Developments and applications of methods for palladium- and copper-catalyzed carbon-nitrogen bond formation

• Main Author: Yang, Jeffrey Chih-Yeh
• Other Authors: Stephen L. Buchwald.
• Format: Others
• Language: English
• Published: Massachusetts Institute of Technology 2018
• Subjects: Chemistry.
• Online Access: http://hdl.handle.net/1721.1/118280

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018. === Cataloged from PDF version of thesis. === Includes bibliographical references. === The studies presented in this dissertation are aimed at the development and application of methodologies that enable carbon-nitrogen (C-N) bond formation catalyzed by late transition metals such as palladium and copper. The first part of this thesis focuses on the use of palladium catalysis for the construction of a carbon(sp²)-nitrogen bond in the context of a biphasic continuous-flow system (Chapter 1). The second part of this thesis describes the recent developments of copper-hydride (CuH) catalyzed asymmetric hydroamination for the formation of a-chiral carbon(sp³)-nitrogen bonds from olefins. This work includes the application of CuH catalysis to the synthesis of chiral N-alkyl aziridines (Chapter 2), and the discovery and development of novel electrophilic amines to enable CuH-catalyzed asymmetric hydroamination to directly access primary amines (Chapter 3). Part I. Chapter 1. Use of a "Catalytic" Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch A general, efficient method for C-N cross-coupling has been developed using N,N-dimethyloctanamide as a cosolvent for biphasic continuous-flow applications. In addition to utilizing a proper co-solvent, the described method harnesses the superior mixing abilities of a stainless-steel powder packed tube reactor to efficiently couple a wide range of aryl/heteroaryl halides and aryl/heteroaryl/alkyl amines in a short period of time (< 15 min). The method was also integrated into a two-step sequence that converted phenols into biarylamines via the intermediate of either triflates or tosylates. Lastly, this method was applied to a telescoped three-step continuous-flow synthesis of imatinib, the API of Gleevec®, in good yield without the need of solvent switches, purification of intermediates, or aqueous extraction. Part II. Chapter 2. CuH-Catalyzed Regioselective Intramolecular Hydroamination for the Synthesis of Alkyl-Substituted Chiral Aziridines A general and enantioselective method for the synthesis of N-alkyl-substituted aziridines has been developed. This protocol offers a direct route for the synthesis of alkyl-substituted chiral aziridines from achiral starting materials. A convergent synthesis of allylic hydroxylamine esters has been developed from readily accessed allylic alcohols. The allylic hydroxylamine esters undergo copper hydride-catalyzed intramolecular hydroamination with a high degree of regio- and enantiocontrol to afford the aziridine products in good to excellent yields in highly enantioenriched form. The utility of the products derived from this method is further demonstrated through derivatization of the chiral aziridine products to obtain a diverse array of functionalized enantioenriched amines. Chapter 3. A Novel Electrophilic Nitrogen Source for Copper-Catalyzed Asymmetric Hydroamination for the Synthesis of Chiral Primary Amines A mild and practical method for the catalytic installation of the amino group across olefins has long been recognized as a significant challenge in synthetic chemistry. Despite substantial efforts in this area, to our knowledge, no effective strategy has been developed to directly access chiral primary amines from unsaturated hydrocarbons. While the direct hydroamination of olefins requires harsh conditions, the lack of suitable nitrogen sources has limited the development of potentially more practical formal hydroamination methods for the synthesis of primary amines. Here, we describe a mild and general protocol for the copper-catalyzed hydroamination of olefins to primary amines, utilizing commercially available isoxazole and its derivatives as novel nitrogen sources. This method provides a powerful means to access a broad range of a-chiral branched primary amines and linear primary amines, as demonstrated by the efficient synthesis of Maraviroc and the formal synthesis of other pharmaceutical agents including DMP 777, Rasagiline, Dapoxetine and Bifemelane. === by Jeffrey Chih-Yeh Yang. === Ph. D. in Organic Chemistry