The Preparation and Systematic Evaluation of Ligated Ni(II) Pre-Catalysts (NiPC) in Common Single Electron Cross-Coupling Reactions

Abstract

The advent of single-electron, nickel-mediated cross-coupling reactions has fundamentally transformed how carbon bonds can be forged and is now a mainstay of modern synthesis and medicinal chemistry. Nickel is a prevailing transition metal that facilitates these innovations, and yet despite its obvious competence, standardized practices regarding Ni/ligand preparation and administration, as separate entities or as a single precomplex or catalyst, have not been systematically established. This study investigates the synthesis, isolation, and efficacy of simple, ligated Ni­(II) precatalysts (NiPCs) to expedite and standardize protocols for contemporary single-electron nickel-mediated cross-coupling reactions. We demonstrate the effectiveness of a library of isolated NiPCs in commonly used singleton transformations and high-throughput experimentation (HTE) setups with broad application to pharmaceutical chemistry. By illuminating the practical rules that govern NiPC synthesis and administration, this work equips the community with an actionable understanding to enable wide, normalized adoption of simple NiPC methods.

Single electron (SE) nickel-mediated cross-coupling (NCC) reactions have revolutionized synthetic methodology and established a new cornerstone in contemporary chemical synthesis in the process. , Groundbreaking contributions in nickel-catalyzed cross-electrophile and photoredox cross-couplings , have catalyzed a dramatic expansion of this innovative platform, enabling a plethora of transformative applications across diverse research fields. From the design of DNA-encoded libraries (DELs) to sophisticated polymerization strategies and the synthesis of peptides and small molecule pharmaceuticals, the versatility of SE NCC reactions is undeniable. In medicinal chemistry, these powerful reactions are particularly sought after for their ability to forge Csp ³–Csp ² bonds, unlocking previously inaccessible and valuable chemical landscape. Doing so not only differentiates the physicochemical properties of therapeutic compounds – such as increasing the fraction of sp ³ hybridized carbon centers and improving solubility, but also potentially secures novel intellectual property advantages, marking a strategic leap forward in targeted small molecule synthesis. At the heart of these innovations, nickel catalysis has directly enabled many of these synthetic achievements due to nickel’s dynamic ability to lower the activation and transition state energies required to engage radical intermediates while significantly suppressing β-hydride elimination pathways. However, a survey of contemporary Ni-mediated, SE NCC methodologies within the organic synthesis community revealed numerous protocols for how Ni­(II) (pre)­catalysts are introduced or administered to initiate a reaction mixture. For instance, it has been well described that discrete pre-complexation of Ni­(II) salts and bipyridyl ligands (e.g., 4,4′-di-tert-butyl-2,2′-dipyridyl, dtbbpy) before SE reaction initiation, can lead to optimal reaction yields. , Conversely, reports also exist that do not require discrete pre-complexation to obtain optimal reaction efficiency and yield.

To date, general best practices of nickel (pre)­catalyst administration for SE NCC reactions have not been proposed and remain inconsistent. Consequently, the end-users of SE NCC reactions are often faced with several dilemmas: (1) conflicting or variable (pre)­ligation protocols, (2) indeterminant Ni/L stoichiometry in situ, and (3) additional time and step(s) associated with Ni/L pre-complexing. From a pharmaceutical chemistry perspective, we sought to address these questions by exploring isolable, ligated Ni­(II) precatalysts or complexes (“NiPC”) and their efficacy in common SE NCC transformations.

One application of a simple, isolable Ni­(II) Precatalyst for use in photoredox NCC reactions was reported by the Molander group in 2016. The Molander NiPC, [Ni­(dtbbpy)­(H₂O)₄]­Cl₂, has since been employed in several Ni/Photoredox CC transformations by the group , among other reports in the field. ,− The complex was characterized as a non-hydroscopic (hydrate), bench-stable solid invoking 1:1 Ni/L stoichiometry. Importantly, NiPC 1 did not require special storage and is convenient for immediate use, a key feature for rapid reaction enablement and optimization in industrial settings. Our chemistry teams were curious to further investigate and marry other popular ligands with Ni­(II) salts across diverse structural classes including bipyridyls, 1,10-phenanthrolines, and pyridyl-2-carboxamidines, among others (Figure ), for use in everyday reactions and High Throughput Experimentation (HTE) efforts. The structural diversity of ligand classes depicted in Figure underscores the profound and often unpredictable influence that ligand architecture exerts on SE chemistries, , highlighting a critical need for a more rigorous understanding of NiPC complexation and mechanism. While sporadic reports exist for some privileged NiPCs (such as 1 and several chiral Ni­(II) bisoxazoline salts for enantioselective transformations, for example) the large majority of discrete, isolable Ni­(II) ligated complexes recently popularized in SE NCC reactions, and their efficacy, are undocumented in the literature.

1.

Common classes of ligands employed in Ni/SE cross-couplings reactions, all of which have shown some degree of efficacious utility in the field despite their varied architectures. Common ligands classes have been generally categorized into their most popular use cases, photoredox and heterogenous cross-electrophile couplings, with dtbbpy in the middle of the diagram as the most widely employed in both reactions.

Herein we (1) describe a practical and simple protocol for the preparation of diverse NiPCs, (2) benchmark their reactivity in common SE cross-coupling reactions and applications (e.g., Ni/photoredox and net reductive couplings), and (3) explore their efficacy towards the standardization of reaction setups, workflows, and optimized reaction yields. From the outset, our company reproducibly prepared 200 g of the dtbbpy NiPC 1. In our hands, NiPC 1 is indeed bench-stable, nonhydroscopic, and efficacious after >2 years of benchtop storage, and exhibit many qualities of an ideal catalyst system. Based on precedent, stability/storage, and the early success of dtbbpy NiPC 1, NiX₂·hydrates (e.g., 6H₂O for NiCl₂) were employed as the principal Ni salt/solvate of choice for future studies: NiCl₂·6H₂O for example, is more widely available in bulk and approximately >100× less expensive than NiCl₂(DME). We were pleased to observe successful ligation, synthesis, and isolation of subsequent NiPCs with a host of diverse ligands (e.g., those described in Figure ), including 1,10-phenanthrolines, pyridyl-2-carboxamidines, and diketonates ligands following the general reactions depicted in Scheme . Over the course of these studies, >75 NiPCs were prepared using this ligation platform across ligand classes and Ni salts and will be the subject of future communications.

1. General Procedure for Synthesis of NiPCs: 1 equiv Ligand to 1 equiv NiX₂·XH₂O in EtOH .

^a Solvents administered during reaction and workup may vary depending on ligand solubility, see SI for additional details. (a) Synthesis of NiPCs employed with bidentate bipyridyl (bpy) ligands. By X-ray crystallographic analogy, ligated Ni­(II) hydrates may be isolated when bpy ligands are employed. (b) Synthesis of mono-, bi- and tridentate pyridine-based NiPC synthesis. Note: structures depicted are for convenience based on analogy and cannot be generalized to all ligand classes.

The benchmark reactions in Table were explicitly selected to include a broad diversity of starting reagents and substrates, mechanisms, methods of radical initiation, and importantly, varied published protocols of Ni/L catalyst administration (vida infra) particularly applicable to our mission in pharmaceutical discovery chemistry. Unoptimized reactions were intentionally selected that did not provide a quantitative yield of the desired product to elicit any potential yield differences between Ni ligation methods employed. Three different Ni catalyst ligation Methods were designed and employed in parallel for each benchmarking reaction (see Table , legend): Method (A) Control: the reported literature ligation procedure (often discrete pre-complexation just before reaction initiation, but not always), (B) the requisite Ni salt and ligand added as individual, separate entities (i.e., no pre-complexing), and (C) the isolable, ligated Ni­(II) Precatalyst (NiPC). Under the assumption that the required active Ni species (and oxidation state) could inevitably be obtained in situ regardless of mechanism, we were curious to examine reaction efficiency when starting from different base Ni (pre)­catalysts.

1. Comparison Reactions Examining the Implementation of Ligated Ni­(II) Catalysts (NiPCs) to Reported Literature Reactions. ^e .

^eA standardized Nickel Workflow was evoked, as described in the box “Ligation Methods for Reaction Benchmarking”. Each reaction was run in triplicate, unless otherwise noted, and was carried out on 0.1 mmol scale of limiting reagent from a common preparative stock solution. Reactions were flushed with bubbling nitrogen for 10 min before reaction initiation. Yields reported via LCMS IS (product standards were prepared and normalized with IS, 4,4′-di-tert-butyl-1,1′-biphenyl). Ni­(II) salt to ligand (L) ratios are Ni/L 1:1 unless otherwise noted. The Penn (450 nm) photoreactor M2, set to 100% LED intensity, was used in photoredox reactions. “Lit. Conditions” corresponds to the reported literature protocol was tested, including ligand ratios.

^aThe reactions were run in duplicate.

^bIsolated yield: 0.5 mmol scale.

^cYields were obtained via ¹ H NMR and internal standard (mesitylene as IS).

^dThe reaction was set up under an inert environment using a glovebox.

Ni­(COD)₂ has long been the Ni(0) pre-catalyst of choice in various cross-coupling reactions, including early SE Csp ²–Csp ³ cross-couplings, however, its extreme sensitivities to air and moisture generally stymy its routine use in industrial settings. A seminal Ni/Photoredox Csp ²–Csp ³ cross-coupling of alkyl BF₃K salts from Molander and coworkers employed Ni­(COD)₂ and a glovebox setup,^4a and we were curious to explore if replacing Ni­(COD)₂ with a bench- and air-stable NiPC was feasible in entries 1 and 2 (Table ). Indeed, NiPC 1 was able to reproduce adduct formation in nominal yield (75%) to the literature reaction which was setup in a glovebox using Ni­(COD)₂ in an inert environment (71%, entry 1, Table ), despite the differences in the Ni oxidation state.

In a C–H functionalization reaction in entry 2 (Table ), the researchers initially posited Ni­(COD)₂ was essential for facile oxidative addition of less reactive aryl chlorides, and thorough structural and photophysical studies have since helped elucidate various key mechanistic questions. To our surprise, a bench-top setup using NiPC 1 generated the arylated cyclic ether adduct in 70% yield and was found to outperform the published conditions using Ni­(COD)₂ and a glovebox setup (46% yield, entry 2, Table ). These results are in line with later findings from a different transformation published by the team, employing Ni­(II) salts in place of Ni­(COD)₂.

Next using NiPC 1, a cross-electrophile coupling using Mn as the terminal reductant between a secondary benzylic chloride and an acid chloride was examined (entry 3, Table ). NiPC 1 produced the target ketone in 43% yield, an improvement from the non-complexed NiCl₂·dme and dtbbpy (30%) system reported in the literature. In a cross-electrophile Csp ²–Csp ³ coupling reaction (entry 4, Table ) as reported by the Weix group, our tridentate NiPC 2 [pyridine-2,6-bis­(carboximidamide)] was prepared and employed for the first time. NiPC 2 rescued the non-precomplexed yield and produced the adduct in a nominal 58% yield. Broadly, the results from entries 1-4 suggest that two distinct, isolable NiPCs can facilitate Csp ²–Csp ³ bond-forming reactions in both heterogenous reductive and photoredox reactions with moderate but real improvements in yield.

NiPC 1 was also applied to a photoredox cross-electrophile Csp ³–Csp ³ coupling of a secondary alkyl bromide coupling with methyl tosylate as the source methyl radical (entry 5). The literature Ni complexation conditions afforded the methylated adduct in 45% yield (Method A) and NiPC 1 afforded a slightly enhanced 49% yield (Method C), a slight improvement over both Methods A and B (entry 5, Table ). A set of cross-electrophile Ni/photoredox reactions (using tris­(trimethylsilyl)­silane, TTMSS) were next examined (entries 6 and 7, Table ). In entry 6, NiPC 1 produced the adduct in a comparable 44% yield as assessed to Methods A and B, using just 0.5 mol % NiPC 1. In entry 7, a similar cross-electrophile Ni/photoredox transformation was examined employing a secondary alkyl bromide, NiPC 1 was able to marginally rescue the nonprecomplexed Ni/L yield and produced the adduct in 42% yield.

Late-stage functionalization of small molecules is a prized strategy in discovery chemistry and a photoredox-mediated methylation reaction of C–H alkyls was next selected (entry 8). The reaction calls for ( ^t Bu)₃terpyridine as the ligand and required synthesis of the corresponding complex NiPC 3 following our established synthetic protocol. , While yields are reportedly low for this transformation, NiPC 3 reproduced the yield of reported literature conditions (18% and 17% yields, respectively, entry 8, Table ) with 2-phenylacetamide as the reactant. Lastly, aiming to explore additional NiPC catalyst systems, NiPC 4 was prepared and isolated from pyridine-2,6-bis­(N-cyanocarboxamidine), PyBCam^CN (Ligand A) and NiBr₂·4H₂O, to examine the reductive NCC reaction between aryl and alkyl chloride coupling partners (entry 9, Table ). The literature reports pre-complexing the catalyst components in a glovebox (Method A, 20% yield), however we hypothesized implementing NiPC 4 on the benchtop followed by N₂ sparge could afford similar yield of the adduct. Indeed, the isolated NiPC 4 showed improved yield (Method C, 30% yield) compared to both literature protocol and without any Ni/L pre-complexing (Method B, 22% yield). Furthermore, the final adduct could be isolated in 85% on 0.5 mmol scale, suggesting enhanced efficiency when upscaling. Altogether, these data indicate that isolable NiPCs are promising catalysts for standardizing Ni­(II)-catalyzed workflows that rely on a single, optimized Ni source (e.g., [Ni­(dtbbpy)­(H₂O)₄]­Cl₂, NiPC 1). By providing well-defined, isolable catalysts that fix Ni/L stoichiometry, NiPCs can further enable true “dump-and-stir” protocols and improve reproducibility across routine reaction setups.

High throughput experimentation has become an increasingly important platform in medicinal chemistry for its ability to deliver diverse, controlled and standardized results for new reaction design and discovery. , For example, readily available, shelf-stable Pd­(II) Buchwald Gx Precatalysts have been a mainstay in similar HTE contexts across pharmaceutical synthetic applications. The demonstrated efficacy of NiPCs at the level of single reaction implementation, prompted us to outfit NiPCs in user-friendly catalyst screening kits (10 μmol scale) at the company to enable HTE in SE NCC reactions. When adapting literature protocols to pharmaceutical substrates and intermediates, chemists routinely face highly complex, functionalized molecules that may contain Bro̷nstead or Lewis acids/bases obfuscating desired reactivity, the MSD chemistry informer library of was created to aid in screening against a representative set of challenging motifs.

Accordingly, a NiPC kit was prepared with 12 diverse ligand combinations (2 sets of 12 in microvials) which were deemed to have high probability of success across both heterogenous reductive cross coupling and Ni/photoredox chemistry platforms. NiBr₂·xH₂O NiPCs were selected and synthesized, as preliminary evidence (data not disclosed) suggest Br halide selection could achieve a balanced reactivity profiles compared with Cl or I. Employing functionalized substrate 1a from the MSD informer set, a photoredox cross-electrophile coupling reaction was screened amongst the novel NiPC kit (Figure ). Under the 4CzIPN photocatalyst conditions, a rather surprising NiPCs stood out as superior, ^5,5’‑Mebpy·NiBr₂ in the coupling of 4-bromotetrohydropyran yielding 2a. Upon translating these conditions to 50 umol scale on the benchtop, we were pleased to observe excellent reaction efficacy of 80% conversion to the desired coupled product, outcompeting the more conventional dtbbpy NiPC (55%, LCAP), a discovery only enabled through HTE. Internally, these encouraging proof of concept experiments have allowed us to reproduce and distribute novel NiPC kits for end user applications across chemistry.

2.

MSD’s NiPC catalyst screening kit design (10 μmol scale) with various common ligands applied toward photoredox cross-electrophile coupling reaction applications. NiPCs were prepared according to general procedure outlined in Scheme , and isolated via filtration. The reaction kit was setup in a glovebox and 10 mol % NiPC catalyst loading was employed for each reaction well. A Lumidox 48-position temperature-controlled (chiller set to 15 °C) photoreactor (445 nm LED array) was employed. Yields are reported via LCMS LCAP IS (product standards were prepared and normalized with 0.05 M IS, biphenyl). Reaction with the NiBr₂·xH₂O NiPCs are depicted as their Br₂ complexes; structures are drawn for convenience and may not reflect the reality of Ni-ligand coordination.

We herein describe the preparation, efficacy, and applications of isolable, bench-stable Ni­(II) Precatalysts (NiPCs) for systematic deployment in single electron Ni cross-coupling reactions for the first time. The robust reproducibility of literature reactions promoted the exploration of NiPCs in microscale HTE screening setups, demonstrating rapid diversity-screening for catalyst optimization. Furthermore, we’ve established that NiPCs can effectively replace air-sensitive Ni­(COD)₂ in a pair of notable Ni/Photoredox reactions, circumventing the use of drybox setups. All NiPCs presented herein have proven efficacious for >2 years. We demonstrate NiPCs possess the proclivity to standardize reaction results for end-users looking to simplify their methodologies, scale up and iterate reactions, and execute rapidly on innovative synthetic goals. Much in the way Pd­(II) precatalysts have become a staple in synthesis labs, parallels can be drawn to the practicality of NiPCs as researchers strive to identify more ideal (and increasingly complex) catalyst systems. We are eager for enhanced adoption and use cases of these practices as the synthetic community aligns on more scrupulous Ni­(II) Precatalyst workflows and protocols.

Glossary

Abbreviations

NiPC

nickel precatalyst

4CzIPN

1,2,3,5-tetrakis­(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-tetrakis­(9H-carbazol-9-yl) isophthalonitrile

dtbbpy

4,4′-di-tert-butyl-2,2′-dipyridyl

NCC

nickel-mediated cross-coupling

bpy

bipyridyl

PyBCamCN

pyridine-2,6-bis­(N-cyanocarboxamidine)

SE NCC

single electron nickel-mediated cross-coupling

dtbbpy

4,4′-di-tert-butyl-2,2′-dipyridyl

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00332.

• Experimental details and procedures, NiPC characterization data, X-ray, and NMR spectra of isolated compounds (PDF)­(PDF)

This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

The authors declare the following competing financial interest(s): The authors declare competing financial interests as Merck & Co., Inc., Rahway, NJ, USA stakeholders, stockholders and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA employees.