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
Fast, Acid-Free, and Selective Lactamization of
Lactones in Ionic Liquids
Kristina M. Orrling, Xiongyu Wu, Francesco Russo, and
Mats Larhed*
-
-
counterions such as BF4 and PF6 possess particularly high
thermal stability.14 Furthermore, 1,3-dialkylimidazolium-based
ionic liquids display both weak anionic donor and cationic
acceptor abilities15-17 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]BF4 (3a) and [bmim]PF6 (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.
Organic Pharmaceutical Chemistry, Department of
Medicinal Chemistry, Uppsala Biomedical Center, Uppsala
UniVersity, P.O. Box 574, SE-751 23 Uppsala, Sweden
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 benign2 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
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-
(12) Welton, T. Chem. ReV. 1999, 99, 2071–2083.
(13) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772–
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(14) Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67, 3145–
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M. J. Phys. Chem. B 2006, 110, 19593–19600.
(16) Fujisawa, T.; Fukuda, M.; Terazima, M.; Kimura, Y. J. Phys. Chem. A
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(17) Parvulescu, V. I.; Hardacre, C. Chem. ReV. 2007, 107, 2615–2665.
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(19) Yang, Y.-L.; Kou, Y. Chem. Commun. 2004, 226–227.
(20) Spa¨th, E.; Lintner, J. Ber. Deutsch. Chem. Ges. 1936, 69B, 2727–2731.
(21) Smith, M. B. Sci. Synth. 2005, 21, 647–711.
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(25) Kawahata, N. H.; Brookes, J.; Makara, G. M. Tetrahedron Lett. 2002,
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10.1021/jo8015264 CCC: $40.75
Published on Web 10/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8627–8630 8627