Oxazoline

Oxazoline is a five-membered heterocyclic chemical compound containing one atom each of oxygen and nitrogen. It was likely first synthesized in 1884 but it was not until 5 years later that Siegmund Gabriel correctly assigned the structure. It was named in-line with the Hantzsch–Widman nomenclature and is part of a family of heterocyclic compounds, where it exists between oxazole and oxazolidine in terms of saturation.A fourth isomer exists in which the O and N atoms are adjacent, this is known as isoxazoline. Oxazoline is a five-membered heterocyclic chemical compound containing one atom each of oxygen and nitrogen. It was likely first synthesized in 1884 but it was not until 5 years later that Siegmund Gabriel correctly assigned the structure. It was named in-line with the Hantzsch–Widman nomenclature and is part of a family of heterocyclic compounds, where it exists between oxazole and oxazolidine in terms of saturation. Oxazoline itself has no current applications however compounds containing the ring, which are referred to as oxazolines or oxazolyls, have a wide variety of uses; particularly as ligands in asymmetric catalysis, as protecting groups for carboxylic acids and increasingly as monomers for the production of polymers. The synthesis of 2-oxazoline rings is well established and in general proceeds via the cyclisation of a 2-amino alcohol (typically obtained by the reduction of an amino acid) with a suitable functional group. The overall mechanism is usually subject to Baldwin's rules. A routine route to oxazolines entails reactions of acyl chlorides with 2-amino alcohols. Thionyl chloride is commonly used to generate the acid chloride in situ, care being taken to maintain anhydrous conditions, as oxazolines can be ring-opened by chloride if the imine becomes protonated. The reaction is typically performed at room temperature. If reagents milder than SOCl2 are required, oxalyl chloride can be used. Aminomethyl propanol is the classical precursor to oxazolines using acid chloride method. As applied to fatty acids, the resulting dimethyloxazoline (DMOX) derivatives are amenable to analysis by gas chromatography. Modification of the Appel reaction allows for the synthesis of oxazoline rings. This method proceeds under relatively mild room temperature conditions, however, owing to the large amounts of triphenylphosphine oxide produced, the method is not ideal for large-scale reactions. The use of this method is becoming less common, due to carbon tetrachloride being restricted under the Montreal protocol. The cyclisation of an amino alcohol and an aldehyde produces an intermediate oxazolidine which can be converted to an oxazoline by treatment with a halogen-based oxidising agent (e.g. NBS, or iodine); this potentially proceeds via an imidoyl halide. The method has been shown to be effective for a wide range of aromatic and aliphatic aldehydes however electron rich aromatic R groups, such as phenols, are unsuitable as they preferentially undergo rapid electrophilic aromatic halogenation with the oxidising agent. The use of catalytic amounts of ZnCl2 to generate oxazolines from nitriles was first described by Witte and Seeliger, and further developed by Bolm et al. The reaction requires high temperatures to succeed and is typically performed in refluxing chlorobenzene under anhydrous conditions. A precise reaction mechanism has never been proposed, although it is likely similar to the Pinner reaction; preceding via an intermediate amidine. Limited research has been done into identifying alternative solvents or catalysts for the reaction. Ligands containing a chiral 2-oxazoline ring are used in asymmetric catalysis due to their facile synthesis, wide range of forms and effectiveness for many types of catalytic transformation.