40230-96-4Relevant articles and documents
Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides
Le, Christine M.,Sperger, Theresa,Fu, Rui,Hou, Xiao,Lim, Yong Hwan,Schoenebeck, Franziska,Lautens, Mark
supporting information, p. 14441 - 14448 (2016/11/13)
We report a highly robust, general and stereoselective method for the synthesis of 3-(chloromethylene)oxindoles from alkyne-tethered carbamoyl chlorides using PdCl2(PhCN)2 as the catalyst. The transformation involves a stereo- and regioselective chloropalladation of an internal alkyne to generate a nucleophilic vinyl PdII species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases and can be used to access biologically relevant oxindole cores. Through combined experimental and computational studies, we provide insight into stereo- and regioselectivity of the chloropalladation step, as well as the mechanism for the C-C bond forming process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a high valent PdIV species, which then undergoes facile C-C reductive elimination to form the final product. Overall, the transformation constitutes a formal PdII-catalyzed intramolecular alkyne chlorocarbamoylation reaction.
Design and application of a low-temperature continuous flow chemistry platform
Newby, James A.,Blaylock, D. Wayne,Witt, Paul M.,Pastre, Julio C.,Zacharova, Marija K.,Ley, Steven V.,Browne, Duncan L.
, p. 1211 - 1220 (2014/12/10)
A flow reactor platform technology applicable to a broad range of low temperature chemistry is reported. The newly developed system captures the essence of running low temperature reactions in batch and represents this as a series of five flow coils, each with independently variable volume. The system was initially applied to the functionalization of alkynes, Grignard addition reactions, heterocycle functionalization, and heteroatom acetylation. This new platform has then been used in the preparation of a 20-compound library of polysubstituted, fluorine-containing aromatic substrates from a sequential metalation-quench procedure and can be readily adapted to provide gaseous electrophile inputs such as carbon dioxide using a tube-in-tube reactor.
Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform
Desai, Bimbisar,Dixon, Karen,Farrant, Elizabeth,Feng, Qixing,Gibson, Karl R.,Van Hoorn, Willem P.,Mills, James,Morgan, Trevor,Parry, David M.,Ramjee, Manoj K.,Selway, Christopher N.,Tarver, Gary J.,Whitlock, Gavin,Wright, Adrian G.
supporting information, p. 3033 - 3047 (2013/05/22)
Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase - both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.