Indiummediated onepot synthesis of benzoxazoles or oxazoles from 2nitrophenols or 1aryl2nitroethanones. Jung june lee, jihye kim, young moo jun, byung min lee, byeong hyo kim. The fischer oxazole synthesis has also been useful in the synthesis of 24bromophenyl5phenyloxazole starting with benzaldehyde cyanohydrin and 4bromobenzaldehyde. Mechanism of the van leusen oxazole synthesis the reaction is driven by the unique reactivity of tosmic, which includes acidic protons, sulfinic acid as a leaving group and an isocyano group that contains an. Diaryloxazoles are generally prepared through the fischer oxazole synthesis or robinsongabriel synthesis, where the oxazole ring is constructed via either synthesis. We report herein a onepot synthesis of 2,4,5trisubstituted oxazoles via a. In general, this ring closure reaction is conducted in the presence of pocl 3, p 2 o 5, pcl 5, socl 2, anhydrous hf. Mechanism of the robinsongabriel synthesis of oxazoles. Moreover, cycloaddition of two starting materials, such as. One is a combination of the ugi reaction, which uses 2,4dimethoxybenzylamine, arylglyoxal, carboxylic acid, and isonitrile as components, and a subsequent robinsongabriel reaction. Chemistry a european journal 2011, 17 27, 74807491. Because of the enormous amount and variety of information, it is often a difficult topic to cover for undergraduate and graduate chemistry students, even in simplified form.
Indeed, name reactions are not only the fruit of pioneering organic chemists, but also our contemporaries whose combined dis. The second section describes the synthesis of 2alkynyl. The robinsongabriel synthesis is an organic reaction in which a 2acylaminoketone reacts intramolecularly followed by a dehydration to give an oxazole. With its coverage of 701 organic name reactions and reagents, this threevolume set is the largest, most uptodate major reference work of its kind. Hcchpr21 fischer oxazole synthesis meyers oxazoline method cook. Mechanism of the robinsongabriel synthesis of oxazoles the. Robinsongabriel synthesis the fisher oxazole synthesis synthesis of oxazole from condensation of cyanohydrin and aldehyde.
Synthesis of highly substituted oxazoles through iodineiiimediated reactions of ketones with nitriles. Graham, phd university of pittsburgh, 2006 the first section describes the synthesis of the c1 to c11 side chain of leucascandrolide a. Accordingly, numerous synthetic methods have been described in the literature for construction of the 1,3oxazole ring. Herein, 2,4dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting ugi reagents, an isonitrile and carboxylic acid. Alfred hassner has over 60 years of experience in organic chemistry and has published over 320 scientific articles. Application of the dakin west reaction for the synthesis. Robinsongabriel synthesis an overview sciencedirect topics.
Oxazoles are aromatic compounds but less so than the thiazoles. Development of a method for the synthesis of 2,4,5trisubstituted. Functionalization of preexisting oxazole skeletons is one important strategy to access highly functionalized derivatives, but regioselectivity issues can limit such methods. Heilbron thiazole synthesis n n nn cl oh nbu k cozaar mlosartan merck, j. One of the most reliable methods for constructing the oxazole ring is the cyclodehydration of. The reaction is usually conducted in the presence of sulfuric acid or phosphorus pentachloride and more recently polyphosphoric acid, phosgene or anhydrous hydrogen fluoride have been used. The synthesis of oxazole compounds has attracted a great deal of attention due to the widespread. Organic syntheses based on name reactions 3rd edition. Ugirobinsongabriel reactions directed toward the synthesis of 2,4. Craftsrobinsongabriel synthesis results in highly substituted oxazole, 2acylamino ketones can be prepared from oxazolones via a friedelcrafts reaction. A versatile extension of this cyclodehydration reaction was devel.
These methods are reasonable for the synthesis of diverse. Synthesis of 5acetyloxazoles and 1,2diketones from. The reaction occurs by dissolving the reactants in dry ether and passing through the solution dry, gaseous. Robinsongabriel synthesis 8 formation of oxazole by dehydration of 2acylaminoketones.
Many cyclodehydrating reagents have been suggested for this reaction and polyphosphoric acid has been found to be the. He authored the first three editions of organic synthesis based on name reactions and was editor of three book series on heterocycles, asymmetric synthesis, cycloadditions. The key step of the synthesis is a modified robinsongabriel synthesis of the oxazole. Gabriel synthesis has been elucidated by oxygen labeling.
Zhdankin, in handbook of heterocyclic chemistry third edition, 2010. The other is an aucatalyzed tandem oxazole synthesis using a primary amide, aldehyde, and alkyne. The synthesis of oxazole compounds has attracted a great deal of attention due to the widespread application of oxazole derivatives in biologically active compounds as well as versatile building blocks in organic synthesis 1,2,3. Synthesis and antimicrobial activity a babul reddya,c, r v hymavathib and g narayana swamy a. The first section describes the synthesis of the c1 to c11 side chain of leucascandrolide a. Many cyclodehydrating reagents have been suggested for this reaction and polyphosphoric acid has been found to be. The second section describes the synthesis of 2alkynyl oxazoles and subsequent transformations into a variety of useful motifs.
The synthesis of oxazolecontaining natural products. First reported propylphosphonic anhydride t3p mediated. These are azoles with an oxygen and a nitrogen separated by one carbon. The van leusen oxazole synthesis allows the preparation of oxazoles from aldehydes by reaction with tosylmethyl isocyanide tosmic. This letter discloses a novel concise synthesis of a series of 2,4,5trisubstituted oxazoles via a tandem ugirobinsongabriel sequence. Covers important name reactions relevant to heterocyclic chemistry the field of heterocyclic chemistry has long presented a special challenge for chemists. Classically, the robinsongabriel synthesis was the most common route to oxazoles, which involves dehydration of 2acylaminoketones lister and robinson, 1912. A cyclodehydrating agent is needed to catalyze the reaction it is named after sir robert robinson and siegmund gabriel who described the reaction in 1909 and 1910, respectively.
Robinsongabriel synthesis an overview sciencedirect. Among these, the classical robinsongabriel cyclodehydration of 2acylaminoketones is one of the most important methods for the synthesis of oxazoles. The synthesis of oxazolecontaining natural products thomas h. In general, this ring closure reaction is conducted in the presence of pocl 3, p 2 o 5, pcl 5, socl. Baran, richter essentials of heterocyclic chemistryi. A small library of compounds with oxazole and thiazole scaffolds and structural diversity in both positions 2 and 5 has been synthesized. The synthesis of oxazolecontaining natural products d. Goldcatalyzed tandem reactions of amidealdehydealkyne. Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. Key words oxazole, natural products, bacterial alkaloids, pimprinols ac, total synthesis oxazole ringcontaining compounds are significant representatives of natural products and synthetic pharmaceuticals. Classical methods for oxazole synthesis include robinsongabriel synthesis. Gabriel oxazole synthesis32 and has proved useful in tracking peroxynitrogen and sulfur species in reactions,33,34 and other oxygentransfer reactions.
As such the product of the acid treated ugi intermediate is ideally. Development of a method for the synthesis of 2,4,5. Name reactions in heterocyclic chemistry this book. The robinsongabriel synthesis is an organic reaction in which a 2acylamino ketone reacts intramolecularly followed by a dehydration to give an oxazole. It offers students and professional chemists a valuable resource for conducting experiments and performing a broad range of applications, from pharmaceuticals to plastics to pesticides. Fischer oxazole synthesis bredereck imidazole synthesis. Molecules free fulltext synthesis of highly substituted oxazoles. Ugirobinsongabriel reactions toward the synthesis of 2,4,5. Wipf modified robinsongabriel reaction 83 scheme 15. Comprehensive organic name reactions and reagents, 3. The c1 to c11 side chain was constructed in 9 steps and 7% overall yield. For the purpose of synthesizing highly substituted oxazole compounds, an intramolecular reaction, the socalled robinsongabriel. Rapid synthesis of oxazoles under microwave conditions. A new class of multisubstituted oxazole derivatives.
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