The development of directing group enabled hydroamination strategies to access to 1,2-, 1,3-, and 1,4- diamines with high levels of regio-, chemo-, and stereoselectivity

Vanable, Evan Patrick

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https://hdl.handle.net/2142/105888 Copy

Description

Title

The development of directing group enabled hydroamination strategies to access to 1,2-, 1,3-, and 1,4- diamines with high levels of regio-, chemo-, and stereoselectivity

Author(s)

Vanable, Evan Patrick

Issue Date

2019-07-05

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

Hull, Kami L

Doctoral Committee Chair(s)

Hull, Kami L

Committee Member(s)

• Sarlah, David
• Zimmermann, Steven C
• Girolami, Gregory S

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Hydroamination Directing Groups

Abstract

Carbon-nitrogen bonds are found in many societally important molecules, ranging from bulk commodities such as polymers and agrochemicals to fine chemicals, such as pharmaceuticals and therapeutic candidates. Our interest is primarily in the rapid, convergent, synthesis of the latter. The ability to form these bonds in a selective and mild manner from easily accessible starting materials is highly sought after, and has been a major goal of for many transition-metal catalysis groups, including ours. We have chosen to approach this from the vantage of a hydroamination reaction of olefins, as olefins and amines are both readily accessible. This reaction has the potential to be entirely atom-economical, as well as modular. Another advantage, and concomitant challenge, that comes with this strategy, is the ability to form multiple isomers: there are multiple regio- and stereoisomers which can be formed in this transformation, which we have overcome with careful catalyst selection and a directing group strategy. The synthesis of 1,2-diamines is an efficient manner is an unresolved challenge for organic chemists. The enantioselective synthesis thereof is more challenging yet, and is generally approached through inefficient and step-intensive approaches such as nucleophilic displacement and resolution. We report the mild Rh-catalyzed enantioselective hydroamination of allylamines to afford chiral 1,2-diamines in good yields and excellent enantioselectivities. This transformation is impeccably chemoselective and regioselective, and highly enantioselective. This reaction tolerates a broad scope of secondary cyclic amine nucleophiles, as well as showing that secondary acyclic amine nucleophiles can be used, so long as one substituent is methyl. Future directions for this project include changing the directing group, the nucleophile, and the use of internal allylamines. The transition-metal catalyzed hydroamination of olefins typically proceeds with Markovnikov selectivity. Overturning this typically requires electronically biased substrates such as conjugated alkenes or the use of elaborate workarounds. Herein we report an approach towards the anti-Markovnikov selective hydroamination of electronically unbiased olefins based on control of the aminometallation through a directing group approach to afford 1,4-diamines which are well represented in neurologically active molecules. We demonstrate the tolerance for secondary cyclic amines, secondary acyclic amines, and a variety of substitution adjacent to the amine directing group. We have also studied the mechanism of this transformation, and the results are summarized within. Future directions for this project include changing the nucleophile and the directing group to afford different 1,4-motifs. The hydroamination of electronically unbiased olefins with high regioselectivity has been highly limited. We have evolved our directing group strategy to allow for high levels of regiocontrol when performing the hydroamination of olefins with very little steric or electronic differentiation using aniline nucleophiles. This transformation is catalyzed by an iridium catalyst, and some preliminary mechanistic studies have been performed. In the case of cyclic olefins, high diastereoselectivity is observed. This strategy has multiple interesting future directions, including potential enantioselective hydroamination of internal olefins, use of different nucleophiles, and comprehensive mechanistic studies.

Graduation Semester

2019-08

Type of Resource

text

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http://hdl.handle.net/2142/105888

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Copyright 2019 Evan Vanable

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