Seth B. Herzon, PhD , Yale University
The overall theme of our research has been the development of practical and general methods for the synthesis of complex phosphines and the application of these phosphines to novel metal-catalyzed reactions. While tertiary phosphines, secondary phosphine oxides (SPOs), and related reagents find widespread use in organotransition metal chemistry and catalysis, their synthesis is often not straightforward and presents a roadblock to the development of new catalysts and to the discovery of new reactions. To address this, our laboratory seeks to develop general and straightforward methods for phosphine synthesis. A long-term goal of this program is the creation of a library of P-chiral tertiary phosphines, thereby permitting rapid evaluation of asymmetric transition metal-catalyzed processes. Additionally, we seek to synthesize novel, multifunctional phosphine ligands and incorporate these into transition metal complexes to promote the development of novel catalytic reactions.
The major focus of research during the funding period was the development of practical and general methods for the synthesis of secondary and tertiary phosphine oxides (SPOs and TPOs, respectively). At the end of our first year of funding, we had developed a simple one-step procedure to couple primary phosphines with aldehydes and ketones. Under these conditions, the corresponding secondary phosphine oxides (SPOs) are formed in good to excellent yield from readily available starting materials (eq 1).
The SPO products are useful as ligands for transition metals and as precursors to TPOs, by P-functionalization. Other research groups have shown that copper- or palladium-based catalysts effect the coupling of SPOs with aryl halides to form TPOs. However, these transformations require long reaction times, high temperatures (>100 °C), high catalyst loadings (up to 20%), and are not general in scope.
Our laboratory has recently developed a simple and general method for the P-arylation of SPOs. We have found that a combination of tris(dibenzylideneacetone) dipalladium and Xantphos forms a highly active catalyst for the arylation of SPOs (eq 2). The reactions proceed with one mol percent of palladium, are complete within two hours at room temperature, employ stoichiometric amounts of coupling partners, and are shown to encompass a wide range of SPOs and aryl iodides, including heteroaryl iodides. Mechanistic studies suggest P–C reductive elimination may be rate-determining. A manuscript describing this work is in progress.
Because TPOs may be reduced to tertiary phosphines with either inversion or retention of stereochemistry, this method may be amenable to the production of enantioenriched P-chiral tertiary phosphines. In preliminary studies, we found that using enantioenriched SPO as starting material, the TPO product was formed without detectable loss of enantiomeric excess. Accordingly, we envision that by employing a chiral catalyst in this transformation, a kinetic resolution of SPOs may be possible. Efforts to develop this chemistry are underway.