Article Cite This: Organometallics XXXX, XXX, XXX−XXX
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Advances in Base-Metal Catalysis: Development of a Screening Platform for Nickel-Catalyzed Borylations of Aryl (Pseudo)halides with B2(OH)4 John R. Coombs, Rebecca A. Green, Frederick Roberts, Eric M. Simmons, Jason M. Stevens, and Steven R. Wisniewski*
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Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States S Supporting Information *
ABSTRACT: Investigations into nickel-catalyzed borylation reactions have led to the development of an experimental design of 24 reaction conditions for rapid lead identification. A case study on the borylation of a model aryl bromide with B2(OH)4 prompted a series of mechanistic and stability studies to better understand the catalytic cycle and factors that affect robustness. HTEx was employed to study the effect of a series of scavengers on the remediation of nickel from the reaction stream. These combined results have generated an increased understanding of nickel-catalyzed borylation reactions and set the stage for their expanded use in process chemistry.
T
accessing a variety of potassium (hetero)aryltrifluoroborates (eq 1).9
he reaction of organoboron species to forge carbon− carbon bonds is one of the most utilized transformations in organic chemistry. In fact, the Suzuki−Miyaura coupling is considered one of the two principal “workhorses” of medicinal chemistry and is employed more often than any other crosscoupling reaction.1 Accordingly, efficient access to a diverse array of aryl boron species is essential for enabling such couplings. The classical method for preparing boronic acids,2 metal−halogen exchange followed by transmetalation with a B(OR)3 species and subsequent hydrolysis, requires cryogenic conditions as well as a pyrophoric organometallic reagent that severely limits functional group tolerance. In 1995, Miyaura reported the first palladium-catalyzed borylation of aryl halides with bis(pinacolato)diboron (B2pin2),3 under significantly milder reaction conditions, affording a library of aryl- and heteroarylboronate esters that can be employed in a wide range of transformations. Since Miyaura’s initial report, the development of metalcatalyzed borylation reactions of (hetero)aryl halides4 has gained much attention, which has led to significant improvements that enabled further expansion of the substrate scope, decreased catalyst loadings, and tempered reaction conditions. However, the majority of these transformations still require elevated reaction temperatures (≥80 °C) and until recently, focused on the synthesis of pinacol esters utilizing bis(pinacolato)diboron (B2pin2). In 2010, Molander and Dreher5 reported that tetrahydroxydiboron (B2(OH)4, bisboronic acid or BBA),6,7 a greener diboron source, directly yields boronic acids in one step from the corresponding aryl halide utilizing Buchwald’s XPhos-Pd-G1 and XPhos-Pd-G2 precatalysts.8 As a follow-up study to address the high cost associated with palladium, Molander subsequently reported the nickelcatalyzed borylation of aryl halides and pseudohalides, © XXXX American Chemical Society
These advances in metal-catalyzed borylation reactions have great potential to positively affect process chemistry and development. Implementing B2(OH)4 as a diboron source leads to an improvement in atom economy and greenness that in combination with the significant cost savings from replacing palladium makes nickel-catalyzed borylations an appealing route to arylboronic acids. However, to the best of our knowledge, there is only one reported example of a nickelcatalyzed borylation on a kilogram scale.10 The borylation of a mixture of regioisomeric chloroindazoles with a catalytic system of Ni(NO3)2·6H2O/PPh3 and B2pin2 as a diboron source affords the desired arylboronate esters in 53% isolated yield on an ∼72 kg scale (eq 2). Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Received: May 11, 2018
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DOI: 10.1021/acs.organomet.8b00307 Organometallics XXXX, XXX, XXX−XXX
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Finally, we sought to understand the effect of each of the key class variables12 (ligand, base, solvent) on the overall performance of the borylation reaction. To provide some initial answers to these questions, we employed high-throughput experimentation13 to rapidly investigate the desired transformation and determine the effect of the class variables on the reaction (eq 3). A few
In this paper, we report the development of a workflow for identifying nickel-catalyzed borylations using high-throughput experimentation. The design of this platform was informed by mechanistic insight into the reaction that was gained by studies investigating the stability of B2(OH)4 under various conditions relevant to the catalytic reaction and by kinetic studies to determine the reaction profile. The general screening platform that we have developed was applied to a variety of aryl and heteroaryl (pseudo)halides, in each case providing lead conditions that set the stage for subsequent reaction optimization.
generalizations can be made on the basis of the results. Minimal byproducts, including protodehalogenation and homocoupling, were observed under the majority of the conditions tested. Reaction conversion is directly proportional to product formation such that the reactions with low yield contain significant remaining aryl halide. Of the class variables tested, ligand, base, and solvent were all found to have a significant effect on the outcome of the reaction.14 Interestingly, not only did direct comparison of methanol and ethanol reveal that methanol gave superior results for all reactions tested for this substrate but also further studies of alternative aryl (pseudo)halides showed that methanol performed better than ethanol in every system investigated (vide infra). The addition of a cosolvent (such as THF) was not beneficial to the reaction for the borylation of 3, resulting in incomplete conversion after 16 h.14 The goal of screening a diverse ligand library was to better understand the effect of the steric and electronic properties of the ligands on nickel-catalyzed borylations. A clear trend in ligand size was observed, as both sterically encumbered ligands (cataCXium A, Ata-Phos, Pt-Bu3·HBF4) and simple triarylphosphines (PPh3, Pfur3, P(o-tol)3) performed poorly in the reaction, providing a maximum of 40 AP15 product (area percent of product relative to all other nonsolvent peaks in a liquid chromatography chromatogram). However, biaryl monophosphine ligands with smaller groups such as cyclohexyl and phenyl (as opposed to tert-butyl) performed best, as evidenced by the top-performing ligand, Cy-JohnPhos16 (Figure 1), which afforded the arylboronic acid in >95 AP. It has been noted that the main focus of phosphine ligand development has been for palladium catalysis, which could explain why many common phosphine ligands perform poorly in this, and other, nickel-catalyzed reactions.17,18 The ligand to metal (L/M) ratio was also investigated; similar conversion to the arylboronic acid was observed at 1.1:1 and 2.0:1 L/M ratios with Cy-JohnPhos. Further, utilizing Cy-JohnPhos as a ligand, high levels of conversion to arylboronic acid were observed for all of the nickel precatalysts tested (Ni(NO3)2· 6H2O, NiCl2·6H2O, Ni(acac)2, NiCl2·glyme). Because of its low cost, wide availability, and prior use on scale,6a Ni(NO3)2· 6H2O was chosen as the catalytic precursor for subsequent studies. Notably, catalyst loading could be decreased to 1 mol % without an effect on conversion. As expected, and in alignment with the conditions reported by Molander, trialkylamine bases performed best in the borylation reaction. Under the optimized conditions, diisopropylethylamine (DIPEA) afforded >95 AP 1. Decreasing the amount of DIPEA from 3.0 to 2.0 equiv did not have an effect
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RESULTS AND DISCUSSION Our first venture into nickel-catalyzed borylations was a case study for the development of an arylboronic acid relevant to the BMS portfolio (1). Our strategy toward the synthesis of a desired active pharmaceutical ingredient (API), BMS-986142 (2),11 a reversible inhibitor of the Bruton Tyrosine Kinase (BTK) enzyme, featured the cross-coupling of 1 and a corresponding aryl electrophile (Scheme 1). Scheme 1. Template of Arylboronic Acid 1 on the Reversible Inhibitor of BTK BMS-986142 (2)
There were several key aspects of nickel-catalyzed borylation that we desired to better understand during this case study. To maximize atom economy in the preparation of the requisite arylboronic acid, we focused our studies on coupling reactions with B2(OH)4 as the diboron source, which would in turn directly afford the desired boronic acid, in contrast to the aryl (pinacol)boronate esters prepared by the Genentech/Sumitomo team (eq 2).10 To minimize catalyst cost, we focused on unligated nickel salts, such as Ni(NO3)2·6H2O and NiCl2· 6H2O, as inexpensive precatalysts (ca. ∼$15/mol), relative to ligated nickel complexes (ca. $250/mol for NiCl2(dppp)). We noted that Molander reported that 4-bromoaniline afforded the corresponding arylboron product in 67% yield,9 and since substrate 1 is a substituted aniline, we would need to understand the mass balance in order to improve the conversion for a substrate bearing this functional group. B
DOI: 10.1021/acs.organomet.8b00307 Organometallics XXXX, XXX, XXX−XXX
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(pseudo)halide. With these considerations in mind, and utilizing the knowledge gained from our studies on the borylation of 3 and the stability of B2(OH)4 (vide infra), we sought to design a general set of 24 reaction conditions that can be applied to any aryl (pseudo)halide to quickly and efficiently provide a path forward to develop a nickel-catalyzed borylation process. A standard workflow has been created to run a set of 24 nickel-catalyzed borylation reaction conditions (Figure 3). In
Figure 3. Flow diagram for reaction setup using the general screening platform.
Figure 1. Survey of ligands in the nickel-catalyzed borylation. Reaction conditions: Ni(NO3)2·6H2O (5 mol %), ligand (10 mol %), B2(OH)4 (2.0 equiv), DIPEA (3.0 equiv), MeOH, 20 °C. Legend: (a) reaction with Ni(NO3)2·6H2O (1 mol %), Cy-JohnPhos (2 mol %); (b) reaction with Ni(NO3)2·6H2O (1 mol %), Cy-JohnPhos (1.1 mol %).
the glovebox, predosed ligand vials are added to the reaction plate. A solution of catalyst is then added, and the plate is aged at room temperature for 20 min. A solution of substrate is then added, and the solvent is removed in vacuo via a Genevac apparatus. A solution of B2(OH)4 and base is then added to the first set of 12 ligands. A solution of B2(OH)4, base, and 1,3propanediol is then added to the second set of 12 ligands. After the plate is sealed with a Teflon sheet and lid, it can be removed from the glovebox, and mixed at room temperature overnight. After 16 h, the vials are diluted with MeCN. An aliquot is further diluted into MeCN and subjected to UPLC analysis. The optimization data from several nickel-catalyzed borylation reactions previously studied in our department were compiled and analyzed to develop the 24-reaction design (Figure 4). There were a few trends that helped determine the
on conversion to the desired product, and therefore the conditions selected for further optimization employed 2.0 equiv of DIPEA. Other organic bases (DBU, DBN, TMG, lutidine, pyridine, DMAP)19 led to much lower conversion (85 AP 1.
Figure 2. Survey of bases in the nickel-catalyzed borylation. Reaction conditions: Ni(NO3)2·6H2O (5 mol %), Cy-JohnPhos (10 mol %), B2(OH)4 (2.0 equiv), base (3.0 equiv), MeOH, 20 °C.
Figure 4. Design of the 24-reaction screening platform for nickelcatalyzed borylations.
Development of a General Screening Platform. The conditions developed for the borylation of 3 and those reported by Molander differ in each class variable (precatalyst, ligand, and solvent) except base (DIPEA), revealing that there is more than one set of conditions to access arylboronic acids through a nickel-catalyzed borylation. For process chemistry applications, it is much more important to be able to rapidly optimize a single reaction to make a specific boronic acid in the cheapest, fastest, and most robust way possible, rather than develop a general methodology that is applicable to a library of compounds. Thus, it is entirely possible that the optimal set of conditions developed for the borylation of one aryl (pseudo)halide (e.g., 3) is different from that of another aryl
key variables, and these trends are in alignment with those observed from the optimization of 3. First, methanol was superior to ethanol for each substrate for reactions run at room temperature. Therefore, methanol was selected as the reaction solvent in the design. While trialkylamine bases performed best, no significant difference was observed with DIPEA or triethylamine, and therefore, DIPEA was chosen for the design. The amount of B2(OH)4 was set at 2.0 equiv with the expectation that it could subsequently be reduced in future rounds of optimization. The first variable in the screen is the presence or absence of a diol additive, such as 1,3-propanediol. On the basis of the stability studies with B2(OH)4 (vide infra), there could be a significant increase in stability (and C
DOI: 10.1021/acs.organomet.8b00307 Organometallics XXXX, XXX, XXX−XXX
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Figure 5. Results of subjecting 15 (hetero)aryl (pseudo)halides to the screening platform. Reaction conditions: Ni(NO3)2·6H2O (5 mol %), ligand (10 mol %), B2(OH)4 (2.0 equiv), 1,3-propanediol (0 or 4.0 equiv), DIPEA (3.0 equiv), MeOH, 20 °C. Abbreviation: PD = 1,3-propanediol. Note the solvent in the reaction of phenyl tosylate is 2:1 MeOH/dioxane.
utilized phenol derivatives such as triflates, tosylates, and mesylates. Because aryl N,N-dimethylsulfamates are stable to a wide array of reaction conditions, the sulfamate moiety can be installed early in a route to serve as a protecting group, carried through a series of orthogonal transformations, and then selectively converted to an arylboronic acid at the appropriate stage. However, the use of N,N-dimethylsulfamates as electrophiles with palladium catalysts is highly challenging, usually requiring elevated temperatures.21 A single example of the borylation of an aryl N,N-dimethylsulfamate was reported by Molander, who showed that phenyl N,N-dimethylsulfamate affords the phenylboronic acid in 71% yield under the standard nickel-catalyzed conditions (eq 1) at 80 °C. Given the lack of prior borylation studies, aryl N,N-dimethylsulfamates were the last class of substrates investigated, which were prepared in one step from the corresponding phenols. We were pleased to find that subjecting three different aryl sulfamates to the screening platform showed that in all cases the desired boronic acids could be obtained in >80 AP at room temperature. It is valid to note that although the favored ligand from the earlier studies, Cy-JohnPhos, was high-yielding in many cases, it was not always the best ligand for each individual substrate. This highlights the value of employing a broad screening platform as an initial investigation into such transformations, especially when one substrate is of specific interest in a synthetic route. Investigations Into B2(OH)4 Stability. With regard to the potential scale-up of any nickel-catalyzed borylation employing B 2 (OH)4, it is important to note the safety of the tetrahydroxydiboron reagent; it is an energetic material but is not considered shock or impact sensitive. Through internal safety testing, we determined that the ADT24 (adiabatic decomposition temperature for 24 h) is 76 °C thus B2(OH)4 is most safely handled at temperatures lower than 76 °C. Hence, it is of interest to develop and scale up reactions that are run under milder reaction temperatures, namely at ambient temperature or minimal heating, and avoid running reactions at temperatures higher than 76 °C. Furthermore, the decomposition of B2(OH)4 releases hydrogen; therefore, both the borylation reaction and the subsequent workup should be well-studied before scaling up.7a
conversion) from the addition of a diol. The most critical class variable is the ligand. Twelve different ligands were selected, including the top-performing ligands from the optimization and representatives from various types of phosphines (ferrocenyl, bidentate, monodentate, simple triarylphosphines, Buchwald biarylphosphine ligands). As discussed previously, the goal of this screening platform is not to identify fully optimized conditions in the first round of screening but rather provide a starting point informed by previous investigations to provide a path forward for subsequent optimization. Further optimization into metal and ligand loading and amounts of reagents would be required to develop a process. However, applying these 24 reactions can quickly provide a lead set of conditions for further optimization. A library of (hetero)aryl (pseudo)halides were screened to test the utility of the 24-reaction design (Figure 5).20 Because aryl bromides and chlorides are generally preferred substrates for use on scale, we focused our efforts on these electrophiles, with a total of 10 electron-poor, electron-rich, and sterically hindered (hetero)aryl bromides and chlorides subjected to the 24-reaction conditions. In general, more ligands were identified as hits with aryl bromides than with aryl chlorides, presumably due to the increased reactivity of the C−Br bond. However, it is notable that at least one set of conditions afforded >80 AP product for each aryl halide tested. Surprisingly, there was not a significant ligand effect for the borylation of 4-iodoanisole, as all reaction conditions provided ≥83 AP product. In contrast to the case for aryl halides, lower conversions were generally observed for the borylation of phenyl tosylate; however, one possible explanation for this observation is that the screen was performed in 2:1 MeOH/dioxane because of the limited solubility of the phenyl tosylate substrate in pure methanol, and the addition of co-solvents was previously found to lead to decreased reactivity in nickel-catalyzed borylation (vide supra). Although broadly effective for the borylation of aryl bromides and chlorides, a significant potential application of this methodology lies in the borylation of aryl sulfamates due to the prevalence and inexpensive nature of phenols in comparison to the corresponding aryl halides and the increased stability of sulfamates in comparison to more commonly D
DOI: 10.1021/acs.organomet.8b00307 Organometallics XXXX, XXX, XXX−XXX
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results of this study in combination with the observation that similar conversion is observed with all studied nickel precursors, there could be an advantage to using NiCl2· 6H2O to prevent decomposition of B2(OH)4 on a multikilogram scale, where the charging of reagents can be a timeconsuming process. Robustness of the Borylation. To probe the functional group compatibility of the nickel-catalzyed borylation, Glorius’ robustness study26 was conducted. The most general reaction conditions using NiCl2·6H2O (2 mol %) and CyJohnPhos (2.2 mol %) with 1.2 equiv of B2(OH)4 and 2.0 equiv of DIPEA were chosen for the test reaction with 4-bromoanisole. Twenty-two different additives were spiked into the reaction at 1.0 equiv in order to determine the likely scope and limitations of the borylation reaction. The results can be seen in Table 1. Without an additive, the borylation proceeds to 98.4 AP with a calculated NMR yield of 98%. On the basis of the amounts of product formed in the screen, there is a direct correlation between conversion and the amount of additive remaining. A number of functional groups, including alkyl chloride, ketone, aniline, phenol, amide, and ester, as well as heterocycles such as indole and furan, both had a negligible effect on product formation and were unaffected by the reaction conditions. However, terminal and internal alkynes are not compatible with this chemistry, leading to significantly reduced product formation as well as substantial consumption of the alkyne (entries 3 and 8). Terminal alkenes and an aliphatic alcohol did not hinder product formation but showed some instability to the reaction conditions, while other functionalities such as a pyridine, benzofuran, or aryl nitrile were largely unchanged but led to decreased levels of product formation. As this reaction is run at room temperature with low catalyst loading, modification of the reaction conditions could improve conversion for some substrates, especially for the heterocyclic additives with lower conversion. Determining Reaction Kinetics. To determine the effect of the (pseudo)halide on the rate of the reaction, a series of kinetic experiments were conducted. The same biphenyl substituent was employed for the aryl bromide and chloride (eq 4). Parallel experiments were performed in the presence
During our studies of nickel-catalyzed borylations of various aryl halides relevant to current projects within our department, we discovered that improved yields can be obtained for difficult substrates by the addition of 2.0 equiv of a diol (generally 1,3-propanediol or neopentyl glycol) relative to B2(OH)4. Reports in the literature suggest that the addition of a diol to the borylation reaction mixture can convert tetrahydroxydiboron (or its synthetic precursor tetrakis(dimethylamino)diboron) to the corresponding bis(diolato)diboron species.7a,22 This species is capable of undergoing palladium-catalyzed borylation to afford the corresponding boronate ester, which can be isolated as the organotrifluoroborate or cross-coupled with an aryl halide in a onepot reaction. In order to probe the effect of the diol in the case of nickel-catalyzed borylations, we performed a series of stability experiments with B2(OH)4 (Figure 6).23
Figure 6. Results of the B2(OH)4 stability study. Abbreviations: EG = ethylene glycol, PD = 1,3-propanediol, DMAc = dimethylacetamide, L/M = Ligand-to-metal ratio. Reaction conditions: Ni(NO3)2·6H2O/ Cy-JohnPhos. 3−5 mol % of Ni, 4.0 equiv of DIPEA, 2.0 equiv of diol.
Unless otherwise noted, these experiments were conducted with degassed solvents in a glovebox with a stock solution of B2(OH)4 in methanol that was stirred at room temperature overnight.24 The stability of B2(OH)4 was significantly higher under a nitrogen atmosphere than in an air atmosphere for reactions conducted in either MeOH or EtOH. In MeOH under N 2 , the addition of a diol further slows the decomposition. However, the addition of DIPEA causes an increase in the decomposition of B2(OH)4. Interestingly, in all of the solvents investigated under N2 (EtOH, MeOH, DMAc), with and without diol, the majority of the B 2 (OH) 4 decomposition occurs in the first hour, followed by a stable solution of B2(OH)4.25 The stability of B2(OH)4was next studied in the presence of an array of nickel precursors and monitored using 11B NMR. Interestingly, B2(OH)4 is significantly more stable to nickel halides (NiCl2·6H2O, NiCl2·glyme, NiBr2·6H2O) in comparison to other nickel precatalysts (Ni(NO3)2·6H2O, Ni(OAc)2·6H2O). Further, the addition of base or diol to Ni(NO3)2·6H2O did not prevent decomposition. However, the addition of Cy-JohnPhos ligand had a profound effect. At a 1.1:1 L/M ratio, which is the optimal ratio for the borylation of 3, 78% decomposition is observed after 24 h. In contrast, an increased L/M ratio of 3:1 led to only 34% observed decomposition after 24 h, while after 1 h only 7% decomposition is observed. The addition of ligand does not prevent decomposition in the presence of base, with nearly complete decomposition of the B2(OH)4 observed within 1 h in the presence of DIPEA. On the basis of the
and absence of 1,3-propanediol as an additive (Figure 7).27 Similar kinetic profiles were observed with and without 1,3propanediol, indicating that it does not affect the initial rate of the reaction, but the conversion does tail after approximately 1 h reaction time. Rather, the role of the diol is likely to stabilize the B2(OH)4 such that the rate of diboron decomposition is slower than the rate of the borylation reaction. The kinetics of the borylation of the corresponding N,N-dimethylsulfamate and aryl chloride showed that the rate of borylation was ArBr > ArCl ≈ ArOSONMe2.27 Nickel Remediation. Removal of residual metal catalysts from reaction streams is a large area of focus and concern for the development of chemical processes.28 Robust control is required29 to ensure that the catalyst is effectively and efficiently removed from the product stream without negatively E
DOI: 10.1021/acs.organomet.8b00307 Organometallics XXXX, XXX, XXX−XXX
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Organometallics Table 1. Glorius’ Robustness Study of the Nickel Borylationb
a
Calculated from a 1 g borylation of 4-bromoanisole. bThe standard reaction is run in the presence of 1 molar equiv of the additive. The yield of the product and remaining starting material is given as an HPLC area percent. Additive results are provided using GC/FID. The amount of additive remaining is also provided.
aqueous wash. The layers were filtered or split, and then the organic layer was concentrated to determine the residual Ni in the organic stream (Figure 8). All treatments decreased the amount of Ni by at least 50% relative to the untreated reaction stream. Surprisingly, simple aqueous washes greatly reduce the amount of residual nickel in the organic layer. The best results were observed with 1 M oxalic acid and 1 M citric acid at 99 AP). Mp: >250 °C. 1H NMR (500 MHz, d6DMSO): δ 7.86 (s, 2H), 6.86−6.84 (m, 1H), 6.61−6.58 (m, 2H), 4.63 (s, 2H), 2.10 (s, 3H). 13C NMR (125.8 MHz, d6-DMSO): δ 146.3, 125.7, 124.1, 121.2, 115.0, 17.5. IR (neat) 3295, 1597, 1453, 1366, 1345, 1093, 904, 823, 722 cm−1. HRMS (ESI): m/z calcd for C7H11BNO2 [M + H]+ 152.0877, found 152.0871. Optimization of the Borylation of 3. The borylation of 3 was optimized via high-throughput experimentation following the general procedure shown below. Because 3 is highly soluble in MeOH, the literature procedure was adapted as described herein. In the glovebox, predosed ligand vials were added to the reaction plate. A solution of catalyst (25 μL of a 0.02 M solution of Ni(NO3)2·6H2O in MeOH) was then added, and the plate was aged at room temperature for 20 min. A solution of substrate (25 μL of a 0.4 M solution in tetrahydrofuran) was then added. A solution of B2(OH)4 and base (50 μL of a 0.4 and 0.6 M solution in MeOH, respectively) was then added to the first set of 12 ligands. A solution of B2(OH)4, base, and 1,3-propanediol (50 μL of 0.4, 0.6, and 0.8 M solutions in MeOH, respectively) was then added to the second set of 12 ligands. The plate was sealed with a Teflon sheet and lid, removed from the glovebox, and mixed at room temperature overnight. After 16 h, the
Figure 7. Kinetic study of the borylation of 4-bromobiphenyl: (orange series) standard conditions from eq 4; (blue series) addition of 4.0 equiv of 1,3-propanediol.
Figure 8. Results from the nickel remediation study. Legend: (a) DTC = ammonium pyrrolidinedithiocarbamate.
wherein 96 AP of the product was observed at the end of the reaction. After changing to MeTHF and washing twice with water, the boronic acid was isolated via an unoptimized crystallization in 80% yield (eq 5).37 The workup and isolation
were conducted under N2, with the residual nickel tracked through the workup, and 490 ppm of residual Ni was measured in the isolated solid, suggesting that in many cases a simple aqueous wash may be sufficient to remove the majority of nickel38 from borylation reactions.
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CONCLUSION Employing nickel as a catalyst for the borylation of aryl (pseudo)halides on scale has the potential to offer many advantages in comparison to palladium, including lower cost and wider substrate scope. However, the uncertainty around the nickel-catalyzed borylations and the way residual nickel can G
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Organometallics vials were diluted with MeCN (500 μL). An aliquot (40 μL) was further diluted into MeCN (1 mL) and subjected to UHPLC analysis. BBA Decomposition Studies Procedure. In a 40 mL vial equipped with a septum cap and magnetic stir bar was charged tetrahydroxydiboron (500 mg) followed by the appropriate solvent (10 mL, 20 mL/g BBA). Where applicable, the appropriate diol additive (2.0 equiv), base (4.0 equiv), and/or Ni catalyst (5%) were charged. In order to avoid pressure buildup, the vial was loosely sealed or a vent needle was inserted into the septum cap. The reaction mixture was stirred at room temperature for 24 h. All experiments under inert conditions were performed in the glovebox. All experiments in air were performed on the benchtop. BBA Decomposition Studies with Ni/CyJohnPhos Precomplexation Procedure. A 40 mL vial equipped with a septum cap and magnetic stir bar was brought into the glovebox and charged with Ni(NO3)2·6H2O (5%) followed by CyJohnPhos. Next, MeOH (10 mL) was charged, and the reaction mixture was stirred at 50 °C for 20−30 min. The reaction mixture was cooled to room temperature, and the appropriate additive (diol and/or base) was charged. Finally, tetrahydroxydiboron (500 mg) was charged, and the reaction mixture was stirred in the glovebox at room temperature for 24 h. The reaction vessel was loosely sealed in order to avoid pressure buildup. General Procedure for the Nickel Remediation Study. In a 40 mL scintillation vial with a stir bar was charged 1-bromo-3,5dimethoxybenzene (3.48 g, 16.0 mmol, 100 mass %) followed by degassed methanol (25 mL). The mixture was aged with stirring and slight heat until dissolution. N,N-Diisopropylethylamine (3.51 g, 27.2 mmol, 100 mass %) was then added followed by tetrahydroxydiboron (1.50 g, 16.2 mmol, 97 mass %). In a separate 20 mL scintillation vial with a stir bar was charged nickel nitrate hexahydrate (38.9 mg, 0.134 mmol, 100 mass %) and CyJohnPhos (52 mg, 0.148367 mmol, 100 mass %) followed by methanol (10 mL). The mixture was aged with stirring and slight heat until dissolution. Both vials were brought into the glovebox, where they were evacuated and purged 5× with N2. In the glovebox, the contents of the 40 mL vial were transferred to a 100 mL RBF with a stir bar. The vial was rinsed with MeOH (5 mL) and the rinse transferred to the RBF. The contents of the 20 mL vial were then transferred to the same vial. The vial was rinsed with MeOH (5 mL) and the rinse transferred to the RBF. The RBF was sealed with a rubber septum and the mixture aged overnight with stirring under N2. After ∼16 h, the reaction stream was changed into MeTHF by concentrating to a minimum, charging 50 mL of MeTHF, and repeating that put/take 3×. MeTHF (∼20 vol, 60 mL) was charged. Solids were filtered and submitted for residual metal analysis. Vials 1− 22 were treated with the appropriate aqueous solution or solid scavenger. Note that ethylenediamine and DTC were added neat. In these vials was charged 2 mL of the above MeTHF stream, and the mixtures were stirred for 30 min. Water was placed in the ethylenediamine and DTC vials, and the mixtures were stirred for 30 min. The mixtures in the carbon treatment vials were filtered into 8 mL tubes. The organic phase from each vial was removed via pipet and transferred to an 8 mL vial. All of the isolated organic phases were concentrated via a Genevac apparatus and submitted for residual Ni analysis by ICP/MS. Kinetic Study. In the glovebox, an 8 mL vial was charged with the aryl (pseudo)halide substrate (0.36 mmol) and B2(OH)4 (2.0 equiv). MeOH (2.6 mL) was added, followed by DIPEA (2.0 equiv), PD if applicable (0 or 4.0 equiv), and p-xylene (10 μL) as an internal standard. The mixtures were stirred until fully dissolved (typically
