Development and application of palladium-catalyzed carbon-nitrogen bond forming reactions

Chapter 1. Pd-Catalyzed Cross-Coupling of a-Substituted Optically Active Amines with Aryl Bromides. The palladium-catalyzed coupling reaction of enantiomerically enriched a-substituted amines with aryl bromides is described. The choice of ligand in the palladium-catalyzed coupling reaction is critical to the formation of chiral aniline products without erosion of optical purity. While Pd/P(otolyl) 3 successfully catalyzes the intramolecular aryl amination of optically active asubstituted amines, intermolecular coupling reactions with this catalyst system gives racemized products. In contrast, the corresponding intermolecular coupling reaction of optically active amines with aryl bromides employing Pd/bis(phosphine) catalysts gives products with no decrease in enantiomeric excess. The development of the Pd/Bl NAP-catalyst (BINAP = 2,2'-bis(diphenylphosphino)-1, 1 '-binaphthyl) for the coupling reaction of amines with aryl bromides is described. The use of this catalyst system provides coupled products in significantly improved yields when primary amine substrates are utilized, as well as preventing racemization of chiral substrates. A mechanism for the observed racemization with the Pd/P( o-tolyl)3 catalyst is proposed. A discussion on the difference in reactivity between Pd/P( o-tolyl)3 and Pd/bis(phosphine) catalysts is presented. The utility of this methodology is demonstrated in the synthesis of ( S)-2-methylcarboxylate-N-acetylindoline, which is a key intermediate in the synthesis of a potent ACE inhibitor. Chapter 2. Pd-Catalyzed Amination of Halog enated Heterocycles. Aminopyridines are efficiently synthesized under mild conditions by the cross coupling reaction of 2-, 3-, and 4-bromopyridines, and 2-chloropyridines with primary and secondary amines utilizing Pd/bis(phosphine)-catalysts A variety of aminopyridines were prepared including mono-, di-, tri-, and tetrapyridylamine products. Application of this reaction to the amination of various nitrogen containing halogenated heterocycles is discussed. Chapter 3. A Palladium-Catalyzed Method for the Preparation of lndoles via the Fischer lndole Synthesis. A Pd-catalyzed method for the preparation of N-aryl benzophenone hydrazones is described. The use of 1-2.5 mol % of a Pd/BINAP based catalyst provides N-aryl benzophenone hydrazones in good yields. Using a Pd/9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) catalyst the desired hydrazones are produced in excellent yields and at 0.1 mol % of catalyst. The N-aryl benzophenone hydrazones are converted to indole products via an in situ hydrolysis/Fischer cyclization protocol. A procedure that extends this methodology to the synthesis of N-alkyl indoles via the intermediacy of N-aryl-N-alkyl benzophenone hydrazones is described. Similarly, the Pd-catalyzed preparation of diaryl benzophenone hydrazones, followed by the hydrolysis/Fischer cyclization protocol affords N-aryl indole products in good yields.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

1999

Author dc:creator

• Wagaw, Seble-Hiwot Teshome, 1971-

Advisor dc:contributor.advisor

• Stephen L. Buchwald.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/9522

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/9522