1. Synthesis of a Borylated Ibuprofen Derivative through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions
Alexis C Ravenscroft, Amanda D Swistok, Brian V Popp, Steven W Knowlden, Randika T Abeysinghe J Vis Exp . 2022 Nov 30;(189). doi: 10.3791/64571.
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of boron functionalized NSAIDs (bora-NSAIDs) was synthesized under mild conditions via the copper-catalyzed regioselective boracarboxylation of vinyl arenes using carbon dioxide (CO2 balloon) and a diboron reductant at room temperature. This original method was performed primarily in a glovebox or with a vacuum gas manifold (Schlenk line) under rigorous air-free and moisture-free conditions, which often led to irreproducible reaction outcomes due to trace impurities. The present protocol describes a simpler and more convenient benchtop method for synthesizing a representative bora-NSAID, bora-ibuprofen. A Suzuki-Miyaura cross-coupling reaction between 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester produces 4-isobutylstyrene. The styrene is subsequently boracarboxylated regioselectively to provide bora-ibuprofen, an α-aryl-β-boryl-propionic acid, with good yield on a multi-gram scale. This procedure allows for the broader utilization of copper-catalyzed boracarboxylation in synthetic laboratories, enabling further research on bora-NSAIDs and other unique boron-functionalized drug-like molecules.
2. Asymmetric nickel-catalyzed hydrocyanation of vinylarenes by applying homochiral xantphos ligands
W Goertz, P W van Leeuwen, P C Kamer, D Vogt Chemistry . 2001 Apr 17;7(8):1614-8. doi: 10.1002/1521-3765(20010417)7:83.0.co;2-e.
New homochiral xantphos-type diphosphonite ligands with binaphthoxy substituents have been prepared and characterized by NMR spectroscopy. These ligands have been applied in the nickel-catalyzed hydrocyanation of styrene and other vinylarenes. Enantioselectivities up to 63% ee have been obtained by using 4-isobutylstyrene as a substrate. Addition of an excess of ligand strongly inhibits the hydrocyanation reaction since the bis-chelate nickel complexes formed are highly stable and catalytically inactive.
3. Tunable ligands for asymmetric catalysis: readily available carbohydrate-derived diarylphosphinites induce high selectivity in the hydrovinylation of styrene derivatives
T V RajanBabu, Haengsoon Park J Am Chem Soc . 2002 Feb 6;124(5):734-5. doi: 10.1021/ja0172013.
Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphonites prepared from readily available carbohydrates in conjunction with a highly dissociated counterion ([3,5-(CF3)2-C6H3)4B]- or SbF6-) effect the hydrovinylation of 4-bromostyrene or 4-isobutylstyrene under ambient pressure of ethylene with the best overall selectivities reported to date for these important substrates. In a prototypical synthesis of a 2-arylpropionic acid, 3-(4-bromophenyl)-1-butene (prepared in 98% isolated yield and 89% ee from 4-bromostyrene) has been transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, ozonolysis, and subsequent oxidation of the resulting aldehyde.
