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Parameterization of Phosphine Ligands Demonstrates Enhancement of Nickel Catalysis Via Remote Steric Effects Kevin Wu and Abigail G

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Parameterization of Phosphine Ligands Demonstrates Enhancement of Nickel Catalysis Via Remote Steric Effects Kevin Wu and Abigail G ARTICLES PUBLISHED ONLINE: 6 MARCH 2017 | DOI: 10.1038/NCHEM.2741 Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects Kevin Wu and Abigail G. Doyle* The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment—cone angle and % buried volume—are not equivalent, despite their treatment in the literature. ver the past 50 years, Pd-catalysed cross-coupling has partners17. In this context, our group reported Ni-catalysed Suzuki evolved to become one of the most useful strategies for couplings of N,O-acetals and O,O-acetals that deliver 2-arylated – – – 1 18,19 Ocarbon carbon (C C) and C heteroatom bond formation . heterocycles using triphenylphosphine (PPh3) as a ligand .A The development of new ligands for Pd has been arguably the mechanistic study suggested a pathway involving boroxine-assisted most important contributor to the advancement of these ionization of the acetals followed by Ni-catalysed coupling of the methods, enabling reactions with a broad range of substrates resulting iminium or oxocarbenium ions20. Accordingly, we were under mild and efficient conditions2–4. By contrast, the field of able to develop an asymmetric variant of the N,O-acetal coupling nickel-catalysed cross-coupling has witnessed tremendous activity using a chiral phosphonite ligand for Ni (ref. 21). We recently con- over the past two decades5, but minimal effort has been dedicated sidered whether this strategy could be expanded to offer a general to the identification of new ligand sets (Fig. 1a)6–9. Furthermore, Csp3–C bond-forming approach to ether synthesis from a broad phosphines developed for Pd catalysis have generally proven ineffec- range of readily available and stable acyclic and cyclic acetals in tive for Ni (refs 10–12). According to the example set by Pd, the combination with boronic acids (Fig. 1b). This reaction would design of new ligands for Ni should facilitate the refinement of exist- offer an expedient synthesis of benzylic ethers—highly valuable ing methods and the identification of new chemical transform- pharmacophores in medicinal chemistry22—which are most commonly ations. Here, we report the development of a new class of constructed by C–O bond formation. phosphines and demonstrate that these bench-stable ligands facili- The coupling of benzaldehyde dimethyl acetal 1 with para-fluoro- tate a Ni-catalysed Csp3 Suzuki coupling reaction that failed with phenyl boroxine was chosen as the model system for optimization known ligand architectures for Ni and Pd. Quantitative molecular (Fig. 2a). This coupling was anticipated to be more challenging than parameterization of these ligands and multivariate correlation our previously described Suzuki coupling of chromene acetals, with reaction outcome are conducted13,14. These studies reveal that because the Csp3–O bond of chromene acetals experiences significant two of the most frequently used parameters to describe ligand bond weakening due to conjugation, and addition of Ni to the benzo- steric effects—cone angle and buried volume—are not equivalent, pyrylium delivers a stabilized π-allyl intermediate20, both not possible despite their reported treatment in the literature15,16. Indeed, it is with simple acetals. Indeed, application of the previously identified L1 2 precisely their difference that provides an intuitive as well as quan- conditions using PPh3 as ligand only yielded trace ether at elev- titative rationale for their success and for the failure of ligands devel- ated temperature. By contrast, use of tricyclohexylphosphine (PCy3, oped for Pd. We expect that the new phosphines in this study will L2), one of the most common phosphines used for Ni-catalysed find application in other Ni-catalysed coupling reactions. cross-coupling5,17, afforded modest amounts of product (29% yield). t L3 Moreover, the insight gained from molecular parameterization More hindered trialkylphosphines (tert-butylphosphine, P Bu3, ) should serve as a general design principle for the identification of were ineffective, as were N-heterocyclic carbenes (L4). Alkyl arylpho- new ligands tailored for Ni. sphines, which possess intermediate steric hindrance and electronic The field of Ni catalysis has recently witnessed rapid growth character to trialkylphosphines and triarylphosphines, were also eval- owing to the base metal’s low cost and unique properties compared uated. Unsubstituted alkyl diarylphosphines (cyclohexyl diphenyl- fi L9 to its precious-metal sibling, Pd. One of the most signi cant contri- phosphine, PCyPh2 and cyclopentyl diphenylphosphine, L11 L2 L5 butions of Ni catalysis to cross-coupling methodology has been PCypPh2 ) were less effective than . However, PCy2Ph ( ) enabling the use of substrates bearing abundant and relatively delivered similar yields to PCy3, as did the less hindered cyclopentyl 2– 3– L8 inert Csp O and Csp O bonds as electrophilic coupling variant PCyp2Ph ( ). More decorated versions of these ligand Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA. *e-mail: [email protected] NATURE CHEMISTRY | VOL 9 | AUGUST 2017 | www.nature.com/naturechemistry 779 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2741 a on a gram scale as air-stable solids that could be stored on the bench Pd Discovery Method development Ligand & catalyst design for over a month without oxidation or decomposition. We found that, within the alkyl diarylphosphine ((alkyl)PAr2) 1970s 1980s 1990s 2000s 2010s Present platform, 2-substitution on the aryl groups was detrimental to reac- tivity (L12), consistent with earlier observations using Buchwald Ni Discovery Method development ligands L6 and L7. Ligands with electron-withdrawing groups at the 3,5-positions were also ineffective (L15). In contrast, ligands t R bearing bulky, electron-donating substituents ( Bu) at the 3,5-pos- itions (L13, L16) afforded improved reactivity over the parent PtBu 3 t ligands (L9, L10), providing 67 and 68% yield of the desired ether Bu2P N R PCy2 Pd Fu iPr iPr product, respectively. We questioned whether inclusion of larger Major advances in substituents at the 3,5-positions would further improve ligand per- Pd-catalysed NN formance. The 2,4,6-tri-isopropylphenyl (TRIP) group has proven R R cross-coupling iPr of high utility in ligand and catalyst design as a very bulky substitu- Hermann Beller Buchwald ent. For reasons of synthetic accessibility, we investigated modifi- cation of the (alkyl)2PAr framework with this substituent. L17 TRIP Gratifyingly, the catalyst system using demonstrated further Phosphines 2 i improvement, delivering in 78% yield. designed for Pd Pr Ni The superior yields with L16 and L17 could be due to greater cat- mostly ineffective PCyp2 New reactions alyst stability, improved rates of reaction, or both. To probe this Few efforts towards iPr iPr Greater efficiency question, NMR timepoint experiments were conducted to qualitat- Ni ligand development Expanded scope ively assess reaction progress with various ligands (Fig. 2b). Ligands Novel phosphine L16 and L17 exhibited greater rates than L2, thus suggesting these ligands generate more active Ni catalysts. Furthermore, these time- point studies illustrate that the catalyst system with L17 affords b superior yields to L16, despite having a lower initial rate and an OR Ni, ligand OR Additive-free Suzuki coupling from simple materials induction period. OR Ar Ar–B(OR')2 Valuable benzylic ether Next, we sought to understand what structural features of the new products ligands are responsible for their significantly improved rate and cata- lyst stability. In particular, we sought to quantify the steric and elec- Figure 1 | Design of new ligands for Ni catalysis enables Suzuki coupling of tronic properties of these ligands using numerical parameters and benzylic acetals. a, Ligand development in Pd versus Ni-catalysed cross- search for statistical correlations with reaction yield. The electronic coupling. Ligands engineered for Pd catalysis have facilitated many advances properties of the ligands were evaluated using the computationally in cross-coupling, including the discovery of altogether new transformations derived minimum electrostatic potential (Vmin) parameter, which cor- and the refinement of existing methods such that they can be used for relates with the Tolman electronic parameter23. No strong correlation large-scale synthesis. By contrast, minimal effort has been directed at ligand 2 with yield was observed using Vmin alone (r = 0.18, Supplementary design for Ni-catalysed cross-coupling,
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