Ni/Photoredox-Catalyzed C(sp 3 )−C(sp 3 ) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors
Aziridines are readily available C(sp 3 ) precursors that afford valuable β-functionalized amines upon ring-opening. In this article, we report a Ni/photoredox methodology for C(sp 3 )−C(sp 3 ) cross-coupling between aziridines and methyl/1⁰/2⁰ aliphatic alcohols activated as benzaldehyde dialkyl acetals. Orthogonal activation modes of each alkyl coupling partner facilitate cross-selectivity in the C(sp 3 )−C(sp 3 ) bond-forming reaction: the benzaldehyde dialkyl acetal is activated via hydrogen atom abstraction and βscission via bromine radical (generated in situ from single-electron oxidation of bromide), whereas the aziridine is activated at the Ni center via reduction. We demonstrate that an Ni(II) azametallacycle, conventionally proposed in aziridine cross-coupling, is not an intermediate in the productive cross-coupling. Rather, stoichiometric organometallic and linear free energy relationship (LFER) studies indicate that aziridine activation proceeds via Ni(I) oxidative addition, a previously unexplored elementary step.
INTRODUCTION<!>Reaction Optimization<!>Table 1. Optimization of aziridine alkylation with benzaldehyde dialkyl acetals.<!>Me<!>Substrate scope<!>Table 2. Reaction substrate scope with aziridines and benzaldehyde dialkyl acetals.<!>Possible mechanistic pathways<!>Mechanistic Investigations<!>Scheme 2. Crossover experiment and stoichiometric studies with azametallacycle IIa.<!>Scheme 3. Reactivity of benzylbromide 7a.<!>Ni(0)−Ni(I)−N(III) mechanistic pathway<!>Scheme 4. Stoichiometric studies with Ni(I) complex.<!>Proposed Catalytic Cycle<!>Scheme 6. Proposed mechanistic pathway and off-cycle pathways.<!>CONCLUSION
<p>Selective cross-coupling of two different carbon electrophiles, commonly known as cross-electrophile coupling, has emerged as an enabling strategy for C-C bond formation. 1 These processes often operate on readily available and stable organic (pseudo)halides under mild conditions. Extensive progress has been made in developing C(sp 3 )-C(sp 2 ) cross-electrophile coupling reactions, with Ni catalysis offering a particularly general platform. 2 Mechanistic studies on select Ni-catalyzed reactions have revealed that distinct, hybridization-dependent activation mechanisms give rise to the cross-selectivity with C(sp 2 ) and C(sp 3 ) electrophiles. 3,4 In contrast, methods for selective coupling of two C(sp 3 ) electrophiles remain underdeveloped, owing to the more subtle differences in reactivity between the two reaction partners (Figure 1A). 5 Nevertheless, there has been important recent progress made in this area using Ni 6 or Cu catalysis 7 with chemical reductants and electrochemical methods. 8 These approaches typically rely on substrate stoichiometry, differences in (pseudo)halide identities or differences in substitution at the carbon center to achieve selectivity. Alternatively, redox-neutral metallaphotoredox catalysis 9 can provide a platform for the development of chemoselective C(sp 3 )-C(sp 3 ) cross coupling in part by relying on orthogonal redox-dependent activation mechanisms of the two alkyl coupling partners. This approach offers the opportunity to use nontraditional reaction partners beyond alkyl (pseudo)halides while retaining many of the positive attributes of cross-electrophile coupling. For example, researchers have recently found success coupling two C(sp 3 ) fragments arising from carboxylic acids, activated alcohols, alkyl halides, and C-H bonds. 10 These examples highlight how the identification of strategies that engage distinct classes of C(sp 3 ) coupling partners in C(sp 3 )-C(sp 3 ) bond formation can be of broad value from a synthetic and mechanistic perspective. our lab, 11 Michael, 12 Jamison, 13 Takeda/Minakata, 14 May 15 and Xiao 16 has demonstrated that coupling reactions with aziridines can afford access to substituted ethylamines, important nitrogen-containing motifs in medicinal chemistry (Figure1B). 17 Organometallic nucleophiles such as organozinc halides or organoboron reagents, have been employed as coupling partners to form both C(sp 3 )-C(sp 2 ) and C(sp 3 )-C(sp 3 ) bonds (Figure 1B, top). Recently, our lab demonstrated that aziridines can also participate in cross-electrophile coupling reactions with aryl iodides, using either a stoichiometric inorganic reductant 18 or a photo-assisted reductive coupling (PARC) strategy. 19 Like other C(sp 3 )-C(sp 2 ) cross-electrophile coupling reactions, these methods take advantage of the difference in hybridization of each coupling partner to impart selectivity (Figure 1A, bottom). 20 Unfortunately, direct extension of the methods for crossselective C(sp 3 )-C(sp 3 ) coupling with unactivated alkyl halides was not possible as both precursors undergo indiscriminate reduction at the Ni center. To address this challenge, we questioned whether we could design a selective redox-neutral C(sp 3 )−C(sp 3 ) cross coupling with aziridines by using an alternative C(sp 3 ) partner where the activation mode is decoupled from that of aziridines. Herein, we report progress toward this goal in the development of a redox-neutral Ni/photoredox-catalyzed alkylation of aziridines to generate 2°-Me, 2°-1°, 2°-2° alkyl bonds (Figure 1C). The method facilitates the synthesis of a range of b-substituted sulfonamides that were previously inaccessible by traditional cross-coupling methods with aziridines. Benzaldehyde dialkyl acetals serve as the second C(sp 3 ) coupling partner in the method, functioning to activate unactivated alcohols toward homolytic C(sp 3 )-O cleavage in an oxidative process 21 that is orthogonal to aziridine activation via reduction. Differentiation of the activation modes affords an opportunity to independently tune the rate of reaction of the two partners to achieve crossselectivity using easy to manipulate variables like light intensity. Mechanistic studies suggest that these conditions favor a Ni(0)−(I)−(III) cycle wherein aziridine activation does not occur via Ni(0) oxidative addition, but rather via Ni(I), an elementary step that has no prior stoichiometric or catalytic precedent. 22,23 RESULTS AND DISCUSSION</p><!><p>We began reaction optimization using 2-(4-fluorophenyl)-1-(p-tolylsulfonyl)aziridine (1a) and benzaldehyde dimethyl acetal (2a) as a methyl radical precursor. On the basis of prior studies, including our own recent work, 21 we explored the use of halide salts as precursors to halogen radicals for HAT. We were pleased to find that using 2.5 mol% Ni(cod)2, 5 mol% NH4Br (E1/2 [Br − /Br•] = +0.80 V vs SCE in DCE), and 2 mol% Ir[dF(Me)ppy]2(dtbbpy)PF6(Ir II /Ir III * = +0.97V vs SCE in MeCN) 2g,24 with a 427 nm Kessil lamp at 25 ℃, the desired cross-coupled product 3a was formed in 22% yield (Table 1, entry 1). Because hydrolysis of the acetal 2a was also observed under these conditions, we next evaluated non-protic bromide salts, including LiBr, which led to the formation of 3a in 32% yield (Table 1, entry 2). In both these reactions, numerous undesired side products also accompanied product formation, including the dimerized aziridine (4), sulfonamide 5, 25 and the direct product of cross-coupling with the 3° carbon of the acetal (6). Since 4 and 5 both presumably arise from unproductive consumption of an azanickellacycle intermediate, we hypothesized that increasing the rate of methyl radical formation from 2a might lead to better selectivity for the cross-coupled product 3a. 26 Consistent with this hypothesis, we found that simply adding another lamp and increasing the lamp intensity, variables that should both differentially impact the HAT cycle, afforded 3a in 70% yield (Table 1, entry 3-4). Increasing the acetal equivalents from 1.8 to 2.4 also afforded a modest improvement in the yield of 3a (Table 1, entry 5).</p><!><p>Reactions performed on 0.1 mmol scale, with 1-fluoronaphthalene as the external standard ( 19 F NMR yield for 3,4,6, 1 H NMR yield for 5). Entries 1-2 were performed at 0.04M, and entries 3-10 were performed at 0.057M. For reactions with 25% intensity, vials were placed 1.5 cm away from Kessil lamp and for 50% intensity, vials were placed 3cm away. Entries without (rsm) showed full conversion of the aziridine. a NH4Br was used instead of LiBr b Three fans were used to cool the reaction. c No fans were used to cool the reaction. Reaction with either no light, no photocatalyst, no nickel, or no nickel/ligand all gave 0% yield of the desired product.</p><p>Although the conditions in entry 5 afforded a high yield of the desired product, we sought to test the robustness of the reaction under a more simplified light set-up. Interestingly, while only one lamp with fan-cooling afforded 34% yield of 3a, simply removing the fans to increase the reaction temperature gave a significant increase in the yield of 3a to 72% (Table 1, Entry 6,7), potentially because higher temperatures facilitate βscission and increases the concentration of Me radical in solution. Finally, evaluation of Ni precatalyst identity showed that NiBr2•glyme gave a 10% increase in yield over Ni(cod)2 (Table 1, Entry 8). Yield (%)</p><!><p>With these optimized reaction conditions, we were pleased to find that 3a can be obtained in useful yield even with reduced equivalents of the acetal (Table 1, Entries 9 & 10). Moreover, although NiBr2•glyme can serve as the sole source of bromide for HAT, control reactions omitting LiBr led to diminished reactivity, consistent with previous observations that the counter cation of the additive may facilitate stabilization of the anionic sulfonamide and product release (Table, Entry 11). 20c</p><!><p>Methylation of C(sp 3 ) carbons is a powerful strategy in medicinal chemistry that can lead to an increase in potency, higher selectivity among bioreceptors, alteration in solubility, and enhanced protection against enzyme metabolism. 27 Accordingly, amines and sulfonamides bearing β-methyl groups are a highly sought structural motif in pharmaceuticals. 28 Nevertheless, methylation of aziridines has only been accomplished with highly nucleophilic organometallic reagents, such as Grignard reagents, organocuprates, and AlMe3, and often results in poor regioselectivity. 29 Moreover, there have been no reports of successful Ni-or Pd-catalyzed cross-coupling of aziridines with methyl nucleophiles. 11-14 Therefore, with the optimized reaction conditions in hand, we investigated the scope of the reaction with various aziridines using benzaldehyde dimethyl acetal as a methylating reagent.</p><p>We were excited to find that a broad range of styrenyl aziridines were compatible with this Ni/photoredox methylation reaction (Table 2). Substrates bearing electron-deficient groups such as p-CF3 (3b) or p-CN (3c) gave the b-methylated sulfonamide products in 77% and 50% yield, respectively. An unsubstituted styrenyl aziridine (3d) as well as those baring electrondonating groups such as p-t-Bu (3e) or p-OPh (3f) also afforded the methylated products in good yield. The reaction showed minimal sensitivity to steric hindrance on the arene, with 3g formed in 59% yield.</p><!><p>Reactions performed on 0.2 mmol scale. 0.48 mmol of the acetal coupling partner was used. a 48 h instead of 20 h b Ratio of ringclosed to ring-opened isomers. c 5,5'-difluoro-2,2'-bipyridine was used instead dtbbpy. 'rr' denotes regiomeric ratio of branched/linear ring opened aziridines. d 1:1 dr at the benzylic stereogenic censer of the trans cyclobutane.</p><p>As sulfonamides have been frequently employed in medicinal chemistry, we also investigated aziridines with sulfonyl substituents other than a tosyl group. Both aryl (3h-3j) and alkyl sulfonamides, 30 such as methanesulfonamide (3k) 30c and cyclopropanesulfonamide (3l) 30d,e were tolerated in the reaction, albeit the alkyl sulfonamides were formed as mixtures of regioisomers with methylation favoring the benzylic position. Finally, an unsubstituted aziridine was also converted to the deuteromethyl-and methylated products 3m and 3n in 75% and 76% yield, respectively. A current limitation of the methodology is that aliphatic aziridines give poor conversion to the product, even with prolonged reaction times (3o).</p><p>We next explored the scope of the acetal partner using 2-(4fluorophenyl)-1-(p-tolylsulfonyl)aziridine (1a). We found that deuteromethyl (3p) as well as other unactivated linear alkyl groups such as Et (3q), n-propyl (3r), n-pentyl (3s), and isoamyl (3t) all afforded the desired products in 52-83% yield. Alkyl groups bearing heteroatom substitution (3u) were also competent substrates, albeit lower yielding. Moreover, β−substituted alkyl coupling partners such as neopentyl (3v) were effective in the reaction. As another example, a methylene cyclobutyl group could be transferred in 51% yield (3w), wherein both the direct cross-coupling (3w1) and the radical ring-opened terminal alkene (3w2) were observed in a 4:1 ratio.</p><p>We were also excited to observe reactivity between 2⁰ alkyl coupling partners and aziridines, given that cross-coupling of 2⁰ alkyl groups with aziridines is not feasible under reported Negishi conditions. 11,13 Moreover, 2⁰−2⁰ C−C bond formation presents a particular challenge in cross-electrophile strategies, with only a few examples reported to date. 6d,e When testing the reactivity between 2⁰ alkyl coupling partners and aziridines, we found that application of 5,5'-difluoro-2,2'-bipyridine rather than dtbbpy as ligand enabled higher conversion to the desired product (See supporting information). Both cyclic and acyclic secondary alkyl groups underwent coupling. The reaction was most efficient with cyclobutane derivatives (3x and 3y). A decrease in yield was observed as the ring size was expanded to cyclopentylation (3z). Interestingly, use of isopropyl acetal as the 2⁰ coupling partner afforded cross-coupled product with a 1:1.5 ratio of branched and linear propyl groups (3aa). Isomerization was also observed when using an unsubstituted aziridine as coupling partner (3ab), indicating that isomerization is not restricted to only congested 2⁰−2⁰ C-C bond formation (vide infra).</p><!><p>Oxidative addition of aziridines to Ni(0) has been established in stoichiometric studies, 22 with the resulting Ni(II) azametallacycle proposed as a common catalytic intermediate in crosscoupling reactions with aziridines. [11][12][13]15,16,23 Therefore, at the outset of our reaction design, we initially hypothesized that the oxidative addition of Ni(0) I to generate Ni(II) azametallacycles II would be operative; subsequent capture of the alkyl radical to generate Ni(III) III followed by reductive elimination would furnish the desired product (Scheme 1, eq1). Alternatively, Ni(II) complex IV could instead arise via oxidative addition of Ni(0) to benzylbromide 7 generated in situ, given the catalytic presence of bromide in solution (Scheme 1, eq 2). 19,23b Nevertheless, the generation of linear/branched isomers using acyclic secondary alkyl reaction partners appeared inconsistent with these pathways (Table 2, 3aa, 3ab). In particular, β-hydride elimination and reinsertion should be much more favorable at a low-valent Ni(I) VI center as opposed to the Ni (III) intermediate III in eqs 1 and 2 since isomerization necessitates a vacant coordination site and an intermediate with a relatively long lifetime. 31 Interestingly, the intermediacy of a Ni(I) alkyl VI would imply that aziridine activation takes place by Ni(I)−Ni(III) oxidative addition, an elementary step that does not have precedent in stoichiometric studies for aziridines (Scheme 1, eq3). Or an analogous Ni(I)−Ni(III) pathway could also be proposed with benzyl bromide 7 (Scheme 1, eq 4).</p><!><p>To interrogate the mechanism of aziridine activation, we first sought to synthesize the Ni(II) II oxidative adduct and test its intermediacy in the coupling reaction (Scheme 1, eq1). Complex IIa was independently synthesized by reacting Ni(cod)2 with 1a in the presence of dtbbpy (Scheme 2A). The stoichiometric reaction of IIa under the standard reaction conditions did not result in the formation of product. Instead, IIa underwent conversion (30%) to a mixture of aziridine dimer 4a, sulfonamide 5 and reduced aziridine (see supporting information). To determine if IIa accesses a catalytically-relevant intermediate and if the attached aziridine in the Ni complex can be directly converted to the desired methylated product, a crossover experiment was designed using p-CF3 styrenyl aziridine 1b as a substrate in the presence of 10 mol % azametallacycle IIa as the sole nickel catalyst source (Scheme 2B). However, less than 1% of the product originating from IIa (3a) was obtained, whereas the product from 1b was formed in 32% yield. These results provide evidence against the pathway shown in Scheme 1, eq 1. Furthermore, when a time-course experiment was performed, IIa was never spectroscopically observed (see supporting information for details).</p><!><p>[ Next, we investigated the intermediacy of benzylbromide 7, pertinent to Scheme 1, eq2 or eq4, which could be generated by the 7.5% of bromide (2.5% from NiBr2•glyme and 5% from LiBr) in the reaction mixture. When benzyl bromide 7a was subjected to the reaction, only 1% of the product was generated. Instead, the majority of bromide 7a was converted to dimer 4a and reduced aziridine 8 (Scheme 3A).</p><!><p>(A) Reaction performed 0.1 mmol scale using stoichiometric amount of benzylbromide 7a vs. (B) catalytic amount of benzylbromide 7a (0.01 mmol) and aziridine (0.09 mmol). Ar 1 = p-F-benzene Ar 2 = p-CF3-benzene. Yields are based on 0.1 mmol 1-fluoronaphthalene as the external standard by 19 F NMR.</p><p>When 7a was used in catalytic quantities in the presence of aziridine 1b, as a way to simulate the catalytic formation of 7a under the standard condition, 1.6% of the product originating from 7a was observed, whereas the product derived from 1b was formed in 51% yield (Scheme 3B). Based on these observations, we propose that any in situ generated 7 most likely leads to off-cycle byproducts, presumably via oxidative addition of the benzyl bromide or halogen abstraction to generate the benzylic radical, followed by free-radical recombination, a common off-cycle pathway in aryl benzylation with benzylic halides. 32</p><!><p>Taken together, these data are most consistent with a Ni(0)−Ni(I)−Ni(III) pathway wherein Ni(I) undergoes oxidative addition to the aziridine (Scheme 1, eq 3). Since this step has not been previously observed, we sought direct experimental evidence for the stoichiometric oxidative addition of Ni(I) to aziridine 1a. Unfortunately, an isolable dtbbpyNi(I)(alkyl) complex has not previously been prepared. However, in their investigation of the reactivity of CO2 at Ni(I), the Martin group reported the synthesis of a (mesityl-phenanthroline)Ni(I)(CH2t-Bu) VII (Scheme 4). 33 Therefore, we sought to test this Ni(I) alkyl complex for oxidative addition reactivity with 1a. Prior to exploring stoichiometric studies with VII, we established that mesityl-substituted phenanthroline (L 2 ) gives similar yield as dtbbpy (L 1 ) in the catalytic reaction. Indeed, mesityl-substituted phenanthroline afforded 33% yield of 3v, in close agreement with the 36% yield of 3v seen with dtbbpy (Scheme 4A).</p><!><p>(A) Control experiments with L 1 (4,4'-di-tert-butylbipyridine) and L 2 (2,9-dimesityl-1,10-phenanthroline) (B) Reactivity of L2Ni(CH2t-Bu) complex VII with aziridine 1a.</p><p>Having confirmed the catalytic competence of L 2 , we turned our attention to the stoichiometric reaction (Scheme 4B). VII was generated in situ, by adding a solution of neopentylMgBr to L 2 Ni(I)Br, 32 with the resulting complex then subjected to aziridine 1a. This led to a full consumption of the aziridine, affording 11% of the cross-coupled product 3v and 28% of enamide 9, which could result from oxidative addition at the Ni(I) center, followed by elimination. 34 It is possible that enamide 9 serves as a source for sulfonamide formation 5, which is observed under the catalytic conditions with L 1 and L together, these data support the catalytic relevance of a Ni(I) species for aziridine activation.</p><p>Having established the catalytic relevance of Ni(I), we sought to understand the mechanism of aziridine activation via Ni(I) by evaluating the impact of aziridine substitution on the catalytic reaction outcome (Hammett analysis). Rather than using the relative rate of product formation as a readout, we chose to use the branched/linear ratio of product arising from alkylation with i-Pr acetal 2aa. Isomerization of the Ni(I)(i-Pr) can occur prior to oxidative addition, and aziridines that undergo faster oxidative addition to Ni(I) should therefore afford higher branched/linear ratios of the product according to our proposed mechanism (Scheme 5A).</p><p>Two sites of the aziridine were independently evaluated: the benzene sulfonamide (Scheme 5B) and the benzylic arene (Scheme 5C). When the electronics on the arene ring of the sulfonamide were varied, we observed a high linear correlation between the log(kX/kH) (k = branched/linear) with a positive ρ value (R 2 = 0.98, ρ = 1.1) (Scheme 5B). The positive, but relatively low magnitude, slope indicates that electron-withdrawing groups on the sulfonamide facilitate faster oxidative addition, consistent with either a single-electron transfer or concerted oxidative addition. When the electronics of the benzylic aryl group were modified and plotted against Hammett-Brown constants σ + , 35 or with Jiang's spin-delocalization substituent constants σJJ • (indicative of a radical stabilization effect), 36 a negative correlation was observed with log (kx/kH) (for σ + , R 2 = 0.76, ρ = -0.15; for σ JJ • R 2 = 0.87, ρ = -0.15) (Scheme 5B). The negative slopes for both σ + and σJJ • indicate that a more electron-donating group on the benzylic fragment facilitates oxidative addition. The correlation with σJJ • also suggests a buildup of radical character on the benzylic carbon. These trends are consistent with analyses of benzyl halide oxidative addition to Co(I), 37 where it is proposed that after halogen abstraction by Co(I) to generate a benzylic radical, a radical addition back onto the Co(II) metal center generates Co(III); it is the latter step which would be accelerated by electron-donating (nucleophilic) benzyl groups.</p><p>Overall, the opposite slope of ρ for the arene on the sulfonamide versus the arene on the benzylic site is most consistent with a single electron transfer oxidative addition, where Ni(I) reduces the aziridine to generate a Ni(II)-sulfonamide complex and a benzylic radical, which is followed by recombination of benzylic radical to afford Ni(III). 11a The observed LFERs are inconsistent with a concerted oxidative addition, which would be expected to have a positive ρ value for both experiments. Although SN2-type oxidative addition has been proposed for Ni(0) and negative ρ values have been observed for Lewis-acidcatalyzed nucleophilic ring opening of styrenyl aziridines, 38 the higher R 2 for a radical descriptor σJJ • over σ + and the low magnitude of the ρ value are inconsistent with this mechanism. 38 It is also worth noting that these results contradict the possibility of isomerization occurring at Ni(III) (Scheme 1, eq1), where more electron-deficient arenes on the benzylic site would also be expected to lead to faster reductive elimination and reduced isomerization (i.e.. both ρ values > 0). 39 Furthermore, the higher magnitude of the ρ value of sulfonamide arene than that of the styrenyl arene further corroborates the lack of participation of benzyl bromide 7a as a productive intermediate in the catalytic cycle (Scheme 1, eq 2 or 4).</p><!><p>On the basis of our mechanistic investigations, we propose the following catalytic cycle (Scheme 6A, black). Upon irradiation with blue light, the excited Ir photocatalyst oxidizes bromide anion. The resulting bromine radical can abstract the 3⁰ benzylic C−H of the benzaldehyde dialkyl acetal, followed by β−scission to generate the alkyl radical and ester byproduct. 21b Concurrently, the NiBr2•glyme precatalyst can be reduced to Ni(0) I by Ir(II) to enter the Ni catalytic cycle, which can capture the alkyl radical generated from the β−scission event. This proposed competition of light-mediated cross-reactivity with off-cycle speciation pathways is further supported by comparing the relative product and dimer formation with varying light intensity (Scheme 6C, see SI for details). For example, when performing a time-course study comparing the ratio of product 3a to dimer 4a at high versus low light intensity (64 kLux, Table 1, condition 7 vs 4.5 kLux, condition 6), the lower light intensity conditions result in the formation of nearly 1:1 ratio of the desired product to the dimer. Suppression of offcycle speciation is therefore partially dependent on having sufficient light penetration to favor the productive catalytic pathway.</p><!><p>a Strong light emission: 50% light intensity where the vials were placed 3 cm away from the Kessil lamp, maintained at 38 ℃. Weak light emission: 25% light intensity where the vials were placed 20 cm away from the Kessil lamp while heating in an oil bath at 38 ℃.</p><!><p>In conclusion, we have developed a C(sp 3 )-C(sp 3 ) cross-coupling methodology between aziridines and benzaldehyde dialkyl acetals as latent alkyl radical sources. The transformation employs a diverse set of styrenyl aziridines with varying substitution on the sulfonamide. Moreover, methyl, 1⁰ and 2⁰ unactivated aliphatic coupling partners can be installed efficiently. The orthogonal activation of each coupling component and ligation at distinct Ni oxidation states imparts cross-selectivity between two C(sp 3 ) precursors. Specifically, mechanistic studies support a pathway for activation of aziridines via Ni(I)-Ni(III) oxidative addition, distinct from the commonly proposed oxidative addition of aziridines to Ni(0). These mechanistic studies shed light on the nature of the activation modes for unconventional C(sp 3 ) precursors, which we anticipate can lead to the expansion of C(sp 3 )-C(sp 3 ) cross-coupling methodologies in future studies.</p>