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. 2023 Jun 26;145(27):14705–14715. doi: 10.1021/jacs.3c02649

Mechanistic Investigation of Ni-Catalyzed Reductive Cross-Coupling of Alkenyl and Benzyl Electrophiles

Raymond F Turro †, Julie LH Wahlman †, Z Jaron Tong †, Xiahe Chen §, Miao Yang §, Emily P Chen †, Xin Hong ∥, Ryan G Hadt ‡, K N Houk ⊥, Yun-Fang Yang §,*, Sarah E Reisman †,*
PMCID: PMC10347553  PMID: 37358565

Abstract

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Mechanistic investigations of the Ni-catalyzed asymmetric reductive alkenylation of N-hydroxyphthalimide (NHP) esters and benzylic chlorides are reported. Investigations of the redox properties of the Ni-bis(oxazoline) catalyst, the reaction kinetics, and mode of electrophile activation show divergent mechanisms for these two related transformations. Notably, the mechanism of C(sp3) activation changes from a Ni-mediated process when benzyl chlorides and Mn0 are used to a reductant-mediated process that is gated by a Lewis acid when NHP esters and tetrakis(dimethylamino)ethylene is used. Kinetic experiments show that changing the identity of the Lewis acid can be used to tune the rate of NHP ester reduction. Spectroscopic studies support a NiII–alkenyl oxidative addition complex as the catalyst resting state. DFT calculations suggest an enantiodetermining radical capture step and elucidate the origin of enantioinduction for this Ni-BOX catalyst.

1. Introduction

Ni-catalyzed reductive cross-couplings (RCCs) of organic electrophiles have emerged as useful reactions for C(sp2)–C(sp3) bond formation.1 These reactions provide direct access to cross-coupled products from readily available organic electrophiles, such as halides, precluding the need to pregenerate an organometallic coupling partner. The use of a metal powder (Mn0, Zn0) or an organic electron donor such as tetrakis(dimethylamino)ethylene (TDAE)2 provides reducing equivalents to render the system catalytic in Ni. Ni-catalyzed RCC reactions can also be driven electrochemically using either sacrificial anodes or paired electrolysis systems.3 A key challenge in the development of these reactions is achieving selectivity for the cross-coupled product over possible homo-coupling products; this requires a catalyst that oxidatively adds each electrophile in sequence or a catalyst system with mechanistically distinct modes of activating each coupling partner. Despite this challenge, several different Ni catalysis systems have been developed that afford high selectivity for cross-coupled products.1,4,5

Our lab has developed several Ni-catalyzed asymmetric reductive alkenylation (ARA) reactions (Figure 1), which leverage the intermediacy of C(sp3) radicals to enable stereoconvergent, enantioselective bond formation.6−8 In 2014, we reported an ARA between benzylic chlorides and alkenyl bromides using cyclopropyl-containing IndaBOX ligand L1 and Mn0 as the terminal reductant (Figure 1a).6 We subsequently developed a related ARA that uses the same ligand (L1), but employs redox-active N-hydroxyphthalimide (NHP) esters as the C(sp3) coupling partner.7 In this case, TDAE was used as the reductant, and trimethylsilyl bromide (TMSBr) was identified as a key additive (Figure 1b). In addition to chiral ligand L1 being optimal for both reactions, the use of DMA as solvent and NaI as an additive was shared between the two transformations. Given their similarities, we identified this pair of transformations as well suited for investigating the mechanism of Ni-catalyzed RCCs and how the mechanism might change depending on the C(sp3) coupling partner.

Figure 1.

Figure 1

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Ni-catalyzed asymmetric reductive cross-coupling between alkenyl and benzylic electrophiles.

Since many RCCs use heterogeneous terminal reductants, the mechanisms of these reactions have been difficult to elucidate. Nonetheless, insightful studies of reductive arylation have been disclosed by the groups of Weix9 and Diao;10 these systems have primarily focused on reactions in which catalytically relevant NiII(aryl)X complexes can be isolated and characterized. Diao and coworkers have also recently investigated bi(oxazoline)10a,10b and pyridine-oxazoline10c ligands in reductive arylation; however, mechanistic studies of reductive alkenylation and of Ni-catalysts supported by chiral bis(oxazolines) such as L1 are lacking.11 Here, we report our mechanistic investigations of two L1·Ni-catalyzed ARA reactions. In this study, we sought to (1) determine the kinetic driving forces and resting state for the homogeneous reaction of alkenyl bromide 1a with NHP ester 2b; (2) investigate the redox properties of the L1·NiIIX2 precatalysts and determine whether L1·Ni0 is accessible using common reductants; (3) interrogate the mechanism of electrophile activation for both 2a and 2b; (4) use computational methods to understand the enantioselectivity determining step. These studies have revealed that chloride 2a and NHP ester 2b are activated through distinct mechanisms and provide insights that can guide the optimization of reaction conditions for Ni-catalyzed RCC reactions.

2. Results and Discussion

2.1. Reaction Kinetics of TDAE-Mediated RCC

Since the TDAE-driven L1·Ni-catalyzed ARA6 is homogeneous and does not suffer from an induction period, we initiated our mechanistic investigation by determining the kinetic orders in 1a, 2b, and Ni under standard reaction conditions (Figure 2a). For this, we employed variable time normalization analysis12 (VTNA) to analyze the results of different excess experiments (Figure 2b–d). These experiments revealed a first order rate dependence on the concentration of NHP ester 2b (Figure 2c). The rate dependence on [1a] appears to be 0th order at concentrations similar to the standard conditions (0.1 and 0.2 M 1a, Figure 2b); however, a fractional inverse rate dependence is observed at higher concentrations of 1a (Figure 2b, Figure S27). Moreover, at higher [1a], minor amounts of dienyl homodimer are observed; the slight inverse rate dependence is proposed to derive from this off-cycle pathway. We note that inverse order in C(sp2) electrophile has been observed previously by Weix et al. for a related (bpy)Ni-catalyzed RCC of aryl and alkyl halides.9a Interestingly, there is an apparent 0th order rate dependence on L1·NiBr2 at loadings similar to the optimized conditions (5 and 10 mol %, Figure 2d); however, a positive rate dependence develops at low catalyst loadings (<1 mol %). The observation that the catalyst loading does not influence the rate of product formation has not been previously reported for Ni-catalyzed RCC reactions.9b,10a

Figure 2.

Figure 2

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(a) Standard conditions for different excess experiments on TDAE-mediated ARA. Different excess VTNA experiments with varying initial concentrations of (b) alkenyl bromide 1a, (c) NHP ester 2b, and (d) catalyst L1·NiBr2. Impact of [L1·NiBr2] on the rate of conversion of (e) alkenyl bromide 1a, (f) NHP ester 2b, and (g) byproduct 4. Concentrations determined vs dodecane internal standard using GC-FID.

To further investigate this unusual rate dependence, the concentration of 1a, 2b, and homodimer 4 were monitored over time, at different concentrations of Ni (Figure 2e-g). The conversion of alkenyl bromide 1a shows a clear rate dependence on the concentration of Ni (Figure 2e). In contrast, the rate of conversion of NHP ester 2b is independent of [Ni]: even in experiments where L1·NiIIBr2 is omitted, 2b is consumed at the same rate as when using 20 mol % Ni (Figure 2f). Correspondingly, as the concentration of Ni decreases, the yield of cross-coupled product 3a decreases and the yield of homocoupled product 4 (formed as a 1:1 diastereomeric mixture) increases (Figure 2g). These data are consistent with generation of a cage-escaped benzylic radical from 2b by a non-Ni-catalyzed process. This represents a distinct mode of NHP ester activation for the L1·Ni-catalyzed RCC in comparison to the (bpy)Ni-mediated coupling of NHP esters reported by Weix et al.13 and Baran et al.,14 in which a (bpy)NiI–Ar is proposed to reduce the NHP ester by single electron transfer (SET). In a preprint article, Rousseaux reported a similar finding, in which the combination of Zn0 and TMSCl initiates decarboxylation of an NHP ester as a part of a Ni-catalyzed RCC process.15

2.2. Reduction of Ni(II) Precatalyst and Oxidative Addition of Alkenyl Bromide

Given the kinetic data (vide supra), we sought to investigate the reduction of the Ni precatalyst and the ability of the resulting species to oxidatively add the alkenyl bromide. We first used cyclic voltammetry (CV) to determine the reduction potentials of L1·NiIIBr2 and L1·NiIICl2; these complexes (isolable as crystalline solids) catalyze the reductive alkenylations of both benzylic chlorides and NHP esters in comparable yields and slightly improved ee relative to in situ catalyst generation.6,7 Electrochemically, L1·NiIICl2 and L1·NiIIBr2 exhibit irreversible reduction waves at Ep/2 = −1.47 and −1.23 V vs Fc0/+, respectively (Figure 3a). These reduction events have a large peak separation with the corresponding oxidation events, suggesting that a chemical change, such as halide loss, occurs rapidly upon one electron reduction. More detailed electrochemical studies of these precatalysts, performed by Hadt and coworkers,16 support a single-electron reduction event to give a L1·NiIX·DMA species. Notably, these studies suggest that reduction to L1·Ni0 does not proceed within the solvent window of DMA.

Figure 3.

Figure 3

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Reduction of precatalysts L1·NiX2 used in ARA reactions and reactivity of reduced species with 1a. (a) 1 mM L1·NiBr2 and L1·NiCl2, 0.1 M TBAPF6 in DMA, ν = 100 mv/s, V vs Fc0/+; (b) −77 K X-band (9.4 GHz) perpendicular EPR spectra; for detailed instrument parameters and simulations, see SI Section 7.1. (c) 1 mM L1·NiCl2 with sequential additions of 1a (0–0.1 M), 0.1 M TBAPF6 in DMA, ν = 100 mv/s. V vs Fc0/+.

To verify the ability of TDAE to reduce L1·NiIIBr2 to L1·NiIBr, a solution of L1·NiIIBr2 in DMA was treated with TDAE (E1/2 = −1.1 V vs Fc0/+); the resulting solution was frozen and analyzed by electron paramagnetic resonance (EPR) spectroscopy. A strong signal at g = 2.02 is assigned to the organic TDAE+• radical,17 and the weaker signal (g1 = 2.07, g2 = 2.08, g3 = 2.330) is assigned to a reduced L1·NiIBr species (Figure 3b, SI Section 7.3). The same L1·NiIBr signal is observed when L1·NiIIBr2 is reduced with Ni(cod)2. When Zn0 is used as the reductant, more pronounced changes are observed, which could potentially arise from the interaction between a L1·NiI species with the ZnII formed upon oxidation (Figure S69).18 We note that electrochemical and spectroscopic studies by Hadt and coworkers suggest that DMA can bind to both L1·NiI and L1·NiII redox states.16 Given the strong variation of EPR signals and speciation of L1·NiI species observed herein, no formal assignments of the EPR signals are provided. Nevertheless, these data support the presence of L1·NiIX species forming from reduction under cross-coupling reaction conditions, and the nature of these species is clearly dependent on the reaction conditions.

A time course of the Zn0 reduction of L1·NiCl2 revealed that the observed EPR signals decrease over time (Figures S72–S74) in concert with a change in the corresponding UV–vis–NIR spectra (Figures S75 and S76), and the terminal EPR-silent mixture was catalytically inactive. Attempts to isolate L1·NiIX complexes were unsuccessful; this might be due to the formation of L1·NiI oligomers in the absence of electrophiles 1 and 2 or due to the difference in stability between DMA-bound and unbound species.10a,19,20

To test whether the putative L1·NiICl species formed upon reduction of L1·NiIICl2 can react with alkenyl bromide 1a, a series of CV studies were performed in the presence of 1a (Figure 3c). A concentration-dependent increase in current was observed as [1a] increased, which was accompanied by a loss of reoxidation current. Taken together, these studies are consistent with reaction between L1·NiIX and alkenyl bromide 1a.

2.3. Catalyst Resting State

At this stage, we sought to determine the resting state of the Ni catalyst under the reaction conditions. If a NiI or NiIII intermediate were the resting state, then it could be observable by EPR. The Ni-catalyzed reaction of 1a and 2b was performed using 2 mol % L1·NiBr2 under otherwise standard conditions, and aliquots were removed, filtered, and frozen in an EPR tube. No signal corresponding to a metal-based radical was observed by EPR; instead, a signal consistent with an organic radical was observed, which decreased in intensity over time (Figure S77). This species was assigned as the TDAE radical cation by comparison to an independently prepared sample (Figure S67) and previously reported spectra.16 Although this does not rule out a NiI or NiIII resting state, we sought to investigate other possibilities.

Given the rapid reaction of L1·NiCl with alkenyl bromide 1a (Figure 3c) and prior RCC mechanistic studies,9b,10a we hypothesized that the catalyst resting state likely resides after oxidative addition of the C(sp2)-electrophile. To monitor the reaction by in situ19F NMR, 19F-labeled alkenyl bromide 1b was used and all alkenyl bromide-derived species were tracked over the course of the reaction (Figure 4a). Upon the addition of TDAE (0. 23 mmol, 1.5 equiv) to a solution of 1b (0.15 mmol), 2b (0.15 mmol), L1·NiBr2 (0.015 mmol, 10 mol %), TMSBr (0.15 mmol), and NaI (0.075 mmol) in DMA-d9, several new signals appeared that were assigned to product 3b (δ = −116.5 ppm), homocoupled diene 5b (δ = −115 ppm), and a new species (broad signal at δ = −120 ppm, Figure 4b).21 This species persisted throughout the reaction, maintaining steady concentration corresponding to 15 μmol or 10 mol %, which is the concentration of L1·NiBr2 used in the reaction. When this experiment was repeated with 20 mol % L1·NiBr2, the concentration of this species corresponded to 17 mol % (25 μmol) for the first 2.5 h of catalysis and then decreased as the reaction approached the last few turnovers, eventually disappearing at the end of the reaction (Figure 4c). Although attempts to isolate this species or prepare it independently have been unsuccessful due to its instability, we propose that this intermediate is the diamagnetic NiII oxidative addition complex 7b.22 We note that Diao and coworkers reported a dimagnetic (phen)NiIIArBr resting state, observable by 1H NMR, for a Ni-catalyzed 1,2-dicarbofunctionalization reaction.10b

Figure 4.

Figure 4

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Reaction monitoring by 19F NMR tracking the consumption of 1b and the formation of 1b-derived species. The reaction was run at 0 °C using C6F6 as an internal standard.

2.4. Mechanism of NHP Ester Activation

Given that the kinetic studies revealed that the NHP ester 2b is not reduced by Ni, we hypothesized that it is instead reduced by TDAE. To test this hypothesis, NHP ester 2b was treated with TDAE in DMA and the formation of homodimer 4 was monitored as an indirect measurement of benzylic radical generation. In the absence of additional additives, the mixture of 2b and TDAE results in minimal conversion to homodimer 4, even at ambient temperature (Figure 5a, purple). This can be rationalized by the difference in reduction potential of NHP ester 2b (Ep/2 = −1.62 V vs Fc0/+), which is 0.5 V more cathodic than TDAE (E1/2 = −1.11 V vs Fc0/+); the irreversible loss of CO2 following SET does not appear to be sufficient to drive the thermodynamically unfavorable process. Similarly, the mixture of 2b, TDAE, and NaI also fail to produce homodimer 4 (Figure 5a, green).

Figure 5.

Figure 5

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Studies investigating the influence of Lewis acids on the rate of radical generation from TDAE reduction of 2b. Yields and time course data analyzed by GC-FID with n-dodecane internal standard.

In contrast, when TDAE is added to a mixture of 2b and TMSBr (1.0 equiv), 2b is converted to 4 at a rate that is comparable to the rate of 2b conversion in the catalytic reaction (Figure 5a, teal). We note that TMSBr is essential to form 3a in high yields under standard reaction conditions (19% yield 3a when TMSBr is excluded). The rate is increased further (krel = 1.5) when both TMSBr and NaI are present, presumably through the in situ generation of TMSI (Figure 5a, maroon). We propose that the silyl halide additive functions as a Lewis acid to lower the reduction potential23 of the NHP ester and enable reduction by TDAE.

2.5. Altering Rate of Radical Generation through Lewis Acid Selection

The observation that a Lewis acid gates NHP ester reduction inspired us to question whether the rate of radical generation could be tuned by using TDAE in combination with different Lewis acids, similar to Weix and coworkers’ work tuning the rate of radical generation by using derivatized NHP esters.24 To test this, we measured the rate of radical generation (as d[4]/dt) in the presence of a variety of Lewis acids (Figure 5b). The more sterically hindered triethylsilyl bromide (TESBr) results in a 3-fold decrease in the rate (krel = 0.34) of radical generation. Further investigation of different silyl halides revealed an intuitive trend in sterics (TBS < TES < TMS), with larger groups slowing down radical generation, as well as the leaving group identity (Cl < Br < OTf < I),25 with the better leaving group accelerating radical generation (Figure 5c). As observed with TMSBr (Figure 5a, purple), addition of NaI as a co-additive to various R3Si–Cl additives can increase the rate by more than 2-fold. Increasing the concentration of TMSBr increases the rate (krel = 1.68), presumably by driving the equilibrium to increase the concentration of silylated NHP ester 8 (Figure 6). Additionally, non-silyl Lewis acids can also increase the rate of 2b reduction by TDAE. We have quantified the ability of several common additives26 to modulate the rate of radical generation, with rates spanning three orders of magnitude (Figure 5b).

Figure 6.

Figure 6

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Proposed mechanism for the TDAE-mediated Ni-catalyzed coupling between NHP esters and alkenyl bromides under standard conditions (see Figure 2a).

After demonstrating that the rate of NHP ester activation can be tuned with different Lewis acid additives, we sought to investigate how the yield of product was effected by the silyl additive. Although the ARA reaction between 1a and 2b was initially reported using TMSBr, we observed that at lower catalyst loadings, increased amounts of benzyl dimer 4 are formed (Figure 2g). We hypothesized that a slower rate of radical generation could improve the yield of 3a at low catalyst loadings by better matching of the relative concentrations of the resting state species (7) and benzylic radical. Given that TESBr decreases the rate of benzylic radical formation by 3-fold, we performed a series of experiments varying the concentration of L1·NiBr2 in the presence of either TMSBr or TESBr (Figure 5d). First, we note that for this well-performing substrate pair, high yields can be maintained using 1 mol % L1·NiBr2. Second, we found that TMSBr performs better relative to TESBr when 20 mol % L1·NiBr2 is used (higher concentration of resting state 7) and performs worse than TESBr at 0.5 mol % L1·NiBr2, when rapid release of benzyl radical would outpace radical capture by resting state 7 (Figure 5d). Using 0.5 mol % L1·NiBr2, higher yield of 3a was obtained with TESBr (84% yield) than with TMSBr (72% yield), which we propose results from the slower release of the benzyl radical. Analysis of the product profiles for each bromosilane shows that the ratio of cross-coupled to homocoupled products reaches a maxima at 2.5 mol % Ni for TMSBr (krel = 1.0) and 1 mol % Ni for TESBr (krel = 0.34) (Figures S78 and S79), which is consistent with the trends observed in yield. Using these conditions (1 mol % L1·NiBr2 and 1.0 equiv TESBr), the reaction can be performed on the gram scale to give product 3a in 81% yield and 94% ee (SI Section 8.2). We propose that monitoring the conversion of starting materials as well as the yield of product and alkyl homodimer at different [Ni] can help chemists identifying the optimal combination of catalyst loading and silyl additive for new substrate combinations.

Taken together, a mechanism for the TDAE-mediated Ni-catalyzed RCC is proposed in Figure 6. Upon reduction of the Ni precatalyst, the resulting L1·NiIBr (6-Br) rapidly reacts with alkenyl bromide to give NiIII species 9, which can be reduced to furnish resting state species 7. Given Hadt and coworker’s studies,16 it is possible that DMA is coordinated to 6 during oxidative addition. While the reductant in this oxidative addition–reduction sequence is not known, we propose that the oxidative addition step is fast and reversible since we can observe the formation of halide scrambling products 1a-I and 1a-Cl (when a Cl– source is present).7,27 The NiII complex 7 can then intercept NHP ester-derived radical 10 to give NiIII complex 11, which can undergo reductive elimination to give product 3. NHP ester 2b is activated by TMSBr followed by reduction with TDAE in the turnover-limiting step. This reduced species undergoes N–O homolysis and subsequent decarboxylation to give 10 (Figure 6).

2.6. Reaction Kinetics of the Mn-Mediated Ni-Catalyzed RCC

Kinetic studies of the heterogeneous metal-powder conditions (Figure 1a) proved more challenging than the homogeneous TDAE-mediated reaction. We observe long induction periods (up to 90 min) and reaction times of 6 h using previously reported conditions.6 The induction period and reaction times can be shortened to 30 and 100 min, respectively, by preactivating the Mn0 with HCl. The use of Zn0 powder further improved the reaction times (5–10 min induction period and 45 min reaction times, Figure S16) and provided a product in comparable yield and with only slightly lower enantioselectivity as Mn0 (Zn: 91% yield, 90% ee; Mn: 96% yield, 96% ee). Both Mn0 and Zn0 gave reactions with linear rates of product formation, indicative of mass transport-limited reduction; however, Zn0 displayed a less significant stir rate dependence that saturated >1000 rpm (Figure S15). The use of 6 equiv Zn0 slightly increased the reaction rate by a factor of 1.1, similar to observations by Weix and Biswas9b and Diao and Lin10a in related arylation reactions (Figure S17). These modified reaction conditions (Figure 7a) enabled the collection of reproducible kinetic data allowing us to kinetically observe the next slowest step after mass transported-limited heterogeneous reduction.9a,28

Figure 7.

Figure 7

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(a) Standard conditions used the Zn-mediated ARA kinetics experiments. (b) Kinetics experiments varying initial concentrations of 1a, benzyl chloride 2a, and catalyst L1·NiCl2. (c) CV studies of sequential addition of 2a (0–0.1 M) to 1 mM L1·NiCl2. (d) CV studies L1·NiCl2 reacting with either 1a or 2a or both 1a and 2a (0.1 M TBAPF6 in DMA, ν = 100 mv/s. V vs Fc0/+). (e) Mn-mediated stoichiometric reactions of L1·NiCl2 with 1a and with 2a. (f) Proposed mechanism for the Mn-mediated Ni-catalyzed coupling between benzyl chlorides and alkenyl bromides. Concentrations determined by GC-FID vs dodecane internal standard.

Kinetics experiments reveal a first-order rate dependence on [L1·NiCl2], unlike the TDAE system, across catalyst loadings ranging from 5 to 20 mol % (Figure 7b). The reaction exhibits a negative first-order rate dependence on [1a]0. A similar inverse dependence on the C(sp)2 partner has been observed by Weix and Biswas.9b The rate dependence on [2a]0 is more complex: a fractional positive rate dependence was observed at 1.0 and 2.0 equivalents of 2a, but the rate decreases again when >2.0 equiv 2a is employed (Figure 7b). Notably, as [2a]0 increases, the ee of 3a decreases. Taken together, these data might indicate that there are competing mechanisms that depend on the concentration of [2a]0. One possibility is that when [2a] ≫ [1a], the reaction of L1·NiIX with 2a begins to compete with the reaction between L1·NiIX and 1a, therefore reversing the order of oxidative addition of the electrophiles to Ni.

2.7. Ni-Mediated Electrophile Activation

To interrogate the role of Ni in the activation of benzylic chloride 2a, a DMA solution of 2a was treated with Mn0 (3.0 equiv) and NaI (0.5 equiv) and the formation of homodimer 4 was monitored (see SI, Section 4.3). No conversion of 2a or formation of 4 was observed at 0 or 23 °C, even with extended reaction times. In contrast, when 2a was subjected to identical conditions but L1·NiIICl2 was added, 2a was cleanly converted to homodimer 4 over 60 min (Figure 7e). These findings suggest that L1·NiIX can activate 2a.

CV studies were also performed to investigate the reaction of in situ generated L1·NiICl with 1a and 2a. CVs were acquired for L1·NiIICl2 (1.0 mM) in the presence of varying concentrations of 1a (1–100 mM), which showed a concentration-dependent current with cathodic shifting of the onset potential and loss of the anodic return wave (Figure 7c). This current likely results from the reaction of the reduced L1·Ni complex reacting with 2a, presumably corresponding to the catalytic homocoupling to give 4. The same studies were performed in the presence of alkenyl bromide 1a, which also showed a concentration-dependent current (Figure 3c). In the presence of 100 mM 1a and 2a, regardless of the order of addition, a catalytic current consistent with the reaction with 1a is observed (Figure 7d).

This is consistent with the Mn-mediated Ni-catalyzed homodimerization reactions of 1a and 2a, in which the conversion of 1a is faster than the conversion of 2a under otherwise identical conditions (Figure 7e). Taken together with the CV studies, these data qualitatively suggests that the reductively generated L1·NiICl reacts faster with 1a and is consistent with previous RCC studies investigating the relative rates of Ni(I) complexes with aryl and alkyl electrophiles.9b,10a,12

Based on our experimental studies, a proposed mechanism for the Mn-mediated Ni-catalyzed ARA is shown in Figure 7f. Upon reduction of precatalyst L1·NiIICl2, the resulting complex 6 reacts with alkenyl bromide 1 in an oxidative addition–eduction step to give L1·Ni(II) complex 7. This could proceed by a bimolecular oxidative addition as proposed by Diao and Lin,10a or by reduction of the transiently formed Ni(III) species by Mn0. Ni-catalyzed halogen atom transfer (XAT)29 from the benzylic chloride gives rise to a cage-escaped radical 10 that can be captured by 7 to yield product 3 following reductive elimination. We again note that both 6 and 7 are in equilibrium with DMA-bound complexes,14 and DMA coordination might facilitate the oxidative addition of 1 or XAT from 2a.

The mechanism shown in Figure 7f is consistent with our observation that L1·NiIX (6) can react with both 1a and 2a but that 1a reacts with 6 more rapidly. This mechanism is also consistent with the observed inverse dependence on [1a]0: complex 6 is partitioned between two processes. When 1a reacts with 6, it effectively reduces the concentration of 6 available to react with 2a. If benzylic radical generation by the reaction of 6 with 2a is the rate-controlling step (the studies in Figure 7e show that reaction of 6 with 2a is slower than with 1a), then increased [1a] would be expected to decrease the rate of reaction between 6 and 2a and therefore the overall rate of product formation. We note that we cannot rule out the possibility that 7 is reduced and that the corresponding L1·NiI(alkenyl) species, which is calculated to be a stronger reductant,16 mediates the XAT; however, we would not expect a significant inverse rate dependence on 1a for such a process. In addition, recent studies by Diao and coworkers have suggested that similar (biox)NiII(aryl)X complexes are unlikely to be reduced by Mn0.10b

2.8. Computational Investigation into the Origin of Enantioselectivity

To explore the origins of enantioinduction, the structures and relative Gibbs free energies of the competing transition states for addition of radical 10 to resting state complex 7 were computed (Figure 8a). The free energy difference between TS1-S and TS1-R is computed to be 3.0 kcal/mol, which slightly overestimates the enantioselectivity for the reaction. In both transition states, the smallest substituent of the approaching benzyl radical (10), hydrogen, is pointing toward the sterically bulky part of the ligand (highlighted in blue in Figure 8a). This allows the largest substituent, the phenyl group, to project away from this region of the ligand in the favored transition state TS1-S. In the disfavored transition state TS1-R, the phenyl group is proximal to the bulky region of the ligand. This results in an almost perfectly staggered approach of the benzyl radical with respect to the Ni ligands in TS2-S, while steric repulsion from the ligand forces the benzyl radical to adopt a more eclipsed conformation in TS1-R.30 Subsequent reductive elimination for 11-S is facile with a computed barrier of 0.9 kcal/mol (Figure 8b) for the major pathway. This is in contrast to previously reported computational results for a related Ni-photoredox coupling, which proposed a reversible radical addition and enantiodetermining reductive elimination;31 however, this mechanism is consistent with recently published experimental results that measure a rapid reductive elimination from a NiIII complex that is analogous to 11.32 These calculations suggest the facial selectivity of the enantiodetermining radical addition is influenced by the steric environment of BOX ligand L1.

Figure 8.

Figure 8

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Calculated potential energy surface of enantiodetermining radical capture step and subsequent reductive elimination.

3. Conclusions

In summary, we have investigated two Ni-catalyzed asymmetric RCC reactions to determine how changing the reductant and C(sp3) electrophile influences the reaction mechanism. These reactions proceed through a NiI/III cycle with fast activation of the alkenyl bromide electrophile by a NiI species. Both reactions have a rate-determining activation of the C(sp3) electrophile to furnish a cage-escaped benzyl radical. We have demonstrated that Ni is not required for NHP ester activation; instead, the combination of TDAE and TMSBr results in reductive decarboxylation to give the benzylic radical. The radical can then be intercepted by a NiII–alkenyl resting state that we were able to detect spectroscopically. In the case of the Mn0-mediated ARA with benzylic chlorides, we propose that L1·NiIX generates the benzylic radical by an XAT process. This is a subtle distinction from the mechanism proposed by Diao for the (biox)Ni-catalyzed RCC between aryl halides and benzylic chlorides,10b which did not suggest an explicit role for Ni in generating the radical from the benzylic halide.

The fact that reduction of NHP esters by TDAE is Lewis acid-mediated, rate controlling, and independent of the alkenyl bromide activation has significant implications for the development of other Csp3–Cspn RCCs. This mechanistic regime allows for independent tuning of the rates of electrophile activation where d[Csp3]/dt can be tuned with additives and d[Csp2]/dt through catalyst design. It is our hope that these findings aid in the adoption of C(sp2)–X reductive couplings with NHP ester fragments in more complex settings by providing a framework to guide reaction optimization.

Acknowledgments

Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis are gratefully acknowledged for access to analytical equipment. S.E.R. acknowledges financial support from the NIH (R35GM118191). Fellowship support for J.L.H.W. was provided by the NSF (DGE-1144469). K.N.H. is grateful to the National Science Foundation (CHE-1764328) for financial support of this research. R.G.H. acknowledges support from the NIH (National Institute of General Medical Sciences, R35-GM142595). Y.-F. Y. is grateful to the National Natural Science Foundation of China (21978272), the Fundamental Research Funds for the Provincial Universities of Zhejiang (RF-C2022006), and the Province-Ministry Co-Construct State Key Laboratory of Green Chemistry-Synthesis Technology at Zhejiang University of Technology for financial support of this research. The authors would like to thank Dr. David VanderVelde for assistance with NMR experiments, Dr. Jay Winkler for assistance with CV experiments, and Dr. Paul Oyala of Caltech for assistance with EPR measurements. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the Beckman Institute X-ray Crystallography Facility at Caltech, as well as the Caltech CCE NMR facility and Multiuser Mass Spectrometry Laboratory, which is also supported by the NSF CRIF program (CHE-0541745).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c02649.

  • Experimental procedures, characterization data (1H and 19F NMR) for all new compounds, and coordination geometries for DFT optimized compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja3c02649_si_001.pdf (6MB, pdf)

References

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ja3c02649_si_001.pdf (6MB, pdf)

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