Palladium-catalyzed cross-coupling reactions enable organic chemists to form C-C bonds in targeted positions and under mild conditions. Although phosphine ligands have been intensively researched, in the search for even better cross-coupling catalysts attention has recently turned to the use of N-heterocyclic carbene (NHC) ligands, which form a strong bond to the palladium center. PEPPSI (pyridine-enhanced precatalyst preparation, stabilization, and initiation) palladium precatalysts with bulky NHC ligands have established themselves as successful alternatives to palladium phosphine complexes. This Review shows the success of these species in Suzuki-Miyaura, Negishi, and Stille-Migita cross-couplings as well as in amination and sulfination reactions.

A continuous-flow microwave reactor with a unique pressure control device is described. The reactor has been designed to withstand extremely high pressure without the involvement of a conventional backpressure-creating device that commonly results in carryover and cross-contamination problems. The reactor efficiency has been evaluated by product conversions using two model reactions, namely, the Claisen rearrangement and the synthesis of benzimidazole.

Palladiumkatalysierte Kreuzkupplungen versetzten Organiker in die Lage, C‐C‐Bindungen gezielt und unter milden Reaktionsbedingungen zu einzuführen. Während Phosphanliganden in diesen Umsetzungen am intensivsten erforscht wurden, sind seit kurzem auf der Suche nach leistungsfähigeren Katalysatoren für Kreuzkupplungen auch N‐heterocyclische Carbenliganden (NHC), die eine starke Bindung zum Palladiumzentrum bilden, beachtet worden. PEPPSI‐Pd‐Präkatalysatoren (“Pyridin‐verstärkte Präkatalysatorherstellung, ‐stabilisierung und ‐initiierung”) mit sperrigen NHC‐Liganden haben sich mittlerweile als Alternative neben Palladium‐Phosphan‐Komplexen etabliert. Über ihre Leistungsfähigkeit in Suzuki‐Miyaura‐, Negishi‐ und Stille‐Migita‐Kreuzkupplungen sowie in Aminierungen und Sulfinierungen berichtet dieser Aufsatz.

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Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (compound 1) as the correct structure of the previously reported DHFR inhibitor 1,4-bis-{(iminothioureidomethyl)aminomethyl}-3,6-dimethyl-benzene (compound 2). The fact that compound 1 has an uncharacteristic structure for DHFR inhibitors, and an affinity (KI of 11.5 nM) comparable to potent inhibitors such as methotrexate and trimethoprim, made this inhibitor of interest for further analysis. We have conducted a characterization of the primary interactions of compound 1 and DHFR using a combination of X-ray structure and SAR analysis. The crystal structure of E. coli DHFR in complex with compound 1 and NADPH reveals that one portion of this inhibitor exploits a unique binding surface, the M20 loop. The importance of this interface was further confirmed by SAR analysis and additional structural characterization.