Ligand switchable site selectivity in C–H alkenylation of thiophenes by turnover-limiting step control

Evans, Rebecca; Sampson, Jessica; Wang, Long; Lückemeier, Lukas; Carrow, Brad P.

doi:10.1039/d1cc03456a

Cited by 11 publications

(16 citation statements)

References 29 publications

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“…Carrow and Fernández-Ibáñez (Scheme A,B, respectively) independently showed that the electrophilic Pd(II) species derived from thioether ligands selectively functionalized the electron-rich C2 position. , Furthermore, our electron-deficient PzNPy ligand containing two ester groups provides a similar role, suitable for the C2-alkenylation of 3-substituted thiophenes (Scheme C). The selectivity was reversed with pyridine as a ligand (Scheme D) . Based on this result, Carrow and co-workers performed thorough mechanistic studies and suggested a switch in the site-selectivity-determining step from the C–H cleavage to the C–C bond-forming step when the ligand was changed from the thioether to pyridine.…”

Section: Regiodivergent Alkenylation Of Five-membered Heteroarenes Wi...mentioning

confidence: 95%

“…The selectivity was reversed with pyridine as a ligand (Scheme 10D). 54 Based on this result, Carrow and co-workers performed thorough mechanistic studies and suggested a switch in the site-selectivity-determining step from the C−H cleavage to the C−C bond-forming step when the ligand was changed from the thioether to pyridine. The preferential alkenylation at the unhindered C5 position was further improved by the substituted pyridine and PzNPy ligands, as shown by van Gemmeren 57 and our group, 48 respectively (Scheme 10E,F).…”

Section: Thiophenementioning

confidence: 99%

“…The switchable site selectivity by these ligand systems is consistently observed in the transformations of 3-substituted thiophenes (see section ). This transformation was further investigated to reveal the switch of the mechanism from reversible to irreversible C–H activation processes …”

Section: Regiodivergent Alkenylation Of Five-membered Heteroarenes Wi...mentioning

confidence: 99%

“…This transformation was further investigated to reveal the switch of the mechanism from reversible to irreversible C−H activation processes. 54…”

Section: Pyrrolementioning

confidence: 99%

“…Furthermore, the solvent effect was critical for the development of an alternative 1:1 coupling reaction through the Scheme 10. Regiodivergent Alkenylation of 3-Methylthiophene by (A, D) Carrow, 53,54 formation of a C−N bond (Scheme 11B,C). 59 In contrast to diphenylacetylene, 4-octyne does not exert a stabilizing effect on the rhodacycle, facilitating the reductive formation of the C−N bond.…”

Section: Pyrazolementioning

confidence: 99%

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Transition-Metal-Catalyzed Divergent C–H Functionalization of Five-Membered Heteroarenes

Jeong

Joo

2021

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Conversion of common reactants to diverse products is a key objective of organic syntheses. Recent developments in transition-metal-catalyzed C−H functionalization have increased the interest in such conversions. Both the position of functionalization and the type of the substituent can be varied, allowing systematic diversification of common structural cores. Because five-membered heteroarenes (pyrazole, imidazole, thiazole, pyrrole, and thiophene) are ubiquitous in pharmaceuticals and organic functional materials, the selective C−H functionalization of these heterocyclic cores facilitates both the optimization of their physicochemical properties and streamlining of their preparation. In addition, the parent forms of these heterocycles are more readily available and inexpensive than any other derivatives of their families. Hence, their nondirected C−H functionalization is highly desirable. Although various regioselective reactions have been developed, many of them target the most reactive site; hence, except for some extensively studied arylation reactions, regiodivergent functionalization of two or more sites has been limited. This Account summarizes our work on the regiodivergent, nondirected C−H functionalization of five-membered heteroarenes with alkenes and alkynes. These unsaturated hydrocarbons are readily available, and all the composing atoms can be incorporated into products with high atom efficiency. Furthermore, the installed alkenyl groups can be transformed to other useful functional groups.To achieve comparable selectivity to that observed in the traditional reactions of these heteroarenes with highly electrophilic reagents and strong bases, a transition metal catalytic system was carefully devised with a more streamlined synthesis. A judicious choice of metals, ligands, acid and base additives, and solvents orchestrates divergent transformations using electronic and steric effects of the heteroarenes. Although C−H cleavage is a rate-and site-selectivity-determining step in most cases, the subsequent steps involving the formation of C−C bonds are often more critical than the other steps. For the C−H cleavage step, modulating the electronic properties of catalysts to make them electrophilic allows preferential alkenylation at the nucleophilic position. In addition, the presence of an internal base that can be exploited for concerted metalation−deprotonation of the acidic C−H bond offers alternative regioselectivity. Furthermore, we developed our own ligand system based on a conformationally rigid pyrazolonaphthyridine scaffold that enables aerobic C−H alkenylation reactions with steric control. We showed that the electronic and steric effects of heteroarenes can be further extended to chemodivergent reactions with norbornene derivatives. Depending on whether the palladacycle is formed, heteroarenes selectively undergo 1:2 annulation with norbornene derivatives and threecomponent reactions with other azoles through the Pd−norbornene adducts or Catell...

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Section: Regiodivergent Alkenylation Of Five-membered Heteroarenes Wi...mentioning

confidence: 95%

Section: Thiophenementioning

confidence: 99%

Section: Regiodivergent Alkenylation Of Five-membered Heteroarenes Wi...mentioning

confidence: 99%

“…This transformation was further investigated to reveal the switch of the mechanism from reversible to irreversible C−H activation processes. 54…”

Section: Pyrrolementioning

confidence: 99%

Section: Pyrazolementioning

confidence: 99%

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Transition-Metal-Catalyzed Divergent C–H Functionalization of Five-Membered Heteroarenes

Jeong

Joo

2021

Acc. Chem. Res.

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Site‐Selective C−H Arylation of Diverse Arenes Ortho to Small Alkyl Groups

et al. 2022

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Catalytic systems for direct C−H activation of arenes commonly show preference for electronically activated and sterically exposed C−H sites. Here we show that a range of functionally rich and pharmaceutically relevant arene classes can undergo site‐selective C−H arylation ortho to small alkyl substituents, preferably endocyclic methylene groups. The C−H activation is experimentally supported as being the selectivity‐determining step, while computational studies of the transition state models indicate the relevance of non‐covalent interactions between the catalyst and the methylene group of the substrate. Our results suggest that preference for C(sp2)−H activation next to alkyl groups could be a general selectivity mode, distinct from common steric and electronic factors.

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Sulfur in Waste‐Free Sustainable Synthesis: Advancing Carbon–Carbon Coupling Techniques

Shlapakov,

Kobelev,

Burykina

et al. 2024

Angewandte Chemie

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This review explores the pivotal role of sulfur in advancing sustainable carbon‐carbon (C–C) coupling reactions. The unique electronic properties of sulfur, as a soft Lewis base with significant mesomeric effect make it an excellent candidate for initiating radical transformations, directing C–H‐activation, and facilitating cycloaddition and C–S bond dissociation reactions. These attributes are crucial for developing waste‐free methodologies in green chemistry. Our mini‐review is focused on existing sulfur‐directed C–C coupling techniques, emphasizing their sustainability and comparing state‐of‐the‐art methods with traditional approaches. The review highlights the importance of this research in addressing current challenges in organic synthesis and catalysis. The innovative use of sulfur in photocatalytic, electrochemical and metal‐catalyzed processes not only exemplifies significant advancements in the field but also opens new avenues for environmentally friendly chemical processes. By focusing on atom economy and waste minimization, the analysis provides broad appeal and potential for future developments in sustainable organic chemistry.

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Ligand switchable site selectivity in C–H alkenylation of thiophenes by turnover-limiting step control

Abstract: The origin of switchable site selectivity during Pd-catalysed C–H alkenylation of heteroarenes has been examined through More O’Ferrall–Jencks, isotope effect, and DFT computational analyses, which indicate substitution of ionic thioether...

Cited by 11 publications

References 29 publications

Transition-Metal-Catalyzed Divergent C–H Functionalization of Five-Membered Heteroarenes

Transition-Metal-Catalyzed Divergent C–H Functionalization of Five-Membered Heteroarenes

Site‐Selective C−H Arylation of Diverse Arenes Ortho to Small Alkyl Groups

Sulfur in Waste‐Free Sustainable Synthesis: Advancing Carbon–Carbon Coupling Techniques

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