A new route towards N-(α-methoxybenzyl)aziridines

Article abstract of DOI:10.1016/S0040-4039(02)02838-1

A new synthesis of N-(α-methoxyarylmethyl)-2,2-dimethylaziridines is presented. Different benzaldehydes were converted into the corresponding imines upon reaction with 2-bromo-2-methylpropylamine. Treatment of the latter imines with sodium methoxide affor

Full text of DOI:10.1016/S0040-4039(02)02838-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1137–1139
A new route towards N-(a-methoxybenzyl)aziridines
Matthias D’hooghe, Arn Hofkens 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 22 November 2002; accepted 16 December 2002
Abstract—A new synthesis of N-(a-methoxyarylmethyl)-2,2-dimethylaziridines is presented. Different benzaldehydes were con-
verted into the corresponding imines upon reaction with 2-bromo-2-methylpropylamine. Treatment of the latter imines with
sodium methoxide afforded N-(a-methoxyarylmethyl)-2,2-dimethylaziridines in good yields. © 2003 Elsevier Science Ltd. All
rights reserved.
1
. Introduction
aziridine 3. This aziridine, which appeared to be sensi-
tive to polymerization, was converted into 2-amino-2-
methylpropylamine hydrobromide 4, upon reaction
with HBr (Scheme 1).
Although N-(alkoxymethyl)aziridines are known to1
posses antitumor activity, as studied in mice and rats,
very few papers could be found concerning the synthe-
sis of these compounds. N-(Ethoxymethyl)aziridine was
prepared by reaction of aziridine (ethyleneimine) with
ethyl halomethyl ethers in ethanol,
dimethoxymethyl)aziridine was synthesized by reaction
of aziridine with chloroform in the presence of sodium
methoxide, the latter reaction giving rise to bis- and
tris-aziridino compounds too. Since especially N-(a-
alkoxybenzyl)aziridines seem to exhibit potential anti-
However, the observed regioselectivity of the ring open-
4
ing of aziridine 3 was different than reported. In the
2a,b
while N-
cited
reference,
1-bromo-2-methylpropyl-2-amine
(
hydrobromide salt was proposed as the reaction
product, indicating that bromide would have attacked
the less hindered carbon atom of the intermediate aziri-
2c
5
–7
dinium salt. As known from literature data,
ring
1
opening of aziridinium ions is nucleophile-dependent.
Gmeiner and co-workers demonstrated that ring open-
ing occurs at the more hindered position with bro-
cancer activity, a new synthesis of N-(a-methoxy-
arylmethyl)-2,2-dimethylaziridines 7 is presented. Dif-
ferent benzaldehydes 5 were converted into the corre-
sponding imines 6 by condensation with 2-bromo-
5,6
mide. Based on these findings, and on the obtained
spectrometric data of compound 4, it has to be con-
cluded that the reported structure should be corrected,
as well as the articles concerning some kinetic studies of
2
-methylpropylamine hydrobromide 4, in the presence
of triethylamine. Treatment of these functionalized
imines with sodium methoxide afforded N-(a-methoxy-
arylmethyl)-2,2-dimethylaziridines 7 in good yields.
8,9
this compound. Furthermore, some other synthetic
routes towards 2-bromo-2-methylpropylamine (salts)
10–13
are known.
2
. Results and discussion
The synthesis of 2-bromo-2-methylpropylamine hydro-
bromide 4 was performed in accordance with the litera-
3
,4
ture.
2-Amino-2-methyl-1-propanol 1 was treated
with sulfuric acid, and the thus obtained ammonium
sulfate 2 was further transformed into 2,2-dimethyl-
Keywords: aziridines; b-haloamines; aldimines.
*
Corresponding author. Tel.: +00-32(9)-264-5951; fax: +00-32(9)-
2
64-6243; e-mail: norbert.dekimpe@rug.ac.be
Scheme 1.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02838-1

1
138
M. D’hooghe et al. / Tetrahedron Letters 44 (2003) 1137–1139
Table 1. Synthesis of N-(a-methoxyarylmethyl)-2,2-
dimethylaziridines 7
a
Entry
Ratio 7:8
94:6
Compound
Bp
Yield (%)
1
2
3
7a
7b
7c
50–55°C/
51
85
54
0
.010 mmHg
52–56°C/
.020 mmHg
70–73°C/
.015 mmHg
97:3
0
95:5
Scheme 2.
0
a
The ratio was derived from the 1H NMR spectrum of the reaction
mixture and from GC analysis
When benzaldehydes 5 were reacted with 2-bromo-2-
methylpropylamine hydrobromide 4 in the presence of
Et N and MgSO the corresponding new imines 6 were
3
4
isolated in high yields (Scheme 2). Decomposition of
these thermolabile imines 6 was observed upon distilla-
tion. In the last step, imines 6 were treated with sodium
methoxide in methanol, resulting in the desired N-(a-
methoxyarylmethyl)-2,2-dimethylaziridines 7, in good
yields (Scheme 3).
The synthesis of aziridines 7 can be rationalized consid-
ering a nucleophilic addition of methoxide across the
imino bond, followed by an intramolecular nucleophilic
substitution. Alternatively, compounds
6
might
undergo first intramolecular substitution by the imino
nitrogen after which the iminium ion is trapped by
methoxide to give the final products 7. The elimination
products 8, i.e. 2-azadienes, which by the way could not
be formed when 1-bromo-2-methylpropyl-2-amine was
used instead of 2-bromo-2-methylpropylamine (see cor-
rection of the literature above), were isolated in small
quantities (2–3%). Purification of the title compounds
was performed by a distillation process (Table 1). A
similar procedure was evaluated for the synthesis of
N-(a-methoxybenzyl)aziridine 10, starting from N-(2-
chloroethyl)imine 9, but instead an elimination of HCl,
followed by addition of MeOH, resulted in the forma-
tion of N-(benzylidene)-1-methoxyethylamine 11
Scheme 4.
(
2×Cortho,arom. and 2×Cmeta,arom.), 128.35 (Cpara,arom.),
−1
1
1
1
8
2
37.57 (Cquat.,arom.); IR (NaCl, cm ): w=1446, 1373,
+
337, 1162, 1075; MS (70 eV): m/z (%): no M , 160 (6),
59 (16), 158 (10), 122 (10), 121 (100), 104 (10), 91 (14),
2 (10), 77 (16), 70 (43), 55 (11). Spectrometric data of
-bromo-2-methylpropylamine hydrobromide 4:
1
H
NMR (D O, 60 MHz): l 1.41 (6H, s, 2×Me), 3.61 (2H,
2
1
3
s, CH2); C NMR (D O, 67 MHz): l 24.85 (2×Me),
2
4
0.80 (CH ), 55.11 (CBr).
(
Scheme 4). Imine 9 was synthesized from benzaldehyde
2
and 2-chloroethylamine hydrochloride in the presence
1
4
of triethylamine.
3
. Conclusions
Spectrometric data 1 of N-(a-methoxybenzyl)-2,2-
dimethylaziridine 7a: H NMR (CDCl , 270 MHz): l
A new and efficient procedure for the preparation of
N-(a-methoxyarylmethyl)-2,2-dimethylaziridines, com-
pounds with potential anticancer activity, was devel-
oped. Furthermore, it was shown that the synthesis of
2-bromo-2-methylpropylamine hydrobromide from 2,2-
dimethylaziridine 3 has to be corrected in the literature.
3
0
.90–1.50 (7H, m, 2×Me and (H
6 CH)N), 1.64 (1H, s,
(
HCH
6
)N), 3.27 (3H, s, OMe), 4.29 (1H, s, NCHO),
1
3
7
.20–7.50 (5H, m, C H ); C NMR (CDCl , 67 MHz):
6
5
3
l 18.0 (2×Me), 26.42 (C
6
Me ), 38.45 (CH N), 53.73
OMe), 95.54 and 96.62 (NCHO), 127.49 and 128.26
2
2
(
Scheme 3.

M. D’hooghe et al. / Tetrahedron Letters 44 (2003) 1137–1139
1139
Acknowledgements
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the I.W.T. and Ghent University for financial support.
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