Robinson–Gabriel synthesis

Recently, a solid-phase version of the Robinson–Gabriel synthesis has been described. The reaction requires trifluoroacetic anhydride to be used as the cyclodehydrating agent in ethereal solvent and the 2-acylamidoketone be linked by the nitrogen atom to a benzhydrylic-type linker.{{cite journal |last1=Pulici |first1=M. |last2=Quartieri |first2=F |last3=Felder |first3=E.R. |date=April 13, 2005 |title=Trifluoroacetic Anhydride-Mediated Solid-Phase Version of the Robinson-Gabriel Synthesis of Oxazoles|journal=J. Comb. Chem. |volume=7 |issue=3 |pages=463–473 |doi=10.1021/cc049831h |pmid=15877475}}

File:Friedel-Crafts and Robinson-Gabriel Synthesis.gif

A one-pot diversity-oriented synthesis has been developed via a Friedel-Crafts/Robinson–Gabriel synthesis using a general oxazolone template. The combination of aluminum chloride as the Friedel–Crafts Lewis acid and trifluoromethanesulfonic acid as the Robinson-Gabriel cyclodehydrating agent were determined to generate the desired products.{{cite journal |last1=Keni |first1=M. |last2=Tepe |first2=J.J. |date=April 9, 2005 |title=One-Pot Friedel-Crafts/Robinson-Gabriel Synthesis of Oxazoles using Oxazolone Templates |journal=J. Org. Chem. |volume=70 |issue=10 |pages=4211–4213 |doi=10.1021/jo0501590 |pmid=15876123}}

A popular extension of the Robinson-Gabriel cyclodehydration has been reported by Wipf et al. to allow the synthesis of substituted oxazoles from readily available amino acid derivatives. This is achieved through the side-chain oxidation of β-keto amides with the Dess-Martin reagent followed by the cyclodehydration of intermediate β-keto amides with triphenylphosphine, iodine, and triethylamine.{{cite journal |last1=Wipf |first1=P. |last2=Miller |first2=C.P. |date=April 6, 1993 |title=A New Synthesis of Highly Functionalized Oxazoles |journal=J. Org. Chem. |volume=58 |issue=14 |pages=3604–3606 |doi=10.1021/jo00066a004}}

Additionally, a coupled Ugi and Robinson–Gabriel synthesis has been reported, beginning with the Ugi reagents and ending with an oxazole core within the molecule. The oxazole is formed from the Ugi intermediate, which is ideal to undergo Robinson-Gabriel cyclodehydration with sulfuric acid.{{cite journal |last1= Shaw |first1= A. Y. |last2= Xu |first2= Z. |last3= Hulme |first3= C. |year= 2012 |title= Ugi,Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles|journal= Tetrahedron Lett. |volume= 53 |pages= 1998–2000 |doi=10.1016/j.tetlet.2012.02.030 |issue= 15 |pmid= 23559684 |pmc= 3613284}}

Many cyclodehydrating agents have been discovered to be of use in the Robinson–Gabriel synthesis. Historically, the dehydration agent is concentrated sulfuric acid. To date, the reaction has been shown to proceed with a variety of other agents including phosphorus pentachloride, phosphorus pentoxide, phosphoryl chloride, thionyl chloride, phosphoric acid-acetic anhydride, polyphosphoric acid, and hydrogen fluoride among others.{{cite book |last=Turchi |first=I. |date=Sep 15, 2009 |title=The Chemistry of Heterocyclic Compounds, Oxazoles |doi=10.1002/9780470187289 |isbn= 9780471869580|publisher= John Wiley & Sons |pages= 3|series=Chemistry of Heterocyclic Compounds: A Series of Monographs |volume=45 |hdl=2027/mdp.39015078685115 }}

Oxazoles have been found to be common substructures in multiple naturally isolated compounds and have thus garnered attention within the chemical and pharmaceutical community. The Robinson–Gabriel synthesis has been used during multiple studies dealing with molecules that incorporate an oxazole, among them diazonamide A,{{cite journal |last1=Nicolaou |first1=K.C. |last2=Hao |first2=J. |last3=Reddy |first3=M.V. |last4=Rao |first4=P.B. |last5=Rassias |first5=G. |last6=Snyder |first6=S.A. |last7=Huang |first8=D.Y.-K. |last8=Chen |last9=Brenzovich |first9=W.E. |last10=Giuseppone |first10=N. |last11=Giannakakou |first11= P. |last12=O'Brate |first12=Aurora |date=September 18, 2004 |title=Chemistry and Biology of Diazonamide A: Second Total Synthesis and Biological Investigation |journal=J. Am. Chem. Soc. |volume=126 |issue=40 |pages=12897–12906 |doi=10.1021/ja040093a |first7=Xianhai |pmid=15469287}} diazonamide B,{{cite journal |last1=Zhang |first1=J |last2=Ciufolini |first2=M.A. |year=2011 |title=An Approach to the Bis-oxazole Macrocycle of Diazonamides |journal= Org. Lett. |volume=13 |issue=3 |pages=390–393 |doi=10.1021/ol102678j |pmid=21174393}} bis-phosphine platinum (II) complexes,{{cite journal |last1=Kindahl |first1=T |last2=Ellingsen |first2=P.G. |last3=Lopes |first3=C. |last4=Brannlund |first4=C. |last5=Lindgren |first5=M. |last6=Eliasson |first6=Bertil |year= 2012 |title=Photophysical and DTF Characterization of Novel Pt(II)-coupled 2,5-Diaryloxazoles from Nonlinear Optical Absorption |journal= J. Phys. Chem. A |volume=116 |issue=47 |pages=11519–11530 |doi=10.1021/jp307312v |pmid=23102256|bibcode=2012JPCA..11611519K}} mycalolide A,{{cite journal |last1=Hoffman |first1=T.J. |last2=Kolleth |first2=A. |last3=Rigby |first3=J.H. |last4=Arseniyadis |first4=S. |last5=Cossy |first5=J. |year= 2010 |title=Stereoselective Synthesis of the C1-C11 and C12-C34 Fragments of Mycalolide A |journal=Org. Lett. |volume=12 |issue=15 |pages=3348–3351 |doi=10.1021/ol101145t |pmid=20670003}} (−)-muscoride A.{{cite journal |last1=Wipf |first1=P. |last2=Venkatraman |first2=S. |year=1996 |title=Total Synthesis of (−)-Muscoride A |journal=J. Org. Chem. |volume=61 |issue=19 |pages=6517–6522 |doi=10.1021/jo960891m |pmid=11667514}}

Eric Biron et al. developed a solid-phase synthesis of 1,3-oxazole-based peptides on solid phase from dipeptides by oxidation of the side-chain followed by Wipf and Miller's cyclodehydration of β-ketoamides described above.{{cite journal |last1=Biron |first1=E. |last2=Chatterjee |first2=J. |last3=Kessler |first3=H |year=2006 |title=Solid-Phase Synthesis of 1,3-Azole-Based Peptides and Peptidomimetics |journal=Org. Lett. |volume=8 |issue=11 |pages=2417–2420 |doi=10.1021/ol0607645 |pmid=16706540}}

Lilly Research Laboratories has disclosed the structure of a described dual PPARα/γ agonist that has possible beneficial impact on type 2 diabetes. The Robinson-Gabriel cyclodehydration is the second part of a two reaction synthesis of the agonist. Starting with aspartic acid β esters undergoing acylation to differentiate the first substituent, linked to carbon-2, followed by Dakin-West conversion to keto-amide to introduce the second substituent, and ending with the Robinson-Gabriel cyclodehydration at 90°C for 30 minutes with either phosphorus oxychloride in dimethylformamide or catalytic sulfuric acid in acetic anhydride.{{cite journal |last1=Godfrey |first1=A.G. |last2=Brooks |first2=D.A. |last3=Hay |first3=L.A. |last4=Peters |first4=M. |last5=McCarthy |first5=J.R. |last6=Mitchell |first6=D. |year=2003 |title=Application of the Dakin-West Reaction for the Synthesis of Oxazole-Containing Dual PPARα/γ Agonist |journal=J. Org. Chem. |volume=68 |issue=7 |pages=2623–2632 |doi=10.1021/jo026655v |pmid=12662031}}

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