Overcoming Halide Inhibition of SuzukiâMiyaura Couplings with Biaryl

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Overcoming Halide Inhibition of Suzuki−Miyaura Couplings with Biaryl Monophosphine-Based Catalysts Jose ́ J. Fuentes-Rivera,† Mary E. Zick,† M. Alexander Düfert,*,‡ and Phillip J. Milner*,† †

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States BASF SE, Carl-Bosch-Straße 38, D-67056 Ludwigshafen, Germany

‡

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S Supporting Information *

ABSTRACT: The Suzuki−Miyaura reaction is one of the most widely employed transformations in synthetic chemistry. Despite extensive investigation, questions remain about the mechanistic nature of the transmetalation step when catalysts based on advanced ligands such as biaryl monophosphines are used, impeding the development of improved catalysts. Here we demonstrate that the often overlooked halide salt (KX) generated as a byproduct of cross-coupling renders the transmetalation step reversible with SPhos-based catalysts, leading to severe reaction inhibition with (hetero)aryl iodides. Stoichiometric and kinetic studies reveal that halide inhibition likely originates from disfavoring the formation of a highly reactive Pd−OH intermediate. We demonstrate that changing the organic solvent in the biphasic reaction mixture from tetrahydrofuran to toluene is sufficient to minimize this inhibition and enable the general Suzuki−Miyaura coupling of (hetero)aryl iodides. Our studies suggest that halide inhibition may be a more general problem in cross-coupling reactions, especially those involving reversible transmetalation processes. KEYWORDS: Suzuki−Miyaura, inhibition, palladium catalysis, cross-coupling, aryl iodide

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INTRODUCTION

Modern catalytic systems based on biaryl monophosphine ligands such as SPhos (L1) and the associated precatalysts (P1) are highly reactive, allowing for the use of unstable boronic acids while exhibiting excellent functional group tolerance.4−6 However, certain Suzuki−Miyaura cross-couplings remain challenging, such as those of nitrogen-containing heteroarenes.7 Because the oxidative addition and C−C bondforming reductive elimination steps of the proposed catalytic cycle are expected to proceed rapidly with modern catalysts,8−10 transmetalation is likely the problematic step in many of these reactions (Figure 1).11 Therefore, transmetalation remains a pivotal but poorly understood process in Suzuki−Miyaura cross-coupling reactions, especially with catalysts based on biaryl monophosphine ligands. Suzuki−Miyaura couplings are well-known to proceed most efficiently in the presence of a base (e.g., K3PO4, K2CO3, KOH) and under biphasic conditions.12−16 It has been proposed that OH− facilitates the transmetalation step of the catalytic cycle.10−12 Indeed, isolated Ln·Pd(Ar)X (X = Br, I) complexes generally do not undergo stoichiometric reaction with boronic acids in the absence of exogenous OH−,10,17 although certain Pd−Cl complexes have recently been shown to react directly with arylboronic acids.18 On the basis of these findings, two competing mechanistic roles for OH− have been proposed (Figure 1).12,19−21 In Pathway I, exhaustive reaction of the organoboron precursor with OH− produces an arylboronate (R−B(OH)3−), which then reacts directly with

The Pd-catalyzed Suzuki−Miyaura cross-coupling of organoboron reagents with aryl (pseudo)halides is one of the most widely used reactions to construct C−C bonds (Figure 1).1−3

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Figure 1. Proposed mechanistic pathways for the Suzuki−Miyaura coupling and the structures of the biaryl monophosphine ligand SPhos (L1), monomeric L1·Pd(Ph)Cl, and precatalyst P1. © XXXX American Chemical Society

Received: June 5, 2019

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DOI: 10.1021/acs.oprd.9b00255 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

the Ln·Pd(Ar)X (X = Cl, Br, I) intermediate formed after oxidative addition.20 Consistent with this mechanistic hypothesis, most arylboron species undergo rapid partial conversion to arylboronates under basic biphasic conditions,12,22−25 and preformed arylboronates are competent reaction partners.26,27 In Pathway II, the Ln·Pd(Ar)X intermediate instead reacts with OH− to form an Ln·Pd(Ar)OH species,10,19,28,29 which in turn reacts with the boronic acid nucleophile.10,12 Indeed, previous stoichiometric studies have shown that isolated Ln·Pd(Ar)OH complexes undergo rapid transmetalation with boronic acids.10,11,14 Elegant studies by Hartwig,11 Jutand and Amatore,10,15 Schmidt,30,31 and Denmark32−34 favor reaction via Pd−OH intermediates (Pathway II) with simple supporting ligands under biphasic conditions. To guide future kinetic modeling and catalyst development, we set out to investigate the mechanism(s) of transmetalation in Suzuki−Miyaura couplings using an L1-based catalyst. During the course of this investigation, we unearthed a surprising inhibitory effect on catalytic reactions by the halide (X−) generated as a byproduct of cross-coupling. This inhibition is most pronounced for (hetero)aryl iodides, leading to poor conversions for these substrates. Stoichiometric studies suggest that inhibition likely occurs because X− renders Pathway II reversible and increasingly disfavored as the reaction proceeds. On the basis of this mechanistic understanding, we demonstrate that simply changing the organic solvent from tetrahydrofuran (THF) to toluene can overcome this undesirable halide inhibition and drive the Suzuki− Miyaura couplings of (hetero)aryl iodides to full conversion.

Figure 2. Determination of reagent orders for the Suzuki−Miyaura coupling of PhCl and PhB(OH)2. Standard reaction conditions: PhCl (0.50 mmol), phenylboronic acid (0.50 mmol), L1·Pd(Ph)Cl (0.01 mmol, 2.0%), K3PO4 (1.00 mmol), THF (2.0 mL), H2O (1.0 mL), room temperature, 400 rpm stirring rate. Conversion was determined by gas chromatography relative to dodecane as an internal standard. The kinetics shown for the 2× PhCl experiment are shifted down by 100% to facilitate comparison and were conducted using 1.9 mL of THF.

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RESULTS AND DISCUSSION Inhibitory Effect of KX on Catalytic Reactions. To investigate whether transmetalation is the rate-determining step of Suzuki−Miyaura couplings using an L1-based catalyst, we first evaluated the kinetics of the standard coupling of chlorobenzene (PhCl) and phenylboronic acid (PhB(OH)2) under biphasic conditions (Figure 2; see Supporting Information (SI) section 5 for details). For these studies, the oxidative addition complex L1·Pd(Ph)Cl (which exists as a mixture of monomer and μ-Cl dimer in solution)7,35 was chosen as the Pd source to avoid issues of inhibition by species generated upon catalyst activation.36,37 The presence of two phases complicates the kinetic analysis of these reactions, as it leads to nonequilibrium effects. Nonetheless, the aryl halide, arylboronic acid, and catalyst partition nearly exclusively into the organic layer, and OH− and the arylboronate partition nearly exclusively into the aqueous layer, suggesting that the proposed catalytic cycles occur primarily in the organic phase and that transmetalation occurs at or near the THF−water interface.12,16 The kinetics of the standard reaction could be modeled equally well with first-order (k1 = 9.3 × 10−5 s−1, R2 = 0.9973) and second-order (k2 = 4.7 × 10−4 M−1 s−1, R2 = 0.9996) kinetic models (Figures S1 and S2), assuming that all of the starting material is present in the organic phase during the reaction (i.e., [PhCl]0 ≈ [dodecane] = 0.25 M).16 Notably, rapid consumption of 3−10% of the starting material in the first 2 min of the reaction was observed in nearly all cases, followed by slower conversion. As has been previously reported,10,22,24,25 the difference in the kinetics observed in the first few minutes of these reactions is likely due to the time required for PhB(OH)2 (in the organic phase) and PhB(OH)3− (in the aqueous phase) to equilibrate and precludes the use of initial rates to determine the orders with respect to

the reagents. Therefore, the relative rates of reactions at 15−30 min were employed instead (Table 1). Table 1. Summary of Rates for the Reactions in Figure 2 conditions standard 2× PhCl 2× PhB(OH)2 2× K3PO4 1 /2× L1·Pd(Ph)Cl

Δ[PhCl]/Δt at 15−30 min (M/min) −1.1 −1.2 −2.7 −1.1 −0.9

× × × × ×

10−3 10−3 10−3 10−3 10−4

relative rate at 15−30 min 1.0 1.0 2.2 1.0 0.75

On the basis of Figure 2 and Table 1, the reaction exhibits a positive order with respect to [PhB(OH)2] and [L1·Pd(Ph)Cl] and zero order with respect to [PhCl] and [K3PO4]. The zeroth-order rate dependence on the concentration of base likely arises because OH− can intercept the catalyst only at the THF−H2O interface;16 indeed, faster conversion with a clear second-order kinetic profile was observed when the reaction mixture was stirred more rapidly (Figures S19−S21), suggesting that diffusion at the THF−water interface is at least partially rate-determining. Additionally, the observed order of 1/2 with respect to the catalyst concentration arises because the catalyst resting state is primarily a μ-Cl dimer in solution.7,35 These kinetic findings are consistent with previous mechanistic studies10 and suggest that either transmetalation or reductive elimination is the rate-determining step of the catalytic cycle in Figure 1, although mixing of the organic and aqueous phases also plays a role in the reaction kinetics. In addition, these studies unveil that the most reliable methods to B



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accelerate sluggish Suzuki−Miyaura couplings with L1-based catalysts are to increase the concentration of arylboronic acid (when possible) and to ensure thorough mixing of the biphasic reaction mixture. We sought to further corroborate that transmetalation is the likely rate-determining step in these reactions by investigating the effect of the halide in the starting material on the reaction kinetics (Figure 3; see SI section 6 for details). The observed

Table 2. Effect of Added KX on Suzuki−Miyaura Couplingsa

additivea

% conv. after 30 min

% conv. after 60 min

none KI KBr KCl KClb

22 5 8 15 2

33 8 13 24 3

a

Standard reaction conditions: PhCl (0.50 mmol), phenylboronic acid (0.50 mmol), L1·Pd(Ph)Cl (0.01 mmol, 2.0%), K3PO4 (1.00 mmol), THF (2.0 mL), H2O (1.0 mL), KX (0.50 mmol), room temperature, 400 rpm stirring rate. Conversion was determined by gas chromatography relative to dodecane as an internal standard. b2.50 mmol of KCl (5 equiv relative to PhCl).

addition of 5 equiv of KCl significantly inhibited the desired reaction (3% conversion after 60 min), confirming that the inhibitory role of X−should be particularly problematic for syntheses involving multiple cross-coupling reactions in a single pot. A similar inhibitory effect was also observed for the faster Suzuki−Miyaura coupling of 3-chloroanisole with 2,6-difluorophenylboronic acid, which led to poor conversions in the presence of added KI due to competing protodeborylation (Figure S9).5 Notably, Jutand and Amatore previously observed that exogenous Br− has an inhibitory effect on the rate of Suzuki−Miyaura couplings with PPh3-based catalysts,10 and Schmidt demonstrated that exogenous halide binds to Pd under ligand-free conditions.31 This unexpected reaction inhibition by halide salts contributes to the slow couplings of aryl iodides and should also retard reactions involving multiple cross-couplings of polyhalogenated substrates. Stoichiometric Studies of Transmetalation and the Origin of Halide Inhibition. To elucidate the molecular origin of halide inhibition with L1-based catalysts, we turned to stoichiometric studies of the transmetalation step (see SI section 8 for details). Specifically, the reactivities of the complexes L1·Pd(Ph)X (X = Cl, Br, I, OH) with various boron nucleophiles were studied to determine whether Pathway I and/or Pathway II is viable under catalytically relevant conditions (Figure 4). No reaction was observed upon exposure of L1·Pd(Ph)Cl to a slight excess (1.6 equiv) of PhB(OH)2 in THF/H2O (Figure S10). However, rapid conversion of L1·Pd(Ph)Cl and PhB(OH)2 (50% conversion in PhI is again consistent with transmetalation occurring before or during the rate-determining step in these reactions. The reaction kinetics with PhBr could be fit well with a first-order kinetic model, yielding k1 = 5.0 × 10−5 s−1 (kCl/kBr = 1.9; Figure S7). However, the coupling of PhI could not be fit well with a first-order kinetic model (R2 = 0.8611; Figure S8), as this reaction exhibits rapid initial consumption of starting material followed by very slow conversion thereafter. Notably, this reaction did not proceed to full conversion even after 24 h (Table S11). This finding suggests that the sluggish reactivity of aryl iodides is due in part to catalyst decomposition38 or inhibition of the desired reaction by KI.10,31,39,40 To evaluate any potential inhibition by the halide salts generated during Suzuki−Miyaura reactions, we examined the coupling of PhCl and phenylboronic acid in the presence of KX salts (Table 2; see SI section 7 for details). Under the standard reaction conditions, the desired reaction proceeds to 33% conversion within 60 min at room temperature. However, the addition of just 1 equiv of KI led to significant inhibition, with only 8% conversion during the same window. Both KBr (13% conversion) and KCl (24% conversion) displayed an inhibitory effect on the reaction as well. Importantly, the C



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reactivity of the L1·Pd(Ph)X (X = Cl, Br, I) complexes toward exogenous OH− to investigate the first step of this pathway. Both 31P NMR and reaction calorimetry measurements (Figures S15 and S16) demonstrated that the exchange of L1·Pd(Ph)Cl with excess OH− to produce an apparent equimolar equilibrium with L1·Pd(Ph)OH is complete in I).41 Instead, the halide-dependent partitioning of KX into the organic phase (KI > KBr > KCl; see SI section 4 for details), where the Pd species exclusively resides,16 accounts for the pronounced halide-dependent thermodynamic shift toward L1·Pd(Ph)X. These results corroborate both that the first step of Pathway II is reversible and that the X− generated during catalytic reactions drives this equilibrium toward L1·Pd(Ph)X, increasingly disfavoring the formation of L1·Pd(Ph)OH and slowing down Pathway II as the reaction progresses. Even if Pathway I is operative under catalytic conditions, this effect should still lead to a decrease in the reaction rate, at least for aryl bromides and iodides, due to the slower reaction of the L1·Pd(Ph)X (X = Br,

Figure 4. Reaction kinetics for the stoichiometric reactions of the L1· Pd(Ph)X (X = I, Br, Cl) complexes with PhB(OH)3K to probe the viability of Pathway I and of L1·Pd(Ph)OH with PhB(OH)2 to probe the viability of Pathway II. Reaction conditions: L1·Pd(Ph)X (0.05 mmol, 1.00 equiv), PhB(OH)3K or PhB(OH)2 (0.08 mmol, 1.60 equiv), THF (1.0 mL), H2O (0.1 mL), room temperature. Conversion was monitored using a gas chromatography assay as described in the SI. Lines are included between data points as visual guides. The monomeric structures of the Pd complexes are shown for simplicity.

ison of the reactivities of the L1·Pd(Ph)X (X = Cl, Br, I) complexes toward PhB(OH)3K reveals a clear trend: whereas L1·Pd(Ph)Br reacts only slightly slower than L1·Pd(Ph)Cl (k2 = 0.14 M−1 s−1; kCl/kBr ≥ 3.5), L1·Pd(Ph)I reacts significantly more slowly (k2 = 0.01 M−1 s−1; kCl/kI ≥ 49) (Figure 4).11,30,40 These stoichiometric results corroborate that Pathway I, if operative under catalytic conditions, would be extremely slow for aryl iodides. We next studied the reactivity of L1·Pd(Ph)OH with PhB(OH)2 to investigate the viability of Pathway II (Figure 4). As previously reported,7 L1·Pd(Ph)OH can be readily prepared from L1·Pd(Ph)Cl by treatment with aqueous K3PO4. The stoichiometric reaction of L1·Pd(Ph)OH with PhB(OH)2 is less mechanistically ambiguous than that of L1· Pd(Ph)X (X = Cl, Br, I) with PhB(OH)3K, since it should proceed exclusively via Pathway II.11 Importantly, the reaction between isolated L1·Pd(Ph)OH and 1.60 equiv of PhB(OH)2 was found to be extremely rapid (∼50% conversion in 2 min), confirming that the second step of Pathway II is rapid under stoichiometric conditions (Figure 4). Fitting the kinetics of this stoichiometric reaction yielded a lower bound of 0.49 M−1 s−1 for the second-order rate constant k2 (Figure S14),16 comparable to that for the reaction of L1·Pd(Ph)Cl with PhB(OH)3K. Having confirmed that the second step of Pathway II is viable under stoichiometric conditions, we next studied the D



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Figure 6. Suzuki−Miyaura couplings of (hetero)aryl iodides with arylboronic acids in toluene/H2O. Standard reaction conditions: aryl iodide (0.50 mmol), arylboronic acid (0.75 mmol), P1 (0.01 mmol, 2.0%), K3PO4 (1.00 mmol), toluene (2.0 mL), H2O (1.0 mL), 100 °C, 1000 rpm stirring rate, 14 h. Isolated yields are shown.

because of the poor reactivity of (hetero)aryl iodides, precluding the use of unstable (hetero)arylboronic acids under these conditions.5 Nonetheless, a toluene/H2O reaction mixture minimizes I− inhibition and enables the general crosscoupling of (hetero)aryl iodide substrates using L1-based catalysts. We hypothesize that these conditions will also prove beneficial to reactions involving multiple cross-coupling processes in one pot as well.

Figure 5. Equilibria between L1·Pd(Ph)OH and L1·Pd(Ph)X (X = Cl, Br, I) in the presence of exogenous KX, as determined by 31P NMR spectroscopy. Reaction conditions: L1·Pd(Ph)OH (0.01 mmol, 1.00 equiv), THF (0.5 mL), aqueous 1.5 M K2CO3 (218 μL, 40.0 equiv), KX (0−50 equiv). Lines are included between data points as visual guides. The monomeric structures of the Pd complexes are shown for simplicity.

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CONCLUSION The combined catalytic and stoichiometric studies presented here confirm that the increasing concentration of KX generated during catalytic Suzuki−Miyaura reactions retards the rate of product formation when L1-based catalysts are used. This inhibition is more pronounced in the order Cl < Br < I, rendering the couplings of (hetero)aryl iodides sluggish under catalytic conditions. Our stoichiometric studies confirm that this effect arises because exogenous X− drives the equilibrium between L1·Pd(Ph)OH and L1·Pd(Ph)X toward L1·Pd(Ph)X, slowing down Pathway II as the reaction progresses. However, this inhibitory effect can be overcome simply by switching the organic solvent from THF to toluene, thereby minimizing the concentration of KI in the organic phase. We anticipate that these reaction conditions will be comparable in scope and scalability to those for standard Suzuki−Miyaura couplings using L1-based catalysts and allow the use of (hetero)aryl iodides in addition to aryl chlorides and bromides for these reactions. While we have focused on Suzuki−Miyaura couplings here, halide inhibition would be expected for any cross-coupling exhibiting a reversible transmetalation step,45,46 such as those for which reductive elimination is ratedetermining. Therefore, future studies will focus on determining whether these cross-coupling reactions can be accelerated by sequestering exogenous X− from the reaction mixture.

I) complexes with PhB(OH)3K compared with the reaction of L1·Pd(Ph)OH with PhB(OH)2 (Figure 4). The observed inhibitory effect of KCl on the reaction of aryl chlorides (Table 2) supports that Pathway I, if operative, is also slower than Pathway II for these substrates. Overall, these stoichiometric findings corroborate that the inhibitory role of exogenous X− on catalytic reactions is likely to disfavor the formation of the reactive L1·Pd(Ar)OH intermediate and arises from the partial solubility of KX salts in the organic phase. Overcoming the Inhibitory Effect of I−. On the basis of our stoichiometric studies, we hypothesized that removing the KI generated during the couplings of aryl iodides from the organic phase should lead to higher conversions under catalytic conditions. Consistently, a survey of bases revealed that only Ag2O leads to full conversion of PhI under the standard reaction conditions at room temperature, due to sequestration of I− as insoluble AgI (Table S11).12,17,42−44 Unfortunately, the use of AgO was not generalizable to more complex substrates, likely because of the redox noninnocence of Ag+. Previous studies have demonstrated that using toluene as the reaction solvent can also overcome I− inhibition of Pdcatalyzed reactions because of the poor solubility of KI in nonpolar solvents (see SI section 4).39 Gratifyingly, simply switching the organic phase from THF to a less polar solvent such as Et2O or toluene led to higher conversions of PhI under the standard reaction conditions (Table S12). In particular, the use of toluene as the organic phase was sufficient to enable the Suzuki−Miyaura couplings of a range of (hetero)aryl iodides with commercially available P1 as the catalyst source (Figure 6). These reactions had to be conducted at high temperatures

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00255. Experimental details and data from kinetic measurements and equilibrium experiments (PDF) E



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(13) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven, T. R. Mechanistic Studies of the Suzuki Cross-Coupling Reaction. J. Org. Chem. 1994, 59 (26), 8151−8156. (14) Miyaura, N. Cross-Coupling Reaction of Organoboron Compounds via Base-Assisted Transmetalation to Palladium(II) Complexes. J. Organomet. Chem. 2002, 653 (1−2), 54−57. (15) Amatore, C.; Jutand, A.; Le-Duc, G. Mechanistic Origin of Antagonist Effects of Usual Anionic Bases (OH−, CO32−) as Modulated by Their Countercations (Na+, Cs+, K+) in PalladiumCatalyzed Suzuki−Miyaura Reactions. Chem. - Eur. J. 2012, 18 (21), 6616−6625. (16) Röhlich, C.; Wirth, A. S.; Köhler, K. Suzuki Coupling Reactions in Neat Water as the Solvent: Where in the Biphasic Reaction Mixture Do the Catalytic Reaction Steps Occur? Chem. - Eur. J. 2012, 18 (48), 15485−15494. (17) Yunker, L. P. E.; Ahmadi, Z.; Logan, J. R.; Wu, W.; Li, T.; Martindale, A.; Oliver, A. G.; McIndoe, J. S. Real-Time Mass Spectrometric Investigations into the Mechanism of the Suzuki− Miyaura Reaction. Organometallics 2018, 37 (22), 4297−4308. (18) Chen, L.; Sanchez, D. R.; Zhang, B.; Carrow, B. P. Cationic Suzuki−Miyaura Coupling with Acutely Base-Sensitive Boronic Acids. J. Am. Chem. Soc. 2017, 139 (36), 12418−12421. (19) Matos, K.; Soderquist, J. A. Alkylboranes in the Suzuki− Miyaura Coupling: Stereochemical and Mechanistic Studies. J. Org. Chem. 1998, 63 (3), 461−470. (20) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. Computational Characterization of the Role of the Base in the Suzuki−Miyaura Cross-Coupling Reaction. J. Am. Chem. Soc. 2005, 127 (25), 9298−9307. (21) Ortuño, M. A.; Lledós, A.; Maseras, F.; Ujaque, G. The Transmetalation Process in Suzuki−Miyaura Reactions: Calculations Indicate Lower Barrier via Boronate Intermediate. ChemCatChem 2014, 6 (11), 3132−3138. (22) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; LloydJones, G. C.; Murray, P. M. Aryl Trifluoroborates in Suzuki−Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride. Angew. Chem., Int. Ed. 2010, 49 (30), 5156−5160. (23) Lima, C. F. R. A. C.; Rodrigues, A. S. M. C.; Silva, V. L. M.; Silva, A. M. S.; Santos, L. M. N. B. F. Role of the Base and Control of Selectivity in the Suzuki−Miyaura Cross-Coupling Reaction. ChemCatChem 2014, 6 (5), 1291−1302. (24) Gonzalez, J. A.; Ogba, O. M.; Morehouse, G. F.; Rosson, N.; Houk, K. N.; Leach, A. G.; Cheong, P. H.-Y.; Burke, M. D.; LloydJones, G. C. MIDA Boronates Are Hydrolysed Fast and Slow by Two Different Mechanisms. Nat. Chem. 2016, 8 (11), 1067−1075. (25) Lennox, A. J. J.; Lloyd-Jones, G. C. Organotrifluoroborate Hydrolysis: Boronic Acid Release Mechanism and an Acid-Base Paradox in Cross-Coupling. J. Am. Chem. Soc. 2012, 134 (17), 7431− 7441. (26) Oberli, M. A.; Buchwald, S. L. A General Method for Suzuki− Miyaura Coupling Reactions Using Lithium Triisopropyl Borates. Org. Lett. 2012, 14 (17), 4606−4609. (27) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Cyclic Triolborates: Air- and Water-Stable Ate Complexes of Organoboronic Acids. Angew. Chem., Int. Ed. 2008, 47 (5), 928−931. (28) Nelson, D. J.; Nolan, S. P. Hydroxide Complexes of the Late Transition Metals: Organometallic Chemistry and Catalysis. Coord. Chem. Rev. 2017, 353, 278−294. (29) Yaman, T.; Harvey, J. Suzuki−Miyaura Coupling Revisited: An Integrated Computational Study. Faraday Discuss. 2019, DOI: 10.1039/C9FD00051H. (30) Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Role of a Base in Suzuki−Miyaura Reaction. Russ. J. Gen. Chem. 2011, 81 (7), 1573− 1574. (31) Kurokhtina, A. A.; Larina, E. V.; Yarosh, E. V.; Schmidt, A. F. Role of the Base and Endogenous Anions in “Ligand-Free” Catalytic Systems for the Suzuki−Miyaura Reaction. Kinet. Catal. 2016, 57 (3), 373−379.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

José J. Fuentes-Rivera: 0000-0002-8861-6752 Phillip J. Milner: 0000-0002-2618-013X Funding

Initial financial support of this project was provided by the National Institutes of Health (GM46059) and the German Research Foundation (postdoctoral fellowship for M.A.D.). Further support was provided by Cornell University. Notes

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Prof. Stephen L. Buchwald for helpful discussions, guidance, mentorship, and initial financial support of this work. REFERENCES

(1) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95 (7), 2457−2483. (2) Suzuki, A. Cross-Coupling Reactions Of Organoboranes: An Easy Way To Construct C-C Bonds (Nobel Lecture). Angew. Chem., Int. Ed. 2011, 50 (30), 6722−6737. (3) Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?: Miniperspective. J. Med. Chem. 2016, 59 (10), 4443−4458. (4) Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki− Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands. Acc. Chem. Res. 2008, 41 (11), 1461−1473. (5) Kinzel, T.; Zhang, Y.; Buchwald, S. L. A New Palladium Precatalyst Allows for the Fast Suzuki−Miyaura Coupling Reactions of Unstable Polyfluorophenyl and 2-Heteroaryl Boronic Acids. J. Am. Chem. Soc. 2010, 132 (40), 14073−14075. (6) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and Preparation of New Palladium Precatalysts for C-C and C-N CrossCoupling Reactions. Chem. Sci. 2013, 4 (3), 916−920. (7) Düfert, M. A.; Billingsley, K. L.; Buchwald, S. L. Suzuki−Miyaura Cross-Coupling of Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and Mechanistic Investigation. J. Am. Chem. Soc. 2013, 135 (34), 12877−12885. (8) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. Catalysts for Suzuki−Miyaura Coupling Processes: Scope and Studies of the Effect of Ligand Structure. J. Am. Chem. Soc. 2005, 127 (13), 4685−4696. (9) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. A New Class of Easily Activated Palladium Precatalysts for Facile C-N Cross-Coupling Reactions and the Low Temperature Oxidative Addition of Aryl Chlorides. J. Am. Chem. Soc. 2008, 130 (21), 6686−6687. (10) Amatore, C.; Jutand, A.; Le-Duc, G. Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki−Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base. Chem. - Eur. J. 2011, 17 (8), 2492−2503. (11) Carrow, B. P.; Hartwig, J. F. Distinguishing Between Pathways for Transmetalation in Suzuki−Miyaura Reactions. J. Am. Chem. Soc. 2011, 133 (7), 2116−2119. (12) Lennox, A. J. J.; Lloyd-Jones, G. C. Transmetalation in the Suzuki−Miyaura Coupling: The Fork in the Trail. Angew. Chem., Int. Ed. 2013, 52 (29), 7362−7370. F



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(32) Thomas, A. A.; Zahrt, A. F.; Delaney, C. P.; Denmark, S. E. Elucidating the Role of the Boronic Esters in the Suzuki−Miyaura Reaction: Structural, Kinetic, and Computational Investigations. J. Am. Chem. Soc. 2018, 140 (12), 4401−4416. (33) Thomas, A. A.; Denmark, S. E. Pre-Transmetalation Intermediates in the Suzuki−Miyaura Reaction Revealed: The Missing Link. Science 2016, 352 (6283), 329−332. (34) Thomas, A. A.; Wang, H.; Zahrt, A. F.; Denmark, S. E. Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)Boronate Complexes in the Suzuki−Miyaura Reaction. J. Am. Chem. Soc. 2017, 139 (10), 3805−3821. (35) Brazier, J. B.; Newton, M. A.; Barreiro, E. M.; Adrio, L. A.; Naya, L.; Hii, K. K. M. Solvent-Dependent Nuclearity, Geometry and Catalytic Activity of [(SPhos)Pd(Ph)Cl]2. Dalton Trans. 2017, 46 (22), 7223−7231. (36) Ingoglia, B. T.; Buchwald, S. L. Oxidative Addition Complexes as Precatalysts for Cross-Coupling Reactions Requiring Extremely Bulky Biarylphosphine Ligands. Org. Lett. 2017, 19 (11), 2853−2856. (37) Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. Identification of the Effective Palladium(0) Catalytic Species Generated in Situ from Mixtures of Pd(Dba)2 and Bidentate Phosphine Ligands. Determination of Their Rates and Mechanism in Oxidative Addition. J. Am. Chem. Soc. 1997, 119 (22), 5176−5185. (38) Milner, P. J.; Maimone, T. J.; Su, M.; Chen, J.; Müller, P.; Buchwald, S. L. Investigating the Dearomative Rearrangement of Biaryl Phosphine-Ligated Pd(II) Complexes. J. Am. Chem. Soc. 2012, 134 (48), 19922−19934. (39) Fors, B. P.; Davis, N. R.; Buchwald, S. L. An Efficient Process for Pd-Catalyzed C-N Cross-Coupling Reactions of Aryl Iodides: Insight Into Controlling Factors. J. Am. Chem. Soc. 2009, 131 (16), 5766−5768. (40) Ho, C. C.; Olding, A.; Smith, J. A.; Bissember, A. C. Nuances in Fundamental Suzuki−Miyaura Cross-Couplings Employing [Pd(PPh3)4]: Poor Reactivity of Aryl Iodides at Lower Temperatures. Organometallics 2018, 37 (11), 1745−1750. (41) Grushin, V. V. Palladium Fluoride Complexes: One More Step toward Metal-Mediated C-F Bond Formation. Chem. - Eur. J. 2002, 8 (5), 1006−1014. (42) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. Dramatic Rate Enhancement of Suzuki Diene Synthesis. Its Application to Palytoxin Synthesis. J. Am. Chem. Soc. 1987, 109 (15), 4756−4758. (43) Markó, I. E.; Murphy, F.; Dolan, S. Efficient Synthesis of the Left-Hand Subunit of Milbemycin β3 Using a Suzuki Coupling Reaction. Tetrahedron Lett. 1996, 37 (14), 2507−2510. (44) Zou, G.; Reddy, Y. K.; Falck, J. R. Ag(I)-Promoted Suzuki− Miyaura Cross-Couplings of n-Alkylboronic Acids. Tetrahedron Lett. 2001, 42 (41), 7213−7215. (45) Cotter, W. D.; Barbour, L.; McNamara, K. L.; Hechter, R.; Lachicotte, R. J. Thermodynamics and Mechanism of the Reversible Tin-to-Palladium Transmetalation of the Furyl Group. J. Am. Chem. Soc. 1998, 120 (42), 11016−11017. (46) Shen, Q.; Ogata, T.; Hartwig, J. F. Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and StructureActivity Relationships. J. Am. Chem. Soc. 2008, 130 (20), 6586−6596.

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