2016 Paul N. Rylander Award Address: Enabling Palladium

Article pubs.acs.org/OPRD

2016 Paul N. Rylander Award Address: Enabling Palladium/ Phosphine-Catalyzed Cross-Coupling Reactions for Practical Applications Work from the Organic Reactions Catalysis Society Meeting 2016 Anil S. Guram* Art of Elements, LLC, 1176 Tourmaline Drive, Thousand Oaks, California 91320, United States ABSTRACT: Cross-coupling reactions are beginning to find increasing utility in academia and industry. This article follows the 2016 Paul N. Rylander Award lecture at the 26th Organic Reactions Catalysis Society (ORCS) conference and provides summaries of our key contributions to the field of cross-coupling catalysis. KEYWORDS: Buchwald−Hartwig reaction, cross-coupling catalysis, high-throughput experimentation, oxidations, reductions, Suzuki−Miyaura reaction

1. INTRODUCTION

2. THE BUCHWALD−HARTWIG REACTION In 1983, the Migita group reported the reaction of aryl bromides with an amino-tin reagent in the presence of a palladium−phosphine catalyst to afford aryl amines.4 This was the first reaction to employ unactivated aryl halide substrates and a palladium/phosphine catalyst to form aryl amines. Unfortunately, however, this reaction was of limited utility because of access, stability, and handling concerns of the amino-tin reagents. The report described the use of only one N,N-diethylaminotributyltin reagent, and only N,N-diethylanilines were prepared; the reaction remained mostly unutilized and uncited for over a decade. Nonetheless, the prevalence of aryl C−N bond in organic compounds of significance to pharmaceutical, agrochemical, and electronic material industries prompted the Buchwald and Hartwig groups to undertake research efforts to understand and address the specific concerns of the Migita reaction and develop new and general methods for the catalytic conversion of aryl halides to aryl amines. To address the hydrolytic instability and handling concerns of the amino-tin reagents, the Buchwald group, in 1994, reported a clever transamination-Pd catalysis protocol (Scheme 1).5 In this protocol a single amino-tin reagent of a low boiling amine (N,N-diethylamine) was utilized and reacted with a variety different amines with concomitant removal of the low boiling amine to rapidly generate a variety of new amino-tin reagents. The new amino-tin reagents were then reacted without isolation with aryl bromides in the presence of palladium/phosphine catalyst to afford a variety of aryl amines. This significantly expanded the scope of the Migita reaction by allowing for diversity not only in the aryl fragment but also in the amine fragment. Slight improvement in yields were also observed most likely due to in situ use of the amino-tin reagents which precluded handling and quality deterioration issues of these unstable reagents. But, the overall concerns regarding the stability,

The cross-coupling reactions of nucleophiles with organic electrophiles in the presence of Group 8−11 metal catalysts, mostly based on copper, nickel, and palladium organometallic complexes, provide a powerful synthetic methodology for the construction of a wide range of C−C, C−N, C−O, C−H, C−P, C−S, and C−F bonds.1 The enormous academic and industrial significance of these reactions was validated by the 2010 Nobel Prize in chemistry to Prof. A. Suzuki, Prof. E. Negishi, and Prof. R. Heck. The palladium-catalyzed Suzuki−Miyaura C−C and Buchwald−Hartwig C−N cross-coupling reactions, in particular, are of substantial interest owing to the prevalence of the biaryl and arylamine units in industrially significant organic compounds. As such, these two reactions have been widely studied, developed, and utilized in both academia and industry. This article highlights our key contributions aimed at enabling these cross-coupling reactions for practical industrial applications. Specifically, this article provides brief summaries of our work, at various institutions, on the palladium-catalyzed C−N crosscoupling reactions leading to the invention of the Buchwald− Hartwig reaction, development of novel catalysts for enabling the practical utility of industrially relevant aryl chloride reactants in both these reactions, development of new alternative reactions based on cross-coupling strategies, and development of novel catalysts for Suzuki−Miyaura reactions of reactants of relevance to the synthesis of pharmaceuticals and electronic materials. It is to be noted that this article includes contents of our 2016 Rylander Award address at the 2016 ORCS Biennial Meeting and focuses mainly on our disclosable contributions to the field of cross-coupling catalysis. Discussions and citations of external contributions are limited to those contributions which were both influential and pertinent to us in the time period of our contributions. For a more comprehensive view of the subject topic, readers are encouraged to refer to our original articles and general key books and review articles on the subject topic.1−3 © 2016 American Chemical Society

Received: July 8, 2016 Published: September 28, 2016 1754

DOI: 10.1021/acs.oprd.6b00233 Org. Process Res. Dev. 2016, 20, 1754−1764

Organic Process Research & Development

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Scheme 1. Transamination-Pd/L Catalysis for the Conversion of Aryl Bromides to Aryl Amines

toxicity, and reaction processing arising from amino-tin reagents remained and were likely to continue to limit the future practical synthetic utility of this reaction. The elimination of the amino-tin reagent in this reaction required consideration of both empirical and mechanistic observations. The role of the amino-tin reagent, as proposed by the Migita group, was to effect the transmetalation step of the catalytic cycle in which the LnPd(II) (Ar)Br intermediate is converted to a LnPd(II) (Ar)NR1(R2) intermediate (Scheme 2). The mechanistic studies of the Hartwig group

Scheme 3. Tin-Free Pd/Phosphine-Catalyzed Conversion of Aryl Bromides to Aryl Amines

Scheme 2. Catalytic Cycle for Pd/P(o-Toluyl)3-Catalyzed Conversion of ArBr to ArNR1(R2)

Buchwald−Hartwig reaction. Today, the Buchwald−Hartwig reaction is one of the most popular cross-coupling reaction in academia and industry and has found utility for the preparation of many industrially significant intermediates to pharmaceuticals, OLEDs, fluorescent probes, PET agents, agrochemicals, and polymers.2

3. ARYL CHLORIDES AS REACTANTS IN CROSS-COUPLING REACTIONS Prior to 1997, cross-coupling reactions mostly employed aryl iodides or aryl bromides as electrophiles, and the reactions of aryl chlorides, in general, were limited to activated substrates (e.g., aryl chlorides substituted with electron-withdrawing groups). The general and productive cross-coupling reactions of aryl chlorides were slow to develop mainly because of difficulties in activation of the comparatively stronger C−Cl bond to oxidative addition and the lack of suitable catalysts. Nonetheless, the development of cross-coupling reactions of aryl chlorides was of significant interest because of cost, availability, and reactor productivity benefits of aryl chlorides compared to other aryl halides. Early efforts demonstrated the potential of Pd/phosphine catalysts based on existing electron-rich trialkylphosphine and related ligands for Buchwald−Hartwig reactions of aryl chlorides; however, the scope and efficiency of these reactions remained fairly limited.8 3.1. High Throughput Experimentation, Catalyst Discovery, and Catalyst Scope. To extend the industrial utility of cross-coupling reactions, we at Symyx utilized high-throughput

subsequently established that n = 1 in the key palladium− phosphine intermediates of the catalytic cycle particularly when L = tris(o-toluyl)phosphine (Scheme 2).6 The utility of aminoborane reagents to replace amino-tin reagents in these reactions was established by the Buchwald group.7a All of these findings and observations indicated the feasibility of alternative transmetalation pathways (Scheme 2) and eventually led the Buchwald and Hartwig groups to develop the tin-free Pd/phosphine-catalyzed reaction in which aryl bromides were reacted directly with amines in the presence of a suitable base to afford the desired aryl amines in high yields (Scheme 3).7 This was essentially the beginning of the Buchwald−Hartwig reaction. Since the original contributions, we and the groups of Buchwald, Hartwig, Beller, Nolan, Herrmann, Koie, Yamamoto, and Nishiyama among others have made many important contributions to this reaction.2 All of these contributions over many years have significantly improved the scope and utility of the 1755



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Scheme 4. Symyx Illustrative High Throughput Catalyst Discovery Tools

Scheme 5. Symyx Illustrative High Throughput Catalyst Discovery Workflow

Scheme 6. Illustrative Phosphine Ligand Library Synthesis and Members

tools and workflows that were developed and utilized. Advanced commercial versions of these HT methods continue to be utilized for catalyst discovery efforts in both academia and industry.

(HT) methods for the discovery and development of novel catalysts for cross-coupling reactions of aryl chlorides. Schemes 4 and 5 illustrates some of the Symyx high throughput catalyst discovery 1756



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The HT methods were utilized for syntheses of phosphine ligand libraries. The phosphine ligands bearing ortho-substituents were specifically targeted based on prior knowledge of beneficial influence of ortho substituents in catalysts for crosscoupling reactions (for e.g, the original phosphine ligand in Buchwald−Hartwig reaction employed the ortho methyl group substituted tris(o-toluyl)phosphine ligand). Scheme 6 illustrates some of the synthetic methods and phosphine ligands prepared in this study.9 Short and divergent synthetic methods from readily available compounds were generally utilized in the preparation of the phosphine ligand libraries. The HT methods were also utilized for screening of phosphine ligand libraries. The phosphine ligand libraries were screened using model Buchwald−Hartwig reactions to identify suitable catalysts and conditions (Scheme 7).9 The phosphine ligands A

Scheme 8. Illustrative Scope of Pd/Phosphine B Catalyst in the Buchwald−Hartwig Reaction

Scheme 7. Screening of Pd/Phosphine Catalysts Using Model Reactions

was minimized at lower temperatures or in the presence of excess of the primary alkyl amine. The Pd(dba)2/phosphine B catalyst was found to be equally efficient in catalyzing the Buchwald− Hartwig reactions of aryl bromides and iodides with secondary alkyl amines affording the desired aryl amines in high yields. Overall, these reactions belonged in the initial class of related reactions based on designer Pd/phosphine ligand catalysts to provide significant improvements in efficiency of the Buchwald− Hartwig reactions of aryl chlorides.10 The Pd/phosphine B catalyst was also found to exhibit broad scope for the Suzuki−Miyaura reactions of wide variety of aryl chlorides and aryl boronic acids (Scheme 9).11 Aryl chlorides and aryl boronic acids with both electron-withdrawing and electrondonating substituents, including ortho-substituents, participated effectively to afford the desired biaryls in high yields. The Pd(dba)2/phosphine B catalyst was found to be equally efficient in catalyzing the Suzuki−Miyaura reactions of aryl bromides and iodides with aryl boronic acids affording the desired biaryls in high yields. Overall, these and the concurrently reported reactions by others represent among the first examples of more general, mild, and efficient reactions for the utilization of aryl chlorides in Suzuki−Miyaura reaction.12,13 3.2. Mechanistic Studies of Phosphine Ligand Structure and Activity Relationships. The observed differences in catalyst performance of Pd/phosphine catalysts derived from seemingly similar phosphine ligands A and A′ were intriguing. Mechanistic studies revealed that the catalyst activity differences resulted due to unanticipated generation and involvement of structurally different Pd/phosphine catalyst intermediates with the two phosphine ligands. It was found and confirmed by

and B were found to afford the most efficient palladium/ phosphine catalysts for these reaction. The phosphine ligand A with phenyl groups on the phosphorus was found to provide efficient Pd/phosphine catalyst for the reactions of aryl bromides but was not effective for the reactions of aryl chlorides. The comparatively electron-rich phosphine ligand B with cyclohexyl groups on the phosphorus was found to provide efficient Pd/ phosphine catalyst for the reactions of both aryl bromides and chlorides. Many other phosphine ligands with similar ligand structures including the phosphine ligand A′ (vide infra) in which the Me group in phosphine ligand A was replaced with a H atom was notably found to be comparatively less efficient. The Pd(dba)2/phosphine B catalyst was found to exhibit broad scope for the Buchwald−Hartwig reaction of a wide variety of aryl chlorides and amines (Scheme 8).9 Aryl chlorides containing both electron-donating and electron-withdrawing substituents reacted efficiently with variety of secondary cyclic and acyclic alkyl amines to afford the desired aryl amines in high yields. These reactions were complete within 1 h, and only trace (99% selectivity to OTBN. The phosphine E, in particular, was found to exhibit a very high turnover number (TON) and frequency (TOF) (Scheme 12).

Scheme 9. Illustrative Scope of Pd/Phosphine B Catalyst for the Suzuki−Miyaura Reaction

Scheme 10. Solution Structures of Catalyst Intermediates with Different Phosphine Ligands

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Scheme 11. Solid-State Structures of Catalyst Intermediates with Different Phosphine Ligands

Scheme 12. Pd/Phosphine Catalysts for the Suzuki−Miyaura Reaction to OTBN

Scheme 13. Mechanistic Pathways in Pd/L-Catalyzed C−X Bond (X = N, O) Forming Reactions

In one reaction, catalyst and conditions were optimized to enable the use of chlorobenzene as an inexpensive oxidant for Pd/phosphine-catalyzed oxidation of alcohols (Scheme 14). Scheme 14. Pd/PCy2(Biaryl)-Catalyzed Oxidation of Alcohols

3.4. Alternative Reactions Based on Cross-Coupling Reactions of Aryl Chlorides. The hydrodehalogenation of the aryl halide electrophile is a common inefficiency observed in the in the Buchwald−Hartwig C−X (X = N, O) cross-coupling reactions of aryl halides with aliphatic amine and alcohol nucleophiles which contain a β-hydrogen atom. Mechanistically, as shown in Scheme 13, this inefficiency results when the LnPdII(Ar)(X− CH(R1)R2) catalytic intermediate undergoes the undesired βhydride elimination more rapidly than the desired reductive elimination to afford the LnPdII(Ar)H intermediate. The LnPdII(Ar)H intermediate then undergoes reductive elimination to afford the hydrodehalogenated aryl product with the regeneration of the LnPd0 intermediate. This observed inefficiency of cross-coupling reactions was explored using HT methods. HT methods were used to identify and develop catalyst and conditions that optimize this inefficiency and provide alternative and useful reactions.14

The oxidation reactions of cyclic and bicyclic secondary alcohols were found to proceed most efficiently to afford the industrially important ketones in high yields.15 The oxidation reactions of primary and secondary benzylic alcohols were also efficient affording the desired aldehyde and ketones in high yields. The oxidation of certain unhindered aliphatic alcohols and activated benzylic alcohols resulted in the formation of ester products in high yields. 1759



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Scheme 16. Synthesis of Illustrative New Pd/R1−Ar−PR2 Catalysts

In another reaction, catalyst and conditions were optimized to enable isopropanol (IPA) as an inexpensive reductant for Pd/phosphine-catalyzed hydrodechlorination of chlorinated aromatics.14 The reduction reactions of variety of chlorinated aromatics proceeded efficiently and selectively in the presence of the mild K2CO3 base resulting in the formation of the hydrodehalogenated products in high yields (Scheme 15). Scheme 15. Pd/PCy2(2,4,5-Tri-isopropyl-Ph)-Catalyzed Reduction of Halogenated Aromatics

The reduction of brominated aromatics was equally efficient. The hydrogen/hydride sensitive functional groups such as CC, −NO2, and −CO were compatible and unaffected under these mild reaction conditions. In general, a catalyst TON of 1000−2000 and faster reactions were observed in these reactions. Both the oxidation and reduction reactions were found to be influenced by the steric and electronic properties of the phosphine ligand, aryl halide, and alcohol reactants. In general, the oxidative addition of aryl chlorides required an electron-rich phosphine ligand; however the β-hydride elimination and reductive elimination appeared to be influenced by the combined steric properties of the phosphine ligand, aryl halide, and alcohol reactants. Sterically demanding phosphine were found to be suitable with smaller reactants and vice versa. Overall, the Pd/ligand-catalyzed oxidation and reduction reactions were similar to related non-O2 and non-H2/H−-based reactions but offered milder reactions conditions, higher efficiency, and/or wider scope.16,17 These reactions provide alternatives to traditional O2 and H2/H− based reactions and offer attractive options in situations where safety/hazard concerns, lack of capability, and/or substrate sensitivity issues preclude the use of traditional reactions. The concept of these reactions was also extended to direct conversion of aldehydes to esters and amides.18

employed in reactions involving heteroatom-containing reactants.21 In 2005, the Itoh group reported that DtBPF bisphosphine ligand [DtBPF = bis(di-t-butylphophino)ferrocene] afforded somewhat more efficient Pd/ligand catalysts for the reactions of heteroatom-containing reactants.20c The Itoh group also experimentally established that the state-of-the-art bulky monodentate phosphine ligands which provided efficient Pd/phosphine catalysts for efficient cross-coupling reactions of simple aryl reactants were more prone to displacement from the Pd center by heteroatom-containing reactants. Nonetheless, while DtBPF bisphosphine ligand provided some improvement in catalyst performance in these reactions, the catalyst TON and catalyst scope remained generally low. To extend the industrial utility of Suzuki−Miyaura reaction to heteroatom-substituted heteroaryl reactants, we relied on rational and iterative ligand design and synthesis strategy, which essentially focused on making ligands that were electronically similarly but sterically less bulky than the state-of-the-art bulky monodentate phosphine ligands. We found that reducing the bulk of the state-of-the-art monodentate phosphine ligands (such as PtBu3, PR2(biaryl) (R = Cy, tBu), and ligands A/B) either by replacing one of the alkyl groups of the trialkylphosphine ligands and/or removing the ortho-substituents in ortho-substituted dialkylarylphsophine ligands provided phosphine ligands which were less prone to displacement from the Pd center by the heteroatom-containing reactants. Thus, a variety of R1−Ar−PR2 ligands were prepared by Pd-catalyzed C−P bond forming reaction between readily available R−Ar−Br and HPR2 starting materials. To facilitate

4. SUZUKI−MIYAURA REACTIONS OF HETEROATOM-CONTAINING REACTANTS The increasing prevalence of heteroatom-substituted heterobiaryl units in biologically active compounds has made the Suzuki−Miyaura reaction of heteroatom-substituted heteroaryl chlorides/bromides and heteroaryl boronic acids very important and industrially desirable.19 Unfortunately, however, such reactions were rather inefficient due to the propensity of such heteroatom-containing reactants to bind and deactivate the palladium catalysts.20 Therefore, until about 2005, Suzuki− Miyaura reactions were limited to simple aryl halides and aryl boronic acids, and protection/deprotection strategies were 1760



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Scheme 17. Illustrative Scope of Catalyst H in Suzuki−Miyaura Reactions

handling, storage, and use, the air-stable L2PdCl2 complexes were prepared from the reaction of the new phosphine ligands with (COD)PdCl2 (Scheme 16).22,23 The performance of the new catalysts was explored for Suzuki−Miyaura reactions of heteroatom-containing reactants. While most of these catalysts were found to be less prone to deactivation by such substrates and generally exhibited superior performance to Pd/DtBPF catalyst for cross-coupling reactions of both aryl and heteroaryl reactants,24 the catalyst Pd−H was found to exhibit comparatively higher efficiency (TON, TOF, and selectivity) and scope. This catalyst was found to efficiently catalyze the Suzuki−Miyaura reactions of a variety of heteroatom-substituted six-membered aryl/heteroaryl chlorides with a diverse range of aryl/heteroarylboronic acids/esters (Scheme 17) to afford the desired products in high yields.25 A variety of electronic and steric variations as well as heteroatom-substituents on the reactants were well tolerated. Interestingly, it was observed that a variety of bases and solvents could be successfully employed in these reactions enabling many processing options for industrial applications. The reaction of 2-chlorobenzonitrile with p-tolylboronic acid was found to proceed to completion in the presence of only 0.01 mol % (TON 10 000) of catalyst Pd−H to afford the desired industrially significant intermediate, OTBN (o-tolylbenzonitrile), in high yield. The catalyst Pd−H was also found to efficiently catalyze the Kumada reaction of aryl/heteroaryl bromides with alkyl and aryl magnesium reagents (Grignard reagents) under very mild

Scheme 18. Illustrative Examples of Complex H-Catalyzed Kumada Reactions

conditions of low temperature to afford the desired products in high yields (Scheme 18). The functional groups such as chlorides, fluorides, and esters were found to be compatible under these mild reaction conditions. The catalyst Pd−H 1761



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Scheme 19. Illustrative 31P NMR Studies

Scheme 20. 31P NMR Studies of Catalytically Active Pd/Phosphine Intermediate

The unique utility of these new PdCl2{PR2(Ar-R1)} catalysts in catalyzing Suzuki−Miyaura and related cross-coupling reactions was investigated and understood by 31P NMR studies of phosphine ligand H in comparison to the previous state-ofthe-art phosphine ligands. As anticipated, the propensity of phosphine ligand H to be less prone to displacement from the Pd

was found to be similarly effective in catalyzing the related Negishi reactions with organozinc reagents. Notably, the Negishi reactions of NH2-substituted heteroaryl chlorides with alkylzinc reagents could be performed at remarkably low catalyst loadings (0.4 mol % catalyst Pd−H in the presence of added ZnCl2). 1762



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center leading to catalyst loss was clearly evident by 31P NMR spectroscopy (Scheme 19). The Scheme 19 shows series of 31 P NMR spectra of an illustrative o-R-PhPCy2 ligand (e.g., ligand B on left) and the phosphine ligand H (on the right). The 31 P NMR spectra labeled I show the resonance of the free phosphine ligand. The 31P NMR spectra labeled II show the downfield-shifted resonances of the phosphine ligands bound to the Pd metal center consistent with coordination of the phosphine ligand to the metal center. The 31P NMR spectra labeled III show the resonances present after addition of excess of 2-aminopyrimidine (APY). In the case of the previous state-ofthe-art phosphine ligand, only one phosphine resonance corresponding to an unbound phosphine is observed which is indicative of complete displacement of the phosphine ligand from the Pd center potentially leading to complete loss of the palladium/phosphine intermediates. In the case of phosphine ligand H, three phosphine resonances corresponding to catalyst Pd−H, free phosphine ligand H, and a new resonance corresponding to a mixed PdCl2(H)(APY) species in 1:1:1 ratio were observed indicative of potentially no loss of the palladium/ phosphine intermediates. The related 31P NMR studies of (H)2Pd(Ar)Br intermediate in the presence of an excess of APY conclusively established that displacement of the phosphine ligands bound to the Pd center also does not occur in catalytically relevant Pd/phosphine intermediates based on phosphine ligand H even at elevated temperatures (Scheme 20). Thus, the monodentate phosphine ligands in the new catalyst were found to be less readily displaced from the Pd metal center by the heteroatom-containing reactants compared to the previous state-of-the-art monodentate phosphine ligands. This unique stability to heteroatom-containing reactants most likely contributes to the unique utility of these catalysts for efficient C−C cross-coupling reactions of such reactants. It is therefore not surprising that these catalysts have attracted enormous interest and utility as catalysts of choice for cross-coupling reactions of interest to both academia and industry. In the academic setting, these catalysts have most notably used in PTC (phase transfer catalysis) cocatalyzed aqueous phase crosscoupling reactions as well as the development of reactions other than cross-coupling reactions involving heteroatom-containing reactants.26 In the industrial setting, these catalysts have most notably been used in the preparation of intermediates to many APIs (including Ledipasvir, one of the two active ingredients of Gilead’s Harvoni) as well as various electronic materials.27

high catalyst TON, selectivity, and scope in these reactions is important from both economic and ecologic viewpoints. We at Art of Elements, LLC focus on our core competencies in industrial catalysis (including catalyst design and synthesis), process chemistry, and high throughput experimentation to develop and offer innovative services and products to industry clients interested in improving the efficiencies of their crosscoupling and other metal-catalyzed reactions and processes.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The author declares no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

Parts of this material are based upon work supported by the National Science Foundation under Grant No. 1621126. A.S.G. is truly grateful to the entire ORCS organization and BASF (sponsor) for the 2016 Paul N. Rylander Award. A.S.G. is indebted to his academic advisors, Prof. Richard F. Jordan (University of Chicago) and Prof. Stephen L. Buchwald (MIT), for support, education, and training in organometallic chemistry and catalysis. A.S.G. is thankful to all his co-workers and colleagues at Syracuse University, University of Iowa, MIT, Union Carbide, Symyx, and Amgen for an enjoyable, educational, and stimulating scientific environment. A.S.G. is particularly thankful to Dr. Alan M. Allgeier (Sr. Principal Scientist, DuPont), Dr. Anthony F. Volpe, Jr. (Head of R&D Center, Clariant), Dr. Jason S. Tedrow (Scientific Director, Amgen), Dr. Shawn D. Walker (Director, Amgen), Krishnakumar Ranganathan (Scientist-2, Teva), Dr. Xiang Wang (Sr. Research Scientist, Gilead), and Dr. Jinkun Huang (CEO, Xiling Lab) for their support in recent efforts. A.S.G. thanks Dr. Kai Rossen (Editorin-Chief, OPR&D) and OPR&D for the opportunity to publish this work in OPR&D.

(1) (a) Applied Cross-Coupling Reactions; Nishihara, Y., Ed.; Springer: New York, 2013. (b) Cross-Coupling Reactions. A Practical Guide. In Topics in Current Chemistry; Miyaura, N., Vol. Ed.; Springer: New York, 2002; Vol. 129. (c) de Vries, J. G. Palladium-Catalyzed Coupling Reactions. In Organometallics as Catalysts in the Fine Chemical Industry, Topics in Organometallics Chemistry; Beller, M., Blaser, H.-U., Eds.; Springer-Verlag: Berlin, 2012, Vol. 42; pp 1−34. (2) For recent reviews on Buchwald−Hartwig reaction, see (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27−50. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534−1544. (c) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23−29. (d) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599−1626. (3) For recent reviews on the Suzuki−Miyaura reaction, see (a) Maluenda, I.; De Navarro, O. Molecules 2015, 20, 7528−7557. (b) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270−5298. (c) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419−2440. (d) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176−4211. (f) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633−9695. (g) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359−1470. (4) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 12, 927− 928.

5. FORWARD VIEW The cross-coupling reactions have emerged as simple, versatile, and dominant synthetic methods for the construction of many organic compounds of interest to academia and industry. The Suzuki−Miyaura, Negishi, Kumada, and Buchwald−Hartwig reactions in particular are likely to gain increased utility due to increasing need, awareness, and improvements in these reactions. While significant research and development efforts have greatly enabled these reactions for practical industrial applications, many significant challenges remain. High catalyst loadings are still utilized in many industrial cross-coupling processes and particularly those involving challenging heteroatom-containing reactants. Some of these processes also suffer from selectivity issues. The need to access certain classes of compounds directly using these reactions also remains. Also, oftentimes less than optimum catalysts and conditions are chosen and utilized in industrial processes because of lack of one universally effective catalyst system for these reactions. Addressing these needs for 1763



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2016 Paul N. Rylander Award Address: Enabling Palladium

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