46043-G1
Catalytic Enantio- and Diastereoselective Allylations With Nucleophilic pi-Allylpalladium Complexes
Efficient catalytic reactions enable the production of bulk and fine chemicals from petroleum-based resources. Despite the advanced state of synthetic chemistry serious challenges remain. As such, the development of new catalytic processes is a critical component of petroleum research. In this project we are developing a new chemical reactions, umpolung allylation reaction of electrophiles by π-allylpalladium intermediates. Current methods for allylation reactions require toxic or expensive allylating agents. The proposed methods are atom-economical, generate non-toxic byproducts, and employ inexpensive starting materials as feedstocks. Therefore, these reactions would be practical for the preparation of pharmaceutical agents and fine chemicals.
In the first year of funding from the PRF we demonstrated that N-heterocyclic carbene (NHC)-ligated allylpalladium complexes are a new class of nucleophiles, that they react with aldehydes and that they catalyze allylation reactions of aldehydes.
In the second year of funding from the PRF we developed a new redox alkylation reaction of aldehydes and ketones. The discovery of this new reaction stemmed from our studies of palladium-catalyzed redox allylation reactions. We demonstrated that catalytic silver salts, in conjunction with Mn0, could provide facile alkylation of aldehydes and ketones. We also performed experiments to elucidate the mechanism of the reaction. The results of our studies have been reported in a publication: Barczak, N.T.; Jarvo E.R. Eur. J. Org. Chem., 2008, 33, 5507-5510.
The results obtained using PRF funding in year one for the development of nucleophilic allylpalladium complexes as catalytic intermediates in allylation reactions also served as key preliminary results for the development of other projects in my lab that were pursued in year 2 (without direct support from PRF funds). We have developed allylation reactions of N-acylpyrroles (Shaghafi, M. B.; Kohn, B. L.; Jarvo, E. R. Org. Lett. 2008, 10, 4743-4736), α,β-unsaturated alkylidinemalononitriles (Waetzig, J. D.; Swift, E. C.; Jarvo, E. R. Tetrahedron, 2008, in press), and redox allylation reactions of imines (Grote, R. E.; Jarvo, E.R. Org. Lett. 2009, 11, 485-488).
Silver-Catalyzed, Manganese-Mediated Catalytic Redox Alkylation Reactions.
We hypothesized that a catalytic allylation reaction of electrophiles using allylic halides could be achieved by a redox mechanism. We demonstrated the first silver-catalyzed redox allylation reaction of aldehydes and ketones and determined that Mn0 is a suitable reducing agent for this reaction. A variety of aromatic and aliphatic aldehydes and ketones are suitable electrophiles in this reaction. For example, aryl chlorides, nitriles, electron-donating and electron-withdrawing groups are tolerated. We have also demonstrated the benzylation of aldehydes and ketones is possible using benzyl bromide as a nucleophile precursor.
These reactions are extremely practical because the catalyst and reagents are very inexpensive and the byproducts, manganese salts, are non-toxic. We have performed mechanistic studies to elucidate the identity of the nucleophilic intermediate in these reactions. Substrates which incorporate radical clocks were prepared to probe for the addition of allylic radicals to the carbonyl and for ketyl radical formation. No cyclization reactions were observed; therefore we propose that a nucleophilic alkylmanganese intermediate is formed over the course of the reaction. Our future studies in this area will focus on the development of other C–C bond forming reactions that proceed through organometallic intermediates generated by single electron transfer from an inorganic or organometallic catalyst with an organic substrate.
