Synthesis of Mannich type products via a three-component coupling reaction Ghanshyam Pandey, Ravi P. Singh, Ashish Garg and Vinod K. Singh * Department of Chemistry, Institute of Technology, Kanpur 208016, India Received 22 September 2004; revised 11 January 2005; accepted 21 January 2005 Abstract—The reactions of alkyl nitriles, acetyl chloride, aldehydes and b-ketoesters or simple ketones was studied for the one-pot synthesis of b-acetamido carbonyl compounds. It was observed that the reaction proceeds in the absence of Lewis acids. However, a Lewis acid catalyzes the reaction and several were tested. It was found that whereas Cu(OTf) 2 is suitable for the coupling of b-keto- esters with aldehydes, Sc(OTf) 3 is the best for ketones. A possible mechanism is proposed based on the isolation and characteriza- tion of an intermediate. Ó 2005 Elsevier Ltd. All rights reserved. One-pot transformations, particularly multi-component reactions (MCR) 1 are of current interest to organic chemists. Since the first MCR reported in 1850 by Strec- ker, 2 this methodology has emerged as an efficient and powerful tool in modern synthetic organic chemistry allowing the facile creation of several new bonds in a one-pot transformation. Very recently, transition metal catalyzed MCR reactions of aldehydes, ketones and amines (Mannich reactions) were reported. 3 Recently, we reported cycloaddition reactions of aziridines and azetidines with nitriles, which were proposed to proceed in a Ritter fashion. 4 Based on this assumption, it can be 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.01.118 * Corresponding author. Fax: +91 512 2597436; e-mail: vinodks@iitk.ac.in Table 1. Effect of Lewis acid on the three-component coupling to give b-acetamido-carbonyl compounds PhCHO MeO 2 CCH 2 COCH 3 Ph AcHN CH 3 O COOM A B e Ph AcHN Ph O + Lewis acid, CH 3 CN, AcCl, rt, 30 h or or PhCOCH 3 Entry Lewis acid Isolated yield (%) A B 1 Nil 15 30 2 Zn(OTf) 2 (10 mol %) 20 60 3 Bi(OTf) 3 (10 mol %) 44 69 4 Sn(OTf) 3 (10 mol %) 36 68 5 Sc(OTf) 3 (10 mol %) 47 82 6 Cu(OTf) 2 (10 mol %) 65 64 7 Yb(OTf) 3 (10 mol %) — 75 8 BF 3 ®OEt 2 (100 mol %) — 78 9 BF 3 ®OEt 2 (10 mol %) — 48 10 CuCl 2 (100 mol %) — 79 11 BiCl 3 (100 mol %) — 77 12 LaCl 3 (100 mol %) — 77 13 LiClO 4 (100 mol %) — 59 14 InCl 3 (100 mol %) — 19 Tetrahedron Letters 46 (2005) 2137–2140 Tetrahedron Letters