Oxazoline is a five-memberedheterocyclicorganic compound with the formulaC3H5NO. It is the parent of a family of compounds calledoxazolines (emphasis on plural), which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are the unsaturated analogues ofoxazolidines, and they are isomeric withisoxazolines, where the N and O are directly bonded. Two isomers of oxazoline are known, depending on the location of the double bond.
2‑oxazoline, 3‑oxazoline, and 4‑oxazoline (from left to right)
Threestructural 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 certainazomethine ylides[2] but are otherwise rare. 3‑Oxazolines are even less common but have been synthesisedphotochemically[3] and by the ring opening ofazirines.[4] These three forms do not readily interconvert and hence are nottautomers.
A fourth isomer exists in which the O and N atoms are adjacent, this is known asisoxazoline.
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 anamino acid) with a suitable functional group.[5][6][7] The overall mechanism is usually subject toBaldwin's rules.
The usual route to oxazolines entails reaction ofacyl 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 bychloride if theimine becomes protonated.[8] The reaction is typically performed at room temperature. If reagents milder than SOCl2 are required,oxalyl chloride can be used.[9]Aminomethyl propanol is a popular precursor amino alcohol.[10][11]
Modification of theAppel reaction allows for the synthesis of oxazoline rings.[12] This method proceeds under relatively mild conditions, however, owing to the large amounts oftriphenylphosphine oxide produced, is not ideal for large-scale reactions. The use of this method is becoming less common, due tocarbon tetrachloride being restricted under theMontreal Protocol.
The cyclisation of an amino alcohol and analdehyde produces an intermediateoxazolidine which can be converted to an oxazoline by treatment with a halogen-basedoxidising agent (e.g.NBS,[13] oriodine[14]); this potentially proceeds via animidoyl halide. The method has been shown to be effective for a wide range ofaromatic andaliphatic aldehydes however electron rich aromatic R groups, such asphenols, are unsuitable as they preferentially undergo rapidelectrophilic aromatic halogenation with the oxidising agent.
The use of catalytic amounts ofZnCl2 to generate oxazolines fromnitriles was first described by Witte and Seeliger,[15][16] and further developed by Bolmet al.[17] The reaction requires high temperatures to succeed and is typically performed in refluxingchlorobenzene underanhydrous conditions. A precise reaction mechanism has never been proposed, although it is likely similar to thePinner reaction; preceding via an intermediateamidine.[18][19] Limited research has been done into identifying alternative solvents or catalysts for the reaction.[20][21]
Ligands containing a chiral 2-oxazoline ring are used inasymmetric catalysis due to their facile synthesis, wide range of forms and effectiveness for many types of catalytic transformation.[22][23]
2-Substituted oxazolines possess a moderatelyhard N-donor.Chirality is easily incorporated by using 2-amino alcohols prepared by the reduction ofamino 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[24] and resistant to nucleophiles, bases, radicals, and weak acids[25] as well as being fairly resistant to hydrolysis and oxidation;[5] thus it can be expected to remain stable in a wide range of reaction conditions.
^abWenker, H. (1938). "Syntheses from Ethanolamine. V. Synthesis of Δ2-Oxazoline and of 2,2'-Δ2-Dioxazoline".Journal of the American Chemical Society.60 (9):2152–2153.Bibcode:1938JAChS..60.2152W.doi:10.1021/ja01276a036.
^Vedejs, E.; Grissom, J. W. (1988). "4-Oxazoline route to stabilized azomethine ylides. Controlled reduction of oxazolium salts".Journal of the American Chemical Society.110 (10):3238–3246.Bibcode:1988JAChS.110.3238V.doi:10.1021/ja00218a038.
^Armesto, Diego; Ortiz, Maria J.; Pérez-Ossorio, Rafael; Horspool, William M. (1983). "A novel photochemical 1,2-acyl migration in an enol ester. The synthesis of 3-oxazoline derivatives".Tetrahedron Letters.24 (11):1197–1200.doi:10.1016/S0040-4039(00)86403-5.
^Sá, Marcus C. M.; Kascheres, Albert (1996). "Electronically Mediated Selectivity in Ring Opening of 1-Azirines. The 3-X Mode: Convenient Route to 3-Oxazolines".The Journal of Organic Chemistry.61 (11):3749–3752.doi:10.1021/jo9518866.PMID11667224.
^abWiley, Richard H.; Bennett, Leonard L. (1949). "The Chemistry of the Oxazolines".Chemical Reviews.44 (3):447–476.doi:10.1021/cr60139a002.S2CID95217957.
^Frump, John A. (1971). "Oxazolines. Their preparation, reactions, and applications".Chemical Reviews.71 (5):483–505.doi:10.1021/cr60273a003.
^Gant, Thomas G.; Meyers, A.I. (1994). "The chemistry of 2-oxazolines (1985–present)".Tetrahedron.50 (8):2297–2360.doi:10.1016/S0040-4020(01)86953-2.
^Holerca, Marian N.; Percec, Virgil (2000). "1H NMR Spectroscopic Investigation of the Mechanism of 2-Substituted-2-Oxazoline Ring Formation and of the Hydrolysis of the Corresponding Oxazolinium Salts".European Journal of Organic Chemistry.2000 (12):2257–2263.doi:10.1002/1099-0690(200006)2000:12<2257::AID-EJOC2257>3.0.CO;2-2.
^Evans, David; Peterson, Gretchen S.; Johnson, Jeffrey S.; Barnes, David M.; Campos, Kevin R.; Woerpel, Keith A. (1998). "An Improved Procedure for the Preparation of 2,2-Bis[2-[4(S)- tert-butyl-1,3-oxazolinylpropane [(S,S)-tert-Butylbis(oxazoline)] and Derived Copper(II) Complexes".J. Org. Chem.63 (13):4541–4544.doi:10.1021/jo980296f.
^Albert I. Meyers; Mark E. Flanagan (1993). "2,2'-Dimethoxy-6-Formylbiphenyl".Org. Synth.71: 107.doi:10.15227/orgsyn.071.0107.
^Vorbrüggen, Helmut; Krolikiewicz, Konrad (1993). "A simple synthesis of Δ2-oxazines, Δ2-oxazines, Δ2-thiazolines and 2-substituted benzoxazoles".Tetrahedron.49 (41):9353–9372.doi:10.1016/0040-4020(93)80021-K.
^Schwekendiek, Kirsten; Glorius, Frank (2006). "Efficient Oxidative Synthesis of 2-Oxazolines".Synthesis.2006 (18):2996–3002.doi:10.1055/s-2006-950198.
^Ishihara, Midori; Togo, Hideo (2007). "Direct oxidative conversion of aldehydes and alcohols to 2-imidazolines and 2-oxazolines using molecular iodine".Tetrahedron.63 (6):1474–1480.doi:10.1016/j.tet.2006.11.077.
^Witte, Helmut; Seeliger, Wolfgang (1972). "Simple Synthesis of 2-Substituted 2-Oxazolines and 5,6-Dihydro-4H-1,3-oxazines".Angewandte Chemie International Edition in English.11 (4):287–288.doi:10.1002/anie.197202871.
^Witte, Helmut; Seeliger, Wolfgang (1974). "Cyclische Imidsäureester aus Nitrilen und Aminoalkoholen".Justus Liebigs Annalen der Chemie.1974 (6):996–1009.doi:10.1002/jlac.197419740615.
^Bolm, Carsten; Weickhardt, Konrad; Zehnder, Margareta; Ranff, Tobias (1991). "Synthesis of Optically Active Bis(2-oxazolines): Crystal Structure of a 1,2-Bis(2-oxazolinyl)benzene ZnCl2 Complex".Chemische Berichte.124 (5):1173–1180.doi:10.1002/cber.19911240532.
^Makarycheva-Mikhailova, A. V.; Kukushkin, V. Y.; Nazarov, A. A.; Garnovskii, D. A.; Pombeiro, A. J. L.; Haukka, M.; Keppler, B. K.; Galanski, M. (2003). "Amidines Derived from Pt(IV)-Mediated Nitrile−Amino Alcohol Coupling and Their Zn(II)-Catalyzed Conversion into Oxazolines".Inorganic Chemistry.42 (8):2805–13.doi:10.1021/ic034070t.PMID12691592.
^Cornejo, A.; Fraile, J. M.; García, J. I.; Gil, M. J.; Martínez-Merino, V.; Mayoral, J. A.; Pires, E.; Villalba, I. (2005). "An Efficient and General One-Pot Method for the Synthesis of Chiral Bis(oxazoline) and Pyridine Bis(oxazoline) Ligands".Synlett (15):2321–2324.doi:10.1055/s-2005-872672.hdl:10261/270962.S2CID95389965.
^McManus, Helen A.; Guiry, Patrick J. (2004). "Recent Developments in the Application of Oxazoline-Containing Ligands in Asymmetric Catalysis".Chemical Reviews.104 (9):4151–4202.doi:10.1021/cr040642v.PMID15352789.
^Hargaden, Gráinne C.; Guiry, Patrick J. (2009). "Recent Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis".Chemical Reviews.109 (6):2505–2550.doi:10.1021/cr800400z.PMID19378971.
^Loo, Yim Fun; O'Kane, Ruairi; Jones, Anthony C.; Aspinall, Helen C.; Potter, Richard J.; Chalker, Paul R.; Bickley, Jamie F.; Taylor, Stephen; Smith, Lesley M. (2005). "Deposition of HfO2 and ZrO2 films by liquid injection MOCVD using new monomeric alkoxide precursors".Journal of Materials Chemistry.15 (19): 1896.doi:10.1039/B417389A.
^Hoogenboom, Richard (12 October 2009). "Poly(2-oxazoline)s: A Polymer Class with Numerous Potential Applications".Angewandte Chemie International Edition.48 (43):7978–7994.doi:10.1002/anie.200901607.PMID19768817.
^Kelly, Andrew M; Wiesbrock, Frank (15 October 2012). "Strategies for the Synthesis of Poly(2-Oxazoline)-Based Hydrogels".Macromolecular Rapid Communications.33 (19):1632–1647.doi:10.1002/marc.201200333.PMID22811405.
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