Distinguishing Competing Mechanistic Manifolds for C(acyl)–N Functionalization by a Ni/N-Heterocyclic Carbene Catalyst System

Carboxylic acid derivatives are appealing alternatives to organohalides as cross-coupling electrophiles for fine chemical synthesis due to their prevalence in biomass and bioactive small molecules as well as their ease of preparation and handling. Within this family, carboxamides comprise a versatile electrophile class for nickel-catalyzed coupling with carbon and heteroatom nucleophiles. However, even state-of-the-art C(acyl)–N functionalization and cross-coupling reactions typically require high catalyst loadings and specific substitution patterns. These challenges have proven difficult to overcome, in large part due to limited experimental mechanistic insight. In this work, we describe a detailed mechanistic case study of acylative coupling reactions catalyzed by the commonly employed Ni/SIPr catalyst system (SIPr = 1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidine). Stoichiometric organometallic studies, in situ spectroscopic measurements, and crossover experiments demonstrate the accessibility of Ni(0), Ni(I), and Ni(II) resting states. Although in situ precatalyst activation limits reaction efficiency, the low concentrations of active, SIPr-supported Ni(0) select for electrophile-first (closed-shell) over competing nucleophile-first (open-shell) mechanistic manifolds. We anticipate that the experimental insights into the nature and controlling features of these distinct pathways will accelerate rational improvements to cross-coupling methodologies involving pervasive carboxamide substrate motifs.


General Considerations
All air-and moisture-sensitive techniques were carried out using standard Schlenk technique on a Schlenk line or a high-vacuum line 1 or in an M. Braun glovebox containing an atmosphere of N2.
The glovebox was equipped with vacuum feed-throughs, a cold well, and a freezer for storing samples at -30 °C. Colors are described in comparison to the complete list of Prismacolor colored pencils. 2 Column chromatography was performed on SiliaFlash P60 (230-400 mesh) silica gel from SiliCycle using standard glass columns. Thin-layer chromatography (TLC) was performed using aluminum-backed plates pre-coated with silica gel and a fluorescent indicator for visualization upon UV irradiation.

Materials
Reagents were purchased in reagent grade from commercial suppliers and used without further purification unless described otherwise. Bis(cyclooctadiene) nickel [Ni(cod)2] was purchased from Strem and stored at -30 °C in the glovebox. SIPr•HCl was prepared according to a reported literature procedure. 3 [(SIPr)Ni( 6 −C6H6)] (6) was synthesized according to a modified literature procedure. 4 [(SIPr)Ni(−OPh)]2 dimer 7 was prepared as described previously. 5 Solvents (acetonitrile, diethyl ether, n-pentane, tetrahydrofuran, and toluene) used for air-and moisture-sensitive manipulations were dried and deoxygenated by passage through an activated alumina column and stored over activated molecular sieves. 6,7 Deuterated solvents used for NMR spectroscopy of air-and moisture-sensitive compounds were stirred over sodium (C6D6, THF-d8) or calcium hydride (CD3CN) and distilled prior to storage in the glovebox.

Instrumentation and Software
Nuclear Magnetic Resonance (NMR) and Electron Paramagnetic Resonance spectroscopies were performed at the University of Rochester, Department of Chemistry, Magnetic Resonance Facility. NMR spectra were recorded at 25 °C on a Bruker 400 or 500 Avance I spectrometer operating at: 400.13 or 500.20 MHz ( 1 H NMR), 100.25 or 125.78 MHz ( 13 C{ 1 H} NMR), or 376.43 MHz ( 19 F{ 1 H} NMR). Chemical shifts for 1 H and 13 C are reported in parts per million downfield from tetramethylsilane (SiMe4) and are referenced in ppm relative to the NMR solvent according to literature values: 7 δ( 1 H) = 7.16, δ( 13 C) = 128.1 for C6D6.; δ( 1 H) = 7.26, δ( 13 C) = 77.2 for CDCl3. Chemical shifts for 19 F are reported in parts per million downfield from neat CFCl3 and are referenced in ppm relative to α,α,α-trifluorotoluene (PhCF3) added as an internal standard. 1 H NMR data for diamagnetic substances are reported as follows: chemical shift, (multiplicity, coupling constant in Hz, integration) where s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. 13 C and 19 F NMR data for diamagnetic substances are reported as lists of chemical shifts. NMR spectra were processed using the MestReNova software suite. Electron paramagnetic resonance (EPR) spectra were recorded at 10 K, 9.38 GHz on a Bruker EMXplus spectrometer equipped with a 4119HS cavity and an Oxford ESR-900 helium flow cryostat. EPR spectra were fit using EasySpin in Matlab. 8 Mass spectrometry was performed at the University of Rochester, Department of Chemistry, Instrumentation Facility. Liquid Chromatography Mass Spectrometry (LC-MS) data were collected performed using Agilent Technology 1260 Infinity II LC system with an Advion Expression CMS detector using electrospray ionization (ESI). Gas chromatography Mass Spectrometry (GC-MS) data were collected on a Shimadzu GCMS-2010 using helium carrier gas and a ZB-XLB 0.25 mm x 30 m x 0.25 um (Phenomenex) column and EI (Electron Impact) ionization at 70 V and 60 uA emission current.

[(SIPr)
Ni( 6 −C6H6)] (6) was synthesized according to a modified literature procedure. 4 In a nitrogen-filled glovebox, three separate scintillation vials were prepared. Vial A was charged with Ni(cod)2 (0.0185 g, 0.067 mmol, 1.0 equiv.). Vial B was charged with SIPr•HCl (0.0295 g, 0.07 mmol, 1.1 equiv.), and a magnetic stir bar. Vial C was charged with KO t Bu (0.0078 g, 0.070 mmol, 1.0 equiv.) and 2 mL C6H6. Vial C was added to vial B, then rinsed with an additional 1 mL of C6H6. Vial B was stirred for ~ 5 min at room temperature, then vial A was added to vial B. The mixture was stirred, then transferred to a 100 mL solvent tube and sealed under N2. The flask was brought outside of the glovebox and degassed through a freeze-pump-thaw sequence (3x). The flask was frozen in a liquid N2 bath, then H2 (2.4 atm) was added via vacuum gas transfer. The reaction mixture was thawed slowly, then returned to the glovebox and stirred for 30 minutes at room temperature under H2 atmosphere. Upon completion, the mixture was filtered through celite with C 6 H 6 (~ 12 mL) and concentrated in vacuo to a crimson lake-colored solid (0.0333 g, 94%). If necessary, the complex was purified by recrystallization from HMDSO. Spectral data were in accordance with the literature. 4,13

General Procedure for Oxidative Addition of Twisted Amides:
In a nitrogen-filled glovebox, a scintillation vial was charged with [(SIPr)Ni(( 6 −C6H6)] (6) (0.040 g, 0.074 mmol, 1.0 equiv.), amide (1) (0.074 mmol, 1.0 equiv), and a magnetic stir bar. C6H6 (3 mL) was added, and the reaction was stirred at room temperature for 2 hours. After 2 hours, the mixture was concentrated in vacuo and washed 3 times with pentane, which was decanted to yield a yellow solid. The solid was dried in vacuo and characterized via NMR prior to recrystallization.

Attempted Oxidative Addition with Alternative Substrates:
In a nitrogen-filled glovebox, two separate 1-dram vials were charged with (A) [(SIPr)Ni(( 6 −C6H6)] (6) (1.0 equiv, 0.09 mmol) and (B) amide (1.0 equiv., 0.09 mmol). The [Ni] complex from vial A was transferred to vial B as using small portions of C6D6 (0.7 mL total). All contents of vial B were transferred to a JYoung NMR tube using a glass pipet, which was then sealed and removed from the glovebox. The JYoung NMR tube was kept at room temperature (~22 °C), monitoring periodically by 1 H NMR spectroscopy. If little-to-no conversion was observed after 3 hours, the vial was transferred to a 50 °C in a bead bath, and 1 H NMR spectra was collected periodically at 25 °C. Conversion was monitored through the disappearance of diagnostic signals corresponding to 1 and 6 correlated with the appearance of new resonances. If new products were detected as a substantial portion of the crude material, the JYoung tube was returned to the glovebox and the contents transferred to a scintillation via. The mixture was concentrated in vacuo and washed 3 times with pentane, which was decanted to yield a yellow solid. The solid was dried in vacuo and characterized via NMR prior to recrystallization.

With N-methyl-N-phenylpicolinamide (1h)
negligible conversion was observed after 3 hours at ambient temperature. Upon heating to 50 °C for 21 hours, increased levels of a new product were detected. However, attempts to isolate and characterize the product(s) fully were unsuccessful. Figure S11. 1 H NMR (400 MHz, C6D6) spectra monitoring reactivity between 1h and 6.

With N-methyl-N-(pyridin-2-yl)benzamide (1i)
near-complete consumption of 6 was observed within 3 hours at ambient temperature; however, remaining amide 1i was also observed. Single-crystals suitable for X-ray diffraction analysis were obtained from the crude material and revealed to formation of oxidative addition complex 8i (see Section 8.5). However, attempts to isolate analytically pure material have not been successful.

Catalytic Reactions with In Situ Precatalyst Generation
Catalytic reactions were performed in analogy to the procedure reported originally. 14 In an N2-filled glovebox, a 1-dram vial was charged with [Ni(cod)2] (10 mol %), SIPr (10 mol %), amide (0.1 mmol ,1.0 equiv.), and a magnetic stir bar. C6H6 or C6D6 (0.4 mL) was added, and the mixture was stirred. A 0.1 mL aliquot of MeOH stock solution (1.2 M) in C6H6 or C6D6 was added, and the mixture was stirred to dissolve evenly (Vtot = 0.5 mL, 0.2 M). At this point, the mixture was either (i) transferred to a JYoung NMR tube or (ii) the vial was then sealed with a PTFE-lined screw cap and removed from the glovebox. The reaction mixture was stirred and heated at 80 C in a bead bath (JYoung NMR tube) or a sand-filled heating block on a heating stir plate (vial) for 16 hours. Upon cooling to room temperature, the vial was opened to expose the catalyst to air. The reaction mixture was diluted with DCM (1 mL) and filtered through a silica plug with additional DCM (12-15 mL) and concentrated in vacuo. For 1 H NMR analysis, CH2Br2 was used as an internal standard to calculate conversion and yields. Trifluorotoluene was used as an internal standard for 19 F{ 1 H} NMR when applicable. Representative results are summarized below Table S1. Representative results obtained for esterification of twisted amides using in situ catalyst generation from [Ni(cod) 2 ] and SIPr under standard conditions.

General Procedure:
In an N2-filled glovebox, a 1-dram vial was charged with Ni precatalyst 6, 7, or 8 (10 mol %), amide (0.1 mmol, 1.0 equiv.) and a magnetic stir bar. C 6 H 6 or C 6 D 6 (1 mL, 0.2 M) and MeOH (0.12 mmol, 1.2 equiv.) were added via syringe. At this point, the mixture was either (i) transferred to a JYoung NMR tube or (ii) the vial was then sealed with a PTFE-lined S16 screw cap and removed from the glovebox. The reaction mixture was heated to the indicated temperature in a bead bath (JYoung NMR tube) or a sand-filled heating block on a heating stir plate (vial) for 16 hours. Upon cooling to room temperature, the vial was opened to expose the catalyst to air. The reaction mixture was diluted with DCM (1 mL) and filtered through a silica plug with additional DCM (10-12 mL) to afford crude material for analysis. For 1 H NMR analysis, CH2Br2 was used as an internal standard to calculate conversion and yields. Trifluorotoluene was used as an internal standard for 19 F{ 1 H} NMR when applicable. Representative results obtained using single-component precatalyst 6 are summarized below.

Tests for Catalytic Competence of Ni(I):
In a nitrogen-filled glovebox, a 1-dram vial was charged with Ni(I) (~10 mol%, 0.013 mmol), amide 1a or 1c (1.0 equiv., 0.13 mmol), and a PTFEcoated magnetic stir bar. Toluene or toluene-d8 (0.7mL) was added using a glass microliter syringe, and the reagents were stirred to dissolve. Methanol (1.2 equiv., 0.15 mmol) was then added to this solution using a glass microliter syringe. The vial was sealed, removed from the glovebox, and maintained at 80 °C in a heated aluminum block while stirring. After 16 hours, the reaction mixture was filtered through a short silica plug using additional toluene or toluene-d8 (~0.3mL). 1,3,5 trimethoxy benzene (1 equiv., 0.13 mmol) was added as an internal standard, and the product mixture was analyzed by both 1 H NMR and GC-MS.
With amide 1a: Methyl benzoate (4) was generated in 22% yield upon use of [(SIPr)Ni(OPh)]2 (7) as a precatalyst. However, no new products were detected upon use of Ni(I) generated from comproportionation of 6 and 8c as a precatalyst.
With amide 1c: Methyl benzoate (4) was generated in 26% yield upon use of Ni(I) (generated from comproportionation of 6 and 8c) as a precatalyst.

Crossover Experiment
In a nitrogen-filled glovebox, a 1-dram vial was charged with [(SIPr)Ni(C6H6)] (1.0 equiv., 0.04 mmol), amide 1a (1.0 equiv, 0.04 mmol), double fluorine-labelled amide 1e (1.0 equiv, 0.04 mmol), and a magnetic stir bar. C6H6 (3 mL) was added, and the reaction mixture was stirred at room temperature. After 3.5 hours, a small aliquot was removed for GCMS analysis, and the mixture was concentrated in vacuo. A GCMS sample was prepared in Et2O. Experimental ratios of amide starting materials and crossover products were determined via GCMS. A control experiment was conducted using the same method as described above but done in the absence of [Ni] precatalyst. In an N2-filled glovebox, a 1-dram vial was charged with amides 1a (1.0 equiv., 0.1 mmol) and 1e (1.0 equiv., 0.1 mmol), and a magnetic stir bar. C6H6 (3 mL, 0.03 M) was added to the vial, which was stirred at room temperature inside the glovebox for 3.5 hours. Upon completion, the vial was removed from the box and an aliquot was removed for GCMS sample preparation in Et2O. Experimental ratios of amide starting materials were determined via GCMS. No crossover products were detected.

Comproportionation Experiments
The viability of comproportionation between Ni(0) source 6 and Ni(II) source 8c was assessed under various conditions to obtain a qualitative assessment of its relevance to catalysis. No reaction was observed at room temperature (~22 °C) over the course of several hours. Figure S13. 1 H NMR (400 MHz, C6D6) spectra monitoring for reactivity between 6 and 8c at rt.
Upon heating to 80 °C (the standard temperature for catalytic conditions), gradual conversion to Ni(I) was observed over several hours. As such, Ni(I) species are likely not present at early stages of catalytic reactions but may accumulate at longer reaction times, resulting in a gradual catalyst deactivation process and degraded chemoselectivity (especially for slow-reacting substrates). S19 Figure S14. 1 H NMR (400 MHz, C6D6) spectra monitoring for reactivity between 6 and 8c at 80 °C.
Diagnostic features observed using 1 H NMR and EPR are highlighted in Figures S15 and S16.    Figure S16. X-band EPR (THF glass, 10 K) spectrum of species generated from the comproportionation of 6 and 8c.

General Procedures:
In a nitrogen-filled glovebox, a 1-dram vial was charged with Ni(cod)2 (10 mol %, 0.01 mmol), SIPr (10 mol %, 0.01 mmol), and a magnetic stir bar. Toluene-d8 (0.3 mL) was added to the 1-dram vial, which was stirred for 30 minutes at room temperature. Amide 1a (1.0 equiv., 0.1 mmol) was weighed into a GC vial, and 1,3,5-trimethoxybenzene internal standard (1.0 equiv., 0.1 mmol) was weighed into a separate GC vial. After 30 minutes, the internal standard was added as a solid to the 1-dram vial containing the precatalyst mixture. A portion of toluene-d8 (0.2 mL) was added to the GC vial to rinse out additional solid and was decanted into the 1-dram vial. The same addition procedure was repeated for amide 1a. The reaction mixture was stirred for a minute at room temperature, then transferred to a JYoung NMR tube using a pipet. Additional toluene-d8 (0.3 mL such that Vtot = 1.0 mL, 1.0 M) was used to effect a quantitative transfer. The sample was then sealed under N2, removed from the glovebox, and loaded into a Bruker 500 MHz NMR spectrometer. A pseudo 2D mode was used to collect 1H NMR spectra at 5-minute intervals using the parameters described in Table X. After the first scan, the sample was replaced by a dummy JYoung NMR tube with toluene-d8 (1 mL). The sample was pumped back into the glovebox, after which methanol (1.2 equiv., 0.12 mmol) was added directly to the NMR tube, which was sealed again under N2. The JYoung NMR tube was removed from the glovebox, after which it was inverted, then frozen in a liquid N2 bath to arrest the reaction during transport. The sample was then thawed, inverted to mix, and loaded into the NMR spectrometer. The sample was run for the remainder of the pseudo 2D experiment overnight (8 hours total). The next day, the sample was removed, characterized by 1 H NMR, then opened to air. The contents of the JYoung NMR tube were decanted into a 1-dram vial, to which CH2Br2 internal standard (1.0 equiv., 0.1 mmol) was added. The vial was shaken to mix, then filtered through a silica plug into an NMR tube and analyzed by 1 H NMR to obtain analytical yields of methyl benzoate (4). Alternatively, in a nitrogen-filled glovebox, two separate 1-dram vials were charged with (A) [(SIPr)Ni(toluene)] (10 mol %, 0.009 mmol) and (B) amide 1a (1.0 equiv., 0.09 mmol). The [Ni] complex from vial A was transferred to vial B as using small portions of toluene-d8 (0.7 mL total). Methanol (1.2 equiv., 0.11 mmol) was added to this solution using a microliter glass syringe. All contents of vial B were transferred to a JYoung NMR tube using a glass pipet, which was then sealed and removed from the glovebox. The JYoung NMR tube was kept at 80°C in a bead bath, and 1 H NMR spectra was collected at 25 °C at the indicated time intervals. Conversion was monitored through the relative integrals of diagnostic signals for amide 1a and ester 4. After 21h, the reaction mixture was filtered through a silica plug and 1,3,5 trimethoxy benzene internal standard (1 equiv., 0.09 mmol) was added as an internal standard, and a final 1H NMR spectrum was collected to obtain analytical yields of methyl benzoate (4), which were within 2-4% of the values expected from ratios obtained during the reaction time-course.

Reaction Time-course at 80 °C:
Initial reaction time-course experiments were conducted at 80°C in toluene-d8 to most closely resemble standard catalytic conditions. Initial rates were too fast to collect data at low conversion. Nonetheless, three key observations were noted.
(2) Using the in situ precatalyst activation protocol in toluene-d8 resulted in precatalyst speciation challenges analogous to those noted in benzene-d6. Namely, [Ni(cod)2] persisted as a major component of the Ni-containing species throughout the course of the reaction rather than accessing the active SIPr-supported form. See Figure S20.      Remaining 1a

General Procedure:
A single crystal was placed onto a thin glass optical fiber or a nylon loop and mounted on a Rigaku XtaLAB Synergy-S Dualflex diffractometer equipped with a HyPix-6000HE HPC area detector for data collection at 100.00(10) K. A preliminary set of cell constants and an orientation matrix were calculated from a small sampling of reflections. 15 short preexperiment was run, from which an optimal data collection strategy was determined. The full data collection was carried out using a PhotonJet (Cu) X-ray source with a detector distance of 34.0 mm. Series of frames were collected in 0.50° steps in ω at different 2θ, κ, and φ settings. After the intensity data were corrected for absorption, the final cell constants were calculated from the xyz centroids of strong reflections from the actual data collection after integration. 15 Structures were solved using SHELXT2 16 and refined using SHELXL. 17 The space group was determined based on systematic absences and intensity statistics. Most or all non-hydrogen atoms were assigned from the solution. Full-matrix least squares / difference Fourier cycles were performed which located any remaining non-hydrogen atoms. All non-hydrogen atoms were refined with anisotropic displacement parameters.
Data collection, structure solution, and structure refinement were conducted at the X-ray Crystallographic Facility, B04 Hutchison Hall, Department of Chemistry, University of Rochester.

Catalytic Cycle
A catalytic cycle summarizing the key observations and conclusions is depicted in Figure S32.