Aza Diels-Alder Reaction of N-Arylimines with Pyruvate Derivatives:

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Aza Diels-Alder Reaction of N-Arylimines with Pyruvate Derivatives: A Route to 2-Phenyl-Quinoline-4-Carboxylates and 2-Phenyl-Quinoline-4-Carboxamides Dorothée Duvelleroy, Cécile Perrio, Marie-Claire Lasne Laboratoire de Chimie Moléculaire et Thio-organique, UMR CNRS 6507, ENSICAEN and University of Caen-Basse-Normandie, 6 Boulevard du Maréchal Juin, 14050 CAEN cedex E.mail: duvelleroy@ismra.fr Research for a rapid synthesis of 2-phenylquinoline 4-carboxylic derivatives: starting from easily available precursors adaptable for the development of radioligands of NK-3 receptors, analogues of the selective antagonist Talnetant for medical imaging using positron emission tomography. Bennacef, I.; Tymciu, S.; Dhilly, M.; Mongin, F.; Queguiner, G.; Lasne, M.-C.; Barré, L.; Perrio, C. J. Org. Chem 2004 69 (7), 2622-2625. AIM BACKGROUND Giardina, G. A. M. ; Sarau, H. M. ; Farina, C. ; A. D. ; Grugni, M. ; Raveglia, L. F. ; Schmidt, D. B.; Rigolio, R.; Luttmann, M.; Vecchietti, V.; Hay, D. W. P., J. Med. Chem., 1997, 40, 1794-1807 Pfitzinger Doebner Aboul-Enein, H. A.; Ibrahim, S. A. J. Fluorine Chem. 1992, 59, 233-237. Pfitzinger and Doebner reactions are the two main approaches currently used for the construction of a 4-substituted quinolinic structure. However, both of them present several limitations such as long reaction times, low yields, lack of reproductibility, or need for strong basic conditions incompatible with sensitive substituents. Recently, the aza-Diels-Alder reaction of N-arylimines with 2-methoxypropene was successfully applied by Makioka et coll. to the synthesis of quinolines. However, only 4-methyl-2-phenylquinoline was synthesized. Makioka Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthesis 1995, 801. RESULTS Optimization of the conditions We anticipated that the reaction of N-arylimines 2 with enol ether 3, derived from pyruvic esters or pyruvic amides could yield quinoline-4-carboxylic derivatives 1. Lewis Acid ( 50 mol %) Solvent Times Activation (barb, W, °C) Yield % Yb(OTf)3a CH3CN 3 min 150 W e InI3 36 InBr3 30 InCl3 57 24h Reflux, 90°C 41 CH3CN/ CH2Cl2 High Pressure (16 Kbar, 60°C) 10 Influence of the nature of Y and Z in 3 a- 40 mol %. b- apparatus:PSIKA Acrylic compound Y Z InCl3 (eq.) Yield % (isolated) 3a OEt OMe 1 24 0.5 57 3b OTf 20 3c Br 4 (polymerization of 3c) 3d NHiPr 36 Other results: Solvent (yield %): EtOH (18), Toluene (0), DMF (0), CH2Cl2/CH3CN (1/1) (25), H2O/CH3CN (1/1) (0), THF/CH3CN (1/1) (11), Perfluoro(methylcyclohexane) (39), [bbim]Br (0), [bbim]BF4 (0). Synthesis of 2-phenylquinoline-4-carboxylates and carboxamides Synthesis of acrylic derivatives 3 Y R1 R2 R3 Yield % (isolated) OEt H 57 F 40 NHiPr 6-F 25 (S)-NHCHPh Et 47 35 49 8-F 53 48 Tranchant, M.J.; Dalla, V.; Jabin, I.; Decroix, B.; Tetrahedron 2002, 58, 8425-8432. Rachon, J.; Goedken, V.; Walkorsky, H.M.; J.Org.Chem. 1989, 54, 1006-1012. CONCLUSION A rapid synthesis of 2-phenylquinoline-4-carboxylates and carboxamides has been developed, according to an aza Diels-Alder reaction of N-arylimines with electron enriched acrylic acid derivatives : - microwave activation (3 min, 150 W) indium (III) chloride catalysis (0.5 eq for Y= OEt and 1 eq. for Y= NHR1) yields up to 57 % with ethyl-2-methoxyacrylate or with 2-methoxyacrylamide.