Oxazoline

Oxazoline

Names
IUPAC name 2-oxazoline
Systematic IUPAC name 4,5-dihydrooxazole
Other names Δ2-oxazoline
Identifiers
CAS Number	504-77-8 (2-oxazoline) N 95879-85-9 (3-oxazoline) N 6569-13-7 (4-oxazoline) N
ChemSpider	61465 Y
Jmol 3D model	Interactive image
PubChem	68157
InChI InChI=1S/C3H5NO/c1-2-5-3-4-1/h3H,1-2H2 Y Key: IMSODMZESSGVBE-UHFFFAOYSA-N Y
SMILES N\1=C\OCC/1
Properties
Chemical formula	C3H5NO
Molar mass	71.08 g·mol−1
Density	1.075
Boiling point	98 °C (208 °F; 371 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Oxazoline is a five-membered heterocyclic chemical compound containing one atom each of oxygen and nitrogen. It was first characterised in 1889 and was named in-line with the Hantzsch–Widman nomenclature. It 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.

Isomers

2‑oxazoline, 3‑oxazoline, and 4‑oxazoline (from left to right)

Three structural isomers of oxazoline are possible depending on the location of the double bond, however only 2‑oxazolines are common. 4‑Oxazolines are formed as intermediates during the production of certain azomethine ylides but are otherwise rare. 3‑Oxazolines are even less common but have been synthesised photochemically and by the ring opening of azirines. These three forms do not readily interconvert and hence are not tautomers.

Synthesis

The synthesis of 2-oxazoline rings is well established and has been the topic of several literature reviews (most notably in 1949, 1971, and 1994). In general the synthesis proceeds via the cyclisation of a 2-amino alcohol (typically obtained by the reduction of amino acids) with a suitable functional group; the mechanism of which is subject to Baldwin's rules. Many methods exist for doing this however the current literature is dominated by 4 main processes:

From carboxylic acids using thionyl chloride

Owing to its simplicity and general reliability SOCl₂ is one of the most commonly used reagents for the synthesis of oxazoline rings, however it is often necessary 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 and is a rare example of a carbonyl oxygen acting as a nucleophile and is similar to the Robinson–Gabriel synthesis. If milder regents are required then SOCl₂ may be replaced with oxalyl chloride.

From carboxylic acids using the Appel reaction

Modification of the classic 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, it is unsuitable for large scale reactions. The use of this method is becoming less common, due to carbon tetrachloride being restricted under the Montreal protocol.

From aldehydes via oxazolidines

The cyclisation of an amino alcohol and an aldehyde produces an oxazolidine, this can be converted to an oxazoline by treatment with a strong halogen-based oxidising agent (examples include: NBS, pyridinium tribromide, 1,3-diiodo-5,5-dimethylhydantoin (DIH), and iodine,). This method has been shown to be effective for a wide range of aromatic and aliphatic aldehydes; however electron rich aromatic compounds, such as phenols, are unsuitable as they preferentially undergo rapid electrophilic aromatic halogenation with the oxidising agent.

From nitriles using the Witte Seeliger reaction (ZnCl₂)

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

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.

2-Substituted oxazolines can be prepared by many methods and possess a moderately hard N-donor. Chirality is easily incorporated by using 2-amino alcohols prepared by the reduction of amino acids; which are both optically pure and inexpensive. As the stereocentre in such oxazolines is adjacent to the coordinating N-atom, it can influence the selectivity of processes occurring at the metal centre. The ring is thermally stable and resistant to nucleophiles, bases, radicals, and weak acids as well as being fairly resistant to hydrolysis and oxidation; thus it can be expected to remain stable in a wide range of reaction conditions.

Major classes of oxazoline based ligand include:

• Bis-oxazolines (BOX)
• Phosphinooxazolines (PHOX)
• Tris-oxazolines (TRISOX)

Notable specialist oxazoline ligands include:

• Phenol-oxazolines
• Bis(oxazolinato)s
• Trisoxazolinylborate ligands

Polymers

2-Oxazolines can undergo living cationic ring-opening polymerisation to form poly(2-oxazoline)s. These are polyamides and can be regarded as analogues of peptides; they have numerous potential applications and have received particular attention for their biomedical uses.

See also

Structural analogues

• Benzoxazole: where the oxazoline is fused onto a benzene ring.
• Oxazole: which has two double bonds
• Oxazolidine: which has no double bonds
• Thiazoline: where the oxygen is replaced by sulphur

Other pages

• Aminorex a drug bearing an oxazoline ring
• Asinger reaction an alternative method of synthesis