Sustainable Strategies for the Scalable Production of Widely Used Small Precursors

Abstract

The aim of this thesis is to design and apply enabling technologies such as flow chemistry, microwave reactors, immobilised reagents and scavengers to expedite complex chemical syntheses of widely used small precursors.
Chapter 1 introduces the significance of sustainable synthesis, contextualising current methodologies and technologies within broader societal and industrial demands. The increasing need for affordable, efficient, and scalable chemical products continues to drive innovation in safer, environmentally conscious, and sustainable synthesis strategies. The research comprises three interconnected projects, grouped into two thematic parts:
• Part I: Sustainable valorisation of recycled materials containing carbohydrate sources
• Part II: Methodology development for small, broadly applicable building blocks: 2-hydroxy-6-methoxyacetophenone and 2-hydroxy-6-methoxybenzaldehyde.
Part I explores laboratory synthesis optimisation for industrial-scale applications, addressing real-world environmental challenges. A key focus is the valorisation of lactose derived from cheese whey waste. This project applies the García González reaction in flow reactors to convert carbohydrates into high-value C-glycosalfuran derivatives. Using D-(+)-glucose and D-(+)-galactose as model monosaccharides, reaction yields ranged from 78% to 85%. The García González reaction achieved 98% lactose consumption, yielding products with exceptional stability in aqueous media—making them promising candidates for synthesising materials requiring robust water-phase resilience.


Part II comprises two projects addressing regioselectivity challenges frequently encountered in electrophilic aromatic substitution reactions. Specifically, the focus lies in synthesising two target compounds: 2-hydroxy-6-methoxybenzaldehyde and 2-hydroxy-6-methoxyacetophenone. The benzaldehyde derivative was synthesised via a three-step sequence employing the Casnati–Skattebøl reaction, which enabled ortho-selective formylation using an Et₃N–MgCl₂ system. To access the acetophenone analogue, a novel synthetic approach was developed. This involved the preparation of the coumarin precursor 5-methoxy-4-methylcoumarin, followed by ozonolysis to achieve complete functional conversion of the alkene moiety, ultimately yielding 2-hydroxy-6-methoxyacetophenone.