analysis of various approaches to the formation of anti-Markovnikov hydroamination products. A short discussion of the reaction development, scope, and the mechanism are also provided. Finally, the extension of this methodology to the preparation of hindered anilines from aryl boronic esters is presented.The synthesis of alkyl amines is one of the most important and common tasks encountered in the preparation of biologically active molecules. 1 A recent analysis of reactions used in pharmaceutical industry suggests that this task is almost exclusively accomplished by either reductive amination of carbonyl compounds or by substitution of alkyl halides or sulfonates. 2 The synthesis of alkyl amines from most other precursors usually requires functional-group interconversion, followed by amination using one of the two standard methods. As a result, the development of new reactions for direct amination of other functional groups has attracted a lot of attention as a way to facilitate the synthesis of alkyl amines.Alkenes are particularly attractive as synthetic precursors. They are readily available and have orthogonal reactivity to that of polar functional groups found in biologically active molecules. The most direct approach to obtain alkyl amines from alkenes is by addition of an amine across an alkene double bond. 3 This transformation has been the focus of numerous studies ever since initial reports of metalcatalyzed hydroamination under mild conditions appeared more than two decades ago. 4 Today, intramolecular hydroamination can be accomplished with a broad substrate scope and with a number of different catalysts. 5,6 Intermolecular hydroamination is significantly less developed, with most successful examples being focused on the formation of the Markovnikov hydroamination product. 4a,7,8 The formation of the other regioisomer, the antiMarkovnikov product, still represents a major synthetic challenge.For many transition-metal-catalyzed hydroamination reactions, the regiodeterming step is alkene insertion into a metal-amido bond. In a recent computational study of a rhodium-catalyzed propene hydroamination, Hartwig and co-workers found that alkene 1,2-insertion to give the Markovnikov product was both kinetically and thermodynamically preferred over 2, 1-insertion. 9 This finding underlines the difficulties in developing metal-catalyzed anti-Markovnikov hydroamination of alkenes.Despite these challenges, there are several examples of the anti-Markovnikov hydroamination of alkenes. In a seminal contribution, Tobin Marks described the lanthanide-catalyzed intermolecular hydroamination of vinylarenes and vinylsilanes with alkyl amines to give linear (anti-Markovnikov) products (Scheme 1). 10 The origin of regioselectivity is attributed to directing effects of the aryl group during alk...

A practical catalytic method for the synthesis of sterically hindered anilines is described. The amination of aryl and heteroaryl boronic esters is accomplished using a catalyst prepared in situ from commercially available and air-stable copper(i) triflate and diphosphine ligand. For the first time, the method can be applied to the synthesis of both secondary and tertiary anilines in the presence of a wide range of functional groups. Esters, aldehydes, alcohols, aryl halides, ketones, nitriles, and nitro arenes are all compatible with the reaction conditions. Finally, even the most sterically hindered anilines can be successfully prepared under mild reaction conditions. Overall, the new method addresses significant practical limitations of a transformation previously developed in our lab, and provides a valuable complement to the existing methods for the synthesis of anilines.