Late stage C―H activation of a privileged scaffold; synthesis of a library of benzodiazepines

A library of over twenty 5-(2-arylphenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ones has been formed by a microwave-mediated late-stage palladium-catalysed arylation of 1,4-benzodiazepines using diaryliodonium salts. This can also be applied to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam, and subsequent N-alkylation and/or H/D exchange allows further diversification towards elaborated pharmaceuticals and their 3,3'-deuterated analogues

sp2 Carbon-Hydrogen Bond (C-H) Functionalization

Abstractsp2 Carbon-Hydrogen Bond (C-H) FunctionalizationbySirilata YotphanDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor Robert G. Bergman, ChairChapter 1. A review of the Bergman/Ellman group literature on rhodium-catalyzed direct sp2 C-H bond functionalization reactions is presented. In addition, some well-known late transition-metal catalyzed sp2 C-H bond functionalization reactions are described. These synthetic methods have valuable applications for organic chemistry and enable access to a number of interesting organic compounds and derivatives. These examples highlight the importance of this type of transformation and provide the background from which the results described in Chapters 2-5 may be viewed.Chapter 2. Bridgehead bicyclic unsaturated enamines were prepared by a tandem rhodium-catalyzed C-H bond activation/alkenylation/electrocyclization of alkyne-tethered unsaturated imines. These strained bicyclic enamines exhibit unique reactivity: for example, they lead to N-alkylated products upon treatment with alkylating reagents and undergo double bond isomerization to alleviate ring strain upon reduction.Chapter 3. An efficient method is reported for the preparation of multicyclic pyridines and quinolines by a rhodium-catalyzed intramolecular C-H bond functionalization process. The method shows good scope for branched and unbranched alkyl substituents on the pyridine ring and at the R position of the tethered alkene group. Starting materials capable of undergoing olefin isomerization to provide terminal 1,1-disubstituted alkenes also proved to be effective substrates.Chapter 4. A method for the direct arylation of benzotriazepines is reported, employing an aryl iodide as the coupling partner, copper iodide as the catalyst, and lithium tert-butoxide as the base. A variety of electron-rich, electron-poor, and sterically hindered aryl iodides are compatible with the reaction conditions. The arylation reaction can also be performed outside a glovebox in air without a significant decrease in yield. Furthermore, convenient microwave conditions for carrying out this transformation are reported.Chapter 5. The reaction of isopropyl Grignard reagent and 3-bromoquinoline leads to formation of interesting 3,4-disubstituted quinoline products in significant yields. This transformation was extensively studied for 3-bromoquinoline as the substrate, isopropyl magnesium chloride as the nucleophile, and a Brønsted acid or 3-bromopropene as electrophiles. A brief survey of this transformation, identification of the reaction limitations, and a suggested mechanism are reported in this Chapter

Iodine-Catalyzed Oxidative Cross-Coupling of Indoles and Azoles: Regioselective Synthesis of <i>N</i>‑Linked 2‑(Azol-1-yl)indole Derivatives

A highly efficient iodine-catalyzed regioselective oxidative cross-coupling of an indole C–H bond and azole N–H bond is described. This metal-free reaction can be easily carried out at room temperature under mild and environmentally friendly conditions and provides a series of <i>N</i>-linked 2-(azol-1-yl)­indole derivatives in moderate to excellence yields

Quinoxalinones as A Novel Inhibitor Scaffold for EGFR (L858R/T790M/C797S) Tyrosine Kinase: Molecular Docking, Biological Evaluations, and Computational Insights

Combating acquired drug resistance of EGFR tyrosine kinase (TK) is a great challenge and an urgent necessity in the management of non-small cell lung cancers. The advanced EGFR (L858R/T790M/C797S) triple mutation has been recently reported, and there have been no specific drugs approved for this strain. Therefore, our research aimed to search for effective agents that could impede the function of EGFR (L858R/T790M/C797S) TK by the integration of in silico and in vitro approaches. Our in-house quinoxalinone-containing compounds were screened through molecular docking and their biological activity was then verified by enzyme- and cell-based assay. We found that the four quinoxalinone-containing compounds including CPD4, CPD15, CPD16, and CPD21 were promising to be novel EGFR (L858R/T790M/C797S) TK inhibitors. The IC50 values measured by the enzyme-based assay were 3.04 &plusmn; 1.24 nM; 6.50 &plusmn; 3.02 nM,10.50 &plusmn; 1.10 nM; and 3.81 &plusmn; 1.80 nM, respectively, which are at a similar level to a reference drug; osimertinib (8.93 &plusmn; 3.01 nM). Besides that, they displayed cytotoxic effects on a lung cancer cell line (H1975) with IC50 values in the range of 3.47 to 79.43 &mu;M. In this proposed study, we found that all screened compounds could interact with M793 at the hinge regions and two mutated residues including M790 and S797; which may be the main reason supporting the inhibitory activity in vitro. The structural dynamics revealed that the screened compounds have sufficient non-native contacts with surrounding amino acids and could be well-buried in the binding site&rsquo;s cleft. In addition, all predicted physicochemical parameters were favorable to be drug-like based on Lipinski&rsquo;s rule of five, and no extreme violation of toxicity features was found. Altogether, this study proposes a novel EGFR (L858R/T790M/C797S) TK inhibitor scaffold and provides a detailed understanding of compounds&rsquo; recognition and susceptibility at the molecular level