Aza DielsAlder Reaction of NArylimines with Pyruvate Derivatives

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 AIM 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. BACKGROUND 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 Pfitzinger 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 Doebner Makioka, Y. ; Shindo, T. ; Taniguchi, Y. ; Takaki, K. ; Fujiwara, Y. Synthesis 1995, 801. Aboul-Enein, H. A. ; Ibrahim, S. A. J. Fluorine Chem. 1992, 59, 233 -237. 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. Influence of the nature of Y and Z in 3 Lewis Acid ( 50 mol %) Solvent Times Activation (barb, W, °C) Yield % Yb(OTf)3 a CH 3 CN 3 min 150 W e In. I 3 CH 3 CN 3 min 150 W 36 In. Br 3 CH 3 CN 3 min 150 W 30 In. Cl 3 CH 3 CN 3 min 150 W 57 In. Cl 3 CH 3 CN 24 h Reflux, 90°C 41 In. Cl 3 CH 3 CN/ CH 2 Cl 2 24 h High Pressure (16 Kbar, 60°C) 10 a- 40 mol %. b- apparatus: PSIKA Acrylic compound Y Z In. Cl 3 (eq. ) Yield % (isolated) 3 a OEt OMe 1 24 3 a OEt OMe 0. 5 57 3 b OEt OTf 0. 5 20 3 c OMe Br 0. 5 4 (polymerization of 3 c) 3 d NHi. Pr OMe 1 57 3 d NHi. Pr OMe 0. 5 36 Synthesis of acrylic derivatives 3 Other results: Solvent (yield %): Et. OH (18), Toluene (0), DMF (0), CH 2 Cl 2/CH 3 CN (1/1) (25), H 2 O/CH 3 CN (1/1) (0), THF/CH 3 CN (1/1) (11), Perfluoro(methylcyclohexane) (39), [bbim]Br (0), [bbim]BF 4 (0). Synthesis of 2 -phenylquinoline-4 -carboxylates and carboxamides Y R 1 R 2 R 3 Yield % (isolated) OEt H H H 57 OEt H H F 40 NHi. Pr H H H 57 NHi. Pr 6 -F H H 25 (S)-NHCHPh Et H H H 47 (S)-NHCHPh Et H H F 35 (S)-NHCHPh Et 6 -F H H 49 (S)-NHCHPh Et 8 -F H H 53 (S)-NHCHPh Et H F H 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= NHR 1) - yields up to 57 % with ethyl-2 -methoxyacrylate or with 2 -methoxyacrylamide.