Transition metal catalyzed cross-coupling has found applications in diverse areas of chemistry, such as total synthesis, materials and bioorganic chemistry, and is considered to be one of the most general synthetic methods. Typically, the most active cross-coupling catalysts involve Pd complexes with sterically demanding, electron-rich phosphine or N-heterocyclic carbene (NHC) ancillary ligands. A major advance in cross-coupling over the last twenty years is the development of specialized phosphine and NHC based ligands that can promote the fundamental steps in catalysis such as oxidative addition and reductive elimination. The use of these ligands has resulted in new reactions, expanded substrate scopes, milder conditions and lower catalyst loadings. However, although these ligands stabilize monoligated Pd0, which is proposed to be the active species in many cross-coupling reactions, they often have comparable expense to the Pd source. Consequently the traditional route for generating the active species, addition of excess ligand to a Pd0 precursor, is not attractive. Therefore, a number of well-defined PdII precatalysts with a 1:1 Pd to ligand ratio, which are reduced to L-Pd0 under the conditions employed in cross-coupling, have been developed and are now commercially available.
A key feature in the effectiveness of a precatalyst is the rate and efficiency of their conversion into the monoligated Pd0 active species under the catalytic conditions. Recently, we explored the activation of commercially available precatalysts of the type (η3-allyl)Pd(NHC)(Cl). It was demonstrated that the efficiency of activation is related to two factors: (a) the rate of activation of the ligated precatalyst scaffold to form the active L-Pd0 species, and (b) comproportionation between L-Pd0 and the starting precatalyst, which forms an essentially unreactive PdI μ-allyl dimer of the form (μ-allyl)(μ-Cl)Pd2(L)2 and removes L-Pd0 from the reaction mixture (Scheme 1). Furthermore, we showed that the best monomeric precatalysts, which contain substituents in the 1-position of the allyl ligand, are highly active because they are less likely to comproportionate with L-Pd0 to form PdI dimers. However, surprisingly, even in the case of the most active 1-substituted precatalysts some Pd (~35%) is trapped as a PdI dimer.
Guided by our mechanistic studies we designed new precatalysts of the form (η3-1-tBu-indenyl)Pd(L)(Cl) (L = NHC or PR3) (Figure 1a). These precatalysts are synthesized from the unligated dimer (η3-1-tBu-indenyl)(μ-Cl)2Pd2 (Figure 1b), which is a bench stable compound that can be prepared in one pot from 1-tBu-indene, PdCl2, NaCl and weak base on a large (40 g) scale. Our new precatalyst features a 1-substituted indenyl ligand and both increases the rate at which PdII is converted to Pd0 and prevents comproportionation to a PdI dimer. We demonstrated that our precatalyst scaffold is either the most active system reported to date or comparable to the best systems currently known for challenging cross-coupling reactions such as: (i) Suzuki-Miyaura reactions which use heteroaryl boronic acids, alkyl trifluoroboronate salts or aryl chlorides with unprotected indazoles and benzimidazoles as substrates, (ii) Suzuki-Miyaura reactions that generate sterically congested tetra-ortho substituted products, (iii) Buchwald-Hartwig reactions with sterically congested secondary amines; and (iv) αlpha-arylation reactions with heteroaryl ketones. The new precatalyst is licensed to Strem Chemicals, Sigma-Aldrich and Aspira Scientific and is commercially available with 7 different ligands, including both NHC and phosphine ligands. An unligated dimeric precursor, which can be used for rapid screening is also commercially available. Future work will focus on establishing if the new system is also superior for other cross-coupling reactions.
In general, the most active catalysts for cross-coupling are based on Pd. Although the use of Pd often leads to catalytic systems with high activity, the long term use of Pd is not optimal as it is a relatively rare and expensive resource. Furthermore, Pd has a relatively high level of toxicity, and as a result, a significant amount of time intensive and costly purification is required before pharmaceuticals that are produced using Pd based catalysis can be administered to patients. In contrast, the base metals, such as Ni, are inexpensive, abundant and have lower levels of toxicity. Alongside these intrinsic advantages, currently Ni precatalysts are more efficient than Pd based systems for a number of cross-coupling reactions. For example, Ni based systems are superior to Pd for performing Suzuki-Miyaura reactions involving carbamate, carbonate, sulfamate, acyliminium, and sp3-based substrates. Nevertheless, in general, Ni catalyzed Suzuki-Miyaura reactions require high temperatures and high catalyst loadings, long reaction times, and have limited substrate scope. Frequently, the cost benefit of using Ni over Pd is offset by one or more of these problems. Additionally, there have been few mechanistic studies of Ni based precatalysts for the Suzuki-Miyaura reaction, which complicates the rational design of improved systems.
We recently compared the catalytic performance and activation of a series of related dppf-supported Ni0, NiI and NiII complexes (Figure 2). To our surprise at elevated temperature all precatalysts studied gave comparable activity. This was the first time a NiI complex had demonstrated similar efficiency to a Ni0 or NiII precatalyst for a Suzuki-Miyaura reaction, with most previous NiI precatalysts giving very poor efficiency and requiring a strong base. Additionally, we investigated the speciation of Ni during Suzuki-Miyaura reactions using our family of Ni0, NiI and NiII compounds. EPR and paramagnetic NMR spectroscopy indicated that all of the precatalysts formed a significant quantity (>70%) of the catalytically active NiI complex, (dppf)Ni(Cl), during catalysis. Although our preliminary studies clearly indicate that a NiI species is forming during catalysis, at this stage the exact role of the NiI species is unclear. For example, it could be acting as a catalyst resting state or it may be directly part of the catalytic cycle. Nevertheless, using our early mechanistic studies as a guide, we were able to demonstrate that the bench stable NiII precatalyst (o-tolyl)Ni(dppf)(Cl) (otolNiII), which forms NiI during catalysis, is particularly active. In fact, it is able to perform Suzuki-Miyaura reactions involving heterocyclic substrates relevant to the synthesis of pharmaceuticals at room temperature and at low catalyst loading (Figure 3); this marks the first time these reactions were performed under such mild conditions and the precatalyst is now commercially available. The goal of future work in this area is to understand the role that NiI is playing in cross-coupling reactions using dppf and other common phosphine ligands and utilize the information to design improved precatalysts.