'Metal-Free' Cycloaddition Methodology
Lead Research Organisation:
University of Bath
Department Name: Chemistry
Abstract
There is still a great demand for versatile methodology that enables the synthesis of structurally diverse aromatic/heteroaromatics using commercially available/easily prepared substrates and mild reagents/conditions that are amenable to scale-up. Many heteroaromatics can be prepared via a de-novo approach involving tandem condensation of two (or more) coupling partners to afford ring systems that subsequently aromatise. This approach may also be used for the construction of benzenoid rings, with [4+2] cycloaddition reactions of heteroaromatic dienes with alkyne dienophiles having been used to prepare benzenoid ring systems for natural product synthesis. However, the widespread use of this benzannulation methodology for drug discovery and other commercial applications is currently restricted by the limited range of commercial availability pyrene/diazine substrates. 5-Membered thiophenes may also be use as dienes, however these reactions often require forcing conditions and extended reaction times, with their resulting sulphide cycloadducts requiring oxidation to their corresponding sulfones for SO2 elimination/aromatisation to occur. Oxazoles can be used as an alternative diene source, with their bicyclic adducts readily undergoing elimination/dehydration for the Kondrateva synthesis of substituted pyridines, however they often require forcing conditions and highly activated dienophiles which limits the widespread applicability of this methodology.
We will first establish versatile methodology for the synthesis of N-hydroxy and N-acyloxy derivatives of pyrroles, imidazoles, azoles, indoles, aza-indoles, isoindolines and aza-isoindolines. These substrates will be accessed via either N-oxidation of their parent heterocycles, or via de-novo syntheses that incorporate a hydroxylamine derivative. The Diels-Alder reactivity of these heterocyclic dienes towards a reactive dienophile such as DMAD will then be investigated for the synthesis of a wide range of monocyclic and bicyclic arenes/heterocycles. In this optimisation phase, a range of reaction parameters (e.g. temperature, solvent, time, etc..), heterocyclic dienes containing different functionalities (e.g. Ar-NO2 vs Ar-OMe) and different substitution patterns (e.g. 2- vs 3-substituted Aryl-N-oxides) will be investigated to establish the scope and limitation of this cycloaddition methodology. Once we have established its reactivity profile, we will investigate reaction of N-oxy-heterocyclic substrates with different types of electron-deficient alkyne dienophiles, with the aim of increasing the structural diversity of the arenes/heterocycles that can be prepared.
Once we have established the reactivity profile of our [4+2] cycloaddition methodology we will then investigate whether it can be used as core technology for drug-delivery applications, whereby NO cleavage results in direct formation of the aromatic ring of a drug molecule (or a fluorophore).
We will first establish versatile methodology for the synthesis of N-hydroxy and N-acyloxy derivatives of pyrroles, imidazoles, azoles, indoles, aza-indoles, isoindolines and aza-isoindolines. These substrates will be accessed via either N-oxidation of their parent heterocycles, or via de-novo syntheses that incorporate a hydroxylamine derivative. The Diels-Alder reactivity of these heterocyclic dienes towards a reactive dienophile such as DMAD will then be investigated for the synthesis of a wide range of monocyclic and bicyclic arenes/heterocycles. In this optimisation phase, a range of reaction parameters (e.g. temperature, solvent, time, etc..), heterocyclic dienes containing different functionalities (e.g. Ar-NO2 vs Ar-OMe) and different substitution patterns (e.g. 2- vs 3-substituted Aryl-N-oxides) will be investigated to establish the scope and limitation of this cycloaddition methodology. Once we have established its reactivity profile, we will investigate reaction of N-oxy-heterocyclic substrates with different types of electron-deficient alkyne dienophiles, with the aim of increasing the structural diversity of the arenes/heterocycles that can be prepared.
Once we have established the reactivity profile of our [4+2] cycloaddition methodology we will then investigate whether it can be used as core technology for drug-delivery applications, whereby NO cleavage results in direct formation of the aromatic ring of a drug molecule (or a fluorophore).
Organisations
People |
ORCID iD |
Steven Bull (Primary Supervisor) | |
Ben EMERY (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/N509589/1 | 01/10/2016 | 30/09/2021 | |||
1940015 | Studentship | EP/N509589/1 | 01/10/2017 | 30/09/2021 | Ben EMERY |
Description | [4+2] Cycloaddition methodology for the synthesis of functionalised aromatic scaffolds |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Presented current scope of the project at the 258th ACS National Meeting & Exposition in San Diego, USA. The conference was international and attracted 15000 attendees from around the world ranging from postgraduate students, academic PI's and industrial chemists. |
Year(s) Of Engagement Activity | 2019 |