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Synthesis 2024; 56(11): 1741-1748
DOI: 10.1055/a-2204-8921
paper
New Trends in Organic Synthesis from Chinese Chemists

Phosphine Ligand Effects in Nickel-Catalyzed Alkene Migratory Hydroalkylation

Qing-Wei Zhu‡
a   Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, P. R. of China
,
Deguang Liu‡
a   Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, P. R. of China
,
Zhen Li
a   Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, P. R. of China
,
Jia-Wang Wang
b   School of Plant Protection, Anhui Agricultural University, Hefei 230036, P. R. of China
,
Wan Nie 
a   Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, P. R. of China
c   Department of Computer Science, City University of Hong Kong, Hong Kong SAR, P. R. of China
,
Xi Lu  ∗
a   Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, P. R. of China
,
Yao Fu∗
a   Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, P. R. of China
› Author Affiliations

Financial support was received from the National Science Foundation of Anhui Province (2208085J26 and 2208085QB36) and the China Postdoctoral Science Foundation (2023TQ0343)
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Abstract

Catalytic alkene hydroalkylation has provided to be an efficient method for synthesizing C(sp3) centers, from readily available and inexpensive alkene starting materials through alkene hydrometallation followed by cross-coupling. One of the major tasks in this field is to develop diverse ligands to achieve regioselective control. Herein, we report the investigation of nickel–triphenylphosphine-catalyzed remote hydroalkylation of alkenyl amides to access α-branched amines. Various alkenes and alkyl iodides are suitable substrates to deliver the desired products with excellent regioselectivities (>20:1 regioisomeric ratio). Density functional theory calculations reveal the reaction mechanism.


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Key words

alkene hydroalkylation - nickel catalysis - phosphine ligand effects - migratory hydroalkylation - alkenyl amides - α-branched amines

Carbon centers of sp3 type are ubiquitous in active molecules, such as natural products and drug molecules, and they constitute the most common structural unit in small organic molecules and material molecules.[1] The development of green, efficient, and highly selective methods for constructing C(sp3) centers is therefore of great significance.[2] In recent years, catalytic alkene hydroalkylation has provided an efficient method for synthesizing C(sp3) centers from readily available and inexpensive alkene starting materials through alkene hydrometallation followed by a cross-coupling mechanism.[3] Moreover, by regulating the relative activity of β-H elimination and reductive elimination, chain-walking processes could be used to enrich the regioselectivities of alkene hydroalkylation. β-H elimination and metal-hydride reinsertion, a previously recognized side reaction process, has been developed as a powerful technology for selective functionalization at unactivated and even challenging reaction sites, providing a novel approach to selectively regulating the construction of multi-level high-saturation molecules (Figure [1]A).[4]

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Figure 1 Representative ligands in alkene hydroalkylation and nickel-phosphine-catalyzed alkenyl amide migratory hydroalkylation (this work); Tf, triflyl.
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Figure 2 Comparison of ligand properties and strategies for switching regioselectivity. HOMO, highest occupied molecular orbital; NBO, natural bond orbital.

One of the major tasks in the research field of alkene hydroalkylation is to develop diverse ligands or strategies to achieve regioselective divergence and enantioselective control (Figure [1]B).[5] For example, Fu (USTC) and Liu (THU) reported that nickel-catalyzed bipyridine ligands enabled anti-Markovnikov hydroalkylation of unactivated terminal alkenes.[6] Zhu (NJU) realized nickel-catalyzed alkene migratory hydrofunctionalization with C2-substituted bipyridine ligands.[7] Fu (Caltech) made a breakthrough by realizing the enantioconvergent alkene hydroalkylation with secondary and tertiary electrophiles via an asymmetric radical coupling strategy using a chiral nickel–bis(oxazoline) catalyst.[8] On the other hand, Hu (EPFL) succeeded in the enantioselective alkene hydroalkylation via an asymmetric alkene hydrometallation strategy using a chiral nickel–bioxazoline catalyst.[9] More recently, Lu (USTC) and Fu (USTC) built up a chiral cobalt–bis(oxazoline) for the enantioselective hydroalkylation of fluoroalkenes, realizing stereochemical control without the assistance of auxiliary groups.[10] Overall, nitrogen-containing ligands played important roles in alkene hydroalkylation, especially, nickel-catalyzed alkene hydroalkylation. The authors were curious whether the widely used phosphine ligands in palladium chemistry could play a regulatory role in nickel-catalyzed alkene hydroalkylation.[11] An inspiring example was reported by Yang (NUS) and Koh (NUS), wherein a nickel–triphenylphosphine system could be used to catalyze alkene migratory hydroalkylation at the β-position to an 8-aminoquinaldine directing auxiliary (Figure [1]C).[12] Inspired by this elegant work, we wished to systematically investigate the phosphine ligand effects in nickel-catalyzed alkene migratory hydroalkylation.

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Figure 3 Reaction conditions optimization. Reagents and conditions: 1 (0.10 mmol, 1.0 equiv), 2 (0.20 mmol, 2.0 equiv), nickel catalyst (0.01 mmol, 10 mol%), silane (0.30 mmol, 3.0 equiv), base (0.30 mmol, 3.0 equiv) in solvent (0.80 mL, 0.125 M) for 12 h under argon atmosphere. Yields and regioisomeric ratios were determined by gas chromatography (GC) analysis with triphenylmethane as an internal standard. Yield refers to the total yield for the mixture of all regioisomers. Regioisomeric ratio (r.r.) refers to the ratio of the desired product 3 to the sum of all other isomers. a Ligand (0.02 mmol) was added. b Ligand (0.015 mmol) was added. Piv, pivaloyl; Cy, cyclohexyl; DEMS, diethoxymethylsilane; PMHS, polymethylhydrosiloxane; diglyme, 2-methoxyethyl ether; DMAc, N,N-dimethylacetamide; DMF, N,N-dimethylformamide; r.r., regioisomeric ratio; n.r., no reaction.

Our group is committed to developing metal-hydride-catalyzed alkene hydroalkylation.[6] [10] [13] In 2022, Lu (USTC) reported an example of temperature-regulated switchable site-selective alkene hydroalkylation using a single nickel–bis(oxazoline) catalyst with which regiodivergent alkylated products were generated from the same starting alkene materials.[13h] Herein, we report the investigation of nickel–triphenylphosphine catalyzed remote hydroalkylation of alkenyl amides to access α-branched protected amines (Figure [1]D). Benefiting from the large atomic radii, low electronegativity, and easily tunable electronic properties and configurations, phosphine ligands represent potentially applicable structures to replace the configurations formed by the coordination of N- or O-atoms of the bis(oxazoline) moiety in our previous model.

At the beginning of this study, we investigated the properties of bis(oxazoline) with monodentate/bidentate phosphine ligands (Figure [2]). The results of DFT calculations indicated that the phosphine ligands have similar HOMO orbital energies to the bis(oxazoline) ligand, which implied that it was justified to consider phosphine as an alternative for bis(oxazoline) ligand. The degree of electron transfer from the ligand to the NiBr2 fragment could be used as a measure of coordination strength to some extent, and it was apparent that the phosphine ligand possessed more electron-donating capacity. Evaluation of the steric environment also suggested that phosphine ligands tended to have more steric resistance. The above information made us curious about the performance of the nickel–phosphine system in remote hydroalkylation of alkenyl amides to access α-branched amines.

Next, we explored nickel–phosphine-catalyzed alkene migratory hydroalkylation between alkenyl amide 1 with alkyl iodide 2 to synthesize α-branched, protected amine 3 (Figure [3]). We determined that NiCl2(PPh3)2 as a catalyst with DEMS and KF in DMAc was critical for the success of the migratory α-alkylation, and 94% GC yield (88% isolated yield) with >20:1 regioisomeric ratio was obtained. It is worth mentioning that PMHS, as an inexpensive waste in the silicon chemical industry, could be used as an alternative silane with 87% GC yield and >20:1 regioisomeric ratio.

With the optimized reaction conditions, we investigated the substrate scope of this nickel–phosphine-catalyzed alkene migratory hydroalkylation (Figure [4]). All cases, regardless of different alkenes or alkyl iodides, delivered excellent regioselectivities (>20:1 regioisomeric ratio). In addition to Piv, other protecting groups could be used, such as Bz and Ac (4, 5). The successful synthesis of product 6 demonstrated that the presence of oxygen atoms on the alkene chain did not affect the migratory direction or the regioselectivity. This reaction was also applicable to internal alkenes (7–9). The coupling efficiency and regioselectivity were not significantly affected by the (E)- or (Z)-configurations. Efficient conversion of primary alkyl iodides with different substituents was feasible (10–20). However, alkyl iodides with large steric hindrance resulted in moderate yields (10, 11). Due to the mild conditions, this reaction accommodated many functional groups that are commonly found in drug molecules. For instance, ester (13), methoxy (14), and trifluoromethyl (15) groups posed no problem during the transformation. Aryl bromide (16), aryl chloride (17), and aryl fluoride (18) were well tolerated. Finally, heterocycles such as thiophene (19) and pyrrole (20) were also compatible.

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Figure 4 Substrate scope of alkene migratory hydroalkylation. Reagents and conditions: alkenes (0.20 mmol, 1.0 equiv), alkyl iodides (0.40 mmol, 2.0 equiv), NiCl2(PPh3)2 (0.02 mmol, 10 mol%), DEMS (0.60 mmol, 3.0 equiv), KF (0.60 mmol, 3.0 equiv) in DMAc (1.60 mL, 0.125 M) for 12 h under argon atmosphere. Isolated yield.

Taking into account the previously reported results,[13h] [14] we proposed the corresponding catalytic cycle as shown in Figure [5]A. In this case, the reaction would undergo the steps of halogen-atom abstraction (A→B), Ni-H generation (B→C), hydrometallation (C→D), Ni-migration (D→E), radical addition (E→F), and reductive elimination (F→A). To further elucidate the mechanistic details, DFT calculations were carried out, as presented in Figure [5]B and Figure [5]C. The calculations indicated that the combination of the alkyl radical produced by the halogen atom abstraction step with the Ni(I) species IN1 could be regarded as a thermodynamically stable state (IN2), which was exothermic by 5.6 kcal/mol with respect to the isolated alkyl radicals (Figure [5]B). Subsequently, the Gibbs free energy profiles on a simplified reaction model involving regioselectivity-determining steps were established (Figure [5]C). From IN4, for β-selectivity, only radical addition and reductive elimination steps were required (Figure [5]C, left), facing an overall energy barrier of 17.2 kcal/mol. Competing with this were the additional α-H activation and hydromatallation steps, which led to the generation of α-selective products (Figure [5]C, right). Apparently, for this Ni-catalyzed system, further α-H activation and hydrometallation required a lower energy barrier (ΔG ≠ TS3–IN4 = 6.2 kcal/mol) relative to the direct reductive elimination step (left). Subsequently, the alkyl radical was released from IN2 and trapped by IN8 to give the corresponding Ni(III) species IN9, which underwent subsequent reductive elimination to give the α-selective product P1, accompanied by an energy barrier of 7.4 kcal/mol. The total energy barrier for generating the α-selective product was significantly lower.

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Figure 5 Proposed mechanism and DFT calculations

To explore the genesis of the selectivity more thoroughly, we performed a detailed computational analysis of the steps involved, as shown in Figure [6]. However, the reductive elimination I step was hard to match with the α-H activation and hydrometallation II. Fortunately, the rate-determining step for α-selectivity was reductive elimination II, which differed from the previous studies[13h] and offered the possibility of characterization for the reductive elimination step. The total energy barrier of only 6.2 kcal/mol for the α-H activation and hydromatallation step implies that the step was readily achievable. However, the process was thermodynamically unfavorable as the obtained Ni(II) species IN8 was not as stable as IN4, which hinted at the kinetically driven property of Ni migration (Figure [6]A). Subsequently, we performed a distortion/interaction energy analysis of the two reductive elimination transition states to find the critical determinants of the selectivity (Figure [6]B).[15]

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Figure 6 Thermodynamic and kinetic analysis of selectivity determining steps

The amide fragment was separated from the transition state to obtain the distortion and interaction energy. The difference (ΔΔE) of the two transition states indicated that the interaction energy became dominant, which might be attributed to the incipient back-bonding of N atoms with the Ni center. This was also confirmed by the %buried volume of catalytic centers, which revealed that the steric variability is not significant in all quadrants, and even TS1 possessed a smaller %buried volume.

In conclusion, we have reported a nickel–phosphine-catalyzed alkenyl amide migratory hydroalkylation to access α-branched protected amines. Commercially available and inexpensive NiCl2(PPh3)2 was selected as the catalyst for the migratory α-alkylation. Various alkenes and alkyl iodides are suitable substrates to deliver the desired products with excellent regioselectivities (>20:1 regioisomeric ratio). The mild reaction conditions enable the compatibility of many synthetically valuable functional groups. Finally, density functional theory calculations explain the success of triphenylphosphine as a suitable migratory α-alkylation ligand. Further studies for achieving enantioselectivity using chiral phosphine ligands are ongoing in our lab.

Target products were purified by flash column chromatography on silica gel (300–400 mesh). The yield of the target products refers to isolated yield. The r.r. value refers to the regioisomeric ratio of the target product to the sum of all other isomers and was determined by GC and 1H NMR analysis. The structures of target products were determined by NMR and HRMS analyses. 1H NMR, 13C NMR, and 19F NMR spectra were recorded with a Bruker 400 MHz spectrometer and a Bruker 500 MHz spectrometer at 295 K in CDCl3. Data for 1H NMR are reported as chemical shift (δ, ppm), multiplicity, coupling constant (Hz), and integration. Data for 13C NMR are reported as chemical shift (δ, ppm), multiplicity, and coupling constant (Hz). Data for 19F NMR are reported as chemical shift (δ, ppm), multiplicity, and coupling constant (Hz). Chemical shifts are reported using the residual solvent CHCl3 as the internal reference for 1H NMR (δ = 7.260 ppm) and CDCl3 peak as the internal reference for 13C NMR (δ = 77.160 ppm). High-resolution mass spectral analysis (HRMS) data were acquired with a Water XEVO G2 Q-TOF (Waters Corporation). Gas chromatographic (GC) analysis was acquired with a Shimadzu GC-2010 plus Series GC system equipped with a flame-ionization detector. All DFT calculations were performed with the Gaussian 16, Rev. C01 program. The geometry optimizations were computed with default convergence thresholds and without symmetry constraints, using the PBE0 density functional.


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Migratory Hydroalkylation of Alkenes; General Procedure

Under air, a 10-mL screw-cap test tube equipped with a magnetic stirrer was charged with NiCl2(PPh3)2 (0.02 mmol, 10 mol%) and potassium fluoride (0.6 mmol, 3.0 equiv) (Note a: if the alkene or the alkyl halide were solid, they were also added at this step; Note b: if alkyl bromides were used, 1.0 equiv NaI were added at this step). The test tube was evacuated and backfilled with argon three times, then DMAc (1.5 mL) was added, followed by the alkene (0.2 mmol, 1.0 equiv) and alkyl halide (0.4 mmol, 2.0 equiv). After the reaction, the solution was cooled to 0 °C, DEMS (0.6 mmol, 3.0 equiv) was added dropwise via syringe, and the solution was stirred at 10 °C for 12 h. The reaction mixture was diluted with H2O followed by extraction with EtOAc, dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the target product.


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N-(1-(Naphthalen-2-yloxy)heptan-4-yl)pivalamide (3)

The product was obtained by following the General Procedure.

Yield: 64.2 mg (94% yield); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.78–7.67 (m, 3 H), 7.46–7.38 (m, 1 H), 7.36–7.28 (m, 1 H), 7.15–7.10 (m, 2 H), 5.34 (d, J = 9.1 Hz, 1 H), 4.14–4.07 (m, 2 H), 4.06–3.97 (m, 1 H), 1.95–1.81 (m, 2 H), 1.81–1.70 (m, 1 H), 1.61–1.46 (m, 2 H), 1.45–1.29 (m, 3 H), 1.20 (s, 9 H), 0.92 (t, J = 7.2 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 178.2, 157.0, 134.7, 129.4, 129.0, 127.7, 126.8, 126.4, 123.6, 119.0, 106.7, 67.7, 48.5, 38.8, 37.8, 32.1, 27.8, 25.8, 19.3, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C22H32NO2 +: 342.2428; found: 342.2435.


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N-(1-(Naphthalen-2-yloxy)heptan-4-yl)benzamide (4)

The product was obtained by following the General Procedure.

Yield: 44.8 mg (62%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.78–7.67 (m, 5 H), 7.51–7.45 (m, 1 H), 7.44–7.37 (m, 3 H), 7.36–7.30 (m, 1 H), 7.16–7.10 (m, 2 H), 5.92 (d, J = 9.1 Hz, 1 H), 4.34–4.20 (m, 1 H), 4.12 (t, J = 6.2 Hz, 2 H), 2.02–1.81 (m, 3 H), 1.75–1.36 (m, 5 H), 0.95 (t, J = 7.3 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 167.4, 157.0, 135.0, 134.7, 131.4, 129.5, 129.1, 128.7, 127.7, 126.9, 126.8, 126.4, 123.6, 119.0, 106.9, 67.7, 49.4, 37.9, 32.1, 25.9, 19.4, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C24H28NO2 +: 362.2115; found: 362.2122.


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N-(1-(Naphthalen-2-yloxy)heptan-4-yl)acetamide (5)

The product was obtained by following the General Procedure.

Yield: 38.87 mg (65%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.81–7.68 (m, 3 H), 7.48–7.39 (m, 1 H), 7.37–7.28 (m, 1 H), 7.18–7.09 (m, 2 H), 5.31 (d, J = 9.2 Hz, 1 H), 4.08 (t, J = 6.2 Hz, 2 H), 4.06–3.95 (m, 1 H), 1.98 (s, 3 H), 1.96–1.81 (m, 2 H), 1.80–1.70 (m, 1 H), 1.58–1.47 (m, 2 H), 1.44–1.30 (m, 3 H), 0.92 (t, J = 7.1 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.9, 156.9, 134.6, 129.4, 129.0, 127.7, 126.8, 126.4, 123.6, 118.9, 106.7, 67.6, 48.9, 37.7, 31.9, 25.8, 23.7, 19.2, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C19H26NO2 +: 300.1958; found: 300.1967.


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N-(1-Methoxy-7-(naphthalen-2-yloxy)heptan-4-yl)pivalamide (6)

The product was obtained by following the General Procedure.

Yield: 53.5 mg (72%); colorless oil; r.r. >20:1.

1H NMR (400 MHz, CDCl3): δ = 7.77–7.69 (m, 3 H), 7.45–7.39 (m, 1 H), 7.35–7.29 (m, 1 H), 7.15–7.10 (m, 2 H), 5.52 (d, J = 8.9 Hz, 1 H), 4.08 (td, J = 6.2, 1.7 Hz, 2 H), 4.05–3.96 (m, 1 H), 3.38 (t, J = 6.0 Hz, 2 H), 3.32 (s, 3 H), 1.92–1.71 (m, 3 H), 1.70–1.43 (m, 5 H), 1.19 (s, 9 H).

13C NMR (126 MHz, CDCl3): δ = 178.2, 156.8, 134.5, 129.3, 128.8, 127.6, 126.7, 126.3, 123.5, 118.9, 106.6, 72.4, 67.5, 58.6, 48.4, 38.7, 32.0, 31.9, 27.7, 26.0, 25.7.

HRMS (ESI): m/z [M + H]+ calcd for C23H34NO3 +: 372.2533; found: 372.2533.


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N-(1-(Naphthalen-2-yloxy)nonan-4-yl)pivalamide (7)

The product was obtained by following the General Procedure.

Yield: 64.3 mg (87%) colorless oil; r.r. >20:1.

1H NMR (400 MHz, CDCl3): δ = 7.78–7.69 (m, 3 H), 7.46–7.40 (m, 1 H), 7.35–7.30 (m, 1 H), 7.16–7.10 (m, 2 H), 5.34 (d, J = 9.0 Hz, 1 H), 4.09 (t, J = 6.1 Hz, 2 H), 4.05–3.95 (m, 1 H), 1.94–1.70 (m, 3 H), 1.61–1.47 (m, 2 H), 1.43–1.24 (m, 7 H), 1.20 (s, 9 H), 0.89–0.85 (m, 3 H).

13C NMR (101 MHz, CDCl3): δ = 178.2, 156.8, 134.5, 129.3, 128.9, 127.6, 126.7, 126.3, 123.5, 118.9, 106.6, 67.5, 48.7, 38.7, 32.0, 31.7, 27.7, 25.7, 25.5, 22.5, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C24H36NO2 +: 370.2741; found: 370.2737.


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N-(1-(Naphthalen-2-yloxy)nonan-4-yl)pivalamide (8)

The product was obtained by following the General Procedure.

Yield: 65.8 mg (89%); colorless oil; r.r. >20:1.

The NMR and HRMS data of 8 were the same as those of 7.


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N-(1-Phenylnonan-4-yl)pivalamide (9)

The product was obtained by following the General Procedure.

Yield: 51.0 mg (84%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.29–7.25 (m, 2 H), 7.20–7.14 (m, 3 H), 5.22 (d, J = 9.0 Hz, 1 H), 4.00–3.89 (m, 1 H), 2.69–2.53 (m, 2 H), 1.67–1.59 (m, 3 H), 1.58–1.41 (m, 2 H), 1.39–1.22 (m, 7 H), 1.19 (s, 9 H), 0.89–0.83 (m, 3 H).

13C NMR (101 MHz, CDCl3): δ = 177.8, 142.3, 128.4, 128.3, 125.7, 48.6, 38.7, 35.6, 35.3, 34.8, 31.7, 27.7, 27.6, 25.5, 22.5, 13.9.

HRMS (ESI): m/z [M + H]+ calcd for C20H34NO+: 304.2635; found: 304.2633.


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N-(Decan-4-yl)pivalamide (10)

The product was obtained by following the General Procedure.

Yield: 24.6 mg (51%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 5.25 (d, J = 9.1 Hz, 1 H), 3.99–3.81 (m, 1 H), 1.52–1.42 (m, 2 H), 1.35–1.24 (m, 12 H), 1.19 (s, 9 H), 0.93–0.84 (m, 6 H).

13C NMR (126 MHz, CDCl3): δ = 176.8, 47.6, 37.6, 36.5, 34.3, 30.7, 28.2, 26.6, 24.7, 21.5, 18.1, 13.0, 13.0.

HRMS (ESI): m/z [M + H]+ calcd for C15H32NO+: 242.2478; found: 242.2479.


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N-(1-Cyclopentylpentan-2-yl)pivalamide (11)

The product was obtained by following the General Procedure.

Yield: 20.6 mg (43%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 5.26 (d, J = 9.0 Hz, 1 H), 4.01–3.89 (m, 1 H), 1.84–1.68 (m, 4 H), 1.64–1.55 (m, 2 H), 1.51–1.40 (m, 4 H), 1.35–1.27 (m, 3 H), 1.19 (s, 9 H), 1.14–1.00 (m, 2 H), 0.90 (t, J = 7.0 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 177.6, 48.2, 41.8, 38.6, 38.0, 37.1, 33.0, 32.9, 27.7, 25.1, 25.0, 19.0, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C15H30NO+: 240.2322; found: 240.2323.


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N-(1-(Naphthalen-2-yl)hexan-3-yl)pivalamide (12)

The product was obtained by following the General Procedure.

Yield: 43.61 mg (70%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.85–7.70 (m, 3 H), 7.65–7.58 (m, 1 H), 7.52–7.36 (m, 2 H), 7.35–7.28 (m, 1 H), 5.33 (d, J = 9.0 Hz, 1 H), 4.12–4.01 (m, 1 H), 2.79 (t, J = 8.1 Hz, 2 H), 1.96–1.87 (m, 1 H), 1.81–1.71 (m, 1 H), 1.59–1.49 (m, 1 H), 1.46–1.28 (m, 3 H), 1.18 (s, 9 H), 0.92 (t, J = 7.2 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 177.9, 139.6, 133.6, 132.0, 128.0, 127.6, 127.4, 127.2, 126.2, 125.9, 125.1, 48.8, 38.7, 37.5, 37.1, 32.6, 27.6, 19.1, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C21H30NO+: 312.2322; found: 312.2322.


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5-Pivalamidooctyl Benzoate (13)

The product was obtained by following the General Procedure.

Yield: 46.7 mg (70%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 8.08–7.91 (m, 2 H), 7.58–7.49 (m, 1 H), 7.45–7.37 (m, 2 H), 5.28 (d, J = 9.0 Hz, 1 H), 4.36–4.22 (m, 2 H), 4.01–3.84 (m, 1 H), 1.84–1.67 (m, 2 H), 1.59–1.26 (m, 8 H), 1.16 (s, 9 H), 0.89 (t, J = 7.2 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 178.0, 166.7, 132.9, 130.4, 129.6, 128.4, 64.8, 48.5, 38.7, 37.7, 35.1, 28.7, 27.7, 22.5, 19.2, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C20H32NO3 +: 334.2377; found: 334.2385.


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N-(1-(2-Methoxyphenoxy)heptan-4-yl)pivalamide (14)

The product was obtained by following the General Procedure.

Yield: 56.5 mg (85%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 6.89 (d, J = 3.5 Hz, 4 H), 5.45 (d, J = 8.9 Hz, 1 H), 4.03 (t, J = 6.4 Hz, 2 H), 4.00–3.91 (m, 1 H), 3.86 (d, J = 0.8 Hz, 3 H), 1.87–1.81 (m, 2 H), 1.75–1.68 (m, 1 H), 1.56–1.46 (m, 2 H), 1.41–1.27 (m, 3 H), 1.18 (s, 9 H), 0.90 (t, J = 7.2 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 178.0, 149.4, 148.3, 121.0, 120.9, 113.4, 111.8, 68.7, 55.8, 48.4, 38.7, 37.5, 31.6, 27.6, 25.5, 19.1, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C19H32NO3 +: 322.2377; found: 322.2377.


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N-(1-(3-(Trifluoromethyl)phenyl)heptan-4-yl)pivalamide (15)

The product was obtained by following the General Procedure.

Yield: 58.4 mg (85%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.47–7.30 (m, 4 H), 5.23 (d, J = 9.2 Hz, 1 H), 4.07–3.84 (m, 1 H), 2.79–2.46 (m, 2 H), 1.68–1.58 (m, 2 H), 1.57–1.23 (m, 6 H), 1.18 (s, 9 H), 0.89 (t, J = 7.2 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 178.1, 143.3, 131.9, 130.6 (q, J = 31.8 Hz), 128.8, 125.1 (q, J = 3.8 Hz), 124.3 (q, J = 272.2 Hz), 122.7 (q, J = 3.8 Hz), 48.3, 38.8, 37.7, 35.4, 35.0, 27.8, 27.7, 19.3, 14.1.

19F NMR (376 MHz, CDCl3): δ = –62.55.

HRMS (ESI): m/z [M + H]+ calcd for C19H29F3NO+: 344.2196; found: 344.2205.


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4-Pivalamidoheptyl 2-Bromobenzoate (16)

The product was obtained by following the General Procedure.

Yield: 66.8 mg (84%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.85–7.71 (m, 1 H), 7.68–7.62 (m, 1 H), 7.43–7.27 (m, 2 H), 5.32 (d, J = 9.0 Hz, 1 H), 4.34 (t, J = 6.4 Hz, 2 H), 4.04–3.95 (m, 1 H), 1.83–1.67 (m, 3 H), 1.51–1.31 (m, 5 H), 1.20 (s, 9 H), 0.91 (t, J = 7.1 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 178.1, 166.3, 134.2, 132.5, 132.4, 131.2, 127.2, 121.4, 65.5, 48.4, 38.7, 37.6, 32.0, 27.6, 25.3, 19.1, 14.0.

HRMS (ESI): m/z [M + H]+ calcd forC19H29BrNO3 +: 398.1325; found: 398.1330.


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N-(8-(2,6-Dichlorophenoxy)octan-4-yl)pivalamide (17)

The product was obtained by following the General Procedure.

Yield: 53.9 mg (72%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.29 (d, J = 8.1 Hz, 2 H), 6.98 (t, J = 8.1 Hz, 1 H), 5.37 (d, J = 9.0 Hz, 1 H), 4.08–3.96 (m, 3 H), 1.93–1.76 (m, 4 H), 1.64–1.31 (m, 6 H), 1.21 (s, 9 H), 0.93 (t, J = 7.1 Hz, 3 H).

13C NMR (126 MHz, CDCl3): δ = 178.2, 151.7, 129.6, 129.0, 125.0, 73.3, 48.5, 38.8, 37.9, 31.8, 27.8, 26.7, 19.3, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C19H30Cl2NO2 +: 374.1648; found: 374.1665.


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6-Pivalamidononyl 2-(2-Fluoro-[1,1′-biphenyl]-4-yl)propanoate (18)

The product was obtained by following the General Procedure.

Yield: 84.3 mg (90%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.56–7.51 (m, 2 H), 7.47–7.33 (m, 4 H), 7.18–7.09 (m, 2 H), 5.24 (d, J = 9.0 Hz, 1 H), 4.10–4.05 (m, 2 H), 3.93–3.83 (m, 1 H), 3.75 (q, J = 7.2 Hz, 1 H), 1.62–1.56 (m, 2 H), 1.53 (d, J = 7.2 Hz, 3 H), 1.49–1.37 (m, 2 H), 1.35–1.22 (m, 9 H), 1.18 (s, 9 H), 0.88 (t, J = 6.4 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 177.9, 174.0, 160.8, 142.0 (d, J = 7.8 Hz), 141.9 (d, J = 7.7 Hz), 135.5, 130.7, 130.7, 128.9, 128.9, 128.4, 127.6, 123.6 (d, J = 6.3 Hz), 123.5 (d, J = 6.3 Hz), 115.2 (d, J = 23.5 Hz), 115.2 (d, J = 23.6 Hz), 64.9, 64.9, 48.5, 45.0, 38.7, 37.5, 37.5, 35.3, 28.4, 27.7, 25.7, 25.5, 19.1, 18.3, 14.0.

19F NMR (471 MHz, CDCl3): δ = –117.78.

HRMS (ESI): m/z [M + H]+ calcd for C30H42FO3 +: 470.3065; found: 470.3065.


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7-Pivalamidodecyl Thiophene-2-carboxylate (19)

The product was obtained by following the General Procedure.

Yield: 36.8 mg (50%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 7.81–7.60 (m, 1 H), 7.57–7.34 (m, 1 H), 7.07–6.94 (m, 1 H), 5.19 (d, J = 9.0 Hz, 1 H), 4.21 (t, J = 6.6 Hz, 2 H), 3.89–3.78 (m, 1 H), 1.69–1.63 (m, 2 H), 1.44–1.21 (m, 12 H), 1.12 (s, 9 H), 0.83 (t, J = 6.9 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 177.8, 162.3, 134.0, 133.2, 132.1, 127.7, 65.1, 48.6, 38.7, 37.6, 35.3, 29.1, 28.6, 27.7, 25.8, 25.7, 19.1, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C20H34NO3S+: 368.2254; found: 368.2253.


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4-Pivalamidoheptyl 1-Methyl-1H-pyrrole-2-carboxylate (20)

The product was obtained by following the General Procedure.

Yield: 54.8 mg (85%); colorless oil; r.r. >20:1.

1H NMR (500 MHz, CDCl3): δ = 6.96–6.91 (m, 1 H), 6.80–6.76 (m, 1 H), 6.13–6.09 (m, 1 H), 5.31 (d, J = 9.0 Hz, 1 H), 4.21 (t, J = 6.4 Hz, 2 H), 4.02–3.94 (m, 1 H), 3.92 (s, 3 H), 1.76–1.64 (m, 3 H), 1.49–1.32 (m, 5 H), 1.20 (s, 9 H), 0.91 (t, J = 7.1 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 178.0, 161.2, 129.4, 122.5, 117.7, 107.8, 63.6, 48.4, 38.7, 37.6, 36.7, 31.9, 27.6, 25.5, 19.1, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C18H31N2O3 +: 323.2329; found: 323.2330.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The numerical calculations were performed on the supercomputing system in the Supercomputing Center of the University of Science and Technology of China.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2204-8921.
  • Supporting Information

Corresponding Authors

Xi Lu
Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China
Hefei 230026
P. R. of China   

Yao Fu
Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China
Hefei 230026
P. R. of China   

Publication History

Received: 12 October 2023

Accepted after revision: 06 November 2023

Accepted Manuscript online:
06 November 2023

Article published online:
04 December 2023

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Zoom Image
Figure 1 Representative ligands in alkene hydroalkylation and nickel-phosphine-catalyzed alkenyl amide migratory hydroalkylation (this work); Tf, triflyl.
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Figure 2 Comparison of ligand properties and strategies for switching regioselectivity. HOMO, highest occupied molecular orbital; NBO, natural bond orbital.
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Figure 3 Reaction conditions optimization. Reagents and conditions: 1 (0.10 mmol, 1.0 equiv), 2 (0.20 mmol, 2.0 equiv), nickel catalyst (0.01 mmol, 10 mol%), silane (0.30 mmol, 3.0 equiv), base (0.30 mmol, 3.0 equiv) in solvent (0.80 mL, 0.125 M) for 12 h under argon atmosphere. Yields and regioisomeric ratios were determined by gas chromatography (GC) analysis with triphenylmethane as an internal standard. Yield refers to the total yield for the mixture of all regioisomers. Regioisomeric ratio (r.r.) refers to the ratio of the desired product 3 to the sum of all other isomers. a Ligand (0.02 mmol) was added. b Ligand (0.015 mmol) was added. Piv, pivaloyl; Cy, cyclohexyl; DEMS, diethoxymethylsilane; PMHS, polymethylhydrosiloxane; diglyme, 2-methoxyethyl ether; DMAc, N,N-dimethylacetamide; DMF, N,N-dimethylformamide; r.r., regioisomeric ratio; n.r., no reaction.
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Figure 4 Substrate scope of alkene migratory hydroalkylation. Reagents and conditions: alkenes (0.20 mmol, 1.0 equiv), alkyl iodides (0.40 mmol, 2.0 equiv), NiCl2(PPh3)2 (0.02 mmol, 10 mol%), DEMS (0.60 mmol, 3.0 equiv), KF (0.60 mmol, 3.0 equiv) in DMAc (1.60 mL, 0.125 M) for 12 h under argon atmosphere. Isolated yield.
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Figure 5 Proposed mechanism and DFT calculations
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Figure 6 Thermodynamic and kinetic analysis of selectivity determining steps