Pd-PEPPSI-IPent(Cl): a highly effective catalyst for the selective cross-coupling of secondary organozinc reagents.

No migration? No problem! A series of new N-heterocyclic carbene based Pd complexes has been created and evaluated in the Negishi cross-coupling of aryl and heteroaryl chlorides, bromides, and triflates with a variety of secondary alkylzinc reagents. The direct elimination product is nearly exclusively formed; in most examples there is no migratory insertion at all.

Identification of a higher-order organozincate intermediate involved in Negishi cross-coupling reactions by mass spectrometry and NMR spectroscopy.

Negishi cross-coupling reactions were analyzed in solution by mass spectrometry and NMR spectroscopy to identify both the effect of LiBr as an additive as well as the purpose of 3-dimethyl-2-imidazolidinone (DMI) as a co-solvent. The results suggest that the main role of DMI is to facilitate a higher order bromozincate formation during the addition of LiBr.

On the role of additives in alkyl-alkyl Negishi cross-couplings.

An additives study for the alkyl-alkyl Negishi reaction using an NHC-Pd catalyst revealed that bromide salts promote coupling while the cation is mechanistically benign. A double titration revealed that the cross-coupling begins at a 1 : 1 ratio of LiBr : (n)BuZnBr, suggesting that a higher-order zincate, presumably Li(m)Zn((n)Bu)Br(3)((2-m)-), is the active transmetalating agent.

Density functional theory investigation of the alkyl-alkyl Negishi cross-coupling reaction catalyzed by N-heterocyclic carbene (NHC)-Pd complexes.

A novel mechanism is proposed for the Pd-1,3-(2,6-diisopropylphenyl)imidazolyl-2-ylidene (1) catalyzed Negishi reaction. DFT computations supported by atoms-in-molecules (AIM) analyses of non-truncated models show that a "steric wall" created by the N-substituent on the ligand guides reactants to and from the Pd center. Notably, transmetalation and not oxidative addition is found to be rate-limiting. Additionally, a key Pd-Zn interaction (approximately = 2.4 A, rho(b) approximately = 0.0600 au) is identified in the mechanism. This interaction persists beyond reductive elimination and, in combination with the ligand, facilitates reductive elimination by creating a highly sterically crowded environment in the coordination sphere of the Pd center.

Pd-catalyzed aryl amination mediated by well defined, N-heterocyclic carbene (NHC)-Pd precatalysts, PEPPSI.

Pd-N-heterocyclic carbene (NHC)-catalyzed Buchwald-Hartwig amination protocols mediated by Pd-PEPPSI precatalysts is described. These protocols provide access to a range of hindered and functionalized drug-like aryl amines in high yield with both electron-deficient and electron-rich aryl- and heteroaryl chlorides and bromides. Variations in solvent polarity, base and temperature are tolerated, enhancing the scope and utility of this protocol. A mechanistic rationalization for base strength (pKb) requirements is also provided.

Biaryls made easy: PEPPSI and the Kumada-Tamao-Corriu reaction.

An easily employed, highly versatile Kumada-Tamao-Corriu (KTC) protocol utilizing the PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization and Initiation) precatalysts 1 and 2 is detailed. The ease-of-use of these catalysts and the synthesis of a wide range of hindered biaryls, large coupling partners and drug-like heterocycles, in high yield, makes the PEPPSI-KTC protocol very attractive. The high reactivity of the PEPPSI system allowed a tetra-ortho-substituted heterocycle, 11 to be synthesized at room temperature for the first time using any protocol. The PEPPSI protocols also tolerated the Boc protecting group and phenols required no protection in modified conditions. A relatively large scale (10 g) reaction was also performed with no loss in performance. Furthermore, PEPPSI-IPr, 1, was compared to previously reported highly active phosphine ligands 42, 43, and 44 and was shown to result in significantly better yields under identical conditions. Finally, we demonstrated that the PEPPSI catalyst system is very adept at performing sequential KTC coupling reactions, analogous to multicomponent reactions, which allow complex polyaryl and polyheteroaryl architectures to be produced in one single operation.

A user-friendly, all-purpose Pd-NHC (NHC=N-heterocyclic carbene) precatalyst for the negishi reaction: a step towards a universal cross-coupling catalyst.

We have developed the first user-friendly Negishi protocol capable of routinely cross-coupling all combinations of alkyl and aryl centers. The use of an easily synthesized, air stable, highly active, well-defined precatalyst PEPPSI-IPr (1; PEPPSI=pyridine-enhanced precatalyst preparation, stabilization and initiation; IPr=diisopropylphenylimidazolium derivative) substantially increases the scope, reliability, and ease-of-use of the Negishi reaction. All organohalides and routinely used pseudohalides were excellent coupling partners, with the use of chlorides, bromides, iodides, triflates, tosylates, and mesylates resulting in high yield of the coupled product. Furthermore, all reactions were performed by using general laboratory techniques, with no glove-box necessary as the precatalyst was weighed and stored in air. Utilization of this methodology allowed for the easy synthesis of an assortment of sterically encumbered biaryls and druglike heteroaromatics, demonstrating the value of the PEPPSI-IPr system. Furthermore, this is also the first time Pd-NHC (NHC=N-heterocyclic carbene) methodology has surpassed the related phosphine-ligated Negishi processes both in activity and use.

Easily prepared air- and moisture-stable Pd-NHC (NHC=N-heterocyclic carbene) complexes: a reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction.

The synthesis of NHC-PdCl(2)-3-chloropyridine (NHC=N-heterocyclic carbene) complexes from readily available starting materials in air is described. The 2,6-diisopropylphenyl derivative was found to be highly catalytically active in alkyl-alkyl Suzuki and Negishi cross-coupling reactions. The synthesis, ease-of-use, and activity of this complex are substantial improvements over in situ catalyst generation and all current Pd-NHC complexes. The utilization of complex 4 led to the development of a reliable, easily employed Suzuki-Miyama protocol. Employing various reaction conditions allowed a large array of hindered biaryl and drug-like heteroaromatic compounds to be synthesized without difficulty.

Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst.

A high-yielding cross-coupling reaction of unactivated alkyl bromides possessing beta-hydrogens with alkylzinc halides utilizing a Pd/N-heterocyclic carbene (NHC) catalyst at room temperature is described. A variety of Pd sources, Pd2(dba)3, Pd(OAc)2, or PdBr2, with the commercially available ligand precursor 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr.HCl) successfully coupled 1-bromo-3-phenylpropane with n-butylzinc bromide in THF/NMP. An investigation of different NHC precursors showed that the bulky 2,6-diisopropylphenyl moiety was necessary to achieve high coupling yields (75-85%). The corresponding ethyl analogue was moderately active (11%). A range of unsymmetrical NHC precursors were prepared and evaluated. The ligand precursor containing one 2,6-diisopropylphenyl and one 2,6-diethylphenyl afforded the coupling product in 47% yield, clearly suggesting a direct relationship between the steric topography created by the flanking N-substituents and catalyst activity. Under optimal conditions, a number of alkyl bromides and alkylzinc halides possessing common functional groups (amide, nitrile, ester, acetal, and alkyne) were effectively coupled (61-92%). It is noteworthy that beta-substituted alkyl bromides and alkylzinc halides successfully underwent cross-coupling. Also, under these conditions alkyl chlorides were unaffected.

The first Negishi cross-coupling reaction of two alkyl centers utilizing a Pd-N-heterocyclic carbene (NHC) catalyst.

The development of an NHC-based system capable of cross-coupling sp(3)-sp(3) centers in high yield has been a long-standing challenge. This communication describes the use of a Pd-NHC catalytic system that achieves room-temperature Negishi cross-couplings of unactivated, primary bromides and alkyl organozinc reagents with a variety of functionality. [reaction: see text]

Electronic nature of N-heterocyclic carbene ligands: effect on the Suzuki reaction.

Suzuki reactions of aryl chlorides and arylboronic acids with a range of electronically different N-heterocyclic carbene ligands derived from N,N-diadamantylbenzimidazolium salts are reported. Results indicate that an electron-rich NHC ligand enhances the rate of oxidative addition. However, reductive elimination is unchanged by the electronic nature of the supporting ligand and is primarily affected by the steric environment.