A new entry towards the synthesis of 1-substituted 3-azetidinones

Article abstract of DOI:10.1016/S0040-4039(01)00113-7

The synthesis of 1-substituted 3-azetidinones, starting from readily accessible N-(alkylidene)- or N-(arylidene)-2,2,3-tribromopropylamines, is disclosed.

Full text of DOI:10.1016/S0040-4039(01)00113-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2373–2375
A new entry towards the synthesis of 1-substituted 3-azetidinones
Dirk De Smaele, Yves Dejaegher, Guillaume Duvey and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
Received 15 November 2000; revised 8 January 2001; accepted 17 January 2001
Abstract—The synthesis of 1-substituted 3-azetidinones, starting from readily accessible N-(alkylidene)- or N-(arylidene)-2,2,3-tri-
bromopropylamines, is disclosed. © 2001 Published by Elsevier Science Ltd.
Azetidine derivatives, carrying a carbonyl group at
position 2, occupy a special place in heterocyclic chem-
istry. Natural and synthetic azetidin-2-one derivatives
are known as antibiotic compounds.1–4 Much less wide-
spread are azetidin-3-one derivatives (Fig. 1), e.g. 1,
which are not yet found in nature. However, very
recently, 3,3-dihydroxyazetidine 2, the hydrate of aze-
tidin-3-one, has been isolated from the supernatant of a
culture of Bacillus cereus and has been found to act as
a growth-promoting factor for several strains of
Bifidobacterium.5
epoxyketones,13 oxidation of 3-azetidinols14 and
ozonization of 3-alkylidene-1-substituted azetidines.15
In this communication, we wish to present an easy
entry towards 2,4-unsubstituted azetidin-3-ones 9 start-
ing from N-(alkylidene)- or N-(arylidene)-2,2,3-tribromo-
propylamines 6. The new tribromoimines 6 were syn-
thesized from 2-bromoallylamine 4, which can easily be
synthesized via a well-established procedure, starting
from allyl bromide.16 Two pathways can be followed in
the synthesis of imines 6 (Scheme 1). Condensation of
2-bromoallylamine 4 with benzaldehyde and subse-
quent bromination of the intermediate N-(benzylidene)-
2-bromoallylamine 5 yields imine 6a.
Considerable research in this area has been done
towards the synthesis of 1,3,3-trinitroazetidine
3
(TNAZ), an energetic material which is sensitive to
detonation on impact.6–10 Most syntheses of this com-
pound start from the 2,4-unsubstituted azetidin-3-one,
which is converted to the oxime and treated with nitric
acid.6–8
With the use of other aldehydes, this pathway is not
useful since the necessary prolonged bromination of the
corresponding imines leads to partial hydrolysis to the
aldehyde again. An alternative route can be followed
where the 2-bromoallylamine is first protected as the
hydrobromide salt, then brominated to give the inter-
mediate 7 and afterwards condensed with the aldehyde,
giving the corresponding tribromoimines 6 in excellent
yields. It was noticed by the authors that the latter
compounds 6 exhibit an irritating effect on the eyes.
The most important synthetic routes towards azetidin-
3-ones include cyclization of a-amino-a%-diazoketones,11
ring closure of a-amino-a%-halo-12 or a-amino-a%,b%-
The cyclization of N-(alkylidene)- or N-(arylidene)-
2,2,3-tribromo-propylamines
6 with excess sodium
borohydride in methanol under reflux, results in the
azetidine derivatives 8 (Scheme 2). Under the applied
conditions, the imino function of compounds 6 was
reduced and the resulting intermediate g-bromoamines
were cyclized to afford the corresponding 3,3-dibro-
moazetidines. The latter intermediates were not isolated
but were found to be converted readily by methanolysis
to aminoacetals 8 in isolated yields of 47–54%. This
synthetic scheme gives the possibility of creating new
Figure 1.
Keywords: 3-azetidinones; azetidines; bromoimines.
* Corresponding author. Tel.: +32 (0)9 264.59.51; fax: +32 (0)9
264.62.43; e-mail: norbert.dekimpe@rug.ac.be
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00113-7

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D. De Smaele et al. / Tetrahedron Letters 42 (2001) 2373–2375
Scheme 1.
Scheme 2.
access to azetidin-3-ones by hydrolysis of the acetal.
Previously, the hydrolysis of ethyl 3-methoxy-2-phenyl-
Currently, further transformations of these 2,4-unsub-
stituted azetidin-3-ones are under investigation.
3-[(trimethylsilyl)oxy]-1-azetidine
carboxylate
by
aqueous hydrochloric acid has been reported.17
References
In the present case, hydrochloric acid seemed to have a
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strates 8. Several hydrolytic conditions for the conver-
sion of acetals to the corresponding ketones were tried
out without success (e.g. 5 equiv. 2 M HCl, 4 h reflux;
10 equiv. 2 M HCl, 4 h reflux; 5 equiv. 4 M HCl, 4 h
reflux; 5 equiv. 12 M HCl, 4 h reflux, …). However, the
use of concentrated sulfuric acid permitted us to per-
form the desired transformation of acetals 8 into aze-
tidin-3-ones 9. The azetidin-3-ones 9a–f were obtained
in 62–93% yield.18 The 1-substituted azetidin-3-ones 9
so obtained are labile compounds and start decompos-
ing after 8 hours at room temperature. According to
literature references, only azetidin-3-one derivatives
with sterically demanding14b,c or electron-with-
drawing11b,c,14 substituents on nitrogen are stable
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(5H, broad s, C6H5); 13C NMR (CDCl3, 68 MHz) l 63.45
(C6H5C6 H2N), 75.06 (CH2NCH2), 127.51 (ꢀCpara), 128.37
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.