Aryl–Fluoride Bond-Forming Reductive Elimination from Nickel(IV) Centers Elizabeth A. Meucci, † Alireza Ariafard,¥ Allan J. Canty,¥ Jeff W. Kampf, † and Melanie S. Sanford†,* †Department of Chemistry, University of Michigan, 930 N University Ave, Ann Arbor, MI 48109, USA ¥School of Natural Sciences – Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia ABSTRACT: The treatment of pyridine- and pyrazole-ligated NiII !-aryl complexes with Selectfluor results in C(sp2)– F bond formation under mild conditions. With appropriate design of supporting ligands, diamagnetic NiIV !-aryl fluoride intermediates can be detected spectroscopically and/or isolated during these transformations. These studies demonstrate for the first time that NiIV !-aryl fluoride complexes participate in challenging C(sp2)–F bond-forming reductive elimi- nation to yield aryl fluoride products. Supporting Information Placeholder INTRODUCTION A more recent advance in the field of Ni-mediated Over the past decade, there has been significant pro- fluorination came in a 2012 report by Ritter and cowork- gress in the development of Pd, Cu, and Ag-mediated/cat- ers demonstrating oxidatively-induced aryl–F and aryl– alyzed methods for the formation of aryl-fluoride 18F coupling reactions of NiII(!-aryl) complexes.16 These bonds.1,2 These protocols are finding increasing applica- transformations were proposed to proceed via high-valent tion in the synthesis of fluorine-containing pharmaceuti- Ni intermediates. However, the structures and oxidation cal candidates3 as well as 18F-labelled radiotracers.4 Given states (NiIII versus NiIV) of these species were not identi- that the C(sp2)–F bond-formation is typically the most fied in the original report. More recently, Ritter has challenging step of these transformations,5 fundamental shown that the stoichiometric reaction of the NiII model studies of C(sp2)–F reductive elimination from transition complex A with Selectfluor affords a transient metal !-aryl fluoride complexes have been critical for the NiIII(aryl)(F) species with proposed structure B (Figure advancement of this field. 2a,c,d,6-11 For instance, organo- 1A). 17 Intermediate B was detected in situ via EPR spec- metallic investigations of C(sp2)–F coupling at Pt, Pd, Cu, troscopy and shown to undergo C(sp2)–F coupling upon and Ag complexes6a,2a,h,7b,8 have guided the identification heating to 70 ºC. These results implicate the feasibility of of ligand scaffolds that are most effective for promoting aryl–F bond formation from NiIII centers. However, key this transformation. Related studies have provided critical questions remain about what other classes of ligands and insights into the types of electrophilic fluorinating rea- oxidation states of Ni enable this transformation. gents that enable oxidatively-induced C(sp2)–F bond-for- A. Ritter (2017): Oxidatively-Induced C–F Coupling from Proposed NiIII Intermediate 2g,6a,9,12 mation at different metals. Furthermore, stoichio- O2N Cl NO2 N metric studies have provided detailed information about O 2BF4 O N N 2 S S factors impacting the selectivitity of productive C(sp )–F N O F N O (Selectfluor) N II coupling versus competing side reactions like carbon-het- Ni N N NiIII 13 8c,d,14 CH3CN 70 ºC F eroatom and phosphorus-fluorine bond-forming –40 ºC N F pathways. (A) (B) Moving forward, a key frontier for this field is to find Characterized by EPR new transition metals/oxidation states that participate in B. This Work: Oxidatively-Induced C–F Coupling from Isolable NiIV Intermediates this challenging transformation, in order to further ex- Cl N pand the scope and diversity of synthetic methods for 2BF4 N 2 F C(sp )–F bond formation. Nickel has been known to me- F L L1 L (Selectfluor) IV L diate the formation of C–F bonds under oxidative condi- NiII Ni NiII L L L CH3CN 35-50 ºC tions since the introduction of the Simons Process in the 1 25 ºC L 1930s. This electrochemical fluorination method involves Detected in situ F the use of Ni-plated anodes to access perfluorinated mol- or isolated Figure 1. Intermediates in oxidatively-induced aryl–F coupling ecules.15 from organometallic NiII complexes. (A) NiIII intermediate detected by Ritter. (B) This work (NiIV intermediate detected resulted in a significantly improved ratio of 2 to 3 (40% and isolated). and 23% yield, respectively) (Scheme 1b). This result demonstrates the feasibility of selective aryl–F coupling Recent work from our group has shown that multi- from Ni complexes supported by pyridine ligands. dentate pyridine- and pyrazole-containing ligands sup- The reactions in Scheme 1 proceed rapidly at room port organometallic NiIII and NiIV complexes that partici- temperature, and no intermediates are detected by 19F pate in challenging reductive elimination reactions, in- NMR or EPR spectroscopy. Thus, we next sought to de- 3 2 cluding C(sp )–heteroatom and C(sp )–CF3 cou- sign systems that would enable the detection and isolation plings.18,19,20 We hypothesized that analogous ligand sys- of high-valent Ni intermediates in analogous transfor- tems might enable the isolation and reactivity studies of mations. Previous work has shown that organometallic high-valent Ni(!-aryl)(F) intermediates. We demonstrate NiIII and NiIV complexes are stabilized by ligands that are herein that a variety of pyridine and pyrazole-ligated NiII rigid, multidentate, and strongly electron donating.13-15,23 complexes participate in oxidatively-induced C(sp2)–F As such, we envisioned that NiII precursor 5, which con- bond formation upon treatment with Selectfluor. Further- tains bidentate bipyridine and biphenyl ligands, could al- more, we show for the first time that several of these low for intermediates of this oxidatively-induced fluori- transformations proceed via detectable and even isolable nation to be observed at room temperature (Scheme 2). IV Ni !-aryl fluoride intermediates (Figure 1B). II Scheme 2. Synthesis of Ni complex 5 Ni(PEt3)4 RESULTS AND DISCUSSION N II + + NiII The Ni complex 1 was selected as an initial model THF N 25 ºC, 0.5 h system for exploring oxidatively-induced aryl-fluoride N N (5) coupling at Ni. The pyridine donor ligands of 1 are simi- (77%) lar to those employed in a variety of Ni-catalyzed carbon– Complex 5 was prepared via the treatment of heteroatom cross-coupling reactions.21 Additionally, pre- Ni(PEt3)4 with biphenylene in the presence of 2,2’-bipyr- vious work from our group has demonstrated that the idine. The NiII product was isolated in 77% yield as an + treatment of 1 with Cl oxidants (e.g., PhICl2) results in analytically pure dark blue solid and was characterized by C(sp2)–Cl and C(sp2)–Br bond formation to afford a mix- 1H and 13C NMR spectroscopy. X-ray quality crystals ture of 2-(2-chlorophenyl)pyridine (53%) and 2-(2-bro- were obtained by recrystallization from a tetrahydrofu- mophenyl)pyridine (25%).22 Based on these results, we ran/acetone solution of 5 at –35 ºC, and an ORTEP dia- hypothesized that the use of F+ oxidants might induce an gram is shown in Figure 2. The most notable feature of analogous C(sp2)–F coupling reaction to generate 2. In- this structure is the significant distortion from the square deed, the reaction of 1 with Selectfluor for 0.5 h at 25 ºC plane, with an angle of 24.2º between the N1–Ni–N2 and afforded 2 in modest (16%) yield (Scheme 1). However, C11–Ni–C22 planes. the major product of this reaction was 2-(2-bromo- a) b) phenyl)pyridine (3, 70% yield), which is derived from competitive C(sp2)–Br bond formation. C22 N1 Ni1 Scheme 1. Oxidatively-induced aryl–fluoride coupling from 1 C11 N2 (a) 2.5 equiv N Br Selectfluor NiII + N F N Br N CH3CN (2) (3) (1) 25 ºC, 0.5 h 16% 70% Figure 2. ORTEP diagram for complex 5. Hydrogen atoms (b) have been omitted for clarity, thermal ellipsoids drawn at 50% BArF 2.5 equiv probability. Bond lengths (Å): Ni1"N1 = 1.952, Ni1"N2 = L 1 equiv NaBArF N Selectfluor NiII 1.964, Ni1"C11 = 1.902, Ni1"C22 = 1.898 and bond angles 2-picoline N N F CH3CN (deg): N1"Ni1"N2 = 82.6, C11"Ni1"C22 = 83.8. CH3CN (4) 25 ºC, 0.5 h (2) 25 ºC, 0.5 h 40% L = 2-picoline or CH3CN formed in situ The treatment of 5 with 1.3 equiv of Selectfluor in MeCN at room temperature resulted in an immediate We reasoned that the formation of the undesired aryl color change from purple to orange. This coincided with bromide product 3 could be minimized by abstraction of the appearance of a 19F NMR resonance at –417.6 ppm, the bromide ligand from 1 prior to oxidation with Select- implicating the formation of a diamagnetic nickel fluo- fluor. The treatment of 1 with 1 equiv of sodium ride intermediate.24 1H NMR spectroscopic analysis of tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF) this species shows eight aromatic signals that each inte- in the presence of 4 equiv of 2-picoline resulted in the grate to two protons (Figure S4). Furthermore, analysis of precipitation of NaBr, accompanied by the formation of a solution of in situ-generated 6 by EPR spectroscopy did II the cationic Ni complex 4. As predicted, the subsequent not show the presence of any paramagnetic species (Fig- in situ oxidation of this intermediate with Selectfluor ure S10). These data along with the observed reactivity of 2 this complex (vide infra) implicate a symmetrical NiIV 0.025 cation with fluoride and solvent ligands at the axial posi- IV Aryl–F tions (Scheme 3). The observation of this putative Ni 0.02 fluoride intermediate (6) stands in notable contrast to Rit- ter’s oxidation of NiII complex A with Selectfluor, which 0.015 yielded a NiIII-fluoride (B, Figure 1a).