N-Containing Biomass for the Sustainable Synthesis of N-Heterocycles via Cyclization Reactions
by Kui Zeng
Date of Examination:2022-06-10
Date of issue:2022-07-22
Advisor:Prof. Dr. Kai Zhang
Referee:Prof. Dr. Manuel Alcarazo
Referee:Prof. Dr. Carsten Mai
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EnglishThe N-containing compounds from biomass, including chitin, chitosan and D-glucosamine, are one of the largest sustainable native biobased materials on earth. Human processing of the sustainable chitin/chitosan/D-glucosamine-containing raw materials exhibits only a very minor fraction of all the chitin produced annually in nature, while the major fraction maintains intact. In order to reduce the high reliance on non-renewable feedstocks, chitin/chitosan/D-glucosamine as a substitute has been increasingly utilized for value-added functional materials and important chemical feedstocks through diverse routes, mainly including chemical modifications, transformations, as ligands or catalysts in organic synthetic pathways. Despite the tremendous progress on the usage of the N-containing biomass, it is still a great challenge to directly utilize it to prepare important N-heterocyclic compounds though cyclization reactions. The targeted cleavage of C−N bonds of alkyl primary amines in chitin, chitosan and D-glucosamine via a metal-free pathway and the conjunction of nitrogen in the synthesis of imidazo[1,5-a]pyridines are still highly challenging. In publication 1, we reported an anomeric stereoauxiliary approach for the synthesis of a wide range of imidazo[1,5-a]pyridines after cleaving the C−N bond of D-glucosamine (α-2° amine) from biobased resources. This new approach expands the scope of readily accessible imidazo[1,5-a]pyridines relative to existing state-of-the-art methods. A key strategic advantage of this approach is that the α-anomer of D-glucosamine is capable of C−N bond cleavage through a seven-membered ring transition state. Using this novel method, a series of imidazo[1,5-a]pyridine derivatives (more than 80 examples) were synthesized from pyridine ketones (including para-dipyridine ketone) and aldehydes (including para-dialdehyde). Moreover, imidazo[1,5-a]pyridines derivatives containing diverse important deuterated C(sp2)−H and C(sp3)−H bonds were also efficiently achieved. In publication 2, we discribed a facile and efficient one-pot methodology that enables nitrogen interception directly from chitosan/chitin for the synthesis of a broad range of important N-heterocycles imidazo[1,5-a]pyridines (52 examples). This strategy is featured by directly synthesizing tridentate ligands and important deuterated imidazo[1,5-a]pyridines. In particular, an extended range of various functional moieties on imidazo[1,5-a]pyridine backbone are tolerated with high efficiency under these mild and catalyst-free conditions. Diverse aminocatalysis modes have been discovered over the last decades, while sustainable aminocatalyst with native chiral skeleton from biomass for the regioselective annulations reaction are highly desirable but not realized yet. In publication 3, a stereoauxiliary aminocatalysis strategy from β-anomeric glucosamine was achieved through the regioselective annulation of pyridine ketone with α,β-unsaturated aldehyde for the construction of trisubstituted indolizine-2-carbaldehydes. Using our strategy with native chiral skeleton for the regioselective control, a highly expanded range of commercially available but oxidatively sensitive α,β-unsaturated aldehydes can act as coupling partners for the efficient preparation of readily accessible trisubstituted indolizine-2-carbaldehydes via one-pot pathway. The thesis is a cumulative work with 3 publications. Two of them are published in peer-reviewed journals and the third one is in preparation. The background, the objective of the studies, results, discussions, general conclusions, perspectives and experimental section are shown in sections 1-5.
Keywords: N-Containing Biomass; Cyclization Reactions; N-Heterocycles