6852
J. Org. Chem. 2001, 66, 6852-6856
Rhodium-Catalyzed Asymmetric 1,4-Addition of Organoboron Reagents to 5,6-Dihydro-2(1H)-pyridinones. Asymmetric Synthesis of 4-Aryl-2-piperidinones Taichi Senda, Masamichi Ogasawara, and Tamio Hayashi* Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
[email protected] Received April 16, 2001
Catalytic asymmetric synthesis of 4-aryl-2-piperidinones was realized for the first time by asymmetric 1,4-addition of arylboron reagents to 5,6-dihydro-2(1H)-pyridinones in the presence of a chiral bisphosphine-rhodium catalyst. In the reaction introducing 4-fluorophenyl group, the use of 4-fluorophenylboroxine and 1 equiv (to boron) of water at 40 °C gave the highest yield of the arylation product with high enantioselectivity (98% ee). The (R)-4-(4-fluorophenyl)-2-piperidinone obtained here is a key intermediate for the synthesis of (-)-Paroxetine. Introduction Enantiomerically pure 4-aryl-2-piperidinones are key intermediates for the synthesis of biologically active compounds. They are readily converted into pharmacologically important molecules such as Baclofen homologues1 and 3,4-disubstituted piperidines represented by (-)-Paroxetine.2,3 Although considerable efforts have been made for their synthesis, to our best knowledge, asymmetric catalysis has not been applied to the synthesis of 4-aryl-2-piperidinones. We have previously reported that a rhodium complex coordinated with binap ligand catalyzes the asymmetric 1,4-addition of organoboron reagents to electron-deficient olefins including R,β-unsaturated ketones,4 esters,5 1-alkenylphosphonates,6 and 1-nitroalkenes7 to give the corresponding arylation or alkenylation products with high enantioselectivity, usually over 95% ee.8 Here we wish to report the use of R,βunsaturated lactams9 as substrates for the rhodiumcatalyzed asymmetric arylation, which provides a new * To whom correspondence should be addressed. Fax: 81-75-7533988. (1) For example, Karla, R.; Ebert, B.; Thorkildsen, C.; Herdeis, C.; Johansen, T. N.; Nielsen, B.; Krogsgaard-Larsen, P. J. Med. Chem. 1999, 42, 2053. (2) Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41, 5647. (3) (a) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004. (b) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074. (c) Amat, M.; Hidalgo, J.; Bosch, J. Tetrahedron Asymmetry 1996, 7, 1591. (4) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1998, 39, 8479. (c) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1999, 40, 6957. (d) Takaya, Y.; Ogasawara, M.; Hayashi, T. Chirality 2000, 12, 469. (5) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047. (6) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591. (7) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716. (8) For reviews on asymmetric 1,4-addition of organometallic reagents: (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c) Tomioka, K.; Nagaoka, Y. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 31.1.
Scheme 1
efficient and general route to optically active 4-aryl-2piperidinones (Scheme 1). Results and Discussion As the first target compound to be synthesized by the rhodium-catalyzed asymmetric addition, 4-(4-fluorophenyl)-2-piperidinone was chosen because it is known to be readily converted into (-)-Paroxetine by reported procedures.2 Under our standard conditions used for the reaction of R,β-unsaturated ketones,4 that is, 3 mol % of the rhodium catalyst coordinated with (R)-binap10 in dioxane/H2O (10/1) at 100 °C for 3 h, the reaction of N-benzyl-5,6-dihydro-2(1H)-pyridinone (1) with 4-fluorophenylboronic acid (2a) (5 equiv to 1) gave only a poor yield (17%) of the arylation product, N-benzyl-4-(4fluorophenyl)-2-piperidinone (3a) whose enantiomeric purity is 92%. Considering that the reaction of 1 with phenylboronic acid (2b) gave a good yield (70%) of the phenylation product 3b under the same reaction conditions, the low yield is ascribed mainly to the use of 4-fluorophenylboronic acid (2a). It turned out that the hydrolysis of 2a giving fluorobenzene is very fast under the reaction conditions and the boronic acid 2a is consumed before the 1,4-addition is completed. We tried (9) Recently one example of the rhodium-catalyzed asymmetric 1,4addition to a linear R,β-unsaturated amide has been reported: Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951. (10) (a) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629. (b) Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1989, 67, 20. (c) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (d) Cai, D.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 7180.
10.1021/jo0103930 CCC: $20.00 © 2001 American Chemical Society Published on Web 09/27/2001
Asymmetric Synthesis of 4-Aryl-2-piperidinones
J. Org. Chem., Vol. 66, No. 21, 2001 6853
Table 1. Asymmetric 1,4-Addition of Arylboronic Acid 2 or Arylboroxine 4 to N-Benzyl-5,6-dihydro-2(1H)-pyridinone (1) Catalyzed by (R)-binap-Rhodium(I) Complexesa entry
ArB(OH)2 2 or (ArBO)3 4
solvent
ligand
temp (°C)
time (h)
yieldb (%) of 3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
4-FC6H5B(OH)2 (2a) 4-FC6H5B(OH)2 (2a) (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a) PhB(OH)2 (2b) (PhBO)3 (4b)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (4-FC6H5BO)3 (4a)/H2Od (PhBO)3 (4b)/H2Od (4-ClC6H5BO)3 (4c)/H2Od
dioxane/H2O (10/1) dioxane dioxane dioxane dioxane/H2O (10/1) dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane
(R)-binap (R)-binap (R)-binap (R)-binap (R)-binap (R)-binap (R)-binap (R)-binap* (R)-u-binap (R)-H8-binap (R)-binap* (R)-binap* (R)-binap* (R)-binap* (R)-binap (R)-binap
100 100 100 100 100 100 40 40 40 40 100 80 60 20 40 60
3 3 3 3 3 3 12 12 12 12 12 12 12 12 12 6
17 (3a) 33 (3a) 36 (3a)
