What Industrial Chemists WantâAre Academics Giving It to Them?

Review Cite This: Organometallics XXXX, XXX, XXX−XXX

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What Industrial Chemists WantAre Academics Giving It to Them? Colin Diner† and Michael G. Organ*,†,‡ †

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Centre for Catalysis Research and Innovation (CCRI) and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada ‡ Department of Chemistry, York University, 4700 Keele Street, Toronto M3J 1P3, Canada ABSTRACT: This perspective describes the formation of strategic partnerships between our academic laboratory and researchers at three major chemical organizations (the Dow Chemical Company, Eli Lilly and Company, and Abbvie Pharmaceuticals) to address fundamental aspects of Pd-mediated catalysis to prepare compounds of high importance to biomedical science. The paper chronicles the description of a synthetic problem, the evolution of the approach to solving this challenge, and the creation of methodologies and commercially available catalysts that not only are available to the teams mentioned herein but to all scientists worldwide. he “circle of life” for the development of synthetic methodology was once explained to me by a VP at Sigma-Aldrich as follows: “Academics get tax dollars to conduct research, they develop new technology that may be industrially useful, if it is companies adapt or develop it, and these companies have sales and pay salaries, all of which create tax dollars thereby completing the circle.” This philosophy would imply that academic research is quite arbitrary relative to the needs of those in our society who are most apt to put the outcomes to use. Historically speaking, “pure” academic research was indeed conducted for the most part in isolation from the potential uses of these studies by industry. In fact, many academics would frown upon research that had the “applied scent” on it. Some feel that the next big thing is more likely to come from pie in the sky research, not from the perceived to be incremental advancements associated with solving immediate industrial problems. Our group has worked closely with industry for more than two decades, which began with the premise that “a dollar will get you a dollar”. That is, we envisioned that we would agree to address very specific problems that a company was immediately facing with an equal ability for us to pursue anything that we wished. What we soon came to realize was that the two different pursuits, in fact, were not so different and that our company collaborators were interested in all of our projects. In retrospect, the reason for this should be selfevident. New products arising from the chemical industry, by and large, need to be just thatnew. More potent drugs, more efficient electronics, more durable materials, etc. all require chemical matter with ever-improving qualities. The ability to create a novel chemical architecture and then to manufacture it at scale is limited to what we currently know about assembling molecules. Therefore, industry is every bit interested in “pie in the sky” chemistry to boldly go (into chemical space) where no one has gone before, to quote one of my intellectual and creative heroes, Gene Roddenberry.

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In this perspective we will discuss some targeted case studies of catalysis projects where the impetus of the project originated with company collaborators that together with our team grew into a generalized program to more broadly address the assembly of interesting and relevant molecules using the power of catalysts developed in our laboratory (Figure 1). In 2012 a collaborative effort between Eli Lilly and Company and our research group was set in motion to develop bench-stable precatalysts capable of linking secondary alkyl fragments with (hetero)arenes in a highly regioselective manner. The Lilly team was a diverse one comprised of both medicinal (Michael Rodriguez) and process chemists (Michael Kopach, Yu Lu, and David Mitchell). The driving force behind this project was to boost the molecular complexity of the compound collection at Lilly, and increasing the C(sp3) content of molecules in that collection is generally viewed now as a good step in this direction.1 While cross-coupling has greatly empowered discovery chemistry in the pharma industry, the coupling of only C(sp2) centers has led to collections of relatively “flat” compounds that have by and large had less than desirable success in the clinic. The development of methodology to couple together not only primary but especially secondary alkyl centers2 could markedly improve the biomedical properties of drug candidates. A common issue in the cross-coupling reaction of secondary C(sp3) organometallic reagents with aryl (pseudo)halides is the formation of “rearranged” side products. These undesired regioisomers are a result of β-hydride elimination (BHE) from transmetalation (TM) intermediate 1 to form the olefincoordinated metal hydride complex 2 and, after reinsertion, the Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Received: November 6, 2018

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DOI: 10.1021/acs.organomet.8b00818 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

Figure 1. Pd-PEPPSI catalyst structures discussed in this article.

Scheme 1

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Organometallics Scheme 2

could prove fruitful here. Indeed, computational studies revealed an important trend in the relationship between ligand architecture and regioselectivity; groups on the ligand backbone (positions 4 and 5 on the imidazole) increase the rate of RE not through electronic effects (as would be expected for chlorines at these positions) but rather through sterics. Increasing the size of these substituents from H to Cl pushes the N-aryl groups on the NHC toward Pd and its organic fragments into closer proximity (Scheme 1c).5 This spatial intervention enhances the difference in activation energies (ΔΔE) between RE and BHE, favoring the former and significantly disfavoring the latter. While we had demonstrated the capability of Pd-PEPPSIIPentCl in the cross-coupling of secondary alkylzincs with sixmembered-ring (hetero)aryl halides,5 surprisingly and frustratingly, we found that trying the analogous couplings with fivemembered-ring heterocyclic OA partners led to predominantly rearranged products. 6 It is possible that the loss of regioselectivity in these couplings stems from the smaller bond angles of a five-membered ring, which leaves more room for the four-membered-ring BHE-TS as opposed to the threemembered-ring RE-TS (Scheme 2a). However, when the heteroatom in the OA partner was removed from indole, benzofuran, or benzothiophene to create the all-carbon analogue (i.e., indene), there was zero rearrangement, unlike the case for the first three, which all underwent significant rearrangement using Pd-PEPPSI-IPentCl. Consequently, contraction of the ΔΔE value of the Ar−Pd−alkyl intermediate seemed more likely due to the greater electron richness of these rings, which was even more troubling, as it is a more difficult ligand feature to build around or overcome. We hypothesized that increasing the steric bulk around the metal sufficiently could “force” the desired outcome of RE over MI in these five-membered-ring heterocyclic systems irrespective of electronic perturbations. Direct comparisons of IPent, IPentCl, IHept, and IHeptCl in the difficult Negishi coupling of i-PrZnBr with various 2- or 3-halogenated indoles,

rearranged side product 3 (Scheme 1a). This issue is best illustrated in the coupling between an isopropylzinc reagent, bearing the maximum and statistically unfavorable six βhydrogen atoms, and an electron-rich oxidative addition (OA) partner, which provides the marginally stabilized aryl Pd(II) intermediate 4 that is more reluctant to undergo reductive elimination (RE). The situation here is further exacerbated because isomerization/migratory insertion (MI) leads to a primary metal−alkyl intermediate that is energetically more stable than both the secondary metal−alkyl and olefincoordinated metal hydride. In 2009 the Buchwald group reported that the bulky dialkylbiarylphosphine ligand CPhos in conjunction with Pd(OAc)2 provided a catalytic system as one solution to this problem.3 In 2011 our group demonstrated that increasing steric bulk around the Pd center (from Pd-PEPPSI-IPr to PdPEPPSI-IPent) in 1 significantly enhances the branched to linear ratio in this difficult coupling by 1 order of magnitude (Scheme 1b).4 While the regioselectivity in this example was quite high, the substrate scope and regioselectivities for other acyclic secondary alkylzincs left room for improvement. Building on the principles that increasing the ligand’s steric bulk and that electron-withdrawing groups (on the ligand, the oxidative addition partner, or both) will increase the rate of RE relative to BHE, our team developed a new suite of Pd-PEPPSI precatalysts with different NHC architectures. Pd-PEPPSIIPentCl emerged as a highly reactive catalyst for the regioselective cross-coupling of a broad range of both cyclic and acyclic secondary alkylzincs under mild conditions with highly functionalized (hetero)aryl chlorides, bromides, and triflates.5 To assist in pinning down how ligand features translated into improved selectivity in this transformation, we drew on another existing industrial partner of the Organ group, the Dow Chemical Company. Dr. Robert Froese, a long-term collaborator, had developed a strong computational understanding of other catalysis projects, so we hoped that his skills C


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are predisposed to BHE, including secondary 2-heteroarylalkylzincs and cyclic allylzinc reagents. Recent collaborative efforts between our group and Drew Bogdan and Stevan Djuric at Abbvie have merged two formerly separate areas of our research, Pd-NHC catalysis and flow chemistry, into one project.9 Our ultimate goal was to enable efficient Negishi cross-couplings of secondary alkylzinc reagents with a durable and recyclable silica-supported PdPEPPSI-type catalyst.10 While Pd-catalyzed C−C bond forming reactions had been reported in flow, these were generally limited to C(sp2)−C(sp2) Suzuki reactions.11 Additionally, the heterogeneous and often biphasic nature of Suzuki reactions makes them less adaptable to flow chemistry than Negishi couplings. Initially we focused on the cross-coupling of primary alkylzinc reagents with aryl halides using an immobilized PdPEPPSI-IPr catalyst linked to silica particles through the nonlabile NHC moiety. By employing Furstner’s approach toward the synthesis of nonsymmetrical NHC ligands,12 we

benzothiophenes, and benzofurans gave a hint that our hypothesis was true, that chlorine substitution on the NHC with a simultaneous increase in the size of the alkyl chains on the N-aryl was necessary to reach the maximum desired impact. The reactions were complete within 1 h at low catalyst loading and appeared to enjoy the same functional group compatibility as our previously reported Negishi couplings.7 A more detailed investigation of this catalyst in Negishi couplings of secondary alkylzinc reagents established it to be a highly general system that works well with both five- and sixmembered-ring (hetero)aryl chlorides and bromides (Scheme 2b).8 The scope of electrophiles amenable to this crosscoupling reaction was extended to medicinally relevant heteroarenes such as free indoles, azaindoles, quinolones, pyrazoles, and isothiazoles. Notably, even 2,6-disubstituted OA partners could participate in this reaction at room temperature in 30 min. In like manner, the nucleophile scope was extended to alkylzincs bearing electrophilic esters (not compatible with organolithium or Grignard reagents) as well as reagents that D


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Scheme 5

(nonrearranged) products (Scheme 3b) under flow conditions. Highly congested o-biaryls were also accessible with this catalyst systemhighlighting the versatility of the Pd-PEPPSIIPent ligand framework in cross-coupling chemistry. Various control experiments were conducted in both of these studies to confirm that it was indeed the silica-supported NHC-bound catalyst that was effecting these transformations as opposed to Pd-NHC impurities reversibly adhering to the silica surface. As almost all drugs on the market contain at least one nitrogen atom, the development of highly efficient and selective methods for the creation of C−N bonds is of the highest priority in the pharmaceutical sector. Working in concert with Dow and Eli Lilly, we found that Pd-PEPPSIIPentCl was also an efficient catalyst for the monoarylation of primary alkylamines.13 The monoarylation of primary alkylamines is often plagued by “overarylation”, resulting in a significant amount of N,N-diarylalkylamine side products. This problem is a predictable result of the catalytic cycle (Scheme 4a) and rate-limiting step(s) for Buchwald−Hartwig (BH) reactions using NHC ligands. When an alkylamine is coupled

were able to append a terminal alkyne to one of the N-aryl moieties, paving the way for a copper-catalyzed click reaction to enable catalyst tethering to the silica support. The PEPPSIIPr-SiO2 catalyst was an effective catalyst for the cross-coupling of primary alkylzinc reagents with (hetero)aryl bromides and some activated chlorides. In our second generation of PEPPSI-type silica-supported catalysts, we targeted the IPent ligand scaffold due to its demonstrated ability to couple secondary alkylzincs with aryl halides.4 A slight variation of the Pd-PEPPSI-IPr-SiO2 catalyst preparation was utilized (Scheme 3a), commencing with imidazolium formation followed by salt metathesis, desilylation, a click reaction, and palladium ligation. Then, a two-step process anchoring the catalyst to the silica support and passivation of the silica surface provided Pd-PEPPSI-IPent-SiO2 with an approximately 0.1 mmol/g catalyst loading. This catalyst demonstrated superb reactivity (residence times as brief as 3.3 min) in the room-temperature crosscoupling of various secondary alkylzincs and deactivated (hetero)aryl halides with high selectivity for the branched E


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retrosynthetic reasons to approach them through N-arylation of a 2-aminopyridine intermediate.28 Again, we found that Pd-PEPPSI-IPentCl in conjunction with NaBHT (vide supra) was an ideal approach toward this class of molecules.29 A variety of N-aryl-2-aminopyridines, some with electrophilic functionalities and/or two heteroaromatic moieties, could be accessed in good yields (Scheme 5a). Almost as important as the reaction scope, we were able to confirm the hypothesis that it is the 2-aminopyridine motif in the products that poisons the catalyst in this pairing. This was done through some interesting physical organic experiments, including a dosing experiment that demonstrates the effect of increasing concentrations of a strongly coordinating N-aryl-2-aminopyridine on the efficiency of this reaction (Scheme 5b). In another study using the computational strength of Dow, we were able to effect very difficult BH cross-couplings under mild conditions between electron-deficient anilines and electron-rich (hetero)aryl chlorides.15 An example would be the reaction of pentafluoroaniline with 4-chloroanisole maybe at first glance a facile reaction given the above discussion, but this is far from true. Although deprotonation of the metal-bound amine is almost certainly rate limiting for NHC-Pd-catalyzed BH reactions of alkylamines,13 it is less clear if it is deprotonation or rather amine coordination when less basic/nucleophilic anilines are coupledfor electrondeficient anilines the latter appears more likely. With regard to the electrophile, using an electron-rich OA partner hampers essentially every step of the catalytic cycle. Also, while precatalyst activation is trivial for cross-couplings of organometallic reagents and alkylamines bearing β-hydrogens, it is nebulous how this process proceeds with anilines (Scheme 6a). A careful look into the effect of ligand architecure (IPr vs Ipent, H vs Me or Cl on the imidazole) and coupling yield early in the study hinted that the larger isopentyl groups and substituents on the ligand backbone were optimal for this type of coupling. Indeed, the aforementioned Pd-catalyzed coupling of pentafluoroaniline was achieved for the first time under relatively mild conditions (80 °C, carbonate base). We have previously posited that Pd is more electrophilic when the IPent ligand is ued (as opposed to IPr), most likely due to an elongated Pd−CNHC14 bond, and this effect could be accentuated by the electronegative chlorine substituents. Therefore, the active IPentCl catalyst is uniquely suited to

using carbonate as base, it is most likely the deprotonation step (Dep) of the catalytic cycle that is rate-limiting,14 not coordination (Coor), OA, or RE. Also, the pKa value of the Pd(II)−alkylammonium intermediate (ca. 8−10)15 is significantly higher than that of Pd(II)−anilinium (ca. 4);16 therefore, the product of alkylamine arylation (an aniline) is more reactive under typical BH conditions in comparison to the starting materiala classic kinetics conundrum. One approach for overcoming this problem is to employ bulky, electron-rich monodentate ligands such as NHCs (IPr(NMe2)2,17 IPr, SIMes, etc.18) or phosphanes (BrettPhos,19 cataCXium A20) that can often effectively use sterics to discriminate between the alkylamine starting material and the aniline product. Another approach is to use bulky, bidentate, and potentially hemilabile ligands (e.g., JosiPhos,21 the DalPhos family,22 and BippyPhos23) that are more inclined to bind and couple primary amines. A common theme among almost all of these catalytic systems is the requirement for aggressive and bulky bases such as KOt-Bu and LiHMDS. We hypothesized that the sterically hindered nature of PdPEPPSI-IPentCl in conjunction with a bulky base would be a suitable system for this task. When NaBHT was employed, this proved to be the case, with the added benefit of high functional group tolerance due to the mild and hindered nature of the phenolate anion (BHT pKa ca. 11). Indeed, the reaction was capable of coupling both five- and six-membered (hetero)aryl bromides and chlorides bearing sensitive functionalities, including enolizable ketones, esters, silyl ethers, and even azides at moderate temperatures (50−80 °C).13 Substitution of NaBHT with 2 equiv of LiHMDS even allowed the coupling of electrophiles bearing a Brønsted acidic functionality such as carboxylic acids, phenols, primary alcohols, and free indoles (Scheme 4b). N-Aryl-2-aminopyridines are valuable intermediates and targets for both the medicinal24 and materials chemistry25 communities. Access to this motif through otherwise broadly applicable BH conditions can be hampered due to catalyst poisoning by the product and/or starting material. In point of fact, multiple examples of 2-aminopyridine complexes with group 10 metals have been reported.26 While these motifs can often be reached from an aniline and a 2-halopyridine through a tactful choice of BH procedures,23,27 it is often desirable for F


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BH couplings discussed above,35 and the small size of the aniline products relative to N-substituted anilines making catalyst discrimination of starting material, product, and sideproduct even more difficult (Scheme 7a). Initial attempts using Pd-PEPPSI-IPentCl in conjunction with ammonia in dioxane were met with generally excellent conversions but low chemoselectivity for monoarylation.36 Increasing the ligand bulk from R = Et to R = n-Pr caused a slight increase in selectivity, while a further increase in alkyl chain length to n-Bu saw a dip in selectivity. Further enhancing bulk by branching Pd-PEPPSI-IHept Cl to Pd-PEPPSIDiMeIHeptCl(allyl)Cl, where R = i-Bu, now led to an impressive 40:1 preference for monoarylation (Scheme 7b). The scope of (hetero)aryl halides that can be aminated using this catalyst includes electron-rich and electron-deficient (hetero)arenes such as 2-mercaptobenzoxazole, pyridines, pyrimidines, pyridazines, and pyrazines. Of particular note was the high tolerance using these conditions for sensitive functional groups such as esters, nitriles, enolizable ketones, primary alcohols, and nitro groups. Conversions and selectivity for substrates with steric bulk around the site of oxidative addition (orthosubstituted haloarenes or 1-halonaphthalenes) were often equal to or better when Pd-PEPPSI-IPentCl was employed, presumably because the substrate now provided sufficient sterics to better discriminate the hindered aniline product from ammonia. The cross-coupling of primary and secondary amides with (hetero)aryl halides for the synthesis of N-(hetero)aryl amides is an appealing synthetic method, especially in medicinal chemistry, where the smorgasbord of commercially available and pharmacologically relevant (hetero)aryl halides can rapidly establish structure−activity relationships from synthetic amide intermediates. The clear value of this reaction has attracted

enable deprotonation and coordination of the less cooperative electron-deficient anilines. The last piece of the puzzle in reaching a room-temperature coupling was enabling facile catalyst activation. We had previously observed in C−S couplings (another situation where precatalyst reduction is not trivial30) that replacement of the 3-chloropyrdine precatalyst stabilizer with an o-picoline ligand could drastically lower the temperature at which coupling could proceed.31 The logic from our previous studies tracked well, and by employing Pd-PEPPSI-IPentCl-o-picoline we were able to perform the BH coupling of a range of electronrich chloroarenes with electron-deficient anilines at room temperature with Cs2CO3 (Scheme 6b). Our previous collaborative work with Eli Lilly on the monoarylation of alkylamines with Pd-PEPPSI-IPentCl led us to question if a similar problem could be solved with Pd-PEPPSItype catalyststhe amination of (hetero)aryl halides with ammonia. The direct coupling of ammonia, rather than an ammonia surrogate that must be further reacted to reveal the actual desired NH2 group, was desired by the Process Group at Lilly to improve efficiency and manufacturing environmental factor (E factor). This coupling has been a difficult hurdle in BH arylations for the same reasons that the monoarylation of primary alkylamines is difficult: i.e., overarylation (the aniline product is generally more reactive than ammonia). For this reason the same types of phosphane ligands employed in the monoarylation of alkylamines have also been used for the (hetero)arylation of ammonia (Josiphos,32 Mor-DalPhos,33 and dialkylbiarylphosphines34). Compounding issues when ammonia is coupled with (hetero)aryl halides include its ability to potentially displace phosphanes, shutting down catalysis, (L)PdArNH2 intermediates being less apt to RE than the corresponding (L)PdArNHR intermediates encountered in the G


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areas of high importance. This fertile, interdisciplinary assembly of computational, analytical, and synthetic chemists and engineers has come together to understand reactions at the molecular level and put this new knowledge to work to produce milligram to kilogram quantities of important compounds. This combination of academic and industrial chemists is a very cost effective and sustainable approach to solving problems of high importance to ensure the health, safety, and wellbeing of our society.

significant interest from the catalysis community, but it has only been in the past decade that broadly applicable catalytic systems have appeared.37 The main hurdle in developing this chemistry is avoiding stable κ2-amidate Pd complexes that can form under the reaction conditions and shut down catalysis.38 The use of bidentate23 or extremely bulky phosphane39 ligands that retard κ2-amidate formation has been a general approach toward overcoming this issue. In collaboration with the Eli Lilly team, we thought it prudent to investigate the applicability of Pd-PEPPSI-type catalysts with a large steric footprint to this reaction. PdPEPPSI-DiMeIHeptCl(cinnamyl)Cl in conjunction with a boron Lewis acid emerged as a highly active catalytic system for the (hetero)arylation of primary amides (Scheme 8a) under moderate reaction conditions (80−90 °C, carbonate base).40 While the role of boron Lewis acids in the cross-couplings of pyridine-type electrophiles with amides has been previously ascribed to coordination of the pyridine nitrogen to boron (lowering the electron density at Pd and enabling RE),41 in our system the Lewis acid appears to enable catalysis by forming boron amidate salts in the reaction mixture that more readily transmetalate to Pd (Scheme 8b). Thorough control studies were carried out as a part of this report (e.g., using radical scavengers TEMPO and galvanoxyl) to help rule out other mechanistic possibilities such as radical intermediates brought about by boron. In conclusion, it would appear that what industrial chemists want is indeed what all chemists wantthe best possible scientific outcome. The interactions of our academic group with a wide cross section of chemists in the materials science and pharmaceutical sectors, at both the discovery and process scales, has led to new catalysts42 and processes to assemble precious chemical matter for applications in a diverse array of

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AUTHOR INFORMATION

Corresponding Author

*E-mail for M.G.O.: [email protected]. ORCID

Michael G. Organ: 0000-0002-4625-5696 Notes

The authors declare the following competing financial interest(s): The PI and his team members receive royalty payments for the catalysts described in this manuscript.

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REFERENCES

(1) (a) Lovering, F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515. (b) Dandapani, S.; Marcaurelle, L. A. Current strategies for diversity-oriented synthesis. Curr. Opin. Chem. Biol. 2010, 14, 362. (c) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752. (2) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkylorganometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417. H


Review

Organometallics (3) Han, C.; Buchwald, S. L. Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2009, 131, 7532. (4) Ç alimsiz, S.; Organ, M. G. Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halides using Pd−PEPPSI− IPent. Chem. Commun. 2011, 47, 5181. (5) Pompeo, M.; Froese, R. D. J.; Hadei, N.; Organ, M. G. PdPEPPSI-IPentCl: A Highly Effective Catalyst for the Selective CrossCoupling of Secondary Organozinc Reagents. Angew. Chem., Int. Ed. 2012, 51, 11354. (6) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. The Selective CrossCoupling of Secondary Alkyl Zinc Reagents to Five-Membered-Ring Heterocycles Using Pd-PEPPSI-IHeptCl. Angew. Chem., Int. Ed. 2015, 54, 9502. (7) (a) McCann, L. C.; Organ, M. G. On The Remarkably Different Role of Salt in the Cross-Coupling of Arylzincs From That Seen With Alkylzincs. Angew. Chem., Int. Ed. 2014, 53, 4386. (b) McCann, L. C.; Hunter, H. N.; Clyburne, J. A. C.; Organ, M. G. Higher-Order Zincates as Transmetalators in Alkyl−Alkyl Negishi Cross-Coupling. Angew. Chem., Int. Ed. 2012, 51, 7024. (8) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Pd-PEPPSI-IHeptCl: A General-Purpose, Highly Reactive Catalyst for the Selective Coupling of Secondary Alkyl Organozincs. Chem. - Eur. J. 2016, 22, 14531. (9) (a) Ullah, F.; Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.; Organ, M. G. Scaling Out by Microwave-Assisted, Continuous Flow Organic Synthesis (MACOS): Multi-Gram Synthesis of Bromoand Fluoro-benzofused Sultams Benzthiaoxazepine-1,1-dioxides. Chem. - Eur. J. 2010, 16, 10959. (b) Shore, G.; Organ, M. G. GoldFilm-Catalysed Hydrosilylation of Alkynes by Microwave-Assisted, Continuous-Flow Organic Synthesis (MACOS). Chem. - Eur. J. 2008, 14, 9641. (10) Price, G. A.; Bogdan, A. R.; Aguirre, A. L.; Iwai, T.; Djuric, S. W.; Organ, M. G. Continuous flow Negishi cross-couplings employing silica-supported Pd-PEPPSI−IPr precatalyst. Catal. Sci. Technol. 2016, 6, 4733. (11) Mennecke, K.; Kirschning, A. Immobilization of NHC-Bearing Palladium Catalysts on Polyvinylpyridine; Applications in SuzukiMiyaura and Hartwig-Buchwald Reactions under Batch and Continuous-Flow. Synthesis 2008, 2008, 3267. (12) Fürstner, A.; Alcarazo, M.; César, V.; Lehmann, C. W. Convenient, scalable and flexible method for the preparation of imidazolium salts with previously inaccessible substitution patterns. Chem. Commun. 2006, 2176. (13) Sharif, S.; Rucker, R. P.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Froese, R. D. J.; Organ, M. G. Selective Monoarylation of Primary Amines Using the Pd-PEPPSI-IPentCl Precatalyst. Angew. Chem., Int. Ed. 2015, 54, 9507. (14) Hoi, K. H.; Ç alimsiz, S.; Froese, R. D. J.; Hopkinson, A. C.; Organ, M. G. Amination with Pd−NHC Complexes: Rate and Computational Studies on the Effects of the Oxidative Addition Partner. Chem. - Eur. J. 2011, 17, 3086. (15) Pompeo, M.; Farmer, J. L.; Froese, R. D. J.; Organ, M. G. Room-Temperature Amination of Deactivated Aniline and Aryl Halide Partners with Carbonate Base Using a Pd-PEPPSI-IPentClo-Picoline Catalyst. Angew. Chem., Int. Ed. 2014, 53, 3223. (16) Hoi, K. H.; Coggan, J. A.; Organ, M. G. Pd-PEPPSI-IPentCl: An Effective Catalyst for the Preparation of Triarylamines. Chem. Eur. J. 2013, 19, 843. (17) Zhang, Y.; César, V.; Lavigne, G. Efficient and Versatile Buchwald−Hartwig Amination of (Hetero)aryl Chlorides Using the Pd−PEPPSI-IPr(NMe2)2 Precatalyst in the Presence of Carbonate Base. Eur. J. Org. Chem. 2015, 2015, 2042. (18) (a) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. Amination Reactions of Aryl Halides with Nitrogen-Containing Reagents Mediated by Palladium/Imidazolium Salt Systems. J. Org. Chem. 2001, 66, 7729. (b) Broggi, J.; Clavier, H.; Nolan, S. P. NHeterocyclic Carbenes (NHCs) Containing N-C-Palladacycle Com-

plexes: Synthesis and Reactivity in Aryl Amination Reactions. Organometallics 2008, 27, 5525. (19) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. A Highly Active Catalyst for Pd-Catalyzed Amination Reactions: CrossCoupling Reactions Using Aryl Mesylates and the Highly Selective Monoarylation of Primary Amines Using Aryl Chlorides. J. Am. Chem. Soc. 2008, 130, 13552. (20) Tewari, A.; Hein, M.; Zapf, A.; Beller, M. Efficient palladium catalysts for the amination of aryl chlorides: a comparative study on the use of phosphium salts as precursors to bulky, electron-rich phosphines. Tetrahedron 2005, 61, 9705. (21) Shen, Q.; Ogata, T.; Hartwig, J. F. Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and Structure− Activity Relationships. J. Am. Chem. Soc. 2008, 130, 6586. (22) Lundgren, R. J.; Sappong-Kumankumah, A.; Stradiotto, M. A Highly Versatile Catalyst System for the Cross-Coupling of Aryl Chlorides and Amines. Chem. - Eur. J. 2010, 16, 1983. (23) Crawford, S. M.; Lavery, C. B.; Stradiotto, M. BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald−Hartwig Amination of (Hetero)aryl Chlorides. Chem. - Eur. J. 2013, 19, 16760. (24) Chen, W.; Zhan, P.; Rai, D.; De Clercq, E.; Pannecouque, C.; Balzarini, J.; Zhou, Z.; Liu, H.; Liu, X. Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays. Bioorg. Med. Chem. 2014, 22, 1863. (25) Araki, K.; Mutai, T.; Shigemitsu, Y.; Yamada, M.; Nakajima, T.; Kuroda, S.; Shimao, I. 6-Amino-2,2′-bipyridine as a new fluorescent organic compound. J. Chem. Soc., Perkin Trans. 2 1996, 2, 613. (26) Kempe, R. The Strained η2-NAmido−NPyridine Coordination of Aminopyridinato Ligands. Eur. J. Inorg. Chem. 2003, 2003, 791. (27) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.; Valente, C. PdCatalyzed Aryl Amination Mediated by Well Defined, N-Heterocyclic Carbene (NHC)−Pd Precatalysts, PEPPSI. Chem. - Eur. J. 2008, 14, 2443. (28) Rao, D. N.; Rasheed, S.; Aravinda, S.; Vishwakarma, R. A.; Das, P. Base and ligand free copper-catalyzed N-arylation of 2-amino-Nheterocycles with boronic acids in air. RSC Adv. 2013, 3, 11472. (29) Khadra, A.; Mayer, S.; Organ, M. G. Pd-PEPPSI-IPentCl: A Useful Catalyst for the Coupling of 2-Aminopyridine Derivatives. Chem. - Eur. J. 2017, 23, 3206. (30) Sayah, M.; Organ, M. G. Potassium Isopropoxide: For Sulfination It is the Only Base You Need! Chem. - Eur. J. 2013, 19, 16196. (31) Sayah, M.; Lough, A. J.; Organ, M. G. Sulfination by Using PdPEPPSI Complexes: Studies into Precatalyst Activation, Cationic and Solvent Effects and the Role of Butoxide Base. Chem. - Eur. J. 2013, 19, 2749. (32) Vo, G. D.; Hartwig, J. F. Palladium-Catalyzed Coupling of Ammonia with Aryl Chlorides, Bromides, Iodides, and Sulfonates: A General Method for the Preparation of Primary Arylamines. J. Am. Chem. Soc. 2009, 131, 11049. (33) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. A P. N-Ligand for Palladium-Catalyzed Ammonia Arylation: Coupling of Deactivated Aryl Chlorides, Chemoselective Arylations, and Room Temperature Reactions. Angew. Chem., Int. Ed. 2010, 49, 4071. (34) Cheung, C. W.; Surry, D. S.; Buchwald, S. L. Mild and Highly Selective Palladium-Catalyzed Monoarylation of Ammonia Enabled by the Use of Bulky Biarylphosphine Ligands and Palladacycle Precatalysts. Org. Lett. 2013, 15, 3734. (35) Klinkenberg, J. L.; Hartwig, J. F. Slow Reductive Elimination from Arylpalladium Parent Amido Complexes. J. Am. Chem. Soc. 2010, 132, 11830. (36) Lombardi, C.; Day, J.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Farmer, J. L.; Organ, M. G. Selective CrossCoupling of (Hetero)aryl Halides with Ammonia To Produce Primary Arylamines using Pd-NHC Complexes. Organometallics 2017, 36, 251. I


Review

Organometallics (37) Yin, J.; Buchwald, S. L. Palladium-Catalyzed Intermolecular Coupling of Aryl Halides and Amides. Org. Lett. 2000, 2, 1101. (38) Fujita, K.-i.; Yamashita, M.; Puschmann, F.; Alvarez-Falcon, M. M.; Incarvito, C. D.; Hartwig, J. F. Organometallic Chemistry of Amidate Complexes. Accelerating Effect of Bidentate Ligands on the Reductive Elimination of N-Aryl Amidates from Palladium(II). J. Am. Chem. Soc. 2006, 128, 9044. (39) (a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. PdCatalyzed Amidations of Aryl Chlorides Using Monodentate Biaryl Phosphine Ligands: A Kinetic, Computational, and Synthetic Investigation. J. Am. Chem. Soc. 2007, 129, 13001. (b) Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. Pd-Catalyzed NArylation of Secondary Acyclic Amides: Catalyst Development, Scope, and Computational Study. J. Am. Chem. Soc. 2009, 131, 16720. (40) Sharif, S.; Day, J.; Hunter, H. N.; Lu, Y.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Cross-Coupling of Primary Amides to Aryl and Heteroaryl Partners Using (DiMeIHeptCl)Pd Promoted by Trialkylboranes or B(C6F5)3. J. Am. Chem. Soc. 2017, 139, 18436. (41) Shen, Q.; Hartwig, J. F. Lewis Acid Acceleration of C−N BondForming Reductive Elimination from Heteroarylpalladium Complexes and Catalytic Amidation of Heteroaryl Bromides. J. Am. Chem. Soc. 2007, 129, 7734. (42) Precatalysts Pd-PEPPSI-IPentCl, Pd-PEPPSI-IHeptCl, and PdPEPPSI-DiMeIHeptCl(cinnamyl)Cl are all commercially available from Total Synthesis Ltd. (totalsynthesis.ca).

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