Mechanistic Studies on the Cu-Catalyzed Three-Component Reactions of Sulfonyl Azides, 1-Alkynes and Amines, Alcohols, or Water: Dichotomy via a Common Pathway Eun Jeong Yoo, † Ma˚rten Ahlquist,* ,‡ Imhyuck Bae, † K. Barry Sharpless, ‡ Valery V. Fokin,* ,‡ and Sukbok Chang* ,† Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea, and Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 ahlquist@caltech.edu; fokin@scripps.edu; sbchang@kaist.ac.kr ReceiVed April 3, 2008 Combined analyses of experimental and computational studies on the Cu-catalyzed three-component reactions of sulfonyl azides, terminal alkynes and amines, alcohols, or water are described. A range of experimental data including product distribution ratio and trapping of key intermediates support the validity of a common pathway in the reaction of 1-alkynes and two distinct types of azides substituted with sulfonyl and aryl(alkyl) groups. The proposal that bimolecular cycloaddition reactions take place initially between triple bonds and sulfonyl azides to give N-sulfonyl triazolyl copper intermediates was verified by a trapping experiment. The main reason for the different outcome from reactions between sulfonyl and aryl(alkyl) azides is attributed to the lability of the N-sulfonyl triazolyl copper intermediates. These species are readily rearranged to another key intermediate, ketenimine, into which various nucleophiles such as amines, alcohols, or water add to afford the three-component coupled products: amidines, imidates, or amides, respectively. In addition, the proposed mechanistic framework is in good agreement with the obtained kinetics and competition studies. A computational study (B3LYP/LACV3P*+) was also performed confirming the proposed mechanistic pathway that the triazolyl copper intermediate plays as a branching point to dictate the product distribution. Introduction Tandem reactions, 1 performed with a cascade, domino, or zipper type, can link a series of reaction steps together in a single operation. In general, an initial step generates a reactive intermediate that undergoes further transformations with either strategically positioned reactive centers in the same molecule or other compounds in the reaction mixture. Over the past decades, tandem reactions have gained a wide interest since they can offer extremely high efficiency and selectivity without relying on a series of elaborate separate operations. However, the fact that only a few practically useful catalytic tandem reactions are available to date 2 may be attributed to a poor compatibility of catalysts with reacting functional groups in the subsequent steps. Copper-catalyzed azide-alkyne cycloaddition (CuAAC), 3 which is the best known click reaction, 4 is an efficient way to produce 1,4-disubstituted 1,2,3-triazoles. The scope of the reaction is very broad with respect to both components. 3 † Korea Advanced Institute of Science and Technology. ‡ The Scripps Research Institute. (1) Bunce, R. A. Tetrahedron 1995, 51, 13103–13159. (2) (a) de Meijere, A.; von Zezschwitz, P.; Nu¨ske, H.; Stulgies, B. J. Organomet. Chem. 2002, 653, 129–140. (b) Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Process Res. DeV. 2003, 7, 622–640. (c) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. ReV. 2004, 33, 302–312. (d) Yoshida, M. J. Pharm. Soc. Jpn. 2004, 124, 425–435. 10.1021/jo800733p CCC: $40.75  2008 American Chemical Society 5520 J. Org. Chem. 2008, 73, 5520–5528 Published on Web 06/17/2008