A novel synthesis of 3-aminoazetidines by ring transformation of 2-(bromomethyl)aziridines

Article abstract of DOI:10.1016/S0040-4039(00)01844-X

A one-step approach to the biologically interesting 3-aminoazetidines is described. The reaction concerns a ring transformation of 1-arylsulfonyl-2-(halomethyl)aziridines with aliphatic amines under various reaction conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01844-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10295–10298
A novel synthesis of 3-aminoazetidines by ring
†
transformation of 2-(bromomethyl)aziridines
‡
Michinori Karikomi 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 30 March 2000; revised 11 October 2000; accepted 19 October 2000
Abstract
A one-step approach to the biologically interesting 3-aminoazetidines is described. The reaction
concerns a ring transformation of 1-arylsulfonyl-2-(halomethyl)aziridines with aliphatic amines under
various reaction conditions. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 3-aminoazetidines; aziridines; ring transformation.
Azetidines are an interesting class of four-membered heterocyclic compounds in terms of
1
biological activities. 3-Aminoazetidines 3 have received attention in recent years because of
2
their antibacterial activities. In most cases, 3-aminoazetidine derivatives have been obtained by
functional group transformation of 3-hydroxyazetidines 2. The preparation of the 3-hydroxyaze-
tidines 2 by the reaction of epihalohydrins 1 with amines has been known for a long time
3
(
Scheme 1). However, this reaction gives mostly low yields, although some improved methods
4
have been published.
Scheme 1.
*
Corresponding author.
Dedicated to Prof. Dr. Gabor Bernath on the occasion of his 65th birthday.
On leave from Utsunomiya University, Department of Applied Chemistry, Faculty of Engineering, Yoto 7-1-2,
†
‡
Utsunomiya 321-8585, Japan.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01844-X

10296
In the course of our synthetic study concerning small ring heterocycles, we were interested in
exploring the possibility of constructing such 3-aminoazetidines by ring transformation of
5
appropriately functionalized N-arylsulfonylaziridines.
Activated aziridines which possess an electron withdrawing group on nitrogen exhibit similar
6
reactivities as oxiranes towards nucleophiles such as amines. Accordingly, we found a new
synthetic method for 3-aminoazetidines
3
by the reaction of N-arylsulfonyl-2-
(
halomethyl)aziridines 4a with aliphatic amines. In this reaction, 3-aminoazetidines 5 are
obtained as N-sulfonyl-protected derivatives by a one-step reaction without any further func-
tional group transformation.
N-p-Toluenesulfonyl-2-(bromomethyl)aziridine
4a
and
N-methanesulfonyl-2-(bromo-
methyl)aziridine 4b were easily obtained from allyl bromide by a modification of a method
5
described in the literature. N-Benzenesulfonyl-2-(chloromethyl)aziridine 4c was also obtained
by a similar method using chlorine gas instead of bromine.
When a solution of N-p-toluenesulfonyl-2-(bromomethyl)aziridine 4a in tetrahydrofuran was
refluxed with 2.4 equivalents of benzylamine (Method A) for 5 h, N-benzyl-3-p-toluenesulfonyl-
amidoazetidine 5a was obtained in 28% yield. Also 40% of 1,3-di(N-benzylamino)-2-p-toluene-
sulfonylamide 6a was obtained as an undesirable side product. These observations can be
explained by considering a second nucleophilic displacement process by the excess of benzyl-
amine. In order to improve the yield of 5a and to avoid the formation of 6a, 1.2 equivalents of
7
benzylamine and 1.2 equivalents of triethylamine were used (Method B). As expected, 5a was
obtained in an higher yield of 37% (Scheme 2). On the other hand, when the reaction of
aziridine 4a was conducted in the presence of 2.4 equivalents of benzylamine at room
temperature, the formation of 3-aminoazetidine 5a was not observed (Method C). From the
mechanistic point of view the reaction proceeds via a nucleophilic opening of 1-sulfonyl-2-(bro-
momethyl)aziridines 4a, affording intermediate 3-halo-2-(N-sulfonyl)amidopropanes 7, which
undergo ring closure by intramolecular nucleophilic substitution to the title azetidines 5.
Scheme 2.
As presented in Table 1, the same reaction did not give good results in toluene or methanol
(
entries 4, 5). THF appeared to be the solvent of choice. With the purpose of activation of the
8
aziridine 4a, Yb(OTf) was added as a Lewis catalyst , but no azetidine 5a was produced at all
3
(
entry 6). In order to extend the scope and synthetic utility of the reaction, the reactions of other
commercially available amines were studied. 1-Cyclohexyl- and 1-t-butyl-3-p-toluene–sulfonyl-
amidoazetidines (5b, 5c) were easily synthesized from 4a in moderate yields (entries 7–9).

10297
Table 1
Ring transformation of 1-sulfonyl-2-(halomethyl)aziridines 4 into 1-alkyl-3-aminoazetidines 5
1
2
a
b
Entry
R
X
R
Solvent
Method
Yield of 5 (%)
1
2
3
4
5
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
Me
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
t-Bu
THF
THF
THF
Toluene
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
A
B
C
28
37
0
19
Trace
0
38
15
13
0
0
0
36
27
22
28
c
B
B
c
d
6
B
A
B
B
B
B
B
B
B
B
B
7
8
9
0
1
2
3
4
5
6
t-Bu
Cyclohexyl
Diphenylmethyl
p-Tol
PhCH2
PhCH2
t-Bu
1
1
1
1
1
1
1
Ph
Ph
Ph
PhCH2
PhCH2
4-CF C H
3
6
4
a
b
c
See Scheme 1.
Isolated yield.
The reaction has conducted in another solvent.
d
1
0 mol% of Yb(OTf) was used.
3
In the case of t-butylamine, a considerable amount of N-t-butyl-p-toluenesulfonylamide 8
and a small amount of aziridine derivative 9 were obtained. This observation confirms that the
sterically hindered amine cannot have easy access towards the aziridine ring of 4a (Scheme 3).
However, diphenylmethylamine and p-toluidine did not give the corresponding azetidine
under the given reaction conditions (entries 10 and 11). The reaction of 1-methanesulfonyl-2-
(
bromomethyl)azetidine 4b with benzylamine in THF under reflux did not give the desired
azetidine 5 (entry 12).
On the other hand, treatment of aziridine 4c or 4d with benzylamine gave azetidine 5d in 36
and 22% isolated yield, respectively (entries 13 and 15). In the case of N-(4-trifluoromethylben-
zenesulfonyl)aziridine 4e, the electron-withdrawing influence did not give a remarkable influence
on the yield of azetidine 5e (entry 16).

10298
Scheme 3.
In conclusion, an efficient and straightforward method for the preparation of protected
-aminoazetidines was developed. These azetidines were obtained by a one-step conversion from
-arylsulfonyl-2-(bromomethyl)aziridines. The yields are low but acceptable in view of the
3
1
one-step procedure and known difficulties in the preparation of 3-aminoazetidines.
References
1. For leading references on azetidines, see: (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331–358. (b) De
Kimpe, N. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.; Elsevier Science, 1996; Vol. 1B, pp.
508–545.
2
. (a) Bacque, E.; Paris, J.-M.; Bitoux, S. L. Synth. Commun. 1995, 25, 803. (b) Frigola, J.; Pares, J.; Corbera, J.;
Vano, D.; Marce, R.; Torrens, A.; Mas, J.; Valenti, E. J. Med. Chem. 1993, 36, 801. (c) Jones, R. N. Eur. J. Clin.
Microbiol. Infect. Dis. 1992, 11, 188. (d) Jesus, G.; Marta, R.; Domingo, G.-V.; Angels, X. M.; Garcia, J.;
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(
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3
4
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. Gensler, W. J. J. Am. Chem. Soc. 1948, 70, 1843.
. For a review, see: (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b) Padwa, A.; Woolhouse, A. D.
In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 7.
. In a typical procedure for Method B, benzylamine (0.64 g, 6.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were
added to a stirred solution of 1-p-toluenesulfonyl-2-(bromomethyl)aziridine 4a (1.45 g, 5.0 mmol) in dry THF (15
ml) and the mixture was refluxed for 5 h. Then water was added, and the reaction mixture was extracted three
7
times with dichloromethane. The organic phases were washed with brine, dried (MgSO ) and the solvent was
4
evaporated in vacuo. The residue was chromatographed on silica gel (ethyl acetate:petroleum ether 1:1).
1
-Benzyl-3-p-toluenesulfonylamido)azetidine 5a was obtained in 37% yield and 1,3-di(N-benzylamino)-2-p-tolue-
1
nesulfonylamide 6a in 19% yield. The spectroscopic data of 5a are as follows: H NMR (270 MHz, CDCl ) l 2.42
3
(
7
1
3H, s), 2.76 (2H, td, J=6.6, 2.0 Hz), 3.45 (2H, td, J=6.6, 2.0 Hz), 3.50 (2H, s), 3.95 (1H, m), 5.25 (1H, br s),
13
.0–7.2 (7H, m), 7.6–7.7 (2H, m); C NMR (67.5 MHz, CDCl ) l 21.56, 44.08, 61.78, 63.23, 126.99, 127.22,
3
−
1
26.39, 129.85, 137.28, 137.41, 143.70. IR (neat) 3261, 3029, 2839, 1597, 1495, 1328, 1150 cm ; MS (70 eV, rel.
+
intensity) m/z 317 (0.17, M +1), 161 (58), 120 (54), 91 (100).
8. Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 1994, 40, 7395.
.