Ni(I)–X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis

4 hours ago - ... Performance in the Hydrogen Isotope Exchange in Pharmaceuticals ... been proposed as key intermediates in a host of catalytic transf...
0 downloads 0 Views 2MB Size
Subscriber access provided by WEBSTER UNIV

Article

Ni(I)–X Complexes Bearing a Bulky #-Diimine Ligand: Synthesis, Structure and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals Cayetana Zarate, Haifeng Yang, Máté J. Bezdek, David Hesk, and Paul J. Chirik J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00939 • Publication Date (Web): 02 Mar 2019 Downloaded from http://pubs.acs.org on March 2, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Ni(I)–X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis, Structure and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals Cayetana Zarate,a Haifeng Yang,b Máté J. Bezdek,a David Hesk,b† and Paul J. Chirik*a a

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States

b

MRL, Merck & Co, Inc., Rahway, New Jersey 07065, United States

ABSTRACT: The synthesis and spectroscopic characterization of a family of Ni–X (X = Cl, Br, I, H) complexes supported by the bulky αdiimine chelate N,N’-bis(1R,2R,3R,5S)-(−)-isopinocampheyl-2,3-butanediimine (ipcADI) are described. Diimine-supported, threecoordinate nickel(I)–X complexes have been proposed as key intermediates in a host of catalytic transformations such as C–C and C– heteroatom cross-coupling and C–H functionalization but have until now remained synthetically elusive. A combination of structural, spectroscopic, electrochemical, and computational studies were used to establish the electronic structure of each monomeric (ipcADI)NiX (X = Cl, Br, I) complex as a nickel(I) derivative supported by a redox-neutral α-diimine chelate. The dimeric nickel hydride, [(ipcADI)Ni(µ2-H)]2, was prepared and characterized by X-ray diffraction; however, magnetic measurements and 1H NMR spectroscopy support monomer formation at ambient temperature in THF solution. This nickel hydride was used as a precatalyst for the hydrogen isotope exchange (HIE) of C–H bonds in arenes and pharmaceuticals. By virtue of the multisite reactivity and high efficiency, the new nickel precatalyst provided unprecedented high specific activities (50–99 Ci/mmol) in radiolabeling, meeting the threshold required for radioligand binding assays. Use of air-stable and readily synthesized nickel precursor, (ipcADI)NiBr2, broad functional group tolerance and compatibility with polar protic solvents are additional assets of the nickel-catalyzed HIE method.

A. Three-coordinate nickel(I) complexes supported by N,N-bidentate ligands a

INTRODUCTION

N,N-bidentate ligand

Electronically-unsaturated, low-coordinate nickel(I) complexes have been implicated in a range of catalytic C–C and C–X bond forming reactions.1,2 In particular, nickel(I) complexes supported by bipyridine, phenanthroline, and bis(oxazoline) chelates have been proposed as key intermediates in the cross-coupling of alkyl halides3 and esters, cross-electrophile coupling,5 and Ni/photoredox dual catalysis6 (Figure 1A). Diimine nickel(I) complexes have also been implicated in olefin hydrofunctionalization7 reactions and C–H activation processes.8 Specifically, our research group and that of Diao and coworkers have independently demonstrated the catalytic utility of nickel(I) complexes supported by α-diimine (DI) ligands, invoking [(DI)Ni–R] (R = alkyl, heteroaryl, H) intermediates.7a-c,8b In all cases, these three-coordinate compounds have eluded isolation, structural characterization and determination of the electronic structures due to rapid dimerization or high reactivity.9,10 Reported examples of isolable nickel(I) complexes rely on strongfield, sterically demanding ligands such as β-diketiminates (nacnac),11 N-heterocyclic carbenes (NHC)12 and phosphines13,14 (Figure 1B). In complexes of this type, however, the resulting steric hindrance surrounding the metal often attenuates reactivity and, when catalytically relevant, these species are either proposed to be off-cycle deactivation products15,16 or have ill-defined roles in catalysis.17,18 Thus, complexes that are both spectroscopically observable and catalytically competent are attractive to provide fundamental insights for the rational design and synthesis of next generation nickel catalysts for a range of transformations.

R3 N

R

N

N R

Ni

N

X

bpy

4

R2

N

R1

O

Ni

phen

R4 O

R2 X

N R1

Ni box

R1

R1 R2 X

N N

Ni DI

Isolation/study elusive

R2

X

Isolated/characterized (this work)

B. Selected structurally characterized three-coordinate nickel(I)–X complexes Large anionic ligandb tBu iPr

tBu i Pr

Large, strong σ-donor ligand c Ar N

N iPr Ni L N iPr

tBunacnac

iPr iPr

N Ar Ni

N

Cl iPr N

IPr

P P

Ni

X

Fe

Ph 2 P Ni

X

P Ph 2

iPr

dppf

dtbpe

a

Figure 1. Three-coordinate nickel(I)–X complexes. Proposed key catalytic intermediates in C–C and C–heteroatom bond-forming reactions (ref. 3–8). bRef. 11. cRef. 12 and 13. In catalytic C–H functionalization, nickel(I) complexes have been implicated in the C–H bond-cleavage step.8b,19 Our laboratory has reported that the nickel hydride dimer, [(iPrDI)Ni(µ2-H)]2 (1, Figure 2A) (iPrDI = N,N’-bis(2,6-diisopropylphenyl)-2,3-butanediimine)20 is an effective precatalyst for hydrogen isotope exchange (HIE) in organic molecules.8b,21 HIE is the most straightforward method for introducing deuterium or tritium labels in active pharmaceutical ingredients (APIs) for examination of their pharmacokinetic and pharmacodynamic (PK/PD) properties.21,22 From a more fundamen-

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 12

tal perspective, this transformation is also an ideal platform to understand the role of nickel(I) complexes in catalytic C–H activation.

new opportunities in radioligand binding assays28 and other diagnostics in evaluation of drug efficacy and safety.22

A. First generation α-diimine nickel hydride HIE precatalysta

Scheme 1. Synthesis and Structural Characterization of αDiimine Ni–X Complexes

iPr

1/2

iPr

N iPr

N

Ni

H H

iPr

N

iPr

Ar Ni

azine

N

N

iPr

Ni

H

D 2 or T2

N

Ni(COD) 2 (1.0 equiv.) ipc ADI (1.0 equiv.)

ipc ADI

1/2 N

Ni

N

H H

ipc

ipc Ni

N

D 2 or T2

Ni H

[(ipc ADI)Ni(µ 2-H)]2 (2) labile dimer

arene

or ipc ADAI (1.1 equiv.)

Ni

X

X = Cl (7), 82% X = Br (8), 81% X = I (9), 95%

X = Me, X = Cl (3), 81% = Me, X = Br (4), 80% = Me, X = I (5), 73% = H, X = Br (6), 86% N

R =H

SA = 50–99 Ci/mmol (T )

(this work)

Figure 2. Catalytic relevance of α-diimine nickel(I) hydride complexes in HIE of pharmaceuticals. aSee ref. 8b. SA = Specific activity. The nickel precatalyst 1 introduced deuterium and tritium in C(sp2)–H sites of azines, one of the most prevalent structures in lead compounds,23 including representative pharmaceuticals.8b Precatalyst 1 offered improved handling being less air- and moisture-sensitive and more functional group tolerant than previously reported bis(arylimidazol-2-ylidene)pyridine iron bis(dinitrogen), [(CNC)Fe(N2)2] HIE precatalyst.24,25 The latter exhibited orthogonal selectivity from state-of-the-art iridium HIE catalysts21,26 by activating sterically accessible C–H bonds without interference from directing groups. Mechanistic insights on the mode of action of 1 suggest dissociation of the dimer into a monomeric nickel(I) active form for C–H activation (Figure 2A).7a,8b The robustness of the dimer limited the HIE performance of 1 as the scope was confined to strongly σ-donating substrates like azines that could induce formation of the active monomer.27 Consistent with this proposal, the HIE reactivity of 1 was restricted to C(sp2)–H sites adjacent to nitrogen in electron-deficient N-heteroarenes that, in combination with the low concentration of active monomer, resulted in improvable levels of isotopic incorporation. These observations motivated the design of next generation nickel hydride precatalysts bearing a bulky and electron-releasing α-diimine with the goal of destabilizing the hydride dimer and, therefore, enhancing monomer formation. The potential impact of this strategy extends beyond HIE8b as monomeric α-diimine nickel hydrides have been implicated in alkene hydrosilylation,7a hydrogenation,7b and reductive cyclization catalysis.7c Dissociative formation of a monomeric α-diimine nickel hydride may also significantly expand the scope of HIE to include non-nucleophilic substrates as well as increase overall isotopic incorporation and hence enable biological applications (Figure 2B). Here we describe the synthesis, structural characterization and catalytic HIE performance of a second generation nickel hydride precatalyst, [(ipcADI)Ni(µ2-H)]2 (2) (ipcADI = N,N’bis(1R,2R,3R,5S)-(−)-isopinocampheyl-2,3-butanediimine). This labile dimer dissociates at ambient temperature in THF solution as supported by 1H NMR spectroscopy and magnetic measurements. Related and rare examples of monomeric nickel(I) halides, [(ipc ADI)NiX] (X = Cl, Br, I) were also prepared and further demonstrate the success of the ligand design principle. Increased concentrations of monomeric nickel hydride translated to improved HIE performance, accessing previously unreactive sites and resulting in broader scope and unprecedented high specific activities that open

[(ipc ADI)NiX] N

N R R R R

R

Additional labeled sites proposed active catalyst

R

THF, 23 °C, 16 h

D n(Tn)

Broad scope

N

X

R

NiX 2

N

Ni

SA = 2–26 Ci/mmol (T )

B. Second generation nickel precatalyst with superior HIE performance

N

N N

THF, 23 °C, 3–20 min - COD

R = Me

Restricted to azines

proposed active catalyst

robust dimer

A. Synthesis of α-diimine Ni–X complexesa

R R

[(iPrDI)Ni(µ 2-H)]2 (1)

D(T)

N

(T)D

iPr

N

Ar

iPr

Ni(COD) 2 (1.0 equiv.) ipc ADAI (1.0 equiv.) THF, 23 °C, 30 min - COD

N

Br

Ni

ipc

Br Ni ipc

N

N

[(ipc ADAI)NiBr]2 (10), 83%

B. Solid-state structure of [(ipc ADI)NiBr] (8) and [(ipc ADAI)NiBr]2 (10)b

8

10

a NiX2 = NiCl2⋅DME, NiBr2⋅DME or NiI2. bSolid-state structure of 8 and 10 at 30 % probability ellipsoids. Hydrogen atoms omitted for clarity.

RESULTS AND DISCUSSION Synthesis and Characterization of Three-Coordinate αDiimine Nickel(I) Complexes. Our studies commenced with the synthesis of (ipcADI)NiX complexes. Metalation of the free diimine, ipcADI was accomplished by straightforward addition to a THF solution containing NiX2⋅DME (X = Cl, Br; DME = dimethoxyethane) or NiI2. The corresponding nickel dihalides, (ipcADI)NiX2 (3–5, Scheme 1A) were obtained in 73-81% yield after stirring for 16 h in THF at 23 °C followed by isolation. Comproportionation of (ipcADI)NiX2 and Ni(COD)2 in the presence of one equivalent of ipc ADI furnished (ipcADI)NiX (7–9) as paramagnetic green solids in 81–95% yield after 3–20 min in THF at 23 °C. Solid-state magnetic moments of 1.8–2.2(1) µB (298 K, magnetic susceptibility balance) were measured for 7–9, consistent with an S = ½ ground state for each complex. The structures of 7–9 were determined by single crystal X-ray diffraction and monomeric, three-coordinate, Y-shaped geometries around the nickel center were observed in each case. The solid-state structure of 8 is presented in Scheme 1B as a representative example.29 The Ni–Br bond distance of 2.2813(9) Å is statistically shorter than those observed in related α-diimine nickel complexes with bridging bromide ligands.30 Also notable is the proximal positioning of the methylene bridges of each ipc substituent to the nickel center that increases the overall steric crowding around it and likely contributes to the stabilization of the monomeric structure.31 The threecoordinate geometry was also observed in 9, which contains a more polarizable iodide ligand with an elongated Ni–I bond distance of

ACS Paragon Plus Environment

2

Page 3 of 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

2.4565(12) Å. The structural features observed for the series of (ipADI)NiX halide complexes are in stark contrast to the analogous nickel(I) halide complexes supported by 1,1'bis(diphenylphosphino)ferrocene (dppf) where the chloride and bromide congeners are monomers13j,32 but the iodide complex is a dimer.13k To our knowledge, compounds 7–9 constitute the first examples of three-coordinate nickel(I)–X complexes stabilized by a bidentate π-accepting ligand.9 Such species are often invoked as key intermediates in a wide range of catalytic cross-coupling and hydrofunctionalization reactions1,2a,3–8 but have not, until now, been observed directly. c

A.

B.

roborated by EPR spectroscopy as well as DFT calculations. The Xband EPR spectrum of the representative halide 829 exhibits an isotropic signal (g = 2.212) in fluid toluene at 298 K, and a rhombic signal (gx = 2.310, gy = 2.205, gz = 2.135) in toluene glass at 10 K (Figure 3A, B), in agreement with an S =1/2 ground state assignment by magnetic susceptibility measurements (vide supra). The deviation of the g-values from ge = 2.002 in the low-temperature EPR spectrum of 8 suggests that the singly occupied molecular orbital (SOMO) is principally nickel-based. The DFT-computed Mulliken spin density plots of 8, calculated at the B3LYP level of theory, support this view as evidenced by a primarily metal-based SOMO (Figure 3C). The electronic properties of 8 were also examined by cyclic voltammetry (CV). The electrochemical data were collected at 23 °C in a 1 mM THF solution with 0.2 M [nBu4N][PF6] as the supporting electrolyte and exhibits a reversible anodic wave at E1/2 = -1.34 V (vs Fc/Fc+) assigned as the formal Ni(I)/Ni(II) redox couple (see Supporting Information). The CV of 8 also exhibits an irreversible cathodic peak with EPC = -2.52 V that likely corresponds to a reduction event leading to a formally Ni(0) complex that is unstable on the timescale of the electrochemical experiment, presumably due to dissociation of the bromide ligand as proposed for related diimine nickel complexes.34

Scheme 2. Synthesis and Structural Characterization of Labile α-Diimine Ni–H Complex

C.

A. Synthesis of [(ipc ADI)Ni(µ 2-H)]2 N NaHBEt 3 (1.0 equiv.)

[(ipc ADI)NiBr] 8

Figure 3. (a) X-band EPR spectrum of 8 recorded at 298 K in toluene (g = 2.212, Gaussian Broadening = 3.5). (b) X-band EPR spectrum of 8 recorded at 10 K in toluene (gx = 2.310, gy = 2.205, gz = 2.135; gstrain(x) = 0.044, gstrain(y) = 0.023, gstrain(z) = 0.022). (c) Spin density plot for 8 obtained from a Mulliken population analysis in a full-molecule gas phase DFT calculation at the B3LYP level of theory. With monomeric Ni–X complexes in hand, the structural effects of varying the Cimine substitution in the α-diimine chelate was explored. ipc Synthesis of the ADAI (N,N’-bis(1R,2R,3R,5S)-(−)isopinocampheyl-1,2-ethanediimine) variants was accomplished by a similar metalation/comproportionation route (Scheme 1A). The corresponding nickel(I) bromide complex (10) is dimeric in the solid state with Ni–Br distances of 2.4209(5) and 2.4752(5) Å (Scheme 1B). The structural data demonstrate that the absence of Cimine methyl substituents in the backbone of the diimine enables rotation of the ipc substituents around the Nimine–Cipc bond and the reduced steric protection about the nickel center likely opens a pathway to dimerization through bridging of the halides. The analogous aryl-substituted α-diimine Ni(I)–Br complex, [(iPrDI)NiBr]2, is also dimeric in the solid state,30 supporting the notion that both the sterically demanding Nimine substitution and the nature of Cimine groups in ipc ADI play a key role in stabilizing monomeric Ni–X complexes. The unique coordination geometries observed for 7–9 motivated additional study into their electronic structures. Distortions in the bond distances of supporting ligands are established indicators of the redox state of a chelate. For α-diimines, Cimine–Nimine and Cimine– C’imine bond distances are established diagnostics for assigning the redox state of the ligand.33 The relevant bond metrics for 7–9 are reported in Table 1 and, by comparison to average values characteristic of a generic α-diimine ligand in its neutral, radical anion, and closed-shell dianion forms,33 are most consistent with a neutral αdiimine chelate and hence an overall nickel(I) oxidation state for each halide derivative. This electronic structure assignment was cor-

Et 2O (thawing solution), 4 min - NaBr, - BEt 3

1/2

N

Ni

H H

ipc

ipc Ni

N

N

[(ipc ADI)Ni(µ 2-H)]2 (2), 94%

B. Solid-State Structure of [(ipc ADI)Ni(µ 2-H)]2a

2

a

Solid-state structure of 2 at 30% probability ellipsoids. One isopinocampheyl imine substituent and hydrogen atoms have been omitted for clarity. Bridging hydride ligands were not located.

ACS Paragon Plus Environment

3

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 12

Table 1. Representative Bond Distances (Å) and Angles (deg) [(ipc ADI)NiCl] (7)a

[(ipc ADI)NiBr] (8)

[(ipc ADI)NiI] (9)a

[(ipc ADI)Ni(µ 2-H)]2] (2)b

[(iPrDI)Ni(µ 2-H)]2] (1)b,f

(RDI (ox))0g

(RDI • )1-g

(RDI (red))2-g

Ni1–N1

1.950(6)

1.955(4)

Ni1–N2

1.947(6)

1.943(4)

1.946(6)

1.916(4)

1.915(3)







1.946(6)

1.916(4) c

1.920(3)





N1–C1

1.285(10)



1.289(7)

1.302(9)

1.313(6)

1.318(4)

1.29

1.35

1.38

N2–C2 C1–C2

1.295(9)

1.299(6)

1.301(9)

1.313(6) d

1.313(4)

1.29

1.35

1.38

1.485(10)

1.480(7)

1.478(9)

1.438(11) e

1.438(5)

1.47

1.41

Ni1–X1 (X = Cl, Br, I)

1.36

2.147(2)

2.2813(9)

2.4565(12)











Ni1–Ni2







2.3391(9)

2.3563(9)







N1–Ni1–N2

81.9(3)

81.93(17)

82.1(2)

82.8(3)

81.34(12)







a

Bond distances and angles correspond to one of two crystallographically independent molecules. bBond distances and angles correspond to one of two (DI)Ni units of the dimer. For metrics of second unit, see Supporting information. cNi1–N1i generated by symmetry. dN1i–C1i generated by symmetry. eC1–C1i. fValues from ref. 20. gValues from ref. 33 where (RDI(ox))0 corresponds to a generic α-diimine ligand in its neutral form, (RDI•)1− corresponds to a generic α-diimine ligand in its one-electron reduced radical monanionic form, and (RDI(red))2− corresponds to a generic α-diimine ligand in its closed-shell, two-electron reduced, dianionic form. Average values generated from crystallographic analysis of α-diimine complexes with unambiguously assigned ligand oxidation states.

Synthesis, Characterization and Solution Behavior of ipc ADI Nickel Hydride Complex. Having demonstrated the ability of the ipcADI ligand to stabilize monomeric (ipcADI)NiX complexes, synthesis of a catalytically relevant nickel hydride was pursued. As noted previously, the steric profile in the ipcADI chelate could potentially destabilize the dimeric structure observed for [(iPrDI)Ni(µ2-H)]2 (1),8b in turn increasing active monomer concentration in solution thereby resulting in a HIE precatalyst with higher activity and broader applicability (Figure 2). As shown in Scheme 2A, addition of one equivalent of NaHBEt3 to a thawing diethyl ether solution of (ipcADI)NiBr (8) and subsequent stirring for 3 minutes yielded the desired hydride complex [(ipcADI)Ni(µ2-H)]2 (2) as a brown solid in 94% yield after isolation (see Supporting information). In contrast to the nickel(I) halide complexes (7–9), 2 is dimeric in the solid state as established by single-crystal X-ray diffraction (Scheme 2B). Notably, the five-membered C2N2Ni chelate planes are nearly perpendicular in 2 with a dihedral angle of 88.7°, in contrast to the 48.2° twist observed in the solid-state structure of 1,20 likely a result of the steric encumbrance of the vicinal ipc groups. Despite this marked structural difference, a Ni–Ni contact of 2.3391(9) Å observed for 2 is comparable to a bond distance of 2.3563(9) Å in 1 (Table 1). As supported by the population of two orbitals with significant ipc ADI π* character (see DFT calculations in Supporting Information) and observations of perturbations to the bond distances of the chelate with respect to its neutral form, the relatively stronger field hydride ligand in 2 promotes the redox-activity of the ligand in its radical anionic form.35 The electronic structure of 2 is best described as two nickel(II) centers each ligated to a one-electron reduced αdiimine chelate, as previously described for 1.7a,40 The tendency of nickel(II) ions to form four-coordinate complexes, as well as the presence of smaller hydride ligands, are likely driving forces for dimerization. The molecularity of 2 is preserved in benzene solution as indicated by the 1H and 13C NMR spectra, consistent with a diamagnetic, C2-symmetric dimer. The 1H NMR spectrum of 2 collected in benzene-d6 exhibits a diagnostic signal at –1.58 ppm assigned as the ipc ADI methyl backbone resonance and confirmed by comparison to the 1H and 2H NMR spectra of the independently synthesized d12isotopolog (see Supporting information). In addition, the 1H NMR spectrum of 2 exhibits a hydride resonance at -29.30 ppm, consistent with previously reported chemical shifts for bridging nickel hydride complexes.36 Further evidence for the presence of hydride ligands was obtained from the reactivity of the complex. Treatment of a benzene-d6 solution of 2 with CCl4 (excess) at 23 °C furnished CHCl3 and [(ipcADI)NiCl2] (3). Likewise, addition of 1-hexene (5.0 equiv.) to 2 in benzene-d6 resulted in isomerization of the 𝛼-olefin to yield 2-

hexene over the course of 20 hours at 23 °C (see Supporting information). Both observations are hallmarks of the reactivity of transition metal hydride complexes and thus support the formulation of 2 as [(ipcADI)Ni(µ2-H)]2.36 Unlike related bridging hydride nickel complexes, 2 does not eliminate H2 upon exposure to alkenes (5.0 equiv. 1-hexene) or N2 (1 atm) at 23 °C in benzene-d6 over the course of 20 h and was stable for up to 6 months at 23 °C in THF.37,38 Interestingly, the solution behavior of 2 in THF-d8 is distinct from that observed in benzene-d6. The 1H NMR spectrum of 2 in THF-d8 exhibits significantly broadened signals that sharpen upon evaporation of the solvent and reconstitution of the residue in benzene-d6. This observation demonstrates that the changes in the spectrum do not arise from irreversible decomposition. Addition of ferrocene to a THF-d8 solution of 2, containing a capillary with ferrocene in THFd8, revealed a shift between both ferrocene proton resonances (4.11 ppm vs 3.66 ppm), suggesting that the generation of a paramagnetic nickel compound is responsible for the peak broadening.39 Based on the demonstrated stabilization of monomeric nickel(I) complexes by ipc ADI chelate with doublet ground states (see above), the observed paramagnetism supports the reversible, THF-promoted dimer dissociation to generate a monomeric nickel hydride complex (see Supporting information). By contrast, [(iPrDI)Ni(µ2-H)]2 (1) is diamagnetic in both benzene-d6 and THF-d8 as established by 1H NMR spectroscopy,40 further supporting the ligand design principle where introduction of the electron-releasing and sterically demanding ipc ADI is expected to disrupt dimer stability.41 Unlike 1H NMR spectra, UV-Vis spectra of 2 collected in both benzene and THF solution exhibit very similar features (see Supporting information). It is likely that the concentration of the monomeric nickel complex in THF is not sufficient to significantly alter the absorbance profile of the mixture.

Deuteration of Arenes. The catalytic HIE performance of 2 was initially assayed using D2 gas as a readily handled and economic surrogate of T2, the preferred radioisotope source in pharmaceutical applications.42 The deuteration of representative pyridines and diazines, known to be preferentially labeled with 1 at positions adjacent to the nitrogen atom,8b was initially assayed. Similar reaction conditions to those used with 1 were applied: 1 mol% precatalyst, 4 atm D2, THF as solvent, 45 °C, 24 h.8b As reported in Table 2, 2 quantitatively exchanged Cα(sp2)–H bonds (11a–d, 11f–k) with high isotopic incorporation in sterically hindered positions (11c, 11g) inaccessible with 1 and (H4-iPrCNC)Fe(N2)2.8b,24 Remarkably, 2 also facilitated HIE of less activated C–H bonds and enabled deuteration at γ(11a–c, 11f–h) and β-positions (11f, 11g) of the (di)azine ring, sites that are inert when 1 was used as a precatalyst. Biologically active N-heteroarenes such as alkaloids (11g, 11h) and xanthine deriv-

ACS Paragon Plus Environment

4

Page 5 of 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

atives (11i–11k) were efficiently labeled with 2 despite the presence of other potential reactive sites. It is noteworthy that enantiomeric purity was retained in nicotine (11g) and that the ketone was tolerated in pentoxifylline (11k) despite precedent for carbonyl insertion reactivity with Ni–H bonds.36 While directed C(sp2)–H bonds in aryl rings ortho to N-heteroarenes were labeled with both 1 and 2, significantly higher levels of deuterium incorporation were obtained with precatalyst 2 (11f). Undirected positions within the aryl ring such as C(sp2)–H bond para to the pyridinyl ring in 11f were exchanged exclusively using 2. Complete deuteration occurred in the most acidic C1–H sites in oxazole, together with partial incorporation in the C3–H and C4–H sites (11l). While the presence of thiazole, a frequently encountered heterocycle in modern drug pipelines, has proven detrimental for several transition metal HIE precatalysts such as 18b or (H4-iPrCNC)Fe(N2)2,24 2 promoted deuteration in this elusive ring with moderate levels of isotopic incorporation (11m).

Table 2. H/D Exchange in Arenesa,b,c

N N

H H

n

X

Dn

Ni

11a–p

N

n

X

N

ipc

n = 1, 2

Deuteration of APIs. Given the outstanding performance with

ipc Ni

[ 2H]11a–p

[(ipc ADI)Ni(µ 2-H)]2, 2 (1 mol%) D 2 (4 atm), THF, 45 °C, 24 h

Unlabeled with [(iPrDI)Ni(µ 2-H)]2, 1

Electron-deficient arenes D 99%

D

N

D

D

D 93% N

92%

D

19%

93%

D

N

D

N

97%

99%

D

13% D

10%

N

D 97%

[ 2H]11d d

D

N Me

D

99%

D

D [ 2H]11f g

[ 2H]11e e,f

N

20%

92%

F D 98%

97%

D

[ 2H]11c

22%

D D

97%

Me

99%

D 81%

D 98% F

F

N

Me [ 2H]11b

99%

[ 2H]11a

F

Me

99%

N

D

99%

D 6%

D 15% D

D 43%

99%

N H D

N

98%

[ 2H]11g nicotine

D 99%

[ 2H]11h rac-anabasine

O O Me O

N

Me

D N 98%

N Me

O

O

Me N

O

[ 2H]11i h caffeine

O

N

N

D N 98%

N Me

O

Me

Me N

N

[ 2H]11j h doxofylline

D N 99%

N Me

O

[ 2H]11k h pentoxifylline

Electron-rich heteroarenes D 28% N D 38%

O

D 16% N D 99%

[ 2H]11l e,f

D 23%

S

14% D

D 50%

[ 2H]11mf,g

D 99%

D N 99% Me

[ 2H]11n g

D N 99% Me [ 2H]11o g

D >99%

common substructures in pharmaceutics and agrochemicals.23a Labeling these challenging heterocycles by homogeneous HIE catalysts typically requires N-directing groups26d or results in only moderate levels of isotopic incorporation.24 Labile nickel hydride dimer 2 provided excellent levels of isotopic enrichment in both Nmethylpyrrole (11n) and N-methylindole (11o). Quantitative labeling of furan at the C2–H position (11p) clearly establishes that the utility of 2 extends beyond the labeling of N-heterocycles. These features taken together with the exchange of arenes containing acidic C–H bonds such as polyfluoroarenes (11e), significantly expands the family of compounds that can be labeled with the new generation nickel precatalyst 2. Remarkably, although C(sp2)–F bond activation has been shown to be thermodynamically favored over C(sp2)–H bond cleavage with low-valent nickel complexes,43 no defluorination was detected in 11e. Overall, the superior activity/scope of 2 in the deuteration of arenes is consistent with the catalyst design principle invoking the favored generation of a catalytically active and potentially more hydridic nickel hydride.44 Importantly, accessing this reactive, potentially more hydridic active species increases both the overall synthetic utility and isotopic incorporation of the HIE method.

O

D >99%

[ 2H]11p d,e

a Reactions conducted with 0.60 mmol 11, 1.0 mol% 2 and 4 atm D2 in THF at 45 °C for 24 h. b%D incorporation was determined by 1H NMR integration relative to an unlabeled C–H site and corroborated by quantitative 13C{1H} NMR spectroscopy. cUnreactive sites with 1 are labeled with blue dots. d%D incorporation was determined by quantitative 13C{1H}} NMR integration. eReaction conducted with 5 mol% 2. f%D incorporation was determined by 1H NMR integration relative to an internal standard and corroborated by quantitative 13 C{1H} NMR spectroscopy. gReaction conducted with 10 mol% 2. h Reaction conducted with 0.14 mmol 11c–k, 12.5 mol% 2 and 1 atm D2.

(hetero)arenes observed with 2, the isotopic labeling of more complex APIs was targeted. Owing to the presence of functional groups that can serve as possible catalyst poisons and the common poor solubility in common organic solvents of these complex molecules, the deuteration of APIs poses additional challenges in catalytic C–H activation as compared to relatively unfunctionalized (hetero)arenes. Using precatalyst 2, a representative family of azine-containing pharmaceuticals and APIs were deuterated with significantly higher overall isotopic enrichment in comparison to 1. The superior results obtained with 2 are likely a composite of two factors: first, higher levels of incorporation were obtained with 2 in positions that can be labeled with both precatalysts and second, 2 was effective for the deuteration of additional sites (Table 3, 12a–g).45 Furthermore, precatalyst 2 not only labeled new sites in azaarenes relative to 1 (βand γ-positions) but was also effective for labeling C(sp2)–H bonds ortho- to –fluorine and alkoxy groups on arenes (12f, 12g). These results are particularly noteworthy given that fluoro- and alkoxyarenes are found in numerous lead compounds as well as pharmaceuticals and yet labeling of such substrates is challenging with 1 and, for the former, with (H4-iPrCNC)Fe(N2)2. These results demonstrate that 2 can be applied to pharmaceuticals that remain unlabeled with 1 (12i) or with both 1 and (H4-iPrCNC)Fe(N2)2 (12h),46 and complements other HIE protocols limited to the labeling of Nheterocycles.8b,45c,47 In addition to the generally high levels of deuterium incorporation observed for complex APIs with 2, additional features of its catalyst performance are worth highlighting. Precatalyst 2 was tolerant of functional groups that often serve as poisons for transition metal catalysts such as -NH and -OH groups as well as N-heterocycle-rich compounds, and is also compatible with aryl chlorides and fluorides, ethers, ketones, acetals, esters, secondary and tertiary amides, trifluoromethyl groups, and sulfoxides. The high fidelity of the reactions, or high chemical recovery yields (81–99 % yield), as well as the generally low levels of unlabeled substrates remaining at the completion of each reaction are also salient features of the methodology.

The higher reactivity and broader applicability of 2 as a HIE precatalyst is also illustrated by the deuteration of electron-rich heteroarenes outside the scope of 1 (11n–p). Pyrroles and indoles are

ACS Paragon Plus Environment

5

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 12

Table 3. H/D Exchange in APIs with 2a,b,c,d

N N

Ni

R

Dn

H

ipc

H

Ni

X

N

X

N

ipc

12a–i

R [ 2H]12a–i

[(ipc ADI)Ni(µ 2-H)]2, 2 (12.5 mol%) D 2 (1 atm), THF, 45 °C, 24 h 16%

95%

D

96%

D

D N

N

D

O

D

F

O

N

D 95%

N

93%

97% D

D

7%

96%

D 98% N

D

4% Me (x3) D

20%

D

Me MK-6096 (Merck) 4.98 D/molecule, 0.00% unlabeled, 99% yield with 1: 2.96 D/molecule e

MK-5395 (Merck) 5.11 D/molecule, 0.00% unlabeled, 83% yield with 1: 1.67 D/molecule e O

D

Me

D

D

O

N

O

OMe

N

8%

OMe N

[ 2H]12d, Buspirone (BMS) 2.04 D/molecule, 0.00% unlabeled, 98% yield with 1: 1.34 D/molecule g

N

[ 2H]12e, Etoricoxib (Merck) 1.39 D/molecule, 1.07% unlabeled, 82% yield with 1: 0.74 D/molecule e

D 6%

Cl

O F D

N 80% D D

D 45%

10%

O

D

66% D 66%

N OH

9%

Flumazenil (Roche) 1.40 D/molecule, 17.01% unlabeled, 98% yield with 1: 0.78 D/molecule g

[ 2H]12f, Papaverine 4.76 D/molecule, 0.00% unlabeled, 85% yield with 1: 1.68 D/molecule e H 88% N D O O D

F

N

77%

OMe

10% D

O

O

D 98%

D

98% 98% D

MeO

10%

Me

Me N

D

D

N

[ 2H]12g,

D 97%

D 98%

12%

19% D

N

EtO

Varenicline (Pfizer)f 3.58 D/molecule, 0.00% unlabeled, 90% yield with 1: 3.28 D/molecule e

Cl

N N

95% D

D 99%

[ 2H]12c,

O S

N 80%

[ 2H]12b,

95%

D 99%

D

O

Me

14% D

88%

HN Me

[ 2H]12a,

N HN

D N

92%

D

O

D

92%

80%

CF 3

12%

N

[ 2H]12h,

(Janssen)h

Haloperidol 1.52 D/molecule, 11.54% unlabeled, 89% yield with 1: 0.36 D/molecule g

16%

D D 95%

50%

D

D

68%

F 68% Paroxetine (GSK)h 3.85 D/molecule, 0.87% unlabeled, 81% yield with 1: 0.00 D/molecule g [ 2H]12i,

a

Reactions conducted with 0.14 mmol 12, 12.5 mol% 2 and 1 atm D2 in THF at 45 °C for 24 h. b%D incorporation was determined by 1H NMR integration relative to an unlabeled C–H site and confirmed by quantitative 13C{1H} NMR spectroscopy and HRMS/IsoPat2 analysis (ref. 48); % unlabeled was determined by HRMS/IsoPat2 analysis. cUnreactive sites with 1 are labeled with blue dots. d% yield refers to chemical recovery yield. eRef. 8b. fReaction carried out at 23 °C. gSee Supporting information. hReaction carried out with 25 mol% 2 at 80 °C in cyclopentyl methyl ether (CPME). A potential drawback of the methodology lies in the synthesis of the well-defined nickel hydride precatalyst 2, which involves a series of transformations whose outcome is sensitive to temperature and scale, and require moisture- and oxygen-free conditions (Schemes 1A and 2A). Because these requirements may limit the application in preparative HIE, efforts were made to develop reaction conditions employing bench stable nickel precursors. As shown in Table 4, precursor (ipcADI)NiBr2 (4), which is air-stable and readily synthesized on multi-gram scale, in conjunction with commercially available NaHBEt3, were effective for the deuteration of representative pharmaceuticals, generating the nickel hydride complex in situ. Importantly, both the degree and sites of deuteration were maintained with this straightforward approach. It is important to note that although H/D exchange reactions using 2 and 4 as nickel precatalysts were conducted in THF solvent to promote the generation of a monomeric active catalyst, a number of APIs are insoluble in this medium. As a result, the use of more polar, pharmaceutically relevant solvents was explored and high levels of isotopic incorporation were equally obtained in the deuteration of a representative API (MK-6096) in MeOH/THF (4:1) with 2 or 4 (see Supporting information). The compatibility of the nickelcatalyzed method with methanol is particularly noteworthy given the anticipated hydricity of the nickel hydride and the encountered instability of transition metal complexes in protic media.49

Tritiation of APIs. The tritiation of APIs was also explored given the importance of the transformation in drug registration and efficacy studies but also because of the additional challenges of a catalytic tritiation method.50 Labeling of metabolically stable sites, compatibility to sensitive functional groups, overall isotope incorporation as well as delivery time are all important metrics.21,22 In general, high specific activity tritiated APIs must have an isotopic enrichment of at least 15 Ci/mmol (0.5 T/molecule). However, specific activities higher than 20 Ci/mmol, often in the range of 50–100 Ci/mmol (2– 4 T/molecule), are required for radioligand binding assays to allow detection of low density binding sites.28,51 Such high levels of isotopic enrichment cannot typically be achieved with late-stage HIE methods8b,19,21,24,26,45a–c,47 and necessitate retrosynthetic pathways that increase the delivery time and radioactive waste. Therefore, clear need exists for developing direct methods that install tritium at various metabolically stable positions of APIs in order to achieve such high specific activities. Table 4. H/D Exchange in APIs with an Air-Stable, Readily-Synthesized Nickel Precatalysta,b,c,d

ACS Paragon Plus Environment

6

Page 7 of 12

Journal of the American Chemical Society c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

N N

Ni

R

R

Br

X

X

(ipc ADI)NiBr2, 4 (25 mol%) NaHBEt 3 (50 mol%) D 2 (1 atm), THF, 45 °C, 24 h

12a–d

70% D

D 95%

95% D

N

Dn

Br

N

O

3%

D O

D 30% F N

D 45%

94% D

N

[ 2H]12aa–ad

D 97%

91%D

N

8%

N

D

47%

CF 3 O

D 9% Me (x3) D 47%

D N 60% HN Me

Me O

Me [ 2H]12aa, MK-6096 4.32 D/molecule, 0.00% unlabeled, 95% yield D 81% N

[ 2H]12ab, MK-5395 3.77 D/molecule, 0.00% unlabeled, 95% yield D 81%

D 98%

11% D

D 98%

81% D

N

HN N D 81%

[ 2H]12ac, Vareniclinee 3.58 D/molecule, 0.00% unlabeled, 93% yield

N

N

O

N

O

N [ 2H]12ad, Buspirone 1.73 D/molecule, 4.28% unlabeled, 98% yield

a

Reactions conducted with 0.14 mmol 12, 25 mol% 4, 50 mol% NaHBEt3 and 1 atm D2 in THF at 45 °C for 24 h. b%D incorporation was determined by 1H NMR integration relative to an unlabeled C– H site and corroborated by quantitative 13C{1H} NMR spectroscopy and HRMS/IsoPat2 analysis; % unlabeled was determined by HRMS/IsoPat2 analysis. cUnreactive sites with 1 are labeled with blue dots. d% yield refers to chemical recovery yield. eReaction carried out at 23 °C. Having demonstrated the high performance and multisite reactivity of the new generation nickel catalyst in the deuteration of arenes and APIs (Tables 2–4), high specific activities required for radioligand synthesis seemed within reach even at the low pressures of T2 gas (∼0.15 atm) that are preferred.21,42 The tritiation of four representative compounds was successfully carried out using (ipcADI)NiBr2 (4) as a precatalyst in combination with NaHBEt3, 0.15 atm T2 and CPME or CPME/NMP (13:1) solvent mixture.52 Remarkably high specific activities of 50–99 Ci/mmol and radiochemical yields ranging 67–562 mCi were obtained (Table 5). As confirmed by 3H NMR spectroscopy, the nickel catalyst incorporated tritium in multiple C(sp2)–H sites in each API, a desirable feature that minimizes the risk of physiological clearance of the isotope label. The mild conditions employed in the nickel-catalyzed method contrast those previously reported, wherein comparable levels of tritium incorporation have only been systematically achieved at elevated temperatures (> 150 °C) in the solid state with heterogeneous supported catalysts.53 Overall, these results demonstrate the unique function and highperformance of the nickel-catalyzed method in achieving tritium incorporations sufficiently high for radioligand binding assays in representative APIs.

CONCLUDING REMARKS In summary, introduction of the sterically demanding and electron-releasing α-diimine chelate (ipcADI) enabled the isolation of elusive monomeric nickel(I) halides (7–9) that are reminiscent of on-cycle intermediates proposed in a range of catalytic C–C and C–X bond formations. Structural, spectroscopic, electrochemical and computational studies established that each complex has a doublet ground state and is best described as a nickel(I) center supported by a redox neutral α-diimine chelate. The bromide variant, (ipcADI)NiBr (8) was used in the synthesis of a labile nickel hydride dimer, [(ip-

ADI)Ni(µ2-H)]2 (2), that likely dissociates in THF solution as supported by 1H NMR spectroscopy and magnetic measurements. Under catalytic deuteration and tritiation conditions, this distinctive dynamic behavior enabled generation of a reactive nickel hydride monomer effective for the exchange of multiple C(sp2)–sites in a diverse range of (hetero)arenes and pharmaceutical compounds with wide functional group compatibility. This result represents a complementary labeling technique of APIs that offers broader scope and greater hydrogen isotope enrichment compared to previously reported HIE methodologies. The tritiation of pharmaceutical compounds was also conducted, providing high specific activities within the requirements for radioligand binding assays (50–99 Ci/mmol), thus addressing a major deficiency among direct H/T exchange methods developed to date. Understanding how the nickel hydride catalyst enables activation of diverse C(sp2)–H bonds under mild and protic conditions are a current focus in our laboratories. It is anticipated that our work will impact nickel catalysis and C–H functionalization fields while expanding the tools currently available for radiolabeling chemists.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental details; characterization data including NMR and EPR spectra of complexes and labeled compounds; electrochemical data; computational methods and results (PDF) Crystallographic information for 2, 7–10 (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected] ORCID Cayetana Zarate: 0000-0002-4002-6147 Máté J. Bezdek: 0000-0001-7860-2894 Paul J. Chirik: 0000-0001-8473-2898 Present Address † Research Triangle Institute, Durham, North Carolina 27709, United States Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS A United States National Science Foundation (NSF) Grant Opportunities for Academic Liaison with Industry (GOALI) grant (CHE1564379) is acknowledged for financial support. C.Z. acknowledges support from a Foundation Ramón Areces postdoctoral fellowship. M.J.B. thanks the Natural Sciences and Engineering Research Council of Canada for a predoctoral fellowship (PGS-D). We thank Kenith Conover and István Pelczer (Princeton University) for assistance with the acquisition of NMR data.

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 12

Table 5. H/T Exchange in APIsa,b,c

N N

Tn

Ni

R

Br

R

Br

X

X

(ipc ADI)NiBr2, 4 (25 mol%) NaHBEt 3 (50 mol%)

12a–c,f

[ 3H]12a–c,f

1 Ci T2, CPME/NMP, 45 °C, 20 h T

T T

T N

N

O

T T

T

T

N

N

O N

N

T

T T

Me T

T

T

O

T

N

T

N

T

T OMe

N

HN

N HN

Me Me [ 3H]12a, MK-6096 d 99.2 Ci/mmol 562.1 mCi

T

CF 3

F

T

Me

T

MeO

T

OMe T

OMe

O [ 3H]12b, MK-5395 53.6 Ci/mmol 219.7 mCi

[ 3H]12c, Vareniclined,e 76.1 Ci/mmol 67.0 mCi

[ 3H]12f, Papaverine 49.5 Ci/mmol 215.7 mCi

a

Reactions conducted with 0.7 µmol 12, 25 mol% 3, 50 mol% NaHBEt3 and 1 Ci T2 (0.15 atm) in CPME/NMP (3:1) at 45 °C for 20 h. bIsotopic incorporation was determined by LC/MS and labeled sites by 3H NMR spectroscopy. cUnreactive sites with 1 are labeled with blue dots. dCPME was e Reaction conducted at 23 °C. used as solvent.

REFERENCES (1) (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances in Homogeneous Nickel Catalysis. Nature 2014, 509, 299–309. (b) Ananikov, V. P. Nickel: The “Spirited Horse” of Transition Metal Catalysis. ACS Catal. 2015, 5, 1964−1971. (c) Campeau, L.-C.; Hazari, N. Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future. Organometallics 2018, 38, 3–35. (2) (a) Zimmermann, P.; Limberg, C. Activation of Small Molecules at Nickel(I) Moieties. J. Am. Chem. Soc. 2017, 139, 4233–4242. (b) Lin, C.-Y.; Power, P. P. Complexes of Ni(I): A “Rare” Oxidation State of Growing Importance. Chem. Soc. Rev. 2017, 46, 5347– 5399. (3) (a) Hu, X. Nickel-Catalyzed Cross Coupling of Non-Activated Alkyl Halides: A Mechanistic Perspective. Chem. Sci. 2011, 2, 1867– 1886. (b) Choi, J.; Fu, G. C. Transition Metal–Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in Cross-Coupling Chemistry. Science 2017, 356, 1–8. (c) Wang, Z.; Yin, H.; Fu, G. C. Catalytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles with Olefins. Nature 2018, 563, 379–383. (d) Sun, S. Z.; Börjesson, M.; Martin-Montero, R.; Martin, R. Site-Selective NiCatalyzed Reductive Coupling of alpha-Haloboranes with Unactivated Olefin. J. Am. Chem. Soc. 2018, 140, 12765−12769. (4) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. Practical Ni-Catalyzed Aryl–Alkyl Cross-Coupling of Secondary Redox-Active Esters. J. Am. Chem. Soc. 2016, 138, 2174–2177. (5) (a) Biswas, S.; Weix, D. J. Mechanism and Selectivity in NickelCatalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2013, 135, 16192−16197. (b) Weix, D. J. Methods and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767−1775. (c) Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79, 4793−4798. (d) Börjesson, M.; Moragas, T.; Gallego, D.; Martin, R. Metal-Catalyzed Carboxylation of Organic (Pseudo)halides with CO2. ACS Catal. 2016, 6, 6739–6749. (6) (a) Twilton, J.; Le, C. C.; Zhang, P.; Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. The Merger of Transition Metal and Photocatalysis. Nat. Rev. Chem. 2017, 1, 0052. (b) Molander, G.; Milligan, J. A.; Phelan, J. P.; Badir, S. O. Recent Advances in Alkyl Carbon-

Carbon Bond Formation by Nickel/Photoredox Cross-Coupling. Angew. Chem., Int. Ed. DOI: 10.1002/anie.201809431. (c) Shields, B. J.; Kudisch, B.; Scholes, G. D.; Doye, A. G. Long-Lived ChargeTransfer States of Nickel(II) Aryl Halide Complexes Facilitate Bimolecular Photoinduced Electron Transfer. J. Am. Chem. Soc. 2018, 140, 3035−3039. (7) (a) Pappas, I.; Treacy, S.; Chirik, P. J. Alkene Hydrosilylation Using Tertiary Silanes with α-Diimine Nickel Catalysts. RedoxActive Ligands Promote a Distinct Mechanistic Pathway from Platinum Catalysts. ACS Catal. 2016, 6, 4105−4109. (b) Léonard, N. G.; Chirik, P. J. Air-Stable α-Diimine Nickel Precatalysts for the Hydrogenation of Hindered, Unactivated Alkenes. ACS Catal. 2018, 8, 342−348. (c) Kuang, Y.; Anthony, D.; Katigbak, J.; Marrucci, F.; Humagain, S.; Diao, T. Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-Controlled trans Selectivity. Chem. 2017, 3, 268−280. (d) Juliá-Hernández, F.; Gaydou, M.; Serrano, E; Van Gemmeren, M.; Martin, R. Ni- and Fe-Catalyzed Carboxylation of Unsaturated Hydrocarbons with CO2. Top Curr Chem (Z) 2016, 374, 45. (8) (a) Palmer, W. N.; Zarate, C.; Chirik, P. J. Benzyltriboronates: Building Blocks for Diastereoselective Carbon−Carbon Bond Formation. J. Am. Chem. Soc. 2017, 139, 2589–2592. (b) Yang, H.; Zarate, C.; Palmer, W. N.; Rivera, N.; Hesk, D.; Chirik, P. J. SiteSelective Nickel-Catalyzed Hydrogen Isotope Exchange in NHeterocycles and Its Application to the Tritiation of Pharmaceuticals. ACS Catal. 2018, 8, 10210−10218. (9) Isolated example of T-shaped, three-coordinate nickel(I)–X complexes stabilized by tridentate bis(oxazolinylmethylidene)pyrrolidinido chelates where the X ligand is embedded in the pincer backbone (NNNRNi): Rettenmeier, C.; Wadepohl, H.; Gade, L. H. Stereoselective Hydrodehalogenation via a Radical-Based Mechanism Involving T-Shaped Chiral Nickel(I) Pincer Complexes. Chem. Eur. J. 2014, 20, 9657–9665. (10) Diimine nickel(I) species, generated via electrochemical reduction of nickel(II) precursors, whose nature has not been unambiguously established: Klein, A.; Kaiser, A.; Sarkar, B.; Wanner, M.; Fiedler, J. The Electrochemical Behaviour of Organonickel Complexes: Mono-, Di- and Trivalent Nickel. Eur. J. Inorg. Chem. 2007, 965–976. (11) Selected references for structurally characterized threecoordinate nickel(I) complexes stabilized by large nacnac ligands: (a) Holland, P. L.; Cundari, T. R.; Perez, L. L.; Eckert, N. A.;

ACS Paragon Plus Environment

Page 9 of 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Lachicotte, R. J. Electronically Unsaturated Three-Coordinate Chloride and Methyl Complexes of Iron, Cobalt, and Nickel. J. Am. Chem. Soc. 2002, 124, 14416–14424. (b) Bai, G.; Wei, P.; Stephan, D. W. A β-Diketiminato-Nickel(II) Synthon for Nickel(I) Complexes. Organometallics 2005, 24, 5901-5908. (c) Eckert, N. A.; Dinescu, A.; Cundari, T. R.; Holland, P. L. A T-Shaped Three-Coordinate Nickel(I) Carbonyl Complex and the Geometric Preferences of Three-Coordinate d9 Complexes. Inorg. Chem. 2005, 44, 7702– 7704. (d) Kogut, E.; Wiencko, H. L.; Zhang, L.; Cordeau, D. E.; Warren, T. H. A Terminal Ni(III)-Imide with Diverse Reactivity Pathways. J. Am. Chem. Soc. 2005, 127, 11248–11249. (12) Selected references for structurally characterized threecoordinate nickel(I) complexes stabilized by large NHC ligands: (a) Miyazaki, S.; Koga, Y.; Matsumoto, T.; Matsubara, K. A New Aspect of Nickel-Catalyzed Grignard Cross-Coupling Reactions: Selective Synthesis, Structure, and Catalytic Behavior of a T-shape ThreeCoordinate Nickel(I) Chloride Bearing a Bulky NHC Ligand. Chem. Commun. 2010, 46, 1932−1934. (b) Davies, C. J. E.; Page, M. J.; Ellul, C. E.; Mahon, M. F.; Whittlesey, M. K. Ni(I) and Ni(II) RingExpanded N-Heterocyclic Carbene Complexes: C–H Activation, Indole Elimination and Catalytic Hydrodehalogenation. Chem. Commun. 2010, 46, 5151–5153. (c) Nagao, S.; Matsumoto, T.; Koga, Y.; Matsubara, K. Monovalent Nickel Complex Bearing a Bulky N-Heterocyclic Carbene Catalyzes Buchwald-Hartwig Amination of Aryl Halides under Mild Conditions. Chem. Lett. 2011, 40, 1036–1038. (d) Zhang, K.; Conda-Sheridan, M.; Cooke, S. R.; Louie, J. N-Heterocyclic Carbene Bound Nickel(I) Complexes and Their Roles in Catalysis. Organometallics 2011, 30, 2546−2552. (e) Matsubara, K.; Fukahori, Y.; Inatomi, T.; Tazaki, S.; Yamada, Y.; Koga, Y.; Kanegawa, S.; Nakamura, T. Monomeric ThreeCoordinate N-Heterocyclic Carbene Nickel(I) Complexes: Synthesis, Structures, and Catalytic Applications in Cross-Coupling Reactions. Organometallics 2016, 35, 3281−3287. (f) Beattie, D. D.; Lascoumettes, G.; Kennepohl, P.; Love, J. A.; Schafer, L. L. Disproportionation Reactions of an Organometallic Ni(I) Amidate Complex: Scope and Mechanistic Investigations. Organometallics 2018, 37, 1392−1399. (13) Selected references for structurally characterized threecoordinate nickel(I) complexes stabilized by large phosphine ligands: (a) Bradley, D. C.; Hursthouse, M. B.; Smallwood, R. J., Welch, A. J. Three-Coordinated Complexes of Cobalt(II) and Nickel(I) Containing Bistrimethylsilylamino- and Triphenylphosphine-Ligands J.C.S. Chem. Comm. 1972, 872–873. (b) Schäfer, H.; Binder, D. Diphosphenkomplexe (DRPE)Ni[η2-(PR')2] und die Struktur von (DCPE)NiP(SiMe3)2. Z. anorg. allg. Chem. 1987, 546, 79–98. (c) Ellis, D. D.; Spek, A. L. Chlorobis(triphenylphosphine)-Nickel(I) Tetrahydrofuran Solvate and an Unsolvated Trigonal Phase of Chlorotris(triphenylphosphine)-Nickel(I). Acta Cryst. 2000, C56, 1067– 1070. (d) Kitiachvili, K. D.; Mindiola, D. J.; Hillhouse, G. L. Preparation of Stable Alkyl Complexes of Ni(I) and Their One-Electron Oxidation to Ni(II) Complex Cations. J. Am. Chem. Soc. 2004, 126, 10554–10555. (e) Iluc, V. M.; Hillhouse, G. L. Arrested 1,2Hydrogen Migration from Silicon to Nickel upon Oxidation of a Three-Coordinate Ni(I) Silyl Complex. J. Am. Chem. Soc. 2010, 132, 11890–11892. (f) Iluc, V. M.; Hillhouse, G. L. Hydrogen-Atom Abstraction from Ni(I) Phosphido and Amido Complexes Gives Phosphinidene and Imide Ligands. J. Am. Chem. Soc. 2010, 132, 15148–15150. (g) Chao, S. T.; Lara, N. C.; Lin, S.; Day, M. W.; Agapie, T. Reversible Halide-Modulated Nickel–Nickel Bond Cleavage: Metal–Metal Bonds as Design Elements for Molecular Devices. Angew. Chem., Int. Ed. 2011, 50, 7529 –7532. (h) Beck, R.; Shoshani, M.; Krasinkiewicz, J.; Hatnean, J. A.; Johnson, S. A. Synthesis and Chemistry of Bis(triisopropylphosphine) Nickel(I) and Nickel(0) Precursor. Dalton Trans. 2013, 42, 1461–1475. (i) Yin, G.; Kalvet, I.; Englert, U.; Schoenebeck, F. Fundamental Studies and Development

of Nickel-Catalyzed Trifluoromethylthiolation of Aryl Chlorides: Active Catalytic Species and Key Roles of Ligand and Traceless MeCN Additive Revealed. J. Am. Chem. Soc. 2015, 137, 4164−4172. (j) Guard, L. M.; Mohadjer Beromi, M.; Brudvig, G. W.; Hazari, N.; Vinyard, D. J. Comparison of dppf-Supported Ni Precatalysts for the Suzuki−Miyaura Reaction: The Observation and Activity of Ni(I). Angew. Chem., Int. Ed. 2015, 54, 13352−13356. (k) Kalvet, I.; Guo, Q.; Tizzard, G. J.; Schoenebeck, F. When Weaker Can Be Tougher: The Role of Oxidation State (I) in P- vs N-LigandDerived Ni-Catalyzed Trifluoromethylthiolation of Aryl Halides. ACS Catal. 2017, 7, 2126−2132. (l) Mohadjer Beromi, M.; Nova, A.; Balcells, A. M.; Brasacchio, D.; Brudvig, G. W.; Guard, L. M.; Hazari, N.; Vinyard, D. J. Mechanistic Study of an Improved Ni Precatalyst for Suzuki−Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species. J. Am. Chem. Soc. 2017, 139, 922−936. (m) Lombardi, B. M. P.; Brown, R. M.; Gendy, C.; Chang, C. Y.; Chivers, T.; Roesler, R. Nickel and Platinum PCP Pincer Complexes Incorporating an Acyclic Diaminoalkyl Central Moiety Connecting Imidazole or Pyrazole Rings. Organometallics 2017, 36, 3250–3256. (n) Mohadjer Beromi, M.; Banerjee, G.; Brudvig, G. W.; Hazari, N.; Mercado, B. Q. Nickel(I) Aryl Species: Synthesis, Properties, and Catalytic Activity. ACS Catal. 2018, 8, 2526−2533. (14) For other structurally characterized three-coordinate (or twocoordinate) nickel(I) complexes stabilized by large anionic or σdonor ligands, see ref. 2b. (15) (a) Ref. 13k, 13l. (b) Bajo, S.; Laidlaw, G.; Kennedy, A. R.; Sproules, S.; Nelson, D. J. Oxidative Addition of Aryl Electrophiles to a Prototypical Nickel(0) Complex: Mechanism and Structure/Reactivity Relationships. Organometallics 2017, 36, 1662−1672. (16) Balcells, D.; Nova, A. Designing Pd and Ni Catalysts for CrossCoupling Reactions by Minimizing Off-Cycle Species. ACS Catal. 2018, 8, 3499−3515. (17) There is not a general consensus on the nature of the active catalysts in cross-coupling reactions catalyzed by NHC nickel(I) complexes. Some reports proposed monomeric [(NHC)NiX] as the active species (ref. 12c–e) while others postulated that oxidative addition takes place in the dimeric [(NHC)NiX]2 (Matsubara, K.; Yamamoto, H.; Miyazaki, S.; Inatomi, T.; Nonaka, K.; Koga, Y.; Yamada, Y.; Veiros, L. F.; Kirchner, K. Dinuclear Systems in the Efficient Nickel-Catalyzed Kumada−Tamao−Corriu Cross-Coupling of Aryl Halides. Organometallics 2017, 36, 255−265). (18) Other coupling reactions were nickel(I) species supported by phosphine ligands (not isolated or unambiguously detected) are proposed as catalytic intermediates: (a) Morrell, D. G.; Kochi, J. K. Mechanistic Studies of Nickel Catalysis in the Cross Coupling of Aryl Halides with Alkylmetals. The Role of Arylalkylnickel(II) Species as Intermediates. J. Am. Chem. Soc. 1975, 97, 7262–7270. (b) Tsou, T. T.; Kochi, J. K. Mechanism of Oxidative Addition. Reaction of Nickel(0) Complexes with Aromatic Halides. J. Am. Chem. Soc. 1979, 101, 6319−6332. (c) Amatore, C.; Jutand, A. Rates and Mechanism of Biphenyl Synthesis Catalyzed by Electrogenerated Coordinatively Unsaturated Nickel Complexes. Organometallics 1988, 7, 2203– 2214. (19) (a) Keen, A. L.; Johnson, S. A. Nickel(0)-Catalyzed Isomerization of an Aryne Complex:  Formation of a Dinuclear Ni(I) Complex via C−H Rather than C−F Bond Activation. J. Am. Chem. Soc. 2006, 128, 1806–1807. (b) Keen, A. L.; Doster, M.; Johnson, S. A. 1,4Shifts in a Dinuclear Ni(I) Biarylyl Complex: A Mechanistic Study of C–H Bond Activation by Monovalent Nickel. J. Am. Chem. Soc. 2007, 129, 810−819. (c) Najafian, A.; Cundari, T. R. C−H Activation of Methane by Nickel−Methoxide Complexes: A Density Functional Theory Study. Organometallics 2018, 37, 3111−3121. (20) Initial reported synthesis of 1: Dong, Q.; Zhao, Y.; Su, Y.; Su, J.H.; Wu, B.; Yang, X.-J. Synthesis and Reactivity of Nickel Hydride

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Complexes of an α-Diimine Ligand. Inorg. Chem. 2012, 51, 13162– 13170. Alternative synthetic route developed by our group and applied in novel olefin hydrogenation and HIE methodologies: ref. 7a and 7b. (21) (a) Hesk, D.; Lavey, C. F.; McNamara, P. Tritium Labeling of Pharmaceuticals by Metal-Catalysed Exchange Methods. J. Labelled Compd. Radiopharm. 2010, 53, 722−730. (b) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C-H Functionalisation for Hydrogen Isotope Exchange. Angew. Chem. Int. Ed. 2018, 57, 2–28. (22) (a) Marathe, P. H., Shyu, W. C.; Humphreys, W. G. The Use of Radiolabeled Compounds for ADME Studies in Discovery and Exploratory Development. Curr. Pharm. Des. 2004, 10, 2991–3008. (b) Elmore, C. S. The Use of Isotopically Labeled Compounds in Drug Discovery. Annu. Rep. Med. Chem. 2009, 44, 515–534. (c) Lockley, W. J. S., McEwen, A.; Cooke, R. Tritium: A Coming of Age for Drug Discovery and Development ADME Studies. J. Label Compd. Radiopharm. 2012, 55, 235–257. (d) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf, L. Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies. Chem. Res. Toxicol. 2012, 25, 532–542. (e) Elmore, C. S.; Bragg, R. A. Isotope Chemistry; A Useful Tool in the Drug Discovery Arsenal. Bioorg. Med. Chem. Lett. 2015, 25, 167–171. (f) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences. Angew. Chem., Int. Ed. 2018, 57, 1758−1784. (23) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. (b) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic Synthesis Provides Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10, 383–394. (24) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. IronCatalysed Tritiation of Pharmaceuticals. Nature 2016, 529, 195−199. (25) Additionally, our group recently reported the ability of [(iPrDI)Co(CH2SiMe3)2] as active precatalyst for the H/D exchange at benzylic C(sp3)–H sites of alkylarenes: Palmer, W. N.; Chirik, P. J. Cobalt-Catalyzed Stereoretentive Hydrogen Isotope Exchange of C(sp3)−H Bonds. ACS Catal. 2017, 7, 5674−5678. (26) Selected references for iridium-catalyzed HIE methods: (a) Brown, J. A.; Cochrane, A. R.; Irvine, S.; Kerr, W. J.; Mondal, B.; Parkinson, J. A.; Paterson, L. C.; Reid, M.; Tuttle, T.; Andersson, S.; Nilsson, G. N. The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange. Adv. Synth. Catal. 2014, 356, 3551−3562. (b) Kerr, W. J.; Reid, M.; Tuttle, T. Iridium-Catalyzed C−H Activation and Deuteration of Primary Sulfonamides: An Experimental and Computational Study. ACS Catal. 2015, 5, 402−410. (c) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M.; Rojahn, P.; Weck, R. Expanded Applicability of Iridium(I) NHC/Phosphine Catalysts in Hydrogen Isotope Exchange Processes with Pharmaceutically-Relevant Heterocycles. Tetrahedron 2015, 71, 1924−1929. (d) Kerr, W. J.; Lindsay, D. M.; Owens, P. K.; Reid, M.; Tuttle, T.; Campos, S. Site-Selective Deuteration of NHeterocycles via Iridium-Catalyzed Hydrogen Isotope Exchange. ACS Catal. 2017, 7, 7182−7186. (e) Burhop, A.; Prohaska, R.; Weck, R.; Atzrodt, J.; Derdau, V. Burgess Iridium(I)-Catalyst for Selective Hydrogen Isotope Exchange. J. Labelled Compd. Radiopharm. 2017, 60, 343−348. (f) Valero, M.; Burhop, A.; Jess, K.; Weck, R.; Tamm, M.; Atzrodt, J.; Derdau, V. Evaluation of a P,N-Ligated Iridium(I) Catalyst in Hydrogen Isotope Exchange Reactions of Aryl and Heteroaryl Compounds. J. Labelled Compd. Radiopharm. 2018, 61, 380−385. (27) For a related pyridine-promoted dissociation of a Ni(I)–X dimer, see ref. 12e.

Page 10 of 12

(28) (a) Bylund, D. B.; Toews, M. L. Radioligand Binding Methods: Practical Guide and Tips. Am. J. Physiol. 1993, 265(5 Pt 1):L421–9. (b) McKinney, M.; Raddatz, R. Practical Aspects of Radioligand Binding. Curr. Protoc. Pharmacol. 2006, 33, 1.3.1. (c) Lever, S. Z.; Fan, K.-H.; Lever, J. R. Tactics for Preclinical Validation of ReceptorBinding Radiotracers. Nucl. Med. Biol. 2017, 44, 4–30. (29) Characterization data of 7 and 9 including solid-state structures, X-band EPR spectra and solid-state magnetic moments is reported in the Supporting Information. Bond metrics are shown on Table 1. (30) Meinhard, D.; Reuter, P.; Rieger, B. Activation of Polymerization Catalysts:  Synthesis and Characterization of Novel Dinuclear Nickel(I) Diimine Complexes. Organometallics 2007, 26, 751–754. (31) 8 is unstable to air but stable in solid state under N2 atmosphere at -35 °C for at least six months. (32) The monomeric/dimeric nature of the solid-state structure of [(dppf)NiBr] depends on the solvent of crystallization. A monomeric solid-state structure was obtained from benzene/hexanes (ref. 13k) while from THF the structure is dimeric (ref. 15b). (33) Muresan, N.; Lu, C. C.; Ghosh, M.; Peters, J. C.; Abe, M.; Henling, L. M.; Weyhermöller, T.; Bill, E.; Wieghardt, K. Bis(αdiimine)iron Complexes: Electronic Structure Determination by Spectroscopy and Broken Symmetry Density Functional Theoretical Calculations. Inorg. Chem. 2008, 47, 4579−4590. (34) Assignment by comparison with electrochemical data of [(iPrDAI)Ni(Mes)Br] (Mes = mesityl; iPrDAI = N,N’-diisopropyl-1,2ethanediimine) reported in ref. 10. (35) Ciszewski, J. T.; Mikhaylov, D. Y.; Holin, K. V.; Kadirov, M. K.; Budnikova, Y. H.; Sinyashin, O.; Vicic, D. A. Redox Trends in Terpyridine Nickel Complexes. Inorg. Chem. 2011, 50, 8630–8635. (36) Eberhardt, N. A.; Guan, H. Nickel Hydride Complexes. Chem. Rev. 2016, 116, 8373−8426. (37) (a) Jonas, K.; Wilke, G. Hydrogen Bonds in a Ni−Ni System. Angew. Chem., Int. Ed. Engl. 1970, 9, 312−313. (b) Pfirrmann, S.; Limberg, C.; Herwig, C.; Stößer, R; Ziemer, B. A Dinuclear Nickel(I) Dinitrogen Complex and its Reduction in Single-Electron Steps. Angew. Chem., Int. Ed. 2009, 48, 3357 –3361. (38) 2 is unstable to air but stable under N2 atmosphere in solid state or in THF solution at -35 °C for at least six months. (39) The magnetism of a benzene-d6 and THF-d8 solution of 2 at 23 °C using ferrocene as an internal standard was determined according to the Evans procedure modified for the use with NMR spectrometer with superconducting (see Supporting Information): (a) Evans, D. F. The Determination of the Paramagnetic Susceptibility of Substances in Solution by Nuclear Magnetic Resonance. J. Chem. Soc. 1959, 2003–2005. (b) Sur, S. K. Measurement of Magnetic Susceptibility and Magnetic Moment of Paramagnetic Molecules in Solution by High-Field Fourier Transform NMR Spectroscopy. J. Magn. Reson. 1989, 82, 169–173. While diamagnetic in benzene-d6, 2 generated paramagnetic species in THF-d8. (40) The EPR spectrum of 1 in Et2O at 298 K reported by Yang and co-workers (see ref. 20) suggested that this complex is paramagnetic. Our group has since devised an alternative synthetic route to 1 (see refs. 7a and 7b) and demonstrated that the compound is indeed diamagnetic based on 1H NMR spectroscopic data (in benzene-d6 and THF-d8) and lack of an EPR signal (in Et2O at 298 K). The spectrum reported by Yang et al. is the sodium salt of the ligand, Na[iPrDI]. The data were readily reproduced from treatment of the free chelate with one equivalent of sodium metal in THF and recording the EPR spectrum in Et2O at 298 K. (41) An alternative explanation for the observed paramagnetism of 2 involves THF coordination, resulting in an altered geometry and magnetism at a nickel center, without disruption of the dimeric core. However, this process would likely be more favored in the less sterically hindered complex 1, which does not exhibit broadened 1H

ACS Paragon Plus Environment

Page 11 of 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

NMR signals that would be expected in the event of reversible THF coordination. (42) T2 is the preferred radioisotope source by virtue of its higher stability, isotopic purity, availability and ease to handle in micromolar scale as compared to other reagents (i.e. THO, MeOT). (43) (a) Reinhold, M.; McGrady, J. E.; Perutz, R. N. A Comparison of C−F and C−H Bond Activation by Zerovalent Ni and Pt:  A Density Functional Study. J. Am. Chem. Soc. 2004, 126, 5268–5276. (b) Johnson, S. A.; Taylor, E. T.; Cruise, S. J. A Combined Experimental and Computational Study of Unexpected C−F Bond Activation Intermediates and Selectivity in the Reaction of Pentafluorobenzene with a (PEt3)2Ni Synthon. Organometallics 2009, 28, 3842–3855. (44) Evidence against the possibility that the more sterically demanding ipcADI chelate dissociates to form catalytically active heterogeneous nickel species was provided by control experiment (see Supporting Information for details). (45) 25 mol% [Ni] was used for comparison with 1 (ref. 8b), although a loading as low as 2 mol% [Ni] is effective for labeling unfunctionalized arenes (Table 2). The cost and loading of the catalyst are relatively unimportant in radiolabeling of APIs given that reactions are generally conducted in a micromolar scale and the principal metrics of success are the T2 pressure and levels of isotopic incorporation. Indeed, high catalyst loadings are routinely employed in the radiolabeling of multi-functional medicinal compounds to boost the isotope enrichment. It is important to note that different HIE methods may require superstoichiometric amounts of precious palladium or iridium catalysts: (a) Yang, H.; Dormer, P. G.; Rivera, N. R.; Hoover, A. J. Palladium(II)-Mediated C-H Tritiation of Complex Pharmaceuticals. Angew. Chem., Int. Ed. 2018, 57, 1883–1887; (b) Salter, R. The Development and Use of Iridium(I) Phosphine Systems for Ortho‐Directed Hydrogen‐Isotope Exchange. J. Labelled Comp. Radiopharm. 2010, 53, 645–657; or stoichiometric formation of preactivated intermediates: (c) Koniarczyk, J. L.; Hesk, D.; Overgard, A.; Davies, I. W.; McNally, A. A General Strategy for Site-Selective Incorporation of Deuterium and Tritium into Pyridines, Diazines, and Pharmaceuticals. J. Am. Chem. Soc. 2018, 140, 1990−1993. (46) Note that higher precatalyst loading (50 mol%) and temperature (80 °C) were employed. (47) Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.; Rivera, N. R.; Colletti, S. L.; Davies, I. W.; MacMillan, D. W. C. PhotoredoxCatalyzed Deuteration and Tritiation of Pharmaceutical Compounds. Science 2017, 358, 1182–1187. (48) Gruber, C. C.; Oberdorfer, G.; Voss, C. V.; Kremsner, J. M.; Kappe, C. O.; Kroutil, W. An Algorithm for the Deconvolution of Mass Spectroscopic Patterns in Isotope Labeling Studies. Evaluation for the Hydrogen-Deuterium Exchange Reaction in Ketones. J. Org. Chem. 2007, 72, 5778–5783. (49) Selected references: (a) Tani, K.; Iseki, A.; Yamagata, T. Facile Oxidative Addition of O–H Bonds of Methanol and Water to IrI Complexes Having Peraryldiphosphane Ligands. Angew. Chem., Int. Ed. 1998, 37, 3381–3383. (b) Blum, O.; Milstein, D. Oxidative Addition of Water and Aliphatic Alcohols by IrCl(trialkylposphine)3. J. Am. Chem. Soc. 2002, 124, 11456−11467. (c) Martínez-Prieto, L. M.; Ávila, E.; Palma, P.; Álvarez, E.; Cámpora, J. β-Hydrogen Elimination Reactions of Nickel and Palladium Methoxides Stabilised by PCP Pincer Ligands. Chem. Eur. J. 2015, 21, 9833–9849. (d) Martínez-Prieto, L. M.; Palma, P.; Álvarez, E.; Cámpora, J. Nickel Pincer Complexes with Frequent Aliphatic Alkoxo Ligands [(iPrPCP)NiOR] (R = Et, nBu, iPr, 2 hydroxyethyl). An Assessment of the Hydrolytic Stability of Nickel and Palladium Alkoxides. Inorg. Chem. 2017, 56, 13086−13099. (e) Zhong, H.; Friedfeld, M. R.; CamachoBunquin, J.; Sohn, H.; Yang, C.; Delferro, M.; Chirik, P. J. Exploring the Alcohol Stability of Bis(phosphine) Cobalt Dialkyl Precatalysts in Asymmetric Alkene Hydrogenation. Organometallics 2018, 38,149–156.

(50) Additional challenges: radioactivity and consequent low preferred pressures of T2 (∼0.15 atm), generally employed micromolar scale and intrinsic kinetic isotope effects (ref. 21, 22). (51) In radioligands, the site of tritium incorporation is generally inconsequential as far as the positions labeled are unexchangeable under physiological conditions. Radioligand binding studies are the most common and convenient assays methods developed for lead compounds approaching a candidate selection decision, although data is typically generated in the lead identification and early phases of the lead optimization process (ref. 2222d, 28). (52) CPME/NMP (13:1) was used as solvent mixture in the tritiation of substrates that are not completely soluble in CPME (MK5395, 12b and papaverine, 12f). (53) Zolotarev, Y. A.; Dadayan, A. K.; Borisov, Y. A.; Kozik, V. S. Solid State Isotope Exchange with Spillover Hydrogen in Organic Compounds. Chem. Rev. 2010, 110, 5425–5446.

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For Table of Contents Use Synthesis & study of relevant 3-coordinate Ni(I) monomers ...

Me Me R n

X n = 1, 2

+ D2 or T2

X = C, N, O, S

N N

R

locking group bulky/aliphatic R

Ni H

Dm(Tm) X

n

Multi-site labeling

Rational catalyst design Improved activity / scope

Broad family of drugs High isotope enrichment (50–100 Ci/mmol)

... leads to improved C–H functionalization

ACS Paragon Plus Environment

Page 12 of 12