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. 2024 Feb 23;146(9):6360–6368. doi: 10.1021/jacs.4c00370

ProPhos: A Ligand for Promoting Nickel-Catalyzed Suzuki-Miyaura Coupling Inspired by Mechanistic Insights into Transmetalation

Jin Yang †, Michelle C Neary ‡, Tianning Diao †,*
PMCID: PMC10921396  PMID: 38391156

Abstract

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Nickel-catalyzed Suzuki–Miyaura coupling (Ni-SMC) offers the potential to reduce the cost of pharmaceutical process synthesis. However, its application has been restricted by challenges such as slow reaction rates, high catalyst loading, and a limited scope of heterocycles. Despite recent investigations, the mechanism of transmetalation in Ni-SMC, often viewed as the turnover-limiting step, remains insufficiently understood. We elucidate the “Ni-oxo” transmetalation pathway, applying PPh2Me as the ligand, and identify the formation of a nickel-oxo intermediate as the turnover-limiting step. Building on this insight, we develop a scaffolding ligand, ProPhos, featuring a pendant hydroxyl group connected to the phosphine via a linker. The design preorganizes both the nucleophile and the nickel catalyst, thereby facilitating transmetalation. This catalyst exhibits fast kinetics and robust activity across a wide range of heteroarenes, with a catalyst loading of 0.5–3 mol %. For arene substrates, the catalyst loading can be further reduced to 0.1 mol %.

Introduction

Biaryl and heteroaryl motifs are prevalent in pharmaceutical products. The aromatic scaffolds provide a platform for the strategic spatial arrangement of substituents, imparting binding affinity and selectivity. Moreover, the aromatic and heteroaromatic rings themselves can engage in various noncovalent interactions with targets, such as π–π stacking, hydrogen bonding, and dipole interactions. The modern synthesis of aromatic frameworks often employs palladium-catalyzed Suzuki–Miyaura coupling (Pd-SMC) between aryl electrophiles, such as halides, and arylboron nucleophiles to construct Csp2–Csp2 bonds (Scheme 1A).1,2 The growing focus on sustainable pharmaceutical production with a minimal environmental impact, along with the motivation to reduce process costs, has led to an increase of interest in pursuing nonprecious metal alternatives to the Pd-SMC process.3 Nickel, belonging to the same group as palladium, emerges as a potential substitute.4−10 However, implementing Ni-SMC in process synthesis poses challenges, including the requirement for high catalyst loading (typically ranging from 5 to 10 mol %),11 which offsets the cost benefit, a slow reaction rate,12 and a limited scope of heteroarenes (Scheme 1B).13,14 The latter limitation may arise from potential catalyst poisoning through coordination.

Scheme 1. Suzuki–Miyaura Coupling (SMC) in the Synthesis of Pharmaceutical Products (A), Challenges Faced in Ni-SMC (B), Mechanistic Inquiries Regarding Transmetalation (C), and Proposed Scaffolding Ligand for Promoting Transmetalation (D).

Scheme 1

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The optimization of transition-metal-catalyzed reactions pivots crucially on ligand design. Recent efforts aimed at improving Ni-SMC have revealed that a monodentate phosphine ligand can facilitate oxidative addition and transmetalation, while a bidentate phosphine ligand can stabilize the catalyst against deactivation.15 This insight resonates with the recent application of Ph2MeP,16 Buchwald-type ligands,17 and dppb (dppb = 1,4-bis(diphenylphosphino)butane)18 in Ni-SMC. While data analysis and machine learning models emerge as powerful tools for identifying new ligands,19 a complementary strategy involves design based on mechanistic understanding. In this study, we demonstrate that the latter approach can lead to novel ligand frameworks that might otherwise evade discovery through the former method.

Prior mechanistic investigations determined that Ni-SMC operates through a Ni(0)/Ni(II) cycle,20,21 with transmetalation of arylboronic acid or ester nucleophiles to nickel identified as the turnover-limiting step, typically facilitated by a base.22−24 Generally, transmetalation can follow one of two possible pathways, distinguished by the role the base plays (Paths A and B, Scheme 1C).25 In Path A, the “boronate” mechanism, the base initially activates the boronic acid or ester by forming a boronate, which subsequently substitutes the halide on the nickel intermediate 1, generating Ni–O–B intermediate 2. In Path B, the “nickel-oxo” mechanism, the base first displaces the halide of 1, resulting in the nickel-oxo intermediate 3. Intermediate 3 is then associated with an arylboronic acid or ester to generate intermediate 2. Studies on Pd-SMC have established Path B to be kinetically viable,26 and NMR characterization has verified the formation of a Pd–O–B intermediate as the pretransmetalation species.27−29 Regarding Ni-SMC, there remains ambiguity regarding the transmetalation pathway, particularly concerning the reactivity of nickel-oxo intermediates 3.30 An investigation of the (PCy3)Ni catalyst supports Path B, suggesting that the formation of a nickel-oxo species before transmetalation represents the turnover-limiting step.23 Another study with a (PPh3)Ni catalyst implies the formation of a nickel-oxo dimer as an off-cycle species, suggesting that the catalytic reaction might be limited by the slow dissociation of the dimer prior to transmetalation.24 These varying proposals highlight the complexity of the transmetalation step in Ni-SMC, whose mechanisms may diverge depending on the specific catalysts and bases used.

In this work, we offer comprehensive insights into the transmetalation pathway using a Ni(PPh2Me) catalyst through kinetic and organometallic studies. We identify the formation of nickel-oxo intermediates as the turnover-limiting step and verify their fast reactivity in transmetalation. These findings led us to develop a phosphine scaffolding ligand featuring a tethered Lewis basic group designed to promote transmetalation (Scheme 1D). This ligand framework enables the colocation and preorganization of the catalyst and nucleophile, thus facilitating transmetalation in an intramolecular fashion.31 Moreover, the basic group could function as a hemilabile ligand, offering protection against catalyst poisoning through heteroatom coordination, while still readily dissociating to maintain high catalytic activity. This work not only unveils a highly reactive catalyst informed by a mechanistic hypothesis but also sets a course for ligand optimization, paving the way for the application of Ni-SMC in pharmaceutical process synthesis.

Results and Discussion

Ligand Design

Diphenylmethylphosphine (Ph2MeP) is currently recognized as one of the most effective catalysts in Ni-SMC.16 To develop a scaffolding ligand, we synthesized a series of ligands featuring hydroxyl, ester, and silyl ether groups tethered to diphenylphosphine through linkages of various lengths (Figure 1A). Our studies began with testing these ligands in a model SMC of 4 and 5 to afford 7 using a catalyst loading of 0.5 mol % at 60 °C. A comparison of their performances against Ph2MeP (entry 1, Figure 1A) after 24 h revealed that the ethanol-tethered phosphine ligand 10, 2-(diphenylphosphino)ethanol, led to a reduced reactivity (entry 2). In contrast, ligands with longer linker tethered basic groups generally enhanced reactivity (entries 3–6). Among these ligands, the propanol-tethered phosphine ligand (ProPhos) 9, 3-(diphenylphosphino)propanol, exhibits the highest activity (entry 3). Protecting the hydroxyl group with a tert-butyldimethylsilyl (TBS) group resulted in decreased reactivity (entry 7). An analysis at the 3 h time point indicated that ProPhos’s enhanced performance is attributed to an acceleration in reaction rate.

Figure 1.

Figure 1

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(A) Time-courses of Ni-SMC that reflect the effect of the ligand. Reaction conditions: [4]0 = 0.50 M, [5]0 or [6]0 = 0.55 M, reactions are monitored by GC with calibrations of the product. (B) Rate laws of Ni-SMC catalyzed by (Ph2MeP)Ni and (ProPhos)Ni catalysts.

The kinetic analysis of the SMC further demonstrates the higher reactivity of ProPhos in comparison with Ph2MeP (Figure 1A). Fitting the time-course data to a first-order kinetic model resulted in kobs for SMC of 4 and 5 catalyzed by 9, 10, and Ph2MeP. The rate with ProPhos 9 (k2) is higher than that with PPh2Me (k3) or 2-(diphenylphosphino)ethanol 10 (k4) by several folds. Applying ProPhos to SMC of 4 with 6 resulted in complete conversion to 8 within 3 h (k1).

The excellent performance of ProPhos prompted us to investigate its coordination with nickel (Figure 2). Combining Ni(cod)2 with 2 equiv of ProPhos at room temperature afforded an orange crystal 11. Analysis of 11 through single crystal X-ray diffraction and NMR spectroscopy revealed that ProPhos coordinates to nickel via the phosphine, while the hydroxyl group remains pendent and does not interact with nickel. In the presence of four equivalents of ProPhos, the reaction afforded a mixture of 11 and Ni(ProPhos)412.

Figure 2.

Figure 2

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Synthesis and X-ray crystal structure of (ProPhos)Ni complexes (atomic displacement parameters at the 50% probability level). Hydrogen atoms bound to carbon have been omitted for clarity.

Kinetics

To probe the mechanistic attributes for the faster rate with ProPhos 9, we determined and compared the kinetic orders of the substrates and the catalysts using Variable Time Normalization Analysis (VTNA).32 With PPh2Me as the ligand, the reaction exhibited first-order dependence on the nickel catalyst and is independent of both [4] and [5] (Figure 1B). In contrast, with ProPhos 9, the rate displayed first-order dependence on both the catalyst and the nucleophile, [5] or [6].

Catalyst Resting State

Subsequently, we determined the catalyst resting state in the (PPh2Me)Ni-catalyzed SMC of o-tolyl bromide and 5 by monitoring the reaction using 31P NMR spectroscopy. During the reaction, we observed a 31P NMR resonance at 8.6 ppm (Figure S57). Independently, we prepared complexes (PPh2Me)2Ni(o-Tol)Cl 13 and (PPh2Me)2Ni(o-Tol)Br 14 through oxidative addition of Ni(PPh2Me)418 to o-Tol chloride and bromide, respectively. By comparing the 31P NMR signals, we infer that the catalyst resting state in the (PPh2Me)Ni-catalyzed SMC is likely (PPh2Me)2Ni(o-Tol)Br 14 (Figures 3A and S57).

Figure 3.

Figure 3

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Organometallic studies of transmetalation in Ni-SMC.

Synergistically, we monitored the (ProPhos)Ni-catalyzed SMC of o-Tol chloride with 5 using 31P NMR spectroscopy for a direct comparison. The reaction mixture displayed a 31P NMR signal at 13.4 ppm, representing the major catalyst species in the resting state (Figure S59). We synthesized Ni(ProPhos)2(o-Tol)Cl 21 through ligand exchange of Ni(TMEDA)Cl(o-Tol) (TMEDA = tetramethylethylenediamine)33,34 with ProPhos 9. Ni(ProPhos)2(o-Tol)Cl 21 displayed a characteristic 31P NMR resonance at 13.4 ppm, which is consistent with the major signal observed during the catalytic reaction. Thus, we attribute the resting state in the (ProPhos)Ni-catalyzed SMC to 21 (Figures 3B and S60).

Organometallic Studies

In our following organometallic studies, we investigated the transmetalation reactivity of Ni(PPh2Me)2(o-Tol)Cl 13 and Ni(ProPhos)2(o-Tol)Cl 21 with boronic acid 6, ester 5, and boronate 15 (Figure 3).35 The formation of boronate 15 from 5 and KOH was a slow process, requiring heating at 70 °C for 16 h. No reaction occurred between 13 and 5, regardless of whether K3PO4 was present. Additionally, the reactions of 13 with both PhB(OH)26 and boronate 15 were slow, forming 19 and 20, respectively, but in low yields (Figure 3A).

Subjecting 13 to KOH resulted in the formation of 16, appearing as a mixture of four diastereomers (Figures S39–S41). The 1H signals of the OH groups were identified at −1.75, −1.87, −3.34, –3.35, −5.31, and −5.51 ppm, diagnostic for cis- and trans-μ-O-dimers, respectively, as previously observed experimentally23 and verified computationally.24 The identity of 16 was further confirmed by HRMS. An analysis of the 1H/31P{1H}-HMBC spectra allowed us to assign the resonances for each diastereomer (Figure S39). Although the coexistence of diastereomers has complicated our attempts to obtain single-crystal structural characterization, 16 underwent C–O bond-forming reductive elimination to form 17, whose structure was elucidated via X-ray crystallography. In contrast to nickel(dihydroxide)6 or nickel(dialkoxide),36 which have been reported to exhibit no reactivity toward nucleophiles, complex 16 reacted rapidly with 5 and 6, to produce 19 and 20, respectively (Figure S83). The reaction of 16 with 15 is slightly slower compared to the reaction of 13 with 15. The modest yields were attributed to complications arising from the comproportionation of 16 with in situ generated 18. In comparing the relative rates of stoichiometric reactions, we labeled the steps in kinetically slow pathways as “slow”, the rate-limiting step in the productive pathway as “rate-determining”, and the rapid processes within the productive pathway as “fast” (Figure 3).

We investigated the transmetalation reactivity of 21 (Figure 3B). Subjecting 21 to either 5 or 15 led to no significant change in the 1H and 31P NMR spectra. Over 16 h at room temperature, the reaction mixture yielded only trace amounts of 20, regardless the presence or absence of K3PO4. However, combining 21 with PhB(OH)26 resulted in the rapid formation of 19, even without K3PO4 (Figure S92); K3PO4 further accelerated the reaction. Upon treating 21 with 4-OMe-C6H4B(OH)222, we observed the formation of a new species 23. The 1H NMR spectrum of 22 displays a resonance at 3.81 ppm, attributed to the OH (Ha), and AA’XX’ aromatic resonances at 7.63 and 6.79 ppm (Hb and Hc) (Figure 3C). In 23, Ha shifts downfield to 4.74 ppm, accompanied by minor downfield shifts of Hb and Hc signals to 7.73 and 6.85 ppm, respectively. A new methyl signal emerges at 3.30 ppm (Hd), which is slightly more upfield compared to the methoxy signal in 22.

In a comparison of the spectra of 23 with that of 21 (Figure 3C), we observed that the OH signal of ProPhos (He) underwent a slight downfield shift from 0.79 to 0.84 ppm. Moreover, the resonance at 3.20 ppm, corresponding to the α-H of the alcohol (Hf′), split into two signals at 3.75 (Hf) and 3.20 (Hg) ppm. Additionally, the signal at 2.72 ppm, corresponding to the methyl group on the o-Tol ligand, shifted upfield to 2.71 ppm (Hh).

Analysis of the 1H NMR spectra led us to assign the series of new resonances to the nickel boronic adduct 23 formed from the association of 21 with 22 followed by the elimination of a water molecule. The connectivity of the H signals of 23 was further verified by 1H COSY and 1H/31P{1H}-HMBC (Figures S64 and S65). To further substantiate the spatial correlation between the nickel catalyst and 22, we conducted 1H-NOESY experiments (cf. Figure S66). The spectra unambiguously established a correlation between Ha at 4.74 ppm and Hf at 3.75 ppm, supporting the bonding connectivity between ProPhos and the boronic acid. The loss of a water molecule and the formation of a three-coordinate boronic ester was substantiated by the 11B NMR signal at 29.3 ppm (Figure S67).28,35 At higher temperature, the equilibrium favors the formation of aryl boroxine 22′, which drives the hydrolysis of 23 (Figure S75). Integration of peaks assigned to 21 and 23 allowed us to estimate the equilibrium constant (K) for the association of 21 with 22 to be approximately 1 at room temperature.

Subsequently, we probed the effect of strong bases on the speciation of the nickel catalyst and transmetalation. Addition of KOH to 21 led to dissociation of chloride and formation of 24 as a mixture of two diastereomers, in which the deprotonated alcohol reaches around to chelate on nickel. However, 24 is inactive with 5, and it reacted with PhB(OH)26 slowly compared to 21, giving 19 in 22% yield over 1 h (Figure S79).

Proposed Mechanisms

Collectively, our data suggest two distinct scenarios for SMC catalyzed by Ni(PPh2Me) and Ni(ProPhos), respectively (Scheme 2). The mechanism of reactions facilitated by PPh2Me follows a classic “nickel-oxo” pathway (Scheme 2A). The rate law (eq 1, Figure 1B), with a first-order dependence on [Ni] and no dependence on either substrate, aligns with a turnover-limiting step involving the formation of the Ni–OH species 25, consistent with previous proposals.23 This proposal is further supported by the observation of 14 as the catalyst’s resting state. Our stoichiometric studies reveal that the nickel-oxo intermediate 25 is stabilized by forming the μ-oxo dimer 16.37,38 In these experiments, we observed a rapid transmetelation of 16 with boronic acids and esters leading to a reductive elimination product via formation of intermediate 26 (Figure 3A). The fast consumption of 16 suggests that the dissociation of 16 to 25 is rapid. In contrast, the slow reaction of 13 with boronate 15, coupled with the even slower formation of boronate 15 from 5 and a base, suggests that the “boronate pathway” is not kinetically competent. Instead, it is plausible that the hydroxide from 15 might displace the halide on nickel, leading to the formation of the nickel-hydroxide intermediate 25 prior to transmetalation.39

Scheme 2. Mechanisms of Ni(PPh2Me) and Ni(ProPhos)-catalyzed SMC.

Scheme 2

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The application of ProPhos led to a different pathway (Scheme 2B). The rate laws (eqs 2 and 3, Figure 1B) indicate that the boron nucleophile is involved during or before the turnover-limiting step. Characterization of the catalyst resting species and organometallic studies suggest that the coordination of the boron nucleophile to the pendant hydroxyl group of ProPhos in 21 to form 23 is indeed a critical pre-equilibrium prior to transmetalation. When ArBPin is used as the nucleophile, the equilibrium predominantly favors dissociation (K ≪ 1). In comparison, when ArB(OH)2 serves as the nucleophile, it exhibits a more favorable coordination to ProPhos (K ≈ 1), resulting in the faster catalytic rate of 6 relative to 5 (Figure 1A). The Lewis acidity of ArBPin is greater than that of ArB(OH)2, due to the tendency of boron to rehybridization from sp2 to sp3 to reduce the angle strain.40 The difference in equilibrium can be attributed to the steric hindrance of ArBPin and the ability of ArB(OH)2 to lose a molecule of water to form nickel boronic ester 23 upon the coordination of ProPhos. NMR experiments characterized the formation of a nickel intermediate, assigned to adduct 23 formed between 21 and ArB(OH)2. The Nuclear Overhauser Effect (NOE) between ProPhos and the boronic acid substantiates the association between these two species. In Ni(ProPhos)-catalyzed SMC, the formation of nickel-oxo intermediate 25 is not necessary. It is noteworthy that strong bases, such as KOH, can inhibit the reaction by fully deprotonating ProPhos, leading to the formation of cyclized species 24. In this context, the formation of the nickel-alkoxy species is detrimental. The transmetalation of 23 to form 28 is expected to be the turnover-limiting step, proceeding via the formation of intramolecular transition state 27.

Comparing the mechanisms of SMC catalyzed by Ni(PPh2Me) and Ni(ProPhos) sheds light on the mechanistic attributes for the rate acceleration observed with Ni(ProPhos) compared to Ni(PPh2Me). With PPh2Me as the ligand, the turnover rate depends on the formation of the nickel-oxo intermediate through ligand exchange of nickel halide with hydroxide, a step enhanced by a stronger base. In contrast, with PhoPhos, the formation of a nickel-oxo intermediate is not essential for transmetalation. The pendant hydroxyl group in ProPhos can coordinate to boronic acids and esters, directing the approach of the nucleophile and facilitating transmetalation without the need for a base. While a weak base is necessary for catalytic turnover, a strong base could inhibit the reaction by deprotonating ProPhos and forming 24. This ligand-based mechanism alteration and the consequent change in turnover-limiting steps present a strategic alternative to the empirical ligand screening approach. The nucleophilicity of the tethered directing group determines the turnover rate and unveils avenues for further optimization.

Synthetic Application of ProPhos

We evaluated the performance of ProPhos in Ni-SMC with respect to its compatibility with heterocycles, which are typically challenging substrates (Scheme 3).16,41 Without extensive catalyst optimization, we employed a mixed solvent system consisting of 2-MeTHF/H2O for ArBPin and iPrOH for ArB(OH)2. Notably, NiCl2·6H2O proved to be effective in iPrOH with a range of boronic acids, yielding the desired products. In pharmaceutical process synthesis, replacing Ni(cod)2 with an air-stable and cost-effective nickel precursor, such as NiCl2·6H2O, is highly desirable for large-scale applications.

Scheme 3. Scope of Ni(ProPhos)-Catalyzed SMC.

Scheme 3

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Conditions: Ni(cod)2 (x mol %), ProPhos (4x mol %), K3PO4 (2.5 equiv), 2-MeTHF/H2O (5:1), 16 h.

NiCl2·6H2O (x mol %), ProPhos (4x mol %), K3PO4 (2.5 equiv), iPrOH, 16 h. % Yield determined by GC with calibrations and isolated % yield in the parentheses.

With a catalyst loading of 0.5–1 mol %, a variety of substrates containing pyridine, quinoline, pyrazole, pyrimidine, and 2-aminopyridine underwent SMC, forming products in high yields. In cases of lower yields, increasing the catalyst loading to 3 mol % was sufficient to improve the performance. Five-membered heterocycles are uncommon examples in Ni-SMC. Pyrazole derivatives 33–35 proved to be compatible with the (ProPhos)Ni catalyst. Moreover, 34 and 41, featuring the typically challenging unprotected 2-amino pyridine, were synthesized with excellent yields using (ProPhos)Ni. Compound 41 was previously unattainable with nickel catalysts and requiring a 6 mol % loading of palladium.42 Additionally, an indole product 36 required no protection by using the (ProPhos)Ni catalyst. Finally, we challenged ProPhos with a catalyst loading as low as 0.1 mol %. Under this condition, the SMC of 4 with 6 proceeded to give a quantitative yield of 8 in 16 h.

Conclusion

Transmetalation plays a vital role in determining the turnover rate and the scope of Ni-SMC. We have elucidated that the formation of a nickel-oxo intermediate is the turnover-limiting step for (PPh2Me)Ni-catalyzed SMC. These insights informed us in designing the ProPhos scaffolding ligand, which alters the turnover-limiting step to transmetalation from a precoordinated intermediate formed between the ligand’s pendant hydroxyl group and boronic acids and esters. This ligand-substrate interaction enables faster catalytic turnover rates by directing the nucleophile toward the nickel center. The (ProPhos)Ni catalyst has demonstrated efficiency in SMC across a broad range of heteroarenes with a catalyst loading of 0.5–3 mol %. In the case of arene substrates, the Ni-SMC can operate at catalyst loadings as low as 0.1 mol %. The strategy of introducing scaffolding ligands to preorganize the nucleophile and catalyst represents a novel avenue for optimizing Ni-SMC toward pharmaceutical process production.

Acknowledgments

T.D. thanks Dr. Sebastien Monfette (Pfizer) for helpful discussions. This work was supported by the NIGMS (R01 GM127778). The X-ray facility at CUNY-Hunter College is supported by the Air Force Office of Scientific Research under award number FA9550-20-1-0158.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c00370.

  • Full experimental procedures, characterization data, and NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja4c00370_si_001.pdf (7.2MB, pdf)

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