Borates as a Traceless Activation Group for Intermolecular Alkylarylation of Ethylene through Photoredox/Nickel Dual Catalysis

Abstract

A formal ethylene alkylarylation reaction with aryl halides and alkyl oxalates enabled by synergistic photoredox/nickel catalysis is reported. This protocol takes advantage of borates as a traceless activation group, achieving the formal ethylene difunctionalized products via a catalytic three-component 1,2-alkylarylation of vinyl borate followed by a base-assisted deborylation process. The mild conditions allow for excellent functional groups compatibility and broad substrate scope.

Development of catalytic methodology to selectively forge new C–C bonds is a fundamental goal pursed by chemists in the arena of organic synthesis. In this context, catalytic dicarbofunctionalization of alkenes, particularly in three-component version, has recently drawn increasing attentions due to its capability to sequentially construct two C–C bonds in one-pot, thus allowing for the facile assembly of complex molecular skeletons from readily available starting materials.[1] [2] Generally, a C-nucleophile and a C-electrophile are selectively incorporated with alkenes via a transition-metal-involved migratory insertion process.[1] Recently, a radical-based conjugated addition strategy enabled by transition-metal catalysts has emerged as an efficient and complementary protocol to install two C–C bonds over alkenes with complementary reactivity and selectivity, offering a new retrosynthetic approach to complex carbon skeleton. [2a–e] ^, [2g,h] Due to the unique properties of nickel,[3] Ni-catalyzed intermolecular radical dicarbofunctionalization of alkenes has recently attracted a significant ­attention.[1`] [e] [f] [g] [h] <sup>,</sup> [2`] [f] [g] [h] A wide array of electronically biased alkenes[4] and even nonactivated alkenes[1c,5] have been incorporated with two carbon-based functionalities with remarkable regio-, chemo-, and even enantioselective control. Generally, the innate polarity of alkenes or a pendant chelation group is required to ensure the requisite reactivity and selectivity in the catalytic dicarbofunctionalizations. There is still lack of efficient methods for such intermolecular dicarbofunctionalization reactions of simple alkenes,[5k] specifically the simplest alkene ethylene, probably due to its inherent simplicity and low reactivity as well as requirement of specific gas hand­ling.

Indeed, limited approaches are known to address the challenging catalytic difunctionalization of ethylene,[6] with a recent elegant example of catalytic intermolecular diarylation of ethylene[6d] enabled by photoredox/nickel dual catalysis (Scheme [1]A). As part of our ongoing research on nickel-catalyzed intermolecular dicarbofunctionalization of alkenes,[4p] [5e] [m] [o] herein, we report a formal three-component 1,2-alkylarylation of ethylene enabled by synergistic photo­redox/nickel catalysis[7] with borates as a traceless activation group. This transformation proceeds via a sequential one-pot procedure, i.e., dual photoredox/Ni-catalyzed 1,2-alkylarylation of vinyl borates to give benzylic borates followed by base-assisted deborylation, affording ethylene alkylarylation products with high efficiency (Scheme [1]C).

Vinyl borates are versatile synthons in organic synthesis. One classical transformation of vinyl borates is transition-metal-catalyzed vinyl cross-coupling reactions via C–B cleavage.[8] Furthermore, the electron-biased nature of vinyl borates allows them to undergo diverse 1,2-dicarbofunctionalization, leading to the formation of valuable alkyl ­borates, as recently disclosed by the groups of Morken, ­Molander, Studer, etc. (Scheme [1]B).[4`] [h] [i] [j] [k] ^, [9]

In 2019, our group disclosed a photoredox/nickel catalyzed 1,2-alkylarylation of diverse alkenes with aryl halides and tertiary alkyl oxalates.[5m] Interestingly, we found that subjection of vinyl borate 1 with 4-bromopyridine 2a and cesium oxalate 3 in the presence of Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, NiCl₂·DME, and 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbpy) into this synergistic protocol only afforded the deborylation product 4a in 84% yield (Scheme [2]A). Considering the easy handling and relatively low cost of vinyl borate, we anticipate that this ‘side reaction’ would provide a complementary protocol to address the challenge in the catalytic difunctionalization of ethylene and therefore have carried out further investigation on this transformation. However, switching bromopyridine 2a to aryl bromide 2b led to a significant decrease in the reaction, only affording the desired alkylarylation–deborylation product 4b in 30% yield together with around 17% of the borate-retaining product 4b′ as well as unknown side products (Scheme [2]B).

A series of screening of photocatalysts, nickel catalysts, ligands, and solvents did not lead to any efficiency improvement (Scheme [2]C, entries 2–7). Pleasingly, we found that exogenous addition of inorganic bases was beneficial to the reaction efficiency, and 0.5 equivalent of Na₂CO₃ proved to be optimal, generating product 4b in 75% isolated yield (entries 8–10). Finally, control experiments confirmed that light, photocatalyst, nickel catalyst, and ligand were all essential to promote this alkylarylation–deboraylation transformation (entries 11–14). It should be noted that ­Molander and coworkers also reported two deborylation cases regarding electron-deficient substituents-incorporated pyridines.[4g] Compared to Molander’s elegant protocol, we surmised that the use of more basic cesium oxalates could be more competent to this deborylation step.

With the optimized conditions established, the substrate scope of this synergistic alkylarylation–deborylation reaction was evaluated. As shown in Scheme [3], pleasingly, a wide range of bromopyridines can be coupled with vinyl borate and tertiary alkyl oxalates in this reaction, allowing for facile construction of linear alkyl-substituted pyridines with high efficiency. No extra base was required in the cases of pyridines. The mild conditions were tolerated with electron-withdrawing (F, CN, CF₃) substituents as well as electron-donating substituents (Me, OMe) on the pyridines (products 4c–k, 62–82% yields). Moreover, substituted 2-bromo- and 3-bromopyridines were also viable

coupling partners, albeit with slightly decreased yields (products 4l–q, 50–64% yields). On the other hand, aryl bromides bearing electron-deficient substituents such as nitriles, ketones, esters, sulfones, and sulfonamides could also be successfully incorporated in the presence of Na₂CO₃, furnishing the formal three-component ethylene alkylarylation products in moderate to high yields (products 4r–v, 58–68% yields). Nonetheless, electron-rich and electron-neutral aryl bromides were not suitable substrates, with most of the starting materials remained. Notably, the reaction of complex aryl bromides, derived from biologically active molecule such as sertraline, smoothly delivered the functionalized deborylation product 4w in synthetic useful yield, further demonstrating the synthetic potential of this protocol. Additionally, a gram-scale reaction was performed with 1 and 2a under the standard conditions, affording the desired product 4a in 45% yield (Scheme [3]).

Next, we explored the scope of alkyl oxalates. As depicted in Scheme [3], both cyclic and linear cesium oxalates underwent the expected dicarbofunctionalization/deborylation reaction smoothly. Oxalated derived from 6-membered carbocycles, nitrogen-based and oxygen-based heterocycles were competitive components (products 5a–d, 60–75% yields). The reaction of oxalates derived from cyclopentanol and cycloheptanol also proceeded with moderate efficiency (products 5e and 5f, 45% and 41% yields). This protocol could be further applicable to a number of polycyclic oxalates that can be readily prepared from the corresponding alcohols such as Cedrol, delivering the formal ethylene insertion products in good yields (products 5g–k, 58–72% yields). Nevertheless, secondary and primary alcohol oxalates failed in this transformation, only resulting in the formation of the competitive alkyl–aryl coupling byproducts under the standard conditions.

Finally, we have conducted a series of experiments to shed some light on the possible pathway for deborylation process. Benzylic borate 4x′ was prepared according to the known procedure.[4g] Control reactions with benzylic borate 4x′ indicated that the deborylation process is promoted by bases such as Na₂CO₃ or cesium oxalates employed as the coupling agents (Scheme [4]A).[10] Moreover, deuterium experiments indicated that water presented in DMSO provided the hydrogen source for this deborylation (Scheme [4]B). Not surprisingly, the deborylation step was found to be substrate dependent. In the cases of aryl bromides, time-course reactions indicated that the alkylarylation–deborylation product gradually formed as vinyl borate and aryl bromide gradually consumed, along with a small amount of benzylic borate intermediate (Scheme [4]C); while in the cases of bromopyridines we did not observe the formation of borate-retaining intermediates at all. When alkenyl bromides were employed, only allylic borate products were obtained even in the presence of Na₂CO₃ or NaOH (Scheme [4]D).

Based on experimental results as well as previous literatures,[4`] [h] [i] [j] [k] the following catalytic reaction mechanism has been proposed. As depicted in Scheme [5, a] single-electron oxidation of cesium alkyl oxalate I by the excited photocatalyst Ir^III generates a tertiary alkyl radical II, which then adds to vinyl boronic ester to generate the corresponding α-boryl radical III. At this juncture, interception of radical III by Ni⁰ complex gives an alkyl-Ni^I complex V, followed by an oxidative addition of aryl bromide to produce the key (aryl)(alkyl)Ni^III intermediate VI. A facile reductive elimination from VI delivers the benzylic borate product VII and Ni(I) species VIII. Finally, the catalytic cycles are closed by single-electron reduction of Ni(I) species VIII by the reducing Ir^II species, regenerating the ground state Ir^III photocatalyst and Ni catalyst. Finally, a base-assisted deborylation of benzylic borate VII would furnish the formal ethylene alkylarylation product.

In conclusion, we have developed an efficient protocol for the formal ethylene dicarbofunctionalization reaction via synergistic photoredox/nickel catalysis.[11] By taking advantage of borates as a traceless activation group, this protocol proceeds via a selective three-component 1,2-alkylarylation of vinyl borate with aryl halides and alkyl oxalates followed by a deborylation process. The mild conditions allow for excellent functional groups compatibility and broad substrate scope regarding alkyl oxalates and (hetero)aryl halides.

No conflict of interest has been declared by the author(s).

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Corresponding Authors

Publication History

Received: 29 October 2020

Accepted after revision: 23 November 2020

Accepted Manuscript online:
23 November 2020

Article published online:
16 December 2020

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
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• References and Notes

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• 11 In a typical procedure, to a flame-dried 8 mL reaction vial was charged with NiCl₂·DME (0.02 mmol, 20 mol%), dtbbpy (0.02 mmol, 20 mol%), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (0.003 mmol, 3 mol%), 4-bromopyridine (2a, 0.1 mmol, 1.0 equiv.), and cesium salt 3a (0.15 mmol, 1.5 equiv.), and the vial was capped. After evacuated and backfilled nitrogen three times, DMSO [0.05 M] and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1, 0.12 mmol, 1.2 equiv.) were added via syringe. The reaction mixture was then irradiated with a 90 W blue LED lamp (at approximately 3 cm away from the light source) with cooling from a fan for 24 h. The reaction was quenched with H₂O, extracted with ethyl acetate. The combined organic layers were dried with Mg₂SO₄, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (hexane/ethyl acetate = 10:1) to afford the product 4a as a pale yellow oil in 84% yield. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 6.0 Hz, 2 H), 7.13 (d, J = 6.0 Hz, 2 H), 2.57–2.50 (m, 2 H), 1.53–1.48 (m, 2 H), 1.48–1.42 (m, 5 H), 1.34–1.27 (m, 5 H), 0.94 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.33, 149.37, 124.07, 43.17, 37.71, 32.87, 29.55, 26.45, 24.86, 22.03. HRMS (ESI+): m/z calcd for C₁₄H₂₂N⁺ [M + H]: 204.1747; found: 204.1741.

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