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Nickel-Catalyzed Allylic Carbonylative Coupling of Alkyl Zinc Reagents with Tert-Butyl Isocyanide

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Nickel-Catalyzed Allylic Carbonylative Coupling of Alkyl Zinc Reagents with Tert-Butyl Isocyanide ARTICLE https://doi.org/10.1038/s41467-020-14320-1 OPEN Nickel-catalyzed allylic carbonylative coupling of alkyl zinc reagents with tert-butyl isocyanide Yangyang Weng1, Chenhuan Zhang1, Zaiquan Tang1, Mohini Shrestha1, Wenyi Huang1, Jingping Qu1*& Yifeng Chen 1* Transition metal-catalyzed carbonylation with carbon nucleophiles is one of the most pro- minent methods to construct ketones, which are highly versatile motifs prevalent in a variety 1234567890():,; of organic compounds. In comparison to the well-established palladium catalytic system, the nickel-catalyzed carbonylative coupling is much underdeveloped due to the strong binding affinity of CO to nickel. By leveraging easily accessible tert-butyl isocyanide as the CO surrogate, we present a nickel-catalyzed allylic carbonylative coupling with alkyl zinc reagent, allowing for the practical and straightforward preparation of synthetically important β,γ- unsaturated ketones in a linear-selective fashion with excellent trans-selectivity under mild conditions. Moreover, the undesired polycarbonylation process which is often encountered in palladium chemistry could be completely suppressed. This nickel-based method features excellent functional group tolerance, even including the active aryl iodide functionality to allow the orthogonal derivatization of β,γ-unsaturated ketones. Preliminary mechanistic studies suggest that the reaction proceeds via a π-allylnickel intermediate. 1 Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. *email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:392 | https://doi.org/10.1038/s41467-020-14320-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-14320-1 ioneering work developed by Heck in the 1970s catapulted resting bisiminoyl Pd intermediate was formed between the Pd- Ppalladium (Pd)-catalyzed three component reactions with iminoacyl species and 1-iminoalkyl zinc reagents (Fig. 1b)33. carbon monoxide (CO) as a powerful strategy for intro- At the outset of our investigation, we recognized several issues duction of carbonyl group1–8. Among these processes, the use of that needed to be addressed in order to develop an effective carbon-based nucleophiles allows for the convenient synthesis of nickel-catalyzed allylic carbonylation. First, the use of nickel ketones with broad applications9. Pd-catalyzed allylic reaction catalysts in carbonylation reactions has been less explored likely represents one of the most prominent carbon–carbon bond- due to the strong binding affinity of CO towards nickel39–53.Asa forming reactions with wide synthetic applications in organic rare example, the Skrydstrup group elegantly succeeded the cat- chemistry, including synthesis of various biologically active nat- alytic carbonylation of primary benzylic electrophile using a ural products, pharmaceuticals, and agrochemicals10–13. Thus, nickel pincer complex with a CO-gen precursor via the slow the allylic carbonylation would be an important strategy for addition of Negishi reagent to circumvent the direct Negishi incorporation of both alkene and carbonyl functionality in one coupling, although the use of allyl electrophiles received limited synthetic protocol, enabling the expedient synthesis of the ver- success with 8% ketone formation51. Additionally, the preference satile β,γ-unsaturated ketones, which are ubiquitous motifs in of imidoylnickel intermediates to undergo further migratory bioactive compounds and utilized as valuable synthetic building insertion with isocyanides to furnish poly(iminomethylene)s is a blocks14–20. The Stille group has realized the Pd-catalyzed allylic well-known process in polymer chemistry54–57, presenting a carbonylative Stille coupling, while the organotin reagents largely major hurdle to access monocarbonylated products. Furthermore, limited on aryl, vinyl, and allyl stannanes21,22. The Tamaru group Zhu and co-workers58 illustrate that the allyl imidoylpalladium has previously developed a Pd-catalyzed allylic carbonylative intermediate is extremely prone to undergo β-H elimination to Negishi coupling with CO to access β,γ-unsaturated ketones23,24. provide the ketenimine intermediate, which could further However, the site selectivity of this process is highly dependent on hydrolyze to β,γ-unsaturated amide59. To overcome these chal- the electronics of the organozinc coupling partner, and a mixture lenges, we envisioned that the use of functional group compatible of the linear and branched coupling products were usually organozinc reagents that are highly effective for transmetallation obtained when simple alkyl Negishi reagents were used (Fig. 1a). might disfavor the overcarbonylation process. Rapid C−C bond Despite the progress in Pd-catalyzed three component reactions formation via reductive elimination would provide the mono- with CO gas, it is still highly imperative to develop practical carbonylated coupling product60,61. Moreover, the β,γ-unsatu- carbonylation utilizing earth abundant transition metal25,26 for rated ketone easily undergoes the undesired isomerization step to functionalized ketone synthesis, especially to circumvent the afford the thermodynamically stable α,β-unsaturated ketone in long-term limitations. the presence of transition metal catalyst62. Herein, we report the Isocyanide is an important array of organic reagent widely used highly regio- and chemoselective nickel-catalyzed allylic carbo- in transition metal catalyzed carbonylations as C-1 source and in nylative Negishi reaction with tert-butyl isocyanide63, which heterocycle synthesis27–38. Despite the progress, the leverage of allows the expedient synthesis of β,γ-unsaturated ketones with functionalized alkyl Negishi reagents for transition metal cata- broad substrate scope under mild conditions (Fig. 1c). lyzed carbonylative coupling with isocyanide still remains extre- mely limited33. Recently, Dechert-Schmitt and Blackmond reported a modular unsymmetrical 1,2-diketone synthesis via Pd- Results catalyzed four-component coupling between an aryl halide, an Optimization of reaction conditions. We started our investi- alkyl zinc reagent and two molecules of tBuNC. In this process, gation by studying the nickel-catalyzed reaction of phenyl allyl a Pd-catalyzed allylic carbonylative Negishi reaction with CO (Tamaru) R [Pd] + CO Alkyl + Alkyl-ZnX Alkyl R LG R + O O Poor regioselectivity b Pd-catalyzed aryl carbonylative Negishi reaction (Dechert–Schmitt and Blackmond) O Br t [Pd] + BuNC Alkyl R + Alkyl-ZnX then H+ R O Double insertion of tBuNC Challenge for monocarbonylation c Ni-catalyzed allylic carbonylative Negishi reaction with tBuNC (this work) [Ni] + tBuNC Alkyl + Alkyl-ZnX R R LG + then H O High regioselectivity High E/Z selectivity No polycarbonylation of isocyanide No alkene isomerization Fig. 1 Development of transition metal-catalyzed carbonylative Negishi reaction. a Pd-catalyzed allylic carbonylative Negishi reaction. b Pd-catalyzed aryl carbonylative Negishi reaction. c Ni-catalyzed allylic carbonylative Negishi reaction. 2 NATURE COMMUNICATIONS | (2020) 11:392 | https://doi.org/10.1038/s41467-020-14320-1 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-14320-1 ARTICLE Table 1 Optimization of the reaction conditions. Entrya Catalyst Ligand Yield (%)b 4a 5 6 c 1 NiCl2·DME — 90 (86) ND 1 2 NiCl2·DME PPh3 27 10 ND 3 NiCl2·DME dppf 5 ND ND 4 NiCl2·DME Phen 82 3 3 5 NiCl2·DME SIPr·HCl 87 2 3 6 Ni(cod)2 — 86 6 ND 7 Pd(dba)2 — 4NDND 8 ——ND ND ND d 9 NiCl2·DME — ND ND ND dppf 1,1′-Ferrocenediyl-bis(diphenylphosphine), SIPr·HCl 1,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride, ND not determined aReaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), 3a (0.3 mmol), catalyst (0.02 mmol), ligand (0.04 mmol), DMA (2 mL), 25 °C, 0.5 h, and then 1 M HCl (2 mL) was added, 25 °C, 0.25 h bCorrected GC yield cIsolated yield within parentheses in 0.2 mmol scale dThe reaction in CO (1 atm) instead of tBuNC i) 10 mol% NiCl2•DME R DMA, 25 °C, 0.5–1 h Ph Ph OAc ++tBuNC RZnX ii) 1 M HCl, 25 °C, 0.25 h O 1a 2 3 4 n C8H17 Et Me Bn Ph Ph Ph Ph O O O O 4a, 86%, E/Z > 20/1 4b, 84%, E/Z > 20/1 4c, 75%, E/Z > 20/1 4d, 85%, E/Z > 20/1 Me Ph Ph Ph Ph Me O O O 4e, 75%, E/Z > 20/1 4f, 85%, E/Z > 20/1 4g, 71%, E/Z > 20/1 Ph F Ph Cl Ph CN 3 4 2 O O O 4h, 85%, E/Z > 20/1 4i, 62%, E/Z > 20/1 4j, 73%, E/Z > 20/1 Ph COOEt Ph OPiv Ph OTBS 4 9 O O O 4k, 78%, E/Z > 20/1 4l, 87%, E/Z > 20/1 4m, 56%, E/Z > 20/1 Me Ph N Ph Ph O O Me Cl O 4n, 70%, E/Z > 20/1 4o, 58%, E/Z > 20/1 4p, 61%a, E/Z > 20/1 F Br Ph Ph Ph O O Br O 4q, 83%, E/Z > 20/1 4r, 91%, E/Z > 20/1 4s, 61%, E/Z > 20/1 Fig. 2 Scope of alkyl zinc reagent for nickel-catalyzed allylic carbonylative Negishi reaction. Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), 3 a (0.3 mmol), NiCl2·DME (0.02 mmol), DMA (2 mL), 25 °C, 0.5 h, and then 1 M HCl. Ni(cod)2 (0.02 mmol), 50 °C. NATURE COMMUNICATIONS | (2020) 11:392 | https://doi.org/10.1038/s41467-020-14320-1 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-14320-1 Fig. 3 Scope of allyl acetate for nickel-catalyzed allylic carbonylative Negishi reaction. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), 3 (0.3 mmol), a b c d NiCl2·DME (0.02 mmol), DMA (2 mL), 25 °C, 0.5 h, and then 1 M HCl. 50 °C; Ni(cod)2 (0.02 mmol); the ratio of regioisomer is 6:1; the ratio of regioisomer is 4:1.
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