Oxazoline#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.{{cite journal|last=Wiley|first=Richard H.|author2=Bennett, Leonard L.|title=The Chemistry of the Oxazolines|journal=Chemical Reviews|volume=44|issue=3|pages=447–476|doi=10.1021/cr60139a002|year=1949|s2cid=95217957 }}{{cite journal|last=Frump|first=John A.|title=Oxazolines. Their preparation, reactions, and applications|journal=Chemical Reviews|volume=71|issue=5|pages=483–505|doi=10.1021/cr60273a003|year=1971}}{{cite journal|last=Gant|first=Thomas G.|author2=Meyers, A.I.|title=The chemistry of 2-oxazolines (1985–present)|journal=Tetrahedron|volume=50|issue=8|pages=2297–2360|doi=10.1016/S0040-4020(01)86953-2|year=1994}} The overall mechanism is usually subject to Baldwin's rules.

The usual route to oxazolines entails reaction 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.{{cite journal|last=Holerca|first=Marian N.|author2=Percec, Virgil|title=¹H NMR Spectroscopic Investigation of the Mechanism of 2-Substituted-2-Oxazoline Ring Formation and of the Hydrolysis of the Corresponding Oxazolinium Salts|journal=European Journal of Organic Chemistry|volume=2000|issue=12|pages=2257–2263|doi=10.1002/1099-0690(200006)2000:12<2257::AID-EJOC2257>3.0.CO;2-2|year=2000}} The reaction is typically performed at room temperature. If reagents milder than SOCl₂ are required, oxalyl chloride can be used.{{cite journal|last1=Evans|first1=David|title=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|journal=J. Org. Chem.|year=1998|volume=63|issue=13|pages=4541–4544|doi=10.1021/jo980296f|last2=Peterson|first2=Gretchen S.|last3=Johnson|first3=Jeffrey S.|last4=Barnes|first4=David M.|last5=Campos|first5=Kevin R.|last6=Woerpel|first6=Keith A.}} Aminomethyl propanol is a popular precursor amino alcohol.{{cite journal|title=2,2'-Dimethoxy-6-Formylbiphenyl|author=Albert I. Meyers |author2=Mark E. Flanagan |journal=Org. Synth.|year=1993|volume=71|page=107|doi=10.15227/orgsyn.071.0107}}{{cite journal |doi=10.15227/orgsyn.098.0117|title=Discussion Addendum for: Preparation of (S)-tert-ButylPy Ox and Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids|year=2021|last1=r. Sardini|first1=Stephen|first2=Brian M.|last2=Stoltz|journal=Organic Syntheses|volume=98|pages=117–130|pmid=36247231 |pmc=9558615 |s2cid=235855642 }}

::File:Oxaz-via-SOCl2-2.png

Modification of the Appel reaction allows for the synthesis of oxazoline rings.{{cite journal|last=Vorbrüggen|first=Helmut|author2=Krolikiewicz, Konrad|title=A simple synthesis of Δ2-oxazines, Δ2-oxazines, Δ2-thiazolines and 2-substituted benzoxazoles|journal=Tetrahedron|volume=49|issue=41|pages=9353–9372|doi=10.1016/0040-4020(93)80021-K|year=1993}} This method proceeds under relatively mild conditions, however, owing to the large amounts of triphenylphosphine oxide produced, 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.

:File:Oxaz-via-Appel2.png

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,{{cite journal|last=Schwekendiek|first=Kirsten|author2=Glorius, Frank|title=Efficient Oxidative Synthesis of 2-Oxazolines|journal=Synthesis|volume=2006|issue=18|pages=2996–3002|doi=10.1055/s-2006-950198|year=2006}} or iodine{{cite journal|last=Ishihara|first=Midori|author2=Togo, Hideo|title=Direct oxidative conversion of aldehydes and alcohols to 2-imidazolines and 2-oxazolines using molecular iodine|journal=Tetrahedron|volume=63|issue=6|pages=1474–1480|doi=10.1016/j.tet.2006.11.077|year=2007}}); 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.

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The use of catalytic amounts of ZnCl₂ to generate oxazolines from nitriles was first described by Witte and Seeliger,{{cite journal|last=Witte|first=Helmut|author2=Seeliger, Wolfgang|title=Simple Synthesis of 2-Substituted 2-Oxazolines and 5,6-Dihydro-4H-1,3-oxazines|journal=Angewandte Chemie International Edition in English|volume=11|issue=4|pages=287–288|doi=10.1002/anie.197202871|year=1972}}{{cite journal|last=Witte|first=Helmut|author2=Seeliger, Wolfgang|title=Cyclische Imidsäureester aus Nitrilen und Aminoalkoholen|journal=Justus Liebigs Annalen der Chemie|volume=1974|issue=6|pages=996–1009|doi=10.1002/jlac.197419740615|year=1974}} and further developed by Bolm et al.{{cite journal|last=Bolm|first=Carsten|author2=Weickhardt, Konrad |author3=Zehnder, Margareta |author4= Ranff, Tobias |title=Synthesis of Optically Active Bis(2-oxazolines): Crystal Structure of a 1,2-Bis(2-oxazolinyl)benzene ZnCl₂ Complex|journal=Chemische Berichte|volume=124|issue=5|pages=1173–1180|doi=10.1002/cber.19911240532|year=1991}} 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.{{Cite journal | doi = 10.1021/ic034070t| pmid = 12691592| title = Amidines Derived from Pt(IV)-Mediated Nitrile−Amino Alcohol Coupling and Their Zn(II)-Catalyzed Conversion into Oxazolines| journal = Inorganic Chemistry| volume = 42| issue = 8| pages = 2805–13| year = 2003| last1 = Makarycheva-Mikhailova | first1 = A. V. | last2 = Kukushkin | first2 = V. Y. | last3 = Nazarov | first3 = A. A. | last4 = Garnovskii | first4 = D. A. | last5 = Pombeiro | first5 = A. J. L. | last6 = Haukka | first6 = M. | last7 = Keppler | first7 = B. K. | last8 = Galanski | first8 = M. }}{{Cite journal | doi = 10.3987/S-1981-01-0361| title = 2-Oxazolines from Amides via Imidates| journal = Heterocycles| volume = 15| page = 361| year = 1981| last1 = i. Meyers | first1 = A. | last2 = Ann Hanagan | first2 = M. | last3 = l. Mazzu | first3 = A. | doi-access = free}} Limited research has been done into identifying alternative solvents or catalysts for the reaction.{{cite journal|last=Cornejo|first=A.|author2=Fraile, J. M. |author3=García, J. I. |author4=Gil, M. J. |author5=Martínez-Merino, V. |author6=Mayoral, J. A. |author7=Pires, E. |author8= Villalba, I. |title=An Efficient and General One-Pot Method for the Synthesis of Chiral Bis(oxazoline) and Pyridine Bis(oxazoline) Ligands|journal=Synlett|issue=15|pages=2321–2324|doi=10.1055/s-2005-872672|year=2005|hdl=10261/270962 |s2cid=95389965 |hdl-access=free }}{{cite journal|last1=Aspinall|first1=Helen C.|last2=Bacsa|first2=John|last3=Beckingham|first3=Oliver D.|last4=Eden|first4=Edward G. B.|last5=Greeves|first5=Nicholas|last6=Hobbs|first6=Matthew D.|last7=Potjewyd|first7=Frances|last8=Schmidtmann|first8=Marc|last9=Thomas|first9=Christopher D.|title=Adding the right (or left) twist to tris-chelate complexes – coordination chemistry of chiral oxazolylphenolates with M3+ ions (M = Al or lanthanide) |journal=Dalton Trans.|date=2014|volume=43|issue=3|pages=1434–1442|doi=10.1039/C3DT52366G|pmid=24201227|url=http://www.rsc.org/suppdata/dt/c3/c3dt52366g/c3dt52366g.pdf}} See the Supplementary Information for details

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{{Main|Bisoxazoline ligand}}

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.{{cite journal|last=McManus|first=Helen A.|author2=Guiry, Patrick J.|title=Recent Developments in the Application of Oxazoline-Containing Ligands in Asymmetric Catalysis|journal=Chemical Reviews|volume=104|issue=9|pages=4151–4202|doi=10.1021/cr040642v|pmid=15352789|year=2004}}{{cite journal|last=Hargaden|first=Gráinne C.|author2=Guiry, Patrick J.|title=Recent Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis|journal=Chemical Reviews|volume=109|issue=6|pages=2505–2550|doi=10.1021/cr800400z|pmid=19378971|year=2009}}

2-Substituted oxazolines 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{{cite journal|last=Loo|first=Yim Fun|author2=O'Kane, Ruairi |author3=Jones, Anthony C. |author4=Aspinall, Helen C. |author5=Potter, Richard J. |author6=Chalker, Paul R. |author7=Bickley, Jamie F. |author8=Taylor, Stephen |author9= Smith, Lesley M. |title=Deposition of HfO₂ and ZrO₂ films by liquid injection MOCVD using new monomeric alkoxide precursors|journal=Journal of Materials Chemistry|year=2005|volume=15|issue=19|page=1896|doi=10.1039/B417389A}} and resistant to nucleophiles, bases, radicals, and weak acids{{cite book|last=Greene|first=T. W.|title=Protective groups in organic synthesis, 2nd ed.|url=https://archive.org/details/protectivegroups00gree_079|url-access=limited|year=1991|publisher=Wiley|location=New York|pages=[https://archive.org/details/protectivegroups00gree_079/page/n101 265]–266 & 433–436}} 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) for example (S)-iPr-PHOX

Notable specialist oxazoline ligands include:

• Tris-oxazolines (TRISOX)
• Bis(oxazolinato)s
• Trisoxazolinylborate ligands

Some 2-oxazolines, such as 2-ethyl-2-oxazoline, undergo living cationic ring-opening polymerisation to form poly(2-oxazoline)s.{{cite journal|last=Kobayashi|first=Shiro|author2=Uyama, Hiroshi|title=Polymerization of cyclic imino ethers: From its discovery to the present state of the art|journal=Journal of Polymer Science Part A: Polymer Chemistry|date=15 January 2002|volume=40|issue=2|pages=192–209|doi=10.1002/pola.10090|bibcode=2002JPoSA..40..192K|doi-access=free}} These are polyamides and can be regarded as analogues of peptides; they have numerous potential applications{{cite journal|last=Hoogenboom|first=Richard|title=Poly(2-oxazoline)s: A Polymer Class with Numerous Potential Applications|journal=Angewandte Chemie International Edition|date=12 October 2009|volume=48|issue=43|pages=7978–7994|doi=10.1002/anie.200901607|pmid=19768817}} and have received particular attention for their biomedical uses.{{cite journal|last=Adams|first=Nico|author2=Schubert, Ulrich S.|title=Poly(2-oxazolines) in biological and biomedical application contexts|journal=Advanced Drug Delivery Reviews|date=1 December 2007|volume=59|issue=15|pages=1504–1520|doi=10.1016/j.addr.2007.08.018|pmid=17904246|url=http://www.dspace.cam.ac.uk/handle/1810/194887}}{{cite journal|last=Kelly|first=Andrew M|author2=Wiesbrock, Frank|title=Strategies for the Synthesis of Poly(2-Oxazoline)-Based Hydrogels|journal=Macromolecular Rapid Communications|date=15 October 2012|volume=33|issue=19|pages=1632–1647|doi=10.1002/marc.201200333|pmid=22811405}}

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The dimethyloxazoline (DMOX) derivatives of fatty acids are amenable to analysis by gas chromatography.

{{Also|Protecting groups}}

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

{{reflist|30em}}