ChemBead Enabled High‐Throughput Cross‐Electrophile Coupling Reveals a New Complementary Ligand

Aguirre, Ana L.; Loud, Nathan L.; Johnson, Keywan A.; Weix, Daniel J.; Wang, Ying

doi:10.1002/chem.202102347

Cited by 35 publications

(33 citation statements)

References 77 publications

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“…Surprisingly, the BpyCam ligand, L14 , was found to be general and to facilitate the cross-coupling reaction between a variety of substrates, although with modest yields. Three examples of cyclobutyl-substituted (hetero)aromatics 139a–c were prepared in 27–28% yield 88 (Scheme 66).…”

Section: Cross-coupling Reaction Between Two Electrophilesmentioning

confidence: 99%

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions

2022

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Section: Cross-coupling Reaction Between Two Electrophilesmentioning

confidence: 99%

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions

2022

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“…Typically, heterogeneous reductants such as Mn 0 and Zn 0 are used as the electron source in XEC reactions because they are inexpensive, air-tolerant, and often operationally simple to use. However, the use of these heterogeneous reductants limits the applications of XEC and related reactions because they are difficult to (i) use on scale due to the need for toxic amide-based solvents and irreproducible kinetics that arise from mass transfer limitations; , (ii) implement in flow chemistry, automated chemical synthesis, or nanomole scale reactions due to engineering problems associated with heterogeneous reaction mixtures; (iii) utilize to control the rates of reduction events in catalysis due to the large number of factors that influence electron transfer from the surface of a solid-state powder to a transition metal catalyst in solution; , and (iv) tune to match the optimal redox potential of a catalyst or substrate due to the inability to readily modulate the reduction potentials of Mn 0 or Zn 0 , respectively.…”

Section: Introductionmentioning

confidence: 99%

Tunable and Practical Homogeneous Organic Reductants for Cross-Electrophile Coupling

et al. 2021

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The syntheses of four new tunable homogeneous organic reductants based on a tetraaminoethylene scaffold are reported. The new reductants have enhanced air stability compared to current homogeneous reductants for metal-mediated reductive transformations, such as cross-electrophile coupling (XEC), and are solids at room temperature. In particular, the weakest reductant is indefinitely stable in air and has a reduction potential of −0.85 V versus ferrocene, which is significantly milder than conventional reductants used in XEC. All of the new reductants can facilitate C(sp2)–C(sp3) Ni-catalyzed XEC reactions and are compatible with complex substrates that are relevant to medicinal chemistry. The reductants span a range of nearly 0.5 V in reduction potential, which allows for control over the rate of electron transfer events in XEC. Specifically, we report a new strategy for controlled alkyl radical generation in Ni-catalyzed C(sp2)–C(sp3) XEC. The key to our approach is to tune the rate of alkyl radical generation from Katritzky salts, which liberate alkyl radicals upon single electron reduction, by varying the redox potentials of the reductant and Katritzky salt utilized in catalysis. Using our method, we perform XEC reactions between benzylic Katritzky salts and aryl halides. The method tolerates a variety of functional groups, some of which are particularly challenging for most XEC transformations. Overall, we expect that our new reductants will both replace conventional homogeneous reductants in current reductive transformations due to their stability and relatively facile synthesis and lead to the development of novel synthetic methods due to their tunability.

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“…Nevertheless, the use of heterogeneous reductants can complicate XEC reactions because it is challenging to (i) Perform XEC reactions on a process scale due to irreproducible kinetics that arise from mass-transfer limitations , and the need for toxic amide-based solvents . (ii) Apply XEC in flow chemistry, automated chemical synthesis, or nanomole scale reactions, where heterogeneous reaction mixtures present engineering problems. (iii) Modify the reductant to match the redox potential of a catalyst or substrate.…”

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confidence: 99%

Homogeneous Organic Electron Donors in Nickel-Catalyzed Reductive Transformations

et al. 2022

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Many contemporary organic transformations, such as Ni-catalyzed cross-electrophile coupling (XEC), require a reductant. Typically, heterogeneous reductants, such as Zn 0 or Mn 0 , are used as the electron source in these reactions. Although heterogeneous reductants are highly practical for preparative-scale batch reactions, they can lead to complications in performing reactions on process scale and are not easily compatible with modern applications, such as flow chemistry. In principle, homogeneous organic reductants can address some of the challenges associated with heterogeneous reductants and also provide greater control of the reductant strength, which can lead to new reactivity. Nevertheless, homogeneous organic reductants have rarely been used in XEC. In this Perspective, we summarize recent progress in the use of homogeneous organic electron donors in Ni-catalyzed XEC and related reactions, discuss potential synthetic and mechanistic benefits, describe the limitations that inhibit their implementation, and outline challenges that need to be solved in order for homogeneous organic reductants to be widely utilized in synthetic chemistry. Although our focus is on XEC, our discussion of the strengths and weaknesses of different methods for introducing electrons is general to other reductive transformations.

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ChemBead Enabled High‐Throughput Cross‐Electrophile Coupling Reveals a New Complementary Ligand

Abstract: Dedicated to the memory of Donald C. Batesky, who first proposed the use of the BpyCam class of ligands.

Cited by 35 publications

References 77 publications

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions

Tunable and Practical Homogeneous Organic Reductants for Cross-Electrophile Coupling

Homogeneous Organic Electron Donors in Nickel-Catalyzed Reductive Transformations

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