Fast, Acid-Free, and Selective Lactamization of Lactones in Ionic Liquids Kristina M. Orrling, Xiongyu Wu, Francesco Russo, and Mats Larhed* Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala UniVersity, P.O. Box 574, SE-751 23 Uppsala, Sweden mats@orgfarm.uu.se ReceiVed July 11, 2008 A fast and acid-free one-pot 0.2-30 mmol microwave methodology for direct ionic liquid-mediated preparation of lactams from lactones and primary amines has been devel- oped. The protocol was investigated with a wide range of primary amines and a handful of lactones, including sub- strates with acid-sensitive substituents. Both γ-lactams and δ-lactams were, despite the complete absence of a Brønsted acid, obtained in useful to excellent yields after only 35 min of microwave processing. In modern drug discovery chemistry, access to direct synthetic methods for quick and robust generation of new, tunable chemical core structures from commercially available reactants is of great importance. 1 There is also a growing demand for efficient one-pot tandem reactions to quickly prepare target compounds. As such synthetic transformations avoid both time- consuming and costly intermediate purifications and reduce the need for protective groups, they are also inherently more environmentally benign 2 and atom efficient. 3,4 Microwave heating (MW) using dedicated instrumentation has become an increasingly popular tool due to the fast heating, ease of operation, and high reaction control. 5-8 Since the introduction of 1,3-dialkylimidazolium-based ionic liquids as reaction medium for microwave-accelerated organic synthesis, 9-11 these charged solvents have attracted increasing interest because of their negligible vapor pressure and polar characteristics. 12,13 Due to their charged nature, ionic liquids can provide fast volumetric microwave heating to high temperatures. Ionic liquids of the 1,3-dialkylimidazolium class with non-nucleophilic counterions such as BF 4 - and PF 6 - possess particularly high thermal stability. 14 Furthermore, 1,3-dialkylimidazolium-based ionic liquids display both weak anionic donor and cationic acceptor abilities 15-17 and have been reported to promote acid- catalyzed reactions without addition of an external acid at high temperatures. 18 Since 1,3-dialkylimidazolium cations with non- nucleophilic counterions lack acidic properties, the increased reaction rates might instead be due to their strong polar nature. 19 In the literature, there are several previously reported procedures to provide lactams from lactones, 20,21 either directly or via hydroxyamide formation, and subsequent substitution of the activated or unactivated hydroxy group. From a synthetic point of view, the available protocols involve either long reaction times at high temperatures, 20,22 harsh reaction conditions using Brønsted acids, 23 or multistep transformations. 24,25 Many of these protocols are run at high temperatures for several days and/or are not compatible with reactive functional groups. As part of an ongoing medicinal chemistry program, we needed a rapid and smooth method for preparation of a diverse set of N-alkylated and ring-functionalized γ- and δ-lactams by direct reaction between a primary amine (1) and the corre- sponding lactone (2). Herein we report a fast, acid-free, one- pot, two-step microwave-accelerated lactone to lactam synthesis method in which the 1-butyl-3-methylimidazolium salts [bmim]BF 4 (3a) and [bmim]PF 6 (3b) promote the ring-closing step. To the best of our knowledge, this ionic liquid-mediated lactamization route provides a unique method for direct synthesis of different γ- and δ-lactams. As there are previous reports on successful high-temperature synthesis of lactams (4) directly from amines and lactones without any additives, 20 it was our original intention to transfer these protocols into a microwave-assisted method in order to facilitate the experimental procedure, to reduce the reaction time, and to improve product purities. Benzylamine (1a, 3 equiv) and γ-butyrolactone (2a, 1 equiv) served as model substrates in the initial neat experiments (Table 1). All reactions studied were conducted sequentially in disposable borosilicate reaction vessels which were sealed under air and processed with thermocon- (1) Edwards, P. J.; Allart, B.; rews, M. J. I.; Clase, J. A.; Menet, C. Curr. Opin. Drug DiscoV. DeV. 2006, 9, 425–444. (2) Horvath, I. T.; Anastas, P. T. Chem. ReV. 2007, 107, 2169–2173. (3) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–81. (4) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765, 767– 769. (5) Larhed, M.; Hallberg, A. Drug DiscoV. 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