Date of Award

June 2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Keywords

Alkylation, Benzylic, Friedel-Crafts, Indole, Rearrangement, Trichloroacetimidates

Subject Categories

Physical Sciences and Mathematics

Abstract

Allylic trichloroacetimidates have been previously shown to be versatile substrates for the synthesis of C-N bonds through [3,3]-sigmatropic rearrangements. This work explores a similar reaction, the rearrangement of benzylic trichloroacetimidates to access benzylic trichloroacetamides. The benzylic rearrangement was shown to proceed under two different sets of conditions: thermal and Lewis-acid catalyzed (TMSOTf). The corresponding secondary benzylic trichloroacetamides were produced in good to high yields with either protocol. The convenience of having two protocols was demonstrated in the study as it allows for extensibility and flexibility of the substrate scope. The usefulness of the benzylic rearrangement of trichloroacetimidates was demonstrated in the synthesis of trichloroacetamide derivatives, such as the corresponding benzyl amine. A cationic pathway is proposed for this reaction based on the available data.

The alkylation of many heteroatom nucleophiles with trichloroacetimidates has recently been demonstrated by the Chisholm group, proving that trichloroactimidates are competent alkylating agents. This work has now been extended using benzylic trichloroacetimidates as electrophiles for the Friedel-Crafts alkylation reaction with indoles under Lewis acid catalysis. These reactions proceeded well even with electron-deficient benzyl structures. C3-Monobenzylated indoles were produced in excellent yields with high regioselectivity, an important feature since a common challenge with indoles is polyalkylation. The development of this facile procedure to access C3-monoalkylated indoles facilitated the formation of several interesting indole frameworks, which are known to possess important medicinal and pharmacological properties.

Studies towards the selective C3-alkylation of indoles showed that a small amount of the 3,3’-indolenine was being formed as a competing side product. Progress towards an efficient protocol that takes advantage of the nucleophilicity of the C3 position of indoles to build a quaternary center directly with trichloroacetimidates has been discussed. The modular synthesis of indoles with different trichloroacetimidates was possible using Lewis acid-catalyzed conditions was also investigated. While there are reports on the electrophilic addition of electrophiles to indoles for the synthesis of 3,3’-indolenines, this method is differentiated because it does not use any transition-metal catalyst or strong base. Additionally, this methodology is envisioned to be applied in the synthesis of spirocycles from bis-trichloroacetimidates, which are three-dimensional in structure and prominent in medicinal chemistry.

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