Oxazoline

Oxazoline
Names
IUPAC name
2-oxazoline
Systematic IUPAC name
4,5-dihydrooxazole
Other names
Δ2-oxazoline
Identifiers
504-77-8 (2-oxazoline) 
95879-85-9 (3-oxazoline) 
6569-13-7 (4-oxazoline) 
ChemSpider 61465 Yes
Jmol-3D images Image
PubChem 68157
Properties
Molecular formula
 C3H5NO
Molar mass 71.08 g·mol−1
Density 1.075 [1]
Boiling point 98 °C (208 °F; 371 K)[1]
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
  verify (what is: Yes/?)
Infobox references

Oxazoline is a five-membered heterocyclic chemical compound containing one atom each of oxygen and nitrogen. It was first characterised in 1889[2] 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[3] but are otherwise rare. 3‑Oxazolines are even less common but have been synthesised photochemically[4] and by the ring opening of azirines.[5] 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,[6] 1971,[7] and 1994[8]). 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.[9] 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.[10]

From carboxylic acids using the Appel reaction

Modification of the classic reaction allows for the synthesis of oxazoline rings.[11] 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,[12] pyridinium tribromide,[13] 1,3-diiodo-5,5-dimethylhydantoin (DIH),[14] and iodine,[15]). 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,[16][17] and further developed by Bolm et al.[18] 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.[19][20] Limited research has been done into identifying alternative solvents or catalysts for the reaction.[21]

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.[22][23]

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[24] and resistant to nucleophiles, bases, radicals, and weak acids[25] as well as being fairly resistant to hydrolysis and oxidation;[26] thus it can be expected to remain stable in a wide range of reaction conditions.

Major classes of oxazoline based ligand include:

Notable specialist oxazoline ligands include:

Polymers

2-Oxazolines can undergo living cationic ring-opening polymerisation to form poly(2-oxazoline)s.[27] These are polyamides and can be regarded as analogues of peptides; they have numerous potential applications[28] and have received particular attention for their biomedical uses.[29][30]

See also

Structural analogues

Other pages

References

  1. ↑ 1.0 1.1 Wenker, 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. doi:10.1021/ja01276a036.
  2. ↑ Gabriel, S. (1889). "Zur Kenntniss des Bromäthylamins". Berichte der deutschen chemischen Gesellschaft 22 (1): 1139–1154. doi:10.1002/cber.188902201248.
  3. ↑ 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. doi:10.1021/ja00218a038.
  4. ↑ 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.
  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. PMID 11667224.
  6. ↑ Wiley, Richard H.; Bennett, Leonard L. (1949). "The Chemistry of the Oxazolines". Chemical Reviews 44 (3): 447–476. doi:10.1021/cr60139a002.
  7. ↑ Frump, John A. (1971). "Oxazolines. Their preparation, reactions, and applications". Chemical Reviews 71 (5): 483–505. doi:10.1021/cr60273a003.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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-oxazolinyl]]propane [(S,S)-tert-Butylbis(oxazoline)] and Derived Copper(II) Complexes". J. Org. Chem 63 (13): 4541–4544. doi:10.1021/jo980296f.
  11. ↑ 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.
  12. ↑ Schwekendiek, Kirsten; Glorius, Frank (2006). "Efficient Oxidative Synthesis of 2-Oxazolines". Synthesis 2006 (18): 2996–3002. doi:10.1055/s-2006-950198.
  13. ↑ Sayama, Shinsei (2006). "A Convenient Synthesis of Oxazolines and Imidazolines from Aromatic Aldehydes with Pyridinium Hydrobromide Perbromide in Water". Synlett 2006 (10): 1479–1484. doi:10.1055/s-2006-941597.
  14. ↑ Takahashi, Shogo; Togo, Hideo (2009). "An Efficient Oxidative Conversion of Aldehydes into 2-Substituted 2-Oxazolines Using 1,3-Diiodo-5,5-dimethylhydantoin". Synthesis 2009 (14): 2329–2332. doi:10.1055/s-0029-1216843.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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. doi:10.1021/ic034070t.
  20. ↑ i. Meyers, A.; Ann Hanagan, M.; l. Mazzu, A. (1981). "2-Oxazolines from Amides via Imidates". Heterocycles 15: 361. doi:10.3987/S-1981-01-0361.
  21. ↑ 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.
  22. ↑ 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. PMID 15352789.
  23. ↑ 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. PMID 19378971.
  24. ↑ 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.
  25. ↑ Greene, T. W. (1991). Protective groups in organic synthesis, 2nd ed. New York: Wiley. pp. 265–266 & 433–436.
  26. ↑ Wiley, Richard H.; Bennett, Leonard L. (1949). "The Chemistry of the Oxazolines". Chemical Reviews 44 (3): 447–476. doi:10.1021/cr60139a002.
  27. ↑ Kobayashi, Shiro; Uyama, Hiroshi (15 January 2002). "Polymerization of cyclic imino ethers: From its discovery to the present state of the art". Journal of Polymer Science Part A: Polymer Chemistry 40 (2): 192–209. Bibcode:2002JPoSA..40..192K. doi:10.1002/pola.10090.
  28. ↑ 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.
  29. ↑ Adams, Nico; Schubert, Ulrich S. (1 December 2007). "Poly(2-oxazolines) in biological and biomedical application contexts". Advanced Drug Delivery Reviews 59 (15): 1504–1520. doi:10.1016/j.addr.2007.08.018. PMID 17904246.
  30. ↑ 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. PMID 22811405.