Multicomponent One-pot One-step Synthesis of 1,2,3-Triazoles via Cu/Pd Catalysis
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In modern synthetic chemistry, the formation of multiple C-C bonds in a limited number of steps to access both diversity and complexity has become an important challenge. In recent years, significant research has been devoted to the synthesis of 1,2,3-triazole containing compounds in a multimetal-catalyzed domino sequence due to the remarkable biological activity and pharmaceutical potency of these compounds. Considering the increasing significance of 1,2,3-triazoles in synthetic chemistry, mixing all of the starting components in a one-pot, one-step process to create the final triazole product will be highly efficient with respect to time, cost and simplicity of performance. A number of published papers illustrated the diverse applications of 1,2,3-triazoles (e.g., palladium-mediated couplings and direct C-H bond functionalization). Similarly, this work demonstrates the development of a highly efficient and practical approach to the synthesis of these versatile triazole-containing motifs via a one-pot, one-step cascade process that involves Sonogashira, Heck and carbopalladation/annulation reactions.%%%%M.Sc.%%%%2017-11-23 00:00:00Keywords:
Sonogashira coupling
Annulation
One-pot synthesis
Domino
Triazole
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An efficient one‐pot synthesis of 1,2,3‐triazoles via the three‐component coupling reaction between propargyl bromide, secondary amines, and 3‐azidopyridine in the presence of CuI as catalyst has been presented. The reaction is highly regioselective and afforded novel 1,4‐disubstituted‐1,2,3‐triazoles in excellent yields by the [3 + 2] Huisgen cycloaddition reaction. This method avoids isolation and handling of terminal acetylenes. The ease of purification has made this methodology clean and safe for the synthesis of 1,2,3‐triazoles with a broad scope.
Propargyl
One-pot synthesis
Propargyl bromide
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An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The strategy is very general and able to endow target compounds with the highest possible number of diversity points. Notably, four new chemical bonds and two aromatic rings are formed in a one-pot fashion.
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A novel and efficient synthesis of 4-iminotetrahydropyrimidin-2-one derivatives was developed through a Cu(I)-catalyzed three-component tandem reaction employing propargylamines, isocyanates, and sulfonyl azides as starting materials. A wide range of polysubstituted 4-sulfonyliminotetrahydropyrimidin-2-ones, which might be useful in biological chemistry and medicinal science, were conveniently and efficiently assembled in one pot.
Tandem
Cascade reaction
Sulfonyl
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One-pot synthesis
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Heterocycles are found in a plethora of natural products and active ingredients and their preparation touches the very core of Organic Synthesis. Therefore, efficient syntheses of heterocycles are of paramount importance.
The goal of this thesis was the development of novel one-pot reactions based on palladium- and/or copper-catalysis for the efficient synthesis of heterocycles or their precursors. Starting from simple building blocks and using simple catalyst systems, diverse functional molecules should be prepared by these methodologies.
In the context of this work following goals were accomplished:
1) Development of a three-component synthesis of difficult-to-access 2,4-disubstituted pyrroles based on Sonogashira coupling.
2) Conception and methodological establishment of a pseudo four-component synthesis of 1,4-di(hetero)aryl substituted 1,3-diynes via sequential Sonogashira alkynylation-Glaser homocoupling.
3) Establishment of a decarbonylative alkynylation of heteroaromatic glyoxylyl chlorides as a new variation of Sonogashira coupling. On this basis a conceptually novel three-component synthesis of ynones, which are important building blocks in many heterocycle syntheses, was devised.
4) Conception and methodological establishment of a novel three-component synthesis of heterocyclic ynediones via catenation of glyoxylation and subsequent catalytic Stephens-Castro alkynylation in a one-pot fashion. Because the chemistry of ynediones is scarcely explored, the selective synthesis of 5-acyl pyrazoles was chosen to exemplify the synthetic potential of these reactive intermediates.
5) N-Heteroaromatic carboxylic acids and a-oxo carboxylic acids can be in situ activated with oxalyl chloride for Sonogashira or Stephens-Castro alkynylations and allow for the first time an efficient transformation of notoriously difficult N-heterocyclic substrates.
6) The sequentially Pd-catalyzed Masuda borylation–Suzuki coupling synthesis, which was established as a one-pot process, offers a direct and efficient strategy for the synthesis of 3-(hetero)aryl substituted (aza)indoles and 2,4-di(hetero)aryl substituted pyrroles. Besides the synthesis of 7-azaindole derivatives as analogs of variolin B this methodology was transposed to the preparation of symmetrical heterocycle-bridged bisindoles and to concise total syntheses of the marine alkaloids meridianin G, meridianin A, and hyrtinadine A. The obtained compounds were biologically evaluated in collaboration with
Merck Serono, Darmstadt, on human cancer cell lines and on a broad panel of kinases, emphasizing that this methodology opens a rapid and efficient access to biologically active lead structures.
7) Conception and methodological establishment of a three-component Sonogashira coupling–azide-alkyne cycloaddition (Click reaction) sequence for the preparation of (aza)indolyl substituted triazoles. By this methodology a new lead structure for selective PDK1 inhibitors was found.
All presented one-pot syntheses can be conducted under mild reaction conditions and are broad with respect to the substrate range. They are preparatively very simple, start from simple reactants and utilize simple catalyst systems. Moreover, the synthetic versatility of oxalyl chloride as a reagent in catalytic couplings for the introduction of the C1-carbonyl synthon (surrogate for carbon monoxide) is successfully demonstrated for the first time.
Sonogashira coupling
Alkynylation
Oxalyl chloride
Organic Synthesis
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The copper-catalysed azide-alkyne cycloaddition (CuAAC) is a highly efficient reaction and is the cornerstone of “click” chemistry. However, unlike many common metal-mediated transformations asymmetric CuAAC variants are relatively sparse. This thesis details asymmetric “click” reactions with Chapter 1 introducing the CuAAC and the asymmetric variants already present in the literature. Chapter 2 outlines research demonstrating the first example of kinetic resolution of an alkyne via a CuAAC reaction. Selectivity factors of up to 22.1 ± 0.5 were obtained and triazoles and alkynes were obtained in ≤ 80% enantiomeric excess (ee). This chapter also contains a study on the simultaneous kinetic resolution of azides and alkynes; azides were obtained in >30% \(e\)\(e\), alkynes in >40% \(e\)\(e\) and a triazolic diastereomeric product was obtained in up to 90% \(e\)\(e\). In Chapter 3 the Bull-James three-component boronic acid assembly is successfully employed for the kinetic resolution of primary amine alkynes with selectivity factors of up to 4.1 obtained. The principle behind the assembly is also elaborated upon in this chapter leading to its use in both dynamic combinatorial chemistry and as a pedagogical tool. Chapter 4 details work on atropisomerism in triazolic systems. A series of novel triazoles, iodotriazoles and triazolium salts were successfully synthesised and their atropisomeric stability probed. Chapter 5 presents feasibility studies towards the asymmetric synthesis of 5,5’-bis(triazoles) and ruthenium olefin metathesis catalysts in the formation of 1,5-triazoles.
Kinetic resolution
Alkyne
Diastereomer
Atropisomer
Triazole
1,2,3-Triazole
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This thesis defense presentation describes the development of
transition-metal-catalyzed transformations of fused pyridotriazoles, as well as
monocyclic N-sulfonyl-1,2,3-triazoles, which allows efficient synthesis of
various valuable nitrogen-containing compounds.
One major focus of Part I lies in subsequent section describing the
development of a general and efficient rhodium-catalyzed reaction of
pyridotriazoles with amides and amines, allowing facile synthesis of valuable picolylamine derivatives, providing expeditious access to various disubstituted imidazopyridines in a one-pot manner via the subsequent cyclization. With this method, we broke the structural limitation of pyridotriazoles (activating group at C7-position, EWG at C3-position). Moreover, the imidazopyridines obtained with this protocol are not accessible by previously reported transannulation reaction of pyridotriazoles with nitriles. Another focus of Part I is the discovery of copper-catalyzed intramolecular transannulation reaction of pyridotriazoles with internal alkynes, offering efficient construction of various tri-, tetra-, and pentacyclic fused indolizines. It is not only the first intramolecular transannulation reaction of pyridotriazoles, but also for the first time it is shown that this reaction could also be triggered by Lewis acids.
In Part II, we developed a method for expeditious access to various 5,5-fused pyrroles from easily available N-sulfonyl-1,2,3-triazoles. Moreover, it
can also be used to efficiently construct spiro systems, as well as fused tetrahydropyrrolo-pyrrole cores. In contrast to previously reported methods where ylides are key intermediates, preliminary mechanistic study reveals that a Rh-carbene-alkyne metathesis step is involved in this transformation.
Pyrrole
Alkyne
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A cascade Cross-Dehydrogenative-Coupling (CDC)/cyclization methodology has been developed for the synthesis of diverse scaffolds.
Coupling reaction
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One-pot copper-catalyzed three-component reaction: a modular approach to functionalized 2-quinolones
A copper-catalyzed three-component annulation for the synthesis of functionalized 2-quinolones was developed. Three reactions including an SN2, a Knoevenagel, and finally C-N bond formation are involved in the designed cascade reaction using 2-bromoacylarenes, 2-iodoacetamide, and nucleophiles as the three components. A new catalytic system was discovered during the study and this modular approach is highly efficient to access functionalized 2-quinolone derivatives, compatible with a broad range of functional groups, scalable, and step-economic. Further derivatization of the obtained product demonstrates the synthetic utility of this method.
Annulation
Knoevenagel condensation
Cascade reaction
Benzimidazole
Component (thermodynamics)
SN2 reaction
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Abstract There is a continuous need for designing new and improved synthetic methods aiming at minimizing reaction steps while increasing molecular complexity. In this respect, catalytic, one-pot cascade methodologies constitute an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity. Herein, we describe two general and efficient cascade procedures for the synthesis of spiro-fused heterocylces. This transformation combines selective nucleophilic substitution (S N 2′), palladium-catalyzed Heck and C–H activation reactions in a cascade manner. The use of allylic ammonium salts and specific Pd catalysts are key to the success of the transformations. The synthetic utility of these methodologies is showcased by the preparation of 48 spiro-fused dihydrobenzofuranes and indolines including a variety of fluorinated derivatives.
SN2 reaction
Cascade reaction
Stereoisomerism
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