Aryl–Fluoride Bond-Forming Reductive Elimination from Nickel(IV) Centers Elizabeth A

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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 σ-aryl complexes with Selectfluor results in C(sp2)– F bond formation under mild conditions. With appropriate design of supporting ligands, diamagnetic NiIV σ-aryl fluoride intermediates can be detected spectroscopically and/or isolated during these transformations. These studies demonstrate for the first time that NiIV σ-aryl fluoride complexes participate in challenging C(sp2)–F bond-forming reductive elimination to yield aryl fluoride products.

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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(σ-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 σ-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 mation at different metals.2g,6a,9,12 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(σ-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). NiIV σ-aryl fluoride intermediates (Figure 1B). Scheme 2. Synthesis of NiII 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). 0.01

Scheme 3. Aryl–fluoride bond formation from putative NiIV in- Concentration (M) 0.005 termediate (6) BF4 Complex 6 1.3 equiv F 0 N Selectfluor N 0 20 40 60 80 100 120 140 NiII NiIV N MeCN, 25 ºC, 1 min N Time (mins) (35%) (5) NCMe (6) Figure 3. Reaction profile for C(sp2)–F bond formation from 6. 19 Characterized by F NMR Reaction monitored by 19F NMR spectroscopy using 4-fluoroan- spectroscopy (–417.6 ppm) isole as an internal standard. 35 ºC, 2 h BF4 Further insight into the reactivity of 5 was obtained N NCMe NiII by conducting a computational analysis of the transfor- N2H4 N 27 F –[Ni] mations depicted in Scheme 3. Gaussian 09 was used at 28 (8) F (7) the B3LYP level of density functional theory (DFT) for

Characterized by 19F NMR geometry optimization (see SI for complete details). spectroscopy (–118.7 ppm) These studies focused on intermediates that are expected (quantitative yield based on 6) to lead to the experimentally observed isomer of complex 6. On the basis of these calculations, an energetically Heating an acetonitrile solution of in situ-generated 6 plausible pathway for the formation of 6 is shown in Fig- for 2 h at 35 ºC resulted in disappearance of the Ni–F res- ure 4. It commences with the transfer of one electron from onance at –417.6 ppm and concomitant formation of an 19 5 to Selectfluor to generate A. Interaction of the organo- aryl–fluoride signal at –118.7 ppm in the F NMR spec- metallic product A with solvent (MeCN) affords the NiIII trum. This is consistent with C(sp2 )–F bond-forming re- intermediate A-MeCN, which then receives the F atom ductive elimination from 6 to afford the diamagnetic NiII from the reduced Selectfluor to form 6.29,30 Conversion of product 7. 19 F NMR spectroscopic monitoring of this re- 6 to other isomers is precluded by the low barrier for reaction shows that the rate of consumption of 6 closely ductive elimination (see Figure S24 for details). Overall, tracks that of the formation of this aryl fluoride product the favorability of each step within the oxidation pathway (Figure 3). Furthermore, the yield of this product is quan- depicted in Figure 4 shows the competence of Selectfluor titative relative to the initial concentration of 6. as an oxidant for accessing NiIV species from NiII precur- The proposed NiII complex 7 could not be isolated sors. cleanly. As such, a reductive work-up with hydrazine was We also evaluated the possibility that complex 6 performed to release the s-aryl ligand from Ni, and both might exist as a NiIII species that is antiferromagnetically GC and NMR spectroscopic analysis of the isolated or- coupled to a ligand centered radical. However, all at- ganic product confirmed the formation of aryl fluoride tempts to optimize for a structure containing two unpaired 25,26 8. Overall, these experiments demonstrate the first ex- electrons of opposite spin by DFT were unsuccessful, ei- 2 ample of C(sp )–F coupling from a detectable ther directly or via an attempted triplet state exhibiting IV Ni (aryl)(F) complex. expulsion of MeCN from the coordination sphere. In con-

2 Cl Cl N N N N F F MeCN N N N F N NiII NiIII NiIII NiIV N N N N NCMe Cl NCMe Cl (5) N (A) (A-MeCN) N (6) 0 (0) -23.6 (-19.9) -31.2 (-33.8) -51.5 (-57.4) N N F Figure 4. Relative energies of intermediates in SET pathway for reaction of 5 with Selectfluor to afford 6. Energies DG (DH) in kcal/mol relative to 5. trast, the proposed diamagnetic NiIV structure for complex 6 underwent facile optimization. We next calculated a pathway for reductive elimination from complex 6, resulting in an overall reaction 3 profile (Figure 5) consistent with the experimentally ob- ºC, and the solid-state structure is shown in Figure 6. served process in Scheme 3. Both dissociative and con- Overall, the data are all consistent with a diamagnetic oc- certed mechanisms were considered (see SI for complete tahedral NiIV–fluoride structure in both solution and the details), revealing a preference for a concerted mecha- solid state. nism that proceeds through a single transition state (TS- 6/7) with ΔG† = 9.3 kcal/mol to afford reductive elimination product 7. This low barrier is consistent with experimental observations that in situ generated 6 undergoes N1

2 N4 C C(sp )–F bond formation under mild conditions (2 h at 35 Ni1 7

ºC). C7 N 4 F N NiIV N Figure 6. ORTEP diagram for complex 10. Hydrogen atoms NCMe have been omitted for clarity, thermal ellipsoids drawn at 50% (6) -42.2 (-48.5) probability. Bond lengths (Å): Ni1−N1 = 1.888, Ni1−N4 = (TS-6/7) -51.5 (-57.4) 2.031, Ni1−C7 = 1.952 and bond angles (deg): N4−Ni1−N4 = F N 84.9, C7−Ni1−C7 = 84.0. Ni N NCMe Complex 10 is stable at –35 ºC for several hours in MeCN. However, heating a MeCN solution of 10 at 50 ºC for 12 h results in complete consumption of this NiIV species and the formation of an aryl fluoride product in -95.7 (-100.0) 10% yield as determined by 19F NMR spectroscopy (d – N NCMe NiII N 118.1 ppm). Previous investigations of aryl–oxygen coupling from similar NiIV complexes revealed that reductive F (7) elimination yields could be improved by conducting this Figure 5. Energy profile for C(sp2)–F bond formation from 6. En- reaction in ethereal solvents.32 Similarly, the yield of the ergies DG (DH) in kcal/mol relative to 5. aryl-fluoride product improved to 60% by changing the solvent from MeCN to THF. We hypothesize that this These calculations motivated us to seek experimental aryl fluoride product is the NiII-s-aryl complex 11 evidence in support of the single-electron transfer mech- (Scheme 5); however, this species proved challenging to anism for the oxidation of 5 with Selectfluor. The addi- isolate cleanly. As such, a reductive work-up with hydra- tion of 1 equiv of TEMPO to this oxidation reaction com- zine was performed to release the s-aryl ligand from Ni, pletely inhibited formation of complex 6. These results, and GC analysis confirmed the identity of the organic in addition to the well precedented one-electron reactivity product as aryl fluoride 8. Overall, these studies of com- of Selectfluor, are consistent with a pathway like that de- plex 10 represent the first demonstration of C(sp2)–F cou- picted in Figure 4.31 pling from an isolated NiIV complex. A final set of studies focused on designing a IV Ni (aryl)(fluoride) complex that could be isolated and IV Scheme 5. Aryl–fluoride bond formation from (Tp)Ni (C6H4- fully characterized. Our previous work has shown that re- o-C6H4)(F) (10) placing the neutral bidentate 2,2’-bipyridyl ligand with the anionic tridentate tris(pyrazolyl)borate (Tp) ligand HB N N dramatically enhances the stability of high-valent Ni N N HB N N 18 II N complexes. As such, we reacted the anionic TpNi com- IV N Ni II L N N THF, 50 ºC Ni N H plex 9 with Selectfluor in MeCN. Within 30 min at 25 ºC N N 2 4 F 12 h – [Ni] F this transformation afforded the NiIV–F complex 10, (10) F (8) which was isolated in 48% yield (Scheme 4). (11) Characterized by 19F NMR spectroscopy (–118.1 ppm) IV Scheme 4. Synthesis of (Tp)Ni (C6H4-o-C6H4)(F) (10) (60% yield)

HB N N K N We next used DFT to interrogate whether reductive HB N N N N elimination from complex 10 proceeds via a concerted or 1.3 equiv Selectfluor N NiIV II N N Ni MeCN, 25 ºC, 30 min N dissociative mechanism. Figure 7 illustrates the energy N F profiles for these two different pathways. The barriers for (9) (48%) (10) C(sp2)–F bond-forming reductive elimination in this sys- 19F NMR shift at –423.0 ppm tem range from approximately 20 to 23 kcal/mol, con- Complex 10 was characterized via 1H, 19F, and 11B sistent with the much slower rate of reductive elimination NMR spectroscopy. In addition, X-ray quality crystals of from 10 compared to that from the bipyridine complex 6. 10 were obtained via recrystallization from MeCN at –35 These calculations show a relatively small 3.2 kcal/mol 4

Figure 7. Energy profile for the reductive elimination steps from complex 10. Complex I also forms an adduct with solvent THF, at ΔG (ΔH) 9.0 (0.6) kcal/mol. Energies ΔG (ΔH) in kcal/mol. preference for the concerted pathway (via TS_10/IV) Corresponding Author compared to the dissociative pathway (via TS_I/II). *[email protected] Notes SUMMARY AND CONCLUSIONS The authors declare no competing financial interests. In conclusion, this communication demonstrates that the treatment of a variety of nitrogen-ligated σ-aryl NiII ORCID complexes with Selectfluor results in C(sp2)–F coupling. Melanie S. Sanford: 0000-0001-9342-9436 In several of these systems, diamagnetic NiIV σ-aryl fluo- Allan J. Canty: 0000-0003-4091-6040 ride intermediates were detected and/or isolated. These Alireza Ariafard: 0000-0003-2383-6380 results demonstrate the viability of C(sp2)–F bond-form- Elizabeth A. Meucci: 0000-0002-7306-0982 ing reductive elimination from NiIV complexes under mild conditions. In addition, they stand in interesting contrast to NiIII mediated fluorination reactions demonstrated ACKNOWLEDGMENT by Ritter. Future work will focus on leveraging these re- This work was supported by the National Science Foun- sults to develop NiII/IV-catalyzed fluorination reactions. dation Grant CHE-1111563, the Australian Research Council, and the Australian National Computing Infra- structure. E.A.M thanks Rackham Graduate School (RMF) ASSOCIATED CONTENT and NSF for graduate fellowships. We gratefully Experimental details, optimization tables, and complete acknowledge funding from NSF Grant CHE-0840456 for X- characterization data for all new compounds. This material ray instrumentation. is available free of charge via the Internet at http://pubs.acs.org. REFERENCES

AUTHOR INFORMATION

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