- Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C-C and C-N Cross-Coupling of Multiply Chlorinated Arenes through Substrate-Ligand Electrostatic Interactions
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Use of attractive noncovalent interactions between ligand and substrate is an emerging strategy for controlling positional selectivity. A key question relates to whether fine control on molecules with multiple, closely spaced reactive positions is achievable using typically less directional electrostatic interactions. Herein, we apply a 10-piece "toolkit"comprising of two closely related sulfonated phosphine ligands and five bases, each possessing varying cation size, to the challenge of site-selective cross-coupling of multiply chlorinated arenes. The fine tuning provided by these ligand/base combinations is effective for Suzuki-Miyaura coupling and Buchwald-Hartwig coupling on a range of isomeric dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes.
- Golding, William A.,Schmitt, Hendrik L.,Phipps, Robert J.
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supporting information
p. 21891 - 21898
(2021/01/11)
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- Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis: I. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines
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In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2>6,7,8-Cl3>7-Cl~8-Cl>5,6,7,8-Cl4>5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.
- Bondinell,Chapin,Girard,Kaiser,Krog,Pavloff,Schwartz,Silvestri,Vaidya,Lam,Wellman,Pendleton
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p. 506 - 511
(2007/10/02)
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