Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor–Acceptor Complex Photoactivation

Polites, Viktor C.; Badir, Shorouk O.; Keeß, Sebastian; Jolit, Anaïs; Molander, Gary A.

doi:10.1021/acs.orglett.1c01558

Cited by 53 publications

(56 citation statements)

References 35 publications

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“…From these studies, it is clear that subtle changes to the relative concentrations among the three components is crucial for overall efficiency. Control experiments show the importance of the unique iron precatalyst and ligand combination to achieve good yields (entries [9][10][11][12]. Finally, to Table 1.…”

Section: Resultsmentioning

confidence: 95%

General and Practical Route to Diverse 1,3-(Difluoro)alkyl bicyclo[1.1.1]-Aryl Pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Coupling

Rentería-Gómez

Lee

Yin

et al. 2022

Preprint

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Bicyclo[1.1.1]pentanes (BCPs) are of great interest to the agrochemical, materials, and pharmaceutical industries. In particular, synthetic methods to access 1,3-dicarbosubsituted BCP-aryls have recently been developed but most protocols rely on stepwise C-C bond formation via initial manipulation of BCP core to make the BCP-electrophile or -nucleophile followed by a second step (e.g., transition-metal mediated cross-coupling step) to form the second key BCP-aryl bond. Moreover, despite prevalence of C-F bonds in bioactive compounds, one pot, multicomponent cross-coupling methods to directly functionalize BCP to the corresponding fluoroalkyl BCP-aryl scaffolds are lacking. In this work, we describe a conceptual different approach to access diverse (fluoro)alkyl BCP-aryls at low temperatures and fast reaction times enabled by an iron-catalyzed multicomponent radical cross-coupling reaction from readily available (fluoro)alkyl halides, bicyclo[1.1.1]pentane, and Grignard reagents. Further, experimental and computational mechanistic studies provide insights into mechanism and ligand effects on the nature of C-C bond formation. Finally, these studies are used to develop a new method to rapidly access synthetic versatile 1-(fluoro)alkyl,3-bromo and -iodo BCPs via bisphosphine iron catalysis.

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Section: Resultsmentioning

confidence: 95%

General and Practical Route to Diverse 1,3-(Difluoro)alkyl bicyclo[1.1.1]-Aryl Pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Coupling

Rentería-Gómez

Lee

Yin

et al. 2022

Preprint

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“…Dihydropyridines and related partially saturated nitrogen heterocycles can demonstrate divergent reactivity under blue light compared to that of under dark reaction conditions. Such compounds are weak reductants in the absence of light and typically act as excellent H-atom donors. − In contrast to this, under blue light, their excited state can serve as a strong single-electron reductant. ,− This ability to act as a strong reductant under blue light conditions have been used in Ni-catalyzed cross-coupling reactions to generate alkyl radicals and to reduce Ni complexes. ,− On the other hand, in Ni-catalyzed cross-coupling reactions of aryl halides with electrophiles, reduction of the initial oxidative addition product, L-Ni(II)(Ar)(X) species, to an L-Ni(I)Ar can be a rate-determining step, as this step is a heterogeneous reaction occurring at the interface of solution/Zn (X = halide). ,− …”

Section: Resultsmentioning

confidence: 99%

Light-Promoted Dearomative Cross-Coupling of Heteroarenium Salts and Aryl Iodides via Nickel Catalysis

2022

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Partially saturated nitrogen heterocycles are versatile building blocks for the preparation of other nitrogen heterocycles. For example, dihydropyridines can be converted to pyridines, tetrahydropyridines, and piperidines through oxidation, reduction, and functionalization reactions, respectively. Dearomatization of heteroarenes is an attractive approach for the synthesis of partially saturated heterocycles such as dihydropyridines due to the wide availability of heteroarenes. Significant research efforts have been dedicated to the addition of nucleophiles to various heteroarenium salts in this direction using organoboron or organometallic reagents. The availability of organoboron and organometallic coupling partners has been an important limitation to this chemistry. Direct coupling of electrophiles with heteroareniums could significantly improve the scope of these dearomatization reactions due to the wider availability of electrophiles compared to nucleophiles such as organoboron and organometallic reagents. Herein, we report the coupling of aryl iodides with pyridinium and related heteroarenium salts catalyzed by Ni/bpp and an Ir photocatalyst using Zn as a terminal reductant. This methodology tolerates a wide range of functional groups and allows the coupling of aryl and heteroaryl iodides, thus significantly expanding the scope of nitrogen heterocycle scaffolds that could be prepared through dearomatization of heteroarenes. The reaction products have been further functionalized to prepare various nitrogen heterocycles. Initial mechanistic studies indicate that the reaction described herein goes through a unique mechanism involving dimers of dihydroheteroarenes.

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“…[11] Moreover, in some cases our yields with bicyclo-[1.1.1]pentane carboxylic acid NHP esters and aryl iodides were superior to the best yields reported under photochemical conditions with aryl bromides (3 ab, 67 % vs. 24 %; 3 ad, 42 % vs. 31 %; 3 ae, 50 % vs. 33 %; no aryl iodide couplings were reported in the previous study). [15] However, the coupling to form 3 ad from the corresponding aryl bromide was low-yielding (2 %).…”

Section: Resultsmentioning

confidence: 99%

Control of Redox‐Active Ester Reactivity Enables a General Cross‐Electrophile Approach to Access Arylated Strained Rings**

et al. 2022

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Strained rings are increasingly important for the design of pharmaceutical candidates, but cross‐coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all‐carbon quaternary centers is the coupling of abundant strained‐ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel‐catalyzed cross‐electrophile approach that couples a variety of strained ring N‐hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t‐BuBpyCamCN, an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96‐well plates.

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Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor–Acceptor Complex Photoactivation

Cited by 53 publications

References 35 publications

General and Practical Route to Diverse 1,3-(Difluoro)alkyl bicyclo[1.1.1]-Aryl Pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Coupling

General and Practical Route to Diverse 1,3-(Difluoro)alkyl bicyclo[1.1.1]-Aryl Pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Coupling

Light-Promoted Dearomative Cross-Coupling of Heteroarenium Salts and Aryl Iodides via Nickel Catalysis

Control of Redox‐Active Ester Reactivity Enables a General Cross‐Electrophile Approach to Access Arylated Strained Rings**

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