Indium-mediated facile synthesis of 3-unsubstituted ꢀ-lactams
Bimal K. Banik,* Anjan Ghatak and Frederick F. Becker
The University of Texas, M. D. Anderson Cancer Center, Department of Molecular Pathology,
Box-089, 1515 Holcombe Blvd., Houston, TX 77030, USA
1
Received (in Cambridge, UK) 10th April 2000, Accepted 14th June 2000
Published on the Web 30th June 2000
A simple synthesis of 3-unsubstituted ꢀ-lactams was
achieved through indium-mediated reaction of imines with
ethyl bromoacetate.
Synthesis of β-lactams and their biological application is an
increasingly active area. Because of the recent developments in
using β-lactams as synthons for the synthesis of several natural
and non-natural products, research on this topic has gained
tremendous attention in spite of the clinical resistance of some
organisms to the β-lactam antibiotics.1 Monocyclic β-lactams
with diverse substituents have been of considerable interest
to the synthetic community in the past few decades. The use of
3-unsubstituted β-lactams in synthetic chemistry is widespread2
and consequently a few methods have been reported for the
synthesis of this type of β-lactams.
Scheme 2
ester could be explained by the decomposition of the imine
1a in the presence of the iodoester, Reformatsky-type addition
to the resulting benzaldehyde and a subsequent elimination
reaction. These results indicated that the nature of the halo-
esters is important in this indium-mediated reaction. The
iodoester was moderately effective, while the bulkier tert-butyl
ester was not effective at all. However, methyl and ethyl bromo-
esters were equally effective and the yields were comparable.
In conclusion, we have demonstrated a simple and rapid
synthesis10,11 of several 3-unsubstituted β-lactams by indium-
mediated reaction with ethyl bromoacetate or methyl bromo-
acetate. An ultrasound-promoted synthesis of 3-unsubstituted
β-lactam using ethyl bromoacetate, zinc and imines has been
reported12 (e.g. 2e, 82%). However, prior activation of zinc was
necessary and imines containing only aryl groups were found
to produce β-lactams. In our case, β-lactams having a wide
range of substituents at nitrogen, such as arylalkyl, aryl and
allyl groups, could be prepared. In general, imines obtained
from arylalkylamines produced the β-lactams in higher yield
than those obtained from aryl- or allylamines. Other advan-
tages of this procedure are its use of commercially available
indium13 powder without any pre-treatment and that no extra
equipment, like ultrasound, is needed.
In continuation of our studies3 on metal-induced oxidation–
reduction reactions, we became interested in indium-mediated
reduction4 and addition reactions to imines. Our study on
indium-mediated reaction of imines with bromoesters cul-
minated in a facile synthesis of 3-unsubstituted β-lactams and
the results are reported below.
The synthetic application of indium metal is growing.5–8
This metal has been used for the allylation of imines7 in the
presence of allyl bromide and for the addition to a keto group
in some β-lactams.8 These reports indicated that under appro-
priate conditions, indium can be used in conjunction with allyl
bromide and that 4-membered cyclic amides are stable under
indium treatment. We have combined these two approaches
for the facile synthesis of 3-unsubstituted β-lactams by indium-
mediated addition of a bromoester to imines.
Reaction of various imines 1 with ethyl bromoacetate in
the presence of indium metal using anhydrous tetrahydrofuran
as the solvent produced the β-lactams 2 (Scheme 1). It was
Acknowledgements
We gratefully acknowledge the funding support received for
this research project from The Golden Family Fund for Cancer
Research and NIH Cancer Center Support Grant, 5-P30-
CA16672-25, and in particular the shared resources of the
Pharmacology and Analytical Center Facility and Centralized
Histopathology Laboratory.
Scheme 1
found that the imines 1a–1f derived from arylalkylamines,
allylamine and p-anisidine produced only the β-lactams 2a–2f
(Table 1). Alternatively, imines derived from aniline (1g and 1h)
produced the β-lactams (2g and 2h) along with the β-amino
esters (3a and 3b) (Table 1, entries 7 and 8). This indicated that
the basicity of the β-amino ester9 is an important factor in the
cyclization reaction.
In order to establish the effects of using other haloesters, a
few reactions with tert-butyl bromoacetate, methyl bromo-
acetate and ethyl iodoacetate were investigated with imine 1a
(Scheme 2). No reaction was observed with tert-butyl bromo-
acetate and the imine 1a was recovered unchanged from this
reaction. Methyl bromoacetate and ethyl iodoacetate gave 2a
in 65 and 48% yields respectively. However, a small amount of
unsaturated ester 4 (8%) was also formed from the reaction of
1a and ethyl iodoacetate. The formation of the unsaturated
Notes and references
1 For some recent examples, see: (a) A. K. Bose, B. K. Banik,
C. Mathur, D. R. Wagle and M. S. Manhas, Tetrahedron, Sym-
posium in Print, 2000, 0000; (b) M. S. Manhas, B. K. Banik,
A. Mathur, J. E. Vincent and A. K. Bose, Tetrahedron, Symposium
in Print, 2000, 0000; (c) A. K. Bose, M. S. Manhas, B. K. Banik and
V. Srirajan, in The Amide Linkage: Selected Structural Aspects in
Chemistry, Biochemistry, and Material Science, eds. A. Greenberg,
C. M. Breneman and J. F. Liebman, Wiley-Interscience, New York,
2000, p. 157.
2 The usefulness of 3-unsubstituted β-lactams has been documented,
see: A. K. Bose, M. S. Manhas, A. Mathur and D. R. Wagle, in
DOI: 10.1039/b002833i
J. Chem. Soc., Perkin Trans. 1, 2000, 2179–2181
This journal is © The Royal Society of Chemistry 2000
2179
Banik, Bimal K.
