A mild and efficient one-step synthesis of quinolines Surya K. De * and Richard A. Gibbs Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Cancer Center, Purdue University, West Lafayette, IN 47906, USA Received 8 December 2004; revised 12 January 2005; accepted 17 January 2005 Available online 29 January 2005 Abstract—2-Aminoaryl ketones undergo condensation with a-methylene ketones in the presence of a catalytic amount of Y(OTf) 3 at room temperature under mild conditions to afford the corresponding polysubstituted quinolines in excellent yields. Ó 2005 Elsevier Ltd. All rights reserved. Quinolines are very important compounds because of their pharmacological properties. Members of this fam- ily have wide applications in medicinal chemistry, being used as antimalarial, antiinflammatory agents, anti- asthamatic, antibacterial, antihypertensive, and tyrosine kinase inhibiting agents. 1–3 In addition, quinolines are valuable synthons used for the preparation of nano and mesostructures with enhanced electronic and pho- tonic properties. 4 Despite their importance from phar- macological, industrial, and synthetic point of views, comparatively few methods for their preparation have been reported. Although other methods such as Skraup, Doebner von Miller, and Combes procedures have been reported 5,6 for the preparation of quinolines, the Fried- lander annulation is one of the most simple and straight- forward methods for the synthesis of poly-substituted quinolines. The Friedlander synthesis is an acid or base catalyzed condensation followed by a cyclodehydration between 2-aminoaryl ketone and a second carbonyl compound containing a reactive a-methylene group. Generally, this reaction is carried out by refluxing an aqueous or alcoholic solution of reactants in the pres- ence of base at high temperature. 7 Under thermal or base catalysis conditions, o-aminobenzophenone fails to react with simple ketones such as cyclohexanone and b-keto esters. 8 Recently, modified methods employ- ing ZnCl 2 , phosphoric acid, Bi(OTf) 3 , silver phospho- tungstate, sodium fluoride, and AuCl 3 have been reported for the synthesis of quinolines. 9 However, many of these procedures have significant drawbacks such as low yields of the products, long reaction times, harsh reaction conditions, difficulties in work-up, and the use of stoichiometric and/or relatively expensive re- agents. Moreover, the main disadvantage of almost all existing methods is that the catalysts are destroyed in the work-up procedure and cannot be recovered or re- used. Thus, the development of more efficient proce- dures for the synthesis of quinolines is still needed. Recently, there has been growing considerable interest in the use of lanthanide triflates in organic synthesis 10 as they are water stable and reusable. The reagent Y(OTf) 3 is commercially available and significantly less expensive than Sc(OTf) 3 . Like lanthanide triflates, Y(OTf) 3 is also water tolerable, reusable, and efficient catalyst 11 and can be used for the preparation of qunin- oline derivatives. As part of a continuing effort in our laboratory toward the development of new methods in organic synthesis, 12 we became interested in the possibility of developing a one pot synthesis of 2,3,4-trisubstituted quinolines. The Friedlander condensation of 2-aminobenzophenone with ethyl acetoacetate in the presence of a catalytic amount of yttrium triflate at room temperature results in the formation of ethyl 2-methyl-4-phenylquinoline- 3-carboxylate in 92% yield (Scheme 1). Similarly, various 1,3-diketones reacted with 2-aminoaryl ketones 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.01.075 * Corresponding author. Tel.: +1 765 743 9702; fax: +1 765 494 1414; e-mail: skd125@pharmacy.purdue.edu NH 2 O R R 1 R 2 O Y(OTf) 3 N R R 2 R 1 + CH 3 CN, rt Scheme 1. Tetrahedron Letters 46 (2005) 1647–1649 Tetrahedron Letters