Nickel-catalyzed reductive 1,2-alkylarylation of alkenes via a 1,5-hydrogen atom transfer (HAT) cascade

Abstract

N-centered radical-mediated remote C(sp³)–H functionalization via HAT processes has been successfully applied in the difunctionalization of alkenes, serving as an elegant and robust method to convert readily available alkenes into various functionalized molecules. However, HAT strategy-enabled difunctionalization of alkenes using electrophiles as functionalizing reagents remains underexplored. In this study, we report a nickel-catalyzed regioselective reductive three-component 1,2-alkylarylation of alkenes with O-oxalate hydroxamic acid esters and aryl iodides. This radical addition/cross-coupling cascade reaction involves amidyl radical-triggered intramolecular 1,5-HAT and nickel-catalyzed reductive coupling processes under mild reaction conditions with good coupling efficiency. Additionally, this approach can be extended to the reductive 1,2-alkylarylation of alkynes, providing an efficient method for the synthesis of multi-substituted alkenes from easily accessible starting materials.

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Introduction

Alkenes are among the most valuable and readily available building blocks and they have been extensively applied in organic synthesis, medicinal chemistry, and materials science.¹ Along with the development of transition metal-catalyzed cross-coupling reactions, the difunctionalization of alkenes has proved to be an appealing and efficient strategy for the rapid construction of complex skeletons via the simultaneous formation of two new bonds across the π system.² Among these methods, nickel-catalyzed reductive difunctionalization stands out, as it directly employs readily available electrophiles as functionalizing agents.³ This approach bypasses the need for unstable organometallics, which require additional synthesis steps and are sensitive to many functional groups, offering advantages in step economy, atom efficiency, and operational simplicity.⁴ For example, the Nevado group achieved nickel-catalyzed three-component reductive alkylarylation of alkenes using alkyl iodides and aryl iodides as radical precursors and coupling partners, respectively.⁵ Similarly, the Chu group reported intermolecular reductive carboacylation of alkenes with fluoroalkyl iodides and acyl chlorides as coupling agents.⁶ Despite significant progress made by these groups and others,⁷ further developing novel and efficient alkene difunctionalization protocols through nickel-catalyzed radical relay or concerted migratory insertion remains highly desirable.

Aliphatic C(sp³)–H bonds are commonly found in nearly all organic substances, including pharmaceuticals, petroleum, and functional materials.⁸ Consequently, the direct functionalization of these widespread C(sp³)–H bonds for the rapid synthesis of valuable organic compounds has gained significant importance in organic synthesis.⁹ However, the high similarity in bond dissociation energies and electronic properties among multiple aliphatic C(sp³)–H bonds presents a major challenge for achieving site-specific C(sp³)–H bond functionalization.¹⁰ Over the past few years, inspired by the Hofmann–Löffler–Freytag (HLF) reaction,¹¹ nitrogen-centered radical (e.g., amidyl or sulfonamidyl radicals) mediated intramolecular hydrogen atom transfer (HAT) processes emerged as a powerful strategy for the direct transformation of C(sp³)–H bonds at specific positions to various C(sp³)–C and C(sp³)–Y (Y = N, S, P, F, etc.) bonds.¹² Mechanistically, a hydrogen atom is transferred from a carbon center to a nitrogen center, forming a highly reactive carbon-centered radical species, which is then trapped by a radical partner to achieve regioselective incorporation of a wide range of external functional groups (Scheme 1a).¹³ Given the growing interest of chemists in alkene difunctionalization,¹⁴ the Li group pioneered a copper-catalyzed fluoroamide-directed remote benzylic C(sp³)–H functionalization enabling the difunctionalization of alkenes with N-fluoro-2-methylbenzeneamides and nucleophiles, including alcohols, indoles, and pyrroles (Scheme 1b).¹⁵ Our group has also developed a copper-catalyzed alkylarylation of alkenes via N-centered radical-mediated remote benzylic C(sp³)–H activation using nucleophilic arylboronic acids as coupling partners.¹⁶ Nevertheless, HAT strategy-enabled alkene difunctionalization using electrophiles as functionalizing reagents remains underexplored. Building on our ongoing interest in remote C(sp³)–H functionalization and nickel-catalyzed cross-electrophile coupling reactions,¹⁷ we report herein a nickel-catalyzed intermolecular reductive 1,2-alkylarylation of alkenes using O-oxalate hydroxamic acid esters and aryl iodides in the presence of Mn (Scheme 1c), demonstrating good coupling efficiency and high regioselectivity.

Scheme 1 Background and reaction design.

Results and discussion

The investigation began with the selection of O-oxalate hydroxamic acid ester 1a, benzyl acrylate 2a, and 4-iodobenzoic acid methyl ester 3a as model substrates (details provided in the ESI†). Using NiCl₂·DME as the catalyst, bipyridine ligand L1, and Mn powder as the reductant, we were pleased to obtain the desired product 4a with a 13% yield (Table 1, entry 1). Given the critical role of solvents in cross-electrophile coupling, we initially tested several solvents (entries 2–5), discovering that a mixture of DMA/THF in a 2 : 1 ratio (v/v) was optimal. Screening of Ni salts revealed that the reactions could be catalyzed by both Ni(II) and Ni(0), with NiCl₂·DME proving to be the most effective (entries 6 and 7). Further optimization of the reactant ratios increased the yield to 36% (entry 8). We also explored various bidentate N-containing ligands (L1–L7), finding that L2 provided the best efficiency (entries 9 and 10). The yield of 4a could be increased to 78% when using MgBr₂ as an additive, which could accelerate the reduction of Ni^II intermediates or assist in activating the surface of Mn¹⁸ (entries 11–13). Control experiments confirmed that the Ni salt, ligand, and reductant are all essential components for the successful transformation (entries 14–16).

Table 1 Reaction condition optimization^a,b

Entry	Ni cat.	Ligand	Additive	Solvent	Yield^c (%)
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.2 mmol), 3a (0.3 mmol, 1.5 equiv.), Ni cat. (10 mol%), ligand (12 mol%), Mn (3.0 equiv.), additive (1.0 equiv.), solvent (1.5 mL), Ar, 30 °C, and 18 h. b Oxa = OCOCO2Me. c Isolated yield. d 1a (0.4 mmol, 2.0 equiv.) was used. e Without Mn.
1	NiCl2·DME	L1		THF	13
2	NiCl2·DME	L1		DMA	20
3	NiCl2·DME	L1		Et2O	0
4	NiCl2·DME	L1		1,4-Dioxane	0
5	NiCl2·DME	L1		DMA/THF = 2 : 1	27
6	NiI2	L1		DMA/THF = 2 : 1	11
7	Ni(COD)2	L1		DMA/THF = 2 : 1	19
8^d	NiCl2·DME	L1		DMA/THF = 2 : 1	36
9^d	NiCl2·DME	L2		DMA/THF = 2 : 1	45
10^d	NiCl2·DME	L3–L7		DMA/THF = 2 : 1	25–44
11^d	NiCl2·DME	L2	MgCl2	DMA/THF = 2 : 1	65
12^d	NiCl2·DME	L2	LiCl	DMA/THF = 2 : 1	Trace
13	NiCl 2 ·DME	L2	MgBr 2	DMA/THF = 2 : 1	78
14^d		L2	MgBr2	DMA/THF = 2 : 1	0
15^d	NiCl2·DME		MgBr2	DMA/THF = 2 : 1	0
16^d^,^e	NiCl2·DME	L2	MgBr2	DMA/THF = 2 : 1	0

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Having established the optimum reaction conditions (Table 1, entry 13), we explored the diversity and practicality of the reaction substrates (Scheme 2). We first examined the scope of electron-deficient alkenes. As expected, acrylates bearing alkyl, alkoxy, and succinimidyl groups were efficiently converted to the desired products (4a–4h) with yields ranging from 31% to 78%. Additionally, the gram-scale reaction of 2a produced 4a in a 62% yield, demonstrating robust scalability. Besides various acrylates, other alkenes, such as acrylamide, acrylonitrile, and vinyl phosphonate, also served as suitable coupling partners, yielding products 4i–4k in moderate yields. Notably, vinylboronic acid pinacol ester was readily incorporated into the reaction protocol, affording the corresponding product 4l in 67% yield, which offers potential for further derivatization through palladium-catalyzed Suzuki–Miyaura cross-coupling reactions. However, the reaction currently faces limitations with styrenes and unactivated alkenes. We subsequently evaluated different structural motifs surrounding the targeted C(sp³)–H bond. Both sterically hindered and oxygen-adjacent C(sp³)–H bonds were successfully functionalized, producing products 5a–5i with isolated yields of 38–66% and excellent regioselectivity. Introducing methyl or ethyl groups into the aliphatic backbone to create sterically hindered tertiary C(sp³)–H bonds did not significantly reduce product yields (5b and 5c). The amino acid-derived hydroxamic ester reacted smoothly, generating the corresponding product 5h in a relatively low yield. The secondary C(sp³)–H bond in the rigid adamantyl substrate can also be functionalized, affording target product 5j with a yield of 47%. The hydroxamic ester 1k containing acyclic secondary carbon reactive sites is also capable of this transformation under standard conditions (5k), but the yield is low and accompanied by the generation of a two-component by-product 5k′, which is probably due to the instability of the secondary alkyl radicals and their high propensity to undergo a direct coupling with aryl iodides. Finally, a series of aryl iodides were examined. Notably, when the substituent was located at the meta position of the phenyl group, the yield of product 6a was similar to that of 4a. However, when the substituent was in the ortho position, the yield of product 6b drastically decreased to 31%, indicating a significant steric hindrance caused by the ortho substituent. A range of electron-deficient substituents were tolerated, yielding the corresponding products 6c–6k in moderate to good yields. The reaction also showed compatibility with multi-substituted aryl iodides, producing products 6l and 6m in 36% and 65% yields, respectively. Compared to electron-deficient aryl iodides, electron-rich aryl iodides, such as OAc-substituted iodobenzene, were more challenging to use as coupling agents, yielding product 6n in lower yields. Additionally, heteroaryl iodides or aryl iodides derived from natural products or drugs were efficiently incorporated into the three-component reaction, as demonstrated by the successful isolation of products 6o–6q with satisfactory yields. Unfortunately, aryl bromides and aryl chlorides turned out to be unsuitable precursors for this reaction (see Table S3 in ESI† page S7 for the investigated substrates).

Scheme 2 Substrate scope for the alkylarylation of alkenes. Reaction conditions: 1 (0.4 mmol, 2.0 equiv.), 2 (0.2 mmol), 3 (0.3 mmol, 1.5 equiv.), NiCl₂·DME (10 mol%), bpy (12 mol%), Mn (3.0 equiv.), MgBr₂ (1.0 equiv.), DMA/THF (2/1, v/v, 1.5 mL), Ar, 30 °C, and 18 h. Isolated yields. ^a The reaction was carried out on a 3.0 mmol scale and reacted for 36 h. ^b Aryl bromide was used. ^c Aryl chloride was used. ^d Using NiCl₂ instead of NiCl₂·DME to react at 50 °C for 24 h in a ratio of 1k : 2a : 3a = 1 : 2 : 1.5.

Transition metal-catalyzed dicarbofunctionalization of alkynes is a powerful approach for constructing multi-substituted alkenes.¹⁹ However, there are only a few examples of nickel-catalyzed intermolecular reductive dicarbofunctionalization of alkynes using two different electrophiles.²⁰ Building on the results described above, we investigated the extension of our methodology to the reductive 1,2-alkylarylation of alkynes. As illustrated in Scheme 3, using hydroxamic ester 1a and 4-iodobenzoic acid methyl ester 3a as model coupling partners, various aryl alkynes with both electron-withdrawing and electron-donating groups were successfully transformed under slightly modified reaction conditions (see Table S2 in ESI† pages S4 and S5 for optimized conditions), yielding the corresponding products 8a–8i in moderate yields. Heteroaryl-substituted alkynes, such as those containing thiophenes, also served as suitable substrates, producing heteroaromatic-containing products (8j and 8k) in 48% and 63% yields, respectively.

Scheme 3 Substrate scope for the alkylarylation of alkynes. Reaction conditions: 1a (0.4 mmol, 2.0 equiv.), 7 (0.2 mmol), 3a (0.3 mmol, 1.5 equiv.), Ni(PCy₃)Cl₂ (10 mol%), L12 (12 mol%), Mn (3.0 equiv.), MgCl₂ (1.0 equiv.), DMA/THF (2/1, v/v, 1.5 mL), Ar, 30 °C, and 18 h. Isolated yields.

We conducted preliminary studies to gain further insights into the mechanism of this reaction. The addition of the radical trapping agent 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) completely suppressed the desired alkylarylation reaction, and the TEMPO adduct was detected via high-resolution mass spectrometry (HR-MS) (Scheme 4a). This result suggests that the alkylarylation reaction proceeds through a radical pathway. The TEMPO adduct was also detected when the reaction of 1a with TEMPO was conducted in the presence of Mn or stoichiometric Ni(COD)₂ (Scheme 4b), indicating that both Mn and Ni(0) can reduce 1a. Additionally, we synthesized the Ar–Ni^II–I complex Ni-1 ²¹ and evaluated its catalytic efficiency. In the stoichiometric reaction of Ni-1 with hydroxamic ester 1a and acrylate 2a, no detectable amount of 6c was observed. However, when 10 mol% of Ni-1 was used as the catalyst, the desired product 6c was obtained in a 52% yield (Scheme 4c). These results suggest that Ni-1 is unlikely to be a reactive intermediate in this cascade transformation, indicating that oxidative addition of the Ni(0) species to aryl iodide is improbable.²²

Scheme 4 Mechanistic studies.

Based on mechanistic studies and the relevant literature,²³ a plausible mechanism is depicted in Scheme 5. The reduction of compound 1 by both Ni(0) and Mn via single-electron transfer (SET) processes generates Ni(I) and amide radical A. This radical undergoes an intramolecular 1,5-HAT to form carbon-centered radical B. The radical addition of radical B to alkene 2 produces radical C. Radical C is then captured by a Ni(I) species to yield Ni(II) intermediate D. Following reduction by Mn, the oxidative addition of Ni(I) intermediate E with aryl iodide 3 forms Ni(III) complex F. Reductive elimination of Ni(III) complex F generates the desired product along with Ni(I) species. Finally, the reduction of Ni(I) by Mn regenerates Ni(0) to finish the catalytic cycle.

Scheme 5 Proposed mechanism.

Conclusions

In conclusion, a nickel-catalyzed 1,2-alkylarylation of alkenes with O-oxalate hydroxamic acid esters and aryl iodides has been successfully developed under reductive conditions. The reaction relies on amidyl radical-triggered 1,5-HAT and uses electrophiles as functionalizing reagents with good coupling efficiency and high regioselectivity. This mild protocol facilitates the sequential construction of two vicinal C–C bonds through the addition of two different electrophiles across the π-system, effectively avoiding the use of sensitive organometallic reagents and significantly expanding the scope of HAT strategy-enabled alkene difunctionalization reactions. Moreover, this protocol can be extended to the reductive 1,2-alkylarylation of alkynes, providing an alternative method to access important multi-substituted alkenes from readily available starting materials.

Author contributions

Xi Chen performed the experiments and wrote the manuscript and ESI.† Qiang Wang coordinated the experiments and analyses. Xiao-Ping Gong and Rui-Qiang Jiao checked the manuscript and prepared some of the substrates and the ESI.† Xue-Yuan Liu and Yong-Min Liang conceived this project and provided guidance. All authors discussed the results and commented on the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSF 22171114 and 22371097).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2388081. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01875c

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