Synthesis of 4-Alkoxy-8-hydroxyquinolines † Juha P. Heiskanen, Walaa A. E. Omar, Mari K. Ylikunnari, Kirsi M. Haavisto, Maria J. Juan, and Osmo E. O. Hormi* Department of Chemistry, UniVersity of Oulu, P.O. Box 3000, 90014 Oulu, Finland osmo.hormi@oulu.fi ReceiVed October 19, 2006 Quinolines with a hydroxyl group at the 8-position and an alkoxy group at the 4-position are rare compounds. In this paper the synthesis of five 4-alkoxy-8-hydroxyquinolines is reported. The key reaction in the synthetic route is a selective protection of the hydroxyl group at C-atom 8 in 4,8-dihydroxyquinoline with a tosyl group and the hydrolytic removal of the protective group after the alkylation. The tosyl group is stable during the alkylations with various alkylating agents in the presence of sodium hydride. Introduction Substituted quinoline compounds can be found in many applications. In medicine they have attracted interest as anti- malarial drugs 1 and therapeutic drugs for inflammatory diseases. 2 Quinolobactin, a naturally occurring quinoline, has been identi- fied as a siderophore that pseudomonas produce to complex iron. 3 Other important applications of 8-hydroxyquinolines deriva- tives such as tris(8-hydroxyquinoline) aluminum (Alq 3 ) exploit their unique electronic characteristics, and considerable attention has recently been focused on their potential utility as electron transporter and light-emitting layer in organic light-emitting devices (OLEDs). 4 A computer simulations for Alq 3 has predicted that its optical properties can be modified by changing the substitution pattern of 8-hydroxyquinoline. Particularly, an electron-donor group at C-atom 4 of 8-hydroxyquinoline increases the intrinsic luminescence yield. 5 Protection of the functional group is required frequently when a chemical reaction is to be carried out selectively at one reactive site in a multifunctional compound. Previously 6 it has been shown that the 8-hydroxyl group of 4,8-dihydroxylquinoline can be alkylated prior to the alkylation of the hydroxyl group at the 4-position. The yield of the alkylated compound was low, and moreover it was not proven that the alkyl group at 8-position can be removed without a simultaneous removal of the alkyl group at 4-position. In this paper, we describe a selective protection of the 8-hydroxyl group in 4,8-dihydroxyquinoline with an easily removable tosyl group. The protected compound can be synthesized in an almost quantitative yield and was found to be stable enough in the consequent alkylation step. The stability of the tosyl group in 4-hydroxy-8-tosyloxyquinoline can be utilized to produce 4-alkoxy-8-tosyloxyquinolines that undergo hydrolysis in an alkaline environment readily to afford 4-alkoxy-8-hydroxyquinolines. Potentially, 4-hydroxy-8-tosyl- oxyquinoline can also serve as a starting material in the synthe- sis of other 4-position heteroatom functionalized 8-tosyl- oxyquinolines and their derivatives. 7 Results and Discussion The commercially available xanthurenic acid 1 was decar- boxylated to give 4,8-dihydroxyquinoline 2 in a excellent (96%) yield 8 (Scheme 1). The hydroxyl group at the 8-position was easily deprotonated by using a 1:1 molar ratio of NaOH to the diol 2. The tosyl † Contribution from the Empart group of Infotech Oulu. (1) Novak, I.; Kovac, B. J. Org. Chem. 2004, 69, 5005. (2) Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.; Asano, M.; Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. J. Med. Chem. 2004, 47, 2853. (3) (a) Pierre, J.; Baret, P.; Serratrice, G. Curr. Med. Chem. 2003, 10, 1077. (b) Mossialos, D.; Meyer, J. M.; Budzikiewicz, H.; Wolff, U.; Koedam, N.; Baysse, C.; Anjaiah, V.; Cornelis, P. Appl. EnViron. Microbiol. 2000, 66, 487. (4) Tang, C. W.; Van Slyke, S. A. Appl. Phys. Lett. 1987, 51, 913. (5) Curioni, A.; Andreoni, W. IBM J. Res. DeV. 2001, 45, 101. (6) Dempcy, R. O.; Kutyavin, I. V.; Mills, A. G.; Lukhtanov, E. A.; Meyer, R. B. Nucleic Acids Res. 1999, 27, 2931. (7) Synthetic procedure to produce other 4-position-substituted 8-tosyl- oxyquinoline, and its derivatives will be published during our future work. 920 J. Org. Chem. 2007, 72, 920-922 10.1021/jo062175i CCC: $37.00 © 2007 American Chemical Society Published on Web 01/04/2007