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Published in final edited form as: J Am Chem Soc. 2025 Jan 6;147(2):1667–1676. doi: 10.1021/jacs.4c12334

Ni-Catalyzed Regioselective Alkylarylation of Unactivated Alkenes in Amines Enabled by Cooperative Ligand Effects of Nitriles and Electron-Deficient Alkenes

Vivek Aryal 1, Supuni I N Hewa Inaththappulige 1, Ayush Acharya 1, Ramesh Giri 1
PMCID: PMC13102162  NIHMSID: NIHMS2162327  PMID: 39763054

Abstract

We report a Ni-catalyzed vicinal alkylarylation of unactivated alkenes in γ,δ- and δ,ε-alkenylamines with aryl halides and alkylzinc reagents. The reaction is enabled by amine coordination and can use all primary, secondary and tertiary amines. The reaction constructs two new C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds and produces δ- and ε-arylamines with C(sp3)-branching at the γ- and δ-positions. A variety of aryl and heteroaryl iodides, and both the primary and secondary alkylzinc reagents can be used as coupling carbon sources. Mechanistic studies suggest that the reaction is enabled by a cooperative effect of organic nitriles and electron-deficient alkenes (EDAs) as ligands.

Graphical Abstract

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INTRODUCTION

Metal-catalyzed formation of two carbon-carbon (C-C) bonds across vicinal C(sp2) sites in unactivated alkenes, often termed dicarbofunctionalization, is challenging yet a powerful technique in engineering molecular complexity rapidly from simple feedstock chemicals.1–6 In recent years, a number of significant studies have emerged to substantiate its competency in expeditious generation of complex molecules such as natural products,7–10 bioactive molecules,11–13 pharmaceuticals14–15 and polymers.16 Yet significant challenges persist, in particular, with regard to preventing β-H elimination from β-H-C(sp3)-[M] intermediates17–24 and regioselectively placing two discrete carbon sources across the vicinal C(sp2) sites.25–31 The most common strategy to address these problems is the use of a coordinating group to induce proximity bias at the vicinal sites for regiocontrol and subsequently generate transient metallacycles to address β-H elimination. However, this strategy is largely successful for alkenes bearing strongly coordinating groups like 8-aminoquinolines,25,32–40 picoline26 and imines41–42 since the transient metallacycles need to be remarkably stable to navigate both transmetallation and reductive elimination while resisting β-H elimination in the succeeding steps.43–49

Three-component dicarbofunctionalization of unactivated alkenes assisted by native functional groups is formidably challenging. These native functional groups coordinate to metals weakly prompting rapid dissociation of the heteroatoms from the transient and fluxional metallacycles, and inducing β-H elimination.21–22 To date, carbonyl groups, such as ketones,27,50–51 esters,52 amides53–56 and carboxylic acids,57 have been successfully shown to serve as a coordinating group for alkene dicarbofunctionalization, typically for C(sp2)-C(sp2) and perfluoroalkyl-C(sp3)-C(sp2) bond formation. Simple amines are yet to participate in this class of reaction. The use of amines as a coordinating group is challenging since the aminyl β-H-C(sp3)-N-[M] site in the N-[M] metallacycles (2-4) (Scheme 1) can undergo β-H elimination to form imines in addition to the β-H-C(sp3)-[M] sites to generate the Heck products.58–59 Alkenylamines can also undergo cyclization in the presence of transition metal catalysts.60–63 Additionally, the introduction of an alkyl group through transmetallation with alkylorganometallic reagents39,42 further complicates the situation with β-H elimination because it introduces extra β-H-C(sp3) to metallacycles (4) already bearing multiple β-H’s.64–75 Since C(sp3)-C(sp3) reductive elimination that establishes the second C-C bond is typically turnover-limiting for this class of reactions,42,11b,13c the in-cycle resting state metallacycle (dialkyl [β-H-C(sp3)]2[M] species), and other pre-reductive elimination intermediates relish protracted residence time further favoring β-H elimination. Therefore, a key to the success of using weakly coordinating native functional groups such as amines is to promote the C(sp3)-C(sp3) reductive elimination. Herein, we disclose a combination of nitriles and EDAs as ligands and Ni as a catalyst that enables alkylarylation of unactivated alkenes in amines with alkylzinc reagents and aryl halides by promoting C(sp3)-C(sp3) reductive elimination from a dialkylnickel(II) species.

Scheme 1.

Scheme 1.

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Problems associated with using amine as a coordinating group for alkene difunctionalization involving alkylorganometallic reagents

RESULTS AND DISCUSSION

Our studies began with examining reaction parameters by varying solvents with different polarity for the alkylarylation of alkenylamine 5 with n-pentylzinc bromide (6) and iodobenzene with Ni(cod)2 as a catalyst (Table 1A). Only trace amounts of the product 8 was observed in most solvents except in MeCN, DMF and DMSO, which generated 8 in 10–12% yields (entries 7–9). Addition of 5 mol% dimethyl fumarate (DMFu) (10) increased the product yield moderately in some solvents but significantly in MeCN (entries 5–10).

Table 1.

Evaluation of solvents with different polarity and revelation of the nitrile effecta

graphic file with name nihms-2162327-t0002.jpg
A C
entry solvents yields of product 8 entry solvents yields of product 9
w/o DMFu w/ DMFu (%) w/o DMFu (%) w/ DMFu (%)
1 pentane trace trace 1 pentane 0 64
2 toluene trace trace 2 toluene 8 83
3 Et2O trace 5 3 Et2O 7 81
4 DCM trace trace 4 DCM 0 48
5 THF trace 30 5 THF 20 76
6 dioxane trace 10 6 dioxane 21 84
7 MeCN 12 64 7 MeCN 24 98
8 DMF 11 40 8 DMF 24 70
9 DMSO 10 28 g DMSO 39 68
10 NMP trace 23 10 NMP 20 63
B. For the reaction of 6 in MeCN
graphic file with name nihms-2162327-t0003.jpg
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a

1H NMR yields with 1,3,5-trimethoxybenzene as a standard.

We surmised that both DMFu and MeCN could be playing a cooperative role to increase the efficiency of the reaction. In particular, EDAs including DMFu have been known to promote Ni-catalyzed reactions by facilitating C(sp3)-C(sp3) reductive elimination,51,55,76–87 Similarly, organic nitriles have also been shown previously to enhance the reactivity of Ni-catalysts by promoting C(sp3)-C(sp3) reductive elimination.88–90 In addition, nitriles also promote Ni-catalyzed reactions by generating more reactive Ni-species91–96 and decreasing the energetic span.97 Therefore, we decided to examine the effects of sterically and electronically varied EDAs and RCN in the reaction. EDAs such as dimethyl maleate (11), trans-stilbene (12) and fumaronitrile (13), and dimethyl acetylenedicarboxylate (14) as their alkyne variant generated the product 8 in MeCN (Table 1B). EDAs 11 and 13 showed efficiency similar to DMFu (10) while 12 and 14 furnished the product in lower yields. Similarly, we utilized a mixture of 5 equiv of RCN and 5 mol% DMFu as a ligand dyad in low to non-coordinating solvents, such as toluene and pentane, to examine the potential role of organic nitriles. Pleasingly, the product 8 was formed in high yields in both toluene and pentane in the presence of MeCN (Table 2, entry 1). Examination of additional nitriles, such as isopropyl nitrile (iPrCN), pivalonitrile (PivCN), 1-piperidinecarbonitrile (PipCN) and benzonitrile (PhCN), in the presence of 5 mol% DMFu also furnished the product 8 in consistently high yields similar to MeCN (entries 2–5). The outcomes of these experiments evidently suggest that both EDAs and RCN collaborate in the reaction to increase the reaction efficiency.

Table 2.

Evaluation of sterically and electronically varied nitriles with and without DMFua

graphic file with name nihms-2162327-t0004.jpg
entry Nitriles w DMFu (5 mol%) yields of 8 w/o DMFu
toluene (%) pentane (%) toluene (%) pentane (%)
1 MeCN 79 79 6 62
2 iPrCN 75 91 17 48
3 PivCN 72 97 7 35
4 PipCN 70 81 37 46
5 PhCN 65 74 34 63
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a

1H NMR yields with 1,3,5-trimethoxybenzene as a standard.

Moreover, we conducted control experiments with 5 equiv of RCN in toluene and pentane in the absence of DMFu in order to deduce the independent role of nitrile in the reaction. All RCN examined increased the product yields to significant levels in toluene and pentane without DMFu (Table 2). These outcomes sharply contrast with the results of similar reactions conducted with 5 mol% DMFu in the absence of any nitrile in which only traces of the product 8 was observed (Table 1A, entries 1–2). It can be inferred from the control experiments that both DMFu and RCN operate uniquely in the catalytic cycle and that RCN is capable of promoting the reaction independent of DMFu, likely by facilitating reductive elimination and modulating Ni-intermediates preceding pre-reductive elimination intermediates. Moreover, the reactivity difference in toluene and pentane without DMFu (Table 2) also highlights the subtle effect of solvent coordination on the structure of reaction intermediates,98 and that the efficient nitrile coordination in nonpolar pentane generates more reactive intermediates99 and promotes the alkylarylation reaction. Overall, reactions containing both the nitrile and DMFu furnish the product 8 in the highest yield, suggesting their cooperative role in executing the alkylarylation reaction.100

We conducted additional experiments to further probe the role of nitrile and its exceptionality in promoting the reaction. First, we examined the reactivity of 3-cyanopropylzinc bromide (7), which can provide an innate nitrile to function as a ligand in the absence of an exogenous nitrile, such as MeCN. Indeed, 3-cyanopropylzinc bromide (7) furnished the product 9 in low to moderate yields in several solvents in the absence of DMFu and in universally high yields in all the solvents examined in the presence of 5 mol% DMFu and without any nitrile added (Table 1C). Second, we conducted a comparative reactivity study between 3-cyanopropylzinc bromide (7) and 2-(1,3-dioxan-2-yl)ethyl)zinc bromide (15) containing nitrile-N and ether-O for binding. The purpose of this experiment is to determine if the product enhancing effect is unique to a nitrile and is not just a simple function of a heteroatom binding that could stabilize and enhance the reactivity of a catalyst. Since an η1-bond nitrile and an ether are both weakly-binding labile ligands,101–103 the comparative study should assist in discerning the nitrile’s uniqueness from the heteroatom effect in the reaction. The comparative study showed that both nitrile and ether-containing alkylzinc reagents 7 and 15 reacted to furnish the corresponding products 9 and 16 in high yields in MeCN or in toluene with 5 equiv MeCN but only the nitrile-containing alkylzinc reagent 7 produced the product 9 in high yields in toluene or pentane in the presence of DMFu without an exogenous nitrile (Table 3). These experiments strongly support the distinctive role of nitriles as ligands in the reaction.

Table 3.

Inference of the role of nitrile by comparative studiesa

graphic file with name nihms-2162327-t0005.jpg
product (R) toluene (%) pentane (%) MeCN (%) toluene/5 equiv MeCN (%)
graphic file with name nihms-2162327-t0006.jpg 83 97 99 79
graphic file with name nihms-2162327-t0007.jpg 9 6 99 99
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a

1H NMR yields with 1,3,5-trimethoxybenzene as a standard.

Next, we conducted kinetic experiments by in situ 19F NMR spectroscopy to obtain reaction profiles and determine the effects of nitriles on the rate of the reaction (Fig. 1). The kinetic profile for the reaction of alkenylamine 5 with n-pentylzinc bromide (6) and 4-fluoroiodobenzene in toluene (Scheme 2) shows a dramatic rate and efficiency enhancements in the presence of MeCN with the formation of the product 17 in high yield (80%) (Fig. 1a, red and blue). In contrast, the reaction of 3-cyanopropylzinc bromide (7) in toluene displays a fast reaction with high yield of the product 18 (94%) without an exogenous nitrile (green) due to the presence of the innate nitrile for binding. The difference in the yield and kinetic profile between n-pentylzinc bromide (Fig. 1a, blue) and 3-cyanopropylzinc bromide (Fig. 1a, green) also suggests the stabilization of Ni-intermediates and their prevention from deactivation by the binding of the intramolecular nitrile. Moreover, monitoring the reactions of n-pentylzinc bromide (6) in toluene in the presence of different nitriles (Fig. 1b) demonstrate that the reactions with nitriles that are both sterically more encumbered and electronically more π-accepting than MeCN are not only slower but also generate the product 17 in lower yields. These results of rate enhancement, and steric and electronic effects on the rate suggest the involvement of nitriles at the rate-limiting step (RLS).

Figure 1.

Figure 1.

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(a) Effects of MeCN and intramolecular nitrile on the rate of reaction in toluene. Red: reaction of CH3(CH2)4ZnBr (6) in the absence of MeCN. Blue: reaction of CH3(CH2)4ZnBr (6) in the presence of 5 equiv. MeCN. Green: reaction of CN(CH2)3ZnBr (7) in the absence of MeCN. (b) Effects of various nitriles on the rate of reaction in toluene. Red: reaction of CH3(CH2)4ZnBr (6) in the absence of any nitrile. Blue: reaction of CH3(CH2)4ZnBr (6) in the presence of MeCN. Green: reaction of CH3(CH2)4ZnBr (6) in the presence of iPrCN. Black: reaction of CH3(CH2)4ZnBr (6) in the presence of pivCN. Pink: reaction of CH3(CH2)4ZnBr (6) in the presence of PhCN. Aqua: reaction of CH3(CH2)4ZnBr (6) in the presence of PipCN. (c) Reaction rates with increasing concentration of MeCN. (d) Reaction rates with increasing concentration of DMFu. (e) Displacement of cod from 0.010 mmol Ni(cod)2. Blue: in the presence of MeCN. Red: in the presence of PipCN. Green: in the presence of alkenylamine 5. Black: in the presence of DMFu. (f) Relative rates of reaction of CH3(CH2)4ZnBr (6) and CN(CH2)3ZnBr (7) in MeCN. *(scale: MeCN, × 1.0; pipCN, × 1.0; alkenylamine 5, × 0.10; DMFu, × 0.010).

Scheme 2.

Scheme 2.

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Reaction Scheme for Kinetic Studies by 19F NMR

We conducted further experiments to determine the dependance of the rate of the reaction on the concentrations of MeCN and DMFu. First, we measured the rates for the reaction of n-pentylzinc bromide (6) using different concentrations of MeCN in the presence of 5 mol% DMFu in toluene (Fig 1c). The reaction rate increased with the increasing amounts of MeCN from 5 equiv to 10 and 20 equiv but remained the same with 40 equiv. In addition, the rates of the reactions with 20 and 40 equiv of MeCN in toluene were similar to the rate of the reaction performed in MeCN as the sole solvent suggesting that a saturation of nitrile binding is attained at the rate-limiting step. Second, we measured the rates of the reaction using different concentrations of DMFu (5, 10 and 20 mol%) with 5 mol% Ni(cod)2 in the presence of 5 equiv of MeCN in toluene (Fig. 1d). The rates of the reaction remained similar at all concentrations of DMFu indicating efficient binding of DMFu with Ni(cod)2 in a 1:1 molar ratio at the rate-limiting step.

Additionally, we examined the binding efficacy of MeCN, pipCN, DMFu and alkenylamine 5 to Ni in toluene and their effects on the dissociation of 1,5-cyclooctadiene (cod) from Ni(cod)2 (0.010 mmol) (Fig. 1e). At reaction concentrations with 5 mol% Ni(cod)2 and 5 equiv MeCN (100 equiv to Ni) in toluene, MeCN (blue) was capable of displacing approx. 10% cod from Ni(cod)2. 51% cod is displaced by MeCN at 640 equiv to Ni and 100% cod dissociated from Ni(cod)2 in pure MeCN as a solvent. PipCN (red) was much more effective than MeCN with 90% displacement observed at just 20 equiv to Ni(cod)2. Likewise, alkenylamine 5 (green) was also capable of displacing cod from Ni(cod)2. At the reaction concentration of alkenylamine 5 (20 equiv to Ni), approx. 50% cod is displaced, and the cod dissociation begins to level off at about 72% cod displacement with 128 equiv of alkenylamine 5. DMFu (black) displaces the cod most effectively with 85% cod displaced by 1:1 molar ratio of DMFu to cod.104 These experiments suggest that DMFu, alkenylamines and nitriles (MeCN and PipCN) are all effective to displace cod from Ni(cod)2. In relative terms, DMFu is most effective in displacing cod followed by PipCN, alkenylamines and then MeCN, respectively. The result of the efficient displacement of cod from Ni(cod)2 by an equimolar DMFu is also consistent with the reaction attaining saturation kinetics with the 1:1 molar ratio of DMFu to Ni(cod)2 (Fig. 1d).

Next, we focused our studies on deducing the effective binding mode of nitriles. Nitriles are capable of binding to transition metals in both η1 (head-on) through N and η2 (side-on) via C≡N.101 We conducted comparative rate measurements and competition studies for the reactions of n-pentylzinc bromide (6) and 3-cyanopropylzinc bromide (7) in MeCN to deduce the binding mode of nitriles. Our rate measurement studies indicated that while the reaction of 3-cyanopropylzinc bromide (7) was more efficient than that of n-propylzinc bromide (6) (89% vs 70%) (Fig. 1f), the reaction of the former that contains an intramolecular nitrile for binding proceeded much slower than the reaction of the latter that doesn’t have innate nitrile. This experiment suggests that coordination to Ni by the intramolecular CN group is not desirable, potentially due to the formation of four-coordinate nickallabicycle 19 (Scheme 3) that increases the kinetic barrier for C(sp3)-C(sp3) bond-forming reductive elimination. Moreover, competition experiments between n-pentylzinc bromide (6) and 3-cyanopropylzinc bromide (7) in toluene and pentane without and with 5.0 equiv MeCN, and MeCN as the sole solvent (Table 4) showed that the reaction of n-pentylzinc bromide (6) proceeded preferentially over the 3-cyanopropylzinc bromide (7). These outcomes are in sharp contrast to the results of the independent reactions of n-pentylzinc bromide (6) and cyanopropylzinc bromide (7) in which the former is much less reactive than the latter. This is evident from the results in Table 1 for the reaction of n-pentylzinc bromide (6) in toluene, pentane and MeCN in the presence of 5 mol% DMFu, which produced trace, trace and 64% of the product 8 (Table 1A, entries 1, 2, 7) while those of 3-cyanopropylzinc bromide (7) generated 64%, 83% and 98% of the product 9, respectively (Table 1C, entries 1, 2, 7). These experiments further confirm that the productive pathway requires an intermolecular coordination of a nitrile and the intramolecular nitrile coordination is detrimental. Overall, the outcomes of the rate and competition studies along with the reactivity in different sol- that the most reactive species for reductive elimination is the one vents in the presence and absence of nitriles and DMFu suggests that contains both nitrile and DMFu (21) followed by the intermolecular nitrile coordinated species lacking DMFu (20) and the least reactive is the intermediate with intramolecular nitrile binding (19) (Scheme 3).

Scheme 3.

Scheme 3.

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Pre-reductive elimination (pre-RE) dialkylnickel(II) species with relative reactivities.

Table 4.

Competition experimenta

graphic file with name nihms-2162327-t0008.jpg
product (R) toluene (%) pentane (%) MeCN (%) toluene/5 equiv MeCN (%)
graphic file with name nihms-2162327-t0009.jpg trace trace trace trace
graphic file with name nihms-2162327-t0010.jpg 7 52 42 32
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a

1H NMR yields with 1,3,5-trimethoxybenzene as a standard.

Based on our mechanistic studies and prior literature reports, we propose a catalytic cycle in Scheme 4. Since DMFu displaces cod stoichiometrically, we believe that the reaction is initiated by a (DMFu)Ni(MeCN)n (22) generated in situ from Ni(cod)2, DMFu and MeCN. The catalyst 22 performs oxidative addition of ArX followed by the binding of the alkenylamine and migratory insertion of Ar to the bound alkene to generate species 25. The intermediate 25 then undergoes transmetallation and addition of MeCN to create the five-coordinate 27 for the subsequent C(sp3)-C(sp3) bond-forming reductive elimination at the rate-limiting step. Prior reports have demonstrated that a four-coordinate (bipy)Ni(II)(alkyl)2 complex only undergoes C(sp3)-C(sp3) reductive elimination through a five-coordinate (bipy)(EDA)Ni(II)(alkyl)2 upon binding an EDA.78–79 Mechanistic studies have also supported the existence of analogous five-coordinate Ni(II) intermediates, which promote carbon-carbon bond-forming reductive elimination in catalytic reactions.85,87 Carbon-carbon reductive elimination is generally faster from five-coordinate complexes than from four or six-coordinate species105–106 and the preference is generally attributed to the configurational lability of the structure.77,107

Scheme 4.

Scheme 4.

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Proposed catalytic cycle.

Upon understanding the roles of nitriles and EDAs, we examined the scope of alkylarylation of γ,δ- and δ,ε-alkenes in amines with 5 mol% DMFu in MeCN for simplicity (Table 5). We initially examined the scope by the reaction of alkenylamine 5 containing γ,δ-alkenes with iodobenzene and different alkylzinc reagents (Table 5a). The reaction could be performed in good to excellent yields with primary alkylzinc reagents with no functional group (8) and those containing functional groups such as nitriles (9), protected aldehydes (16), esters (28) and alkenes (29). Similarly, both unfunctionalized acyclic and cyclic secondary alkylzinc reagents (30, 31) and functionalized secondary alkylzinc reagents containing oxygen and nitrogen heterocycles (32, 33) could be implemented for coupling.

Table 5.

Coupling of terminal alkenes with primary alkylzinc reagents and aryl halidesa

graphic file with name nihms-2162327-t0011.jpg
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a

Reactions were run in 0.5 mmol scale in 2.5 mL MeCN unless stated otherwise. About 3–10% Heck products are observed in all reactions.

b

Reaction run in 2.5 mL toluene with 5 equiv MeCN.

c

Reaction run in 2.5 mL pentane with 5 equiv MeCN.

d

ArBr was used instead of ArI at 40 °C for 12 h.

Additionally, we examined the scope of amines and aryl iodides in combination with different functionalized and unfunctionalized alkylzinc reagents (Table 5B–D). The reaction could be conducted with primary, secondary and tertiary amines. For example, the δ,ε-alkenes present in primary alkylamine and aniline were difunctionalized with aryl iodides and alkylzinc reagents to afford the corresponding alkylarylation products (34, 35) (Table 5B). Similarly, the γ,δ-alkene in secondary cyclohexylalkylamine 5 could be alkylarylated with a variety of aryl iodides and alkylzinc reagents in good to excellent yields (17, 18, 36-42) (Table 5C). An amine derived from amino acid also served as a coordinating group and enabled alkylation of a γ,δ-alkene tethered to the amino acid (43). In addition, the reaction is compatible with secondary benzylamine and its variants containing pyridine and thiophene (44-46). The alkylarylation reaction could also be conducted with secondary alkylarylamines derived from aniline bearing moderately electron-withdrawing and electron-donating groups (47-49). Likewise, γ,δ-alkenes could be alkylaryalted using both the cyclic and acyclic tertiary alkylamines based on piperidine, morpholine and 3-(cyclohexylamino)-1-cyanopropane (50-52) (Table 5D). Additionally, the γ,δ-alkene present at the ortho position of an aryl ring was alkylarylated using N,N-dimethylaniline as the tertiary amine for coordination (53). The structure of the alkylarylation product 50 was confirmed as its HCl salt by a single crystal X-ray crystallography. The aryl, alkyl or benzyl substitution on the amines or their primary, secondary or tertiary variations had no different effect on the product yield since all varieties of amines generated products in similar yields. However, the alkylarylation reaction was largely applicable to terminal alkenes and internal alkenes produced no products.

The alkylarylation reaction also showed a good scope of aryl halides. For example, the reaction proceeded with a variety of moderately electron-poor and electron-rich aryl iodides bearing functional groups such as alkyl, F, Cl, OMe and SMe. Sensitive functional groups like 1,3-dioxolyl, nitrile, ester, dihalide and amide are well tolerated. The reaction is also compatible with coordinating and sterically bulky groups such as iPr, CN, OMe at the ortho-position of aryl iodides (38-40). More importantly, the method allows to introduce heterocycles like quinoline (41), benzothiobene(42) and N-phenyl-2-piperidinone (46) in the difunctionalized products. We have also given the yields obtained for reactions run in toluene and pentane with 5 mol% DMFu and 5 equiv of MeCN for comparison (Table 5, notes b and c). In general, product yields for the reactions of both functionalized (16, 28, 50, 51) and unfunctionalized (8, 17, 30, 31, 44) alkylzinc reagents run in toluene and pentane with 5 mol% DMFu and 5 equiv of MeCN are consistently higher than those run with 5 mol% DMFu in MeCN as a solvent. The reactions can also be conducted with aryl bromides instead of aryl iodides although they require a slightly elevated temperature and longer reaction time (8, 9, 30, 42, 44, 51) (Table 5, note d).

CONCLUSIONS

We disclose a Ni-catalyzed alkylarylation reaction that difunctionalizes unactivated alkenes in γ,δ- and δ,ε-alkenylamines through the formation of two new C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. The reaction can be conducted with primary, secondary and tertiary amines bearing γ,δ- and δ,ε-alkenes. A variety of aryl and heteroaryl iodides, and functionalized primary and secondary alkylzinc reagents can be used as coupling partners. Mechanistic studies reveal that the reaction is promoted by a cooperative effect of organic nitriles and electron-deficient alkenes potentially through stabilizing nickel species and promoting C(sp3)-C(sp3) reductive elimination.

Supplementary Material

SI

Experimental procedures and characterization data for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

CCDC number 2382144 for compound 35•HCl contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/

ACKNOWLEDGMENT

We gratefully acknowledge the NIH NIGMS (R35GM133438) and The Pennsylvania State University for support of this work. The X-ray instrument was funded by the NIH SIG S10 grants (1S10OD028589-01 and 1S10RR023439-01).

Footnotes

The authors declare no competing financial interests.

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