Nickel-catalyzed C(sp²)–H bond aminoalkylation of alkenes and arenes for the synthesis of δ-amino acid derivatives

Abstract

We report a highly efficient Ni-catalyzed C(sp²)–H bond aminoalkylation strategy for the synthesis of optically pure amine-containing molecules. This protocol features straightforward operation, readily accessible chiral building blocks derived from natural α-amino acids, and compatibility with late-stage functionalization of drug molecules. Mechanistic investigations reveal a Ni(II)/Mn cooperative catalytic cycle, enabling cross-coupling with β-iodoalkylamines while effectively suppressing β-elimination side reactions. The method exhibits broad substrate scope for both aromatic amides and acrylamides, affording diverse δ-amino acid derivatives in moderate to excellent yields (42–99% yield, up to 99% ee). Notably, gram-scale synthesis and late-stage diversification of bioactive molecules (e.g., estrone, shikimic acid) underscore its synthetic utility.

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Introduction

Enantioenriched amines are critical compounds with widespread applications in diverse pharmaceutical agents,¹ chiral ligands for asymmetric synthesis,² and key intermediates for constructing γ- or δ-lactams and highly functionalized piperidine cores³ (Fig. 1). Current methodologies⁴ primarily rely on asymmetric catalysis⁵ or stoichiometric functionalization of preformed chiral amines,⁶ both of which are constrained by limitations in substrate versatility and stereochemical control. Direct functionalization of inert C(sp²)–H bonds with chiral amine surrogates offers a promising alternative, yet challenges persist in achieving high enantioselectivity and suppressing β-hydride or amino elimination during alkylation.⁷

Fig. 1 Representative examples of drugs with chiral amine cores.

Nickel-catalyzed C(sp²)–H alkylation mediated by N,N-bidentate directing groups, particularly 8-aminoquinoline auxiliaries, has emerged as a robust platform for C(sp²)–C(sp³) bond construction.⁸ However, only a few examples of C(sp²)–H bond alkylation with β-functionalized alkyl coupling partners, such as allylation⁹ and trifluoroethylation,¹⁰ have been reported, owing to competing β-elimination pathways (Fig. 2a). Thus, our strategy aims to develop a catalytic system that suppresses undesired β-hydride or amino elimination while enabling C(sp²)–H bond aminoalkylation of alkenes and arenes. This protocol employs readily available chiral building blocks, β-iodoamines derived from natural α-amino acids, to facilitate facile access to enantiopure amines.

Fig. 2 Strategy for the synthesis of chiral amines through Ni-catalyzed C–H bond aminoalkylation.

Herein, we address these limitations through a Ni(II)/Mn dual catalytic system leveraging β-iodoalkylamines derived from natural α-amino acids. This approach enables enantioselective C(sp²)–H aminoalkylation while circumventing β-hydride or amino elimination, providing a practical route to chiral amines inaccessible via conventional methods (Fig. 2b).

Results and discussion

Our study commenced with evaluating the Ni(II)-catalyzed C(sp²)–H bond aminoalkylation (Table 1). Initially, the reaction of benzamide 1a with β-iodoalkylamine 2a was attempted using Ni(OTf)₂/PPh₃ as the catalyst and Na₂CO₃ as the base in toluene at 150 °C for 12 h. However, no desired cross-coupling product 3a was detected (entry 1). We hypothesized that adding a reductant might enhance this conversion, so zinc powder and manganese powder were tested separately. Fortuitously, manganese powder afforded the coupling product 3a in a 23% isolated yield (entry 3). Subsequent solvent screening identified isobutyronitrile (IBN) as the optimal solvent, yielding improved results (entries 3–6). Further evaluation of nickel salts identified the triphenylphosphine-coordinated complex Ni(PPh₃)₂Cl₂ as optimal, increasing the yield of 3a to 61% (entries 5, 7 and 8). Solvent mixing experiments showed that a 1 : 1 (v/v) IBN/toluene mixture was most suitable for this transformation (entries 9–11). Notably, other bidentate directing groups, such as, 2-pyridinylmethylamine (II), 2-aminopyridine (III), and 2-aminopyridine N-oxide (IV), failed to promote this aminoalkylation. The optimized conditions for the Ni(II)-catalyzed C(sp²)–H bond aminoalkylation comprised Ni(PPh₃)₂Cl₂ as the catalyst, Na₂CO₃ as the base, IBN/toluene (1 : 1 v/v) as the solvent, manganese powder as the reductant, and a reaction temperature of 150 °C for 12 hours, with effective guidance from an 8-aminoquinoline bidentate directing group (see SI for details).

Table 1 Reaction optimization^a

Entry	Ni catalyst	Ligand	Additive	Solvent	Yield^b
a Reactions were performed with benzamide 1a (0.2 mmol, 1.0 equiv.), β-iodoalkylamine 2a (0.4 mmol, 2.0 equiv.), Ni catalyst (0.1 equiv.), PPh3 (0.2 equiv.), Na2CO3 (2.0 equiv.), additive (2.0 equiv.), solvent under N2 at 150 °C for 12 h. b Isolated yields. Phth = phthalimidyl.
1	Ni(OTf)2	PPh3	—	PhMe	0
2	Ni(OTf)2	PPh3	Zn	PhMe	Trace
3	Ni(OTf)2	PPh3	Mn	PhMe	23
4	Ni(OTf)2	PPh3	Mn	1,4-Dioxane	Trace
5	Ni(OTf)2	PPh3	Mn	IBN	57
6	Ni(OTf)2	PPh3	Mn	DMF	21
7	NiCl2	PPh3	Mn	IBN	25
8	Ni(PPh3)2Cl2	—	Mn	IBN	61
9	Ni(PPh3)2Cl2	—	Mn	IBN/PhMe (1 : 2)	Trace
10	Ni(PPh3)2Cl2	—	Mn	IBN/PhMe (1 : 1)	70
11	Ni(PPh3)2Cl2	—	Mn	IBN/DMA (1 : 1)	51

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After identifying the optimal conditions (Table 1, entry 10), the scope of aromatic amides was investigated, as shown in Scheme 1. ortho-Aminoalkylation of various benzamides bearing ortho-, meta-, and para-substituted groups generated the corresponding products 3a–k in moderate to excellent yields. We found that para-substituted benzamides 1d–e were prone to double aminoalkylation. By adjusting the amount of benzamides, the products 3d–e of mono-aminoalkylation could be obtained in 70% and 50% yields. For meta-substituted substrates 1f–k, aminoalkylation selectively occurred at the less hindered C–H bonds, with good tolerance to diverse functional groups. Additional aromatic amides, such as 2-naphthamide 1l and 2-thienamide 1m, also furnished cross-coupling products 3l–m. Moreover, the Ni(II)/Mn catalytic system was applied to gram-scale synthesis of product 3h.

Scheme 1 Scope of aromatic amides. ^aReactions were conducted on 0.2 mmol scale under the optimized conditions. Isolated yields. ^bAromatic amide 1 (0.4 mmol, 2.0 equiv.), β-iodoalkylamine 2a (0.2 mmol, 1.0 equiv.).

Next, we expanded the utility of this method by exploring acrylamides (Scheme 2). For α-alkyl-substituted acrylamides 1n–o, E-configured α,β-unsaturated δ-amino acid derivatives 3n–o were obtained in good yields, with the E configuration of 3n confirmed by 2D-NMR (see SI for details). α,β-Di-substituted acrylamides 1p–q also participated efficiently, yielding E/Z mixtures 3p–q in excellent yields, which were readily separated by column chromatography. The predominant formation of the E-isomers from acyclic alkenes 1n–q likely arose from steric and thermodynamic control. Furthermore, cyclic acrylamides 1r–s reacted with β-iodoalkylamine 2a to afford single δ-amino acid derivatives 3r–s, with one product 3s exhibiting >99% ee by HPLC. No racemization of the chiral amine 3s was observed.

Scheme 2 Scope of acrylamides. ^aReactions were conducted on 0.2 mmol scale under the optimized conditions. Isolated yields. ^bNi(cod)₂ (0.1 equiv.) instead of Ni(PPh₃)₂Cl₂ (0.1 equiv.).

The potential of this protocol for late-stage functionalization of bioactive molecules was further explored. As revealed in Scheme 3, the chiral amino center could be successfully introduced into the pharmaceutical frameworks of estrone, 16-dehydropregnenolone acetate, (−)-perillic acid, and shikimic acid in 51%, 49%, 61%, and 84% yields, respectively, demonstrating its synthetic utility in organic and pharmaceutical chemistry.

Scheme 3 Late-stage diversification of bioactive molecules. Reactions were conducted on 0.2 mmol scale under the optimized conditions. Isolated yields.

Chiral β-iodoalkylamines 2b–f, which was readily prepared from natural α-amino acids,¹¹ were employed to explore this aminoalkylation (Scheme 4). To our delight, diverse enantiopure δ-amino acid derivatives 4a–e were synthesized in moderate to excellent yields, with functional groups such as free indole and benzyl hydroxyl groups showing compatibility. Replacing the N-protecting groups of β-iodoalkylamines with dibenzyl (2f) or tert-butoxycarbonyl (2g) abolished cross-coupling.

Scheme 4 Scope of β-iodoalkylamines. Reactions were conducted on 0.2 mmol scale under the optimized conditions. Isolated yields.

To investigate the reaction mechanism, control experiments were first performed to assess the formation of aminoalkyl manganese species. When β-iodoalkylamine 2b was treated with manganese powder or under standard conditions in an IBN/toluene mixture (Scheme 5a), most of 2b was recovered, ruling out the generation of aminoalkyl manganese intermediates. Next, mechanistic studies focused on identifying the active nickel species (Scheme 5b). Omission of Mn powder reduced the yield to 28%. Using a Ni(0) complex instead of Ni(II)/Mn provided 3a in 52% yield (without Mn), consistent with reports that Ni(I) species are critical in C(sp²)–H alkylation.¹²

Scheme 5 Control experiments.

Based on these results and literature precedents,¹³ a mechanistic hypothesis for this nickel-catalyzed C(sp²)–H bond aminoalkylation reaction is proposed as shown in Fig. 3. First, the nickel(II) precatalyst is reduced to a nickel(I) complex (L_nNi^IX) via Mn-mediated electron transfer under the assistance of a phosphine ligand, which coordinates with the N,N-bidentate directing group of aromatic amides or acrylamides 1 to form the active intermediate A. Then, N,N-director-assisted C–H activation generates a nickelacycle B under the promotion of sodium carbonate. Next, oxidative addition of B with β-iodoalkylamines 2 generates a nickel(III) intermediate C, which is followed by reductive elimination of C to D, thus forming the C(sp²)–C(sp³) bond. Finally, after the protonolysis of D, the nickel(I) catalyst is regenerated to complete the catalytic cycle.

Fig. 3 Mechanistic hypothesis.

Conclusions

In summary, we have developed an efficient and practical synthetic method for the preparation of enantiopure amine-containing molecules via Ni-catalyzed C(sp²)–H bond aminoalkylation of aromatic amides and acrylamides with β-iodoalkylamines. This method features a user-friendly catalytic system, readily accessible chiral building blocks derived from natural α-amino acids, and robust stereochemical fidelity (no racemization). Its utility is highlighted by gram-scale synthesis and late-stage functionalization of bioactive pharmaceuticals. Mechanistic studies support a Ni(II)/Mn cooperative cycle involving Ni(I) intermediates, providing insights into C(sp²)–H functionalization pathways. The broad application potential of this method in the synthesis of chiral amine-containing pharmaceuticals and complex molecules is further underscored.

Author contributions

J.-S. T. conceived and supervised the project. R.-Q. Li, D.-Y. L., J.-S. T., J. T. and Y.-X. Y. performed experiments and analyzed the experimental data. D.-Y. L. and R.-Q. Li prepared the ESI. J.-S. T. wrote the paper and T.-P. L. reviewed it. All authors discussed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data associated with this study are available in the article and supplementary information (SI), including additional experimental details, synthetic procedures, and spectroscopic data for all new compounds. Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01273b.

Acknowledgements

We gratefully acknowledge the Natural Science Basic Research Plan of Shaanxi Province (2023-JC-YB-109), the Fundamental Research Funds for the Central Universities (D5000210701) from the financial support.

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Footnote

† These authors contributed equally to this work.

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