Oxazoline is a five-membered heterocyclic organic compound with the formula . It is the parent of a family of compounds called oxazolines (emphasis on plural), which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are the unsaturated analogues of , and they are isomeric with , where the N and O are directly bonded. Two isomers of oxazoline are known, depending on the location of the double bond.
Oxazoline itself has no applications however oxazolines have been widely investigated for potential applications. These applications include use as in asymmetric catalysis, as protecting groups for and increasingly as for the production of .
Isomers
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| | 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
A fourth isomer exists in which the O and N atoms are adjacent, this is known as isoxazoline. |
Synthesis
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.
From carboxylic acids
The usual route to oxazolines entails reaction of
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 SOCl
2 are required,
oxalyl chloride can be used.
Aminomethyl propanol is a popular precursor amino alcohol.
- :
Modification of the Appel reaction allows for the synthesis of oxazoline rings.
From aldehydes
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
Oxidizing agent (e.g. NBS,
or
iodine); this potentially proceeds via an
imidoyl chloride. 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.
From nitriles
The use of catalytic amounts of ZnCl
2 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.
[ See the Supplementary Information for details]
Applications
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 possess a moderately HSAB theory N-donor. Chirality is easily incorporated by using 2- 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
Major classes of oxazoline based ligand include:
-
Bis-oxazolines (BOX)
-
Phosphinooxazolines (PHOX) for example (S)-iPr-PHOX
Notable specialist oxazoline ligands include:
Polymers
Some 2-oxazolines, such as 2-ethyl-2-oxazoline, 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.
Analysis of fatty acids
The dimethyloxazoline (
DMOX) derivatives of fatty acids are amenable to analysis by gas chromatography.
Protecting groups
Oxazolines are a rare protecting group for
esters.
See also
Structural analogues
Other pages
-
Aminorex a drug bearing an oxazoline ring
