PEPPSI™ Catalyst - Introduction, Advantages and Applications

Scheme 1 illustrates the strong ability of PEPPSI™ catalyst to effect cross-couplings (sp²–sp² Negishi) under mild reaction conditions. The aryl bromide was completely converted to 4-methyl-4′- methoxylbiphenyl in two hours at room temperature, whereas alternative Pd systems require overnight reaction times to reach adequate conversions. Another compelling feature of the PEPPSI™ system is the low (1 mol %) loadings in Negishi couplings, wherein sp³–sp³ couplings have been achieved in short (30 min) reaction times with high conversions. Previous NHC protocols involving alkyl–alkyl coupling reactions had not been accomplished successfully in high yield.

Negishi Substrate Scope: sp3−sp2 couplings

The range of substrates successfully applied in the Negishi reaction for sp³(RX)–sp²(RZnX) couplings includes both electron donating and electron withdrawing substituents on the arylzinc reaction partner. It is worth noting the coupling of chiral (S)-citronellyl bromide in which the final product does not show an observable erosion of enantiopurity (compound 1). The mild nature of the PEPPSI™ catalyst tolerates pendant alkenyl and alkynyl functional groups as well as the often sensitive TMS group (2–3). Isolated product yields in this coupling class are all greater than 80%.

Buchwald-Hartwig Amination

The indole moiety is one important element in organic compounds that exhibit pharmacological activity. The most popular method utilized for indole synthesis is the Fischer indole synthesis, wherein an N-acyl hydrazone is transformed into the indole architecture through a sigmatropic rearrangement. As a complement to that well-known methodology, the Organ group has reacted a vinyl halide with various 2-bromoanilines in the presence of PEPPSI™ to afford 2-substituted indoles in good yields (Scheme 3).⁴ This elegant strategy is being applied toward the expeditious preparation of N-alkyl and N-aryl-indoles for combinatorial libraries.