Dearomative functionalization of simple arenes: Reduction and palladium-catalyzed syn-1,4-aminofunctionalizations

Okumura, Mikiko

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Description

Title

Dearomative functionalization of simple arenes: Reduction and palladium-catalyzed syn-1,4-aminofunctionalizations

Author(s)

Okumura, Mikiko

Issue Date

2019-03-29

Director of Research (if dissertation) or Advisor (if thesis)

Sarlah, David

Doctoral Committee Chair(s)

Sarlah, David

Committee Member(s)

• Denmark, Scott E.
• Hergenrother, Paul J.
• Mitchell, Douglas A.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Dearomatization, catalysis

Abstract

Aromatic compounds represent one of the most abundant classes of organic molecules, and are suitable precursors for synthesizing functionalized alicyclic hydrocarbon frameworks. Accordingly, many unique and enabling dearomative transformations have been developed and applied to the total synthesis of complex bioactive compounds. However, a significant challenge remains to be addressed in this field. That is, simple and non-activated arenes, such as benzene and naphthalene, have seldom been employed in the dearomative functionalization reactions due to their extreme inertness. Considering a wide availability of such simple arenes, the development of novel dearomative methods for non-activated arenes which would allow site-selective introduction of functionality with concomitant loss of aromaticity would provide ideal platforms for accessing alicyclic structures with functional and stereochemical diversity. To this end, this thesis is based on the development of a dearomative strategy that employs an arenophile, such as N-methyl-1,2,4-triazoline-3,5-dione (MTAD), which undergo a visible- light-mediated formal [4+2] para-cycloaddition with simple arenes. The resulting dearomatized arene-arenophile cycloadduct possesses multiple functional handles, which can be further elaborated in situ to a variety of functional groups. Based on this concept, Chapter 2 discusses the application of olefin chemistry to achieve a site-selective reduction of the parent arenes. On the other hand, Chapters 3–6 describe an alternative mode of activating the arene-arenophile cycloadduct through transition metal-catalysis. An arenophile-mediated dearomative syn-1,4- aminofunctionalization protocol was established using palladium complexes as catalysts and with carbon-, nitrogen-, and oxygen-based nucleophiles. The key features of these processes compared to existing dearomatization reactions are: 1) amenable aromatic substrates encompassing a wide range of non-activated arenes as well as heteroarenes, 2) selective installation of functional groups to the dearomatized arene occurs in a single pot, 3) broad functional group compatibility, and 4) functionalization of least aromatic, non-activated aromatic ring within the polynuclear arenes. In each chapter, derivatizations of the resulting dearomatized products were explored through a variety of functional group elaboration. Based on the arenophile cycloreversion/fragmentation and olefin functionalization, highly functionalized alicyclic motifs with defined stereogenic centers were synthesized, most of which are not synthetically accessible using other existing dearomatization reactions. Furthermore, the versatility of the arenophile-mediated dearomatization strategy was also demonstrated by enabling novel disconnections towards the synthesis of natural products and bioactive compounds. This is highlighted by the facile synthesis of Sertraline, one of the best-selling antidepressant.

Graduation Semester

2019-05

Type of Resource

text

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Copyright and License Information

Copyright 2019 Mikiko Okumura

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