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The Robinson–Gabriel synthesis is an 
The 2-acylamino-ketone starting material can be synthesized using the
Protonation of the keto moiety (1) is followed by
A
organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, Mechanistic Organ ...
in which a 2-acylamino-ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
reacts intramolecularly followed by a dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
to give an oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a weak ...
. A cyclodehydrating agent is needed to catalyze the reaction It is named after Sir Robert Robinson and Siegmund Gabriel
Siegmund Gabriel (7 November 1851 – 22 March 1924) was a German chemist.
Scientific career
Siegmund Gabriel began studying chemistry at the University of Berlin in 1871. He continued his studies at the University of Heidelberg in 1872 wi ...
who described the reaction in 1909 and 1910, respectively.
The 2-acylamino-ketone starting material can be synthesized using the Dakin–West reaction The Dakin–West reaction is a chemical reaction that transforms an amino-acid into a keto-amide using an acid anhydride and a base, typically pyridine. It is named for Henry Drysdale Dakin (1880–1952) and Randolph West (1890–1949). In 2016 Sch ...
.
Reaction mechanism
Protonation of the keto moiety (1) is followed by cyclization
A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...
(2) and dehydration (3), the oxazole ring is less basic that the starting 2-acylamidoketone and so may be readily neutralized (4). Labeling studies have determined that the amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
oxygen is the most Lewis basic and therefore is the one included in the oxazole.
Modifications
Recently, a solid-phase version of the Robinson–Gabriel synthesis has been described. The reaction requirestrifluoroacetic anhydride
Trifluoroacetic anhydride (TFAA) is the acid anhydride of trifluoroacetic acid. It is the perfluorinated derivative of acetic anhydride.
Preparation
Trifluoroacetic anhydride was originally prepared by the dehydration of trifluoroacetic acid with ...
to be used as the cyclodehydrating agent in ethereal solvent and the 2-acylamidoketone be linked by the nitrogen atom to a benzhydrylic-type linker.
A one-pot
In chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy separ ...
diversity-oriented synthesis has been developed via a Friedel-Crafts/Robinson–Gabriel synthesis using a general oxazolone template. The combination of aluminum chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
as the Friedel-Craft Lewis acid and trifluoromethanesulfonic acid
Triflic acid, the short name for trifluoromethanesulfonic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the strongest known acids. Triflic acid is mainly used in research as a catalyst for es ...
as the Robinson-Gabriel cyclodehydrating agent were determined to generate the desired products.
A popular extension of the Robinson-Gabriel cyclodehydration has been reported by Wipf ''et al.'' to allow the synthesis of substituted oxazoles from readily available amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
derivatives. This is achieved through the side-chain oxidation of β-keto amides with the Dess-Martin reagent followed by the cyclodehydration of intermediate β-keto amides with triphenylphosphine, iodine, and triethylamine.
Additionally, a coupled Ugi and Robinson–Gabriel synthesis has been reported, beginning with the Ugi reagents and ending with an oxazole core within the molecule. The oxazole is formed from the Ugi intermediate, which is ideal to undergo Robinson-Gabriel cyclodehydration with sulfuric acid.
Cyclodehydrating agents
Many cyclodehydrating agents have been discovered to be of use in the Robinson–Gabriel synthesis. Historically, the dehydration agent is concentratedsulfuric acid
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular formu ...
. To date, the reaction has been shown to proceed with a variety of other agents including phosphorus pentachloride
Phosphorus pentachloride is the chemical compound with the formula PCl5. It is one of the most important phosphorus chlorides, others being PCl3 and POCl3. PCl5 finds use as a chlorinating reagent. It is a colourless, water-sensitive and moist ...
, phosphorus pentoxide
Phosphorus pentoxide is a chemical compound with molecular formula P4 O10 (with its common name derived from its empirical formula, P2O5). This white crystalline solid is the anhydride of phosphoric acid. It is a powerful desiccant and dehydra ...
, phosphoryl chloride
Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from phosp ...
, thionyl chloride
Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a chlorinating reagent, with approximately per year bein ...
, phosphoric acid-acetic anhydride Phosphoric may refer to:
*Phosphoric acid
*Phosphoric anhydride, see phosphorus pentoxide
See also
*Phosphorus
Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white ph ...
, polyphosphoric acid
A phosphoric acid, in the general sense, is a phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is bonded to four oxygen (O) atoms, one of them through a double bond, arranged as the corners of a tetrahedron. ...
, and anhydrous hydrogen fluoride
A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achie ...
among others.
Applications
Oxazoles have been found to be common substructures in multiple naturally isolated compounds and have thus garnered attention within the chemical and pharmaceutical community. The Robinson–Gabriel synthesis has been used during multiple studies dealing with molecules that incorporate an oxazole, among them Diazonamide A, Diazonamide B, bis-phosphine platinum (II) complexes, Mycalolide A, (−)-Muscoride A. Eric Biron ''et al.'' developed a solid-phase synthesis of 1,3-oxazole-based peptides on solid phase from dipeptides by oxidation of the side-chain followed by Wipf and Miller's cyclodehydration of β-ketoamides described above. Lilly Research Laboratories has disclosed the structure of a described dual PPARα/γ agonist that has possible beneficial impact on type 2 diabetes. The Robinson-Gabriel cyclodehydration is the second part of a two reaction synthesis of the agonist. Starting with aspartic acid β esters undergoingacylation
In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent.
Because they form a strong electrophile when treated with ...
to differentiate the first substituent, linked to carbon-2, followed by Dakin-West conversion to keto-amide to introduce the second substituent, and ending with the Robinson-Gabriel cyclodehydration at 90°C for 30 minutes with either phosphorus oxychloride
Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from pho ...
in DMF or catalytic sulfuric acid in acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a col ...
.
References
{{DEFAULTSORT:Robinson-Gabriel synthesis Intramolecular condensation reactions Heterocycle forming reactions Name reactions