Enantiospecific and Iterative SuzukiâMiyaura Cross-Couplings

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Cite This: J. Am. Chem. Soc. 2017, 139, 18124−18137

Enantiospecific and Iterative Suzuki−Miyaura Cross-Couplings Jason P. G. Rygus‡ and Cathleen M. Crudden*,‡,§ ‡

Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, Ontario K7L 3N6, Canada Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8601, Japan

§

boron-based nucleophiles in stereoconvergent processes, the reader is referred to other work in this area.8

ABSTRACT: The Suzuki−Miyaura cross-coupling reaction has emerged as one of the most powerful methods for the construction of carbon−carbon bonds. Though most widely utilized for the synthesis of sp2−sp2 linkages, the use of this reaction to form stereochemistry-bearing sp2− sp3 bonds has received widespread attention over the past decade. This Perspective highlights approaches to the synthesis of enantioenriched molecules via the Suzuki− Miyaura reaction. Particular focus is placed on the use of enantiomerically enriched organoboron compounds as coupling partners in stereospecific processes, as well as the development of enantioconvergent and group-selective reactions. In addition, progress in the development of chemoselective, iterative cross-coupling methods will be discussed.

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RESULTS AND DISCUSSION π-Directed Couplings. Inspired by the facile synthesis of chiral boronic esters derived from hydroboration chemistry,9 our group set out to examine the applicability of these species in cross-coupling chemistry. At the time, the only precedent for enantiospecific Suzuki−Miyaura cross-coupling was found in cyclopropylated substrates.10,11 This work added to existing literature documenting the feasibility of Suzuki−Miyaura crosscouplings employing cyclopropyl organoboron species.10a,12,13 Cyclopropyl substituents are specialized because of the unique hybridization at carbon in the cyclopropyl unit and because geometrical requirements suppress β-hydride elimination. Therefore, extrapolation to simple aliphatic boranes was nontrivial. The cross-coupling of larger alicyclic compounds was described subsequently and independently by Fu,14 Molander,15 and van den Hoogenband16 (Chart 1). This was an

INTRODUCTION

The Suzuki−Miyaura cross-coupling1 is the number one method for forming carbon−carbon bonds in the pharmaceutical industry,2 and is frequently utilized in the construction of organic materials. In fact, the Suzuki−Miyaura reaction is so frequently employed that many consider it responsible for overpopulating the libraries of pharmaceutical compounds with flat, sp 2 carbon-rich molecules.3 Such molecules have suboptimal pharmacokinetic properties and appear to be more likely to cause off-target activity, possibly due to their flat structures and resulting target promiscuity.3,4 Recognizing the ubiquity and power of the Suzuki−Miyaura reaction, Burke has proposed to employ this reaction for the automated synthesis of common organic molecules.5 For this to be widely effective in the synthesis of three-dimensional molecules, access to cross-coupling approaches capable of generating stereocenters is critical, as is the need for iterative protocols. Thus, the development of enantiospecific, enantioselective, or enantioconvergent cross-coupling methods is of importance beyond the synthetic community. This Perspective covers the use of Suzuki−Miyaura crosscoupling chemistry for the creation of C−C bonds with stereochemistry, with a focus on the use of chiral enantiomerically enriched boronic esters. Enantioconvergent approaches will also be covered in this context. The use of these advanced methods in iterative coupling processes will be presented. Due to space limitations, the use of chiral electrophiles in Suzuki−Miyaura cross-couplings and nonmetal-catalyzed C−C bond-forming processes will not be covered.6 The reader is also directed to several pertinent reviews.7 In addition, for recent advances in the use of non© 2017 American Chemical Society

Chart 1. Alicyclic Organoboron Compounds Used in Early Examples of Secondary Cross-Coupling

important advance since these examples are free of ring strain. However, in unsymmetrical cases, it was shown that β-hydride induced isomerization was facile even under optimized conditions. However, this work was of great significance in that it provided evidence that key steps such as transmetalation were feasible for hindered secondary systems. The ready accessibility of phenethylboronic esters 6, (Chart 2) via enantioselective hydroboration,9 combined with the biological activity of multiply arylated alkanes17 and difficulties with the enantioselective synthesis of 1,1-diarylalkanes, made phenethylboronic esters the target of our initial studies. However, initial attempts at involving these substrates in Suzuki−Miyaura cross-couplings were met with failure. Careful reaction mixture analysis indicated that the starting boronic ester was left largely untouched under most reaction Received: August 6, 2017 Published: November 17, 2017 18124

DOI: 10.1021/jacs.7b08326 J. Am. Chem. Soc. 2017, 139, 18124−18137

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Journal of the American Chemical Society conditions.18 This led us to focus on the transmetalation as the problematic step. The use of Ag2O as a base for achiral boronic acids that are resistant to transmetalation was described by Kishi,19 and in our system gave the first successful result. Optimization with increasing amounts of PPh3 relative to Pd gave the next key improvement in yield, likely by suppressing βhydride elimination through occupying empty sites on Pd.18 The oxidative sensitivity of more electron rich alkylated phosphines to stoichiometric Ag2O limited the number of phosphine ligands that could be screened. Bidentate ligands shut the reaction down, and in early optimizations, only minor improvements in yield were noted with aryl phosphines other than PPh3. Thus, our optimized conditions were relatively simple: either Pd(PPh3)4 with an additional 4 equiv (to Pd) of PPh3, or 8 equiv of PPh3 to Pd(dba)2 or Pd2(dba)3.18 Subsequent work showed that a 6:1 PPh3:Pd ratio gave the desired product in 90% yield with high enantiospecificity (e.s.), although 4:1 ratios did result in lower yields.20 Interestingly, isomeric linear borane 8 was unreactive under these conditions (eq 1), which became the starting point for our development of iterative cross-couplings, as will be described below.

from our group did show some correlation with electronic effects (see Chart 6 later in the text). By comparison with known compounds, we were able to demonstrate that the reaction proceeded with overall retention of configuration.18 Applications of this reaction in the synthesis of complex molecules have been reported by Burke22 and Itami.23 Allylic boronic esters were also shown to undergo crosscoupling.24 Together with the Aggarwal group, we investigated both the enantiospecificity and mechanism of the allylic crosscoupling.25 Like benzylic boronic esters, these substrates react with retention of configuration; in fact, even higher levels of retention were observed compared with benzylic systems. However, allylic boronic esters have the added complication of providing a mixture of SE and SE′ products. In the majority of cases, the reaction proceeds via SE′ transposition or γsubstitution (Chart 3). However, when the allyl unit is part Chart 3. Cross-Coupling of Secondary Allylic Boronic Esters with Aryl Iodides

Chart 2. Cross-Coupling of Secondary Benzylic Boronic Esters with Aryl Iodides18

of a styrenyl system, a higher proportion of direct coupling without allylic transposition is observed. This is likely due to a thermodynamic preference to retain the styrene unit in the product; however, the lower yield of the product in this case makes a more detailed analysis of mechanism difficult. As expected for allylic systems, the geometry of the olefin in the product was connected to the transfer of chirality.26 Thus, (R,E)-12 and (R,Z)-12 gave opposite enantiomers, as shown in Scheme 1. This is fully expected for a syn-SE′ mechanism as Scheme 1. Impact of Olefin Geometry on the Stereochemical Outcome of Transmetalation of Secondary Allylic Boronic Esters Other work in our laboratory centered around the addition of K2CO3 in addition to Ag2O, which gave improved enantiomeric ratios in some cases.21 We subsequently showed that this was likely due to its action as an internal drying agent. The addition of water at 350 ppm was shown to lead to a significant drop in e.r. of the product, and for reactions run under strictly anhydrous conditions, K2CO3 had little effect.20 Under these relatively simple conditions, a variety of chiral benzylic boronic esters could be coupled with high levels of stereocontrol. (Chart 2). Although few trends were observed in terms of the stereospecificity of the reaction, further studies 18125


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Journal of the American Chemical Society

(Scheme 3). Enantiospecificities were in the similar range obtained previously; however, the ability to control α- or γselectivity by the nature of the catalyst provides considerable versatility to this method. Propargylic boronic esters also undergo stereospecific crosscoupling reactions, as demonstrated by the Aggarwal group.30 Again, reaction occurs via an SE′ mechanism, which results in an interesting synthesis of chiral allenes where atom-centered chirality is transformed to axial chirality (eq 2). Much like allylic couplings, the reaction takes place with exceptional enantiospecificity.

illustrated in Scheme 1. Consistent with this proposal, deuterated substrates failed to show scrambling, which would be expected if the reaction proceeded through a π-allyl-type mechanism.25 Morken employed unsymmetrical terminally disubstituted allylic boranes in this reaction, leading to quaternary centers with control of stereochemistry.27 The reaction proceeds with high γ-selectivities and excellent enantiospecificities. Mechanistic studies excluded any significant π-allyl formation as part of the reaction manifold, consistent with Aggarwal and Crudden’s prior work. When followed up with a Pd/Ccatalyzed hydrogenation, the stereospecific cross-coupling provides a powerful method for the synthesis of chiral, enantioenriched hydrocarbons (Scheme 2).27 Scheme 2. Synthesis of Quaternary Centers via CrossCoupling of Terminally Disubstituted Allylic Boronic Esters27

Subsequently, our group set out to develop a method for the preparation of enantioenriched triarylmethanes by crosscoupling, which required a feasible synthesis of enantioenriched bis-benzylic boronic esters 28 as the starting material.31 To achieve this, we employed the Aggarwal enantioselective deprotonation, boronic ester quench, and 1,2-migration as shown in Scheme 4.32 Scheme 4. Synthesis of Dibenzylic Boronic Esters via an Enantioselective Lithiation/1,2-Migration Sequence31

In a related 2013 report, the Buchwald group described the cross-coupling of terminally substituted allylboronates with aryl halides.28 The reaction was shown to proceed with high αselectivity using the bulky t-BuXPhos ligand, while γ-selectivity was achieved using less bulky ligands. The Hall group has described the cross-coupling of allylic boronic esters contained within heterocyclic frameworks, specifically compounds of types 18 and 21, prepared using enantioselective borylation of achiral cyclic enol ethers and enamines.29 Substrates 18 and 21 were shown to undergo stereoretentive cross-couplings with high γ-selectivities when XPhos was employed as the ligand, yielding products 20 and 23. Moderately high levels of α-selectivity could be obtained with when the cross coupling of 18 was carried out the electron poor ligand P(p-C6H4CF3)3 (Scheme 3).29 In the amine series, α-selectivity could be achieved with PEPPSI-type catalysts

It should be noted that this method, although applicable to a wide range of boronic esters, required extra care in the synthesis of dibenzylic substrates such as 28. The higher stability of the intermediate organolithium compound afforded by its benzylic nature results in an increased reversibility in the boronic ester trapping reaction. This problem was solved through the use of smaller substituents on boron. This resulted in a faster rate of trapping of the configurationally labile organolithium species (which was formed under thermodynamic control) as well as reduced reversibility in boronate formation resulting in a change from virtually racemic to 96% e.e. Similar approaches have been employed by the Aggarwal group for substrates prone to reversibility in the borate formation step.30 With a route to enantioenriched dibenzylic boronic esters developed, we then reacted these species under the Suzuki− Miyaura cross-coupling conditions previously developed in our laboratory (Chart 4). Cross-coupling indeed proceeded with high levels of stereospecificity and good yields, resulting in a reliable preparation of chiral, enantioenriched triarylmethanes.31 Although numerous methods exist for the preparation of racemic triarylmethanes, there are only a limited number of enantioselective/-specific preparations.33

Scheme 3. Regiodivergent Cross-Coupling of Heterocyclic Secondary Allylic Boronic Esters29

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Chart 5. Possible Effect of Silver on π-Directed Couplings by Facilitating Transmetalation

Chart 4. Synthesis of Enantioenriched Triarylmethanes via Stereospecific Cross-Coupling of Dibenzylic Boronic Esters31

Suginome and Ohmura35 were the first to demonstrate this when they showed that boronic ester 31 underwent SM crosscoupling with high levels of enantiospecificity (Scheme 5). The Scheme 5. Carbonyl-Directed Cross-Coupling of Secondary Boronic Esters with Inversion of Stereochemistry and Rationale for Observed Reactivity35,37

Interestingly, under different conditions, the Liao group subsequently showed that cross-coupling of closely related dibenzylic potassium trifluoroborate salts with aryl triflates occurs with inversion of stereochemistry using a Pd(OAc)2/ PCy 3 catalyst system. 34 The conditions employed are significantly different from those used in Chart 4; however, the observation of a switch in stereochemical outcome without significant deviation in the substrate is noteworthy, and highlights the need for more research into understanding the transfer of chirality in this area. In this section, all of the examples presented benefited from some type of π-system adjacent to the B−C bond in question. Thus, couplings of benzylic, allylic, propargylic, and doubly benzylic organoboron species have been described. Although the presence of the adjacent π-system undoubtedly accelerates the reaction by weakening of the B−C bond, this is not the only effect; otherwise coupling of, for example, organoborane 6 would occur under traditional conditions and not require the presence of silver oxide to promote transmetalation. Similarly, the silver oxide effect seems confined to or enhanced by boranes bearing a π-system. Considering these two facts, the effect of silver may be to facilitate transmetalation by initial complexation to the π−systems present in the substrate classes described herein (Chart 5). The reactivity of 29b under nonsilver oxide-promoted conditions stands in contrast to this, but may be explained by an overall higher reactivity of these doubly benzylic systems. Carbonyl-Directed Couplings. In addition to the πdirected couplings described above, the other major class of chiral boronic esters that can be induced to participate in stereospecific cross-coupling reactions are those that contain amide or ester substituents in proximity to the key C−B bond.

nature of the R group on the amide played a significant role, with tBu giving the best results (>97% e.s.). Unlike π-directed cross-couplings described in the previous section, the reaction occurred with inversion of stereochemistry, a trend borne out in all subsequent amide/ester−promoted cross-couplings of chiral boronic esters. To explain the observed inversion, an SN2-like transition state in which the amide coordinates to the departing “BPin” unit was invoked (Scheme 5, bottom left). Consistent with this hypothesis, Ohmura and Suginome subsequently showed that performing the reaction in the presence of Lewis or Brønsted acids that bind to the amide carbonyl result in increasing levels of retentive coupling products.36 Of the Lewis acids examined, Zr(OiPr)4·iPrOH was optimal, giving the product of retention in up to 93% e.s. It was proposed that in this case, 18127


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Scheme 7. Stereoretentive Cross-Coupling of γ-Borylated Amides42

transmetalation occurs from a structure not involving amide coordination to boron (31′) which transmetalates to Pd via a four-membered cyclic transition state with retention of configuration (Scheme 5). The fact that the coupling occurs at all after removing the coordinating ability of the amide carbonyl is notable, given the general resistance of crowded boronic esters such as 31 to cross-coupling, although the benzylic nature of the substrate certainly assists in the overall transformation. In 2010, the Molander group employed chiral boronic esters such as 33 in cross-coupling reactions to give arylated derivatives in high yields, with high enantiospecificity, again arising from inversion of configuration (Scheme 6, top).37a The Scheme 6. Carbonyl-Directed Cross-Coupling of Secondary Boronic Esters with Inversion of Stereochemistry35,37

activate the boron substituent, but certainly illustrates that there are many mechanistic details remaining to be elucidated about these types of cross-coupling reactions. In addition to carbonyl-type activating groups, Suginome43 and Morken44 have shown that appropriately positioned hydroxyl groups can be powerful directing groups to activate the cross-coupling of otherwise unreactive chiral C−B bonds. In 2011, Suginome described the cross-coupling of cyclic boronamide 44, which proceeded in high yield with complete retention of stereochemistry (Scheme 8).43 Since the nascent Scheme 8. Cross-Coupling of Cyclic Boronamides43

substrates for these transformations could be readily prepared by Rh-catalyzed hydroboration of acrylamides using Takacs chemistry,38 or by Cu-catalyzed borylation using conditions developed by Yun.39 The Hall group demonstrated that invertive coupling could even be achieved with an ester as the directing group,37b but only in substrates such as 35 that are more reactive by virtue of having geminal boron substituents (Scheme 6, bottom). Shibata,40 Morken,41 and others have shown that the presence of one boron substituent in close proximity (geminal or vicinal) to another enables more facile C−B bond activation. Enantioenriched geminal diboron compound 35 was prepared by Cu-catalyzed borylation of the corresponding βborylated acrylate.37b The use of Suginome’s “dan” protecting group (1,8-diaminonaphthalene) in the starting material rendered that boron substituent unreactive, enabling the coupling of the geminal BPin group. Conversion of the Bdan group to a BF3 substituent after the first coupling was not sufficient to permit coupling with the weakly directing ester group. Instead, this group had to be converted into amide 37, which was then reactive in a second stereospecific (invertive) cross-coupling (Scheme 6) to afford 38. Takacs has described several interesting borylated amides 39 and 41 which undergo cross-coupling reactions with retention of stereochemistry, in contrast to the examples presented above.42 In particular, amides in which the boryl substituent is in the γ-position cross-couple with retention in both cyclic42a and acyclic42b systems (Scheme 7). This interesting effect may be related to the specific geometries required for the amide to

alcohol is contained within the direct coordination sphere of boron, it may not be considered a formal directing group; however, the ability of this substructure to undergo crosscoupling is certainly notable, since related acetate 46 was unreactive. In 2015, the Morken group showed definitively that hydroxyl groups act as internal activating groups for the cross-coupling of secondary C−B bonds.44 A variety of vicinally diborated compounds (47) were prepared by diboration of the corresponding olefins. Remarkably, substrates containing a free hydroxyl β to a Bpin substituent were shown to undergo selective cross-coupling at the less reactive secondary position (Scheme 9), demonstrating that the directing effect of a hydroxyl group is sufficient to overcome the inherent reactivity biases in terminal vicinal diboronates.44 Notably, if the hydroxyl is protected as a silyl ether, or if it is in the α- or γ-position, cross-coupling occurs solely at the linear C−B bond. Unlike the carbonyl-directed cross-couplings described in Scheme 6, which proceed with inversion of stereochemistry due to formation of an intramolecular “ate” complex, hydroxyl directed cross-coupling occurs with retention of configuration. Cyclic bis(boronate) 51 is an 18128


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Journal of the American Chemical Society Scheme 9. Hydroxyl-Directed Cross-Coupling44

Scheme 10. Use of Unactivated Secondary Alkylboron Reagents in Suzuki−Miyaura Coupling45−47

interesting substrate with two boronic esters on secondary carbons. Despite this fact, complete selectivity for the β-boronic ester closer to the hydroxyl group was observed. Concomitant oxidation accompanied the reaction, which is proposed to result from β-hydride elimination at the alcohol carbon and loss of the arene derived from the aryl halide. Nondirected Couplings. Yun and co-workers employed a strategy similar to that used by Hall, employing geminally diborylated compound 54 in which one boron is protected by the dan group. As expected, reaction occurred only at the BF3 substituent not the Bdan group.45 However, as the C−B bond was neither π- nor carbonyl-activated, the overall process proceeded in only 15% yield, although with high enantiospecificity (Scheme 10A). High-yielding cross-couplings of unactivated boranes have been reported by two groups. Molander has demonstrated that chiral organoboranes such as 56, in which the stereocenter also contains an ether, undergo cross-coupling, but only when the ether substituent is benzylic (Scheme 10B).46 Substrates bearing simple alkyl ethers or non-benzylic substituents were completely unreactive. The need for a benzylic group in proximity to the C−B bond suggests the importance of coordinating groups in the substrate and that these couplings may be categorized along with π-directed couplings. Overall the transformation occurs with high yields and exceptional enantiospecificities. Thus far, there is only one example of a Suzuki−Miyaura cross-coupling on a chiral substrate without any directing groups, which comes from the laboratories of Biscoe (Scheme 10C).47 To develop this reaction, Biscoe employed Buchwald’s Pd(II) precatalyst 61 ligated with PtBu3. This precatalyst is known to very effectively generate Pd(0), and presumably the presence of a single ligated PtBu3 is critical to enable coupling of a crowded, unactivated C−B bond while preventing catalyst decomposition. Interestingly, the reaction proceeds with inversion of configuration, suggesting a nucleophilic-type mechanism for transmetalation similar to that proposed by Aggarwal6f and Kabalka48 for electrophile trapping of chiral borates. Group-Selective Cross-Couplings. Although stereospecific couplings of organoboron compounds represent a significant advance in cross-coupling chemistry, the need for chiral, enantiopure starting materials is certainly a limitation.

Two recent strategies address this head on. The first involves the development of group selective cross-couplings. The use of geminal diboron species such as 62 in stereoselective cross-couplings takes advantage of the increased reactivity described by Shibata49 for geminally diborylated species compared to isolated organoboranes. Thus, starting from 62, Morken demonstrated that cross-coupling with aryl iodides occurs with high enantioselectivities when carried out with a large excess of base and chiral taddol-derived phosphoramidate ligand 64 (Chart 6).41 Transmetalation takes place with inversion of configuration, and mechanistic Chart 6. Group-Selective Cross-Coupling of Geminal Diboron Compounds41

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Journal of the American Chemical Society studies provide strong evidence for an enantiotopic group selection process during transmetalation. The Hall group published a related stereoconvergent crosscoupling of geminal bis(boronic esters), which included ligand optimization, additive effects, scale up, and mechanistic studies implicating the hydrolysis of the boronate ester prior to reaction.50 Applying this concept to the cross-coupling of geminal diboron compounds with vinyl halides results in the synthesis of enantioenriched allyl boronates (Scheme 11).51 In this case,

Scheme 12. Cross-Coupling of Potassium Alkyltrifluoroborate Salts via Dual Photoredox/CrossCoupling Catalysis53

Scheme 11. Group-Selective Coupling of Geminal Diboronic Esters with Vinyl Halides51

Two possible mechanisms have been proposed for the crosscoupling process through DFT calculations: in the first (depicted in red, Scheme 12), addition of the newly generated radical 75 to nickel(0) complex 77 generates Ni(I)-alkyl species 78. Subsequent oxidative addition of an aryl bromide generates nickel(III) complex 79.54 Alternatively, oxidative addition of the aryl halides to nickel(0) may precede addition of the radical species to the resulting nickel(II) complex 80 (blue pathway). Both mechanisms are energetically feasible and converge at a common nickel(III) intermediate 79, from which reductive elimination forms the desired arylated product 81 and nickel(I) species 82. Single-electron reduction of 82 by the reduced photocatalyst 76 regenerates both the active nickel(0) catalyst 77 and the ground-state photocatalyst 73, completing the catalytic cycles. Computational studies have suggested that the barrier to reductive elimination from 79 is larger than that of the radical dissociation process.54 Thus, in the presence of a chiral ligand, the resulting diastereomeric nickel(III) complexes 79 undergo interconversion via homolysis and recombination of the nickel−Csp3 bond prior to stereoretentive reductive elimination. Due to the difference in rate of reductive elimination between the two diastereomeric complexes, net enrichment of one stereoisomer in the resulting cross-coupled product is observed, rendering the reaction stereoconvergent. Although enantioselectivities remain modest at present (Scheme 13), the development of a novel stereoconvergent manifold for crosscoupling of alkylboranes provides a wealth of new opportunity in this area. Following this initial disclosure, a range of protocols for the cross-coupling of substituted secondary alkyltrifluoroborates via single electron transmetalation have been reported.53 In

Josiphos-type ligands (70) provided optimal enantioselectivity.51 The use of 10B-labeled enantiomerically enriched diboronate 67 revealed that the transmetalation occurred with inversion of stereochemistry (Scheme 11), as was observed with the phosphoramidate catalytic system mentioned above (Chart 6). The choice of ancillary ligand on boron was found to be important, with pinacol boronic esters affording increased yield and selectivity relative to the neopentyl or 2,4dimethylpentane-2,4-diol analogues. This suggests that the bis(boronic acid) species is not the active transmetalation species. Enantioconvergent Cross-Couplings. The development of single-electron transmetalation chemistry via photoredox/ nickel dual catalysis by the Molander group has offered a groundbreaking new approach to stereoconvergent crosscoupling of secondary alkylboron reagents.52 The key step (Scheme 12) is the generation of an alkyl radical (75) by reaction of photoexcited Ir catalyst 74 with alkyltrifluoroborates (71) through a single electron transfer (SET) event in the photoredox catalytic cycle (depicted in green, Scheme 12). In the presence of a nickel cross-coupling catalyst, the resulting radical is then trapped by nickel to generate an organometallic species. Unlike classical two-electron transmetalation processes, which are redox neutral, this process results in a one electron oxidation at the metal center. If the radical generated is prochiral, a stereocenter is generated upon trapping. 18130


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Scheme 14. Selective Cross-Coupling of Bdan Groups58a,60

Scheme 13. Stereoconvergent Cross-Coupling of Secondary Boron Reagents via Photoredox/Nickel Dual Catalysis52

particular, alpha substitutions at the C−B bond are well tolerated, including α-alkoxymethyl (86), α-aminomethyl (87), and α-trifluoromethylbenzyl (88) coupling partners (Chart 7). Chart 7. Examples of Alkyltrifluoroborates Successfully Used in Dual Nickel/Photoredox-Catalyzed Arylation Reactions53

The first example of cross-coupling of secondary alkyl βtrifluoroboratoketones (89) and -esters with aryl bromides was reported using Ni/photoredox dual catalysis.55 Reaction of the corresponding amide derivatives have previously been reported under traditional Pd catalysis (see section on carbonyl directed coupling), while the ketone- and ester-derived substrates were ineffective under these conditions. The synthesis of novel 2arylflavonones was also reported from 2-trifluoroboratochromanone precursors (90).56 Thus, in a relatively short time, single-electron transmetalation has emerged as a powerful platform for the design of new cross-coupling methods, affording access to unique products not easily obtained by traditional cross-coupling chemistry.53 The ability to use these processes in the synthesis of highly enantioenriched products is certainly the next goal in this area. In addition to the opportunity to develop enantioconvergent protocols, this reaction scheme provides novel methods for differentiating between related C−B bonds based on their propensity to form radicals, as will be described in the next section. Iterative Cross-Couplings. The ability to control the reactivity of related functional groups within a molecule is critical in organic synthesis, and this level of control is starting to be seen in cross-coupling chemistry. Chemoselectivity in Suzuki−Miyaura cross-couplings can refer to substrates containing multiple electrophiles or multiple nucleophiles. Chemoselectivity with regards to the electrophile will not be covered herein, and instead the reader is referred to a recent review of the area.57 In general, the chemoselective reaction of one boron substituent in the presence of another is controlled by two methods: the use of protecting groups on boron to prevent transmetalation, or the design of conditions that promote transmetalation of one C−B bond in the presence of another. In 2007, the Suginome and Burke groups independently reported the development of protecting groups for boron.58 The Suginome approach involved the use of the 1,8diaminonaphthalene (dan) group (Scheme 14),58a which blocks the ability of boron to participate in cross-couplings due to

strong donation of electron density from N to B (92). ArylBdan esters were shown to be inert to transmetalation relative to aryl boronic acids58a and pinacol esters.59 Thus, molecules could be designed containing both an electrophile and nucleophile and prevented from reacting with each other by virtue of a protecting group on boron. After the desired coupling reaction, acid hydrolysis was employed to reveal the parent boronic acid which can be used for further crosscoupling. Diborylated alkene 94, in which one boron is protected by a dan group and the other as a pinacol ester,60 was shown to undergo completely selective coupling at the internal Bpin group rather than the terminal Bdan. This is in sharp contrast to the excellent terminal selectivity observed in analogous bis(pinacolato)ester compounds,61 a clear demonstration of the inhibitory effect of the Bdan group. Burke’s approach to boron protecting groups employed a multidentate ligand derived from N-methylimidodiacetic acid (MIDA)58b to inhibit coupling by donation of the nitrogen lone pair to the empty p-orbital on boron (97), resulting in rehybridization from sp2 to sp3. BMIDA groups are unreactive toward transmetalation and can therefore be carried through cross-couplings as handles for further functionalization after basic hydrolysis to restore the parent boronic acid. The Burke group demonstrated that iterative Suzuki− Miyaura cross-couplings using MIDA-protected halogenated boronic acid building blocks can be readily accomplished.58b After coupling at the halide of 97 with a reactive organoborane (Scheme 15), hydrolysis of 98 using aqueous base reveals the parent boronic acid 99, which can be used for subsequent crosscoupling reactions. This control of reactivity enables multiple iterative cross-couplings (Scheme 15). The widening scope of organoboron species that can be employed in cross-coupling chemistry (aryl, alkenyl, alkyl, and chiral aliphatic) then provides the exciting possibility to employ the Suzuki−Miyaura cross-coupling in the automated preparation of many types of organic molecules. 18131


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Journal of the American Chemical Society Scheme 15. Development of MIDA Boronates58b

identical or closely related. Although out of order chronologically, we will begin with closely related but distinct boron substituents, since this is more closely related to the protecting group approach. For this strategy to be successful, there must be inherent differences in selectivity imparted by the ancillary substituents, and interchange of the substituents on boron must be slower than cross-coupling. In 2016, the Hoveyda group prepared a molecule with two different boryl substituents and employed it in an iterative selective Suzuki−Miyaura cross-coupling strategy (Scheme 17).62 First, a pinacol boron group was installed by copperScheme 17. Selective Coupling of a Primary Alkylborane in the Presence of a Boronic Ester62

This concept was demonstrated in 2015 when Burke reported an automated process in which the synthesis of many types of small molecules was accomplished using bifunctional BMIDA haloboronic acid building blocks.5 Each coupling “step” consists of three stages (Scheme 16): Scheme 16. Iterative Cross-Coupling of Bifunctional Haloboronate Building Blocksa

catalyzed enantioselective allylic substitution of allylic phosphate 100 and bis(pinacolatoboryl)methane. The resulting homoallyl boronic ester 101 was then subjected to hydroboration with 9-BBN, affording diboron product 102. In the presence of a vinyl iodide using Pd(dppf)Cl2 as a catalyst, crosscoupling occurred selectively at the trialkylborane in the presence of the less Lewis-acidic BPin substituent. Cross-coupling of the second boron substituent was induced by revealing an adjacent alcohol, which was found to promote copper-catalyzed allylation to generate 104.62 The alcohol functionality was critical in promoting this reaction, as only trace product was observed with the corresponding silyl ether. The ability to differentiate these two C−B bonds is also likely a function of relative reactivity in the transmetalation event. The Watson group employed a similar strategy,63 but in their case, the two boron species were a pinacol boronic ester and a free boronic acid. Selectivity is then achieved due to faster transmetalation of the former through kinetic discrimination by the palladium(II) pre-transmetalation intermediate. In this case, careful control over reaction conditions was necessary to prevent pinacol equilibration. Chemoselectivity was demonstrated by reaction between two separate molecules rather than one molecule with two different types of boranes (Scheme 18). As expected, the amount of water was found to have a substantial impact on the selectivity of the reaction as excess water promotes scrambling of the pinacol group and equilibration between the two boron species.64 Sequestration of the boronic acid in the bulk aqueous phase as the conjugate boronate under alkaline aqueous conditions was also found to contribute to decreases in selectivity. The different phase

a

Shown in the bottom section are two examples of compounds prepared using automated synthesis.5

deprotection of the BMIDA group, cross-coupling, and purification. MIDA boronates were shown to possess an extremely high affinity for silica in MeOH/Et2O mixtures, allowing for the facile removal of byproducts and excess reagents. Conversely, boronates were rapidly eluted upon washing with THF, enabling a straightforward purification sequence. The deprotection−coupling−purification procedure was fully automated, culminating in the development of “smallmolecule synthesizer” capable of cleanly synthesizing a diverse library of small molecules using a single general, automated platform, including a range of macrocyclic and polycyclic natural products. Although functional group manipulations must still be carried out off line, the concept of automating the synthesis of small molecules is potentially transformational.5 This brings us to the second approach to control selectivity and reactivity in Suzuki−Miyaura cross-coupling reactions. In addition to the powerful use of protecting groups, several groups have harnessed the inherent reactivity differences of closely related C−B bonds to affect iterative cross-coupling reactions. In this case, the substituents on boron are either 18132


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Journal of the American Chemical Society Scheme 18. Chemoselective cross-coupling by control of boron speciation.63

Scheme 19. Selective Cross-Coupling of Primary Boronic Esters in Vicinal Diboron Compounds Prepared by Diboration of Terminal Olefins66,67

transfer behavior of boronic acids and pinacol esters was also harnessed to develop a chemoselective phase-transfer oxidation.65 Overall, this work shows that a detailed understanding of the relative reactivity of organoboron compounds and precise control of speciation can result in high levels of chemoselectivity. In coupling reactions employing completely identical substituents on boron, Morken66 and Fernandez67 were pioneers, employing the low reactivity of chiral secondary C− B bonds to enable sequential reaction of two C−B bonds in vicinal diboron species. In 2004, the Morken group66 demonstrated that vicinal 1,2diboronates (113) derived from the enantioselective diboration of terminal aliphatic olefins undergo selective cross-coupling at the linear aliphatic C−B bond (Scheme 19A). The secondary C−B bond, which is unaffected by the cross-coupling reaction despite the absence of a protecting group, is then available for subsequent transformations. The use of microwave irradiation was found to accelerate the reaction while still leaving the secondary C−B bond untouched. Since methods had not been reported to enable coupling of the secondary chiral C−B bond at the time, it was transformed through oxidation to the corresponding alcohol (114) or Matteson-style homologation.66 In later work, Morken clearly demonstrated that although coupling only occurs at the linear boronic ester substituent, the presence of the internal secondary boronic ester is critical in order to observe coupling.68 The Fernandez group also reported a diboration−linear selective cross-coupling sequence (Scheme 19B) of aliphatic olefins,67 after which oxidation of the secondary C−B bond could be affected. In both approaches, the initial selective cross-coupling was made possible by significant differences in reactivity between primary and secondary C−B bonds. Because of the lack of efficient methods at the time for cross-coupling of secondary C−B bonds, other reactions (oxidation, amination, homologation) were employed to transform this species. In one notable exception, a second cross-coupling could be employed if the secondary C−B bond was adjacent to an activating hydroxyl group.44 As previously noted (Chart 2, eq 1), our group observed dramatic differences in reactivity between chiral secondary benzylic C−B bonds (which were reactive) and linear achiral C−B bonds (which were not), during our initial study of the cross-coupling of secondary benzylic organoboranes.18 We saw

a

Diboronates were prepared by diboration of the corresponding olefin and used in situ. Yields are over three-step diboration−coupling− oxidation sequence. For full details, see the accompanying references.

this as a significant opportunity to widen the scope of iterative cross-coupling approaches without the need for protecting groups and to enable multiple back-to-back cross-coupling reactions. Building this observation into an iterative coupling approach, we began by examining vicinal diboronates 118, which contain both a linear and secondary benzylic pinacol boronic ester. These compounds are readily prepared by the high-yielding and enantioselective diboration of styrene derivatives.69 The use of Pd(OAc)2 and dicyclohexylbiaryl phosphines RuPhos or SPhos with simple inorganic bases was found to promote selective transmetalation of the linear C−B bond (119), without any reaction at the secondary C−B bond (Scheme 20).20 Substrates that were prone to deboronation benefitted from the use of higher proportions of water in mixed organic/aqueous solvent systems, which may be due to a decrease in the effective pH of the organic phase as more water is added.70 Subsequent silver oxide-promoted Pd-catalyzed cross-coupling of the benzylic C−B bond afforded a variety of 1,1,2triarylethanes (120) in good to moderate yields with a good tolerance of electronic variation in substrate.20 Stereoretention for these cross-couplings was generally around 90%, slightly lower than observed in the couplings of simpler 1-phenylethyl boronic esters, but still acceptable. No regioisomeric products resulting from β-hydride elimination were observed.20 To test the generality of the concept of selective transmetalation, we employed substrates 121 containing an aryl Csp2−B bond and a secondary Csp3−B bond. As expected, the aryl Csp2−B bond undergoes preferential transmetalation and cross-coupling. The use of tri-tert-butylphosphine71 was found to be optimal, as the use of triarylphosphines during initial 18133


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Journal of the American Chemical Society Scheme 20. Iterative Cross-Coupling of Polyborylated Substrates20

systems.20 Further studies are ongoing in our group to explore the mechanistic implications of these observations. As a more dramatic illustration of the use of multiply borylated compounds in iterative coupling, we examined the reactivity of trisborylated compound 124 containing an aryl B− Csp2 bond, a primary B−Csp3 bond, and a secondary benzylic B−Csp3 bond. Under Fu-type conditions,71 selective crosscoupling at the aryl B−Csp2 bond was observed. Subsequent coupling of the primary position was accomplished in the same reaction flask using RuPhos as a ligand along with higher

optimization resulted in undesired arylated products derived from P−Ph activation (Scheme 20).72 The resulting π-extended biphenyl boronic esters (122) were then subjected to the silver oxide promoted cross-coupling conditions.18 Although most substrates coupled with high levels of enantiospecificity, the electronics of the distal ring on the biphenyl boronic ester were found to have a significant impact on the stereochemical outcome of the reaction. Electronwithdrawing substituents (i.e., 4-phenacyl) led to significantly higher losses of enantiomeric purity than electron rich 18134


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such as a π-system or a Lewis-basic heteroatom or carbonyl group in order to participate in high-yielding stereospecific cross-coupling reactions. In this regard, the 2014 report from the Biscoe group on the use of unactivated secondary alkylboron reagents represents a significant development in the field.47 Further examples in which similarly unsubstituted organoboron species are engaged in cross-coupling will be essential for the stereocontrolled introduction of increasingly diverse molecular frameworks employing cross-coupling chemistry. The stereochemical outcome of these reactions is highly dependent on the nature of the substrate, as well as the choice of additive and reaction conditions. Efforts to further understand the underlying mechanistic features responsible for the stereochemical outcome represent a fertile area for future research. Elucidating the role of crucial additives, as well as understanding the prerequisites for reactivity of a given boron reagent is an important step in the development of new methodologies for stereoselective synthesis. In recent years, the Denmark group has reported remarkable advances on the detection and characterization of pre-transmetalation intermediates in Suzuki−Miyaura reactions,74 and a combined study by Lloyd-Jones and Burke75 provided much needed insight into the mechanism of action of MIDA boronates. Further study on the underlying mechanism of transmetalation will likely offer new insights into reaction design. Though still being developed, single-electron transmetalation has emerged as a remarkable advance in the development of cross-coupling methodology of sp3 hybridized organometallic compounds.53 A complete re-imagining of the mechanism of transmetalation permitted the development of this powerful coupling method, which has been shown to both outperform traditional two-electron chemistry in some cases as well as offer unique orthogonal reactivity. The continued development of stereoconvergent methods represents an important advance in asymmetric catalysis and should constitute a thriving area of research for years to come. The generation of enantioenriched quaternary carbon centers via cross-coupling reactions represents an important challenge that is still in its infancy. To this end, the use of tertiary boronic esters as competent cross-coupling partners in Suzuki−Miyaura reactions remains an unsolved problem of great interest. Two independent reports emerged in 2010 describing the limited cross-coupling activity of tertiary organoboron compounds. The de Meijere group reported that a (1-cyclopropylcyclopropyl)boronate underwent cross-coupling with a variety of aryl bromides and iodides in modest yield with no observable rearrangement of products, 76 while Wang and Kiefer demonstrated the alkylation of aryl iodides using tert-butyl-9BBN.77 The Molander group recently described a landmark report on the construction of achiral quaternary carbon centers through photoredox/nickel dual catalysis of tertiary organotrifluoroborate reagents, the most detailed description of tertiary boron nucleophiles in Suzuki−Miyaura cross-coupling to date.78 The seminal work of Aggarwal on the cross-coupling of tertiary propargylic boronic esters (Scheme 5) remains the sole example of stereospecific cross-coupling of a tertiary boron compound.30 While these reports offer an exciting entry into the field of tertiary cross-coupling, a general approach to the use of tertiary coupling partners in stereospecific cross-coupling remains elusive, and will surely be the focus of considerable research efforts in the coming years. In the meantime, stereospecific

proportions of water, utilizing the same organic solvent, temperature, and inorganic base. While differentiating between an aryl C−B bond and a chiral benzylic C−B bond may be unsurprising due to the substantial differences in reactivity between the two, the selective reaction of an aryl C−B bond in the presence of a reactive primary B−Csp3 bond is quite remarkable. Furthermore, the similarity of the conditions employed demonstrates the significant effect of carbon hybridization on C−B transmetalation rates. After filtration through a silica gel plug, the resulting benzylic boronic esters could be subjected to silver oxide-promoted cross-coupling conditions to generate the triarylated product 125 in moderate yield over the three-step sequence. A single regioisomer was prepared, demonstrating the highly chemoselective nature of the reaction sequence.20 Another orthogonal cross-coupling in which two boron substituents are sequentially cross-coupled without the use of protecting groups has been described by the Molander group.73 In this case, single electron-type transmetalation takes place through the use of photoredox/nickel dual catalysis (see Scheme 13) and selectively activates sp3-hybridized trifluoroborate salts (127) in the presence of sp2-hybridized boron reagents (126, Scheme 21).73 The former are more reactive Scheme 21. Iterative Cross-Coupling Using Photocatalysis73

under the classical two-electron transmetalation regime of palladium catalysis. Reaction of benzyl trifluoroborate salt 127 and brominated aryl boronic ester 126 under dual-catalytic cross-coupling conditions resulted in selective activation of the sp3-hybridized boronate, affording borylated diarylmethane 128. The pendant boronic ester functionality was preserved in this reaction, and no evidence of biaryl formation or oligomerization through sp2−sp2 cross-coupling was noted. It was further demonstrated that the aryl boronic ester moiety in 128 could undergo subsequent functionalization through Pd-catalyzed Suzuki coupling (129), oxidation, or Rhcatalyzed conjugate addition. Notably, MIDA boronates were also tolerated as inert sp2-hybridized boron reagents in this reaction, suggesting that this methodology may have further applications in the automated iterative synthesis previously reported by Burke.5

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OUTLOOK The field of stereospecific and stereoselective Suzuki−Miyaura cross-coupling has witnessed considerable advances in the past decade. However, several important problems remain unsolved. As described in this Perspective, secondary alkylboron reagents typically require activation from an adjacent functional group, 18135


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the Chemical Society-Perkin Transactions 1 2000, 1609−1613. (d) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 2000, 65, 9194−9200. (11) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198−7199. (12) Fang, G.-H.; Yan, Z.-J.; Deng, M.-Z. Org. Lett. 2004, 6, 357− 360. (13) Wang, X.-Z.; Deng, M.-Z. J. Chem. Soc., Perkin Trans. 1 1996, 2663−2664. (14) Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020−4028. (15) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130, 9257−9259. (16) van den Hoogenband, A.; Lange, J. H. M.; Terpstra, J. W.; Koch, M.; Visser, G. M.; Visser, M.; Korstanje, T. J.; Jastrzebski, J. T. B. H. Tetrahedron Lett. 2008, 49, 4122−4124. (17) Palchaudhuri, R.; Nesterenko, V.; Hergenrother, P. J. J. Am. Chem. Soc. 2008, 130, 10274−10281. (18) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024−5025. (19) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756−4758. (20) Crudden, C. M.; Ziebenhaus, C.; Rygus, J. P. G.; Ghozati, K.; Unsworth, P. J.; Nambo, M.; Voth, S.; Hutchinson, M.; Laberge, V. S.; Maekawa, Y.; Imao, D. Nat. Commun. 2016, 7, 11065. (21) Glasspoole, B. W.; Oderinde, M. S.; Moore, B. D.; Antoft-Finch, A.; Crudden, C. M. Synthesis 2013, 45, 1759−1763. (22) Li, J. Q.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774− 13777. (23) Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2015, 54, 846−851. (24) Glasspoole, B. W.; Ghozati, K.; Moir, J.; Crudden, C. M. Chem. Commun. 2012, 48, 1230−1232. (25) Chausset-Boissarie, L.; Ghozati, K.; LaBine, E.; Chen, J. L.-Y.; Aggarwal, V. K.; Crudden, C. M. Chem. - Eur. J. 2013, 19, 17698− 17701. (26) Denmark, S. E.; Werner, N. S. J. Am. Chem. Soc. 2010, 132, 3612−3620. (27) Potter, B.; Edelstein, E. K.; Morken, J. P. Org. Lett. 2016, 18, 3286−3289. (28) Yang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 10642− 10645. (29) (a) Ding, J.; Rybak, T.; Hall, D. G. Nat. Commun. 2015, 5, 5474. (b) Rybak, T.; Hall, D. G. Org. Lett. 2015, 17, 4156−4159. (30) Partridge, B. M.; Chausset-Boissarie, L.; Burns, M.; Pulis, A. P.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2012, 51, 11795−11799. (31) Matthew, S. C.; Glasspoole, B. W.; Eisenberger, P.; Crudden, C. M. J. Am. Chem. Soc. 2014, 136, 5828−5831. (32) (a) Bagutski, V.; French, R. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 5142−5145. (b) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778−782. (33) (a) Taylor, B. L. H.; Harris, M. R.; Jarvo, E. R. Angew. Chem., Int. Ed. 2012, 51, 7790−7793. (b) Shi, B. F.; Maugel, N.; Zhang, Y. H.; Yu, J. Q. Angew. Chem., Int. Ed. 2008, 47, 4882−4886. (c) Zhou, Q.; Srinivas, H. D.; Dasgupta, S.; Watson, M. P. J. Am. Chem. Soc. 2013, 135, 3307−3310. (d) Nambo, M.; Crudden, C. M. ACS Catal. 2015, 5, 4734−4742. (34) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem., Int. Ed. 2015, 54, 12134−12138. (35) Ohmura, T.; Awano, T.; Suginome, M. Chem. Lett. 2009, 38, 664−665. (36) Awano, T.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2011, 133, 20738−20741. (37) (a) Sandrock, D. L.; Jean-Gérard, L.; Chen, C.-y.; Dreher, S. D.; Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108−17110. (b) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894−899. (38) Smith, S. M.; Takacs, J. M. J. Am. Chem. Soc. 2010, 132, 1740− 1741. (39) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48, 6062−6064.

transition-metal-free couplings reported by the Aggarwal group of tertiary boronic esters with aryllithium reagents are a powerful alternative.6c Among the many challenges in the Suzuki−Miyaura reaction, stereoselective sp3−sp3 coupling reactions represents the final frontier in cross-coupling methodology.79 The development of such a method of carbon−carbon bond formation between an unactivated, enantioenriched sp3 boron reagent and an sp3 electrophile would afford unprecedented synthetic utility.

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Cathleen M. Crudden: 0000-0003-2154-8107 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This paper is dedicated to Howard Alper on the occasion of his 75th birthday. C.M.C. acknowledges the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding of the work from her laboratory described in this article. J.P.G.R. thanks NSERC, the Ontario Government and Queen’s University for funding.

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Enantiospecific and Iterative SuzukiâMiyaura Cross-Couplings

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