Unleashing the Power of Potassium 2-Ethylhexanoate as a Mild and Soluble Base for Pd-Catalyzed C–N Cross-Coupling The formation of C–N bonds by Pd-catalyzed cross-coupling is one of the most widely practiced reactions in chemical synthesis. Typical reaction conditions involve either a strong base, which limits the scope of substrates, or an insoluble, inorganic base, which complicates running reactions on a large scale. Reaction conditions for C–N couplings with a base that is both mild and soluble are needed. We report the discovery of a combination of a phosphorinane ligand (L147) and a soluble carboxylate base, potassium 2-ethylhexanoate (K-2-EH), which leads to the coupling of a wide range of base-sensitive coupling partners. To explore the enhanced substrate scope of the reaction with this base and catalyst, we evaluated the scope using representative reactants selected from published partners, using chemical descriptors and clustering to ensure their chemical diversity. These results show that the combination of this phosphorinane ligand and K-2-EH can couple primary aliphatic amines, amides, sulfonamides, and heteroaromatic nucleophiles as well as acidic secondary nitrogen nucleophiles, such as arylamines, heteroarylamines, and amides, with a range of electrophiles. A side-by-side comparison to form selected coupling products in the presence of a range of previously reported bases and ligands showed that the products that decomposed under standard reaction conditions were stable with K-2-EH as a base. Finally, models of quantitative structure–reactivity relationships, trained on ligand screening data, were developed to help reveal the structural features that engender reactivity.

Cool work here in #JACSasap from the @hartwiggroup.bsky.social and AbbVie improving C-N couplings with a lipophilic/soluble alkyl carboxylate as the base
Will be helpful for parallel applications where liquid dosing is important as well as for flow synth
#ChemSky #ChemChat

A very cool chemical reaction showing 2 separate generic heterocycles fusing into one. Over the reaction arrow it says “one pot one reagent solvent heat”.

Tired of building 6/5 heterocycles?

Try the Monster Mash!
(It’s a Heterocycle Smash!)
[Wrong holiday, sorry]

Het fusion coming soon to a #JACSasap near you
#ChemSky #ChemChat

Site-, Stereo-, and Chemoselective Enzymatic Halogenation of Terpenoids by a Substrate Masquerade Enzymatic halogenation of C–H bonds is a promising approach to synthesize chlorine-containing compounds. However, few halogenases chlorinate C(sp3)–H bonds of molecules lacking a carrier protein, and ...

This is such a neat idea from the @narayanlab.bsky.social and the @hartwiggroup.bsky.social now in #JACSasap fooling enzymes with a removable binding ligand to accept non-native substrates #ChemSky

#ChemPubs Very cool selective 3-fluoridation of pyridines via #PyridineAbuse ring opening-ring closing from the Andy McNally lab #CSUchem now out in #JACSasap
Some excellent scope in here
Nice work by all

Helping to clean up #ChemSky I’ll be using #ChemPubs for new and cool papers (new #JACSasap highlight coming in a minute)