Thesis
Investigating novel reagents in organic synthesis
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16482
- Person Identifier (Local)
- 201880664
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- (i) The combination of two simple reagents (Et3SiH/KOtBu), also known as the Grubbs-Stoltz reagent, was reported in the literature to mediate reactions through several different mechanisms: single electron transfer (SET), hydride transfer and hydrogen atom transfer (HAT). However, the exact mechanism operating for the rearrangement of N-arylindoles e.g., 1.163 to 9,10-dihydroacridine products e.g., 1.164 discovered in the Murphy group was not well understood. [graphic element here] Mechanistic studies were carried out to gain more understanding about the rearrangement pathway. The isolation of an aniline intermediate 1.236 from one of the reactions was indicative that the reaction possibly proceeds through a C2-N bond cleavage step. Experiments performed with Et3SiD confirmed that two equivalents of hydrogen atoms are transferred, as a part of the mechanism, from the Et3SiH reagent to the dihydroacridine product 1.164. Mechanistic studies with N-heteroarylindole substrates indicated that the C2-N cleavage step is likely to involve SET processes. (ii) A novel Grubbs-Stoltz reagent-mediated rearrangement of indolenines e.g., 1.320 was discovered that produced indole products e.g., 1.331 and quinolines e.g., 1.332. [graphic element here] Mechanistic studies provided evidence that a SET mechanism was operating in the conversion of indolenine 1.320 to indole 1.331 that proceeds through the expulsion of an allyl group as an allyl radical. The complex rearrangement of indolenine 1.320 to quinoline 1.332 was achieved via a HAT route. Theoretical and experimental studies indicated that two carbon atoms were lost from 1.320, in the rearrangement to quinoline 1.332, possibly as acetaldehyde. (iii) An interesting intermolecular alkylation of diarylmethanes with ether solvents (THF and 1,4-dioxane) was observed in the presence of Et3SiH and KOtBu. An unprecedented intramolecular deoxygenative alkylation methodology was developed for the cyclisation of 5,5-diarylpentanols to diarylcyclopentanes and 3,3-diarylpropanols to diarylcyclopropanes that was facilitated by the Grubbs-Stoltz reagent. [graphic element here] A novel intramolecular dissociative σ*(C-C) - σ*(C-O) electron transfer process was proposed to be operating in the C-O cleavage step in the cyclisation pathway. Experimental mechanistic studies indicated that radicals and/or radical anions are involved in the alkylation mechanism. (iv) The reactivity of a novel class of aminomethylammonium Mannich salts 2.38a and 2.38b towards a broad range of nucleophiles was explored. These salts successfully engaged in reactions with Grignard and organolithium reagents, lithium acetylides, deprotonated tertiary malonates and nitriles, phenolates, thiolates and deprotonated heterocycles under basic conditions and with nitrogen-based nucleophiles such as indoles, pyrroles and anilines under acidic conditions. They can also be intercepted in situ by acetophenone under neutral conditions. Tosylate salts 2.38a and 2.38b were also successfully employed in reactions, where they acted as methylene transfer agents. [graphic element here] The synthetic utility of aminomethylammonium Mannich salt 2.38b was illustrated by the preparation of the bioactive indolyl neuropeptide Y receptor antagonist 2.72 in a single step from precursor 2.71 and salt 2.38b in quantitative yield. [graphic element here]
- Advisor / supervisor
- Murphy, John
- Resource Type
- DOI
- Funder
- Embargo Note
关系
项目
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File | 2023-03-01 | 限制运用 |