Bisphosphines: A Prominent Ancillary Ligand Class for Application in

Jun 20, 2018 - The Ni-catalyzed Csp2-N cross-coupling of NH substrates and (hetero)aryl (pseudo)halides for the synthesis of (hetero)anilines is in th...
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Bisphosphines: A Prominent Ancillary Ligand Class for Application in Nickel-catalyzed C-N Cross-coupling Christopher M. Lavoie, and Mark Stradiotto ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01879 • Publication Date (Web): 20 Jun 2018 Downloaded from http://pubs.acs.org on June 20, 2018

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Bisphosphines: A Prominent Ancillary Ligand Class for Application in Nickel-catalyzed C-N Cross-coupling Christopher M. Lavoie and Mark Stradiotto* [email protected] Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax, Nova Scotia, Canada, B3H 4R2

ABSTRACT: The Ni-catalyzed Csp2-N cross-coupling of NH substrates and (hetero)aryl (pseudo)halides for the synthesis of (hetero)anilines is in the midst of a resurgence. Reactivity breakthroughs that have been achieved in this field within the past five years have served to establish Ni catalysis as being competitive with, and in some cases superior to, more wellestablished Pd- or Cu-based protocols. Whereas the repurposing of useful ancillary ligands from the Pd domain has been the most frequently employed approach in the quest to develop effective Ni-based catalysts for such transformations, considerable progress has been made as of late in the design of ancillary ligands tailored specifically for use with Ni. Bisphosphine ancillary ligands have proven to be well-suited for such an approach, given their modular and facile syntheses; several variants have emerged recently that are particularly effective in enabling a range of otherwise challenging Ni-catalyzed Csp2-N cross-couplings. This Perspective presents a comprehensive summary of the advancements within the field of Nicatalyzed Csp2-N cross-coupling through the application of the bisphosphine ancillary ligand class. It is our intention that the discussion of key ancillary ligand design concepts and mechanistic considerations presented herein will provide a useful platform for researchers to initiate ancillary ligand design efforts for the development of high-performing Ni cross-coupling catalysts. KEYWORDS: nickel, C-N cross-coupling, ligand design, bisphophines, anilines

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1. INTRODUCTION The palladium-catalyzed Csp2-N cross-coupling (herein C-N) of NH substrates and (hetero)aryl (pseudo)halides (i.e., Buchwald-Hartwig Amination, BHA) represents a widely employed method, along with Chan-Lam coupling, for the synthesis of (hetero)anilines, with applications in the preparation of natural products, pharmaceuticals, functional materials, and beyond.1-7 The rapid evolution of BHA chemistry over the past two decades is due in large part to advances in ancillary ligand and pre-catalyst design,8-11 which afforded generalized protocols devoid of salient limitations associated with early precursors to BHA chemistry (e.g., the use of toxic tin amido reagents, limited functional group compatibility, and elevated reaction temperatures). The development of broadly useful ligand classes for application in BHA was guided by extensive mechanistic analysis, wherein the preponderance of empirical data led to the identification of sterically demanding, relatively electron-rich ancillary ligands as being optimal (Figure 1).12-14 These ancillary ligand characteristics promote the formation of electronrich, low-coordinate LnPd0 species that are pre-disposed towards challenging oxidative additions (e.g., Csp2-Cl). Prominent ancillary ligand classes adhering to these basic design principles include trialkylphosphines (e.g., PtBu3 (L1),15 cataCXium A (L2),16), (hetero)biaryl monophosphines (e.g., RuPhos (L3),13,

17

BrettPhos (L4),17 BippyPhos (L5),18-19), large bite

angle bisphosphines (e.g., XantPhos (L6),20 CyPF-tBu JosiPhos (L7),21-23 dppf (L8),24-25), mixed P,N donors (e.g., Mor-DalPhos (L9),26-29 Me-DalPhos (L10),30), and sterically demanding Nheterocyclic carbenes (NHCs) (e.g., IPr (L11), IMes (L12),31-32),33 which collectively give rise to Pd catalysts capable of promoting the cross-coupling of a broad spectrum of synthetically useful (hetero)aryl electrophiles and NH reagents.

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Figure 1. Prominent bulky, electron-rich ligands used in BHA chemistry. Notwithstanding the broad impact of BHA in synthetic chemistry, both cost and supply limitations of Pd have steered research efforts in the direction of more sustainable amination methodologies that utilize inexpensive, non-precious metals. Among such metals, catalysts based on Ni, Cu, and Fe have each proven effective in enabling C-N cross-coupling (Figure 2). However the scope of compatible reaction partners and mild reaction conditions enabled by use of Ni catalysts currently far exceeds that of Cu34-40 or Fe38, 41-44 catalysts, making Ni the most promising substitute for Pd in such reactions.

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Figure 2. Approaches to metal-catalyzed C-N cross-coupling, and the focus of this review. Beyond the significant cost benefits associated with using Ni in place of Pd, the reactivity profile of Ni can provide useful advantages in cross-coupling chemistry.45-46 For example, the relatively low electronegativity of Ni serves to enhance reactivity with sought-after (hetero)aryl chlorides and phenol derivatives (e.g., ethers, tosylates, mesylates, triflates, sulfamates, etc.),46 which are comparatively less reactive electrophiles under BHA conditions. Furthermore, the expanded range of readily accessible oxidation states (commonly 0 to III),45-46 and greater propensity for single-electron transfer (SET) for Ni leads to an inherently more complex, but potentially useful, mechanistic landscape versus Pd. Whereas Pd0/PdII cycles involving 2e− elementary steps are commonly observed in BHA,14 the situation is much less clear in the case of Ni. Whereas both Ni0/NiII

47-50

and NiI/NiIII

50-52

catalytic cycles have been invoked in Ni

variants of BHA (Figure 3), the existence of elementary processes that link these manifolds (e.g., comproportionation, disproportionation, and SET) creates ambiguity regarding the dominant operative mechanism of catalysis. In fact, the tendency of Ni species to engage in SET processes has been exploited by pairing Ni catalysts with photosensitizers (e.g., [Ir(dtbpy)3]3+, dtbpy = 4,4’-di-tert-butyl-2,2’-dipyridyl),53 which are presumed to facilitate 5 ACS Paragon Plus Environment

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otherwise challenging cross-couplings (e.g., Csp2-N,54 Csp2-O,55 Csp3-Csp256) by modulating the oxidation state of Ni.

Figure 3. A comparison of palladium- and nickel-catalyzed C-N cross-coupling. Given the inherent advantages associated with using Ni in place of Pd, it is surprising that Ni has received comparatively little attention in C-N cross-coupling over the past two decades. The potential for more diverse reactivity and a broader range of accessible oxidation states undoubtedly discouraged Ni catalyst development, thereby contributing in part to the preferential study of Pd catalysts for C-N cross-coupling. Indeed, the complex reactivity characteristics of Ni complicate mechanistic analysis of such catalyst systems, rendering the identification of key ancillary ligand design criteria, and thus the development of highperforming Ni catalysts, rather problematic.57 In the face of these challenges, chemists have routinely defaulted to repurposing ligands that function well in BHA chemistry as a means of developing new Ni-based amination protocols – an approach that is predicated on the assumption that Ni catalysis is governed by Pd-like mechanisms (e.g., a Pd0/PdII cycle), with analogous rate-limiting steps (e.g., oxidative addition). This strategy has proven somewhat effective for the cross-coupling of a limited selection NH substrate/electrophile pairings, with Ni catalysts based on PPh3,58 IPr,59-64 JosiPhos,49, 65-67 dppf,66, 68-73 BINAP47-48 and DPEPhos,74 each exhibiting useful performance. Nonetheless, given the frequent failure of prominent ancillary ligands from the BHA domain in enabling more challenging Ni-catalyzed C-N crosscouplings involving sought after NH substrates, and in consideration of the divergent properties of Ni versus Pd, it is unlikely that repurposing BHA ligands will be a universal solution for 6 ACS Paragon Plus Environment

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developing superlative Ni catalysts for C-N cross-coupling. Consequently, the tremendous potential of Ni in C-N cross-coupling catalysis will remain untapped until our understanding of the mechanistic landscape of Ni-catalyzed C-N cross-coupling, and the influence of ancillary ligation on the elementary steps therein, rivals that of BHA chemistry. 1.1. Scope of Perspective The aim of this Perspective is to highlight major recent advances made within the burgeoning field of Ni-catalyzed C-N cross-coupling, with an emphasis on the discussion of ancillary ligand classes that have proven particularly useful in enabling highly effective catalysts. Notwithstanding the utility of NHCs,59-63,

75-84

monophosphines,85-86 bipyridines,87-90

and various other91-92 ancillary ligand classes, we focus our discussion herein on reports in the academic literature featuring the application of bisphosphine ancillary ligands, appearing up to the end of April 2018. Along with NHCs, bisphosphines have emerged as ‘best-in-class’ ancillary ligands in a diversity of Ni-catalyzed C-N cross-couplings (Figure 2); however, whereas the application of NHCs in such transformations has been comprehensively documented elsewhere,64 a review devoted to documenting the major synthetic advances enabled by use of bisphosphine-ligated Ni catalysts, including recent mechanistic insights gained, has yet to appear. In highlighting key ligand design concepts, we hope to inform the further development of useful ancillary ligands with applications in the field of Ni-catalyzed C-N cross-coupling and beyond. An excellent overview of the development of Ni-catalyzed C-N cross-coupling chemistry has been published by Nicasio and co-workers.93 For guidelines pertaining to the design of Ni cross-coupling catalysts by minimizing off-cycle species, please see a very recent Perspective by Balcells and Nova.57 Finally, given that the benefits of employing appropriately designed Ni pre-catalysts is a recurring theme in this Perspective, readers are directed to a review in this area by Hazari and co-workers.10

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2. ANCILLARY LIGANDS Ni-CATALYZED C-N CROSS-COUPLING: A BRIEF OVERVIEW To provide context for the main discussion of this Perspective regarding the application of bisphosphine ancillary ligands in Ni-catalyzed C-N cross-coupling (Section 3), a brief overview of other prominent ligand classes employed in such transformations is given below. 2.1. Chelating N,N-Donor Ligands The field of Ni-catalyzed C-N cross-coupling employing aryl chlorides was initiated in 1997, when Wolfe and Buchwald68 reported the cross-coupling of electronically varied electrophiles with selected primary and secondary amines, enabled by use of in situ generated Ni catalysts based on dppf (L8) or 1,10-phenanthroline (phen), and employing sodium tert-butoxide as the base. While L8 has since been exploited in a plethora of Ni cross-couplings (e.g., selected examples: Csp2-N,66, 69-70 Csp2-Csp2,94-95 Csp2-SCF3,96-97 Csp2-CF2H,98 Csp2-CN99; the utility of L8 in C-N cross-coupling is described more fully in Section 3.1 of this Perspective), chelating N,Ndonor ligands (e.g., phen,68 3,5,6,8-tetrabromo-1,10-phenanthroline,87 and bipyridine88-89 (bpy)) have seen limited use in Ni-catalyzed C-N cross-coupling since the mid 2000s. This is despite the fact that Wolfe and Buchwald68 observed that the use of phen in place of L8 in some crosscouplings led to improved reactivity and selectivity. Recently there has been considerable interest in the use of Ni catalysts supported by such N,N-donor ligands in the context of metallophotoredox-enabled cross-coupling applications.53 2.2. Monodentate Phosphines Despite figuring prominently in BHA chemistry, monophosphine ancillary ligands including some of those featured in Figure 1 have generally proven inferior to bisphosphines in challenging Ni-catalyzed C-N cross-couplings (e.g., ammonia monoarylation100). Among the useful Ni amination catalysts based on monophosphines that have been reported, most feature simple ligands such as PPh3101 or PMe3,86 and in no cases do such catalysts represent the state-of-the-art. It is unclear as to why monophosphines that perform well in BHA are generally 8 ACS Paragon Plus Environment

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ineffective in Ni-catalyzed C-N cross-couplings. However, the enhanced stability of Ni complexes supported by chelating bisphosphines presumably plays an important role in suppressing catalyst deactivation pathways, which are likely more prevalent in Ni chemistry versus Pd (vide supra).57 For example, recent computational analyses conducted by Maseras and co-workers102 predicts that halide abstraction is competitive with aryl halide oxidative addition for complexes of the type Ni(PMenPh(3-n))4, thus providing a direct route to paramagnetic intermediates (e.g., NiI, NiIII), which may diminish catalytic activity under circumstances where a product-forming Ni0/NiII cycle is operative. It is noteworthy, however, that well-defined Ni coordination complexes supported by monophosphines, including [Ni(PPh3)2Cl2]60,

101

and [Ni(PPh3)2(1-naphthyl)Cl],62,

103

can serve as useful pre-catalyst

precursors, wherein the target pre-catalyst may be obtained via PPh3 substitution with a desired ancillary ligand. 2.3. N-Heterocyclic Carbenes (NHCs) In contrast to monophosphine ligands, NHCs have proven highly effective in enabling both Pd- and Ni-catalyzed C-N cross-coupling chemistry. The seminal report of such Ni-catalyzed aminations utilizing NHC ancillary ligation was disclosed by Fort and co-workers in 2001,104 wherein the coupling of (hetero)aryl chlorides with anilines and secondary cyclic and acyclic amines was enabled by employing mixtures (1:4) of Ni(acac)2 and SIPrHCl (SIPr = 1,3-bis(2,6diisopropylphenyl)dihydroimidazol-2-ylidene), in the presence of NaH and t-BuOH. Tremendous progress has been made since, and Ni catalysts based on NHCs have been shown to promote cross-couplings of a broad spectrum of both (hetero)aryl electrophiles (chlorides,59, 75, 77-78, 80, 84, 105

, bromides,60 tosylates,61,

103, 106

, phosphates,62 pivalates,63 methyl ethers,79 carbamates,82

and sulfamates83), and NH reagents (primary62, anilines,61,

75, 77, 82, 106

82, 106

and secondary amines,61-63,

75, 77-79, 82

hydrazones,60 indole,59 and carbazole59). A common feature of highly

effective amination protocols of this type is the application of well-defined Ni pre-catalysts (e.g., 9 ACS Paragon Plus Environment

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[Ni(NHC)CpCl],75, [Ni(NHC)(allyl)Cl],77 [Ni(NHC)(styrene)2],59, 61 etc.). This has proven to be a superior approach to catalysis, relative to in situ catalyst generation via ligand exchange between a Ni source (e.g., Ni(acac)2, Ni(cod)2, etc.) and the NHC. While only limited mechanistic data pertaining to Ni-catalyzed C-N cross-couplings employing NHC ancillary ligation are available, current literature findings implicate a Ni0/NiII cycle analogous to that proposed for BHA, involving oxidative addition, amine binding and deprotonation, and product forming C-N reductive elimination;78, 80, 103, 107 the last of these steps has been predicted to be rate-limiting for the cross-coupling of aryl carbamates with secondary amines on the basis of DFT analysis.108 Complementary mechanisms involving a NiI/NiIII cycle have also been postulated51 when employing mononuclear, Y-shaped NiI(NHC)X pre-catalysts. In these systems it is proposed that initial amine binding and HX loss, followed by aryl halide oxidative addition to the resultant [NiI(NHC)(amido)] intermediate, and subsequent product-forming C-N reductive elimination from a [NiIII(NHC)(Ar)(amido)X] species occurs. 3. BISPHOSPHINE LIGANDS FOR ENABLING Ni-CATALYZED C-N CROSS-COUPLING Whereas electron-rich, sterically demanding monodentate phosphines (e.g., L1-L5; Figure 1) currently represent some of the most effective ancillary ligands known for application in BHA, these ligands often perform poorly when applied in Ni-catalyzed C-N cross-coupling. Conversely, building on the pioneering 1997 report by Wolfe and Buchwald68 regarding the use of dppf (L8), several other bisphosphines repurposed from BHA chemistry have proven effective for such Ni-catalyzed transformations, including BINAP (L13), DPEPhos (L14), and variants of JosiPhos (L15-L17), with most reports of this type appearing within the past five years (Figure 4). A less well-developed, yet highly effective approach in the pursuit of useful Ni C-N cross-coupling catalysts has involved the rational development of ancillary ligands specifically tailored for use with Ni, including ortho-phenylene bisphosphines (L18-L22; Figure 4) such as PAd-DalPhos (L18). Collectively, such studies involving both repurposed and new 10 ACS Paragon Plus Environment

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bisphosphines have enabled the identification of high-performing Ni catalysts for C-N crosscoupling, while also laying the groundwork for establishing an understanding of the mechanistic landscape associated with such transformations.

Figure 4. Bisphosphine ancillary ligands featured in this Perspective (PS = polystyrene, R = para-tert-butyl).

3.1. 1,1′-Bis(diphenylphosphino)ferrocene (dppf)

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As alluded to earlier in this document, the breakthrough 1997 report by Wolfe and Buchwald68 is commonly viewed as having established Ni-catalyzed C-N cross-coupling as a bona fide synthetic approach, especially given that aryl chloride electrophiles, which are considerably less reactive under BHA conditions, were employed successfully. While many of the ligands from the field of BHA performed poorly in test Ni cross-coupling reactions (e.g., BINAP, dppp, dppe, PPh3, P(o-tolyl)3), the chelating ferrocenyl bisphosphine dppf (L8) was found to be highly effective when used in conjunction with Ni(cod)2. Application of the Ni(cod)2/L8 catalyst system enabled the cross-coupling of electronically diverse aryl chlorides with primary or secondary amines in synthetically useful yields, when conducting reactions at elevated temperatures (70-100 oC) in the presence of sodium tert-butoxide (Scheme 1). Notably, the chelating N,N-donor ligand 1,10-phenanthroline (phen), which is not generally effective under BHA conditions, outperformed the Ni(cod)2/L8 catalyst system in select substrate pairings, affording higher product yields and lower quantities of reduced arene byproduct. Nonetheless, reactions involving phen required higher catalyst loadings than those featuring L8 (5% vs. 2%). In an effort to circumvent the use of air-sensitive Ni(cod)2 as a catalyst precursor, Wolfe and Buchwald employed air-stable pre-catalysts of the type [NiCl2(L8)] (C1), in conjunction with catalytic quantities of MeMgBr as a reducing agent; such mixtures exhibited comparable performance to catalysts generated in situ from Ni(cod)2. While the use of aryl chlorides under the reported conditions generally gave excellent product yields, analogous aryl bromides gave rise to substantial quantities of reduced arene byproducts. Such observations may be rationalized in terms of a mechanism involving electron transfer from Ni to the aryl bromide, and/or deleterious side-reactions involving [Ni(L8)(aryl)Br] intermediates (e.g., comproportionation).

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Scheme 1. The first Ni-catalyzed C-N cross-coupling of (hetero)aryl chlorides. Several years later in 2000, Lipshutz and Ueda71 utilized dppf (L8) ligation for developing the first heterogeneous Ni-based catalyst for the amination of aryl chlorides (Scheme 2). To achieve an active Ni0 catalyst, a NiII salt supported on charcoal is reduced by nBuLi in the presence of L8. Notably, the monodentate ligands examined in this study (PCy3, PPh3, and P(o-tolyl)3) were considerably less effective than L8. Under refluxing conditions in either toluene or 1,4-dioxane, this catalyst system enabled the efficient coupling of aryl chlorides and primary alkylamines, anilines, or secondary cyclic amines, using lithium tertbutoxide as base. While examples of electron-rich (e.g., p-chloroanisole), electron-poor (e.g., pchlorobenzonitrile) and hindered ortho-substituted (e.g., 2-chloro-4-fluorotoluene) substrates are included in this report, the scope of electrophiles is limited to only five examples total, and the capacity for the catalyst system to tolerate broad functionality with respect to both coupling partners is not well-established. Furthermore, the need for high catalyst loadings in select pairings (10/20 % Ni:L8), and two equivalents of the amine coupling partner, are limitations of the protocol.

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Scheme 2. The heterogeneous Ni-catalyzed amination of aryl chlorides. In 2003, the Lipshutz research group reported a simplified protocol109 that does not require pre-reduction of the NiII/C precursor by n-BuLi, and instead achieves an active Ni0 species via an in situ reduction of NiII/C by action of an amine/LiO-t-Bu mixture. In examining the influence of ancillary ligand electronic factors on reaction kinetics, they found that more electron-rich triarylphosphines led to higher reactions (P(p-anisyl)3 > P(p-tolyl)3 > PPh3 ≥ P((ptrifluoromethyl)phenyl)3). This result was not anticipated, given that product-forming C-N reductive elimination is often considered to be rate-limiting in Ni-based C-N cross-coupling, and in this scenario electron-deficient ancillary ligands would be expected to give rise to faster reaction rates. By comparison, L8 afforded superior reaction rates and higher product yields relative to each of the triarylphosphines examined, indicating that chelating bisphosphines are superior to monophosphine ligands when utilized in this particular reaction setting. Given that aryl halide oxidative addition is typically facile with Ni0 species,46 the authors propose that complexation/deprotonation of the amine is likely rate limiting for heterogenous Ni-catalyzed aminations of this type. In considering mechanistic scenarios leading to NiII amido species, a pathway involving initial complexation of tert-butoxide to form a NiII(L)(O-t-Bu) intermediate, followed by subsequent complexation/deprotonation of the amine, is invoked. This proposal is based on the observed reactivity trend for electronically varied triarylphosphines (vide supra), in which electron-rich ligands afforded the fastest rates. Under this proposed mechanism, such ancillary ligands should accelerate complexation/deprotonation of the amine by increasing the basicicity of tert-butoxide in a NiII(L)(O-t-Bu) type intermediate. An important addition to the substrate scope of Ni-catalyzed aminations came in 2011, when Ackermann and co-workers reported72 an efficient synthesis of substituted indoles via sequential Ni-catalyzed C-N cross-coupling/hydroamination of ortho-alkynyl haloarenes (X = Br, I) employing alkyl and aryl amines (Scheme 3). The reaction is promoted by an in situ 14 ACS Paragon Plus Environment

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generated catalyst based on a 1:1 mixture of L8 and Ni(cod)2 (5 mol%), in the presence of NaO-t-Bu (for the C-N cross-coupling step), and KO-t-Bu (for the hydroamination step). Whereas monodentate phosphine ancillary ligands (PPh3, PCy3, (1-Ad)2P(O)H, XPhos) provided unsatisfactory product yields (90% conversion to the target secondary amide product. Further experimentation involving the application of [Ni(L)(o-tolyl)Cl] pre-catalysts derived from L15 and L18 in more challenging amide cross-coupling reactions involving heterocyclic substrates allowed for the identification of the latter ancillary ligand as being superior in this chemistry. In employing the L18-containing 35 ACS Paragon Plus Environment

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pre-catalyst C16, the cross-coupling of structurally diverse primary amides and lactams with activated (hetero)aryl chloride, bromide, triflate, tosylate, mesylate and sulfamate electrophiles was achieved in synthetically useful yields.120 It is worthy of mention that more forcing conditions (5-10 mol% Ni, 90 oC) were required for such amide/lactam cross-couplings in comparison to related transformations of ammonia and primary alkylamines (vide supra).100 Notable limitations encountered in this amide/lactam N-arylation chemistry include the poor reactivity of C16 with unactivated and deactivated (hetero)aryl (pseudo)halides, as well as with secondary amides.

Scheme 13. Ni-catalyzed C-N cross-coupling of primary amides and lactams with (hetero)aryl (pseudo)halides, employing pre-catalyst C16. In a subsequent collaboration with the Bonacorso group, we reported125 on the application of C16 in promoting the first Ni-catalyzed cyclization of in situ generated orthochlorobenzophenone hydrazone derivatives to afford 1H-indazole products, which can be transformed subsequently in a one-pot procedure via Cu-catalyzed N-arylation with (hetero)aryl 36 ACS Paragon Plus Environment

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bromides for the assembly of 1,3-di(hetero)aryl-1H-indazoles (Scheme 14). Notably, neither the CyPF-Cy (L15) nor dppf (L8)-derived [Ni(L)(o-tolyl)Cl] pre-catalysts were effective in enabling the formation of 1H-indazole products (