Unexpected Formation of Hexasubstituted Arenes through a 2-fold Palladium-Mediated Ligand Arylation

Wagen, Corin; Ingoglia, Bryan T.; Buchwald, Stephen L.

doi:10.1021/acs.joc.9b02091

Cited by 4 publications

(4 citation statements)

References 42 publications

(75 reference statements)

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“…Closer inspection reveals an out of plane dihedral angle for the benzenoid ring carbons of 6.06°, which likely occurs to alleviate steric strain between ring substituents. This is consistent with the dihedral angle observed in highly congested hexasubstituted benzenoid rings [26] …”

Section: Resultssupporting

confidence: 89%

“…This is consistent with the dihedralangle observed in highly congested hexasubstituted benzenoid rings. [26] In line with our goal of efficiently accessing 1,2,3,4-tetrasubstituteda renes, we also assessed the scope of severala rynophiles that react by different mechanisms sucha sc ycloaddition and formal s-bond insertion (Table 3). Substituted furan 2d underwent [4+ +2] cycloaddition with the aryne derived from 1a to produce naphthoquinone 3ad in 47 %y ield after acidic workup and stirring open to air (Table3).…”

Section: Resultsmentioning

confidence: 99%

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Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Nilova

Sibbald

Valente

et al. 2021

Chemistry A European J

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Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical,a grochemical, and natural products, is described. [1] In the past, the regioselective syntheses of such compounds have been as ignificant challenge. This work reports am ethod using substituted arynesd erived from aryl(Mes)iodonium salts to access ar ange of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events:1 )ortho-d eprotonation of aryl(Mes)iodonium salts to generate as ubstituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reportedr eaction conditions to generatea rynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor.Ac ompetition experiment furtherr eveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.Scheme1.Selectedexamples and retrosynthesis of 1,2,3,4-substituted benzenoid rings.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Nilova

Sibbald

Valente

et al. 2021

Chemistry A European J

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“…NMR covers a wide range of applications, not limited to the analysis of biological fluids or tissue extracts. The nuclei best suited for NMR spectroscopy in biological systems include 1 H, 19 F, 31 P, 13 C, and 15 N [ 59 ]. ( 1 H) NMR spectroscopy ( 1 H NMR) is commonly used in the profiling of LPC [ 60 ].…”

Section: Lysophosphatidylcholine (Lpc)mentioning

confidence: 99%

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

Ren

Lin

et al. 2022

IJMS

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The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain.

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“…Closer inspection reveals an out of plane dihedral angle for the benzenoid ring carbons of 6.06 °, which is consistent with dihedral angles observed in highly congested hexasubstituted benzenoid rings. 21 As highlighted above, the incorporation of chloride and bromide groups in the aryl diazepinone products provides an opportunity for further functionalization of the benzenoid core. The bromide leaving group in 2j is substituted for an aryl group, an amine, or an alkenyl group via Suzuki, Buchwald-Hartwig, and Heck coupling reactions respectively.…”

mentioning

confidence: 99%

Iodane-Guided C-H Cleavage to Synthesize Densely Functionalized Arenes

Nilova¹,

Sibbald²,

Valente³

et al. 2019

Preprint

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We describe a strategy for the iodane-guided functionalization of sterically congested C-H bonds, which is distinct from electronic, steric or proximity guided C-H functionalization methods. Readily accessible aryl(Mes)iodonium salts serve as the starting materials in these reactions and produce complex 1,2,3,4-substituted arenes via aryne intermediates. This approach is especially powerful when coupled with the innate C-H functionalization reactivity of simple arenes, to replace two C-H bonds with two C-C or C-heteroatom bonds while over-riding steric effects that typically inhibit such reactions. DFT stud-ies reveal a contribution of inductive, resonance, and steric effects on the regioselectivity of C-H cleavage and aryne generatation.

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Unexpected Formation of Hexasubstituted Arenes through a 2-fold Palladium-Mediated Ligand Arylation

Cited by 4 publications

References 42 publications

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

Iodane-Guided C-H Cleavage to Synthesize Densely Functionalized Arenes

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