- Using Data Science To Guide Aryl Bromide Substrate Scope Analysis in a Ni/Photoredox-Catalyzed Cross-Coupling with Acetals as Alcohol-Derived Radical Sources
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Ni/photoredox catalysis has emerged as a powerful platform for C(sp2)–C(sp3) bond formation. While many of these methods typically employ aryl bromides as the C(sp2) coupling partner, a variety of aliphatic radical sources have been investigated. In principle, these reactions enable access to the same product scaffolds, but it can be hard to discern which method to employ because nonstandardized sets of aryl bromides are used in scope evaluation. Herein, we report a Ni/photoredox-catalyzed (deutero)methylation and alkylation of aryl halides where benzaldehyde di(alkyl) acetals serve as alcohol-derived radical sources. Reaction development, mechanistic studies, and late-stage derivatization of a biologically relevant aryl chloride, fenofibrate, are presented. Then, we describe the integration of data science techniques, including DFT featurization, dimensionality reduction, and hierarchical clustering, to delineate a diverse and succinct collection of aryl bromides that is representative of the chemical space of the substrate class. By superimposing scope examples from published Ni/photoredox methods on this same chemical space, we identify areas of sparse coverage and high versus low average yields, enabling comparisons between prior art and this new method. Additionally, we demonstrate that the systematically selected scope of aryl bromides can be used to quantify population-wide reactivity trends and reveal sources of possible functional group incompatibility with supervised machine learning.
- Doyle, Abigail G.,Gandhi, Shivaani S.,Jiang, Shutian,Kariofillis, Stavros K.,Martinez Alvarado, Jesus I.,?urański, Andrzej M.
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supporting information
p. 1045 - 1055
(2022/01/19)
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- Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor
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Due to the biological complexity of the N-methyl-d-aspartate receptor (NMDAR), the development of a positron emission tomography radiotracer for the imaging of NMDAR has met with limited success. Recent studies have established the presence of GluN2A subunit of the NMDAR in the heart and its role in the regulation of intracellular calcium levels. In our efforts to develop an imaging agent for the GluN2A subunit, we designed three new compounds based on a quinoxaline scaffold. The synthesis of the analogues was based on a two-step Kabachnik–Fields reaction in sequence with Suzuki cross-coupling and acid hydrolysis. They exhibited comparable high binding affinity values below 5 nm. A two-step radiolabeling procedure was successfully developed for the synthesis of [18F]1. [18F]1 was obtained in a modest overall radiochemical yield of 5.5 ± 4.2%, a good specific radioactivity of 254 ± 158 GBq/μmol, and a radiochemical purity > 99%. While compounds 2 and 3 showed comparable binding affinity towards NMDAR, sluggish radiolabeling, prevented their further evaluation. For [18F]1, in vitro autoradiography on rat heart slices demonstrated heterogeneous but unspecific accumulation, whereas for the brain a high in vitro specificity towards NMDAR, could be demonstrated.
- Milicevic Sephton, Selena,Vetterli, Peter T.,Pedani, Valentina,Cermak, Stjepko,Chiotellis, Aristeidis,Roscales, Sylvia,Müller Herde, Adrienne,Schibli, Roger,Auberson, Yves P.,Ametamey, Simon M.
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- An N.M.R. Investigation of Ground-State Polarization of Some Substituted Aromatic Systems
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The previously established n.m.r. method for estimating mobile bond orders was applied to the investigation of ground-state polarization of benzene derivatives with ortho or para pairs of +R/-R substituents, naphthalene and five heteroaromatic systems (furan, thiophen, pyrrole, quinoline and pyrazole).Evidence for significant ground-state polarization which is solvent-independent was found in a number of these systems, especially benzene, pyrrole and pyrazole.
- Collins, Michael J.,Hatton, Paul M.,Sternhell, Sever
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p. 1119 - 1134
(2007/10/02)
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