New Classes of Cross-Coupling

New Classes of Cross-Coupling

We developed a palladium-catalyzed process that forms arylamines, aryl sulfides, and arylethers. This reaction has become one of the most widely practiced reactions by medicinal chemists. The catalytic chemistry resulted from our detailed mechanistic experiments on transition metal amide, alkoxo and thiolato complexes. One catalyst we developed leads to the formation of arylamines and aryl sulfides with turnover numbers exceeding 10,000 in many cases and ppm levels of palladium in others. This catalyst also coupled aryl halides with ammonia for the first time to form primary arylamines without any protecting or blocking groups. Another class of catalyst we developed recently contains nickel in place of palladium. This catalyst is the first nickel-based catalyst to couple primary amines with a range of aryl halides. Yet another system based on palladium catalyzes the first thermal coupling of alkyl halides, instead of aryl halides, with a nitrogen nucleophile to form alkyl-nitrogen bonds. These reactions occur preferentially with secondary and tertiary alkyl halides that undergo elimination, rather than substitution, in the absence of the catalyst.

This coupling reaction is useful for total synthesis, medicinal chemistry, and the preparation of electronically important organic materials. At least one drug is manufactured using this chemistry, and countless drug candidates have been prepared by these reactions. At the same time, the catalysis involves unprecedented reactions of transition metal compounds, principally reductive elimination to form carbon-heteroatom bonds. Thus, some students focus on novel inorganic chemistry while others use this reaction as a modular route to nitrogen heterocycles and polyanilines.

We have developed a simple method to convert aryl halides and ketones, esters, amides, cyanoesters, malonates, nitriles, and related compounds to alpha aryl carbonyl compounds and nitriles in the presence of base and a palladium catalyst. Familiar compounds that can be generated from these products include Ibuprofen, Naproxin and Tamoxifen. The reaction occurs in a general fashion and in many cases with low catalyst loadings.

As part of our studies to understand this process, we have generated both O-bound and C-bound palladium enolate complexes. These complexes undergo reductive elimination of the alpha-aryl ketone, ester, or amide product in good yields. Studies on the effects of changing the enolate electronics on reductive elimination rate are in progress.