Phosphorus mediated reactions toward the advancement of C--N and C--C bond formations

New methods for the phosphorus-mediated activation of C--O, N--O, C=O, and C--X bonds are reported herein. The first of which is a Staudinger ligation method, which allows for ready access to a diverse assortment of amides through the direct functionalization of carboxylic acids and azides using a chlorophosphite as a dual activating agent. This procedure complements current amide-bond forming technology by virtue of the highly chemoselective intramolecular acyl migration event, and simplified product isolation due to the aqueous solubility of byproducts generated.;However, we desired to further minimize the phosphorus waste generated from the phosphorus ligation reagent. Therefore, we employed the use of triphenylphosphine, a variety of azides, and a mild, silane reducing agent to afford the corresponding amides. This amidation method retains the chemoselectivity characteristics as displayed in the chlorophosphite Staudinger ligation method, while minimizing phosphine oxide production by employing phenylsilane to regenerate triphenylphosphine.;Our phosphorus-mediated was also applicable to N--O bond activation as shown by our phosphite-mediated approach toward N-toluenesulfonyl amidine construction. This method avoids the direct use of amines, harsh reaction conditions, and the need for a metal catalyst. The ligation is mechanistically related to the Beckmann rearrangement in that oxime geometry dictates migratory aptitude and proceeds with retention of absolute configuration.;Carbonyl C=O bond activation can also be achieved using P(NMe2) 3 toward the synthesis of the 3,3f-spirocyclopropane oxindole core via a Kukhtin-Ramirez reaction with a broad range of aryl and alkyl alkylidene oxindoles. Overall, high yields were obtained of the spirocyclopropanes starting from a variety of readily available alkylidene oxindoles. Moderate diastereoselectivities are observed in sterically encumbered alkylidenes, in which double-bond isomerization is minimized. We were also successful in our efforts to synthesis a 1,1-diester spirocyclopropane, which we envision will be a suitable substrate for ring expansion to the spiropyrrolidinyl series utilizing Lewis-acid activation and an imine nucleophile.;In addition, C--X activation using phosphine additives under ambient conditions was also achieved. The isolation of an unprecedented phosphine-dinuclear zinc bisacetylide complex sheds light on the nature of this enhanced reactivity and provides the impetus for further development of alternative zinc ligand designs. This reliable procedure complements existing alkynylation technology, and lays the foundation for future applications of phosphine-mediated organozinc additions to carbonyl compounds. Additionally, our study illustrates the first example of a chiral phosphine-accelerated enantioselective alkynylzinc addition to aldehydes.;Overall, we have exhibited numerous methods showcasing the power of phosphorus to mediate or enhance reactivity for the synthesis of highly important functional groups such as amides, amidines, spirocyclopropane oxindoles, and propargyl alcohols. It is our hope that these methods are useful to the scientific community for the synthesis of pharmaceutically relevant compounds and biologically active molecules.