Phase Transfer Catalysts Shift the Pathway to Transmetalation in Biphasic Suzuki-Miyaura Cross-Couplings

doi:10.21203/rs.3.rs-3118939/v1

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Phase Transfer Catalysts Shift the Pathway to Transmetalation in Biphasic Suzuki-Miyaura Cross-Couplings

https://doi.org/10.21203/rs.3.rs-3118939/v1

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The Suzuki-Miyaura coupling (SMC) is arguably the most widely used C-C bond forming reaction. Numerous mechanistic studies of the SMC have enabled the use of exceptionally low catalyst loadings while significantly expanding its functional group tolerance. However, the dominant mode of transmetalation operative in SMCs remains controversial and likely depends on the particular conditions employed. Herein we report a detailed mechanistic study of a palladium catalyzed SMC under biphasic reaction conditions. The use of phase transfer catalysts (PTC) resulted in a remarkable 12-fold rate enhancement in the targeted system. Studying the speciation of the arylboron nucleophile and the palladium catalyst revealed that a shift from an oxo-palladium based transmetalation to a boronate based pathway lies at the root of this activity. Furthermore, the robustness of our monitoring platform enabled us to study the impact of different water loadings in biphasic settings. We found that increasing the proportion of the aqueous phase results in significant rate enhancements, contrary to the reaction conditions typically employed in the literature. This rate acceleration matched or surpassed those achieved by manipulating the nature of the organoboron nucleophile. The importance of these findings was highlighted by achieving an exceptionally broad substrate scope with benzylic electrophiles using a 10-fold reduction in catalyst loading relative to literature precedent.

Physical sciences/Chemistry/Catalysis/Catalytic mechanisms

Physical sciences/Chemistry/Catalysis/Homogeneous catalysis

Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms

Since its initial reports in 1979,¹the SMC reaction has grown to become an indispensable tool for C-C bond formation, earning a share of the 2010 Nobel Prize in chemistry.² Its mild reaction conditions and broad substrate scope have led to applications ranging from large scale pharmaceutical synthesis,³ medicinal chemistry library synthesis,⁴ natural product synthesis,⁵ and polymer synthesis.⁶

Consequently, the mechanism of the SMC has attracted substantial attention, particularly regarding the mode of transmetalation where two major pathways have been proposed.^7-8 The L_nPd(aryl)(X) species could react directly with an 8 electron, 4-coordinate (8-B-4) arylboronate producing the required Pd-O-B intermediate (Figure 1, path A). This was an attractive proposal due to the propensity of organoboron species to form 8-B-4 complexes as well as their reactivity in SMC without additional base. However, isolated L_nPd(aryl)(OH) species were reported to rapidly react with 6 electron, 3-coordinate (6-B-3) boronic acids, yielding biaryl products supporting the alternative oxo-palladium pathway (Figure 1, Path B).⁹ Subsequent studies have aimed to elucidate the favored pathway of SMC transmetalation.

Seminal kinetic studies by Hartwig^8b and Amatore^8a under stoichiometric conditions L_nPd(aryl)(OH) is the kinetically favored reactive species, transmetalating with boronic acid under their reaction conditions. Stoichiometric studies by Denmark et al. successfully identified and characterized the critical Pd-O-B intermediate using rapid injection nuclear magnetic resonance (NMR) spectroscopy techniques.^8f,g They highlighted that both pathways could lead to the required intermediate, however transmetalation via L_nPd(aryl)(OH) (Fig. 1, Path B) was more facile under their conditions. In contrast, Milner and coworkers conducted a study under biphasic conditions and obtained kinetic data suggesting both pathways could have similar rates.^8c

Evidence favoring path A had primarily come from a kinetic study by Soderquist et al.^8o using alkylboron species as well as the computational work conducted by Maseras, Ujaque, et al.^8p,q In 2014, Santos, Silva, et al. devised a clever study observing product distributions of competing arylboron nucleophiles which supported that path A was active under their conditions.^8e Recent work by Denmark and coworkers provided strong evidence for the direct transmetalation of an 8-B-4 complex with L_nPd(aryl)(X) under water-free conditions.^8j The consensus from the literature, as emphasized in recent reviews,⁷ is that both pathways are energetically accessible. The relative dominance of one pathway over the other is expected to depend on the concentrations of each species under the particular conditions employed.

Herein we present a comprehensive mechanistic analysis of the SMC reaction under biphasic conditions. Notably, we observed significant increases in reaction rates when employing PTCs. Investigations of the speciation of both the arylboron nucleophile and the palladium catalyst revealed that the dominant pathway of transmetalation shifts from path B to path A with the incorporation of PTCs. Furthermore, we examined the impact of water content in biphasic systems and found that it has a significantly larger effect on reaction kinetics than the nature of the organoboron species. This observation challenges the prevailing focus on the organoboron species as a key optimization handle in these systems while water loading is seldom commented upon. These findings were found to be general, enabling an exceptionally broad scope with benzylic electrophiles at low catalyst loadings.

We chose to study the SMC under biphasic reaction conditions due to the widespread use of these conditions (\(\sim\)50% of SMCs)¹⁰ coupled with the difficulties typically associated with conducting mechanistic studies in such settings. Standard monitoring techniques leveraging infrared (IR) spectroscopy or NMR spectroscopy have difficulties ‘locking’ onto the changing solvent background. The use of ¹³C kinetic isotope effect was used by Joshia et al. and proved a powerful strategy to study the SMC under biphasic reaction conditions.⁸ⁱ However, this strategy would not lend itself to our ultimate goal of probing the impact of different solvent ratios and additives on the SMC. Manual reaction sampling has also been employed to study the SMC,^8c,h,k though reproducibility is typically difficult to achieve in biphasic systems and may explain why these studies tend to limit the proportion of the aqueous phase. Moreover, offline reaction sampling of SMC has been shown to suffer from irreproducibility due to sample aging.^8r Recently, we have developed an automated sampling platform which leverages online high-performance liquid chromatography (HPLC) for reaction analysis.¹¹ Notably, this system was shown to provide highly reproducible sampling in heterogeneous settings and thus provides an ideal tool for the current study.^11a,b

We chose to target the use of benzylic electrophiles as a model system of study for three reasons; 1) they provide a direct route to the diarylmethane motifs which is broadly present in pharmaceutically relevant compounds,¹² supramolecular chemistry,¹³ as well as being important building blocks in their own right (Fig. 1b);¹⁴ 2) mechanistic studies on such systems remain exceptionally sparse;¹⁵ 3) the functional group tolerance of these transformations remain noticeably lacking relative to its C(sp²)-C(sp²) counterpart.^16–17 The prevalence of dialkylbiaryl phosphines in SMCs led us to choose XPhos Pd G2 as a representative catalyst.¹⁸ The use of a weak inorganic base was targeted due to its widespread use in SMC.^10b Thus, the SMC of benzyl bromide (1) with 4-methoxyphenylboronic acid pinacol ester (2) was conducted in a mixture of MeTHF and H₂O as the model system.

The reproducibility of the model reaction was probed on our standard automated sampling platform (Fig. 2). Exceptional overlay between two identical reactions was achieved. This control confirms that the system is well stirred and not operating under mass transfer limiting conditions. Moreover, HPLC allowed us to easily monitor the speciation of 2 to the parent boronic acid under the reaction conditions. Notably, the background rate of hydrolysis of 2 was much slower than the rate of product formation, suggesting transmetalation occurs with 2 directly and not the parent boronic acid (see the supporting information Figure S4).⁸ⁿ

With the validity of our reaction monitoring platform confirmed we turned our attention to probing the order of each individual reagent. This will provide an understanding of the turnover limiting step and catalyst resting state, thus providing a foundation upon which to understand the positive or negative impact of solvent changes and additives. We conducted a series of ‘different excess’ experiments for each reagent which can be seen in Fig. 3. A variable time normalization analysis (VTNA) was conducted for each reagent as well (see Supporting Information Figure S5-S12).¹⁹ The benzyl bromide electrophile 1 was not observed to have any impact on the rate of reaction (Fig. 3a).The order in 2 was determined to be 0.75 supporting its involvement in the turnover limiting step (Fig. 3b).The palladium catalyst and the base were observed to have orders of 1.0 and 1.8 respectively (Fig. 3c and d). From these data, a turnover limiting oxidative addition or reductive elimination can be ruled out as the former would require a positive order in 1 while the latter would exhibit 0th order behavior in all reagents safe for the catalyst. We believe these data are consistent with a rate determining transmetalation coupled with a base mediated pre-equilibrium. However, these data do not provide insight on whether the pre-equilibrium is between L_nPd(aryl)(X) and the arylboronate (Fig. 1, path A) or L_nPd(aryl)(X) and L_nPd(aryl)(OH) (Fig. 1, Path B).

A set of same excess experiments were then conducted and confirmed the catalyst suffered insignificant catalyst degradation, though notable halide inhibition was observed (see the supporting information Figure S13). We wanted to probe this halide inhibition behavior more thoroughly through examination of different halide salts: KCl, KBr, and KI (Fig. 4). KI was the strongest inhibitor while KCl was the weakest. Similar behavior was reported previously in C(sp²)-C(sp²) SMC and was attributed to a greater solubility of KI in the organic phase negatively impacting the pre-equilibrium.^8c Our results further corroborate this hypothesis as considerable electrophile speciation to benzyl iodide (4) was observed in the presence of KI (Fig. 4A, inset) while such speciation remained undetectable in the case of KCl. Several insights can be drawn from this set of experiments; 1) Substitution based speciation of electrophiles should not be ignored when in benzylic systems which could have implications in more complex settings;^{16h,t,17b,l,n} 2) the low inhibition observed by KCl suggest chloride based electrophiles may be ideal when conducting difficult C(sp³)-C(sp²) couplings. The increased reactivity of benzyl chloride electrophiles was confirmed, achieving reaction completion just over 3x faster than the parent benzyl bromide electrophile (see supplementary information Figure S15).

The significant halide inhibition observed led us to target the development of conditions which would minimize this undesired behavior. Milner and coworkers highlighted that moving from THF to toluene in biphasic systems greatly increased reactivity due to the diminished organic phase solubility of the halide salt.^8c However, ethereal solvents are regularly employed in SMC and thus this strategy may not be universal.^10b We hypothesized that increasing the proportion of the aqueous phase in these biphasic systems may decrease the concentration of halide in the organic phase thus improving reactivity. Despite the widespread use of biphasic reaction conditions, we are unaware of studies probing the effect of this variable on turnover rate. We began by holding the total volume of the reaction constant while manipulating the ratio of water relative to MeTHF (Fig. 5). A clear trend is observed where decreasing the proportion of the organic phase leads to significant rate accelerations. This behavior is likely attributed to the fact that the reaction primarily occurs in the organic phase of the reaction system.²⁰ Thus, decreasing the volume of the organic phase concentrates the reaction despite holding the total volume constant.

Though the increased concentration of the organic phase stands as a logical explanation for the observed behavior, we wanted to disentangle this effect from other potential impacts. To this end, we conducted a set of experiments where the volume of MeTHF was held constant while changing the amount of water present in the reaction system (Fig. 6). This reveals a significant rate enhancement when increasing the volume of water despite decreasing the concentration of the overall system and holding the organic phase concentration constant. We believe this behavior could stem from decreasing the concentration of the halide salts in the organic phase. Overall, these results highlight that simply manipulating the ratio of the aqueous and organic layer can have stunning impacts on reaction rates. To place these results into perspective, the rate increases observed by simply manipulating the ratio of the aqueous and organic phase were the same (Fig. 6) or larger (Fig. 5) than the impact of manipulating the identity of the organoboron nucleophile (vide infra, Figure S26) a parameter that has been a central focus in the advancement of the SMC.²¹ These results stand in stark contrast to the typical biphasic SMC where the amount of water present is typically kept low.¹⁰

Although manipulating the solvent composition proved a powerful strategy to improve turnover rates, we wondered if similar improvements could be achieved with the introduction of PTCs. In the case of path A being dominant, a PTC may increase the concentration of the required 8-B-4 species thus pushing the equilibrium towards the Pd-O-B complex. Alternatively, if path B is dominant, a PTC would be expected to push the equilibrium towards the desired L_nPd(aryl)(OH). The use of PTC in SMCs is well documented however,²² determining its primary role in such systems remains difficult to decipher.^20,23 This arises as a result of the competing effects of PTC in SMCs; 1) the ability to influence the concentration of base/boronate in the organic phase, and 2) the ability of PTCs to stabilize palladium nanoparticles thus minimizing the aggregation, and consequently inactivation, of the palladium catalyst. We were surprised to find that, despite the widespread use of biphasic reaction conditions, the use of PTC as additives remains exceptionally rare outside nanoparticle forming systems.

We believe our current system of study provides a unique opportunity to probe the impact of PTC in SMCs without the confounding effect of nanoparticle stabilization. We are unaware of any reports where Buchwald precatalyst derived from dialkylbiarylphosphine were shown to be in a nanoparticle forming regime. Moreover, the catalyst stability observed from the ‘same excess’ experiment suggests this catalyst system is not prone to deactivation (see supplementary information Figure S13), thus any impact observed is unlikely due to nanoparticle formation/stabilization.

A series of experiments were conducted using tetrabutylammonium (TBA) salt additives. To our delight, the addition of 0.10 M tetrabutylammonium bromide (TBAB) resulted in complete consumption of the starting material in under 15 minutes (see supplementary information Figure S17). Thus, at minimum, the addition of the TBAB salt results in a 12-fold increase in turnover rate! To properly monitor such a rapid reaction, significant modifications to the reaction conditions were made including reducing the catalyst loading, base, and reaction temperature. With these milder conditions, tetrabutylammonium iodide (TBAI), bromide (TBAB), chloride (TBACl), and hydroxide (TBAOH) were tested for their ability to promote the reaction (Fig. 7). Notably, significant amounts of speciation of both the electrophile (Fig. 7A, inset) and nucleophile (Fig. 7C) were observed. Given the significant halide inhibition observed vide supra, this suggests the negative impact of halide ion must be mitigated by the presence of the TBA counterion. The significant amount of arylboronic acid (6) observed in the presence of the TBA salts strongly supports an increased organic phase concentration of hydroxide. Finally, all TBA salts, safe for TBAI, resulted in rate accelerations relative to the standard conditions with no additive. TBAOH provided the highest activity, only slightly outperforming TBACl.

The substantial rate acceleration caused by the addition of TBA salts was believed to arise through increasing the organic phase hydroxide concentration which could significantly impact arylboronate concentration (Fig. 1, path A) and/or catalyst speciation (Fig. 1, path B). Alternatively, one may suspect the hydrolysis of 2 to the more reactive 6 could account for such an increase in rate as TBA salts were observed to promote its formation (Fig. 7c). To probe this possibility, we obtained time course data from multiple different organoboron nucleophiles including the parent boronic acid (6) (Fig. 8). A neopentyl glycol based boronic acid ester (7) had the highest reactivity while 2 was the slowest. Importantly, the drastic rate accelerations observed through the introduction of TBA salts are not explained by the differences in reactivity between 2 and 6. Noteworthy is the comparatively limited impact the nature of the organoboron nucleophile had on turnover rate. While the use of 7 was able to achieve just above a 2-fold rate acceleration, the addition of TBAB was able to achieve at minimum a 12-fold rate acceleration.

To better understand the mechanism of action of TBA salts, we conducted speciation experiments of 2 and SPhosPd(Ph)(Cl) due to difficulties in the synthesis of the parent C(sp³) oxidative addition complex. Notably, control experiments revealed the impact of TBA salts is general to the C(sp²)-C(sp²) system as well (see supplementary information Figure S29). To probe the Palladium speciation, we set up our typical biphasic reaction system with SPhosPd(Ph)(Cl) in the absence of 1 and 2. The system was equilibrated (see supplementary information Figure S33) following which a sample of the organic phase was taken and analyzed by ³¹P NMR spectroscopy. We focused on the quantities of monomeric SPhosPd(Ph)(OH), monomeric SPhosPd(Ph)(Cl), and dimeric SPhosPd(Ph)(Cl) as these will dictate reactivity under the reaction conditions (see supporting information for a detailed discussion). Overall, both monomers were present in similar concentrations with the SPhosPd(Ph)(Cl) dimer as the dominant species (Eq. 1). The slight favorability of Pd-Cl complexes is in line with prior reports.^8b,c To our surprise, the same experiment conducted in the presence of TBACl resulted in almost the complete loss of the parent SPhosPd(Ph)(OH) complex with significant shift towards the formation of Pd-Cl complexes (Eq. 1). This can be rationalized through the combination of the weak Pd-OH bond strength, coupled with the preference of PTCs to increase the organic phase concentration of the softer chloride anion relative to hydroxide.²⁴

We then turned our attention to the speciation of 2. In this case, we set up our standard biphasic reaction system in the absence of 1 and the palladium catalyst. A sample of the organic layer was taken for analysis by both ¹⁹F and ¹¹B NMR spectroscopy. Under standard reaction conditions, 8-B-4 species remained below the detection limit in the organic phase of the reaction (Eq. 2). The parent pinacol ester was the dominant species with small amounts of boronic acid byproduct as expected. In contrast, the presence of TBACl led to the organic phase being dominated by the arylboronate species while some of the parent 6-B-3 species remained (Eq. 2). This result can be rationalized through the ability of PTCs to increase the organic phase concentration of hydroxide, coupled with the low pKa of arylboron species (see supporting information for a detailed discussion).²⁴

Overall, these results suggest that without the TBA additive, the standard conditions are likely dominated by the oxo-palladium pathway (Fig. 1, pathway B). Although both the Pd-OH and Pd-Cl species are present in appreciable amounts, the arylboronate remained below the detection limit in the organic phase. Thus, the positive order in base and negative order in halide salts can be interpreted by manipulating the pre-equilibrium of the catalyst in pathway B while the positive order in palladium and 2 arise from the rate determining transfer of the aryl species onto the catalyst. In contrast, the introduction of TBA salts increases the organic phase concentration of both halides and hydroxides. This results in significant shifts in the speciation of the catalyst towards L_nPd(aryl)(Cl), and 2 towards its 8-B-4 complex. These results suggest that the rate enhancements observed from TBA salts result from shifting the dominant mode of transmetalation from the oxo-palladium pathway (Fig. 1, path B) to the boronate pathway (Fig. 1, path A).

To further validate our conclusion, we carried out a series of different excess experiments while in the presence of TBAB (see supplementary information Figure S19-26.). This revealed the system remained in a turnover limiting transmetalation and thus the rate increases observed are not explained by manipulating the kinetic regime. This was followed by a set of experiments set out to study the impact of halide under these new conditions (Fig. 9). A direct comparison of TBAB versus the use of tetrabutylammonium triflate (TBATf) reveals a significant positive impact of the bromide under these conditions. This stands in stark contrast to the comparison of KBr versus potassium triflate (KTf). The later case, as was highlighted earlier, shows a significant negative impact in the halide ion. This fundamental change in the impact of the halide ion further corroborates a change in the dominant mechanism of transmetalation from pathway B to pathway A occurs in the presence of TBA salts.

Following the completion of our mechanistic study, we wanted to probe the impact of the acquired knowledge on both the catalyst loading as well as the substrate scope of this transformation. The former was probed by testing our model substrate at increasingly diminished catalyst loading (Eq. 3). TBAOH was chosen as the additive as it had resulted in the highest catalyst turnover rate (Fig. 7). Notably, loadings as low as 0.001 mol% were possible while retaining exceptionally high yields. A control reaction with no added catalyst confirmed that such reactivity arises from the catalyst and not the presence of trace metals in the starting materials. This result is one of the lowest catalyst loadings reported to date involving benzylic electrophiles.^16–17

We next turned our attention to the substrate scope of this reaction. The use of exceptionally low catalyst loadings (0.1 mol% ≥) for the SMCs with benzylic electrophiles have been reported however the substrate scope of these reports remains exceptionally limited. To our knowledge, reports where at least one heterocyclic substrate is included range from 1.0 mol% to 10 mol% Pd loading¹⁶ with Botella et al.^16b and Chahen et al.^16p having a single example at 0.05 mol% and 0.004 mol% respectively. Thus, we chose to probe the substrate scope using 0.1 mol% catalyst loading. Our model system produced the desired product (3aa) in 93% yield upon scale up and isolation (Scheme 1). We then proceeded to probe the substrate scope of the organoboron coupling partner. Both electron rich (3ba-da) and electron poor (3ea-3fa) aryl nucleophiles proved competent under these conditions. Heterocyclic pyridyl (3ga-ha) nucleophiles produced the product in good yields. The use of thiophene nucleophiles were also well tolerated under the reaction conditions (3ia-la) however, in some cases (3ia-ja) the competitive formation of benzyl alcohol was observed. This issue was largely resolved by replacing TBAOH with TBAB. Pyrrole (3ma) and pyrazole (3na) derivatives were also well tolerated however the latter required the use of slightly higher catalyst loading as well as TBAB to reduce competitive hydrolysis. These conditions are also compatible with the use of a styryl nucleophile with no issues. Finally, we wanted to probe the applicability of our conditions on base labile substrates due to the increased organic phase hydroxide concentration in the presence of TBA salts. An organoboron species bearing a methyl ester (3qa) or an enolizable ketone (3ra) were well tolerated, providing the desired product in an hour with no signs of competitive degradation.

We then turned our attention to the substrate scope of the electrophile (Scheme 2). The use of both electron poor (3ab-ad) and electron rich (3ae) coupling partners were well tolerated under the reaction conditions. Thiophene derivatives provided the desired diarylmethanes in high yield (3af-aag). Notably, these conditions were observed to produce the monocoupled product at the sp³ center selectively over the sp² (3ag) when both are present on the electrophilic motif in line with prior reports.^16h Increasing the loading of the organoboron coupling partner drives the reaction to the dicoupled product (3aag). Lewis basic pyridyl motifs were observed to be competent coupling partners when present within the electrophile (3ah-3aj). Finally, we wanted to probe the applicability of further substitutions at the benzylic center. The introduction of a methyl group resulted in modest yield (3ak). It Is well known that β-hydride elimination can be competitive under such conditions producing styrene as a dominant byproduct.^16f,17j Our optimized conditions provided the desired product in acceptable yield though styrene was observed as a byproduct. Bromodiphenylmethane derivatives have also been reported to be difficult coupling partners in SMCs.^16f We were pleased to obtain the desired product in modest yield again highlighting the significant beneficial effect of the incorporation of PTCs.

In conclusion, we have conducted a thorough kinetic study of the SMC with benzylic electrophiles under biphasic reaction conditions. Our automated sampling system provided a robust platform to achieve reproducible reaction sampling despite the biphasic nature of the reaction mixture. A summary of findings in this study is as follows:

The addition of PTCs resulted in remarkable rate accelerations when used as additives. While these additives are commonly used in Pd nanoparticle catalyzed systems for their stabilizing effects, our results indicate that the observed rate enhancements in our system primarily arise from their phase transfer behavior. Thus, these additives should not be overlooked when optimizing biphasic SMC with molecular Pd catalysts which has to date been scarcely employed.
The rate accelerations of PTCs were found to be the result of a shift in the dominant mode of transmetalation from the oxo-palladium pathway (without additives), to the boronate based pathway (with additives).
Optimizing the solvent ratio when applying biphasic reaction conditions should not be overlooked. Rate accelerations were similar or larger than those observed when changing the nature of the boron species, simply by reducing the volume, or the proportion of the organic layer.
The significant inhibitory effect of KX salts under standard conditions can be explained by an unfavorable effect on the oxo-palladium pre-equilibrium.

The findings in this study were leveraged to develop a SMC of benzylic electrophiles with an exceptionally broad scope while holding the catalyst loading low. Conceptually, the introduction of TBA salts turns the presence of the halide byproduct from a liability to a beneficial species. We believe these findings will be particularly impactful in the development of telescoped processes or cascades, where significant buildup of halide byproducts is inevitable.

SMC, Suzuki-Miyaura Coupling; TBA, Tetrabutyl ammonium; TBAI, Tetrabutylammonium iodide; TBAB, Tetrabutylammonium bromide; TBACl, Tetrabutylammonium chloride; TBAOH, Tetrabutylammonium hydroxide; PTC, Phase transfer catalyst; NMR, Nuclear magnetic resonance; IR, Infrared spectroscopy; HPLC, High performance liquid chromatography.

ASSOCIATED CONTENT

This material is available free of charge via the Internet at http://pubs.acs.org

-Details on the reaction monitoring setup, experiment setup, and characterization data

-Excel spreadsheet containing all the time course data and VTNA analysis

AUTHOR INFORMATION

Corresponding Author

*Jason E. Hein – Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada; orcid.org/0000-0002-4345-3005; Phone: 604-822-2963; Email: [email protected]

Present Addresses

†If an author’s address is different than the one given in the affiliation line, this information may be included here.

Author Contributions

Y.S. conducted all experimental work. All authors contributed to devising the project and the experimental design and analysis. All authors contributed to the preparation of the manuscript and supporting information. All authors have given approval to the final version of the manuscript.

Funding Sources

Financial support was provided by the University of British Columbia, the Canada Foundation for Innovation (CFI-35883), the Natural Science and Engineering Research Council of Canada (RGPIN-2021-03168, Discovery Accelerator Supplement) and the Defense Advanced Research Projects Agency (DARPA) for funding this project under the Accelerated Molecular Discovery Program (Cooperative Agreement No. HR00111920027, dated August 1, 2019).

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

The authors gratefully acknowledge Ms. Paloma Prieto for guidance and conversation in the preparation of this manuscript. The authors further thank Mettler-Toledo Autochem for their generous donation of process analytical equipment (Easy Max 102).

(a) Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Lett. 1979, 20, 3437. (b) Miyaura, N.; Suzuki, A. Stereoselective synthesis of arylated (E)-alkenes by the reaction of alk-1-enylboranes with aryl halides in the presence of palladium catalyst. J. Chem. Soc., Chem. Commun. 1979, 866.
For review on the SMC see: (a) Beletskaya, I. P.; Alonso, F.; Tyurin, V. The Suzuki-Miyaura reaction after the Nobel prize. Coord. Chem. Rev. 2019, 385, 137.
Dunetz, J. R.; Magano, J. Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177.
Boström, J.; Brown, D. G.; Young, R. J.; Keserü, G. M Expanding the medicinal chemistry synthetic toolbox. Nat. Rev. Drug Discov. 2018, 17, 709.
Koshvandi, A. T. K.; Heravi, M. M.; Momeni, T. Current Applications of Suzuki-Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update. Appl. Organometal. Chem. 2018, 32, e4210
Bautista, M. V.; Varni, A. J. ; Ayuso-Carrilo, J. ; Carson, M. C.; Noonan, K. J. T. Pairing Suzuki-Miyaura cross-coupling and catalyst transfer polymerization. Polym. Chem. 2021, 12, 1404.
For reviews on the mechanism of the SMC see: (a) D’Alterio, M. C.; Casals-Cruañas, E.; Tzouras, N.; Talarico, G.; Nolan, S. P.; Poater, A. Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction. Chem. Eur. J. 2021, 27, 13481. (b) 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, 7362. (c) Amatore, C.; Le Duc, G.; Jutand, A. Mechanism of Palladium-Catalyzed Suzuki-Miyaura Reactions: Multiple and Antagonistic Roles of Anionic “Bases” and Their Countercations. Chem. Eur. J. 2013, 19, 10082. (d) Osakada, K.; Nishihara, Y. Transmetallation of boronic acids and their derivatives: mechanistic elucidation and relevance to catalysis. Dalt. Trans. 2022, 51, 777.
(a) 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, 2492. (b) Carrow, B. P.; Hartwig, J. F. Distinguishing Between Pathways for Transmetalation in Suzuki-Miyaura Reactions. J. Am. Chem. Soc. 2011, 133, 2116. (c) Fuentes-Rivera, J. J.; Zick, M. E.; Düfert, M. A.; Milner, P. J. Overcoming Halide Inhibition of Suzuki-Miyaura Couplings with Biaryl Monophosphine-Based Catalysts. Org. Process Res. Dev. 2019, 23, 1631. (d) 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, 4297. (e) 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, 1291. (f) Thomas, A. A.; Denmark, S. E. Pre-Transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link. Science, 2016, 352, 329. (g) 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, 3805. (h) 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, 8151. (i) Joshi, C.; Macharia, J. M.; Izzo, J. A.; Wambua, V.; Kim, S.; Hirschi, J. S.; and Vetticatt, M. J. Isotope Effects Reveal the Catalytic Mechanism of the Archetypical Suzuki-Miyaura Reaction. ACS Catal. 2022, 12, 2959. (j) Delaney, C. P.; Marron, D. P.; Shved, A. S.; Zare, R. N.; Waymouth, R. M.; Denmark, S. E. Potassium Trimethylsilanolate-Promoted, Anhyydrous Suzuki-Miyaura Cross-Coupling Reaction Proceeds via the “Boronate Mechanism”: Evidence for the Alternative Fork in the Trail. J. Am. Chem. Soc. 2022, 144, 4345-4364 . (k) Kedia, S. B.; Mitchell, M. B. Reaction Progress Analysis: Powerful Tool for Understanding Suzuki-Miyaura Reaction and Control of Polychlorobiphenyl Impurity. Org. Process Res. Dev. 2009, 13, 420. (l) Yang, C.; Zhang, L.; Lu, C. ; Zhou, S.; Li, X. ; Li, Y. ; Yang, Y. ; Li, Y. ; Liu, Z. ; Yang, J. ; Houk, K. N. ; Mo, F. ; Guo, X. Unveiling the full reaction path of the Suzuki-Miyaura cross-coupling in a single-molecule junction. Nat. Nanotechnol. 2021, 16, 1214. (m) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones, 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, 5156.(n) 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, 4401-4416. (o) Matos, K.; Soderquist, J. A. Alkylboranes in the Suzuki-Miyaura Coupling: Stereochemical and Mechanistic Studies. J. Org. Chem. 1998, 63, 461-470. (p) García-Melchor, M.; Braga, A. A. C.; Lledós, A.; Ujaque, G.; Maseras, F. Computational Perspective on Pd-Catalyzed C-C Cross-Coupling Reaction Mechanisms. Acc. Chem. Res. 2013, 46, 2626-2634. (q) Ortuño, M. A.; Lledós, A.; Maseras, F.; Ujaque, G. The Transmetalation Process in Suzuki-Miyaura Reactions: Calculations Indicate Lower Barrier via Boronate Intermediate. 2014, 6, 3132-3138. (r) Christensen, M.; Adedeji, F.; Grosser, S.; Zawatzky, K.; Ji, Y.; Liu, J.; Jurica, J. A.; Naber, J. R.; Hein, J. E. Development of an automated kinetic profiling system with online HPLC for reaction optimization. React. Chem. Eng. 2019, 4, 1555.
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Selected publications: (a) Daponte, J. A.; Guo, Y. ; Ruck, R. T.; Hein, J. E. Using an Automated Monitoring Platform for Investigations of Biphasic Reactions. ACS Catal. 2019, 9, 11484. (b) Sato, Y.; Liu, J.; Kukor, A. J.; Culhane, J. C.; Tucker, J. L.; Kucera, D. J.; Cochran, B. M.; Hein, J. E. Real-Time Monitoring of Solid-Liquid Slurries: Optimized Synthesis of Tetrabenazine. J. Org. Chem. 2021, 86, 14069.(c) LaPorte, A. J.; Shi, Y.; Hein, J. E.; Burke, M. D. Stereospecific Csp³ Suzuki-Miyaura cross-coupling that evades β-oxygen elimination. ACS Catal. 2022, 12, 10905-10912. (d) Deem, M. C.; Derasp, J. S.; Malig, T. C.; Legard, K.; Berlinguette, C. P.; Hein, J. E. Ring walking as a regioselectivity control element in Pd-catalyzed C-N cross-coupling. Nat. Commun. 2022, 13, 2869.
(a) Xu, M.; Hou, M.; He, H.; Gao, S. Asymmetric Total Synthesis of Aglacins A, B, and C. Angew. Chem. Int. Ed. 2021, 60, 16655. (b) Choi, Y. L.; Kim, B. T.; Heo, J.-N. Total Synthesis of Laetevirenol A. J. Org. Chem. 2012, 77, 8762. (c) Klotter, F.; Studer, A. Total Synthesis of Resveratrol-Based Natural Products Using a Palladium-Catalyzed Decarboxylative Arylation and an Oxidative Heck Reaction. Angew. Chem. Int. Ed. 2014, 53, 2473. (d) Yang, Y.; Yu, Y.; Li, X.; Li, J.; Wu, Y.; Yu, J. ; Ge, J. ; Ge, J. ; Huang, Z. ; Jiang, L. ; Rao, Y. ; Yang, M. Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with small Molecule To Eliminate Drug-Resistant Malaria. J. Med. Chem. 2017, 60, 1994. (e) Arafa, R. K.; Ismail, M. A.; Wenzler, T.; Brun, R.; Paul, A.; Wilson, W. D.; Alakhdar, A. A.; Boykin, D. W. New antiparasitic flexible triaryl diamidines, their prodrugs and aza analogues: Synthesis, in vitro and in vivo biological evaluation, and molecular modelling studies. Eur. J. Med. Chem. 2021, 222, 113625. (f) Chiellini, G.; Nesi, G.; Digiacomo, M.; Malvasi, R.; Espinoza, S. ; Sabatini, M. ; Frascarelli, S. ; Laurino, A. ; Cichero, E. ; Macchia, M. ; Gainetdinov, R. R.; Fossa, P.; Raimondi, L. ; Zucchi, R.; Rapposelli, S. Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists. J. Med. Chem. 2015, 58, 5096. (g) Sari, O.; Roy, V.; Métifiot, M.; Marchand, C.; Pommier, Y. ; Bourg, S.; Bonnet, P.; Schinazi, R. F.; Agrofoglio, L. A. Synthesis of Dihydropyrimidine α,g-diketobutanoic acid derivatives targeting HIV integrase. Eur. J. Med. Chem. 2015, 104, 127. (h) Yang, Y.; Cao, L.; Gao, H.; Wu, Y.; Wang, Y.; Fang, F.; Lan, T.; Lou, Z.; Rao, Y. Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors. J. Med. Chem. 2019, 62, 4056. (i) Patel, B. A.; Krishnan, R.; Khadtare, N.; Gurukumar, K. R.; Basu, A.; Arora, P.; Bhatt, A.; Patel, M. R.; Dana, D.; Kumar, S.; Kaushik-Basu, N.; Talele, T. T. Design and synthesis of L-and D-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase. Bioorg. Med. Chem. 2013, 21, 3262. (j) Speri, E.; Kim, C.; De Benedetti, S.; Qian, Y.; Lastochkin, E.; Fishovitz, J.; Fisher, J. F.; Mobashery, S. ACS Med. Chem. Lett. 2019, 10, 1148. (k) Pidathala, C.; Amewu, R.; Pacorel, B.; et al. Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium Falciparum Type II NADH: Quinone Oxidoreductase (PfNDH2). J. Med. Chem. 2012, 55, 1831. (l) Juteau, H.; Gareau, Y.; Labelle, M.; Lamontagne, S. ; Tremblay, NM. ; Carrière, M.-C. ; Sawyer, N. ; Denis, D. ; Metters, K. M. Structure-activity relationship on the human EP₃ prostanoid receptor by use of solid-support chemistry. Bioorg. Med. Chem. 2001, 11, 747. (m) Crowley, V. M.; Huard, D. J.; Lieberman, R. L.; Blagg, B. S. Second Generation Grp94-Selective Inhibitors Provide Opportunities for the inhibition of Metastatic Cancer. Chem. Eur. J. 2017, 23, 15775. (n) Wegener, A.; Miller, K. A. Total Synthesis of Avrainvilleol. J. Org. Chem. 2017, 82, 11655.
(a) Wang, S.-Y.; Hunag, J.-Y.; Liang, Y.-P.; He, Y.-J.; Chen, Y.-S.; Zhan, Y.-Y.; Hiraoka, S.; Liu, Y.-H.; Peng, S.-M.; Chan, Y.-T. Multicomponent Self-Assembly of Metallo-Supramolecular Macrocycles and Cages through Dynamic Heteroleptic Terpyridine Complexation. Chem. Eur. J. 2018, 24, 9274. (b) Sala, P. D.; Talotta, C.; Capobianco, A. ; Soriente, A. ; De Rosa, M. ; Neri, P. ; Gaeta, C. Synthesis, Optoelectronic, and Supramolecular Properties of Calix[4]arene-Cycloparaphenylene Hybrid Host. Org. Lett. 2018, 20, 7415. (c) Demay-Drouhard, P.; Du, K.; Samanta, K.; Wan, X. ; Yang, W. ; Srinivasan, R. ; Sue, A. C.-H.; Zuilhof, H. Functionalization at Will of Rim-Differentiated Pillar[5]arenes. Org. Lett. 2019, 21, 3976. (d) Wang, T.; Hu, Z.; Nie, X.; Huang, L.; Hui, M. ; Sun, X. ; Zhang, G. Thermochromic aggregation-induced dual phosphorescence via temperature-dependent sp³-linked donor-acceptor electronic coupling. Nat. Commun. 2021, 12, 1364. (e) Le Gac, S.; Zheng, X.; Girardot, C.; Jabin, I. Efficient Synthesis and Host-Guest Properties of a New Class of Calix[6]azacryptands. J. Org. Chem. 2006, 71, 9233. (f) Haberhauer, G.; Woitschetzki, S.; Füten, C. Encapsulated Guests in the Smallest Spaces: Shrinking Guests by Compression and Investigations under Solvent-Free Conditions. J. Org. Chem. 2015, 80, 8065. (g) Pernia, G. J.; Kilburn, J. D.; Essex, J. W.; Mortishire-Smith, R. J.; Rowley, M. Stabilization of a Cis Amide Bond in a Host-Guest Complex. J. Am. Chem. Soc. 1996, 118, 10220. (h) Gothard, C. M.; Bruns, C. J.; Gothard, N. A.; Grzybowski, B. A.; Stoddart, J. F. Modular Synthesis of Bipyridinium Oligomers and Corresponding Donor-Acceptor Oligorotaxanes with Crown Ethers. Org. Lett. 2012, 14, 5066.
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The sole kinetic study of benzylic halide electrophiles in SMC: Pedro, B. N.; Medio-Simón, Jutand, A. Influence of the ligand of Palladium(0) Complexes on the Rate of the Oxidative Addition of Aryl and Activated Alkyl Bromides: Csp²-Br versus CSp³-Br Reactivity and Selectivity. ChemCatChem 2017, 9, 2136.
Development of SMC procedures of benzylic electrophile with atleast one heterocyclic example: (a) Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Simple Palladium (II) Precatalyst for Suzuki-Miyaura Couplings: Efficient Reactions of Benzylic, Aryl, Heteroaryl, and Vinyl Coupling Partners. Org. Lett. 2007, 9, 5397. (b) Botella, L.; Najera, C. Cross-coupling reactions with boronic acids in water catalysed by oxime-derived palladacycles. J. Organomet. Chem. 2002, 663, 46. (c) Yu, A.; Li, X.; Peng, D.; Wu, Y. ; Chang, J. Cyclopalladated ferrocenylimine as an efficient catalyst for the syntheses of diarylmethane derivatives. Appl. Organometal. Chem. 2012, 26, 301. (d) Vanier, C.; Lorgé, F.; Wagner, A.; Mioskowski, C. Traceless, Solid-Phase Synthesis of Biarylmethane Structures through Pd-Catalyzed Release of Supported Benzylsulfonium Salts. Angew. Chem. Int. Ed. 2000, 39, 1679. (e) Kuriyama, M.; Shinozawa, M.; Hamaguchi, N.; Matsuo, S.; Onomura, O. Palladium-Catalyzed Synthesis of Heterocycle-Containing Diarylmethanes through Suzuki-Miyaura Cross-Coupling. J. Org. Chem. 2014, 79, 5921. (f) Molander, G. A.; Elia, M. D. Suzuki-Miyaura Cross-Coupling Reactions of Benzyl Halides with Potassium Aryltrifluoroborates. J. Org. Chem. 2006, 71, 9198. (g) Zhao, C.; Zha, G.-F.; Fang, W.-Y.; Rakesh, K. P.; Qin, H.-L. Construction of Di(hetero)arylmethanes Through Pd-Catalyzed Direct Dehydroxylative Cross-Coupling of Benzylic Alcohols and Aryl Boronic Acids Mediates by Sulfuryl Fluoride (SO₂F₂). Eur. J. Org. Chem. 2018, 1801. (h) Laha, J. K.; Saima, K. V. P.; Pandey, S.; Solanke, G. ; Vashisht, V. Scope of regioselective Suzuki reactions in the synthesis of arylpyridines and benzylpyridines and subsequent intramolecular cyclizations to azafluorenes and azafluorenones. New J. Chem. 2018¸42, 16069.(i) Zhang, Y.; Feng, M.-T.; Lu, J.-M. N-Heterocyclic carbene-palladium(II)-1-methylimidazole complex catalyzed Suzuki-Miyaura coupling of benzylic chlorides with arylboronic acids or potassim phenyltrifluoroborate in neat water. Org. Biomol. Chem. 2013, 11, 2266. (j) Cao, Z.-C.; Yu, D.-G.; Zhu, R.-Y.; Wei, J.-B. ;Shi, Z.-J. Direct cross-coupling of benzyl alcohols to construct diarylmethanes via palladium catalysis. Chem. Commun. 2015, 51, 2683. (k) Anselmi, E.; Abarbri, M.; Duchêne, A.; Langle-Lamandé, S. ; Thibonnet, J. Efficient Synthesis of Substituted Styrenes and Biaryls (or Heteroaryls) with Regioselective Reactions of ortho-, para-Bromobenzyl Bromide. Synthesis 2012, 44, 2023-2040. (m) Wang, T.; Guo, J.; Wang, X.; Guo, H.; Jia, D.; Wang, H.; Liu, L. Cross coupling of benzylammonium salts with boronic acids using a well-defined N-heterocyclic carbene-palladium(II) precatalyst. RSC Adv. 2019, 9, 5738. (n) Ohsumi, M.; Ito, A.; Nishiwaki, N. Substrate switchable Suzuki-Miyaura coupling for benzyl ester vs. benzyl halide. RSC Adv. 2018, 8, 35056. (o) Nambo, M.; Keske, E. C.; Rygus, J. P. G.; Yim, J. C.-H.; Crudden, C. M. Development of Versatile Sulfone Electrophiles for Suzuki-Miyaura Cross-Coupling Reactions. ACS Catal. 2017, 7, 1108. (p) Chahen, L.; Doucet, H.; Santelli, M. Suzuki Cross-Coupling Reaction of Benzylic Halides with Arylboronic Acids in the Presence of a Tetraphosphine/Palladium Catalyst. Synlett 2003, 1668. (q) Shah, P.; Santana, M. D.; García, J.; Serrano, J. L. ; Naik, M. ; Pednekar, S. ; Kapdi, A. R. [Pd(PPh₃)₂(saccharinate)₂]-general catalyst for Suzuki-Miyaura, Negishi cross-coupling and C-H functionalization of coumaryl and pyrone substrates. Tetrahedron 2013, 69, 1446-1453. (r) Henry, N.; Enguehard-Gueiffier, C.; Thery, I.; Gueiffier, A. One-Pot Dual Substitutions of Bromobenzyl Chloride, 2-Chloromethyl-6-halogenoimidazo[1,2-a]pyridine and –[1,2-b]pyridazine by Suzuki-Miyaura Cross-Coupling Reactions. Eur. J. Org. Chem. 2008, 4824-4827. (s) Langle, S.; Abarbri, M.; Duchene, A. Selective double Suzuki cross-coupling reactions. Synthesis of unsymmetrical diaryl (or heteroaryl) methanes. Tetrahedron Lett. 2003, 44, 9255-9258. (t) Pei, M.-M.; Liu, P.; Liu, Y. ; Lv, X.-M. ; Ma, X.-W. ; Dai, B. Pd-Catalyzed, Highly Selective C(sp²)-Br Bond Coupling Reactions of o-(or m-, or p-) chloromethylbromobenzene with Arylboronic acids. Molecules 2018, 23, 433. (u) Fairlamb, I. J. S.; Schnal, P.; Taylor, R. J. K. Suzuki-Miyaura Cross-Coupling Mediated by trans-PdBr(N-Succ)(PPh₃)₂: A convenient Synthetic Method for Diarylmethanes and Aryl(heteroaryl)-methanes. Synlett 2009, 508-510.
Development of SMC procedures of benzylic electrophile with no heterocyclic examples: (a) Colombel, V.; Rombouts, F.; Oehlrich, D.; Molander, G. A. Suzuki Coupling of Potassium Cyclopropyl- and Alkoxymethyltrifluoroborates with Benzyl Chloride. J. Org. Chem. 2012, 77, 2966. (b) Zhao, G.; Zhang, K.; Wang, L.; Li, J.; Zou, D.; Wu, Y. ; Wu, Y. Efficient synthesis of diarylmethane derivatives by PdCl2 catalyzed cross-coupling reactions of benzyl chlorides with aryl boronic acids in aqueous medium. Tetrahedron Lett. 2015, 56, 6700. (c) Yoon, S.; Hong, M. C.; Rhee, H. Palladium-Catalyzed Benzylation of Arylboronic Acids with N,N-Ditosylbenzylamines. J. Org. Chem. 2014, 79, 4206. (d) Guan, Z.; Li, B.; Hai, G.; Yang, X.; Li, T. ; Tan, B. A highly efficient catalyst for Suzuki-Miyaura coupling reaction of benzyl chloride under mild conditions. RSC Adv. 2014, 4, 36437. (e) John, A.; Shaikh, M. M.; Butcher, R. J.; Ghosh, P. Highly efficient palladium precatalysts of homoscorpionate bispyrazolyl ligands for the more challenging Suzuki-Miyaura cross-coupling of aryl chlorides. Datlton Trans. 2010, 39, 7353. (f) Jin, L.; Wei, W.; Sun N.; Hu, B.; Shen, Z.; Hu, X. Unsymmetrical CNN-palladacycles with geometry-constrained iminopyridyl ligands: an efficient precatalyst in Suzuki coupling for accessing 1,1-diarylalkanes from secondary benzylic bromides. Org. Chem. Front 2018, 5, 2484. (g) Nobre, S. M.; Monteiro, A. L. Synthesis of diarylmethane derivatives from Pd-catalyzed cross-coupling reactions of benzylic halides with arylboronic acids. Tetrahedron Lett. 2004, 45, 8225. (h) Singh, R.; Viciu, M. S.; Kramareva, N.; Navarro, O.; Nolan ,S. P. Simple (Imidazol-2-ylidene)-Pd-Acetate Complexes as Effective Precatalysts for Sterically Hindered Suzuki-Miyaura Couplings. Org. Lett. 2005, 7, 1829. (i) Ghosh, R.; Adarsh, N. N.; Sarkar, A. A Novel, Air-Stable Phosphine Ligand for the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction of Chloro Arenes. J. Org. Chem. 2010, 75, 5320. (j) McLaughlin, M. Suzuki-Miyaura Cross-Coupling of Benzylic Phosphates with Arylboronic Acids. Org. Lett. 2005, 7, 4875. (k) Inés, B.; Moreno, I.; SanMartin, R.; Domínguez, E. A Nonsymmetric Pincer-Catalyzed Suzuki-Miyaura Arylation of Benzyl Halides and Other Nonactivated Unusual Coupling Partners. J. Org. Chem. 2008, 73, 8448. (l) Bandgar, B. P.; Bettigeri ,S. V.; Phopase, J. Palladium catalyzed ligand-free Suzuki cross-coupling reactions of benzylic halides with aryl boronic acids under mild conditions. Tetrahedron Lett. 2004, 45, 6959. (m) Kuwana, R.; Yokogi, M. Suzuki-Miyaura Cross-Coupling of Benzylic Carbonates with Arylboronic Acids. Org. Lett. 2005, 7, 945(n) Chowdhury, S.; Georghiou, P. E. Palladium catalyzed cross-coupling between phenyl- or naphthylboronic acids and benzylic bromides. Tetrahedron Lett. 1999, 40, 7599. (o) Zhao, F.; Tan, Q.; Xiao, F.; Zhang, S.; Deng, G.-J. Palladium-Catalyzed desulfitative Cross-Coupling Reaction of Sodium Sulfinates with Benzyl Chlorides. Org. Lett. 2013, 15, 1520. (p) Wang, T.; Liu, L.; Xu, K.; Xie, H.; Shen, H.; Zhao, W.-X. Synthesis and characterization of trinuclear N-heterocyclic carbene-palladium(II) complexes and their applications in the Suzuki-Miyaura cross-coupling reaction. RSC Adv. 2016, 6, 100690-100695. (q) Micksch, M.; Tenne, M.; Strassner, T. Cyclometalated 2-Phenylimidazole Palladium Carbene Complexes in the Catalytic Suzuki-Miyaura Cross-Coupling Reaction. Organometallics 2014, 33, 3966-3976. (r) Yen, S. K.; Koh, L. L.; Huynh, H. V.; Hor, T. S. A. Benzothiazolin-2-ylidene and Azole Mixed-Ligand Complexes of Palladium. Eur. J. Org. Chem. 2009, 4288-4297. (s) Saha, D.; Ghosh, R.; Sarkar, A. 3-Indolyllphsophines as ligand for palladium in Suzuki-Miyaura coupling reaction of chloroarenes: substituent effects. Tetrahedron 2013, 69, 3951-3960. (t) Srimani, D.; Sarkar, A. Benzaldimines as ligands for palladium in Suzuki-Miyaura reactions. Tetrahedron Lett. 2008, 49, 6304-6307. (u) Inés, B. ; SanMartin, R. Moure, M. J. ; Domínguez, E. Insights into the Role of New Palladium Pincer Complexes as Robust and Recyclable Precatalysts for Suzuki-Miyaura Couplings in Neat Water. Adv. Synth. Catal. 2009, 351, 2124-2132. (v) Zhao, G.; Wang, Z.; Wang, R.; Li, J.; Zou, D.; Wu, Y. Cucurbit[7]uril promoting PdCl₂-Catalyzed cross-coupling reaction of benzyl halides and arylboronic acids in aqueous media. Tetrahedron Lett. 2014, 55, 5319-5322.
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Phase Transfer Catalysts Shift the Pathway to Transmetalation in Biphasic Suzuki-Miyaura Cross-Couplings

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Abstract

Figures

Introduction

Results and Discussion

ABBREVIATIONS

Declarations

References

Table

Additional Declarations

Supplementary Files

Status:

Version 1