Always Be Coupling

Citation: Lin, L.; Schramm, T. K.; Kucheryavy, P.; Lalancette, R. A.; Hansen, A.; Prokopchuk, D. E.  J. Am. Chem. Soc.  2025 ,  ASAP.   https://pubs.acs.org/doi/10.1021/jacs.5c07649 Summary Figure:    Background: C-H functionalization reactions take unactivated carbon-hydrogen bonds (i.e., not very acidic, so not your average enolate) and typically use a transition metal to pull off that hydrogen. Theoretically, "any reaction that activates a carbon-hydrogen bond and makes a product" is an immensely wide net, so for the purposes of analyzing this paper, we'll restrict that towards organometallic reactions that end up forming a carbon-metal bond from a carbon-hydrogen bond.  The paper has a really great introduction to the field, which I will briefly summarize, but I recommend reading through the second paragraph as it is well written. Palladium (and nickel, and other transition metals) often activate C-H bond through a directing group strategy. No...

Citation: Ickes, A. R.; Liles, J. P.; Borlinghaus, N.; Henle, J.; Swiatowiec, R.; Kaushik, N. P.; Braje, W. M.; Harper, K. C.; Shekhar, S.; Sigman, M. S.   Leveraging Data Science to Elucidate Ligand Features for Pd-Catalyzed Enantioretentive  N -Arylations of cyclic a-Substituted Amines in Aqueous Media.  J. Am. Chem. Soc.  ASAP. https://pubs.acs.org/doi/10.1021/jacs.5c07224 Summary Figure:   Background: To my best approximation, Buchwald-Hartwig aminations (or N-Arylation with Ar-X like Ullmann couplings) make up about 6% of all reactions medicinal chemists run (see  The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates | Journal of Medicinal Chemistry ). That's an enormous percentage, given that the only more common classes are condensation, alkylation, and other Pd-catalyzed cross-coupling reactions are more common:   From Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F.,  Angew. Chem. Int. Ed....

 Citation:  Rajabimoghadam, K.; Faialaga, N.H.; Naito, N.; Li, Y.; Liu, R.Y. Photochemical CO Release from a Bench-Stable, Recyclable Organic Platform: Applications to Carbonylative Cross-Coupling.  Org. Lett.   2025 , ASAP.  Summary figure:   Background:  Carbonylation reactions are   really nice 3 component reactions that usually form ketones. I've posted about one of them previously (https://alwaysbecoupling.blogspot.com/2025/03/palladium-promotes-precise-conversions.html) if you want to see an example. The general idea is you can do migratory addition with a metal carbonyl to form a C-C bond, and then eventually reductively eliminate from the metal acyl complex to form another C-C bond.   Usually, there are two difficulties. First, you have to get the relative rates right, or else you can directly couple your R groups. This is also a common issue with other three-component coupling reactions like dicarbofunctionalizations.  Second, y...