40796-00-7Relevant articles and documents
An Electrochemically Promoted, Nickel-Catalyzed Mizoroki-Heck Reaction
Walker, Benjamin R.,Sevov, Christo S.
, p. 7197 - 7203 (2019/08/26)
Despite significant efforts to replace Pd-based catalysts with those of Ni, the Ni-catalyzed Mizoroki-Heck coupling of aryl halides and alkenes remains challenging. This work details the development of a Mizoroki-Heck reaction of aryl halides and a broad range of alkenes that utilizes electrochemistry as a means to promote Ni-catalyzed coupling under mild conditions. Stoichiometric studies implicate low-valent Ni complexes as key intermediates in route to rapid reactions with even unactivated alkenes. As such, electrochemistry is employed to readily provide the reducing potentials necessary to access these reactive intermediates and render the transformation catalytic. Cyclohexenone was found to be an unreactive substrate but a crucial additive that promotes facile electroreduction of the Ni catalyst and functionalization of other alkenes in high yields. Finally, preliminary mechanistic studies suggest that reactions proceed via an electron-chain transfer process that rapidly terminates but is reinitiated upon electroreduction.
Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor
Mistry, Shailesh N.,Lim, Herman,J?rg, Manuela,Capuano, Ben,Christopoulos, Arthur,Lane, J. Robert,Scammells, Peter J.
, p. 647 - 661 (2016/06/01)
Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M1 mAChR. We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). This loss of affinity was rescued with the addition of either one or two methyl groups in the 7- and/or 8-position of the quinazolin-4(3H)-one core. These results demonstrate that the tricyclic benzo[h]quinazolin-4(3H)-one core could be replaced with a quinazolin-4(3H)-one core and maintain functional affinity. As such, the quinazolin-4(3H)-one core represents a novel scaffold to further explore M1 mAChR PAMs with improved physicochemical properties.
Optimization of α-ketooxazole inhibitors of fatty acid amide hydrolase
Kimball, F. Scott,Romero, F. Anthony,Ezzili, Cyrine,Garfunkle, Joie,Rayl, Thomas J.,Hochstatter, Dustin G.,Hwang, Inkyu,Boger, Dale L.
, p. 937 - 947 (2008/09/19)
A series of α-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6, Ki = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between -log Ki and Hammett σp of a magnitude (ρ = 2.7-3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.
